药用昆虫蜣螂对灵芝发酵产物体外抗肿瘤活性的影响

采用体外高通量筛选技术检测了补加药用昆虫蜣螂前后灵芝发酵产物的体外抗肿瘤活性。结果表明,补加和不补加蜣螂发酵后所得的胞内和胞外三萜样品对肉瘤细胞L290、肠癌细胞SW620、血癌细胞K562和肝癌细胞BEL7402都有显著的抑制作用(P<0.05)。在补加蜣螂发酵后,灵芝胞内三萜的抑制作用没有得到增强;但胞外三萜样品对BEL7402细胞的抑制作用得到了增强,补加和不补加蜣螂发酵后所得胞外三萜的抑制率分别为41.74%和32.37%(P<0.05)。由于补加蜣螂发酵后,新生成了胞外三萜lucidone C,因而对lucidone C的抗BEL7402肝癌活性进行了试验。结果显示,lucidone C在100μg/mL时,对BEL7402的抑制率为50.37%,提示lucidone C可能增强了补加蜣螂后灵芝胞外总三萜对BEL7402细胞的抑制作用。     

Targeting AMPA receptor gating processes with allosteric modulators and mutations

Allosteric modulators and mutations that slow AMPAR desensitization have additional effects on deactivation and agonist potency. We investigated whether these are independent actions or the natural consequence of slowing desensitization. Effects of cyclothiazide (CTZ), trichlormethiazide (TCM), and CX614 were compared at wild-type GluR1 and “nondesensitizing” GluR1-L497Y mutant receptors by patch-clamp recording with ultrafast perfusion. CTZ, TCM, or L/Y mutation all essentially blocked GluR1 desensitization; however, the effects of L/Y mutation on deactivation and glutamate EC50 were three to five times greater than for modulators. CTZ and TCM further slowed desensitization of L/Y mutant receptors but paradoxically accelerated deactivation and increased agonist EC50. Results indicate that CTZ and TCM target deactivation and agonist potency independently of desensitization, most likely by modifying agonist dissociation (k_off). Conversely, CX614 slowed desensitization and deactivation without affecting EC50 in both wild-type and L/Y receptors. The S750Q or combined L497Y-S750Q mutations abolished all CTZ and TCM actions without disrupting CX614 activity. Notably, the S/Q mutation also restored L/Y deactivation and EC50 to wild-type levels without restoring desensitization, further demonstrating that desensitization can be modulated independently of deactivation and EC50 by mutagenesis and possibly by allosteric modulators.     

Molecular dynamics analysis of potent inhibitors of M2 proton channel against H1N1 swine influenza virus

The recent H1N1 (swine) influenza pandemic highlighted the urgent need of having effective anti‐viral strategies. In addition to neuraminidase inhibitors, there is another class of anti-viral drug known as M2 inhibitors that were, in the past, effective in treating seasonal influenza. However, due to the emergence of M2 inhibitor‐resistant influenza viruses, this class of drugs was not recommended for clinical usage in the latest influenza pandemic. In order to identify novel M2 inhibitors, we have performed molecular docking using a traditional Chinese medicine database (http://tcm.cmu.edu.tw/index.php). Docking and subsequent de novo designs gave 10 derivatives that have much better docking results than the control. Of these 10 derivatives, the top three, methyl isoferulate_1, genipin_1 and genipin_2, were selected for molecular dynamics simulation. During the simulation run, the top three derivatives all had stable interactions with M2 residues, Ser31 and Ala30. Methyl isoferulate_1 also has stable interaction to His37. Therefore, we recommend these three derivatives for further biomolecular experiments and clinical studies.     

Discovery of novel insomnia leads from screening traditional Chinese medicine database

Insomnia is a prominent modern disease that affects an increasing population. Undesirable side effects of commercial drugs highlight the need to develop novel insomnia drugs. Virtual screening of traditional chinese medicine Database@Taiwan (TCM Database@Taiwan) identified 2-O-Caffeoyl tartaric acid (1), 2-O-Feruloyl tartaric acid (2), and Mumefural (3) as potential agonists for both gamma-amino butyric acid (GABA) or benzodiazepine (BZ) binding sites. The TCM candidates exhibited higher affinity than GABA and Zolpidem, a phenomenon that could be attributed to higher quantity of stabilizing H-bonds. Efficacy profiles using support vector machines and pharmacophore contour also suggest drug potential of the TCM candidates. Fragments added to the de novo derivatives 3a, 3b, 3c for GABA binding site, and 1a, 2a, and 3d for BZ binding site contributed to new binding sites and structural stability, further optimizing binding to GABA or BZ binding sites. Increased opening of the ion channel by candidate ligands provide strong support for their potential biological functions. The dual binding properties of the TCM candidates present a unique opportunity to develop twin-targeting drugs with less side effects. Derivative structures can be used as starting points for developing high affinity GABA_A receptor agonists with specificity towards GABA binding site and BZ binding site.     

Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR–ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.     

中药通过调节小胶质细胞激活改善缺血性脑卒中

炎症反应是造成脑卒中继发性脑损伤的关键因素之一。小胶质细胞作为脑内免疫细胞,在脑卒中的炎症反应具有重要作用。传统观念认为小胶质细胞促进炎症反应加重脑损伤。近年来的研究发现激活的小胶质细胞还能产生抗炎作用来加速脑损伤修复。因此,目前的研究将小胶质细胞分为促炎的M1型和抗炎的M2型。结合目前缺血性脑卒中的神经保护剂相对较少,靶向调控小胶质细胞的极化可能成为脑卒中新的治疗策略。研究发现中药能够通过抑制M1型小胶质细胞,并促进M2型的小胶质细胞来改善缺血性脑损伤,从而展现出对缺血性脑卒中的治疗潜力。本文综述了中药通过调节小胶质细胞极化表型来治疗脑卒中的相关研究,以期为缺血性脑卒中药物开发提供新的思路。     

Traditional Chinese medicine as targeted treatment for epithelial-mesenchymal transition-induced cancer progression

The epithelial-mesenchymal transition (EMT) program, which loosens cell-cell adhesion complexes, endows cells with enhanced migratory and invasive properties. Furthermore, this process facilitates both the development of drug resistance and immunosuppression by tumor cells, which preclude the successful treatment of cancer. Recent research has demonstrated that many signaling pathways are involved in EMT progression. In addition, cancer stem cells (CSCs), vasculogenic mimicry (VM) and the tumor-related immune microenvironment all play important roles in tumor formation. However, there are few reports on the relationships between EMT and these factors. In addition, in recent years, traditional Chinese medicine (TCM) has developed a unique system for treating cancer. In this review, we summarize the crucial signaling pathways associated with the EMT process in cancer patients and discuss the interconnections between EMT and other molecular factors (such as CSCs, VM, and the tumor-related immune microenvironment). We attempt to identify common regulators that might be potential therapeutic targets to thereby optimize tumor treatment. In addition, we outline recent research on TCM approaches that target EMT and thereby provide a foundation for further research on the exact mechanisms by which TCMs affect EMT in cancer.     

中医心理疗法辅助中药治疗斑秃的研究

斑秃患者由于沉重的心理压力和负担,对于本病的恢复具有重要负面影响,与躯体症状形成交互的恶性循环,因此,加强患者的心理调适对于本病的治疗具有重要意义。中医在心理治疗方面有着丰富的经验,中医临床采用的心理治疗方法可概括为：转移注意、劝说开导、暗示开疑、顺情从欲等方法。笔者几年来采用中医心理疗法辅助中药治疗斑秃取得了较好的疗效,在这里与各位同仁共同探讨。     

Pathways through the Border of Biomedicine and Traditional Chinese Medicine: A Meeting of Medical Systems in a Japanese Psychiatry Department

This article examines a meetingof biomedicine and Traditional Chinese Medicine(TCM) in the context of a psychiatry departmentin a Japanese national medical school. Themeeting is explored through stories of fourindividuals, the professor of the departmentand three Chinese physicians studying asexchange students. Global structures of medicalauthority are revealed in the way eachparticipant follows a different trajectorythrough this space, positioning themselves byvirtue of the medical epistemologies theyembody. The particular geography of thismeeting between systems allowed for aproductive synthesis of diagnostic techniques,quite different from the more commontherapeutic syntheses. This synthesis isparticularly important for contemporarypsychiatry because of its ability to attend todimensional as opposed to categorical aspectsof mental health.     

A Kantian Stance on the Intentional Stance

I examine the way in which Daniel Dennett (1987, 1995) uses his 'intentional'and 'design' stances to make the claim that intentionality is derived fromdesign. I suggest that Dennett is best understood as attempting to supplyan objective, nonintentional, naturalistic rationale for our use of intentionalconcepts. However, I demonstrate that his overall picture presupposesprior application of the intentional stance in a preconditional, ineliminable,'sense-giving' role. Construed as such, Dennett's account is almostidentical to the account of biological teleology offered by Kant in TheCritique of Judgement, with the consequence that Dennett's naturalism isuntenable. My conclusions lead to doubts concerning the legitimacy of anyaccount attempting to naturalise intentionality by extracting normativityfrom biology and also point to a novel account of biological function.