阿托伐他汀对压力负荷心肌肥厚大鼠血管紧张素转换酶2表达的干预研究

目的:探讨血管紧张素转化酶2(angiotensin converting enzyme 2,ACE2)在压力负荷心肌肥厚大鼠中的表达以及阿托伐他汀干预对其的影响.方法:SD大鼠随机分为正常对照组(A组)、正常对照加阿托伐他汀组(B组)、假手术组(C组),其余2组通过不完全结扎大鼠腹主动脉构建心肌肥厚模型,并分为阿托伐他汀干预组(D组)[术前l周起灌胃给予5 mg/(kg·d )阿托伐他汀,直至术后4周]和非药物手术组(E组).术后4周检测大鼠左心室质量指数,组织切片染色后光镜检查,并测心肌细胞平均直径及胶原容积百分比,分别用实时RT-PCR法和Western免疫印迹法测定心肌组织中ACE2 mRNA和蛋白水平的表达.结果:E组左心室质量指数、心肌细胞平均直径及胶原容积百分比较A组、B组及C组均显著增加(P<0.01),并且ACE2 mRNA和蛋白表达显著增加(P<0.01).D组上述指标较E组显著下降(P<0.01).结论:心肌肥厚大鼠ACE2 mRNA和蛋白表达显著增加;阿托伐他汀能够有效地延缓压力负荷诱导的心肌肥厚,并能下调ACE2 mRNA和蛋白表达.     

复方五仁醇胶囊含药血清中木脂素类成分的UPLC-MS/MS分析

目的:分析复方五仁醇胶囊大鼠灌胃后消化吸收进入血液的木脂素类成分,以便与该制剂血清药理学研究相结合,阐明其药效物质基础。方法:采用UPLC-MS/MS方法,比较复方五仁醇胶囊含药血清、体外制剂、空白血清及对照品提取离子流色谱图(EIC),并通过质谱图相关离子峰分析,确认进入血液的木脂素类成分。结果:发现制剂中存在的五味子醇甲、五味子醇乙、五味子酯甲、五味子甲素、五味子乙素5个木脂素类成分进入血液。结论:这5个木脂素类成分很可能是复方五仁醇胶囊体内直接作用物质的重要组成部分,结合血清药理学作进一步研究有助于阐明该制剂药效物质基础。     

Decreased inflammation and augmented expression of trophic factors correlate with MOG-induced neuroprotection of the injured nigrostriatal system in the murine MPTP model of Parkinson's disease

The response of the immune system during injury of the central nervous system may play a role in protecting neurons. We have previously reported that immunization with MOG 35–55 prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced injury of the dopaminergic system promotes less dopamine depletion and less dopaminergic damage of neurons in mice. In this study, we evaluate the influence of MOG immunization on the inflammatory reaction that occurs at the place of injury. C57Bl male mice, 2 and 12 months old, received i.p. injections of MPTP (40 mg/kg) and some groups animals also received an additional injection with myelin oligodendrocyte glycoprotein (MOG) 35–55 in CFA 6 days before MPTP administration. MPTP caused a common inflammatory reaction characterized by microglial activation, infiltration of T cells into the substantia nigra and striatum and increased expression of mRNA encoding pro-inflammatory cytokines (IL-1β, TNFα, INFγ) and trophic factors (TGFβ, GDNF). MOG immunization prior to MPTP administration significantly diminished the microglial reaction and reduced the levels of infiltrating CD8+ lymphocytes. The number of CD4+ T cells remained at the same level as in the MPTP group. Expression of pro-inflammatory cytokines was diminished. The mRNA expression of GDNF was significantly higher in the MOG pretreated mice relative to the MPTP group, both in the 2 month old and 12 month old groups. Since MOG immunization prior to MPTP intoxication appears to prevent nigrostriatal injury, the observed decrease of inflammation and increase of GDNF mRNA expression in the injured areas might represent one of the mechanisms of observed neuroprotection.     

Mimic of manganese superoxide dismutase to induce apoptosis of human non-Hodgkin lymphoma Raji cells through mitochondrial pathways

Increased reactive oxygen species (ROS) such as superoxide have been implicated as causal elements of oncogenesis. A variety of cancers have displayed changes in steady-state levels of key antioxidant enzymes, with the mitochondrial form of superoxide dismutase (MnSOD) being commonly implicated. Increasing MnSOD expression suppresses the malignant phenotype in various cancer cell lines and suppresses tumor formation in xenograft and transgenic mouse models. In this study, we examined the anti-proliferation effect of mimic of manganese superoxide dismutase (MnSODm) on human non-Hodgkin lymphoma Raji cells. The results showed that MnSODm significantly reduced the proliferation of Raji cells in a concentration and a time-dependent manner. By flow cytometric analysis, we found that MnSODm treatment resulted in an increased apoptosis in Raji cells. MnSODm also increased the production of ROS and the expression levels of cleaved caspase-9, caspase-3, poly (ADP-ribose) polymerase (PARP) and Bax in Raji cells. Moreover, the expression of Bcl-2 protein showed down-regulation in the MnSODm treatment group. In addition, MnSODm significantly elevated the level of cytochrome c in cytosol. These findings suggest that the activation of the mitochondrial pathway is involved in MnSODm-induced apoptosis in Raji cells.     

Identification and potential role of PSD-95 in Schwann cells

Postsynaptic density-95 (PSD-95) is one of neuronal nitric oxide synthase (nNOS)-anchoring proteins and plays an important role in specifying the sites of reaction of nitric oxide (NO) in the nervous system. The present study aims to investigate the presence of PSD-95 in rat Schwann cells (SCs) and the association of PSD-95 and nNOS with serum-induced SCs proliferation. The expression of both molecules downregulated significantly after 48 h of serum deprivation, and increased gradually to the peak at 12 h, ultimately returned to the control level at 48 h after serum stimulation. The association of PSD-95 with nNOS was observed in Ki67 and BrdU-positive SCs. The selective nNOS inhibitor arrested the cell cycle progress and decreased the proliferating cell nuclear antigen (PCNA) levels. These findings suggested that PSD-95 and nNOS may collectively participate in the proliferation of SCs, providing further evidence for the role of NO during peripheral nerve regeneration.     

Systemic treatment of patients with gastrointestinal stromal tumor: Current status and future opportunities

Imatinib mesylate is considered the standard first-line systemic treatment for patients with advanced gastrointestinal stromal tumor (GIST). Results from recent research have expanded the knowledge of tyrosine kinase inhibitors in management of GIST. In the setting of unresectable and metastatic GIST, long-term follow-up of the B2222 study showed that imatinib 400 and 600 mg/d produced objective responses in 68% of patients and clinical benefit in 84%; it also extended median survival from 19 months in historical controls to 57 months. The MetaGIST analysis in two large phase 3 trials consisting of more than 1600 patients with metastatic and/or unresectable GIST showed that imatinib 800 mg/d compared with the standard 400-mg/d dose conferred a progression-free survival advantage in patients with KIT exon 9 mutations but not in other subpopulations. The higher starting dose does not significantly improve overall survival. The BFR14 trial demonstrated that interrupting imatinib is associated with a high risk of rapid disease progression. For patients with imatinib-intolerant or imatinib-resistant GIST, sunitinib or a variety of investigational agents, including the next-generation kinase inhibitor nilotinib, may be viable options for achieving disease control. In the setting of primary localized GIST, function- sparing surgical resection is the standard treatment approach, but some patients may be at substantial risk of disease recurrence and metastasis depending on tumor size, mitotic count, and possibly other factors. Initial results from ACOSOG Z9001 indicate that adjuvant imatinib for 1 year prolongs recurrence-free survival following surgical resection of larger (at least 3 cm) KIT-expressing GIST. Other ongoing studies are further exploring the role of imatinib in both adjuvant and neoadjuvant therapy. Recent updates to clinical practice guidelines and recommendations now incorporate some of these new findings.     

The association between Parkinson’s disease and Sexual dysfunction: Clinical correlation and therapeutic implications

Sexual function which comprises of desire, arousal, orgasm and satisfaction and pain, involves coordinated physiologic responses from multiple different pathways. Sexual dysfunction (SD) occurs when these domains of the sexual response cycle are affected. SD is a common but under-recognized non-motor feature in Parkinson’s disease (PD), a common age-related neurodegenerative disorder. SD significantly affects the quality of life of PD patients and their partners. Advanced age, gender, hormone deficiency, neuropsychiatric and medical comorbidities contribute to SD in PD. Possible potential pathological mechanisms include vasculogenic, endocrinologic, neurogenic and psychogenic factors. Various therapeutic interventions, both pharmacological and non-pharmacological modalities have been suggested to improve SD in PD. However, erectile dysfunction (ED) is the only SD with evidence-based treatment available. Non-pharmacological therapies are also offering promising evidence in the improvement of SD. A multidisciplinary approach in the assessment, investigation, and treatment is needed to address the real life complex issues (gender and comorbidities, neurobiological, vasoactive, hormonal as well as psychosocial aspects). Future clinical studies with validated and standardized methods in assessing SD as well as experimental models will be necessary for better insight into the pathophysiology. This would facilitate appropriate therapy and improve sexual rehabilitation in PD patients.     

Mn(ii)-Catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases

A Mn(ii)-catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases were developed. The use of MnCl₂ was critical for the ortho-alkenylation of aromatic amines. The general applicability of this procedure was highlighted by the synthesis of 27 vinylanilines, with good regioselectivities. The value of our approach in practical applications was investigated by studying the effects of one of the compounds 3m on 8 week-old adult male rats with azoospermia as a mammalian model. The results show that a small amount of sperm will gradually be produced in the epididymis and testes by treatment of 8 week-old adult male rats with azoospermia with 1 mg kg⁻¹3m after two weeks, while treatment with 10 mg kg⁻¹3m led to obvious sperm production. Notably, if we increase the dose to 100 mg kg⁻¹, there will be a lot of sperm production in the epididymis and testes after two weeks of treatment. The results of this study will be of great significance in research on drugs for treating azoospermia and oligospermia diseases.

A Mn(ii)-catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases were developed.

Alkenyl arylamines are very important intermediates for the synthesis of drug molecules, such as carbamazepine,¹ opipramol,² and indopan³ (Scheme 1). O-Alkenyl arylamines have attracted much attention because of their widespread presence in a variety of heterocycles including indoles, quinolines and cinnolines, which are key structural units for many biologically important compounds.⁴ Moreover, they have also been used as synthetic intermediates in several total synthetic methods.⁵ Therefore, it is of great significance to carry out the ortho-alkenylation reaction of aromatic amines. But it is not an easily accessible process under normal Friedel–Crafts conditions due to the coordination of the Lewis acid with the nitrogen atom of amino group, which leads to the deactivation of the aromatic ring.⁶ To overcome this challenge, chemists began to try other methods to achieve ortho-alkenylation of aromatic amines. Subsequently, several related ortho-alkenylation of aromatic amines with phenylacetylene was reported in the literature.^4a,7 However, the ortho-alkenylation of aromatic amines catalyzed by base metals has not yet been developed, especially manganese. Therefore, it is still very important to develop a Mn-catalyzed ortho-alkenylation reaction of aromatic amines. Notably, there have been more C–H bond functionalization reactions catalyzed by monovalent manganese in recent years, but few of them were catalyzed by divalent manganese.⁸ Ackermann''s research group reported several Mn(ii)-catalyzed ortho-functionalization reactions of arylamides.⁹ In addition, a Mn(ii)-catalysed dehydrogenative annulation of N-aryl anilines with alkenes or alkynes was reported by our group last year.¹⁰Open in a separate windowScheme 1Drug molecules containing alkenyl arylamine skeleton.Herein, we report an example of Mn(ii)-catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases (Scheme 2). In our previous work, divalent manganese is easily oxidized to tetravalent manganese by K₂S₂O₈.¹⁰ This work, we hypothesis the ortho-alkenylation product of aromatic amine will be generated after the oxidant was removed in the system. Based on this hypothesis, we tried a series of manganese catalysts.Open in a separate windowScheme 2Proposed strategy.We began by treating N-benzylaniline and phenylacetylene with toluene as a solvent. Initially, we attempted using various Mn(ii) catalysts to catalyse the ortho-alkenylation of aromatic amines at 120 °C, i.e., MnO, MnSO₄, Mn(OAc)₂, and Mn(acac)₂, as detected by GC analysis, while 73% and 61% yields were observed when MnBr₂ and MnI₂ were used as catalysts (Table 1, entries 1–7). Fortunately, a 80% yield of N-benzyl-2-(1-phenylvinyl)aniline was obtained when using MnCl₂. To improve the reaction efficiency, different solvents, including N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile (CH₃CN), 1,4-dioxane, tetrahydrofuran (THF), 1,2-dichloroethane (DCE), p-xylene, mesitylene and n-hexane were tested (Table 1, entries 8–16). The optimal reaction solvent was found to be toluene. To increase conversion to the N-benzyl-2-(1-phenylvinyl) aniline, we examined a wide range of reaction temperatures (Table 1, entries 17–22). The results show that 120 °C was the optimum temperature, and the corresponding N-benzyl-2-(1-phenylvinyl)aniline was obtained the best yield. It is worth noting that more cyclization products were formed when the temperature is raised to 130 °C. Therefore, temperature is another key factor that drives the reaction forward. Notably, the addition of oxidant will terminate this reaction (see the ESI Table 1^† for details). These results therefore support our initial hypothesis that the ortho-alkenylation product of aromatic amine will be generated after the oxidant was removed.Effects of catalyst, temperature, and solvent. N-Benzylaniline (0.2 mmol), phenylacetylene (0.4 mmol), catalyst (0.04 mmol), solvent (2.0 mL), at 120 °C for 24 h