人参皂苷Rg3立体异构体差异抑制糖尿病调控基因蛋白-PXR机制的分子动力学研究

目的：为进一步了解Rg3对映体的立体化学选择性,对PXR配体结合结构域（PXR ligand-binding domain,PXR-LBD）中20（R/S）-Rg3的结合模式进行建模。方法：使用计算对接,分子动力学（molecular dynamics,MD）和基本动力学分析（essential dynamics analysis,EDA）等技术手段进行建模。结果：PXR中20（S）-Rg3的MM / PB-SA估计结合能大于20（R）-Rg3。两种配合物的RMSFs表明,20（S）-Rg3结合的LBD的迁移率比20（R）型对映体的迁移率降低得多。EDA预测和两个复合物的叠加三维结构都表明20（S）-Rg3在PXR中的结合比20（R）-Rg3更可能与生物学结果一致。结论：以上结果表明,基于目前的模拟结果,PXR中20（S）-Rg3的结合模式比20（R）-Rg3更有可能与生物实验结果吻合。     

细胞色素P450 3A4表达调控机制的研究进展

细胞色素P450 3A4(CYP3A4)的表达具有很强的个体间特异性,会引起复杂的药物相互作用。故明确CYP3A4的表达调控机制,对于指导临床合理用药意义重大。本文从转录前、转录后、翻译后修饰3个阶段对CYP3A4的调控机制进行综述。     

Microbe-metabolite-host axis,two-way action in the pathogenesis and treatment of human autoimmunity

The role of microorganism in human diseases cannot be ignored. These microorganisms have evolved together with humans and worked together with body's mechanism to maintain immune and metabolic function. Emerging evidence shows that gut microbe and their metabolites open up new doors for the study of human response mechanism. The complexity and interdependence of these microbe-metabolite-host interactions are rapidly being elucidated. There are various changes of microbial levels in models or in patients of various autoimmune diseases (AIDs). In addition, the relevant metabolites involved in mechanism mainly include short-chain fatty acids (SCFAs), bile acids (BAs), and polysaccharide A (PSA). Meanwhile, the interaction between microbes and host genes is also a factor that must be considered. It has been demonstrated that human microbes are involved in the development of a variety of AIDs, including organ-specific AIDs and systemic AIDs. At the same time, microbes or related products can be used to remodel body's response to alleviate or cure diseases. This review summarizes the latest research of microbes and their related metabolites in AIDs. More importantly, it highlights novel and potential therapeutics, including fecal microbial transplantation, probiotics, prebiotics, and synbiotics. Nonetheless, exact mechanisms still remain elusive, and future research will focus on finding a specific strain that can act as a biomarker of an autoimmune disease.     

Amino acid metabolism as drug target in autoimmune diseases

In mammals, amino acid metabolism has evolved to control immune responses. Autoimmune diseases are heterogeneous conditions that involve the breakdown of tolerogenic circuitries and consequent activation of autoreactive immune cells. Therefore, critical enzymes along amino acid degradative pathways may be hijacked to keep in check autoimmunity. We examined here current knowledge of indoleamine 2,3-dioxygenase 1 (IDO1) and arginase 1 (ARG1), the main enzymes catabolizing tryptophan and arginine, respectively, in organ-specific and systemic autoimmune diseases as well as in the development of autoantibodies to therapeutic proteins. At variance with neoplastic contexts, in which it is known to act as a pure immunosuppressive molecule, ARG1 exhibited a protective or pathogenetic profile, depending on the disease. In contrast, in several autoimmune conditions, the bulk of data indicated that drugs capable of potentiating IDO1 expression and activity may represent valuable therapeutic tools and that IDO1-based immunotherapeutic protocols could be more effective if tailored to the genetic profile of individual patients.     

Meta‐analysis of massively parallel reporter assays enables prediction of regulatory function across cell types

Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data‐driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta‐analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell‐type‐specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation “Regulation Saturation” Challenge for predicting effects of single‐nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest.     

Effect of Hypoxia on the Muscle Fiber Switching Signal Pathways CnA/NFATc1 and Myostatin in Mouse Myocytes

This study investigated the effects of a CoCl₂-simulated hypoxic environment on the muscle fiber switching signaling pathways calcineurin A/nuclear factor of activated T cells cytoplasmic 1 (CnA/NFATc1) and myostatin. In this study, C2C12 muscle cells were cultured in vitro under CoCl₂-simulated chemical hypoxic conditions, the expression levels of CnA and myostatin were detected through qRT-PCR and Western blot analyses, and a positioning study of NFATc1 was carried out by immunofluorescence labeling. Results showed that CoCl₂ treatment significantly increased the expression levels of CnA and myostatin. Moreover, the position of NFATc1 expression changed; actually, its expression in the nucleus considerably increased. Furthermore, CoCl₂-induced hypoxia inhibited the differentiation of C2C12 cells and reduced the expression levels of many slow- and fast-twitch muscles marker genes, but immunofluorescence staining results showed that the proportion of MyHC I type muscle fiber increased after CoCl₂ treatment. The hypoxic environment simulated by CoCl₂ can activate the signaling pathways CnA/NFATc1 and myostatin and increases the proportion of MyHC I type muscle fibers.     

Emotional interference under low versus high executive control

Previous research has demonstrated that task‐irrelevant emotional distractors interfere with task performance especially under low phasic executive control (i.e., in nonconflict trials). In the present study, we measured medio‐frontal ERPs (N2 and correct‐related negativity, CRN) to elucidate which aspects of task performance are affected by emotional interference in a flanker task. To create emotional interference, negative and neutral pictures were presented during the flanker stimuli. N2 and CRN were reduced after negative pictures, indicating that conflict processing and performance monitoring are both affected by emotional interference. On the behavioral level, prolonged response times after negative pictures were observed under low phasic executive control (i.e., in compatible trials). Additionally, we explored whether emotional interference is modulated not only by phasic changes in executive control (i.e., conflict vs. nonconflict trials) but also by tonic changes in executive control (i.e., low vs. high overall conflict frequency). To this end, the flanker task consisted of two blocks with 25% versus 75% incompatible trials. Prolonged response times after negative pictures in compatible trials were observed only under low tonic executive control but not under high executive control.     

Immunoregulatory role of acid sphingomyelinase in allergic asthma

Acid sphingomyelinase (ASM) is one of the enzymes that catalyzes the breakdown of sphingomyelin to ceramide and phosphorylcholine. In this study, we aimed at elucidating the role of ASM in allergic asthma. We used an ovalbumin-induced murine model of asthma where we compared wild-type and ASM-deficient mice. In wild-type mice, secretory ASM activity in the bronchoalveolar lavage fluid was increased in the acute ovalbumin model, but not in a tolerogenic model. Furthermore, in the absence of ASM, the serum IgE level was reduced, compared with wild-type mice, while an accumulation of interstitial macrophages and foreign antigen-induced regulatory T cells along with exhausted CD4⁺ PD1⁺ T cells was observed in the lungs of ASM^−/− mice. In conclusion, in the absence of ASM, we observed an accumulation of immunosuppressive antigen-induced regulatory T cells expressing Foxp3 and CTLA4 in the lung as well as multinucleated interstitial macrophages and exhausted CD4⁺ PD1⁺ T cells associated with inhibition of serum IgE in asthma.