Metformin is the most commonly prescibed drug for type 2 diabetes mellitus as it is inexpensive, safe, and efficient in ameliorating hyperglycemia and hyperinsulinemia. Numerous epidemiological studies indicate that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many forms of malignancies. Meanwhile, epidemiological and clinical observation studies have shown that metformin use reduces risk of cancer in patients with type 2 diabetes mellitus and improves prognosis and survival rate of the cancer patients. Furthermore, metformin has been used for cancer therapy in clinical trials. Thus, metformin is emerging as a new cancer therapy or adjuvant anticancer drugs. This review summarizes recent progress in studies of metformin use and its molecular mechanism.

Objective:To investigate if downregulation of two mitotic checkpoint proteins, MAD2 and p55CDC, is a frequent event in human prostate cancer and whether decreased expression of these two proteins are associated with progression of prostate cancer. Methods: Using immunohistochemistry technique, the expressions of MAD2 and p55CDC proteins are examined in 46 benign prostate hyperplasia (BPH) and 65 prostate cancer tissues. Differential expressions were compared first between BPH and prostate cancer specimens, and then among prostate cancer samples with different Gleason grades. Results: We found that down regulation of MAD2 and p55CDC expressions was significant in prostate cancer (96% and 83%, respectively) compared to BPH (19.5% and 4.3%, respectively) ( P

Objective To investigate the expressions and the relationship of FEZ1 and p16 in cervical intraepithelial neoplasia (CIN).Methods The expressions of FEZ1 and p16 in 93 cases of CIN and 10 cases of normal cervical specimens were detected by immunohistochemistry.Results The positive expression rates of FEZ 1 were 90.0％ (9/10) of normal cervical specimens,67.9％ (19/28) of CIN I,36.0％ (9/25) of CIN Ⅱ,22.5％(9/40) of CIN Ⅲ.The positive expression rates of p16 were 10.0％(1/10) of normal cervical specimens,32.1％(9/28) of CIN I,76.0％(19/25) of CIN Ⅱ,92.5％(37/40) of CIN Ⅲ.There were significant differences in the positive expression rates of FEZ1 and p16 between CIN Ⅰ and CIN Ⅲ (P ＜ 0.01),there was no significant difference in the positive expression rates of FEZ1 and p16 between CIN Ⅱ and CIN Ⅲ.The expression of FEZ1 and p16 was negatively correlation in CIN (r =-0.712,P＜ 0.01).Conclusion The abnormal high expression of p16 and abnormal low expression of FEZ1 in CIN may be involved in the occurrence and development of CIN,detecting the expressions of the two indexes may be helpful for clinical diagnosis.

Aim To establish a LC-MS/MS method to measure the concentration of ginsenoside Rg1 in intrac-erebral dialysate and compare the probe recovery in vitro and in vivo. Methods The assay was conducted with a ACQUITY UPLC BEH C18(2. 1 mm × 50 mm, 1. 7 μm) . The mobile phase consisted of methanol and ultrapure water and it was detected by gradient elution. The flow rate was 0. 4 mL·min-1 . Specificity, linear range, precision and accuracy, stability were evaluated to investigate the reliability of the method. The recov-ery of ginsenoside Rg1 in probe in vitro and in vivo was compared. Results The retention time of ginsenoside Rg1 was 1. 91 min, the linear range was 0. 1 ~50 μg · L-1 , intra-day and inter-day precisions were less than 15%. The recovery of ginsenoside Rg1 was (4. 05 ± 0. 28)% in vitro and(26. 96 ± 4. 45)% in vi-vo. Conclusion The LC-MS/MS method is accurate, sensitive, and reproducible for quantitative determina-tion of ginsenoside Rg1 in microdialysate. The probe recovery of ginsenoside Rg1 in vivo is higher than in vitro, and both are stable in different concentrations.

Objective : To analyze the status and influencing factors of the intention of people aged 18 to 25 years to primary medical institutions and their satisfaction for health services in Zhejiang Province, so as to provide basis for the improvement of health services in primary medical institutions. Methods: During November and December in 2019,the 18-25 year-old people in Zhejiang Province were recruited to investigate the general information, intention to seek medical advice and satisfaction for health services in primary medical institutions through WeChat. Logistic regression was performed to analyze the influencing factors of the intention and the satisfaction. Importance matrix was used to analyze the key drivers of the satisfaction. Results: Among the 620 people surveyed, with a response rate of 93.37%, 142 (22.90%) chose primary medical institutions for advice. Actually 516 (83.23%) people went to primary medical institutions last year, and 384 ( 74.42% ) of them were satisfied with the health services. The results of multivariate logistic regression analysis showed that the people aged 18-25 years who were under the new rural cooperative medical care system ( OR=3.062, 95%CI: 1.745-5.373 ) and who had records in community health centers ( OR=0.547, 95%CI: 0.308-0.970 ) were more likely to go to primary medical institutions for medical advice; the ability of doctors ( OR=1.478, 95%CI:1.168-1.871 ) ,the drug notification by medical staff ( OR=1.308, 95%CI: 1.065-1.606 ) , routine examination items ( OR=1.523, 95%CI: 1.227-1.889 ) , the ways of payment ( OR=1.168, 95%CI: 1.017-1.340 ) , the comfort of environment ( OR=1.785, 95%CI: 1.437-2.219 ) and the bulletin boards of health knowledge ( OR=1.302, 95%CI: 1.086-1.561 ) were associated with the satisfaction. The results of importance matrix analysis showed that the ability of doctors and routine examination items were the priorities to improve, followed by the drug notification by medical staff; the comfort of environment had competitive advantages; the ways of payment and the bulletin boards of health knowledge needed to be further analyzed. Conclusions The 18-25-year-old people in Zhejiang Province were less intended to seek medical advice in primary medical institutions, which was associated with the type of medical insurance and records in community health centers. They were satisfied with the health services, the ability of doctors and routine examination items were the key drivers.

OBJECTIVE：To pro vide suggestions for imp roving the quality of ethical review of drug clinical trials in China and protecting the rights and interests of subjects. METHODS ：Guided by risk management theory ，the literature research method ， expert opinion method and analytic hierarchy process method were used to sort out the ethical review process of drug clinical trials ， extract and determine the risk factors that affect the quality of ethical review ，and determine the weight of each risk factor. Suggestions were put forward improving the ethical review of drug clinical trials in China. RESULTS & CONCLUSIONS ： Established ethical review risk index system of drug clinical trials included 31 influential factors of 5 aspects；the order of importance（weights）of 5 aspects affecting the quality of ethical review of drug clinical trials was as follows ：the construction of the medical ethics committee （0.263 5），the management of review meetings （0.251 4），follow-up review （0.194 5），the acceptance and processing of review applications （0.189 2），and the management of documents and files （0.101 4）. The influential factors with high weight included “withdrawal of people with conflict of interest in the discussion and voting process （0.078 7）” “timely review or conference discussion of scheme modification ，informed consent modification ，serious adverse events ，etc. （0.070 5）”“clarification and external exhibition of the work process and time of ethical review （0.059 8）”“unified and standardized review standards and approval standards （0.052 1）”，etc. The quality of ethical review can be improved by avoiding people with conflict of interest in the discussion and voting process ，timely reviewing or holding ethics meetings on scheme modification ， informed consent modification ，serious adverse events ，etc.，clarifying the working process and time of ethical review ，and establishing unified and standardized review standards and approval standards.

Adenosine triphosphate (ATP) regeneration systems are essential for efficient biocatalytic phosphoryl transfer reactions. Polyphosphate kinase (PPK) is a versatile enzyme that can transfer phosphate groups among adenosine monophosphate (AMP), adenosine diphosphate (ADP), ATP, and polyphosphate (Poly P). Utilization of PPK is an attractive solution to address the problem of ATP regeneration due to its ability to use a variety of inexpensive and stable Poly P salts as phosphate group donors. This review comprehensively summarizes the structural characteristics and catalytic mechanisms of different types of PPKs, as well as the variations in enzyme activity, catalytic efficiency, stability, and coenzyme preference observed in PPKs from different sources. Moreover, recent advances in PPK-mediated ATP regeneration systems and protein engineering of wild-type PPK are summarized.
Adenosine Triphosphate/metabolism* ; Adenosine Monophosphate ; Polyphosphates/metabolism* ; Catalysis ; Regeneration

Chuanxiong Rhizoma (CX, the dried rhizome of Ligusticum wallichii Franch.), a well-known traditional Chinese medicine, is clinically used for treating cardiovascular, cerebrovascular and hepatobiliary diseases. Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies. Currently, little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells (HSCs). The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous, alkaloid, phenolic acid and phthalide extracts of CX (CX_AE, CX_AL, CX_PA and CX_PHL) and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury. The active compounds of different CX extracts were identified by UPLC-MS/MS. A cholestatic liver injury mouse model induced by bile duct ligation (BDL), and transforming growth factor-β (TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes (HIBECs) and HSC cell line (LX-2 cells) were used for in vivo and in vitro studies. Histological and other biological techniques were also applied. The results indicated that CX_AE, CX_AL and CX_PHL significantly reduced ductular reaction (DR) and improved liver fibrosis in the BDL mice. Meanwhile, both CX_AE and CX_PHL suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β. CX_PHL suppressed the transcription and transfer of plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) from the 'DR-like' cholangiocytes to activated HSCs. Mechanistically, the inhibition of PAI-1 and FN by CX_PHL was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3, followdd by the suppression of histone 3 lysine 9 acetylation (H3K9ac)-mediated transcription in cholangiocytes. In conclusion, CX_PHL exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts, and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.

Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix (ECM). Si-Wu-Tang (SWT), a traditional Chinese medicine (TCM) formula, is known for treating gynecological diseases and liver fibrosis. Our previous studies demonstrated that long non-coding RNA H19 (H19) was markedly upregulated in fibrotic livers while its deficiency markedly reversed fibrogenesis. However, the mechanisms by which SWT influences H19 remain unclear. Thus, we established a bile duct ligation (BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the liver. Our results showed that SWT markedly improved ECM deposition and bile duct reactions in the liver. Notably, SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling, primarily in hepatic stellate cells (HSCs), and influencing cytoskeleton-related angiogenesis and hepatocellular injury. This modulation collectively led to reduced ECM deposition. Through extensive bioinformatics analyses, we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200, miR-211, and let7b, thereby regulating the above cellular regulatory pathways. Meanwhile, SWT reversed H19-related miRNAs and signaling pathways, diminishing ECM deposition and liver fibrosis. However, these protective effects of SWT were diminished with the overexpression of H19 in vivo. In conclusion, our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.
Humans ; RNA, Long Noncoding/genetics* ; Liver Cirrhosis/genetics* ; Liver/metabolism* ; Hepatic Stellate Cells/pathology* ; MicroRNAs/metabolism* ; Extracellular Matrix/metabolism* ; Drugs, Chinese Herbal

OBJECTIVE: To investigate the effects of lead exposure and high fat diet on the hippocampal inflammatory factors and learning-memory in rats. METHODS: A total of 40 specific pathogen free male SD rats were randomly divided into control group,high fat diet group,lead exposure group,combine exposure group,10 rats in each group. Rats in control group were given regular diet and rats in high-fat diet group were given high-fat diet. Rats in lead exposure group were given regular diet and water with 400 mg/L lead acetate. Rats in combine exposure group were given high fat diet and water with 400 mg/L lead acetate. Body weight was measured every other week. The exposure period was 9 weeks. Morris water maze was applied to measure the learning-memory. The content of total cholesterol,triglyceride(TG),low density lipoprotein cholesterol(LDL) and high density lipoprotein cholesterol(HDL) in serum were detected by using microplate reader. The lead content of hippocampus was detected by inductively coupled plasma mass spectrometer. Enzyme-linked immuno sorbent assay was used to detect the content of tumor necrosis factor-α(TNF-α),interleukin(IL)-1β,IL-4,IL-6 and interferon-γ(IFN-γ). RESULTS: Beginning from the third week,the body weight of rats in high fat diet and combine exposure group were significantly higher than that in control group(P < 0. 05). In addition,the body weight of rats in combine exposure group were higher than that in lead exposure group(P < 0. 05). Escape latency and the frequency of crossing platform of rats in high fat diet group,lead exposure group and combine exposure group were significant changed compared with those in control group(P < 0. 05). The escape latency of rats in combine exposure group increased compared with those in high fat diet group and lead exposure group(P < 0. 05). In addition,serum TG and LDL content in high-fat diet group and combine exposure group increased and HDL decreased compared with the control exposure group and lead exposure group(P < 0. 05). Compared with the control group and high fat diet group,the content of lead in hippocampus of lead exposure group and combine exposure group substantially increased(P < 0. 05). The levels of TNF-γ,IL-6,IL-1β,IFN-γ of hippocampus in high fat diet group,lead exposure group and combine exposure group were significantly higher than those in control group(P < 0. 05). Besides,the levels of IL-4 of hippocampus in lead exposure group and combine exposure group were higher than that in control group(P < 0. 05). IL-1β content of rats hippocampus in combine exposure group was higher than that in high-fat diet group or lead exposure group(P < 0. 05). CONCLUSION: Combine lead and high-fat diet exposure can exert a synergy in decrease of learning-memory in rats. IL-1β might involved in the process of synergic neurotoxicity induced by lead and high fat diet.