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Biomedicines, Volume 9, Issue 4 (April 2021) – 116 articles

Cover Story (view full-size image): There are many problems related to data perception, but a problem of believing in one true cause is the most difficult. We are aware that we live in a complex world in which various factors interact, and the effects of these interactions are unpredictable. This complexity bothers us, and we deeply believe that we can reduce complex dependencies to a simple explanation. Sometimes we manage to do it, but we often make a mistake and simplify things too much. Similarly, studies on the pathophysiology of schizophrenia have not yet accurately determined the molecular phenotype of this disorder. View this paper
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Article
Circulating microRNAs Related to Bone Metabolism in HIV-Associated Bone Loss
Biomedicines 2021, 9(4), 443; https://doi.org/10.3390/biomedicines9040443 - 20 Apr 2021
Cited by 1 | Viewed by 1397
Abstract
The pathophysiology of human immunodeficiency virus (HIV)-associated bone loss is complex and to date largely unknown. In this study, we investigated serum expression of microRNAS (miRNAs) linked to bone metabolism in HIV-associated bone loss. This was a case-control study. Thirty male individuals with [...] Read more.
The pathophysiology of human immunodeficiency virus (HIV)-associated bone loss is complex and to date largely unknown. In this study, we investigated serum expression of microRNAS (miRNAs) linked to bone metabolism in HIV-associated bone loss. This was a case-control study. Thirty male individuals with HIV infection (HIV+) and osteoporosis/osteopenia (HIV+/OP+) (cases) and 30 age-matched male HIV+ individuals with normal bone mass (HIV+/OP−) (controls) were included in the analysis. Thirty male individuals matched for age without HIV infection (HIV−), were also included as second controls. The selected panel of miRNAs was as follows: hsa-miRNA-21-5p; hsa-miRNA-23a-3p; hsa-miRNA-24-2-5p; hsa-miRNA-26a-5p; hsa-miRNA-29a-3p; hsa-miRNA-124-3p; hsa-miRNA-33a-5p; and hsa-miRNA-133a-3p. Within the cohort of HIV+ individuals, relative serum expression of miRNA-21-5p and miRNA-23a-3p was significantly lower (p < 0.001) while the expression of miRNA-24-2-5p was significantly higher (p = 0.030) in HIV+/OP+ compared to HIV+/OP−. Expression of miRNA-21-5p demonstrated a sensitivity of 84.6% and a specificity of 66.7 in distinguishing HIV+/OP+ individuals. Expression of circulating miRNAs related to bone metabolism; miRNA-23a-3p, miRNA-24-2-5p, and miRNA-21-5p is significantly altered in HIV+OP+ individuals, in line with data on other causes of osteoporosis, suggesting a common pattern of circulating miRNAs independent of the underlying cause. Full article
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Review
The Role of Microbiome and Virome in Idiopathic Pulmonary Fibrosis
Biomedicines 2021, 9(4), 442; https://doi.org/10.3390/biomedicines9040442 - 20 Apr 2021
Cited by 7 | Viewed by 2175
Abstract
The interest in the lung microbiome and virome and their contribution to the pathogenesis, perpetuation and progression of idiopathic pulmonary fibrosis (IPF) has been increasing during the last decade. The utilization of high-throughput sequencing to detect microbial and/or viral genetic material in bronchoalveolar [...] Read more.
The interest in the lung microbiome and virome and their contribution to the pathogenesis, perpetuation and progression of idiopathic pulmonary fibrosis (IPF) has been increasing during the last decade. The utilization of high-throughput sequencing to detect microbial and/or viral genetic material in bronchoalveolar lavage fluid or lung tissue samples has amplified the ability to identify and quantify specific microbial and viral populations. In stable IPF, higher microbial burden is associated with worse prognosis but no specific microbe has been identified to contribute to this. Additionally, no causative relation has been established. Regarding viral infections, although in the past they have been associated with IPF, causation has not been proved. Although in the past the diagnosis of acute exacerbation of IPF (AE-IPF) was not considered in patients with overt infection, this was amended in the last few years and infection is considered a cause for exacerbation. Besides this, a higher microbial burden has been found in the lungs of patients with AE-IPF and an association with higher morbidity and mortality has been confirmed. In contrast, an association of AE-IPF with viral infection has not been established. Despite the progress during the last decade, a comprehensive knowledge of the microbiome and virome in IPF and their role in disease pathogenesis are yet elusive. Although association with disease severity, risk for progression and mortality has been established, causation has not been proven and the potential use as a biomarker or the benefits of antimicrobial therapeutic strategies are yet to be determined. Full article
(This article belongs to the Special Issue Microbial Ecology in Health and Disease)
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Article
Mineralocorticoid Receptor Antagonists Eplerenone and Spironolactone Modify Adrenal Cortex Morphology and Physiology
Biomedicines 2021, 9(4), 441; https://doi.org/10.3390/biomedicines9040441 - 20 Apr 2021
Cited by 5 | Viewed by 1617
Abstract
Mineralocorticoid receptor antagonists (MRAs) are a class of anti-hypertensive drugs that act by blocking aldosterone action. The aim of this study was to evaluate whether the MRAs spironolactone and eplerenone influence adrenal cortical physiology and morphology. Spontaneous hypertensive rats (SHR, n = 18) [...] Read more.
Mineralocorticoid receptor antagonists (MRAs) are a class of anti-hypertensive drugs that act by blocking aldosterone action. The aim of this study was to evaluate whether the MRAs spironolactone and eplerenone influence adrenal cortical physiology and morphology. Spontaneous hypertensive rats (SHR, n = 18) and normotensive rats (WKY, n = 18) were randomly exposed to a daily dose of spironolactone (n = 6), eplerenone (n = 6), or no drug (n = 6) over 28 days. After that, aldosterone, corticosterone, and 11-deoxycorticosterone plasma concentrations were quantified. Adrenal glands were subjected to morphological analysis to assess lipid droplets content, capsular width, cell proliferation, and steroidogenic proteins expression. The adrenal cortex in untreated SHR showed higher lipid droplet content as than in WKY. In SHR, MRA treatment was associated with higher circulating aldosterone levels and Ki-67 expression in aldosterone-secreting cells. In WKY, the only difference observed after MRA spironolactone treatment was a narrower capsule. There was no difference in abundance of steroidogenic enzyme between groups. In conclusion, MRAs modify adrenal gland function and morphology in SHR. The effects observed within the adrenal glomerulosa with aldosterone-secreting cell proliferation and higher circulating aldosterone levels suggests that MRA treatment provokes activation of the renin angiotensin system. The prognostic value of hyperaldosteronism secondary to MRAs blockade requires further investigation. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Article
Artificially Induced Pluripotent Stem Cell-Derived Whole-Brain Organoid for Modelling the Pathophysiology of Metachromatic Leukodystrophy and Drug Repurposing
Biomedicines 2021, 9(4), 440; https://doi.org/10.3390/biomedicines9040440 - 20 Apr 2021
Cited by 2 | Viewed by 1360
Abstract
Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disease that results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Worldwide, there are between one in 40,000 and one in 160,000 people living with the disease. While there are currently no effective treatments [...] Read more.
Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disease that results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Worldwide, there are between one in 40,000 and one in 160,000 people living with the disease. While there are currently no effective treatments for MLD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of MLD pathogenesis. However, developing brain organoid models is expensive, time consuming and may not accurately reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids could overcome the current limitations. Artificially induced whole-brain organoids (aiWBO) have the potential to greatly expand our ability to model MLD and guide future wet lab research. In this study, we have upgraded and validated our artificially induced whole-brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.2). Using this upgraded NEUBorg, we have generated aiWBO simulations of MLD and provided a novel approach to evaluate factors associated with MLD pathogenesis, disease progression and new potential therapeutic options. Full article
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Article
In Vitro Investigation of Vascular Permeability in Endothelial Cells from Human Artery, Vein and Lung Microvessels at Steady-State and Anaphylactic Conditions
Biomedicines 2021, 9(4), 439; https://doi.org/10.3390/biomedicines9040439 - 19 Apr 2021
Cited by 6 | Viewed by 1442
Abstract
Human anaphylactic reactions largely involve an increase in vascular permeability, which is mainly controlled by endothelial cells (ECs). Due to the acute and serious nature of human anaphylaxis, in vivo studies of blood vessels must be replaced or supplemented with in vitro models. [...] Read more.
Human anaphylactic reactions largely involve an increase in vascular permeability, which is mainly controlled by endothelial cells (ECs). Due to the acute and serious nature of human anaphylaxis, in vivo studies of blood vessels must be replaced or supplemented with in vitro models. Therefore, we used a macromolecular tracer assay (MMTA) to investigate the EC permeability of three phenotypes of human ECs: artery (HAECs), vein (HSVECs) and microvessels from lung (HMLECs). ECs were stimulated with two fast-acting anaphylactic mediators (histamine and platelet-activating factor (PAF)) and one longer-lasting mediator (thrombin). At steady-state conditions, HSVEC monolayers were the most permeable and HMLEC the least (15.8% and 8.3% after 60 min, respectively). No response was found in ECs from artery or vein to any stimuli. ECs from microvessels reacted to stimulation with thrombin and also demonstrated a tendency of increased permeability for PAF. There was no reaction for histamine. This was not caused by missing receptor expression, as all three EC phenotypes expressed receptors for both PAF and histamine. The scarce response to fast-acting mediators illustrates that the MMTA is not suitable for investigating EC permeability to anaphylactic mediators. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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Article
Ecklonia cava Extract and Its Derivative Dieckol Promote Vasodilation by Modulating Calcium Signaling and PI3K/AKT/eNOS Pathway in In Vitro and In Vivo Models
Biomedicines 2021, 9(4), 438; https://doi.org/10.3390/biomedicines9040438 - 19 Apr 2021
Cited by 5 | Viewed by 1848
Abstract
Nitric oxide (NO), an endothelial-derived relaxing factor synthesized by endothelial nitric oxide synthase (eNOS) in endothelial cells, enhances vasodilation by modulating vascular tone. The calcium concentration critically influences eNOS activation in endothelial cells. Thus, modulation of calcium-dependent signaling pathways may be a potential [...] Read more.
Nitric oxide (NO), an endothelial-derived relaxing factor synthesized by endothelial nitric oxide synthase (eNOS) in endothelial cells, enhances vasodilation by modulating vascular tone. The calcium concentration critically influences eNOS activation in endothelial cells. Thus, modulation of calcium-dependent signaling pathways may be a potential therapeutic strategy to enhance vasodilation. Marine algae reportedly possess protective effects against cardiovascular disorders, including hypertension and vascular dysfunction; however, the underlying molecular signaling pathways remain elusive. In the present study, we extracted and isolated dieckol from Ecklonia cava and investigated calcium transit-enhanced vasodilation. Calcium modulation via the well-known M3 muscarinic acetylcholine receptor (AchM3R), which is linked to NO formation, was investigated and the vasodilatory effect of dieckol was verified. Our results indicated that dieckol effectively promoted NO generation via the PI3K/Akt/eNOS axis and calcium transients influenced by AchM3R. We also treated Tg(flk: EGFP) transgenic zebrafish with dieckol to assess its vasodilatory effect. Dieckol promoted vasodilation by enlarging the dorsal aorta diameter, thus regulating blood flow velocity. In conclusion, our findings suggest that dieckol modulates calcium transit through AchM3R, increases endothelial-dependent NO production, and efficiently enhances vasodilation. Thus, E. cava and its derivative, dieckol, can be considered as potential natural vasodilators. Full article
(This article belongs to the Special Issue Biomedicine from the Sea)
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Article
Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro
Biomedicines 2021, 9(4), 437; https://doi.org/10.3390/biomedicines9040437 - 18 Apr 2021
Cited by 12 | Viewed by 3637
Abstract
Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family [...] Read more.
Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics. Full article
(This article belongs to the Section Drug Discovery and Development)
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Article
Antitumor Activity of Pulvomycin via Targeting Activated-STAT3 Signaling in Docetaxel-Resistant Triple-Negative Breast Cancer Cells
Biomedicines 2021, 9(4), 436; https://doi.org/10.3390/biomedicines9040436 - 17 Apr 2021
Cited by 6 | Viewed by 1725
Abstract
Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in [...] Read more.
Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the tumorigenesis and metastasis of numerous cancers, and STAT3 signaling is aberrantly activated in TNBC cells. In this study, a docetaxel-resistant TNBC cell line (MDA-MB-231-DTR) was established, and mechanisms for the antitumor activity of pulvomycin, a novel STAT3 inhibitor isolated from marine-derived actinomycete, were investigated. Levels of activated STAT3 (p-STAT3 (Y705)) increased in docetaxel-resistant cells, and knockdown of STAT3 recovered the sensitivity to docetaxel in MDA-MB-231-DTR cells. Pulvomycin effectively inhibited the proliferation of both cell lines. In addition, pulvomycin suppressed the activation of STAT3 and subsequently induced G0/G1 cell cycle arrest and apoptosis. Pulvomycin also significantly inhibited the invasion and migration of MDA-MB-231-DTR cells through the modulation of epithelial-mesenchymal transition markers. In an MDA-MB-231-DTR-bearing xenograft mouse model, the combination of pulvomycin and docetaxel effectively inhibited tumor growth through STAT3 regulation. Thus, our findings demonstrate that the combination of docetaxel and STAT3 inhibitors is an effective strategy for overcoming docetaxel resistance in TNBC. Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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Review
Design of In Vitro Hair Follicles for Different Applications in the Treatment of Alopecia—A Review
Biomedicines 2021, 9(4), 435; https://doi.org/10.3390/biomedicines9040435 - 16 Apr 2021
Cited by 4 | Viewed by 4262
Abstract
The hair research field has seen great improvement in recent decades, with in vitro hair follicle (HF) models being extensively developed. However, due to the cellular complexity and number of various molecular interactions that must be coordinated, a fully functional in vitro model [...] Read more.
The hair research field has seen great improvement in recent decades, with in vitro hair follicle (HF) models being extensively developed. However, due to the cellular complexity and number of various molecular interactions that must be coordinated, a fully functional in vitro model of HFs remains elusive. The most common bioengineering approach to grow HFs in vitro is to manipulate their features on cellular and molecular levels, with dermal papilla cells being the main focus. In this study, we focus on providing a better understanding of HFs in general and how they behave in vitro. The first part of the review presents skin morphology with an emphasis on HFs and hair loss. The remainder of the paper evaluates cells, materials, and methods of in vitro growth of HFs. Lastly, in vitro models and assays for evaluating the effects of active compounds on alopecia and hair growth are presented, with the final emphasis on applications of in vitro HFs in hair transplantation. Since the growth of in vitro HFs is a complicated procedure, there is still a great number of unanswered questions aimed at understanding the long-term cycling of HFs without losing inductivity. Incorporating other regions of HFs that lead to the successful formation of different hair classes remains a difficult challenge. Full article
(This article belongs to the Special Issue Hair Pathology)
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Article
PET Imaging of GPR44 by Antagonist [11C]MK-7246 in Pigs
Biomedicines 2021, 9(4), 434; https://doi.org/10.3390/biomedicines9040434 - 16 Apr 2021
Cited by 1 | Viewed by 1860
Abstract
A validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist [...] Read more.
A validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist MK-7246 was radiolabeled with carbon-11 and the resulting positron-emission tomography (PET) tracer [11C]MK-7246 was evaluated in a pig model and in vitro cell lines. The [11C]MK-7246 compound demonstrated mainly hepatobiliary excretion with a clearly defined pancreas, no spillover from adjacent tissues, and pancreatic binding similar in magnitude to the previously evaluated GPR44 radioligand [11C]AZ12204657. The binding could be blocked by preadministration of nonradioactive MK-7246, indicating a receptor-binding mechanism. [11C]MK-7246 showed strong potential as a PET ligand candidate for visualization of beta-cell mass (BCM) and clinical translation of this methodology is ongoing. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Review
The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery
Biomedicines 2021, 9(4), 433; https://doi.org/10.3390/biomedicines9040433 - 16 Apr 2021
Cited by 30 | Viewed by 6179
Abstract
Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential [...] Read more.
Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine. Full article
(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)
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Review
Anatomy, Pathophysiology, Molecular Mechanisms, and Clinical Management of Erectile Dysfunction in Patients Affected by Coronary Artery Disease: A Review
Biomedicines 2021, 9(4), 432; https://doi.org/10.3390/biomedicines9040432 - 16 Apr 2021
Cited by 13 | Viewed by 3574
Abstract
Erectile dysfunction (ED) has been defined as the inability to attain or maintain penile erection sufficient for successful sexual intercourse. ED carries a notable influence on life quality, with significant implications for family and social relationships. Because atherosclerosis of penile arteries represents one [...] Read more.
Erectile dysfunction (ED) has been defined as the inability to attain or maintain penile erection sufficient for successful sexual intercourse. ED carries a notable influence on life quality, with significant implications for family and social relationships. Because atherosclerosis of penile arteries represents one of the most frequent ED causes, patients presenting with it should always be investigated for potential coexistent coronary or peripheral disease. Up to 75% of ED patients have a stenosis of the iliac-pudendal-penile arteries, supplying the male genital organ’s perfusion. Recently, pathophysiology and molecular basis of male erection have been elucidated, giving the ground to pharmacological and mechanical revascularization treatment of this condition. This review will focus on the normal anatomy and physiology of erection, the pathophysiology of ED, the relation between ED and cardiovascular diseases, and, lastly, on the molecular basis of erectile dysfunction. Full article
(This article belongs to the Special Issue Vascular Function in Chronic Non-communicable Diseases)
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Article
Biofabrication of Gingival Fibroblast Cell-Laden Collagen/Strontium-Doped Calcium Silicate 3D-Printed Bi-Layered Scaffold for Osteoporotic Periodontal Regeneration
Biomedicines 2021, 9(4), 431; https://doi.org/10.3390/biomedicines9040431 - 16 Apr 2021
Cited by 20 | Viewed by 2372
Abstract
Periodontal disease is a chronic disease that can lead to lose teeth and even tooth loss if left untreated. Osteoporosis and periodontal disease share similar characteristics and associated factors. Current regenerative techniques for periodontal diseases are ineffective in restoring complete function and structural [...] Read more.
Periodontal disease is a chronic disease that can lead to lose teeth and even tooth loss if left untreated. Osteoporosis and periodontal disease share similar characteristics and associated factors. Current regenerative techniques for periodontal diseases are ineffective in restoring complete function and structural integrity of periodontium due to unwanted migration of cells. In this study, we applied the concept of guided tissue regeneration (GTR) and 3D fabricated gingival fibroblast cell-laden collagen/strontium-doped calcium silicate (SrCS) bi-layer scaffold for periodontal regeneration. The results revealed that the bioactive SrCS had a hydroxyapatite formation on its surface after 14 days of immersion and that SrCS could release Sr and Si ions even after 6 months of immersion. In addition, in vitro results showed that the bi-layer scaffold enhanced secretion of FGF-2, BMP-2, and VEGF from human gingival fibroblasts and increased secretion of osteogenic-related proteins ALP, BSP, and OC from WJMSCs. In vivo studies using animal osteoporotic models showed that the 3D-printed cell-laden collagen/SrCS bi-layer scaffold was able to enhance osteoporotic bone regeneration, as seen from the increased Tb.Th and BV/TV ratio and the histological stains. In conclusion, it can be seen that the bi-layer scaffolds enhanced osteogenesis and further showed that guided periodontal regeneration could be achieved using collagen/SrCS scaffolds, thus making it a potential candidate for future clinical applications. Full article
(This article belongs to the Special Issue Tissue Engineering Updates and Perspective in Dentistry)
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Review
177Lu-PSMA Therapy in Metastatic Castration-Resistant Prostate Cancer
Biomedicines 2021, 9(4), 430; https://doi.org/10.3390/biomedicines9040430 - 15 Apr 2021
Cited by 2 | Viewed by 2579
Abstract
The aim of this narrative review is to evaluate the current status of 177Lu-PSMA (prostate specific membrane antigen) therapy for metastatic castration-resistant prostate cancer (mCRPC) in the light of the current literature. We also addressed patient preparation, therapy administration and side effect [...] Read more.
The aim of this narrative review is to evaluate the current status of 177Lu-PSMA (prostate specific membrane antigen) therapy for metastatic castration-resistant prostate cancer (mCRPC) in the light of the current literature. We also addressed patient preparation, therapy administration and side effect profiles. 177Lu-PSMA therapy efficacy was assessed by using prospective trials, meta-analyses and major retrospective trials. Predictors of efficacy were also mentioned. Although there are some different approaches regarding the use of 177Lu-PSMA therapy in different countries, this type of therapy is generally safe, with a low toxicity profile. From the oncological point of view, a PSA (prostate specific antigen) decline of ≥50% was seen in 10.6–69% of patients with mCRPC; whereas progression-free survival (PFS) was reported to be 3–13.7 months in different studies. Consequently, 177Lu-PSMA therapy is a promising treatment in patients with mCRPC, with good clinical efficacy, even in heavily pretreated patients with multiple lines of systemic therapy. Currently, there are ongoing clinical trials in the United States, including a phase III multicenter FDA registration trial. Full article
(This article belongs to the Special Issue Novel Strategy for Treating Castration-Resistant Prostate Cancer)
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Article
Targeting of the Essential acpP, ftsZ, and rne Genes in Carbapenem-Resistant Acinetobacter baumannii by Antisense PNA Precision Antibacterials
Biomedicines 2021, 9(4), 429; https://doi.org/10.3390/biomedicines9040429 - 15 Apr 2021
Cited by 8 | Viewed by 1680
Abstract
Infections by carbapenem-resistant A. baumannii (CRAB), a widespread nosocomial pathogen, are becoming increasingly difficult to prevent and treat. Therefore, there is an urgent need for discovery of novel antibiotics against CRAB. Programmable, precision antisense antibiotics, e.g., based on the nucleic acid mimic PNA [...] Read more.
Infections by carbapenem-resistant A. baumannii (CRAB), a widespread nosocomial pathogen, are becoming increasingly difficult to prevent and treat. Therefore, there is an urgent need for discovery of novel antibiotics against CRAB. Programmable, precision antisense antibiotics, e.g., based on the nucleic acid mimic PNA (peptide nucleic acid) have shown promise in this respect in the form of PNA-BPP (bacteria penetrating peptide) conjugates targeting essential bacterial genes. In the present study, we designed and synthesized a series of PNA-BPPs targeting the translation initiation region of the ftsZ, acpP, or rne gene of CRAB strains. The antimicrobial activity of the compounds and effects on gene expression level was compared to that of analogous mismatch PNA controls. Three antisense conjugates (KFF)3K-eg1-(acpP)PNA (5639), (KFF)3K-eg1-(ftsZ)PNA (5612), and (KFF)3-K-eg1-(rne)PNA (5656) exhibited complete growth inhibition against several CRAB strains at 1–2, 2–8, and 2 µM, respectively, and the compounds were bactericidal at 1–2× MIC. The bactericidal effect was correlated to reduction of target gene mRNA level using RT-qPCR, and the compounds showed no bacterial membrane disruption activity at 1–2× MIC. PNA5612 was tested against a series of 12 CRAB isolates and all were sensitive at 2–8 µM. In addition, the conjugates exhibited no cellular toxicity in the HepG2 cell line (up to 20 μM) and did not shown significant antibacterial activity against other Gram negatives (E. coli, P. aeruginosa). These results provide a starting point for discovery of antisense precision designer antibiotics for specific treatment of CRAB infections. Full article
(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)
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Article
Matrix Stiffness Modulates Mechanical Interactions and Promotes Contact between Motile Cells
Biomedicines 2021, 9(4), 428; https://doi.org/10.3390/biomedicines9040428 - 15 Apr 2021
Cited by 3 | Viewed by 2090
Abstract
The mechanical micro-environment of cells and tissues influences key aspects of cell structure and function, including cell motility. For proper tissue development, cells need to migrate, interact, and form contacts. Cells are known to exert contractile forces on underlying soft substrates and sense [...] Read more.
The mechanical micro-environment of cells and tissues influences key aspects of cell structure and function, including cell motility. For proper tissue development, cells need to migrate, interact, and form contacts. Cells are known to exert contractile forces on underlying soft substrates and sense deformations in them. Here, we propose and analyze a minimal biophysical model for cell migration and long-range cell–cell interactions through mutual mechanical deformations of the substrate. We compute key metrics of cell motile behavior, such as the number of cell-cell contacts over a given time, the dispersion of cell trajectories, and the probability of permanent cell contact, and analyze how these depend on a cell motility parameter and substrate stiffness. Our results elucidate how cells may sense each other mechanically and generate coordinated movements and provide an extensible framework to further address both mechanical and short-range biophysical interactions. Full article
(This article belongs to the Special Issue Advanced Research in Cell Motility)
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Article
Heme-Mediated Activation of the Nrf2/HO-1 Axis Attenuates Calcification of Valve Interstitial Cells
Biomedicines 2021, 9(4), 427; https://doi.org/10.3390/biomedicines9040427 - 15 Apr 2021
Cited by 9 | Viewed by 2450
Abstract
Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid [...] Read more.
Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of a variety of antioxidant genes, and plays a protective role in valve calcification. Heme oxygenase-1 (HO-1), an Nrf2-target gene, is upregulated in human calcified aortic valves. Therefore, we investigated the effect of Nrf2/HO-1 axis in VIC calcification. We induced osteogenic differentiation of human VICs with elevated phosphate and calcium-containing osteogenic medium (OM) in the presence of heme. Heme inhibited Ca deposition and OM-induced increase in alkaline phosphatase and osteocalcin (OCN) expression. Heme induced Nrf2 and HO-1 expression in VICs. Heme lost its anti-calcification potential when we blocked transcriptional activity Nrf2 or enzyme activity of HO-1. The heme catabolism products bilirubin, carbon monoxide, and iron, and also ferritin inhibited OM-induced Ca deposition and OCN expression in VICs. This study suggests that heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs. The anti-calcification effect of heme is attributed to the end products of HO-1-catalyzed heme degradation and ferritin. Full article
(This article belongs to the Special Issue Calcific Aortic Valve Disease and Aortic Stenosis)
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Review
Membrane Carriers and Transporters in Kidney Physiology and Disease
Biomedicines 2021, 9(4), 426; https://doi.org/10.3390/biomedicines9040426 - 14 Apr 2021
Cited by 7 | Viewed by 2174
Abstract
The growing information suggests that chronic kidney disease may affect expression and function of membrane carriers and transporters in the kidney. The dysfunction of carriers and transporters entails deficient elimination of uremic solutes as well as xenobiotics (drugs and toxins) with subsequent clinical [...] Read more.
The growing information suggests that chronic kidney disease may affect expression and function of membrane carriers and transporters in the kidney. The dysfunction of carriers and transporters entails deficient elimination of uremic solutes as well as xenobiotics (drugs and toxins) with subsequent clinical consequences. The renal carriers and transporters are also targets of drugs used in clinical practice, and intentional drug–drug interactions in the kidney are produced to increase therapeutic efficacy. The understanding of membrane carriers and transporters function in chronic kidney disease is important not only to better characterize drug pharmacokinetics, drug actions in the kidney, or drug–drug interactions but also to define the organ pathophysiology. Full article
(This article belongs to the Special Issue Drug Transporters)
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Article
Inhibition of AKT/GSK3β/CREB Pathway Improves the Responsiveness to AMPA Receptor Antagonists by Regulating GRIA1 Surface Expression in Chronic Epilepsy Rats
Biomedicines 2021, 9(4), 425; https://doi.org/10.3390/biomedicines9040425 - 14 Apr 2021
Cited by 10 | Viewed by 1552
Abstract
α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) has been reported as one of the targets for treatment of epilepsy. Although maladaptive regulation of surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) subunit is relevant to the responsiveness to AMPAR antagonists (perampanel and GYKI [...] Read more.
α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) has been reported as one of the targets for treatment of epilepsy. Although maladaptive regulation of surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) subunit is relevant to the responsiveness to AMPAR antagonists (perampanel and GYKI 52466) in LiCl-pilocarpine-induced chronic epilepsy rats, the underlying mechanisms of refractory seizures to AMPAR antagonists have yet been unclear. In the present study, we found that both AMPAR antagonists restored the up-regulations of GRIA1 surface expression and Src family-mediated glycogen synthase kinase 3β (GSK3β)-Ca2+/cAMP response element-binding protein (CREB) phosphorylations to control levels in responders (whose seizure activities were responsive to AMPAR) but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). In addition, 3-chloroacetyl indole (3CAI, an AKT inhibitor) co-treatment attenuated spontaneous seizure activities in non-responders, accompanied by reductions in AKT/GSK3β/CREB phosphorylations and GRIA1 surface expression. Although AMPAR antagonists reduced GRIA2 tyrosine (Y) phosphorylations in responders, they did not affect GRIA2 surface expression and protein interacting with C kinase 1 (PICK1) protein level in both responders and non-responders. Therefore, our findings suggest that dysregulation of AKT/GSK3β/CREB-mediated GRIA1 surface expression may be responsible for refractory seizures in non-responders, and that this pathway may be a potential target to improve the responsiveness to AMPAR antagonists. Full article
(This article belongs to the Special Issue Pathogenesis and Targeted Therapy of Epilepsy)
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Article
Potential Mucosal Irritation Discrimination of Surface Disinfectants Employed against SARS-CoV-2 by Limacus flavus Slug Mucosal Irritation Assay
Biomedicines 2021, 9(4), 424; https://doi.org/10.3390/biomedicines9040424 - 14 Apr 2021
Cited by 1 | Viewed by 1666
Abstract
Preventive measures have proven to be the most effective strategy to counteract the spread of the SARS-CoV-2 virus. Among these, disinfection is strongly suggested by international health organizations’ official guidelines. As a consequence, the increase of disinfectants handling is going to expose people [...] Read more.
Preventive measures have proven to be the most effective strategy to counteract the spread of the SARS-CoV-2 virus. Among these, disinfection is strongly suggested by international health organizations’ official guidelines. As a consequence, the increase of disinfectants handling is going to expose people to the risk of eyes, mouth, nose, and mucous membranes accidental irritation. To assess mucosal irritation, previous studies employed the snail Arion lusitanicus as the mucosal model in Slug Mucosal Irritation (SMI) assay. The obtained results confirmed snails as a suitable experimental model for their anatomical characteristics superimposable to the human mucosae and the different easily observed readouts. Another terrestrial gastropod, Limacus flavus, also known as “ Yellow slug “, due to its larger size and greater longevity, has already been proposed as an SMI assay alternative model. In this study, for the first time, in addition to the standard parameters recorded in the SMI test, the production of yellow pigment in response to irritants, unique to the snail L. flavus, was evaluated. Our results showed that this species would be a promising model for mucosal irritation studies. The study conducted testing among all those chemical solutions most commonly recommended against the SARS-CoV-2 virus. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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Article
Label-Free Assay of Protein Kinase A Activity and Inhibition Using a Peptide-Based Electrochemical Sensor
Biomedicines 2021, 9(4), 423; https://doi.org/10.3390/biomedicines9040423 - 13 Apr 2021
Cited by 5 | Viewed by 1554
Abstract
We propose a simple label-free electrochemical biosensor for monitoring protein kinase activity and inhibition using a peptide-modified electrode. The biosensor employs cys-kemptide (CLRRASLG) as a substrate peptide which was immobilized on the surface of a gold electrode via the self-assembly of the thiol [...] Read more.
We propose a simple label-free electrochemical biosensor for monitoring protein kinase activity and inhibition using a peptide-modified electrode. The biosensor employs cys-kemptide (CLRRASLG) as a substrate peptide which was immobilized on the surface of a gold electrode via the self-assembly of the thiol terminals in cysteine (C) residues. The interaction between protein kinase A (PKA) and adenosine 5′-triphosphate (ATP) on the cys-kemptide immobilized electrode can cause the transfer of ATP terminal phosphates to the peptide substrates at serine (S) residues, which alters the surface charge of the electrode, thus enabling monitoring of the PKA activity via measuring the interfacial electron transfer resistance with electrochemical impedance spectroscopy. The proposed sensor showed reliable, sensitive, and selective detection of PKA activity with a wide dynamic range of 0.1–100 U/mL and a detection limit of 56 mU/mL. The sensor also exhibited high selectivity, rendering it possible to screen PKA inhibitors. Moreover, the sensor can be employed to evaluate the activity and inhibition of PKA in real samples. Full article
(This article belongs to the Special Issue Biosensors at the Aid of Medicine)
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Article
Post-Ischemic Treatment of Recombinant Human Secretory Leukocyte Protease Inhibitor (rhSLPI) Reduced Myocardial Ischemia/Reperfusion Injury
Biomedicines 2021, 9(4), 422; https://doi.org/10.3390/biomedicines9040422 - 13 Apr 2021
Cited by 4 | Viewed by 1527
Abstract
Myocardial ischemia/reperfusion (I/R) injury is a major cause of mortality and morbidity worldwide. Among factors contributing to I/R injury, proteolytic enzymes could also cause cellular injury, expand the injured area and induce inflammation, which then lead to cardiac dysfunction. Therefore, protease inhibition seems [...] Read more.
Myocardial ischemia/reperfusion (I/R) injury is a major cause of mortality and morbidity worldwide. Among factors contributing to I/R injury, proteolytic enzymes could also cause cellular injury, expand the injured area and induce inflammation, which then lead to cardiac dysfunction. Therefore, protease inhibition seems to provide therapeutic benefits. Previous studies showed the cardioprotective effect of secretory leukocyte protease inhibitor (SLPI) against myocardial I/R injury. However, the effect of a post-ischemic treatment with SLPI in an in vivo I/R model has never been investigated. In the present study, recombinant human (rh) SLPI (rhSLPI) was systemically injected during coronary artery occlusion or at the onset of reperfusion. The results show that post-ischemic treatment with rhSLPI could significantly reduce infarct size, Lactate Dehydrogenase (LDH) and Creatine kinase-MB (CK-MB) activity, inflammatory cytokines and protein carbonyl levels, as well as improving cardiac function. The cardioprotective effect of rhSLPI is associated with the attenuation of p38 MAPK phosphorylation, Bax, caspase-3 and -8 protein levels and enhancement of pro-survival kinase Akt and ERK1/2 phosphorylation. In summary, this is the first report showing the cardioprotective effects against myocardial I/R injury of post-ischemic treatments with rhSLPI in vivo. Thus, these results suggest that SLPI could be used as a novel therapeutic strategy to reduce myocardial I/R injury. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Article
MicroRNAs Regulating Tumor and Immune Cell Interactions in the Prediction of Relapse in Early Stage Breast Cancer
Biomedicines 2021, 9(4), 421; https://doi.org/10.3390/biomedicines9040421 - 13 Apr 2021
Viewed by 1592
Abstract
MicroRNAs (miRNAs) are involved in the regulation of immune response and hold an important role in tumor immune escape. We investigated the differential expression of the immunomodulatory miR-10b, miR-19a, miR-20a, miR-126, and miR-155 in the plasma of healthy women and patients with early [...] Read more.
MicroRNAs (miRNAs) are involved in the regulation of immune response and hold an important role in tumor immune escape. We investigated the differential expression of the immunomodulatory miR-10b, miR-19a, miR-20a, miR-126, and miR-155 in the plasma of healthy women and patients with early stage breast cancer and interrogated their role in the prediction of patients’ relapse. Blood samples were obtained from healthy women (n = 20) and patients with early stage breast cancer (n = 140) before adjuvant chemotherapy. Plasma miRNA expression levels were assessed by RT-qPCR. Relapse predicting models were developed using binary logistic regression and receiver operating curves (ROC) were constructed to determine miRNA sensitivity and specificity. Only miR-155 expression was lower in patients compared with healthy women (p = 0.023), whereas miR-155 and miR-10b were lower in patients who relapsed compared with healthy women (p = 0.039 and p = 0.002, respectively). MiR-155 expression combined with axillary lymph node infiltration and tumor grade demonstrated increased capability in distinguishing relapsed from non-relapsed patients [(area under the curve, (AUC = 0.861; p < 0.001)]. Combined miR-19a and miR-20a expression had the highest performance in discriminating patients with early relapse (AUC = 0.816; p < 0.001). Finally, miR-10b in combination with lymph node status and grade had the highest accuracy to discriminate patients with late relapse (AUC = 0.971; p < 0.001). The robustness of the relapse predicting models was further confirmed in a 10-fold cross validation. Deregulation of circulating miRNAs involved in tumor-immune interactions may predict relapse in early stage breast cancer. Their successful clinical integration could potentially address the significance challenge of treatment escalation or de-escalation according to the risk of recurrence. Full article
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Article
Phaseolin Attenuates Lipopolysaccharide-Induced Inflammation in RAW 264.7 Cells and Zebrafish
Biomedicines 2021, 9(4), 420; https://doi.org/10.3390/biomedicines9040420 - 13 Apr 2021
Cited by 8 | Viewed by 2361
Abstract
Kushen (Radix Sophorae flavescentis) is used to treat ulcerative colitis, tumors, and pruritus. Recently, phaseolin, formononetin, matrine, luteolin, and quercetin, through a network pharmacology approach, were tentatively identified as five bioactive constituents responsible for the anti-inflammatory effects of S. flavescentis. However, [...] Read more.
Kushen (Radix Sophorae flavescentis) is used to treat ulcerative colitis, tumors, and pruritus. Recently, phaseolin, formononetin, matrine, luteolin, and quercetin, through a network pharmacology approach, were tentatively identified as five bioactive constituents responsible for the anti-inflammatory effects of S. flavescentis. However, the role of phaseolin (one of the primary components of S. flavescentis) in the direct regulation of inflammation and inflammatory processes is not well known. In this study, the beneficial role of phaseolin against inflammation was explored in lipopolysaccharide (LPS)-induced inflammation models of RAW 264.7 macrophages and zebrafish larvae. Phaseolin inhibited LPS-mediated production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), without affecting cell viability. In addition, phaseolin suppressed pro-inflammatory mediators such as cyclooxygenase 2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in a dose-dependent manner. Furthermore, phaseolin reduced matrix metalloproteinase (MMP) activity as well as macrophage adhesion in vitro and the recruitment of leukocytes in vivo by downregulating Ninjurin 1 (Ninj1), an adhesion molecule. Finally, phaseolin inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB). In view of the above, our results suggest that phaseolin could be a potential therapeutic candidate for the management of inflammation. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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Review
Oncolytic Virotherapy for Cancer: Clinical Experience
Biomedicines 2021, 9(4), 419; https://doi.org/10.3390/biomedicines9040419 - 13 Apr 2021
Cited by 21 | Viewed by 3753
Abstract
Oncolytic viruses are a new class of therapeutics which are largely in the experimental stage, with just one virus approved by the FDA thus far. While the concept of oncolytic virotherapy is not new, advancements in the fields of molecular biology and virology [...] Read more.
Oncolytic viruses are a new class of therapeutics which are largely in the experimental stage, with just one virus approved by the FDA thus far. While the concept of oncolytic virotherapy is not new, advancements in the fields of molecular biology and virology have renewed the interest in using viruses as oncolytic agents. Backed by robust preclinical data, many oncolytic viruses have entered clinical trials. Oncolytic viruses that have completed some levels of clinical trials or are currently undergoing clinical trials are mostly genetically engineered viruses, with the exception of some RNA viruses. Reolysin, an unmodified RNA virus is clinically the most advanced oncolytic RNA virus that has completed different phases of clinical trials. Other oncolytic viruses that have been studied in clinical trials are mostly DNA viruses that belong to one of the three families: herpesviridae, poxviridae or adenoviridae. In this review work we discuss recent clinical studies with oncolytic viruses, especially herpesvirus, poxvirus, adenovirus and reovirus. In summary, the oncolytic viruses tested so far are well tolerated, even in immune-suppressed patients. For most oncolytic viruses, mild and acceptable toxicities are seen at the currently defined highest feasible doses. However, anti-tumor efficacies of oncolytic viruses have been modest, especially when used as monotherapy. Therefore, the potency of oncolytic viruses needs to be enhanced for more oncolytic viruses to hit the clinic. Aiming to achieve higher therapeutic benefits, oncolytic viruses are currently being studied in combination with other therapies. Here we discuss the currently available clinical data on oncolytic viruses, either as monotherapy or in combination with other treatments. Full article
(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)
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Review
Ultrasound Methods in the Evaluation of Atherosclerosis: From Pathophysiology to Clinic
Biomedicines 2021, 9(4), 418; https://doi.org/10.3390/biomedicines9040418 - 13 Apr 2021
Cited by 12 | Viewed by 3052
Abstract
Atherosclerosis is a key pathological process that causes a plethora of pathologies, including coronary artery disease, peripheral artery disease, and ischemic stroke. The silent progression of the atherosclerotic disease prompts for new surveillance tools that can visualize, characterize, and provide a risk evaluation [...] Read more.
Atherosclerosis is a key pathological process that causes a plethora of pathologies, including coronary artery disease, peripheral artery disease, and ischemic stroke. The silent progression of the atherosclerotic disease prompts for new surveillance tools that can visualize, characterize, and provide a risk evaluation of the atherosclerotic plaque. Conventional ultrasound methods—bright (B)-mode US plus Doppler mode—provide a rapid, cost-efficient way to visualize an established plaque and give a rapid risk stratification of the patient through the Gray–Weale standardization—echolucent plaques with ≥50% stenosis have a significantly greater risk of ipsilateral stroke. Although rather disputed, the measurement of carotid intima-media thickness (C-IMT) may prove useful in identifying subclinical atherosclerosis. In addition, contrast-enhanced ultrasonography (CEUS) allows for a better image resolution and the visualization and quantification of plaque neovascularization, which has been correlated with future cardiovascular events. Newly emerging elastography techniques such as strain elastography and shear-wave elastography add a new dimension to this evaluation—the biomechanics of the arterial wall, which is altered in atherosclerosis. The invasive counterpart, intravascular ultrasound (IVUS), enables an individualized assessment of the anti-atherosclerotic therapies, as well as a direct risk assessment of these lesions through virtual histology IVUS. Full article
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Article
The Role of Endothelins, IL-18, and NGAL in Kidney Hypothermic Machine Perfusion
Biomedicines 2021, 9(4), 417; https://doi.org/10.3390/biomedicines9040417 - 13 Apr 2021
Cited by 2 | Viewed by 1286
Abstract
Ischemia-reperfusion injury (IRI) occurring after renal transplantation is a complex biochemical process that can be monitored by specific biomarkers. The roles of those are not yet fully elucidated. The aim of this study was to analyze the concentrations of endothelins (ET-1, ET-2, and [...] Read more.
Ischemia-reperfusion injury (IRI) occurring after renal transplantation is a complex biochemical process that can be monitored by specific biomarkers. The roles of those are not yet fully elucidated. The aim of this study was to analyze the concentrations of endothelins (ET-1, ET-2, and ET-3), interleukin-18 (IL-18), and neutrophil gelatinase-associated lipocalin (NGAL) during the reperfusion of human kidneys grafted from brain dead donors and later transplanted. The study group (n = 44) was analyzed according to the method of kidney storage: Group 1 underwent hypothermic machine perfusion (HMP) in the LifePort perfusion pump (n = 22), and Group 2 underwent static cold storage (SCS) (n = 22). The analysis of kidney function was performed daily during the first seven days after transplantation. The kidneys in Group 1 were characterized by higher absolute concentrations of ET-1, IL-18, and NGAL, as well as a lower concentration of ET-2 (p = 0.017) and ET-3. The relative increase of ET-1 (p = 0.033), ET-2, and ET-3 during reperfusion was lower in this group, while the relative decrease of NGAL was higher. Group 1 was also characterized by significant decrease of IL-18 (p = 0.026) and a tendency for better kidney function based on the higher total diuresis, higher glomerular filtration rate (GFR), higher potassium level, lower serum creatinine, and lower urea concentration during the seven-day postoperative observation period. The long-term beneficial impact of hypothermic machine perfusion on the outcome of transplanted kidneys may rely on the early modified proceedings and intensity of ischemia-reperfusion injury reflected by the dynamics of the concentrations of examined biomarkers. Full article
(This article belongs to the Special Issue Novel Therapies and Surgical Techniques to Improve Kidney Health)
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Review
Silencing Antibiotic Resistance with Antisense Oligonucleotides
Biomedicines 2021, 9(4), 416; https://doi.org/10.3390/biomedicines9040416 - 12 Apr 2021
Cited by 7 | Viewed by 2412
Abstract
Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including [...] Read more.
Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including viral and bacterial infections, genetic disorders, and cancer. To date, drugs approved for utilization in clinics or in clinical trials target diseases other than bacterial infections. Although several groups and companies are working on different strategies, the application of antisense technologies to prokaryotes still lags with respect to those that target other human diseases. In those cases where the focus is on bacterial pathogens, a subset of the research is dedicated to produce antisense compounds that silence or reduce expression of antibiotic resistance genes. Therefore, these compounds will be adjuvants administered with the antibiotic to which they reduce resistance levels. A varied group of oligonucleotide analogs like phosphorothioate or phosphorodiamidate morpholino residues, as well as peptide nucleic acids, locked nucleic acids and bridge nucleic acids, the latter two in gapmer configuration, have been utilized to reduce resistance levels. The major mechanisms of inhibition include eliciting cleavage of the target mRNA by the host’s RNase H or RNase P, and steric hindrance. The different approaches targeting resistance to β-lactams include carbapenems, aminoglycosides, chloramphenicol, macrolides, and fluoroquinolones. The purpose of this short review is to summarize the attempts to develop antisense compounds that inhibit expression of resistance to antibiotics. Full article
(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)
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Review
Chronic Traumatic Encephalopathy: Update on Current Clinical Diagnosis and Management
Biomedicines 2021, 9(4), 415; https://doi.org/10.3390/biomedicines9040415 - 12 Apr 2021
Cited by 7 | Viewed by 3261
Abstract
Chronic traumatic encephalopathy is a disease afflicting individuals exposed to repetitive neurotrauma. Unfortunately, diagnosis is made by postmortem pathologic analysis, and treatment options are primarily symptomatic. In this clinical update, we review clinical and pathologic diagnostic criteria and recommended symptomatic treatments. We also [...] Read more.
Chronic traumatic encephalopathy is a disease afflicting individuals exposed to repetitive neurotrauma. Unfortunately, diagnosis is made by postmortem pathologic analysis, and treatment options are primarily symptomatic. In this clinical update, we review clinical and pathologic diagnostic criteria and recommended symptomatic treatments. We also review animal models and recent discoveries from pre-clinical studies. Furthermore, we highlight the recent advances in diagnosis using diffusor tensor imaging, functional magnetic resonance imaging, positron emission tomography, and the fluid biomarkers t-tau, sTREM2, CCL11, NFL, and GFAP. We also provide an update on emerging pharmaceutical treatments, including immunotherapies and those that target tau acetylation, tau phosphorylation, and inflammation. Lastly, we highlight the current literature gaps and guide future directions to further improve clinical diagnosis and management of patients suffering from this condition. Full article
(This article belongs to the Special Issue Advances Research in Traumatic Encephalopathy)
Review
Undesirable Status of Prostate Cancer Cells after Intensive Inhibition of AR Signaling: Post-AR Era of CRPC Treatment
Biomedicines 2021, 9(4), 414; https://doi.org/10.3390/biomedicines9040414 - 12 Apr 2021
Cited by 6 | Viewed by 1820
Abstract
Recent advances in prostate cancer (PC) research unveiled real androgen receptor (AR) functions in castration-resistant PC (CRPC). Moreover, AR still accelerates PC cell proliferation via the activation of several mechanisms (e.g., mutation, variants, and amplifications in CRPC). New-generation AR signaling-targeted agents, inhibiting extremely [...] Read more.
Recent advances in prostate cancer (PC) research unveiled real androgen receptor (AR) functions in castration-resistant PC (CRPC). Moreover, AR still accelerates PC cell proliferation via the activation of several mechanisms (e.g., mutation, variants, and amplifications in CRPC). New-generation AR signaling-targeted agents, inhibiting extremely the activity of AR, were developed based on these incontrovertible mechanisms of AR-induced CRPC progression. However, long-term administration of AR signaling-targeted agents subsequently induces the major problem that AR (complete)-independent CRPC cells present neither AR nor prostate-specific antigen, including neuroendocrine differentiation as a subtype of AR-independent CRPC. Moreover, there are few treatments effective for AR-independent CRPC with solid evidence. This study focuses on the transformation mechanisms of AR-independent from AR-dependent CRPC cells and potential treatment strategy for AR-independent CRPC and discusses them based on a review of basic and clinical literature. Full article
(This article belongs to the Special Issue Novel Strategy for Treating Castration-Resistant Prostate Cancer)
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