Amplifying hepatic L-aspartate levels suppresses CCl4-induced liver fibrosis by reversing glucocorticoid receptor ß-mediated mitochondrial malfunction.

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor ß (GRß) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRß ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRß signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRß signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.

Transcriptomic profiling of gastrointestinal tracts in dairy cattle during lactation reveals molecular adaptations for milk synthesis.

During lactation, dairy cattle's digestive tract requires significant adaptations to meet the increased nutrient demands for milk production. As we attempt to improve milk-related traits through selective pressure, it is crucial to understand the biological functions of the epithelia of the rumen, small intestine, and colonic tissues in response to changes in physiological state driven by changes in nutrient demands for milk synthesis. In this study, we obtained a total of 108 transcriptome profiles from three tissues (epithelia of the colon, duodenum, and rumen) of five Holstein cows, spanning eight time points from the early, mid, late lactation periods to the dry period. On average 97.06% of reads were successfully mapped to the reference genome assembly ARS-UCD1.2. We analyzed 27,607 gene expression patterns at multiple periods, enabling direct comparisons within and among tissues during different lactation stages, including early and peak lactation. We identified 1645, 813, and 2187 stage-specific genes in the colon, duodenum, and rumen, respectively, which were enriched for common or specific biological functions among different tissues. Time series analysis categorized the expressed genes within each tissue into four clusters. Furthermore, when the three tissues were analyzed collectively, 36 clusters of similarly expressed genes were identified. By integrating other comprehensive approaches such as gene co-expression analyses, functional enrichment, and cell type deconvolution, we gained profound insights into cattle lactation, revealing tissue-specific characteristics of the gastrointestinal tract and shedding light on the intricate molecular adaptations involved in nutrient absorption, immune regulation, and cellular processes for milk synthesis during lactation.

CUX1 attenuates the apoptosis of renal tubular epithelial cells induced by contrast media through activating the PI3K/AKT signaling pathway.

OBJECTIVE: Contrast media (CM) is a commonly applied drug in medical examination and surgery. However, contrast-induced acute kidney injury (CIAKI) poses a severe threat to human life and health. Notably, the CUT-like homeobox 1 (CUX1) gene shows protective effects in a variety of cells. Therefore, the objective of this study was to provide a new target for the treatment of CIAKI through exploring the role and possible molecular mechanism of CUX1 in CIAKI. METHOD: Blood samples were collected from 20 patients with CIAKI and healthy volunteers. Human kidney 2 (HK-2) cells were incubated with 200 mg/mL iohexol for 6 h to establish a contrast-induced injury model of HK-2 cells. Subsequently, qRT-PCR was used to detect the relative mRNA expression of CUX1; CCK-8 and flow cytometry to assess the proliferation and apoptosis of HK-2 cells; the levels of IL(interleukin)-1ß, tumor necrosis factor alpha (TNF-α) and malondialdehyde (MDA) in cells and lactate dehydrogenase (LDH) activity in cell culture supernatant were detect; and western blot to observe the expression levels of CUX1 and the PI3K/AKT signaling pathway related proteins [phosphorylated phosphoinositide 3-kinase (p-PI3K), PI3K, phosphorylated Akt (p-AKT), AKT]. RESULTS: CUX1 expression was significantly downregulated in blood samples of patients with CIAKI and contrast-induced HK-2 cells. Contrast media (CM; iohexol) treatment significantly reduced the proliferation of HK-2 cells, promoted apoptosis, stimulated inflammation and oxidative stress that caused cell damage. CUX1 overexpression alleviated cell damage by significantly improving the proliferation level of HK-2 cells induced by CM, inhibiting cell apoptosis, and reducing the level of LDH in culture supernatant and the expression of IL-1ß, TNF-α and MDA in cells. CM treatment significantly inhibited the activity of PI3K/AKT signaling pathway activity. Nevertheless, up-regulating CUX1 could activate the PI3K/AKT signaling pathway activity in HK-2 cells induced by CM. CONCLUSION: CUX1 promotes cell proliferation, inhibits apoptosis, and reduces inflammation and oxidative stress in CM-induced HK-2 cells to alleviate CM-induced damage. The mechanism of CUX1 may be correlated with activation of the PI3K/AKT signaling pathway.

Ent-eudesmane sesquiterpenoids with anti-neuroinflammatory activity from the marine-derived fungus Eutypella sp. F0219.

In this study, twenty-three ent-eudesmane sesquiterpenoids (1-23) including fifteen previously undescribed ones, named eutypelides A-O (1-15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2-15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1-23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1ß, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents.

Transcriptomic analysis reveals the crosstalk between type 2 diabetes and chronic pancreatitis.

Background and Aims: Mounting evidence highlights a strong association between chronic pancreatitis (CP) and type 2 diabetes (T2D), although the exact mechanism of interaction remains unclear. This study aimed to investigate the crosstalk genes and pathogenesis between CP and T2D. Methods: Transcriptomic gene expression profiles of CP and T2D were extracted from Gene Expression Omnibus, respectively, and the common differentially expressed genes (DEGs) were subsequently identified. Further analysis, such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction, transcription factors (TFs), microRNA (miRNAs), and candidate chemicals identification, was performed to explore the possible common signatures between the two diseases. Results: In total, we acquired 281 common DEGs by interacting CP and T2D datasets, and identified 10 hub genes using CytoHubba. GO and KEGG analyses revealed that endoplasmic reticulum stress and mitochondrial dysfunction were closely related to these common DEGs. Among the shared genes, EEF2, DLD, RAB5A, and SLC30A9 showed promising diagnostic value for both diseases based on receiver operating characteristic curve and precision-recall curves. Additionally, we identified 16 key TFs and 16 miRNAs that were strongly correlated with the hub genes, which may serve as new molecular targets for CP and T2D. Finally, candidate chemicals that might become potential drugs for treating CP and T2D were screened out. Conclusion: This study provides evidence that there are shared genes and pathological signatures between CP and T2D. The genes EEF2, DLD, RAB5A, and SLC30A9 have been identified as having the highest diagnostic efficiency and could be served as biomarkers for these diseases, providing new insights into precise diagnosis and treatment for CP and T2D.

[Clinical study of constructing nomogram model based on multi-dimensional clinical indicators to predict prognosis of knee osteoarthritis].

OBJECTIVE: To analyze the factors affecting the prognosis of patients with knee osteoarthritis, and to construct a nomogram prediction model in conjunction with multi-dimensional clinical indicators. METHODS: The clinical data of 234 patients with knee osteoarthritis who were treated in our hospital from January 2015 to June 2021 were retrospectively analyzed, including 126 males and 108 females；age more than 60 years old for 135 cases, age less than 60 years old for 99 cases. Lysholm knee function score was used to evaluate the prognosis of the patients, and the patients were divided into good prognosis group for 155 patients and poor prognosis group for 79 patients according to the prognosis. The clinical data of the subjects in the experimental cohort were analyzed by single factor and multiple factors. The patients were divided into experimental cohort and verification cohort, the results of the multiple factor analysis were visualized to obtain a nomogram prediction model, the receiver operating characteristic curve（ROC）, calibration curve and decision curve were used to evaluate the model's discrimination, accuracy and clinical benefit rate. RESULTS: The results of multivariate analysis showed that smoking, pre-treatment K-L grades of Ⅲ to Ⅳ, and high levels of interleukin 6 （IL-6） and matrix metallo proteinase-3 （MMP-3） were risk factors for the prognosis of patients with knee osteoarthritis. ROC test results showed that the area under the curve of the nomogram model in the experimental cohort and validation cohort was 0.806[95%CI（0.742, 0.866）] and 0.786[（95%CI（0.678, 0.893）], respectively. The results of the calibration curve showed that the Brier values of the experimental cohort and verification cohort were 0.151 points and 0.134 points, respectively. When the threshold probability value in the decision curve was set to 31%, the clinical benefit rates of the experimental cohort and validation cohort were 51% and 56%, respectively. CONCLUSION: The prognostic model of patients with knee osteoarthritis constructed based on multi-dimensional clinical data has both theoretical and practical significance, and can provide a reference for taking targeted measures to improve the prognosis of patients.

Strategies for developing layered oxide cathodes, carbon-based anodes, and electrolytes for potassium ion batteries.

Lithium-ion batteries (LIBs) have become the most popular portable secondary energy storage facilities. However, the limited lithium resource results in possible unsustainable development. Potassium-ion batteries (PIBs) are considered promising alternatives to LIBs because of their high resource availability, low cost, and environmentally friendly features. In this field, high energy density layered cathodes and carbon-based anodes are also the main research objectives. However, compared to the most appealing alternative sodium-ion batteries (SIBs), despite having various theoretical advantages, PIBs exhibit poorer electrochemical performance in practice. Their poor capacity retention and narrow working voltage range seriously limit their applications. The performance of the electrodes is usually considered an important factor for battery performance, life, and safety. To solve these problems, many significant research studies have been carried out in the last decade, achieving numerous breakthroughs. Nevertheless, there are still many drawbacks and unclear mechanisms. In this comprehensive review, we examine the current state of high-performance layered oxide cathodes, electrolytes, and carbon-based anodes, to identify potential candidates for PIBs. Our focus lies on their structural characteristics, interface properties, underlying mechanisms, and modification techniques. The viewpoints of these advanced strategies are integrated, and concise development suggestions and strategies are subsequently proposed.

Heating tumors with tumor cell-derived nanoparticles to enhance chemoimmunotherapy for colorectal cancer.

Aim: To investigate the mechanism of doxorubicin (DOX)-induced immunogenic cell death (ICD) and to improve immunotherapy efficacy. Materials & methods: In this study, hybrid vesicles containing DOX (HV-DOX) were prepared by thin-film hydration with extrusion, and the formulated nanoparticles were characterized physically. Furthermore, in vitro experiments and animal models were used to investigate the efficacy and new mechanisms of chemotherapy combined with immunotherapy. Results: DOX improved tumor immunogenicity by alkalinizing lysosomes, inhibiting tumor cell autophagy and inducing ICD. HVs could activate dendritic cell maturation, synergistically enhancing chemotherapeutic immunity. Conclusion: The mechanism of DOX-induced ICD was explored, and antitumor immunity was synergistically activated by HV-DOX to improve chemotherapeutic drug loading and provide relevant antigenic information.

CLIC1-mediated autophagy confers resistance to DDP in gastric cancer.

Gastric cancer has been a constant concern to researchers as one of the most common malignant tumors worldwide. The treatment options for gastric cancer include surgery, chemotherapy and traditional Chinese medicine. Chemotherapy is an effective treatment for patients with advanced gastric cancer. Cisplatin (DDP) has been approved as a critical chemotherapy drug to treat various kinds of solid tumors. Although DDP is an effective chemotherapeutic agent, many patients develop drug resistance during treatment, which has become a severe problem in clinical chemotherapy. This study aims to investigate the mechanism of DDP resistance in gastric cancer. The results show that intracellular chloride channel 1 (CLIC1) expression was increased in AGS/DDP and MKN28/DDP, and as compared to the parental cells, autophagy was activated. In addition, the sensitivity of gastric cancer cells to DDP was decreased compared to the control group, and autophagy increased after overexpression of CLIC1. On the contrary, gastric cancer cells were more sensitive to cisplatin after transfection of CLIC1siRNA or treatment with autophagy inhibitors. These experiments suggest that CLIC1 could alter the sensitivity of gastric cancer cells to DDP by activating autophagy. Overall, the results of this study recommend a novel mechanism of DDP resistance in gastric cancer.

Unraveling the Genetic Basis of Feed Efficiency in Cattle through Integrated DNA Methylation and CattleGTEx Analysis.

Feed costs can amount to 75 percent of the total overhead cost of raising cows for milk production. Meanwhile, the livestock industry is considered a significant contributor to global climate change due to the production of greenhouse gas emissions, such as methane. Indeed, the genetic basis of feed efficiency (FE) is of great interest to the animal research community. Here, we explore the epigenetic basis of FE to provide base knowledge for the development of genomic tools to improve FE in cattle. The methylation level of 37,554 CpG sites was quantified using a mammalian methylation array (HorvathMammalMethylChip40) for 48 Holstein cows with extreme residual feed intake (RFI). We identified 421 CpG sites related to 287 genes that were associated with RFI, several of which were previously associated with feeding or digestion issues. Activator of transcription and developmental regulation (AUTS2) is associated with digestive disorders in humans, while glycerol-3-phosphate dehydrogenase 2 (GPD2) encodes a protein on the inner mitochondrial membrane, which can regulate glucose utilization and fatty acid and triglyceride synthesis. The extensive expression and co-expression of these genes across diverse tissues indicate the complex regulation of FE in cattle. Our study provides insight into the epigenetic basis of RFI and gene targets to improve FE in dairy cattle.

Changes in the structural and physicochemical characteristics of sonicated potato flour.

Ultrasound has been widely used for physical modifications of starch because of its effectiveness and environment friendliness; however, only a few reports have focused on the effect of varying ultrasonic treatments on the physicochemical properties of potato flour. In the present study, ultrasound at varying power levels (200, 300, 400, 500, and 600 W) and time intervals (20, 40, 60, 80, and 100 min) were used to obtain sonicated flour. Sonicated potato flour exhibited a significant (P < 0.05) decrease in blue value and oil holding capacity but an increase in swelling power, water solubility, syneresis rate, and transparency. Moreover, ultrasound decreased the RDS content while increasing RS and SDS contents. Thermal properties demonstrated significant (P < 0.05) increases in T0 (64.39℃-83.52℃) and TC (144.29℃-146.87℃) but a decrease in ΔH of the sonicated flour. SEM revealed wrinkles, less debris, and larger particle size at the surface of the sonicated flour. FTIR profiles of all samples exhibited similar characteristics peaks, but the sonicated flour had a higher R1047/1022 value. Additionally, ultrasound did not affect crystalline patterns, but it increased the crystallinity of the sonicated flour. Our study contributes to the understanding of physicochemical property changes of sonicated potato flour, which could have industrial applications.

Sodium Butyrate Induces Mitophagy and Apoptosis of Bovine Skeletal Muscle Satellite Cells through the Mammalian Target of Rapamycin Signaling Pathway.

Sodium butyrate (NaB) is one of the short-chain fatty acids and is notably produced in large amounts from dietary fiber in the gut. Recent evidence suggests that NaB induces cell proliferation and apoptosis. Skeletal muscle is rich in plenty of mitochondrial. However, it is unclear how NaB acts on host muscle cells and whether it is involved in mitochondria-related functions in myocytes. The present study aimed to investigate the role of NaB treatment on the proliferation, apoptosis, and mitophagy of bovine skeletal muscle satellite cells (BSCs). The results showed that NaB inhibited proliferation, promoted apoptosis of BSCs, and promoted mitophagy in a time- and dose-dependent manner in BSCs. In addition, 1 mM NaB increased the mitochondrial ROS level, decreased the mitochondrial membrane potential (MMP), increased the number of autophagic vesicles in mitochondria, and increased the mitochondrial DNA (mtDNA) and ATP level. The effects of the mTOR pathway on BSCs were investigated. The results showed that 1 mM NaB inhibited the mRNA and protein expression of mTOR and genes AKT1, FOXO1, and EIF4EBP1 in the mTOR signaling pathway. In contrast, the addition of PP242, an inhibitor of the mTOR signaling pathway also inhibited mRNA and protein expression levels of mTOR, AKT1, FOXO1, and EIF4EBP1 and promoted mitophagy and apoptosis, which were consistent with the effect of NaB treatment. NaB might promote mitophagy and apoptosis in BSCs by inhibiting the mTOR signaling pathway. Our results would expand the knowledge of sodium butyrate on bovine skeletal muscle cell state and mitochondrial function.

Efficacy and safety of Huashi Baidu granule plus Nirmatrelvir-Ritonavir combination therapy in patients with high-risk factors infected with Omicron (B.1.1.529): A multi-arm single-center, open-label, randomized controlled trial.

BACKGROUND: Huashi Baidu granule (HSBD) and Paxlovid (Nirmatrelvir-Ritonavir) are antiviral Chinese patent medicine and western medicine specially developed for treating coronavirus disease 2019 (COVID-19). Their efficacy and safety in treating COVID-19 are still under investigated. PURPOSE: To assess and compare the efficacy and safety of HSBD, Paxlovid, and the combination in treating high-risk patients infected with SARS-CoV-2 Omicron. STUDY DESIGN: The study was a prospective single-center, open-label, randomized, controlled clinical trial conducted from April 18 to June 5, 2022. (ClinicalTrial.gov registration number: ChiCTR2200059390) METHODS: 312 severe patients aged 18 years and older infected with SARS-CoV-2 Omicron from Shuguang Hospital in Shanghai were randomly allocated to HSBD monotherapy (orally 137 g twice daily for 7 days, n = 105), Paxlovid monotherapy (orally 300 mg of Nirmatrelvir plus 100 mg of Ritonavir every 12 h for 5 days, n = 103), or combination therapy (n = 104). The primary outcome was SARS-CoV-2 nucleic acid negative conversion within 7-day treatment. The secondary outcome included hospital discharging conditions, severe conversion of symptom, and adverse events. RESULTS: Of 312 participants, 85 (82%) of 104 in combination therapy, 71 (68%) of 105 in HSBD monotherapy, and 73 (71%) of 103 in Paxlovid monotherapy had a primary outcome event. The hazard ratios of primary outcome were 1.37 (95% CI 1.03 - 1.84, p = 0.012) for combination versus HSBD, 1.28 (0.98-1.69, p = 0.043) for combination versus Paxlovid, and 0.88 (0.66-1.18, p = 0.33) for HSBD versus Paxlovid. There was no statistical difference of efficacy between HSBD and Paxlovid, while combination therapy exhibited more effective than either alone. For secondary outcomes, the hospital discharging rates within 7 days exhibited the significant increase in combination therapy than in HSBD or Paxlovid monotherapy (71% (74/104) vs 55% (58/105) vs 52% (54/103), p < 0.05). The risk of severe conversion of symptom showed no statistical significance among three interventions (1% (1/104) vs 3% (3/105) vs 3% (3/103), p > 0.05). No severe adverse events occurred among combination therapy and monotherapies in the trial. CONCLUSION: For patients with severe COVID-19, HSBD exhibits similar efficacy to Paxlovid, while combination therapy is more likely to increase the curative efficacy of Omicron variant than monotherapies, with few serious adverse events.

The single-cell transcriptome and chromatin accessibility datasets of peripheral blood mononuclear cells in Chinese holstein cattle.

OBJECTIVES: This study was performed in the frame of a more extensive study dedicated to the integrated analysis of the single-cell transcriptome and chromatin accessibility datasets of peripheral blood mononuclear cells (PBMCs) with a large-scale GWAS of 45 complex traits in Chinese Holstein cattle. Lipopolysaccharide (LPS) is a crucial mediator of chronic inflammation to modulate immune responses. PBMCs include primary T and B cells, natural killer (NK) cells, monocytes (Mono), and dendritic cells (DC). How LPS stimulates PBMCs at the single-cell level in dairy cattle remains largely unknown. DATA DESCRIPTION: We sequenced 30,756 estimated single cells and mapped 26,141 of them (96.05%) with approximately 60,075 mapped reads per cell after quality control for four whole-blood treatments (no, 2 h, 4 h, and 8 h LPS) by single-cell RNA sequencing (scRNA-seq) and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq). Finally, 7,107 (no), 9,174 (2 h), 6,741 (4 h), and 3,119 (8 h) cells were generated with ~ 15,000 total genes in the whole population. Therefore, the single-cell transcriptome and chromatin accessibility datasets in this study enable a further understanding of the cell types and functions of PBMCs and their responses to LPS stimulation in vitro.

Genome-Wide Acetylation Modification of H3K27ac in Bovine Rumen Cell Following Butyrate Exposure.

Butyrate contributes epigenetically to the changes in cellular function and tissue development of the rumen in ruminant animals, which might be achieved by its genetic or epigenetic regulation of gene expression. To explore the role of butyrate on bovine rumen epithelial function and development, this study characterized genome-wide H3K27ac modification changes and super-enhancer profiles in rumen epithelial primary cells (REPC) induced with butyrate by ChIP-seq, and analyzed its effects on gene expression and functional pathways by integrating RNA-seq data. The results showed that genome-wide acetylation modification was observed in the REPC with 94,675 and 48,688 peaks in the butyrate treatment and control group, respectively. A total of 9750 and 5020 genes with increased modification (H3K27ac-gain) and decreased modification (H3K27ac-loss) were detected in the treatment group. The super-enhancer associated genes in the butyrate-induction group were involved in the AMPK signaling pathway, MAPK signaling pathway, and ECM-receptor interaction. Finally, the up-regulated genes (PLCG1, CLEC3B, IGSF23, OTOP3, ADTRP) with H3K27ac gain modification by butyrate were involved in cholesterol metabolism, lysosome, cell adhesion molecules, and the PI3K-Akt signaling pathway. Butyrate treatment has the role of genome-wide H3K27ac acetylation on bovine REPC, and affects the changes in gene expression. The effect of butyrate on gene expression correlates with the acetylation of the H3K27ac level. Identifying genome-wide acetylation modifications and expressed genes of butyrate in bovine REPC cells will expand the understanding of the biological role of butyrate and its acetylation.

Atorvastatin reduces contrast media-induced pyroptosis of renal tubular epithelial cells by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired renal failure. However, there is no effective treatment of CI-AKI, and its mechanism is unknown. Interestingly, atorvastatin has been reported to be effective in renal injury. Therefore, the aim of this study was to explore the effect and possible molecular mechanism of atorvastatin in CI-AKI. METHODS: On the CI-AKI in vitro model, rat tubular epithelial cells (NRK-52E) were treated with 18 mg I/ml meglumine diatrizoate (MEG) and then pretreated with atorvastatin. pcDNA3.1-TLR4 treatment was performed to overexpress toll-like receptor 4 (TLR4) in NRK-52E cells. Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) kits were used to detect NRK-52E cell viability as well as LDH release in each group, respectively; qRT-PCR to determine mRNA expression of TLR4 in cells; western blot to detect protein expression levels of pyroptosis-related proteins (NLRP3, caspase-1, ASC, and GSDMD) and TLR4/MyD88/NF-κB signaling pathway-related proteins (TLR4, MyD88, NF-κBp65, and p-NF-κB p65) in cells. RESULTS: MEG treatment significantly inhibited the viability of NRK-52E cells, increased pro-inflammatory factor levels and promoted pyroptosis, representing successful establishment of a rat tubular epithelial cell (NRK-52E) CI-AKI in vitro model. Notably, atorvastatin increased the activity of MEG-treated NRK-52E cells and alleviated cell injury in a concentration-dependent manner. In addition, atorvastatin significantly down-regulated the expression of TLR4 in MEG-treated NRK-52E cells. However, overexpression of TLR4 inhibited the effects of atorvastatin on increasing cell viability, alleviating cell injury, reducing pro-inflammatory factors (IL-1ß, IL-6, and TNF-α) levels, and inhibiting apoptosis (by down-regulating the expression of NLRP3, caspase-1, ASC, and GSDMD). Furthermore, atorvastatin also inhibited the expression of TLR4/MyD88/NF-κB pathway-related proteins (TLR4, MyD88, and p-NF-κB p65). CONCLUSION: Atorvastatin can attenuate CI-AKI through increasing the activity of MEG-treated renal tubular epithelial cells, relieving cell injury, as well as inhibiting pyroptosis and inflammation. More importantly, the mechanism was achieved by inhibiting the TLR4//MyD88/NF-κB signaling pathway.

Chaihu Shugan San promotes gastric motility in rats with functional dyspepsia by regulating Drp-1-mediated ICC mitophagy.

CONTEXT: Chaihu Shugan San (CHSGS) was effective in the treatment of functional dyspepsia (FD). OBJECTIVE: To investigate the mechanism of CHSGS in FD through dynamin-related protein 1 (Drp-1)-mediated interstitial cells of cajal (ICC) mitophagy. MATERIALS AND METHODS: Forty Sprague-Dawley (SD) rats were randomly divided into control, model, mdivi-1, mdivi-1 + CHSGS and CHSGS groups. Tail-clamping stimulation was used to establish the FD model. Mdivi-1 + CHSGS and CHSGS groups were given CHSGS aqueous solution (4.8 g/kg) by gavage twice a day. Mdivi-1 (25 mg/kg) was injected intraperitoneally once every other week for 4 w. Mitochondrial damage was observed by corresponding kits and related protein expressions were assessed by Immunofluorescence and (or) Western Blot. RESULTS: Compared with the mean value of the control group, superoxide dismutase (SOD) and citrate synthase (CS) in the model group were decreased by 11% and 35%; malondialdehyde (MDA) and reactive oxygen species (ROS) were increased by 1.2- and 2.8-times; ckit fluorescence and protein expressions were decreased by 85% and 51%, co-localization expression of LC3 and voltage dependent anion channel 1 (VDAC1), Drp-1 and translocase of the outer mitochondrial membrane 20 (Tom20) were increased by 10.1- and 5.4-times; protein expressions of Drp-1, Beclin-1, and LC3 were increased by 0.5-, 1.4-, and 2.5-times whereas p62 was decreased by 43%. After mdivi-1 and (or) CHSGS intervention, the above situation has been improved. DISCUSSION AND CONCLUSION: CHSGS could improve mitochondrial damage and promote gastric motility in FD rats by regulating Drp-1-mediated ICC mitophagy.

Synthetic Topological Vacua of Yang-Mills Fields in Bose-Einstein Condensates.

Topological vacua are a family of degenerate ground states of Yang-Mills fields with zero field strength but nontrivial topological structures. They play a fundamental role in particle physics and quantum field theory, but have not yet been experimentally observed. Here we report the first theoretical proposal and experimental realization of synthetic topological vacua with a cloud of atomic Bose-Einstein condensates. Our setup provides a promising platform to demonstrate the fundamental concept that a vacuum, rather than being empty, has rich spatial structures. The Hamiltonian for the vacuum of topological number n=1 is synthesized and the related Hopf index is measured. The vacuum of topological number n=2 is also realized, and we find that vacua with different topological numbers have distinctive spin textures and Hopf links. Our Letter opens up opportunities for exploring topological vacua and related long-sought-after instantons in tabletop experiments.

Access to Sulfur-Containing Bisheterocycles through Base-Promoted Consecutive Tandem Cyclization/Sulfenylation with Elemental Sulfur.

A convenient and efficient tandem cyclization/sulfenylation of o-alkynyl-phenols/-anilines/enaminones for the synthesis of diverse sulfur-containing bisheterocycles has been developed using stable, odorless, and easy-to-handle elemental S8 as a building block under green chemistry conditions. Notably, a one-step simple base-mediated organic transformation affords a benzofuran (indole or chromone) ring and two C-S bonds. Attractive features of this methodology include the absence of a metal catalyst, mild conditions, good functional group tolerance, and valuable product structures.

Butyrate Induces Modifications of the CTCF-Binding Landscape in Cattle Cells.

Butyrate is produced in the rumen from microbial fermentation and is related to several functions, including cell differentiation and proliferation. Butyrate supplementation in calves can accelerate rumen development. DNA-protein interactions, such as the CCCTC-binding factor (CTCF), play essential roles in chromatin organization and gene expression regulation. Although CTCF-binding sites have been identified recently in cattle, a deeper characterization, including differentially CTCF-binding sites (DCBS), is vital for a better understanding of butyrate's role in the chromatin landscape. This study aimed to identify CTCF-binding regions and DCBS under a butyrate-induced condition using ChIP-seq in bovine cells; 61,915 CTCF peaks were identified in the butyrate and 51,347 in the control. From these regions, 2265 DCBS were obtained for the butyrate vs. control comparison, comprising ~90% of induced sites. Most of the butyrate DCBS were in distal intergenic regions, showing a potential role as insulators. Gene ontology enrichment showed crucial terms for the induced DCBS, mainly related to cellular proliferation, cell adhesion, and growth regulation. Interestingly, the ECM-receptor interaction pathway was observed for the induced DCBS. Motif enrichment analysis further identified transcription factors, including CTCF, BORIS, TGIF2, and ZIC3. When DCBS was integrated with RNA-seq data, putative genes were identified for the repressed DCBS, including GATA4. Our study revealed promising candidate genes in bovine cells by a butyrate-induced condition that might be related to the regulation of rumen development, such as integrins, keratins, and collagens. These results provide a better understanding of the function of butyrate in cattle rumen development and chromatin landscape regulation.