The development and benefits of metformin in various diseases / 医学前沿

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.

The epigallocatechin gallate derivative Y reverses drug resistance mediated by the ABCB1 transporter both and

Previously, we reported that Y, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y in reversing drug resistance both and by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

In vitro differentiation of spermatogonial stem cells using testicular cells from Guangxi Bama mini-pig

In this study, we attempted to establish a culture system for in vitro spermatogenesis from spermatogonial stem cells (SSCs) of Bama mini-pig. Dissociated testicular cells from 1-month-old pigs were co-cultured to mimic in vivo spermatogenesis. The testicular cells were seeded in minimum essential medium alpha (α-MEM) supplemented with Knockout serum replacement (KSR). Three-dimensional colonies formed after 10 days of culture. The colonies showed positive staining for SSC-associated markers such as UCHL1, PLZF, THY1, OCT4, Dolichos biflorus agglutinin, and alkaline phosphatase. Induction of SSCs was performed in α-MEM + KSR supplemented with retinoic acid, bone morphogenetic protein 4, activin A, follicle-stimulating hormone, or testosterone. The results showed that STRA8, DMC1, PRM1, and TNP1 were upregulated significantly in the colonies after induction compared to that in testis from 1-month-old pigs, while expression levels of those genes were significantly low compared to those in 2-month-old testis. However, upregulation of ACROSIN was not significant. Replacement of α-MEM and KSR with Iscove's modified Dulbecco's medium and fetal bovine serum did not upregulate expression of these genes significantly. These results indicate that SSCs of Bama mini-pig could undergo differentiation and develop to a post-meiotic stage in α-MEM supplemented with KSR and induction factors.

Phosphatase PP2CB inhibits innate immune response triggered by RNA virus VSV or SeV / 中国免疫学杂志

Objective:To investigate the role of phosphatase PP2CB in the innate immunity against RNA virus and the underlying mechanism.Methods:PP2CB expression in macrophages was silenced with the specific siRNA.The mRNA and protein expression level of type Ⅰ interferon was detected by Q-PCR and ELISA respectively.The phosphorylation level of TBK1 and IRF3 was analyzed by Western blot.Results:RNA virus VSV infection led to the expression change of PP2CB.Overexpression of PP2CB dose-dependently inhibited the activation of IFN-β reporter gene.PP2CB silencing by PP2CB siRNA significantly promoted the production of type Ⅰ interferon triggered by RNA virus VSV or SeV,and inhibited the replication of VSV in macrophages.Furthermore,PP2CB bound TBK1 upon RNA virus infection.PP2CB silencing up-regulated the phosphorylation level of TBK1 and IRF3.Conclusion:Upon RNA virus VSV or SeV infection,phosphatase PP2CB binds TBK1 and inhibits its phosphorylation to negatively regulate the activation of the antiviral innate immune signal pathway,which consequently suppresses the production of type Ⅰ interferon triggered by RNA virus VSV or SeV.

MRI-detected extramural venous invasion for predicting the response to preoperative chemoradiatiotherapy in locally advanced rectal cancer / 中华普通外科杂志

Objective To evaluate the efficacy of MRI-detected extramural venous invasion (mrEMVI) in predicting tumor responses to preoperative chemoradiatiotherapy (pre-CRT) in patients with locally advanced rectal cancer (LARC).Methods The clinicopathological data,tumor response and mrEMVI information of 47 LARC from February 2013 to December 2014 were retrospectively collected.mrEMVI was given 0-4 score according to the degree,3-4 score were defined as mrEMVI positive;patients with mrEMVI positive were divided into three subgroups according to vascular size (large,middle and small).Association between different mrEMVI subgroup and tumor response was analyzed using Fisher exact test.Result 26 patients were mrEMVI positive.18 and 8 patients scored 3 and 4 for mrEMVI positive,respectively;16,6 and 4 patients were small,middle and larger vessels of mrEMVI positive,respectively.Patients with mrEMVI positive had less TRG 0-1 than mrEMVI negative (P =0.019).Scored 4 and larger vessel of mrEMVI positive had less TRG 0-1 than mrEMVI negative (P =0.038 and 0.017).Conclusions mrEMVI positive score 4 or larger vessel predict poor tumor response to pre-CRT in patients of locally advanced rectal cancer.

Risk factor analysis on postoperative complications after laparoscopic total mesorectal excision with preventive terminal ileostomy and timing of stoma closure in rectal cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To summarize the application of protective terminal ileostomy in laparoscopic total mesorectal excision for rectal cancer patients, and explore the risk factors associated with postoperative complications and timing of stoma closure.</p><p><b>METHODS</b>Clinical data of 77 patients with middle or low rectal cancer undergoing laparoscopic total mesorectal excision (TME) with preventive terminal ileostomy in our department from January 2007 to December 2013 were retrospectively analyzed. Independent risk factors associated to postoperative complications of terminal ileostomy were examined by logistic regression and timing of stoma closure was investigated.</p><p><b>RESULT</b>The total postoperative complication morbidity was 57.1% (44/77). Electrolyte disturbance was found in 39 cases (50.6%, 39/77), including 1 case of hypovolemic syncope. Parastomal hernia occurred in 9 cases (11.7%, 9/77). Peristomal dermatitis and subcutaneous abscess was observed in 1 case (1.3%, 1/77). The result of the single factor analysis of the water electrolyte disturbance after operation, the risk factors of P<0.2 were new adjuvant chemotherapy (P=0.094), tumor antigen (P=0.086) and TNM staging (P=0.026); Postoperative parastomal hernia of the single factor analysis results, the risk factors of P<0.2 included uses of antidiabetic drugs (P=0.172), ASA anesthesia (P=0.168) grading and TNM stage(P=0.161); But multivariate analysis revealed no risk factors associated with the above complications (all P>0.05). Sixty-five patients underwent stoma closure during follow-up, including 2 cases (3.1%) within 90 days, 20 cases (30.8%) from 90 to 180 days, and 43 cases (66.2%) more than 180 days.</p><p><b>CONCLUSIONS</b>No risk factors were found to be associated with main postoperative complications of protective terminal ileostomy after laparoscopic TME for rectal cancer patients, such as electrolytes imbalance and parastomal hernia. The timing of stoma closure should be longer than 180 days.</p>