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*

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1-DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.

ObjectiveTo explore the role and molecular mechanism of Weifuchun （WFC） in inhibiting inflammation and alleviating gastric precancerous lesions （GPL）. MethodHuman gastric mucosal epithelial cells （GES-1） were stimulated with N-methyl-N′-nitro-N-nitrosoguanidine （MNNG） for the modeling of GPL （MC cells）， with Caspase-3 inhibition by Z-DEVD-FMK. MC cells were divided into control （20% blank serum）， WFC （15% and 20% WFC-containing serum）， and caspase-3 inhibitor groups. The cell counting kit-8 （CCK-8） was used to examine the viability of GES-1 cells or MC cells. The Transwell assay and 5-acetylidene-2′-deoxyuridine （EdU） staining were employed to examine cell invasion and proliferation， respectively. Flow cytometry was employed to determine the level of reactive oxygen species. Real-time PCR was conducted to determine the mRNA levels of interleukin （IL）-1， IL-6， and tumor necrosis factor （TNF）-α. Gene Expression Omnibus （GEO） was used to analyze the role of pyroptosis in gastric cancer progression. Western blotting was employed to determine the protein levels of nuclear factor-κB （NF-κB） p65， gasdermin E （GSDME）， and Caspase-3. Immunofluorescence staining was employed to detect the NF-κB p65 protein level and nuclear translocation. Hematoxylin-eosin staining was carried out to observe the pathological changes in the gastric mucosa before and after WFC treatment in the patients. ResultCompared with the control group， MC cells presented enhanced proliferation and invasion energy （P<0.01）. Compared with the blank serum group， WFC-containing serum inhibited the proliferation and invasion of MC cells （P<0.01）， down-regulated the mRNA levels of IL-1， IL-6， and TNF-α， and lowered the level of reactive oxygen species （P<0.05， P<0.01）. The transcriptome data at different stages of gastric cancer showed that pyroptosis was involved in gastric cancer progression， and the GSDME level was significantly higher in GPL patients than in the normal group. Compared with the blank serum， WFC-containing serum lowered the level of NF-κB and inhibited the nuclear translocation of NF-κB （P<0.05）， and it inhibited pyroptosis by suppressing the cleavage of Caspase-3 on GSDME （P<0.05， P<0.01）. The analysis of patient specimens further demonstrated that WFC treatment down-regulated the NF-κB level and GSDME cleavage （P<0.01）， inhibited pyroptosis， and alleviated gastric mucosal inflammation and intestinal epithelial metaplasia. ConclusionPyroptosis is involved in the progression of gastric cancer， and WFC inhibits pyroptosis via the NF-κB/GSDME pathway， thereby alleviating gastric mucosal inflammation in GPL.

Objective:To explore the prevalence and independent associated factors of vascular calcification (VC) in non-dialysis chronic kidney disease (CKD) patients of stage 3-5.Methods:It was a single-center cross-sectional observational study. Non-dialysis stage 3-5 CKD patients ≥18 years old who were admitted to the Department of Nephrology, the First Affiliated Hospital of Sun Yat-sen University from May 1, 2022 to December 31, 2022 with VC evaluation were enrolled. The patients' general information, laboratory examination and imaging data were collected. Coronary artery calcification (CAC), thoracic aorta calcification (TAC), abdominal aorta calcification (AAC), carotid artery calcification and aortic valve calcification (AVC) were evaluated by cardiac-gated electron-beam CT (EBCT) scans, lateral lumbar x-ray, cervical macrovascular ultrasound and echocardiography, respectively. The differences in clinical data and the prevalence of VC at different sites of patients with different CKD stages were compared, and the prevalence of VC at different sites of patients in different age groups [youth group (18-44 years old), middle-aged group (45-64 years old) and elderly group (≥65 years old)] and patients with or without diabetes were compared. Multivariate logistic regression analysis was used to analyse the independent associated factors of VC for different areas.Results:A total of 206 patients aged (51±14) years were included, including 129 (62.6%) males. There were 44 patients with CKD stage 3 (21.4%), 51 patients with CKD stage 4 (24.8%), and 111 patients with CKD stage 5 (53.9%). CKD was caused by chronic glomerulonephritis [104 cases (50.5%)], diabetic kidney damage [35 cases (17.0%)], hypertensive kidney damage [29 cases (14.1%)] and others [38 cases (18.4%)]. Among 206 patients, 131 (63.6%) exhibited cardiovascular calcification, and the prevalence of CAC, TAC, AAC, carotid artery calcification, and AVC was 37.9%, 43.7%, 37.9%, 35.9% and 9.7%, respectively. The overall prevalence of VC in young, middle-aged and elderly patients was 24.6%, 73.6% and 97.4%, respectively. With the increase of age, the prevalence of VC in each site gradually increased, and the increasing trend was statistically significant (all P<0.001). The overall prevalence of VC in CKD patients with diabetes was 92.5% (62/67), and the prevalence of VC at each site in the patients with diabetes was significantly higher than that in the patients without diabetes (all P<0.001). Multivariate logistic regression analysis revealed that age (every 10 years increase, OR=2.51, 95% CI 1.77-3.56, P<0.001), hypertension ( OR=5.88, 95% CI 1.57-22.10, P=0.009), and diabetes ( OR=4.66, 95% CI 2.10-10.35, P<0.001) were independently correlated with CAC; Age (every 10 years increase, OR=6.43, 95% CI 3.64-11.36, P<0.001) and hypertension ( OR=6.09, 95% CI 1.33-27.84, P=0.020) were independently correlated with TAC; Female ( OR=0.23, 95% CI 0.07-0.72, P=0.011), age (every 10 years increase, OR=3.90, 95% CI 2.42-6.29, P<0.001), diabetes ( OR=5.37, 95% CI 2.19-13.19, P<0.001) and serum magnesium ( OR=0.01,95% CI 0-0.35, P=0.014) were independently correlated with AAC. Moreover, age and diabetes were independently correlated with carotid artery calcification, AVC and overall VC Conclusions:The prevalence of VC in non-dialysis CKD patients of stage 3-5 is 63.59%, of which CAC reaches 37.9%, TAC is the most common one (43.7%), while AVC is the least one (9.7%). Age and diabetes are the independent associated factors for VC of all sites except TAC, while hypertension is an independent associated factor for both CAC and TAC.

To investigate the existence of tick-borne pathogens infection of rodents at the border of China and the Demo-cratic People's Republic of Korea(DPRK).PCR was used to detect the spotted fever group rickettsiae(SFGR)ompA gene,Ehrlichia chaffeensis(Ec)and Anaplasma phagocytophilum(Ap)16S rRNA,Candidatus Neoehrlichia mikurensis(CNm)groEL gene,Bartonella(Ba)rpoB gene,and Francisella tularensis(Ft)fopA gene in rodents samples collected from Ji'an of Jilin province and Kuandian of Liaoning Province.The positivity rates of 132 wild rats spleen samples,SFGR,Ec,Ap,CNm,Ba,and Ft were 9.85％,12.88％,5.30％,3.79％,51.52％,and 6.06％,respectively,with statistical differences in in-fection rates(x2=149.236,P=0.000).The infection rate of Ba was the highest in wild rats in this area.There was no signifi-cant difference in the infection rate of SFGR,Ec,Ap,CNm,and Ft among different rats species,but there were significant differences in the infection rate of Ba(x2=13.36,P=0.010).The infection rate of Apodemus agrarius was the highest.A-mong 132 wild rats specimens,the coinfection rate of the two pathogens was 15.9％(21/132),with Ba as the main species(15/132),and two cases of coinfection with three pathogens were detected.The infection of six tick-borne pathogens is common in wild rats at the China/DPRK border.Co-infection of two or three pathogens indicates a risk of multiple tick-borne pathogens and mixed natural foci of multiple tick-borne infec-tious diseases.

Objective: To explore the association between cardiometabolic diseases (CMD) and quality of life, the association between CMD and perceived stress, and the mediation effect of perceived stress on the association between CMD and quality of life, and to provide evidence for the prevention and treatment of CMD and the improvement of quality of life in these patients. Methods: This is a cross-sectional study. Data were collected by the employees' physical examination of a company in Xi'an in 2021. Multiple linear regression models were used to analyze the association between the status of CMD (divided into three categories: no CMD, presence of one kind of CMD, and with≥2 kinds of CMD (≥2 kinds of CMD were defined as cardiometabolic multimorbidity (CMM)), quality of life, and perceived stress. Mediation analysis with a multi-categorical independent variable was conducted to determine the mediation effect of perceived stress on the association between CMD and quality of life. Results: Among all 4 272 participants, 1 457 (34.1%) participants had one kind of CMD and 677 (15.8%) participants had CMM. The average scores for quality of life and perceived stress were (57.5±15.7) and (16.9±7.9), respectively. Compared with participants without CMD, after adjusting for demographic and lifestyle factors, no statistically significant associations were observed between one kind of CMD and perceived stress or quality of life (both P>0.05). Perceived stress did not mediate the association between one kind of CMD and quality of life. However, participants with CMM had lower quality of life and higher perceived stress than participants without CMD. The relative total effect coefficient c (95%CI) and the relative direct effect coefficient c' (95%CI) between CMM and quality of life were -3.71 (-5.04--2.37) and -2.52 (-3.81--1.24) (both P<0.05), respectively. The relative indirect effect coefficient a₂b (95%CI) of perceived stress on the association between CMM and quality of life was -1.18 (-1.62--0.77) (P<0.05). The mediation effect size was 31.8%. Conclusions: CMM is negatively associated with quality of life and positively associated with perceived stress. Perceived stress partially mediates the association between CMM and quality of life. Our results suggest that, in addition to preventing and treating CMM actively, efforts should be taken to relieve the perceived stress of people with CMM to improve their quality of life.
Humans ; Quality of Life ; Cross-Sectional Studies ; Cardiovascular Diseases/complications* ; Stress, Psychological

This study aimed to investigate the underlying mechanism of Zhenwu Decoction in the treatment of heart failure by regulating electrical remodeling through the transient outward potassium current(I_(to))/voltage-gated potassium(Kv) channels. Five normal SD rats were intragastrically administered with Zhenwu Decoction granules to prepare drug-containing serum, and another seven normal SD rats received an equal amount of distilled water to prepare blank serum. H9c2 cardiomyocytes underwent conventional passage and were treated with angiotensin Ⅱ(AngⅡ) for 24 h. Subsequently, 2%, 4%, and 8% drug-containing serum, simvastatin(SIM), and BaCl_2 were used to interfere in H9c2 cardiomyocytes for 24 h. The cells were divided into a control group [N, 10% blank serum + 90% high-glucose DMEM(DMEM-H)], a model group(M, AngⅡ + 10% blank serum + 90% DMEM-H), a low-dose Zhenwu Decoction-containing serum group(Z1, AngⅡ + 2% drug-containing serum of Zhenwu Decoction + 8% blank serum + 90% DMEM-H), a medium-dose Zhenwu Decoction-containing serum group(Z2, AngⅡ + 4% drug-containing serum of Zhenwu Decoc-tion + 6% blank serum + 90% DMEM-H), a high-dose Zhenwu Decoction-containing serum group(Z3, AngⅡ + 8% drug-containing serum of Zhenwu Decoction + 2% blank serum + 90% DMEM-H), an inducer group(YD, AngⅡ + SIM + 10% blank serum + 90% DMEM-H), and an inhibitor group(YZ, AngⅡ + BaCl_2 + 10% blank serum + 90% DMEM-H). The content of ANP in cell extracts of each group was detected by ELISA. The relative mRNA expression levels of ANP, Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 were detected by real-time quantitative PCR. The protein expression of Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 was detected by Western blot. I_(to) was detected by the whole cell patch-clamp technique. The results showed that Zhenwu Decoction at low, medium, and high doses could effectively reduce the surface area of cardiomyocytes. Compared with the M group, the Z1, Z2, Z3, and YD groups showed decreased ANP content and mRNA level, increased protein and mRNA expression of Kv4.2, Kv4.3, DPP6, and KChIP2, and decreased protein and mRNA expression of Kv1.4, and the aforementioned changes were the most notable in the Z3 group. Compared with the N group, the Z1, Z2, and Z3 groups showed significantly increased peak current and current density of I_(to). The results indicate that Zhenwu Decoction can regulate myocardial remodeling and electrical remodeling by improving the expression trend of Kv1.4, Kv4.2, Kv4.3, KChIP2, and DPP6 proteins and inducing I_(to) to regulate Kv channels, which may be one of the mechanisms of Zhenwu Decoction in treating heart failure and related arrhythmias.
Rats ; Animals ; Myocytes, Cardiac ; Atrial Remodeling ; Rats, Sprague-Dawley ; Heart Failure/metabolism* ; RNA, Messenger/metabolism* ; Potassium

Objective To establish a dual wavelength HPLC method to compare the content changes of seven active components:monoglycoside,loganin,swertin,paeoniflorin,gallic acid,5-hydroxymethyl furfural and paeonol in Liuwei Dihuang Decoction(hereinafter referred to as"Liuweidihuang Decoction")before and after the preparation of Cornus wine;To explore the effect and mechanism of Liu(Shan)and Liu(Jiu)on 90 days after ovariectomy in postmenopausal osteoporosis model rats.Methods ①The contents of seven active ingredients in the Cornus wine mixed with Liuwei Dihuang Decoction were determined by dual wavelength HPLC.Chromatographic conditions:hypersil C18 chromatography(4.6 mm×250 mm,5 μm),mobile phase acetonitrile-0.3%phosphoric acid,gradient elution(0-7 min,0%-8%acetonitrile;7-15 min,8%-10%;15-20 min,10%-15%;20-30 min,15%-23%;30-50 min,23%-45%),flow rate 0.6 mL·min-1,detection wavelength:240 nm(monoglycoside,loganin,swertin,paeoniflorin),274 nm(gallic acid,5-hydroxymethyl furfural,paeonol),column temperature 30℃,injection volume 20 μL.②6-8 month old SD rats,divided into sham-operated group,model group,positive drug group,shanshuang flesh with Liuwei Dihuang Decoction group(liu(shan)group)and wine cornelian flesh withLiuwei Dihuang Decoction group(liu(wine)group),dosing started on the 5 d after ovariectomy,weighed weekly,and 5 rats from each group were taken at 90 d after surgery,weighed,anaesthetized,serum taken,bilateral femurs,and organs(uterus,spleen,liver,both kidneys and heart)were weighed.Serum calcium(Ca),phosphorus(P)and estradiol(E2)levels were measured using a fully automated biochemical instrument and chemiluminescent microparticle immunoassay,respectively;bone mineral density(BMD)values were measured using a dual-energy X-ray bone densitometer.HE staining was used to observe the morphological changes of bone tissue in rats.Results ①All the seven potent ingredients mentioned above were contained in the Liuwei Dihuang Decoction before and after the wine preparation of Cornu Cervi Pantotrichum,and the total content of the seven potent ingredients in liu(wine)was higher than that in liu(shan)(P<0.01).Among them,gallic acid and 5-hydroxymethylfurfural were higher in Liu(Jiu)than in Liu(Shan)(P<0.01),while the content of monosidine was lower than in Liu(Shan)(P<0.01).②Comparison with the sham-operated group:90 d after surgery,the serum Ca,P,E2 levels and uterine index of rats in the model group decreased(P<0.01),the BMD value decreased(P<0.01),and the degree of structural damage to bone tissue The degree of damage to the bone tissue structure was deepened,manifested by enlargement of the bone marrow cavity,gradual increase of adipocytes,dilution of the bone trabeculae arrangement,reduction of the number of bone trabeculae or even fracture.③Compared with the model group,90 d after surgery,the serum E2,Ca,P levels and uterine index of the rats in the liu(shan)and liu(wine)groups increased(P<0.05),the bone tissue structure of the liu(shan)and liu(wine)groups improved significantly,and the BMD value increased significantly(The liver and spleen indices of the liu(wine)groups increased(P<0.05).Conclusion The combination of the wine preparation of Cornus officinalis and its use in the formula of LiuWei Di Huang Decoction both contain monosidine,strychnine,sweretin,paeoniflorin,gallic acid,5-hydroxymethyl furfural(5-HMF)and tannin,and can effectively interfere with PMOP.Among them,the anti-osteoporotic effect of Liu Wei Di Huang Tang,which was formulated with wine and dogwood,was better than that of Liu Wei Di Huang Tang,which was formulated with Cornus officinalis,and the former contained more 5-HMF and gallic acid than the latter,which may provide some experimental basis for the selection of wine and dogwood in the 2020 edition of the Pharmacopoeia and the clinical application of Liu Wei Di Huang Tang in the prevention and treatment of PMOP.

ObjectiveIn the past， many studies have reported the mode of colorectal cancer（CRC） metastasis， but there is still a lack of research based on long-term follow-up and death as the end point to summarize the location， mode and related survival data of CRC metastasis. MethodsThe data of 373 dead patients with colorectal cancer in the Sixth Affiliated Hospital of Sun Yat-sen University were reviewed， and the location， mode， incidence and survival data of tumor metastasis were statistically analyzed. Results334 patients （89.5%） died of tumor related death. The liver metastasis rate was 51.5%， the lung metastasis rate was 40.4%， and the peritoneal metastasis rate was 55.7%. The number of patients with liver， lung or peritoneal metastasis only was 27 （8%）， 21 （6.3%） and 63 （18.9%） respectively. The prognosis of patients with simple lung metastasis was better （P<0.01）. There were 66 patients （19.7%） with simultaneous metastasis of liver， lung and peritoneum， and the prognosis was the worst （P<0.01）. ConclusionNot all dead colorectal cancer patients have simultaneous metastasis of liver， lung and peritoneum. There are differences in the location and mode of metastasis in different patients， which is related to survival.

This study aims to explore the toxicity mechanism of Rhododendri Mollis Flos(RMF) based on serum metabolomics and network toxicology. The toxic effect of RMF on normal rats was evaluated according to the symptoms, serum biochemical indexes, and histopathology. Serum metabolomics was combined with multivariate statistical analysis to search endogenous differential metabolites and related metabolic pathways. The toxic components, targets, and signaling pathways of RMF were screened by network toxicology technique, and the component-target-metabolite-metabolic pathway network was established with the help of serum metabolomics. The result suggested the neurotoxicity, hepatotoxicity, and cardiotoxicity of RMF. A total of 31 differential metabolites and 10 main metabolic pathways were identified by serum metabolomics, and 11 toxic components, 332 related target genes and 141 main signaling pathways were screened out by network toxicology. Further analysis yielded 7 key toxic components: grayanotoxin Ⅲ,grayanotoxinⅠ, rhodojaponin Ⅱ, rhodojaponin Ⅴ, rhodojaponin Ⅵ, rhodojaponin Ⅶ, and kalmanol, which acted on the following 12 key targets: androgen receptor(AR), albumin(ALB), estrogen receptor β(ESR2), sex-hormone binding globulin(SHBG), type 11 hydroxysteroid(17-beta) dehydrogenase(HSD17 B11), estrogen receptor α(ESR1), retinoic X receptor-gamma(RXRG), lactate dehydrogenase type C(LDHC), Aldo-keto reductase(AKR) 1 C family member 3(AKR1 C3), ATP binding cassette subfamily B member 1(ABCB1), UDP-glucuronosyltransferase 2 B7(UGT2 B7), and glutamate-ammonia ligase(GLUL). These targets interfered with the metabolism of gamma-aminobutyric acid, estriol, testosterone, retinoic acid, 2-oxobutyric acid, and affected 4 key metabolic pathways of alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism, steroid hormone biosynthesis, and retinol metabolism. RMF exerts toxic effect on multiple systems through multiple components, targets, and pathways. Through the analysis of key toxic components, target genes, metabolites, and metabolic pathways, this study unveiled the mechanism of potential neurotoxicity, cardiotoxicity, and hepatotoxicity of RMF, which is expected to provide a clue for the basic research on toxic Chinese medicinals.
Animals ; Cardiotoxicity ; Chemical and Drug Induced Liver Injury ; Drugs, Chinese Herbal/toxicity* ; Hormones ; Metabolomics ; Rats