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Caffeine is one of the most popular consumed psychostimulants that mitigates several neurodegenerative diseases. Nevertheless, the roles and molecular mechanisms of caffeine in HIV-associated neurocognitive disorders (HAND) remain largely unclear. Transactivator of transcription (Tat) is a major contributor to the neuropathogenesis of HAND in the central nervous system. In the present study, we determined that caffeine (100 µM) treatment significantly ameliorated Tat-induced decreased astrocytic viability, oxidative stress, inflammatory response and excessive glutamate and ATP release, thereby protecting neurons from apoptosis. Subsequently, SIRT3 was demonstrated to display neuroprotective effects against Tat during caffeine treatment. In addition, Tat downregulated SIRT3 expression via activation of EGR1 signaling, which was reversed by caffeine treatment in astrocytes. Overexpression of EGR1 entirely abolished the neuroprotective effects of caffeine against Tat. Furthermore, counteracting Tat or caffeine-induced differential expression of SIRT3 abrogated the neuroprotection of caffeine against Tat-triggered astrocytic dysfunction and neuronal apoptosis. Taken together, our study establishes that caffeine ameliorates astrocytes-mediated Tat neurotoxicity by targeting EGR1/SIRT3 signaling pathway. Our findings highlight the beneficial effects of caffeine on Tat-induced astrocytic dysfunction and neuronal death and propose that caffeine might be a novel therapeutic drug for relief of HAND. [ABSTRACT FROM AUTHOR]

Background: TNF-α processing inhibitor-1 (TAPI-1) is a known metalloproteinase inhibitor with potential anti-inflammatory effects. However, its anti-cancer effects on esophageal squamous cell carcinoma (ESCC) have not been uncovered. Aim: In the present study, the effects of TAPI-1 on ESCC cell viability, migration, invasion, and cisplatin resistance and the underlying molecular mechanisms were investigated in TE-1 and Eca109 cells. Methods: To this end, TE-1 and Eca109 cells were exposed to TAPI-1 for indicated time intervals. Cell viability was assessed using cell counting kit-8 assay and apoptosis was evaluated using flow cytometry assay. Migration and invasion were assessed using Transwell assays. Gene expressions were analyzed using quantitative reverse transcription polymerase chain reaction. The activation of NF-κB signaling pathway was elucidated via Western blot and chromatin immunoprecipitation assay. Results: We observed that higher doses (10, 20 μM) of TAPI-1 inhibited ESCC cell viability, while a lower dose (5 μM) of TAPI-1 inhibited ESCC cell migration and invasion and enhanced the chemosensitivity of ESCC cells to cisplatin. Moreover, TAPI-1 suppressed the activation of NF-κB signaling and the target genes expression in the stage of transcription initiation. Furthermore, blocking NF-κB signaling in advance could abolish all the effects of TAPI-1 on ESCC cells. Conclusion: Overall, these results indicated that TAPI-1 impairs ESCC cell viability, migration, and invasion and facilitates cisplatin-induced apoptosis via suppression of NF-κB signaling pathway. TAPI-1 may serve as a potential adjuvant agent with cisplatin for ESCC therapy. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is one of the microvascular complications of diabetes mellitus and a major pathological feature of neovascular DR. These patients potentially experience vision impairment and blindness. Platelet-derived growth factor receptor β (PDGFRβ), fibroblast growth factor receptor 1 (FGFR1), and vascular endothelial growth factor receptor 2 (VEGFR2) are implicated in the DR pathogenesis. Nintedanib (BIBF1120) is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of VEGFR2, FGFR1, and PDGFRβ. In this study, intravitreal injection of BIBF1120 blocked the phosphorylation of VEGFR2, FGFR1, PDGFRβ, and MAPK signaling pathway proteins in a streptozotocin (STZ)-induced diabetic retinopathy mouse model. In in vitro cell experiments, BIBF1120 did not change cellular activity under normal conditions, while it further suppressed the tube formation, migration, and proliferation of high glucose-induced human retinal microvascular endothelial cells (HRMECs). Additionally, BIBF1120 blocked the phosphorylation of p38, JNK, and ERK1/2 in high glucose-treating HRMECs. Our results indicate that the BIBF1120 treatment can be a novel potential drug to protect against DR. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is a rare and refractory autoimmune disease, and Qi Shen Di Huang (QSDH) drug formulary is an in-hospital herbal decoction with proven clinical efficacy in treating MG. Currently, most of the research on the QSDH drug formulary has concentrated on its clinical efficacy, and there is a lack of systematic study on the material basis. The active compounds and their mechanism of action have not been entirely determined. Therefore, this study sought to identify the active compounds in the QSDH drug formulary and analyze the key targets and potential mechanisms. We used ultra-performance liquid chromatography Q Exactive-mass spectrometry (UHPLC-QE-MS) and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database to identify and screen 85 active ingredients corresponding to 59 potential targets (17 herbs) associated with myasthenia gravis, and further identified AKT1 as the primary core target and the PI3K/AKT signaling pathway as the most substantial enriched pathway. Molecular docking and UPLC-MS analysis identified quercetin, luteolin, wogonin, kaempferol, laccasein, and epigallocatechin gallate are the core compounds of the QSDH drug formulary. In vivo rat studies showed that the QSDH drug formulary reduced Lennon's clinical score and decreased acetylcholine receptor antibody levels in peripheral blood rats with experimental autoimmune myasthenia gravis. In addition, the QSDH drug formulary downregulated P-PI3K/PI3K and P-Akt/Akt protein expression. Collectively, these findings describe the role and potential mechanism of the QSDH drug formulary in the treatment of MG, which exerts potential value by acting on AKT targets and regulating the PI3K/AKT signaling pathway and providing a theoretical reference for QSDH drug formulary application in the clinical treatment of MG. [ABSTRACT FROM AUTHOR]

Background. Fructus mume pills (FMPs) have been clinically proven to be effective for treating ulcerative colitis (UC). However, the therapeutic and protective mechanisms have not been fully studied. Aim. We aimed to explore the mechanism of FMPs in an acetic acid (AA)-induced ulcerative colitis rat model. Methods. The targets, GO terms, and KEGG pathways for the FMPs and UC were screened and constructed using network pharmacology. A possible mechanism was verified in a 4% AA-induced colitis rat model. Colitis activity and state were evaluated using the disease activity index, and colon ulceration and intestinal mucosal damage were determined by histopathological observation through HE, AB-PAS, and Masson pathological staining. The concentrations of TNF-α, IL-6, IL-8, IL-10, MPO, MMP9, CXCR1, eNOS, and VEGF were measured to evaluate vascular permeability effects. Results. The network pharmacology results showed 108 active compounds, and 139 FMP-related targets were identified. Twenty-nine targets were identified for FMPs against UC, which included MMP9, MMP3, ESR1, PTGS1, PPARA, MPO, and NOS2. A total of 1,536 GO terms and 41 pathways were associated with FMP treatment of UC. The pharmacological evaluation showed that FMPs attenuated inflammation in AA-induced colitis by reducing the serum concentrations of TNF-α, IL-6, IL-8, and IL-10 and the colonic concentrations of MPO, MMP9, and CXCR1. FMPs ameliorated hyperpermeability by reducing the colonic VEGF and eNOS concentrations. FMPs also significantly decreased the VEGFA, VEGFR2, Src, and eNOS protein expressions in colon tissue through the VEGF-PI3K/Akt-eNOS signaling pathway. Conclusion. These results suggest that FMPs control UC inflammation by regulating inflammatory cytokine concentrations. FMPs alleviate AA-induced UC by regulating microvascular permeability through the VEGF-PI3K/Akt-eNOS signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Norwogonin is a natural flavone with three phenolic hydroxyl groups in skeletal structure and has excellent antioxidant activity. However, the neuroprotective effect of norwogonin remains unclear. Here, we investigated the protective capacity of norwogonin against oxidative damage elicited by hypoxia in PC12 cells. Methods: The cell viability and apoptosis were examined by MTT assay and Annexin V-FITC/PI staining, respectively. Reactive oxygen species (ROS) content was measured using DCFH-DA assay. Lactate dehydrogenase (LDH), malondialdehyde (MDA) and antioxidant enzyme levels were determined using commercial kits. The expression of related genes and proteins was measured by real-time quantitative PCR and Western blotting, respectively. Results: We found that norwogonin alleviated hypoxia-induced injury in PC12 cells by increasing the cell viability, reducing LDH release, and ameliorating the changes of cell morphology. Norwogonin also acted as an antioxidant by scavenging ROS, reducing MDA production, maintaining the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and decreasing the expression levels of HIF-1α and VEGF. In addition, norwogonin prevented cell apoptosis via inhibiting the expression levels of caspase-3, cytochrome c and Bax, while increasing the expression levels of Bcl-2 and the ratio of Bcl-2/Bax. Conclusions: Norwogonin attenuates hypoxia-induced injury in PC12 cells by quenching ROS, maintaining the activities of antioxidant enzymes, and inhibiting mitochondrial apoptosis pathway. [ABSTRACT FROM AUTHOR]

To explore the molecular mechanism of the effect of Bacillus cereus PAS38 on the immunity of broilers, sixty 7-day-old broilers were divided into two groups with three replicates. The control group was fed with basal diet, and the treatment group was fed with basal diet containing Bacillus cereus PAS38 1×106 CFU/g. Thymus and bursa of fabricius were taken from two groups of broilers at the age of 42 days, total RNA was extracted, differential gene library was constructed by SSH technology, and immune-related differential genes were screened. Then, we used siRNA to interfere with the expression of some differential genes in the original generation lymphocytes of broiler blood to detect the change of cytokines mRNA expression level. A total of 42 immune-related differentially expressed genes were screened, including 22 up-regulated genes and 20 down-regulated genes. When 7 differentially up-regulated genes associated with enhanced immune function were interfered with in lymphocytes, some immune-promoting cytokines were down-regulated. These results showed that Bacillus cereus PAS38 might up-regulate the expression of JCHAIN, PRDX1, CD3E, CDK6 and other genes in immune organs of broilers, thereby affecting the development of immune organs, the expression of various cytokines and the transduction of immune signals, improving the immune capacity of broilers. [ABSTRACT FROM AUTHOR]

Background. A large number of proinflammatory/anti-inflammatory cytokines are produced in the extracellular matrix (ECM) after myocardial infarction (MI), and the inflammatory pathways activated by these inflammatory stimuli are involved in the regulation of lesions with excessive accumulation of ECM. Wenxin granules can play a protective role against MI, but the mechanism of its effect on the inflammatory pathway and ECM collagen expression is still unclear. Objective. To verify the effect of Wenxin granules on the inflammatory pathway and collagen expression after MI. Method. The proximal left anterior descending coronary artery in rats was ligated to induce acute MI. Then, animals were randomly assigned to the model group, the Carvedilol group, and the Wenxin Granules group. In addition, sham operation rats were used as the control group. 10 rats were allocated in each group. Gavage was given once a day for 4 weeks. The changes of cardiac hemodynamics were detected by the catheter method, morphological changes were observed by HE staining, and myocardial tissue collagen volume was counted by Immunohistochemistry combined with Masson staining, and the expression of inflammatory TGFβ-p38/JNK MAPK signal pathway markers was detected by Western blot. Results. Wenxin granules could significantly improve the hemodynamics, so that the fibrosis scar was relatively dense and uniform, and the residual myocardium was relatively neat, while Collagen type I and III volume and TGFβ expression levels were lessened. Although there were no differences in the expression of CTGF, p38, and JNK proteins, their phosphorylation levels showed significant differences. Conclusion. Wenxin granules can affect the inflammation-related TGFβ-p38/JNK MAPK signaling pathway and change the structural properties of myocardium and scar after MI by attenuated collagen deposition in the left ventricular myocardial tissue to improve cardiac function. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) patients are at high risk of potential lethal arrhythmia. Gap junction and microRNA-1 (miR-1) are both arrhythmia generating conditions. The present study investigated whether Wenxin Granules (Wenxin-Keli, WXKL) could prevent potential lethal arrhythmia by improving gap junctions and miR-1 following MI. Male Sprague-Dawley rats were divided randomly into control, model, metoprolol, low dose WXKL, and high dose WXKL groups. The MI rat model was created by coronary artery ligation. Treatments were administrated intragastrically to the rats for 4 weeks. Conventional transmission electron microscopy was performed to observe the ultrastructure of gap junctions. Quantitative real-time PCR and western blotting were used to detect the expression of miR-1, protein kinase C (PKC), and related proteins. Additionally, a programmatic electrophysiological stimulation test was performed to detect the ventricular fibrillation threshold (VFT). WXKL protected the ultrastructure of the gap junctions and their constituent Cx43 by regulating miR-1 and PKC mediated signal transduction and increased the VFT significantly in the rat MI model. The results suggested that WXKL is an effective alternative medicine to prevent potentially lethal arrhythmia following MI. [ABSTRACT FROM AUTHOR]

Abstract: Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that plays a vital role in the signal transduction of cancers. Hsp90 inhibitors are able to inhibit Hsp90 or the complex of Hsp90 and co-chaperones resulting in the degradation of Hsp90-dependent client proteins through the ubiquitination-proteasome pathway, thereby leading to the growth inhibition of tumor cells. This review will briefly discuss the molecular structure and biological function of Hsp90, and focus on a summary of recent progress in the development and testing of natural Hsp90 inhibitors and their different means by which they interact with Hsp90. [Copyright &y& Elsevier]

The process of atherosclerosis (AS) is complicated. Transcriptomics technology can assist in discovering the underlying mechanisms and exploring the key targets of Traditional Chinese Medicine (TCM) against atherosclerosis. This study aimed to investigate targets and signaling pathways significantly related to AS and the potential intervention targets of Xuefu Zhuyu decoction by transcriptomics. AS models were established by subjecting ApoE-/-mice to an 8-week high-fat diet. Structural changes and plaque formation in the aortic root were observed using hematoxylin-eosin staining (HE staining), while Oil Red O staining was employed to visualize lipid deposition within the aortic root plaque. Movat staining and immunohistochemical staining were conducted to examine the components present in the aortic root plaque. Macrophage content within the plaque was observed through immunofluorescence. Additionally, mRNA sequencing was performed on aortic tissues to identify differentially expressed genes. Enrichment analysis was performed using GO and KEGG analysis. Visualization of the protein-protein interaction (PPI) network was achieved using Cytoscape 3.7.1 and STRING. Western blotting (WB) was employed to assess the protein expression of major differentially expressed genes in the aortic tissue. The drug freeze-dried powder of Xuefu Zhuyu decoction was prepared and the RAW264.7 cells were induced by lipopolysaccharide (LPS) to build an in vitro model. Real-time quantitative PCR was employed to measure the mRNA expression of major differential genes. After ApoE-/- mice were fed with an 8-week high-fat diet, observable changes included the thinning of the aortic root wall, the accumulation of foam cells within the plaque, and the formation of cholesterol crystals in the model group. Treatment with Xuefu Zhuyu (XFZY) decoction for 12 weeks significantly reduced the lipid deposition and the number of macrophages (P < 0.05) and significantly increased the collagen content within the plaque (P < 0.01). Enrichment analysis revealed a high enrichment of the Cytokine-cytokine receptor interaction pathway and Chemokine signaling pathway. Noteworthy genes involved in this response included Ccl12 , Ccl22 , Cx3cr1 , Ccr7 , Ccr2 , Tnfrsf25 , and Gdf5. Xuefu Zhuyu decoction significantly downregulated the expression of CX3CL1 and CX3CR1 (P < 0.05) and upregulated the expression of GDF5 (P < 0.01). Compared with control group, in cell models, the mRNA expressions of Ccl12 , Ccl22 , and Ccr2 were significantly upregulated (P < 0.05 or P < 0.01). Xuefu Zhuyu decoction significantly downregulated the expression of Ccl12 , Ccl22 , Cx3cr1 , Ccr7 and Ccr2 (P < 0.05 or P < 0.01). Xuefu Zhuyu decoction demonstrates effective regulation of plaque components, retarding plaque progression and preserving plaque stability by modulating lipid metabolism and inflammatory responses. Subsequent transcriptome analysis identified the Cytokine-cytokine receptor interaction and Chemokine signaling pathway as potential key pathways for the therapeutic effects of Xuefu Zhuyu decoction. This insight not only provides crucial avenues for further exploration into the mechanisms underlying Xuefu Zhuyu decoction but also offers valuable perspectives and hypotheses for enhancing disease prevention and treatment strategies. [Display omitted] • XFZY reduced lipid deposition and macrophage infiltration, increased collagen of plaques. • Cytokine-cytokine receptor interaction and Chemokine signaling pathways were enriched in AS. • XFZY downregulated CX3CL1 and CX3CR1, and upregulated GDF5. [ABSTRACT FROM AUTHOR]

The traditional Chinese medicine (TCM) formula Banxia Xiexin decoction (BXD) has definite therapeutic effect in treating stress-induced gastric ulceration (SIGU) and many other gastrointestinal diseases, but its effect on gastric lymphatic pumping (GLP) remains unclear. Elucidating the role of GLP in SIGU and BXD treatment, and exploring the molecular mechanisms of GLP regulation. In vivo GLP imaging were performed on SIGU rat model, and the lymphatic dynamic parameters were evaluated. Gastric antrum tissues and serum were collected for macroscopic, histopathological and ulcerative parameters analysis. Gastric lymphatic vessel (GLV) tissues were collected for RNA-Seq assays. Differentially expressed genes (DEGs) were screened from RNA-Seq result and submitted for transcriptomic analysis. Key DEGs and their derivative proteins were measured by qRT-PCR and WB. GLP was significantly suppressed in SIGU rats. BXD could recover GLP, ameliorate stomach lymphostasis, and alleviate the ulcerative damage. Transcriptome analysis of GLV showed the top up-DEGs were concentrated in smooth muscle contraction signaling pathway, while the top the down-DEGs were concentrated in energy metabolism pathways especially fatty acid degradation pathway, which indicated BXD can promote lymphatic smooth muscle contraction, regulate energy metabolism, and reduce fatty acid degradation. The most possible target of these mechanisms was the lymphatic smooth muscle cells (LSMCs) which drove the GLP. This speculation was further validated by the qRT-PCR and WB assessments for the level of key genes and proteins. By activating the smooth muscle contraction signaling pathway, restoring energy supply, modulating energy metabolism program and reducing fatty acid degradation, BXD effectively recovered GLP, mitigated the accumulation of inflammatory cytokines and metabolic wastes in the stomach, which importantly contributes to its efficacy in treating SIGU. [Display omitted] • Banxia Xiexin decoction significantly recovered gastric lymphatic pumping hampered by stress-induced gastric ulceration. • Banxia Xiexin decoction activated the smooth muscle contraction signaling pathway in lymphatic smooth muscle cells. • Banxia Xiexin decoction modulated energy metabolism and reduced fatty acid degradation in lymphatic smooth muscle cells. • Gastric lymphatic pumping recovery and lymphostasis clearance were important for curing stress-induced gastric ulceration. [ABSTRACT FROM AUTHOR]

Aberrant angiogenesis is a hallmark of cancer and is critically associated with tumor progression. Perivascular cells are essential components of blood vessels, and the role of tumor perivascular cell-derived extracellular vesicles (TPC-EVs) in angiogenesis remains elusive. In the present study, using genetic mouse models and pharmacological inhibitors, we found that ablation of perivascular cells inhibited angiogenesis in allografted colorectal cancer tumors. Further studies demonstrated that TPC-EVs promoted the proliferation, migration, invasion, viability, and tube formation of HUVECs. They also facilitated vessel spouting in rat aortic rings and induced neovascularization in chick chorioallantoic membranes (CAMs). Silencing of Gas6 or blockade of the Axl pathway suppressed TPC-EV-induced angiogenesis in vitro and ex vivo. Moreover, inhibition of the Gas6/Axl signaling pathway impaired TPC-EV-mediated angiogenesis in vivo. Our findings present a deeper insight into the biological functions of TPCs and TPC-EVs in tumor angiogenesis and demonstrate that TPC-EV-derived Gas6 could be an attractive and innovative regulator of tumor angiogenesis. [ABSTRACT FROM AUTHOR]

• Vanadium compounds initiate signaling causing membrane protein aggregation. • Novel mechanism of signal transduction involving two tyrosine kinase receptors. • Novel mechanism of signal transduction involving a G protein-coupled receptor. • Perturbations in lipid order caused by vanadium compounds drive cell signaling. • Location of vanadium compound interactions with model membrane systems. As a first-row transition metal, vanadium can undergo numerous hydrolytic and chemical reactions in eukaryotic cells under physiological conditions. In model membrane systems, vanadium compounds interact with the lipid surfactants and either partially or fully penetrate the lipid interface. In eukaryotic cells, vanadium compounds interact with the plasma membrane lipid bilayer and drive signaling by three membrane proteins, identified to date, that function as receptors for physiologically important hormones. Perturbations in lipid order caused by vanadium compounds indirectly drive cell signaling by receptors that, in response to changes in lipid order, become concentrated in plasma membrane rafts. Importantly, this response occurs without binding of ligand to its receptor or direct interactions between receptor and vanadium compounds. We review here results reported for two tyrosine kinase receptors, the insulin receptor involved in regulating glucose uptake into cells and the Type I Fcε receptors (FcεRI) involved in allergic responses. In addition, we examine the effects of vanadium compounds on a G protein-coupled receptor, the luteinizing hormone receptor (LHR), which is important in reproductive functions in both males and females. Together these observations document a novel mechanism of drug action that may be generalizable to other plasma membrane proteins using rafts to signal. [ABSTRACT FROM AUTHOR]

Luteinizing hormone receptors (LHR), expressed at physiological numbers <30,000 receptors per cell, translocate to and signal within membrane rafts following binding of human chorionic gonadotropin (hCG). Similarly LHR signal in cells when treated with bis(maltolato)oxovanadium(IV) (BMOV), bis(ethylmaltolato)oxovanadium(IV) (BEOV) or VOSO 4 , which decrease membrane lipid packing. Overexpressed LHR (>85,000 receptors per cell) are found in larger clusters in polarized homo-transfer fluorescence resonance energy transfer (homo-FRET) studies that were not affected by either hCG or vanadium compounds. Intracellular cyclic adenylate monophosphate (cAMP) levels indicate that only clustered LHR are active and produce the intracellular second messenger, cAMP. When LHR are over-expressed, cell signaling is unaffected by binding of hCG or vanadium compounds. To confirm the existence of intact complex, the EPR spectra of vanadium compounds in cell media were obtained using 1 mM BMOV, BEOV or VOSO 4. These data were used to determine intact complex in a 10 μM solution and verified by speciation calculations. Effects of BMOV and BEOV samples were about two-fold greater than those of aqueous vanadium(IV) making it likely that intact vanadium complex are responsible for effects of LHR function. This represents a new mechanism for activation of a G protein-coupled receptor; perturbations in the lipid bilayer by vanadium compounds lead to aggregation and accumulation of physiological numbers of LHR in membrane raft domains where they initiate signal transduction and production of cAMP, a second messenger involved in signaling. Luteinizing hormone receptors (LHR) accumulate in plasma membrane rafts upon binding of human chorionic gonadotropin (hCG) and initiate signal transduction. The action of hCG is mimicked by bis(maltolato)oxovanadium(IV) which interacts with membrane lipids, reduces lipid packing and, through a different mechanisms than hCG, causes LHR aggregation and signal transduction. Unlabelled Image • Luteinizing hormone receptors (LHR) accumulate in rafts following binding of human chorionic gonadotropin • LHRs in rafts initiate cell signaling • Bis(maltolato)oxovanadium(IV) interacts with membrane lipids and decreases lipid packing • Reduced lipid packing causes aggregation of LHRs in membrane microdomains where receptors signal. [ABSTRACT FROM AUTHOR]

Banxia Xiexin Decoction (BXD) is a traditional Chinese medical formula applied to gastrointestinal (GI) motility disorders. Previous studies showed that miR-451-5p was down-regulated in rats with GI motility disorders induced by gastric electrical dysrhythmia. Interstitial cells of Cajal (ICCs) are pacemakers for GI motility, while loss of ICCs is responsible for GI motility disturbance. Thus, the underlying interaction mechanisms for BXD regulating ICCs apoptosis via miR-451-5p remain to be explored. In this work, the main objectives were to examine the efficacy of BXD on ICCs via miR-451-5p both in GI motility disorders rats model and in vitro, as well as the potential contributions of SCF/c-kit signaling. Rats with gastric electrical dysrhythmia were established in male SD rats by using a single-day diet and a double fasting method (drinking diluted hydrochloric acid water during the period) for 4 weeks. The gastric slow wave (GSW) recording, RT-qPCR, and western blot were performed to examine the effects of BXD on ICCs apoptosis in rats with GED and miR-451-5p expression. In vitro assays included CCK-8, flow cytometry analysis, RT-qPCR, and western blot were applied to investigate the potential molecular mechanism of BXD on ICCs apoptosis via miR-451-5p. BXD promoted gastric motility, reduced ICCs apoptosis, and elevated miR-451-5p in GED rats. In addition, miR-451-5p was significantly up-regulated in ICCs after BXD treatment compared with that in ICCs with miR-451-5p inhibitor transfection. Meanwhile, high miR-451-5p expression with either BXD treatment or miRNA mimics enhanced ICCs proliferation and inhibit apoptosis. Moreover, overexpression of miR-451-5p can reverse G0/G1 arrest in ICCs by BXD treatment. Further, SCF and c-kit protein levels were detected to demonstrate that modulation of miR-451-5p by BXD treatment was involved in this signaling. Through this study, we demonstrated that BXD could promote ICCs proliferation and inhibit apoptosis via miR-451-5p and may involve the modulations of SCF/c-kit signaling, thus suggesting a new therapy basis for GI motility dysfunction from the perspective of modulation of ICCs apoptosis by targeting miR-451-5p. [Display omitted] • Banxia Xiexin Decoction improves gastric motility. • Inhibition of miR-451-5p expression induces interstitial cells of Cajal apoptosis. • Banxia Xiexin Decoction increases miR-451-5p expression. • The protective mechanism involves in SCF/c-kit signaling pathway. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (5'-adenosine monophosphate-activated protein kinase, AMPK)/mammalian target of rapamycin (mTOR) is an important signaling pathway maintaining normal cell function and homeostasis in vivo. The AMPK/mTOR pathway regulates cellular proliferation, autophagy, and apoptosis. Ischemia-reperfusion injury (IRI) is secondary damage that frequently occurs clinically in various disease processes and treatments, and the exacerbated injury during tissue reperfusion increases disease-associated morbidity and mortality. IRI arises from multiple complex pathological mechanisms, among which cell autophagy is a focus of recent research and a new therapeutic target. The activation of AMPK/mTOR signaling in IRI can modulate cellular metabolism and regulate cell proliferation and immune cell differentiation by adjusting gene transcription and protein synthesis. Thus, the AMPK/mTOR signaling pathway has been intensively investigated in studies focused on IRI prevention and treatment. In recent years, AMPK/mTOR pathway-mediated autophagy has been found to play a crucial role in IRI treatment. This article aims to elaborate the action mechanisms of AMPK/mTOR signaling pathway activation in IRI and summarize the progress of AMPK/mTOR-mediated autophagy research in the field of IRI therapy. • The mechanism of AMPK/mTOR mediated autophagy in IRI was summarized. • The preclinical results of AMPK/mTOR treatment IRI with drugs were reviewed. • The role of AMPK/mTOR in multiple organs was summarized. [ABSTRACT FROM AUTHOR]

• The mouse model of cerebral ischemia/reperfusion(MCAO/R) cerebral infarction tissue was where the expression level of BRG1 was initially identified. • The expression level of BRG1 was initially identified in the model of glucose-oxygen deprivation and glucose-reoxygenation(OGD/R) in BV2 cells. • It was discovered for the first time that BRG1 expression levels might impact how BV2 cells are activated. • BRG1 can decrease microglial activation and ROS generation through the KEAP1-NRF2/HO-1 signaling pathway, BRG1 is a key factor in the process of apoptosis and oxidative damage; however, its role in the pathophysiology of ischemic stroke is unclear. Here, we discovered that during middle cerebral artery occlusion (MCAO) reperfusion in mice, microglia were significantly activated in the cerebral cortex of the infarct area, and BRG1 expression was increased in the mouse MCAO/R model, peaking at 4 days. In microglia subjected to OGD/R, BRG1 expression increased and peaked at 12 h after reoxygenation. After ischemic stroke, in vitro changing the expression of BRG1 expression levels greatly altered the activation of microglia and the production of antioxidant and pro-oxidant proteins. Knocking down BRG1 expression levels in vitro increased the inflammatory response, promoted microglial activation, and decreased the expression of the NRF2/HO-1 signaling pathway after ischemic stroke. In contrast, overexpression of BRG1 dramatically reduced the expression of NRF2/HO-1 signaling pathway and microglial activation. Our research reveals that BRG1 reduces postischemic oxidative damage via the KEAP1-NRF2/HO-1 signaling pathway, protecting against brain ischemia/reperfusion injury. Using BRG1 as a pharmaceutical target to inhibit inflammatory responses to reduce oxidative damage may be a unique way to explore techniques for the treatment of ischemic stroke and other cerebrovascular illnesses. [ABSTRACT FROM AUTHOR]

Sam68 (Src-associated substrate during mitosis of 68 KDa), also known as KHDRBS1 (KH domain containing, RNA binding, signal transduction associated 1), belongs to the prototypic member of the signal transduction activator of RNA (STAR) family of RNA-binding proteins. Sam68 is implicated in various cellular processes including RNA metabolism, apoptosis, signal transduction. Previous researches demonstrated that Sam68 regulated nuclear transcription factor kappa B (NF-κB) to induce inflammation. However, the expression and biological functions of Sam68 in ulcerative colitis (UC) are not clear. In this study, we reported for the first time that Sam68 was up-regulated in intestinal epithelial cells (IECs) of patients with UC. In DSS-induced mouse colitis model, we observed the overexpression of Sam68 accompanied with increased levels of IEC apoptotic markers (active caspase-3 and cleaved PARP) and NF-κB activation indicators (p-p65 and p-IκB) in colitis IECs. Co-localization of Sam68 with active caspase-3 (and p-p65) in IECs of the DSS-induced colitis group further indicated the possible involvement of NF-κB-mediated IEC apoptosis. Applying TNF-α-treated HT-29 cells as an in vitro IEC inflammation model, we confirmed the positive correlation amomg Sam68, NF-κB activation and caspase-dependent apoptosis. Immunofluorescence and immunoprecipitation assay identified nuclear translocation and physical interaction of Sam68 and NF-κB subunits in TNF-α-treated HT-29 cells. Besides, depletion of Sam68 by RNA interference greatly alleviated NF-κB activation and apoptosis in TNF-α-treated HT-29 cells. Taken together, our results indicated that Sam68 modulates apoptosis of intestinal epithelial cells via mediating NF-κB activation in UC. [ABSTRACT FROM AUTHOR]

ErbB3 binding protein-1 (EBP1) belongs to a family of DNA/RNA binding proteins implicated in cell growth, differentiation and apoptosis. Previous data demonstrated that EBP1 regulates phosphorylation of Akt to drive tumor progress. However, the expression and biological functions of EBP1 in ulcerative colitis (UC) remain unclear. In this study, we reported for the first time that EBP1 was down-regulated in intestinal epithelial cell (IECs) of patients with UC. In DSS-induced colitis, we observed the down-regulation of EBP1 accompanied with the elevated levels of proinflammatory cytokines (IL-1β, IL-6 and IL-8) and Akt activation indicators (phosphorylated Akt) in colitis IECs, indicating the possible involvement of EBP1 in regulation of intestinal inflammation via mediating Akt in UC. Employing the TNF-α-treated HT-29 cells as an IEC inflammatory model, we confirmed the negative correlation of EBP1 with Akt activation and Akt-dependent inflammation progress in vitro . EBP1 knocking down and over-expression significantly regulated TNF-α-induced Akt activation and proinflammatory cytokines expression in HT-29 cells. Taken together, our data suggested that EBP1 participates in the regulation of intestinal inflammation via mediating Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis is crucial for carcinogenesis and other angiogenic processes. Arenobufagin, one of the major components of toad venom, is a traditional Chinese medicine used for cancer therapy. It inhibits cell growth in several cancer cell lines. However, little is known about arenobufagin''s anti-angiogenic activity. In this study, we showed that arenobufagin inhibited vascular endothelial growth factor (VEGF)-induced viability, migration, invasion and tube formation in human umbilical vein endothelial cells (HUVECs) in vitro. Arenobufagin also suppressed sprouting formation from VEGF-treated aortic rings in an ex vivo model. Furthermore, we found that arenobufagin blocked angiogenesis in a matrigel plugs assay. Computer simulations suggested that arenobufagin interacted with the ATP-binding sites of VEGFR-2 by docking. In addition, arenobufagin inhibited VEGF-induced VEGFR-2 auto-phosphorylation and suppressed the activity of VEGFR-2-mediated signaling cascades. Taken together, our findings demonstrate that arenobufagin is a specific inhibitor of VEGF-mediated angiogenesis. [Copyright &y& Elsevier]

Abstract: Damage-associated molecular patterns (DAMPs) are signals released from dying cells evoking the immune system response in several inflammatory disorders. In normal situations, many of DAMPs are nuclear or cytosolic proteins with defined intracellular function, but they could be found on the cell surface following tissue injury. The biological function of the translocated DAMPs is still not well known and an efficient delivery of these molecules on the cell surface is required to clarify their biological effects. In this study, we demonstrated that an unclassical secretory signal peptide, N-terminal 18 amino acids of HASPB (HASPB-N18), could efficiently deliver Hsp60, Hsp70, and HMGB1 on the cell surface. Furthermore, the delivery of these molecules on the cell surface by HASPB-N18 is not limited to a special cell line because several cell lines could use this delivery signal to deliver these molecules on the cell surface. Moreover, we demonstrated that Hsp60 on the cell surface delivered by HASPB-N18 could be recognized by a soluble form of LOX-1, which implies that DAMPs on the cell surface delivered by HASPB-N18 have a proper conformation during transport. Therefore, delivery of DAMPs by HASPB-N18 is a reliable model to further understand the biological significance of DAMPs on the cell surface. [ABSTRACT FROM AUTHOR]