The clinical antiprotozoal drug nitazoxanide has been demonstrated to improve the experimental diabetes mellitus, lipid metabolism disorders, atherosclerosis and inhibit inflammation. Since the pathogenesis of heart failure with preserved ejection (HFpEF) is multifactorial and closely associated with the aforementioned diseases, we aim to study the effect of nitazoxanide on high-fat diet (HFD) plus L-NAME (N ω-nitro-l-arginine methyl ester)-induced HFpEF and metabolic syndrome in mice. We found that oral nitazoxanide improved cardiac hypertrophy, cardiac fibrosis, cardiac diastolic dysfunction, increased blood pressure, impaired exercise tolerance, impaired glucose handling, serum lipid disorders, hepatic steatosis, increased weight of white adipose tissues and kidney fibrosis in HFD + L-NAME-treated mice. In the established HFD + L-NAME-induced HFpEF and metabolic syndrome mouse model, therapeutic treatment with nitazoxanide rescued HFD + L-NAME-induced pathological phenotypes as mentioned above. The in vitro experiments revealed that tizoxanide, the active metabolite of nitazoxanide, increased the basal mitochondria metabolism of cardiomyocytes, inhibited cardiomyocyte hypertrophy and collagen secretion from cardiac fibroblasts, and relaxed phenylephrine- and U46619-induced constriction of rat mesenteric arteries, indicating that the direct effect of tizoxanide might partly contribute to the protective effect of nitazoxanide against HFpEF in vivo. The present study suggests that nitazoxanide might be a potential drug for HFpEF and metabolic syndrome therapy.

Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis. It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis. Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile. We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in HepG2 cells. Gavage administration of nitazoxanide inhibited high-fat diet (HFD)-induced increases of liver weight, blood and liver lipids, and ameliorated HFD-induced renal lipid accumulation in hamsters. Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers. In the hamsters with pre-existing hyperlipidemia and hepatic steatosis, nitazoxanide also showed therapeutic effect. Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet (WD)-induced hepatic steatosis in Apoe ^-/- mice. The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.

Objective:To evaluate the effect of dexmedetomidine mixed with dexamethasone on efficacy of ropivacaine for popliteal sciatic nerve block in the patients undergoing ankle surgery.Methods:A total of 120 patients of either sex, aged 30-64 yr, with body mass index of 19.6-29.7 kg/m 2, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, undergoing elective ankle surgery, were divided into 4 groups ( n=30 each) by a random number table method: control group (group C), dexmedetomidine group (group DD), dexamethasone group (group DM), and dexmedetomidine plus dexamethasone group (group DD+ DM). In group C, 0.5% ropivacaine 30 ml was injected around the popliteal sciatic nerve guided by ultrasound combined with a nerve stimulator.Dexmedetomidine 1 μg/kg, dexamethasone 10 mg and dexmedetomidine 1 μg/kg plus dexamethasone 10 mg were added to 0.5% ropivacaine in group DD, group DM and group DD+ DM, respectively.The analgesic time, consumption of sufentanil and adverse reactions were recorded after popliteal sciatic nerve block. Results:Compared with group C, the analgesic time was significantly prolonged, the consumption of sufentanil was reduced, and the incidence of nausea and vomiting was decreased in group DD, group DM and group DD+ DM ( P<0.05). Compared with group DD and group DM, the analgesic time was significantly prolonged, and the consumption of sufentanil was reduced in group DD+ DM ( P<0.05). No itching, drowsiness, hypotension, bradycardia or respiratory depression occurred in each group. Conclusion:Dexmedetomidine mixed with dexamethasone can effectively enhance the efficacy of ropivacaine for popliteal sciatic nerve block in the patients undergoing ankle surgery.

Objective: To investigate the diagnosis and treatment of adult small bowel torsion in order to improve early diagnosis and improve prognosis. Methods: Clinical data of 43 cases of small bowel torsion from January 2012 to December 2017 were collected. All of them were confirmed by surgery as small bowel torsion. After admission, white blood cell count > 18 × 10⁹/L was found in 5 patients; and hemoglobin<100 g/L was found in 5 patients; abdomen CT examination in 39 patients showed 33 cases had intestinal torsion; 14 cases suggested possible mesenteric and root torsion. Results: All patients underwent surgical treatment. During the operation, there were 11 cases with intestinal torsion ≥ 720°; 13 cases underwent simple bowel torsion in surgical operation; 4 cases underwent decompression combined with reduction of the bowel; 1 case was treated with reduction and jejunostomy; and small intestine resection was performed for intestinal necrosis. Twenty-two patients had small bowel resection and jejunostomy was performed in 3 cases. The small intestine was resected 7-240 cm, with an average of about 66 cm. Conclusions Small bowel torsion should be diagnosed and operated as soon as possible. The suspected necrotic bowel should be removed and more healthy intestine should be reserved. The patient′s vital signs should be observed dynamically after operation to prevent the occurrence of intestinal necrosis and septic shock, to avoid excessive intestinal necrosis that would lead to postoperative short bowel syndrome, and to improve the patient's cure rate and reduce hospital stay.

OBJECTIVETo investigate the expression of interleukin-9 (IL-9) in colon cancer tissues and its clinical significance.

METHODSImmunohistochenmistry and qRT-PCR were used to detect the expressions of IL-9 protein and mRNA in 92 colon cancer tissues and paired adjacent normal tissues. The correlation of IL-9 expressions with the clinicopathological features and prognosis of the patients was analyzed.

RESULTSIL-9 protein and mRNA expressions were significantly higher in adjacent normal tissues than in the colon cancer tissues ( < 0.001). In colon cancer patients, IL-9 expression was significantly correlated with TNM stage (=0.013), Ducks stage (=0.025) and lymph node metastasis (=0.004) but not with gender, age, tumor size, differentiation or hepatic metastasis ( > 0.05). The survival time of colon cancer patients with positive IL-9 expression was significantly longer than that of patients negative for IL-9 expression (=0.015).

CONCLUSIONSIL-9 expression is lowered in colon cancer tissues compoved with in the adjacent normal tissues. IL-9 expression is negatively correlated with TNM staging, Ducks staging and lymph node metastasis but positively with good prognosis, suggesting its important role in the tumor microenvironment of colon cancer.

Our previous studies found that mitochondrial uncouplers CCCP and niclosamide inhibited artery constriction and the mechanism involved AMPK activation in vascular smooth muscle cells. BAM15 is a novel type of mitochondrial uncoupler. The aim of the present study is to identify the vasoactivity of BAM15 and characterize the BAM15-induced AMPK activation in vascular smooth muscle cells (A10 cells). BAM15 relaxed phenylephrine (PE)-induced constricted rat mesenteric arteries with intact and denuded endothelium. Pretreatment with BAM15 inhibited PE-induced constriction of rat mesenteric arteries with intact and denuded endothelium. BAM15, CCCP, and niclosamide had the comparable IC value of vasorelaxation in PE-induced constriction of rat mesenteric arteries. BAM15 was less cytotoxic in A10 cells compared with CCCP and niclosamide. BAM15 depolarized mitochondrial membrane potential, induced mitochondrial fission, increased mitochondrial ROS production, and increased mitochondrial oxygen consumption rate in A10 cells. BAM15 potently activated AMPK in A10 cells and the efficacy of BAM15 was stronger than that of CCCP, niclosamide, and AMPK positive activators metformin and AICAR. In conclusion, BAM15 activates AMPK in vascular smooth muscle cells with higher potency than that of CCCP, niclosamide and the known AMPK activators metformin and AICAR. The present work indicates that BAM15 is a potent AMPK activator.

Our previous studies found that mitochondrial uncouplers induced vasodilation. Triclosan, the broad spectrum antibacterial agent, is the active ingredient in soaps and toothpastes. It was reported that triclosan induced mitochondrial uncoupling, so we aim to investigate the effects of triclosan on vascular function of rat mesenteric arteries and aorta. The isometric tension of rat mesenteric artery and thoracic aorta was recorded by multi-wire myograph system. The cytosolic [Ca], mitochondrial reactive oxygen species (mitoROS), and mitochondrial membrane potential of smooth muscle cells (A10 cells) were measured using laser scanning confocal microscopy. Triclosan treatment relaxed phenylephrine (PE)- and high K(KPSS)-induced constriction, and pre-treatment with triclosan inhibited PE- and KPSS-induced constriction of rat mesenteric arteries. In rat thoracic aorta, triclosan also relaxed PE- and KPSS-induced constriction. Triclosan induces vasorelaxation without involving Kchannel activation in smooth muscle cells of arteries. Triclosan treatment increased cytosolic [Ca], mitochondrial ROS production and depolarized mitochondrial membrane potential in A10 cells. In conclusion, triclosan induces mitochondrial uncoupling in vascular smooth muscle cells and relaxes the constricted rat mesenteric arteries and aorta of rats. The present results suggest that triclosan would indicate vasodilation effect if absorbed excessively.

Mitochondria are morphologically dynamic organelles which undergo fission and fusion processes. Our previous study found that arterial constriction was always accompanied by increased mitochondrial fission in smooth muscle cells, whereas inhibition of mitochondrial fission in smooth muscle cells was associated with arterial relaxation. Here, we used the typical vasorelaxants, verapamil and phentolamine, to further confirm the coupling between arterial constriction and mitochondrial fission in rat aorta. Results showed that phentolamine but not verapamil induced vasorelaxation in phenylephrine (PE)-induced rat thoracic aorta constriction. Verapamil, but not phentolamine, induced vasorelaxation in high K(KPSS)-induced rat thoracic aorta constriction. Pre-treatment with phentolamine prevented PE- but not KPSS-induced aorta constriction and pre-treatment with verapamil prevented both PE- and KPSS-induced aorta constriction. Transmission electron microscopy (TEM) results showed that verapamil but not phentolamine inhibited KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells, and verapamil prevented both PE- and KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells. Verapamil inhibited KPSS-induced excessive mitochondrial fission in cultured vascular smooth muscle cells (A10). These results further demonstrate that arterial relaxation is coupled to inhibition of mitochondrial fission in arterial smooth muscle cells.

Our previous work found that DMH1 (4-[6-(4-isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl]quinoline) was a novel autophagy inhibitor. Here, we aimed to investigate the effects of DMH1 on chemotherapeutic drug-induced autophagy as well as the efficacy of chemotherapeutic drugs in different cancer cells. We found that DMH1 inhibited tamoxifen- and cispcis-diaminedichloroplatinum (II) (CDDP)-induced autophagy responses in MCF-7 and HeLa cells, and potentiated the anti-tumor activity of tamoxifen and CDDP for both cells. DMH1 inhibited 5-fluorouracil (5-FU)-induced autophagy responses in MCF-7 and HeLa cells, but did not affect the anti-tumor activity of 5-FU for these two cell lines. DMH1 itself did not induce cell death in MCF-7 and HeLa cells, but inhibited the proliferation of these cells. In conclusion, DMH1 inhibits chemotherapeutic drug-induced autophagy response and the enhancement of efficacy of chemotherapeutic drugs by DMH1 is dependent on the cell sensitivity to drugs.

Objective:To identify the epitope of mAb15A11 which is specific against RA associated autoantigen cartilage oligomeric matrix protein ( COMP ).Methods: A filamentous phage library displaying random linear dodecapeptides was used to mapping the epitope of mAb15A11.After three rounds of screenings,40 phage clones were selected at random and sequenced.The specificity of phages was confirmed by enzyme immunoassays.Homology search by ClustalW2 and structure analysis by PyMol to identified the epitope amino acid sequence.Western blot analysis of COMP and ELISA analysis of COMP-derived peptides were used to confirm epitope′s characterization.Results: After repeated screenings using bio-panning method, 2 clones were identified, which interacted specifically with mAb 15A11.Homology search did not find succession consensus sequence within COMP molecular,which indicated that the epitope was not linear.PyMol Structure analysis identified the rationality of conformational epitope.Western blot analysis and ELISA of EDTA-treated COMP further prove an conformational structure of the epitope recognized by mAb 15A11.ELISA analysis of COMP-derived peptides demonstrated both disulfide bonds between 229 C-243 C and 237 C-253 C and every epitope amino acid of 232 G,238 H,240 H,241 A,244 V,247 R and 251 R were essential to the binding of mAb 15A11 with COMP.Conclusion: In this study, the potential B cell antigentic epitopes of mAb 15A11 was identified by phage display library.The epitope amino acids sequence and char-acterization were also recognized.It may have important theoretical value for the study of reaction mechanism of COMP antibody and antigen and may also show application significance in the detection of rheumatoid arthritis.