Exploring the causal link between circulating cytokines and sarcopenia traits: A Mendelian randomization analysis.

BACKGROUND: Previous observational studies have linked circulating cytokines to sarcopenia, but their causal relationship remains unclear. This study employed Mendelian Randomization (MR) to investigate the causal links between circulating cytokines and sarcopenia-related traits using genetic data. METHODS: A two-sample bidirectional MR analysis was conducted using data from individuals of European ancestry, utilizing genome-wide association studies (GWAS) statistics. The study selected instrumental single nucleotide polymorphisms (SNPs) significantly associated with circulating cytokines and applied multiple MR methods, including inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR-PRESSO. The traits analyzed were appendicular lean mass (ALM) and grip strength. Heterogeneity, robustness, and consistency of results were assessed using Cochran's Q statistic, MR-Egger regression, and "leave-one-out" sensitivity analyses. RESULTS: The IVM-MR analysis showed a casual association between genetically predicted circulating levels of interleukin-16 and both ALM and grip strength (ALM: OR = 0.990, 95% CI: 0.980-1.000, p = .049; grip strength: OR = 0.971, 95% CI: 0.948-0.995, p = .020). Additionally, interferon-gamma-induced protein 10 (IP-10), interleukin-1-beta (IL-1ß), and hepatocyte growth factor (HGF) were correlated with ALM and vascular endothelial growth factor (VEGF), interleukin-12 (IL-12), and interleukin-5 (IL-5) with grip strength. Comparable results were confirmed via the MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates. CONCLUSION: The results suggest a significant causal effect of inflammatory cytokines on sarcopenia, offering new avenues for therapeutic target development. However, the study's focus on a European ancestry cohort limits its generalizability to other populations. Future research should aim to include diverse ethnic groups to validate and broaden these findings, thereby enhancing our understanding of sarcopenia's mechanisms in a global context.

Research on Patients’ Trust Risk Points and Promotion Path from the Perspective of Online Health Community / 中国医学伦理学

Online health community is a new medical treatment mode combining the Internet and medical treatment. Patients can get medical services through the network. However, it cannot be ignored that patients’ trust will be affected by the uncertainty of online medical information, the unsafe factors of patients’ private information, the insufficient standardization of the diagnosis and treatment process, and other issue in the process of using this new medical treatment mode. By taking measures such as improving the information quality in online health community, enhancing patients’ cognitive ability of health information, perfecting privacy protection measures in online health community, advancing patients’ participation in online health community and ensuring the standardization of diagnosis and treatment process, patients’ trust can be improved.

Therapy of replenishing and regulating for manic episode in bipolar disorder: study protocol for a prospective, double-blind, randomized controlled trial.

Bipolar disorder (BD) is a chronic and recurrent disorder characterized by biphasic mood episodes of mania or hypomania and depression. It affects more than 1% of the global population and is a leading cause of disability in young people. Currently available treatments for BD are still fairly limited in terms of efficacy, with high rates of non-adherence, non-response, and undesirable side effects. Traditional Chinese medicine (TCM) has a long history and rich experience in stabilizing mania and improving quality of life. Aiming at rebalancing and in BD, therapy of replenishing and regulating (RYRY therapy) has been in clinical use for years in China. The present prospective, double-blind, randomized controlled trial is designed to investigate the efficacy and safety of RYRY therapy for bipolar mania and its possible mechanism from the point of regulating gut microbiota and anti-inflammation. A total of 60 eligible participants will be recruited from Beijing Anding Hospital. They will be randomized to either the study group or the control group in a ratio of 1∶1. Participants allocated to the study group will receive RYRY granule, while placebo granule will be applied in the control group. Participants in both groups will be prescribed conventional therapy for manic episode in BD. Four scheduled visits will be conducted over 4 weeks. Outcome measurements include Young Mania Rating Scale, TCM Symptom Pattern Rating Scale, Treatment Emergent Symptom Scale, levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α and the gut microbial community profile of stool samples. Safety outcomes and adverse events will also be recorded. In this study, we set a number of scientific and objective assessments to evaluate the efficacy of RYRY therapy and study into its possible mechanism, hopefully offering clinicians an alternative approach to BD.

Rat and mouse bone marrow mesenchymal stem cells can spontaneously express troponin T.

PURPOSE: This study aims to investigate whether the bone marrow mesenchymal stem cells (BMSCs) of rat and mice can spontaneously express troponin T (cTnT) in vitro. METHODS: The BMSCs of rats and mice were cultured in vitro. The expression of cTnT in the BMSCs of rats and mice was detected by immunofluorescence, immunohistochemistry, and Western blot. The detection of cTnT and α-sarcomeric actin coexpression on the surface of BMSCs was determined using immunofluorescence and qRT-PCR. RESULTS: In rats and mice, cTnT expression was detected in a portion of BMSCs. The positive rates of cTnT in rats and mice were approximately 10-52 % and 27-60 %, respectively. According to the results of the Western blot analysis, the gray values of cTnT in rats and mice were 0.64 ± 0.02 and 1.08 ± 0.03, respectively. Additionally, the surface of BMSCs can express cTnT and α-sarcomeric actin, which is a marker for striated muscle. CONCLUSION: The BMSCs of rats and mice can spontaneously express cTnT and automatically differentiate striated muscles in vitro.

WITHDRAWN: Hidrosmin Attenuates Inflammatory Response Induced by IL1ß by Suppressing the Activation of NF-κB Involving Nrf2/HO1 Pathway in Human Osteoarthritis Chondrocytes

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Influence of shared medical appointments on health-related quality of life and quality of sleep in patients after liver transplantation / 中华健康管理学杂志

Objective:To observe the influence of shared medical appointments on health-related quality of life and quality of sleep in patients after liver transplantation.Methods:By randomized controlled study, a total of 124 patients after liver transplantation were included from our hospital from January 2018 to January 2019, and according to the lottery method, all subjects were divided into the routine management group ( n=64) who received routine outpatient intervention and the shared medical management group ( n=60) who received shared medical appointments management. The health-related quality of life and quality of sleep were investigated and compared by post-liver transplant quality of life questionnaire (pLTQ) and Pittsburgh sleep quality index (PSQI) before intervention (the day of discharge) and after intervention (the end of the last shared outpatient service). Results:After intervention, the dimension scores of worry, economics, body function, emotional function, health service, complication and total score of pLTQ were improved in tow groups than before intervention [the routine management group: (41.90±7.61), (18.13±4.22), (22.22±5.10), (14.92±3.28), (20.39±4.87), (14.63±3.99), and (132.19±37.09) vs (32.25±5.55), (12.77±3.47), (17.58±4.72), (9.23±1.38), (15.17±4.81), (10.89±1.51) and (98.00±29.03) score, t=8.20, 7.85, 3.58, 12.79, 6.10, 7.01, 5.81, all P<0.001; shared medical management group: (46.12±7.92), (24.16±5.34), (25.55±5.42), (17.90±3.60), (24.81±5.12), (17.93±3.60) and (155.47±41.00) vs (32.57±5.69), (12.81±3.82), (17.00±4.70), (9.60±1.39), (15.39±4.84), (11.00±3.52) and (98.37±28.96) score, t=10.76, 13.39, 9.23, 16.66, 10.36, 10.66, 8.81, all P<0.001], and those in the shared medical management group were higher than those in routine management group ( t=3.03, 6.95, 3.53, 4.82, 4.93, 4.83, 3.32, all P<0.05). After intervention, the total score of PSQI scale were lower than before intervention in the routine management group [(10.48±2.14) vs (11.89±2.45) score, t=3.47, P=0.001], and the dimensions score of sleep quality, full-sleep time, sleep time, sleep efficiency, sleep disorders, daytime function, hypnotic and total score of PSQI were lower than before intervention in the shared medical management group [(1.41±0.32), (0.54±0.13), (1.17±0.26), (1.11±0.35), (1.21±0.27), (1.30±0.33), (1.08±0.21) and (8.05±1.75) vs (1.88±0.53), (0.86±0.37), (1.84±0.41), (2.05±0.56), (1.39±0.33), (1.47±0.43), (1.22±0.32) and (11.71±2.43) score, t=-5.88, -6.32, -10.69, -11.03, -3.27, -2.43, -3.65, -9.47, all P<0.05], and those in the shared medical management group were lower than those in routine management group ( t=-6.68, -6.39, -10.43, -10.97, -2.62, -2.12, -3.54, -6.90, all P<0.05). Conclusion:Shared medical appointments model can improve the health-related quality of life and quality of sleep in patients after liver transplantation, and improve the effectiveness of outpatient intervention.

Relationship between blood uric acid level and plasma atherogenic index in patients with type 2 diabetes / 中国综合临床

Objective:To explore the correlation between serum uric acid level and atherogenic index of plama (AIP) in patients with type 2 diabetes mellitus (T2DM).Methods:A retrospective analysis of 485 T2DM patients hospitalized in the First Hospital of Qin Huangdao was performed in August 2019 to August 2021. They were divided into atherogenic phenotype group (the case group, AIP≥0.06, n=326) and non atherogenic phenotype group (the control group, AIP<0.06, n=159) with AIP=0.06 as the cut-off point. The age, sex, body mass index, uric acid, triglyceride, total cholesterol, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol, glycosylated hemoglobin, smoking history and coronary heart disease history were compared between the two groups. The data processing using sample t-test and chi-square test. Pearson correlation analysis and multivariate logistic regression analysis were performed. Results:Body mass index (27.7±3.6) kg/m 2, systolic pressure (138.4±17.5) mmHg, uric acid (351.6±93.0) μmol/L, triglyceride (3.0±3.4) mmol/L and the proportion of men (61.6%(201/326)), coronary heart disease history (24.3%(79/326)) and smoking history (33.5%(109/326)) in case group were higher than those in control group (25.8±3.5) kg/m 2, (132.2±17.7) mmHg, (291.6±73.8) μmol/L, (1.0±0.3) mmol/L, (51.6%(82/159)), (15.7%(25/159)), (19.5%(31/159)) and the level of high density lipoprotein-cholesterol (1.1±0.3) mmol/L was lower than that in control group (1.3±0.3) mmol/L,with all statistically significant differences ( t=5.43, P<0.001; t=3.64, P<0.001; t=7.70, P=0.001; t=10.40, P<0.001; χ 2=4.47, P=0.034;χ 2=4.60, P=0.032;χ 2=10.11, P=0.001; t=5.18, P<0.001). The prevalence of hyperuricemia in case group (21.5%(70/326)) was 4.3 times higher than that in control group (5.0%(8/159)). AIP was positively correlated with body mass index ( r=0.300, P<0.001), uric acid ( r=0.343, P<0.001), systolic pressure ( r=0.117, P=0.010), diastolic pressure (r=0.119, P=0.009), triglyceride ( r=0.724, P<0.001), total cholesterol ( r=0.226, P<0.001), while that was negatively correlated with high density lipoprotein-cholesterol ( r=-0.185, P<0.001). Logistic regression analysis showed that after excluding the interference of other factors, uric acid was still related to AIP ( OR=3.727, 95% CI=1.702-8.158, P=0.001), and the risk of AIP increase increased with the increase of uric acid level. Conclusion:The level of serum uric acid in T2DM patients is related to AIP, and high uric acid is an independent risk factor for AIP in T2DM patients.

Research progress on pharmacological mechanism of polygona-polysaccharose / 国际中医中药杂志

Polygona-polysaccharose is an important indicator to measure the quality of Polygonati Rhizoma. The polygona-polysaccharose has the effect of lowering blood sugar, regulating blood lipid, anti-fatigue, improving learning and memory ability. The Polygonati Rhizoma, as a Chinese herbal medicine with homology of medicine and food, has a good prospect and application value in the development of food and health products.

Dexmedetomidine can not reduce the incidence of acute and chronic kidney disease after laparoscopic radical nephrectomy: a propensity score matching-based analysis / 南方医科大学学报

OBJECTIVE@#To investigate the effect of dexmedetomidine (DEX) on renal function after laparoscopic radical nephrectomy.@*METHODS@#We reviewed the clinical data of 282 patients with renal cell carcinoma (RCC), who underwent laparoscopic radical nephrectomy (LRN) in the Department of Urology, Third Medical Center of PLA General Hospital from November, 2020 and June, 2022.According to whether DEX was used during the operation, the patients were divided into DEX group and control group, and after propensity score matching, 99 patients were finally enrolled in each group.The incidence of acute kidney injuries were compared between the two groups.Serum creatinine (sCr) data within 3 months to 1 year after the operation were available in 51 patients, including 26 in DEX group and 25 in the control group, and the incidence of chronic kidney disease (CKD) was compared between the two groups.@*RESULTS@#After propensity score matching and adjustment for significant covariates, there were no significant differences in postoperative levels of sCr, cystatin C (CysC), β2-microglobulin (β2-MG), hemoglobin (Hb), or C-reactive protein (CRP), extubation time, incidence of AKI, or length of hospital stay between the two groups (P>0.05).The intraoperative urine volume was significantly higher in DEX group than in the control group (P < 0.05).A significant correlation between AKI and CKD was noted in the patients (P < 0.05).The incidence of CKD did not differ significantly between the two groups (P>0.05).@*CONCLUSION@#DEX can not reduce the incidence of AKI or CKD after LRN.

T cell immunotherapy mediated by dual-affinity aptamer targeted liposome / 药学学报

Redirecting immune cells to the tumor cells and enhancing its anti-tumor immune response is a very promising cancer treatment strategy. AS1411 aptamers have high affinity for malignant tumors with high nucleolin expression, and cytotoxic T lymphocyte associated protein 4 (CTLA-4) aptamers can specifically bind to CTLA-4, which is expressed by T cells. In this study, a dual-affinity aptamer targeted liposome (Dat. Lipo) was constructed based on AS1411 aptamer and CTLA-4 aptamer, and its immunotherapeutic effect on T cells was studied. After the aptamer was modified with cholesterol, Dat. Lipo was prepared by instillation method; its effect of redirecting T cells was determined by confocal micrographs; its T cell immunotherapy effect was evaluated by cell counting kit-8 (CCK8) and T cell penetration was evaluated by tumor spheroids. The results showed that compared with liposomes loaded with one type aptamer, Dat. Lipo could effectively promote the redirection of T cells to tumor cells; Dat. Lipo had good biosafety and immunotherapeutic effect on MCF-7 and HepG2 cells in a concentration-dependent manner; Dat. Lipo could also promote T cells to infiltrate into the tumor spheroids and enhance the immunotherapy effect of T cells in different dimensions. In summary, Dat. Lipo can use the high affinity of aptamers to redirect T cells to tumor cells, enhance the effect of immunotherapy, and has a promising application prospect in tumor therapy. This study was approved by the Examination Committee of Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital.

Research progress on correction schemes of hyperopia for patients of different ages / 国际眼科杂志(Guoji Yanke Zazhi)

Among typical hyperopia patients, the light is focused behind the retina, resulting in blurry vision either at a distance or near. Frequent and excessive accommodationis prone to visual fatigue and internal strabismus, and children may even develop amblyopia, which requires timely correction and a careful design of an individualized correction scheme to avoid problems above. Due to the age-related physiological changes in the refractive system, the accommodation of hyperopic patients varies greatly at different ages and doctors need to design reasonable correction schemes according to different refractive characteristics. This article will review the existing hyperopia correction methods, compare their advantages, disadvantages and indications, and summarize the clinical manifestations of hyperopia patients of different ages and the clinical progress of the corresponding correction plan, hoping to provide a reference for the clinical correction of hyperopia.

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions / 医学前沿

With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations ("target-dependent resistance") and in the parallel and downstream pathways ("target-independent resistance"). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.

A nested case-control study on the association of neonatal cord blood selenium, iron and copper with congenital heart disease / 中华预防医学杂志

Objective: To investigate the relationship between the levels of selenium, iron and copper in cord blood of neonates and the risk of congenital heart disease (CHD), and analyze their interaction effects. Methods: The subjects were obtained from the birth cohort in Lanzhou area established from 2010 to 2012. A baseline survey was conducted in the first trimester, and the follow-up was conducted in the second trimester, third trimester and 42 days after delivery. The umbilical vein blood was collected from newborns at delivery, and information on their birth outcomes was extracted from medical records. A nested case-control study was used to select 97 neonates with CHD newly diagnosed by echocardiography as the case group, and 194 neonates were selected as the control group by 1∶2 matching according to their mother's age, block and CHD onset time. Inductively coupled ion mass spectrometry was used to detect the concentrations of selenium, iron and copper in neonatal cord blood. The element exposure was categorized into three groups, the low, medium and high concentrations, according to the quartiles Q1 and Q3 of selenium, iron and copper concentrations in the control group. The association between cord blood selenium, iron and copper concentrations and CHD was analyzed by conditional logistic regression model using medium concentration as the reference standard. The association of their interactions with CHD was analyzed by a phase multiplication model. Results: The M (Q1, Q3) concentration of neonatal cord blood copper was 746.12 (467.48, 759.74) μg/L in the case group and 535.69 (425.21, 587.79) μg/L in the control group, with a statistically significant difference between the two groups (P<0.05). After adjustment for confounders, logistic regression models showed that the risk of CHD development was increased in neonates with either high copper in cord blood (OR=4.062, 95%CI: 2.013-8.199) or high copper combined with high iron (OR=3.226, 95%CI: 1.343-7.750). No correlation was observed between selenium and iron concentrations and the development of CHD in neonates. There was a multiplicative interaction between copper and iron in cord blood on the risk of developing CHD (OR=1.303, 95%CI: 1.056-1.608). Conclusion: There is a multiplicative interaction between iron and copper elements. The high copper and the high copper combined with high iron in umbilical cord blood are risk factors for neonatal CHD.

Functional biomaterials for comprehensive periodontitis therapy

Periodontitis is an inflammatory disease caused by bacterial infection directly, and the dysregulation of host immune-inflammatory response finally destroys periodontal tissues. Current treatment strategies for periodontitis mainly involve mechanical scaling/root planing (SRP), surgical procedures, and systemic or localized delivery of antimicrobial agents. However, SRP or surgical treatment alone has unsatisfactory long-term effects and is easy to relapse. In addition, the existing drugs for local periodontal therapy do not stay in the periodontal pocket long enough and have difficulties in maintaining a steady, effective concentration to obtain a therapeutic effect, and continuous administration always causes drug resistance. Many recent studies have shown that adding bio-functional materials and drug delivery systems upregulates the therapeutic effectiveness of periodontitis. This review focuses on the role of biomaterials in periodontitis treatment and presents an overview of antibacterial therapy, host modulatory therapy, periodontal regeneration, and multifunctional regulation of periodontitis therapy. Biomaterials provide advanced approaches for periodontal therapy, and it is foreseeable that further understanding and applications of biomaterials will promote the development of periodontal therapy.

Effect of Liangfang Wenjing Decoction on expression of key glycolytic enzymes in uterus and ovaries of rats with coagulating cold and blood stasis syndrome / 中国中药杂志

This study aimed to investigate the relationship between coagulating cold and blood stasis syndrome and glycolysis, and observe the intervention effect of Liangfang Wenjing Decoction(LFWJD) on the expression of key glycolytic enzymes in the uterus and ovaries of rats with coagulating cold and blood stasis. The rat model of coagulating cold and blood stasis syndrome was established by ice-water bath. After modeling, the quantitative scoring of symptoms were performed, and according to the scoring results, the rats were randomly divided into a model group and LFWJD low-, medium-and high-dose groups(4.7, 9.4, 18.8 g·kg~(-1)·d~(-1)), with 10 in each group. Another 10 rats were selected as the blank group. After 4 weeks of continuous administration by gavage, the quantitative scoring of symptoms was repeated. Laser speckle flowgraphy was used to detect the changes of microcirculation in the ears and uterus of rats in each group. Hematoxylin-eosin(HE) staining was used to observe the pathological morphology of uterus and ovaries of rats in each group. The mRNA and protein expressions of pyruvate dehydrogenase kinase 1(PDK1), hexokinase 2(HK2) and lactate dehydrogenase A(LDHA) in the uterus and ovaries of rats were examined by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. The rats in the model group showed signs of coagulating cold and blood stasis syndrome, such as curl-up, less movement, thickened veins under the tongue, and reduced blood perfusion in the microcirculation of the ears and uterus, and HE staining revealed a thinning of the endometrium with disorganized arrangement of epithelial cells and a decrease in the number of ovarian follicles. Compared with the model group, the treatment groups had alleviated coagulating cold and blood stasis, which was manifested as red tongue, reduced nail swelling, no blood stasis at the tail end as well as increased blood perfusion of the microcirculation in the ears and uterus(P<0.05 or P<0.01). Among the groups, the LFWJD medium-and high-dose groups had the most significant improvement in coagulating cold and blood stasis, with neatly arranged columnar epithelial cells in uterus, and the number of ovarian follicles was higher than that in the model group, especially mature follicles. The mRNA and protein expressions of PDK1, HK2, LDHA in uterus and ovaries were up-regulated in the model group(P<0.05 or P<0.01), while down-regulated in LFWJD medium-and high-dose groups(P<0.05 or P<0.01). The LFWJD low-dose group presented a decrease in the mRNA expressions of PDK1, HK2 and LDHA in uterus and ovaries as well as in the protein expressions of HK2 and LDHA in uterus and HK2 and PDK1 in ovaries(P<0.05 or P<0.01). The therapeutic mechanism of LFWJD against coagulating cold and blood stasis syndrome is related to the down-regulation of key glycolytic enzymes PDK1, HK2 and LDHA, and the inhibition of glycolytic activities in uterus and ovaries.

Immune regulation mechanism of Saposhnikoviae Radix polysaccharide based on zebrafish model / 中国中药杂志

The immunomodulatory effect of Saposhnikoviae Radix polysaccharide(SRP) was evaluated based on the zebrafish mo-del, and its mechanism was explored by transcriptome sequencing and real-time fluorescence-based quantitative PCR(RT-qPCR). The immune-compromised model was induced by navelbine in the immunofluorescence-labeled transgenic zebrafish Tg(lyz: DsRed), and the effect of SRP on the density and distribution of macrophages in zebrafish was evaluated. The effect of SRP on the numbers of macrophages and neutrophils in wild-type AB zebrafish was detected by neutral red and Sudan black B staining. The content of NO in zebrafish was detected by DAF-FM DA fluorescence probe. The content of IL-1β and IL-6 in zebrafish was detected by ELISA. The differentially expressed genes(DEGs) of zebrafish in the blank control group, the model group, and the SRP treatment group were analyzed by transcriptome sequencing. The immune regulation mechanism was analyzed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment, and the expression levels of key genes were verified by RT-qPCR. The results showed that SRP could significantly increase the density of immune cells in zebrafish, increase the number of macrophages and neutrophils, and reduce the content of NO, IL-1β, and IL-6 in immune-compromised zebrafish. The results of transcriptome sequencing analysis showed that SRP could affect the expression level of immune-related genes on Toll-like receptor pathway and herpes simplex infection pathway to affect the release of downstream cytokines and interferon, thereby completing the activation process of T cells and playing a role in regulating the immune activity of the body.

Establishment of a novel co-cultured liver cancer model based on tumor microenvironment / 中华肿瘤杂志

Objective: To construct a new co-cultured liver cancer research model composed of activated hepatic stellate cells (aHSC) and liver cancer cells, explore the efficacy difference between it and traditional model, so as to establish a liver cancer research model in vitro and in vivo that can reflect the real clinical efficacy. Methods: A new co-culture model of liver cancer consisting of aHSC and liver cancer cells was constructed. The differences in efficacy between the new co-culture model and the traditional single cell model were compared by cytotoxicity test, cell migration test, drug retention test and in vivo tumor inhibition test. Western blot was used to detect the drug-resistant protein P-gp and epithelial-mesenchymal transition-related proteins. Masson staining was used to observe the deposition of collagen fibers in tumor tissues of tumor-bearing mice. CD31 immunohistochemical staining was used to observe the microvessel density in tumor tissues of tumor-bearing mice. Results: The cytotoxicity of single cell model and co-culture model was dose-dependent. With the increase of curcumin (CUR) concentration, the cell viability decreased, but the cell viability of single cell model decreased faster than that of co-culture model. When the concentration of CUR was 10 μg/ml, the cell viability of the co-culture model was 62.3% and the migration rate was (28.05±3.68)%, which were higher than those of the single cell model [38.5% and (14.91±5.92)%, both P<0.05]. Western blot analysis showed that the expressions of P-gp and vimentin were up-regulated in the co-culture model, which were 1.55 and 2.04 fold changes of the single cell model, respectively. The expression of E-cadherin was down-regulated, and the expression level of E-cadherin in the single cell model was 1.17 fold changes of the co-culture model. Drug retention experiment showed that the co-culture model could promote drug efflux and reduce drug retention. In vivo tumor inhibition experiment showed that the m-HSC+ H22 co-transplantation model had faster tumor growth and larger tumor volume than those of the H22 single cell transplantation model. After CUR treatment, the tumor growths of m-HSC+ H22 co-transplantation model and H22 single cell transplantation model were inhibited. Masson staining showed that the deposition of collagen fibers in tumor tissues of m-HSC+ H22 co-transplantation model mice was more than that of H22 single cell transplantation model. CD31 immunohistochemical staining showed that the microvessel density in tumor tissue of m-HSC+ H22 co-transplantation model was higher than that of H22 single cell transplantation model. Conclusions: The aHSC+ liver cancer cell co-culture model has strong proliferation and metastasis ability and is easy to be resistant to drugs. It is a new type of liver cancer treatment research model superior to the traditional single cell model.

Molecular mechanism of Cigu Xiaozhi formula interfering with HSC-T6 cell activation by regulating HIF-1α signaling pathway based on computer aided drug design / 药学学报

In this study, we investigated the effect of Cigu Xiaozhi formula on HSC-T6 activity in hypoxic microenvironment based on network pharmacology and computer-aided drug design, and predicted and verified its possible targets and related signaling pathways. The potential active components and targets of Cigu Xiaozhi formula were screened by searching Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Encyclopaedia of Traditional Chinese Medicine (ETCM) and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) databases, and the liver fibrosis related targets retrieved from Gene Cards and Pharm GK database were integrated to obtain the potential targets of Cigu Xiaozhi formula in the treatment of liver fibrosis. GO enrichment analysis and KEGG signaling pathway enrichment analysis were performed on Omic Share platform, and Cytoscape software was used to construct the "potential active ingredient-key target-pathway" network. The active components and target proteins were subjected to molecular docking analysis by Auto Dock software. According to the results of molecular dynamics simulation and binding free energy calculation, the top 5 active components with degree were scored. The active components stigmasterol and β-sitosterol were subjected to molecular docking. CoCl2 was used to induce HSC-T6 cells to construct hypoxia model in vitro. The cell viability was detected by CCK-8 assay, and the optimal time and concentration of hypoxia model of HSC-T6 cells was determined to be 100 µmol·L-1 CoCl2 for 24 h. Under hypoxia condition, HSC-T6 cells were activated, the wound healing rate was significantly increased, and the fluorescence signal of activation marker protein α-smooth muscle actin (α-SMA) was significantly enhanced. However, 6% drug-containing serum could inhibit the activation of HSC-T6 cells, and the wound healing rate was significantly decreased, and the fluorescence signal of α-SMA was significantly weakened. Further studies showed that the expressions of hypoxia-inducible factor-1α (HIF-1α), α-SMA and key proteins of Hedgehog (Hh) signaling pathway in HSC-T6 cells were up-regulated under hypoxia, while the expressions of HIF-1α, α-SMA, Patched-1 (Ptch-1) and glioma related oncogene homology-1 (Gli-1) were down-regulated in 6% drug-containing serum group, the YC-1 group and the cyclopamine group. These results indicated that HIF-1α and Hh signaling pathways were involved in the activation of HSC-T6 cells, and the traditional Chinese medicine Cigu Xiaozhi formula could inhibit the activation of HSC-T6 cells, and the mechanism may be related to the inhibition of HIF-1α expression and the blocking of Hh signaling pathway. In conclusion, Cigu Xiaozhi formula can inhibit the activation of HSC-T6 cells by directly acting on HIF-1α and Hh signaling pathway, and exert an anti-hepatic fibrosis effect. The animal experimental protocol has been reviewed and approved by Laboratory Animal Ethics Committee of Gansu University of Chinese Medicine, in compliance with the Institutional Animal Care Guidelines.

Canonical WNT pathway inhibition reduces ATP synthesis rates in glioblastoma stem cells.

BACKGROUND: The conserved stem cell signaling network canonical Wingless (WNT) plays important roles in development and disease. Aberrant activation of this pathway has been linked to tumor progression and resistance to therapy. Industry and academia have substantially invested in developing substances, which can efficiently and specifically block the WNT signaling pathway. However, a clear clinical proof of the efficacy of this approach is still missing. Studies on the metabolomics dysregulation of cancer cells have led to innovations in oncological diagnostics. In addition, modulation of cancer cell metabolome is at the base of promising clinical oncology trials currently underway. While onco-protein activation can have profound metabolic outcomes, the involvement of stem cell signals, such as the WNT pathway, in tumor cell metabolomics is yet insufficiently characterized. MATERIAL AND METHODS: We determined live cell metabolism and bioenergetics in pathophysiological relevant, WNT-dependent glioblastoma stem cell (GSC) models. We quantified those parameters in cells with canonical WNT activity and in isogenic cells where WNT activity had been inhibited by short hairpin RNA against ß-catenin. Furthermore, we applied computational analysis of RNA sequencing to verify our functional findings in independent GSCs cohorts. RESULTS: The investigated collection of disease models allows the separation in tumors with low, moderate and high base line metabolic activity. Suppression of canonical WNT signaling led to significant reduction of total, mitochondrial, and glycolytic ATP production rates. Elevated canonical WNT transcription signature in GSCs positively correlated with transcription levels of mitochondrial ATP synthesis, whereas non-canonical WNT gene expression signature did not. CONCLUSION: The applied disease modeling technology allows the recapitulation of inter-tumoral heterogeneous metabolic properties of glioblastoma. Our data show for the first time that inhibition of canonical WNT signaling in alive GSCs functionally correlates with energy inhibition and glucose homeostasis. As this correlation occurs in GSCs from different transcriptional or epigenetic transcriptional subtypes, our results suggest that developing therapies directed against glycolysis/ATP-synthesis may be a promising strategy to overcome therapy resistance due to inter-tumoral heterogeneity and offers starting point to impair downstream signal WNT.

The clinicopathological characteristics and outcomes of IgA nephropathy with predominant lambda or kappa light-chain deposition.

PURPOSE: IgA nephropathy (IgAN) patients with monoclonal light-chain deposition may be at potential risk of hematological progression. However, whether the clinical characteristics of the patients with predominant lambda or kappa light-chain deposition were consistent with monoclonal light-chain deposition is limited to anecdotes. METHODS: We retrospectively studied patients in whom immunofluorescence showed IgA-alone deposits (n = 617) between January 2016 and January 2020. We divided the patients into two groups, the predominant lambda or kappa light-chain deposition group and the control group. Predominant lambda or kappa light-chain deposition was defined as the deposition intensity of kappa or lambda being + - and the other deposition intensity being ≥ 2 + . RESULTS: Nineteen patients had predominant lambda or kappa light-chain deposition. The patients had a median age of 32 years. The median proteinuria was 0.9 g/day. The median eGFR was 79.8 ml/min per 1.73 m2. Two patients had a mildly abnormal FLC ratio, but serum immunofixation electrophoresis showed polyclonal immunoglobulin. Eighteen patients showed lambda light chain-dominated deposition. In electron microscopy, organized structures in dense deposits were not observed in all patients. Nine patients with proteinuria ≥ 1.0 g/day received corticosteroids and immunosuppressants. The median follow-up time was 21 months. The rate of proteinuria remission was 50%. The clinical and pathological characteristics and outcomes were not significantly different between the predominant lambda or kappa light-chain deposition group and the control group. CONCLUSION: The result for IgAN patients with predominant kappa/lambda light-chain deposition seemed to be the same as that of IgAN patients with light-chain codeposition. However, as this was a single-center study with a small size, further multicenter studies and long-term follow-up are needed to confirm our findings.