STING agonism turns human T cells into interferon-producing cells but impedes their functionality.

The cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) axis is the predominant DNA sensing system in cells of the innate immune system. However, human T cells also express high levels of STING, while its role and physiological trigger remain largely unknown. Here, we show that the cGAS-STING pathway is indeed functional in human primary T cells. In the presence of a TCR-engaging signal, both cGAS and STING activation switches T cells into type I interferon-producing cells. However, T cell function is severely compromised following STING activation, as evidenced by increased cell death, decreased proliferation, and impaired metabolism. Interestingly, these different phenotypes bifurcate at the level of STING. While antiviral immunity and cell death require the transcription factor interferon regulatory factor 3 (IRF3), decreased proliferation is mediated by STING independently of IRF3. In summary, we demonstrate that human T cells possess a functional cGAS-STING signaling pathway that can contribute to antiviral immunity. However, regardless of its potential antiviral role, the activation of the cGAS-STING pathway negatively affects T cell function at multiple levels. Taken together, these results could help inform the future development of cGAS-STING-targeted immunotherapies.

[Mechanism of Panlongqi Tablets intervening in vertebral artery type of cervical spondylosis in rats through PI3K/AKT signaling pathway based on network pharmacology and experimental verification].

This study aimed to further explore the relevant mechanism of action by network pharmacology integrated with animal experimental verification based on previous proven effective treatment of vertebral artery type of cervical spondylosis(CSA) by Panlongqi Tablets. Bionetwork analysis was performed to establish drug-disease interaction network, and it was found that the key candidate targets of Panlongqi Tablets were enriched in multiple signaling pathways related to CSA pathological links, among which phosphatidylinositol 3-kinase(PI3 K)/serine-threonine kinase(AKT/PKB) signaling pathway was the most significant. Further, mixed modeling method was used to build the CSA rat model, and the rats were divided into normal, model, Panlongqi Tablets low-, medium-and high-dose(0.16, 0.32, 0.64 g·kg~(-1)) and Jingfukang Granules(positive drug, 1.35 g·kg~(-1)) groups. After successful modeling, the rats were administered for 8 consecutive weeks. Pathological changes of rat cervical muscle tissues were detected by hematoxylin-eosin(HE) staining, and the content of interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), vascular endothelial cell growth factor(VEGF) and chemokine(C-C motif) ligand 2(CCL2) in rat serum and/or cervical tissues was determined by enzyme-linked immunosorbent assay(ELISA). Western blot was employed to detect the protein expression levels of chemokine(C-C motif) receptor 2(CCR2), PI3 K, AKT, phosphorylated AKT(p-AKT), I-kappa-B-kinase beta(IKK-beta/IKKß), nuclear factor kappa B(NF-κB P65) and phosphorylated nuclear factor kappa B(NF-κB p-P65) in rat cervical tissues, and positive expression of p-NF-κB P65 in rat cervical muscle tissues was detected by immunofluorescence. The results showed that Panlongqi Tablets at different doses improved the degree of muscle fibrosis and inflammation in cervical muscle tissues of CSA rats, and reduced the content of inflammatory factors IL-1ß, TNF-α, VEGF, CCL2 and CCR2 in serum and/or cervical tissues. The protein expression levels of PI3 K, p-AKT, IKKß and p-NF-κB P65 as well as the nuclear entry of p-NF-κB P65 in cervical tissues were down-regulated. These findings suggest that Panlongqi Tablets can significantly inhibit the inflammatory response of CSA rats, and the mechanism of action may be related to the down-regulation of the activation of PI3 K/AKT signaling pathway.

[Effect of Jianpi Huogu Formula on function damage of vascular endothelial cells induced by glucocorticoid].

This study aimed to observe the intervention effect of Jianpi Huogu Formula(JPHGF) on the functional damage of vascular endothelial cells caused by glucocorticoid, and explore its action mechanism from the PI3 K/Akt and mitogen activated protein kinase(MAPK) signaling pathways. The extracted thoracic aorta ring of normal SD rats were intervened first with vascularendothelial growth factor(VEGF, 20 µg·L-1) and/or sodium succinate(MPS, 0. 04 g·L-1) in vitro and then with JPHGF(8, 16, and 32 µg·L-1) for five mcontinuous ethylpdays, rednisolofollowed nebythe statistics of the number, length, and area of microvessels budding fromvascular rings. In addition, the human umbilical vein endothelial cells(HUVECs) induced by VEGF(20 µg·L-1) were added with MPS(0. 04 g·L-1) and then with JPHGF(8, 16, and 32 µg·L-1) for observing the migration, invasion, and luminal formation abilities of HUVECs in the migration, invasion and luminal formation experiments. The protein expression levels of PI3 K, p-Akt, p-JN K, and p-ERK in HUVECs were assayed by Western blot. The results showed that JPHGF dose-dependently improved the num-ber,length, and area of microvessels in MPS-induced rat thoracic aortic ring, reversed the migration, invasion and lumen formation abiliti es of HUVECs reduced by MPS, and up-regulated the protein expression levels of PI3 K, p-Akt, and p-JNK in HUVECs. All thesehave suggested that JPHGF exerts the protective effect against hormone-induced damage to the angiogenesis of vascular endothelial cells by activating the PI3 K/Akt and MAPK signaling pathways, which has provided reference for exploring the mechanism of JPHGF in treating s teroid-induced avascular necrosis of femoral head(SANFH) and also the experimental evidence for enriching the scientific connotationof spleen-invigorating and blood-activating therapy.

Chromatin remodeler INO80 mediates trophectoderm permeability barrier to modulate morula-to-blastocyst transition.

Inositol requiring mutant 80 (INO80) is a chromatin remodeler that regulates pluripotency maintenance of embryonic stem cells and reprogramming of somatic cells into pluripotent stem cells. However, the roles and mechanisms of INO80 in porcine pre-implantation embryonic development remain largely unknown. Here, we show that INO80 modulates trophectoderm epithelium permeability to promote porcine blastocyst development. The INO80 protein is highly expressed in the nuclei during morula-to-blastocyst transition. Functional studies revealed that RNA interference (RNAi)-mediated knockdown of INO80 severely blocks blastocyst formation and disrupts lineage allocation between the inner cell mass and trophectoderm. Mechanistically, single-embryo RNA sequencing revealed that INO80 regulates multiple genes, which are important for lineage specification, tight junction assembly, and fluid accumulation. Consistent with the altered expression of key genes required for tight junction assembly, a permeability assay showed that paracellular sealing is defective in the trophectoderm epithelium of INO80 knockdown blastocysts. Importantly, aggregation of 8-cell embryos from the control and INO80 knockdown groups restores blastocyst development and lineage allocation via direct complementation of the defective trophectoderm epithelium. Taken together, these results demonstrate that INO80 promotes blastocyst development by regulating the expression of key genes required for lineage specification, tight junction assembly, and fluid accumulation.

[Comparative study on chronic multiple organ injury in normal rats caused by high dose of Tripterygium Glycosides Tablets from 6 different manufacturers].

The aim of this paper was to compare different effects of Tripterygium Glycosides Tablets from 6 different manufacturers on multiple organ injuries in rats and to explore mechanism of hepatotoxicity preliminarily from the perspective of apoptosis and oxidative stress. Rats were randomly divided into the groups normal, Zhejiang, Hunan, Hubei, Shanghai, Jiangsu and Fujian(7 groups with 16 rats in each group, sex in half). Rats were given Tripterygium Glycosides Tablets at 144 mg·kg~(-1)·d~(-1)(16 times the clinical equivalent dose) once a day according to its corresponding group like rats in Zhejiang group was given Tripterygium Glycosides Tablets from Zhejiang manufactures continuously for 20 days with the life and death situation of mice to be observed, then rats were executed to detect various indicators. RESULTS:: showed that 8 female rats in Zhejiang group died after 15 days of administration, the serum NEUT of rats in Hubei, Fujian and Shanghai groups was significantly lower than that of normal rats. The serum AST, ALT and/or TBiL levels were increased in all rats, and serum BUN and/or CRE levels of rats were also increased in Hunan, Hubei, Fujian and Shanghai groups. In dosage groups, testicular and ovarian coefficients of rats were reduced, the number of sperm were significant decreased while the rate of sperm malformation increased and sperm dynamics parameters of normal, especially in Jiangsu and Zhejiang groups. Liver histopathology and apoptosis of liver cells were observed in dosage groups, especially in Jiangsu and Hubei groups. In liver, Nrf2, HO-1 and Bcl-2 were inhibited and the protein expression level of Bax were increased simultaneously in dosage groups. These results showed that all Tripterygium Glycosides Tablets from 6 manufacturers could lead to chronic multiple organ injuries with disparate specialties in rats, and Jiangsu and Zhejiang groups were more toxic. It could be the mechanism promoting mitochondrial mediated Bax/Bcl-2 cell apoptosis signaling pathway and negatively regulating Nrf2/HO-1 oxidative stress signaling pathway that Tripterygium Glycosides Tablets from 6 different manufacturers resulted in chronic liver injury, the results above were for reference only in subsequent study.

[Meta-analysis on safety of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis].

To systematically evaluate the adverse drug reaction(ADR) of Tripterygium Glycosides Tablets(TGT) in the treatment of rheumatoid arthritis(RA). Four Chinese databases(CNKI, VIP, WanFang, SinoMed) and three English databases(Cochrane Library, EMbase, PubMed), from the time of database establishing to August 2019, were systematically retrieved to collect literature on the treatment of all types of RA with TG. Screening literature and extracting data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria, with data being extracted and Meta-analyzed. There were 79 studies included, randomized controlled trials(RCT) containing TGT in the treatment group, non-randomized controlled trials(non-RCT), case series, case reports, and RCT containing TGT only in the control group were covered. There were in the control group; 765 ADR of 2 214 patients in 30 RCT(treatment group given TGT), 11 non-RCT and 7 case reports. The results of Meta-analysis of these 48 literatures showed that the overall incidence of ADRs was 0.23(95%CI[0.22,0.24]); ADR mainly occured in the reproductive, gastrointestinal, skin and accessories, blood, hepatobiliary system damage and the incidence of ADR in systems mentioned about respectively were 0.14(95%CI[0.12,0.17]),0.07(95%CI[0.06,0.08]),0.06(95%CI[0.04,0.07]),0.04(95%CI[0.03,0.05]),0.04(95%CI[0.03,0.05]). Further subgroup analysis results showed that the incidence of total ADR, especially the gastrointestinal, reproductive and cutaneous ADR of patients with treatment alone was higher than that in those paients with MTX or MTX+LEF therapy; The incidence of ADR, especially the gastrointestinal ADR, was also positively correlated with daily dose and course of treatment, while the incidence of different systems ADR was also correlated with different drug manufacturers, for instance, damage on the female reproductive system occurs most frequently in Hunan manufacture TGT administration, same as the damage on skin and accessories induced by TGT from Jiangsu manufacture. Above all, The clinical treatment of TGT for RA will cause multi-system ADR, with the highest incidence in the reproductive system, followed by the gastrointestinal system, which is closely related to the way of medication(monotherapy), daily dose, course of medication and drug manufacturer. Therefore, it is recommended that, in the treatment of RA, using TGT in combination, low dose or short-course medication, take measures to protect the reproductive system, stomach and liver, and paying attention to the drug manufacturer as well response of patients during administration should be valued to avoid ADRs to the maximum possibility.