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Biomedicines, Volume 12, Issue 6 (June 2024) – 209 articles

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16 pages, 787 KiB  
Review
Tissue-Resident Memory T Cells in Gastrointestinal Cancers: Prognostic Significance and Therapeutic Implications
by Hiromichi Sato, Sikun Meng, Tomoaki Hara, Yoshiko Tsuji, Yasuko Arao, Kazuki Sasaki, Shogo Kobayashi, Eric di Luccio, Takaaki Hirotsu, Taroh Satoh, Yuichiro Doki, Hidetoshi Eguchi and Hideshi Ishii
Biomedicines 2024, 12(6), 1342; https://doi.org/10.3390/biomedicines12061342 - 17 Jun 2024
Abstract
Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response [...] Read more.
Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response within nonlymphoid tissues. In this review, we summarize the characteristics and functions of Trm cells and discuss their profound implications for patient outcomes in gastrointestinal cancers. Positioned strategically in peripheral tissues, Trm cells have functions beyond immune surveillance, affecting tumor progression, prognosis, and response to immunotherapy. Studies indicate that Trm cells are prognostic markers and correlate positively with enhanced survival. Their presence in the tumor microenvironment has sparked interest in their therapeutic potential, particularly with respect to immune checkpoint inhibitors, which may improve cancer treatment. Understanding how Trm cells work will not only help to prevent cancer spread through effective treatment but will also contribute to disease prevention at early stages as well as vaccine development. The role of Trm cells goes beyond just cancer, and they have potential applications in infectious and autoimmune diseases. This review provides a thorough analysis of Trm cells in gastrointestinal cancers, which may lead to personalized and effective cancer therapies. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Cancer in Digestive Organs)
15 pages, 814 KiB  
Article
Exploring Periodontal Conditions, Salivary Markers, and Systemic Inflammation in Patients with Cardiovascular Diseases
by Carmen Silvia Caloian, Petra Șurlin, Andreea Ciurea, Dana Pop, Bogdan Caloian, Daniel Corneliu Leucuța, Adrian Bogdan Țigu, Giulio Rasperini, Iulia Cristina Micu, Alina Stanomir, Andrada Soancă and Alexandra Roman
Biomedicines 2024, 12(6), 1341; https://doi.org/10.3390/biomedicines12061341 - 17 Jun 2024
Abstract
(1) Background: This cross-sectional investigation appreciated the role of serum C-reactive protein (CRP), several hematologic-cell markers, and salivary inflammation-related molecules [calprotectin (S100A8/A9), interleukin-1β (IL-1β), kallikrein] to predict periodontitis in patients with atherosclerotic cardiovascular disease (ACVD), arrhythmia, or both. Also, we appreciated the relationship [...] Read more.
(1) Background: This cross-sectional investigation appreciated the role of serum C-reactive protein (CRP), several hematologic-cell markers, and salivary inflammation-related molecules [calprotectin (S100A8/A9), interleukin-1β (IL-1β), kallikrein] to predict periodontitis in patients with atherosclerotic cardiovascular disease (ACVD), arrhythmia, or both. Also, we appreciated the relationship between the inflammatory burden and periodontal destruction with the type of cardiac pathology. (2) Methods: Demographic, behavioral characteristics, periodontal indicators, blood parameters, and saliva samples were collected. (3) Results: All 148 patients exhibited stage II or III/IV periodontitis. Stage III/IV cases exhibited significantly increased S100A8/A9 levels (p = 0.004). A positive correlation between S100A8/A9 and IL-1β [0.35 (<0.001)], kallikrein [0.55 (<0.001)], and CRP [0.28 (<0.001)] was observed. Patients with complex cardiac involvement had a significantly higher number of sites with attachment loss ≥ 5 mm [19 (3–30)] compared to individuals with only arrhythmia [9 (3.25–18)] or ACVD [5 (1–12)] [0.048♦ {0.162/0.496/0.14}]. (4) Conclusions: Severe, extensive attachment loss may be indicative of patients with complex cardiac conditions, which underscores the essential role of periodontal status in relation to systemic diseases. The correlations between the rising trends of the inflammatory parameters suggest a potential interconnection between oral and systemic inflammation. Full article
(This article belongs to the Section Immunology and Immunotherapy)
22 pages, 4002 KiB  
Article
Cannabinol Regulates the Expression of Cell Cycle-Associated Genes in Motor Neuron-like NSC-34: A Transcriptomic Analysis
by Alessandra Trainito, Agnese Gugliandolo, Luigi Chiricosta, Stefano Salamone, Federica Pollastro, Emanuela Mazzon and Maria Lui
Biomedicines 2024, 12(6), 1340; https://doi.org/10.3390/biomedicines12061340 - 17 Jun 2024
Abstract
Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ9-tetrahydrocannabinol in Cannabis sativa L. and exhibits anti-oxidant, [...] Read more.
Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ9-tetrahydrocannabinol in Cannabis sativa L. and exhibits anti-oxidant, analgesic, anti-bacterial, and anti-inflammatory effects. In this study, we explored the biological effects of 20 µM CBN (6.20 µg/mL) on differentiated NSC-34 cells by MTT assay and next-generation sequencing analysis on the transcriptome. KEGG and Gene Ontology enrichment analyses have been performed to evaluate potential CBN-associated processes. Our results highlighted the absence of any cytotoxic effect of CBN. The comparative transcriptomic analysis pointed out the downregulation of Cdkn2a, Cdkn2c and Cdkn2d genes, which are known to suppress the cell cycle. Ccne2, Cdk2, Cdk7, Anapc11, Anapc10, Cdc23, Cdc16, Anapc4, Cdc27, Stag1, Smc3, Smc1a, Nipbl, Pds5a, Pds5b, and Wapl genes, renowned for their role as cell cycle progression activators, were instead upregulated. Our work suggests that CBN regulates the expression of many genes related to the cell cycle, which are required for axonal maturation, migration, and synaptic plasticity, while not affecting the expression of genes involved in cell death or tumorigenesis. Full article
(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids 2.0)
19 pages, 11185 KiB  
Article
Pharmacological Potential of Three Berberine-Containing Plant Extracts Obtained from Berberis vulgaris L., Mahonia aquifolium (Pursh) Nutt., and Phellodendron amurense Rupr.
by Alexandra Ciorîță, Sabina-Emanuela Erhan, Maria Loredana Soran, Ildiko Lung, Augustin Catalin Mot, Sergiu Gabriel Macavei and Marcel Pârvu
Biomedicines 2024, 12(6), 1339; https://doi.org/10.3390/biomedicines12061339 - 17 Jun 2024
Abstract
Three berberine-containing plant extracts were investigated for their pharmacological properties. The stems and leaves of Berberis vulgaris, Mahonia aquifolium, and Phellodendron amurense were characterized through scanning electron microscopy. The plant extracts obtained from fresh stem barks were further analyzed through high-performance [...] Read more.
Three berberine-containing plant extracts were investigated for their pharmacological properties. The stems and leaves of Berberis vulgaris, Mahonia aquifolium, and Phellodendron amurense were characterized through scanning electron microscopy. The plant extracts obtained from fresh stem barks were further analyzed through high-performance liquid chromatography, revealing berberine concentrations, among berbamine and palmatine. The plant extracts were further tested for their anticancer potential against 2D and 3D human skin melanoma (A375) and lung adenocarcinoma (A549) cell lines. The concentrations at which 50% of the cells are affected was determined by the viability assay and it was shown that B. vulgaris, the plant extract with the highest berberine concentration, is the most efficient inhibitor (0.4% extract concentration for the 2D model and 3.8% for the 3D model). The membrane integrity and nitrate/nitrite concentration assays were consistent with the viability results and showed effective anticancer potential. For further investigations, the B. vulgaris extract was used to obtain silver nanoparticles, which were characterized through transmission electron microscopy, energy dispersive spectroscopy, and X-ray diffraction. The formed nanoparticles have a uniform size distribution and are suited for future investigations in the field of biomedical applications, together with the B. vulgaris plant extract. Full article
(This article belongs to the Special Issue Phytochemicals: Current Status and Future Prospects)
12 pages, 556 KiB  
Article
Electromyographic Characteristics of Postactivation Effect in Dopamine-Dependent Spectrum Models Observed in Parkinson’s Disease and Schizophrenia
by Alexander Meigal, Liudmila Gerasimova-Meigal, Anna Kuzmina, Elena Antonen, Alexandra Peskova and Mark Burkin
Biomedicines 2024, 12(6), 1338; https://doi.org/10.3390/biomedicines12061338 - 17 Jun 2024
Abstract
This study aimed to test the hypothesis that the postactivation effect (PAE, involuntary normal muscle tone) is modified by dopaminergic mechanisms. The PAE was tested with surface electromyography (sEMG) in the “off medication” phase in participants with Parkinson’s disease (PDoff) and [...] Read more.
This study aimed to test the hypothesis that the postactivation effect (PAE, involuntary normal muscle tone) is modified by dopaminergic mechanisms. The PAE was tested with surface electromyography (sEMG) in the “off medication” phase in participants with Parkinson’s disease (PDoff) and in the “on medication” state in participants with schizophrenia (SZon), which modeled hypodopaminegic conditions, and in participants with PD “on medication” (PDon) and in participants with SZ “off medication” (SZoff) state which modeled the hyperdopaminergic conditions. Healthy age-matched participants constituted the control group (HC, n = 11). In hyperdopaminergic models, PAE was triggered in 71.3% of participants in SZoff and in 35.7% in PDon conditions. In the hypodopaminergic models, PAE was triggered in 12% in SZon and in 21.4% in PDoff conditions. In the HC group, PAE was present in 91% of participants. In the HC and PD groups, the mean frequency and correlation dimension of sEMG at PAE was higher than that during voluntary isometric contraction. In conclusion, in hypodopaminergic models, PAE triggering was inhibited. The manifestations and EMG characteristics of PAE in people with PD or SZ may indicate dopaminergic dysfunction. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
17 pages, 3923 KiB  
Article
The Role of Macrophage Inhibitory Factor in TAA-Induced Liver Fibrosis in Mice: Modulatory Effects of Betaine
by Tatjana Radosavljevic, Dusan Vukicevic, Jasmina Djuretić, Kristina Gopcevic, Milica Labudovic Borovic, Sanja Stankovic, Janko Samardzic, Milica Radosavljevic, Danijela Vucevic and Vladimir Jakovljevic
Biomedicines 2024, 12(6), 1337; https://doi.org/10.3390/biomedicines12061337 - 17 Jun 2024
Abstract
Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and [...] Read more.
Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF−/− C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF−/−; MIF−/−+Bet; TAA group, which received TAA; TAA+Bet; MIF−/−+TAA; and MIF−/−+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-β1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-β1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-β1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver. Full article
(This article belongs to the Section Gene and Cell Therapy)
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15 pages, 1351 KiB  
Article
The Endothelial Glycocalyx in Pig-to-Baboon Cardiac Xenotransplantation—First Insights
by Martin Bender, Jan-Michael Abicht, Bruno Reichart, Maria Leuschen, Felicia Wall, Julia Radan, Elisabeth Neumann, Maren Mokelke, Ines Buttgereit, Sebastian Michel, Reinhard Ellgass, Katja Gieseke, Stig Steen, Audrius Paskevicius, Joachim Denner, Antonia W. Godehardt, Ralf R. Tönjes, Christian Hagl, David Ayares, Eckhard Wolf, Michael Schmoeckel, Paolo Brenner, Martin B. Müller and Matthias Länginadd Show full author list remove Hide full author list
Biomedicines 2024, 12(6), 1336; https://doi.org/10.3390/biomedicines12061336 - 16 Jun 2024
Viewed by 324
Abstract
Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation. Despite these achievements, acute vascular rejection still presents a challenge for long-term xenograft acceptance and new insights into innate and adaptive immune [...] Read more.
Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation. Despite these achievements, acute vascular rejection still presents a challenge for long-term xenograft acceptance and new insights into innate and adaptive immune responses as well as detailed characterizations of signaling pathways are necessary. In allotransplantation, endothelial cells and their sugar-rich surface—the endothelial glycocalyx—are known to influence organ rejection. In xenotransplantation, however, only in vitro data exist on the role of the endothelial glycocalyx so far. Thus, in the current study, we analyzed the changes of the endothelial glycocalyx components hyaluronan, heparan sulfate and syndecan-1 after pig-to-baboon cardiac xenotransplantations in the perioperative (n = 4) and postoperative (n = 5) periods. These analyses provide first insights into changes of the endothelial glycocalyx after pig-to-baboon cardiac xenotransplantation and show that damage to the endothelial glycocalyx seems to be comparable or even less pronounced than in similar human settings when current strategies of cardiac xenotransplantation are applied. At the same time, data from the experiments where current strategies, like non-ischemic preservation, growth inhibition or porcine cytomegalovirus (a porcine roseolovirus (PCMV/PRV)) elimination could not be applied indicate that damage of the endothelial glycocalyx also plays an important role in cardiac xenotransplantation. Full article
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28 pages, 10163 KiB  
Article
External Support of Autologous Internal Jugular Vein Grafts with FRAME Mesh in a Porcine Carotid Artery Model
by Jaroslav Chlupac, Jan Frank, David Sedmera, Ondrej Fabian, Zuzana Simunkova, Iveta Mrazova, Tomas Novak, Zdenka Vanourková, Oldrich Benada, Zdenek Pulda, Theodor Adla, Martin Kveton, Alena Lodererova, Ludek Voska, Jan Pirk and Jiri Fronek
Biomedicines 2024, 12(6), 1335; https://doi.org/10.3390/biomedicines12061335 - 16 Jun 2024
Viewed by 171
Abstract
Background: Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in [...] Read more.
Background: Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in a preclinical model. Methods: We performed autologous internal jugular vein interposition grafting in porcine carotid arteries for one month. Four grafts were supported with a FRAME mesh, while seven unsupported grafts served as controls. The conduits were examined through flowmetry, angiography, macroscopy, and microscopy. Results: The one-month patency rate of FRAME-supported grafts was 100% (4/4), whereas that of unsupported controls was 43% (3/7, Log-rank p = 0.071). On explant angiography, FRAME grafts exhibited significantly more areas with no or mild stenosis (9/12) compared to control grafts (3/21, p = 0.0009). Blood flow at explantation was higher in the FRAME grafts (145 ± 51 mL/min) than in the controls (46 ± 85 mL/min, p = 0.066). Area and thickness of neo-intimal hyperplasia (NIH) at proximal anastomoses were similar for the FRAME and the control groups: 5.79 ± 1.38 versus 6.94 ± 1.10 mm2, respectively (p = 0.558) and 480 ± 95 vs. 587 ± 52 μm2/μm, respectively (p = 0.401). However, in the midgraft portions, the NIH area and thickness were significantly lower in the FRAME group than in the control group: 3.73 ± 0.64 vs. 6.27 ± 0.64 mm2, respectively (p = 0.022) and 258 ± 49 vs. 518 ± 36 μm2/μm, respectively (p = 0.0002). Conclusions: In our porcine model, the external mesh FRAME improved the patency of vein-to-carotid artery grafts and protected them from stenosis, particularly in the mid regions. The midgraft neo-intimal hyperplasia was two-fold thinner in the meshed grafts than in the controls. Full article
17 pages, 734 KiB  
Review
The Importance of Sleep in Overcoming Childhood Obesity and Reshaping Epigenetics
by Erika Richter, Priyadarshni Patel, Jeganathan Ramesh Babu, Xu Wang and Thangiah Geetha
Biomedicines 2024, 12(6), 1334; https://doi.org/10.3390/biomedicines12061334 - 15 Jun 2024
Viewed by 258
Abstract
The development of childhood obesity is a complex process influenced by a combination of genetic predisposition and environmental factors, such as sleep, diet, physical activity, and socioeconomic status. Long-term solutions for decreasing the risk of childhood obesity remain elusive, despite significant advancements in [...] Read more.
The development of childhood obesity is a complex process influenced by a combination of genetic predisposition and environmental factors, such as sleep, diet, physical activity, and socioeconomic status. Long-term solutions for decreasing the risk of childhood obesity remain elusive, despite significant advancements in promoting health and well-being in school and at home. Challenges persist in areas such as adherence to interventions, addressing underlying social determinants, and individual differences in response to treatment. Over the last decade, there has been significant progress in epigenetics, along with increased curiosity in gaining insights into how sleep and lifestyle decisions impact an individual’s health. Epigenetic modifications affect the expression of genes without causing changes to the fundamental DNA sequence. In recent years, numerous research studies have explored the correlation between sleep and the epigenome, giving a better understanding of DNA methylation, histone modification, and non-coding RNAs. Although significant findings have been made about the influence of sleep on epigenetics, a notable gap exists in the literature concerning sleep-related genes specifically associated with childhood obesity. Consequently, it is crucial to delve deeper into this area to enhance our understanding. Therefore, this review primarily focuses on the connection between sleep patterns and epigenetic modifications in genes related to childhood obesity. Exploring the interplay between sleep, epigenetics, and childhood obesity can potentially contribute to improved overall health outcomes. This comprehensive review encompasses studies focusing on sleep-related genes linked to obesity. Full article
(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)
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16 pages, 1633 KiB  
Review
Unveiling the Significance of HLA and KIR Diversity in Underrepresented Populations
by Lucía Santiago-Lamelas, Patricia Castro-Santos, Ángel Carracedo, Jordi Olloquequi and Roberto Díaz-Peña
Biomedicines 2024, 12(6), 1333; https://doi.org/10.3390/biomedicines12061333 - 15 Jun 2024
Viewed by 183
Abstract
Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless [...] Read more.
Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless depths of complexity. In recent years, a surge of high-powered genome-wide association studies (GWASs) utilizing single nucleotide polymorphism (SNP) arrays has occurred, significantly advancing our understanding of disease pathogenesis. Additionally, advances in HLA reference panels have enabled higher resolution and more reliable imputation, allowing for finer-grained evaluation of the association between sequence variations and disease risk. However, it is essential to note that the majority of these GWASs have focused primarily on populations of Caucasian and Asian origins, neglecting underrepresented populations in Latin America and Africa. This omission not only leads to disparities in health care access but also restricts our knowledge of novel genetic variants involved in disease pathogenesis within these overlooked populations. Since the KIR and HLA haplotypes prevalent in each population are clearly modelled by the specific environment, the aim of this review is to encourage studies investigating HLA/KIR involvement in infection and autoimmune diseases, reproduction, and transplantation in underrepresented populations. Full article
(This article belongs to the Special Issue Advanced Research of HLA in Diseases)
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11 pages, 1181 KiB  
Article
Role of Spinal Cholecystokinin Octapeptide, Nociceptin/Orphanin FQ, and Hemokinin-1 in Diabetic Allodynia
by Takafumi Hayashi, Syu-ichi Kanno, Chizuko Watanabe, Damiana Scuteri, Yasuyuki Agatsuma, Akiyoshi Hara, Giacinto Bagetta, Tsukasa Sakurada and Shinobu Sakurada
Biomedicines 2024, 12(6), 1332; https://doi.org/10.3390/biomedicines12061332 - 15 Jun 2024
Viewed by 151
Abstract
A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical [...] Read more.
A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn. Full article
20 pages, 852 KiB  
Review
Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis
by Eloisa Romano, Irene Rosa, Bianca Saveria Fioretto and Mirko Manetti
Biomedicines 2024, 12(6), 1331; https://doi.org/10.3390/biomedicines12061331 - 14 Jun 2024
Viewed by 277
Abstract
In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial [...] Read more.
In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial cells with different outcomes. Indeed, once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts, or acquire a senescence-associated secretory phenotype characterized by the release of exosomes and several profibrotic and proinflammatory mediators. In this narrative review, we aimed to give a comprehensive overview of recent studies dealing with the cellular and molecular mechanisms underlying SSc defective angiogenesis and the related endothelial cell dysfunctions, mainly the endothelial-to-mesenchymal transition process. We also discussed potential novel vascular treatment strategies able to restore the angiogenic process and reduce the endothelial-to-mesenchymal transition in this complex disease. Full article
(This article belongs to the Special Issue Angiogenesis)
15 pages, 1194 KiB  
Article
Importance of T1-Mapping Sequence in Patients with Hypertrophic Cardiomyopathy without Foci of Non-Ischemic Myocardial Injury in Late Gadolinium Enhancement Sequence
by Natalia Zdebik, Rafał Poręba and Paweł Gać
Biomedicines 2024, 12(6), 1330; https://doi.org/10.3390/biomedicines12061330 - 14 Jun 2024
Viewed by 250
Abstract
Background: The aim of this study was to assess the importance of T1-mapping sequences in the diagnosis of hypertrophic cardiomyopathy (HCM) in patients without foci of non-ischemic myocardial injury in classic cardiac magnetic resonance (CMR) sequences. Methods: Two groups were compared: 28 patients [...] Read more.
Background: The aim of this study was to assess the importance of T1-mapping sequences in the diagnosis of hypertrophic cardiomyopathy (HCM) in patients without foci of non-ischemic myocardial injury in classic cardiac magnetic resonance (CMR) sequences. Methods: Two groups were compared: 28 patients with HCM, without any foci of myocardial injury in the late gadolinium enhancement (LGE) sequence (HCM group), and 28 patients without cardiomyopathy (CON group). Classic CMR sequences and T1-mapping sequences were performed. The following parameters were assessed: T1 time of the whole left ventricular myocardium, T1 time of myocardium in the basal, middle and apical layers of the left ventricle, and T1 time in individual segments of the left ventricular myocardium. Myocardial extracellular volume (ECV) was assessed similarly. Results: ECV was significantly higher in the HCM group than in the CON group, for the whole left ventricular myocardium, for the basal and apical layers of the left ventricle, and for segments 1–3, 8, and 13–16 of the left ventricle. Regression analysis showed that a higher left-ventricular mass index (LVMI), a higher body mass index and older age are factors independently associated with a higher ECV of the whole myocardium but only in the group with LVMI ≥ 131.84 g/m2. Conclusion: In patients with HCM without foci of non-ischemic myocardial injury, higher ECV values of the left ventricular myocardium are observed. Full article
18 pages, 3334 KiB  
Article
The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer
by Elena A. Sarf, Elena I. Dyachenko and Lyudmila V. Bel’skaya
Biomedicines 2024, 12(6), 1329; https://doi.org/10.3390/biomedicines12061329 - 14 Jun 2024
Viewed by 264
Abstract
In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, [...] Read more.
In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, and 59 healthy controls. Before treatment, saliva samples were obtained from all participants, and the content of VEGF and cytokines in saliva was determined by an enzyme-linked immunosorbent assay, as well as the content of amino acids by high-performance liquid chromatography. It was found that VEGF was positively correlated with the level of pro-inflammatory cytokines IL-1β (r = 0.6367), IL-6 (r = 0.3813), IL-8 (r = 0.4370), and IL-18 (r = 0.4184). Weak correlations were shown for MCP-1 (r = 0.2663) and TNF-α (r = 0.2817). For the first time, we demonstrated changes in the concentration of VEGF and related cytokines in saliva in different molecular biological subtypes of breast cancer depending on the stage of the disease, differentiation, proliferation, and metastasis to the lymph nodes. A correlation was established between the expression of VEGF and the content of aspartic acid (r = −0.3050), citrulline (r = −0.2914), and tryptophan (r = 0.3382) in saliva. It has been suggested that aspartic acid and citrulline influence the expression of VEGF via the synthesis of the signaling molecule NO, and then tryptophan ensures tolerance of the immune system to tumor cells. Full article
(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)
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17 pages, 2376 KiB  
Review
Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO
by Gordan Srkalovic, Sally Nijim, Maya Blanka Srkalovic and David Fajgenbaum
Biomedicines 2024, 12(6), 1328; https://doi.org/10.3390/biomedicines12061328 - 14 Jun 2024
Viewed by 242
Abstract
TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be [...] Read more.
TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be seen in pathological contexts outside of iMCD, but it is unclear if those cases should be considered representative of a different disease entity or simply a severe presentation of other infectious, malignant, and rheumatological diseases. While interleukin-6 (IL-6) is an established driver of iMCD-TAFRO pathogenesis in a subset of patients, the etiology is unknown. Recent case reports and literature reviews on TAFRO patients suggest that vascular endothelial growth factor (VEGF), and the interplay of VEGF and IL-6 in concert, rather than IL-6 as a single cytokine, may be drivers for iMCD-TAFRO pathophysiology, especially renal injury. In this review, we discuss the possible role of VEGF in the pathophysiology and clinical manifestations of iMCD-TAFRO. In particular, VEGF may be involved in iMCD-TAFRO pathology through its ability to activate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Further elucidating a role for the VEGF-IL-6 axis and additional disease drivers may shed light on therapeutic options for the treatment of TAFRO patients who do not respond to, or otherwise relapse following, treatment with IL-6 targeting drugs. This review investigates the potential role of VEGF in the pathophysiology of iMCD-TAFRO and the potential for targeting related signaling pathways in the future. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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17 pages, 3646 KiB  
Article
DNA Damage and Senescence in the Aging and Alzheimer’s Disease Cortex Are Not Uniformly Distributed
by Gnanesh Gutta, Jay Mehta, Rody Kingston, Jiaan Xie, Eliana Brenner, Fulin Ma and Karl Herrup
Biomedicines 2024, 12(6), 1327; https://doi.org/10.3390/biomedicines12061327 - 14 Jun 2024
Viewed by 277
Abstract
Alzheimer’s disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. The connection between aging and the loss of genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells has been reported to increase with age, and their senescence-associated secreted products are likely contributing factors to age-related illnesses. We tracked DNA damage with 53BP1 and cellular senescence with p16 immunostaining of human post-mortem brain samples. We found that DNA damage was significantly increased in the BA9 region of the AD cortex compared with the same region in unaffected controls (UCs). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V and then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell-by-cell basis, we found that the intensities of the two markers were tightly linked in the AD but not the UC brain. To test whether DNA damage was a causal factor in the emergence of the senescence program, we used etoposide treatment to damage the DNA of cultured mouse primary neurons. While DNA damage increased after treatment, after 24 h, no change in the expression of senescence-associated markers was observed. Our work suggests that DNA damage and cellular senescence are both increased in the AD brain and increasingly coupled. We propose that in vivo, the relationship between the two age-related processes is more complex than previously thought. Full article
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12 pages, 3320 KiB  
Article
Platelet-Rich Fibrin Increases CXCL8 Expression in Gingival Fibroblasts
by Atefe Imani, Layla Panahipour, Natalia dos Santos Sanches, Lei Wang and Reinhard Gruber
Biomedicines 2024, 12(6), 1326; https://doi.org/10.3390/biomedicines12061326 - 14 Jun 2024
Viewed by 264
Abstract
Platelet-rich fibrin (PRF), the coagulated plasma of fractionated blood, is widely used to support tissue regeneration in dentistry, and the underlying cellular and molecular mechanisms are increasingly being understood. Periodontal connective tissues steadily express CXCL8, a chemokine that attracts granulocytes and lymphocytes, supporting [...] Read more.
Platelet-rich fibrin (PRF), the coagulated plasma of fractionated blood, is widely used to support tissue regeneration in dentistry, and the underlying cellular and molecular mechanisms are increasingly being understood. Periodontal connective tissues steadily express CXCL8, a chemokine that attracts granulocytes and lymphocytes, supporting homeostatic immunity. Even though PRF is considered to dampen inflammation, it should not be ruled out that PRF increases the expression of CXCL8 in gingival fibroblasts. To test this hypothesis, we conducted a bioassay where gingival fibroblasts were exposed to PRF lysates and the respective serum. We show here that PRF lysates and, to a lesser extent, PRF serum increased the expression of CXCL8 by the gingival fibroblasts, as confirmed by immunoassay. SB203580, the inhibitor of p38 mitogen-activated protein kinase, reduced CXCL8 expression. Consistently, PRF lysates and, to a weaker range, the PRF serum also caused phosphorylation of p38 in gingival fibroblasts. Assuming that PRF is a rich source of growth factors, the TGF-β receptor type I kinase inhibitor SB431542 decreased the PRF-induced expression and translation of CXCL8. The findings suggest that PRF lysates and the respective serum drive CXCL8 expression by activating TGF-β and p38 signaling in gingival fibroblasts. Full article
(This article belongs to the Special Issue Cell Biology in Dentistry: Second Edition)
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15 pages, 3817 KiB  
Article
Effects of Lithium Ions on tPA-Induced Hemorrhagic Transformation under Stroke
by Valentina A. Babenko, Elmira I. Yakupova, Irina B. Pevzner, Alexey D. Bocharnikov, Ljubava D. Zorova, Kseniya S. Fedulova, Oleg A. Grebenchikov, Artem N. Kuzovlev, Andrey V. Grechko, Denis N. Silachev, Parvaneh Rahimi-Moghaddam and Egor Y. Plotnikov
Biomedicines 2024, 12(6), 1325; https://doi.org/10.3390/biomedicines12061325 - 14 Jun 2024
Viewed by 260
Abstract
Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on [...] Read more.
Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on HT mechanisms are still unknown. In our study, we use the models of photothrombosis (PT)-induced brain ischemia and oxygen-glucose deprivation (OGD) to investigate the effect of Li+ on tPA-induced changes in brain and endothelial cell cultures. We found that tPA did not affect lesion volume or exacerbate neurological deficits but disrupted the blood–brain barrier. We demonstrate that poststroke treatment with Li+ improves neurological status and increases blood–brain barrier integrity after thrombolytic therapy. Under conditions of OGD, tPA treatment increased MMP-2/9 levels in endothelial cells, and preincubation with LiCl abolished this MMP activation. Moreover, we observed the effect of Li+ on glycolysis in tPA-treated endothelial cells, which we hypothesized to have an effect on MMP expression. Full article
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11 pages, 5610 KiB  
Article
Mode of the Interaction of Efflux Inhibitor Phenylalanyl-arginyl-β-naphtylamide with Bacterial Cells
by Sandra Sakalauskaitė, Valeryia Mikalayeva, Simona Sutkuvienė and Rimantas Daugelavičius
Biomedicines 2024, 12(6), 1324; https://doi.org/10.3390/biomedicines12061324 - 14 Jun 2024
Viewed by 232
Abstract
An increased efflux activity is one of the major reasons for bacterial antibiotic resistance. The usage of efflux pump inhibitors could be a promising approach to restoring the activity of inefficient antibiotics. The interaction of the RND family efflux pump inhibitor phenylalanyl-arginyl-β-naphthylamide (PAβN) [...] Read more.
An increased efflux activity is one of the major reasons for bacterial antibiotic resistance. The usage of efflux pump inhibitors could be a promising approach to restoring the activity of inefficient antibiotics. The interaction of the RND family efflux pump inhibitor phenylalanyl-arginyl-β-naphthylamide (PAβN) with Salmonella enterica ser. Typhimurium cells was assayed using traditional microbiological techniques and a novel PAβN-selective electrode. Monitoring the PAβN concentration in the medium using the electrode enabled the real-time measurements of this compound’s interaction with bacterial cells. We showed that S. Typhimurium cells accumulate a high amount of PAβN because of its high affinity to lipopolysaccharides (LPSs), the major constituent of the outer layer of the outer membrane, and does not affect the functioning of the plasma membrane. EDTA enhanced the binding of PAβN to S. Typhimurium cells and the purified E. coli LPSs, but the energization of the cells by glucose does not affect the cell-bound amount of this inhibitor. Polycationic antibiotic Polymyxin B released both the cells accumulated and the suspended LPS-bound PAβN. Full article
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10 pages, 2657 KiB  
Article
Identifying Molecular Pathophysiology and Potential Therapeutic Options in Iatrogenic Tracheal Stenosis
by Russell Seth Martins, Joanna Weber, Bryan Johnson, Jeffrey Luo, Kostantinos Poulikidis, Mohammed Jawad Latif, Syed Shahzad Razi, Al Haitham Al Shetawi, Robert S. Lebovics and Faiz Y. Bhora
Biomedicines 2024, 12(6), 1323; https://doi.org/10.3390/biomedicines12061323 - 14 Jun 2024
Viewed by 273
Abstract
Introduction: While most patients with iatrogenic tracheal stenosis (ITS) respond to endoscopic ablative procedures, approximately 15% experience a recalcitrant, recurring disease course that is resistant to conventional management. We aimed to explore genetic profiles of patients with recalcitrant ITS to understand underlying pathophysiology [...] Read more.
Introduction: While most patients with iatrogenic tracheal stenosis (ITS) respond to endoscopic ablative procedures, approximately 15% experience a recalcitrant, recurring disease course that is resistant to conventional management. We aimed to explore genetic profiles of patients with recalcitrant ITS to understand underlying pathophysiology and identify novel therapeutic options. Methods: We collected 11 samples of granulation tissue from patients with ITS and performed RNA sequencing. We identified the top 10 most highly up- and down-regulated genes and cellular processes that these genes corresponded to. For the most highly dysregulated genes, we identified potential therapeutic options that favorably regulate their expression. Results: The dysregulations in gene expression corresponded to hyperkeratinization (upregulation of genes involved in keratin production and keratinocyte differentiation) and cellular proliferation (downregulation of cell cycle regulating and pro-apoptotic genes). Genes involved in retinoic acid (RA) metabolism and signaling were dysregulated in a pattern suggesting local cellular RA deficiency. Consequently, RA also emerged as the most promising potential therapeutic option for ITS, as it favorably regulated seven of the ten most highly dysregulated genes. Conclusion: This is the first study to characterize the role of hyperkeratinization and dysregulations in RA metabolism and signaling in the disease pathophysiology. Given the ability of RA to favorably regulate key genes involved in ITS, future studies must explore its efficacy as a potential therapeutic option for patients with recalcitrant ITS. Full article
(This article belongs to the Special Issue Assessment and Treatment of Respiratory Disorders)
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35 pages, 1327 KiB  
Review
A Review of MicroRNAs and lncRNAs in Atherosclerosis as Well as Some Major Inflammatory Conditions Affecting Atherosclerosis
by Jernej Letonja and Danijel Petrovič
Biomedicines 2024, 12(6), 1322; https://doi.org/10.3390/biomedicines12061322 - 13 Jun 2024
Viewed by 234
Abstract
It is generally accepted that atherosclerosis is a chronic inflammatory disease. The link between atherosclerosis and other inflammatory diseases such as psoriasis, type 2 diabetes mellitus (T2DM), and rheumatoid arthritis (RA) via metabolic, inflammatory, and immunoregulatory pathways is well established. The aim of [...] Read more.
It is generally accepted that atherosclerosis is a chronic inflammatory disease. The link between atherosclerosis and other inflammatory diseases such as psoriasis, type 2 diabetes mellitus (T2DM), and rheumatoid arthritis (RA) via metabolic, inflammatory, and immunoregulatory pathways is well established. The aim of our review was to summarize the associations between selected microRNAs (miRs) and long non-coding RNAs (lncRNAs) and atherosclerosis, psoriasis, T2DM, and RA. We reviewed the role of miR-146a, miR-210, miR-143, miR-223, miR-126, miR-21, miR-155, miR-145, miR-200, miR-133, miR-135, miR-221, miR-424, let-7, lncRNA-H19, lncRNA-MEG3, lncRNA-UCA1, and lncRNA-XIST in atherosclerosis and psoriasis, T2DM, and RA. Extracellular vesicles (EVs) are a method of intracellular signal transduction. Their function depends on surface expression, cargo, and the cell from which they originate. The majority of the studies that investigated lncRNAs and some miRs had relatively small sample sizes, which limits the generalizability of their findings and indicates the need for more research. Based on the studies reviewed, miR-146a, miR-155, miR-145, miR-200, miR-133, and lncRNA-H19 are the most promising potential biomarkers and, possibly, therapeutic targets for atherosclerosis as well as T2DM, RA, and psoriasis. Full article
(This article belongs to the Section Immunology and Immunotherapy)
13 pages, 3486 KiB  
Article
Expression of HOXB7 in the Lung of Patients with Idiopathic Pulmonary Fibrosis: A Proof-of-Concept Study
by Anna Valeria Samarelli, Roberto Tonelli, Giulia Raineri, Ilenia Mastrolia, Matteo Costantini, Luca Fabbiani, Virginia Catani, Tiziana Petrachi, Giulia Bruzzi, Dario Andrisani, Filippo Gozzi, Alessandro Marchioni, Valentina Masciale, Beatrice Aramini, Valentina Ruggieri, Giulia Grisendi, Massimo Dominici, Stefania Cerri and Enrico Clini
Biomedicines 2024, 12(6), 1321; https://doi.org/10.3390/biomedicines12061321 - 13 Jun 2024
Viewed by 329
Abstract
Background: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found [...] Read more.
Background: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found involved in various cancers. Methods: Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls. Results: The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, p = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50–75%)—measured with high-resolution computer tomography—compared to those with a lower extent (0–25%) (difference between means = 25.74 ± 6.72, p = 0.004). Conclusions: The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF. Full article
(This article belongs to the Special Issue Phenotypes and Endotypes in Interstitial Lung Diseases)
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22 pages, 2728 KiB  
Review
New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists
by Ferenc Sztanek, László Imre Tóth, Attila Pető, Marcell Hernyák, Ágnes Diószegi and Mariann Harangi
Biomedicines 2024, 12(6), 1320; https://doi.org/10.3390/biomedicines12061320 - 13 Jun 2024
Viewed by 259
Abstract
Guidelines for the management of obesity and type 2 diabetes (T2DM) emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain over the long term. Medication options are [...] Read more.
Guidelines for the management of obesity and type 2 diabetes (T2DM) emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain over the long term. Medication options are already available to treat obesity, which can help reduce appetite and/or reduce caloric intake. Incretin-based peptides exert their effect through G-protein-coupled receptors, the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and glucagon peptide hormones are important regulators of insulin secretion and energy metabolism. Understanding the role of intercellular signaling pathways and inflammatory processes is essential for the development of effective pharmacological agents in obesity. GLP-1 receptor agonists have been successfully used, but it is assumed that their effectiveness may be limited by desensitization and downregulation of the target receptor. A growing number of new agents acting on incretin hormones are becoming available for everyday clinical practice, including oral GLP-1 receptor agonists, the dual GLP-1/GIP receptor agonist tirzepatide, and other dual and triple GLP-1/GIP/glucagon receptor agonists, which may show further significant therapeutic potential. This narrative review summarizes the therapeutic effects of different incretin hormones and presents future prospects in the treatment of T2DM and obesity. Full article
23 pages, 1700 KiB  
Review
Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors
by Sotiria Stavropoulou De Lorenzo, Athina Andravizou, Harry Alexopoulos, Iliana Michailidou, Alexandros Bokas, Evangelia Kesidou, Marina-Kleopatra Boziki, Dimitrios Parissis, Christos Bakirtzis and Nikolaos Grigoriadis
Biomedicines 2024, 12(6), 1319; https://doi.org/10.3390/biomedicines12061319 - 13 Jun 2024
Viewed by 239
Abstract
The use of immune checkpoint inhibitors (ICIs) for the treatment of various advanced and aggressive types of malignancy has significantly increased both survival and long-term remission rates. ICIs block crucial inhibitory pathways of the immune system, in order to trigger an aggravated immune [...] Read more.
The use of immune checkpoint inhibitors (ICIs) for the treatment of various advanced and aggressive types of malignancy has significantly increased both survival and long-term remission rates. ICIs block crucial inhibitory pathways of the immune system, in order to trigger an aggravated immune response against the tumor. However, this enhanced immune activation leads to the development of numerous immune-related adverse events (irAEs), which may affect any system. Although severe neurological irAEs are relatively rare, they carry a high disability burden, and they can be potentially life-threatening. Therefore, clinicians must be alert and act promptly when individuals receiving ICIs present with new-onset neurological symptoms. In this narrative review, we have collected all the currently available data regarding the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of post-ICI neurological irAEs. This review aims to raise physicians’ awareness, enrich their knowledge regarding disease pathogenesis, and guide them through the diagnosis and management of post-ICI neurological irAEs. Full article
17 pages, 2816 KiB  
Article
The Prognostic Value of Proliferative Activity in Cutaneous Melanoma: A Pilot Study Evaluating the Mitotic Rate and Ki67 Index to Predict Patient Outcomes
by Dana Antonia Tapoi, Ancuța-Augustina Gheorghișan-Gălățeanu, Laura Maria Gosman, Diana Derewicz and Mariana Costache
Biomedicines 2024, 12(6), 1318; https://doi.org/10.3390/biomedicines12061318 - 13 Jun 2024
Viewed by 266
Abstract
Proliferative activity in cutaneous melanomas can be appreciated both histopathologically by counting mitotic figures and immunohistochemically through the Ki67 index, but the prognostic value of each method is still a matter of debate. In this context, we performed a retrospective study on 33 [...] Read more.
Proliferative activity in cutaneous melanomas can be appreciated both histopathologically by counting mitotic figures and immunohistochemically through the Ki67 index, but the prognostic value of each method is still a matter of debate. In this context, we performed a retrospective study on 33 patients diagnosed with cutaneous melanomas between 2013 and 2018 in order to evaluate progression-free survival and overall survival. Multivariate Cox proportional hazards regression was performed by considering both clinical histopathological and immunohistochemical features. The mitotic rate was significantly independently associated with both outcomes, while the Ki67 index was not an independent prognostic factor. However, the Ki67 predictive accuracy could be improved by establishing both a cut-off value and a standardized protocol for evaluating its expression. Until these desiderata are met, the mitotic rate remains superior to the Ki67 index for predicting prognosis in cutaneous melanomas, as also has the advantage of being easily interpreted in a standard histopathological examination regardless of the pathologist’s experience and with no further financial expenses. Importantly, this is one of very few articles that has shown perineural invasion to be an independent prognostic factor for both progression-free survival and overall survival in cutaneous melanomas. As a consequence, this parameter should become a mandatory feature in the histopathological evaluation of cutaneous melanomas as it can improve the identification of patients who are at high risk for disease progression. Full article
25 pages, 2458 KiB  
Review
The Multifaceted Nature of Macrophages in Cardiovascular Disease
by Cindy X. Li and Lixia Yue
Biomedicines 2024, 12(6), 1317; https://doi.org/10.3390/biomedicines12061317 - 13 Jun 2024
Viewed by 249
Abstract
As the leading cause of mortality worldwide, cardiovascular disease (CVD) represents a variety of heart diseases and vascular disorders, including atherosclerosis, aneurysm, ischemic injury in the heart and brain, arrythmias, and heart failure. Macrophages, a diverse population of immune cells that can promote [...] Read more.
As the leading cause of mortality worldwide, cardiovascular disease (CVD) represents a variety of heart diseases and vascular disorders, including atherosclerosis, aneurysm, ischemic injury in the heart and brain, arrythmias, and heart failure. Macrophages, a diverse population of immune cells that can promote or suppress inflammation, have been increasingly recognized as a key regulator in various processes in both healthy and disease states. In healthy conditions, these cells promote the proper clearance of cellular debris, dead and dying cells, and provide a strong innate immune barrier to foreign pathogens. However, macrophages can play a detrimental role in the progression of disease as well, particularly those inflammatory in nature. This review will focus on the current knowledge regarding the role of macrophages in cardiovascular diseases. Full article
(This article belongs to the Special Issue Macrophages in Cardio-Renal Diseases)
15 pages, 2304 KiB  
Article
Effect of 5-Aminolevulinic Acid (5-ALA) in “ALADENT” Gel Formulation and Photodynamic Therapy (PDT) against Human Oral and Pancreatic Cancers
by Domenica Lucia D’Antonio, Simona Marchetti, Pamela Pignatelli, Samia Umme, Domenico De Bellis, Paola Lanuti, Adriano Piattelli and Maria Cristina Curia
Biomedicines 2024, 12(6), 1316; https://doi.org/10.3390/biomedicines12061316 - 13 Jun 2024
Viewed by 332
Abstract
Oral squamous-cell and pancreatic carcinomas are aggressive cancers with a poor outcome. Photodynamic therapy (PDT) consists of the use of photosensitizer-induced cell and tissue damage that is activated by exposure to visible light. PDT selectively acts on cancer cells, which have an accumulation [...] Read more.
Oral squamous-cell and pancreatic carcinomas are aggressive cancers with a poor outcome. Photodynamic therapy (PDT) consists of the use of photosensitizer-induced cell and tissue damage that is activated by exposure to visible light. PDT selectively acts on cancer cells, which have an accumulation of photosensitizer superior to that of the normal surrounding tissues. 5-aminolevulinic acid (5-ALA) induces the production of protoporphyrin IX (PpIX), an endogenous photosensitizer activated in PDT. This study aimed to test the effect of a new gel containing 5% v/v 5-ALA (ALAD-PDT) on human oral CAL-27 and pancreatic CAPAN-2 cancer cell lines. The cell lines were incubated in low concentrations of ALAD-PDT (0.05%, 0.10%, 0.20%, 0.40%, 0.75%, 1.0%) for 4 h or 8 h, and then irradiated for 7 min with 630 nm RED light. The cytotoxic effects of ALAD-PDT were measured using the MTS assay. Apoptosis, cell cycle, and ROS assays were performed using flow cytometry. PpIX accumulation was measured using a spectrofluorometer after 10 min and 24 and 48 h of treatment. The viability was extremely reduced at all concentrations, at 4 h for CAPAN-2 and at 8 h for CAL-27. ALAD-PDT induced marked apoptosis rates in both oral and pancreatic cancer cells. Elevated ROS production and appreciable levels of PpIX were detected in both cell lines. The use of ALA-PDT as a topical or intralesional therapy would permit the use of very low doses to achieve effective results and minimize side effects. ALAD-PDT has the potential to play a significant role in complex oral and pancreatic anticancer therapies. Full article
(This article belongs to the Special Issue Photodynamic Therapy (3rd Edition))
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13 pages, 396 KiB  
Article
miR-155 and miR-21 as Diagnostic and Therapeutic Biomarkers for Ulcerative Colitis: There Is Still a Long Way to Go
by Danusia Onisor, Olga Brusnic, Claudia Banescu, Claudia Carstea, Maria Sasaran, Mircea Stoian, Calin Avram, Adrian Boiceanu, Alina Boeriu and Daniela Dobru
Biomedicines 2024, 12(6), 1315; https://doi.org/10.3390/biomedicines12061315 - 13 Jun 2024
Viewed by 246
Abstract
(1) Elucidating the role of miRNAs (miRs) in ulcerative colitis may provide new insights into disease pathogenesis, diagnosis, treatment, and monitoring We aimed to investigate whether plasma levels of miR-21-5p and miR-155-5p may be used to differentiate between patients with organic disease such [...] Read more.
(1) Elucidating the role of miRNAs (miRs) in ulcerative colitis may provide new insights into disease pathogenesis, diagnosis, treatment, and monitoring We aimed to investigate whether plasma levels of miR-21-5p and miR-155-5p may be used to differentiate between patients with organic disease such as ulcerative colitis (UC) and Clostridioides difficile infection (CDI), and patients with functional disease such as irritable bowel syndrome with diarrhea (IBS-D). (2) Serological samples were collected to quantify miR-155 and -21 expression, which was carried out through quantitative real-time polymerase chain reaction (qRT-PCR), from 84 patients: 34 with acute UC (group 1), 17 with CDI (group 2), and 33 with IBS-D (control group). (3) In this study, we found that the expression levels of miR-155-5p were almost the same for the two conditions and the control group (UC: 4.22 ± 1.61, CDI: 3.94 ± 1.62, IBS-D: 4.26 ± 1.26), with no significant differences either for ΔCt- or for ΔΔCt-derived parameters (p = 0.74 and p = 0.73, respectively). For miR-21, ΔCt levels presented significantly higher values among the ulcerative colitis group (p < 0.01), but the most important expression fold change was noticed in patients with CDI (UC:4.11 ± 8,46, CDI: 4.94 ± 9.68, IBS-D: 2.83 ± 5.41). (4) Circulating miR-155 and miR-21 were upregulated in UC, CDI, and IBS-D, but differentiation was not possible among them. But their involvement in the pathogenesis of the three diseases makes them suitable for improving the accuracy of diagnosis and facilitating the development of personalized treatment strategies. Full article
(This article belongs to the Special Issue MicroRNA and Its Role in Human Health)
25 pages, 842 KiB  
Review
Unraveling the Cardiac Matrix: From Diabetes to Heart Failure, Exploring Pathways and Potential Medications
by Bogdan-Sorin Tudurachi, Larisa Anghel, Andreea Tudurachi, Radu Andy Sascău, Răzvan-Liviu Zanfirescu and Cristian Stătescu
Biomedicines 2024, 12(6), 1314; https://doi.org/10.3390/biomedicines12061314 - 13 Jun 2024
Viewed by 382
Abstract
Myocardial infarction (MI) often leads to heart failure (HF) through acute or chronic maladaptive remodeling processes. This establishes coronary artery disease (CAD) and HF as significant contributors to cardiovascular illness and death. Therefore, treatment strategies for patients with CAD primarily focus on preventing [...] Read more.
Myocardial infarction (MI) often leads to heart failure (HF) through acute or chronic maladaptive remodeling processes. This establishes coronary artery disease (CAD) and HF as significant contributors to cardiovascular illness and death. Therefore, treatment strategies for patients with CAD primarily focus on preventing MI and lessening the impact of HF after an MI event. Myocardial fibrosis, characterized by abnormal extracellular matrix (ECM) deposition, is central to cardiac remodeling. Understanding these processes is key to identifying new treatment targets. Recent studies highlight SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RAs) as favorable options in managing type 2 diabetes due to their low hypoglycemic risk and cardiovascular benefits. This review explores inflammation’s role in cardiac fibrosis and evaluates emerging anti-diabetic medications’ effectiveness, such as SGLT2i, GLP1-RAs, and dipeptidyl peptidase-4 inhibitors (DPP4i), in preventing fibrosis in patients with diabetes post-acute MI. Recent studies were analyzed to identify effective medications in reducing fibrosis risk in these patients. By addressing these areas, we can advance our understanding of the potential benefits of anti-diabetic medications in reducing cardiac fibrosis post-MI and improve patient outcomes in individuals with diabetes at risk of HF. Full article
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15 pages, 960 KiB  
Article
Postprandial Plasma Glucose between 4 and 7.9 h May Be a Potential Diagnostic Marker for Diabetes
by Yutang Wang, Yan Fang, Christopher L. Aberson, Fadi J. Charchar and Antonio Ceriello
Biomedicines 2024, 12(6), 1313; https://doi.org/10.3390/biomedicines12061313 - 13 Jun 2024
Viewed by 327
Abstract
Postprandial glucose levels between 4 and 7.9 h (PPG4–7.9h) correlate with mortality from various diseases, including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4–7.9h could diagnose diabetes. Two groups of participants were involved: Group [...] Read more.
Postprandial glucose levels between 4 and 7.9 h (PPG4–7.9h) correlate with mortality from various diseases, including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4–7.9h could diagnose diabetes. Two groups of participants were involved: Group 1 (4420 participants) had actual PPG4–7.9h, while Group 2 (8422 participants) lacked this measure but had all the diabetes diagnostic measures. Group 1 underwent multiple linear regression to predict PPG4–7.9h using 30 predictors, achieving accuracy within 11.1 mg/dL in 80% of the participants. Group 2 had PPG4–7.9h predicted using this model. A receiver operating characteristic curve analysis showed that predicted PPG4–7.9h could diagnose diabetes with an accuracy of 87.3% in Group 2, with a sensitivity of 75.1% and specificity of 84.1% at the optimal cutoff of 102.5 mg/dL. A simulation on 10,000 random samples from Group 2 revealed that 175 participants may be needed to investigate PPG4–7.9h as a diabetes diagnostic marker with a power of at least 80%. In conclusion, predicted PPG4–7.9h appears to be a promising diagnostic indicator for diabetes. Future studies seeking to ascertain its definitive diagnostic value might require a minimum sample size of 175 participants. Full article
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