Cinobufotalin prevents bone loss induced by ovariectomy in mice through the BMPs/SMAD and Wnt/β-catenin signaling pathways

Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.

Innovative pathways allow safe discharge of mild acute pancreatitis from the emergency room

Acute pancreatitis(AP)is a leading cause of gastrointestinal-related hospitalizations in the United States,resulting in 300000 admissions per year with an estimated cost of over$2.6 billion annually.The severity of AP is determined by the presence of pancreatic complications and end-organ damage.While moderate/severe pancreatitis can be associated with significant morbidity and mortality,the majority of patients have a mild presentation with an uncomplicated course and mortality rate of less than 2%.Despite favorable outcomes,the majority of mild AP patients are admitted,contributing to healthcare cost and burden.In this Editorial we review the performance of an emergency department(ED)pathway for patients with mild AP at a tertiary care center with the goal of reducing hospitalizations,resource utilization,and costs after several years of implementation of the pathway.We discuss the clinical course and outcomes of mild AP patients enrolled in the pathway who were successfully discharged from the ED compared to those who were admitted to the hospital,and identify predictors of successful ED discharge to select patients who can potentially be triaged to the pathway.We conclude that by implementing innovative clinical pathways which are established and reproducible,selected AP patients can be safely discharged from the ED,reducing hospitalizations and healthcare costs,without compromising clinical outcomes.We also identify a subset of patients most likely to succeed in this pathway.

Paclitaxel induces human KOSC3 oral cancer cell apoptosis through caspase pathways

Background:Paclitaxel is a compound derived from Pacific yew bark that induces various cancer cell apoptosis.However,whether it also has anticancer activities in KOSC3 cells,an oral cancer cell line,is unclear.Methods:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,flow cytometry,and western blotting assays were carried out to assess cell viability,subG1 phase of the cell cycle,and apoptosis-related protein expression,respectively.Results:Ourfindings indicate that paclitaxel could inhibit cell viability and increase the expression of apoptotic markers,including plasma membrane blebbing and the cleavage of poly ADP-ribose polymerase in KOSC3 cells.Also,the treatment with paclitaxel remarkably elevated the percentage of the subG1 phase in KOSC3 cells.In addition,treatment with a pan-caspase inhibitor could recover paclitaxel-inhibited cell viability.Moreover,caspase-8,caspase-9,caspase-7,and BH3 interacting domain death agonist(Bid)were activated in paclitaxel-treated KOSC3 cells.Conclusions:Paclitaxel induced apoptosis through caspase cascade in KOSC3 cells.

Multi-disciplinary Pathways to Computing:A Scalable and Col aborative Approach to Capitalize on the Demand for Computer Science Education

The number of students demanding computer science(CS)education is rapidly rising,and while faculty sizes are also growing,the traditional pipeline consisting of a CS major,a CS master’s,and then a move to industry or a Ph.D.program is simply not scalable.To address this problem,the Department of Computing at the University of Illinois has introduced a multidisciplinary approach to computing,which is a scalable and collaborative approach to capitalize on the tremendous demand for computer science education.The key component of the approach is the blended major,also referred to as“CS+X”,where CS denotes computer science and X denotes a non-computing field.These CS+X blended degrees enable win-win partnerships among multiple subject areas,distributing the educational responsibilities while growing the entire university.To meet the demand from non-CS majors,another pathway that is offered is a graduate certificate program in addition to the traditional minor program.To accommodate the large number of students,scalable teaching tools,such as automatic graders,have also been developed.

Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy

Diabetic peripheral neuropathy is a common complication of diabetes mellitus.Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies.However,existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research.Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy,it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods.This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods.Various metabolic mechanisms(e.g.,polyol,hexosamine,protein kinase C pathway)are associated with diabetic peripheral neuropathy,and researchers are looking for more effective treatments through these pathways.

The biological functions and metabolic pathways of valine in swine

Valine is an essential amino acid and a type of branched-chain amino acid. Due to the involvement of branchedchain amino acids in various metabolic pathways, there has been a surge of interests in valine nutrition and its role in animal physiology. In pigs, the interactions between valine and other branched-chain amino acids or aromatic amino acids are complex. In this review, we delve into the interaction mechanism, metabolic pathways, and biological functions of valine. Appropriate valine supplementation not only enhances growth and reproductive performances, but also modulates gut microbiota and immune functions. Based on past observations and interpretations, we provide recommended feed levels of valine for weaned piglets, growing pigs, gilts, lactating sows, barrows and entire males. The summarized valine nutrient requirements for pigs at different stages offer valuable insights for future research and practical applications in animal husbandry.

Effects of different doses of glucose and fructose on central metabolic pathways and intercellular wireless communication networks in humans

Fructose and glucose are often widely used in food processing and may contribute to many metabolic diseases.To observe the effects of different doses of glucose and fructose on human metabolism and cellular communication,volunteers were given low,medium,and high doses of glucose and fructose.Serum cytokines,glucose,lactate,nicotinamide adenine dinucleotide(NADH)and metabolic enzymes were assayed,and central carbon metabolic pathway networks and cytokine communication networks were constructed.The results showed that the glucose and fructose groups basically maintained the trend of decreasing catabolism and increasing anabolism with increasing dose.Compared with glucose,low-dose fructose decreased catabolism and increased anabolism,significantly enhanced the expression of the inflammatory cytokine interferon-γ(IFN-γ),macrophage-derived chemokine(MDC),induced protein-10(IP-10),and eotaxin,and significantly reduced the activity of isocitrate dehydrogenase(ICDH)and pyruvate dehydrogenase complexes(PDHC).Both medium and high doses of fructose increase catabolism and anabolism,and there are more cytokines and enzymes with significant changes.Furthermore,multiple cytokines and enzymes show strong relevance to metabolic regulation by altering the transcription and expression of enzymes in central carbon metabolic pathways.Therefore,excessive intake of fructose should be reduced to avoid excessive inflammatory responses,allergic reactions and autoimmune diseases.

Exploring the Pathways of Leprosy Patients from Their Communities to a Diagnosis in the Districts of Mayuge, Yumbe and Kasese-Uganda

Background: Leprosy is known to cause disability that leads to severe outcomes like stigma, discrimination, mental health problems and participation restriction. Furthermore, in cases of infectious leprosy, longer delays increase the risk for the spread of the disease. Despite being preventable and curable, a significant proportion of new leprosy patients (39%) in 2019 had grade 2 (Described as Visible disability) at the time of diagnosis signifying late presentation. The aim of this study was to describe patient journeys from first symptoms suggestive of leprosy to a diagnosis and individual and community level factors associated with health seeking behavior of leprosy patients. Methods: This was a cross-sectional explorative study implemented in Kasese, Mayuge and Yumbe districts .A structured questionnaire was used to collect quantitative data. Qualitative assessment included patients, family members, health workers, voluntary health teams and the district health team. Descriptive statistics were presented in terms of percentages, frequency tables, pie Charts and graphs for easy interpretation and discussion. Results: The results indicate that 53% of the respondents identified as female. The median age of the respondents being 34 years, with a range of 1 to 76 years (Mean: 44.7, Mode: 65, Standard-Deviation: 19.6, Kurtosis: 0.6). The most common first symptom noticed by respondents was skin lesions (65%) followed by deformities (18%) (P value = 0.05%) occurring mostly in the feet (P-value = 0.48). Majority (52%) of the patients had taken more than 24 months (SD 18.72 OR 2.75) for a diagnosis to be made with a maximum delay of over 60 months. The most common cause of delay in seeking health care was lack of knowledge on leprosy (P value=Conclusions: There was a delay of 2 years in seeking health care for the majority of the patients. Key barriers to early diagnosis were lack of knowledge and infrastructure. Community sensitization and strengthening capacity building are needed to achieve early diagnosis of leprosy and proper management.

TCGA-based analysis of oncogenic signaling pathways underlying oral squamous cell carcinoma

Background:Oral squamous cell carcinoma(OSCC)represents a prevalent malignancy in the oral and maxillofacial area,having a considerable negative impact on both the quality of life and overall survival of affected individuals.Our research endeavors to leverage bioinformatic approaches to elucidate oncogenic signaling pathways,with the ultimate goal of gaining deeper insights into the molecular underpinnings of OSCC pathogenesis,and thus laying the groundwork for the development of more effective therapeutic and preventive strategies.Methods:Differential expression analysis was performed on mRNA data from tumor and normal tissue groups to identify genes associated with OSCC,using The Cancer Genome Atlas database.Predictions of oncogenic signaling pathways linked to differentially expressedmRNAs were made,and these results were presented visually using R software,using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichments.Results:GO and KEGG analyses of 2938 differentially expressed genes in OSCC highlighted their significant involvement in various biological processes.Notably,these processes were related to the extracellular matrix,structural organization,connective tissue development,and cell cycle regulation.Conclusions:The comprehensive exploration of gene expression patterns provides valuable insights into potential oncogenic mechanisms in OSCC.

Jianpi Gushen Huayu decoction ameliorated diabetic nephropathy through modulating metabolites in kidney,and inhibiting TLR4/NF-κB/NLRP3 and JNK/P38 pathways

BACKGROUND Jianpi Gushen Huayu Decoction(JPGS)has been used to clinically treat diabetic nephropathy(DN)for many years.However,the protective mechanism of JPGS in treating DN remains unclear.AIM To evaluate the therapeutic effects and the possible mechanism of JPGS on DN.METHODS We first evaluated the therapeutic potential of JPGS on a DN mouse model.We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics.Furthermore,we examined the effects of JPGS on c-Jun N-terminal kinase(JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB)/NOD-like receptor family pyrin domain containing 3(NLRP3).RESULTS The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress.Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice.A total of 51 differential metabolites were screened.Pathway analysis results indicated that nine pathways significantly changed between the control and model groups,while six pathways significantly altered between the model and JPGS groups.Pathways related to cysteine and methionine metabolism;alanine,tryptophan metabolism;aspartate and glutamate metabolism;and riboflavin metabolism were identified as the key pathways through which JPGS affects DN.Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors.CONCLUSION JPGS could markedly treat mice with streptozotocin(STZ)-induced DN,which is possibly related to the regulation of several metabolic pathways found in kidneys.Furthermore,JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathwaymediated apoptosis in DN mice.

Teaching Pathways of Curriculum Civics and Politics in Physical Education Courses of Higher Vocational Colleges and Universities in Chongqing

This paper firstly analyses the due evaluation indexes of curriculum civics and politics in physical education of higher vocational colleges and,based on the indexes,puts forward suggestions to improve the quality of teaching curriculum civics and politics in physical education of higher vocational colleges and universities in Chongqing.It involves maintaining steadfast adherence to professional attributes,unwavering commitment to Sanquan education,and thorough exploration of professional civics and political elements.This approach also entails supplementing extracurricular civics and political resources and utilizing a variety of methods such as contextual teaching and role-modeling to the fullest extent.At the same time,we increase the opportunities for civics and political practice inside and outside the classroom and develop teaching evaluation and assessment in civics and politics.

Deoxyribonucleic acid methylation driven aberrations in pancreatic cancer-related pathways

Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.

Transcriptome-based analysis of key genes and pathways affecting the linoleic acid content in chickens

Linoleic acid is an essential polyunsaturated fatty acid that cannot be synthesized by humans or animals themselves and can only be obtained externally.The amount of linoleic acid present has an impact on the quality and flavour of meat and indirectly affects consumer preference.However,the molecular mechanisms influencing the deposition of linoleic acid in organisms are not clear.As the molecular mechanisms of linoleic acid deposition are not well understood,to investigate the main effector genes affecting the linoleic acid content,this study aimed to screen for hub genes in slow-type yellow-feathered chickens by transcriptome sequencing(RNA-Seq)and weighted gene coexpression network analysis(WGCNA).We screened for candidate genes associated with the linoleic acid content in slow-type yellow-feathered broilers.A total of 399 Tiannong partridge chickens were slaughtered at 126 days of age,fatty acid levels were measured in pectoral muscle,and pectoral muscle tissue was collected for transcriptome sequencing.Transcriptome sequencing results were combined with phenotypes for WGCNA to screen for candidate genes.KEGG enrichment analysis was also performed on the genes that were significantly enriched in the modules with the highest correlation.A total of 13310 genes were identified after quality control of transcriptomic data from 399 pectoral muscle tissues.WGCNA was performed,and a total of 26 modules were obtained,eight of which were highly correlated with the linoleic acid content.Four key genes,namely,MDH2,ATP5B,RPL7A and PDGFRA,were screened according to the criteria|GS|>0.2 and|MM|>0.8.The functional enrichment results showed that the genes within the target modules were mainly enriched in metabolic pathways.In this study,a large-sample-size transcriptome analysis revealed that metabolic pathways play an important role in the regulation of the linoleic acid content in Tiannong partridge chickens,and MDH2,ATP5B,RPL7A and PDGFRA were screened as important candidate genes affecting the linoleic acid content.The results of this study provide a theoretical basis for selecting molecular markers and comprehensively understanding the molecular mechanism affecting the linoleic acid content in muscle,providing an important reference for the breeding of slow-type yellowfeathered broiler chickens.

Effect of vitamin supplementation on polycystic ovary syndrome and key pathways implicated in its development:A Mendelian randomization study

BACKGROUND Many epidemiologic investigations have explored the relationship between viatmins and polycystic ovary syndrome(PCOS).However,the effectiveness of vitamin,vitamin-like nutrient,or mineral supplementation in reducing the risk of PCOS remains a subject of debate.AIM To investigate the impact of plasma levels of vitamins A,B12,D,E,and K on PCOS and key pathways implicated in its development,namely,insulin resistance,hyperlipidemia,and obesity,through Mendelian randomization(MR)analysis.METHODS Single nucleotide polymorphisms associated with vitamin levels were selected from genome-wide association studies.The primary analysis was performed using the random-effects inverse-variance-weighted approach.Complementary analyses were conducted using the weighted median,MR-Egger,MR-robust adjusted profile score,and MR-PRESSO approaches.RESULTS The results provided suggestive evidence of a decreased risk of PCOS with genetically predicted higher levels of vitamin E(odds ratio[OR]=0.118;95%confidence interval[CI]:0.071–0.226;P<0.001)and vitamin B12(OR=0.753,95%CI:0.568–0.998,P=0.048).An association was observed between vitamin E levels and insulin resistance(OR=0.977,95%CI:0.976–0.978,P<0.001).Additionally,genetically predicted higher concentrations of vitamins E,D,and A were suggested to be associated with a decreased risk of hyperlipidemia.Increased vitamins K and B12 levels were linked to a lower obesity risk(OR=0.917,95%CI:0.848–0.992,P=0.031).CONCLUSION The findings of this MR study suggest a causal relationship between increased vitamins A,D,E,K,and B12 levels and a reduced risk of PCOS or primary pathways implicated in its development.

Conduction pathways of resource endowment affecting carbon intensity:Based on interprovincial data in China

By establishing a mathematical model and a basic analytical framework for the impact of resource endowments on carbon intensity,a traditional panel model without spatial panel effects was firstly constructed,a Durbin-Wu-Hausman test was conducted,and the model was set as a fixed-effects model based on the statistical values;secondly,the traditional panel model without spatial effects was estimated,and LM tests and robustness tests were conducted on the regression residuals.The LM test was then used to remove the fixed effect terms by the de-meaning method,and the Matlab 7.0 software was used to estimate the model.The stepwise introduction of variables was used to observe the effect of each variable on economic growth and to analyze the relationship between the magnitude and significance of the regression parameters of each variable.Finally,the path of conduction effect of resource endowment through mediating variable sinfluencing economic growth and carbon emissions,and thus carbon intensity,was constructed.The conclusion is that carbon intensity is inversely proportional to economic growth for a given level of carbon emissions.Therefore,if resource endowment promotes economic growth through mediating variables,it will lead to a decrease in carbon intensity,which is conducive to the achievement of emission reduction targets;conversely,if resource endowment hinders economic growth through mediating variables,it will lead to an increase in carbon intensity,which is not conducive to the achievement of emission reduction targets.

Analysis of Differential Gene Expression and Core Canonical Pathways Involved in the Epithelial to Mesenchymal Transition of Triple Negative Breast Cancer Cells by Ingenuity Pathway Analysis

Triple Negative Breast Cancer (TNBC) is a malignant form of cancer with very high mortality and morbidity. Epithelial to Mesenchymal Transition (EMT) is the most common pathophysiological change observed in cancer cells of epithelial origin that promotes metastasis, drug resistance and cancer stem cell formation. Since the information regarding differential gene expression in TNBC cells and cell signaling events leading to EMT is limited, this investigation was done by comparing transcriptomic data generated by RNA isolation and sequencing of a EMT model TNBC cell line in comparison to regular TNBC cells. RNA sequencing and Ingenuity Pathway Software Analysis (IPA) of the transcriptomic data revealed several upregulated and downregulated gene expressions along with novel core canonical pathways including Sirtuin signaling, Oxidative Phosphorylation and Mitochondrial dysfunction events involved in EMT changes of the TNBC cells.

Research on Practical Pathways of Strengthening Labor Education for College and University Students in the New Era

Labor education is an essential component of college and university education that can help students to develop a strong work ethic,acquire practical skills,and better understand the value of work.Strengthening labor education for college and university students is an urgent need of the high-quality development of the society and the internal requirement of promoting the all-round development of individuals.This study analyzes the importance of strengthening labor education for college and university students in the new era and proposes four practical pathways which draw on labor courses and campus activities,social practices,scientific research projects,and internships.After implementing these pathways,a survey of 967 students showed that students’understanding and awareness of labor was deepened,their hands-on skills and interests in science and labor practices were improved,and they became more cordially respectful to the working class.Taken together,the exploration and practice of these pathways helps college and university students to recognize their abilities,strengths,and interests,and guides them to form good labor habits that permeate all aspects of their studies and lives.

The mechanisms of melanogenesis inhibition by glabridin:molecular docking,PKA/MITF and MAPK/MITF pathways

Glabridin is the main ingredient of hydrophobic fraction in licorice extract and has been shown to have anti-melanogenesis activity in skins.However,the underlying mechanism(s)remain not completely understood.The aim of this study is thus to elucidate the possible mechanisms related to the melanogenesis suppression by glabridin in cultured B16 murine melanoma cells and in UVA radiation induced hyperpigmentation model of BALB/c mice as well.Molecular docking simulations revealed that between catalytic core residues and the compound.The treatment by glabridin significantly downregulated both transcriptional and/or protein expression of melanogenesis-related factors including melanocyte stimulating hormone receptor(MC1R),microphthalmia-associated transcription factor(MITF),tyrosinase(TYR),TYR-related protein-1(TRP-1)and TRP-2 in B16 cells.Both PKA/MITF and MAPK/MITF signaling pathways were found to be involved in the suppression of melanogenesis by glabridin in B16 cells.Also in vivo glabridin therapy significantly reduced hyperpigmentation,epidermal thickening,roughness and inflammation induced by frequent UVA exposure in mice skins,thus beneficial for skin healthcare.These data further look insights into the molecular mechanisms of melanogenesis suppression by glabridin,rationalizing the application of the natural compound for skin healthcare.

Calcitriol attenuates liver fibrosis through hepatitis C virus nonstructural protein 3-transactivated protein 1-mediated TGF β1/Smad3 and NF-κB signaling pathways

BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy options are still lacking.Our group identified hepatitis C virus nonstructural protein 3-transactivated protein 1(NS3TP1) by suppressive subtractive hybridization and bioinformatics analysis,but its role in diseases including hepatic fibrosis remains undefined.Therefore,additional studies on the function of NS3TP1 in hepatic fibrosis are urgently needed to provide new targets for treatment.AIM To elucidate the mechanism of NS3TP1 in hepatic fibrosis and the regulatory effects of calcitriol on NS3TP1.METHODS Twenty-four male C57BL/6 mice were randomized and separated into three groups,comprising the normal,fibrosis,and calcitriol treatment groups,and liver fibrosis was modeled by carbon tetrachloride(CCl4).To evaluate the level of hepatic fibrosis in every group,serological and pathological examinations of the liver were conducted.TGF-β1 was administered to boost the in vitro cultivation of LX-2 cells.NS3TP1,α-smooth muscle actin(α-SMA),collagen I,and collagen Ⅲ in every group were examined using a Western blot and real-time quantitative polymerase chain reaction.The activity of the transforming growth factor beta 1(TGFβ1)/Smad3 and NF-κB signaling pathways in each group of cells transfected with pcDNA-NS3TP1 or siRNA-NS3TP1 was detected.The statistical analysis of the data was performed using the Student’s t test.RESULTS NS3TP1 promoted the activation,proliferation,and differentiation of hepatic stellate cells(HSCs)and enhanced hepatic fibrosis via the TGFβ1/Smad3 and NF-κB signaling pathways,as evidenced by the presence of α-SMA,collagen I,collagen Ⅲ,p-smad3,and p-p65 in LX-2 cells,which were upregulated after NS3TP1 overexpression and downregulated after NS3TP1 interference.The proliferation of HSCs was lowered after NS3TP1 interference and elevated after NS3TP1 overexpression,as shown by the luciferase assay.NS3TP1 inhibited the apoptosis of HSCs.Moreover,both Smad3 and p65 could bind to NS3TP1,and p65 increased the promoter activity of NS3TP1,while NS3TP1 increased the promoter activity of TGFβ1 receptor I,as indicated by coimmunoprecipitation and luciferase assay results.Both in vivo and in vitro,treatment with calcitriol dramatically reduced the expression of NS3TP1.Calcitriol therapy-controlled HSCs activation,proliferation,and differentiation and substantially suppressed CCl4-induced hepatic fibrosis in mice.Furthermore,calcitriol modulated the activities of the above signaling pathways via downregulation of NS3TP1.CONCLUSION Our results suggest that calcitriol may be employed as an adjuvant therapy for hepatic fibrosis and that NS3TP1 is a unique,prospective therapeutic target in hepatic fibrosis.

Water Extract of Rice False Smut Balls Activates Nrf2/HO-1 and Apoptosis Pathways,Causing Liver Injury

Ustiloxins are vital cyclopeptide mycotoxins originally isolated from rice false smut balls that form in rice spikelets infected by the fungal pathogen Ustilaginoidea virens.The toxicity of the water extract of rice false smut balls(RBWE) remains to be investigated.Studies have shown that RBWE may be toxic to animals,but toxicological evidence is still lacking.In this study,we found that the IC50 values of RBWE to BNL CL.2 cells at 24 and 48 h were 40.02 and 30.11 μg/m L,respectively,with positive correlations with dose toxicity and time toxicity.After treatment with RBWE,the number of BNL CL.2 cells decreased significantly,and the morphology of BNL CL.2 cells showed atrophy and wall detachment.RBWE induced DNA presynthesis phase arrest of BNL CL.2 cells,increased the proportion of apoptotic cells and inhibited cell proliferation.RBWE up-regulated reactive oxygen species(ROS) levels and lowered mitochondrial membrane potentials.Additionally,Western blot and q RT-PCR results suggested that RBWE exerted the above effects by promoting the Nrf2/HO-1 and caspase-induced apoptosis pathways in vitro and in vivo.The contents of alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase,and total bile acids in the serum of mice from Institute of Cancer were significantly up-regulated by RBWE.At the same time,RBWE can lead to increases in ROS and malondialdehyde contents,decreases in contents of oxidized glutathione,glutathione and reduced glutathione,as well as decrease in catalase and superoxide dismutase activities in mouse liver tissues,demonstrating that oxidative stress occurred in mice.Moreover,liver damage was further detected by haematoxylin-eosin staining and electron microscopy to verify the damage to the mice caused by RBWE.In general,RBWE may cause hepatotoxicity in vivo and in vitro via the apoptosis pathway,which provides a reference for hepatotoxicity and its mechanism of action.