Current Issues in Molecular Biology

2026

Jump to: 2025, 2024, 2023

15 pages, 460 KB

Open AccessReview

Targeted Medical Therapy for Vestibular Schwannomas: Evidence, Limits, and Future Directions—A Scoping Review

by Athena Eliana Arsie, Carlotta Muneretto, Matteo Seno, Marta Gaffeo, Riccardo Nocini, Luca Sacchetto, Silvia Palma and Daniele Monzani

Curr. Issues Mol. Biol. 2026, 48(3), 292; https://doi.org/10.3390/cimb48030292 - 9 Mar 2026

Viewed by 499

Abstract

Background: Vestibular schwannomas (VSs) are benign tumors that can cause significant morbidity, particularly in neurofibromatosis 2 (NF2) patients, in whom conventional treatments have important limitations. Merlin is a tumor suppressor protein encoded by the Neurofibromin 2 (NF2) gene, and the loss of its [...] Read more.

Background: Vestibular schwannomas (VSs) are benign tumors that can cause significant morbidity, particularly in neurofibromatosis 2 (NF2) patients, in whom conventional treatments have important limitations. Merlin is a tumor suppressor protein encoded by the Neurofibromin 2 (NF2) gene, and the loss of its function leads to the activation of multiple signaling pathways, providing a rationale for targeted pharmacological therapies. Agents such as bevacizumab and other receptor tyrosine kinase inhibitors (TKIs) have shown variable efficacy but remain limited by toxicity and inconsistent responses. This review aims to evaluate the efficacy and safety of targeted therapies for VSs. Methods: This study was conducted according to PRISMA 2020 guidelines, using a PICO-based search of PubMed, EMBASE, and Scopus to identify studies on pharmacological therapies for VSs published between 2000 and 2025. Eligible human studies included clinical trials and observational studies reporting efficacy, safety, neuroimaging and audiological outcomes. Results: In total, 23 studies were analyzed, predominantly involving NF2-associated VSs. Treatment with bevacizumab was the most frequently investigated medical therapy and yielded the most consistent tumor control along with occasional hearing improvement, albeit with frequent but mostly manageable adverse events. Other targeted agents, including everolimus and TKIs, demonstrated limited or variable efficacy with acceptable toxicity profiles. Conclusions: VSs, particularly in NF2 patients, can cause significant morbidity and are often poorly managed by surgery or radiotherapy. Consequently, targeted medical therapies, especially anti-angiogenic agents, have emerged as valuable alternatives. Bevacizumab shows the most consistent benefits in tumor control, hearing stabilization, and quality of life, despite heterogeneous responses and notable toxicity. Evidence suggests that treatment discontinuation may lead to rapid tumor rebound, highlighting the need for long-term or maintenance strategies and careful monitoring. Future studies are needed to evaluate medical therapy integration with conventional treatments. Full article

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21 pages, 18202 KB

Open AccessArticle

MSTN and TCF12 as Candidate Immunometabolic Signatures in Glioma-Associated Foam Cells: Insights from Integrated Multi-Omics Analysis

by Xu Liu, Zhuo Song, Zhijia Sun, Chen Liu, Xiaoli Kang, Huilian Qiao, Xinzhuo Tu, Teng Li, Zhiguang Fu and Yingjie Wang

Curr. Issues Mol. Biol. 2026, 48(3), 289; https://doi.org/10.3390/cimb48030289 - 9 Mar 2026

Viewed by 410

Abstract

The glioma tumor microenvironment (TME) exhibits profound heterogeneity that drives tumor progression and therapy resistance. By integrating single-cell RNA sequencing (eleven samples) and spatial transcriptomics (two samples), the cellular components of the glioma microenvironment were deconvoluted, revealing tumor-associated foam cells (TAFCs) as the [...] Read more.

The glioma tumor microenvironment (TME) exhibits profound heterogeneity that drives tumor progression and therapy resistance. By integrating single-cell RNA sequencing (eleven samples) and spatial transcriptomics (two samples), the cellular components of the glioma microenvironment were deconvoluted, revealing tumor-associated foam cells (TAFCs) as the most abundant and centrally connected subtype. The high expression of two prognostic candidate genes, growth differentiation factor 8 (GDF-8, also known as myostatin, MSTN) and transcription factor 12 (TCF12), in TAFCs was found to be correlated with poor overall survival. These two genes were associated with M2 macrophage infiltration, altered cholesterol homeostasis, and immunosuppressive signaling. Regulatory network and pathway analyses, based on computational motif enrichment and co-expression analysis, linked them to ribosome, Notch signaling, DNA repair, and cell-cycle pathways. Pseudotime trajectories revealed dynamic expression during differentiation. Additionally, drug sensitivity prediction analysis demonstrated that MSTN expression was significantly associated with sensitivity to paclitaxel and VE-822, while TCF12 expression showed potential associations with sensitivity to cytarabine, olaparib, Wee1 inhibitor, paclitaxel, and VE-822. Logistic regression analysis combining clinical parameters with MSTN and TCF12 expression effectively achieved risk stratification for glioma, with higher composite scores predicting worse 2- and 3-year survival outcomes. Calibration curves demonstrated high consistency between nomogram-predicted overall survival probabilities and actual observed outcomes. Immunofluorescence confirmed upregulated expression of MSTN and TCF12 in glioma tissues and their co-localization with macrophages. In conclusion, this study identified TAFCs as the central cells in the glioma microenvironment, with their signature genes MSTN and TCF12 representing candidate immunometabolic signatures associated with macrophage-mediated immunosuppression and metabolic reprogramming in glioma, suggesting their potential as biomarkers for patient stratification and as targets for immunometabolic therapies. Full article

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2025

Jump to: 2026, 2024, 2023

24 pages, 3842 KB

Open AccessArticle

NUMB in Endometrial Pathology: From Adenomyosis Expression Patterns to Endometrial Cancer Survival Implications

by Walid Shaalan, Nourhan Hassan, Mohamed Gamal Ibrahim, Benedikt Schäfgen, Kathrin Haßdenteufel, Julia Gallwas, Ludwig Kiesel, Andreas N. Schüring and Martin Götte

Curr. Issues Mol. Biol. 2025, 47(12), 1027; https://doi.org/10.3390/cimb47121027 - 10 Dec 2025

Cited by 1 | Viewed by 572

Abstract

Adenomyosis, a prevalent gynecologic condition involving invasion of endometrial tissue into the myometrium, remains poorly understood in terms of its molecular pathogenesis. Numb, an important regulator of cellular destiny and stem cell maintenance, has been implicated in numerous proliferative diseases; however, the role [...] Read more.

Adenomyosis, a prevalent gynecologic condition involving invasion of endometrial tissue into the myometrium, remains poorly understood in terms of its molecular pathogenesis. Numb, an important regulator of cellular destiny and stem cell maintenance, has been implicated in numerous proliferative diseases; however, the role for Numb in adenomyosis has not yet been investigated. This research examines the degree to which Numb protein may play a role in the pathogenesis of adenomyosis and additional invasive endometrial diseases. This study analyzed Numb protein expression in tissues from 21 adenomyosis patients and 14 controls using immunohistochemistry. Numb levels were evaluated in eutopic endometrium, ectopic lesions, and myometrium. Additionally, comprehensive bioinformatics analyses were performed including TCGA expression analysis, STRING protein–protein interaction network analysis, and Kaplan–Meier survival analysis to elucidate the clinical significance and mechanistic role of NUMB in endometrial pathology linked to invasive growth. Compared to controls (p < 0.001), adenomyosis patients’ eutopic endometrium and myometrium showed considerably higher levels of numb expression. It was predominantly observed in single cells rather than clusters. No significant variation was noted across menstrual cycle phases. Elevated Numb levels in the myometrium suggest a potential role in tissue invasion. TCGA analysis revealed significant associations between NUMB alterations and expression patterns in endometrial carcinoma, with copy number alterations showing a dose-dependent relationship with the expression levels. STRING network analysis identified NUMB as a central hub protein with 20 high-confidence interactions, particularly enriched in Notch signaling pathway components (FDR = 1.0 × 10⁻¹⁵). Kaplan–Meier survival analysis demonstrated that endometrial carcinoma patients with NUMB alterations had significantly better overall survival compared to unaltered cases (p = 9.119 × 10⁻³), with 92% vs. 73% survival at 100 months. This study presents new evidence of elevated Numb expression in adenomyosis, suggesting that it may play a part in the pathophysiology of the disease and that it is a useful marker for dysregulation of endometrial stem cells. The comprehensive bioinformatics analyses establish NUMB as a central regulator of endometrial homeostasis with significant prognostic value in endometrial malignancies, providing mechanistic insights into the pathogenesis of invasive endometrial diseases and identifying potential therapeutic targets. Full article

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20 pages, 682 KB

Open AccessReview

Genetic and Epigenetic Biomarkers for the Early Oral Cancerization Risk in Periodontitis Patients

by Giorgia M. Marmo, Morena Munzone, Alessandro Polizzi, Roberto Campagna, Marco Mascitti and Gaetano Isola

Curr. Issues Mol. Biol. 2025, 47(11), 933; https://doi.org/10.3390/cimb47110933 - 9 Nov 2025

Cited by 3 | Viewed by 1413

Abstract

Oral squamous cell carcinoma (OSCC) remains one of the most prevalent and aggressive malignancies worldwide, with late diagnosis contributing to poor survival rates. Recent evidence suggests that periodontitis may act as a co-factor in development of OSCC through persistent inflammation, microbial dysbiosis, and [...] Read more.

Oral squamous cell carcinoma (OSCC) remains one of the most prevalent and aggressive malignancies worldwide, with late diagnosis contributing to poor survival rates. Recent evidence suggests that periodontitis may act as a co-factor in development of OSCC through persistent inflammation, microbial dysbiosis, and subsequent tissue remodeling. Identifying molecular signatures that link periodontitis with early oral cancerization is therefore of paramount importance for risk assessment, prevention, and timely intervention. This narrative review aims to provide an integrative overview of the current knowledge on molecular, genetic, and epigenetic biomarkers associated with oral cancer risk in patients with periodontitis. Specifically, periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum promote oral cancerization by modulating molecular, genetic, and epigenetic pathways, including p53, Cyclin D1, Ki-67, p16^INK4A, DNA methylation, histone modifications, and microRNA regulation. Therefore, this review provides a discussion about the role of inflammatory mediators, oxidative stress-related molecules, microbial-derived products, genetic markers and epigenetic mechanisms as early molecular signals of malignant transformation. The study of these salivary biomarkers (salivaomics) has emerged as a promising non-invasive diagnostic tool, although variability in sampling, biomarker stability, and confounding factors such as coexisting periodontal disease remain significant limitations. By synthesizing the available evidence, this review summarizes recent evidence linking periodontitis to oral cancerization, highlights potential salivary, proteomic, and inflammatory biomarkers, and considers the role of periodontal therapy in improving inflammatory profiles and modulating tumor-related biomarkers. Finally, it explores future perspectives, including the integration of Artificial Intelligence (AI) to enhance biomarker-based diagnosis and risk stratification in OSCC patients. Full article

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12 pages, 1285 KB

Open AccessArticle

Endoplasmic Reticulum Stress Drives VEGF Gene Expression in Monocytic Cells

by Fatemah Bahman, Taha Nadeem, Abdulrahman Alayyaf, Ashraf Al Madhoun, Fahd Al-Mulla, Sardar Sindhu and Rasheed Ahmad

Curr. Issues Mol. Biol. 2025, 47(10), 839; https://doi.org/10.3390/cimb47100839 - 13 Oct 2025

Cited by 1 | Viewed by 1082

Abstract

Obesity is characterized by chronic low-grade inflammation and oxidative stress, conditions that disrupt metabolic homeostasis and promote vascular endothelial growth factor (VEGF) expression. While hypoxia and fatty acid-induced oxidative stress are known regulators of VEGF, the contribution of endoplasmic reticulum (ER) stress in [...] Read more.

Obesity is characterized by chronic low-grade inflammation and oxidative stress, conditions that disrupt metabolic homeostasis and promote vascular endothelial growth factor (VEGF) expression. While hypoxia and fatty acid-induced oxidative stress are known regulators of VEGF, the contribution of endoplasmic reticulum (ER) stress in monocytic cells remains unclear. In this study, we investigated the interplay between ER stress and metabolic stress in regulating VEGF expression using THP-1 monocytic cells. Metabolic stress was induced by palmitic acid (PA) and ER stress by thapsigargin (TG). Co-treatment with PA and TG significantly increased VEGF mRNA and protein levels compared to PA alone. This effect was accompanied by enhanced reactive oxygen species (ROS) production and upregulation of ER stress markers, including CHOP, ATF6, and IRE1. Pretreatment with the antioxidant curcumin markedly reduced VEGF expression and ROS levels, indicating a ROS-dependent mechanism. Additionally, PA+TG co-treatment elevated transcripts of antioxidant defense genes such as SOD2 and NRF2, suggesting a compensatory cellular response to oxidative stress. These findings demonstrate that ER stress amplifies VEGF induction in monocytic cells under lipotoxic conditions through ROS-mediated pathways, highlighting a potential mechanism linking metabolic stress, inflammation, and angiogenesis in obesity-related disorders. Full article

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13 pages, 526 KB

Open AccessReview

Metformin as a Disease-Modifying Agent in Autosomal Dominant Polycystic Kidney Disease: A Systematic Review of Preclinical and Clinical Evidence

by Aleksandra Maciejczyk and Mariusz Niemczyk

Curr. Issues Mol. Biol. 2025, 47(9), 715; https://doi.org/10.3390/cimb47090715 - 3 Sep 2025

Cited by 3 | Viewed by 2599

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disorder marked by cyst growth and progressive renal failure. This systematic review aims to summarize current preclinical and clinical evidence on the potential role of metformin in ADPKD, focusing on its effects [...] Read more.

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disorder marked by cyst growth and progressive renal failure. This systematic review aims to summarize current preclinical and clinical evidence on the potential role of metformin in ADPKD, focusing on its effects on glucose metabolism, kidney function, inflammation, and survival. A comprehensive search was conducted in PubMed and Google Scholar up to June 2025, following PRISMA guidelines. Forty-two articles met the inclusion criteria and were analyzed. Included studies examined metformin use in ADPKD patients or models and reported outcomes such as renal function, cyst growth, metabolic markers, and mortality. In preclinical studies, it reduced cyst formation, improved kidney structure, and decreased inflammation. Clinical studies confirmed its safety and suggested benefits in slowing kidney function decline, especially in early-stage ADPKD. Metformin may be a promising supportive therapy in ADPKD due to its metabolic and anti-inflammatory effects. Full article

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15 pages, 1484 KB

Open AccessArticle

Effect of Sperm DNA Fragmentation and Chromatin Decondensation on PLCζ Efficacy in Infertile Patients

by Soukaina Azil, Ismail Kaarouch, Debbie Montjean, Marie-Hélène Godin Pagé, Rosalie Cabry, Noureddine Louanjli, Bouchra Ghazi and Moncef Benkhalifa

Curr. Issues Mol. Biol. 2025, 47(9), 707; https://doi.org/10.3390/cimb47090707 - 1 Sep 2025

Cited by 3 | Viewed by 1749

Abstract

This study aimed to describe phospholipase C zeta (PLCζ) deficiency from patients who experienced oocyte fertilization failure following intracytoplasmic sperm injection (ICSI) and to investigate the relationship between sperm DNA fragmentation, chromatin decondensation, and PLCζ. A total of 135 patients participated in this [...] Read more.

This study aimed to describe phospholipase C zeta (PLCζ) deficiency from patients who experienced oocyte fertilization failure following intracytoplasmic sperm injection (ICSI) and to investigate the relationship between sperm DNA fragmentation, chromatin decondensation, and PLCζ. A total of 135 patients participated in this study—65 fertile men and 70 infertile patients— and semen samples were obtained to analyze concentration, motility, and morphology. PLCζ protein levels were assessed by immunofluorescence and quantitative techniques, DNA fragmentation by TUNEL essay, and chromatin decondensation by aniline blue staining. The proportion of spermatozoa presenting PLCζ was significantly lower in infertile patients (18.41 ± 18.84%) compared to fertile controls (67.31 ± 13.79%) (p < 0.001). A significant decrease in PLCζ protein levels was observed in infertile patients compared to fertile controls, which was the same for localization patterns for each region (acrosomal, equatorial, and combination of these regions). Significant correlations were also observed between sperm parameters and PLCζ levels, DNA fragmentation, and chromatin decondensation. Furthermore, a statistically significant correlation was detected between the percentage of spermatozoa presenting PLCζ and DNA integrity (p < 0.001). In summary, DNA fragmentation and chromatin decondensation are associated with alterations in the localization patterns and reduced protein levels of PLCζ, which may contribute to total fertilization failure. Full article

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8 pages, 567 KB

Open AccessArticle

TP53 Mutations in Chagasic Megaesophagus

by Aparecida Perpetuo Fedossi Silveira, Ricardo Quiterio Sartori, Lilian Castiglioni, Heidi Lacerda Alves da Cruz, Eumildo de Campos Junior, Cinara Cássia Brandão and Luiz Carlos de Mattos

Curr. Issues Mol. Biol. 2025, 47(4), 229; https://doi.org/10.3390/cimb47040229 - 27 Mar 2025

Viewed by 1033

Abstract

Patients carrying Chagasic megaesophagus (CME) are at high risk for esophageal carcinoma. We aimed to investigate mutations in the TP53 in patients carrying CME. Blood samples from 114 patients with Chagas disease (CD) were used. The samples were subjected to PCR-SSCP analysis and [...] Read more.

Patients carrying Chagasic megaesophagus (CME) are at high risk for esophageal carcinoma. We aimed to investigate mutations in the TP53 in patients carrying CME. Blood samples from 114 patients with Chagas disease (CD) were used. The samples were subjected to PCR-SSCP analysis and DNA sequencing in exons 5 and 7 of the TP53 gene. We observed mutations in the exon 5 codon 184 (GAT > AAT) in 14.8% of G1 (11/74), 10% of G2 (4/40), and 5% of G3 (2/40). We also observed the codon 185 mutation (AGC > AGG) in 14.8% of G1 (11/74), 10% of G2 (4/40), and 7.5% of G3 (3/40). Regarding Exon 7, a mutation (G > T) was observed in the intronic region in 2.7% of G1 (2/74), 7.5% of G2 (3/40), and none of G3 (0/40). Our study showed, for the first time, simultaneous mutations at codons 184 and 185 of the TP53 gene in patients with CME and Chagasic patients without megaesophagus. More studies are needed to assess whether the simultaneous presence of mutations at codons 184 and 185 increases the risk of developing esophageal carcinoma in these patients. Full article

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13 pages, 1798 KB

Open AccessReview

Circulating Nucleosomes and Histones in the Development of Lung Injury and Sepsis

by Saugata Dutta, Sauradeep Dutta, Payaningal R. Somanath, S. Priya Narayanan, Xiaoyun Wang and Duo Zhang

Curr. Issues Mol. Biol. 2025, 47(2), 133; https://doi.org/10.3390/cimb47020133 - 19 Feb 2025

Cited by 3 | Viewed by 3469

Abstract

Cellular nucleosomes—the structural and functional units of chromatin—are inherently present in cells. During cellular damage or cell death, nucleosomes are released into circulation, either actively or passively. Once released, nucleosomes can become immunogenic entities through various mechanisms. The nucleosomal proteins in nucleosomes, called [...] Read more.

Cellular nucleosomes—the structural and functional units of chromatin—are inherently present in cells. During cellular damage or cell death, nucleosomes are released into circulation, either actively or passively. Once released, nucleosomes can become immunogenic entities through various mechanisms. The nucleosomal proteins in nucleosomes, called histones, play a pivotal role in inducing immunogenicity. However, intact nucleosomes are more immunogenic than the histones alone, as nucleosomal double-stranded deoxyribonucleic acid (dsDNA) enhances its immunogenic potential. Our recent study has shown that circulating histones are predominantly nucleosomal histones rather than free histones. Consequently, circulating histones primarily function as integral parts of circulating nucleosomes rather than acting independently. Circulating nucleosomes and their associated histones are implicated in the pathogenesis of a wide array of diseases. Notably, they are critical in the pathogenesis of lung injury and sepsis. These diseases have high morbidity and mortality rates and lack early diagnostic biomarkers. Further investigation is required to fully elucidate the role of circulating nucleosomes and their associated histones in disease processes. This review aims to discuss the current understanding of circulating nucleosomes and histones in the pathogenesis of lung injury and sepsis, with a focus on the underlying mechanisms. Full article

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2024

Jump to: 2026, 2025, 2023

13 pages, 2047 KB

Open AccessArticle

Open-Label Clinical Trial on the Impact of Autologous Dendritic Cell Therapy on Albuminuria and Inflammatory Biomarkers (Interleukin-6, Interleukin-10, Tumor Necrosis Factor α) in Diabetic Kidney Disease (DKD)

by Jonny, Enda Cindylosa Sitepu, Bhimo Aji Hernowo, Linda Chiuman, I Nyoman Ehrich Lister and Terawan Agus Putranto

Curr. Issues Mol. Biol. 2024, 46(12), 13662-13674; https://doi.org/10.3390/cimb46120816 - 2 Dec 2024

Cited by 4 | Viewed by 2816

Abstract

The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, leading to a higher incidence of diabetic kidney disease (DKD), a major risk factor for end-stage kidney disease (ESKD). This study investigates the effects of autologous dendritic cell (DC) therapy on albuminuria [...] Read more.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, leading to a higher incidence of diabetic kidney disease (DKD), a major risk factor for end-stage kidney disease (ESKD). This study investigates the effects of autologous dendritic cell (DC) therapy on albuminuria and inflammatory biomarkers (IL-6, IL-10, and TNF-α) in DKD patients. An open-label clinical trial was conducted with 69 DKD outpatients at the Gatot Soebroto Army Central Hospital (RSPAD GS). Each subject received a single DC injection, with evaluations of urinary albumin-creatinine ratio (UACR) and inflammatory biomarkers at baseline and 4 weeks post-intervention. UACR was measured weekly, while eGFR, IL-6, IL-10, and TNF-α levels were assessed at baseline and week 4. Results indicated a significant reduction in median UACR from 250 mg/g at baseline to 153 mg/g in week 1, with sustained lower levels over 4 weeks (p < 0.05). No significant change of eGFR was found (p = 0.478). TNF-α levels also significantly decreased from 2.16 pg/mL to 1.92 pg/mL (p = 0.03), while IL-6 (p = 0.83) and IL-10 (p = 0.11) showed no significant change. The reduction in UACR and TNF-α suggests that DC therapy may alleviate albuminuria through anti-inflammatory mechanisms primarily suppressing TNF-α. No significant change in IL-10 levels implies that the anti-inflammatory effect is not mediated by IL-10 enhancement. This study demonstrates the potential of DC therapy as adjunct therapy to reduce albuminuria in DKD patients, with further research needed to explore long-term efficacy, long-term safety, and dosing strategies. Full article

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13 pages, 621 KB

Open AccessReview

An Actual Insight into the Pathogenic Pathways of Ankylosing Spondylitis

by Emilia-Daniela Păsăran, Andreea Elena Diaconu, Corina Oancea, Andra-Rodica Bălănescu, Sorina Maria Aurelian and Corina Homentcovschi

Curr. Issues Mol. Biol. 2024, 46(11), 12800-12812; https://doi.org/10.3390/cimb46110762 - 11 Nov 2024

Cited by 9 | Viewed by 5172

Abstract

Spondyloarthritis refers to a broad group of conditions that include ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis associated with Crohn’s disease or ulcerative colitis. They have been classified by the ASAS group (ASsessment in Ankylosing Spondylitis) into axial spondyloarthritis and peripheral [...] Read more.

Spondyloarthritis refers to a broad group of conditions that include ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis associated with Crohn’s disease or ulcerative colitis. They have been classified by the ASAS group (ASsessment in Ankylosing Spondylitis) into axial spondyloarthritis and peripheral spondyloarthritis. Common features include the absence of autoantibodies, genetic predisposition, and clinical aspects such as axial joint involvement, peripheral manifestations, and extra-articular involvement. However, the pathogenic mechanisms remain complex and incompletely elucidated, despite the fact that the specialized literature has described several pathways that act in synergy: genetic predisposition, environmental factors (infections and mechanical stress), or innate and acquired immune mechanisms. Finally, an inflammatory response is triggered by the recruitment of a large number of inflammatory cells and the release of innate cytokines in the affected areas: joints or periarticular or extraarticular tissues. The current article aims to update and systematize the knowledge accumulated so far on this topic, focusing on the mechanisms that have been involved in the onset, progression, and severity of ankylosing spondylitis. Full article

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23 pages, 2506 KB

Open AccessArticle

Impact of Hyponatremia and ADH Secretion in MIS-C and COVID-19: An Integrative Approach of Prognostic and Diagnostic Markers

by Diana-Andreea Ciortea, Carmen Loredana Petrea (Cliveți), Sorin Ion Berbece, Silvia Fotea, Iolanda Cristina Vivisenco, Gabriela Gurău, Mădălina Nicoleta Matei and Aurel Nechita

Curr. Issues Mol. Biol. 2024, 46(11), 11749-11771; https://doi.org/10.3390/cimb46110698 - 22 Oct 2024

Cited by 6 | Viewed by 2327

Abstract

The COVID-19 pandemic has introduced challenges in pediatric care, especially due to the emergence of Multisystem Inflammatory Syndrome in Children (MIS-C), a severe condition associated with SARS-CoV-2 infection. This study investigated the impact of hyponatremia and antidiuretic hormone (ADH) secretion corelated to clinical [...] Read more.

The COVID-19 pandemic has introduced challenges in pediatric care, especially due to the emergence of Multisystem Inflammatory Syndrome in Children (MIS-C), a severe condition associated with SARS-CoV-2 infection. This study investigated the impact of hyponatremia and antidiuretic hormone (ADH) secretion corelated to clinical outcomes in these patients. We conducted a retrospective cohort study, including 118 pediatric patients, with a detailed sub-cohort analysis of 53 patients for ADH secretion markers. Hyponatremia, defined by age-specific sodium thresholds, was present in 47.22% of MIS-C cases and 28.04% of COVID-19 cases. Ordinal logistic regression analysis revealed that severe hyponatremia significantly increased the likelihood of more severe clinical outcomes (β = 3.514, p < 0.001). A significant correlation was found between hyponatremia and prolonged hospitalization. For ADH secretion, a predictive model using ridge regression was analysed, which demonstrated that serum sodium level, U/P ratio, and hospitalization duration are key predictors of SIADH. This model fit was assessed using the ROC curve with an AUC of 0.96, indicating reliable model performance. Our findings underscore the significant role of hyponatremia on the clinical severity and hospitalization outcome of COVID-19 and MIS-C in pediatric patients. Full article

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15 pages, 2671 KB

Open AccessReview

Pathophysiology, Treatment, and Prognosis of Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome: A Review

by Takuya Kakutani, Riko Kamada and Yotaro Tamai

Curr. Issues Mol. Biol. 2024, 46(10), 11255-11269; https://doi.org/10.3390/cimb46100668 - 9 Oct 2024

Cited by 7 | Viewed by 3884

Abstract

TAFRO syndrome, first reported in 2010, is a systemic inflammatory disease with a rapid onset and potentially fatal course if not treated promptly and appropriately. The name is derived from the initial letters describing the characteristic symptoms of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal [...] Read more.

TAFRO syndrome, first reported in 2010, is a systemic inflammatory disease with a rapid onset and potentially fatal course if not treated promptly and appropriately. The name is derived from the initial letters describing the characteristic symptoms of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly. It is sometimes considered a special subtype of idiopathic multicentric Castleman disease (iMCD) because lymph node biopsies often reveal the pathology findings seen in iMCD. However, its clinical manifestations and prognoses are not well documented. Since the clinical manifestations and prognoses of TAFRO syndrome differ significantly from those of iMCD, it is recognized as an independent disease concept and considered to partially overlap with the pathology of MCD. The pathogenesis of TAFRO syndrome remains largely unknown. Due to the lack of appropriate treatment, it often presents with multiple organ dysfunction and fatality. In this review, we summarized new findings on the pathogenesis of TAFRO syndrome and discussed current effective therapies and future treatment strategies. Full article

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19 pages, 2523 KB

Open AccessArticle

Integrative Analyses of Mitophagy-Related Genes and Mechanisms Associated with Type 2 Diabetes in Muscle Tissue

by Wangjia Mao, Guannan Zong, Yuan Gao, Shen Qu and Xiaoyun Cheng

Curr. Issues Mol. Biol. 2024, 46(9), 10411-10429; https://doi.org/10.3390/cimb46090619 - 18 Sep 2024

Cited by 2 | Viewed by 1989

Abstract

Type 2 diabetes (T2D) represents the most prevalent metabolic condition that is primarily distinguished by a range of metabolic imbalances, including hyperglycemia, hyperlipidemia, and insulin resistance (IR). Currently, mitophagy has become increasingly recognized as an important process involved in the pathogenesis and progression [...] Read more.

Type 2 diabetes (T2D) represents the most prevalent metabolic condition that is primarily distinguished by a range of metabolic imbalances, including hyperglycemia, hyperlipidemia, and insulin resistance (IR). Currently, mitophagy has become increasingly recognized as an important process involved in the pathogenesis and progression of T2D. Therefore, it is very important to explore the role of mitochondrial damage and autophagy-related genes in T2D. This study investigated the role of mitophagy in the development of T2D, and 12 MRHGs associated with T2D were identified using bioinformatic analysis and machine learning methods. Our findings provide the first insight into mitophagy-related genes and their mechanisms in T2D. This study aimed to investigate possible molecular targets for therapy and the underlying mechanisms involved in T2D. This information might be useful to further elucidate the pathogenesis of T2D-related diseases and identify more optimal therapeutic approaches. Full article

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16 pages, 324 KB

Open AccessCase Report

A New Case of Paediatric Systemic Lupus Erythematosus with Onset after SARS-CoV-2 and Epstein-Barr Infection—A Case Report and Literature Review

by Carmen Loredana Petrea (Cliveți), Diana-Andreea Ciortea, Magdalena Miulescu, Iuliana-Laura Candussi, Sergiu Ioachim Chirila, Gabriela Isabela Verga (Răuță), Simona-Elena Bergheș, Mihai Ciprian Râșcu and Sorin Ion Berbece

Curr. Issues Mol. Biol. 2024, 46(8), 8642-8657; https://doi.org/10.3390/cimb46080509 - 7 Aug 2024

Cited by 9 | Viewed by 4439

Abstract

Viral infections caused by exposure to viruses such as Epstein–Barr, cytomegalovirus, or Parvovirus B19 have always been considered predisposing environmental factors for the onset of autoimmune diseases. More recently, autoimmune mechanisms such as molecular mimicry, T-cell activation, transient immunosuppression and inflammation have also [...] Read more.

Viral infections caused by exposure to viruses such as Epstein–Barr, cytomegalovirus, or Parvovirus B19 have always been considered predisposing environmental factors for the onset of autoimmune diseases. More recently, autoimmune mechanisms such as molecular mimicry, T-cell activation, transient immunosuppression and inflammation have also been observed in cases of SARS-CoV-2 infection. Several newly diagnosed autoimmune disorders have been reported post-COVID-19, such as COVID-19-associated multisystemic inflammatory syndrome in children (MIS-C), type 1 diabetes mellitus, systemic lupus erythematosus, or rheumatoid arthritis. In this article, we present a new case of paediatric systemic lupus erythematosus (SLE) with haematological (macrophage activation syndrome), renal (stage 2), cutaneous (urticarial vasculitis) and digestive involvement, onset three and a half months post-COVID-19. In the dynamics, de novo infection generated by Epstein–Barr exposure was associated. The diagnosis was confirmed based on EULAR/ACR 2019 criteria. The aim of the article is to present a possible correlation between SARS-CoV-2 and Epstein–Barr as extrinsic factors in triggering or activating paediatric systemic lupus erythematosus. Keywords: paediatric systemic lupus erythematosus; post-COVID-19; Epstein–Barr; SARS- CoV-2; case report; paediatric patient. Full article

27 pages, 5634 KB

Open AccessReview

The Role of Estrogen across Multiple Disease Mechanisms

by Xiuting Xiang, Praneetha Palasuberniam and Rahmawati Pare

Curr. Issues Mol. Biol. 2024, 46(8), 8170-8196; https://doi.org/10.3390/cimb46080483 - 29 Jul 2024

Cited by 16 | Viewed by 8942

Abstract

Estrogen is a significant hormone that is involved in a multitude of physiological and pathological processes. In addition to its pivotal role in the reproductive system, estrogen is also implicated in the pathogenesis of a multitude of diseases. Nevertheless, previous research on the [...] Read more.

Estrogen is a significant hormone that is involved in a multitude of physiological and pathological processes. In addition to its pivotal role in the reproductive system, estrogen is also implicated in the pathogenesis of a multitude of diseases. Nevertheless, previous research on the role of estrogen in a multitude of diseases, including Alzheimer’s disease, depression, cardiovascular disease, diabetes, osteoporosis, gastrointestinal diseases, and estrogen-dependent cancers, has concentrated on a single disease area, resulting in a lack of comprehensive understanding of cross-disease mechanisms. This has brought some challenges to the current treatment methods for these diseases, because estrogen as a potential therapeutic tool has not yet fully developed its potential. Therefore, this review aims to comprehensively explore the mechanism of estrogen in these seven types of diseases. The objective of this study is to describe the relationship between each disease and estrogen, including the ways in which estrogen participates in regulating disease mechanisms, and to outline the efficacy of estrogen in treating these diseases in clinical practice. By studying the role of estrogen in a variety of disease mechanisms, it is hoped that a more accurate theoretical basis and clinical guidance for future treatment strategies will be provided, thus promoting the effective management and treatment of these diseases. Full article

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17 pages, 2485 KB

Open AccessArticle

Epigenetic and Molecular Alterations in Obesity: Linking CRP and DNA Methylation to Systemic Inflammation

by Ciprian Cucoreanu, Adrian-Bogdan Tigu, Madalina Nistor, Radu-Cristian Moldovan, Ioana-Ecaterina Pralea, Maria Iacobescu, Cristina-Adela Iuga, Robert Szabo, George-Calin Dindelegan and Constatin Ciuce

Curr. Issues Mol. Biol. 2024, 46(7), 7430-7446; https://doi.org/10.3390/cimb46070441 - 13 Jul 2024

Cited by 12 | Viewed by 2886

Abstract

Obesity is marked by excessive fat accumulation in the adipose tissue, which disrupts metabolic processes and causes chronic systemic inflammation. Commonly, body mass index (BMI) is used to assess obesity-related risks, predicting potential metabolic disorders. However, for a better clustering of obese patients, [...] Read more.

Obesity is marked by excessive fat accumulation in the adipose tissue, which disrupts metabolic processes and causes chronic systemic inflammation. Commonly, body mass index (BMI) is used to assess obesity-related risks, predicting potential metabolic disorders. However, for a better clustering of obese patients, we must consider molecular and epigenetic changes which may be responsible for inflammation and metabolic changes. Our study involved two groups of patients, obese and healthy donors, on which routine analysis were performed, focused on BMI, leukocytes count, and C-reactive protein (CRP) and completed with global DNA methylation and gene expression analysis for genes involved in inflammation and adipogenesis. Our results indicate that obese patients exhibited elevated leukocytes levels, along with increased BMI and CRP. The obese group revealed a global hypomethylation and upregulation of proinflammatory genes, with adipogenesis genes following the same trend of being overexpressed. The study confirms that obesity is linked to systematic inflammation and metabolic dysfunction through epigenetic and molecular alterations. The CRP was correlated with the hypomethylation status in obese patients, and this fact may contribute to a better understanding of the roles of specific genes in adipogenesis and inflammation, leading to a better personalized therapy. Full article

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18 pages, 2336 KB

Open AccessArticle

Free Salivary Amino Acid Profile in Breast Cancer: Clinicopathological and Molecular Biological Features

by Lyudmila V. Bel’skaya, Elena A. Sarf and Denis V. Solomatin

Curr. Issues Mol. Biol. 2024, 46(6), 5614-5631; https://doi.org/10.3390/cimb46060336 - 5 Jun 2024

Cited by 14 | Viewed by 2751

Abstract

The study of salivary amino acid profiles has attracted the attention of researchers, since amino acids are actively involved in most metabolic processes, including breast cancer. In this study, we analyzed the amino acid profile of saliva in a sample including all molecular [...] Read more.

The study of salivary amino acid profiles has attracted the attention of researchers, since amino acids are actively involved in most metabolic processes, including breast cancer. In this study, we analyzed the amino acid profile of saliva in a sample including all molecular biological subtypes of breast cancer to obtain a more complete picture and evaluate the potential utility of individual amino acids or their combinations for diagnostic purposes. This study included 116 patients with breast cancer, 24 patients with benign breast disease, and 25 healthy controls. From all patients, strictly before the start of treatment, saliva samples were collected, and the quantitative content of 26 amino acids was determined. Statistically significant differences between the three groups are shown in the content of Asp, Gly, Leu + Ile, Orn, Phe, Pro, Thr, and Tyr. To differentiate the three groups from each other, a decision tree was built. To construct it, we selected those amino acids for which the change in concentrations in the subgroups was multidirectional (GABA, Hyl, Arg, His, Pro, and Car). For the first time, it is shown that the amino acid profile of saliva depends on the molecular biological subtype of breast cancer. The most significant differences are shown for the luminal B HER2-positive and TNBC subgroups. In our opinion, it is critically important to consider the molecular biological subtype of breast cancer when searching for potential diagnostic markers. Full article

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15 pages, 758 KB

Open AccessReview

Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

by Xiangyi Ma, Xinyu Li, Qi Sun, Fuxiao Luan and Jing Feng

Curr. Issues Mol. Biol. 2024, 46(6), 5307-5321; https://doi.org/10.3390/cimb46060317 - 27 May 2024

Cited by 9 | Viewed by 5617

Abstract

Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and [...] Read more.

Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and epigenetics underlying RB tumorigenesis remains a major challenge. Conventional clinical treatment options are limited, and despite the continuous identification of genetic loci associated with cancer pathogenesis, the development of targeted therapies lags behind. This review focuses on the reported genomic and epigenomic alterations in retinoblastoma, summarizing potential therapeutic targets for RB and providing insights for research into targeted therapies. Full article

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14 pages, 1059 KB

Open AccessReview

Adverse Skeletal Muscle Adaptations in Individuals Born Preterm—A Comprehensive Review

by Nick L. Dobson, Danielle E. Levitt, Hui Ying Luk and Heather L. Vellers

Curr. Issues Mol. Biol. 2024, 46(5), 4551-4564; https://doi.org/10.3390/cimb46050276 - 10 May 2024

Cited by 7 | Viewed by 3818

Abstract

Infants born preterm face an increased risk of deleterious effects on lung and brain health that can significantly alter long-term function and quality of life and even lead to death. Moreover, preterm birth is also associated with a heightened risk of diabetes and [...] Read more.

Infants born preterm face an increased risk of deleterious effects on lung and brain health that can significantly alter long-term function and quality of life and even lead to death. Moreover, preterm birth is also associated with a heightened risk of diabetes and obesity later in life, leading to an increased risk of all-cause mortality in young adults born prematurely. While these preterm-birth-related conditions have been well characterized, less is known about the long-term effects of preterm birth on skeletal muscle health and, specifically, an individual’s skeletal muscle hypertrophic potential later in life. In this review, we discuss how a confluence of potentially interrelated and self-perpetuating elements associated with preterm birth might converge on anabolic and catabolic pathways to ultimately blunt skeletal muscle hypertrophy, identifying critical areas for future research. Full article

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14 pages, 3076 KB

Open AccessReview

Ex Vivo-Generated Tolerogenic Dendritic Cells: Hope for a Definitive Therapy of Autoimmune Diseases

by Jonny, Enda Cindylosa Sitepu, Chairul A. Nidom, Soetojo Wirjopranoto, I. Ketut Sudiana, Arif N. M. Ansori and Terawan Agus Putranto

Curr. Issues Mol. Biol. 2024, 46(5), 4035-4048; https://doi.org/10.3390/cimb46050249 - 28 Apr 2024

Cited by 13 | Viewed by 7398

Abstract

Current therapies for autoimmune diseases are immunosuppressant agents, which have many debilitating side effects. However, dendritic cells (DCs) can induce antigen-specific tolerance. Tolerance restoration mediated by ex vivo-generated DCs can be a therapeutic approach. Therefore, in this review, we summarize the conceptual framework [...] Read more.

Current therapies for autoimmune diseases are immunosuppressant agents, which have many debilitating side effects. However, dendritic cells (DCs) can induce antigen-specific tolerance. Tolerance restoration mediated by ex vivo-generated DCs can be a therapeutic approach. Therefore, in this review, we summarize the conceptual framework for developing ex vivo-generated DC strategies for autoimmune diseases. First, we will discuss the role of DCs in developing immune tolerance as a foundation for developing dendritic cell-based immunotherapy for autoimmune diseases. Then, we also discuss relevant findings from pre-clinical and clinical studies of ex vivo-generated DCs for therapy of autoimmune diseases. Finally, we discuss problems and challenges in dendritic cell therapy in autoimmune diseases. Throughout the article, we discuss autoimmune diseases, emphasizing SLE. Full article

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Graphical abstract

11 pages, 5212 KB

Open AccessBrief Report

Dual Immunoglobulin Domain-Containing Cell Adhesion Molecule Increases Early in Renal Tubular Cell Injury and Plays Anti-Inflammatory Role

by Jin Han, Ju-Min Yook, Se-Hyun Oh, Yu Kyung Chung, Hee-Yeon Jung, Ji-Young Choi, Jang-Hee Cho, Sun-Hee Park, Chan-Duck Kim, Yong-Lim Kim, Seungwoo Han and Jeong-Hoon Lim

Curr. Issues Mol. Biol. 2024, 46(3), 1757-1767; https://doi.org/10.3390/cimb46030115 - 26 Feb 2024

Cited by 3 | Viewed by 2664

Abstract

Dual immunoglobulin domain-containing cell adhesion molecule (DICAM) is a type I transmembrane protein that presents in various cells including renal tubular cells. This study evaluated the expression and protective role of DICAM in renal tubular cell injury. HK-2 cells were incubated and treated [...] Read more.

Dual immunoglobulin domain-containing cell adhesion molecule (DICAM) is a type I transmembrane protein that presents in various cells including renal tubular cells. This study evaluated the expression and protective role of DICAM in renal tubular cell injury. HK-2 cells were incubated and treated with lipopolysaccharide (LPS, 30 μg/mL) or hydrogen peroxide (H₂O₂, 100 μM) for 24 h. To investigate the effect of the gene silencing of DICAM, small interfering RNA of DICAM was used. Additionally, to explain its role in cellular response to injury, DICAM was overexpressed using an adenoviral vector. DICAM protein expression levels significantly increased following treatment with LPS or H₂O₂ in HK-2 cells. In response to oxidative stress, DICAM showed an earlier increase (2–4 h following treatment) than neutrophil gelatinase-associated lipocalin (NGAL) (24 h following treatment). DICAM gene silencing increased the protein expression of inflammation-related markers, including IL-1β, TNF-α, NOX4, integrin β1, and integrin β3, in H₂O₂-induced HK-2 cell injury. Likewise, in the LPS-induced HK-2 cell injury, DICAM knockdown led to a decrease in occludin levels and an increase in integrin β3, IL-1β, and IL-6 levels. Furthermore, DICAM overexpression followed by LPS-induced HK-2 cell injury resulted in an increase in occludin levels and a decrease in integrin β1, integrin β3, TNF-α, IL-1β, and IL-6 levels, suggesting an alleviating effect on inflammatory responses. DICAM was elevated in the early stage of regular tubular cell injury and may protect against renal tubular injury through its anti-inflammatory properties. DICAM has a potential as an early diagnostic marker and therapeutic target for renal cell injury. Full article

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18 pages, 3450 KB

Open AccessArticle

Prevalence of TERT Promoter Mutations in Orbital Solitary Fibrous Tumors

by David Sinan Koca, Vladimir Kolpakov, Jana Ihlow, Maximilian von Laffert, Katharina Erb-Eigner, Hermann Herbst, Karen Kriese, Leonille Schweizer and Eckart Bertelmann

Curr. Issues Mol. Biol. 2024, 46(2), 1467-1484; https://doi.org/10.3390/cimb46020095 - 10 Feb 2024

Cited by 3 | Viewed by 2757

Abstract

The orbital manifestation of a solitary fibrous tumor (SFT) is exceptionally rare and poses specific challenges in diagnosis and treatment. Its rather exceptional behavior among all SFTs comprises a high tendency towards local recurrence, but it rarely culminates in metastatic disease. This raises [...] Read more.

The orbital manifestation of a solitary fibrous tumor (SFT) is exceptionally rare and poses specific challenges in diagnosis and treatment. Its rather exceptional behavior among all SFTs comprises a high tendency towards local recurrence, but it rarely culminates in metastatic disease. This raises the question of prognostic factors in orbital SFTs (oSFTs). Telomerase reverse transcriptase (TERT)-promoter mutations have previously been linked to an unfavorable prognosis in SFTs of other locations. We analyzed the prevalence of TERT promoter mutations of SFTs in the orbital compartment. We performed a retrospective, descriptive clinico-histopathological analysis of nine cases of oSFTs between the years of 2017 and 2021. A TERT promoter mutation was present in one case, which was classified with intermediate metastatic risk. Local recurrence or progress occurred in six cases after primary resection; no distant metastases were reported. Multimodal imaging repeatedly showed particular morphologic patterns, including tubular vascular structures and ADC reduction. The prevalence of the TERT promoter mutation in oSFT was 11%, which is similar to the prevalence of extra-meningeal SFTs of the head and neck and lower than that in other extra-meningeal compartments. In the present study, the TERT promoter mutation in oSFT manifested in a case with an unfavorable prognosis, comprising aggressive local tumor growth, local recurrence, and eye loss. Full article

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12 pages, 1626 KB

Open AccessArticle

A Smooth Muscle Cell-Based Ferroptosis Model to Evaluate Iron-Chelating Molecules for Cardiovascular Disease Treatment

by Sarah El Hajj, Laetitia Canabady-Rochelle, Isabelle Fries-Raeth and Caroline Gaucher

Curr. Issues Mol. Biol. 2024, 46(2), 1348-1359; https://doi.org/10.3390/cimb46020086 - 4 Feb 2024

Cited by 5 | Viewed by 3079

Abstract

Dysregulation of iron homeostasis causes iron-mediated cell death, recently described as ferroptosis. Ferroptosis is reported in many chronic diseases, such as hepatic cancer, renal, and cardiovascular diseases (heart failure, atherosclerosis). However, there is a notable scarcity of research studies in the existing literature [...] Read more.

Dysregulation of iron homeostasis causes iron-mediated cell death, recently described as ferroptosis. Ferroptosis is reported in many chronic diseases, such as hepatic cancer, renal, and cardiovascular diseases (heart failure, atherosclerosis). However, there is a notable scarcity of research studies in the existing literature that explore treatments capable of preventing ferroptosis. Additionally, as far as the author is aware, there is currently no established model for studying ferroptosis within cardiovascular cells, which would be essential for assessing metal-chelating molecules with the potential ability to inhibit ferroptosis and their application in the treatment of cardiovascular diseases. In this study, a smooth muscle cell-based ferroptosis model is developed upon the inhibition of the system X_c⁻ transporter by erastin associated or not with Fe(III) overload, and its rescue upon the introduction of well-known iron chelators, deferoxamine and deferiprone. We showed that erastin alone decreased the intracellular concentration of glutathione (GSH) without affecting peroxidized lipid concentrations. Erastin with ferric citrate was able to decrease intracellular GSH and induce lipid peroxidation after overnight incubation. Only deferiprone was able to rescue the cells from ferroptosis by decreasing lipid peroxidation via iron ion chelation in a 3:1 molar ratio. Full article

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15 pages, 1382 KB

Open AccessArticle

Deep Immunophenotyping of Circulating T and B Cells in Relapsing Adult-Onset Still’s Disease

by Valentina Myachikova, Igor Kudryavtsev, Artem Rubinstein, Arthur Aquino, Dmitry Isakov, Alexey Golovkin and Alexey Maslyanskiy

Curr. Issues Mol. Biol. 2024, 46(2), 1177-1191; https://doi.org/10.3390/cimb46020075 - 1 Feb 2024

Cited by 2 | Viewed by 2702

Abstract

Adult-onset Still’s disease (AOSD) is a complex systemic inflammatory disorder, categorized as an ‘IL-1 driven’ inflammasomapathy. Despite this, the interaction between T and B cells remains poorly understood. We conducted a study, enrolling 7 patients with relapsing AOSD and 15 healthy control subjects, [...] Read more.

Adult-onset Still’s disease (AOSD) is a complex systemic inflammatory disorder, categorized as an ‘IL-1 driven’ inflammasomapathy. Despite this, the interaction between T and B cells remains poorly understood. We conducted a study, enrolling 7 patients with relapsing AOSD and 15 healthy control subjects, utilizing deep flow cytometry analysis to examine peripheral blood T- and B-cell subsets. T-cell and B-cell subsets were significantly altered in patients with AOSD. Within CD4+ T cells, Th2 cells were decreased. Additionally, Th17 cell and follicular Th cell subsets were altered within CD45RA–CD62L+ and CD45RA–CD62L– Th cells in patients with AOSD compared to healthy controls. We identified changes in CD8+ T cell maturation and ‘polarization’ in AOSD patients, with an elevated presence of the TEMRA CD8+ T cell subset. Furthermore, the percentage of Tc1 cells was decreased, while the frequency of CCR6–CXCR3– Tc2 cells was elevated. Finally, we determined that the frequency of CD5+CD27– B cells was dramatically decreased in patients with AOSD compared to healthy controls. Further investigations on a large group of patients with AOSD are required to evaluate these adaptive immunity cells in the disease pathogenesis. Full article

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2023

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8 pages, 578 KB

Open AccessBrief Report

Random Allelic Expression in Inherited Retinal Disease Genes

by Collin J. Richards and Jose S. Pulido

Curr. Issues Mol. Biol. 2023, 45(12), 10018-10025; https://doi.org/10.3390/cimb45120625 - 13 Dec 2023

Viewed by 1971

Abstract

Inherited retinal diseases (IRDs) are a significant contributor to visual loss in children and young adults, falling second only to diabetic retinopathy. Understanding the pathogenic mechanisms of IRDs remains paramount. Some autosomal genes exhibit random allelic expression (RAE), similar to X-chromosome inactivation. This [...] Read more.

Inherited retinal diseases (IRDs) are a significant contributor to visual loss in children and young adults, falling second only to diabetic retinopathy. Understanding the pathogenic mechanisms of IRDs remains paramount. Some autosomal genes exhibit random allelic expression (RAE), similar to X-chromosome inactivation. This study identifies RAE genes in IRDs. Genes in the Retinal Information Network were cross-referenced with the recent literature to identify expression profiles, RAE, or biallelic expression (BAE). Loss-of-function intolerance (LOFI) was determined by cross-referencing the existing literature. Molecular and biological pathways that are significantly enriched were evaluated using gene ontology. A total of 184 IRD-causing genes were evaluated. Of these, 31 (16.8%) genes exhibited RAE. LOFI was exhibited in 6/31 (19.4%) of the RAE genes and 18/153 (11.8%) of the BAE genes. Brain tissue exhibited BAE in 107/128 (83.6%) genes for both sexes. The molecular pathways significantly enriched among BAE genes were photoreceptor activity, tubulin binding, and nucleotide/ribonucleotide binding. The biologic pathways significantly enriched for RAE genes were equilibrioception, parallel actin filament bundle assembly, photoreceptor cell outer segment organization, and protein depalmitoylation. Allele-specific expression may be a mechanism underlying IRD phenotypic variability, with clonal populations of embryologic precursor cells exhibiting RAE. Brain tissue preferentially exhibited BAE, possibly due to selective pressures against RAE. Pathways critical for cellular and visual function were enriched in BAE, which may offer a survival benefit. Full article

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22 pages, 1350 KB

Open AccessReview

A Synopsis of Hepatitis C Virus Treatments and Future Perspectives

by Christian Medina, Alexis Hipólito García, Francis Isamarg Crespo, Félix Isidro Toro, Soriuska José Mayora and Juan Bautista De Sanctis

Curr. Issues Mol. Biol. 2023, 45(10), 8255-8276; https://doi.org/10.3390/cimb45100521 - 11 Oct 2023

Cited by 8 | Viewed by 7580

Abstract

Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune [...] Read more.

Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN–RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients’ treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV–HCV and HCV–HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV–HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma. Full article

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13 pages, 5000 KB

Open AccessArticle

Tryptase-Positive Mast Cells Promote Adipose Fibrosis in Secondary Lymphedema through PDGF

by Takashi Nuri, Denan Jin, Shinji Takai and Koichi Ueda

Curr. Issues Mol. Biol. 2023, 45(10), 8027-8039; https://doi.org/10.3390/cimb45100507 - 30 Sep 2023

Cited by 1 | Viewed by 2730

Abstract

Lymphedema is a chronic and progressive condition that causes physical disfigurement and psychological trauma due to the accumulation of lymphatic fluid in the interstitial space. Once it develops, lymphedema is difficult to treat because it leads to the fibrosis of adipose tissue. However, [...] Read more.

Lymphedema is a chronic and progressive condition that causes physical disfigurement and psychological trauma due to the accumulation of lymphatic fluid in the interstitial space. Once it develops, lymphedema is difficult to treat because it leads to the fibrosis of adipose tissue. However, the mechanism behind this remains unclear. The purpose of this study was to investigate the involvement of mast cells (MCs) in the adipose tissues of patients with lymphedema. We found that fibrosis spread through blood vessels in the adipose tissues of lymphedema patients, and the expression of the collagen I and III genes was significantly increased compared to that of those in normal adipose tissue. Immunostaining of vimentin and α-smooth muscle actin showed that fibroblasts were the main cellular components in severely fibrotic regions. Toluidine blue staining confirmed a significant increase in the number of MCs in the adipose tissues of lymphedema patients, and immunostaining of serial sections of adipose tissue showed a significant increase in the number of tryptase-positive cells in lymphedema tissues compared with those in normal adipose tissues. Linear regression analyses revealed significant positive correlations between tryptase and the expressions of the TNF-α, platelet-derived growth factor (PDGF)-A, and PDGFR-α genes. PDGF-A–positive staining was observed in both fibroblasts and granules of tryptase-positive MCs. These results suggest that MC-derived tryptase plays a role in the fibrosis of adipose tissue due to lymphedema directly or in cooperation with other mediators. Full article

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11 pages, 1195 KB

Open AccessArticle

Investigation of Genetic Factors and Clinical Data in Breast Cancer Highlights the Importance of Breastfeeding and Cancer History

by Amanda Mercês, Rebecca da-Silva-Cruz, Caio S. Silva, Rommel Burbano, Ândrea Ribeiro-dos-Santos and Giovanna C. Cavalcante

Curr. Issues Mol. Biol. 2023, 45(10), 7933-7943; https://doi.org/10.3390/cimb45100501 - 28 Sep 2023

Cited by 1 | Viewed by 1787

Abstract

Breast cancer (BC) is the type of neoplasm that most affects women worldwide. It is known that one of the hallmarks of cancer is the resistance to cell death with the evasion of apoptosis. Considering the relevance of TP53, BCL2, CASP3, [...] Read more.

Breast cancer (BC) is the type of neoplasm that most affects women worldwide. It is known that one of the hallmarks of cancer is the resistance to cell death with the evasion of apoptosis. Considering the relevance of TP53, BCL2, CASP3, and CASP9 genes for the occurrence of the intrinsic apoptosis, this study investigated the distribution of the genetic variants rs17880560 (TP53), rs11269260 (BCL2), rs4647655 (CASP3), rs4645982, and rs61079693 (CASP9), as well as genetic ancestry and clinical data, in a BC cohort from the Brazilian Amazon that other variants in these genes might play a role in this process. In the present study, 22 breast cancer tissues and 10 non-cancerous tissues were used, therefore, 32 samples from different patients were subjected to genotyping. We observed that breastfeeding and cancer history were factors that need to be considered for BC (p = 0.022). Therefore, this study contributed to a greater understanding of intrinsic apoptosis in BC, reinforcing previous data that suggest that the history of cancer might be a condition that affects the development of BC and that breastfeeding may act as a protective factor for this type of cancer. We recommend more studies on the genetic factors investigated here, aiming at a future with tools that can help in the early diagnosis. Full article

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17 pages, 676 KB

Open AccessReview

Gender Differences in Insulin Resistance: New Knowledge and Perspectives

by Tiziana Ciarambino, Pietro Crispino, Gloria Guarisco and Mauro Giordano

Curr. Issues Mol. Biol. 2023, 45(10), 7845-7861; https://doi.org/10.3390/cimb45100496 - 27 Sep 2023

Cited by 75 | Viewed by 12060

Abstract

Insulin resistance is the main mechanism in a whole series of pathological conditions, which are not only of metabolic interest but also of a systemic type. This phenomenon means that the body’s cells become less sensitive to the hormone insulin, leading to higher [...] Read more.

Insulin resistance is the main mechanism in a whole series of pathological conditions, which are not only of metabolic interest but also of a systemic type. This phenomenon means that the body’s cells become less sensitive to the hormone insulin, leading to higher levels of insulin in the blood. Insulin resistance is a phenomenon that can be found in both men and women and in particular, in the latter, it is found mainly after menopause. Premenopause, hormonal fluctuations during the menstrual cycle, and the presence of estrogen can affect insulin sensitivity. Androgens, such as testosterone, are typically higher in men and can contribute to insulin resistance. In both sexes, different human body types affect the distribution and location of body fat, also influencing the development of diabetes and cardiovascular disease. Insulin resistance is also associated with some neurological and neurogenerative disorders, polycystic ovary syndrome, atherosclerosis, and some of the main neoplastic pathologies. A healthy lifestyle, including regular physical activity, a balanced diet, and self-maintenance, can help to prevent the onset of insulin resistance, regardless of gender, although the different habits between men and women greatly affect the implementation of preventative guidelines that help in fighting the manifestations of this metabolic disorder. This review may help to shed light on gender differences in metabolic diseases by placing a necessary focus on personalized medical management and by inspiring differentiated therapeutic approaches. Full article

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17 pages, 2395 KB

Open AccessArticle

MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma

by Masaki Murata, Vladimir Bilim, Yuko Shirono, Akira Kazama, Kaede Hiruma, Masayuki Tasaki and Yoshihiko Tomita

Curr. Issues Mol. Biol. 2023, 45(9), 7432-7448; https://doi.org/10.3390/cimb45090470 - 11 Sep 2023

Cited by 2 | Viewed by 2383

Abstract

The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic [...] Read more.

The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3β in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3β. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3′ untranslated region of GSK-3β, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3β protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3β expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field. Full article

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