SVDF: enhancing structural variation detect from long-read sequencing via automatic filtering strategies.

Structural variation (SV) is an important form of genomic variation that influences gene function and expression by altering the structure of the genome. Although long-read data have been proven to better characterize SVs, SVs detected from noisy long-read data still include a considerable portion of false-positive calls. To accurately detect SVs in long-read data, we present SVDF, a method that employs a learning-based noise filtering strategy and an SV signature-adaptive clustering algorithm, for effectively reducing the likelihood of false-positive events. Benchmarking results from multiple orthogonal experiments demonstrate that, across different sequencing platforms and depths, SVDF achieves higher calling accuracy for each sample compared to several existing general SV calling tools. We believe that, with its meticulous and sensitive SV detection capability, SVDF can bring new opportunities and advancements to cutting-edge genomic research.

SIRT3/AMPK signaling pathway regulates lipid metabolism and improves vulnerability to atrial fibrillation in Dahl salt sensitive rats.

BACKGROUND: Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3) / AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. METHODS: The study involved 7-week-old male Dahl salt-sensitive that were fed either high-salt diet (8% NaCl; DSH group) or normal diet (0.3% NaCl; DSN group). Then DSH group were administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of SBP, the expression levels of lipid metabolism-related biomarker, pathological examination of atrial fibrosis and lipid accumulation, as well as AF inducibility and AF duration. RESULTS: DSH decrease SIRT3, phosphorylation-AMPK and VLCAD expression, increased FASN and FABP4 expression and concentrations of FFA and TG, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. CONCLUSIONS: We have confirmed that high-salt diet can result in hypertension, associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.

The Protective Role of Transcript-Induced in Spermiogenesis 40 in Cerebral Ischemia-Reperfusion Injury.

Prompt reperfusion after cerebral ischemia is important to maintain neuronal survival and reduce permanent disability and death. However, the resupply of blood can induce oxidative stress, inflammatory response and apoptosis, further leading to tissue damage. Here, we report the versatile biological roles of transcript-induced in spermiogenesis 40 (Tisp40) in ischemic stroke. We found that the expression of Tisp40 was upregulated in ischemia/reperfusion-induced brain tissues and oxygen glucose deprivation/returned -stimulated neurons. Tisp40 deficiency increased the infarct size and neurological deficit score, and promoted inflammation and apoptosis. Tisp40 overexpression played the opposite role. In vitro, the oxygen glucose deprivation/returned model was established in Tisp40 knockdown and overexpression primary cultured cortical neurons. Tisp40 knockdown can aggravate the process of inflammation and apoptosis, and Tisp40 overexpression ameliorated the aforementioned processes. Mechanistically, Tisp40 protected against ischemic stroke via activating the AKT signaling pathway. Tisp40 may be a new therapeutic target in brain ischemia/reperfusion injury.

Design, Fabrication, and Characterization of a Planar Three-Electrode Trigger Switch Based on Flexible Printed Circuit Process.

An exploding foil initiator system (EFIs) is essential in modern weaponry for its safety and reliability. As the main component of EFIs, the performance of the switch is critical to EFIs. In this study, a planar three-electrode trigger switch was designed and fabricated using the Flexible Printed Circuits (FPC) process. Subsequently, the performance of the FPC switch was tested. The results show that the self-breakdown voltage of the FPC switch is stable. In addition, an FPF switch with a 0.6 mm main electrode gap demonstrated consistency, with delay times below 31.75 ns, and a jitter ranging from 1.7 ns to 10.94 ns at 900 V to 1200 V, evidencing the FPC switches' reliability and uniform performance across various voltages. Compared to the Micro-Electro-Mechanical Systems (MEMS) switches of similar dimensions, the FPC switches achieved a faster high-current attainment with less inductance, showing a 5% reduction in loop inductance. The repetitive testing results demonstrate that the FPC switch maintains consistent output performance, with stable peak currents, peak current time, and delay time over 50 action cycles, highlighting its repeatability. The FPC switch was assembled with an EFI chip and capacitor into an integrated system, which was subsequently able to successfully detonate HNS-IV at 1000 V/0.22 µF, proving the FPC switch's potential in low inductance applications.

A Micro Bridge-Wing-Thickened Low-Energy Exploding Foil Initiator Chip.

To enhance the energy efficiency of exploding foil initiator systems (EFIs) and mitigate energy loss due to ablation in the bridge-wing regions, a low-energy bridge-wing-thickened EFI chip was designed and fabricated. Computational analysis revealed that increasing the thickness of the bridge flanks significantly reduces ablation within the bridge region during the electrical explosion. The refinement of the design led to the adoption of a bridge flank thickness of 19 µm, with the bridge area dimensions specified as 0.25 mm × 0.25 mm × 4 µm. This bridge-wing-thickened EFI chip was produced by employing micro-electro-mechanical systems (MEMS) technology and underwent rigorous performance evaluations. The empirical results closely matched the computational predictions, thereby corroborating the precision of the proposed model in simulating the temperature distribution seen during the explosion process. Notably, this enhanced EFI design achieves a flyer velocity of 3800 m/s at a condition of 900 V/0.22 µF, signifying a significant advancement in EFI system efficiency and performance.

Identification of the molecular subtypes and signatures to predict the prognosis, biological functions, and therapeutic response based on the anoikis-related genes in colorectal cancer.

BACKGROUND: Tumors that resist anoikis, a programmed cell death triggered by detachment from the extracellular matrix, promote metastasis; however, the role of anoikis-related genes (ARGs) in colorectal cancer (CRC) stratification, prognosis, and biological functions remains unclear. METHODS: We obtained transcriptomic profiles of CRC and 27 ARGs from The Cancer Genome Atlas, the Gene Expression Omnibus, and MSigDB databases, respectively. CRC tissue samples were classified into two clusters based on the expression pattern of ARGs, and their functional differences were explored. Hub genes were screened using weighted gene co-expression network analysis, univariate analysis, and least absolute selection and shrinkage operator analysis, and validated in cell lines, tissues, or the Human Protein Atlas database. We constructed an ARG-risk model and nomogram to predict prognosis in patients with CRC, which was validated using an external cohort. Multifaceted landscapes, including stemness, tumor microenvironment (TME), immune landscape, and drug sensitivity, between high- and low-risk groups were examined. RESULTS: Patients with CRC were divided into C1 and C2 clusters. Cluster C1 exhibited higher TME scores, whereas cluster C2 had favorable outcomes and a higher stemness index. Eight upregulated hub ARGs (TIMP1, P3H1, SPP1, HAMP, IFI30, ADAM8, ITGAX, and APOC1) were utilized to construct the risk model. The qRT-PCR, Western blotting, and immunohistochemistry results were consistent with those of the bioinformatics analysis. Patients with high risk exhibited worse overall survival (p < 0.01), increased stemness, TME, immune checkpoint expression, immune infiltration, tumor mutation burden, and drug susceptibility compared with the patients with low risk. CONCLUSION: Our results offer a novel CRC stratification based on ARGs and a risk-scoring system that could predict the prognosis, stemness, TME, immunophenotypes, and drug susceptibility of patients with CRC, thereby improving their prognosis. This stratification may facilitate personalized therapies.

Hematopoietic growth factors Regulate Entry of Monocytes into the Adult Brain via Chemokine Receptor CCR5.

Monocytes are circulating macrophage precursors and are generated from bone marrow hematopoietic stem cells. In the adults, monocytes continuously replenish cerebral border-associated macrophages under a physiological condition. Monocytes also rapidly infiltrate into the brain in the settings of pathological conditions. The mechanisms of recruiting monocyte-derived macrophages into the brain under pathological conditions have been extensively studied. However, it remains unclear how monocytes enter the brain for renewal of border-associated macrophages under the physiological condition. Using both in vitro and in vivo approaches, this study reveals that the combination of two hematopoietic growth factors, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF), complementarily and synergistically enhances adhesion of monocytes to cerebral endothelial cells in a dose dependent manner. Cysteine-cysteine chemokine receptor 5 (CCR5) in brain endothelial cells, but not cell adhesion molecules mediating neuroinflammation-related infiltration of monocyte-derived macrophages, modulates the SCF+G-CSF-enhanced monocyte-endothelial cell adhesion. Blocking CCR5 or genetically deleting CCR5 reduces monocyte-endothelial cell adhesion induced by SCF+G-CSF. SCF+G-CSF-enhanced recruitment of bone marrow-derived monocytes/macrophages in cerebral perivascular space is also reduced in adult CCR5 knockout mice. This study demonstrates the contribution of SCF and G-CSF in regulating the entry of monocytes into the adult brain to replenish perivascular macrophages.

Metabolic Recoding of NSUN2-Mediated m5C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m5C-ENO1 Positive Feedback Loop.

The RNA modification, 5-methylcytosine (m5C), has recently gained prominence as a pivotal post-transcriptional regulator of gene expression, intricately intertwined with various tumorigenic processes. However, the exact mechanisms governing m5C modifications during the onset and progression of colorectal cancer (CRC) remain unclear. Here, it is determined that the m5C methyltransferase NSUN2 exhibits significantly elevated expression and exerts an oncogenic function in CRC. Mechanistically, NSUN2 and YBX1 are identified as the "writer" and "reader" of ENO1, culminating in the reprogramming of the glucose metabolism and increased production of lactic acid in an m5C-dependent manner. The accumulation of lactic acid derived from CRC cells, in turn, activates the transcription of NSUN2 through histone H3K18 lactylation (H3K18la), and induces the lactylation of NSUN2 at the Lys356 residue (K356), which is crucial for capturing target RNAs. Together, these findings reveal an intriguing positive feedback loop involving the NSUN2/YBX1/m5C-ENO1 signaling axis, thereby bridging the connection between metabolic reprogramming and epigenetic remodeling, which may shed light on the therapeutic potential of combining an NSUN2 inhibitor with immunotherapy for CRC.

Associations of perfluoroalkyl substances with metabolic-associated fatty liver disease and non-alcoholic fatty liver disease: NHANES 2017-2018.

OBJECTIVES: This study investigated the potential effects of perfluoroalkyl substance (PFAS) in serum on MAFLD, NAFLD, and liver fibrosis. METHODS: Our sample included 696 participants (≥ 18 years) from the 2017-2018 NHANES study with available serum PFASs, covariates, and outcomes. Using the first quartile of PFAS as the reference group, we used weighted binary logistic regression and multiple ordered logistic regression used to analyze the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and multiple ordinal logistic regression to investigate the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and calculated the odds ratio (OR) and 95% confidence interval for each chemical. Finally, stratified analysis and sensitivity analysis were performed according to gender, age, BMI, and serum cotinine concentration. RESULTS: A total of 696 study subjects were included, including 212 NAFLD patients (weighted 27.03%) and 253 MAFLD patients (weighted 32.65%). The quartile 2 of serum PFOA was positively correlated with MAFLD and NAFLD (MAFLD, OR 2.29, 95% CI 1.05-4.98; NAFLD, OR 2.37, 95% CI 1.03-5.47). PFAS were not significantly associated with liver fibrosis after adjusting for potential confounders in MAFLD and NAFLD. Stratified analysis showed that PFOA was strongly associated with MAFLD, NAFLD, and liver fibrosis in males and obese subjects. In women over 60 years old, PFHxS was also correlated with MAFLD, NAFLD, and liver fibrosis. CONCLUSION: The serum PFOA was positively associated with MAFLD and NAFLD in US adults. After stratified analysis, the serum PFHxS was correlated with MFALD, NAFLD, and liver fibrosis.

High salt diet inhibits the expression of Bmal1 and promotes atrial fibrosis and vulnerability to atrial fibrillation in Dahl salt sensitive rats.

BACKGROUND: Hypertension is a risk factor for atrial fibrillation (AF), and brain and muscle arnt-like protein 1 (Bmal1) regulate circadian blood pressure and is implicated in several fibrotic disorders. Our hypothesis that Bmal1 inhibits atrial fibrosis and susceptibility to AF in salt-sensitive hypertension (SSHT) and our study provide a new target for the pathogenesis of AF induced by hypertension. METHODS: The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). An experimental model was used to measure systolic blood pressure (SBP), left atrial ejection fraction (LAEF), left atrial end-volume index (LAEVI), left atrial index (LAFI), AF inducibility, AF duration, and atrial fibrosis pathological examination and the expression of Baml1 and fibrosis-related proteins (TNF-α and α-SMA) in left atrial tissue. RESULTS: DSH increased TNF-α and α-SMA expression in atrial tissue, level of SBP and LAESVI, atrial fibrosis, AF induction rate and AF duration, and decreased Bmal1 expression in atrial tissue, circadian rhythm of hypertension and level of LAEF and LAFI. Our results also showed that the degree of atrial fibrosis was negatively correlated with Bmal1 expression, but positively correlated with the expression of TNF-α and α-SMA. CONCLUSIONS: We demonstrated that a high-salt diet leads to circadian changes in hypertension due to reduction Bmal1 expression, which plays a crucial role in atrial fibrosis and increased susceptibility to AF in SSHT rats.

Effect of comprehensive nursing on the quality of life and swallowing function in individuals diagnosed with ischemic stroke.

BACKGROUND: Ischemic stroke (IS) is a widely recognized disease characterized by high prevalence, mortality, morbidity, disability, and recurrence rates. It ranks prominently in terms of mortality, constituting 60%-80% of stroke cases. AIM: To explore the impact of comprehensive nursing care on the quality of life and swallowing function in individuals diagnosed with IS. METHODS: This study comprised 172 patients with IS admitted to our hospital between February 2018 to March 2021. The participants were divided into two groups, namely the control group (n = 80) receiving routine care and the research group (n = 92) receiving comprehensive care. Various assessment scales, including the standard swallowing function assessment scale (SSA), National Institutes of Health Stroke scale (NIHSS), European stroke scale (ESS), self-rating anxiety scale (SAS), self-rating depression scale (SDS), Barthel index (BI), and the motor function assessment scale (MAS), were employed to evaluate the improvement in swallowing function, neurological deficits, clinical outcomes, anxiety, depression, daily living activities, and motor function before and after care. Furthermore, the study compared the occurrence of adverse reactions during the nursing period, life quality before and after the intervention, rehabilitation compliance, and nursing satisfaction between the two groups. RESULTS: After the nursing intervention, the research group exhibited significantly improved SSA and NIHSS scores compared to the control group (P < 0.05). Moreover, both groups demonstrated significant reductions in SAS and SDS scores (P < 0.05), with the research group showing more obvious advantages (P < 0.05). Compared to the control group, the research group displayed significantly better ESS, BI, and MAS scores (P < 0.05), coupled with a lower incidence of adverse reactions (P < 0.05). Additionally, the research group demonstrated markedly higher levels of life quality, rehabilitation compliance, and nursing satisfaction compared to the control group (P < 0.05). CONCLUSION: Comprehensive nursing effectively improved swallowing function, quality of life, and patient satisfaction, highlighting its clinical significance.

Dronedarone Attenuates Ang II-Induced Myocardial Hypertrophy Through Regulating SIRT1/FOXO3/PKIA Axis.

BACKGROUND AND OBJECTIVES: Long-term pathological myocardial hypertrophy (MH) seriously affects the normal function of the heart. Dronedarone was reported to attenuate left ventricular hypertrophy of mice. However, the molecular regulatory mechanism of dronedarone in MH is unclear. METHODS: Angiotensin II (Ang II) was used to induce cell hypertrophy of H9C2 cells. Transverse aortic constriction (TAC) surgery was performed to establish a rat model of MH. Cell size was evaluated using crystal violet staining and rhodamine phalloidin staining. Reverse transcription quantitative polymerase chain reaction and western blot were performed to detect the mRNA and protein expressions of genes. JASPAR and luciferase activity were conducted to predict and validate interaction between forkhead box O3 (FOXO3) and protein kinase inhibitor alpha (PKIA) promoter. RESULTS: Ang II treatment induced cell hypertrophy and inhibited sirtuin 1 (SIRT1) expression, which were reversed by dronedarone. SIRT1 overexpression or PKIA overexpression enhanced dronedarone-mediated suppression of cell hypertrophy in Ang II-induced H9C2 cells. Mechanistically, SIRT1 elevated FOXO3 expression through SIRT1-mediated deacetylation of FOXO3 and FOXO3 upregulated PKIA expression through interacting with PKIA promoter. Moreover, SIRT1 silencing compromised dronedarone-mediated suppression of cell hypertrophy, while PKIA upregulation abolished the influences of SIRT1 silencing. More importantly, dronedarone improved TAC surgery-induced MH and impairment of cardiac function of rats via affecting SIRT1/FOXO3/PKIA axis. CONCLUSIONS: Dronedarone alleviated MH through mediating SIRT1/FOXO3/PKIA axis, which provide more evidences for dronedarone against MH.

Updates of the role of B-cells in ischemic stroke.

Ischemic stroke is a major disease causing death and disability in the elderly and is one of the major diseases that seriously threaten human health and cause a great economic burden. In the early stage of ischemic stroke, neuronal structure is destroyed, resulting in death or damage, and the release of a variety of damage-associated pattern molecules induces an increase in neuroglial activation, peripheral immune response, and secretion of inflammatory mediators, which further exacerbates the damage to the blood-brain barrier, exacerbates cerebral edema, and microcirculatory impairment, triggering secondary brain injuries. After the acute phase of stroke, various immune cells initiate a protective effect, which is released step by step and contributes to the repair of neuronal cells through phenotypic changes. In addition, ischemic stroke induces Central Nervous System (CNS) immunosuppression, and the interaction between the two influences the outcome of stroke. Therefore, modulating the immune response of the CNS to reduce the inflammatory response and immune damage during stroke is important for the protection of brain function and long-term recovery after stroke, and modulating the immune function of the CNS is expected to be a novel therapeutic strategy. However, there are fewer studies on B-cells in brain function protection, which may play a dual role in the stroke process, and the understanding of this cell is still incomplete. We review the existing studies on the mechanisms of the role of B-cells, inflammatory response, and immune response in the development of ischemic stroke and provide a reference for the development of adjuvant therapeutic drugs for ischemic stroke targeting inflammatory injury.

Dietary calcium is inversely associated with hepatitis B virus infection: an analysis of US National Health and Nutrition Examination Survey (NHANES) 2007-2020.

BACKGROUND: There have been studies on the relationship between hepatitis B virus (HBV) infection and diet. We hypothesized HBV infection is related to dietary calcium intake, but the evidence is limited. This study aimed to examine whether dietary calcium intake is independently related to HBV infection in the United States population. METHODS: A total of 20,488 participants aged over 20 years from the National Health and Nutrition Examination Survey (NHANES), conducted from 2007 to 2020, were included in this study. Pearson correlation was used to test the association between dietary calcium and serum calcium. The relationships of HBV infection with dietary calcium and serum calcium were assessed by logistic regression models. RESULTS: There was a weak correlation between dietary calcium and serum calcium (r = 0.048). Logistic regression models indicated that HBV infection had a linear negative correlation with dietary calcium (OR 0.37; 95%CI 0.19, 0.76). For each additional 10 mg dietary calcium, the possibility of HBV infection was reduced by 63%. Hepatitis B positive participants had lower serum calcium content than negative participants. Stratified analysis shown the linear relationship between calcium and HBV infection varied among sex, race/ethnicity, and body mass index. CONCLUSION: Our findings demonstrated HBV infection was linearly and inversely correlated with dietary calcium. The current study is expected to offer a fresh perspective on reducing HBV infection.

Inverse associations of cord blood mitochondrial DNA copy number with childhood adiposity.

OBJECTIVE: The objective of this study was to examine associations between umbilical cord mitochondrial DNA copy number (mtDNAcn) and adiposity across childhood. METHODS: In a prospective birth cohort of Dominican and African American children from New York City, New York (1998-2006), mtDNAcn was measured in cord blood. Children (N = 336) were evaluated for their height, weight, and bioimpedance at age 5, 7, 9, and 11 years. We used linear mixed-effects models to assess associations of mtDNAcn tertiles in cord blood with child BMI, BMI z scores, fat mass index, and body fat percentage. Latent class growth models and interactions between mtDNAcn and child age or child age2 were used to assess associations between age and adiposity trajectories. RESULTS: BMI was, on average, 1.5 kg/m2 higher (95% CI: 0.58, 2.5) in individuals with mtDNAcn in the low- compared with the middle-mtDNAcn tertile. Results were similar for BMI z score, fat mass index, and body fat percentage. Moreover, children in the low-mtDNAcn group had increased odds of being in an "increasing" or "high-stable" adiposity class. CONCLUSIONS: Lower mtDNAcn at birth may predict greater childhood adiposity, highlighting the potential key role of perinatal mitochondrial function in adiposity during development.

TRIM65 promotes vascular smooth muscle cell phenotypic transformation by activating PI3K/Akt/mTOR signaling during atherogenesis.

BACKGROUND AND AIMS: Tripartite motif (TRIM65) is an important member of the TRIM protein family, which is a newly discovered E3 ligase that interacts with and ubiquitinates various substrates and is involved in diverse pathological processes. However, the function of TRIM65 in atherosclerosis remains unarticulated. In this study, we investigated the role of TRIM65 in the pathogenesis of atherosclerosis, specifically in vascular smooth muscle cells (VSMCs) phenotype transformation, which plays a crucial role in formation of atherosclerotic lesions. METHODS AND RESULTS: Both non-atherosclerotic and atherosclerotic lesions during autopsy were collected singly or pairwise from each individual (n = 16) to investigate the relationship between TRIM65 and the development of atherosclerosis. In vivo, Western diet-fed ApoE-/- mice overexpressing or lacking TRIM65 were used to assess the physiological function of TRIM65 on VSMCs phenotype, proliferation and atherosclerotic lesion formation. In vitro, VSMCs phenotypic transformation was induced by platelet-derived growth factor-BB (PDGF-BB). TRIM65-overexpressing or TRIM65-abrogated primary mouse aortic smooth muscle cells (MOASMCs) and human aortic smooth muscle cells (HASMCs) were used to investigate the mechanisms underlying the progression of VSMCs phenotypic transformation, proliferation and migration. Increased TRIM65 expression was detected in α-SMA-positive cells in the medial and atherosclerotic lesions of autopsy specimens. TRIM65 overexpression increased, whereas genetic knockdown of TRIM65 remarkably inhibited, atherosclerotic plaque development. Mechanistically, TRIM65 overexpression activated PI3K/Akt/mTOR signaling, resulting in the loss of the VSMCs contractile phenotype, including calponin, α-SMA, and SM22α, as well as cell proliferation and migration. However, opposite phenomena were observed when TRIM65 was deficient in vivo or in vitro. Moreover, in cultured PDGF-BB-induced TRIM65-overexpressing VSMCs, inhibition of PI3K by treatment with the inhibitor LY-294002 for 24 h markedly attenuated PI3K/Akt/mTOR activation, regained the VSMCs contractile phenotype, and blocked the progression of cell proliferation and migration. CONCLUSIONS: TRIM65 overexpression enhances atherosclerosis development by promoting phenotypic transformation of VSMCs from contractile to synthetic state through activation of the PI3K/Akt/mTOR signal pathway.

Zishen Yutai Pills Promote Angiogenesis at the Maternal-Fetal Interface in Recurrent Spontaneous Abortion Mice by Regulating miR-187/VEGF Axis.

Ethnopharmacological Relevance: Zishen Yutai pills (ZYP), a traditional Chinese patent medicine, was listed in China in 1981. It is composed of 15 traditional Chinese medicines and has the effects of regulating menstruation, helping pregnancy, and preventing abortion. In clinical practice, it is effective in preventing habitual and threatened miscarriages, and continuing to explore its mechanism of action is very meaningful research. Aim of the Study: To explore the possible mechanism of ZYP promoting angiogenesis at the maternal-fetal interface in recurrent spontaneous abortion (RSA). Materials and Methods: In vitro experiments, placental trophoblast cells (PTCs) were isolated from the placental tissue of RSA mice and divided into six groups: Control group, Model group, ZYP group, miR-187 inhibitor NC group, miR-18 7 inhibitor group, and miR-187 inhibitor+ZYP group. Cell viability and cell cycle were measured using CCK8 and flow cytometry, respectively. The expression levels of miR-187, VEGF, VEGF-R1, and VEGF-R2 were measured using RT-qPCR, WB, and IF staining. Animal experiments first establish an RSA mice model (CBA/J × DBA/2) and then randomly divide the mice into four groups (n=10): normal pregnancy group, RSA model group, ZYP group, and progesterone capsule group. Observed the changes in embryo absorption rate, pathological morphology of decidual tissue, and ultrastructure of vascular endothelial cells in each group of mice. RT-qPCR, WB, and IF staining methods were used to determine the expression of miR-187, VEGF, VEGF-R1, and VEGF-R2. Results: In vitro, ZYP promoted the viability of PTCs and regulated their cell cycle, and ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2 levels. miR-187 inhibitor showed the same effects, and further ZYP intervention enhanced the effects. In vivo, ZYP remarkably reduced embryo resorption rates, and improved the pathological morphology of decidual tissues and ultrastructure of vascular endothelial cells. Moreover, ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2. Conclusion: In summary, ZYP can regulate the expression of VEGF via miR-187, then promote the angiogenesis at the maternal-fetal interface, and playing a therapeutic role in RSA.

Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT. METHODS: We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE-/- mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE-/- mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV). RESULTS: These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration. CONCLUSIONS: H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.

Natural products in traditional Chinese medicine: molecular mechanisms and therapeutic targets of renal fibrosis and state-of-the-art drug delivery systems.

Renal fibrosis (RF) is the end stage of several chronic kidney diseases. Its series of changes include excessive accumulation of extracellular matrix, epithelial-mesenchymal transition (EMT) of renal tubular cells, fibroblast activation, immune cell infiltration, and renal cell apoptosis. RF can eventually lead to renal dysfunction or even renal failure. A large body of evidence suggests that natural products in traditional Chinese medicine (TCM) have great potential for treating RF. In this article, we first describe the recent advances in RF treatment by several natural products and clarify their mechanisms of action. They can ameliorate the RF disease phenotype, which includes apoptosis, endoplasmic reticulum stress, and EMT, by affecting relevant signaling pathways and molecular targets, thereby delaying or reversing fibrosis. We also present the roles of nanodrug delivery systems, which have been explored to address the drawback of low oral bioavailability of natural products. This may provide new ideas for using natural products for RF treatment. Finally, we provide new insights into the clinical prospects of herbal natural products.

m6A and m5C modification of GPX4 facilitates anticancer immunity via STING activation.

Cancer immunotherapy is arguably the most rapidly advancing realm of cancer treatment. Glutathione peroxidase 4 (GPX4) has emerged as the vital enzyme to prevent lipid peroxidation and maintain cellular redox homeostasis. However, the mechanism of GPX4 in the regulation of cancer immunotherapy of colon adenocarcinoma (COAD) are incompletely understood. In pan-cancer analysis, we found that GPX4 showed remarkably upregulated expression and exhibited significant association with overall survival in multiple cancer types, especially COAD. Furthermore, upregulated GPX4 expression was positively correlated with increased immune cells infiltration and enhanced expression of immunomodulators. Mechanistically, RBM15B- and IGFBP2-mediated N6-methyladenosine (m6A) modification and NSUN5-mediated 5-methylcytosine (m5C) modification of GPX4 facilitated anticancer immunity via activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) signaling by maintaining redox homeostasis in COAD. The risk model and nomogram model constructed based on the GPX4-derived genes further confirmed the prognostic and treatment-guiding value of GPX4. In all, our study demonstrated that m6A and m5C modification of GPX4 may be a promising target for cancer immunotherapy via activating the cGAS-STING signaling pathway in COAD.