Ectopic CD4+ T cells in choroid plexus mediate neuropsychiatric lupus symptoms in mice via interferon-γ induced microglia activation.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a disabling and potentially life-threatening complication of SLE. This study aims to investigate whether ectopic CD4+ T cells in the choroid plexus mediate NPSLE in mice. Intracerebroventricular (ICV) injection of anti-CD4 antibody effectively depleted CP-resident CD4+ T cells and alleviated NPSLE-like symptoms in MRL/lpr mice. Following ICV injection, the majority of isolated lupus CD4+ T cells from donor MRL/lpr mice predominantly stayed in the CP for at least 28 days in recipient C57BL/6 mice, while nearly all isolated CD4+ T cells from MRL/MpJ mice disappeared within 7 days. ICV injection of lupus CD4+ T cells resulted in NPSLE-like symptoms, including impaired behavioral performances, increased microglial activation, and abnormal microstructure changes. Flow cytometry analysis revealed that the majority of isolated lupus CD4+ T cells were positive for IFN-γ. Neutralizing intracerebral IFN-γ alleviated NPSLE-like symptoms in MRL/lpr mice. Moreover, ICV injection of anti-IFN-γ antibody or microglial depletion by PLX3397 benefited most NPSLE-like symptoms in lupus CD4+ T-treated mice, while ICV injection of IFN-γ mimicked most NPSLE-like symptoms. In conclusion, CP-resident lupus CD4+ T cells contribute to NPSLE-like symptoms in mice via Interferon-γ induced microglia activation. Depleting CP-resident lupus CD4+ T cells, interferon-γ, or activated microglia may be potential therapeutic targets for NPSLE.

Efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients: a meta-analysis.

OBJECTIVE: This study aims to determine the efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients. METHODS: We searched Cochrane Library, PubMed, Embase, and ClinicalTrials.gov databases until July 27, 2022. Both randomized control trials (RCTs) and cohort studies were included and analyzed separately. The outcomes included mortality, incidence of invasive mechanical ventilation (IMV), ventilation improvement rate (need oxygen therapy to without oxygen therapy), secondary infection, and adverse events (AEs). The odds ratio (OR) with a 95% confidence interval (CI) was calculated by a random-effects meta-analysis model. RESULTS: Five RCTs and 2 cohort studies with 1726 COVID-19 patients were recruited (n = 866 in the GM-CSF antibody group and n = 891 in the control group). GM-CSF antibodies treatment reduced the incidence of IMV, which was supported by two cohort studies (OR 0.16; 95% CI 0.03, 0.74) and three RCTs (OR 0.62; 95% CI 0.41, 0.94). GM-CSF antibodies resulted in slight but not significant reductions in mortality (based on two cohort studies and five RCTs) and ventilation improvement (based on one cohort study and two RCTs). The sensitive analysis further showed the results of mortality and ventilation improvement rate became statistically significant when one included study was removed. Besides, GM-CSF antibodies did not increase the risks of the second infection (based on one cohort study and five RCTs) and AEs (based on five RCTs). CONCLUSION: GM-CSF antibody treatments may be an efficacious and well-tolerant way for the treatment of COVID-19. Further clinical evidence is still warranted.

Guidelines on the treatment with integrated traditional Chinese medicine and western medicine for severe coronavirus disease 2019.

Severe Coronavirus Disease 2019 (COVID-19) is characterized by numerous complications, complex disease, and high mortality, making its treatment a top priority in the treatment of COVID-19. Integrated traditional Chinese medicine (TCM) and western medicine played an important role in the prevention, treatment, and rehabilitation of COVID-19 during the epidemic. However, currently there are no evidence-based guidelines for the integrated treatment of severe COVID-19 with TCM and western medicine. Therefore, it is important to develop an evidence-based guideline on the treatment of severe COVID-19 with integrated TCM and western medicine, in order to provide clinical guidance and decision basis for healthcare professionals, public health personnel, and scientific researchers involved in the diagnosis, treatment, and care of COVID-19 patients. We developed and completed the guideline by referring to the standardization process of the "WHO handbook for guideline development", the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and the Reporting Items for Practice Guidelines in Healthcare (RIGHT).

Locus coeruleus tyrosine hydroxylase positive neurons mediated the peripheral and central therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) in MRL/lpr mice.

OBJECTIVE: This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in MRL/lpr mice. METHODS: MRL/lpr mice were treated with taVNS for ten weeks. Locus coeruleus (LC) tyrosine hydroxylase positive (TH+) neurons were selectively lesioned by stereotactic injection of 6-hydroxydopamine (6-OHDA) or selectively activated by chemogenetic methods. Sympathetic denervation was conducted by intraperitoneal injection of 6-OHDA. RESULTS: TaVNS activated the TH + neurons in LC. TaVNS produced central therapeutic effects by reducing the number of hippocampal microglia, and increasing the number of surviving LC TH+ neurons in MRL/lpr mice. TaVNS also retarded the development of lymphadenectasis and splenomegaly, decreased the proportion of double-negative T (DNT) cells, and alleviated nephritis in MRL/lpr mice. The lesion of LC TH+ neurons eliminated both these central and peripheral therapeutic effects of taVNS, while chemogenetic activation of LC TH+ neurons mimicked most central and peripheral protective effects of taVNS in MRL/lpr mice. Furthermore, taVNS regulated the autonomic nervous system in MRL/lpr mice. CONCLUSION: This study provides direct evidence that taVNS can retard the development of peripheral and central symptoms of SLE, which is mediated by the LC TH+ neurons.

Tripterygium wilfordii Hook F combination therapy with methotrexate for rheumatoid arthritis: An updated meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory arthropathy. Tripterygium wilfordii Hook F (TwHF) is common herbal medicine for the treatment of RA in China. However, many important issues, such as efficacy, safety and optimal doses of the combination therapy of TwHF and Methotrexate (MTX) for RA remain to be evaluated. AIMS OF THE STUDY: This study aims to evaluate the efficacy and safety of combination therapy of TwHF and MTX for RA by meta-analysis of randomized clinical trials (RCTs). MATERIAL AND METHODS: Relevant literature was searched from English (PubMed, Web of Science, EMBASE, and Cochrane library) and Chinese databases (WanFang, VIP, CNKI) until December 2021. Response rates and rates of adverse events (AEs) were independently extracted and analyzed. RESULTS: Fourteen randomized controlled trials (RCTs) were included with a total of 1446 patients, which included eight new RCTs with a total of 803 new patients when compared with the previous meta-analysis (Wang et al., 2017). Compared to MTX monotherapy, TwHF + MTX was revealed a higher effective rate (RR = 1.15, 95% CI: 1.10, 1.21), partial remission rate (RR = 1.27, 95% CI: 1.15, 1.40) and remission rate (RR = 1.31, 95% CI: 1.11, 1.55). The addition of TwHF benefited the clinical symptoms (such as tender joint count) and most laboratory indexes (such as the tumor necrosis factor-α). According to the subgroup analyses, the efficacy of the TwHF + MTX seems to be positively associated with the dose of TwHF (10 mg/d vs 30-60 mg/d), negatively related to the dose of MTX (∼10 mg/w vs ∼15 mg/w) and methodological risk of bias of included RCTs, and unrelated to the duration of therapy (12-week vs 24-week). For safety, the addition of TwHF did not increase the risk of most AEs and even reduced the risk of infection and liver AEs. CONCLUSION: Combining TwHF with MTX may be a superior strategy in the treatment of RA compared with MTX monotherapy. The optimal combination of TwHF + MTX therapy might be TwHF at 30-60 mg/d with MTX (∼10 mg/w). Further high-quality double-blind RCTs may be able to change the conclusions of our study, which are still warranted.

Efficacy and safety of traditional Chinese medicine for the treatment of epilepsy: A updated meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of Traditional Chinese Medicine (TCM) in the treatment of epilepsy. METHODS: A comprehensive search of the database in both Chinese and English was performed. Data from the selected studies were extracted and analyzed independently by two authors. RESULTS: 30 randomized controlled trials (RCTs) were included in the meta-analysis with a total of 2471 patients. Among them, 4 trials (n = 235) focused on TCM monotherapy, while the other 26 trials (n = 2236) assessed the benefit of TCM as an add-on therapy to antiseizure medications (ASMs). For the efficacy, the meta-analysis found (1) The effective rate in TCM monotherapy group was higher than that in control group (OR = 4.92, 95 % CI: 2.29-10.57, Z = 4.08, P 0.0001); (2) The add-on of TCM also increased the effective rate (OR = 3.37, 95 % CI: 2.65-4.30, Z = 9.85, P 0.00001) and seizure freedom rate (OR = 1.93, 95 % CI: 1.53-2.44, Z = 5.58, P 0.00001). In terms of safety, the add-on of TCM reduced the rate of total adverse events (OR = 0.46, 95 % CI: 0.31-0.67, Z = 3.96, P 0.0001) as well as adverse events of the gastrointestinal and nervous system. 26 different TCM prescriptions were used in these included RCTs. Among them, the 5 most frequently used herbs were Acorus tatarinowii (19 out of 26), Glycyrrhiza uralensis (13 out of 26), Gastrodia elata (12 out of 26), Pinellia ternata (11 out of 26) and Poria cocos (11 out of 26). CONCLUSION: This study suggested that TCM may be a relatively efficacious and safe clinical strategy for the treatment of epilepsy. Several limitations still exist, such as the risk of bias in the included studies, the diversified composition of TCM prescriptions, and the relatively low quality of study design.

Azithromycin pretreatment exacerbates atopic dermatitis in trimellitic anhydride-induced model mice accompanied by correlated changes in the gut microbiota and serum cytokines.

Atopic dermatitis (AD) is a common inflammatory skin disease. This study aims to investigate the effect of azithromycin (AZI) pretreatment, a common macrolide-type antibiotic, on the trimellitic anhydride (TMA) induced AD-like symptoms in mice. AZI (25 mg/kg, once daily, 5 days) was administered intragastrically before the 10-day TMA challenge. AD-like symptoms were assessed by ear thickening, scratching behavior, and pathological or immunofluorescence staining; Cytokines in the skin tissue and serum were measured by cytometric bead array; and the compositions of gut microbiota were assessed by 16S rRNA gene sequencing. AZI pretreatment accelerated the development of ear thickening and enhanced the severity of developed AD-like symptoms. AZI pretreatment promoted the infiltrations of neutrophil-like cells, T cells, and mast cells in ear skin. AZI pretreatment elevated the levels of IL-4, IL-6, and IL-17A in the ear skin of AD model mice, but it increased serum TNF-α and IL-6. AZI-pretreatment increased four gut bacterial genera (Bacteroides, Candidatus_Saccharibacteria_unclassified, Acetatifactor, Firmicutes_unclassified) but depleted three short-chain fatty acids producing gut bacterial genera (Alistipes, Clostridiales_unclassified, Butyricicoccus). AD-associated symptoms were positively associated with skin IL-4 and IL-17A, serum TNF-α, and IL-6, and Acetatifactor, but they negatively correlated to the three decreased gut bacterial genera (Alistipes, Clostridiales_unclassified, Butyricicoccus). Thus, our results demonstrate that AZI exposure deteriorates TMA-induced AD-like symptoms in mice, which is related to the imbalances of gut microbiota and skin/serum cytokines.