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Schematic illustration of the mechanisms by which Gastrodin regulate the JAK2/STAT3 signaling pathway ameliorate mitochondria injury in cerebral ischemia – reperfusion (By Figdraw). During ischemia and hypoxia, mitochondria sustain damage, impairing energy production and prompting excessive ROS generation, thereby causing mtDNA leakage. The release of mtDNA during mitochondrial dysfunction can activate TLR9 signaling, instigating a pro-inflammatory response. Pro-inflammatory cytokines activate JAK2 kinases, leading to rapid phosphorylation of STAT3, which subsequently translocates into the nucleus and acts as a transcription factor, enhancing the expression of various pro-inflammatory cytokines. Gastrodin inhibits the occurrence and development of cerebral ischemia–reperfusion injury by regulating JAK2/STAT3 signaling pathway. [Display omitted] • Gastrodin significantly attenuated cerebral ischemia–reperfusion injury. • Gastrodin mitigated MCAO- or OGD/R-induced oxidative stress and mitochondrial damage. • Gastrodin's suppression of mtDNA/TLR9 signaling is linked to the inhibition of inflammation. • The therapeutic effect of Gastrodin is primarily due to the inhibition of the JAK2/STAT3 signaling pathway. The pathway of Janus-activated kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) (termed as JAK2/STAT3) plays an active role in stroke-related inflammation induced by ischemic stress. Gastrodin, the primary compound in Gastrodia elata Bl , has been identified for its notable neuroprotective effects and demonstrated to ameliorate cerebral ischemia–reperfusion but its exact mechanisms governing this defense are still unclear. This study aims to investigate whether gastrodin can regulate mitochondrial function via the JAK2/STAT3 pathway to limit cerebral ischemia–reperfusion. In vivo , gastrodin significantly reduced infarct volume, improved neurobiological function, attenuated neuronal apoptosis, oxidative stress, mitochondrial impairment, mtDNA leakage, and inflammatory responses. At the cellular level, gastrodin administration rescued OGD/R-induced cell apoptosis, oxidative stress, and mitochondrial dysfunction. Mechanistically, gastrodin notably suppressed Toll-like receptor 9 (TLR9) expression, important for the recognition of disrupted endogenous DNA to produce inflammatory reactions. Furthermore, gastrodin mitigated inflammation by inhibiting JAK2/STAT3 signaling, influencing inflammatory factors to aggravate inflammation. Notably, the effects of gastrodin were abolished by Coumermycin A1 (C-A1), a JAK2 agonist, validating the role of JAK2/STAT3 signaling. In summary, gastrodin enhances the protective effect against mitochondrial damage in ischemic stroke by inhibiting JAK2/STAT3 signaling. Gastrodin is a possible therapy for cerebral ischemia. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress have drawn more and more interest in the realm of cardiovascular disease. In many different disorders, IL-37 acts as an anti-inflammatory and suppressor of inflammation. This study aimed to investigate whether IL-37 could alleviate cardiac hypertrophy by reducing inflammation and oxidative stress. In vivo , a cardiac hypertrophy model was induced by 14 d of daily isoproterenol (ISO, 30 mg/kg/d) injection, followed by weeks of treatment with recombinant human IL-37 (1000 ng/animal), administered three times weekly. Assessments concentrated on markers of inflammation and oxidative stress, apoptosis, myocardial disease, and cardiac shape and function. In vitro , neonatal rat cardiomyocytes (NRCMs) were subjected to ISO (10 µM) to establish a cardiomyocytes hypertrophy model. Subsequent IL-37 treatment (100 ng/ml) was applied to determine its cardioprotective efficacy and to elucidate further the underlying mechanisms involved. Significant cardioprotective benefits of IL-37 were seen (in vitro as well as in vivo), primarily through the reduction of oxidative stress, inflammation, apoptosis, and heart hypertrophy markers. Furthermore, IL-37 treatment was associated with a decrease in JAK2 and STAT3 phosphorylation. It is interesting to note that WP1066, a JAK2/STAT3 inhibitor, exhibited antioxidant and anti-inflammatory properties comparable to IL-37, as well as synergistic effects when mixed with the latter. ISO-induced cardiac hypertrophy is lessened by IL-37 through the reduction of oxidative stress and inflammation. Additionally, the effects of IL-37 are closely related to inactivation of the JAK2/STAT3 signaling pathway. It is anticipated that IL-37 will one day be used to treat cardiovascular illnesses such as heart hypertrophy. [ABSTRACT FROM AUTHOR]

• Exploring the role of the JAK2/STAT3 signaling pathway in sepsis-associated diaphragm dysfunction. • Revealing the antioxidant role of Anisodamine in septic diaphragmatic dysfunction. • Anisodamine relieves sepsis-related diaphragmatic dysfunction. There is an increasing tendency for sepsis patients to suffer from diaphragm atrophy as well as mortality. Therefore, reducing diaphragm atrophy could benefit sepsis patients' prognoses. Studies have shown that Anisodamine (Anis) can exert antioxidant effects when blows occur. However, the role of Anisodamine in diaphragm atrophy in sepsis patients has not been reported. Therefore, this study investigated the antioxidant effect of Anisodamine in sepsis-induced diaphragm atrophy and its mechanism. We used cecal ligation aspiration (CLP) to establish a mouse septic mode and stimulated the C2C12 myotube model with lipopolysaccharide (LPS). After treatment with Anisodamine, we measured the mice's bodyweight, diaphragm weight, fiber cross-sectional area and the diameter of C2C12 myotubes. The malondialdehyde (MDA) levels in the diaphragm were detected using the oxidative stress kit. The expression of MuRF1, Atrogin1 and JAK2/STAT3 signaling pathway components in the diaphragm and C2C12 myotubes was measured by RT-qPCR and Western blot. The mean fluorescence intensity of ROS in C2C12 myotubes was measured by flow cytometry. Meanwhile, we also measured the levels of Drp1 and Cytochrome C (Cyt-C) in vivo and in vitro by Western blot. Our study revealed that Anisodamine alleviated the reduction in diaphragmatic mass and the loss of diaphragmatic fiber cross-sectional area and attenuated the atrophy of the C2C12 myotubes by inhibiting the expression of E3 ubiquitin ligases. In addition, we observed that Anisodamine inhibited the JAK2/STAT3 signaling pathway and protects mitochondrial function. In conclusion, Anisodamine alleviates sepsis-induced diaphragm atrophy, and the mechanism may be related to inhibiting the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Tofacitinib, a small molecule JAK inhibitor, has been widely used to reduce inflammation and inhibit progression of bone destruction in rheumatoid arthritis. STAT3, a downstream signaling molecule of JAK, plays a key role in the activation of signaling in response to inflammatory cytokines. Thus, targeting STAT3 may be an inspiring strategy for treating osteoclast-related diseases such as rheumatoid arthritis. In this study, we first investigated the effects of Stattic, a STAT3 inhibitor, on receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis. Stattic inhibited osteoclast differentiation and bone resorption in RANKL-induced RAW264.7 cells in a dose-dependent manner. Stattic also suppressed RANKL-induced upregulation of osteoclast-related genes tartrate-resistant acid phosphatase, matrix metalloproteinase 9, cathepsin K, RANK, tumor necrosis factor receptor-associated factor 6, and osteoclast-associated receptor in RAW264.7 cells. Moreover, Stattic exhibited an inhibitory effect on cell proliferation and cell cycle progression at higher dosages. At the molecular level, Stattic inhibited RANKL-induced activation of STAT3 and NF-κB pathways, without significantly affecting MAPK signaling. In addition, Stattic inhibited RANKL-induced expression of osteoclast-related transcription factors c-Fos and NFATc1. Importantly, Stattic also prevented bone loss caused by ovariectomy. Together, our data confirm that Stattic restricts osteoclastogenesis and bone loss by disturbing RANKL-induced STAT3 and NF-κB signaling. Thus, Stattic represents a novel type of osteoclast inhibitor that could be useful for conditions such as osteoporosis and rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Hepatic stellate cells (HSCs) are universally acknowledged to play a core role in the pathogenesis of hepatic fibrosis. HSCs when activated are characterized by dramatic loss of intracellular lipid droplets. Accumulative evidence has suggested that recovery of lipid droplets could suppress HSC activation. However, the underlying molecular mechanisms still remain largely unclear. In this study, we found that the expression and activity of nuclear factor (erythroid-derived 2) - like 2 (Nrf2) were decreased in activated HSCs and negatively correlated with hepatic fibrosis severity in human liver specimens. Nrf2 overexpression, in contrast to Nrf2 deficiency, induced the accumulation of lipid droplets via decreasing the expression of lipolytic gene peroxisome proliferator-activated receptor alpha (PPARα) and increasing the expression of genes involved in lipogenesis and retinoic acid responsiveness, including CCAAT/enhancer-binding protein alpha, PPARγ, retinoid X receptor alpha, and retinoic acid receptor beta. Consequently, HSCs regained its lipocyte phenotype and expressed reduced alpha-smooth muscle actin and collagen type I. Consistently, disruption of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling by AG490 or Stattic could also induce lipocyte phenotype. Noticeably, Nrf2 overexpression by a genetic approach disrupted JAK2/STAT3 signaling and increased the expression of suppressor of cytokine signaling 3 (SOCS3) but not other protein inhibitors of activated STATs. Gain- or loss-of function of SOCS3 revealed that Nrf2 inhibited JAK2/STAT3 signaling via inducing SOCS3 expression. In conclusion, Nrf2 activation induced lipocyte phenotype in HSCs via enhancing SOCS3-dependent feedback inhibition on JAK2/STAT3 cascade. Nrf2 could be a target molecule for antifibrotic strategy. [ABSTRACT FROM AUTHOR]

The excessive or prolonged production of inflammatory mediators can result in numerous chronic diseases, such as rheumatoid arthritis, atherosclerosis, diabetes, and cancer. Therefore, for many inflammatory-related diseases, pharmaceutical intervention is required to restrain the excessive release of such inflammatory mediators. Novel therapeutics and mechanistic insight are sought for the management of chronic inflammatory diseases. Resokaempferol (RES) is a type of flavonoid recently reported to demonstrate anti-cancer properties. However, the anti-inflammatory capacity of RES has not been studied to date. Therefore, this study investigated whether RES is capable of suppressing the inflammatory response to lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and the mechanism by which this is achieved. We found that RES attenuated the LPS-induced production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP-1) and IL-6. RES also inhibited the nuclear translocation of signal transducer and activator of transcription (STAT) 3 and reduced the LPS-mediated phosphorylation of Janus kinase (JAK) 2 and STAT3 at the sites of Ser727 and Tyr705. RES also inhibited the activation of NF-κB and JNK/p38 MAPK signaling pathways in LPS-induced RAW264.7 cells. Additionally, RES inhibited the activation of the JAK2/STAT3 pathway in exogenous IL-6-activated RAW264.7 macrophages. We conclude that RES inhibits the inflammatory response in activated macrophages by blocking the activation of the JAK2/STAT3 pathway by both LPS and IL-6 signaling. [ABSTRACT FROM AUTHOR]

• Piceatannol lightened oxidative injury and collagen synthesis in lung tissues during pulmonary fibrosis. • Piceatannol inhibited the activation and collagen synthesis of TGF-β-induced lung fibroblasts. • JAK2 activation abolished the effects of piceatannol in TGF-β-induced lung fibroblasts. Pulmonary fibrosis (PF) is characterized by oxidative injury and excessive collagen synthesis in lung fibroblasts, causing impaired pulmonary function and chronic lung injury. Piceatannol, a dietary polyphenol, possesses vital pharmacological effects in metabolic disorders, cancers, cardiovascular disease and infectious disease; however, its role in PF is still not completely elucidated. Mice (8 to 10 weeks old) were administered bleomycin (BLM) intratracheally (2 U/kg) to establish an in vivo PF model. Murine primary lung fibroblasts were isolated and stimulated with TGF-β (10 ng/mL) for 48 h to induce its activation. Meanwhile, mice or primary lung fibroblasts were treated with different doses of piceatannol to observe its protective roles. Pulmonary function and arterial blood gas were detected to assess pulmonary physiological status. Collagen deposition and the mRNA levels of profibrotic genes were determined by H&E staining and RT-PCR. Meanwhile, the protein and mRNA markers, as well as end-product of oxidative stress were detected in vivo and in vitro. The results showed that pulmonary function was significantly impaired in BLM-induced mice, accompanied by elevated oxidative stress and excessive collagen synthesis. Piceatannol significantly improved pulmonary function and decreased oxidative injury as well as collagen synthesis in mice with PF. Mechanically, piceatannol treatment significantly inhibited the activation of JAK2/STAT3 signaling pathway in BLM-induced mice and TGF-β-induced lung fibroblasts. Additional findings also demonstrated that coumermycin A1 (C-A1), an agonist of JAK2, could abolish the effects of piceatannol on TGF-β-induced lung fibroblasts and reactivated the phosphorylation STAT3. Taken together, our study demonstrated that piceatannol could protect against oxidative injury and collagen synthesis during PF in a JAK2/STAT3 signaling pathway-dependent manner. [ABSTRACT FROM AUTHOR]

[Display omitted] • mRTBI inhibits Wnt-1/PKC-α and JAK-2/STAT-3 pathways. • GFAP have an important role in repetitive trauma injury. • Morin protects against mRTBI via upregulating Wnt-1/PKC-α & JAK-2/STAT-3 cues. • Morin leveled off GFAP offering neuroprotection. • Stimulation of Wnt-1/PKC-α and IL-10/JAK-2/STAT-3 promotes cell survival in mRTBI. The slightly available data about the pathogenesis process of mild repetitive traumatic brain injury (mRTBI) indicates to the necessity of further exploration of mRTBI consequences. Several cellular changes are believed to contribute to the cognitive disabilities, and neurodegenerative changes observed later in persons subjected to mRTBI. We investigated glial fibrillary acidic protein (GFAP), the important severity related biomarker, where it showed further increase after multiple trauma compared to single one. To authenticate our aim, Morin (10 mg/kg loading dose, then twice daily 5 mg/kg for 7 days), MK-801 (1 mg/kg; i.p) and their combination were used. The results obtained has shown that all the chosen regimens opposed the upregulated dementia markers (Aβ1-40, p (Thr231)Tau) and inflammatory protein contents/expression of p (Ser53s6)NF-κBp65, TNF-α, IL-6,and IL-1β and the elevated GFAP in immune stained cortex sections. Additionally, they exerted anti-apoptotic activity by decreasing caspase-3 activity and increasing Bcl-2 contents. Saving brain tissues was evident after these therapeutic agents via upregulating the non-canonical Wnt-1/PKC-α cue and IL-10/ p (Tyr(1007/1008))JAK-2/ p (Tyr705)STAT-3 signaling pathway to confirm enhancement of survival pathways on the molecular level. Such results were imitated by correcting the injury dependent deviated behavior, where Morin alone or in combination enhanced behavior outcome. On one side, our study refers to the implication of two survival signaling pathways; viz., the non-canonical Wnt-1/PKC-α and p (Tyr(1007/1008))JAK-2/ p (Tyr705)STAT-3 in single and repetitive mRTBI along with distorted dementia markers, inflammation and apoptotic process that finally disrupted behavior. On the other side, intervention through affecting all these targets by Morin alone or with MK-801 affords a promising neuroprotective effect. [ABSTRACT FROM AUTHOR]