Involvement Of Pathway Research Articles

Enhancing perceptual, attentional, and working memory demands through variable practice schedules: insights from high-density EEG multi-scale analyses.

Contextual interference (CI) enhances learning by practicing motor tasks in a random order rather than a blocked order. One hypothesis suggests that the benefits arise from enhanced early perceptual/attentional processes, while another posits that better learning is due to highly activated mnemonic processes. We used high-density electroencephalography in a multi-scale analysis approach, including topographic analyses, source estimations, and functional connectivity, to examine the intertwined dynamics of attentional and mnemonic processes within short time windows. We recorded scalp activity from 35 participants as they performed an aiming task at three different distances, under both random and blocked conditions using a crossover design. Our results showed that topographies associated with processes related to perception/attention (N1, P3a) and working memory (P3b) were more pronounced in the random condition. Source estimation analyses supported these findings, revealing greater involvement of the perceptual ventral pathway, anterior cingulate and parietal cortices, along with increased functional connectivity in ventral alpha and frontoparietal theta band networks during random practice. Our results suggest that CI is driven, in the random compared to the blocked condition, by enhanced specific processes such as perceptual, attentional, and working memory processes, as well as large-scale functional networks sustaining more general attentional and executive processes.

Targeting high-mobility-group-box-1-mediated inflammation: a promising therapeutic approach for myocardial infarction.

Myocardial ischemia, resulting from coronary artery blockage, precipitates cardiac arrhythmias, myocardial structural changes, and heart failure. The pathophysiology of MI is mainly based on inflammation and cell death, which are essential in aggravating myocardial ischemia and reperfusion injury. Emerging research highlights the functionality of high mobility group box-1, a non-histone nucleoprotein functioning as a chromosomal stabilizer and inflammatory mediator. HMGB1's release into the extracellular compartment during ischemia acts as damage-associated molecular pattern, triggering immune reaction by pattern recognition receptors and exacerbating tissue inflammation. Its involvement in signaling pathways like PI3K/Akt, TLR4/NF-κB, and RAGE/HMGB1 underscores its significance in promoting angiogenesis, apoptosis, and reducing inflammation, which is crucial for MI treatment strategies. This review highlights the complex function of HMGB1 in the pathogenesis of myocardial infarction by summarizing novel findings on the protein in ischemic situations. Understanding the mechanisms underlying HMGB1 could widen the way to specific treatments that minimize the severity of MI and enhance patient outcomes.

Role of Phenylpropanoid Pathway in Genetic Regulation and Physiological Adaptation in Arsenic Stressed Rice Genotypes

This study investigates the role of the phenylpropanoid pathway in arsenic (As) contaminated rice genotypes under natural conditions, exploring the intricate relationship between genetic regulation and physiological adaptation. Differential approaches adapted by rice genotypes to counteract As exposure are elucidated here through analysis of enzyme activities and related gene expression patterns, docking simulations, and nutrient dynamics. Enzymatic analysis from the phenylpropanoid pathway revealed significant variations across rice genotypes, with Mini mansoori exhibiting notably higher activity levels of key enzymes (PAL, C4H, 4CL, CHI, DFR and F3H) compared to Sampoorna and Pioneer. Additionally, the gene expression profiling unveiled differential responses, with Mini mansoori and Pioneer demonstrating higher expression of genes (OsPAL, OsCHS, OsCHI, OsF3H, OsF3'H, OsFLS, OsDFR, and OsLAR) associated with As resistance and tolerance, compared to Sampoorna. Enrichment analysis emphasized the involvement of cinnamic acid biosynthesis and related pathways. Molecular docking depicted certain proteins, such as Os4CL, OsFLS, OsDFR, and OsLAR susceptible to As binding, potentially affecting enzymatic activity. Ionomic analysis unveiled that Mini mansoori maintained higher levels of essential nutrients such as Na, Ca, P, Mn, Mg, and Zn in grains. However, this contrasted with Pioneer and Sampoorna, which experienced nutrient imbalance likely due to higher As accumulation. Chlorophyll fluorescence analysis depicted that Mini mansoori and Pioneer maintained better photosynthetic efficiency under As toxicity compared to Sampoorna. Moreover, network analysis highlights the critical role of Mg and Na interaction with essential phenolics and flavonoids, in combating the stress. Harnessing this understanding, targeted breeding effort could yield As-resistant rice varieties with enhanced nutrient and flavonoid contents, addressing both food safety and malnutrition in affected regions.

Tanshinone IIA potentiates the therapeutic efficacy of glucocorticoids in lipopolysaccharide-treated HEI-OC1 cells through modulation of the FOXP3/Nrf2 signaling pathway.

Glucocorticoids (GCs) are commonly used to treat sudden sensorineural hearing loss (SSNHL), although some patients are resistant to this therapeutic approach. Clinical studies have demonstrated the efficacy of tanshinone IIA (TA) in combination with GC for managing various human ailments. However, it remains unclear whether TA can mitigate GC resistance in SSNHL. Our aim is to elucidate the role of NRF2-induced transcriptional regulation of HDAC2 in influencing GC resistance and investigate the involvement of TA-related molecular pathways in GC resistance. Here, HEI-OC1 cells are treated with lipopolysaccharide (LPS) to establish an in vitro model for SSNHL. The cells are subsequently treated with dexamethasone (DXE) or DXE+TA. RT-qPCR and western blot analysis are used to measure the mRNA and protein levels of Forkhead box P3 (FOXP3), nuclear factor erythroid 2-related factor 2 (NRF2), and histone deacetylase 2 (HDAC2). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays are carried out to assess cell proliferation. Flow cytometry analysis is performed to evaluate apoptosis. Mechanistic studies involve chromatin immunoprecipitation (ChIP), luciferase reporter, and DNA pull-down assays. Our results show that treatment with TA+DEX significantly increases proliferation and suppresses apoptosis in LPS-treated HEI-treated OC1 cells. TA upregulates HDAC2 expression by activating NRF2-mediated transcription of HDAC2, with the NRF2-HDAC2 binding site located at bases 419-429 (ATGACACTCCA) in the promoter sequence of HDAC2. Furthermore, TA upregulates FOXP3 expression to activate NRF2 transcription, with the predicted FOXP3-binding site located at bases 864-870 (GCAAACA) in the promoter sequence of NRF2. In summary, these findings suggest that TA enhances the therapeutic effects of GC on the proliferation and apoptosis of HEI OC1 cells by increasing FOXP3/Nrf2 expression. These results indicate that TA may be promising for ameliorating GC resistance in patients with SSNHL.

Vitamin C Alleviates Heat-Stress-Induced Damages in Pig Thoracic Vertebral Chondrocytes via the Ubiquitin-Mediated Proteolysis Pathway

Heat stress can impair organismal growth by inducing ubiquitination, proteasome-mediated degradation, and subsequent cellular damage. Vitamin C (VC) has been shown to potentially mitigate the detrimental effects of abiotic stresses on cells. Nevertheless, the impact of heat stress on growth plate chondrocytes remains unclear, and the underlying protective mechanisms of VC in these cells warrant further investigation. In this study, we focused on pig thoracic vertebral chondrocytes (PTVCs) that are crucial for promoting the body’s longitudinal elongation and treated them with 41 °C heat stress for 24 h, under varying concentrations of VC. Our findings reveal that, while oxidative stress induced by heat triggers apoptosis and inhibits the ubiquitin-mediated proteolysis pathway, the addition of VC alleviates heat-stress-induced oxidative stress and apoptosis, mitigates cell cycle arrest, and promotes cellular viability. Furthermore, we demonstrate that VC enhances the ubiquitin-proteasome proteolysis pathway by promoting the expression of ubiquitin protein ligase E3A, which thereby stabilizes the ubiquitin-mediated degradation machinery, alleviates the apoptosis, and enhances cell proliferation. Our results suggest the involvement of the ubiquitin-mediated proteolysis pathway in the effects of VC on PTVCs under heat stress, and offer a potential strategy to make use of VC to ensure the skeletal growth of animals under high temperature pressures in summer or in tropical regions.

Trifolin Attenuates Hypertension-Mediated Cardiac Injury by Inhibiting Cardiomyocyte Apoptosis: Mechanistic Insights and Therapeutic Potential

BackgroundHypertension-induced cardiac disease is a common complication and a significant contributor to mortality in hypertensive patients, largely due to cardiomyocyte apoptosis. Although Trifolin has been identified as a potential antihypertensive compound, its therapeutic role in hypertension-induced cardiac injury remains uncertain. PurposeThis study aims to evaluate the protective effects of Trifolin and explore the underlying mechanisms of its action against hypertension-induced cardiac injury. MethodsIn vivo, mice were infused with Angiotensin II (AngII, 500 ng/kg/min) or saline via osmotic pumps and treated with Trifolin (0.1, 1.0, or 10.0 mg/kg/day) or Valsartan (10 mg/kg/day) for four weeks. In vitro, H9C2 cells were stimulated with AngII (1 μM) and treated with Trifolin (25, 50, or 100 μM). Various assays, including echocardiography, hematoxylin and eosin staining, TUNEL assay, Annexin-V/propidium iodide staining, and JC-1 staining, were used to assess Trifolin's therapeutic effects on hypertension-related cardiac injury and cardiomyocyte apoptosis. Potential pharmacological mechanisms were analyzed through network pharmacology and confirmed via Western blotting. ResultsTrifolin treatment improved cardiac function by increasing left ventricular ejection fraction and fractional shortening while reducing tissue disorganization in AngII-treated mice. It also reduced cardiomyocyte apoptosis, reversing the upregulation of Bax and cleaved caspase-3 and the downregulation of Bcl-2. Network pharmacology identified 314 common targets of Trifolin linked to hypertensive heart disease, with involvement in apoptosis, MAPK, PI3K/AKT, and HIF-1 signaling pathways. Trifolin treatment increased p-PI3K/PI3K and p-AKT/AKT ratios while decreasing p-ERK/ERK, p-p38 MAPK/p38 MAPK, and p-JNK/JNK ratios in both mouse and cell models. ConclusionTrifolin alleviates AngII-induced cardiac injury and cardiomyocyte apoptosis, potentially through the regulation of MAPK, PI3K/AKT, and HIF-1 signaling pathways.

Taohe Chengqi decoction improves diabetic cognitive dysfunction by alleviating neural stem cell senescence through HIF1α-driven metabolic signaling

ObjectiveType 2 diabetes mellitus (T2DM) is characterized by numerous long-term complications, in which progressive cognitive decline represents a significant risk factor for dementia and other neurodegenerative disorders. Taohe Chengqi decoction (THCQ) is a common traditional Chinese formula for treating T2DM; however, the neuroprotective effect of THCQ on diabetes-associated cognitive dysfunction remains unclear. Hence, the present study investigated the therapeutic effects of THCQ on cognitive impairment associated with T2DM and elucidated the underlying mechanisms. MethodsA stable high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM mouse model was established and received intragastrical THCQ administration. Blood and tissue samples were investigated for biochemical parameters and neuropathology, whereas hippocampal tissue underwent transcriptome analyses and the role of neural stem cell (NSC) senescence was detected both in vivo and in vitro. Network pharmacology analysis and subsequent primary NSC experiments were conducted to explore the involvement of the HIF1α signaling pathway in THCQ-mediated hippocampal NSC senescence. Furthermore, a lentivirus vector overexpressing HIF1α was used to verify the THCQ potential therapeutic effects on HIF1α/PDKs metabolic signaling that influenced NSC senescence. ResultsTHCQ alleviated cognitive dysfunction and metabolic abnormalities in HFD/STZ mice, and relieved hippocampal neurodegeneration. Transcriptome analyses and validation experiments revealed THCQ-induced neuroprotective effects by targeting high glucose-mediated hippocampal neuropathy and NSC senescence. Bioinformatic analysis indicated that HIF1α signaling played a significant role in THCQ therapeutic outcomes; while HIF1α overexpression impaired the effects of THCQ on high glucose-induced metabolic disorders and NSC senescence. ConclusionThe present study demonstrated that THCQ improved diabetic cognitive dysfunction and hippocampal neurogenesis, the effects of which were mainly attributed to the restoration of metabolic homeostasis and inhibition of NSC senescence through HIF1α signaling. Our results provide novel insights into the therapeutic framework for diabetic neuropathy and indicate that THCQ might be a promising candidate for the management of T2DM-related cognitive disorders.

Inflammatory and cardiac biomarkers in pulmonary arterial hypertension: The prognostic role of IL-34

BackgroundPulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery pressure with significant morbidity and mortality. Inflammatory processes are crucial in PAH pathogenesis, with inflammatory cells and mediators present early in disease progression. IL-34 involvement in inflammatory pathways suggests that IL-34 could be an important player in the progression of PAH, influencing both pulmonary pressures and vascular changes. ObjectiveThe purpose of this study was to investigate the correlation between IL-34 levels and pulmonary arterial hypertension (PAH), aiming to enhance the understanding of the molecular mechanisms underlying PAH and explore IL-34′s potential as a biomarker. MethodsConsecutive PAH patients diagnosed via right-heart catheterization at Malatya Turgut Ozal Eğitim ve Araştırma Hastanesi (Dec 2022 - Apr 2024) were enrolled. Patients were classified into low-risk and high-risk groups based on comprehensive risk assessments that included clinical parameters, hemodynamic measurements and biomarkers, in-line with ESC/ERS guidelines. Serum IL-34, hs-CRP, and NT-proBNP levels were measured and compared with those of healthy controls. Echocardiographic assessments and statistical analyses, including ROC analysis, were conducted to evaluate biomarker significance and predictive capabilities. ResultsThe mean age of low-risk and high-risk PAH patients was 42 ± 7.2 years and 45 ± 5.5 years, respectively. The mean age of the control group was 40 ± 6.4 years. Males comprised 54.29 % of the low-risk group, 56 % of the high-risk group, and 53.3 % of the control group. IL-34 and hs-CRP levels were significantly elevated in PAH patients compared to controls. IL-34 correlated positively with systolic pulmonary artery pressure, RA area, and NT-proBNP levels. Multivariate analysis revealed that IL-34 and hs-CRP were independent predictors of PAH. IL-34 levels>29.8 pg/mL predicted PAH with 78 % sensitivity and 69 % specificity, while levels >44.4 pg/mL predicted high-risk PAH with 84 % sensitivity and 77 % specificity. ConclusionElevated IL-34 and hs-CRP levels are associated with PAH severity and right ventricular dysfunction, suggesting IL-34′s potential as a diagnostic and prognostic biomarker. Further research is needed to validate these findings and explore IL-34-targeted therapies in pH management.

Downregulation of CTRP1 Reduces Radio-resistance in Glioblastoma Cells by Inhibiting the Expression of CD133 after X-ray and Carbon Ion Irradiation

Glioblastomas (GBMs), the most prevalent primary malignant brain tumors, present significant challenges due to their invasive nature, high recurrence rates, and limited treatment options. Radiotherapy is a cornerstone in the management of GBMs; however, resistance to treatment poses a substantial obstacle. This study investigates the role of adipokine C1q/TNF-related protein 1 (CTRP1) in the radio-sensitivity of GBMs, utilizing both X-ray and carbon ion irradiation. Expression analyses revealed elevated CTRP1 and CD133 levels in GBMs tissues, which were associated with poor patient survival. Carbon ion irradiation demonstrated superior growth inhibition compared to X-ray, particularly in U87 (high CD133) cells. Moreover, CTRP1 expression increased following radiation exposure, especially after X-ray treatment. Knockdown of CTRP1 enhanced radio-sensitivity by reducing cell proliferation and increasing apoptosis, while exacerbating oxidative stress. Bioinformatics analysis revealed CTRP1's involvement in DNA damage repair pathways. Our findings establish a novel connection between CTRP1 and cellular radio-sensitivity. Targeting CTRP1, especially in U87 (high CD133) cells, enhances GBMs radio-sensitivity, offering potential therapeutic avenues.

Airway epithelial cells promote in vitro airway smooth muscle cell proliferation by activating the Wnt/β-catenin pathway

Asthma is a common chronic inflammatory airway disease, imposing a substantial health and economic burden on society and individuals. Current treatments primarily focus on symptom relief and lung function improvement, often failing to address the underlying pathology. Thus, exploring new therapeutic approaches is crucial. Airway smooth muscle cells (ASMCs) play a key role in regulating airway tone and airflow, while abnormal ASMCs proliferation contributes to airway remodeling in asthma. Airway epithelial cells (AECs), serving as the first barrier against pathogens and allergens, also have critical immune functions.This study focuses on the interaction between AECs and ASMCs, as AECs are more accessible for drug delivery due to their location at the airway surface. Investigating this relationship could facilitate novel interventions targeting AECs to inhibit pathological ASMCs activity. In our experiment, we isolated ASMCs and AECs from healthy mice and found that AECs significantly promoted ASMCs proliferation in co-culture. RNA sequencing revealed that this process might be linked to the activation of the canonical Wnt signaling pathway in ASMCs. By using Wnt pathway inhibitors (endo-IWR1) and siRNA to disrupt Wnt receptors, we reversed this phenotype. This finding suggests that AECs may promote ASMCsproliferation by activating the Wnt pathway in ASMCs. The Wnt/β-catenin pathway appears to play an important role in ASMCs proliferation, indicating that future pathological studies should consider the potential involvement of the Wnt pathway in airway remodeling.

Neurocognitive impairments in rat offspring after maternal exposure to Vortioxetine: Involvement of BDNF, apoptosis and cholinergic mediated signaling pathways

Neurocognitive impairments in rat offspring after maternal exposure to Vortioxetine: Involvement of BDNF, apoptosis and cholinergic mediated signaling pathways

Siling Decoction Ameliorates Adenine-Induced Renal Fibrosis in Rats by the AKT/IKKβ/NFκB Signaling Pathway

ObjectiveInvestigating how Siling decoction (SLD) mitigates fibrosis in rats with chronic kidney disease CKD (chronic kidney disease) through network pharmacology analysis and experimental verification. MethodsInitially, the primary active components and their target actions of SLD (Fuling, Zhuling, Zexie, and Baizhu) were identified by the TCMSP database and liquid chromatography mass spectrometry (LC-MS). Treatment targets for renal fibrosis were screened through databases such as GeneCard, OMIM, PharmGkb, and GEO. Subsequently, a drug-disease-target network was constructed and subjected to PPI analysis. Intersecting targets underwent GO and KEGG pathway enrichment analyses. Renal fibrosis model was induced by adenine gavage, then treat with SLD. Masson, Sirius red, immunohistochemistry, and Western blot were used to detect renal function and fibrosis-related indicators. The mechanism was further validated in vitro experiments. ResultsNetwork pharmacology analysis identified 100 common targets associated with the active components of SLD, including core genes such as AKT1 and CCND1. GO enrichment analysis revealed that the top three biological processes impacted include response to xenobiotic stimulus, response to nutrient levels and response to oxidative stress. These processes involved cellular components such as membrane raft, membrane microdomain and synaptic membrane, with molecular functions predominantly associated with ubiquitin-like protein ligase binding, ubiquitin protein ligase binding, DNA-binding transcription factor binding, and RNA polymerase II-specific DNA binding transcription factor binding. KEGG pathway enrichment analysis indicated potential involvement of pathways like Lipid and atherosclerosis, PI3K-AKT signaling pathway, and prostate cancer are likely involved in the anti-fibrotic effect of SLD. Notably, the highlighted was the AKT/IKKβ/NFκB signaling pathway as a key mechanism. These findings were further confirmed in vivo and in vitro. ConclusionThe SLD effectively ameliorates adenine-induced chronic kidney disease fibrosis in rats, potentially by inhibiting the AKT/IKKβ/NFκB signaling pathway.

Unveiling the Complexities: Exploring Mechanisms of Anthracycline-Induced Cardiotoxicity.

The coexistence of cancer and heart disease, both prominent causes of illness and death, is further exacerbated by the detrimental impact of chemotherapy. Anthracycline-induced cardiotoxicity is an unfortunate side effect of highly effective therapy in treating different types of cancer; it presents a significant challenge for both clinicians and patients due to the considerable risk of cardiotoxicity. Despite significant progress in understanding these mechanisms, challenges persist in identifying effective preventive and therapeutic strategies, rendering it a subject of continued research even after three decades of intensive global investigation. The molecular targets and signaling pathways explored provide insights for developing targeted therapies, emphasizing the need for continued research to bridge the gap between preclinical understanding and clinical applications. This review provides a comprehensive exploration of the intricate mechanisms underlying anthracycline-induced cardiotoxicity, elucidating the interplay of various signaling pathways leading to adverse cellular events, including cardiotoxicity and death. It highlights the extensive involvement of pathways associated with oxidative stress, inflammation, apoptosis, and cellular stress responses, offering insights into potential and unexplored targets for therapeutic intervention in mitigating anthracycline-induced cardiac complications. A comprehensive understanding of the interplay between anthracyclines and these complexes signaling pathways is crucial for developing strategies to prevent or mitigate the associated cardiotoxicity. Further research is needed to outline the specific contributions of these pathways and identify potential therapeutic targets to improve the safety and efficacy of anthracycline-based cancer treatment. Ultimately, advancements in understanding anthracycline-induced cardiotoxicity mechanisms will facilitate the development of more efficacious preventive and treatment approaches, thereby improving outcomes for cancer patients undergoing anthracycline-based chemotherapy.

Pathogenesis of psoriatic arthritis: new insights from a bone marrow perspective.

Psoriatic arthritis is an immune-mediated disease that primarily affects the skin and joints. It falls under the umbrella term of rheumatic diseases, which describes a group of closely related yet distinct disorders with many common underlying molecular pathways. Despite the distinct clinical manifestation of each disorder, the shared therapeutic strategies attest to the commonality of cellular and molecular underpinnings. Herein we provide a concise yet comprehensive overview of the interleukin (IL)-23/IL-17 axis and its involvement in mechanistic pathways leading to the pathogenesis of this dual skin and joint clinical manifestation which is characteristic of psoriatic arthritis and other rheumatic diseases. The interconnection between activated innate immune cells and adaptive immunity has transformed current thinking to include other organs such as the bone marrow as potential tissue of disease origin. A plethora of animal models and genetic studies converge on the critical role of IL-23/IL-17 axis, and highlight the importance of myeloid cell activation as common pathways between autoinflammatory and autoimmune diseases and chronic inflammation. These findings underscore the intricate immune mechanisms involved in inflammatory arthritis and highlight molecular mechanisms in disease pathogenesis. These insights pave the way for the development of novel diagnostic and therapeutic strategies, with a focus on translating these findings into improved clinical practice.

Being associated with multiple diseases, CD79a, as a B-cell marker plays an important role in disease treatment and prognosis

CD79a, a membrane glycoprotein critical for B-cell receptor (BCR) signaling, plays a vital role in B-cell development and immune responses. It serves as a marker for normal and tumor B-cells and is implicated in the progression of various diseases, including B-cell lymphomas, leukemia, autoimmune disorders, and other systemic diseases such as neurological, hematological, and respiratory disorders. This review provides a comprehensive analysis of the discovery, molecular structure, and function of CD79a, along with its regulatory mechanisms at the transcriptional and post-translational levels. CD79a’s involvement in signaling pathways and its potential as a therapeutic target for novel treatments, such as chimeric antigen receptor-T (CAR-T) cell therapy and bispecific antibodies, are also explored. The review highlights emerging therapeutic strategies targeting CD79a, emphasizing its significance in the prognosis of CD79a-related diseases and the ongoing need for further research to optimize clinical interventions.

Targeting Wnt Pathways with Small Molecules as New Approach in Cardiovascular Disease.

The increasing incidences of morbidity and mortality associated with cardiovascular diseases represent significant difficulties for clinical treatment and have a major impact on patient health. Wnt signaling pathways are highly conserved and are well known for their regulatory roles in embryonic development, tissue regeneration, and adult tissue homeostasis. Wnt signaling is classified into two distinct pathways: canonical Wnt/β-catenin signaling and noncanonical pathways, including planar cell polarity and Wnt/Ca2+ pathways. A growing body of experimental evidence suggests the involvement of both canonical and non-canonical Wnt signaling pathways in the development of cardiovascular diseases, including myocardial hypertrophy, arrhythmias, diabetic cardiomyopathy, arrhythmogenic cardiomyopathy, and myocardial infarction. Thus, to enhance patient quality of life, diagnosing and treating cardiac illnesses may require a thorough understanding of the molecular functions played by the Wnt pathway in these disorders. Many small-molecule inhibitors specifically target various components within the Wnt signaling pathways, such as Frizzled, Disheveled, Porcupine, and Tankyrase. This study aims to present an overview of the latest findings regarding the functions of Wnt signaling in human cardiac disorders and possible inhibitors of Wnt, which could lead to novel approaches for treating cardiac ailments.

Bromodomain and extraterminal domain (BET) promote autophagy in buffalo sertoli cells

Sertoli cells (SCs) play a pivotal role in spermatogenesis, with autophagy modulation being an evolutionarily conserved mechanism for maintaining cellular homeostasis and protecting spermatogenic cells against apoptosis. The bromodomain and extraterminal domain (BET) family are transcriptional regulators of autophagy. This study investigated the relationship between BET inhibition and autophagy in buffalo SCs. Our findings reveal that BET inhibition suppresses cell proliferation and alters the biological characteristics of SCs. RNA-seq analysis demonstrated significant downregulation of autophagy-related genes upon BET inhibition. Moreover, our bioinformatics analysis suggested the involvement of the PI3K-AKT signaling pathway in autophagy regulation within buffalo SCs. Immunofluorescence and Transmission electron microscopy observations indicated that BET inhibition results in autophagosome accumulation and impedes autophagosome-lysosome degradation, thereby compromising autophagy activity and flux. In summary, this study sheds light on the indispensable role of BET proteins in autophagy and paves the way for further investigations into the mechanisms governing BET protein-mediated autophagy regulation and its implications for male reproduction.

The pertinence of resistin gene single nucleotide polymorphism G > A and its expression in oral cancer

Background/aimOral cancer (OC) is the leading cause of fatalities in Pakistan among males due to inadequate oral hygiene and chewing habits. However, genetic susceptibility patterns also play a critical role in disease progression. Since the frequency of Resistin (RETN) SNP (Single nucleotide polymorphism) rs3219175 is unknown; there is a requirement for early diagnosis of the OC. Therefore, the current study aims to determine the frequency of targeted SNP and develop a safe, simple, and fast alternative technique for better treatment using a real-time PCR assay with HRM (high-resolution melting curve) analysis. Materials and methodsA case-control study was conducted on 35 Oral squamous cell carcinomas (OSCC) diagnosed patients and 35 healthy individuals. HRM and RT-PCR results were analysed by the bioinformatics analyses. ResultsThe frequency of RETN SNP rs3219175 genotypes GG and GA in male patients was 16 (46 %) and 5 (14 %) respectively and in females 8 (23 %) and 6 (17 %) respectively. The chi-square test of independence consummated the assessment between males and females in both control and patients. The relation between these variables was significant (p < 0.05). The interaction network of String 8.3 demonstrates strong interactions at a high confidence score, which helps to characterize functional disorders that may be a causative factor for oral pathology. Reactome and KEGG data were acquired to rule out the pathway involvement of the targeted gene. MuPIT software was used to identify the 3D structure or RETN and their expected mutation effect. ConclusionThis study provides baseline data regarding the frequency of RETN SNP rs3219175 among the Pakistani population. For further clarification of their stage in cancer emergence and growth, large-scale studies must be conducted. This study might be helpful in the precision medicine approach and provide better therapeutic for OSCC patients.

The peritumoral edema index and related mechanisms influence the prognosis of GBM patients.

Peritumoral brain edema (PTBE) represents a characteristic phenotype of intracranial gliomas. However, there is a lack of consensus regarding the prognosis and mechanism of PTBE. In this study, clinical imaging data, along with publicly available imaging data, were utilized to assess the prognosis of PTBE in glioblastoma (GBM) patients, and the associated mechanisms were preliminarily analyzed. We investigated relevant imaging features, including edema, in GBM patients using ITK-SNAP imaging segmentation software. Risk factors affecting progression-free survival (PFS) and overall survival (OS) were assessed using a Cox proportional hazard regression model. In addition, the impact of PTBE on PFS and OS was analyzed in clinical GBM patients using the Kaplan-Meier survival analysis method, and the results further validated by combining data from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). Finally, functional enrichment analysis based on TCIA and TCGA datasets identified several pathways potentially involved in the mechanism of edema formation. This study included a total of 32 clinical GBM patients and 132 GBM patients from public databases. Univariate and multivariate analyses indicated that age and edema index (EI) are independent risk factors for PFS, but not for OS. Kaplan-Meier curves revealed consistent survival analysis results between IE groups among both clinical patients and TCIA and TCGA patients, suggesting a significant effect of PTBE on PFS but not on OS. Furthermore, functional enrichment analysis predicted the involvement of several pathways related mainly to cellular bioenergetics and vasculogenic processes in the mechanism of PTBE formation. While these novel results warrant confirmation in a larger patient cohort, they support good prognostic value for PTBE assessment in GBM. Our results indicate that a low EI positively impacts disease control in GBM patients, but this does not entirely translate into an improvement in OS. Multiple genes, signaling pathways, and biological processes may contribute to the formation of peritumoral edema in GBM through cytotoxic and vascular mechanisms.

The effect of CD38 inhibition in age-associated vascular dysfunction

Abstract Introduction Aging is characterized by age-related vascular dysfunction, mainly caused by endothelial dysfunction and arterial stiffness. Levels of nicotinamide adenine dinucleotide (NAD) decrease with aging and accordingly, NAD is thought to be involved in the progression of age-related vascular dysfunction. Recent studies reported the involvement of CD38 in NAD regulation; indeed, its inhibition significantly prolongs the lifespan of progeroid and aged mice. However, whether CD38 is involved in the progression of age-related vascular dysfunction remains to be investigated. Methods CD38 expression was investigated in aortic homogenates of young (12-16 weeks) and aged (18-24 months) C57BL/6 wild-type mice, as well as in vitro in young (passage 5-7) and senescent (passage 14-15) primary human aortic endothelial cells (HAECs). Ex vivo tension myograph experiments were performed on thoracic aortas isolated from aged C57BL/6 mice (22-24 months old) pre-incubated for 1 hour with CD38-specific inhibitor, 78c, or DMSO as control. The effect of CD38 inhibition was also observed in vitro in senescent HAECs. Results A significant upregulation of CD38 expression was detected in the aortas of aged mice compared to the young ones as well as in senescent HAECs compared to young cells. Ex vivo tension myograph experiments showed a significant increase in endothelium-dependent relaxation responses to acetylcholine upon CD38 inhibition. The improvement of endothelial function was prevented by the addition of endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME), but not by the COXs inhibitor, indomethacin, indicating that the observed effect achieved by CD38 inhibition is eNOS dependent. The involvement of the eNOS pathway was further supported by the in vitro finding in HAECs of increased eNOS activation upon CD38 inhibition. Conclusion The herein-reported data suggests an involvement of CD38 in the development of age-related endothelial dysfunction. Further studies are ongoing to investigate the underlying molecular mechanisms as well as the effect of long-term CD38 inhibitor supplementation on the progression of age-related vascular dysfunction.