Current Issues in Molecular Biology

48 pages, 6137 KiB

Open AccessReview

The Inflammatory Link of Rheumatoid Arthritis and Thrombosis: Pathogenic Molecular Circuits and Treatment Approaches

by Theodora Adamantidi, Maria Stavroula Pisioti, Sofia Pitsouni, Chatzikamari Maria, Karamanis Georgios, Vasiliki Dania, Nikolaos Vordos, Xenophon Krokidis and Alexandros Tsoupras

Curr. Issues Mol. Biol. 2025, 47(4), 291; https://doi.org/10.3390/cimb47040291 (registering DOI) - 18 Apr 2025

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation that primarily affects the joints but can also involve extra-articular organs. Its multifactorial etiology remains incompletely understood, necessitating further investigation into its underlying mechanisms. The primary therapeutic goal in RA management [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation that primarily affects the joints but can also involve extra-articular organs. Its multifactorial etiology remains incompletely understood, necessitating further investigation into its underlying mechanisms. The primary therapeutic goal in RA management is to achieve disease remission or maintain low RA activity to prevent long-term morbidity. RA therapies aim to mitigate joint damage, reduce disability, and prevent systemic complications such as cardiovascular diseases. In addition to pharmacological treatments, non-pharmacological interventions—including physiotherapy, occupational therapy, and lifestyle modifications such as smoking cessation, regular exercise, and adherence to a balanced diet—play a crucial role in managing the disease. Beyond joint inflammation, RA has been strongly associated with an increased risk of thrombosis, contributing significantly to both morbidity and mortality. The link between RA and thrombotic events arises from a complex interplay of inflammatory pathways, endothelial dysfunction, and coagulation abnormalities. This review provides an in-depth analysis of the mechanisms driving the association between thrombo-inflammatory manifestations and the incidence of RA, the impact of RA treatment on thrombosis prevalence, and potential therapeutic strategies for managing both conditions concurrently. By integrating recent advancements in rheumatoid arthritis (RA) pathophysiology and thrombo-inflammatory research, this paper provides a comprehensive resource on the inflammatory link between RA and thrombosis while discussing and comparing current and emerging treatment approaches. Further investigation into these mechanisms could facilitate the development of targeted therapies that reduce the risk of thrombosis in patients with RA. Full article

(This article belongs to the Special Issue Molecular Research in Osteoarthritis and Osteoarticular Diseases)

18 pages, 3192 KiB

Open AccessReview

FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency

by Samuele Roncareggi, Brian M. Iritani and Francesco Saettini

Curr. Issues Mol. Biol. 2025, 47(4), 290; https://doi.org/10.3390/cimb47040290 (registering DOI) - 18 Apr 2025

Abstract

Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for [...] Read more.

Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D. Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function. Evidence from murine models suggests that FNIP1 loss disrupts immune cell development and mitochondrial homeostasis. However, FNIP1 deficiency in humans remains incompletely characterized, and its full phenotypic spectrum is likely underestimated. Notably, FNIP1-deficient patients exhibit immunological and hematological abnormalities, immune dysregulation, and metabolic perturbations, emphasizing its role in cellular adaptation to stress. Understanding the mechanistic basis of FNIP1 dysfunction in human tissues will be critical for delineating its contributions to immune and metabolic disorders and identifying targeted interventions. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)

6 pages, 182 KiB

Open AccessEditorial

Editorial for Special Issue “Phytochemicals in Cancer Chemoprevention and Treatment”

by Wojciech Trybus, Ewa Trybus and Aneta Węgierek-Ciuk

Curr. Issues Mol. Biol. 2025, 47(4), 289; https://doi.org/10.3390/cimb47040289 - 18 Apr 2025

Abstract

Despite significant progress in the treatment of cancer patients, modern oncological therapy faces numerous challenges that are primarily related to the lack of response to treatment caused by the resistance of cancer cells to chemotherapeutics [...] Full article

(This article belongs to the Special Issue Phytochemicals in Cancer Chemoprevention and Treatment)

21 pages, 18989 KiB

Open AccessArticle

In Silico Identification of Potential Antagonists Targeting the HPV16 E2-E1 Interaction: A Step Toward Novel Therapeutics for Cervical Cancer

by Jesús Alonso Gandara-Mireles, Verónica Loera Castañeda, Julio Cesar Grijalva Ávila, Ignacio Villanueva Fierro, Cynthia Mora Muñoz, Hugo Payan Gándara, Guadalupe Antonio Loera Castañeda, Leslie Patrón Romero and Horacio Almanza Reyes

Curr. Issues Mol. Biol. 2025, 47(4), 288; https://doi.org/10.3390/cimb47040288 - 18 Apr 2025

Abstract

Human papillomavirus (HPV) infection is the most prevalent sexually transmitted disease, and a primary cause of persistent infection leading to cervical cancer (CC). CC remains one of the most common malignancies among women worldwide, with approximately 660,000 new cases and 350,000 deaths annually. [...] Read more.

Human papillomavirus (HPV) infection is the most prevalent sexually transmitted disease, and a primary cause of persistent infection leading to cervical cancer (CC). CC remains one of the most common malignancies among women worldwide, with approximately 660,000 new cases and 350,000 deaths annually. In Mexico, this cancer accounts for 13.9% of female deaths. Currently, no antiviral treatment exists for HPV infection. Available therapies for dysplasia and CC focus on the destruction or surgical removal of infected tissue using cytotoxic agents. While the prophylactic HPV vaccine effectively prevents new infections, it does not benefit the millions already infected, underscoring the urgent need for novel therapeutic strategies. This study aimed to identify potential antagonists for the interaction between the HPV16 E2 and E1 proteins through in silico screening. A virtual screening was performed targeting the TAD of the HPV16 E2 protein (PDB ID: 1DTO) using the Maybridge HitFinder™ small molecule library. Six molecules with the best binding energies were identified: 11419, 11829, 10756, 10708, 10632, and 10726. Among these, molecules 10756, 10708, 10632, and 10726 demonstrated promising potential as antagonists, interacting with Tyr19 and/or Glu39 residues. These findings highlight potent therapeutic candidates against HPV-related diseases. Full article

(This article belongs to the Special Issue Molecular Biology in Drug Design and Precision Therapy)

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29 pages, 1210 KiB

Open AccessReview

Recent Advances in Bone Tissue Engineering: Enhancing the Potential of Mesenchymal Stem Cells for Regenerative Therapies

by Milena Kostadinova, Miryana Raykovska, Radoil Simeonov, Stephan Lolov and Milena Mourdjeva

Curr. Issues Mol. Biol. 2025, 47(4), 287; https://doi.org/10.3390/cimb47040287 - 17 Apr 2025

Abstract

Bone tissue engineering (BTE) has emerged as a promising strategy for addressing bone defects and disorders that cannot be repaired through traditional methods. This field leverages the potential of various biomaterials, cells, and bioactive factors to promote bone regeneration. Mesenchymal stem cells (MSCs) [...] Read more.

Bone tissue engineering (BTE) has emerged as a promising strategy for addressing bone defects and disorders that cannot be repaired through traditional methods. This field leverages the potential of various biomaterials, cells, and bioactive factors to promote bone regeneration. Mesenchymal stem cells (MSCs) have gained significant attention due to their osteogenic potential, which can be enhanced through osteoinductive factors. Osteoinductive factors, including growth factors like BMPs, TGF-β, VEGF, and IGF, play a crucial role in stimulating the osteodifferentiation process, thereby promoting bone regeneration. Furthermore, bioprinting technologies have opened new avenues for precisely designing scaffolds that can mimic the native bone architecture and provide a conducive environment for MSC differentiation. The integration of bioprinting with mesenchymal stem cells and osteoinductive factors has the potential to revolutionize regenerative therapies by allowing for the creation of patient-specific bone grafts. This review highlights the latest developments in MSC-based therapies, the role of osteoinductive factors, and the impact of bioprinting in advancing BTE. It also discusses future directions for improving the efficacy and clinical translation of these technologies. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)

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18 pages, 1315 KiB

Open AccessReview

FGFRL1: Structure, Molecular Function, and Involvement in Human Disease

by Lina Guan, Li Feng, Chaoli Wang and Yongen Xie

Curr. Issues Mol. Biol. 2025, 47(4), 286; https://doi.org/10.3390/cimb47040286 - 17 Apr 2025

Abstract

FGFRL1 (fibroblast growth factor receptor-like 1) is a newly identified member of the FGFR family. Its extracellular domain resembles the four conventional FGFRs, while its intracellular part lacks the tyrosine kinase domain necessary for FGF-mediated signal transduction. At first, it was only considered [...] Read more.

FGFRL1 (fibroblast growth factor receptor-like 1) is a newly identified member of the FGFR family. Its extracellular domain resembles the four conventional FGFRs, while its intracellular part lacks the tyrosine kinase domain necessary for FGF-mediated signal transduction. At first, it was only considered a “decoy receptor”. However, recent studies have demonstrated that FGFRL1 is a multifunctional molecule involved in prenatal and postnatal growth of cartilage and osteogenesis, the development of embryonic kidney and diaphragm, the modulation of cellular biological behaviors, and cell signal transduction. The functional abnormalities of FGFRL1 contribute to human diseases including congenital disease, hypertension, osteoporosis, degenerative diseases of the central nervous system, and different kinds of tumors. The present review summarizes the research progress of FGFRL1, especially its subcellular location, molecular function, and associated human disease. These data may offer valuable resources for further studying the molecular function of FGFRL1 and disclosing the mechanism of its related human diseases. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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25 pages, 370 KiB

Open AccessReview

The Expanding Role of GLP-1 Receptor Agonists: Advancing Clinical Outcomes in Metabolic and Mental Health

by Mohamad Al Qassab, Mohammad Mneimneh, Ahmad Jradi, Bassem Derbas, Dana Dabboussi, Justine Khoury Baini, Nadia Katrib, Nadim Chaarani, Philippe Attieh, Amjad Kanaan, Frederic Harb, Sami Azar and Hilda E. Ghadieh

Curr. Issues Mol. Biol. 2025, 47(4), 285; https://doi.org/10.3390/cimb47040285 - 17 Apr 2025

Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have emerged as a promising therapeutic option beyond their established role in managing type 2 diabetes mellitus (T2DM) and obesity. Recent research has highlighted their beneficial effects on liver, kidney, and cardiovascular health, mediated by both [...] Read more.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have emerged as a promising therapeutic option beyond their established role in managing type 2 diabetes mellitus (T2DM) and obesity. Recent research has highlighted their beneficial effects on liver, kidney, and cardiovascular health, mediated by both direct and indirect mechanisms. In the liver, GLP-1 RAs contribute to the improvement of metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing hepatic fat accumulation, inflammation, and oxidative stress. Additionally, they enhance insulin sensitivity and lipid metabolism. Similarly, in diabetic kidney disease (DKD), GLP-1 RAs exhibit renoprotective properties by mitigating inflammation, oxidative stress, and glomerular hypertension. Furthermore, they promote natriuresis and stabilize renal function. Moreover, GLP-1 RAs present significant cardiovascular benefits, including improved myocardial function, reduced atherosclerosis progression, enhanced endothelial health, and decreased major adverse cardiovascular events (MACEs). Additionally, emerging evidence suggests GLP-1 RAs may exert substantial neuropsychiatric benefits, including reductions in depressive symptoms, anxiety, substance use behaviors, and lowering the risk of Alzheimer’s disease, Parkinson’s disease, and other dementias likely mediated by the modulation of neurotransmitter systems and neuroinflammation. Genetic polymorphisms in the GLP1R gene also impact the therapeutic response, highlighting the importance of personalized medicine in optimizing GLP-1 RA efficacy. This review synthesizes preclinical and clinical evidence supporting the multifaceted effects of GLP-1 RAs across multiple organ systems, highlighting their therapeutic potential beyond glycemic control. As research advances, further exploration of their mechanisms of action and long-term clinical outcomes, safety and effectiveness across diverse patient populations will be essential in optimizing their use in treating metabolic and neuropsychiatric conditions. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

12 pages, 1832 KiB

Open AccessArticle

Increased Brain Glutathione Levels by Intranasal Insulin Administration

by Taisuke Kawashima, Wattanaporn Bhadhprasit, Nobuko Matsumura, Chisato Kinoshita and Koji Aoyama

Curr. Issues Mol. Biol. 2025, 47(4), 284; https://doi.org/10.3390/cimb47040284 - 17 Apr 2025

Abstract

Background: This paper investigates the effect of intranasal insulin administration on brain glutathione (GSH) levels and elucidates the potential mechanism by which insulin enhances antioxidant defenses in the brain. Methods: C57BL/6J mice were intranasally administered insulin (2 IU/day) or saline for 7 days. [...] Read more.

Background: This paper investigates the effect of intranasal insulin administration on brain glutathione (GSH) levels and elucidates the potential mechanism by which insulin enhances antioxidant defenses in the brain. Methods: C57BL/6J mice were intranasally administered insulin (2 IU/day) or saline for 7 days. GSH levels were measured in the brain and liver. Blood glucose concentrations and daily food intake were also monitored. Protein levels of excitatory amino acid carrier-1 (EAAC1), its interaction with glutamate transport-associated protein 3-18(GTRAP3-18), and activated AMP-activated protein kinase (AMPK) were assessed. Results: Insulin-treated mice exhibited significantly higher GSH levels in the hippocampus and midbrain compared to saline-treated controls, while no significant differences were found in liver GSH levels, blood glucose concentrations, or food intake. EAAC1 expression increased in both the cytosolic and plasma membrane fractions of insulin-treated mouse brains. Furthermore, the interaction between EAAC1 and its negative regulator, GTRAP3-18, along with activated AMPK levels, was reduced in insulin-treated mice. Conclusions: Intranasal insulin administration enhances brain GSH levels through a mechanism involving EAAC1 upregulation and reduced AMPK activation. These findings suggest that intranasal insulin could be a promising strategy for enhancing antioxidant defenses against neurodegeneration in the brain. Full article

(This article belongs to the Special Issue Molecular and Pharmacological Insights into Bioactive Compounds: Pathways to Therapeutics)

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28 pages, 339 KiB

Open AccessReview

The Role of HSP47 in Thrombotic Disorders: Molecular Mechanism and Therapeutic Potential

by Minodora Teodoru, Oana-Maria Stoia, Maria-Gabriela Vladoiu and Alexandra-Kristine Tonch-Cerbu

Curr. Issues Mol. Biol. 2025, 47(4), 283; https://doi.org/10.3390/cimb47040283 - 17 Apr 2025

Abstract

This review aims to analyze the role of heat shock protein 47 (HSP47) in thrombosis and evaluate its potential as a therapeutic target for deep vein thrombosis (DVT). A systematic literature review was conducted using PubMed, Scopus, and Web of Science to identify [...] Read more.

This review aims to analyze the role of heat shock protein 47 (HSP47) in thrombosis and evaluate its potential as a therapeutic target for deep vein thrombosis (DVT). A systematic literature review was conducted using PubMed, Scopus, and Web of Science to identify studies on HSP47, thrombosis, and collagen, selecting only relevant and methodologically rigorous articles. HSP47 regulates platelet function and collagen interaction, playing a key role in deep vein thrombosis (DVT). HSP47, known for stabilizing collagen, also improves platelet–collagen binding and thrombus formation. In addition, reduced HSP47 levels reduce platelet adhesion, resulting in reduced thrombus formation, while inhibitors that target HSP47 decrease platelet aggregation in animal models. Naturally low levels of HSP47 during prolonged immobility are also found in hibernating mammals, such as bears, and are associated with reduced formation of thrombi, indicating a possible natural mechanism of thrombo-protection. This observation could inform new therapeutic approaches. Current studies use in vitro platelet aggregation assays, flow chamber assays, and collagen binding studies to investigate the role of HSP47 in clotting. This review aims to synthesize existing evidence to better understand HSP47’s role in clot formation and explore its potential as a target for novel DVT therapies. Full article

(This article belongs to the Special Issue Cerebrovascular Diseases: From Pathogenesis to Treatment)

14 pages, 749 KiB

Open AccessReview

Molecular Mechanisms and Potential Therapeutic Targets of Ischemia–Reperfusion Injury in Kidney Transplantation

by Aaron J. Huang, Gaurav K. Sharma, Rohan Parikh, Zhaosheng Jin, Frank S. Darras and Sergio D. Bergese

Curr. Issues Mol. Biol. 2025, 47(4), 282; https://doi.org/10.3390/cimb47040282 - 17 Apr 2025

Abstract

End-stage renal disease (ESRD) is a serious and lethal disease that carries with it a high morbidity and mortality rate if left untreated. Treating ESRD is conducted via renal replacement therapy and/or kidney transplantation, with the latter being the preferred option given the [...] Read more.

End-stage renal disease (ESRD) is a serious and lethal disease that carries with it a high morbidity and mortality rate if left untreated. Treating ESRD is conducted via renal replacement therapy and/or kidney transplantation, with the latter being the preferred option given the better outcomes and quality of life for the patients. However, as ESRD rises in prevalence, kidney transplantation rates remain largely unchanged. In every kidney transplantation, ischemia–reperfusion injury (IRI) is inevitable and the effect this has on the kidney depends based on donor type. IRI works through a variety of molecular mechanisms, primarily mitochondrial oxidative stress and programmed cell death mechanisms. Given the urgency to ensure the best outcomes for these limited kidney transplants, there has been a continued effort to find various potential therapeutic mechanisms to counteract IRI preoperatively, intraoperatively, and postoperatively. These include hypothermic machine perfusion, ischemic conditioning, nanoparticle removal of free radicals, peptide-based therapies, microRNA, and more. There is an ongoing effort to find the best way to mitigate IRI in kidney transplantation and this is being achieved through a better understanding of the molecular mechanisms of IRI. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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17 pages, 1705 KiB

Open AccessArticle

Associating Patient Responses with Drug Sensitivity in Non-Small Cell Lung Carcinoma Using an Immunoassay on Patient-Derived Cell Cultures

by Ana Podolski-Renić, Sofija Jovanović Stojanov, Dragana Marić, Jelena Dinić, Miodrag Dragoj, Ana Stepanović, Ema Lupšić, Milica Pajović, Sofija Glumac, Maja Ercegovac and Milica Pešić

Curr. Issues Mol. Biol. 2025, 47(4), 281; https://doi.org/10.3390/cimb47040281 - 17 Apr 2025

Abstract

Background/Objectives: Non-small cell lung carcinoma (NSCLC) is characterized by its diverse molecular profiles and varying responses to treatment, highlighting the importance of precision medicine in optimizing therapeutic outcomes. A promising approach involves using patient-derived cellular models, which provide insights into the unique [...] Read more.

Background/Objectives: Non-small cell lung carcinoma (NSCLC) is characterized by its diverse molecular profiles and varying responses to treatment, highlighting the importance of precision medicine in optimizing therapeutic outcomes. A promising approach involves using patient-derived cellular models, which provide insights into the unique biology of individual tumors and their responsiveness to treatment. Methods: We established short-term primary cell cultures from thirteen patients with NSCLC of different subtypes and stages, including both cancer and stromal cells. To evaluate the ex vivo cytotoxicity and selectivity of eight chemotherapeutics and erlotinib, we employed an immunoassay, and the results were analyzed using an automated imaging system. Scoring of the obtained results was also performed. The ex vivo responses to cisplatin, etoposide, and paclitaxel were correlated with the patients’ responses to therapy. We used Kaplan–Meier analysis to assess progression-free survival (PFS) differences among patient groups. Results: NSCLC cells exhibited significant variability in their responses to drugs, with stromal cells demonstrating greater sensitivity. Tumors at stages I-III responded to multiple treatments, whereas stage IV cells showed considerable resistance. Erlotinib effectively reduced cancer cell growth at lower doses but plateaued at higher concentrations. The immunoassay indicated 67% sensitivity and 100% specificity in predicting patient responses to chemotherapy. Sensitivity to etoposide and paclitaxel correlated with progression-free survival (PFS). Conclusions: A personalized treatment strategy, such as our immunoassay based on the ex vivo responses of cancer patients’ cells, can guide treatment decisions and, in some cases, serve as surrogate biomarkers for tumor types that lack actionable biomarkers. Full article

(This article belongs to the Section Molecular Medicine)

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12 pages, 250 KiB

Open AccessArticle

Evaluation of miRNA Profile and Its Relationship with Metabolic Disorders in Obese and Pre-Obese Patients

by Kürşat Kargün, Erhan Aygen, Mehmet Fatih Ebiloğlu, Naci Ömer Alayunt and Lütfiye Kadıoğlu Dalkılıç

Curr. Issues Mol. Biol. 2025, 47(4), 280; https://doi.org/10.3390/cimb47040280 - 17 Apr 2025

Abstract

Obesity is a growing global public health concern, with its prevalence rapidly increasing in Turkey, leading to severe consequences. Genetic factors, particularly mutations in structural genes and microRNAs (miRNAs) involved in gene expression regulation have been widely investigated in obesity research. This study [...] Read more.

Obesity is a growing global public health concern, with its prevalence rapidly increasing in Turkey, leading to severe consequences. Genetic factors, particularly mutations in structural genes and microRNAs (miRNAs) involved in gene expression regulation have been widely investigated in obesity research. This study aimed to explore the role of obesity-associated miRNAs and their potential interaction with vascular response alterations. A total of 60 obese and pre-obese patients and 26 age- and sex-matched healthy controls from the General Surgery Department of Fırat University Medicine School were included. The expression levels of 93 miRNAs were analyzed in 86 samples using the Fluidigm Biomark RT-PCR system, with 5S RNA as the housekeeping gene. Significant differences were observed in weight, BMI, cholesterol, triglyceride levels, and lymphocyte counts between the groups (p < 0.0001). Several miRNAs, including hsa-miR-148a-3p, hsa-miR-503-3p, hsa-miR-34a-5p, and hsa-miR-199a-3p, were significantly downregulated in obese patients. Additionally, gender-specific differences in miRNA expression were identified. These findings indicate that miRNAs play a crucial role in obesity pathophysiology and could serve as potential biomarkers and therapeutic targets for obesity treatment. Full article

(This article belongs to the Section Molecular Medicine)

16 pages, 4955 KiB

Open AccessArticle

Genome-Wide Association Study (GWAS) on Reproductive Seasonality in Indigenous Greek Sheep Breeds: Insights into Genetic Integrity

by Danai Antonopoulou, George Symeon, Konstantinos Zaralis, Meni Avdi, Ilias S. Frydas and Ioannis A. Giantsis

Curr. Issues Mol. Biol. 2025, 47(4), 279; https://doi.org/10.3390/cimb47040279 - 16 Apr 2025

Abstract

A key feature in sheep biology is reproduction seasonality which concerns the cyclical occurrence of natural breeding, which therefore does not take place throughout the year. Since sheep are short-day breeders, the amount of daylight has an impact on their reproductive activity. The [...] Read more.

A key feature in sheep biology is reproduction seasonality which concerns the cyclical occurrence of natural breeding, which therefore does not take place throughout the year. Since sheep are short-day breeders, the amount of daylight has an impact on their reproductive activity. The melatonin receptor subtype 1A (MTNR1A) gene is the primary gene that has been linked with seasonality. Nonetheless, information regarding the potential genetic association between other loci and the seasonality of sheep reproduction is scarce. Genome-wide association study (GWAS) is considered a cutting-edge methodology for comprehending the genetic architecture of complex traits since it enables the discovery of many markers linked to different features. In the present study, three indigenous Greek sheep breeds were investigated using GWAS—two of which presented strict patterns of reproduction seasonality, i.e., the Florina and Karagkouniko breeds, while the third one, i.e., the Chios breed had the ability to exhibit estrus throughout the year—in an attempt to detect the genetic loci linked with reproduction seasonality. All three breeds of investigated animals were purebred with Chios and Florina breeds originating from the Greek national stationary stock, whereas Karagkouniko originated from a commercial farm. Interestingly, a significant genetic differentiation of the national stationary stock groups was suggested by principal component analysis, phylogenetic analysis, and admixture and spatial point patterns, with these two breeds being less heterogeneous. This finding highlights the value of stationary stocks towards the maintenance of genetic integrity in indigenous sheep, demonstrating the Greek station’s critical role in the conservation of native sheep breeds. On the other hand, according to the GWAS data analysis, no genetic loci were correlated with reproduction seasonality, emphasizing the MTNR1A gene as the main determinant of the seasonality in native non genetically improved breeds. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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19 pages, 1056 KiB

Open AccessReview

Cytokine Therapy in Bladder Cancer: Mechanisms, Efficacy, and Future Prospects

by Hayden J. Oyler, Layne G. Bruton, Austin J. Maher, Darien A. Yu, Nicholas W. Shely, Mark R. Wakefield and Yujiang Fang

Curr. Issues Mol. Biol. 2025, 47(4), 278; https://doi.org/10.3390/cimb47040278 - 15 Apr 2025

Abstract

Cytokine therapy is a rapidly evolving field in bladder cancer research, with treatments designed to enhance immune responses, improve targeting, and promote tumor cell recognition and elimination. This review explores pro-inflammatory cytokines, anti-inflammatory cytokines, engineered cytokines and fusion proteins, and combination therapies. Challenges [...] Read more.

Cytokine therapy is a rapidly evolving field in bladder cancer research, with treatments designed to enhance immune responses, improve targeting, and promote tumor cell recognition and elimination. This review explores pro-inflammatory cytokines, anti-inflammatory cytokines, engineered cytokines and fusion proteins, and combination therapies. Challenges include risks of toxicity, immune suppression, and the potential for promoting metastasis. Despite these obstacles, the potential successes of cytokine therapies highlight the importance of continued investigation into their use for developing safe, effective, and minimally invasive treatments for bladder cancer. Full article

(This article belongs to the Special Issue The Molecular Basis of Immunotherapy in Cancer Treatment)

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13 pages, 1603 KiB

Open AccessArticle

Repositioning Fluoxetine as a TRPV3 Channel Inhibitor to Alleviate Skin Inflammation and Pruritus

by Ling Zhang, Junjie Chang, Yimei Xu, Qi Ge and Congxiao Zhang

Curr. Issues Mol. Biol. 2025, 47(4), 277; https://doi.org/10.3390/cimb47040277 - 15 Apr 2025

Abstract

Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel prominently present in the skin. It plays a role in diverse physiological and pathological functions like inflammation of the skin, pain sensations in the skin, and persistent itchiness. Overactive TRPV3 channels contribute [...] Read more.

Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel prominently present in the skin. It plays a role in diverse physiological and pathological functions like inflammation of the skin, pain sensations in the skin, and persistent itchiness. Overactive TRPV3 channels contribute to numerous inflammatory skin diseases, and this highlights the therapeutic potential of its inhibitors. Using a drug repurposing screening approach, we identified fluoxetine—a clinically established antidepressant agent—as a potent inhibitor of TRPV3 channel activation, demonstrating its therapeutic potential for skin inflammation alleviation. During whole-cell patch-clamp recordings, fluoxetine exhibits a selective inhibitory effect on macroscopic TRPV3 currents in a concentration-dependent fashion. The IC₅₀ value is measured as 10.23 ± 2.34 μM. On the single-channel scale, fluoxetine leads to a reduction in both single-channel conductance and the open probability of the channel. In the course of animal experiments, fluoxetine mitigates carvacrol-induced TRPV3-related skin inflammation. It lessens the severity of dorsal lesions and ear edema in mice. Our study not only identified TRPV3 as a novel target of fluoxetine and provides new ideas for the treatment of TRPV3-mediated skin diseases with fluoxetine, but also provides a valuable tool molecule for further understanding TRPV3 channel pharmacology. Full article

(This article belongs to the Section Molecular Pharmacology)

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9 pages, 3436 KiB

Open AccessArticle

A Phylogenetic Analysis Based on Whole Genome Re-Sequencing of 41 Dendrobium Species

by Feng-Ping Zhang, Xue-Wei Fu, Han-Run Li and Shi-Bao Zhang

Curr. Issues Mol. Biol. 2025, 47(4), 276; https://doi.org/10.3390/cimb47040276 - 15 Apr 2025

Abstract

The genus Dendrobium (Orchidaceae) is highly renowned for its great medicinal and ornamental values. However, due to morphological similarities among closely related taxa within this genus, certain species are frequently subject to misidentification and adulteration in the market. Traditional morphological taxonomy and limited [...] Read more.

The genus Dendrobium (Orchidaceae) is highly renowned for its great medicinal and ornamental values. However, due to morphological similarities among closely related taxa within this genus, certain species are frequently subject to misidentification and adulteration in the market. Traditional morphological taxonomy and limited DNA markers prove challenging in effectively differentiating among them. Here, we generated an extensive single nucleotide polymorphism (SNP) dataset through whole genome re-sequencing (WGRS) of 41 Dendrobium species to evaluate its effectiveness in species identification. The phylogenetic relationships of 41 Dendrobium species were explored based on the SNP dataset, and then divergence times at each node were estimated. We found that the whole genome re-sequencing method achieved a 100% identification rate for all 41 species examined, indicating that whole genome re-sequencing could be employed to accurately authenticate Dendrobium species. Furthermore, phylogenetic analysis revealed that the sect. Dendrobium was polyphyletic. In addition, the divergence time analysis suggested that Dendrobium originated since the Oligocene. These findings provide valuable genetic data resources for further systematic studies of the rare and endangered Dendrobium species. Full article

(This article belongs to the Section Molecular Plant Sciences)

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20 pages, 8028 KiB

Open AccessArticle

A New Method for Preparation of Decellularized Human Scaffolds for Facial Reconstruction

by Elise Lupon, Aylin Acun, Alec R. Andrews, Ruben Oganesyan, Hyshem H. Lancia, Laurent Lantieri, Mark A. Randolph, Curtis L. Cetrulo, Jr., Alexandre G. Lellouch and Basak E. Uygun

Curr. Issues Mol. Biol. 2025, 47(4), 275; https://doi.org/10.3390/cimb47040275 - 14 Apr 2025

Abstract

Vascularized composite allotransplantation (VCA) has emerged as a robust alternative for addressing anatomically complex defects but requires a toxic lifelong immunosuppressive regimen. Tissue engineering offers the promise of creating recipient-specific alternative grafts using a decellularization and recellularization approach. In this article, we establish [...] Read more.

Vascularized composite allotransplantation (VCA) has emerged as a robust alternative for addressing anatomically complex defects but requires a toxic lifelong immunosuppressive regimen. Tissue engineering offers the promise of creating recipient-specific alternative grafts using a decellularization and recellularization approach. In this article, we establish a reliable protocol for human face decellularization by immersion as a new tool in the development of engineered graft alternatives for reconstructive surgery. Three cadaveric face grafts were immersed in 1% sodium dodecyl sulfate for 216 h followed by 1% Triton X-100 for 48 h, without perfusion through the pedicle. We determined that decellularization was successfully accomplished for three facial specimens as confirmed by histological evaluation and quantification of DNA content. The extracellular components including collagen, glycosaminoglycans, elastin, and matrix-bound growth factors were preserved. Vascular architecture did not show significant differences between native and decellularized grafts as imaged by X-ray angiography. The mechanical strength of the grafts was not altered after decellularization. We also showed that the decellularized grafts were biocompatible in vitro and in vivo allowing cell engraftment. As a result, we have successfully developed a protocol to yield a clinical size decellularized graft suitable for generating a recellularized, potentially non-immunogenic graft for facial reconstruction. Full article

(This article belongs to the Special Issue Advances and Challenges in Organ Decellularization and Recellularization)

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15 pages, 1622 KiB

Open AccessArticle

Rutin Ameliorates BHBA-Induced Inflammation and Lipid Accumulation in Calf Hepatocytes Through NF-κB Signaling Pathway

by Kun Yang, Haixia Zhao, Min Gao, Honglian Hu and Dabiao Li

Curr. Issues Mol. Biol. 2025, 47(4), 274; https://doi.org/10.3390/cimb47040274 - 14 Apr 2025

Abstract

When subclinical ketosis (SCK) occurs in dairy cows, it leads to an excessive production of β-hydroxybutyrat (BHBA), which disrupts liver lipid metabolism and triggers a series of inflammatory responses. Rutin (RT), a flavonoid extracted from plants, exhibits diverse biological activities. However, its potential [...] Read more.

When subclinical ketosis (SCK) occurs in dairy cows, it leads to an excessive production of β-hydroxybutyrat (BHBA), which disrupts liver lipid metabolism and triggers a series of inflammatory responses. Rutin (RT), a flavonoid extracted from plants, exhibits diverse biological activities. However, its potential to mitigate BHBA-induced liver inflammation and lipid accumulation in dairy cows remains unexplored. In this study, we investigated the effect of RT on the BHBA-induced injury of hepatocytes and the possible mechanism. First, hepatocytes were treated with BHBA (0, 0.3, 0.6, 1.2, 2.4 mM) to assess its effects on inflammation impairment and lipid accumulation. Second, hepatocytes were pretreated with RT (0, 25, 50, 100, 150 μg/mL) to evaluate its protective effects. Third, hepatocytes were divided into five treatment groups: blank control, BHBA treatment, RT + BHBA treatment, NF-κB activator (PDTC) + BHBA treatment, and RT + PDTC + BHBA treatment. This experiment further explored the underlying mechanism of RT in mitigating BHBA-induced hepatocyte injury. The results demonstrated that RT at 100 and 150 μg/mL mitigated the increases in hepatocyte interleukin-1 beta (IL-1β), IL-6, triglyceride (TG), and total cholesterol (TC) contents induced by high concentrations of BHBA (p < 0.05). Compared to the BHBA treatment, 100 μg/mL RT significantly downregulated the relative protein expression of P-NF-κB p65 and the relative mRNA expression of NF-κB p65, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6, peroxisome proliferator-activated receptor gamma (PPARγ), and microsomal triglyceride transfer protein (MTP), while upregulating the relative mRNA expression of IKBα (p < 0.05). Additionally, these effects were more pronounced with the combined pretreatment of the PDTC and RT. In conclusion, RT inhibits BHBA-triggered hepatocyte inflammation and lipid accumulation by modulating the NF-κB signaling pathway, implying that RT may be a promising target for ameliorating damage in SCK cows. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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42 pages, 4471 KiB

Open AccessReview

The Hallmarks of Ageing in Human Immunodeficiency Virus Infection and the Impact of Antiretroviral Therapy on Telomeres: A Molecular Perspective

by Miruna-Maria Apetroaei, Stella Baliou, Petros Ioannou, Persefoni Fragkiadaki, Gabriela Ștefan, Marina Ionela (Ilie) Nedea, George-Traian-Alexandru Burcea-Dragomiroiu, Bruno Ștefan Velescu, Anca Oana Docea, Denisa Ioana Udeanu, Aristidis Tsatsakis and Andreea Letiția Arsene

Curr. Issues Mol. Biol. 2025, 47(4), 273; https://doi.org/10.3390/cimb47040273 - 12 Apr 2025

Abstract

Ageing is a complex and unavoidable physiological process which, in simple terms, consists of a progressive deterioration in the functionality of cells, tissues and organs, culminating in an increased risk of developing chronic pathologies. Telomeres, the repetitive nucleotide structures at the end of [...] Read more.

Ageing is a complex and unavoidable physiological process which, in simple terms, consists of a progressive deterioration in the functionality of cells, tissues and organs, culminating in an increased risk of developing chronic pathologies. Telomeres, the repetitive nucleotide structures at the end of chromosomes, ensure genomic integrity and modulate cellular senescence. The progressive shortening of telomere length with each cell division directly correlates with an increased susceptibility to developing chronic pathologies. However, this shortening, normally physiological and inevitable, can be markedly accelerated in the presence of chronic infections, such as HIV-1 infection, by sustained and continuous activation of the immune system, chronic inflammation, generation of oxidative stress, or direct alterations produced by viral proteins. Thus, in this narrative review, we discuss the 12 hallmarks of ageing in the context of HIV-1 infection, as understanding the molecular changes induced by HIV-1 through these well-established pillars could provide a holistic approach to the management of HIV-positive patients. At the same time, considering that telomeres are at the centre of all these changes, an assessment of the impact of antiretroviral therapy on telomere length is necessary to guide clinical decisions. The ultimate goal of this research is to develop personalised therapies to increase the quality of life and health outcomes of HIV patients. Full article

(This article belongs to the Special Issue Research on Virus-Induced Cellular and Molecular Responses)

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