Life | Editor’s choice Articles

15 pages, 2725 KB

Open AccessEditor’s ChoiceArticle

Differential Expression of Anti-Inflammatory RNA Binding Proteins in Lupus Nephritis

by Raouia Fakhfakh, Emna Bouallegui, Hana Houssaini, Nesrine Elloumi, Fatma Dhafouli, Olfa Abida, Hend Hachicha, Sameh Marzouk, Zouhir Bahloul, Khawla Kammoun, Tahia Boudawara and Hatem Masmoudi

Life 2022, 12(10), 1474; https://doi.org/10.3390/life12101474 - 23 Sep 2022

Cited by 5 | Viewed by 2938

Abstract

Lupus nephritis (LN) is a type of immunological complex glomerulonephritis characterized by chronic renal inflammation which is exacerbated by infiltrating leukocytes and fueled by a variety of pro-inflammatory cytokines. A profound understanding of the pathogenesis of LN is necessary to identify the optimal [...] Read more.

Lupus nephritis (LN) is a type of immunological complex glomerulonephritis characterized by chronic renal inflammation which is exacerbated by infiltrating leukocytes and fueled by a variety of pro-inflammatory cytokines. A profound understanding of the pathogenesis of LN is necessary to identify the optimal molecular targets. The role of RNA-binding proteins (RBPs) in post-transcriptional gene regulation in the immune system is being explored in greater depth to better understand how this regulation is implicated in inflammatory and autoimmune diseases. Tristetraprolin (TTP), Roquin-1/2, and Regnase-1 are 3 RBPs that play a critical role in the regulation of pro-inflammatory mediators by gating the degradation and/or translational silencing of target mRNAs. In this study, we proposed to focus on the differential expression of these RBPs in immune cells and renal biopsies from LN patients, as well as their regulatory impact on a specific target. Herein, we highlight a novel target of anti-inflammatory treatment by revealing the mechanisms underlying RBP expression and the interaction between RBPs and their target RNAs. Full article

(This article belongs to the Special Issue The Interplay between Immune System and the Kidneys: Games without Frontiers?)

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9 pages, 23712 KB

Open AccessEditor’s ChoiceArticle

Protective Effects of L-2-Oxothiazolidine-4-Carboxylate during Isoproterenol-Induced Myocardial Infarction in Rats: In Vivo Study

by Marija Angelovski, Nikola Hadzi-Petrushev, Dino Atanasov, Aleksandar Nikodinovski, Vadim Mitrokhin, Dimiter B. Avtanski and Mitko Mladenov

Life 2022, 12(10), 1466; https://doi.org/10.3390/life12101466 - 21 Sep 2022

Cited by 3 | Viewed by 2420

Abstract

This study aimed to evaluate the cardioprotective effects of L-2-oxothiazolidine-4-carboxylate (OTC) against isoproterenol (ISO)-induced acute myocardial infarction (MI) in rats. Results demonstrated that OTC treatments inhibited ISO-induced oxidative damage, suppressed lipid peroxidation, and increased superoxide dismutase and catalase activity in the hearts of [...] Read more.

This study aimed to evaluate the cardioprotective effects of L-2-oxothiazolidine-4-carboxylate (OTC) against isoproterenol (ISO)-induced acute myocardial infarction (MI) in rats. Results demonstrated that OTC treatments inhibited ISO-induced oxidative damage, suppressed lipid peroxidation, and increased superoxide dismutase and catalase activity in the hearts of the treated rats compared to those of the untreated controls. The ISO-related NF-κB activation was reduced due to the OTC treatment, and lower degrees of inflammatory cell infiltration and necrosis in the hearts were observed. In summary, OTC treatments exerted cardioprotective effects against MI in vivo, mainly due to enhancing cardiac antioxidant activity. Full article

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19 pages, 1249 KB

Open AccessEditor’s ChoiceReview

Exosomes and Biomaterials: In Search of a New Therapeutic Strategy for Multiple Sclerosis

by Doddy Denise Ojeda-Hernández, Mercedes A. Hernández-Sapiéns, Edwin E. Reza-Zaldívar, Alejandro Canales-Aguirre, Jordi A. Matías-Guiu, Jorge Matías-Guiu, Juan Carlos Mateos-Díaz, Ulises Gómez-Pinedo and Francisco Sancho-Bielsa

Life 2022, 12(9), 1417; https://doi.org/10.3390/life12091417 - 11 Sep 2022

Cited by 19 | Viewed by 6003

Abstract

Current efforts to find novel treatments that counteract multiple sclerosis (MS) have pointed toward immunomodulation and remyelination. Currently, cell therapy has shown promising potential to achieve this purpose. However, disadvantages such as poor survival, differentiation, and integration into the target tissue have limited [...] Read more.

Current efforts to find novel treatments that counteract multiple sclerosis (MS) have pointed toward immunomodulation and remyelination. Currently, cell therapy has shown promising potential to achieve this purpose. However, disadvantages such as poor survival, differentiation, and integration into the target tissue have limited its application. A series of recent studies have focused on the cell secretome, showing it to provide the most benefits of cell therapy. Exosomes are a key component of the cell secretome, participating in the transfer of bioactive molecules. These nano-sized vesicles offer many therapeutical advantages, such as the capacity to cross the blood-brain barrier, an enrichable cargo, and a customizable membrane. Moreover, integrating of biomaterials into exosome therapy could lead to new tissue-specific therapeutic strategies. In this work, the use of exosomes and their integration with biomaterials is presented as a novel strategy in the treatment of MS. Full article

(This article belongs to the Special Issue Multiple Sclerosis: Research in Remyelination, the Next Step)

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13 pages, 1295 KB

Open AccessEditor’s ChoiceReview

HER2 in Metastatic Colorectal Cancer: Pathology, Somatic Alterations, and Perspectives for Novel Therapeutic Schemes

by Mariia Ivanova, Konstantinos Venetis, Elena Guerini-Rocco, Luca Bottiglieri, Mauro Giuseppe Mastropasqua, Ornella Garrone, Nicola Fusco and Michele Ghidini

Life 2022, 12(9), 1403; https://doi.org/10.3390/life12091403 - 9 Sep 2022

Cited by 18 | Viewed by 3950

Abstract

HER2 is an emerging biomarker in colorectal cancer (CRC). This oncogene plays an essential role in regulating cell proliferation, differentiation, migration, and, more in general, tumorigenesis and tumor progression. The most frequent types of HER2 alterations in CRC include gene amplification and missense [...] Read more.

HER2 is an emerging biomarker in colorectal cancer (CRC). This oncogene plays an essential role in regulating cell proliferation, differentiation, migration, and, more in general, tumorigenesis and tumor progression. The most frequent types of HER2 alterations in CRC include gene amplification and missense mutations in 7–8% of CRC, often being mirrored by HER2 protein overexpression, representing founder events in solid tumors, including CRC. There are currently no approved HER2-targeted therapy guidelines for CRC; however, several studies have shown that HER2 can be effectively targeted in meta-static CRC settings. In this review, we discuss the current knowledge of HER2 testing in CRC and the immediate future perspectives for HER2 targeting in the metastatic setting. Full article

(This article belongs to the Special Issue New Insights into the Treatment of Colorectal Cancer in the Era of Precision Medicine)

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9 pages, 875 KB

Open AccessEditor’s ChoiceArticle

Urinary Collectrin (TMEM27) as Novel Marker for Acute Kidney Injury

by Sahra Pajenda, Ludwig Wagner, Daniela Gerges, Harald Herkner, Tamar Tevdoradze, Karl Mechtler, Alice Schmidt and Wolfgang Winnicki

Life 2022, 12(9), 1391; https://doi.org/10.3390/life12091391 - 6 Sep 2022

Cited by 5 | Viewed by 2283

Abstract

Acute kidney injury (AKI) is a leading complication in hospitalized patients of different disciplines due to various aetiologies and is associated with the risk of chronic kidney disease, the need for dialysis and death. Since nephrons are not supplied with pain signals, kidney [...] Read more.

Acute kidney injury (AKI) is a leading complication in hospitalized patients of different disciplines due to various aetiologies and is associated with the risk of chronic kidney disease, the need for dialysis and death. Since nephrons are not supplied with pain signals, kidney injury is mostly diagnosed by serum creatinine with a time delay. Recent work has shown that certain urinary biomarkers are available for early detection of AKI. In total, 155 subjects, including 102 patients with AKI at various stages and 53 subjects without AKI, were enrolled, and their course and laboratory data were recorded. Urinary collectrin (TMEM27) was measured by a commercially available ELISA assay. Changes in serum creatinine were used to determine AKI stage. Patients with AKI presented with significantly lower levels of urinary collectrin compared to patients without AKI (1597 ± 1827 pg/mL vs. 2855 ± 2073; p = 0.001). Collectrin was found to inversely correlate with serum creatinine and stages of AKI. Collectrin levels were lowest in AKI stage III (1576 ± 1686 pg/mL; p = 0.001) and also significantly lower in stage II (1616 ± 2148 pg/mL; p = 0.021) and stage I (1630 ± 1956 pg/mL; p = 0.019) compared to subjects without AKI. An optimal minimum collectrin cut-off value of 1606 [95% CI 1258 to 1954] pg/mL was determined to detect AKI. In conclusion, urinary collectrin represents an indicator of AKI that, unlike all other established AKI biomarkers, decreases with stage of AKI and thus may be associated with a novel pathogenic pathway. Full article

(This article belongs to the Special Issue Innovative Biomarker and Precision Medicine)

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8 pages, 244 KB

Open AccessEditor’s ChoiceArticle

Multiglandular Parathyroid Disease

by Grzegorz Kowalski, Grzegorz Buła, Adam Bednarczyk, Agata Gawrychowska and Jacek Gawrychowski

Life 2022, 12(8), 1286; https://doi.org/10.3390/life12081286 - 22 Aug 2022

Cited by 8 | Viewed by 2503

Abstract

Introduction: Multiglandular parathyroid disease (MGD) is an uncommon cause of primary hyperparathyroidism (pHPT) and has been reported in the literature in 8–33% of patients with pHPT. The aim of our study was to review the clinical characteristics and management of MGD and evaluation [...] Read more.

Introduction: Multiglandular parathyroid disease (MGD) is an uncommon cause of primary hyperparathyroidism (pHPT) and has been reported in the literature in 8–33% of patients with pHPT. The aim of our study was to review the clinical characteristics and management of MGD and evaluation of surgical treatment failures. Methods: We performed a retrospective study of 163 patients with pHPT undergoing parathyroidectomy (PTX) at the Department of General and Endocrine Surgery between 1983 and 2018. All these patients were diagnosed with MGD. This group of patients was compared with a group of 856 patients with solitary disease operated for pHPT in the same period. Results: Among 163 patients—127 (79%) of them had two lesions, 28 (16%) had three, and 8 (5%) four. They were prevalently women over the age of 50. The diagnosis was based on PTH and ionized calcium studies and used sestamibi technetium-99m scintigraphy (MIBI) as well for us. Treatment was surgical. Conclusions: Parathyroidectomy (PTX) for multiglandular parathyroid disease (MGD) is associated with a higher operative risk of failure compared to solitary disease. Preoperative diagnosis and localization of the parathyroid glands is an extremely important element of treatment. Diagnosis is based on PTH and calcium levels. Ultrasonography (USG), MRI, and scintigraphy are very helpful in diagnosis. Mediastinal multiglandular parathyroid disease (MGD) is associated with increased surgical treatment failures. The treatment is surgical and consists of the removal of the masses or complete parathyroidectomy. Based on this study, we support the existence of multiple adenomas and advocate the removal of only macroscopically enlarged parathyroid glands in patients with primary hyperparathyroidism. Full article

(This article belongs to the Special Issue Multiple Endocrine Neoplasia: Basic and Clinical Findings)

18 pages, 1577 KB

Open AccessEditor’s ChoiceArticle

Studies on Biological and Molecular Effects of Small-Molecule Kinase Inhibitors on Human Glioblastoma Cells and Organotypic Brain Slices

by Julia Hörnschemeyer, Timo Kirschstein, Gesine Reichart, Christin Sasse, Jakob Venus, Anne Einsle, Katrin Porath, Michael Linnebacher, Rüdiger Köhling and Falko Lange

Life 2022, 12(8), 1258; https://doi.org/10.3390/life12081258 - 17 Aug 2022

Cited by 5 | Viewed by 2757

Abstract

Glioblastoma is the most common and aggressive primary brain tumor. Multiple genetic and epigenetic alterations in several major signaling pathways—including the phosphoinositide 3-kinases (PI3K)/AKT/mTOR and the Raf/MEK/ERK pathway—could be found. We therefore aimed to investigate the biological and molecular effects of small-molecule kinase [...] Read more.

Glioblastoma is the most common and aggressive primary brain tumor. Multiple genetic and epigenetic alterations in several major signaling pathways—including the phosphoinositide 3-kinases (PI3K)/AKT/mTOR and the Raf/MEK/ERK pathway—could be found. We therefore aimed to investigate the biological and molecular effects of small-molecule kinase inhibitors that may interfere with those pathways. For this purpose, patient-derived glioblastoma cells were challenged with dactolisib, ipatasertib, MK-2206, regorafenib, or trametinib. To determine the effects of the small-molecule kinase inhibitors, assays of cell proliferation and apoptosis and immunoblot analyses were performed. To further investigate the effects of ipatasertib on organotypic brain slices harboring glioblastoma cells, the tumor growth was estimated. In addition, the network activity in brain slices was assessed by electrophysiological field potential recordings. Multi-kinase inhibitor regorafenib and both MK-2206 and dactolisib were very effective in all preclinical tumor models, while with respect to trametinib, two cell lines were found to be highly resistant. Only in HROG05 cells, ipatasertib showed anti-tumoral effects in vitro and in organotypic brain slices. Additionally, ipatasertib diminished synchronous network activity in organotypic brain slices. Overall, our data suggest that ipatasertib was only effective in selected tumor models, while especially regorafenib and MK-2206 presented a uniform response pattern. Full article

(This article belongs to the Special Issue Future Directions in Diagnosis and Treatment of Glioblastoma)

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13 pages, 1606 KB

Open AccessEditor’s ChoiceArticle

The Role of the Precuneus in Human Spatial Updating in a Real Environment Setting—A cTBS Study

by Milos Dordevic, Sonja Hoelzer, Augusta Russo, José C. García Alanis and Notger G. Müller

Life 2022, 12(8), 1239; https://doi.org/10.3390/life12081239 - 15 Aug 2022

Cited by 10 | Viewed by 2488

Abstract

As we move through an environment, we update positions of our body relative to other objects, even when some objects temporarily or permanently leave our field of view—this ability is termed egocentric spatial updating and plays an important role in everyday life. Still, [...] Read more.

As we move through an environment, we update positions of our body relative to other objects, even when some objects temporarily or permanently leave our field of view—this ability is termed egocentric spatial updating and plays an important role in everyday life. Still, our knowledge about its representation in the brain is still scarce, with previous studies using virtual movements in virtual environments or patients with brain lesions suggesting that the precuneus might play an important role. However, whether this assumption is also true when healthy humans move in real environments where full body-based cues are available in addition to the visual cues typically used in many VR studies is unclear. Therefore, in this study we investigated the role of the precuneus in egocentric spatial updating in a real environment setting in 20 healthy young participants who underwent two conditions in a cross-over design: (a) stimulation, achieved through applying continuous theta-burst stimulation (cTBS) to inhibit the precuneus and (b) sham condition (activated coil turned upside down). In both conditions, participants had to walk back with blindfolded eyes to objects they had previously memorized while walking with open eyes. Simplified trials (without spatial updating) were used as control condition, to make sure the participants were not affected by factors such as walking blindfolded, vestibular or working memory deficits. A significant interaction was found, with participants performing better in the sham condition compared to real stimulation, showing smaller errors both in distance and angle. The results of our study reveal evidence of an important role of the precuneus in a real-environment egocentric spatial updating; studies on larger samples are necessary to confirm and further investigate this finding. Full article

(This article belongs to the Section Physiology and Pathology)

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17 pages, 535 KB

Open AccessEditor’s ChoiceReview

Up-Date on Diabetic Nephropathy

by Maria Chiara Pelle, Michele Provenzano, Marco Busutti, Clara Valentina Porcu, Isabella Zaffina, Lucia Stanga and Franco Arturi

Life 2022, 12(8), 1202; https://doi.org/10.3390/life12081202 - 8 Aug 2022

Cited by 78 | Viewed by 8985

Abstract

Diabetes is one of the leading causes of kidney disease. Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide, and it is linked to an increase in cardiovascular (CV) risk. Diabetic nephropathy (DN) increases morbidity and mortality among [...] Read more.

Diabetes is one of the leading causes of kidney disease. Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide, and it is linked to an increase in cardiovascular (CV) risk. Diabetic nephropathy (DN) increases morbidity and mortality among people living with diabetes. Risk factors for DN are chronic hyperglycemia and high blood pressure; the renin-angiotensin-aldosterone system blockade improves glomerular function and CV risk in these patients. Recently, new antidiabetic drugs, including sodium–glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have demonstrated additional contribution in delaying the progression of kidney disease and enhancing CV outcomes. The therapeutic goal is regression of albuminuria, but an atypical form of non-proteinuric diabetic nephropathy (NP-DN) is also described. In this review, we provide a state-of-the-art evaluation of current treatment strategies and promising emerging treatments. Full article

(This article belongs to the Special Issue Hyperglycemia: From Pathophysiology to Therapeutics)

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14 pages, 5983 KB

Open AccessEditor’s ChoiceArticle

Modularity of the Human Musculoskeletal System: The Correlation between Functional Structures by Computer Tools Analysis

by Daniele Della Posta, Jacopo Junio Valerio Branca, Giulia Guarnieri, Cristiana Veltro, Alessandra Pacini and Ferdinando Paternostro

Life 2022, 12(8), 1186; https://doi.org/10.3390/life12081186 - 3 Aug 2022

Cited by 5 | Viewed by 2686

Abstract

Introduction: For many years, anatomical studies have been conducted with a shattered view of the body. Although the study of the different apparatuses provides a systemic view of the human body, the reconstruction of the complex network of anatomical structures is crucial for [...] Read more.

Introduction: For many years, anatomical studies have been conducted with a shattered view of the body. Although the study of the different apparatuses provides a systemic view of the human body, the reconstruction of the complex network of anatomical structures is crucial for the understanding of structural and functional integration. Aim: We used network analysis to investigate the connection between the whole-body osteo-myofascial structures of the human musculoskeletal system. Materials and Methods: The musculoskeletal network was performed using the aNETomy^® anatomical network with the implementation of the open-source software Cytoscape for data entry. Results: The initial graph was applied with a network consisting of 2298 body parts (nodes) and 7294 links, representing the musculoskeletal system. Considering the same weighted and unweighted osteo-myofascial network, a different distribution was obtained, suggesting both a topological organization and functional behavior of the network structure. Conclusions: Overall, we provide a deeply detailed anatomical network map of the whole-body musculoskeletal system that can be a useful tool for the comprehensive understanding of every single structure within the complex morphological organization, which could be of particular interest in the study of rehabilitation of movement dysfunctions. Full article

(This article belongs to the Section Physiology and Pathology)

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5 pages, 758 KB

Open AccessEditor’s ChoiceCase Report

Symptomatic Vascular Compression of Brainstem May Be Managed Conservatively

by Malik Ghannam, Meaghen Berns, Apameh Salari, Lisa Moore and Kevin Brown

Life 2022, 12(8), 1179; https://doi.org/10.3390/life12081179 - 2 Aug 2022

Cited by 1 | Viewed by 4835

Abstract

Medulla compression from vertebral artery abnormality is a very rare occurrence with few cases present in the literature. It has been documented to present with a very wide spectrum of clinical symptomatology ranging from asymptomatic to full hemiplegia. There is currently no treatment [...] Read more.

Medulla compression from vertebral artery abnormality is a very rare occurrence with few cases present in the literature. It has been documented to present with a very wide spectrum of clinical symptomatology ranging from asymptomatic to full hemiplegia. There is currently no treatment algorithm in place to guide clinicians encountering such patients but treatments have historically involved major posterior compartment surgical interventions. This case outlined a patient evaluated for dizziness without any other neurological symptoms or signs, found to have abnormal dilatation, elongation, and tortuosity of the vertebral artery with resultant compression of the medulla oblongata. The patient was managed conservatively after discussion of surgical options. This report outlined an important consideration for management of medullar compression by vertebral artery based on symptom severity with the possibility of postponing surgical or endovascular interventions and opting for conservative management with an anti-platelet regimen, particularly in the short term. Full article

(This article belongs to the Special Issue Neurophysiologic Disease Processes and New Methods of Study)

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23 pages, 1338 KB

Open AccessEditor’s ChoiceReview

Left Ventricular Remodeling after Myocardial Infarction: From Physiopathology to Treatment

by Sabina Andreea Leancă, Daniela Crișu, Antoniu Octavian Petriș, Irina Afrăsânie, Antonia Genes, Alexandru Dan Costache, Dan Nicolae Tesloianu and Irina Iuliana Costache

Life 2022, 12(8), 1111; https://doi.org/10.3390/life12081111 - 24 Jul 2022

Cited by 82 | Viewed by 14879

Abstract

Myocardial infarction (MI) is the leading cause of death and morbidity worldwide, with an incidence relatively high in developed countries and rapidly growing in developing countries. The most common cause of MI is the rupture of an atherosclerotic plaque with subsequent thrombotic occlusion [...] Read more.

Myocardial infarction (MI) is the leading cause of death and morbidity worldwide, with an incidence relatively high in developed countries and rapidly growing in developing countries. The most common cause of MI is the rupture of an atherosclerotic plaque with subsequent thrombotic occlusion in the coronary circulation. This causes cardiomyocyte death and myocardial necrosis, with subsequent inflammation and fibrosis. Current therapies aim to restore coronary flow by thrombus dissolution with pharmaceutical treatment and/or intravascular stent implantation and to counteract neurohormonal activation. Despite these therapies, the injury caused by myocardial ischemia leads to left ventricular remodeling; this process involves changes in cardiac geometry, dimension and function and eventually progression to heart failure (HF). This review describes the pathophysiological mechanism that leads to cardiac remodeling and the therapeutic strategies with a role in slowing the progression of remodeling and improving cardiac structure and function. Full article

(This article belongs to the Special Issue Ischemic Heart Disease in the Context of Different Comorbidities)

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12 pages, 321 KB

Open AccessEditor’s ChoiceArticle

Alzheimer’s Disease Risk Variant rs3865444 in the CD33 Gene: A Possible Role in Susceptibility to Multiple Sclerosis

by Juraj Javor, Mária Bucová, Vladimíra Ďurmanová, Dominika Radošinská, Zuzana Párnická, Daniel Čierny, Egon Kurča, Daniela Čopíková-Cudráková, Karin Gmitterová and Ivana Shawkatová

Life 2022, 12(7), 1094; https://doi.org/10.3390/life12071094 - 21 Jul 2022

Cited by 4 | Viewed by 2761

Abstract

Polymorphisms in genes encoding receptors that modulate the activity of microglia and macrophages are attractive candidates for participation in genetic susceptibility to multiple sclerosis (MS). The aims of the study were to (1) investigate the association between Alzheimer’s disease-linked variant rs3865444:C>A in the [...] Read more.

Polymorphisms in genes encoding receptors that modulate the activity of microglia and macrophages are attractive candidates for participation in genetic susceptibility to multiple sclerosis (MS). The aims of the study were to (1) investigate the association between Alzheimer’s disease-linked variant rs3865444:C>A in the CD33 gene and MS risk, (2) assess the effect of the strongest MS risk allele HLA-DRB1*15:01 on this association, and (3) analyze the correlation of rs3865444 with selected clinical phenotypes, i.e., age of onset and disease severity. CD33 rs3865444 was genotyped in a cohort of 579 patients and 1145 controls and its association with MS risk and clinical phenotypes was analyzed by logistic and linear regression analysis, respectively. Statistical evaluation revealed that rs3865444 reduces the risk of MS in the HLA-DRB1*15:01-positive subpopulation but not in the cohort negative for HLA-DRB1*15:01. A significant antagonistic epistasis between rs3865444 A and HLA-DRB1*15:01 alleles in the context of MS risk was detected by the interaction synergy factor analysis. Comparison of allele and genotype distribution between relapsing-remitting MS, secondary progressive MS, and control groups revealed that rs3865444 C to A substitution may also be associated with a decreased risk of transition of MS to its secondary progressive form, irrespective of the HLA-DRB1*15:01 carrier status. On the other hand, no correlation could be found between rs3865444 and the age of disease onset or MS severity score. Future studies are required to shed more light on the role of CD33 in MS pathogenesis. Full article

(This article belongs to the Special Issue Neurological Diseases: From Molecular Mechanisms to Therapy)

16 pages, 4808 KB

Open AccessEditor’s ChoiceReview

Pathogenesis of Distal Symmetrical Polyneuropathy in Diabetes

by Sasha Smith, Pasha Normahani, Tristan Lane, David Hohenschurz-Schmidt, Nick Oliver and Alun Huw Davies

Life 2022, 12(7), 1074; https://doi.org/10.3390/life12071074 - 19 Jul 2022

Cited by 23 | Viewed by 6798

Abstract

Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying [...] Read more.

Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying therapies and left the reasons for failed therapies uncertain, which is critical given that current management strategies often fail to achieve long-term efficacy. In this article, the pathogenesis of DSPN is reviewed, covering pathogenic changes in the peripheral nervous system, microvasculature and central nervous system (CNS). Furthermore, the successes and limitations of current therapies are discussed, and potential therapeutic targets are proposed. Recent findings on its pathogenesis have called the definition of DSPN into question and transformed the disease model, paving the way for new research prospects. Full article

(This article belongs to the Special Issue Peripheral Diabetic Neuropathy: Symptoms, Causes and Treatment)

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11 pages, 1201 KB

Open AccessEditor’s ChoiceArticle

Finding Emergent Gait Patterns May Reduce Progression of Knee Osteoarthritis in a Clinically Relevant Time Frame

by Dhruv Gupta, Cyril John Donnelly and Jeffrey A. Reinbolt

Life 2022, 12(7), 1050; https://doi.org/10.3390/life12071050 - 14 Jul 2022

Cited by 6 | Viewed by 3064

Abstract

A high contact force between the medial femoral condyle and the tibial plateau is the primary cause of medial compartment knee osteoarthritis (OA). A high medial contact force (MCF) during gait has been shown to be correlated to both the knee adduction moment [...] Read more.

A high contact force between the medial femoral condyle and the tibial plateau is the primary cause of medial compartment knee osteoarthritis (OA). A high medial contact force (MCF) during gait has been shown to be correlated to both the knee adduction moment (KAM) and knee flexion/extension moment (KFM). In this study, we used OpenSim Moco to find gait kinematics that reduced the peaks of the KAM, without increasing the peaks of the KFM, which could potentially reduce the MCF and, hence, the progression of knee OA. We used gait data from four knee OA participants. Our simulations decreased both peaks of the KAM without increasing either peak of the KFM. We found that increasing the step width was the primary mechanism, followed by simulations of all participants to reduce the frontal plane lever arm of the ground reaction force vector about the knee, in turn reducing the KAM. Importantly, each participant simulation followed different patterns of kinematic changes to achieve this reduction, which highlighted the need for participant-specific gait modifications. Moreover, we were able to simulate emerging gait patterns within 15 min, enhancing the relevance and potential for the application of developed methods in clinical settings. Full article

(This article belongs to the Special Issue The Biomechanics of Injury and Rehabilitation)

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14 pages, 1543 KB

Open AccessEditor’s ChoiceArticle

Combination of Two Manipulative Techniques for the Treatment of Cervicogenic Dizziness: A Randomized Controlled Trial

by Andoni Carrasco-Uribarren, Pilar Pardos-Aguilella, Silvia Pérez-Guillén, Carlos López-de-Celis, Jacobo Rodríguez-Sanz and Sara Cabanillas-Barea

Life 2022, 12(7), 1023; https://doi.org/10.3390/life12071023 - 9 Jul 2022

Cited by 5 | Viewed by 4840

Abstract

Cervicogenic dizziness is clinically associated with upper cervical spine dysfunctions. It seems that manual therapy decreases the intensity of dizziness in these subjects, but what happens to pain measured by pressure pain threshold (PPT) has not been studied. Purpose: analyze the short-term effects [...] Read more.

Cervicogenic dizziness is clinically associated with upper cervical spine dysfunctions. It seems that manual therapy decreases the intensity of dizziness in these subjects, but what happens to pain measured by pressure pain threshold (PPT) has not been studied. Purpose: analyze the short-term effects of combination two manipulation techniques protocol in worst dizziness intensity (wVAS), dizziness and cervical disability, upper cervical spine mobility and mechanosensivity of cervical tissue. Methods: Assessor-blinded randomized controlled trial was developed. A total of 40 patients with cervicogenic dizziness were randomly divided into two groups. The experimental group received three treatments consisting of a functional massage and a manipulation technique, and compared with a control group. The wVAS, dizziness handicap inventory (DHI), neck disability index (NDI), UCS mobility, and PPTs were measured. Measurements were made at the baseline, first follow-up 48 h after intervention and second follow-up 1 month after the intervention. Results: at second follow-up wVAS (p < 0.001), NDI (p < 0.001), DHI (p < 0.001), and upper right trapezius (p < 0.022) and right suboccipital (p < 0.043) PPTs showed a difference between groups in favor of the experimental group. Conclusions: apparently, the proposed intervention protocol decreases the intensity of dizziness and the mechanosensitivity of the cervical tissue and improves the feeling of disability due to neck pain and dizziness. Full article

(This article belongs to the Special Issue The Biomechanics of Injury and Rehabilitation)

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13 pages, 1218 KB

Open AccessEditor’s ChoiceReview

Cardio-Oncology Rehabilitation—Present and Future Perspectives

by Boaz Elad, Manhal Habib and Oren Caspi

Life 2022, 12(7), 1006; https://doi.org/10.3390/life12071006 - 7 Jul 2022

Cited by 11 | Viewed by 4927

Abstract

Recent advances in cancer therapy have led to increased survival rates for cancer patients, but also allowed cardiovascular complications to become increasingly evident, with more than 40% of cancer deaths now being attributed to cardiovascular diseases. Cardiotoxicity is the most concerning cardiovascular complication, [...] Read more.

Recent advances in cancer therapy have led to increased survival rates for cancer patients, but also allowed cardiovascular complications to become increasingly evident, with more than 40% of cancer deaths now being attributed to cardiovascular diseases. Cardiotoxicity is the most concerning cardiovascular complication, one caused mainly due to anti-cancer drugs. Among the harmful mechanisms of these drugs are DNA damage, endothelial dysfunction, and oxidative stress. Cancer patients can suffer reduced cardiorespiratory fitness as a secondary effect of anti-cancer therapies, tumor burden, and deconditioning. In the general population, regular exercise can reduce the risk of cardiovascular morbidity, mortality, and cancer. Exercise-induced modifications of gene expression result in improvements of cardiovascular parameters and an increased general fitness, influencing telomere shortening, oxidative stress, vascular function, and DNA repair mechanisms. In cancer patients, exercise training is generally safe and well-tolerated; it is associated with a 10–15% improvement in cardiorespiratory fitness and can potentially counteract the adverse effects of anti-cancer therapy. It is well known that exercise programs can benefit patients with heart disease and cancer, but little research has been conducted with cardio-oncology patients. To date, there are a limited number of effective protective treatments for preventing or reversing cardiotoxicity caused by cancer therapy. Cardiac rehabilitation has the potential to mitigate cardiotoxicity based on the benefits already proven in populations suffering from either cancer or heart diseases. Additionally, the fact that cardiotoxic harm mechanisms coincide with similar mechanisms positively affected by cardiac rehabilitation makes cardiac rehabilitation an even more plausible option for cardio-oncology patients. Due to unstable functional capacity and fluctuating immunocompetence, these patients require specially tailored exercise programs designed collaboratively by cardiologists and oncologists. As the digital era is here, with the digital world and the medical world continuously intertwining, a remote, home-based cardio-oncology rehabilitation program may be a solution for this population. Full article

(This article belongs to the Special Issue Cardio-oncology: From Basic Mechanisms and research to Clinical Practice)

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8 pages, 255 KB

Open AccessEditor’s ChoiceArticle

Fever Correlation with Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) Concentrations in Patients with Isolated Polymyalgia Rheumatica (PMR): A Retrospective Comparison Study between Hospital and Out-of-Hospital Local Registries

by Ciro Manzo, Marcin Milchert, Carlo Venditti, Alberto Castagna, Arvind Nune, Maria Natale and Marek Brzosko

Life 2022, 12(7), 985; https://doi.org/10.3390/life12070985 - 30 Jun 2022

Cited by 4 | Viewed by 3046

Abstract

Background: Polymyalgia rheumatica (PMR) is the most common systemic inflammatory rheumatic disease affecting the elderly. Giant cell arteritis (GCA) is a granulomatous vasculitis affecting the aorta and its branches associated with PMR in up to 20% of cases. In recent studies based on [...] Read more.

Background: Polymyalgia rheumatica (PMR) is the most common systemic inflammatory rheumatic disease affecting the elderly. Giant cell arteritis (GCA) is a granulomatous vasculitis affecting the aorta and its branches associated with PMR in up to 20% of cases. In recent studies based on university hospital registries, fever correlated with the erythrocyte sedimentation rate (ESR) but not with C-reactive protein (CRP) concentrations at the time of diagnosis in patients with isolated PMR. A long delay to a PMR diagnosis was suggested to explain this discrepancy, possibly caused by laboratory alterations (for instance, anemia of chronic disease type) that can influence only ESR. We performed a retrospective comparison study between the university hospital and two out-of-hospital public ambulatory databases, searching for any differences in fever/low-grade fever correlation with ESR and CRP. Methods: We identified all patients with newly diagnosed PMR between 2013 and 2020, only including patients who had a body temperature (BT) measurement at the time of diagnosis and a follow-up of at least two years. We considered BT as normal at <37.2 °C. Routine diagnostic tests for differential diagnostics were performed at the time of diagnosis and during follow-ups, indicating the need for more in-depth investigations if required. The GCA was excluded based on the presence of suggestive signs or symptoms and routine ultrasound examination of temporal, axillary, subclavian, and carotid arteries by experienced ultrasonographers. Patients with malignancies, chronic renal disease, bacterial infections, and body mass index (BMI) > 30 kg/m² were excluded, as these conditions can increase CRP and/or ESR. Finally, we used the Cumulative Illness Rating Scale (CIRS) for quantifying the burden of comorbidities and excluded patients with a CIRS index > 4 as an additional interfering factor. Results: We evaluated data from 169 (73 from hospital and 96 from territorial registries) patients with newly diagnosed isolated PMR. Among these, 77.7% were female, and 61.5% of patients had normal BT at the time of diagnosis. We divided the 169 patients into two cohorts (hospital and territorial) according to the first diagnostic referral. Age at diagnosis, ESR, CRP, median hemoglobin (HB), and diagnostic delay (days from first manifestations to final diagnosis) were statistically significantly different between the two cohorts. However, when we assessed these data according to BT in the territorial cohort, we found a statistical difference only between ESR and BT (46.39 ± 19.31 vs. 57.50 ± 28.16; p = 0.026). Conclusions: ESR but not CRP correlates with fever/low-grade fever at the time of diagnosis in PMR patients with a short diagnosis delay regardless of HB levels. ESR was the only variable having a statistically significant correlation with BT in a multilevel regression analysis adjusted for cohorts (β = 0.312; p = 0.014). Full article

(This article belongs to the Special Issue Innovative Biomarker and Precision Medicine)

22 pages, 1052 KB

Open AccessEditor’s ChoiceReview

Cancer Cachexia and Antitumor Immunity: Common Mediators and Potential Targets for New Therapies

by Konstantinos Rounis, Dimitrios Makrakis, Ioannis Gioulbasanis, Simon Ekman, Luigi De Petris, Dimitris Mavroudis and Sofia Agelaki

Life 2022, 12(6), 880; https://doi.org/10.3390/life12060880 - 12 Jun 2022

Cited by 7 | Viewed by 3945

Abstract

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host’s innate and adaptive immunity. [...] Read more.

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host’s innate and adaptive immunity. Over the last few years, the development of immune checkpoint inhibitors (ICIs) transformed the treatment landscape for a wide spectrum of malignancies, creating an unprecedented opportunity for long term remissions in a significant subset of patients. Early clinical data indicate that CCS adversely impairs treatment outcomes of patients receiving ICIs. We herein reviewed existing evidence on the potential links between the mechanisms that promote the catabolic state in CCS and those that impair the antitumor immune response. We show that the biological mediators and processes leading to the development of CCS may also participate in the modulation and the sustainment of an immune suppressive tumor microenvironment and impaired anti-tumor immunity. Moreover, we demonstrate that the deregulation of the host’s metabolic homeostasis in cancer cachexia is associated with resistance to ICIs. Further research on the interrelation between cancer cachexia and anti-tumor immunity is required for the effective management of resistance to immunotherapy in this specific but large subgroup of ICI treated individuals. Full article

(This article belongs to the Collection Tumor Progression, Microenvironments, and Therapeutics)

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12 pages, 1215 KB

Open AccessEditor’s ChoiceArticle

How Is CYP17A1 Activity Altered in Autism? A Pilot Study to Identify Potential Pharmacological Targets

by Benedikt Andreas Gasser, Johann Kurz, Bernhard Dick and Markus Georg Mohaupt

Life 2022, 12(6), 867; https://doi.org/10.3390/life12060867 - 10 Jun 2022

Cited by 1 | Viewed by 2768

Abstract

Background: Increasing evidence exists that higher levels of androgens can be found in individuals with autism. Evidence yields to a susceptible role of Cytochrome P450 17A1 (CYP17A1) with its catalyzation of the two distinct types of substrate oxidation by a hydroxylase activity (17-alpha [...] Read more.

Background: Increasing evidence exists that higher levels of androgens can be found in individuals with autism. Evidence yields to a susceptible role of Cytochrome P450 17A1 (CYP17A1) with its catalyzation of the two distinct types of substrate oxidation by a hydroxylase activity (17-alpha hydroxylase) and C17/20 lyase activity. However, to what extent steps are altered in affected children with autism versus healthy controls remains to be elucidated. Methods: Urine samples from 48 boys with autism (BMI 19.1 ± 0.6 kg/m², age 14.2 ± 0.5 years) and a matched cohort of 48 healthy boys (BMI 18.6 ± 0.3 kg/m², 14.3 ± 0.5 years) as well as 16 girls with autism (BMI 17.5 ± 0.7 kg/m², age 13.8 ± 1.0 years) and a matched cohort of 16 healthy girls (BMI 17.2 ± 0.8 kg/m², age 13.2 ± 0.8 years) were analyzed for steroid hormone metabolites by gas chromatography-mass spectrometry. Results: The activity of 17-alpha Hydroxylase increased by almost 50%, whereas activity of 17/20 Lyase activity increased by around 150% in affected children with autism. Furthermore, the concentration of Cortisol was higher as compared to the average increase of the three metabolites TH-Corticosterone, 5α-TH-Corticosterone and TH-11β-DH-Corticosterone, indicating, in addition, a stimulation by the CRH-ACTH system despite a higher enzymatic activity. Discussion: As it was shown that oxidative stress increases the 17/20-lyase activity via p38α, a link between higher steroid hormone levels and oxidative stress can be established. However, as glucocorticoid as well as androgen metabolites showed higher values in subjects affected with autism as compared to healthy controls, the data indicate, despite higher CYP17A1 activity, the presence of increased substrate availability in line with the Cholesterol theory of autism. Full article

(This article belongs to the Section Physiology and Pathology)

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12 pages, 4381 KB

Open AccessEditor’s ChoiceArticle

A Seed-Borne Bacterium of Rice, Pantoea dispersa BB1, Protects Rice from the Seedling Rot Caused by the Bacterial Pathogen Burkholderia glumae

by Yusuke Kouzai and Chiharu Akimoto-Tomiyama

Life 2022, 12(6), 791; https://doi.org/10.3390/life12060791 - 26 May 2022

Cited by 15 | Viewed by 4364

Abstract

Seedling rot, caused by the bacterial pathogen Burkholderia glumae, is a major disease of rice. It originates from pathogen-contaminated seeds and is thus mainly controlled by pesticide treatments of seeds. We previously demonstrated that the seed-borne bacteria of rice may be a [...] Read more.

Seedling rot, caused by the bacterial pathogen Burkholderia glumae, is a major disease of rice. It originates from pathogen-contaminated seeds and is thus mainly controlled by pesticide treatments of seeds. We previously demonstrated that the seed-borne bacteria of rice may be a useful and sustainable alternative to pesticides to manage seedling rot, but they are limited in terms of variety. Here, we report that another seed-borne bacterium, Pantoea dispersa BB1, protects rice from B. glumae. We screened 72 bacterial isolates from rice seeds of three genetically different cultivars inoculated or non-inoculated with B. glumae. 16S rRNA gene sequencing revealed that pathogen inoculation affected the composition of culturable seed-borne bacterial communities and increased the presence of Pantoea and Paenibacillus species. Among three Pantoea and Paenibacillus isolates that exhibit tolerance to toxoflavin, a virulence factor of B. glumae, P. dispersa BB1 significantly mitigated the symptoms of rice seedling rot. The culture filtrate of BB1 inhibited the growth of B. glumae in vitro, suggesting that this isolate secretes antibacterial compounds. Seed treatment with BB1 suppressed pathogen propagation in plants, although seed treatment with the culture filtrate did not. Because BB1 did not show pathogenicity in rice, our findings demonstrate that BB1 is a promising biocontrol agent against seedling rot. Full article

(This article belongs to the Collection State of the Art in Plant Science)

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17 pages, 760 KB

Open AccessEditor’s ChoiceReview

Acute and Long-Term Consequences of COVID-19 on Arterial Stiffness—A Narrative Review

by Ioana Mădălina Zota, Cristian Stătescu, Radu Andy Sascău, Mihai Roca, Larisa Anghel, Alexandra Maștaleru, Maria Magdalena Leon-Constantin, Cristina Mihaela Ghiciuc, Sebastian Romica Cozma, Lucia Corina Dima-Cozma, Irina Mihaela Esanu and Florin Mitu

Life 2022, 12(6), 781; https://doi.org/10.3390/life12060781 - 25 May 2022

Cited by 18 | Viewed by 5338

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global coronavirus (COVID-19) pandemic. Although initially viewed as an acute respiratory illness, COVID-19 is clearly a complex multisystemic disease with extensive cardiovascular involvement. Emerging evidence shows that the endothelium plays [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global coronavirus (COVID-19) pandemic. Although initially viewed as an acute respiratory illness, COVID-19 is clearly a complex multisystemic disease with extensive cardiovascular involvement. Emerging evidence shows that the endothelium plays multiple roles in COVID-19 physiopathology, as both a target organ that can be directly infected by SARS-CoV-2 and a mediator in the subsequent inflammatory and thrombotic cascades. Arterial stiffness is an established marker of cardiovascular disease. The scope of this review is to summarize available data on the acute and long-term consequences of COVID-19 on vascular function. COVID-19 causes early vascular aging and arterial stiffness. Fast, noninvasive bedside assessment of arterial stiffness could optimize risk stratification in acute COVID-19, allowing for early escalation of treatment. Vascular physiology remains impaired at least 12 months after infection with SARS-CoV-2, even in otherwise healthy adults. This raises concerns regarding the extent of arterial remodeling in patients with preexisting vascular disease and the potential development of a persistent, chronic COVID-19 vasculopathy. Long-term follow up on larger cohorts is required to investigate the reversibility of COVID-19-induced vascular changes and their associated prognostic implications. Full article

(This article belongs to the Section Medical Research)

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15 pages, 3321 KB

Open AccessEditor’s ChoiceArticle

Role of SaPCR2 in Zn Uptake in the Root Elongation Zone of the Zn/Cd Hyperaccumulator Sedum alfredii

by Jun Ge, Jiayu Lin, Zhiying Wu, Kuan Xu, Jingyu Tao, Haizhong Lin, Shengke Tian and Lingli Lu

Life 2022, 12(5), 768; https://doi.org/10.3390/life12050768 - 23 May 2022

Cited by 2 | Viewed by 2387

Abstract

Zn pollution is a potential toxicant for agriculture and the environment. Sedum alfredii is a Zn/Cd hyperaccumulator found in China and has been proven as a useful resource for the phytoremediation of Zn-contaminated sites. However, the molecular mechanism of Zn uptake in S. [...] Read more.

Zn pollution is a potential toxicant for agriculture and the environment. Sedum alfredii is a Zn/Cd hyperaccumulator found in China and has been proven as a useful resource for the phytoremediation of Zn-contaminated sites. However, the molecular mechanism of Zn uptake in S. alfredii is limited. In this study, the function of SaPCR2 on Zn uptake in S. alfredii was identified by gene expression analysis, yeast function assays, Zn accumulation and root morphology analysis in transgenic lines to further elucidate the mechanisms of uptake and translocation of Zn in S. alfredii. The results showed that SaPCR2 was highly expressed in the root elongation zone of the hyperaccumulating ecotype (HE) S. alfredii, and high Zn exposure downregulated the expression of SaPCR2 in the HE S. alfredii root. The heterologous expression of SaPCR2 in yeast suggested that SaPCR2 was responsible for Zn influx. The overexpression of SaPCR2 in the non-hyperaccumulating ecotype (NHE) S. alfredii significantly increased the root uptake of Zn, but did not influence Mn, Cu or Fe. SR-μ-XRF technology showed that more Zn was distributed in the vascular buddle tissues, as well as in the cortex and epidermis in the transgenic lines. Root morphology was also altered after SaPCR2 overexpression, and a severe inhibition was observed. In the transgenic lines, the meristematic and elongation zones of the root were lower compared to the WT, and Zn accumulation in meristem cells was also reduced. These results indicate that SaPCR2 is responsible for Zn uptake, and mainly functions in the root elongation zone. This research on SaPCR2 could provide a theoretical basis for the use of genetic engineering technology in the modification of crops for their safe production and biological enhancement. Full article

(This article belongs to the Special Issue Uptake, Translocation, and Metabolism of Trace Metals in Plants)

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14 pages, 703 KB

Open AccessEditor’s ChoiceReview

Regulatory Effects of Statins on SIRT1 and Other Sirtuins in Cardiovascular Diseases

by Danial Khayatan, Seyed Mehrad Razavi, Zahra Najafi Arab, Maryam Khanahmadi, Saeideh Momtaz, Alexandra E. Butler, Fabrizio Montecucco, Yuliya V. Markina, Amir Hossein Abdolghaffari and Amirhossein Sahebkar

Life 2022, 12(5), 760; https://doi.org/10.3390/life12050760 - 20 May 2022

Cited by 12 | Viewed by 7320

Abstract

Adverse cardiovascular disease (CVD) outcomes, such as sudden cardiac death, acute myocardial infarction, and stroke, are often catastrophic. Statins are frequently used to attenuate the risk of CVD-associated morbidity and mortality through their impact on lipids and they may also have anti-inflammatory and [...] Read more.

Adverse cardiovascular disease (CVD) outcomes, such as sudden cardiac death, acute myocardial infarction, and stroke, are often catastrophic. Statins are frequently used to attenuate the risk of CVD-associated morbidity and mortality through their impact on lipids and they may also have anti-inflammatory and other plaque-stabilization effects via different signaling pathways. Different statins, including atorvastatin, rosuvastatin, pravastatin, pitavastatin, and simvastatin, are administered to manage circulatory lipid levels. In addition, statins are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase via modulating sirtuins (SIRTs). During the last two decades, SIRTs have been investigated in mammals and categorized as a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs) with significant oxidative stress regulatory function in cells—a key factor in extending cell lifespan. Recent work has demonstrated that statins upregulate SIRT1 and SIRT2 and downregulate SIRT6 in both in vitro and in vivo experiments and clinical trials. As statins show modulatory properties, especially in CVDs, future investigations are needed to delineate the role of SIRT family members in disease and to expand knowledge about the effects of statins on SIRTs. Here, we review what is currently known about the impact of statins on SIRTs and how these changes correlate with disease, particularly CVDs. Full article

(This article belongs to the Section Pharmaceutical Science)

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17 pages, 1398 KB

Open AccessEditor’s ChoiceArticle

SIRT1: Genetic Variants and Serum Levels in Age-Related Macular Degeneration

by Kriste Kaikaryte, Greta Gedvilaite, Alvita Vilkeviciute, Loresa Kriauciuniene, Ruta Mockute, Dzastina Cebatoriene, Reda Zemaitiene, Vilma Jurate Balciuniene and Rasa Liutkeviciene

Life 2022, 12(5), 753; https://doi.org/10.3390/life12050753 - 19 May 2022

Cited by 5 | Viewed by 2963

Abstract

Background: The aim of this paper was to determine the frequency of SIRT1 rs3818292, rs3758391, rs7895833 single nucleotide polymorphism genotypes and SIRT1 serum levels associated with age-related macular degeneration (AMD) in the Lithuanian population. Methods: Genotyping of SIRT1 rs3818292, rs3758391 and rs7895833 was [...] Read more.

Background: The aim of this paper was to determine the frequency of SIRT1 rs3818292, rs3758391, rs7895833 single nucleotide polymorphism genotypes and SIRT1 serum levels associated with age-related macular degeneration (AMD) in the Lithuanian population. Methods: Genotyping of SIRT1 rs3818292, rs3758391 and rs7895833 was performed using RT-PCR. SIRT1 serum level was determined using the ELISA method. Results: We found that rs3818292 and rs7895833 were associated with an increased risk of developing exudative AMD. Additional sex-differentiated analysis revealed only rs7895833 was associated with an increased risk of developing exudative AMD in women after strict Bonferroni correction. The analysis also revealed that individuals carrying rs3818292, rs3758391 and rs7895833 haplotype G-T-G are associated with increased odds of exudative AMD. Still, the rare haplotypes were associated with the decreased odds of exudative AMD. After performing an analysis of serum SIRT1 levels and SIRT1 genetic variant, we found that carriers of the SIRT1 rs3818292 minor allele G had higher serum SIRT1 levels than the AA genotype. In addition, individuals carrying at least one SIRT1 rs3758391 T allele also had elevated serum SIRT1 levels compared with individuals with the wild-type CC genotype. Conclusions: Our study showed that the SIRT1 polymorphisms rs3818292 and rs7895833 and rs3818292-rs3758391-rs7895833 haplotype G-T-G could be associated with the development of exudative AMD. Also, two SNPs (rs3818292 and rs3758391) are associated with elevated SIRT1 levels. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: From Mechanisms to Therapy)

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13 pages, 6581 KB

Open AccessEditor’s ChoiceArticle

Diffusion Tensor Imaging of a Median Nerve by Magnetic Resonance: A Pilot Study

by Kanza Awais, Žiga Snoj, Erika Cvetko and Igor Serša

Life 2022, 12(5), 748; https://doi.org/10.3390/life12050748 - 18 May 2022

Cited by 7 | Viewed by 2773

Abstract

The magnetic resonance Diffusion Tensor Imaging (DTI) is a powerful extension of Diffusion Weighted Imaging (DWI) utilizing multiple bipolar gradients, allowing for the evaluation of the microstructural environment of the highly anisotropic tissues. DTI was predominantly used for the assessment of the central [...] Read more.

The magnetic resonance Diffusion Tensor Imaging (DTI) is a powerful extension of Diffusion Weighted Imaging (DWI) utilizing multiple bipolar gradients, allowing for the evaluation of the microstructural environment of the highly anisotropic tissues. DTI was predominantly used for the assessment of the central nervous system (CNS), but with the advancement in magnetic resonance (MR) hardware and software, it has now become possible to image the peripheral nerves which were difficult to evaluate previously because of their small caliber. This study focuses on the assessment of the human median peripheral nerve ex vivo by DTI microscopy at 9.4 T magnetic field which allowed the evaluation of diffusion eigenvalues, the mean diffusivity and the fractional anisotropy at 35 μm in-plane resolution. The resolution was sufficient for clear depiction of all nerve anatomical structures and therefore further image analysis allowed the obtaining of average values for DT parameters in nerve fascicles (intrafascicular region and perineurium) as well as in the surrounding epineurium. The results confirmed the highest fractional anisotropy of 0.33 and principal diffusion eigenvalue of 1.0 × 10⁻⁹ m²/s in the intrafascicular region, somewhat lower values of 0.27 and 0.95 × 10⁻⁹ m²/s in the perineurium region and close to isotropic with very slow diffusion (0.15 and 0.05 × 10⁻⁹ m²/s) in the epineurium region. Full article

(This article belongs to the Special Issue Imaging in Neurosurgery: State of the Art)

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12 pages, 5462 KB

Open AccessEditor’s ChoiceArticle

Variations in Strain Distribution at Distal Radius under Different Loading Conditions

by Jonas A. Pramudita, Wataru Hiroki, Takuya Yoda and Yuji Tanabe

Life 2022, 12(5), 740; https://doi.org/10.3390/life12050740 - 16 May 2022

Cited by 6 | Viewed by 4747

Abstract

Distal radial fractures exhibit various fracture patterns. By assuming that the strain distribution at the distal radius affects the diversification of the fracture pattern, a parameter study using the finite element model of a wrist developed from computed tomography (CT) images was performed [...] Read more.

Distal radial fractures exhibit various fracture patterns. By assuming that the strain distribution at the distal radius affects the diversification of the fracture pattern, a parameter study using the finite element model of a wrist developed from computed tomography (CT) images was performed under different loading conditions. The finite element model of the wrist consisted of the radius, ulna, scaphoid, lunate, triquetrum, and major carpal ligaments. The material properties of the bone models were assigned on the basis of the Hounsfield Unit (HU) values of the CT images. An impact load was applied to the scaphoid, lunate, and triquetrum to simulate boundary conditions during fall accidents. This study considered nine different loading conditions that combine three different loading directions and three different load distribution ratios. According to the analysis results, the strain distribution at the distal radius changed with respect to the change in the loading condition. High strain concentration occurred in regions where distal radius fractures are commonly developed. The direction and distribution of the load acting on the radius were considered to be factors that may cause variations in the fracture pattern of distal radius fractures. Full article

(This article belongs to the Special Issue The Biomechanics of Injury and Rehabilitation)

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17 pages, 1115 KB

Open AccessEditor’s ChoiceArticle

Antimicrobial Properties of Compounds Isolated from Syzygium malaccense (L.) Merr. and L.M. Perry and Medicinal Plants Used in French Polynesia

by Camille Quenon, Thierry Hennebelle, Jean-François Butaud, Raimana Ho, Jennifer Samaillie, Christel Neut, Tamatoa Lehartel, Céline Rivière, Ali Siah, Natacha Bonneau, Sevser Sahpaz, Sébastien Anthérieu, Nicolas Lebegue, Phila Raharivelomanana and Vincent Roumy

Life 2022, 12(5), 733; https://doi.org/10.3390/life12050733 - 14 May 2022

Cited by 12 | Viewed by 4669

Abstract

A preliminary ethnopharmacological survey, achieved in French Polynesia, led to the collection of the most cited plants among 63 species used to treat “infectious” diseases, with a description of their medicinal uses. Bibliographical investigations and antimicrobial screening permitted the selection of the botanical [...] Read more.

A preliminary ethnopharmacological survey, achieved in French Polynesia, led to the collection of the most cited plants among 63 species used to treat “infectious” diseases, with a description of their medicinal uses. Bibliographical investigations and antimicrobial screening permitted the selection of the botanical species Syzygium malaccense (Myrtaceae) for phytochemical analysis. Leaves of Syzygium malaccense were usually used in mixture with rhizomes of Curcuma longa to treat infectious diseases such as cystitis. The methanolic plant extracts were tested in vitro with an agar microdilution method on 33 bacteria strains and 1 yeast to obtain their Minimal Inhibitory Concentration (MIC), and cytotoxicity against HepG2 cells were evaluated. Antimicrobial synergistic effects of methanolic plant extracts from leaves of Syzygium malaccense and rhizomes from Curcuma longa were also evaluated. The bio-guided isolation of leaf extract from Syzygium malaccense led to the identification of seven alkyl-salicylic acids (anacardic acids or ginkgolic acids C15:0, C15:1, C17:0, C17:1, C17:2, C17:3 and C19:1) described for the first time in this species. All compounds were tested against Staphylococcus aureus (18.75 < MIC < 75.0 µg/mL), Streptococcus pyogenes (2.34 < MIC < 18.75 µg/mL) and Pseudomonas aeruginosa (MIC = 150 µg/mL), and their structure–activity relationships were discussed. The methanolic extract and salicylic derivatives from S. malaccense showed an interesting antimicrobial activity against Gram+ bacteria, without toxicity on hepG2 cells at 400 μg/mL. Moreover, these antibacterial compounds have already been studied for their anti-inflammatory activity, which supports the therapeutic interest of S. malaccense against infectious diseases. Full article

(This article belongs to the Section Plant Science)

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15 pages, 2842 KB

Open AccessEditor’s ChoiceArticle

Data Mining Identifies CCN2 and THBS1 as Biomarker Candidates for Cardiac Hypertrophy

by Markus Johansson, Benyapa Tangruksa, Sepideh Heydarkhan-Hagvall, Anders Jeppsson, Peter Sartipy and Jane Synnergren

Life 2022, 12(5), 726; https://doi.org/10.3390/life12050726 - 12 May 2022

Cited by 5 | Viewed by 4291

Abstract

Cardiac hypertrophy is a condition that may contribute to the development of heart failure. In this study, we compare the gene-expression patterns of our in vitro stem-cell-based cardiac hypertrophy model with the gene expression of biopsies collected from hypertrophic human hearts. Twenty-five differentially [...] Read more.

Cardiac hypertrophy is a condition that may contribute to the development of heart failure. In this study, we compare the gene-expression patterns of our in vitro stem-cell-based cardiac hypertrophy model with the gene expression of biopsies collected from hypertrophic human hearts. Twenty-five differentially expressed genes (DEGs) from both groups were identified and the expression of selected corresponding secreted proteins were validated using ELISA and Western blot. Several biomarkers, including CCN2, THBS1, NPPA, and NPPB, were identified, which showed significant overexpressions in the hypertrophic samples in both the cardiac biopsies and in the endothelin-1-treated cells, both at gene and protein levels. The protein-interaction network analysis revealed CCN2 as a central node among the 25 overlapping DEGs, suggesting that this gene might play an important role in the development of cardiac hypertrophy. GO-enrichment analysis of the 25 DEGs revealed many biological processes associated with cardiac function and the development of cardiac hypertrophy. In conclusion, we identified important similarities between ET-1-stimulated human-stem-cell-derived cardiomyocytes and human hypertrophic cardiac tissue. Novel putative cardiac hypertrophy biomarkers were identified and validated on the protein level, lending support for further investigations to assess their potential for future clinical applications. Full article

(This article belongs to the Special Issue The Molecular Mechanism of Cardiovascular Disease)

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16 pages, 6005 KB

Open AccessEditor’s ChoiceArticle

Biogas Production Potential of Thermophilic Anaerobic Biodegradation of Organic Waste by a Microbial Consortium Identified with Metagenomics

by Lyudmila Kabaivanova, Penka Petrova, Venelin Hubenov and Ivan Simeonov

Life 2022, 12(5), 702; https://doi.org/10.3390/life12050702 - 8 May 2022

Cited by 21 | Viewed by 3716

Abstract

Anaerobic digestion (AD) is a widespread biological process treating organic waste for green energy production. In this study, wheat straw and corn stalks without any harsh preliminary treatment were collected as a renewable source to be employed in a laboratory-scale digester to produce [...] Read more.

Anaerobic digestion (AD) is a widespread biological process treating organic waste for green energy production. In this study, wheat straw and corn stalks without any harsh preliminary treatment were collected as a renewable source to be employed in a laboratory-scale digester to produce biogas/biomethane. Processes parameters of temperature, pH, total solids, volatile solid, concentration of volatile fatty acids (VFA), and cellulose concentration, were followed. The volume of biogas produced was measured. The impact of organic loading was stated, showing that the process at 55 °C tolerated a higher substrate load, up to 45 g/L. Further substrate increase did not lead to biogas accumulation increase, probably due to inhibition or mass transfer limitations. After a 12-day anaerobic digestion process, cumulative volumes of biogas yields were 4.78 L for 1 L of the bioreactor working volume with substrate loading 30 g/L of wheat straw, 7.39 L for 40 g/L and 8.22 L for 45 g/L. The degree of biodegradation was calculated to be 68.9%, 74% and 72%, respectively. A fast, effective process for biogas production was developed from native wheat straw, with the highest quantity of daily biogas production occurring between day 2 and day 5. Biomethane concentration in the biogas was 60%. An analysis of bacterial diversity by metagenomics revealed that more than one third of bacteria belonged to class Clostridia (32.9%), followed by Bacteroidia (21.5%), Betaproteobacteria (11.2%), Gammaproteobacteria (6.1%), and Alphaproteobacteria (5%). The most prominent genera among them were Proteiniphilum, Proteiniborus, and Pseudomonas. Archaeal share was 1.37% of the microflora in the thermophilic bioreactor, as the genera Methanocorpusculum, Methanobacterium, Methanomassiliicoccus, Methanoculleus, and Methanosarcina were the most abundant. A knowledge of the microbiome residing in the anaerobic digester can be further used for the development of more effective processes in conjunction with theidentified consortium. Full article

(This article belongs to the Special Issue The Role of Renewable Resources for Ecology and Human Health)

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12 pages, 2527 KB

Open AccessEditor’s ChoiceArticle

Type 2 Diabetes Mellitus Facilitates Shift of Adipose-Derived Stem Cells Ex Vivo Differentiation toward Osteogenesis among Patients with Obesity

by Margarita Agareva, Iurii Stafeev, Svetlana Michurina, Igor Sklyanik, Ekaterina Shestakova, Elizaveta Ratner, Xiang Hu, Mikhail Menshikov, Marina Shestakova and Yelena Parfyonova

Life 2022, 12(5), 688; https://doi.org/10.3390/life12050688 - 6 May 2022

Cited by 10 | Viewed by 3421

Abstract

Objective: Sedentary behavior with overnutrition provokes the development of obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The main progenitor cells of adipose tissue are adipose-derived stem cells (ADSCs) which can change differentiation, metabolic, and secretory phenotypes under obesity conditions. The purpose [...] Read more.

Objective: Sedentary behavior with overnutrition provokes the development of obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The main progenitor cells of adipose tissue are adipose-derived stem cells (ADSCs) which can change differentiation, metabolic, and secretory phenotypes under obesity conditions. The purpose of this study was to evaluate ADSC osteogenesis activity among patients with obesity in normal glucose tolerance (NGT) and T2DM conditions. Methods: In the study, ADSCs from donors with obesity were used. After clinical characterization, all patients underwent bariatric surgery and ADSCs were isolated from subcutaneous fat biopsies. ADSCs were subjected to osteogenic differentiation, stained with Alizarin Red S, and harvested for real-time PCR and Western blotting. Cell senescence was evaluated with a β-galactosidase-activity-based assay. Results: Our results demonstrated the significantly increased calcification of ADSC on day 28 of osteogenesis in the T2DM group. These data were confirmed by the statistically significant enhancement of RUNX2 gene expression, which is a master regulator of osteogenesis. Protein expression analysis showed the increased expression of syndecan 1 and collagen I before and during osteogenesis, respectively. Moreover, T2DM ADSCs demonstrated an increased level of cellular senescence. Conclusion: We suggest that T2DM-associated cellular senescence can cause ADSC differentiation to shift toward osteogenesis, the impaired formation of new fat depots in adipose tissue, and the development of insulin resistance. The balance between ADSC adipo- and osteogenesis commitment is crucial for the determination of the metabolic fate of patients and their adipose tissue. Full article

(This article belongs to the Special Issue Diabetes Metabolism: Molecular and Integrative Approaches)

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24 pages, 6365 KB

Open AccessEditor’s ChoiceArticle

The Antileukemic and Anti-Prostatic Effect of Aeroplysinin-1 Is Mediated through ROS-Induced Apoptosis via NOX Activation and Inhibition of HIF-1a Activity

by Shou-Ping Shih, Mei-Chin Lu, Mohamed El-Shazly, Yu-Hsuan Lin, Chun-Lin Chen, Steve Sheng-Fa Yu and Yi-Chang Liu

Life 2022, 12(5), 687; https://doi.org/10.3390/life12050687 - 5 May 2022

Cited by 16 | Viewed by 3703

Abstract

Aeroplysinin-1 is a brominated isoxazoline alkaloid that has exhibited a potent antitumor cell effect in previous reports. We evaluated the cytotoxicity of aeroplysinin-1 against leukemia and prostate cancer cells in vitro. This marine alkaloid inhibited the cell proliferation of leukemia Molt-4, K562 cells, [...] Read more.

Aeroplysinin-1 is a brominated isoxazoline alkaloid that has exhibited a potent antitumor cell effect in previous reports. We evaluated the cytotoxicity of aeroplysinin-1 against leukemia and prostate cancer cells in vitro. This marine alkaloid inhibited the cell proliferation of leukemia Molt-4, K562 cells, and prostate cancer cells Du145 and PC-3 with IC₅₀ values of 0.12 ± 0.002, 0.54 ± 0.085, 0.58 ± 0.109 and 0.33 ± 0.042 µM, respectively, as shown by the MTT assay. Furthermore, in the non-malignant cells, CCD966SK and NR8383, its IC₅₀ values were 1.54 ± 0.138 and 6.77 ± 0.190 μM, respectively. In a cell-free system, the thermal shift assay and Western blot assay verified the binding affinity of aeroplysinin-1 to Hsp90 and Topo IIα, which inhibited their activity. Flow cytometry analysis showed that the cytotoxic effect of aeroplysinin-1 is mediated through mitochondria-dependent apoptosis induced by reactive oxygen species (ROS). ROS interrupted the cellular oxidative balance by activating NOX and inhibiting HIF-1α and HO-1 expression. Pretreatment with N-acetylcysteine (NAC) reduced Apl-1-induced mitochondria-dependent apoptosis and preserved the expression of NOX, HO-1, and HIF-1a. Our findings indicated that aeroplysinin-1 targeted leukemia and prostate cancer cells through multiple pathways, suggesting its potential application as an anti-leukemia and prostate cancer drug lead. Full article

(This article belongs to the Section Pharmaceutical Science)

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10 pages, 1246 KB

Open AccessEditor’s ChoiceArticle

N-Methyl-D-Aspartate (NMDA) Receptors in the Prelimbic Cortex Are Required for Short- and Long-Term Memory Formation in Trace Fear Conditioning

by Eui-Ho Park, Nam-Soo Kim, Yeon-Kyung Lee and June-Seek Choi

Life 2022, 12(5), 672; https://doi.org/10.3390/life12050672 - 1 May 2022

Cited by 3 | Viewed by 3500

Abstract

Accumulating evidence suggests that the medial prefrontal cortex (mPFC) has been implicated in the acquisition of fear memory during trace fear conditioning in which a conditional stimulus (CS) is paired with an aversive unconditional stimulus (UCS) separated by a temporal gap (trace interval, [...] Read more.

Accumulating evidence suggests that the medial prefrontal cortex (mPFC) has been implicated in the acquisition of fear memory during trace fear conditioning in which a conditional stimulus (CS) is paired with an aversive unconditional stimulus (UCS) separated by a temporal gap (trace interval, TI). However, little is known about the role of the prefrontal cortex for short- and long-term trace fear memory formation. Thus, we investigated how the prelimbic (PL) subregion within mPFC in rats contributes to short- and long-term trace fear memory formation using electrolytic lesions and d,l,-2-amino-5-phosphonovaleric acid (APV), an N-methyl-D-aspartate receptor (NMDAR) antagonist infusions into PL. In experiment 1, pre-conditioning lesions of PL impaired freezing to the CS as well as TI during the acquisition and retrieval sessions, indicating that PL is critically involved in trace fear memory formation. In experiment 2, temporary blockade of NMDA receptors in PL impaired the acquisition, but not the expression of short- and long-term trace fear memory. In addition, the inactivation of NMDAR in PL had little effect on locomotor activity, pre-pulse inhibition (PPI), or shock sensitivity. Taken together, these results suggest that NMDA receptor-mediated neurotransmission in PL is required for the acquisition of trace fear memory. Full article

(This article belongs to the Special Issue Glutamate Receptors)

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14 pages, 3769 KB

Open AccessEditor’s ChoiceArticle

Curcumin Protects Diabetic Mice against Isoproterenol-Induced Myocardial Infarction by Modulating CB2 Cannabinoid Receptors

by Harshal D. Pawar, Umesh B. Mahajan, Kartik T. Nakhate, Yogeeta O. Agrawal, Chandragouda R. Patil, M. F. Nagoor Meeran, Charu Sharma, Shreesh Ojha and Sameer N. Goyal

Life 2022, 12(5), 624; https://doi.org/10.3390/life12050624 - 22 Apr 2022

Cited by 24 | Viewed by 3988

Abstract

Molecular docking revealed curcumin as a potent CB2 cannabinoid receptor (CB2R) agonist. Since CB2R is involved in cardioprotective functions, we explored its role in ameliorative actions of curcumin against myocardial damage triggered by isoproterenol in diabetic animals. Mice were kept on a high-fat [...] Read more.

Molecular docking revealed curcumin as a potent CB2 cannabinoid receptor (CB2R) agonist. Since CB2R is involved in cardioprotective functions, we explored its role in ameliorative actions of curcumin against myocardial damage triggered by isoproterenol in diabetic animals. Mice were kept on a high-fat diet (HFD) throughout the experiment (30 days). Following 7 days of HFD feeding, streptozotocin was administered (150 mg/kg, intraperitoneal) to induce diabetes. From day 11 to 30, diabetic mice received either curcumin (100 or 200 mg/kg/day, oral), CB2R antagonist AM630 (1 mg/kg/day, intraperitoneal) or both, with concurrent isoproterenol (150 mg/kg, subcutaneous) administration on day 28 and 29. Diabetic mice with myocardial infarction showed an altered hemodynamic pattern and lipid profile, reduced injury markers, antioxidants with increased lipid peroxidation in the myocardium, and elevated glucose and liver enzymes in the blood. Moreover, an increased pro-inflammatory markers, histological severity, myonecrosis, and edema were observed. Curcumin compensated for hemodynamic fluctuations, restored biochemical markers, preserved antioxidant capacity, decreased cytokines levels, and restored cardiac functionality. However, the AM630 pre-treatment attenuated the effects of curcumin. The data suggest the involvement of CB2R in the actions of curcumin such as in the prevention of myocardial stress and in the improvement of the normal status of the myocardial membrane associated with diabetes. Full article

(This article belongs to the Section Physiology and Pathology)

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11 pages, 262 KB

Open AccessEditor’s ChoiceReview

Deprescribing in Palliative Cancer Care

by Christel Hedman, Gabriella Frisk and Linda Björkhem-Bergman

Life 2022, 12(5), 613; https://doi.org/10.3390/life12050613 - 20 Apr 2022

Cited by 16 | Viewed by 7514

Abstract

The aim of palliative care is to maintain as high a quality of life (QoL) as possible despite a life-threatening illness. Thus, the prescribed medications need to be evaluated and the benefit of each treatment must be weighed against potential side effects. Medications [...] Read more.

The aim of palliative care is to maintain as high a quality of life (QoL) as possible despite a life-threatening illness. Thus, the prescribed medications need to be evaluated and the benefit of each treatment must be weighed against potential side effects. Medications that contribute to symptom relief and maintained QoL should be prioritized. However, studies have shown that treatment with preventive drugs that may not benefit the patient in end-of-life is generally deprescribed very late in the disease trajectory of cancer patients. Yet, knowing how and when to deprescribe drugs can be difficult. In addition, some drugs, such as beta-blockers, proton pump inhibitors, anti-depressants and cortisone need to be scaled down slowly to avoid troublesome withdrawal symptoms. In contrast, other medicines, such as statins, antihypertensives and vitamins, can be discontinued directly. The aim of this review is to give some advice according to when and how to deprescribe medications in palliative cancer care according to current evidence and clinical praxis. The review includes antihypertensive drugs, statins, anti-coagulants, aspirin, anti-diabetics, proton pump inhibitors, histamin-2-blockers, bisphosphonates denosumab, urologicals, anti-depressants, cortisone, thyroxin and vitamins. Full article

(This article belongs to the Section Medical Research)

19 pages, 598 KB

Open AccessEditor’s ChoiceReview

Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors

by Jaromir Myslivecek

Life 2022, 12(5), 606; https://doi.org/10.3390/life12050606 - 19 Apr 2022

Cited by 11 | Viewed by 5775

Abstract

The dopaminergic system is one of the most important neurotransmitter systems in the central nervous system (CNS). It acts mainly by activation of the D₁-like receptor family at the target cell. Additionally, fine-tuning of the signal is achieved via pre-synaptic modulation [...] Read more.

The dopaminergic system is one of the most important neurotransmitter systems in the central nervous system (CNS). It acts mainly by activation of the D₁-like receptor family at the target cell. Additionally, fine-tuning of the signal is achieved via pre-synaptic modulation by the D₂-like receptor family. Some dopamine drugs (both agonists and antagonists) bind in addition to DRs also to α₂-ARs and 5-HT receptors. Unfortunately, these compounds are often considered subtype(s) specific. Thus, it is important to consider the presence of these receptor subtypes in specific CNS areas as the function virtually elicited by one receptor type could be an effect of other—or the co-effect of multiple receptors. However, there are enough molecules with adequate specificity. In this review, we want to give an overview of the most common off-targets for established dopamine receptor ligands. To give an overall picture, we included a discussion on subtype selectivity. Molecules used as antipsychotic drugs are reviewed too. Therefore, we will summarize reported affinities and give an outline of molecules sufficiently specific for one or more subtypes (i.e., for subfamily), the presence of DR, α₂-ARs, and 5-HT receptors in CNS areas, which could help avoid ambiguous results. Full article

(This article belongs to the Special Issue The Physiology and Pharmacology of Dopamine Receptors: From Normal Signaling to Pathology)

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26 pages, 1511 KB

Open AccessEditor’s ChoiceReview

Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis

by Hope C. Ball, Andrew L. Alejo, Trinity Kronk, Amanda M. Alejo and Fayez F. Safadi

Life 2022, 12(4), 582; https://doi.org/10.3390/life12040582 - 14 Apr 2022

Cited by 15 | Viewed by 10383

Abstract

The aim of this review is to provide an updated review of the epigenetic factors involved in the onset and development of osteoarthritis (OA). OA is a prevalent degenerative joint disease characterized by chronic inflammation, ectopic bone formation within the joint, and physical [...] Read more.

The aim of this review is to provide an updated review of the epigenetic factors involved in the onset and development of osteoarthritis (OA). OA is a prevalent degenerative joint disease characterized by chronic inflammation, ectopic bone formation within the joint, and physical and proteolytic cartilage degradation which result in chronic pain and loss of mobility. At present, no disease-modifying therapeutics exist for the prevention or treatment of the disease. Research has identified several OA risk factors including mechanical stressors, physical activity, obesity, traumatic joint injury, genetic predisposition, and age. Recently, there has been increased interest in identifying epigenetic factors involved in the pathogenesis of OA. In this review, we detail several of these epigenetic modifications with known functions in the onset and progression of the disease. We also review current therapeutics targeting aberrant epigenetic regulation as potential options for preventive or therapeutic treatment. Full article

(This article belongs to the Special Issue Gene/Stem Cell/Molecular Therapy of Craniofacial and Bone Diseases)

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17 pages, 2202 KB

Open AccessEditor’s ChoiceReview

Insulin Resistance Is Cheerfully Hitched with Hypertension

by Susmita Sinha and Mainul Haque

Life 2022, 12(4), 564; https://doi.org/10.3390/life12040564 - 10 Apr 2022

Cited by 33 | Viewed by 15504

Abstract

Cardiovascular diseases and type 2 diabetes mellitus (T2DM) have risen steadily worldwide, particularly in low-income and developing countries. In the last hundred years, deaths caused by cardiovascular diseases increased rapidly to 35–40%, becoming the most common cause of mortality worldwide. Cardiovascular disease is [...] Read more.

Cardiovascular diseases and type 2 diabetes mellitus (T2DM) have risen steadily worldwide, particularly in low-income and developing countries. In the last hundred years, deaths caused by cardiovascular diseases increased rapidly to 35–40%, becoming the most common cause of mortality worldwide. Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM), which is aggravated by hypertension. Hypertension and diabetes are closely interlinked since they have similar risk factors such as endothelial dysfunction, vascular inflammation, arterial remodeling, atherosclerosis, dyslipidemia, and obesity. Patients with high blood pressure often show insulin resistance and have a higher risk of developing diabetes than normotensive individuals. It has been observed that over the last 30 years, the prevalence of insulin resistance (IR) has increased significantly. Accordingly, hypertension and insulin resistance are strongly related to an increased risk of impaired glucose tolerance, diabetes, cardiovascular diseases (CVD), and endocrine disorders. Common mechanisms, for instance, upregulation of the renin–angiotensin–aldosterone system, oxidative stress, inflammation, and activation of the immune system, possibly have a role in the association between diabetes and hypertension. Altogether these abnormalities significantly increase the risk of developing type 2 diabetes. Full article

(This article belongs to the Section Physiology and Pathology)

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16 pages, 4202 KB

Open AccessEditor’s ChoiceArticle

Dysregulation of the Amniotic PPARγ Pathway by Phthalates: Modulation of the Anti-Inflammatory Activity of PPARγ in Human Fetal Membranes

by Audrey Antoine, Coraline De Sousa Do Outeiro, Coline Charnay, Corinne Belville, Fanny Henrioux, Denis Gallot, Loïc Blanchon, Régine Minet-Quinard and Vincent Sapin

Life 2022, 12(4), 544; https://doi.org/10.3390/life12040544 - 6 Apr 2022

Cited by 4 | Viewed by 2556

Abstract

Phthalates are reprotoxic pollutants that are omnipresent in the environment. Detectable in amniotic fluid, these compounds (with the most concentrated being mono-2-ethylhexyl phthalate (MEHP)) are in direct contact with fetal membranes (FMs). They can lead to the premature rupture of FMs by deregulating [...] Read more.

Phthalates are reprotoxic pollutants that are omnipresent in the environment. Detectable in amniotic fluid, these compounds (with the most concentrated being mono-2-ethylhexyl phthalate (MEHP)) are in direct contact with fetal membranes (FMs). They can lead to the premature rupture of FMs by deregulating cellular and molecular pathways, such as, for example, the nuclear transcription factor peroxysome proliferator-activated receptor gamma (PPARγ) pathway. The objective was to study the impact of MEHP on the PPARγ pathway in FMs using amnion and choriodecidua across the three trimesters of pregnancy and the amniotic epithelial AV3 cell model by analyzing (i) PPARγ expression (mRNA and proteins) using RT-qPCR and Western blot assays; (ii) cytotoxicity and cell viability following MEHP treatment by lactate dehydrogenase (LDH) measurement and using Cell-counting Kit 8; and (iii) modulation by MEHP of PPARγ transcriptional activity (using a reporter gene assay) and PPARγ anti-inflammatory properties (by measuring IL6 and IL8 levels). PPARγ is expressed in the human amnion and choriodecidua during the three trimesters of pregnancy and in amniotic cells. In the AV3 cell line, MEHP is not cytotoxic and does not reduce cell viability, but it reduces PPARγ activity, here induced by a classical agonist without influencing its expression. MEHP also reduces PPARγ’s anti-inflammatory properties. In conclusion, PPARγ signaling is dysregulated by MEHP; this paves the way for future explorations to highlight the hypothesis of phthalates as an amniotic PPARγ disruptor that can explain the premature rupture of FMs. Full article

(This article belongs to the Special Issue New Insights into the Placental and Placental Membrane Pathophysiology of Preterm Birth)

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15 pages, 269 KB

Open AccessEditor’s ChoiceReview

Emerging Pharmacological Treatments for Migraine in the Pediatric Population

by Luigi Francesco Iannone, Francesco De Cesaris and Pierangelo Geppetti

Life 2022, 12(4), 536; https://doi.org/10.3390/life12040536 - 5 Apr 2022

Cited by 10 | Viewed by 4581

Abstract

Headaches in children and adolescents have high incidence and prevalence rates, with consequent elevated disability costs to individuals and the community. Pediatric migraine is a disorder with substantial clinical differences compared to the adult form. Few clinical trials have been performed specifically on [...] Read more.

Headaches in children and adolescents have high incidence and prevalence rates, with consequent elevated disability costs to individuals and the community. Pediatric migraine is a disorder with substantial clinical differences compared to the adult form. Few clinical trials have been performed specifically on primary headache in pediatric populations using acute and preventative treatments, often with conflicting findings. The limited high-quality data on the effectiveness of treatments are also due to the high placebo effect, in terms of reductions in both the frequency and intensity of migraine attacks in the pediatric population. The recent introduction of calcitonin gene-related peptide (CGRP) pathway inhibitors and ditans is changing the treatment of migraine, but the majority of the data are still limited to adulthood. Thus, few drugs have indications for migraine treatment in the pediatric age group, and limited evidence gives guidance as to the choice of pharmacotherapy. Herein, we review the current evidence of pharmacological treatments and ongoing clinical trials on acute and preventative treatments in the pediatric population with migraine. Full article

(This article belongs to the Special Issue Migraine and Headache in Children and Adolescents)

38 pages, 2969 KB

Open AccessEditor’s ChoiceReview

Personalized Management and Treatment of Alzheimer’s Disease

by Ramón Cacabelos, Vinogran Naidoo, Olaia Martínez-Iglesias, Lola Corzo, Natalia Cacabelos, Rocío Pego and Juan C. Carril

Life 2022, 12(3), 460; https://doi.org/10.3390/life12030460 - 21 Mar 2022

Cited by 12 | Viewed by 5764

Abstract

Alzheimer’s disease (AD) is a priority health problem with a high cost to society and a large consumption of medical and social resources. The management of AD patients is complex and multidisciplinary. Over 90% of patients suffer from concomitant diseases and require personalized [...] Read more.

Alzheimer’s disease (AD) is a priority health problem with a high cost to society and a large consumption of medical and social resources. The management of AD patients is complex and multidisciplinary. Over 90% of patients suffer from concomitant diseases and require personalized therapeutic regimens to reduce adverse drug reactions (ADRs), drug–drug interactions (DDIs), and unnecessary costs. Men and women show substantial differences in their AD-related phenotypes. Genomic, epigenetic, neuroimaging, and biochemical biomarkers are useful for predictive and differential diagnosis. The most frequent concomitant diseases include hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60–90%), neuropsychiatric disorders (60–90%), and cancer (10%). Over 90% of AD patients require multifactorial treatments with risk of ADRs and DDIs. The implementation of pharmacogenetics in clinical practice can help optimize the limited therapeutic resources available to treat AD and personalize the use of anti-dementia drugs, in combination with other medications, for the treatment of concomitant disorders. Full article

(This article belongs to the Special Issue New Trends in Pharmaceutical Science)

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15 pages, 1168 KB

Open AccessEditor’s ChoiceArticle

When Nothing Goes Right: Risk Factors and Biomarkers of Right Heart Failure after Left Ventricular Assist Device Implantation

by Thomas Schlöglhofer, Franziska Wittmann, Robert Paus, Julia Riebandt, Anne-Kristin Schaefer, Philipp Angleitner, Marcus Granegger, Philipp Aigner, Dominik Wiedemann, Günther Laufer, Heinrich Schima and Daniel Zimpfer

Life 2022, 12(3), 459; https://doi.org/10.3390/life12030459 - 20 Mar 2022

Cited by 4 | Viewed by 3178

Abstract

Right heart failure (RHF) is a severe complication after left ventricular assist device (LVAD) implantation. The aim of this study was to analyze the incidence, risk factors, and biomarkers for late RHF including the possible superiority of the device and implantation method. This [...] Read more.

Right heart failure (RHF) is a severe complication after left ventricular assist device (LVAD) implantation. The aim of this study was to analyze the incidence, risk factors, and biomarkers for late RHF including the possible superiority of the device and implantation method. This retrospective, single-center study included patients who underwent LVAD implantation between 2014 and 2018. Primary outcome was freedom from RHF over one-year after LVAD implantation; secondary outcomes included pre- and postoperative risk factors and biomarkers for RHF. Of the 145 consecutive patients (HeartMate 3/HVAD: n = 70/75; female: 13.8%), thirty-one patients (21.4%) suffered RHF after a mean LVAD support of median (IQR) 105 (118) days. LVAD implantation method (less invasive: 46.7% vs. 35.1%, p = 0.29) did not differ significantly in patients with or without RHF, whereas the incidence of RHF was lower in HeartMate 3 vs. HVAD patients (12.9% vs. 29.3%, p = 0.016). Multivariate Cox proportional hazard analysis identified HVAD (HR 4.61, 95% CI 1.12–18.98; p = 0.03), early post-op heart rate (HR 0.96, 95% CI 0.93–0.99; p = 0.02), and central venous pressure (CVP) (HR 1.21, 95% CI 1.05–1.39; p = 0.01) as independent risk factors for RHF, but no association of RHF with increased all-cause mortality (HR 1.00, 95% CI 0.99–1.01; p = 0.50) was found. To conclude, HVAD use, lower heart rate, and higher CVP early post-op were independent risk factors for RHF following LVAD implantation. Full article

(This article belongs to the Section Medical Research)

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15 pages, 3081 KB

Open AccessEditor’s ChoiceArticle

The Possible Role of the Type I Chaperonins in Human Insulin Self-Association

by Federica Pizzo, Maria Rosalia Mangione, Fabio Librizzi, Mauro Manno, Vincenzo Martorana, Rosina Noto and Silvia Vilasi

Life 2022, 12(3), 448; https://doi.org/10.3390/life12030448 - 18 Mar 2022

Cited by 4 | Viewed by 2910

Abstract

Insulin is a hormone that attends to energy metabolism by regulating glucose levels in the bloodstream. It is synthesised within pancreas beta-cells where, before being released into the serum, it is stored in granules as hexamers coordinated by Zn²⁺ and further packaged [...] Read more.

Insulin is a hormone that attends to energy metabolism by regulating glucose levels in the bloodstream. It is synthesised within pancreas beta-cells where, before being released into the serum, it is stored in granules as hexamers coordinated by Zn²⁺ and further packaged in microcrystalline structures. The group I chaperonin cpn60, known for its assembly-assisting function, is present, together with its cochaperonin cpn10, at each step of the insulin secretory pathway. However, the exact function of the heat shock protein in insulin biosynthesis and processing is still far from being understood. Here we explore the possibility that the molecular machine cpn60/cpn10 could have a role in insulin hexameric assembly and its further crystallization. Moreover, we also evaluate their potential protective effect in pathological insulin aggregation. The experiments performed with the cpn60 bacterial homologue, GroEL, in complex with its cochaperonin GroES, by using spectroscopic methods, microscopy and hydrodynamic techniques, reveal that the chaperonins in vitro favour insulin hexameric organisation and inhibit its aberrant aggregation. These results provide new details in the field of insulin assembly and its related disorders. Full article

(This article belongs to the Special Issue How Cosolvents and Cosolutes Affect Biomolecules Stability and Activity)

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14 pages, 1948 KB

Open AccessEditor’s ChoiceArticle

Single-Cell Image-Based Analysis Reveals Chromatin Changes during the Acquisition of Tamoxifen Drug Resistance

by Han Zhao, Li F. Lin, Joshua Hahn, Junkai Xie, Harvey F. Holman and Chongli Yuan

Life 2022, 12(3), 438; https://doi.org/10.3390/life12030438 - 17 Mar 2022

Cited by 7 | Viewed by 3047

Abstract

Cancer drug resistance is the leading cause of cancer related deaths. The development of drug resistance can be partially contributed to tumor heterogeneity and epigenetic plasticity. However, the detailed molecular mechanism underlying epigenetic modulated drug resistance remains elusive. In this work, we systematically [...] Read more.

Cancer drug resistance is the leading cause of cancer related deaths. The development of drug resistance can be partially contributed to tumor heterogeneity and epigenetic plasticity. However, the detailed molecular mechanism underlying epigenetic modulated drug resistance remains elusive. In this work, we systematically analyzed epigenetic changes in tamoxifen (Tam) responsive and resistant breast cancer cell line MCF7, and adopted a data-driven approach to identify key epigenetic features distinguishing between these two cell types. Significantly, we revealed that DNA methylation and H3K9me3 marks that constitute the heterochromatin are distinctively different between Tam-resistant and -responsive cells. We then performed time-lapse imaging of 5mC and H3K9me3 features using engineered probes. After Tam treatment, we observed a slow transition of MCF7 cells from a drug-responsive to -resistant population based on DNA methylation features. A similar trend was not observed using H3K9me3 probes. Collectively, our results suggest that DNA methylation changes partake in the establishment of Tam-resistant breast cancer cell lines. Instead of global changes in the DNA methylation level, the distribution of DNA methylation features inside the nucleus can be one of the drivers that facilitates the establishment of a drug resistant phenotype in MCF7. Full article

(This article belongs to the Special Issue Epigenetics and Nuclear Architecture)

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13 pages, 1578 KB

Open AccessEditor’s ChoiceReview

Distinguishing Evolutionary Conservation from Derivedness

by Jason Cheok Kuan Leong, Masahiro Uesaka and Naoki Irie

Life 2022, 12(3), 440; https://doi.org/10.3390/life12030440 - 17 Mar 2022

Cited by 1 | Viewed by 3571

Abstract

While the concept of “evolutionary conservation” has enabled biologists to explain many ancestral features and traits, it has also frequently been misused to evaluate the degree of changes from a common ancestor, or “derivedness”. We propose that the distinction of these two concepts [...] Read more.

While the concept of “evolutionary conservation” has enabled biologists to explain many ancestral features and traits, it has also frequently been misused to evaluate the degree of changes from a common ancestor, or “derivedness”. We propose that the distinction of these two concepts allows us to properly understand phenotypic and organismal evolution. From a methodological aspect, “conservation” mainly considers genes or traits which species have in common, while “derivedness” additionally covers those that are not commonly shared, such as novel or lost traits and genes to evaluate changes from the time of divergence from a common ancestor. Due to these differences, while conservation-oriented methods are effective in identifying ancestral features, they may be prone to underestimating the overall changes accumulated during the evolution of certain lineages. Herein, we describe our recently developed method, “transcriptomic derivedness index”, for estimating the phenotypic derivedness of embryos with a molecular approach using the whole-embryonic transcriptome as a phenotype. Although echinoderms are often considered as highly derived species, our analyses with this method showed that their embryos, at least at the transcriptomic level, may not be much more derived than those of chordates. We anticipate that the future development of derivedness-oriented methods could provide quantitative indicators for finding highly/lowly evolvable traits. Full article

(This article belongs to the Special Issue Selected Papers from The 2nd AsiaEvo Conference)

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17 pages, 8142 KB

Open AccessEditor’s ChoiceArticle

Alkanes as Membrane Regulators of the Response of Early Membranes to Extreme Temperatures

by Loreto Misuraca, Antonino Caliò, Josephine G. LoRicco, Ingo Hoffmann, Roland Winter, Bruno Demé, Judith Peters and Philippe M. Oger

Life 2022, 12(3), 445; https://doi.org/10.3390/life12030445 - 17 Mar 2022

Cited by 6 | Viewed by 3924

Abstract

One of the first steps in the origin of life was the formation of a membrane, a physical boundary that allowed the retention of molecules in concentrated solutions. The proto-membrane was likely formed by self-assembly of simple readily available amphiphiles, such as short-chain [...] Read more.

One of the first steps in the origin of life was the formation of a membrane, a physical boundary that allowed the retention of molecules in concentrated solutions. The proto-membrane was likely formed by self-assembly of simple readily available amphiphiles, such as short-chain fatty acids and alcohols. In the commonly accepted scenario that life originated near hydrothermal systems, how these very simple membrane bilayers could be stable enough in time remains a debated issue. We used various complementary techniques such as dynamic light scattering, small angle neutron scattering, neutron spin-echo spectroscopy, and Fourier-transform infrared spectroscopy to explore the stability of a novel protomembrane system in which the insertion of alkanes in the midplane is proposed to shift membrane stability to higher temperatures, pH, and hydrostatic pressures. We show that, in absence of alkanes, protomembranes transition into lipid droplets when temperature increases; while in presence of alkanes, membranes persist for longer times in a concentration-dependent manner. Proto-membranes containing alkanes are stable at higher temperatures and for longer times, have a higher bending rigidity, and can revert more easily to their initial state upon temperature variations. Hence, the presence of membrane intercalating alkanes could explain how the first membranes could resist the harsh and changing environment of the hydrothermal systems. Furthermore, modulating the quantity of alkanes in the first membranes appears as a possible strategy to adapt the proto-membrane behavior according to temperature fluctuations, and it offers a first glimpse into the evolution of the first membranes. Full article

(This article belongs to the Special Issue Biomolecular Dynamics Explored by Incoherent Neutron Spectroscopy)

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7 pages, 1297 KB

Open AccessEditor’s ChoiceCommunication

Why Is the UAG (Amber) Stop Codon Almost Absent in Highly Expressed Bacterial Genes?

by Dominique Belin and Pere Puigbò

Life 2022, 12(3), 431; https://doi.org/10.3390/life12030431 - 16 Mar 2022

Cited by 6 | Viewed by 5579

Abstract

The genome hypothesis postulates that genes in a genome tend to conform to their species’ usage of the codon catalog and the GC content of the DNA. Thus, codon frequencies differ across organisms, including the three termination codons in the standard genetic code. [...] Read more.

The genome hypothesis postulates that genes in a genome tend to conform to their species’ usage of the codon catalog and the GC content of the DNA. Thus, codon frequencies differ across organisms, including the three termination codons in the standard genetic code. Here, we analyze the frequencies of stop codons in a group of highly expressed genes from 196 prokaryotes under strong translational selection. The occurrence of the three translation termination codons is highly biased, with UAA (ochre) being the most prevalent in almost all bacteria. In contrast, UAG (amber) is the least frequent termination codon, e.g., only 321 occurrences (7.4%) in E. coli K-12 substr. W3110. Of the 253 highly expressed genes, only two end with an UAG codon. The strength of the selective bias against UAG in highly expressed genes varies among bacterial genomes, but it is not affected by the GC content of these genomes. In contrast, increased GC content results in a decrease in UAA abundance with a concomitant increase in UGA abundance. We propose that readthrough efficiency and context effects could explain the prevalence of UAA over UAG, particularly in highly expressed genes. Findings from this communication can be utilized for the optimization of gene expression. Full article

(This article belongs to the Section Genetics and Genomics)

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25 pages, 869 KB

Open AccessEditor’s ChoiceReview

Notch Signaling and Cross-Talk in Hypoxia: A Candidate Pathway for High-Altitude Adaptation

by Katie A. O’Brien, Andrew J. Murray and Tatum S. Simonson

Life 2022, 12(3), 437; https://doi.org/10.3390/life12030437 - 16 Mar 2022

Cited by 19 | Viewed by 8333

Abstract

Hypoxia triggers complex inter- and intracellular signals that regulate tissue oxygen (O₂) homeostasis, adjusting convective O₂ delivery and utilization (i.e., metabolism). Human populations have been exposed to high-altitude hypoxia for thousands of years and, in doing so, have undergone natural [...] Read more.

Hypoxia triggers complex inter- and intracellular signals that regulate tissue oxygen (O₂) homeostasis, adjusting convective O₂ delivery and utilization (i.e., metabolism). Human populations have been exposed to high-altitude hypoxia for thousands of years and, in doing so, have undergone natural selection of multiple gene regions supporting adaptive traits. Some of the strongest selection signals identified in highland populations emanate from hypoxia-inducible factor (HIF) pathway genes. The HIF pathway is a master regulator of the cellular hypoxic response, but it is not the only regulatory pathway under positive selection. For instance, regions linked to the highly conserved Notch signaling pathway are also top targets, and this pathway is likely to play essential roles that confer hypoxia tolerance. Here, we explored the importance of the Notch pathway in mediating the cellular hypoxic response. We assessed transcriptional regulation of the Notch pathway, including close cross-talk with HIF signaling, and its involvement in the mediation of angiogenesis, cellular metabolism, inflammation, and oxidative stress, relating these functions to generational hypoxia adaptation. Full article

(This article belongs to the Special Issue Cellular and Functional Response to Hypoxia)

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13 pages, 2168 KB

Open AccessEditor’s ChoiceArticle

2-Fluorofucose Attenuates Hydrogen Peroxide-Induced Oxidative Stress in HepG2 Cells via Nrf2/keap1 and NF-κB Signaling Pathways

by Mengjue Tu, Xingshuo Fan, Jianan Shi, Shengnan Jing, Xiaole Xu and Yuqin Wang

Life 2022, 12(3), 406; https://doi.org/10.3390/life12030406 - 11 Mar 2022

Cited by 5 | Viewed by 3625

Abstract

Fucosylation is one of the most important glycan terminal modifications that affects multiple biological activities of proteins. 2-Fluorofucose (2FF), its specific inhibitor, has recently been reported to reveal numerous biological effects by blocking fucosylation both in vitro and in vivo. The current study [...] Read more.

Fucosylation is one of the most important glycan terminal modifications that affects multiple biological activities of proteins. 2-Fluorofucose (2FF), its specific inhibitor, has recently been reported to reveal numerous biological effects by blocking fucosylation both in vitro and in vivo. The current study aimed to evaluate the effect of 2FF on hydrogen peroxide (H₂O₂)-induced oxidative damage in vitro. In our study, treatment with H₂O₂ increased the level of fucosylation, and 2FF improved the cell viability in H₂O₂-treated HepG2 cells. Our study also showed that 2FF significantly decreased the overproduction of reactive oxygen species (ROS) induced by H₂O₂ and the activities of catalase, glutathione and Mn-superoxide dismutase were remarkably increased by 2FF pretreatment. Furthermore, 2FF attenuated H₂O₂-induced early mitochondria dysfunction. The second part of the study revealed that 2FF enhanced antioxidant capacity by affecting Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Being pretreated with 2FF significantly increased the nuclear translocation of Nrf2 and simultaneously promoted the expression of downstream proteins, such as HO-1 and NQO1. Moreover, 2FF remarkably suppressed the expression of inflammation-associated proteins. Taken together, these data suggest that 2FF might have a potential therapeutic effect for oxidative stress. Full article

(This article belongs to the Section Pharmaceutical Science)

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9 pages, 505 KB

Open AccessEditor’s ChoiceArticle

Genetic Workup for Charcot–Marie–Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years

by Chiara Gemelli, Alessandro Geroldi, Sara Massucco, Lucia Trevisan, Ilaria Callegari, Lucio Marinelli, Giulia Ursino, Mehrnaz Hamedani, Giulia Mennella, Silvia Stara, Giovanni Maggi, Laura Mori, Cristina Schenone, Fabio Gotta, Serena Patrone, Alessia Mammi, Paola Origone, Valeria Prada, Lucilla Nobbio, Paola Mandich, Angelo Schenone, Emilia Bellone and Marina Grandis Show full author list Hide full author list

Life 2022, 12(3), 402; https://doi.org/10.3390/life12030402 - 10 Mar 2022

Cited by 9 | Viewed by 3927

Abstract

Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution [...] Read more.

Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation. Full article

(This article belongs to the Special Issue Rare Neurological Diseases)

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