OBJECTIVES: To investigate whether mesenchymal stem cell-derived exosomes (MSC-Exo) alleviate white matter damage (WMD) in neonatal rats by targeting the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). METHODS: Three-day-old Sprague-Dawley rats were randomly assigned to four groups: Sham, hypoxia-ischemia (HI), MSC-Exo, and MCC950 (NLRP3 inhibitor) (n=24 per group). The WMD model was established by unilateral common carotid artery ligation combined with hypoxia. Exosomes (1×10⁸ particles/μL) were transplanted into the lateral ventricle using stereotaxic guidance. Fourteen days after modeling, hematoxylin-eosin staining was used to observe pathological changes in brain tissue, and transmission electron microscopy was used to assess myelinated axons. Western blotting was performed to detect the expression of myelin basic protein (MBP), NLRP3, caspase-1, and interleukin-1β (IL-1β). Immunohistochemistry was used to measure NLRP3, caspase-1, and IL-1β expression. Twenty-eight days post-modeling, behavioral changes were evaluated using the Morris water maze. RESULTS: In the HI group, marked inflammatory cell infiltration, extensive vacuolation, and decreased numbers of myelinated axons were observed compared to the Sham group. The MSC-Exo group showed reduced inflammatory infiltration, fewer vacuoles, and increased myelinated axons compared to the HI group, while the MCC950 group showed nearly normal cell morphology. Compared to the Sham group, the HI group exhibited decreased MBP expression, fewer platform crossings, shorter time in the target quadrant, increased expression of NLRP3, caspase-1, and IL-1β, and longer escape latency (all P<0.05). Compared to the HI group, the MSC-Exo and MCC950 groups showed increased MBP expression, more platform crossings, longer target quadrant stay, and reduced NLRP3, caspase-1, and IL-1β expression, as well as shorter escape latency (all P<0.05). CONCLUSIONS MSC-Exo may attenuate white matter damage in neonatal rats by targeting the NLRP3 inflammasome and promoting oligodendrocyte maturation.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors* ; Rats, Sprague-Dawley ; White Matter/pathology* ; Inflammasomes/physiology* ; Rats ; Animals, Newborn ; Mesenchymal Stem Cells ; Interleukin-1beta/analysis* ; Male ; Caspase 1/analysis* ; Hypoxia-Ischemia, Brain/therapy* ; Myelin Basic Protein/analysis*

OBJECTIVE: To evaluate the protective effects of gentiopicroside (GPS) against reactive oxygen species (ROS)-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in endothelial cells, aiming to reduce atherosclerosis. METHODS: Eight-week-old male ApoE-deficient mice were randomly divided into 2 groups (n=10 per group): the vehicle group and the GPS treatment group. Both groups were fed a high-fat diet for 16 weeks. GPS (40 mg/kg per day) was administered by oral gavage to the GPS group, while the vehicle group received an equivalent volume of the vehicle solution. At the end of the treatment, blood and aortic tissues were collected for assessments of atherosclerosis, lipid profiles, oxidative stress, and molecular expressions related to NLRP3 inflammasome activation, ROS production, and apoptosis. Additionally, in vitro experiments on human aortic endothelial cells treated with oxidized low-density lipoprotein (ox-LDL) were conducted to evaluate the effects of GPS on NLRP3 inflammasome activation, pyroptosis, apoptosis, and ROS production, specifically examining the role of the sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. SIRT1 and Nrf2 inhibitors were used to confirm the pathway's role. RESULTS: GPS treatment significantly reduced atherosclerotic lesions in the en face aorta (P<0.01), as well as in the thoracic and abdominal aortic regions, and markedly decreased sinus lesions within the aortic root (P<0.05 or P<0.01). Additionally, GPS reduced oxidative stress markers and proinflammatory cytokines, including interleukin (IL)-1 β and IL-18, in lesion areas (P<0.05, P<0.01). In vitro, GPS inhibited ox-LDL-induced NLRP3 activation, as evidenced by reduced NLRP3 (P<0.01), apoptosis-associated speck-like protein containing a CARD, cleaved-caspase-1, and cleaved-gasdermin D expressions (all P<0.01). GPS also decreased ROS production, apoptosis, and pyroptosis, with the beneficial effects being significantly reversed by SIRT1 or Nrf2 inhibitors. CONCLUSION GPS exerts an antiatherogenic effect by inhibiting ROS-dependent NLRP3 inflammasome activation via the SIRT1/Nrf2 pathway.
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Reactive Oxygen Species/metabolism* ; Iridoid Glucosides/therapeutic use* ; NF-E2-Related Factor 2/metabolism* ; Animals ; Atherosclerosis/metabolism* ; Inflammasomes/drug effects* ; Male ; Sirtuin 1/metabolism* ; Signal Transduction/drug effects* ; Humans ; Endothelial Cells/pathology* ; Mice ; Oxidative Stress/drug effects* ; Apoptosis/drug effects* ; Lipoproteins, LDL ; Mice, Inbred C57BL

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.

BACKGROUND:Lycium barbarum polysaccharide has many biological activities and has been found to have potential effects on promoting wound healing. OBJECTIVE:To investigate the mechanism of lycium barbarum polysaccharide in tumor necrosis factor-α-mediated keratinocyte apoptosis and its effect on the healing of burn wounds. METHODS:(1)In vitro experiment:Keratinocytes were divided into four groups:cells were cultured in the α-MEM medium(complete medium)containing 15%fetal bovine serum and 1%glutamine in normal group,cultured in the complete medium containing lycium barbarum polysaccharide in positive control group,cultured in the complete medium containing tumor necrosis factor-α in model group,and cultured in the complete medium containing lycium barbarum polysaccharide and tumor necrosis factor-α in experimental group.After 24 hours of culture,cell proliferation was detected using cell counting kit-8 assay;Cleaved caspase-8,TNF R1,FADD,and LC3 were detected using western blot.Then an autophagy inhibitor group(the complete medium containing 3-methyladenine)and an autophagy inhibitor+lycium barbarum polysaccharide group(the complete medium containing lycium barbarum polysaccharide,tumor necrosis factor-α,and 3-methyladenine)were set up.After 24 hours of culture,keratinocyte apoptosis was detected by flow cytometry.(2)In vivo experiment:Six Sprague-Dawley rats were randomly divided into a control group and an experimental group,with three rats in each group.Four deep Ⅱ degree burn wounds with a diameter of 2 cm were made on the back of each rat.At 24 hours after modeling,mice in the control and experimental groups were coated with normal saline and lycium barbarum polysaccharide solution,respectively,once a day.Wound healing was observed regularly after treatment.Samples were taken 28 days after treatment and the pathologic pattern of the wound was observed. RESULTS AND CONCLUSION:(1)In vitro experiment:Addition of lycium barbarum polysaccharide alone did not affect cell proliferation and apoptosis and the expression of apoptotic and autophagic proteins in keratinocytes.After the addition of tumor necrosis factor α,the proliferation of keratinocytes was inhibited,the apoptotic rate increased,and the expression of apoptotic and autophagic proteins was elevated,while lycium barbarum polysaccharide could antagonize the above effects of tumor necrosis factor-α.Lycium barbarum polysaccharide combined with autophagy inhibitors further reduced the apoptotic rate of keratinocytes.(2)In vivo experiment:The wound healing rate of rats in the experimental group was higher than that of the control group at 12,16,20,24,and 28 days after treatment(P＜0.05,P＜0.01).Hematoxylin-eosin staining results at 28 days after treatment showed an intact and well-defined epidermis of the wound in the experimental group compared with the control group.To conclude,lycium barbarum polysaccharide protects the integrity of skin epidermal tissue and promotes wound healing by inhibiting autophagy and apoptosis of keratinocytes.

Objective To analyze the influencing factors of pancreatic fat deposition in patients with type 2 diabetes mellitus(T2DM),and to explore the relationship between pancreatic fat deposition and islet function.Methods A survey on diabetes prevalence was conducted among 548 residents in the Nicheng community of Pudong New Area from October 2015 to December 2016,including 301 patients with T2DM and 247 subjects with normal glucose tolerance(NGT).General information of the subjects were recorded,blood biochemical and insulin indexes were measured,body composition was measured by dual-energy X-ray absorptiometry,and insulin resistance index(HOMA-IR)and islet cell sensitivity index(HOMA-β)were calculated.Fatty liver and pancreatic fat deposition were detected by ultrasound.Both the T2DM group and NGT group were further divided into two subgroups according to the pancreatic fat deposition.Differences in general demographic information,biochemical and body fat indices among the groups were compared.Multivariate logistic regression was used to analyze the influencing factors of pancreatic fat deposition.Results In the NGT group,the subgroup with pancreatic fat deposition showed higher levels of age,waist circumference,waist-to-hip ratio(WHR),body mass index(BMI),fasting insulin levels(FINS),2-hour postprandial insulin levels(2 h INS),triglycerides(TG),uric acid(UA),alanine aminotransferase(ALT),fatty liver prevalence,abdominal fat percentage,and abdomen-to-hip ratio(AHR),compared with the subgroup without pancreatic fat deposition.High-density lipoprotein cholesterol(HDL-C)and limb fat percentage were lower in the subgroup with pancreatic fat deposition.In the T2DM group,the subgroup with pancreatic fat deposition showed higher levels of waist circumference,BMI,FINS,2 h INS,TG,UA,ALT,aspartate aminotransferase(AST),fatty liver prevalence,and abdominal fat percentage,compared with the subgroup without pancreatic fat deposition,with statistically significant differences(P<0.05).The HOMA-IR and HOMA-β in both NGT and T2DM groups with pancreatic fat deposition were significantly higher than those in the groups without pancreatic fat deposition.The prevalence of insulin resistance also significantly increased,with statistically significant differences(P<0.05).The results of multivariate logistic regression analysis showed that HDL-C,HOMA-β,abdominal fat percentage,age and fatty liver were the influencing factors for pancreatic fat deposition in NGT.Conclusion Elderly individuals with abdominal obesity and fatty liver are more prone to developing pancreatic fat deposition,which can affect islet function and aggravate the insulin resistance.

Human brain banks use a standardized protocol to collect,process and store post-mortem human brains and related tissues,along with relevant clinical information,and to provide the tissue samples and data as a resource to foster neuroscience research according to a standardized operating protocols(SOP).Human brain bank serves as the foundation for neuroscience research and the diagnosis of neurological disorders,highlighting the crucial rule of ensuring the consistency of standardized quality for brain tissue samples.The first version of SOP in 2017 was published by the China Human Brain Bank Consortium.As members increases from different regions in China,a revised SOP was drafted by experts from the China Human Brain Bank Consortium to meet the growing demands for neuroscience research.The revised SOP places a strong emphasis on ethical standards,incorporates neuropathological evaluation of brain regions,and provides clarity on spinal cord sampling and pathological assessment.Notable enhancements in this updated version of the SOP include reinforced ethical guidelines,inclusion of matching controls in recruitment,and expansion of brain regions to be sampled for neuropathological evaluation.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.