BACKGROUND:Recent studies have shown that the occurrence and prevention of osteoporosis often focus on the cellular molecular level,and the mechanism of related signaling pathways is an important way to further understand osteoporosis.At present,traditional Chinese medicine has been proved to play a significant role in alleviating osteoporosis.Kaempferol as an emerging Chinese herbal extract has become the focus of clinical and basic research due to its anti-osteoporosis effectiveness and mechanism of action. OBJECTIVE:To further understand the mechanism underlying the anti-osteoporosis effect of kaempferol active monomer through regulation of related signaling pathways by analyzing and collating domestic and foreign literature. METHODS:"Kaempferol,osteoporosis,osteoblasts,osteoclasts,bone marrow mesenchymal stem cells,signaling pathways"were used as Chinese and English search terms to search CNKI,WanFang,VIP,PubMed,Web of Science and Embase databases for relevant literature published from database inception to February 2023. RESULTS AND CONCLUSION:Kaempferol affects the occurrence and progression of osteoporosis to varying degrees by participating in the regulation of differentiation,proliferation and apoptosis of bone marrow mesenchymal stem cells,osteoblasts and osteoclasts.Kaempferol can prevent and treat osteoporosis by regulating various signaling pathways.Kaempferol can promote the proliferation and differentiation of osteoblasts and inhibit the formation of osteoclasts by interfering with the Wnt/β-catenin signaling pathway to regulate β-catenin protein counting and the formation of β-catenin-TCf/LEF complex.Kaempferol interferes with the RANK/RANKL pathway to maintain the dynamic balance of osteoclasts and bone homeostasis.Kaempferol can promote bone formation by intervening with the PI3K/Akt signaling pathway to upregulate the levels of related osteogenic factors Runx2 and Osterix and promote bone cell calcification.Kaempferol interferes with osteoclast differentiation and inhibits reactive oxygen species activity by regulating the ER/ERK pathway.Kaempferol inhibits the expression of ERK,JNK,p38/MAPK and decreases reactive oxygen species production by interfering with the MAPK pathway,thus protecting osteogenesis.Kaempferol enhances the expression of osteogenic factors,bone morphogenetic protein-2,p-Smad1/5/8,β-catenin and Runx2,inhibits the expression of Peroxisome proliferation-activated receptor,and promotes the differentiation and proliferation of osteoblasts through the BMP/Smad pathway.

Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes.Among these,the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells.Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs.Several preclinical and clinical studies have revealed that the development pathway of B cells,and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites.Therefore,summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.

Objective To investigate the effect of dioscin on uric acid(UA)-induced oxidative stress injury of human renal tubular epithelial cells(HK-2)and its molecular mechanism.Methods HK-2 cells were cultured and divided into four groups:blank group(normal group),model group(uric acid-stimulation modeling),condition control group(UA+DMSO)and dioscin group(UA+dioscin).Oxidative stress injury model was induced by UA in HK-2 cells.Cells viability was detected by CCK-8.ROS level was detected by flow cytometry.Real-time PCR was used to detect the expressions of glycogen synthase kinase 3β(GSK3β),nuclear factor erythroid 2-related factor 2(Nrf2)and heme oxygenase 1(HO-1)at mRNA level,and Western Blot was used to detect the expressions of phosphorylated glycogen synthesis kinase 3β(p-GSK3β),GSK3β,Nrf2 and HO-1 at protein level.Results After stimulation by UA,HK-2 cells viability was obviously decreased,and ROS level was significantly increased(all P＜0.001).When treated with dioscin,HK-2 cells viability was obviously increased,and the ROS level of HK-2 cells was significantly decreased(all P＜0.001).The expressions of Nrf2 and HO-1 decreased at the protein and mRNA levels after stimulation with UA.But the expressions of Nrf2 and HO-1 significantly increased after treated with dioscin(all P＜0.001).Compared with the blank group,the p-GSK3β/GSK3β ratio in the model group decreased significantly at the protein level,but the p-GSK3β/GSK3β ratio increased after treated with dioscin(all P＜0.001).Conclusion Dioscin can alleviate UA-induced oxidative stress injury in HK-2 cells.The mechanism might be that dioscin can promote phosphorylation of GSK3β,and activate Nrf2/HO-1 pathway.

【Objective】 To explore the causal relationship between education level and pancreatitis risk through Mendelian randomization. 【Methods】 A two-sample Mendelian randomization analysis was conducted using genome-wide association study (GWAS) summary data. The GWAS data for education level and pancreatitis were obtained from SSGAC database and the FinnGen database (version R9). Causal relationship between education level and pancreatitis was explored using the inverse variance weighted (IVW), MR-Egger, and weighted median methods. Heterogeneity and directional pleiotropy were evaluated using Cochran’s Q test and funnel plots. 【Results】 Totally 604 SNPs associated with education level were included. The results provided evidence that there was negative relationship between education level and pancreatitis risk. For acute pancreatitis, OR=0.52, 95% CI: 0.44-0.62, P=2.43×10^-14 while for chronic pancreatitis, OR=0.51, 95% CI: 0.41-0.64, P=7.20×10^-9. Results from MR-Egger and weighted median analyses obtained the same results. The results of sensitivity analysis indicated that this study did not violate the basic assumptions of Mendelian randomization. 【Conclusion】 There is a causal relationship between education level and the occurrence of pancreatitis. The educational level is negatively correlated with the risk of pancreatitis.

Objective:To analyze the fail mode of neoadjuvant therapy combined with surgery for locally advanced esophageal squamous cell carcinoma (ESCC) after long-term follow-up.Methods:Clinical data of consecutive 238 patients with locally advanced resectable ESCC who underwent neoadjuvant therapy combined with surgery in Zhejiang Cancer Hospital from September 2012 to October 2019 were retrospectively analyzed. The failure mode in the whole cohort was analyzed after long-term follow-up. The overall survival (OS) and disease free survival (DFS) rates were analyzed by Kaplan-Meier method. Survival differences were determined by log-rank test.Results:The pathological complete response (pCR) rate was 42.0% in 238 patients. After a median follow-up of 46.1 months, tumor progression occurred in 96 patients (40.3%), including 25 patients (10.5%) with local recurrence, 61 patients (25.6%) with distant metastases, and 10 patients (4.2%) with simultaneous local recurrence and distant metastases. The median OS and DFS were 64.7 months and 49.9 months. And the 3-, 5-, and 7-year OS and DFS rates were 70.0%, 52.8%, 36.4% and 63.5%, 42.5%, and 30.0%, respectively. The 3-, 5-, and 7-year locoregional recurrence-free survival rates and distant metastasis-free survival rates were 86.0%, 71.4%, 61.2% and 70.6%, 55.9%, 43.0%. Compared with non-pCR patients, the overall progression rate and distant metastasis rate of pCR patients were lower (26.0% vs. 50.7%, 16.0% vs. 32.6%, both P<0.05). And the 3-, 5-, and 7-year OS (83.0% vs. 60.2%, 69.7% vs. 41.7%, 50.4% vs. 27.7%, all P<0.001) and DFS rates (80.4% vs. 51.4%, 63.9% vs. 31.2%, 45.9% vs. 20.3%, all P<0.001) were significantly better in pCR patients. Conclusions:Distant metastasis is the main failure mode of patients with locally advanced ESCC after neoadjuvant therapy. Patients with postoperative pCR can achieve better long-term survival.

Objective:To analyze the failure patterns and survival after stereotactic body radiotherapy (SBRT) in patients with T 1-2N 0M 0 non-small cell lung carcinoma (NSCLC). Methods:Clinical data of early-stage NSCLC patients who received SBRT at Zhejiang Cancer Hospital from January 2012 to September 2018 were retrospectively analyzed. The primary observed endpoint was the pattern of disease progression, which was divided into intra-field recurrence, regional lymph node recurrence and distant metastasis. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier method. Univariate analysis was conducted by log-rank test, and multivariate analysis was performed by Cox's model.Results:A total of 147 patients with 156 lesions were included. The median follow-up time was 44.0 months (16.5-95.5 months). A total of 57 patients (38.8%) progressed: 14 patients (24.5%) had recurrence with the 1-, 3-, and 5-year local recurrence rates of 2.0%, 10.9%, and 14.3%, respectively; 36 patients (63.2%) had Distant metastasis with the 1-, 3- and 5-year distant metastasis rates of 12.2%, 22.4% and 28.6%, respectively; and 7 patients (12.3%) had recurrence complicated with distant metastasis. The 3-, 5- and 7-year OS rates were 80.5%, 64.2% and 49.9% for all patients, respectively. The median OS was 78.4 months. The 3-, 5- and 7-year PFS rates were 64.8%,49.5% and 41.5%, with a median PFS of 57.9 months (95% CI: 42.3-73.5 months). Univariate and multivariate analyses showed that biologically equivalent dose and age were the factors affecting the efficacy of SBRT (both P<0.05). Conclusion:Distant metastasis is the main failure pattern in patients with T 1-2N 0M 0 NSCLC after SBRT. High-risk population should be selected for further systematic treatment to improve the efficacy.

This study aimed to investigate the effect and mechanisms of Ephedra Herb (EH) extract on adriamycin-induced nephrotic syndrome (NS), providing an experimental basis for the clinical treatment of NS. Hematoxylin and eosin staining, creatinine, urea nitrogen, and kidn injury molecule-1 were used to evaluate the activities of EH extract on renal function. The levels of inflammatory factors and oxidative stress were detected by kits. The levels of reactive oxygen species, immune cells, and apoptosis were measured by flow cytometry. A network pharmacological approach was used to predict the potential targets and mechanisms of EH extract in the treatment of NS. The protein levels of apoptosis-related proteins and CAMKK2, p-CAMKK2, AMPK, p-AMPK, mTOR and p-mTOR in the kidneys were detected by Western blot. The effective material basis of EH extract was screened by MTT assay. The AMPK pathway inhibitor (compound C, CC) was added to investigate the effect of the potent material basis on adriamycin-induced cell injury. EH extract significantly improved renal injury and relieve inflammation, oxidative stress, and apoptosis in rats. Network pharmacology and Western blot results showed that the effect of EH extract on NS may be associated with the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine significantly ameliorated adriamycin-induced NRK-52e cell injury. Methylephedrine also significantly improved the phosphorylation of AMPK and mTOR, which were blocked by CC. In sum, EH extract may ameliorate renal injury via the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine may be one of the material bases of EH extract.
Rats ; Animals ; Doxorubicin/adverse effects* ; Nephrotic Syndrome ; AMP-Activated Protein Kinases/metabolism* ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism* ; Apoptosis

Objective:To analyze the clinicopathological characteristics of patients with unknown etiology of portal hypertension and investigate the efficacy of endoscopic management of gastroesophageal varices in these patients.Methods:Patients with unknown etiology of portal hypertension and gastroesophageal varices who received liver biopsy between January, 2017 and January, 2020 in Zhongshan Hospital were included. The characteristics of pathology, portal computed tomography (CT) angiography, and endoscopy were recorded and follow-up for the occurrence of bleeding after treatment.Results:A total of 31 patients were included and divided into cirrhosis with unknown etiology group ( n=10) and non-cirrhotic portal hypertension group ( n=21). Patients in the non-cirrhotic group were younger [28.0(29.5-49.5) vs 58.5(43.5-65.8), P=0.004] and mostly male (71.4%), and fewer comorbidities including diabetes (4.8% vs 40.0%, P=0.027). The features of pathology finding including vasculopathy, cholestasis, and hepatic sinusoidal dilatation as well as the Sarin classification and bleeding rate of gastroesophageal varices, proportion of patients receiving endoscopic treatment were shown similar between the two groups ( P>0.05). The hepatic venous pressure gradient (HVPG) was significantly lower in the non-cirrhotic group [4.5(2.8-12.8)mmHg vs 12(8-18)mmHg, P=0.018]. Among them, 21 patients received endoscopic treatment, and the bleeding rate had no difference between these two groups after endoscopic treatment ( P=0.751). Conclusions:Non-cirrhotic portal hypertension in a predominantly young male population has similar clinicalpathological characteristics when compared to cirrhotic portal hypertension with unknown etiology. HVPG can not reflect the actual portal pressure in these patients. Endoscopic treatment is the effective treatment option for the prevention of variceal bleeding.

Background: Matrix metalloproteinase-7 (MMP-7) is a proteolytic enzyme involved in wound healing, tissue remodeling by regulating a variety of extracellular matrix and non-matrix substrates, and is an important mediator of tissue damage during inflammation in inflammatory bowel disease (IBD). Aims: To investigate the clinical significance of MMP-7 in IBD. Methods: A total of 38 cases of colon biopsy samples from patients with IBD from January 2019 to January 2021 at the Second Affiliated Hospital of Zhengzhou University were collected, including 20 ulcerative colitis (UC) and 18 Crohn's disease (CD). The paracancerous tissues of 5 patients with colon cancer were served as the control group. The expression of MMP-7 in colon tissue was detected by immunohistochemical staining, and its correlation with C-reactive protein (CRP) and white blood cell (WBC) was analyzed. Results: Compared with the control group, the expression of MMP-7 was significantly up-regulated in both active UC group and severe CD group (P<0.05). The expression of MMP-7 was gradually up-regulated with the increase of severity. The expression of MMP-7 in severe UC and CD group was significantly increased than that in remission UC and CD group (P<0.05). No significant difference in the expression of MMP-7 was found between patients with different gender, age, and whether treated with anti-TNF-α agents (P>0.05). The expression of MMP-7 in colon tissue of patients with active IBD was positively correlated with CRP and WBC (P<0.001). Conclusions: The expression of MMP-7 is correlated with the activity and severity of IBD, but not correlated with gender, age, and whether treated with anti-TNF-α agents. To some extent, MMP-7 can indicate the severity of intestinal inflammation, and may be an important indicator of inflammatory activity in IBD.