STAT3 x TRAF6

Salivary gland (SG) dysfunction is a hallmark manifestation of Sjögren's disease (SjD). While SHP2 has been implicated in several autoimmune diseases, its specific function in SjD remains to be elucidated. Here, we investigated the involvement of SHP2 in SjD-induced SG damage and elucidate the underlying molecular mechanisms. Our findings revealed that SHP2 is elevated in SG tissues of SjD patients and SjD-like animals, with predominant localization to salivary gland epithelial cells (SGECs) of acini and ducts. Notably, pharmacological inhibition of SHP2 with the allosteric inhibitor SHP099 significantly alleviates SG histopathological damage and reduces inflammatory cell infiltration in SjD-like animals. In vitro studies in the human SGEC line A253 revealed that SHP2 inhibition attenuated poly(I:C)-induced SGEC apoptosis and proinflammatory cytokine production. Mechanistically, SHP099 treatment disrupted the IL-17RA/ACT1/TRAF6 signaling axis, phenocopying the effects of SHP2 knockdown and direct IL-17R antagonism, which leads to downregulation of JAK/STAT3 and NF-κB pathways. Collectively, our findings highlight the significant involvement of SHP2 in the pathogenesis of SjD and suggest that targeting SHP2 or its downstream signaling pathways may represent a promising therapeutic approach for SjD treatment.

Dysregulated T‐cell homeostasis is central to the development of immune thrombocytopenia (ITP), characterized by reduced platelet counts. Antigen B (AgB), a key protein in Echinococcus granulosus cyst fluid, modulates T‐cell differentiation and reduces inflammation. Here, we explored the role of AgB in ITP and found that it enhances the generation and function of regulatory T cells (Tregs), boosting their immunosuppressive activity. In our passive ITP murine model, AgB treatment alleviated thrombocytopenia and restored the Treg–helper T‐cell (Th) balance. However, the therapeutic effects of AgB on CD4+ T cells were abolished by Treg depletion, highlighting the essential role of Tregs in AgB's mechanism of action. Moreover, AgB reduced proinflammatory cytokine production and inhibited signal transducer and activator of transcription 3 (STAT3) activation in ITP mice, with STAT3 inhibition negating the effects of AgB in Tregs. AgB promoted STAT3 degradation via tumour necrosis factor receptor‐associated factor 6 (TRAF6)‐mediated ubiquitination. In conclusion, by facilitating TRAF6‐mediated STAT3 ubiquitination, AgB restores T‐cell homeostasis and strengthens Treg immunosuppression, affording a potential therapeutic strategy for ITP.

Endosulfan (ESN) is an organophosphate insecticidal agent that is documented to induce various organ toxicities. Genistein (GEN) is a plant derived polyphenolic compound with excellent biological as well as pharmacological properties. This research was planned to assess the palliative potential of GEN to avert ENS prompted colonic toxicity. Albino rats (n = 36) were involved in this experiment that were divided into the control, ESN (5 mg/kg), ESN (5 mg/kg) + GEN (10 mg/kg), and GEN (10 mg/kg) alone treated group. We found that ENS intoxication upregulated the gene expression of STAT3, JAK1, TRAF6, MyD88, NF-κB, IL- IL-1β, TLR4, TNF-α, and IL-6 while reducing the gene expression of IκB. Moreover, ENS intoxication elevated the levelss of malondialdehyde (MDA) & reactive oxygen species (ROS) while decreasing the activties of glutathione reductase (GSR), catalase (CAT), heme-oxygenase-1 (HO-1), glutathione peroxidase (GPx), glutathione (GSH), superoxide dismutase (SOD), and glutathione S-transferase (GST). Furthermore, ESN administration notably escalated the concentrations of fecal calprotectin whereas reduced the concentrations of fecal elastase, lactase and sucrase. Besides, ESN intake upregulated the levels of Caspase-9, Bax and Caspase-3 while diminishing the levels of Bcl-2. Colonic histology was distorted after ESN provision. Nonetheless, GEN treatment remarkably protected the colonic tissues via regulating abovementioned irregularities owing to its marvelous anti-inflammatory, anti-apoptotic as well as antioxidant potential.