Synthetic (+)-antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities

BACKGROUND AND PURPOSE

The fungal product (+)-antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chemically synthesized (+)-antroquinonol exhibited beneficial metabolic effects in insulin-resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV (DPP IV) activity.

EXPERIMENTAL APPROACH

Effects of (+)-antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP-1-induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin-dependent PI3K/AKT signalling or by insulin-independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet-induced obesity were used to assess effects of acute and chronic treatment with (+)-antroquinonol on glycaemic control in vivo.

KEY RESULTS

The results showed that of (+)-antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clinically used inhibitor, sitagliptin. The phosphorylation of AMPK Thr¹⁷² in differentiated myotubes was significantly increased by (+)-antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)-antroquinonol, the combination of (+)-antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)-antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice.

CONCLUSIONS AND IMPLICATIONS

Chemically synthesized (+)-antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity.     

Fluorescence enhancement of carbon dots by graphene for highly sensitive detection of tetracycline hydrochloride

In this study, fluorescence of self-assembled multilayers (SAMs) of carbon dots (CDs) was found to be enhanced by graphene. The number of polyelectrolyte layers can be tuned to control the distance between CDs and graphene in SAMs. The enhanced fluorescence efficiency was found to be dependent on graphene concentration, degree of graphene reduction, and the distance between CDs and graphene surface. When graphene concentration and polyelectrolyte bilayer number were set to 0.005 mg mL⁻¹ and 3 layers, respectively, fluorescence intensity of CDs could be increased up to 3.2 times. Tetracycline hydrochloride (Tc) could be detected by the established SAMs in the presence of graphene as the sensitivity was 2 orders higher than that of SAMs in the absence of graphene. Limit of detection of this sensing system was 0.9284 nM, which is 1–3 orders of magnitude lower than those of most of reported fluorescence sensors. This method could be successfully applied to detect trace Tc in milk samples.

The fluorescence of carbon dots self-assembled multilayers (CDs SAMs) can be enhanced by graphene, the sensing sensitivity for tetracycline hydrochloride of CDs SAMs with graphene is two orders higher than that of SAMs without graphene.     

Copper-catalyzed aerobic decarboxylative coupling between cyclic α-amino acids and diverse C–H nucleophiles with low catalyst loading

An aerobic decarboxylative cross-coupling of α-amino acids with diverse C–H nucleophiles has been realized using Cu₂(OH)₂CO₃ (1 mol%) as the catalyst under air. This protocol enables highly efficient formation of various C(sp³)–C(sp³), C(sp³)–C(sp²) and C(sp³)–C(sp) bonds under simple conditions without the use of any ligand or extra oxidant, providing a practical approach to numerous nitrogen-containing compounds in good to excellent yields. The efficiency and practicability were also demonstrated by the gram-scale experiment and three-step synthesis of a Rad51 inhibitor.

An aerobic decarboxylative cross-coupling of α-amino acids was realized using 1 mol% Cu₂(OH)₂CO₃ catalyst under ligand free conditions.     

A combination of human leukocyte antigen DQB1*02 and the tumor necrosis factor alpha promoter G308A polymorphism predisposes to an insulin-deficient phenotype in patients with type 2 diabetes

Our previous results have suggested that genes outside the human leukocyte antigen (HLA) class II locus may affect the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes (mixed type 1/2). To study whether the TNF alpha gene could be such a modifying gene, we studied TNF alpha promoter polymorphisms (G-->A substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 patients from mixed type 1/2 families or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNF alpha(308) AA/AG genotype frequency was increased in adult onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P < 0.0001 vs. type 1). The TNF alpha(308) A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P < 0.001 vs. Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P < 0.05 vs. controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in the type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist to hip ratio [0.92 (0.12) vs. 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs. 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. In conclusion, TNF alpha is unlikely to be the second gene in the HLA area responsible for our previous findings in type 1/2 patients. However, we could show an association between TNF alpha(308) polymorphism and the phenotype of common type 2 diabetes.     

Effects of medroxyprogesterone and estradiol on the recovery of spermatogenesis in irradiated rats

Suppression of intratesticular testosterone (ITT) levels is required for spermatogenic recovery in rats after irradiation, but maintenance of peripheral testosterone (T) levels is important for many male functions. Considering the preservation of peripheral T while suppressing ITT, we tested the effects of a combination of a progestin, medroxyprogesterone acetate (MPA), plus T on spermatogenic recovery after irradiation, and compared its effects to those of T alone or T combined with estradiol (E2). Rats were given testicular irradiation (6 Gy) and treated during wk 3-7 after irradiation with MPA + T, or the individual steroids with or without GnRH antagonist (GnRH-ant), or GnRH-ant alone, or T + E2. Whereas GnRH-ant alone stimulated differentiation in 55% of tubules 13 wk after irradiation compared with 0% in irradiated-only rats, the addition of MPA reduced the percentage of tubules showing differentiation to 18%. However, T or MPA alone or the combination of the two induced germ cell differentiation in only 2-4% of tubules. In contrast, E2 stimulated differentiation in 88% of tubules, and T combined with E2 still resulted in differentiation in 30% of tubules. Although both MPA and E2 suppressed ITT levels to approximately 2% of control (2 ng/g testis), MPA was a less effective stimulator of spermatogenic recovery than E2 or GnRH-ant alone. MPA's function as a weak androgen was likely responsible for inhibiting spermatogenic recovery, as was the case for all other tested androgens. Thus, for clinical protection or restoration of spermatogenesis after radiation or chemotherapy by suppressing T production, MPA, at least in the doses used in the present study, is suboptimal. The combination of an estrogen with T appears to be most effective for stimulating such recovery.     

The role of cryosurgery in the treatment of hepatic cancer: a report of 113 cases

From November 1973 to June 1992, cryosurgery with liquid nitrogen (–196°C) was performed on 113 patients with hepatic cancer, including 107 patients with primary liver cancer (PLC) and 6 patients with secondary liver cancer (SLC). Of the 107 PLC patients, the subclinical stage constituted 30.8% (33/107), the moderate stage 61.7% (66/107), and the late stage 7.5% (8/107). There were 32 cases with small PLC (up to 5 cm). Liver cirrhosis was observed in 86.0% (92/107). We designed flat cryoprobes for freezing surface tumors, and single and multiple trocar cryoprobes for freezing tumors deep within the hepatic parenchyma. Intraoperative ultrasound was used for monitoring hepatic cryolesions. There were no operative mortalities and complications, such as rupture of a tumor, delayed bleeding, or bile leakage. The 5-year and 10-year survival rates were 22.0% and 8.2%, respectively, for the 107 PLC patients and 48.8% and 17.1%, respectively, for the 32 patients with small PLC. Of the 6 SLC patients, survival ranged from 2 months to 90 months (average, 23.2 months). One SLC patient has been well for 7 years and 6 months after cryosurgery. These results indicate that cryosurgery, the in situ freezing of cancer, is a safe and effective treatment for unresectable hepatic cancer.Abbreviations PLC primary liver cancer - SLC secondary liver cancer - IOUS intraoperative ultrasound - AFP -fetoprotein Presented in part at the 4th World Congress of Hepato-Pancreato-Biliary Surgery, 7–11 June 1992, Hong Kong     

老年心肌缺血者QTc和QTcd变化及临床意义

测定了６４例老年心肌缺血（ＭＩＳ）患者和２１例心肌梗塞（ＭＩ）患者心电图的ＱＴｃ间期和ＱＴｃ离散度（ＱＴｃｄ），并与心血管神经官能症（ＣＶＮ）及正常老年人进行比较；探讨ＱＴｃ、ＱＴｃｄ与致命性室性心律失常（ＦＶＡ）、心原性猝死（ＣＳＤ）的关系；分析ＭＩ不同部位的ＱＴｃｄ变化以及稳定性心绞痛（ＳＡＰ）和不稳定性心绞痛（ＵＳＡＰ）的ＱＴｃｄ差异。结果：老年女性患者ＱＴｃ较男性长（Ｐ＜０．０５），而ＱＴｃｄ两者无差异；老年ＭＩＳ患者ＱＴｃ和ＱＴｃｄ较正常组明显延长（Ｐ＜０．０１）；ＭＩ前壁、下壁和后壁３组ＱＴｃｄ无明显差异（Ｐ＞０．０５）；ＵＳＡＰ患者ＱＴｃｄ较ＳＡＰ长（Ｐ＜０．０５）。     

Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study.

BACKGROUND & AIMS: Hepatic fibrosis due to chronic HBV infection has enormous socioeconomic impact. Besides strategies targeting virus elimination, prevention or reversal of liver fibrosis is amenable. Given the antifibrotic activity of interferon-gamma (IFN-gamma), a randomized open-labeled multicenter trial was initiated to test IFN-gamma in HBV infection. METHODS: HBsAg-positive patients with biopsy proven hepatic fibrosis (n = 99, stages 2-4, Scheuer criterion) were treated with diammone-glycyrrhizinate and potassium-magnesium aspartate. Sixty-six randomly assigned patients were treated with 50 mug IFN-gamma intramuscularly on a daily basis for 3 months and on alternate days the subsequent 6 months. Efficacy was evaluated by liver biopsy and serologic markers. RESULTS: Fifty-four patients in the IFN-gamma group and 29 patients in the control group completed the study. The hepatic fibrosis score was significantly reduced in 63% of IFN-gamma treated patients compared with 24.1% in the control group by using a semiquantitative scoring system evaluating both liver architecture and fibrotic deposits. Mean values for the total fibrosis score decreased from 13.8 +/- 5.8 to 10.1 +/- 5.1 in the IFN-gamma group (P = .0001), whereas they were unchanged in control subjects (13.2 +/- 6.8 vs 12.6 +/- 4.8, P = .937). The Scheuer system showed 12 out of 54 patients improved >or=1 stage(s) in the IFN-gamma group compared with 1 of 29 in the control group. Antifibrotic activity might be attributed to decreased transforming growth factor-beta signaling via phosphorylated Smad2 and reduced number of activated, alpha-smooth muscle actin positive hepatic stellate cells. CONCLUSIONS: IFN-gamma treatment for 9 months improves fibrosis scores in patients with chronic HBV infection most likely by antagonizing profibrogenic transforming growth factor-beta effects.     

老年肺心病患者吸入一氧化氮后血流动力学与血管调节因子的变化

自的为探讨血管内皮细胞在慢性阻塞性肺疾病（ＣＯＰＤ）肺心病发生发展中的作用，对该病患者血浆内皮细胞释放的舒血管因子──一氧化氮（Ｎｏ）的含量与血管紧张素转换酶（ＡＣＥ）活性进行测定，并观察提供外源性ＮＯ对肺心病晚期患者肺血流动力学的影响。方法采用分光光度法测定９例老年ＣＯＰＤ肺心病晚期患者血浆ＮＯ的含量与ＡＣＥ活性，另有１２例健康老年人作为对照，并应用右心导管技术观察了吸入４０×１０－６ＮＯ２０分钟对晚期肺心病患者肺血流动力学的影响。结果老年肺心病患者血浆ＮＯ含量与ＡＣＥ活性显著降低；吸入ＮＯ后，血浆ＮＯ代谢产物显著增加的同时，肺动脉平均压（ＰＡＰｍ）从４．１±０．７ｋＰａ（１ｋＰａ＝７．５ｍｍＨｇ）降为３．３±０．５ｋＰａ（Ｐ值＜０．０１），肺血管阻力及其指数显著降低，输氧量（ＤＯ２）、心输出量（ＣＯ）增加，右室作功降低。全血谷胱甘肽过氧化物酶（ＧＳＨ－ｐｘ）活力显著降低（３７．３％）。结论老年慢性心病患者血管内皮依赖性舒张因子缺乏，其肺血管内皮可能存在一定的损伤，外源性补充ＮＯ可显著改善肺循环，增加输氧量，而副作用很少，对老年肺心病患者有益     

基质金属蛋白酶在阻塞性肺气肿大鼠模型中的表达及部分细胞因子的水平

目的　观察基质金属蛋白酶 2 (MMP 2 )和MMP 9在阻塞性肺气肿大鼠模型中的表达及白细胞介素 (IL) 1 0和肿瘤坏死因子 (TNF)α的水平。方法　 2 4只雄性Wistar大鼠随机分为 2组 ,每组1 2只 ,阻塞性肺气肿模型组 :将大鼠置于自制有机玻璃染毒箱内进行被动吸烟 (金键牌香烟 ) ,每天 2次 ,每次 1 6支 ,持续 30min ,2次之间间隔 4h ,连续 75d。健康对照组大鼠 2级实验动物房内室温常规饲养。 2组大鼠行第 0 3秒钟用力呼气容积 (FEV0 3)、FEV0 3/用力肺活量 (FVC)、功能残气量 (FRC)的测定。大鼠处死后 ,行支气管肺泡灌洗 ,测支气管肺泡灌洗液 (BALF)中白细胞总数和各分类细胞数、MMP 2和MMP 9的活性及IL 1 0和TNFα的含量。免疫组化法检测支气管、肺组织中MMP 2和MMP 9的表达及其蛋白相对含量。Weigert弹力纤维染色观察弹力纤维的变化。结果　阻塞性肺气肿模型组大鼠支气管黏膜上皮大片脱落 ,管壁及周围大量的单核细胞和淋巴细胞浸润 ;肺泡结构紊乱 ,肺泡壁变薄或断裂 ,肺泡弹性减弱 ,呈囊状扩张 ,肺泡腔扩大 ,部分融合成肺大疱。与健康对照组相比 ,阻塞性肺气肿模型组大鼠FEV0 3[(5 1 2± 0 42 )ml]、(FEV0 3/FVC)× 1 0 0 % [(71 1 5± 9 84) ]显著降低 ,FRC[(7 2 2± 2 1 8)ml]显著增加 (P值均 <