Altered Gene Expression Research Articles

Genomic Insights into Drug Abuse: The Role of DNA and Protein-Coding Regions in Addiction and Genetic Mutation

Abstract This paper explores the genetic and epigenetic impacts of drug abuse, focusing on how chronic drug use can induce mutations in DNA, particularly within protein-coding regions, and alter gene expression through mechanisms such as DNA methylation. The study highlights the significant role of these genetic changes in the brain's reward pathways, which contribute to the development and persistence of addiction. Through a comprehensive literature review, the paper identifies key genetic factors associated with addiction susceptibility and the long-term effects of drug-induced epigenetic modifications. A proposed research framework is presented, emphasizing the need for longitudinal studies to track epigenetic changes over time, targeted genomic analysis to identify critical mutations, and the integration of multi-omics approaches to provide a holistic understanding of drug abuse's impact on the genome. The paper also addresses ethical considerations, including the importance of protecting genetic privacy and preventing stigmatization based on genetic findings. The study concludes that advancing our understanding of the genetic and epigenetic mechanisms underlying addiction can lead to more effective, personalized treatment strategies and inform public health policies aimed at mitigating the effects of drug abuse.

CHARM and EvoETR: Precision epigenetic tools for gene silencing.

With the advent of gene editing technologies like CRISPR/Cas9, it has become possible to edit genomic regions of interest for research and therapeutic purposes. These technologies have also been adapted to alter gene expression without changing their DNA sequence, allowing epigenetic edits. While genetic editors make edits by cutting the genome at specified regions, epigenetic editors leverage the same targeting mechanism but act based on the epigenetic modifier fused to them, such as a methyltransferase. Here, we discuss two recently employed epigenetic editors (epi-editors) that silenced target genes involved in disease to mitigate their effects. Neumann etal. reported the construction of an epigenetic editor called CHARM that could methylate and silence the prion gene in mouse brains and subsequently switch itself off. Additionally, Capelluti etal. developed an epi-editor called EvoETR that knocked down Pcsk9 in the murine liver to reduce LDL levels. We aim to highlight the design principles underlying the design of these epi-editors to inform future editor designs.

Arene Ruthenium Complexes Specifically Inducing Apoptosis in Breast Cancer Cells

Monocationic arene ruthenium complexes (RuL1–RuL4) incorporating phenothiazinyl-hydrazinyl-thiazole ligands (L1–L4) have been synthesized, characterized and evaluated as anticancer agents. Their cytotoxicity, antiproliferative activity and alteration of apoptotic gene expression were studied on three cancer cell lines, a double positive breast cancer cell line MCF-7 and two triple negative breast cancer cell lines Hs578T and MDA-MB-231. All arene ruthenium complexes were able to reduce the viability of the breast cancer cell lines, with the highest cytotoxicities being recorded for the [(p-cymene)RuL3Cl]+ (RuL3) complex on the MCF-7 (IC50 = 0.019 µM) and Hs578T cell lines (IC50 = 0.095 µM). In the double positive MCF-7 breast cancer cells, the complexes [(p-cymene)RuL1Cl]+ (RuL1) and [(p-cymene)RuL2Cl]+ (RuL2) significantly upregulated pro-apoptotic genes including BAK, FAS, NAIP, CASP8, TNF, XIAP and BAD, while downregulating TNFSF10. In the triple negative breast cancer cell line Hs578T, RuL1 reduced TNFSF-10 and significantly upregulated BAK, CASP8, XIAP, FADD and BAD, while complex RuL2 also increased BAK and CASP8 expression, but had limited effects on other genes. The triple negative MDA-MB-231 cancer cells treated with RuL1 upregulated NOD1 and downregulated p53, while RuL2 significantly downregulated p53, XIAP and TNFSF10, with minor changes in other genes. The significant alterations in the expression of key apoptotic genes suggest that such complexes have the potential to target cancer cells.

The influence of melanoma extracellular vesicles on benign melanocytes: a role for PRAME in modulation of the tumor microenvironment

Melanoma is an aggressive skin cancer with a high tendency for metastasis and resistance to conventional therapies. This study explores the role of PRAME (Preferentially Expressed Antigen in Melanoma), a cancer-testis antigen, in melanoma progression, focusing on its function in melanoma-derived extracellular vesicles (EVs) and its impact on benign melanocytes. We show that PRAME is highly expressed in melanoma cell lines, tissues, and patient plasma, and is present in EVs. These EVs transfer PRAME protein and mRNA to benign melanocytes, leading to significant alterations in gene expression, increased cell proliferation, and a more malignant phenotype. Knockout of PRAME in melanoma cells reduces these pro-tumorigenic effects on melanocytes, emphasizing PRAME's role in EV-mediated communication. The detection of PRAME in plasma EVs suggests its potential as a biomarker for monitoring disease progression and therapy response, including in rare melanoma subtypes. These findings highlight PRAME as a key player in melanoma progression and suggest targeting PRAME-containing EVs as a potential therapeutic strategy to inhibit melanoma progression and metastasis.

Multigenerational impact of chronic exposure to mercury chloride on maternal care, puberty, fertility, and hypothalamic function in female mice

Chronic exposure to low doses of mercury, one of the ten most dangerous chemicals for public health, has been associated with problems in fertility. Our study aims to investigate the effect of chronic exposure to a low dose of mercury chloride on the reproductive health of female mice and maternal behavior throughout generations using the maternal lineage for the first and second generations, either by direct exposure with F1 and F2 or via the germ cells with F2'. To our knowledge, these modalities have never been addressed before. Among the main outcomes of our research, we provide evidence that mercury exposure induces multigenerational alterations of maternal care and reproduction in female mice, respectively, through alterations of gene expression in the hypothalamus. The decline in maternal care behaviors observed in all exposed groups involved reduced nursing frequency and grooming/licking behaviors. The reproductive phenotype found across generations in our study directly exposed the F1 and F2, or even in the germline-exposed F2′, is defined by a delay in the vaginal opening, a delay in the first estrus, altered estrous cyclicity, and a decrease in interest in mating behavior observed in the two-choice preference test. These results were accompanied by a reduction in the mRNA expression of kiss1 and Gnrh1 in the hypothalamus, critical hormones in the HPG axis for initiating ovulation and estrous cycles. Furthermore, the F1, F2, and F2′ exposed mice had significantly decreased mRNA expression of Bdnf, which might indicate impaired communication within the neural circuits controlling reproduction. Additionally, increased Tnf-α and Il6 mRNA expression indicates a possible inflammatory response to mercury exposure across generations.

Investigation of CST7 and hsa-miR-4793-5p gene expression in breast cancer

Breast cancer (BC) presents as a worldwide challenge, known as the most frequently diagnosed cancer in women. In 2022, BC was diagnosed in 2.3 million women with 670,000 deaths globally. In this research, our objective was to examine the CST7 and has-miR-4793-5p gene expression in BC tumor tissues and adjacent normal tissues.Using GSE57897 gene expression data from 422 BC samples and 31 breast samples from healthy controls which was based on the Platform GPL18722 (spotted oligonucleotide Homo sapiens microRNA (miRNA) array) in the Gene Expression Omnibus (GEO) and compare with miRNAs with a conserved target location on CST7 mRNA were found using databases. The study population included 60 fresh BC tissue samples and adjacent normal tissues as control. The Quantitative Real-Time PCR was used to evaluate the expression levels of CST7 and has-miR-4793-5p in the breast tissues.The present study, found that CST7 and hsa-miR-4793-5p were significantly increased in tumoral tissues in compare to normal tissues. Further analysis revealed a remarkable association between CST7 and hsa-miR-4793-5p gene expression alteration. ROC curve analysis demonstrated high accuracy for CST7 expression in BC tumors. Comparison of gene expression between different stages and patient family history showed significant findings. Due to the high sensitivity and specificity of the expression changes of these two genes, they are suitable candidates for further investigations to be considered as part of a diagnosis and prognosis panel.

Bee venom loaded into nanoliposomes efficiently eliminates the oxidative damage and improves the mRNA expression of inflammatory mediator genes in aflatoxin B1-exposed rats

In this study, we assess the preventive effect of crude bee venom (CBV), and bee venom-loaded nanoliposomes (BV@NLs) against oxidative damage in rats caused by aflatoxin B1 (AFB1). BV@NLs with an average size and zeta potential of +46.5 mV and 230.9 ± 5.21 nm and PDI of 0.201±0.01 were prepared. Eight groups of male Sprague-Dawley rats received oral treatment for 4 weeks, including the negative control group, AFB1 (80 μg/kg b.w), CBV (0.05 mg/kg b.w), BV@NLs (0.05 or 1 mg/kg b.w), AFB1 plus CBV, and AFB1 plus BV@NL at the two tested doses. Samples of tissue and blood were obtained for various histological, biochemical, and hematological studies. The findings revealed that AFB1 alone produced substantial alterations in hematology, biochemistry, lipid profile, oxidative indices, serum cytokines, and gene expression, along with DNA damage, and histological abnormalities in the liver and kidneys. None of the investigated parameters changed when CBV or BV@NLs were administered alone. However, combination treatments with CBV or BV@NLs with AFB1 significantly improved and relieved the oxidative damage caused by AFB1, with BV@NLs being more effective than CBV and the high dosage outperforming the low dose. It might be stated that nanoliposomes are promising effective drug delivery for bee venom to enhance its efficiency and overcome the challenges associated with its applications.

Cellular senescence impairs tendon extracellular matrix remodeling in response to mechanical unloading.

Musculoskeletal injuries, including tendinopathies, present a significant clinical burden for aging populations. While the biological drivers of age-related declines in tendon function are poorly understood, it is well accepted that dysregulation of extracellular matrix (ECM) remodeling plays a role in chronic tendon degeneration. Senescent cells, which have been associated with multiple degenerative pathologies in musculoskeletal tissues, secrete a highly pro-inflammatory senescence-associated secretory phenotype (SASP) that has potential to promote ECM breakdown. However, the role of senescent cells in the dysregulation of tendon ECM homeostasis is largely unknown. To assess this directly, we developed an invitro model of induced cellular senescence in murine tendon explants. This novel technique enables us to study the isolated interactions of senescent cells and their native ECM without interference from age-related systemic changes. We document multiple biomarkers of cellular senescence in induced tendon explants including cell cycle arrest, apoptosis resistance, and sustained inflammatory responses. We then utilize this invitro senescence model to compare the ECM remodeling response of young, naturally aged, and induced-senescent tendons to an altered mechanical stimulus. We found that both senescence and aging independently led to alterations in ECM-related gene expression, reductions in protein synthesis, and tissue compositional changes. Furthermore, MMP activity was sustained, thus shifting the remodeling balance of aged and induced-senescent tissues towards degradation over production. Together, this demonstrates that cellular senescence plays a role in the altered mechano-response of aged tendons and likely contributes to poor clinical outcomes in aging populations.

Enterococcus faecalis co-cultured with oral cancer cells exhibits higher virulence and promotes cancer cell survival, proliferation, and migration: an in vitro study.

Introduction. Enterococcus faecalis is a common pathogen associated with many oral diseases and is often isolated from oral cancer patients. However, limited information is available on its key virulence gene expression in oral cancer cell microenvironment and cancer cell behaviour in co-culture studies.Hypothesis. E. faecalis overexpresses virulence genes when co-cultured with oral cancer cells and possibly alters the tumour microenvironment, promoting oral cancer proliferation and survival.Aim. To investigate altered virulence gene expression in E. faecalis and oral cancer cell behaviour using in vitro co-culture experiments.Methodology. Cal27 cells were co-cultured with E. faecalis and assessed for their cell proliferation, apoptosis, migration and clonogenicity using standard cell culture assays. The levels of reactive oxygen species (ROS) and inflammatory cytokines, along with proliferative, angiogenic and apoptotic biomarker expressions, were also assessed. E. faecalis adherence to cancer cells was demonstrated by the gentamicin protection assay. Real time-PCR was used to analyse the expression of virulence genes.Results. Co-culture of Cal27 cells with E. faecalis showed significantly higher cell proliferation, migration and clonogenicity compared to the control (P<0.01). A significant increase in the levels of ROS and inflammatory cytokines and overexpression of Ki67, vascular endothelial growth factor, extracellular signal-regulated kinase 1/2, phosphoinositide 3 kinase and Akt was observed in the co-culture group. E. faecalis also downregulated p53 and Bax genes while upregulated Bcl-2. The virulence genes GelE, Asa and Ace were overexpressed in E. faecalis co-cultured with Cal27 cells.Conclusion. The results from this study indicate the possible risks of E. faecalis infection in oral cancer. An effective antibiotic strategy against E. faecalis to prevent complications associated with oral diseases, including cancer, is needed.

Immune Microenvironment Alterations and Identification of Key Diagnostic Biomarkers in Chronic Kidney Disease Using Integrated Bioinformatics and Machine Learning.

Chronic kidney disease (CKD) involves complex immune dysregulation and altered gene expression profiles. This study investigates immune cell infiltration, differential gene expression, and pathway enrichment in CKD patients to identify key diagnostic biomarkers through machine learning methods. We assessed immune cell infiltration and immune microenvironment scores using the xCell algorithm. Differentially expressed genes (DEGs) were identified using the limma package. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed to evaluate pathway enrichment. Machine learning techniques (LASSO and Random Forest) pinpointed diagnostic genes. A nomogram model was constructed and validated for diagnostic prediction. Spearman correlation explored associations between key genes and immune cell recruitment. The CKD group exhibited significantly altered immune cell infiltration and increased immune microenvironment scores compared to the normal group. We identified 2335 DEGs, including 124 differentially expressed immune-related genes. GSEA highlighted significant enrichment of inflammatory and immune pathways in the high immune score (HIS) subgroup, while GSVA indicated upregulation of immune responses and metabolic processes in HIS. Machine learning identified four key diagnostic genes: RGS1, IL4I1, NR4A3, and SOCS3. Validation in an independent dataset (GSE96804) and clinical samples confirmed their diagnostic potential. The nomogram model integrating these genes demonstrated high predictive accuracy. Spearman correlation revealed positive associations between the key genes and various immune cells, indicating their roles in immune modulation and CKD pathogenesis. This study provides a comprehensive analysis of immune alterations and gene expression profiles in CKD. The identified diagnostic genes and the constructed nomogram model offer potent tools for CKD diagnosis. The immunomodulatory roles of RGS1, IL4I1, NR4A3, and SOCS3 warrant further investigation as potential therapeutic targets in CKD.

Multi-omics analysis of peach-like aroma formation in fruits of wild strawberry (Fragaria nilgerrensis)

The unique fruity aroma of strawberries enhances their appeal to consumers. Fragaria nilgerrensis, a wild strawberry distributed in Southwest China and known for its distinctive peach-like aroma, represents a valuable resource for improving the fragrance of cultivated strawberries. However, the molecular mechanism underlying the peach-like aroma biosynthesis remains largely unexplored. In this study, we integrated metabolomic and transcriptomic data across four developmental stages of F. nilgerrensis fruits to construct a detailed profile of volatile organic compounds (VOCs) and the associated gene expression alterations during fruit maturation. Our findings reveal that γ-decalactone, δ-decalactone, and γ-undecalactone are the primary compounds responsible for the pronounced peach-like aroma, with their levels showing a significant correlation with the activity of the FngFAD2 enzyme. The silencing of the FngFAD2 gene through tobacco rattle viral (TRV) induction resulted in notable reductions in both the peach-like aroma and lactone content in the fruit. In addition, integrating dual luciferase assays, yeast one-hybrid (Y1H) and subcellular localization experiments, we also identified three transcription factors (FngDOF1.2, FngWRKY3, and FngWRI1) that enhance FngFAD2 expression. These findings elucidate the molecular regulatory network involved in the complex developmental process of peach-like flavor in strawberry fruits. Additionally, our research also provides a foundation for the utilization of the wild strawberry as well as improving the flavor and quality of cultivated strawberries.

Determining the effect of long non-coding RNA maternally expressed gene 3 (lncRNA MEG3) on the transcriptome profile in cervical cancer cell lines

This study investigates the role of the long non-coding RNA Maternally Expressed Gene3 (lncRNA MEG3) gene in cervical cancer, as evidenced by its downregulation in cancerous cell lines. The study demonstrates the effects of the overexpression of lncRNA MEG3 in cervical cancer cell lines, particularly in C33A and CaSki. Through comprehensive analyses, including Next-Generation Sequencing (NGS), alterations in global mRNA expression were analyzed. In C33A cells, 67 genes were upregulated, while 303 genes were downregulated. Similarly, in CaSki cells, 221 genes showed upregulation and 248 genes displayed downregulation. Gene ontology and KEGG pathway analyses were conducted to gain insight into potential mechanisms. Furthermore, the study delves into gene regulatory networks, uncovering intricate interactions among genes. The RNA sequencing data were confirmed for eight genes: PAX3, EGR2, ROR1, NRP1, OAS2, STRA6, CA9, and EDN2 by Real-time PCR. The findings illuminate the complex landscape of gene expression alterations and pathways impacted by the overexpression of lncRNA MEG3. The impact of MEG3 on the overall cervical cancer cells' mRNA profile is reported for the first time. New biomarkers for the prognosis of cervical cancer are also reported in this study. Moreover, identifying specific genes within the regulatory networks provides valuable insights into potential therapeutic targets for managing cervical cancer.

RAC2 as a Tumor-Suppressive Biomarker Associated with T Cell Infiltration in Breast Cancer.

Background: RAC2 is critical in regulating the homeostasis of hematopoietic stem cells. Nonetheless, its role in breast cancer (BC) remains unclear, necessitating further investigation. Methods: The expression of RAC2 in the BC and healthy tissues was acquired from The Cancer Genome Atlas. Its validity was further assessed using datasets from the gene expression omnibus database. The Tumor Immune Single-cell Hub database was used to collect and analyze the single-cell RNA sequencing datasets of BC. The diagnostic relevance of RAC2 was evaluated using receiver operating characteristic curves. Further assessment was carried out via enrichment analyses; Gene Set Analysis, immune scoring, single-cell sequencing, and immunohistochemical analysis were conducted to confirm the relationship between RAC2 expression and immune infiltration. Results: RAC2 expression was notably heightened in BC (p < 0.001). It was observed that a better prognosis was linked to heightened expression of RAC2 (p < 0.01), with the diagnostic efficacy of the marker noted to be good (area under the curve = 0.858). We found a lower percentage of protumor immune cells and a greater proportion of antitumor immune cells in the high RAC2. Our analysis revealed alterations in gene expression and an enriched network of immune pathways influenced by RAC2. Notably, cytotoxic genes, chemokines, chemokine receptors, immunostimulators, and immunosuppressive molecules positively correlated with RAC2 expression. RAC2 expression reliably predicted how patients would respond to two different therapeutic approaches in BC. Conclusions: The RAC2 was found to be a key biomarker in BC in the current study, demonstrating considerable potential as a prognostic and diagnostic marker. These results highlight the RAC2 potential to improve precision medicine strategies and treatment outcomes for patients with BC.

Decoding physiological and pathological roles of innate immune cells in eye diseases: the perspectives from single-cell RNA sequencing.

Single-cell RNA sequencing (scRNA-seq) has facilitated a deeper comprehension of the molecular mechanisms behind eye diseases and has prompted the selection of precise therapeutic targets by examining the cellular and molecular intricacies at the single-cell level. This review delineates the pivotal role of scRNA-seq in elucidating the functions of innate immune cells within the context of ocular pathologies. Recent advancements in scRNA-seq have revealed that innate immune cells, both from the periphery and resident in the retina, are actively engaged in various stages of multiple eye diseases. Notably, resident microglia and infiltrating neutrophils exhibit swift responses during the initial phase of injury, while peripheral monocyte-derived macrophages exhibit transcriptomic profiles akin to those of activated microglia, suggesting their potential for long-term residence within the retina. The scRNA-seq analyses have underscored the cellular heterogeneity and gene expression alterations within innate immune cells, which, while sharing commonalities, exhibit disease-specific variations. These insights have not only broadened our understanding of the cellular and molecular mechanisms in eye diseases but also paved the way for the identification of candidate targets for targeted therapeutic interventions. The application of scRNA-seq technology has heralded a new era in the study of ocular pathologies, enabling a more detailed appreciation of the roles that innate immune cells play across a spectrum of eye diseases.

DNA methylation and non-coding RNAs in metabolic disorders: Epigenetic Roles of Nutrients, Dietary Patterns and Weight Loss Interventions for Precision Nutrition.

Dysregulation of epigenetic processes and abnormal epigenetic profiles are associated with various metabolic disorders. Nutrition, as an environmental factor, can induce epigenetic changes through both direct exposure and transgenerational inheritance, continuously altering gene expression and shaping the phenotype. Nutrients consumed through food or supplementation, such as vitamin B12, folate, vitamin B6, and choline, play a pivotal role in DNA methylation, a critical process for gene regulation. Additionally, there is mounting evidence that the expression of non-coding RNAs (ncRNAs) can be modulated by the intake of specific nutrients and natural compounds, thereby influencing processes involved in the onset and progression of metabolic diseases. Evidence suggests that dietary patterns, weight-loss interventions, nutrients and nutritional bioactive compounds can modulate the expression of various miRNAs and DNA methylation levels, contributing to development of metabolic disorders such as obesity and type 2 diabetes. Furthermore, several studies have proposed that DNA methylation and microRNA (miRNA) expression could serve as biomarkers for the effects of weight-loss programs. Despite ongoing debate regarding the effects of nutrient supplementation on DNA methylation levels and the expression of ncRNAs, certain DNA methylation marks and ncRNA expressions might predict the risk of metabolic disorders and act as biomarkers for forecasting the success of therapies within the framework of precision medicine and nutrition. The role of DNA methylation and miRNA expression as potential mediators of the effects of weight loss underscores their potential as biomarkers for the outcomes of weight loss programs. This highlights the influence of dietary patterns and weight-loss interventions on the regulation of miRNA expression and DNA methylation levels, suggesting an interaction between these epigenetic factors and the body's response to weight loss.

Antioxidants as adjuvant in cancer therapy: A systematic review

While cancer therapies can effectively remove malignant cells from the body, their efficacy is mostly limited to a number of harmful side effects. Antioxidant treatment is therefore frequently necessary to lessen these negative effects by lowering reactive species levels and minimizing chronic oxidative damage. Antioxidants have a crucial role in inhibiting the production of reactive nitrogen and oxygen species as well as their activities. Reviewing the role of antioxidants in the development or prevention of cancer was the goal of this study. It is thought that antioxidants can both prevent and treat different kinds of cancer. As of right now, cancer prevention and treatment have primarily involved consuming natural antioxidant substances. These are unquestionably cell-type- and Reactive Oxygen Species (ROS)-specific, as evidenced by alterations in gene expression, cellular activities, and mechanisms of cell death. By decreasing hydrogen donors or quenching singlet oxygen and postponing oxidative reactions in cancer cells that are actively developing, natural antioxidants eliminate an overabundance of free radical intermediates. The primary topics covered in this study are antioxidant categorization, metabolic regulation, and antioxidant involvement in cancer treatment.

Nephro- and Cardiotoxic Effects of Etoricoxib: Insights into Arachidonic Acid Metabolism and Beta-Adrenergic Receptor Expression in Experimental Mice.

Background: Etoricoxib is a widely used anti-inflammatory drug, but its safety profile concerning cardiovascular and renal health remains inadequately explored. This study aimed to assess the nephro- and cardiotoxic effects of etoricoxib in a murine model, with a focus on its impact on arachidonic acid-metabolizing enzymes and beta-adrenergic receptors associated with drug-induced toxicity. Methods: Thirty-five BALB/C mice were randomly assigned to five groups: control, low-dose etoricoxib, high-dose etoricoxib, low-dose celecoxib, and high-dose celecoxib (a well-known nephro- and cardiotoxic NSAID). The treatments were administered for 28 days, after which hearts and kidneys were excised for physical and histopathological analysis, and the expression of arachidonic acid-metabolizing enzymes (cytochrome P450s, lipoxygenases, cyclooxygenases) and beta-1 adrenergic receptor (adrb1) and angiotensin-converting enzyme (ace2) genes were quantified using quantitative reverse transcription PCR (qRT-PCR). Results: Etoricoxib administration resulted in dose-dependent nephro- and cardiotoxic effects. Renal histology revealed glomerular atrophy or hypertrophy and significant damage to the proximal and distal convoluted tubules, including epithelial flattening, cytoplasmic vacuolation, and luminal widening. Cardiac analysis showed disorganized muscle fibers and hyaline degeneration. These changes were associated with altered gene expression: the downregulation of cox2, cyp1a1, and cyp2c29 in the kidneys and the upregulation of cyp4a12, cox2, and adrb1, along with the downregulation of cyp2c29 and ace2 in the heart. Conclusions: Etoricoxib induces nephro- and cardiotoxicity, marked by alterations in arachidonic acid metabolism and beta-adrenergic signaling pathways. The drug affects the expression of arachidonic acid-metabolizing enzymes and adrb1 in the heart while downregulating cox2 and other related enzymes in the kidneys. These findings underscore the need for caution when prescribing etoricoxib, particularly in patients with pre-existing renal or cardiac conditions.

Cognitive impairments and neurobiological changes induced by unilateral vestibular dysfunction in mice

The vestibular system is essential for balance and spatial orientation, and its dysfunction can lead to cognitive deficits. This study investigates the effects of unilateral vestibular dysfunction (UVL) on cognitive function and the underlying neurobiological changes in mice. We established a unilateral labyrinthectomy (UL) model in mice and assessed cognitive function at 28 days post-surgery using a comprehensive battery of behavioral tests. We found significant impairments in spatial reference memory, working memory, and synaptic plasticity in UL mice, which persisted despite compensation for vestibular and postural motor deficits. Immunofluorescence staining revealed enhanced activation of c-Fos in the hippocampal dentate gyrus (DG) at various time points post-UL, suggesting a role of the hippocampus in cognitive deficits following UVL. RNA sequencing of the DG identified differentially expressed genes (DEGs) and altered pathways related to cognitive function, synaptic plasticity, and neuronal activation. Quantitative real-time PCR (qRT-PCR) validated the expression changes of selected genes. Our findings indicate that UVL leads to persistent cognitive impairments in mice, associated with altered neuronal activation and gene expression in the hippocampus. This study offers valuable insights into the neurobiological mechanisms underlying cognitive deficits associated with UVL. Moreover, it underscores the importance of early cognitive screening in patients with vestibular diseases, as this approach is instrumental in comprehensive condition assessment, precise diagnosis, targeted treatment, and effective rehabilitation.

Testosterone replacement has a beneficial effect on the hemostatic system by altered gene expression of coagulation factors

This study aimed to investigate the effects of testosterone replacement therapy on hemostasis and some procoagulant gene expression in mice. 42 mice were randomly divided into two groups of non-orchiectomized (non-ORX) and orchiectomized (ORX) with three subgroups (n = 7) each, were subcutaneously administered with sesame oil (control), 2 and 20 mg/kg/week testosterone enanthate. Orchiectomized mice were allowed to recover for one week before treatment. On the 7th week of treatment, blood samples were collected for coagulation parameters analysis and measurement of plasma testosterone levels. Moreover, quantitative real-time PCR analysis was performed on liver samples to assess the expression of factor IX, factor X, and prothrombin genes. The results showed that supraphysiological doses (20 mg/kg) of testosterone significantly increased plasma testosterone levels in all groups, while physiological doses (2 mg/kg) only increased testosterone levels in non-ORX animals. Although testosterone administration had no effect on prothrombin time (PT) and activated partial thromboplastin time (aPTT), supraphysiological doses reduced bleeding time and clotting time. Furthermore, platelet count increased in a dose-dependent manner with testosterone enanthate treatment. The expression of coagulation factors was also decreased with supraphysiological doses of testosterone. In conclusion, testosterone had significant effects on primary hemostasis and common coagulation pathway, including increased platelet number and aggregation, decreased clotting time, and altered gene expression of coagulation factors.

Alteration of the metabolite interconversion enzyme in sperm and Sertoli cell of non-obstructive azoospermia: a microarray data and in-silico analysis

Numerous variables that regulate the metabolism of Sertoli cells and sperm have been identified, one of which is sex steroid hormones. These hormones play a vital role in maintaining energy homeostasis, influencing the overall metabolic balance of the human body. The proper functioning of the reproductive system is closely linked to energy status, as the reproductive axis responds to metabolic signals. The aim of this study was to investigate the gene expression patterns of metabolite interconversion enzymes in testicular cells (Sertoli cells and spermatogonia) of non-obstructive azoospermia (NOA) patients, as compared to normal controls, to understand the molecular mechanisms contributing to NOA. We used microarray and bioinformatics techniques to analyze 2912 genes encoding metabolite interconversion enzymes, including methyltransferase, monooxygenase, transmembrane reductase, and phosphohydrolase, in both testicular cells and normal samples. In sperm, the upregulation of MOXD1, ACAD10, PCYT1A, ARG1, METTL6, GPLD1, MAOA, and CYP46A1 was observed, while ENTPD2, CPT1C, ADC, and CYB5B were downregulated. Similarly, in the Sertoli cells of three NOA patients, RPIA, PIK3C3, LYPLA2, CA11, MBOAT7, and HDHD2 were upregulated, while NAA25, MAN2A1, CYB561, PNPLA5, RRM2, and other genes were downregulated. Using STRING and Cytoscape, we predicted the functional and molecular interactions of these proteins and identified key hub genes. Pathway enrichment analysis highlighted significant roles for G1/S-specific transcription, pyruvate metabolism, and citric acid metabolism in sperm, and the p53 signaling pathway and folate metabolism in Sertoli cells. Additionally, Weighted Gene Co-expression Network Analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq) were performed to validate these findings, revealing significant alterations in gene expression and cellular distribution in NOA patients. Together, these results provide new insights into the molecular mechanisms underlying NOA and identify potential therapeutic targets.