This study aimed to explore the therapeutic mechanisms of Colquhounia Root Tablets(CRT) in treating diabetic kidney disease(DKD) by integrating biomolecular network mining with animal model verification. By analyzing clinical transcriptomics data, an interaction network was constructed between candidate targets of CRT and DKD-related genes. Based on the topological eigenvalues of network nodes, 101 core network targets of CRT against DKD were identified. These targets were found to be closely related to multiple pathways associated with type 2 diabetes, immune response, and metabolic reprogramming. Given that immune-inflammatory imbalance driven by metabolic reprogramming is one of the key pathogenic mechanisms of DKD, and that many core network targets of CRT are involved in this pathological process, receptor for advanced glycation end products(RAGE)-reactive oxygen species(ROS)-phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)-nuclear factor-κB(NF-κB)-NOD-like receptor family pyrin domain containing 3(NLRP3) signaling axis was selected as a candidate target for in-depth research. Further, a rat model of DKD induced by a high-sugar, high-fat diet and streptozotocin was established to evaluate the pharmacological effects of CRT and verify the expression of related targets. The experimental results showed that CRT could effectively correct metabolic disturbances in DKD, restore immune-inflammatory balance, and improve renal function and its pathological changes by inhibiting the activation of the RAGE-ROS-PI3K-AKT-NF-κB-NLRP3 signaling axis. In conclusion, this study reveals that CRT alleviates the progression of DKD through dual regulation of metabolic reprogramming and immune-inflammatory responses, providing strong experimental evidence for its clinical application in DKD.
Animals ; Diabetic Nephropathies/metabolism* ; Receptor for Advanced Glycation End Products/genetics* ; NF-kappa B/genetics* ; Signal Transduction/drug effects* ; Rats ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Phosphatidylinositol 3-Kinases/genetics* ; Reactive Oxygen Species/metabolism* ; Humans ; Plant Roots/chemistry* ; Rats, Sprague-Dawley ; Tablets/administration & dosage*

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective To investigate the effect of Modified Renshen Wumei Decoction on the TLR4/MyD88/pNF-κBp65 signaling pathway and elucidate the potential mechanism by which this formula repairs the intestinal mucosal barrier in diarrheal rats.Methods Twelve rats were randomly selected from a total of 48 rats to serve as the blank control group(CK),while the remaining 36 rats were used to establish a disease model via a compound method.After 14 days of model preparation,the rats were randomly divided into three groups:the model group(MC),the western medicine group(MV),and the traditional Chinese medicine group(MRWD).Each of the four groups(including CK)received corresponding interventions for 7 days.The concentrations of serum diamine oxidase(DAO),D-lactic acid(D-Lac),interleukin-1β(IL-1β),IL-6,IL-10,tumor necrosis factor-α(TNF-α),mucin 2(MUC2),MUC4,MUC6,and colonic homogenate secretory immunoglobulin A(SIgA)were measured using ELISA.Additionally,the protein and gene expressions of colonic toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells p65(pNF-κBp65),occludin,claudin-1,and zonula occludens-1(ZO-1)were analyzed by Western blot and RT-PCR.Results(1)Intestinal mucosal injury markers:Compared with the blank group,the serum levels of DAO and D-Lac in the model group were significantly increased(P<0.05).Compared with the model group,both the Chinese medicine group and Western medicine group significantly decreased the serum levels of DAO(P<0.001),while the traditional Chinese medicine group also significantly reduced the serum levels of D-Lac(P<0.05).There was no significant difference in the changes of DAO and D-Lac serum levels between the Chinese medicine group and Western medicine group(P>0.05).(2)Inflammatory indicators:Compared with the blank group,the model group exhibited significant upregulation of TLR4,MyD88,pNF-κ Bp65 protein and gene expression,as well as serum levels of IL-1β,IL-6,and TNF-α(P<0.05),along with a significant decrease in IL-10 serum levels(P<0.05).Compared with the model group,both the Chinese medicine group and Western medicine group significantly downregulated TLR4,MyD88,pNF-κBp65 protein and gene expression,as well as serum levels of IL-1β,IL-6,and TNF-α(P<0.05),and significantly upregulated IL-10 serum levels(P<0.05).There was no significant difference in serum levels of TLR4,MyD88,pNF-κBp65 protein,gene expression,and IL-1β,IL-6,IL-10,and TNF-α between the Chinese medicine group and Western medicine group(P>0.05).(3)Intestinal mucosal barrier factors:Compared with the blank group,the model group exhibited significant downregulation in MUC2,MUC6,SIgA content,as well as Claudin-1,ZO-1 protein and gene expression,and Occludin protein expression(P<0.05).Compared with the model group,both Chinese and Western medicine groups significantly upregulated the content of MUC2 and SIgA,as well as the protein and gene expression of Claudin-1 and ZO-1(P<0.05).The traditional Chinese medicine group also significantly increased the content of MUC6 and Occludin protein expression(P<0.05).No significant differ-ences were observed between the Chinese and Western medicine groups in terms of MUC2,MUC6,SIgA serum content,and Claudin-1 and ZO-1 gene expression(P>0.05).However,the Western medicine group showed better Claudin-1 protein expression than the Chinese medicine group(P<0.05),while the ZO-1 protein expression was higher in the traditional Chinese medicine group compared to the Western medicine group(P<0.05).Conclusion Modified Renshen Wumei Decoction exerts an intestinal mucosal barrier repair effect in diarrhea rats by modulating the TLR4/MyD88/pNF-κBp65 signaling pathway.

AIM:To evaluate the safety and toler-ability of single dose oral BTK inhibitor YZJ-3058 tablets under fasting conditions in healthy adults,as well as the pharmacokinetic and pharmacologi-cal characteristics of YZJ-3058 and its metabolites.METHODS:A total of 22 healthy subjects were en-rolled in this experiment and administered a single dose orally.They were divided into three groups:50 mg,100 mg,and 200 mg.Among them,2 sub-jects were enrolled in the 50 mg dose group,and 10 subjects were enrolled in the 100 mg and 200 mg dose groups,respectively.RESULTS:In healthy subjects,YZJ-3058 tablets were administered orally on an empty stomach at doses of 50,100,and 200 mg,with a median Tmax of 1.25 to 2.00 hours and an average Cmax of 62.85,89.44,and 99.20 ng/mL,re-spectively.The average AUC0-t was 183.87,297.72,and 453.98 h·ng-1·mL,respectively.The average AUC0-∞ was 189.30,321.33,and 551.44 h·ng-1·mL,and the median t1/2 was 1.16,5.06,and 7.97 hours,respectively.After a single oral administration of 50,100,and 200 mg YZJ-3058 tablets,the highest target occupancy rate was achieved at 4 hours.The average BTK occupancy rates at 24 hours after ad-ministration were 88.95％,96.73％,and 99.24％,re-spectively.The average BTK occupancy rates at 48 hours after administration were 75.65％,89.80％,and 96.68％,respectively.No serious adverse events or adverse events leading to withdrawal oc-curred,and all subjects had good tolerability.CON-CLUSION:YZJ-3058 tablets have good safety and tolerability for single oral administration on an empty stomach in healthy subjects within the dose range of 50-200 mg.Cmax and AUC increase with dose,with fast absorption and saturation.The ter-minal elimination rate gradually slows down with dose increase,and it has a significant and sus-tained occupying effect on BTK targets.

Objective:To explore the independent risk factors for uremic encephalopathy(UE)in maintenance hemodialysis(MHD)patients and provide evidence for early clinical warning and intervention.Methods:A case-control study was conducted,enrolling 67 MHD patients diagnosed with UE(UE group)at Laibin People's Hospital from January 2010 to December 2024,and 67 non-UE patients during the same period(control group).Demographic characteristics,dialysis parameters,laboratory indicators,and infection events were collected.Univariate and multivariate logistic regression analyses were used to identify independent risk factors for UE.Results:The UE group had significantly higher rates of infection(58.2％vs.29.9％),serum creatinine(789 vs.702 μmol/L),and iPTH levels(568 vs.385 pg/mL)compared to the control group(P＜0.05).Multivariate analysis revealed that concurrent infection(OR=3.022,95％CI:1.312-6.958),elevated serum creatinine(OR=1.004,95％CI:1.000-1.008),and elevated iPTH(OR=1.002,95％CI:1.001-1.003)were independent risk factors for UE(P＜0.05).The combined prediction model achieved an AUC of 0.878(95％CI:0.822-0.934),with 82.1％sensitivity and 80.6％specificity.Conclusion:Infection,elevated serum creatinine,and elevated iPTH significantly increase the risk of UE in MHD patients.Clinical management should emphasize infection prevention,toxin clearance optimization,and parathyroid function regulation to reduce UE incidence.

AIM:To evaluate the safety and toler-ability of single dose oral BTK inhibitor YZJ-3058 tablets under fasting conditions in healthy adults,as well as the pharmacokinetic and pharmacologi-cal characteristics of YZJ-3058 and its metabolites.METHODS:A total of 22 healthy subjects were en-rolled in this experiment and administered a single dose orally.They were divided into three groups:50 mg,100 mg,and 200 mg.Among them,2 sub-jects were enrolled in the 50 mg dose group,and 10 subjects were enrolled in the 100 mg and 200 mg dose groups,respectively.RESULTS:In healthy subjects,YZJ-3058 tablets were administered orally on an empty stomach at doses of 50,100,and 200 mg,with a median Tmax of 1.25 to 2.00 hours and an average Cmax of 62.85,89.44,and 99.20 ng/mL,re-spectively.The average AUC0-t was 183.87,297.72,and 453.98 h·ng-1·mL,respectively.The average AUC0-∞ was 189.30,321.33,and 551.44 h·ng-1·mL,and the median t1/2 was 1.16,5.06,and 7.97 hours,respectively.After a single oral administration of 50,100,and 200 mg YZJ-3058 tablets,the highest target occupancy rate was achieved at 4 hours.The average BTK occupancy rates at 24 hours after ad-ministration were 88.95％,96.73％,and 99.24％,re-spectively.The average BTK occupancy rates at 48 hours after administration were 75.65％,89.80％,and 96.68％,respectively.No serious adverse events or adverse events leading to withdrawal oc-curred,and all subjects had good tolerability.CON-CLUSION:YZJ-3058 tablets have good safety and tolerability for single oral administration on an empty stomach in healthy subjects within the dose range of 50-200 mg.Cmax and AUC increase with dose,with fast absorption and saturation.The ter-minal elimination rate gradually slows down with dose increase,and it has a significant and sus-tained occupying effect on BTK targets.

Objective:To explore the independent risk factors for uremic encephalopathy(UE)in maintenance hemodialysis(MHD)patients and provide evidence for early clinical warning and intervention.Methods:A case-control study was conducted,enrolling 67 MHD patients diagnosed with UE(UE group)at Laibin People's Hospital from January 2010 to December 2024,and 67 non-UE patients during the same period(control group).Demographic characteristics,dialysis parameters,laboratory indicators,and infection events were collected.Univariate and multivariate logistic regression analyses were used to identify independent risk factors for UE.Results:The UE group had significantly higher rates of infection(58.2％vs.29.9％),serum creatinine(789 vs.702 μmol/L),and iPTH levels(568 vs.385 pg/mL)compared to the control group(P＜0.05).Multivariate analysis revealed that concurrent infection(OR=3.022,95％CI:1.312-6.958),elevated serum creatinine(OR=1.004,95％CI:1.000-1.008),and elevated iPTH(OR=1.002,95％CI:1.001-1.003)were independent risk factors for UE(P＜0.05).The combined prediction model achieved an AUC of 0.878(95％CI:0.822-0.934),with 82.1％sensitivity and 80.6％specificity.Conclusion:Infection,elevated serum creatinine,and elevated iPTH significantly increase the risk of UE in MHD patients.Clinical management should emphasize infection prevention,toxin clearance optimization,and parathyroid function regulation to reduce UE incidence.

Objective To investigate the effect of Modified Renshen Wumei Decoction on the TLR4/MyD88/pNF-κBp65 signaling pathway and elucidate the potential mechanism by which this formula repairs the intestinal mucosal barrier in diarrheal rats.Methods Twelve rats were randomly selected from a total of 48 rats to serve as the blank control group(CK),while the remaining 36 rats were used to establish a disease model via a compound method.After 14 days of model preparation,the rats were randomly divided into three groups:the model group(MC),the western medicine group(MV),and the traditional Chinese medicine group(MRWD).Each of the four groups(including CK)received corresponding interventions for 7 days.The concentrations of serum diamine oxidase(DAO),D-lactic acid(D-Lac),interleukin-1β(IL-1β),IL-6,IL-10,tumor necrosis factor-α(TNF-α),mucin 2(MUC2),MUC4,MUC6,and colonic homogenate secretory immunoglobulin A(SIgA)were measured using ELISA.Additionally,the protein and gene expressions of colonic toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells p65(pNF-κBp65),occludin,claudin-1,and zonula occludens-1(ZO-1)were analyzed by Western blot and RT-PCR.Results(1)Intestinal mucosal injury markers:Compared with the blank group,the serum levels of DAO and D-Lac in the model group were significantly increased(P<0.05).Compared with the model group,both the Chinese medicine group and Western medicine group significantly decreased the serum levels of DAO(P<0.001),while the traditional Chinese medicine group also significantly reduced the serum levels of D-Lac(P<0.05).There was no significant difference in the changes of DAO and D-Lac serum levels between the Chinese medicine group and Western medicine group(P>0.05).(2)Inflammatory indicators:Compared with the blank group,the model group exhibited significant upregulation of TLR4,MyD88,pNF-κ Bp65 protein and gene expression,as well as serum levels of IL-1β,IL-6,and TNF-α(P<0.05),along with a significant decrease in IL-10 serum levels(P<0.05).Compared with the model group,both the Chinese medicine group and Western medicine group significantly downregulated TLR4,MyD88,pNF-κBp65 protein and gene expression,as well as serum levels of IL-1β,IL-6,and TNF-α(P<0.05),and significantly upregulated IL-10 serum levels(P<0.05).There was no significant difference in serum levels of TLR4,MyD88,pNF-κBp65 protein,gene expression,and IL-1β,IL-6,IL-10,and TNF-α between the Chinese medicine group and Western medicine group(P>0.05).(3)Intestinal mucosal barrier factors:Compared with the blank group,the model group exhibited significant downregulation in MUC2,MUC6,SIgA content,as well as Claudin-1,ZO-1 protein and gene expression,and Occludin protein expression(P<0.05).Compared with the model group,both Chinese and Western medicine groups significantly upregulated the content of MUC2 and SIgA,as well as the protein and gene expression of Claudin-1 and ZO-1(P<0.05).The traditional Chinese medicine group also significantly increased the content of MUC6 and Occludin protein expression(P<0.05).No significant differ-ences were observed between the Chinese and Western medicine groups in terms of MUC2,MUC6,SIgA serum content,and Claudin-1 and ZO-1 gene expression(P>0.05).However,the Western medicine group showed better Claudin-1 protein expression than the Chinese medicine group(P<0.05),while the ZO-1 protein expression was higher in the traditional Chinese medicine group compared to the Western medicine group(P<0.05).Conclusion Modified Renshen Wumei Decoction exerts an intestinal mucosal barrier repair effect in diarrhea rats by modulating the TLR4/MyD88/pNF-κBp65 signaling pathway.

Objective:To investigate the effect of tripartite motif-containing protein 59 (TRIM59) on glucose metabolism in macrophages and its role in regulating hypoxia-inducible factor-1α (HIF-1α)/IL-10 axis in macrophages under inflammatory conditions.Methods:The differentially expressed genes between macrophages with high expression of TRIM59 and control cells transfected with empty TRIM59 plasmid were analyzed by GO and KEGG. The expression of HIF-1α by RAW264.7 macrophages with high expression of TRIM59 was detected at different time points after lipopolysaccharide (LPS) stimulation by RT-qPCR and Western blot. Bone marrow was isolated from TRIM59-cKO and TRIM59 flox/flox mice and induced to differentiate into bone marrow-derived macrophages (BMDMs). These BMDMs were stimulated with LPS and the supernatants of cell culture were collected at 3, 6, 12 and 24 h after stimulation to detect IL-10 level by ELISA. In addition, mouse models of cecal ligation and puncture (CLP) were established, and bronchoalveolar lavage fluid (BALF) samples were collected at the same time points to detect IL-10 level by ELISA. Histopathological changes in lung tissues were observed after HE staining. Results:There was a significant change in glucose metabolism-related genes in macrophages with high expression of TRIM59, and the content of lactic acid increased significantly. Compared with the control group, the expression of HIF-1α at mRNA level in BMDMs from TRIM59-cKO mice decreased after LPS stimulation ( P<0.05); the level of IL-10 increased at 3 h and 24 h in the TRIM59-cKO group, but there was no significant difference in IL-10 level at 6 h or 12 h between the two groups. In the TRIM59-cKO mouse model of CLP, the levels of IL-10 in the BALF samples increased with time, but decreased at 24 h. The level of IL-10 was higher in the TRIM59-cKO mouse model group than that in the control group at each time point ( P<0.05 or P<0.01). Conclusions:TRIM59 can inhibit inflammation and lung injury by decreasing HIF-1α-mediated lactate secretion and IL-10 expression in macrophages. This study provides a new idea for developing novel anti-sepsis drugs based on TRIM59.