This study aimed to explore changes of gut microbiota in experimental model rats with psychological suboptimal health state (PSHS). The experimental rats were given a variety of stresses, including orphaned, uncertain empty bottle stress, circadian disorder and other stresses to simulate PSHS caused by various stress events in human life. Open field test, elevated cross maze, blood biochemical indexes and other auxiliary models were used to evaluate the experimental animal model. Changes of gut microbiota were studied by 16S rRNA gene high-throughput sequencing. All experimental protocols were approved by the Animal Ethics Committee of the Biomedical Research Laboratory of Shanxi University. Compared with the control group, the body weight of PSHS group gained slowly (P < 0.01). In addition, the numbers of crossings and rearings in the open field test, and the percentage of time and entries in the open arms, were significantly reduced compared to the control group (P < 0.05). But there were no significant change in the percentage of sucrose preference, blood biochemical, blood routine examination and so on. Gut microbiota analyses showed that the diversity of gut microbiota in PSHS model rats changed, and the relative abundances of 10 species of gut microbiota changed significantly (P < 0.05, P < 0.01), including Bacilli, Lactobacillales, Lactobacillaceae, Lactobacillus, Clostridia, Clostridiales, Blautia, Coriobacteriales, Coriobacteriaceae, and Adlercreutzia. To some extent, the established PSHS model rats reflect the state of humans with PSHS. By studying the changes of gut microbiota in the animal model with PSHS, this study provided an important reference for explaining the physiological change due to PSHS and formulating relevant measures of intervention.

Transforming growth factor-β (TGF-β) belongs to a group of biologically active cytokines that bind to its receptors to activate Smad signaling and non-Smad signaling pathways. The biological functions of TGF-β include promoting cell epithelial-mesenchymal transition, tissue fibrosis, angiogenesis and tumor immune evasion, as well as dual effects of cancer suppression and cancer promotion. Given the fact that the ligand-and receptors-mediated abnormal activation of TGF-β signaling pathways play an important role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis, more than a dozen small-molecule inhibitors have been developed to block the TGF-β signaling pathways, providing a novel method for controlling the development of these diseases. At present, pirfenidone, an inhibitor for TGF-β production, has been approved for treatment of idiopathic pulmonary fibrosis, while the inhibitors of TGFβRI/ALK5 for therapeutics of tumors or myelodysplastic syndromes, including LY2157299, EW-7197 and LY3200882, are in the phase Ⅰ to Ⅲ clinical trials, with additional ones inhibiting TGFβRs such as SB-431542, LY2109761, TP-0427736, and IN-1130 being in the preclinical phase. This paper reviews recent advances in research of small-molecule inhibitors targeting TGF-β and its receptors.

Using CBBR as the parent core constructed in our lab, we designed and synthesized 15 novel compounds with diverse structures for evaluation of anti-bacterial activities. Structure activity relationship studies revealed that ① ring C was essential for the activity; ② 7, 8-or 8, 13-disubstituted CBBR derivatives showed ideal activities, weaker or similar to those corresponding to 7-, 8-, or 13-monosubstituted CBBR derivatives. Among those, compound 9a showed the most potential activity against MRSA/VISA isolates with MIC values of 1-2 μg·mL^-1, much better than Lev. 9a also displayed higher stability in the plasma and liver microsomes. Molecular docking indicated that 9a might target bacterial DNA Topo Ⅳ ParE subunit, indicating a mode of action distinct from current antibacterial drugs on market. The results provided key scientific evidence for developing such compounds into a new family of anti-MRSA drugs.

The herb pair is the simple and exquisite experience summary accumulated by generations of traditional Chinese medicine (TCM) experts in the process of long-term herbal prescription for curing diseases. Although it is only a combination of two herbs, it is cleverly matched and properly proportioned, which can well interpret TCM characteristics of "great combination and artful application". Moreover, the herb pair is an intermediate point between single herb and several TCM formulae, which implicates certain regularity and some connotation of many TCM formulae for diagnosis and treatment based on an overall analysis of the illness and the patient's condition. Our team has long been focusing on the complexity of drug interactions and the diversity of TCM components to carry out systematic research on herb pair by using modern scientific and technological knowledge and approaches. As results, a series of modern research approaches and strategies formed for the compatibility effect and bio-active components of the herb pair. By representing the principles and application characteristics of these approaches, this paper provides important support for elucidating scientific connotation of compatibility regularity of herb pairs and application of formulae optimization, as well as explorative ideas and approaches for modern research on other herb pairs.

The long-term use of antibiotics in clinical practice leads to bacterial variation and resistance. In addition, the excessive or improper use of antibiotics in medical and agricultural fields increases the occurrence of bacterial resistance. In 2017, the World Health Organization has for the first time released a list of 12 bacteria or bacterial families that pose the greatest threat to human health and for which new antibiotics are desperately needed, and three quarters of them are Gram-negative bacteria. Gram-negative bacteria has multi-layered cell wall that prevents many antibiotics from accessing their targets. Therefore, it is very difficult to develop drugs against Gram-negative bacteria, no new class of antibiotic has been approved for Gram-negative pathogens in over fifty years. Here, we summarized recent advances in the study of new antibacterial agents with different mechanisms of action against Gram-negative pathogens.

This study aimed to investigate apoptosis induction of ginsenoside compound K (ginsenoside CK) in human liver cancer SMMC-7721 cells and the involvement of TGF-β1/Smads signaling pathway. MTT assay was used to detect cell viability following ginsenoside CK treatment in SMMC-7721 cells. Annexin V-FITC/PI assay was used to detect apoptosis. After ginsenoside CK, or TGF-β1/Smads pathway activator TGFβ1 and inhibitor LY2109761 treatment, the TGF-β1/Smads pathway proteins and apoptosis proteins were detected by Western blot. The results showed that ginsenoside CK inhibited the proliferation of SMMC-7721 cells in a dose-and time-dependent manner. Annexin V-FITC/PI showed that ginsenoside CK induced apoptosis in SMMC-7721 cells. Meanwhile, ginsenoside CK inhibited the expression of Smad2/3, p-Smad2/3, Smad4, but promoted Smad7 expression, cleavage of caspase-3 and down-regulated Bcl-2/Bax. Compared with TGFβ1 treatment alone, levels of Smad2/3, p-Smad2/3, Smad4 and the ratio of Bcl-2/Bax were down-regulated, whereas Smad7 or cleaved caspase-3 was up-regulated in the ginsenoside CK+TGF-β1 group. In addition, Smad2/3, p-Smad2/3 and Smad4 expression were decreased in LY2109761 group. Compared with LY2109761 group, cleaved caspase-3 expression and Bcl-2/Bax have no significant change in ginsenoside CK+LY2109761 group. Taken together, our results showed that ginsenoside CK induced apoptosis in SMMC-7721 cells, and such induction is related to inhibiting TGF-β1/Smads signaling pathway.

Stroke is a common disease with complex and diverse clinical manifestations. Fufang Longmai Ningfang has been found to exhibit therapeutic effect on stroke, but its molecular mechanism for treating stroke remains unclear. The aim of this study was to investigate the molecular mechanism of Fufang Longmai Ningfang in the treatment of ischemic stroke by using the method of network pharmacology to define the active ingredients, target and molecular pathway of Fufang Longmai Ningfang. The TCMSP database was used to obtain the potential active components of Fufang Longmai Ningfang in the treatment of stroke. The CNKI database was used to verify the literature. The target was predicted and screened by PharmMapper and UniProt database. The target protein group was collected by TTD database. The Cytoscape software was used to construct a "component-target" network map, "component-target-disease" network map, and "target protein interaction" network map. The EAGLE algorithm was used for cluster analysis, the KEGG database was used for pathway analysis, and the SYBYL software was used for molecular docking for bioactivity verification. We found 39 potential active ingredients and 17 potential effective targets related to stroke. The representative active ingredients were ligustrazine, dioscin, and puerarin, and the related targets were MMP9, NOS3, NOS2, KDR, ALB, IL2, TGFB2, and CPB among others. The study found that carbon metabolism and HIF-1 signaling pathway are the main molecular pathways for treatment of stroke by Fufang Longmai Ningfang. The treatment of ischemic stroke by Fufang Longmai Ningfang may involve reduction of inflammatory response, enhancement of vascular permeability and inhibition of cerebral ischemia-reperfusion injury, providing a theoretical basis for their clinical use.

Deformation or failure of organs is the final stage involving fibrosis, caused by fibrous scars composed of excess extracellular matrix proteins. Cellular senescence means a stable stagnation state with no proliferation, during which the senescent cells maintain biochemical metabolism but promote excessive expression of extracellular matrix proteins due to secreting inflammatory factors, which contribute to the development of various organ fibrosis including myocardial fibrosis, and pulmonary fibrosis. It has been shown that both the incidence of organ fibrosis and the number of senescent cells increase with age. This review mainly summarizes mechanisms of cellular senescence and its contribution to the process of various organ fibrosis. Current anti-fibrotic drug therapy focused on cellular senescence is discussed. Cellular senescence has profound implications in the pathogenesis of fibrotic diseases and provides a new target for new effective treatments.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by excessive activation of autoreactive T cells and B cells, abundant production of autoantibodies and multiple joint involvement. Under the influence of heredity and environment, the disorder of innate immunity and adaptive immunity is the fundamental cause of the disease. In recent years, with rapid development of immunometabolism, milestone has been made in regulating the differentiation and function of immune cells through different energy metabolism pathways and related molecules. Many studies have shown that Trp-IDO1, 2/TDO2-Kyn metabolic pathway mediates the pathogenesis and development of autoimmune diseases such as RA. This review summarizes the role of tryptophan (Trp), kynurenine (Kyn) and other metabolites in this metabolic pathway, as well as the role of rate-limiting enzymes indoleamine 2, 3-dioxygenase 1 (IDO1), indoleamine 2, 3-dioxygenase 2 (IDO2) and tryptophan-2, 3-dioxygenase 2 (TDO2) in mediating RA inflammatory immune response and synovitis inflammation. This provides an important basis for elucidating the new pathological mechanism of RA and discovering new drug targets.

The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (< 32℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H & E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.