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To investigate the role of BDNF/TrkB signaling in Central Post-Stroke Pain (CPSP) and to investigate whether this signaling is related to the analgesic effect of optogenetics. This study was conducted in two parts. First, 40 rats were acquired and randomly divided into four groups: Sham, CPSP, CPSP + ANA-12 (inhibitor of the BDNF/TrkB signaling pathway), and CPSP + 1% DMSO. The Sham group received a saline injection into the Ventral Posterolateral Nucleus of the Thalamus (VPL), whereas the other three groups were injected with type IV collagenase. Additionally, the two groups of CPSP rats were separately injected with ANA-12 or 1% DMSO in the VPL. Second, 50 rats were acquired and randomly divided into five groups: Sham, CPSP, CPSP + NpHR, CPSP + NpHR + BDNF, and CPSP + NpHR + PBS. From day 3 after collagenase injection, rats in the three NpHR groups received yellow laser stimulation at a wavelength of 589 nm six times a day for 12 consecutive days. Subsequently, two groups of stimulated rats were separately injected with BDNF or PBS in the VPL. Optogenetic therapy effectiveness and potential mechanisms were evaluated using pain threshold tests and molecular biology, among other methods. According to the pain threshold test results, optogenetic therapy and ANA-12 injection reversed aberrant CPSP while downregulating BDNF and TrkB. Conversely, exogenous BDNF injection reversed the therapeutic effect of optogenetics on pain. The BDNF/TrkB signaling pathway in the ascending pain modulation system may crucially modulate CPSP in rats. Furthermore, optogenetic therapy could suppress BDNF/TrkB signaling in the ascending pain modulation system, potentially alleviating thalamic hemorrhage-induced Neuropathic Pain (NP). Show less

Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.). Show less

The internal milieu of the body is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. Guided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signaling pathways involved in arterial chemosensory function. Here, we report the presence of the MC4R (melanocortin 4 receptor) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (mammalian achaete-scute homolog 1; Collectively, our data indicate a primarily pathophysiological role of melanocortin signaling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease. Show less

Phosgene, used in large-scale industrial production, is highly toxic and irritant. Accidental exposure can lead to varying degrees of injuries, with severe cases potentially resulting in acute lung injury or acute respiratory distress syndrome, resulting in a mortality rate of 40%-50%. The indirect damages of phosgene (inflammation and oxidative stress) are considered important factors in phosgene-induced acute lung injury (P-ALI). The expression of Liver X Receptor α (LXRα) significantly reduces during periods of inflammation. LXRs were initially discovered to be highly expressed in the liver, whereas LXRs are expressed in immune cells and vascular endothelial cells, playing a significant role in anti-inflammatory and antioxidant responses. LXRα may have pulmonary protection in P-ALI. However, evidence to verify this association is still lacking. In this study, rats were divided into six groups to explore the potential role of LXRα in P-ALI. This study found that GW3965 effectively activated LXRα, upregulated its expression and downregulated the levels of proinflammatory cytokines, inhibited malondialdehyde activity while enhancing superoxide dismutase activity, suppressed apoptosis and ameliorated the pathological processes of P-ALI, ultimately exerting pulmonary protection in P-ALI. Further validation revealed that the pulmonary protective effect of LXRα may be associated with the PI3K/Akt and NF-kB signalling pathways. Show less

HNSCC is a highly aggressive cancer of the head and neck region, and there is an urgent need to find novel potential targets for its diagnosis and treatment. Long non-coding RNAs (lncRNAs) have emerged as important therapeutic and diagnostic targets for multiple cancers, including HNSCC. LINC01518 promotes the proliferation of oesophageal cancer cells, but the involvement of LINC01518 in HNSCC pathophysiology is unknown. We show that LINC01518 expression is significantly upregulated in high-grade HNSCC tumor samples in comparison to normal tissue, and transforming growth factor- β (TGF-β) promotes LINC01518 expression in HNSCC cell lines. Loss-of-function studies suggest that LINC01518 promotes cell proliferation, migration, and invasion in HNSCC cells. In addition, LINC01518 depletion sensitizes HNSCC cells to cisplatin-mediated apoptosis. Mechanistically, LINC01518 acts as a competitive endogenous RNA and binds to miR-1-3p and miR-216b-5p, resulting in up-regulation of their target genes Slug and GRP78, respectively. Our findings suggest that LINC01518 is an attractive therapeutic target for HNSCC. Show less

Gastric cancer is aggressive with poor prognosis due to high invasion and metastasis rates, a hallmark of cancer. The Snail family (SNAI1 and SNAI2) drives EMT, enabling epithelial cells to gain migratory and invasive traits. We used "limma" package to identify genes with differential expression between high and low levels of SNAI1/SNAI2 in TCGA stomach adenocarcinoma dataset, intersecting these with cancer invasion and metastasis genes obtained from 5 databases. Using Cox regression analysis, we developed a risk score model and created a nomogram incorporating clinical data. The model's prognostic accuracy was validated with survival and ROC analyses in both TCGA and GEO datasets. Additionally, we performed WGCNA and constructed a ceRNA network to investigate gene interactions, and used CIBERSORT analysis to evaluate immune cell composition in the tumor microenvironment. We developed 5 and 9 risk signatures and nomograms incorporating clinical data. Survival analysis showed high-risk patients had worse overall survival than low-risk patients. WGCNA identified a lightyellow module associated with SNAI1 and SNAI2 expressions, emphasizing extracellular matrix organization. CeRNA network analyses found 6 common hub genes linked to SNAI1 and SNAI2. Immune profiling showed that SNAI1 expression was related to 8 types of immune cells, while SNAI2 was connected to 6, indicating their roles in influencing the tumor microenvironment. This study highlights the significant prognostic impact of SNAI1 and SNAI2 in stomach adenocarcinoma, linking their high expression to poorer survival and aggressive tumor behavior, while also identifying potential therapeutic targets through comprehensive computational analysis. Show less

Epithelial protein lost in neoplasm (EPLIN), an actin-binding protein, has been described as both a tumor promoter and tumor suppressor in different cancers. The roles of EPLIN isoforms (α/β) remain largely unknown and could explain these opposing views. We observed distinct EPLIN isoform localization in breast cancer cells; EPLINα is recruited to actin in plasma membrane ruffles and endosomes, while EPLINβ resides on stress fibers. EPLINα localizes to early endosomes in an actin-dependent manner, where it interacts with Rab21, an established regulator of β1-integrin endosomal trafficking. This supports β1-integrin recycling and cell migration. Using proximity biotinylation (BioID), we identified coronin 1C as an EPLIN-proximal protein, which also localizes at Rab21-containing endosomes and controls integrin recycling downstream of EPLINα. EPLINα expression was linked to increased breast cancer cell motility, and a high EPLINα-to-EPLINβ ratio correlated with a mesenchymal phenotype in patient samples. Our work identifies previously unknown EPLIN-isoform-specific functions relevant to breast cancer and beyond. Show less

HUWE1, a member of HECT E3 ubiquitin ligase family, is implicated in a variety of cellular processes. Recent studies find that HUWE1 also plays critical roles in germ cell development and inactivation of HUWE1 causes germ cell loss in both male and female mice. In this study, we found that Huwe1 was also highly expressed in testicular Sertoli cells. Inactivation of Huwe1 in Sertoli cells resulted in loss of cell polarity, which in turn caused germ cells loss and male infertility. Further study revealed that dysregulation in the expression of cytoskeletal and adhesion-related molecules, as well as a significant increase in EMT-related trans-factors SNAI1&2 in Huwe1-deficient Sertoli cells. Intriguingly, the protein level of WT1 was significantly increased in Huwe1-deficient Sertoli cells, and overexpression of Wt1 in Sertoli cells also caused the defects in spermatogenesis which was consistent with Huwe1 CKO mouse model. Furthermore, the defect of spermatogenesis in Huwe1 CKO mice was partially rescued by deleting one allele of Wt1 gene. Mechanistic studies revealed that WT1 interacts with HUWE1 protein and it could be ubiquitinated by HUWE1. Our study demonstrates that HUWE1 is involved in the establishment of Sertoli cell polarity mainly by regulating the protein level of WT1 gene. Show less

Clinically, Alzheimer's disease (AD) is characterized by progressive cognitive decline due to neuronal and synaptic degeneration. Neurofilament light chain (NfL) and total tau (T-tau) reflect neurodegeneration, NfL putatively more related to white and T-tau to grey matter. This study examines how cerebrospinal fluid (CSF) neurodegeneration markers (T-tau, NfL or both) are correlated with synaptic markers and clinical progression. We included 331 individuals with (n = 212) and without (n = 119) pathological CSF Aβ42/40 ratios. Associations between CSF NfL, T-tau, and the synaptic biomarkers neurogranin and BACE1 were assessed using Pearson's correlation. Group differences in synaptic marker levels were evaluated using linear regression comparing individuals with isolated pathological T-tau, NfL, or both, versus biomarker-negative individuals. Clinical progression to MCI or dementia was assessed using a Cox proportional hazards model (n = 257; mean follow-up = 3.75 years). Linear regression and Cox proportional hazards models included age, sex, and dichotomized APOE-ε4 carriership as covariates. T-tau had a stronger correlation with neurogranin(r = 0.84) and BACE1(r = 0.73) than NfL(r = 0.51 and 0.48; p < 0.001). Group-wise comparisons confirmed this, showing that only individuals with pathological T-tau-alone or with NfL-had significantly higher synaptic marker levels (p < 0.001). Only the combination of pathological T-tau and NfL was associated with a significantly increased risk of clinical progression(HR=6.79; p < 0.001). These findings suggest that T-tau is more closely related to early synaptic dysfunction in AD than NfL. The combined elevation of both biomarkers, linked to greater clinical decline, supports a dual contribution of grey- and white matter degeneration to disease progression. Show less

For workers in the industry, occupational exposure to indium compounds induces pulmonary disorders, such as interstitial pneumonia. Moreover, lung cancer has been reported in both humans and rodents exposed to indium compounds by inhalation. However, the biological mechanism underlying indium-induced disorders is poorly understood. Epithelial-mesenchymal transition (EMT)-the cellular process of losing epithelial and acquiring mesenchymal characteristics-is linked to fibrosis and cancer progression. Therefore, we examined whether indium exposure elicits EMT in vitro. A549 human alveolar epithelial cells treated with indium chloride at doses of 0-500 μg/mL for 24 h were used to analyze EMT marker expression and cytoarchitecture. Significant downregulation of CDH1 mRNA expression as an epithelial marker after treatments at 125, 250, and 500 μg/mL occurred dose-dependently; conversely, the mesenchymal marker SNAI1 was upregulated. Consistent with mRNAs, the expression levels of EMT marker proteins (i.e., E-cadherin, ZO1, SNAIL, and Vimentin) were changed significantly by treatment. While NF-κB signaling was activated in treated cells, indium-dependent changes of CDH1 and SNAI1 mRNA expression were not affected by BAY 11-7082, an NF-κB inhibitor, suggesting that NF-κB activation may be dispensable for indium-induced EMT. Fibroblast-like morphological characteristics, such as actin stress fiber formation and cell elongation, along with deconstruction of cell-cell adhesion complexes, were observed in treated cells. Overall, our study is the first to demonstrate that EMT is caused by indium compounds. This will contribute biologically to understanding the mechanism of EMT induction and clinically to unveiling the pathophysiology of indium lung disease. Show less

Endothelial-to-mesenchymal transition (EndMT) induced by dysfunctional pulmonary artery endothelial cells (PAECs) is regarded as an initiating and pivotal factor in pulmonary hypertension (PH). This study focuses on identifying a novel therapeutic target for regulating EndMT in PH. A comprehensive analysis of 2 hypoxic PAECs datasets yielded 310 overlapping upregulated and 229 downregulated differentially expressed genes (DEGs). These upregulated DEGs were primarily enriched in HIF-1 signalling pathway and glycolysis/gluconeogenesis, while downregulated only in spliceosome, as indicated by KEGG. Through PPI network analysis and the application of MCC algorithms, 5 hub genes were identified among these upregulated DEGs: GAPDH, LDHA, ALDOA, PFKL, and PFKP. Their enrichment in the 2 aforementioned pathways was confirmed by cross-pathway DEGs analysis and ClueGo. Among the hub genes, LDHA was chosen as the key gene based upon expression and correlation analysis of the validation set from PH patients. Subsequent GSEA also revealed the enrichment of LDHA in these 2 pathways. Additionally, the increased expression of LDHA protein in tissues and cells was confirmed, and the elevated enzymatic activity of LDHA in clinical serum samples was also verified. From 2 online databases, 4 LDHA inhibitors were filtered out, and the stable binding between the inhibitors and the LDHA protein was confirmed through molecular docking and molecular dynamics simulation. Finally, the experimental results indicated that one of the inhibitors FX11 reversed EndMT by inhibiting the lactate-SNAI1 axis, thereby alleviating hypoxia-induced PH. The potential of LDHA as a therapeutic target for PH by modulating EndMT was proposed in this study. Show less

The natural compound pterostilbene (PTE) has multiple cardiovascular protective effects. However, its effects on pulmonary arterial hypertension (PAH)-associated vascular remodeling remain to be elucidated. This study investigated the effects of PTE on monocrotaline (MCT)-induced PAH in rats Experimental PAH was established by subcutaneous injection of MCT (50 mg/kg) in Sprague-Dawley rats, which were then randomly divided into vehicle or PTE (15 mg/kg via gavage) treatment groups. Endothelial-to-mesenchymal transition (EndMT) was modeled in hPAECs by treating with transforming growth factor-β, tumor necrosis factor-α, and interleukin-1β in combination. In rats with MCT-induced PAH, administration of PTE resulted in a reduction in right ventricular systolic pressure, thereby alleviating right ventricular hypertrophy. This was accompanied by mitigation of the remodeling of pulmonary arteries. PTE mitigates MCT-induced PAH and vascular remodeling in rats, at least in part, by inhibiting HMGA-mediated EndMT, suggesting that PTE may be a useful complementary medicine in the treatment of PAH. Show less

In this study, we investigated gene expression related to cholesterol efflux receptors in individuals at high cardiovascular risk undergoing Mediterranean dietary interventions. Through transcriptomic analysis, we examined samples from two randomized controlled trials: PREDIMED and PREDIMED-Plus, with 151 and 89 elderly adults, respectively. Blood cells were isolated at baseline and after a 12-month intervention. In the PREDIMED trial, participants followed different Mediterranean diets: one supplemented with extra-virgin olive oil (traditional Mediterranean diet enriched with extra-virgin olive oil [MedDiet-EVOO]), another with nuts (MedDiet enriched with nuts MedDiet-Nuts [MedDiet-Nuts]), and a low-fat control diet. The PREDIMED-Plus trial compared an energy-reduced Mediterranean diet (Er-MedDiet) with physical activity to an ad libitum Mediterranean diet. Over time, mild but significant upregulation of genes like ATP binding cassette subfamily A member 1 (ABCA1), retinoid X receptor alpha (RXRA), retinoid X receptor beta (RXRB), and Nuclear Receptor Subfamily 1 Group H Member 3 (NR1H3) was observed in response to MedDiet-EVOO, MedDiet-Nuts, and Er-MedDiet. Notably, RXRA expression was higher in both MedDiet-EVOO and MedDiet-Nuts compared to the control diet. Differences in gene expression, particularly RXRA, ATP binding cassette subfamily G member 1 (ABCG1), NR1H3, and Peroxisome Proliferator Activated Receptor Delta (PPARD), were evident between MedDiet-Nuts and the control diet. In the PREDIMED-Plus trial, no significant differences in gene expression were found between dietary groups. Principal component analysis (PCA) and linear discriminant analysis (LDA) showed overlapping gene expression profiles across different Mediterranean diet interventions. In conclusion, our study highlights the cardiovascular health benefits of long-term adherence to a Mediterranean diet, both normocaloric and hypocaloric, primarily reflected by mild upregulation of cholesterol efflux-related genes-specifically involving RXRA, RXRB, ABCA1, ABCG1, Nuclear Receptor Subfamily 1 Group H Member 2(NR1H2), and PPARD-among elderly adults at high cardiovascular risk. This suggests a potential mechanism by which these diets may exert cardiovascular protective effects. Show less

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with tumor progression often driven by dysregulated oncogenic pathways. USP6NL, a known regulator of endocytic trafficking, has recently been implicated in tumorigenesis. However, its precise role in CRC remains unclear, and more studies are still needed to deepen our understanding of underlying mechanisms implicated in its oncogenic role. Therefore, silencing USP6NL could provide a novel therapeutic strategy by concurrently disrupting several oncogenic mechanisms, creating a new avenue for CRC management, particularly in patients who develop resistance against conventional therapies. This study investigates the impact of USP6NL knockdown on CRC cell morphology, proliferation, apoptosis, migration, angiogenesis, and metabolic adaptation, providing mechanistic insights into its oncogenic functions. HCT116 colorectal cancer cells were transfected with USP6NL-specific siRNA. Immunocytochemistry was used to confirm successful silencing, functional assays were performed to assess changes in cell morphology using phase-contrast and scanning electron microscopy, and colony formation and wound healing assays were performed to assess cell clonogenic capacity and migration, respectively, in addition to apoptosis assay via flow cytometry, and RT²-Profiler PCR array to measure variation in gene expression of 84 cancer-related genes. Statistical analyses were performed to evaluate significant differences between control and USP6NL-silenced groups. USP6NL depletion led to profound morphological changes, including membrane blebbing, cell shrinkage, and loss of adhesion, reflecting late apoptotic features of cells. These findings were further supported by flow cytometry, which confirmed increased apoptosis, with a higher proportion of late apoptotic cells (20.99% in USP6NL knockdown vs. 2.69% in control, p = 0.042). Colony formation assays revealed a significant reduction in the clonogenic potential, suggesting a critical role of USP6NL in promoting CRC cell proliferation (p ≤ 0.05). The wound healing assay demonstrated impaired migration in USP6NL-silenced cells, with a marked delay in wound closure (p = 0.0201 at 48 h). Gene expression analysis revealed a significant downregulation of VEGFC (-8.62-fold) and ANGPT2 (-4.03-fold), impairing angiogenesis and suppressing FOXC2, SNAI1, and SNAI2, indicating EMT inhibition. Additionally, CASP9, APAF1, and BCL2L11 were upregulated, confirming the activation of intrinsic apoptosis, while metabolic regulators HIF1A and LDHA were downregulated, suggesting impaired tumor hypoxic adaptation. This study establishes USP6NL as a key modulator of CRC progression, regulating proliferation, apoptosis, migration, angiogenesis, and metabolic pathways. The loss of USP6NL leads to EMT suppression, apoptosis induction, and reduced tumor cell viability, positioning it as a potential therapeutic target in colorectal cancer. Further investigations are warranted to explore USP6NL's interactions in oncogenic signaling networks and its feasibility as a target for CRC therapy. It could serve as a promising therapeutic target in colorectal cancer, potentially enhancing tumor cell death and limiting metastasis. Targeting USP6NL could also provide a novel approach in combination with existing therapies, improving treatment efficacy and reducing side effects. Show less

The Epstein-Barr virus (EBV) infection status varies among BL subtypes. There are unresolved questions regarding the contribution of EBV, which is strongly associated with Burkitt lymphoma, to BL pathogenesis. Differences between EBV-positive and EBV-negative BL have been previously reported. A long-debated and studied topic is the differing origins of EBV-positive and EBV-negative BL cells. Studies have suggested that miRNAs, which are post-transcriptional elements involved in many pathways, play a role in this process. In our study, in silico analyses and a literature review were used to identify miRNAs potentially involved in lymphoma and B lymphocyte development pathways. Three miRNAs (miR-182, miR-320a, miR-144) targeting the Show less

β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently prevents Snail degradation by blocking recognition of E3 ubiquitin ligases FBXL14. Furthermore, either targeting Snail Kbhb modification or CBP inhibitor decreases cancer metastasis and enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells. Collectively, our study reveals that Kbhb of Snail is critical to promote metastasis and provides a potential therapeutic strategy. Show less

Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the microRNAs arising from the lack of the antioxidant transcription factor Nrf2 lead to cancer metastasis. However, much less is known about the regulation of microRNAs by Nrf1, even though it acts as an essential determinon of cell homoeostasis by governing the transcriptional expression of those driver genes contributing to the EMT involved in its metastasis. In this study, distinct EMT phenotypes resulted from specific knockouts of Nrf1 and Nrf2 in HepG2 cells, as accompanied by their differential migratory and invasive capabilities. The Show less

In recent years, combination chemotherapy with therapeutic nucleic acids has emerged as a promising strategy to enhance the effectiveness of cancer therapy. However, developing an effective co-delivery system to simultaneously transport both chemotherapeutic drugs and nucleic acids remains challenging. Herein, we fabricated cholesterol-conjugated polyion complex nanoparticles (PCNs) for combination delivery of hydrophobic paclitaxel (PTX) and hydrophilic miR-34a. Cholesterol was conjugated to polyethylenimine (PEI) and hyaluronic acid (HA), producing C-PEI and C-HA, respectively. PTX was initially encapsulated within the hydrophobic core formed by the self-assembly of C-HA and C-PEI, yielding polyion complex nanoparticles (PTX@C-HA/C-PEI PCNs). Subsequently, the negatively charged miR-34a was electrostatically complexed with the cationic C-PEI moieties to generate miR-34a/PTX@C-HA/C-PEI PCNs. These PCNs exhibited a nanoscale structure with a uniform size distribution and demonstrated low cytotoxicity in colon cancer cells. Fluorescence microscopy confirmed efficient cytosolic delivery of C-HA/C-PEI PCNs in colon carcinoma cells. Furthermore, combination delivery of PTX and miR-34a using C-HA/C-PEI PCNs exhibited significantly enhanced transfection efficiency and cellular uptake for human colon cancer cells. Notably, PTX/miR-34a@C-HA/C-PEI PCNs effectively downregulated critical oncogenic targets, including Show less

Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific enhancer factor 2 A (MEF2A) is implicated in cardiac fibroblast activation, its role in MF remains unclear. We manipulated MEF2A expression in cardiac fibroblasts (CFs) through knockdown and overexpression, and assessed fibrosis markers, migration, and RhoA signaling. Binding of MEF2A to the Snail1 promoter was predicted using JASPAR and validated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Rescue experiments with Snail1 overexpression and RhoA inhibition were performed. An angiotensin II (Ang II)-induced MF mouse model was used to evaluate cardiac function by echocardiography and to assess collagen deposition through picrosirius red (PSR) staining. MEF2A was significantly upregulated in Ang II-induced fibrotic hearts and CFs. MEF2A knockdown reduced α-SMA and Col1a1 expression, inhibited CF migration, and suppressed activation of the Snail1/RhoA/α-SMA pathway. ChIP and luciferase assays confirmed the direct binding of MEF2A to the Snail1 promoter. Inhibition of RhoA signaling reversed MEF2A-induced myofibroblast activation and migration. Rescue experiments showed that Snail1 overexpression restored the fibrotic phenotype suppressed by MEF2A knockdown. In vivo, MEF2A knockdown improved left ventricular function, reduced collagen deposition (PSR staining), and lowered heart weight/tibia length ratios. MEF2A promotes myocardial fibrosis by directly activating Snail1 and engages the RhoA/α-SMA pathway. Targeting MEF2A offers a promising therapeutic strategy to attenuate MF and improve heart function. Show less

Voghera pepper (VP) extracts were demonstrated to have anti-oxidant ability in several cell types. This study aimed to assess whether VP-extracts could lower oxidative stress and modulate thyroid cancer (TC) cells behavior Extracts were analyzed using the LC-DAD-MS system. Thyroid cell lines, both normal (NHT) and cancerous (TPC-1 and 8505C) were treated with increasing concentrations of Yellow (YVP) and Green (GVP) VP-extracts over time. Viability and proliferation were assessed in all cell types. Changes in Reactive-oxygen-species (ROS) production by TPC-1 and 8505C were assessed by flow-cytometry. The mRNA expression of anti-oxidant mediators ( Treatment with GVP or YVP reduced the viability of TPC-1 and 8505C but not those of NHT, without effects on cells proliferation. GVP and YVP reduced basal and H This is the first demonstration of the potential beneficial effects of VP extracts in TC in terms of reduction of oxidative stress, increase of antioxidant markers, and modulation of markers of metastasis and de-differentiation in TC cells. Show less

Metabolites are pivotal in the biological process underlying type 2 diabetes (T2D) and its cardiovascular complications. Nevertheless, their contributions to these diseases have not been comprehensively evaluated, particularly in East Asian ancestry. This study aims to elucidate the metabolic underpinnings of T2D and its cardiovascular complications and leverage multi-omics integration to uncover the molecular pathways involved. This study included 1180 Chinese participants from the Zhejiang Metabolic Syndrome Cohort (ZMSC). A total of 1912 metabolites were profiled using high-coverage widely targeted and non-targeted metabolic techniques. Multivariable logistic regression models and orthogonal partial least squares discriminant analysis were used to identify T2D-related metabolites. A metabolome-wide genome-wide association study (GWAS) in ZMSC, followed by two-sample Mendelian randomization (MR) analyses, was conducted to explore potential causal metabolite-T2D associations. To enhance cross-ancestry generalizability, MR analyses were conducted in European ancestry to explore the potential causal effects of serum metabolites on T2D and its cardiovascular complications. Furthermore, multi-omics evidence was integrated to explore the underlying molecular mechanisms. We identified six metabolites associated with T2D in Chinese, supported by metabolome analysis and genetic-informed causal inference. These included two potential protective factors (PC [O-16:0/0:0] and its derivative LPC [O-16:0]) and four potential risk factors ([R]-2-hydroxybutyric acid, 2-methyllactic acid, eplerenone, and rauwolscine). Cross-ancestry metabolome-wide analysis further revealed four shared potential causal metabolites, highlighting the potential protective role of creatine for T2D. Through multi-omics integration, we revealed a potential regulatory path initialized by a genetic variant near CPS1 (coding for a urea cycle-related mitochondrial enzyme) influencing serum creatine levels and subsequently modulating the risk of T2D. MR analyses further demonstrated that nine urea cycle-related metabolites significantly influence cardiovascular complications of T2D. Our study provides novel insights into the metabolic underpinnings of T2D and its cardiovascular complications, emphasizing the role of urea cycle-related metabolites in disease risk and progression. These findings advance our understanding of circulating metabolites in the etiology of T2D, offering potential biomarkers and therapeutic targets for future research. WHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: Metabolites are crucial for understanding diabetes biology.Multi-omics integration aids in revealing complex mechanisms. WHAT IS THE KEY RESEARCH QUESTION?: How do serum metabolites affect diabetes and its cardiovascular outcomes? WHAT IS NEW?: Novel diabetes-related metabolites identified in Chinese populations.Consistent metabolites associated with diabetes and glycemic traits in East Asians and Europeans.Emphasizing the role of urea cycle pathway in cardiometabolic disease. HOW MIGHT THIS STUDY INFLUENCE CLINICAL PRACTICE?: Findings could guide diabetes prevention and personalized management strategies. Show less

Hyperlipidemia and chronic kidney disease (CKD) are well-established risk factors for cardiovascular disease and act synergistically to promote vascular inflammation and disease progression. However, the mechanisms underlying this synergetic effect remain largely unknown. Using a mouse model combining hyperlipidemia (via high-fat diet feeding, HFD) with 5/6 nephrectomy-induced CKD, we made the following significant findings: 1) HFD + CKD upregulated 1179 genes in mouse aortas and induced prominent reactive oxygen species (ROS), far more than either HFD or CKD alone. 2) HFD + CKD upregulated 86 CRISPRi-identified mitochondrial ROS regulators, 36 CRISPRi-identified cellular ROS regulators, and 19 GSEA-collected ROS regulators. These changes were associated with the upregulations of 48 cytokines, 7 highest toxicity uremic toxin receptors-including CD1D, FCGRT, AHR, IL6RA AGER, NR1H3 and NPY5R-in aortas. 3) These uremic toxin receptors emerged as novel promoters of inflammation and trained immunity. Deficiencies in CD1D, AHR, AGER, and the trained immunity promoter SET7 each downregulated up to 5.5 % of the genes upregulated by HFD + CKD. Conversely, activation of NR1H3 using an agonist upregulated up to 12.2 % of these genes. 4) The expression of 46 cytokine genes was strongly associated with NR1H3 upregulation. 5) The NR1H3 agonist also induced the expression of 28 ROS regulators, including YBX2, a novel anti-ROS transcription factor and RNA-binding protein, suggesting a potential negative feedback mechanism. YBX2 deficiency increased the cellular ROS level, while YBX2 overexpression suppressed 27 proinflammatory genes induced by HFD + CKD. Our findings provide novel insights into the role of the NR1H3-YBX2 axis in regulating inflammation accelerated by hyperlipidemia and CKD. Show less

Anorexia nervosa (AN) is a mental disorder marked by a significantly low body weight. Differentially methylated CpG sites have been reported to be involved in body weight regulation. Methylation pattern may change during considerable weight gain by in-patient treatment. Consequently, we aimed to (1) replicate the hypomethylation at the NR1H3 gene locus (identified in our previous epigenome-wide association study) in independent study groups of 189 female patients with AN and 67 healthy-lean female controls, and (2) identify regions associated with large weight gain associated DNA methylation changes in three patients with AN through whole-genome bisulfite sequencing in CD14 Show less

This study was aimed at identifying the effects of liver X receptor alpha (LXRα) on sepsis-induced acute lung injury (ALI) and clarifying its novel regulatory mechanisms using bioinformatics and experimental methods. Bioinformatics analysis of the differentially expressed genes and functional annotations were performed. Lipopolysaccharide (LPS) was administered intraperitoneally for sepsis-induced ALI in a mouse model; then, the LXR agonist T0901317 (T0) was administered to the mice along with RAW264.7 macrophages for LXRα activation. We then performed hematoxylin and eosin staining, estimated the total protein in the bronchoalveolar lavage fluid, and detected the expressions of TNFα and IL6 by reverse transcription polymerase chain reaction to evaluate the inflammatory injury in the lung tissues. Autophagy was detected via immunohistochemistry, transmission electron microscopy, and Western blotting. RNA sequencing was then used to analyze the autophagy-related genes regulated by LXRα, and the cells were transfected with S100A8-siRNA to determine whether LXRα regulated inflammatory damage by regulating the autophagy-related gene S100A8. The clinical correlation between LXRα and S100A8 was determined through analysis of human transcriptome data. The bioinformatics analyses revealed that LXRα (NR1H3) was downregulated in sepsis-induced ALI models and that LXRα might regulate autophagy. The animal- and cell-based experiments further verified these findings. The LXR agonist T0 was found to alleviate lung damage and reduce the expressions of inflammatory factors in the lung tissues and cells. After inhibiting autophagy with 3-methyladenine, the protective effects of T0 on inflammatory damage were shown to be inhibited. Subsequently, RNA sequencing of the macrophages was performed, and four genes ( The findings of this study suggest that T0 attenuates sepsis-induced pulmonary injury by promoting macrophage autophagy via suppression of S100A8 expression. Show less

Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia and glucose intolerance, hallmark features of type 2 diabetes. While SEC16 homologue B (SEC16B), an endoplasmic reticulum export factor, has been linked to obesity, type 2 diabetes and lipid metabolism, its role in glucose regulation remains poorly defined. This study aims to investigate SEC16B's contribution to glucose homeostasis by systematically dissecting its conserved physiological mechanisms across species. To interrogate SEC16B's role, we combined Drosophila genetics (RNA interference-mediated dSec16 knockdown) with murine models (Sec16b deletion) under standard or high-fat diet conditions. Glucose and insulin tolerance tests assessed glucose homeostasis. Mechanistic insights into beta cell dysfunction were derived from immunostaining, glucose-stimulated insulin secretion assays and RNA-seq profiling of murine pancreatic islets. Both disruption of dSec16 in Drosophila and Sec16b deletion in mice triggered glucose intolerance under standard diet conditions, recapitulating conserved metabolic dysfunction. In addition, Sec16b loss impaired glycaemic control in mice fed a high-fat diet. Mechanistically, Sec16b deficiency impairs insulin secretion by downregulating cholinergic signalling and compromising intracellular Ca Our study reveals SEC16B, a genome-wide association study-identified obesity risk gene, as an evolutionarily conserved regulator of glucose homeostasis. By linking SEC16B to cholinergic-driven insulin secretion and calcium dynamics, we resolve a mechanistic gap in beta cell dysfunction and metabolic disease. This finding provides novel insights into the mechanisms underlying glucose homeostasis and may enhance our understanding of potential treatments for metabolic diseases. Show less

To identify novel genetic loci associated with differences in serum etonogestrel concentrations among contraceptive implant users. We conducted a cross-sectional analysis in which we enrolled healthy, reproductive-aged (age 18-45 years) participants who had been using etonogestrel implants for 12-48 months. Participants underwent a single-time blood draw for measurement of serum etonogestrel concentrations by liquid chromatography-tandem mass spectrometry and the extraction of DNA from whole blood. We genotyped participants using the Illumina Infinium Global Diversity Array with Enhanced PGx and imputed genotyping results using the TOPMed imputation server. We performed genome-wide complex trait analysis using a linear mixed model leave-one-chromosome-out association analysis to identify genetic variants associated with serum etonogestrel concentrations. We enrolled 900 etonogestrel implant users, with a median age of 22.3 years (range 18.0-41.5 years), median body mass index (BMI) 26.0 (range 18.5-52.0), and median duration of implant use 27 months (range 12-48 months). Most participants self-reported their race as White (49.3%) and ethnicity as Hispanic or Latina (52.9%). Participants had a median serum etonogestrel concentration of 126.9 pg/mL (range 39.4-695.1 pg/mL). Including BMI, duration of implant use, and three principal components as covariates in the genome-wide complex trait analysis, we identified no genetic variants with minor allele frequencies at or above 5% that were associated with serum etonogestrel concentrations at genome-wide significance ( Despite enhanced coverage for known pharmacogenomic variants, we found no significant associations between interindividual variability in contraceptive implant pharmacokinetics and genetic loci directly involved in exogenous steroid hormone metabolism. ClinicalTrials.gov, NCT03092037. Show less

The widespread detection of antibiotics in aquatic environments, particularly in effluent-receiving surface waters, poses significant ecological and public health concerns due to their role in promoting antimicrobial resistance. Accurate trace-level antibiotic measurement is essential for environmental risk assessment and for improving wastewater treatment strategies. This study presents the development, optimization, and validation of two complementary liquid chromatography-mass spectrometry (LC-MS) workflows for the simultaneous quantification of nine antibiotics across five therapeutic classes in creek water impacted by a Common Effluent Treatment Plant (CETP). The performance of a triple quadrupole LC-MS/MS system (LC-QqQ-MS) was compared to that of a high-resolution Orbitrap mass spectrometer (LC-Orbitrap-HRMS). Both instruments demonstrated excellent linearity ( Show less

Senescence of mesenchymal stem cells in bone tissue (BMSCs), the primary progenitors of osteoblasts, is a key contributor to age-related osteopenia and osteoporosis. Aged cells exhibit elevated cellular stress and abnormal accumulation of stress granules (SGs), which contain G-quadruplex (G4) structured nucleic acids and G4-binding proteins. Dhx36, a helicase that unwinds G4 structure, may play a protective role in this context. In this study, we investigated the function of Dhx36 in BMSCs and bone homeostasis by silencing Dhx36 expression in vitro and in vivo. Dhx36 deficiency increased SG formation and impaired their resolution in BMSCs. This was accompanied by reduced expression of G4-containing autophagyrelated genes and diminished autophagic activity. Loss of Dhx36 also enhanced senescence features and impaired BMSC osteogenic differentiation. Dhx36 expression was significantly lower in bone tissue and BMSCs from aged mice, compared to young mice. Moreover, 8-week-old mice with BMSC-specific Dhx36 knockout exhibited reduced bone volume and trabecular number, indicating premature bone loss. Analysis of public singlecell RNA sequencing data further showed that stress induced by 5-fluorouracil in mice suppressed Dhx36 expression in BMSCs, and downregulated genes related to ossification and osteoblast differentiation. Collectively, our findings identify Dhx36 as a regulator of BMSC aging, linking SG dynamics and autophagy to bone homeostasis, and suggest Dhx36 as a potential therapeutic target to prevent age-related bone loss. [BMB Reports 2025; 58(12): 501-510]. Show less