Intrauterine infusion of clinically graded human umbilical cord-derived mesenchymal stem cells for the treatment of poor healing after uterine injury: a phase I clinical trial.

BACKGROUND: Intrauterine adhesion and cesarean scar diverticulum are the main complications of poor healing after uterine injury. Human umbilical cord MSCs transplantation has been regarded as the most potential treatment in the clinic, the safety and efficacy of which in the clinic, however, remains unclear. METHODS: In this study, ten patients were enrolled: six with intrauterine adhesion and four with cesarean scar diverticulum. All the patients were injected with human umbilical cord MSCs twice into the uterus. Beside the chest X-ray, ECG and abdominal ultrasound, many laboratory tests including blood routine, liver and renal function, ovarian function, tumor biomarkers, and immune function were used to estimate the safe after stem cell transplanted. In addition, the efficacy of stem cell transplanted was shown by the endometrial thickness, the volume of the uterus, and cesarean scar diverticulum based on 3D ultrasound imaging. RESULTS: We found that all results of these laboratory tests were normal in these enrolled patients before and after cell injection. Meanwhile, the results of the chest X-ray and ECG were also normal in the treatment process. The abdominal ultrasound showed that the size of the left and right kidneys was inconsistent in one patient after cell therapy, while those of other patients were normal. In addition, endometrial thickness, the volume of the uterus, and cesarean scar diverticulum showed an improving tendency, but no significant difference was noted. CONCLUSION: In summary, intrauterine injection of clinically graded human umbilical cord MSCs was safe for poor healing after uterus injury. Trial registration NCT03386708. Registered 27 December 2017, https://clinicaltrials.gov/ct2/show/NCT03386708?cond=CSD&cntry=CN&draw=2&rank=2.

Adding Sodium-Glucose Co-Transporter 2 Inhibitors to Sulfonylureas and Risk of Hypoglycemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Hypoglycemia is an important event that could be related to increased mortality in patients with diabetes. The risk of hypoglycemia is not clearly illustrated to increase when Sodiumglucose co-transporter 2 (SGLT-2) inhibitors are used concomitantly with sulfonylureas. The present study will assess the risk of hypoglycemia associated with the concomitant use of SGLT-2 inhibitors and sulfonylureas compared with placebo and sulfonylureas. Method: We searched Medline, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov and identified the randomized trials comparing SGLT-2 inhibitors with placebo for type 2 diabetes treated with sulfonylureas. The risk of bias in each trial was assessed using the Cochrane tool. The risk ratio of hypoglycemia was measured using the Mantel Haenszel method. We also performed subgroup analysis to examine the dosage effects. The number needed to harm (NNH) was measured according to the duration of intervention. Results: A total of 12 studies, including 3761 participants, were enrolled in our systematic review and meta-analysis. The risk ratio of hypoglycemia was 1.67 (95% CI 1.42 to 1.97). The NNH was 13 (95% CI 9 to 21) for a treatment duration of 24 weeks or less, 11 (8 to 18) for 25 to 48 weeks, and 7 (5 to 10) for more than 48 weeks. Subgroup analysis showed that no difference was found between higher and lower doses of SGLT-2 inhibitors. The risk ratio related to lower dose SGLT-2 inhibitors was 1.56 (95% CI 1.30 to 1.88), and the risk ratio related to higher dose SGLT-2 inhibitors was 1.70 (95% CI 1.42 to 2.04). Conclusions: The risk of hypoglycemia was significantly increased in subjects treated with SGLT-2 inhibitors compared with placebo. Addition of SGLT-2 inhibitors to sulfonylureas would lead to one more case of hypoglycemia in every 13 patients with a treatment duration less than 24 weeks. This suggests that a decrease in sulfonylureas dose may be an important recommendation when adding SGLT-2 inhibitors to sulfonylureas.

Alpha-mangostin improves endothelial dysfunction in db/db mice through inhibition of aSMase/ceramide pathway.

Diabetic vascular complications are the leading causes of death and disability in patients with diabetes. Alpha-mangostin has been reported to have anti-diabetic capacity in recent years. Here, we investigated the protective function of alpha-mangostin on endothelium in vitro and in vivo experiments. We also observed that alpha-mangostin improved impaired endothelium-dependent vasodilation (EDV) of diabetic animals while it limited the aSMase/ceramide pathway and up-regulated eNOS/NO pathway in aortas from diabetic mice. Meanwhile, alpha-mangostin inhibited elevated aSMase/ceramide pathway and reversed impaired EDV induced by high glucose in isolated mouse aortas. In addition, alpha-mangostin increased phosphorylation of eNOS and NO production in high glucose-treated aortas. Alpha-mangostin normalized high glucose-induced activation of aSMase/ceramide pathway and improved eNOS/NO pathway in endothelial cells with high glucose. In conclusion, alpha-mangostin regulates eNOS/NO pathway and improves EDV in aortas of diabetic mice through inhibiting aSMase activity and endogenous ceramide accumulation.

Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic disorder diseases, which include a histological spectrum of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Dysregulated metabolism of sphingomyelin in the liver plays a critical role in the pathogenesis of NAFLD. Ceramides are central molecules of sphingolipid biosynthesis and catabolism and play an important role in insulin resistance, apoptosis, and inflammation. In addition, apoptosis is a main contributor to the development of NAFLD. This study detected whether the inhibition of ceramide synthesis ameliorated hepatic steatosis and fibrosis in rats with NAFLD. Sprague-Dawley rats were used to establish the NAFLD model. Here, we showed that hepatic ceramide, steatosis, and fibrosis increased in liver tissue from rats with NAFLD. Chronic treatment with myriocin inhibited ceramide and lipid accumulation and improved fibrosis in liver tissue samples of high fat diet (HFD)-fed rats. In addition, hepatic inflammation and apoptosis were markedly ameliorated in HFD-fed rats treated with myriocin. Furthermore, myriocin treatment regulated the expression of pro-apoptosis and anti-apoptosis proteins by inactivating the c-Jun N-terminal kinase (JNK) signaling pathway in the liver of HFD-fed rats. Collectively, ceramide plays an important role in the pathogenesis of NASH and may represent a potential therapeutic strategy to prevent NAFLD.

Inhibition of acid sphingomyelinase activity ameliorates endothelial dysfunction in db/db mice.

Acid sphingomyelinase (aSMase) plays an important role in endothelial dysfunction. Here, we show that elevated aSMase activity and ceramide content were reduced by desipramine treatment in diabetic animals. The inhibitor of aSMase, desipramine, improved vascular dysfunction in db/db mice. High glucose (HG)-induced up-regulation of aSMase activity and ceramide levels were restored by treatment with aSMase siRNA or desipramine in endothelial cells. In addition, aSMase siRNA or desipramine treatment increased the release of nitric oxide (NO) and the phosphorylation of endothelial NO synthase (eNOS) in diabetic mouse aortas and aortic endothelial cells with HG.These results indicate that inhibition of aSMase/ceramide pathway improves endothelium-dependent vascular relaxation (EDR) largely through regulating the eNOS/NO pathway in diabetic animals.

[Identification of interacting proteins with NF-κB in different status of uterine smooth muscle in labor].

OBJECTIVE: To analyze the differentially expressed proteins which interacted with NF-kappaB in the uterine lower segment smooth muscle tissues under different status of labor onset, and to provide a new foundation on the mechanisms for labor onset.
 Methods: NF-κB P65 protein expression in smooth muscle tissues from the term non-labor group, natural term labor group and drug-induced term labor group was analyzed by Western blot. Co-immunoprecipitation and SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) were performed to detect the proteins interacting with NF-κB p65 in the NF-κB p65 complexes. The components of the complex were identified by LC-ESI-MS/MS (liquid chromatography-tandem electrospray mass spectrometry) and database analysis. The identified differentially expressed proteins were confirmed by Western blot.
 Results: Positive expression of NF-κB was detected in all of the three groups. 10 differentially expressed proteins were identified by LC-ESI-MS/MS in human lower segment myometrium tissues in the term non-labor group and natural term labor group, mean while, 5 differentially expressed proteins were identified in the term non-labor group and the drug-induced labor group. 3 differential expression proteins were detected in all of the 3 groups, including Heat shock 70, Annexin A6 and Desmin, which were verified by Western blot. These proteins were mainly involved in chaperone, signal transduction, cell structure, and energy metabolism process, respectively.
 Conclusion: NF-κB expressed in uterine smooth muscle cells is involved in the process of initiation and regulation of labor onset through a number of proteins relevant to signal transduction, cell structure and energy metabolism.

[Modified cesarean hysterectomy for placenta previa percreta in the third trimester via peritoneum lateral approach].

OBJECTIVE: To investigate the application of modified cesarean hysterectomy for placenta previa percreta in the third trimester via peritoneum lateral approach. METHODS: Data of 8 patients at 34 weeks or more gestation, who underwent cesarean hysterectomy for placenta previa percreta in Xiangya Hospital, Central South University, between January 2008 and December 2011, were analyzed retrospectively. The patients were divided into a modified cesarean hysterectomy by peritoneum lateral approach group (modified group, n=4) and a conventional cesarean hysterectomy group (conventional group, n=4), according to the principles of the case-control and the operation performed by the same doctor. The incidence of blood loss, the number of transfusions of RBC, and the ocurrnce of complications were compared between the 2 groups. RESULTS: The blood loss in the modified group and the conventional group was (2280±687) mL and (6150±2023) mL, and the number of transfusions of RBC was (4.5±2.1) U and (11.7±8.9) U, respectively. There was no coagulation disorder and ureteral injury in the modified group whereas there were 2 disorders and 1 injury in the conventional group. Two patients with bladder laceration were observed in the 2 groups. CONCLUSION: Large amounts of bleeding will be onset in the placenta previa percreta. Modified cesarean hysterectomy for placenta previa percreta can reduce the blood loss and the incidence of related complications in the operation.

[Selective arterial occlusion in the treatment of placenta percreta in late trimester of pregnancy].

OBJECTIVE: To evaluate the value of selective arterial occlusion in the treatment of placenta percreta in late trimester of pregnancy. METHODS: Fifteen clinical patients ( gestational age ≥34 weeks), diagnosed with placenta percreta in Xiangya Hospital of Central South University from January 2003 to December 2010, were retrospectively analyzed. According to whether the selective arterial occlusion was used or not, the 15 patients were divided into 2 groups: an arterial occlusion group (n=8) and a non-arterial occlusion group (n=7). Based on the time of occlusion, the arterial occlusion group was divided into a prophylactic occlusion subgroup (n=4) and a remedial occlusion subgroup (n=4) (including 1 patient who was performed after the iliac artery balloon was taken out ). The blood loss, the rate of hysterectomy and complications were compared between the arterial occlusion group and the non-arterial occlusion group. RESULTS: In all 15 patients, the average amount of blood loss was 3813 mL, and the rate of hysterectomy was 73.3% (11/15). The recent complication rate was 20.0% (3/15, including 2 blood coagulation dysfunctions and 1 lower extremity thrombosis), and long-term complication was not found. The average amount of blood loss in the occlusion group was 2512 mL, the hysterectomy rate was 62.5%(5/8); while the average amount of bleeding was 5549 mL and the hysterectomy rate was 85.7% in the non-occlusion group (6/7). There was significant difference between the 2 groups (P<0.05). The average amount of blood loss and the rate of hysterectomy in the prophylactic occlusion subgroup were lower than those in the remedial occlusion subgroup (1350 mL vs 3600 mL, 60.0% vs 66.7%, P<0.05). CONCLUSION: Patients with placenta percreta in the third trimester of pregnancy may encounter severe postpartum hemorrhage, and the rate of hysterectomy is high. The amount of blood loss and the rate of hysterectomy may be reduced by the selective arterial occlusion before or in the cesarean section, but cannot be avoided completely.