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Abstract Objectives MicroRNAs are considered as a class of potential biomarkers for HF. This study aimed to retrospectively evaluate the diagnostic and prognostic value of microRNA423-5p in patients with HF. Methods The observational group comprised 98 patients diagnosed with HF due to coronary atherosclerotic heart disease (n = 45), hypertension (n = 26), or cardiac valve insufficiency (n = 27). Conversely, the control group consisted of 30 healthy volunteers without any history of HF. These patients were further classified into heart function class II (n = 33), class III (n = 32), and class IV (n = 33) according to the NYHA classification. Of these patients, 33 were diagnosed with HF with mid-range ejection fraction (HFmrEF) and the remaining 65 with HF with reduced ejection fraction (HFrEF). The diagnostic and prognostic significance of microRNA423-5p in patients with HF was assessed through laboratory parameter assessments (microRNA423-5p and B-type natriuretic peptide test, BNP), cardiac ultrasound evaluations (left ventricular ejection fraction, LVEF), and subsequent follow-up assessments. Results In this study, we found that patients with HF exhibited notably elevated levels of microRNA423-5p and BNP, as well as significantly lower LVEF values. A significant positive correlation between microRNA423-5p and BNP indicators was validated. In addition, our study also revealed an elevation in the level of microRNA423-5p correlating with the progression of the HF. The combined evaluation of LEVF, BNP, and microRNA423-5p demonstrated superior diagnostic efficacy in comparison to the solitary use of BNP. Conclusions Elevated levels of microRNA423-5p in the serum of patients with HF suggest its potential utility as a novel biomarker for both the diagnosis and prognosis of this condition.

Abstract Background High glucose levels are key factors and key contributors to several cardiovascular diseases associated with cardiomyocyte injury. Ferroptosis, which was identified in recent years, is a mode of cell death caused by the iron-mediated accumulation of lipid peroxides. Neuregulin-4 (Nrg4) is an adipokine that has protective effects against metabolic disorders and insulin resistance. Our previous study revealed that Nrg4 has a protective effect against diabetic myocardial injury, and the aim of this study was to investigate whether Nrg4 could attenuate the occurrence of high glucose-induced ferroptosis in cardiomyocytes. Methods We constructed an in vivo diabetic myocardial injury model in which primary cardiomyocytes were cultured in vitro and treated with Nrg4. Changes in ferroptosis-related protein levels and ferroptosis-related indices in cardiomyocytes were observed. In addition, we performed back-validation and explored signalling pathways that regulate ferroptosis in primary cardiomyocytes. Results Nrg4 attenuated cardiomyocyte ferroptosis both in vivo and in vitro. Additionally, the AMPK/NRF2 signalling pathway was activated during this process, and when the AMPK/NRF2 pathway was inhibited, the beneficial effects of Nrg4 were attenuated. Conclusion Nrg4 antagonizes high glucose-induced ferroptosis in cardiomyocytes via the AMPK/NRF2 signalling pathway.

The widespread utilization of synthetic musks (SMs) in various consumer and personal care products (PCPs) has led to human external exposure through dermal absorption, inhalation of volatile fragrances, and ingestion of contaminated foods, dust, and liquids. Nonetheless, investigations comparing external and internal exposures in humans remain limited in China, particularly regarding internal exposure assessments in blood, which have lacked follow-up over the past decade. In this study, data concerning the concentrations of SMs in 135 blood samples (68 females and 67 males) obtained from residents of Shanghai are provided, representing the sole publication within the last decade on this topic. The findings suggest a potential association between SM concentrations in females and their income and ages. Additionally, the concentrations in blood are higher than in urine, suggesting that relying solely on urine assessments may underestimate health risks associated with internal exposure. Furthermore, data on internal exposure in human fluids reveal SMs' potential transfer to infants via breast milk, posing substantial threat. Noteworthy, we quantify total external exposure across various pathways for Chinese population. Our findings indicate that PCPs are identified as the predominant source of external exposure for adolescents and adults. However, in the case of infants and children, food ingestion, and PCPs dermal absorption make substantial contributions, representing 80.53 % and 16.06 % of the total for infants, and 69.96 % and 22.40 % for children, respectively. Notably, the total estimated daily intake (EDI), derived from urine analysis, falls notably below the total external exposure. While the contribution of each SM exhibits considerable variability, which can be ascribed to the distinct metabolic pathways of these compounds in vivo. Hence, additional research on the metabolism and transformation of SMs in humans is urgently needed for better human health risk assessment in the future.

Abstract Background Acute lung injury (ALI) is strongly associated with hospitalization and mortality in patients with sepsis. Recent evidence suggests that pyroptosis mediated by NLRP3(NOD-, LRR- and pyrin domain-containing 3) inflammasome activation plays a key role in sepsis. However, the mechanism of NLRP3 inflammasome activation in sepsis-induced lung injury remains unclear. Results in this study, we demonstrated that NLRP3 inflammasome was activated by the down-regulation of heat shock protein family A member 8 (HSPA8) in Lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-treated mouse alveolar epithelial cells (AECs). Geranylgeranylacetone (GGA)-induced HSPA8 overexpression in cecum ligation and puncture (CLP) mice could significantly reduce systemic inflammatory response and mortality, effectively protect lung function, whilst HSPA8 inhibitor VER155008 aggravated this effect. The inhibition of HSPA8 was involved in sepsis induced acute lung injury by promoting pyroptosis of AECs. The down-regulation of HSPA8 activated NLRP3 inflammasome to mediate pyroptosis by promoting the degradation of E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2). In addition, when stimulated by LPS and ATP, down-regulated SKP2 promoted pyroptosis of AECs by further attenuating ubiquitination of NLRP3. Adeno-associated virus 9-SKP2(AAV9-SKP2) could promote NLRP3 ubiquitination and degradation, alleviate lung injury and inhibit systemic inflammatory response in vivo. Conclusion in summary, our study shows there is strong statistical evidence that the suppression of HSPA8 mediates alveolar epithelial pyroptosis by promoting the degradation of E3 ubiquitin ligase SKP2 and subsequently attenuating the ubiquitination of NLRP3 to activate the NLRP3 inflammasome, which provides a new perspective and therapeutic target for the treatment of sepsis-induced lung injury.

Abstract Background Diabetic angiogenesis is closely associated with disabilities and death caused by diabetic microvascular complications. Advanced glycation end products (AGEs) are abnormally accumulated in diabetic patients and are a key pathogenic factor for diabetic angiogenesis. The present study focuses on understanding the mechanisms underlying diabetic angiogenesis and identifying therapeutic targets based on these mechanisms. Methods In this study, AGE-induced angiogenesis serves as a model to investigate the mechanisms underlying diabetic angiogensis. Mouse aortic rings, matrigel plugs, and HUVECs or 293T cells were employed as research objects to explore this pathological process by using transcriptomics, gene promoter reporter assays, virtual screening and so on. Results Here, we found that AGEs activated Wnt/β-catenin signaling pathway and enhanced the β-catenin protein level by affecting the expression of β-catenin degradation-related genes, such as FZDs (Frizzled receptors), LRPs (LDL Receptor Related Proteins), and AXIN1. AGEs could also mediate β-catenin Y142 phosphorylation through VEGFR1 isoform5. These dual effects of AGEs elevated the nuclear translocation of β-catenin and sequentially induced the expression of KDR (Kinase Insert Domain Receptor) and HDAC9 (Histone Deacetylase 9) by POU5F1 and NANOG, respectively, thus mediating angiogenesis. Finally, through virtual screening, Bioymifi, an inhibitor that blocks VEGFR1 isoform5-β-catenin complex interaction and alleviates AGE-induced angiogenesis, was identified. Conclusion Collectively, this study offers insight into the pathophysiological functions of β-catenin in diabetic angiogenesis.

Osteosarcoma (OS) is an aggressive and highly lethal bone tumor, highlighting the urgent need for further exploration of its underlying mechanisms. In this study, we conducted analyses utilizing bulk transcriptome sequencing data of OS and healthy control samples, as well as single cell sequencing data, obtained from public databases. Initially, we evaluated the differential expression of four tumor microenvironment (TME)-related gene sets between tumor and control groups. Subsequently, unsupervised clustering analysis of tumor tissues identified two significantly distinct clusters. We calculated the differential scores of the four TME-related gene sets for Clusters 1 (C1) and 2 (C2), using Gene Set Variation Analysis (GSVA, followed by single-variable Cox analysis. For the two clusters, we performed survival analysis, examined disparities in clinical-pathological distribution, analyzed immune cell infiltration and immune evasion prediction, assessed differences in immune infiltration abundance, and evaluated drug sensitivity. Differentially expressed genes (DEGs) between the two clusters were subjected to Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA). We conducted Weighted Gene Co-expression Network Analysis (WGCNA) on the TARGET-OS dataset to identify key genes, followed by GO enrichment analysis. Using LASSO and multiple regression analysis we conducted a prognostic model comprising eleven genes (ALOX5AP, CD37, BIN2, C3AR1, HCLS1, ACSL5, CD209, FCGR2A, CORO1A, CD74, CD163) demonstrating favorable diagnostic efficacy and prognostic potential in both training and validation cohorts. Using the model, we conducted further immune, drug sensitivity and enrichment analysis. We performed dimensionality reduction and annotation of cell subpopulations in single cell sequencing analysis, with expression profiles of relevant genes in each subpopulation analyzed. We further substantiated the role of ACSL5 in OS through a variety of wet lab experiments. Our study provides new insights and theoretical foundations for the prognosis, treatment, and drug development for OS patients.

A facile, transition-metal-free, HFIP-promoted method for the synthesis of triarylmethanes through direct Friedel-Crafts reactions of imidazo[1,2-a]pyridines with chlorohydrocarbon derivatives has been described, which allows for efficient synthesis of triarylmethanes containing imidazo[1,2-a]pyridines in good to satisfactory yields at room temperature. This transformation features simple operation, excellent functional group tolerance, and a broad substrate scope.

Hypophosphatemic vitamin D-resistant rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. In this report, the SMUSHi005-A human induced pluripotent stem cell (hiPSC) line was successfully established from the PBMCs of a female patient carrying the PHEX mutation with c.1586–1586+1 delAG. The iPSC line has been confirmed to have a normal karyotype. The displayed cells clearly exhibit characteristics similar to embryonic stem cells, expressing pluripotency markers and demonstrating the ability to differentiate into three germ layers.

INF2 mutations cause Charcot-Marie-Tooth disease (CMT), and /or focal segmental glomerulosclerosis (FSGS) in an autosomal dominant inheritance mode, whose underlying mechanism remains unclear. Here, we report the generation of an iPSC line from a female patient with CMT and FSGS. The iPSC line from the patient's PBMCs carried a heterozygous INF2 deletion mutation (c.315_323delGCGCGCCGT) within the conserved E2. This line exhibited a normal karyotype, high expression of pluripotency markers, and trilineage differentiation potential. This line can be used to dissect the complex pathomechanism through further induction of differentiation into related cells and as a drug screening tool for INF2-associated diseases.

ABSTRACTHepatitis B virus (HBV) may directly infect human podocytes (HPCs). However, the mechanism of direct infection is unclear. We found that HPCs express sodium taurocholate cotransporting polypeptide (NTCP), a specific receptor for HBV entry into hepatocytes. Thus, we investigated whether NTCP mediates HBV infection and damage in HPCs and further clarified the specific mechanism. We constructed shRNA-NTCP1,2, shRNA-NC, WT-NTCP, and MUT-NTCP and transfected them into HPCs. HPCs were infected with HBV, and HBV infection markers were detected by enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR (RT-qPCR). The functional changes in HPCs were detected by Transwell migration and scratch assays, apoptosis was evaluated by flow cytometry (FCM), and podocytoskeletal proteins (nephrin, CD2AP, and synaptopodin) were determined by western blotting (WB). Compared with the control HPCs, HPCs infected with HBV showed increased levels of HBV infection markers and apoptosis along with decreased podocytoskeletal protein expressions, cell vitality, proliferation, and migration. Compared with the HPCs infected with HBV, the HPCs transfected with HBV + shRNA-NTCP, and HBV + MUT-NTCP showed decreased levels of HBV infection markers and apoptosis along with increased podocytoskeletal protein expressions, cell vitality, proliferation, and migration; the opposite effects were observed in the HPCs transfected with HBV + WT-NTCP. Overall, the changes to NTCP affected the susceptibility of HPCs to HBV and modulated HPC damage and repair. NTCP can mediate direct HBV infection and damage human podocytes, and the NTCP 157–165 locus is the main site of HBV entry. The findings provide a new target and theoretical basis for HBV-associated glomerulonephritis.IMPORTANCEThis study identified for the first time that sodium taurocholate cotransporting polypeptide (NTCP) can mediate HBV direct infection and damage to human podocytes, and the NTCP157–165 locus is the main HBV entry site. The findings provide theoretical support for the pathogenesis of direct infection of HBV with kidney tissue. The findings provide a new target and theoretical basis for the treatment of HBV-related glomerulonephritis (HBV-GN). Blocking NTCP is a new target for the treatment of HBV-GN. We found that tacrolimus, a calcineurin inhibitor that blocks NTCP, can effectively treat HBV-GN. This study also provides a theoretical basis for the effective and safe treatment of immunosuppressant tacrolimus for HBV-GN.

In order to investigate effects of fatty acid unsaturation on the gel properties of myosin, four kinds of fatty acids (stearic acid, oleic acid, linoleic acid, and α-linolenic acid) with different saturation was added into hairtail myosin. The changes of gel strength, water holding capacity, chemical forces, rheological properties, gel electrophoresis and protein secondary structure of myosin were analyzed. The results showed that gel strength and water holding capacity of myosin increased first and then decreased with the increasing of fatty acid unsaturation. The gel strength and water holding capacity of myosin-linoleic acid composite system were the highest, increasing by 59.73% and 15.73% compared with control group, respectively. The results of the rheological and electropherogram indicated that the storage modulus (G') and loss modulus (G'') of myosin containing fatty acids were higher than that of control group. The G' and G'' increased first and then decreased with the increasing of fatty acid unsaturation, and reached the maximum value in the myosin-linoleic acid group. However, there was no significant change in protein composition among all the groups. Infrared spectroscopy showed that the unsaturation of fatty acid had no obvious effect on the molecular backbone of myosin, but stearic acid, oleic acid, and linoleic acid promoted the conformation transform of myosin to irregular direction. In summary, fatty acid unsaturation had a significant effect on the gel properties of myosin, and linoleic acid was the best at improving the gel properties of hairtail myosin.

Objective This study aimed to assess the gastric emptying capacity in nondiabetic patients with end-stage kidney disease (ESKD) by ultrasound. Methods Consecutive hemodialysis patients with ESKD (n = 37) and healthy controls (n = 37) were enrolled. All ESKD patients underwent ultrasound examinations on the day of hemodialysis (dialysis day) and the day after hemodialysis (nondialysis day). Standard ultrasound examinations were performed after overnight fasting, immediately after a light meal, and at 6 h after a meal. The antral cross-sectional area and gastric emptying according to the Perlas grading system were evaluated. Results Compared with the controls, patients with ESKD, on both dialysis and non-dialysis days, had significantly larger antral areas when examined in the supine position (p = 0.002 and p = 0.003, respectively), but not in the right lateral decubitus position (p = 0.452 and p = 0.512, respectively). In the supine position, the antral area of ESKD patients before dialysis (8 a.m. on the dialysis day) was larger than that at the same time on the nondialysis day (p = 0.028). The controls had a Perlas grade of either 0 or 1 at 6 h after a meal, whereas five patients (13.5%) and 11 patients (29.7%) in the ESKD group had Perlas grade 2 on the dialysis and non-dialysis days, respectively. Among patients with or without delayed gastric emptying, no differences were detected in the dialysis duration or levels of biochemical markers, except blood urea nitrogen (p = 0.038) and serum creatinine (p = 0.003). Conclusion Nondiabetic patients with ESKD had significantly delayed gastric emptying. Hemodialysis might improve gastric emptying and reduce gastric emptying delay.

In order to explore the changes of Trachurus japonicus freshness quality during frozen storage, the color, conductivity, ice crystal size and morphology, texture, K value, TBA value, Raman spectrum, secondary structure of total protein, total sulfhydryl content, active sulfhydryl content and Ca2+-ATPase activity of myofibrillar protein were investigated during the frozen storage of −18 ℃ for 90 days with vacuum and air packaging. The results showed that the K value, L* value, whiteness value and TBA value of samples both in VP and AP groups increased gradually with the extend of storage time, among which the K value increased by 65.83% and 66.44% after frozen storage for 90 days, respectively. At the same time, the porosity of ice crystal in fish muscle increased gradually, while a* value, b* value, hardness, chewiness and resilience decreased gradually, however the cohesiveness and conductivity increased firstly and then decreased. The α-helix percentage of muscle protein decreased from 63.28% to 43.70% and 41.91%, respectively, while β-folding, β-turning and random curling percentage increased gradually. The total sulfhydryl content and active sulfhydryl content of myofibrillar protein decreased gradually, Ca2+-ATPase activity decreased by 63.58% and 72.52%, respectively. The packaging had little different effect on muscle quality during frozen storage, but had a certain effect on protein biochemical characteristics in which vacuum packaging effect was slightly better than that of air packaging. Correlation analysis showed that K value, whiteness value, TBA value, sulfhydryl content, Ca2+-ATPase activity, total protein secondary structure content of the samples of the two groups were significantly correlated (P

A facile and efficient method has been developed for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted Friedel–Crafts reaction of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines. This strategy could be applied to the direct C(sp2)-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines and afford a series of novel difluoromethylated carbinols in good to satisfactory yields with 29 examples. Furthermore, gram-scale and synthetic transformation experiments have also been achieved, demonstrating its potential applicable value in organic synthesis. This green protocol has several advantages, including being transition metal- and oxidant-free, being carried out at room temperature, having high efficiency, and having a wide substrate scope.

The antioxidative peptides were prepared from the muscle of Pacific saury by enzymatic hydrolysis. Based on the degree of hydrolysis(DH), the content of TCA-soluble peptide, DPPH free radical scavenging rate, Fe3+ reducing power, ·OH radical scavenging rate and O2−· radical scavenging rate, the optimal protease was selected from six kinds of commercial enzyme(neutral protease, alkaline protease, flavour protease, papain, bromelain and trypsin). Single factor experiments were carried out with five factors: Solid-liquid ratio, the amount of enzyme, enzymatic hydrolysis time, temperature and pH, and three factors (solid-liquid ratio, the amount of enzyme and enzymatic hydrolysis time) were selected to optimize the response surface methodology (RSM). And the molecular weight distribution and free amino acid content of the hydrolysate were determined under the optimal conditions. The results showed that the optimal protease was neutral protease. The influence of three factors on the antioxidant activity of the enzymatic hydrolysate were the solid-liquid ratio> the amount of enzyme> enzymatic hydrolysis time. The optimal preparation processes of the antioxidative active peptide were determined as follows: the solid-liquid ratio was 1:2.67 (mass-volume ratio, g/mL), the amount of enzyme was 0.60%, enzymatic hydrolysis time was 4.04 h, temperature was 50 ℃, and pH7.0. Under these conditions, DPPH free radical scavenging rate and Fe3+ reducing power were 92.33% and 0.711 (20 mg/mL), respectively, which were no significant difference with the predicted value (P>0.05). It could be seen that the antioxidative peptide peptide optimized by response surface methodology had high antioxidant activity. Under the optimal conditions, 97.87% of the components with molecular weight less than 3000 Da were the main components of the hydrolysate. A total of 16 kinds of free amino acids were detected, among which essential amino acids accounted for 39.79% and antioxidant active amino acids accounted for 37.01% of the total amino acids. This study provided some reference for the utilization of high value and the development of peptides functional food of Pacific saury.

Since its discovery in the 1960 s, doxorubicin (DOX) has constantly elicited the broadest spectrum of cancerocidal activity against human cancers. However, cardiotoxicity caused by DOX directly as well as its metabolites is a great source of concern over the continuous use of DOX in chemotherapy. While the exact mechanism of DOX-induced cardiotoxicity is yet to be completely understood, recent studies indicate oxidative stress, inflammation, and several forms of cell death as key pathogenic mechanisms that underpin the etiology of doxorubicin-induced cardiotoxicity (DIC). Notably, these key mechanistic events are believed to be negatively regulated by 3,4-dihydroxybenzoic acid or protocatechuic acid (PCA)—a plant-based phytochemical with proven anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Here, we review the experimental findings detailing the potential ameliorative effects of PCA under exposure to DOX. We also discuss molecular insights into the pathophysiology of DIC, highlighting the potential intervention points where the use of PCA as a veritable chemoprotective agent may ameliorate DOX-induced cardiotoxicities as well as toxicities due to other anticancer drugs like cisplatin. While we acknowledge that controlled oral administration of PCA during chemotherapy may be insufficient to eliminate all toxicities due to DOX treatment, we propose that the ability of PCA to block oxidative stress, attenuate inflammation, and abrogate several forms of cardiomyocyte cell death underlines its great promise in the amelioration of DIC.

In order to quickly and accurately non-destructive real-time monitoring of fish freshness, a visual colorimetric array sensor was constructed in this study based on anodized aluminum flakes as the substrate and 13 indicators selected as gas-sensitive materials. The freshness of turbot during storage was measured by using the constructed colorimetric array sensor. The results showed that the total volatile basic nitrogen (TVB-N) value of turbot reached 32.85 mg/100 g when the storage time was more than 22 h at 25 ℃, and the fish was rotten. At this time, the color of the array points in the colorimetric sensor array changed. The RGB values of sensor array points before and after response were extracted and subtracted, and the clustering analysis and principal component analysis were carried out. The results showed that the colorimetric array sensor was able to accurately distinguish the freshness of fish in different storage time periods. In addition, the array sensor was applied to detect the freshness of carp and American redfish at different storage times, and the results showed that there was no significant difference between the TVB-N values predicted by the colorimetric array sensor and the actual measured values. Therefore, it is feasible to apply the sensor to fish freshness monitoring.

Advanced glycation endproducts (AGEs) have been confirmed to play a causative role in the development of diabetic nephropathy (DN). In this study, we revealed that AGE-induced kidney injury with characteristic patterns in different stages and moesin phosphorylation plays a role in these processes. In WT mice treated with AGE-modified bovine serum albumin (AGE-BSA), distinct abnormal angiogenesis in Bowman’s capsule of the kidney emerged early after 1 m under AGE-BSA stimulation, while these neovessels became rare after 6 m. AGE-BSA also induced glomerular hypertrophy and mesangial expansion at 1 m but glomerular atrophy and fibrosis at 6 m. Electron microscopy imaging demonstrated the damage of foot process integrity in podocytes and the uneven thickening of the glomerular basement membrane in the AGE-BSA-treated group, which was more significant after 6 m of AGE-BSA treatment than 1 m. The kidney dysfunction appeared along with these AGE-induced morphological changes. However, these AGE-BSA-induced pathological changes were significantly attenuated in RAGE-knockout mice. Moreover, moesin phosphorylation was accompanied by AGE-BSA-induced alterations and moesin deficiency in mice attenuated by AGE-BSA-induced fibrosis. The investigation on glomerular endothelial cells (GECs) also confirmed that the phosphorylation of moesin T558 is critical in AGE-induced tube formation. Overall, this study suggests that AGEs mediate kidney injury with characteristic patterns by binding with RAGE and inducing moesin phosphorylation.

Aberrant pro-inflammatory activation of Kupffer cells (KCs) is strongly involved in the pathogenesis of septic liver injury. Recent evidence indicates the crucial roles of excessive stimulator of interferon genes (STING) signaling activation during sepsis. However, the role of STING signaling in septic liver injury remains unclear. In this study, we demonstrated that STING signaling was markedly activated in KCs isolated from wild type mice after lipopolysaccharide (LPS) treatment. STING deficiency effectively protected liver function, attenuated systemic inflammatory response and decreased mortality in LPS-treated mice, which were aggravated by STING agonist (DMXAA). Importantly, STING signaling activation in KCs contributed to LPS-induced liver injury through promoting hepatocyte death. Mechanistically, STING signaling could be activated by release of mitochondrial DNA (mtDNA) through dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in LPS-treated KCs. Additionally, LPS stimulation enhanced DRP1-dependent mitochondrial ROS production, which promoted the leak of mtDNA into the cytosol and subsequent STING signaling activation in KCs. The in vivo experiments showed that pharmacological inhibition of DRP1 with Mdivi-1 partially prevented the activation of STING signaling in KCs isolated from LPS-challenged mice, as well as alleviated liver injury and inhibited systemic inflammatory response. In summary, our study comprehensively confirmed that STING signaling senses the DRP1-dependent release of mtDNA in KCs and its activation might play a key role in LPS-induced liver injury, which offers new sights and therapeutic targets for management of septic liver injury.

Cancer, as one of the leading causes of death worldwide, has challenged current chemotherapy drugs. Considering that treatments are expensive, alongside the resistance of tumor cells to anticancer drugs, the development of alternative medicines is necessary. Anemarrhena asphodeloides Bunge, a recognized and well-known medicinal plant for more than two thousand years, has demonstrated its effectiveness against cancer. Timosaponin-AIII (TSAIII), as a bioactive steroid saponin isolated from A. asphodeloides, has shown multiple pharmacological activities and has been developed as an anticancer agent. However, the molecular mechanisms of TSAIII in protecting against cancer development are still unclear. In this review article, we provide a comprehensive discussion on the anticancer effects of TSAIII, including proliferation inhibition, cell cycle arrest, apoptosis induction, autophagy mediation, migration and invasion suppression, anti-angiogenesis, anti-inflammation, and antioxidant effects. The pharmacokinetic profiles of TSAII are also discussed. TSAIII exhibits efficacy against cancer development. However, hydrophobicity and low bioavailability may limit the application of TSAIII. Effective delivery systems, particularly those with tissue/cell-targeted properties, can also significantly improve the anticancer effects of TSAIII.

The aging of endothelial cells plays a critical role in the development of age-related vascular disease. We established a model of endothelial premature senescence by application of Advanced oxidation protein products (AOPPs) modified bovine serum albumin (AOPP-BSA) in human umbilical vein endothelial cells (HUVECs). This cellular senescence was accompanied with endothelial barrier dysfunction and angiogenesis impairment. It was further revealed that these senescent HUVECs underwent apoptosis evasion and the receptor for advanced glycation endproducts (RAGE) played a role in these processes. The AOPP-induced senescence was regulated by the state of autophagy in HUVECs. We further proved that AOPP-BSA attenuated the autophagy of HUVECs, led to p53 SUMOylation at K386, resulting in endothelial senescence. We also established the animal model of vascular senescence by using ApoE−/− mice fed with high-fat diet plus daily injection of AOPP-BSA to verify the role of p53 SUMOylation in vascular senescence. Combined with intraperitoneal injection of rapamycin, the effect of autophagy on AOPP-induced p53 SUMOylation was also confirmed in vivo. Our data indicates that p53 SUMOylation at K386 plays an important role in AOPP-induced endothelial senescence and apoptosis evasion, suggesting that p53 K386 SUMOylation may serve as a potential therapeutic target in protecting against vascular senescence.

As common noble metal, Ag nanoparticles (Ag NPs) have unique physical and chemical properties and it is widely used in daily life, scientific research, industrial production, environment, medical and healthcare systems. Core/shell of Ag nanocomposite have attracted attention due to the significant properties and wide applications by combination with the core and shell. As a mini-review, it is emphasized the approaches for fabrication Ag shell coating on core nanoparticles as core@Ag nanocomposite, including situ growth method, phenol formaldehyde resin method, silane coupling agent method, ultrasound method, PEI method, dopamine method and other methods. The procedures and mechanism for construction of core@Ag nanocomposite are highlighted. The comparison of those approaches, including their advantages and disadvantages are described in detail. At the same time, the properties and applications of Ag NPs are briefly introduced. The current challenges and perspectives in the future for synthesis of core/shell nanocomposite is proposed. The review is very useful for quickly gaining knowledge and experience for synthesis of core@Ag nanocomposite.

As alternatives to antibiotics in feed, probiotic Bacillus carries multiple advantages in animal production. Spores undergo strain-related germination in the gastrointestinal tract, but it is still unknown whether the probiotic function of the Bacillus depends on the germination of spores in vivo. In this study, based on 14 potential probiotic Bacillus strains from fermented food and feed, we detected the germination response of these Bacillus spores in relation to different germinating agents. The results showed the germination response was strain-specific and germinant-related, and nutrient germinant L-alanine significantly promoted the growth of strains with germination potential. Two strains of Bacillus subtilis, S-2 and 312, with or without a high spore germination response to L-alanine, were selected to study their morphological and genic differences induced by L-alanine through transmission electron microscopy and comparative transcriptomics analysis. Consequently, after L-alanine treatment, the gray phase was largely increased under microscopy, and the expression of the germination response genes was significantly up-regulated in the B. subtilis S-2 spores compared to the B. subtilis 312 spores (p < 0.05). The protective effect of L-alanine-induced spore germination of the two strains was comparatively investigated both in the IPEC-J2 cell model and a Sprague–Dawley (SD) rat model challenged by enterotoxigenic Escherichia coli K99. The result indicated that L-alanine helped B. subtilis S-2 spores, but not 312 spores, to decrease inflammatory factors (IL-6, IL-8, IL-1 β, TNF-α; p < 0.05) and promote the expression of occludin in IPEC-J2 cells. Besides, supplement with L-alanine-treated B. subtilis S-2 spores significantly improved the growth of the SD rats, alleviated histopathological GIT lesions, and improved the ratio of jejunal villus length to crypt depth in comparison to the B. subtilis S-2 spores alone (p < 0.05). Improved species diversity and abundance of fecal microbiota were only observed in the group with L-alanine-treated S-2 spores (p < 0.05). The study demonstrates L-alanine works well as a probiotic Bacillus adjuvant in improving intestinal health, and it also provides a solution for the practical and accurate regulation of their use as antibiotic alternatives in animal production.

ObjectiveTo study the role of the receptor for advanced glycation end products (RAGE) in endothelial barrier dysfunction induced by heat stress, to further explore the signal pathway by which RAGE contributes to heat-induced endothelia response, and thereby find a novel target for the clinical treatment of ALI (acute lung injury) induced by heatstroke.MethodsThis study established the animal model of heatstroke using RAGE knockout mice. We observed the role of RAGE in acute lung injury induced by heatstroke in mice by evaluating the leukocytes, neutrophils, and protein concentration in BALF (Bronchoalveolar lavage fluids), lung wet/dry ratio, histopathological changes, and the morphological ultrastructure of lung tissue and arterial blood gas analysis. To further study the mechanism, we established a heat stress model of HUVEC and concentrated on the role of RAGE and its signal pathway in the endothelial barrier dysfunction induced by heat stress, measuring Transendothelial electrical resistance (TEER) and western blot.ResultsRAGE played a key role in acute lung injury induced by heatstroke in mice. The mechanism C-Jun is located in the promoter region of the RAGE gene. C-Jun increased the RAGE protein expression while HSF1 suppressed RAGE protein expression. The overexpressed RAGE protein then increased HUVEC monolayer permeability by activating ERK and P38 MAPK under heat stress.ConclusionThis study indicates the critical role of RAGE in heat stress-induced endothelial hyperpermeability in acute lung injury and suggests that RAGE could be a potential therapeutic target in protecting patients against acute lung injury induced by heatstroke.

Abstract Background The breakdown of alveolar barrier dysfunction contributes to Lipopolysaccharide stimulated pulmonary edema and acute lung injury. Actin cytoskeleton has been implicated to be critical in regulation of epithelial barrier. Here, we performed in vivo and in vitro study to investigate role of TLR4-p38 MAPK-Hsp27 signal pathway in LPS-induced ALI. Methods For in vivo studies, 6–8-week-old C57 mice were used, Bronchoalveolar lavage Fluid /Blood fluorescent ratio, wet-to-dry lung weight ratio, as well as protein concentrations and neutrophil cell counts in BALF were detected as either directly or indirectly indicators of pulmonary alveolar barrier dysfunction. And hematoxylin and eosin staining was performed to estimate pulmonary injury. The in vitro explorations of transepithelial permeability were achieved through transepithelial electrical resistance measurement and testing of FITC-Dextran transepithelial flux in A549. In addition, cytoskeletal rearrangement was tested through F-actin immunostaining. And SB203580 was used to inhibit p38 MAPK activation, while siRNA was administered to genetically knockdown specific protein. Results We showed that LPS triggered activation of p38 MAPK, rearrangement of cytoskeleton which resulted in severe epithelial hyperpermeability and lung edema. A549 pretreated with TLR4 siRNA、p38 MAPK siRNA and its inhibitor SB203580 displayed a lower permeability and fewer stress fibers formation after LPS stimulation, accompanied with lower phosphorylation level of p38 MAPK and Hsp27, which verified the involvement of TLR4-p38 MAPK-Hsp27 in LPS-evoked alveolar epithelial injury. Inhibition of p38 MAPK activity with SB203580 in vivo attenuated pulmonary edema formation and hyperpermeability in response to LPS. Conclusions Our study demonstrated that LPS increased alveolar epithelial permeability both in vitro and in vivo and that TLR4- p38 MAPK- Hsp27 signal pathway dependent actin remolding was involved in this process.

Background/Aims: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process. Methods: Human umbilical vein endothelial cells (HUVECs) were used in the in vitro studies. Trans-endothelial electric resistance and permeability coefficient for dextran (Pd) were measured to analyze cell permeability. Western blotting, immunofluorescence staining and flow cytometry assay were performed to investigate the underlying mechanism. Dextran flux across the mesentery in mice was monitored to investigate in vivo microvascular permeability. Results: we found that AGEs evoked Nox4 membrane translocation, reactive oxygen species production, phosphorylation of Src and VE-cadherin, dissociation of adherens junctions and eventual endothelial hyperpermeability through RAGE-mDia1 binding. Cells overexpressing mDia1 by recombinant adenovirus infection showed stronger cellular responses induced by AGEs. Down-regulation of mDia1 by infection with an adenovirus encoding siRNA or blockade of RAGE-mDia1 binding by transfection with RAGE mutant plasmids into HUVECs abolished these AGE-induced effects. Furthermore, knockdown of mDia1 using an adenovirus or genetical knockout of RAGE in C57 mice rescued AGE-evoked microvascular hyperpermeability. Conclusion: Our study revealed that mDia1 plays a critical role in AGE-induced microvascular hyperpermeability through binding to RAGE.

Abstract Background The association between body mass index (BMI) and clinical outcomes of gastric cancer were still under debate. The aim of the present study was to investigate the impact of BMI on intraoperative conditions, postoperative complications and prognosis of gastric cancer. Methods From October 2008 to March 2015, 1210 gastric cancer patients treated with D2 gastrectomy were enrolled in the present study. Patients were divided into three groups: low BMI group (BMI 0.05). High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes (all P 0.05). Conclusions BMI was inversely associated with tumor size, tumor depth, LNM and tumor stage. High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes. Low BMI was associated with decreased rate of postoperative fever and decreased survival.

Abstract Background The beneficial effects of Lactobacillus probiotics in animal production are often strain-related. Different strains from the same species may exert different weight-gain effect on hosts in vivo. Most lactobacilli are selected based on their in vitro activities, and their metabolism and regulation on the intestine based on strain-related characters are largely unexplored. The objective of the present study was to study the in vivo effects of the three lactobacilli on growth performance and to compare the differential effects of the strains on the faecal microbiota and ileum mucosa proteomics of piglets. Methods Three hundred and sixty piglets were assigned to one of four treatments, which included an antibiotics-treated control and three experimental groups supplemented with the three lactobacilli, L. salivarius G1-1, L. reuteri G8-5 and L. reuteri G22-2, respectively. Piglets were weighed and the feed intake was recorded to compare the growth performance. The faecal lactobacilli and coliform was quantified using quantitative PCR and the faecal microbiota was profiled by denaturing gradient gel electrophoresis (DGGE). The proteomic approach was applied to compare the differential expression of proteins in the ileum mucosa. Results No statistical difference was found among the three Lactobacillus-treated groups in animal growth performance compared with the antibiotics-treated group (P > 0.05). Supplementation of lactobacilli in diets significantly increased the relative 16S rRNA gene copies of Lactobacillus genus on both d 14 and d 28 (P

ObjectivesWe previously reported microvascular leakage resulting from fibrinogen-γ chain C-terminal products (γC) occurred via a RhoA-dependent mechanism. The objective of this study was to further elucidate the signaling mechanism by which γC induces endothelial hyperpermeability. Since it is known that γC binds and activates endothelial αvβ3, a transmembrane integrin receptor involved in intracellular signaling mediated by the tyrosine kinases FAK and Src, we hypothesized that γC alters endothelial barrier function by activating the FAK-Src pathway leading to junction dissociation and RhoA driven cytoskeletal stress-fiber formation.Methods and resultsUsing intravital microscopy of rat mesenteric microvessels, we show increased extravasation of plasma protein (albumin) resulting from γC administration. In addition, capillary fluid filtration coefficient (Kfc) indicated γC-induced elevated lung vascular permeability. Furthermore, γC decreased transendothelial barrier resistance in a time-dependent and dose-related fashion in cultured rat lung microvascular endothelial cells (RLMVECs), accompanied by increased FAK/Src phosphorylation detection by western blot. Experiments with pharmacological inhibition or gene silencing of FAK showed significantly reduced γC-induced albumin and fluid leakage across microvessels, stress-fiber formation, VE-cadherin tyrosine phosphorylation, and improved γC-induced endothelial barrier dysfunction, indicating the involvement of FAK in γC mediated hyperpermeability. Comparable results were found when Src was targeted in a similar manner, however inhibition of FAK prevented Src activation, suggesting that FAK is upstream of Src in γC-mediated hyperpermeability. In addition, γC-induced cytoskeletal stress-fiber formation was attenuated during inhibition or silencing of these tyrosine kinases, concomitantly with RhoA inhibition.ConclusionThe FAK-Src pathway contributes to γC-induced microvascular barrier dysfunction, junction protein phosphorylation and disorganization in a manner that involves RhoA and stress-fiber formation.

Total Panax notoginseng saponin (TPNS) is the main bioactivity compound derived from the roots and rhizomes of Panax notoginseng (Burk.) F.H. Chen. The aim of this study was to investigate the effectiveness of TPNS in treating vascular neointimal hyperplasia in rats and its mechanisms. Male Sprague-Dawley rats were randomly divided into five groups, sham (control), injury, and low, medium, and high dose TPNS (5, 10, and 20 mg/kg). An in vivo 2F Fogarty balloon-induced carotid artery injury model was established in rats. TPNS significantly and dose-dependently reduced balloon injury-induced neointimal area (NIA) (P

Advanced glycation end products (AGEs), produced by the non-enzymatic glycation of proteins and lipids under hyperglycemia or oxidative stress conditions, has been implicated to be pivotal in the development of diabetic vascular complications, including diabetic retinopathy. We previously demonstrated that Src kinase played a causative role in AGE-induced hyper-permeability and barrier dysfunction in human umbilical vein endothelial cells (HUVECs). While the increase of vascular permeability is the early event of angiogenesis, the effect of Src in AGE-induced angiogenesis and the mechanism has not been completely revealed. Here, we investigated the impact of Src on AGE-induced HUVECs proliferation, migration, and tubulogenesis. Inhibition of Src with inhibitor PP2 or siRNA decreased AGE-induced migration and tubulogenesis of HUVECs. The inactivation of Src with pcDNA3/flag-SrcK298M also restrained AGE-induced HUVECs proliferation, migration, and tube formation, while the activation of Src with pcDNA3/flag-SrcY530F enhanced HUVECs angiogenesis alone and exacerbated AGE-induced angiogenesis. AGE-enhanced HUVECs angiogenesis in vitro was accompanied with the phosphorylation of ERK in HUVECs. The inhibition of ERK with its inhibitor PD98059 decreased AGE-induced HUVECs angiogenesis. Furthermore, the inhibition and silencing of Src suppressed the AGE-induced ERK activation. And the silencing of AGEs receptor (RAGE) inhibited the AGE-induced ERK activation and angiogenesis as well. In conclusions, this study demonstrated that Src plays a pivotal role in AGE-promoted HUVECs angiogenesis by phosphorylating ERK, and very likely through RAGE-Src-ERK pathway.

Abstract: A new high-capacity USIM card was introduced and discussed in detail and depth. Its key technology （IC-USB interface, integrated NAND flash chips）was introduced. Compared to traditional SIM card, the high-capacity USIM card has higher transmission rates, larger storage space, and data security storage. The structure and functions of supporting client and management platform were discussed. The influence of this technology may have caused was analyzed.Appropriate suggestions and plantings to the future of business model and application scenario were given.

Increased vascular permeability leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is central to the pathogenesis of heatstroke. Protease-activated receptor 1 (PAR1), the receptor for thrombin, plays a key role in disruption of endothelial barrier function in response to extracellular stimuli. However, the role of PAR1 in heat stress-induced endothelial hyper-permeability is unknown. In this study, we measured PAR1 protein expression in heat-stressed human umbilical venous endothelial cells (HUVECs), investigated the influences of PAR1 on endothelial permeability, F-actin rearrangement, and moesin phosphorylation by inhibiting PAR1 with its siRNA, neutralizing antibody (anti-PAR1), specific inhibitor(RWJ56110), and Xuebijing injection (XBJ), a traditional Chinese medicine used for sepsis treatment, and evaluated the role of PAR1 in heatstroke-related ALI/ARDS in mice by suppressing PAR1 with RWJ56110, anti-PAR1and XBJ. We found that heat stress induced PAR1 protein expression 2h after heat stress in endothelial cells, caused the release of endothelial matrix metalloprotease 1, an activator of PAR1, after 60 or 120 min of heat stimulation, as well as promoted endothelial hyper-permeability and F-actin rearrangement, which were inhibited by suppressing PAR1 with RWJ56110, anti-PAR1 and siRNA. PAR1 mediated moesin phosphorylation, which caused F-actin rearrangement and disruption of endothelial barrier function. To corroborate findings from in vitro experiments, we found that RWJ56110 and the anti-PAR1 significantly decreased lung edema, pulmonary microvascular permeability, protein exudation, and leukocytes infiltrations in heatstroke mice. Additionally, XBJ was found to suppress PAR1-moesin signal pathway and confer protective effects on maintaining endothelial barrier function both in vitro and in vivo heat-stressed model, similar to those observed above with the inhibition of PAR1. These results suggest that PAR1 is a potential therapeutic target in heatstroke.

The proximate composition, amino acid, fatty acid and mineral elements of wild and farmed Conger myriaster muscle were compared. Results indicated that the lipid content of farmed fish was significantly higher, while moisture content was significantly lower than that of the wild fish (P<0.05). The contents of all essential amino acids (EAA), half essential amino acids (HEAA) and Tyr, Asp, Glu were significantly higher in farmed Conger myriaster than that in wild fish (P<0.05). The ratios of the WEAA/WTAA (39.92% vs 39.77%) and WEAA/WNEAA (84.29% vs 82.37%) were similar in farmed and wild Conger myriaster (P>0.05). n-3 polyunsaturated fatty acids (PUFAs), n-6 PUFAs and total PUFAs content were lower in wild than that in farmed Conger myriaster (P<0.05). Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were higher in farmed than wild Conger myriaster (P<0.05). Farmed fish showed significant high content in K and Mg but low in Hg, As and Pb compared to wild fish (P<0.05). In a word, farmed Conger myriaster under investigation have high nutritional qualities and positive health benefits, it is a potentially healthier alternative to the wild Conger myriaster. [ABSTRACT FROM AUTHOR]