Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Objective To explore the effect and mechanism of anti-mesangial cell-proliferation-peptide 2(AMPP2)on mesangial cell proliferation induced by transforming growth factor β1(TGF-β1).Methods Mesangial cells were cultured in vitro and treated with TGF-β1(10 μg/L)and AMPP2(10 ng/L).According to different intervention factors,mesangial cells were divided into four groups:the control group,the AMPP2 group,the TGF-β1 group and the TGF-β1+AMPP2 group.The proliferation activity of mesangial cells was detected by CCK-8.The relative protein expression of cyclin dependent kinase 4(CDK-4),cyclin dependent kinase 6(CDK-6),proliferating cell nuclear antigen(PCNA),α-smooth muscle actin(α-SMA),collagen-Ⅰ(COL-Ⅰ)and fibronectin(FN)were examined by Western blot assay.The relative mRNA expression of α-SMA,COL-Ⅰ and FN were detected by qPCR.Results Compared with the control group,proliferation activity of mesangial cells was significantly increased in the TGF-β1 group(P＜0.05).The proliferation activity of mesangial cells was markedly decreased in the TGF-β1+AMPP2 group compared with that of the TGF-β1 group(P＜0.05).Compared with the control group,protein levels of CDK-4,CDK-6,PCNA,α-SMA,COL-Ⅰand FN in cells were significantly increased in the TGF-β1 group(P＜0.05),as well as the mRNA levels of α-SMA,COL-Ⅰand FN(P＜0.05).In the TGF-β1+AMPP2 group,the protein and mRNA levels of α-SMA,COL-Ⅰand FN and the protein levels of CDK-4,CDK-6 and PCNA were markedly decreased compared with those of the TGF-β1 group(P＜0.05).Compared with the control group,levels of p-SMAD3/SMAD3 was remarkably upregulated in the TGF-β1 group(P＜0.05),while levels of p-SMAD3/SMAD3 was remarkably downregulated in the TGF-β1+AMPP2 group compared with those of the TGF-β1 group(P＜0.05).Conclusion AMPP2 may inhibit mesangial cell proliferation by regulating TGF-β1/SMAD3 pathway.

Objective To investigate the effect and molecular mechanism of tRF-1:30-Gln-CTG-4(tRF-1:30)on the expression of inflammatory factors in high glucose(HG)-induced renal tubular epithelial cells(RTECs).Methods RTECs were divided into the control group,the HG group,the HG+tRF-1:30 mimic group,the HG+tRF-1:30 negative control(NC)group,the HG+si-IKZF2 group and the HG+si-NC group.Real-time quantitative polymerase chain reaction(RT-qPCR)was used to detect the expression levels of tRF-1:30,tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),monocyte chemoattractant protein-1(MCP-1)and IKAROS family zinc finger protein 2(IKZF2).Enzyme-linked immunosorbent assay(ELISA)was used to detect levels of TNF-α,IL-6 and MCP-1.Protein expression of IKZF2 was detected by Western blot assay.Dual-luciferase reporter assay was used to detect the targeting relationship between tRF-1:30 and IKZF2.Results The expression levels of inflammatory factors were elevated in HG-induced RTECs,and the expression level of tRF-1:30 was decreased(P＜0.05).Overexpression of tRF-1:30 significantly decreased expression levels of inflammatory factors in HG-induced RTECs(P＜0.05),and the expression level of IKZF2 was significantly increased(P＜0.05).Further knockdown of IKZF2 can inhibit the release of inflammatory factors,and the expression level of IKZF2 was down-regulated after overexpression of tRF-1:30.Double luciferase reporting experiment further verified the possible targeting relationship between tRF-1:30 and IKZF2.Conclusion Overexpression of tRF-1:30 inhibits the expression of inflammatory factors in HG-induced RTECs by target binding and negatively regulating the expression of IKZF2.

Objective:To investigate the expulsion rate of GyneFix postpartum intrauterine device (PPIUD) placed immediately after cesarean section within one year and its influencing factors.Methods:A prospective cohort study was conducted. Women who volunteered to use a GyneFix PPIUD placed immediately after cesarean section (within 10 min after placenta delivery) for postpartum contraception were recruited from September 2017 to November 2020. The relevant information was collected through questionnaires before, during and 24 h after cesarean section. Outpatient follow-up was conducted at 42 d, 3 months, 6 months and 12 months after delivery to obtain information on expulsion of GyneFix PPIUD and unwanted pregnancy. Life table and Cox regression model were used to analyze the cumulative expulsion rate and related influencing factors.Results:A total of 470 subjects were recruited and 461 (98%) subjects were eligible for this study. The cumulative expulsion rate of GyneFix PPIUD within one year after cesarean section was 8.4% (95% CI: 7.0%-9.8%). Multivariate Cox regression analysis showed that women aged >35 years had significantly lower risk of PPIUD expulsion than those aged <25 years ( HR=0.16, 95% CI: 0.04-0.64). The risk of GyneFix PPIUD was not statistically significantly associated with cesarean section history and breastfeeding mode (all P>0.05). Nevertheless, this risk was statistically significant between hospitals. The Pearl index of contraceptive failure of the device was 2.37 (95% CI: 1.09-4.50) per 100 person-years. The rate of contraceptive failure was not associated with maternal age, breastfeeding mode, and history of cesarean delivery (all P>0.05). Conclusion:The one-year cumulative expulsion rate of GyneFix PPIUD placed immediately after cesarean section is 8.4%. Young mothers were at a higher risk of expulsion than their older counterparts. The device users should be counseled regarding the signs of expulsion. In case of expulsion, women should be offered reinsertion or other contraceptive methods. The training of service skills of GyneFix PPIUD should be strengthened in order to mitigate the risk of the device expulsion.

Objective:To investigate the expulsion rate of GyneFix postpartum intrauterine device (PPIUD) placed immediately after cesarean section within one year and its influencing factors.Methods:A prospective cohort study was conducted. Women who volunteered to use a GyneFix PPIUD placed immediately after cesarean section (within 10 min after placenta delivery) for postpartum contraception were recruited from September 2017 to November 2020. The relevant information was collected through questionnaires before, during and 24 h after cesarean section. Outpatient follow-up was conducted at 42 d, 3 months, 6 months and 12 months after delivery to obtain information on expulsion of GyneFix PPIUD and unwanted pregnancy. Life table and Cox regression model were used to analyze the cumulative expulsion rate and related influencing factors.Results:A total of 470 subjects were recruited and 461 (98%) subjects were eligible for this study. The cumulative expulsion rate of GyneFix PPIUD within one year after cesarean section was 8.4% (95% CI: 7.0%-9.8%). Multivariate Cox regression analysis showed that women aged >35 years had significantly lower risk of PPIUD expulsion than those aged <25 years ( HR=0.16, 95% CI: 0.04-0.64). The risk of GyneFix PPIUD was not statistically significantly associated with cesarean section history and breastfeeding mode (all P>0.05). Nevertheless, this risk was statistically significant between hospitals. The Pearl index of contraceptive failure of the device was 2.37 (95% CI: 1.09-4.50) per 100 person-years. The rate of contraceptive failure was not associated with maternal age, breastfeeding mode, and history of cesarean delivery (all P>0.05). Conclusion:The one-year cumulative expulsion rate of GyneFix PPIUD placed immediately after cesarean section is 8.4%. Young mothers were at a higher risk of expulsion than their older counterparts. The device users should be counseled regarding the signs of expulsion. In case of expulsion, women should be offered reinsertion or other contraceptive methods. The training of service skills of GyneFix PPIUD should be strengthened in order to mitigate the risk of the device expulsion.

OBJECTIVE To provide reference for improving the classification management of prescription drugs and non- prescription drugs in China by learning from the classification management system of prescription drugs and non-prescription drugs in Canada. METHODS The content and experience of classification management system of prescription drugs and non-prescription drugs in Canada were analyzed， and the thinking of the classification management of prescription drugs and non-prescription drugs in China was proposed. RESULTS ＆＆CONCLUSIONS According to the classification of prescription drugs and non-prescription drugs， drugs can be divided into class Ⅰ drugs， class Ⅱ drugs， class Ⅲ drugs， unclassified drugs in Canada. Specific evaluation factors and management requirements have been established for drug classification. Canada has established a set of systematic management systems and technical standards， which has reference value for improving the classification management system in China. It is suggested to further improve the drug classification management system and supporting policies， strengthen fine classification management of prescription drugs and non-prescription drugs and improve classification registration and transformation review standards in China， by learning from Canadian prescription drug and non-prescription drug system and management model.

OB JECTIVE To explore the construction of system of pharmacoeconomic evaluation fo r Chinese patent medicine in preventing and treating major chronic diseases. METHODS The problems in pharmacoeconomic evaluation of Chinese patent medicine for preventing and treating major chronic diseases were analyzed. Based on the problem ，the pharmacoeconomic theory ， tools and methods that can be used to systematically evaluate the prevention and treatment of major chronic diseases by Chinese patent medicine were explored to build the relevant pharmacoeconomic evaluation system. RESULTS & CONCLUSIONS Traditional Chinese medicine shows the advantages in the prevention and treatment of major chronic diseases. This unique advantage needed to be explored ，reflected and proved in the pharmacoeconomic evaluation. The pharmacoeconomic evaluation of Chinese patent medicine had made some progress in recent years. However ，there were still deficiencies of theory and methodology in the pharmacoeconomic evaluation for the advantages of Chinese patent medicine in preventing and treating major chronic diseases. It was difficult to truly and comprehensively reflect the value of Chinese patent medicine by simply applying the economic evaluation indicators and technologies of chemical medicine. It is necessary to focus on the unique pharmacoeconomic attributes of Chinese patent medicine ，excavate the economic value indicators of Chinese patent medicine for “preventive treatment of disease ” and playing the self-regulation role of human body ，comprehensively consider the pharmacoeconomic particularity of Chinese patent medicine in respects of research design ，research angle ，target population ，intervention measures and control selection ，research time limit and evaluation method ，etc. Through the use of system modeling ，real-world research and the establishment of Chinese medicinal quality of life scale that reflects the characteristics of TCM ，the economic value of Chinese patent medicine in the prevention and treatmen t of major chronic diseases is reflected comprehensively，so as to reflect the advantage of Chinese patent medicine in preventing and treating major chronic diseases.

Objective:To compare the clinical effects of microwave ablation (MWA) and surgical resection in the treatment of small hepatocellular carcinoma(SHCC).Methods:Sixty five SHCC patients with intact clinical data, treated in the Center of Hepatobiliary Surgery, Peking University People's Hospital between Feb 2005 and Aug 2012, were enrolled in this study. Among them, 30 patients were treated by MWA, and the other 35 by hepatectomy. Follow-up was conducted from Mar 2013 to Feb 2021. The differences in long-term survival, intraoperative blood loss, operative time, postoperative complications, performance status (PS), and postoperative hospital stay were compared between the two groups.Results:The survival probability at 1, 3, 5 and 10 years was 93.2%, 82.5%, 55.6% and 41.2%, respectively, in the MWA group, and 97.1%, 82.6%, 67.2% and 48.3%, in the resection group ( P=0.347). The MWA group had less perioperative complications, less blood loss, shorter operation time, better PS score and better hospital stay than the surgical resection group (all P<0.001).There was no statistically significant difference in the survival rate between BCLC stage 0~A1 and A2~A4 patients( P=0.773, 0.536). Conclusions:Microwave ablation in the treatment of small hepatocellular carcinoma can achieve similar results as hepatectomy with less traumatic,better postoperative PS score and shorter postoperative hospital stay.

Objective:To explore the effect of different intensity electrical stimulation combined with biofeedback pelvic floor muscle training on postpartum pelvic floor dysfunction (PFD) in vaginal delivery patients.Methods:Seven hundred and twenty patients with PFD after vaginal delivery from January 2017 to April 2019 in Jinshan Branch of Shanghai Sixth People′s Hospital were selected. The patients were divided into control group (358 cases) and observation group (362 cases) by random digits table method. The control group was treated with conventional electric stimulation combined with biofeedback pelvic floor muscle training, and the observation group was treated with enhanced electric stimulation combined with biofeedback pelvic floor muscle training. The electrophysiological indexes of pelvic floor, incidence of stress urinary incontinence (SUI), pelvic organ prolapse/urinary incontinence function questionnaire (PISQ-12) score and the 6 measurement points of quantitative stage of pelvic organ prolapse (POP-Q) staging method after treatment were compared between 2 groups. The 6 measuring points were 3 cm from central line of anterior wall of vagina to edge of the hymen (Aa point), furthest point in the upper part of anterior wall of vagina between top of vagina or anterior vault to Aa point (Ba point), 3 cm point from central line of vaginal posterior wall to hymen (Ap point), farthest point of posterior vaginal vault or upper part of posterior vaginal wall from top of vagina to Ap point (Bp point), farthest point of the top of vagina after cervix or hysterectomy (C point) and position of posterior fornix in presence of cervix (D point).Results:The fatigue degree of class Ⅰ muscle fibers, fatigue degree of class Ⅱ muscle fibers, average electromyography value of pre rest, average electromyography value of slow muscle, average electromyography value of post rest, maximum electromyography value of fast muscle and dynamic vaginal pressure in observation group were significantly better than those in control group: (- 2.51 ± 0.22)% vs. (- 3.29 ± 0.37)%, (- 2.89 ± 0.27)% vs. (- 3.18 ± 0.32)%, (3.41 ± 0.39) μV vs. (2.91 ± 0.28) μV, (30.12 ± 0.22) μV vs. (28.29 ± 0.37) μV, (3.14 ± 0.55) μV vs. (2.51 ± 0.30) μV, (39.89 ± 0.27) μV vs. (38.18 ± 0.32) μV and (76.92 ± 28.18) cmH 2O(1 cmH 2O=0.098 kPa) vs. (69.10 ± 30.66) cmH 2O, and there were statistical differences ( P<0.01). The incidence of SUI and PISQ-12 score in observation group were significantly lower than those in control group: 14.36% (52/362) vs. 27.09% (97/358) and (28.49 ± 3.61) scores vs. (37.62 ± 3.83) scores, and there were statistical differences ( P<0.01). The Aa, Ba, Ap and C points in observation group were significantly improved than those in control group: (- 2.69 ± 0.21) cm vs. (- 2.38 ± 0.13) cm, (- 2.30 ± 0.52) cm vs. (- 2.21 ± 0.33) cm, (- 2.91 ± 0.35) cm vs. (- 2.85 ± 0.24) cm and (- 5.33 ± 065) cm vs. (- 5.20 ± 056) cm, and there were statistical differences ( t=2.365, 2.469, 2.691 and 2.889; P<0.05); there were no statistical differences in Bp and D points between 2 groups ( P>0.05). Conclusions:After vaginal delivery, the patients with PFD who use strong electric stimulation combined with biofeedback pelvic floor muscle training can significantly improve the pelvic floor electrophysiological index and POP-Q staging, reduce the incidence of SUI, and improve the quality of sexual life.