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OBJECTIVE: To elucidate the functional role and underlying mechanism of Salvia miltiorrhiza bge. f. alba (SMBFA) in patients with type 2 diabetes mellitus (T2DM) accompanied by non-alcoholic fatty liver disease (NAFLD). METHODS: A retrospective analysis was conducted on 90 patients with T2DM-NAFLD who met the inclusion criteria. The control group was comprised of 45 patients treated with Fenofibrate, while the observation group consisted of 45 patients who received SMBFA in addition to the control treatment. An in vivo mouse model of T2DM-NAFLD was established using a high-fat diet combined with streptozotocin. Serum levels of fasting plasma glucose (FPG), 2-hour postprandial glucose (2h PG), hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), and triglyceride (TG) were measured in both patients and mice using an automated biochemical analyzer. Liver indices and function were also evaluated. ELISA assays were performed to quantify inflammatory cytokine levels. Western blotting was utilized to assess the protein levels related to the stimulator of interferon genes (STING)-interferon regulatory factor 3 (IRF3) pathway. RESULTS: After treatment, significant reductions in blood glucose indices, HOMA-IR, lipid metabolism markers, liver function indices, and inflammatory cytokines were observed in both groups of T2DM-NAFLD patients. Notably, the decreases were more pronounced in the observation group compared to the control group. Similarly, in T2DM-NAFLD mouse models, the levels of these parameters were significantly lower in the observation group than in the normal control (NC) group. Additionally, SMBFA suppressed the elevated levels of STING, p-IRF3, and p-TANK-binding kinase 1 in the T2DM-NAFLD mice. CONCLUSION: SMBFA exhibits the potential to regulate glucose and lipid metabolism, inhibit insulin resistance, and protect liver function by modulating the STING signaling pathway.

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Neuroinflammation is crucial in the onset and progression of dopaminergic neuron loss in Parkinson's disease (PD). We aimed to determine whether 3-N-Butylphthalide (NBP) can protect against PD by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and the inflammatory response of microglia. MitoSOX/MitoTracker/Hoechst staining was used to detect the levels of mitochondrial reactive oxygen species (ROS) in BV2 cells. Quantitative Real-Time Polymerase Chain Reaction was used to measure the levels of free cytoplasmic mitochondrial DNA (mtDNA) in BV2 cells and mouse brain tissues. Behavioral impairments were assessed using rotarod, T-maze, and balance beam tests. Dopaminergic neurons and microglia were observed using immunohistochemical staining. Expression levels of cGAS, STING, nuclear factor kappa-B (NfκB), phospho- NfκB (p-NfκB), inhibitor of NfκBα (IκBα), and phospho-IκBα (p-IκBα) proteins in the substantia nigra and striatum were detected using Western Blot. NBP decreased mitochondrial ROS levels in rotenone-treated BV2 cells. NBP alleviated behavioral impairments and protected against rotenone-induced microgliosis and damage to dopaminergic neurons in the substantia nigra and striatum of rotenone-induced PD mice. NBP decreased rotenone-induced mtDNA leakage and mitigated neuroinflammation by inhibiting cGAS-STING pathway activation. NBP exhibited a protective effect in rotenone-induced PD models by significantly inhibiting the cGAS-STING pathway. Moreover, NBP can alleviate neuroinflammation, and is a potential therapeutic drug for alleviating clinical symptoms and delaying the progression of PD. This study provided insights for the potential role of NBP in PD therapy, potentially mitigating neurodegeneration, and consequently improving the quality of life and lifespan of patients with PD. The limitations are that we have not confirmed the exact mechanism by which NBP decreases mtDNA leakage, and this study was unable to observe the actual clinical therapeutic effect, so further cohort studies are required for validation.

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Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve the therapeutic outcomes of immunotherapy. However, the "constantly active" mode of current STING agonist delivery strategies typically leads to off-target toxicity and hyperimmunity. To address this critical issue, herein a metal-organic frameworks-based nanoagonist (DZ@A7) featuring tumor-specific and near-infrared (NIR) light-enhanced decomposition is constructed for precisely localized STING activation and photodynamic-metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria-targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia-responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger-associated molecular pattern that activates the cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS-STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitated the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes for primary tumor eradication, which also established a long-term anti-tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR-triggered, agonist-free, and tandem-amplified activation of the cGAS-STING pathway, thereby offering a distinct paradigm for photodynamic-metalloimmunotherapy.

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Although chemotherapy has the potential to induce tumor immunotherapy via immunogenic cell death (ICD) effects, how to control the intensity of the immune responses still deserves further exploration. Herein, a controllable ultrasound (US)-triggered chemo-immunotherapy nanoagonist is successfully synthesized by utilizing the pH and reactive oxygen species (ROS) dual-responsive PEG-polyphenol to assemble sonosensitizer zinc oxide (ZnO) and doxorubicin (DOX). The PZnO@DOX nanoparticles have an intelligent disassembly to release DOX and zinc ions in acidic pH conditions. Notably, US irradiation generates ROS by sonodynamic therapy and accelerates the drug release process. Interestingly, after the PZnO@DOX+US treatment, the injured cells release double-stranded DNA (dsDNA) from the nucleus and mitochondria into the cytosol. Subsequently, both the dsDNA and zinc ions bind with cyclic GMP-AMP synthase and activate the stimulator of interferon genes (STING) pathway, resulting in the dendritic cell maturation, ultimately promoting DOX-induced ICD effects and antigen-specific T cell immunity. Therefore, chemotherapy-induced immune responses can be modulated by non-invasive control of US.

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We hypothesized that minimal change disease (MCD) pathogenesis may be associated with mitochondrial injury, and that the degree of mitochondrial injury at the time of diagnosis may serve as a valuable prognostic marker. We compared urinary mitochondrial DNA (mtDNA) at the time of diagnosis in patients with MCD and age- and sex-matched healthy controls (MHC) (n = 10 each). We analyzed the site and signal intensity of immunohistochemical (IHC) staining of stimulator of interferon genes (STING) using kidney tissues at the time of diagnosis in patients with MCD. Patients with MCD were divided into high (n = 6) and low-intensity (n = 14) subgroups according to the signal intensity. Urinary mtDNA levels were elevated in the MCD groups more than in the MHC group (p < 0.001). Time-averaged proteinuria and frequency of relapses during the follow-up period were higher in the high-intensity than in the low-intensity subgroup (1.18 ± 0.54 vs. 0.57 ± 0.45 g/day, p = 0.022; and 0.72 ± 0.60 vs. 0.09 ± 0.22 episodes/year, p = 0.022, respectively). Mitochondrial injury may be associated with MCD pathogenesis, and the signal intensity of STING IHC staining at the time of diagnosis could be used as a valuable prognostic marker in MCD.

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Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E-deficient (ApoE-/-) mouse with CKD (CKD/ApoE-/- mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD-associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE-/- mice are comprehensively investigated. Using multi-omics analysis and targeted and VSMC-specific gene knockout mice, VSMCs are identified as both type-I-interferon (IFN-I)-responsive and IFN-I-productive cells. Mechanistically, mitochondrial damage resulting from CKD-induced oxidative stress primes the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to trigger IFN-I response in VSMCs. Enhanced IFN-I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN-I response remarkably attenuates CKD-associated plaque vulnerability. These findings reveal that IFN-I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD-associated plaque vulnerability. Mitigating IFN-I response may hold promise for the treatment of CKD-associated cardiovascular diseases.