ObjectiveTo explore effect of Xianlian Jiedu prescription on the recurrence of colorectal cancer （CRC） and investigate the related mechanisms. MethodsA postoperative recurrence model was established in 25 Balb/c mice by injecting CT26 cells subcutaneously into the armpit， followed by surgical removal of 99% of the subcutaneous tumor. The mice were randomly divided into model group， low-dose Xianlian Jiedu prescription （XLJDP-L） group （6.45 g·kg^-1·d^-1）， medium-dose Xianlian Jiedu prescription （XLJDP-M） group （12.9 g·kg^-1·d^-1）， high-dose Xianlian Jiedu prescription （XLJDP-H） group （25.8 g·kg^-1·d^-1）， and 5-fluorouracil （5-FU） group （1×10^-3 g·kg^-1·d^-1）. The mice were euthanized after 14 days of continuous intervention， and recurrent tumor tissue was harvested. Hematoxylin and eosin （HE） staining was used to observe pathological and morphological changes in the recurrent tumor tissue. Immunohistochemistry （IHC） was employed to assess the expression of proliferating cell nuclear antigen （Ki67）， vascular endothelial growth factor （VEGF）， and platelet-endothelial cell adhesion molecule （CD31） in recurrent tumor tissue. The Western blot was used to detect the protein expression levels of angiopoietin-2 （ANG-2）， VEGF， phosphorylated-protein kinase B （p-Akt）， protein kinase B （Akt）， phosphorylated-phosphatidylinositol 3-kinase （p-PI3K）， and phosphatidylinositol 3-kinase （PI3K） in recurrent tumor tissue. ResultsBefore treatment， there were no statistical differences in tumor volume， tumor weight， and body mass among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group， indicating model stability. After treatment， compared with those in the model group， the tumor volume and tumor weight in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01）， showing dose dependency. Meanwhile， there were no significant differences in body weight among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group. HE staining showed that compared with that in the model group， tumor tissue in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group had loosely arranged cells， increased intercellular spaces， small and shriveled nuclei， light staining， fewer mitotic figures and atypical nuclei， and increased necrotic areas. IHC showed that compared with those of the model group， the positive rates of Ki67， VEGF， and CD31 in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01） in a dose-dependent manner. Western blot results showed that compared with those of the model group， the protein expression levels of ANG-2 and VEGF in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly downregulated （P<0.05， P<0.01）， and the p-Akt/Akt and p-PI3K/PI3K ratios were significantly decreased in a dose-dependent manner （P<0.05， P<0.01）. ConclusionXianlian Jiedu prescription significantly inhibits the recurrence of CRC in mice after subcutaneous tumor surgery. The mechanism may involve regulating the PI3K/Akt pathway and downregulating key angiogenic proteins such as ANG-2， VEGF， and CD31.

Background Workers in the cable manufacturing industry are exposed to high-speed machinery and equipment for a long time, coupled with heavy workload, which poses significant risks to their physical health. However, the issue of occupational injuries in this industry has not received enough attention yet. Objective To understand the incidence of occupational injury of workers in cable manufacturing industry and to analyze the influencing factors. Method A basic information questionnaire and an occupational injury questionnaire were developed to investigate the occupational injuries of 1 343 workers in a cable manufacturing enterprise in the past year, and a total of 1 225 valid questionnaires were recovered, with an effective rate of 91.2%. Descriptive statistics were used to characterize the causes, injury locations, injury types, and other characteristics of employees’ occupational injuries. Chi-square test was used to analyze the occupational injury status of groups with different demographic characteristics, occupational characteristics, lifestyles, and interpersonal relationships. Logistic regression was used to analyze the influencing factors of occupational injuries. Result The incidence of occupational injuries among workers in a cable manufacturing enterprise in the past year was 8.6%, which mainly happened in male workers (80.0%) and occurred from May to July in summer (45.7%). The main causes were mechanical injuries (32.4%) and object blows (27.6%). The main sources of damage were machinery and equipment (36.2%) as well as raw materials and products (15.2%). The main injuries were located in upper limbs (53.3%) and lower limbs (22.9%). The main types of injuries were fractures (33.3%) and abrasions/contusions/puncture wounds (19.0%). The results of univariate analysis showed that there were statistically significant variations in the incidence of occupational injuries by gender, overtime, pre-job training, years of service in current position, alcohol consumption, physical exercise per week, and co-worker relationship (P<0.05). The logistic regression model showed that workers who exercised less than twice a week, did not participate in pre-job training, worked overtime, and had fair/poor/very poor colleague relationship had a higher risk of occupational injury, while women had a lower risk of occupational injury. Conclusion The distribution of occupational injury population is mainly male, and the time distribution is mainly from May to July. Gender, physical exercise, pre-job training, overtime, and colleague relationship are the influencing factors of occupational injuries. We should strengthen pre-job training, arrange work hours reasonably, and create a good working atmosphere to reduce the occurrence of occupational injuries.

Background Social psychological factors have emerged as a key area of research in occupational injury prevention. Occupational stress, a significant component of social psychology, has garnered widespread attention due to its potential impact on occupational injury. Objective To analyze the factors influencing occupational stress among cable manufacturing workers and explore the relationship between occupational stress and occupational injury, and to provide scientific evidence for reducing occupational stress and injury. Methods A questionnaire on basic demographics, occupational injury, and occupational stress (Effort-Reward Imbalance, ERI) was used to investigate 1343 workers in a cable enterprise. Chi-square test was employed to analyze the distribution of occupational stress across different worker characteristics. Logistic regression was used to identify factors influencing occupational stress, and a decision tree model was applied to assess the impact of occupational stress on injury risk. Results A total of 1225 valid questionnaires were collected, yielding a response rate of 91.2%. The positive rate of occupational stress was 28.7%, while the incidence of occupational injury in the past year was 8.6%. The results of univariate analysis revealed that workers who had experienced occupational injuries had a higher positive rate of occupational stress compared to those without injuries (P<0.05), and there were significant differences in the distribution of occupational stress by genders, overtime work, shift work, daily working hours, fatigue levels, sleep duration, family relationships, and colleague relationships (P<0.05). The logistic regression results showed that individuals who worked shifts, had fair/poor/very colleague relationships, and frequently worked overtime had a higher risk of occupational stress (P<0.05). The final decision tree model confirmed that occupational stress was a risk factor for occupational injury. Additional factors influencing occupational injury included physical exercise, colleague relationships, pre-job training participation, and gender. Workers who exercised less than twice per week and experienced occupational stress had a significantly higher risk of injury (23.6%) compared to those without occupational stress (10.9%). Conclusion Shift work, colleague relationships, and overtime work are correlated with the positive rate of occupational stress among cable manufacturing workers. Implementing a reasonable work schedule and fostering a positive work environment are recommended. Reducing occupational stress may help lower the risk of occupational injuries in this industry.

Guided by the turbidity toxin theory， it is believed that the key pathogenesis of constipation-predominant irritable bowel syndrome is the obstruction of turbidity toxin and the disruption of intestinal function. Treatment is based on the principles of dispelling turbidity toxin and promoting intestinal function. The clinical patterns can be divided into three types， turbidity toxin heat accumulation pattern， turbidity toxin combined with liver depression and qi stagnation pattern， and turbidity toxin combined with qi and yin deficiency pattern. The treatment can respectively use self-prescribed Tongfu Jiangzhuo Formula （通腑降浊方） to clear heat and unblock the bowels， direct the turbid downward and resolve toxins； use self-prescribed Shugan Jiangzhuo Formula （疏肝降浊方） to soothe the liver and move qi， direct the turbid downward and resolve toxins； use self-prescribed Mazhi Jiangzhuo Formula （麻枳降浊方） to boost qi and nourish yin， moisten the intestines to remove turbidity and resolve toxins.

Objective To establish a model of radiation-induced myocardial fibrosis in mice, and study the effect of TGF-β/SMAD pathway on radiation-induced myocardial fibrosis in mice and the protective effect of pirfenidone capsules (PFD) on radiation-induced myocardial fibrosis. Methods Male C57BL/6J mice were randomly divided into control group, irradiation group, and drug intervention groups (low-dose PFD + irradiation group and high-dose PFD + irradiation group). After radiation exposure, the control group and the irradiation group were given sodium carboxymethyl cellulose by gavage, while the low-dose PFD + irradiation group and the high-dose PFD + irradiation group were given PFD at 150 and 300 mg/kg daily by gavage for 12 consecutive weeks, respectively. The body weights of mice were measured and recorded weekly. The pathological changes of heart tissues in mice were observed by H&E and Masson’s trichrome staining. The expression levels of TGF-β, SMAD2, and SMAD3 mRNAs in mouse heart tissues were detected by RT-PCR. The expression levels of TGF-β, SMAD2, and SMAD3 proteins in mouse heart tissues were detected by Western blot. The expression levels of CK and CK-MB in mouse heart tissues were detected by blood biochemical tests. Results H&E and Masson’s trichrome staining showed severe myocardial fibrosis in the irradiation group compared with the control group. Compared with the irradiation group, the two groups with drug intervention showed reduced heart disease and myocardial fibrosis. RT-PCR and Western blot showed that the expression levels of TGF-β, SMAD2, and SMAD3 were up-regulated in the irradiation group compared with the other three groups (P < 0.05). The expression levels of TGF-β, SMAD2, and SMAD3 were down-regulated in the two groups treated with PFD compared with the irradiation group (P < 0.05). The expression levels of CK and CK-MB in mouse heart tissues were down-regulated in the two groups treated with PFD compared to irradiation group (P < 0.05). Conclusion Radiation has long-term effects on normal heart tissue, causing myocardial damage and promoting myocardial fibrosis. The up-regulation of TGF-β/SMAD pathway is related to the formation of radiation-induced myocardial fibrosis. PFD can mitigate the progression of myocardial fibrosis and protect heart tissue by down-regulating TGF-β/SMAD pathway.

BACKGROUND:Studies have shown that metformin has anti-inflammatory,anti-tumor,anti-aging and vasoprotective effects,and can inhibit the progression of osteoarthritis,but its specific mechanism of action remains unclear. OBJECTIVE:To investigate the mechanism of metformin on cartilage protection in a rat model of osteoarthritis. METHODS:Forty male Sprague-Dawley rats were randomly divided into four groups(n=10 per group):blank,control,sham-operated,and metformin groups.The blank group did not undergo any surgery.In the sham-operated group,the joint cavity was exposed.In the model group and the metformin group,the modified Hulth method was used to establish the osteoarthritis model.At 1 day after modeling,the rats in the metformin group were given 200 mg/kg/d metformin by gavage,and the model,blank,and sham-operated groups were given normal saline by gavage.Administration in each group was given for 4 weeks consecutively.Hematoxylin-eosin staining,toluidine blue staining,and safranin O-fast green staining were used to observe the morphological structure of rat knee joints.Immunohistochemical staining and western blot were used to detect the protein expression of SOX9,type Ⅱ collagen,a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5),Beclin1,P62,phosphatidylinositol 3-kinase(PI3K),p-PI3K,protein kinase B(AKT),p-AKT,mammalian target of rapamycin(Mtor),and p-Mtor in rat cartilage tissue. RESULTS AND CONCLUSION:The results of hematoxylin-eosin,toluidine blue and safranin O-fast green staining showed smooth cartilage surface of the knee joints and normal histomorphology in the blank group and the sham-operated group,while in the model group,there was irregular cartilage surface of the knee joint and cartilage damage,with a decrease in the number of chondrocytes and the content of proteoglycans in the cartilage matrix.In the metformin group,there was a significant improvement in the damage to the structure of the cartilage in the knee joints of the rats,and the cartilage surface tended to be smooth,with an increase in the number of chondrocytes and the content of proteoglycans in the cartilage matrix.Immunohistochemistry staining and western blot results showed that compared with the control and sham-operated groups,the expression of SOX9,type Ⅱ collagen,and Beclin1 proteins in the cartilage tissue of rats in the model group was significantly decreased(P<0.05).Conversely,the expression of ADAMTS5,P62,as well as p-PI3K,p-AKT,and p-Mtor proteins was significantly increased(P<0.05).Furthermore,compared with the model group,the expression of SOX9,type Ⅱ collagen,and Beclin1 proteins in the cartilage tissue of rats in the metformin group was significantly increased(P<0.05),while the expression of ADAMTS5,P62,as well as p-PI3K,p-AKT,and p-Mtor proteins was significantly decreased(P<0.05).To conclude,Metformin can improve the autophagy activity of chondrocytes and reduce the degradation of cartilage matrix in osteoarthritis rats by inhibiting the activation of PI3K/AKT/Mtor signaling pathway,thus exerting a protective effect on articular cartilage.

This study aims to explore the mechanism of Buyang Huanwu Decoction(BHD) in promoting angiogenesis after oxygen-glucose deprivation/reoxygenation(OGD/R) of mouse brain microvascular endothelial cell line(brain-derived Endothelial cells.3, bEnd.3) based on the caveolin-1(Cav1)/Yes-associated protein 1(YAP1)/hypoxia-inducible factor-1α(HIF-1α) signaling pathway. Ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was used to analyze the blood components of BHD. The cell counting kit-8(CCK-8) method was used to detect the optimal intervention concentration of drug-containing serum of BHD after OGD/R injury of bEnd.3. The lentiviral transfection method was used to construct a Cav1 silent stable strain, and Western blot and polymerase chain reaction(PCR) methods were used to verify the silencing efficiency. The control bEnd.3 cells were divided into a normal group(sh-NC control group), an OGD/R model + blank serum group(sh-NC OGD/R group), and an OGD/R model + drug-containing serum group(sh-NC BHD group). Cav1 silent cells were divided into an OGD/R model + blank serum group(sh-Cav1 OGD/R group) and an OGD/R model + drug-containing serum group(sh-Cav1 BHD group). The cell survival rate was detected by the CCK-8 method. The cell migration ability was detected by a cell migration assay. The lumen formation ability was detected by an angiogenesis assay. The apoptosis rate was detected by flow cytometry, and the expression of YAP1/HIF-1α signaling pathway-related proteins in each group was detected by Western blot. Finally, co-immunoprecipitation was used to verify the interaction between YAP1 and HIF-1α. The results showed astragaloside Ⅳ, formononetin, ferulic acid, and albiflorin in BHD can all enter the blood. The drug-containing serum of BHD at a mass fraction of 10% may be the optimal intervention concentration for OGD/R-induced injury of bEnd.3 cells. Compared with the sh-NC control group, the sh-NC OGD/R group showed significantly decreased cell survival rate, cell migration rate, mesh number, node number, and lumen length, significantly increased cell apoptotic rate, significantly lowered phosphorylation level of YAP1 at S127 site, and significantly elevated nuclear displacement level of YAP1 and protein expression of HIF-1α, vascular endothelial growth factor(VEGF), and vascular endothelial growth factor receptor 2(VEGFR2). Compared with the same type of OGD/R group, the sh-NC BHD group and sh-Cav1 BHD group had significantly increased cell survival rate, cell migration rate, mesh number, node number, and lumen length, a significantly decreased cell apoptotic rate, a further decreased phosphorylation level of YAP1 at S127 site, and significantly increased nuclear displacement level of YAP1 and protein expression of HIF-1α, VEGF, and VEGFR2. Compared with the sh-NC OGD/R group, the sh-Cav1 OGD/R group exhibited significantly decreased cell survival rate, cell migration rate, mesh number, node number, and lumen length, a significantly increased cell apoptotic rate, a significantly increased phosphorylation level of YAP1 at S127 site, and significantly decreased nuclear displacement level of YAP1 and protein expression of HIF-1α, VEGF, and VEGFR2. Compared with the sh-NC BHD group, the sh-Cav1 BHD group showed significantly decreased cell survival rate, cell migration rate, mesh number, node number, and lumen length, a significantly increased cell apoptotic rate, a significantly increased phosphorylation level of YAP1 at the S127 site, and significantly decreased nuclear displacement level of YAP1 and protein expression of HIF-1α, VEGF, and VEGFR2. YAP1 protein was present in the protein complex precipitated by the HIF-1α antibody, and HIF-1α protein was also present in the protein complex precipitated by the YAP1 antibody. The results confirmed that the drug-containing serum of BHD can increase the activity of YAP1/HIF-1α pathway in bEnd.3 cells damaged by OGD/R through Cav1 and promote angiogenesis in vitro.
Drugs, Chinese Herbal/pharmacology* ; Animals ; Mice ; Signal Transduction/drug effects* ; Glucose/metabolism* ; Caveolin 1/genetics* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; YAP-Signaling Proteins ; Oxygen/metabolism* ; Endothelial Cells/metabolism* ; Cell Line ; Adaptor Proteins, Signal Transducing/genetics* ; Neovascularization, Physiologic/drug effects* ; Cell Hypoxia/drug effects* ; Angiogenesis

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Objective To analyze the clinical features of chronic obstructive pulmonary disease (COPD) patients with heart failure (HF) in Nanjing and explore the influencing factors. Methods A total of 773 COPD inpatients were selected from January 2021 to January 2024 in Nanjing Combined Hospital of Traditional Chinese and Western Medicine, Nanjing Qixia District Hospital, Nanjing Lishui District People's Hospital, Nanjing Pukou District Hospital of Traditional Chinese Medicine and Nanjing First Hospital., and were divided into 2 groups according to the presence or absence of combined HF. The general data and medical records of the two groups were compared, the clinical characteristics of COPD patients with HF were summarized, and the influencing factors of COPD patients with HF were analyzed by multivariate logistic regression. Results Among the 242 patients (31.31%) with COPD had HF, chronic paroxysmal dyspnea was the most common first symptom, 169 patients (69.83%) had left heart failure, 63 patients (30.17%) were diagnosed as right heart failure or global heart failure , 17 patients (7.02%) had myocardial infarction. Multivariate logistic regression analysis showed that the risk of HF was 1.678 times and 1.691times higher in COPD groups ≥ 50 years old and male COPD groups than in < 50 years old and female groups, respectively; the risk of HF was 1.491 times higher in COPD groups engaged in physical work than in physical work groups; the risk of HF was 1.447 times and 1.580 times higher in COPD groups with hypertension and coronary heart disease than in COPD groups without hypertension and coronary heart disease, respectively; the risk of HF was 1.859 times higher in COPD groups smoking>400 vial/year than in COPD groups≤400 vial/ year; the risk of HF was 1.757 times higher in COPD groups with acute exacerbation frequency≥2 times/year than in COPD groups<2 times/year; the above differences were statistically significant (P<0.05). Conclusion Attention should be paid to elderly, male and heavy physical work group of COPD patients. Active treatment of hypertension and coronary heart disease, effective tobacco control and reduction of the frequency of acute exacerbation are effective ways to reduce the risk of HF in COPD patients in Nanjing.