Huogu I formula prevents steroid-induced osteonecrosis in rats by down-regulating PPARγ expression and activating Wnt/LRP5/β-catenin signaling

Objective

To investigate the effects of Huogu I formula on regulation of lipid metabolism in steroid-induced osteonecrosis of the femoral head (SONFH) rats and verify our hypothesis that Huogu I formula regulates lipid metabolism by down-regulating peroxisome proliferator-activated receptor gamma (PPARγ) expression and activating Wnt signaling pathways.

Methods

Eighty-five rats were divided into four groups: control, model, Huogu 15 g/kg and Huogu 30 g/kg. Six weeks later, animals were anaesthetized, femora were dissected for histopathological examination of the osteonecrotic changes and repair processes, micro computed tomography (Micro-CT)-based micro-angiography was performed to assess vascularization. Serum lipid levels were detected by haematological examination. The expressions of PPARγ, Wnt3a, low density lipoprotein receptor-related protein 5 (LRP5) and β-catenin were evaluated by immunohistochemistry, Western blot and quantitative real-time polymerase chain reaction analyses.

Results

The incidence of osteonecrosis, ratio of empty lacuna, adipose tissue area and adipocyte perimeter in the bone marrow were dramatically lower in the Huogu I formula treatment groups. By micro-CT quantification, Huogu I formula treatment dose-dependently increased vessel volume, vessel surface, percentage of vessel volume and vessel thickness of the femoral heads of SONFH rats. Levels of serum lipid in Huogu 15 g/kg and Huogu 30 g/kg groups reduced significantly. Huogu I formula treatment could suppress the expression of PPARγ and increase the expressions of Wnt3a, LRP5 and β-catenin at both protein and mRNA levels.

Conclusion

The results of our present study highlight the lipid-lowering potential of Huogu I formula, and provide further evidence of the involvement of the PPARγ inhibition and Wnt/LRP5/β-catenin signaling activation in the effects of Huogu I formula.     

Effects of total lignans from Eucommia ulmoides barks prevent bone loss in vivo and in vitro

Ethnopharmacological relevance

The present study systematically investigate the in vivo and in vitro effect of total lignans (TL) extracted from Eucommia ulmoides Oliv. barks on bone formation using ovariectomy rat model and primary cultures of rat osteoblasts.

Materials and methods

Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (SHAM) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17α-ethinylestradiol (E₂, 25 μg/kg/day); OVX with TL of graded doses (20, 40, or 80 mg/kg/day). The treatment began 4 weeks after the surgery and lasted for 16 weeks. in vitro experiments were performed to determine the potential mechanisms of the anti-osteoporotic effect of TL.

Results

Treatment with TL significantly prevent OVX-induced decrease in biomechanical quality of femur such as maximum stress and Young?s modulus. The mechanical changes were associated with the prevention of a further BMD decrease or even with some improvements in microarchitecture. TL inhibited BMD decrease in the femur caused by OVX, which was accompanied by a significant decrease in skeletal remodeling, as was evidenced by the decreased levels of the bone turnover markers. μCT analysis of the femoral metaphysis showed how to prevent the deterioration of trabecular microarchitecture. TL induced primary osteoblastic cell proliferation and differentiation, inhibition of osteoclastogenesis through an increase in osteoprotegrin (OPG) and a decrease in NF-κB ligand (RANKL) expression in vitro.

Conclusions

We concluded that TL treatment can effectively suppress the loss of bone mass induced by OVX and in vitro evidence suggests this could be through actions on both osteoblasts and osteoclasts.     

Hygrocins a and B, naphthoquinone macrolides from Streptomyces hygroscopicus

Two new naphthoquinone macrolides, hygrocins A (1) and B (2), were isolated from the fermentation broth of Streptomyces hygroscopicus. Hygrocin A is not stable due to the presence of an active methylene group (C-22), which undergoes intramolecular aldol condensation with the quinone ring to yield a gamma-lactam derivative, 6. Its structural elucidation was achieved by chemical conversion to 3, an unusual diazomethane derivative, and confirmed by its alkaline hydrolysis product 4, hydrogenation derivative 5, and "degradation" product 6. The structure of hygrocin B was determined by combined chemical and spectroscopic methods.     

痛风性关节炎急性发作的中西医结合治疗研究

目的研究以化痰解郁通淋汤为主的中西医结合方法治疗急性痛风性关节炎的临床疗效和安全性。方法 133例急性痛风性关节炎患者,随机分为中西医结合组(治疗组)72例和对照组61例,两组均予以低嘌呤饮食、多饮水、禁酒、禁用利尿剂,并予碳酸氢钠及醋酸泼尼松治疗。对照组予秋水仙碱。治疗组用中药化痰解郁通淋汤,中药口服1日1剂,每周5剂,休息2日;共观察2周。治疗前后分别比较患者的临床症状与体征的变化,并取血清样本,测定血尿酸(SUA)、白细胞(WBC)总数及超敏C反应蛋白(hs-CRP)、血肌酐(SCr)、血尿素氮(BUN)、丙氨酸氨基转移酶(ALT)等实验室指标。结果治疗组总有效率为87.5%(63/72),对照组为81.9%(50/61),治疗组疗效优于对照组(P<0.05)。(2)两组治疗前后中医症状体征积分比较差异有统计学意义(P<0.05),且治疗组优于对照组(P<0.01)。(3)治疗后治疗组SUA、TWBC及hs-CRP等指标均明显改善。两组SUA水平均显著降低(P<0.01),且治疗组优于对照组(P<0.01);(4)在药物安全性方面,治疗组1例、对照组2例出现食欲减退、上腹部饱胀不适、恶心、呕吐,肝功能示谷丙转氨酶轻度升高,发热、皮疹等不良反应,经过对症处理后不良反应减轻,均能坚持服药。两组不良反应比较差异无统计学意义(P>0.05)。结论化痰解郁通淋汤结合常规西药治疗急性痛风性关节炎有较好的疗效和安全性。     

Flavonoids from Millettia nitida var. hirsutissima with their anticoagulative activities and inhibitory effects on NO production

Two new compounds, (2R)-7,3′-dihydroxy-6,4′-methoxyflavan (1) and (3R)-7,4′-dihydroxy-2′-methoxyisoflavan (2), along with 12 known flavonoids (3–14), were isolated from the vine stems of Millettia nitida var. hirsutissima. The structures of the isolated compounds were elucidated based on spectroscopic analyses and comparison of literature data. All of the isolates were evaluated for their effects on in-vitro anticoagulative assay and on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophages. As a result, all compounds showed weak antiplatelet aggregation activities and compounds 4, 5, 7, 8 and 9 demonstrated antithrombin activity with a good dose–effect relationship from 5 to 100 μg mL^?1 in rabbit plasma. Compounds 8, 9, 10 and 14 exhibited inhibitory effects on LPS-induced NO production in RAW264.7 macrophages with IC₅₀ values of 4.79 ± 0.20, 8.23 ± 0.35, 5.23 ± 0.11 and 6.30 ± 0.30 μg mL^?1, respectively.     

重庆市4所高校医院抗菌药物使用情况分析

目的为抗菌药物临床应用管理提供参考。方法调取4所高校校医院在卫生部抗菌药物临床应用专项整治活动通知发布前后1年内所有门诊处方,对比抗菌药物使用变化情况。结果抗菌药物购用品种较多,使用率较高,存在滥用现象。通知发布前后,抗菌药物使用情况无明显变化。结论基层医院是一个庞大的群体,抗菌药物合理使用状况不容乐观,滥用现象不容忽视,应加强管理。     

Pharmacometrics of nutraceutical sulforaphane and its implications in prostate cancer prevention

Sulforaphane (SFN), found in broccoli and other cruciferous vegetables, has a beneficial effect in chemoprevention of prostate cancer, whose incidence and associated mortality have gradually increased worldwide. There is great enthusiasm for bench-to-bedside development of SFN as a potent chemopreventive agent, possibly alone or as an adjunct to existing chemotherapyregimens, in the oncology care setting to reduce toxicity of chemotherapeutics and potentially enhance their cancer cell-kill efficacy. In this review, we appreciate existing knowledge on SFN using a pharmacometrics approach, which is fast becoming a gold standard in discovery research and validation of New Chemical Entities and New Biological Entities in pharmaceutical industry.We discuss the epistemology of SFN target engagement and quantitative systems pharmacology with due emphasis on mechanistic pharmacology, pharmacodynamics, pharmacogenomics and metabolism of SFN. In addition, we explore the quantitative freeway to SFN translational medicine by assessing the preclinical and clinical PK/metabolism aspects of SFN that form the cornerstone of SFN pharmacometric evaluation, as well as the promise of SFN in prostate cancer. Taken together, we share perspectives on the exciting developments in translational cancer chemoprevention, with emphasis on the pharmacometric aspects, of the nutraceuticalSFN which is currently in clinical trials, and suggest that the pharmacometric approach holds great promise in the SFN translational pharmacology paradigm for prostate cancer.     

Pharmaceutical Technology Licensing: An Analysis in the Field of Cardiovascular Disease

The technological flows and licensing across institutions plays an essential role in the process of pharmaceutical innovation by integrating the competing resources of different institutions and sharing the costs and risks, especially in the current era of open innovation. This article aims to generally describe technology licensing activities on cardiovascular drugs and, based on visualizing technology flows at different stages, to further investigate the multistage leading performers and their licensing strategies. From the IMS R&D Focus, a world-leading database in the healthcare industry, the research sample comprises 632 licensing inventions for cardiovascular drugs from 1980 to 2014. Furthermore, a network-based approach is employed to visualize the technology flows by setting nodes to represent licensing institutions and edges for licensing behavior, and further to analyze institution leaders and licensing strategies through various indicators, e.g., out-degree, in-degree, and betweenness centrality. The results show that technology licensing networks gradually transformed from sparse to dense from the preclinical to marketed stages. There is obvious synergy and complementation among universities, multinational enterprises, and mid- and small-sized enterprises. R&D organizations represented by universities denote themselves as upstream in the pharmaceutical R&D chain. As a hub, multinational enterprises play an important role as technology integrators and show the most frequent technology licensing, both in technology inflows and outflows, whereas various small firms are viewed as satellite partners around multinational enterprises. This work provides valuable insights for pharmaceutical researchers, investors, policymakers, and technology brokers not only in the field of the discovery of cardiovascular drugs but also of other therapeutic drugs.     

Practical considerations for the use of sodium–glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes

Sodium–glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term.