Cardiovascular risk of sitagliptin in treating patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2DM) have a very high risk of cardiovascular related events, and reducing complications is an important evaluation criterion of efficacy and safety of hypoglycemic drugs. Previous studies have shown that the dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP4i), such as sitagliptin, might reduce the incidence of major cardiovascular events (MACEs). However, the safety and efficacy of sitagliptin remains controversial, especially the safety for cardiovascular related events. Here, a systematic review was conducted to assess the cardiovascular safety of sitagliptin in T2DM patients. The literature research dating up to October 2018 was performed in the electronic database. The clinical trials about sitagliptin for T2DM patients were included. Two reviewers independently screened literature according to the inclusion and exclusion criteria. The primary outcome was the MACE, and the secondary outcome was all-cause mortality. Finally, 32 clinical trials composed of 16082 T2DM patients were included in this meta-analysis. The results showed that: there was no significant difference between sitagliptin group and the control group on MACE (odds ratio (OR) = 0.85, 95% confidence intervals (CIs) = 0.63-1.15), myocardial infarction (MI) (OR = 0.66, 95% CI = 0.38-1.16), stroke (OR = 0.83, 95% CI = 0.44-1.54) and mortality (OR = 0.52, 95% CI = 0.26-1.07). These results demonstrated that sitagliptin did not increase the risk of cardiovascular events in patients with T2DM.

Partial ablation of the pancreas of Sprague Dawley® rats by focused ultrasound reveals no significant adverse effects on glycometabolism function.

To investigate the safety of focused ultrasound (FUS) partial ablation on the pancreas of Sprague Dawley® (SD) rats by histopathological examination of the outcome and investigation of glycometabolism function changes after local ablation. A total of 135 healthy SD rats were randomly divided into three groups (n=45 of each): FUS ½ group, FUS » group, and control group. Levels of serum amylase was measured using the enzyme dynamics method, fasting blood glucose was measured by the glucose oxidase-peroxidase method, fasting serum insulin was measured by direct chemiluminescence assay, and an ELISA was used to measure fasting serum glucagon immediately after treatment, and at 2h, 3days, 1, 2, 3 and 4weeks, 3 and 6months after FUS ablation. Pancreatic tissue was stained with hematoxylin and eosin and the pathology of the ablation area was examined under an optical microscope; additionally, the expression of insulin and glucagon was investigated by immunohistochemistry. Compared with the control group, serum amylase and fasting blood glucose levels in the ablation groups rose significantly immediately after operation; fasting blood glucose, serum amylase, serum insulin and glucagon levels in the ablation groups were significantly different at 2h after treatment, and serum amylase levels in the ablation groups remained significantly different on day 3. Histological findings showed that the coagulation necrosis area gradually shrank, with formation of new blood vessels observed at week 3, and new ducts observable in the ablation area at the 3rd month after FUS ablation, but no formation of islets was observed. Expression of insulin and glucagon in the ablation groups were significantly higher than in the control group at 2h after FUS ablation. There were no significant adverse effects on the glycometabolic function of SD rats after FUS ablation, and the influence of FUS treatment on pancreatic functions were minimal.

High intensity focused ultrasound inhibits melanoma cell migration and metastasis through attenuating microRNA-21-mediated PTEN suppression.

High intensity focused ultrasound (HIFU) technology is becoming a potential noninvasive treatment for solid tumor. To explore whether HIFU can be applied to treat melanoma and its metastasis, we investigated the effect of HIFU on murine melanoma model. While there was little influence on cell survival, viability or apoptosis, HIFU exposure suppressed melanoma cell migration in vitro and metastasis in vivo. The expression of microRNA-21(miR-21) was down-regulated and PTEN expression was up-regulated in response to HIFU exposure, which was in concomitant with the reduction of AKT activity. Furthermore, ectopic miR-21 expression suppressed this effect of HIFU. These results demonstrate that HIFU exposure can inhibit AKT-mediated melanoma metastasis via miR-21 inhibition to restore PTEN expression. Therefore, targeting the miR-21/PTEN/AKT pathway might be a novel strategy of HIFU in treatment of melanoma.

The effects of sodium tanshinone IIa sulfonate pretreatment on high glucose-induced expression of fractalkine and apoptosis in human umbilical vein endothelial cells.

The development of diabetes mellitus (DM) and its complications is a chronic inflammatory response process, chemokines and their receptors play an important role in this course of events. The aim of this study is to observe the effects of sodium tanshinone IIa sulfonate (STS) on high glucose-induced fractalkine (FKN) level, and investigate possible mechanisms of STS works. HUVECs cells were employed to explore the effects of STS on FKN protein. TUNEL assay was used to detect the apoptosis rate of HUVECs. Immunohistochemistry was utilized to detect the ß-actin and P-GSK-3ß (Ser9) protein expression. Immunofluorescence was employed to detect FKN protein expression. Real-time RT-PCR was used to examine ß-actin, GSK3ß and FKN mRNA expression. The results indicated that the STS treatment could significantly decrease the apoptosis rate caused by high-glucose (P < 0.05). STS improves ß-catenin and p-GSK-3ß (Ser9) expression, and inhibits FKN levels induced by high glucose. STS inhibited GSK-3ß and FKN mRNA induced by high glucose. In conclusion, STS may play the role of anti- inflammatory by regulate canonical Wnt pathway to inhibit the expression of FKN induced by high glucose.

Preliminary ex vivo feasibility study on targeted cell surgery by high intensity focused ultrasound (HIFU).

High intensity focused ultrasound (HIFU) has become a new noninvasive surgical modality in medicine. A portion of tissue seated inside a patient's body may experience coagulative necrosis after a few seconds of insonification by high intensity focused ultrasound (US) generated by an extracorporeal focusing US transducer. The region of tissue affected by coagulative necrosis (CN) usually has an ellipsoidal shape when the thermal effect due to US absorption plays the dominant role. Its long and short axes are parallel and perpendicular to the US propagation direction respectively. It was shown by numerical computations using a nonlinear Gaussian beams model to describe the sound field in a focal zone and ex vivo experiments that the dimension of the short and long axes of the tissue which experiences CN can be as small as 50µm and 250µm respectively after one second exposure of US pulse (the spatial and pulse average acoustic power is on the order of tens of Watts and the local acoustic spatial and temporal pulse averaged intensity is on the order of 3×10(4)W/cm(2)) generated by a 1.6MHz HIFU transducer of 12cm diameter and 11cm geometric focal length (f-number=0.92). The concept of thermal dose of cumulative equivalent minutes was used to describe the possible tissue coagulative necrosis generated by HIFU. The numbers of cells which suffered CN were estimated to be on the order of 40. This result suggests that HIFU is able to interact with tens of cells at/near its focal zone while keeping the neighboring cells minimally affected, and thus the targeted cell surgery may be achievable.

Non-thermal ablation of rabbit liver VX2 tumor by pulsed high intensity focused ultrasound with ultrasound contrast agent: Pathological characteristics.

AIM: To investigate the pathological characteristics of non-thermal damage induced by pulsed high intensity focused ultrasound (PHIFU) combined with ultrasound contrast agent (UCA), SonoVue (Bracco SpA, Milan, Italy) in rabbit liver VX2 tumor. METHODS: Liver VX2 tumor models were established in 20 rabbits, which were divided randomly into PHIFU combined with ultrasound contrast agent group (PHIFU + UCA group) and sham group. In the PHIFU + UCA group, 0.2 mL of SonoVue was injected intravenously into the tumor, followed by ultrasound exposure of I(SP) 5900 W/cm(2). The rabbits were sacrificed one day after ultrasound exposure. Specimens of the exposed tumor tissues were obtained and observed pathologically under light microscope and transmission electron microscope. The remaining tumor tissues were sent for 2,3,5-Triphenyltetrazolium chloride (TTC) staining. RESULTS: Before TTC staining, tumor tissues in both the sham and the PHIFU + UCA groups resembled gray fish meat. After TTC staining, the tumor tissues were uniformly stained red, with a clear boundary between tumor tissue and normal tissue. Histological examination showed signs of tumor cell injury in PHIFU + UCA group, with cytoplasmic vacuoles of various sizes, chromatin margination and karyopyknosis. Electron microscopic examination revealed tumor cell volume reduction, karyopyknosis, chromatin margination, intercellular space widening, the presence of high electron-density apoptotic bodies and vacuoles in cytoplasm. CONCLUSION: The non-thermal effects of PHIFU combined with UCA can be used to ablate rabbit liver VX2 tumors.