Identification of a novel hypoglycemic small molecule, trans-2, 4-dimethoxystilbene by rectifying gut microbiota and activating hepatic AMPKα-PPARγ pathway through gut-liver axis.

With the increasing prevalence of metabolic disorders, hyperglycemia has become a common risk factor that endangers people's lives and the need for new drug solutions is burgeoning. Trans-2, 4-dimethoxystilbene (TDMS), a synthetic stilbene, has been found as a novel hypoglycemic small molecule from glucose consumption test. Normal C57BL/6 J mice, mouse models of type 1 diabetes mellitus and diet-induced obesity subjected to TDMS gavage were found with lower glycemic levels and better glycemic control. TDMS significantly improved the symptoms of polydipsia and wasting in type 1 diabetic mice, and could rise their body temperature at the same time. It was found that TDMS could promote the expression of key genes of glucose metabolism in HepG2, as do in TDMS-treated liver, while it could improve the intestinal flora and relieve intestinal metabolic dysbiosis in hyperglycemic models, which in turn affected its function in the liver, forming the gut-liver axis. We further fished PPARγ by virtual screening that could be promoted by TDMS both in-vitro and in-vivo, which was regulated by upstream signaling of AMPKα phosphorylation. As a novel hypoglycemic small molecule, TDMS was proven to be promising with its glycemic improvements and amelioration of diabetes symptoms. It promoted glucose absorption and utilization by the liver and improved the intestinal flora of diabetic mice. Therefore, TDMS is expected to become a new hypoglycemic drug that acts through gut-liver axis via AMPKα-PPARγ signaling pathway in improving glycemic metabolism, bringing new hope to patients with diabetes and glucose metabolism disorders.

Incidence and risk factors of postoperative delirium after pancreatic cancer surgery: a retrospective study.

PURPOSE: Postoperative delirium (POD) commonly occurs after major abdominal surgery and is associated with increased morbidity and mortality. There have been many studies on the relationship between POD and various surgeries, but research on POD after pancreatic cancer surgery is limited. The aim of this study was to identify the incidence and risk factors of POD after pancreatic cancer surgery. METHODS: The subjects of this retrospective analysis were 196 patients who were transferred for postoperative care after pancreatic cancer surgery, to a 12-bed critical care medicine ward at Shandong Provincial Hospital, affiliated with Shandong First Medical University, between January 2015 and December 2019. The patients were divided according to whether they suffered POD into a delirium group and a non-delirium group. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit and two independent medical practitioners analyzed all the data. Univariate and multiple logistic regression analyses were performed. RESULTS: The overall delirium incidence was 20.41%, which increased to 29.03% for patients aged ≥ 70 years. POD was associated with age, smoking, the American Society of Anesthesiologists classification, the Acute Physiology and Chronic Health Evaluation II score, and the TNM stage of the cancer. The variables concerning sex, drinking, hypertension, a history of cerebral disease, surgery type, operation time, amount of bleeding, and the intraoperative use of dexmedetomidine did not differ significantly between the two groups. There was no significant difference in the length of ICU stay, with the exclusion of long-term stay for complications, between the groups, but POD tended to prolong the postoperative hospital stay and increase the risk of mortality. There was also a gradual decline in the incidence of POD between 2015 and 2019, especially from 2015 to 2018, after preventive measures were implemented. CONCLUSION: POD is related to many risk factors and worthy of attention. Appropriate management can reduce its incidence or at least shorten its duration.

Recent developments in natural products for white adipose tissue browning.

Excess accumulation of white adipose tissue (WAT) causes obesity which is an imbalance between energy intake and energy expenditure. Obesity is a serious concern because it has been the leading causes of death worldwide, including diabetes, stroke, heart disease and cancer. Therefore, uncovering the mechanism of obesity and discovering anti-obesity drugs are crucial to prevent obesity and its complications. Browning, inducing white adipose tissue to brown or beige (brite) fat which is brown-like fat emerging in WAT, becomes an appealing therapeutic strategy for obesity and metabolic disorders. Due to lack of efficacy or intolerable side-effects, the clinical trials that promote brown adipose tissue (BAT) thermogenesis and browning of WAT have not been successful in humans. Obviously, more specific means still need to be developed to activate browning of white adipose tissue. In this review, we summarized seven kinds of natural products (alkaloids, flavonoids, terpenoids, long chain fatty acids, phenolic acids, else and extract) promoting white adipose tissue browning which can ameliorate the metabolic disorders, including obesity, dislipidemia, insulin resistance and diabetes. Since natural products are important drug sources and the browning property plays a significant role in not only obesity treatment but also in type 2 diabetes (T2DM) improvement, natural products of inducing browning may be an irreplaceable drug discovery orientation for obesity, diabetes and even other metabolic disorders.

Hypoglycemic activity of puerarin through modulation of oxidative stress and mitochondrial function via AMPK.

Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known about its direct effects on diabetes. The aim of our study is to investigate its antidiabetic effect in vivo and in vitro, and explore the underlying mechanism. We used type I diabetic mice induced by streptozotocin to observe the effects of puerarin on glucose metabolism. In addition, oxidative stress and hepatic mitochondrial respiratory activity were evaluated in type I diabetic mice. In vitro, glucose consumption in HepG2 cells was assayed along with the qPCR detection of glucogenesis genes expression. Moreover, ATP production was examined and phosphorylation of AMPK was determined using Western blot. Finally, the molecular docking was performed to predict the potential interaction of puerarin with AMPK utilizing program LibDock of Discovery Studio 2018 software. The results showed that puerarin improved HepG2 glucose consumption and upregulated the glucogenesis related genes expression. Also, puerarin lowered fasting and fed blood glucose with improvement of glucose tolerance in type I diabetic mice. Further mechanism investigation showed that puerarin suppressed oxidative stress and improved hepatic mitochondrial respiratory function with enhancing ATP production and activating phosphorylation of AMPK. Docking study showed that puerarin interacted with AMPK activate site and enhancing phosphorylation. Taken together, these findings indicated that puerarin exhibited the hypoglycemic effect through attenuating oxidative stress and improving mitochondrial function via AMPK regulation, which may serve as a potential therapeutic option for diabetes treatment.

Glucose consumption assay discovers coptisine with beneficial effect on diabetic mice.

Many drugs with anti-diabetic effects regulate glucose consumption in peripheral tissues. Via cellular glucose consumption assays, we identified that coptisine, a main effective constituent from the plant Coptis chinensis, enhanced hepatic and skeletal muscle glucose consumption. We further explored its effects on glucose metabolism in diabetic animals to elucidate its mechanism of action. Our results showed that coptisine did not show cytotoxicity. Intragastric administration of coptisine for ten days in normal ICR mice markedly decreased fasting blood-glucose levels without significant effects on body weight. In alloxan-induced type 1 diabetic mice, intragastric administration of coptisine for 28 days decreased fasting and non-fasting blood-glucose levels as well. In type 2 diabetic KKAy mice, intragastric administration of coptisine for nine weeks improved glucose tolerance. It decreased fasting/non-fasting blood-glucose and fructosamine levels. Coptisine decreased low-density lipoprotein and total cholesterol levels, however, had no significant effect on triglyceride levels. Coptisine increased AMPK phosphorylation while decreasing Akt phosphorylation in HepG2 hepatic cells and C2C12 myotubes. Coptisine also reduced mitochondrial respiration in isolated and cellular mitochondria, suggesting that coptisine lowered cellular energy levels. In particularly, coptisine administration (10-6 M) decreased the mitochondrial oxygen consumption rate (OCR) with a greater extracellular acidification rate (ECAR), resulting in an oxidative-to-glycolysis phosphorylation shifted for cellular energy generation. Our results demonstrate that coptisine acts as an enhancer of peripheral glucose consumption could improve glucose metabolism in diabetic animals. Coptisine may serve as a novel anti-diabetic agent and warrant further evaluation.

MiR-942-3p Promotes the Proliferation and Invasion of Hepatocellular Carcinoma Cells by Targeting MBL2.

MicroRNAs (miRNAs), a subgroup of small noncoding RNAs, play critical roles in tumor growth and metastasis. Accumulating evidence shows that the dysregulation of miRNAs is associated with the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism by which miR-942-3p contributes to HCC remains undocumented. The association between miR-942-3p expression and the clinicopathological characteristics in HCC patients was analyzed by The Cancer Genome Atlas data set. The targets of miR-942-3p were identified by bioinformatic analysis and dual luciferase report assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell assays were performed to assess the functional role of miR-942-3p in HCC cells. Consequently, we found that miR-942-3p expression level was elevated in HCC tissues and cell lines as compared with the normal tissues and was associated with the pathological stage and tumor node metastasis (TNM) stage, acting as an independent prognostic factor of poor survival in patients with HCC. Ectopic expression of miR-942-3p enhanced the proliferation and invasive potential of HCC cells, but inhibition of miR-942-3p expression had the opposite effects. Mannose-binding lectin 2 (MBL2) was further identified as a direct target of miR-942-3p and possessed a negative correlation with miR-942-3p expression and unfavorable survival in patients with HCC. Restoration of MBL2 inhibited the progression of HCC cells and attenuated the tumor-promoting effects induced by miR-942-3p. In conclusion, miR-942-3p may act as an oncogenic factor in HCC cells by targeting MBL2 and provide a potential marker for patients with HCC.

SPK1-transfected UCMSC has better therapeutic activity than UCMSC in the treatment of experimental autoimmune encephalomyelitis model of Multiple sclerosis.

Multiple Sclerosis (MS), is a chronic inflammatory autoimmune disorder of the central nervous system that leads to chronic demyelination with axonal damage and neuronal loss. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for MS. In the current study, we investigated the effects of MSCs derived from the human umbilical cord (UCMSC) transfected by sphingosine kinase 1 (SPK1) gene. All the results showed that transplantation of UCMSCs gene modified by SPK1 (UCMSC-SPK1) dramatically reduce the severity of neurological deficits of the experimental autoimmune encephalomyelitis (EAE) mice, paralleling by reductions in demyelination, axonal loss, and astrogliosis. UCMSC-SPK1 transplantation also could inhibit the development of natural killer (NK) responses in the spleen of EAE mice, and increase the ratio of CD4+ CD25+ FoxP3+ (Treg) T cells. Furthermore, we described that a shift in the cytokine response from Th1/Th17 to Th2 was an underlying mechanism that suppressed CNS autoimmunity. UCMSCs transfected by SPK1 gene potentially offer a novel mode for the treatment of MS, and the specific mechanism of SPK1 in treating MS/EAE.

Emergency Transcatheter Arterial Embolization for Acute Renal Hemorrhage.

The aims of this study were to identify arteriographic manifestations of acute renal hemorrhage and to evaluate the efficacy of emergency embolization. Emergency renal artery angiography was performed on 83 patients with acute renal hemorrhage. As soon as bleeding arteries were identified, emergency embolization was performed using gelatin sponge, polyvinyl alcohol particles, and coils. The arteriographic presentation and the effect of the treatment for acute renal hemorrhage were analyzed retrospectively. Contrast extravasation was observed in 41 patients. Renal arteriovenous fistulas were found in 12 of the 41 patients. In all, 8 other patients had a renal pseudoaneurysm, 5 had pseudoaneurysm rupture complicated by a renal arteriovenous fistula, and 1 had pseudoaneurysm rupture complicated by a renal artery-calyceal fistula. Another 16 patients had tumor vasculature seen on arteriography. Before the procedure, 35 patients underwent renal artery computed tomography angiography (CTA). Following emergency embolization, complete hemostasis was achieved in 80 patients, although persistent hematuria was present in 3 renal trauma patients and 1 patient who had undergone percutaneous nephrolithotomy (justifying surgical removal of the ipsilateral kidney in this patient). Two-year follow-up revealed an overall effective rate of 95.18 % (79/83) for emergency embolization. There were no serious complications. Emergency embolization is a safe, effective, minimally invasive treatment for renal hemorrhage. Because of the diversified arteriographic presentation of acute renal hemorrhage, proper selection of the embolic agent is a key to successful hemostasis. Preoperative renal CTA plays an important role in diagnosing and localizing the bleeding artery.

[Effect of progesterone on MMP-3 expression in neonatal rat brain after hypoxic-ischemia].

OBJECTIVE: To study the effect of progesterone on matrix metalloproteinase-3 (MMP-3) expression in neonatal rat brain after hypoxic-ischemia. METHODS: Followed the hypoxic-ischemia of neonatal rat brain, Evans blue (EB) staining and transmission electron microscopy were used to detect the blood-brain barrier pathological changes on permeability. MMP-3 protein expression in cerebral cortex was measured with Western blot. RESULTS: Transmission electron microscopy results showed that the blood brain barrier in hypoxic-ischemic group changed significantly compare to progesterone group. EB staining results suggested that the blood-brain barrier permeability of hypoxic-ischemic group was significantly increased compared to sham-operated group (P < 0.01). The blood-brain barrier permeability in progesterone group was also decreased in comparison to that of hypoxic-ischemic group (P < 0.05). Western blot image analysis results indicated that MMP-3 protein expression in the hypoxic-ischemic group increased significantly than that in sham-operated group (P < 0.01), and the progesterone group was decreased significantly than that in hypoxic-ischemic group (P < 0.05). CONCLUSION: Progesterone may reduce the blood-brain barrier damage by reducing MMP-3 expression. This might be one of the protective mechanisms in the hypoxic-ischemic brain injury.