This study aimed to investigate the therapeutic effects of Morinda officinalis iridoid glycosides (MOIG) on bone loss of rheumatoid arthritis (RA) rats, and the mechanism of osteoclast function and activity induced by lipopolysaccharide (LPS). RA rats were established by injecting bovin type II collagen. The Bio-ethic Committee of Zhejiang Chinese Medical University approved all experimental protocols associated with this study (IACUC-20180410-03). The collagen-induced arthritis (CIA) rats were administered drug by gavage for 8 weeks; the femoral trabecular micro-structure changes were observed in CIA rats by micro-CT; the LPS-induced osteoclasts model further observed the effect and mechanism of anti-inflammatory osteoporosis in vitro. The results indicated that MOIG could markedly increase bone mineral density (BMD) in CIA rats, improve trabecular micro-structure. In vitro studies demonstrated that MOIG could significantly inhibit osteoclastogensis and differentiation, suppress tartrate resistant acid phosphatase (TRAP) activity, F-actin ring formation, TNF receptor associated factor 6 (TRAF6) recruitment, and inhibitor of nuclear factor kappa-Bα (IκBα) degradation as well as p65 phosphorylation, thereby repressing nuclear factor kappa-B (NF-κB) signaling pathway activation. Subsequently, MOIG effectively inhibited osteoclast nuclear factor of activated T-cells c1 (NFATc1) and cellular oncogene Fos (c-Fos) expression, as well as bone resorption related protein activity including matrix metalloprotein 9 (MMP-9) and cathepsin K (CtsK). Meanwhile, MOIG also repressed the phosphorylation expression of Janus activating kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), thereby inhibiting JAK2/STAT3 signaling pathway activation. Moreover, further studies found that MOIG could suppress glycogen synthase kinase-3β (GSK-3β) activity, and GSK-3β gene silencing could markedly inhibit oetsoclast F-actin ring formation as well as the phosphorylation expression of p65 and STAT3. Of note, compared with GSK-3β gene silencing group, there was no significant difference in the group treated with both MOIG with GSK-3β gene silencing simultaneously. Thus, the results suggested that MOIG may inhibit NF-κB signaling pathway and JAK2/STAT3 signaling pathway activation via regulating GSK-3β, thereby alleviating bone destruction in RA.

OBJECTIVE: To determine the role of Tripterygium wilfordii multiglycoside (TGW) in the treatment of psoriatic dermatitis from a cellular immunological perspective. METHODS: Mouse models of psoriatic dermatitis were established by imiquimod (IMQ). Twelve male BALB/c mice were assigned to IMQ or IMQ₊TGW groups according to a random number table. Histopathological changes in vivo were assessed by hematoxylin and eosin staining. Ratios of immune cells and cytokines in mice, as well as PAM212 cell proliferation in vitro were assessed by flow cytometry. Pro-inflammatory cytokine expression was determined using reverse transcription quantitative polymerase chain reaction. RESULTS: TGW significantly ameliorated the severity of IMQ-induced psoriasis-like mouse skin lesions and restrained the activation of CD45⁺ cells, neutrophils and T lymphocytes (all P<0.01). Moreover, TGW significantly attenuated keratinocytes (KCs) proliferation and downregulated the mRNA levels of inflammatory cytokines including interleukin (IL)-17A, IL-23, tumor necrosis factor α, and chemokine (C-X-C motif) ligand 1 (P<0.01 or P<0.05). Furthermore, it reduced the number of γ δ T17 cells in skin lesion of mice and draining lymph nodes (P<0.01). CONCLUSIONS TGW improved psoriasis-like inflammation by inhibiting KCs proliferation, as well as the associated immune cells and cytokine expression. It inhibited IL-17 secretion from γ δ T cells, which improved the immune-inflammatory microenvironment of psoriasis.
Male ; Animals ; Mice ; Tripterygium ; Psoriasis/drug therapy* ; Keratinocytes ; Skin Diseases/metabolism* ; Cytokines/metabolism* ; Imiquimod/metabolism* ; Dermatitis/pathology* ; Disease Models, Animal ; Mice, Inbred BALB C ; Skin/metabolism*

ObjectiveTo further study the pathogenic role of different types of Chlamydia trachomatis （CT） proteins in tubal factor infertility， evaluate the clinical detection value of Chlamydia trachomatis protein antibody in predicting tubal factor infertility. MethodsA total of 58 cases of tubal factor infertility （TFI）， 41 cases of fertile controls （FC） and 18 cases of infertile controls （IFC） were included. For serum detection， first， CT-IgG ELISA kit was used to detect the expression of CT-IgG in serum of three groups of people； then， 6 kinds of Chlamydia trachomatis proteins were expressed and purified in the early stage to establish the antibody test for these proteins， and ELISA detection method was used to detect the expression of their antibodies in the serum of TFI group， FC group and IFC group， respectively； and finally， the antibody OD value of the 6 kinds of Chlamydia trachomatis proteins in the three groups of subjects were statistically described， and CT-IgG was used as the reference standard to draw the receiver operating characteristic curve （ROC curve） of each CT antibody. The Youden Index determines the cutoff value for each antibody. Taking TFI as the reference class， two disordered multiple classification logistic regression models were established with the FC and IFC groups， respectively； and the reference class was used to explore the value of various antibodies and age in predicting TFI， FC and IFC of Chlamydia trachomatis. The back-off method was used to screen the variables. ResultsThe OD value of CT376 antibody in the TFI group was higher than that in the FC group （0.86 vs. 0.60， P=0.026）. The CT376 antibody OD value in the TFI group was higher than that in the IFC group （0.86 vs. 0.64， P=0.026）. The CT443 antibody OD value in the IFC group was higher than that in the TFI group （0.59 vs. 0.34， P=0.036） and higher than that in the FC group （0.59 vs. 0.30， P=0.02）. The multiple classification logistic regression analysis established between TFI and FC showed that CT-IgG ［P<0.001， OR=0.084， 95%CI （0.025， 0.284）］， CT376 antibody ［P=0.068， OR=0.359， 95%CI （0.120， 1.078）］. CT-IgG is an independent risk factor for tubal infertility， and CT376 antibody cannot be an independent risk factor for tubal infertility. The multiple classification logistic regression analysis established between TFI and IFC showed that among infertile patients， CT-IgG ［P<0.05， OR=0.194， 95%CI （0.046， 0.817）］， CT376 antibody ［P<0.05， OR=0.176， 95%CI （0.038， 0.818）］ and CT381 antibody ［P<0.05， OR=0.112， 95%CI （ 0.016， 0.796）］ were independent risk factors for tubal infertility. ConclusionThe expression of CT376 antibody in tubal infertility patients is higher than that in fertile and infertile controls， suggesting that CT-induced tubal factor infertility may be related to CT376. CT-IgG， and CT376 antibodies are meaningful in predicting CT-induced tubal factor infertility.

Multiple sclerosis(MS) shows the pathological characteristics of "inflammatory injury of white matter" and "myelin repair disability" in the central nervous system(CNS). It is very essential for MS treatment and reduction of disease burden to strengthen repair, improve function, and reduce disability. Accordingly, different from the simple immunosuppression, we believe that key to strengthening remyelination and maintaining the "damage-repair" homeostasis of tissue is to change the current one-way immunosuppression strategy and achieve the "moderate pro-inflammation-effective inflammation removal" homeostasis. Traditional Chinese medicine shows huge potential in this strategy. Through literature research, this study summarized the research on remyelination, discussed the "mode-rate pro-inflammation-effective inflammation removal" homeostasis and the "damage-repair" homeostasis based on microglia, and summed up the key links in remyelination in MS. This review is expected to lay a theoretical basis for improving the function of MS patients and guide the application of traditional Chinese medicine.
Humans ; Multiple Sclerosis/pathology* ; Remyelination/physiology* ; Myelin Sheath/pathology* ; Inflammation/drug therapy* ; Homeostasis

The iron and inflammation homeostasis are closely coupled, forming an integrated functional unit under physiological conditions. "Iron transport balance" has become the key mechanism to maintain iron homeostasis through bidirectional regulation of iron uptake and release and dynamic management of transmembrane concentration. It is also the physiological basis for the inflammatory balance between promotion and resolution. Under pathological conditions, represented by inflammatory bowel disease (IBD), disturbed iron transportation was highly involved in almost every step of inflammatory diseases. Therefore, the iron transporting rebalancing provides the mechanistic basis and effective approach for the normalization of inflammatory microenvironment. Macrophage is the key regulator of inflammation homeostasis and determinant for iron transport balance. Unfortunately, the current clinical transformation based on iron transport balance theory has still been insufficient. Sometimes, this strategy even showed high complexity and contradiction, severely restricting its clinical application. By summarizing the theoretical research progress of iron transport balance, especially its relevance to macrophage phenotypic polarization, this review aims to explore the therapeutic value in inflammation intervention by targeting iron transporting balance. This review will provide the necessary knowledge and hints for the research and development of candidate drugs in treating inflammatory diseases.

Objective: Systematically summarize the research progress of clinical trials of gastric cancer oncology drugs and the overview of marketed drugs in China from 2012 to 2021, providing data and decision-making evidence for relevant departments. Methods: Based on the registration database of the drug clinical trial registration and information disclosure platform of Food and Drug Administration of China and the data query system of domestic and imported drugs, the information on gastric cancer drug clinical trials, investigational drugs and marketed drugs from January 1, 2012 to December 31, 2021 was analyzed, and the differences between Chinese and foreign enterprises in terms of trial scope, trial phase, treatment lines and drug type, effect and mechanism studies were compared. Results: A total of 114 drug clinical trials related to gastric tumor were registered in China from 2012 to 2021, accounting for 3.7% (114/3 041) of all anticancer drug clinical trials in the same period, the registration number showed a significant growth rate after 2016 and reached its peak with 32 trials in 2020. Among them, 85 (74.6%, 85/114) trials were initiated by Chinese pharmaceutical enterprise. Compared with foreign pharmaceutical enterprise, Chinese pharmaceutical enterprise had higher rates of phase I trials (35.3% vs 6.9%, P=0.001), but the rate of international multicenter trials (11.9% vs 67.9%, P<0.001) was relatively low. There were 76 different drugs involved in relevant clinical trials, of which 65 (85.5%) were targeted drugs. For targeted drugs, HER2 is the most common one (14 types), followed by PD-1 and multi-target VEGER. In the past ten years, 3 of 4 marketed drugs for gastric cancer treatment were domestic and included in the national medical insurance directory. Conclusions: From 2012 to 2021, China has made some progress in drug research and development for gastric carcinoma. However, compared with the serious disease burden, it is still insufficient. Targeted strengthening of research and development of investment in many aspects of gastric cancer drugs, such as new target discovery, matured target excavating, combination drug development and early line therapy promotion, is the key work in the future, especially for domestic companies.
China ; Gastrointestinal Agents/therapeutic use* ; Gastrointestinal Neoplasms ; Humans ; Pharmaceutical Preparations ; United States ; United States Food and Drug Administration

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.
Animals ; COVID-19/genetics* ; Macaca mulatta ; SARS-CoV-2/genetics* ; Transcriptome

OBJECTIVE: To compare the clinical efficacy and its effect on serum levels of tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), interleukin 6 (IL-6) and prostaglandin E₂ (PGE₂) between short needling (close-to-bone needling) and conventional acupuncture for knee osteoarthritis (KOA) with blood stasis obstruction. METHODS: A total of 68 KOA patients with blood stasis obstruction were randomized into a short needling group (34 cases, 3 cases dropped off) and a conventional acupuncture group (34 cases, 3 cases dropped off). The same acupoints (Dubi [ST 35], Neixiyan [EX-LE 4], Binzhong [Extra], Liangqiu [ST 34], etc. on the affected side) were selected in the two groups. In the short needling group, short needling technique was adopted, the needles were slowly inserted and the needle bodies were shaken, thus gradually penetrated to the bone. In the conventional acupuncture group, conventional acupuncture was adopted, the needles were penetrated to the muscle. After qi-arrival, Dubi (ST 35) and Neixiyan (EX-LE 4), Zusanli (ST 36) and Liangqiu (ST 34) were connected with CMNS6-1 electronic acupuncture instrument, with disperse-dense wave, 2 Hz/10 Hz in frequency, the current intensity was based on patients' feeling, the needles were retained for 30 min, at the same time, the knee joint was irradiated for 30 min with a special electromagnetic wave apparatus in the two groups. Once every other day, 3 times a week for 4 weeks. Before and after treatment, the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) score, knee joint pain visual analogue scale (VAS) score, inflammatory response related indexes (serum TNF-a, IL-1β, IL-6 and PGE₂) and knee joint ultrasound were observed，and the clinical effect was evaluated in the two groups. RESULTS: After treatment，the pain, stiffness, function scores and total scores of WOMAC were decreased as compared with those before treatment in the two groups (P<0.05), except for the pain score, the changes of above scores in the short needling group were greater than the conventional acupuncture group (P<0.05). After treatment, the VAS scores, serum levels of TNF-a, IL-1β, IL-6, PGE₂ and knee joint synovium thickness, intra-articular effusion were decreased as compared with those before treatment in the two groups (P<0.05), the levels of TNF-a, IL-1β, IL-6 in the short needling group were lower than the conventional acupuncture group (P<0.05). The total effective rate in the short needling group was 87.1% (27/31), which was superior to 83.9% (26/31) in the conventional acupuncture group (P<0.05). CONCLUSION Short needling could improve the knee joint function, relieve the pain and inflammatory response, improve the knee joint synovium inflammatory response, reduce the knee joint intra-articular effusion for KOA patients, its effect is better than conventional acupuncture.
Acupuncture Points ; Humans ; Inflammation ; Interleukin-6 ; Osteoarthritis, Knee/therapy* ; Pain ; Prostaglandins E

Acquired Immunodeficiency Syndrome ; Biopsy, Fine-Needle ; China ; HIV ; Humans ; Sarcoma, Kaposi

OBJECTIVETo study the relationship of Blimp-1 hypoexpression with abnormality of Treg level and pathogenesis of aplastic anemia (AA).

METHODSThe mouse model with AA was established by adminis tration of IFN-γ combined with busulfan. The samples were collected at different day establishing AA model, and the spleen Treg number was detected, the Treg cells were sorted and expression level of prdm-1 was detected.

RESULTSThe number of Tregs in mice with AA was lower than that in control mice, moreover, the level of Treg decrease positively correlated with the AA severity (r=0.805), the higher the expression level of prdm-1, the higher the ratio of Treg/lymphocytes, showing positive correlation between them (r=0.548).

CONCLUSIONBlimp-1 expression may promote the proliferation and differentiation of Treg. The hypoexpression of Blimp-1 mediates the pathogenesis of AA and promotes progression of AA through reducing the proliferation of Treg, and decreacing the number of Treg.