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BACKGROUND In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of the testis-specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain high blood pressure during hypertension. METHODS Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral microinjection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1β, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the BP in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1β and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high BP in hypertensive rats, making it a potential therapeutic target for hypertension. [ABSTRACT FROM AUTHOR]

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men, respectively, worldwide. Although the antitumor activity of chalcones has been extensively studied, the molecular mechanisms of isoliquiritigenin analog 2', 4', 4-trihydroxychalcone (metochalcone; TEC) against carcinomas remain less well understood. In this study, we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner. TEC induced cell cycle arrest in the S-phase, cell migration inhibition in vitro, and reduced tumor growth in vivo. Moreover, transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways. TEC triggered the senescence-associated secretory phenotype (SASP) by repressing the JAK2/STAT3 axis. The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway, highlighting the potential of chalcone in senescence-inducing therapy against carcinomas. [ABSTRACT FROM AUTHOR]

This study explored the effect of Eupatilin on postmenopausal osteoporosis and explored the mechanisms associated with miR-211-5p. First, the rats were given intragastric administration of Eupatilin every day and subcutaneously injected once a week with oligonucleotides or plasmids that interfered with the expression of miR-211-5p or Janus kinase 2 (JAK2). After 4 weeks, a rat model of osteoporosis was established. Then, serum alkaline phosphatase, calcium and phosphorus levels were detected, as well as femur bone mineral density and biomechanical parameters. HE staining and Masson staining were applied for detecting the pathological condition of femur while immunohistochemical staining was for detecting the positive expression of osteocalcin. In addition, MC3T3-E1 cells were transfected with plasmid vectors interfering with miR-211-5p or JAK2, and cell viability, lactate dehydrogenase cytotoxicity, and cell mineralization were subsequently examined. The relationship between miR-211-5p and JAK2/Signal transducer and activator of transcription 3 (STAT3) pathway was analyzed, and the targeting of miR-211-5p and JAK2 was also verified. The experimental results found that Eupatilin improved the pathological conditions of osteoporotic rats by promoting the proliferation and mineralization of osteoblasts. miR-211-5p was down-regulated and JAK2/STAT3 were up-regulated in osteoporotic rats. Upregulation of miR-211-5p further improved the pathological conditions of osteoporotic rats based on Eupatilin treatment. MiR-211-5p inhibited the JAK2/STAT3 pathway. Upregulation of JAK2 reversed the effects of elevated miR-211-5p on osteoporotic rats. Overall, Eupatilin attenuates postmenopausal osteoporosis through elevating miR-211-5p and repressing JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Rosa sterilis (RS) is a characteristic fruit in southwestern China that has numerous health benefits; however, its pharmacological effect needs further clarification, especially with respect to the exploration of its potential anti-breast-cancer effect, as there are still knowledge gaps in this regard. This study was designed to investigate the protective effects of Rosa sterilis juice (RSJ) on breast cancer (BC) through in vitro cellular experiments and by establishing mouse 4T1 breast xenograft tumors. This study also had the aim of elucidating RSJ's underlying mechanisms. RSJ can inhibit cell proliferation, affect cell morphology, and impact the clone formation ability of BC; furthermore, it can promote apoptosis by triggering the mitochondrial apoptosis pathway. In mouse 4T1 breast xenograft tumors, RSJ markedly inhibited tumor growth, relieved the pathological lesions, lowered the expression of Ki67, and regulated the expression of the apoptosis-associated protein. Moreover, we observed that RSJ can inhibit the Jak2/Stat3 signaling pathway both in vivo and in vitro. Overall, our research reveals that RSJ can alleviate BC by triggering the mitochondrial apoptosis pathway and suppressing the Jak2/Stat3 pathway, providing new dietary intervention strategies for BC. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the potential therapeutic applications of (+)-catechin in the treatment of neuropathic pain. In vivo study, 32 SD rats were randomly divided into four groups: sham group, chronic constriction injury (CCI) group, CCI + ibuprofen group and CCI+ (+)-catechin group. They were subjected to behavioural tests, ELISA, immunohistochemistry and Western blotting. The mechanisms involved were investigated using specific inhibitors in cell experiments. Results of in vivo experiments showed that (+)-catechin could reduce the cold sensitivity pain in a rat model of CCI; ELISA and immunohistochemistry results showed that (+)-catechin could decrease the levels of IL-8, IL-6, TNF-α, CCL2 and CCL5 in serum and the expression levels of nNOS, COX2, IL6, TNF-α, IBA-1 and CSF1R in DRG of CCI rats. Finally, western blot confirmed that (+)-catechin could diminish the levels of IL-34/CSF1R/JAK2/STAT3 signalling pathway in DRG of CCI rats. In vitro studies showed that (+)-catechin reduced IL-34 secretion in LPS-induced RSC96 cells. Meanwhile, (+)-catechin administration in LPS-induced Schwann cell–conditioned medium (L-CM) significantly inhibited the proliferation and migration of RAW264.7 cells; in addition, L-CM+(+)-catechin reduced the activation of the CSF1R/JAK2/STAT3 signalling pathway. (+)-Catechin attenuated the Schwann cell-macrophage cascade response in the DRG by modulating the IL34/CSFIR axis and inhibiting activation of the JAK2/STAT3 pathway, thereby attenuating CCI-induced neuropathic pain in rats. [ABSTRACT FROM AUTHOR]

Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti‐CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26‐R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26‐R cells were pretreated with or without BE, followed by transfection with pcDNA‐NC and pcDNA‐JAK2. The proliferation of CT26‐R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26‐R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p‐STAT3, JAK2, PD‐L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p‐STAT3, JAK2, and PD‐L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA‐JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Skin cutaneous melanoma (SKCM) is the skin malignancy with the highest mortality rate, and its morbidity rate is on the rise worldwide. Smoking is an independent marker of poor prognosis in melanoma. The α5-nicotinic acetylcholine receptor (α5-nAChR), one of the receptors for nicotine, is involved in the proliferation, migration and invasion of SKCM cells. Nicotine has been reported to promote the expression of a disintegrin and metalloproteinase 10 (ADAM10), which is the key gene involved in melanoma progression. Here, we explored the link between α5-nAChR and ADAM10 in nicotine-associated cutaneous melanoma. α5-nAChR expression was correlated with ADAM10 expression and lower survival in SKCM. α5-nAChR mediated nicotine-induced ADAM10 expression via STAT3. The α5-nAChR/ADAM10 signaling axis was involved in the stemness and migration of SKCM cells. Furthermore, α5-nAChR expression was associated with ADAM10 expression, EMT marker expression and stemness marker expression in nicotine-related mice homograft tissues. These results suggest the role of the α5-nAChR/ADAM10 signaling pathway in nicotine-induced melanoma progression. [ABSTRACT FROM AUTHOR]

The spleen has an essential role in immune responses regulation and is considered the biggest peripheral immune organ. Citicoline is used for various brain disorders management. This study aimed to examine the using possibility of citicoline to treat γ-radiation-induced splenic inflammation in rats. Eighteen male albino rats were classified into: Group 1 (control) animals were kept as control. Group 2 (γ-radiation) animals were total-body γ-irradiated with 6 Gy. Group 3 (γ-radiation + citicoline) rats were γ-irradiated with 6 Gy, then injected intraperitoneally with citicoline (300 mg/kg/d) 5 min after irradiation for one week. Levels of TNF-α, IL-1β, iNOS, NF-κB, JAK2, and STAT3 were determined in spleen tissue, along with histopathological examination. Rats exposure to gamma-radiation led to elevation in splenic TNF-α, IL-1β, NF-κB, iNOS, JAK2, and STAT3 levels significantly. Treatment with citicoline after gamma-radiation exposure improved this elevation, and modulated gamma-radiation-induced histopathological alterations. This data showed that citicoline inhibited γ-radiation-induced splenic inflammation via suppressing NF-κB and JAK2/STAT3 signaling pathways in spleen tissue. [ABSTRACT FROM AUTHOR]

Background: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. Methods: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. Results: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1β, IL-6, TNF-α, and TGF-β1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-β1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. Conclusion: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-β1, and consequently inhibits FMT and EMT via TGF-β1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent. [ABSTRACT FROM AUTHOR]

Introduction: Although LncRNA JPX has been linked to a number of malignancies, it is yet unknown how it relates to endometrial carcinoma (EC). Investigating the expression, functional activities, and underlying molecular processes of lncRNA JPX in EC was the goal of this work. Methods: RT-qPCR was used to examine the differences in lncRNA/microRNA (miRNA, miR)/mRNA expression between normal cervical and EC tissues or cells. Cell Counting Kit-8, flow cytometry, and transwell were used to evaluate the association between lncRNA JPX/miR-140-3p/phosphoinositide-3-kinase catalytic subunit α (PIK3CA) in Ishikawa and JEC cell lines. The impact of JPX on the downstream janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway was investigated using Western blot analysis. Results: When comparing EC tissues to nearby normal tissues, JPX expression is markedly increased in EC tissues, with greater expression in advanced-stage EC. Furthermore, compared to normal epithelial cells, EC cell lines have higher levels of JPX expression. In Ishikawa and JEC endometrial cancer cell lines, we used siRNA-mediated suppression of JPX to find lower cell viability, increased apoptosis, cell cycle arrest, and reduced migration and invasion. We next verified that miR-140-3p binds to downstream target cells to impede the transcription and translation of PIK3CA, which in turn prevents the growth of Ishikawa and JEC cells. JPX functions as a ceRNA to adsorb miR-140-3p. This procedure required controlling JAK2/STAT3, a downstream signal. Conclusion: JPX enhances the development of Ishikawa and JEC cells and activates downstream JAK2/STAT3 signal transduction via the miR-140-3p/PIK3CA axis, offering a possible therapeutic target for the treatment of EC. [ABSTRACT FROM AUTHOR]

Increased production of reactive oxygen species (ROS) leads to oxidative stress, with its damaging effect extending to the mitochondria and plasma membrane. Further, prolonged inflammation can result in chronic disease development. The marine microdiatom Odontella aurita is recognized for its potential in food and pharmaceutical development. Moreover, it contains antioxidant and anti-inflammatory properties. However, studies regarding the efficacy of their varying extract forms and their underlying mechanisms remain scarce. Therefore, this study aims to explore the antioxidant and anti-inflammatory effects of Odontella aurita extracts obtained using various extraction methods (hot water, 70% ethanol, and chloroform:methanol (CM)). Among the three Odontella aurita extracts, the CM extract demonstrated superior efficacy in protecting RAW 264.7 cells from H2O2-induced cytotoxicity. It significantly lowered the levels of ROS and enhanced the expression of superoxide dismutase and glutathione peroxidase. Furthermore, the CM extract outperformed other extracts in inhibiting LPS-induced nitric oxide production, reducing mRNA levels in nitric oxide synthase, cyclooxygenase, and the proinflammatory cytokines interleukin IL-1β, IL-6, TNFα. Additionally, CM extract effectively suppressed the activation of NF-κB/IκBα and JAK2-STAT3 in LPS-induced RAW 264.7 cells. HPLC–UV analysis revealed a remarkable 33-fold higher fucoxanthin content in CM compared to the ethanol extract. GC–MS analysis identified elevated levels of cholest-5-en-3-ol, phytol, eicosapentaenoic acid methyl ester, methyl palmitate, palmitoleic acid methyl ester, and neophytadiene in the CM extract. These findings suggest that Odontella aurita CM extract is a promising antioxidant candidate for preventing or treating inflammatory diseases, consequently emphasizing its potential for further development. [ABSTRACT FROM AUTHOR]

Cryptotanshinone (CPT), which is an important active ingredient of herbs, has shown great value for research. In particular, CPT exerts antitumor effects on various types of cancer; however, there are relatively few studies of CPT on gastric cancer cells. The objectives of this study were to investigate how CPT affects apoptosis in 5-fluorouracil-resistant SGC-7901 gastric cancer cells (SGC-7901/5-FU cells) and the molecular mechanism underlying its action. In this study, SGC-7901/5-FU cells were treated with 5-fluorouracil (5-FU) and CPT and the viability of the cells was assessed by CCK8 assay. Additionally, cellular apoptosis rates were evaluated using immunofluorescence and flow cytometry. Related gene expression was evaluated using Quantitative Real-time PCR methods and Western Blot, respectively. CPT inhibited SGC-7901/5-FU cell growth. The immunofluorescence results showed that CPT caused nuclear shrinkage in the cells. Quantitative Real-time PCR and Western Blot results also showed CPT decreased the expression of Mcl-1, Bcl-xl and Bcl-2 levels, and increased the expression of Bax. We demonstrated that CPT can inhibit the growth of SGC-7901/5-FU cells, and the mechanism may be related to the inhibition of the JAK2/STAT3 pathway. Additionally, CPT increased the inhibitory effect of 5-fluorouracil on SGC-7901/5-FU cells, an effect that correlated with changes in cellular resistance. [ABSTRACT FROM AUTHOR]

The role of KIAA0040 role in glioma development is not yet understood despite its connection to nervous system diseases. In this study, KIAA0040 expression levels were evaluated using qRT‐PCR, WB and IHC, and functional assays were conducted to assess its impact on glioma progression, along with animal experiments. Moreover, WB was used to examine the impact of KIAA0040 on the JAK2/STAT3 signalling pathway. Our study found that KIAA0040 was increased in glioma and linked to tumour grade and poor clinical outcomes, serving as an independent prognostic factor. Functional assays showed that KIAA0040 enhances glioma growth, migration and invasion by activating the JAK2/STAT3 pathway. Of course, KIAA0040 enhances glioma growth by preventing tumour cell death and promoting cell cycle advancement. Our findings suggest that targeting KIAA0040 could be an effective treatment for glioma due to its role in promoting aggressive tumour behaviour and poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Keloid represents a benign skin tumor with many cancer‐like features. Extracellular vesicles (EVs) derived from human adipose‐derived stem cells (hADSCs) play a role in cell migration of multiple diseases. Aims: This study aimed to investigate the impact of hADSC‐EVs on human keloid fibroblasts (HKFs). Methods: hADSCs were cultured to the 3rd generation, and subsequently assessed for their osteogenic, adipogenic, and chondrogenic differentiative abilities using flow cytometry, alizarin red, oil red O, and alcian blue staining techniques. hADSC‐EVs were isolated through ultracentrifugation and subsequently identified. HKFs at the 3rd generation were subjected to treatment with hADSC‐EVs to observe their endocytosis of EVs by immunofluorescence. CCK‐8, wound healing, and Transwell assays were performed to test HKF proliferation and migration. The levels of autophagy proteins, collagens, and Janus kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) were determined through Western blot analysis. Suppressor of cytokine signaling 1 (SOCS1) expression was determined by RT‐qPCR and Western blot. Results: hADSC‐EVs were successfully isolated from hADSCs. PKH67‐labeled hADSC‐EVs were observed to be endocytosed by HKFs, resulting the inhibition of HKF proliferation, migration, as well as a reduction in collagen deposition. hADSC‐EVs carried SOCS1 into HKFs to suppress HKF autophagy. SOCS1 downregulation in hADSC‐EVs partially nullified the inhibitory effect of hADSC‐EVs on HKFs. hADSC‐EV‐carried SOCS1 inhibited the activation of the JAK2/STAT3 pathway. JAK2/STAT3 pathway activation partially abrogated the suppression of hADSC‐EVs on the proliferation, migration, and collagen deposition of HKF. Conclusion: hADSC‐EVs carried SOCS1 into HKFs and suppressed HKF autophagy, proliferation, migration, and collagen deposition by inactivating the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Postmenopausal osteoporosis (PMOP) poses a significant threat to women's health worldwide. Eupatilin is a key bioactive component of the Chinese herbal medicine Artemisia asiatica Nakai. Recent research reports have proved the inhibitory function of Eupatilin in many diseases. MicroRNAs (miRNAs) are 21–23 nucleotide‐long, single‐stranded, noncoding RNA molecules generated endogenously, and many studies have indicated that miRNAs are involved in the development of osteoporosis. This study explored the role and potential mechanism of Eupatilin underlying PMOP. First, rats were given intragastric administration of Eupatilin every day and subcutaneous injections of oligonucleotides or plasmids that interfered with miR‐211‐5p or janus kinase 2 (JAK2) once a week. After 4 weeks, the PMOP rat model was established. Then, serum alkaline phosphatase, calcium, and phosphorus levels, as well as femur bone mineral density and biomechanical parameters, were detected. Hematoxylin–eosin staining and Masson staining were applied for detecting the pathological condition of femur, and immunohistochemical staining was for detecting osteocalcin. MC3T3‐E1 cells were transfected with plasmid vectors interfering with miR‐211‐5p or JAK2; and cell viability, lactate dehydrogenase cytotoxicity, and cell mineralization were subsequently examined. The relationship between miR‐211‐5p and JAK2/signal transducer and activator of transcription 3 (STAT3) pathway was analyzed. The targeting relation between miR‐211‐5p and JAK2 was also verified. The experimental results revealed that Eupatilin improved the pathological conditions of PMOP rats by promoting the proliferation and mineralization of osteoblasts. MiR‐211‐5p was down‐regulated and JAK2/STAT3 was upregulated in PMOP rats. Upregulation of miR‐211‐5p further improved the pathological conditions of PMOP rats based on Eupatilin treatment. MiR‐211‐5p inhibited the JAK2/STAT3 pathway. JAK2 offset the effects of elevated miR‐211‐5p on PMOP rats. Overall, Eupatilin attenuates PMOP through elevating miR‐211‐5p and repressing JAK2/STAT3 pathway, which suggests the utility of Eupatilin as a potential drug for POMP treatment. [ABSTRACT FROM AUTHOR]

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Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia. [ABSTRACT FROM AUTHOR]

Background: SLC25A17, a peroxisomal solute carrier, has been implicated in various physiological and pathological processes. However, its precise roles and underlying mechanisms in triple-negative breast cancer (TNBC) remain incompletely understood. Methods: The expression and survival data of breast cancer were derived from TCGA and GEO databases. A variety of in vitro assays were conducted, including proliferation, apoptosis, cell cycle, migration, and invasion. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. The levels of autophagy were assessed by mRFP-GFP-LC3 confocal microscopy scanning, western blotting, and electron microscopy. Results: SLC25A17 was highly expressed in breast cancer tissues, which was found to be associated with unfavorable prognosis. Functional assays demonstrated that SLC25A17 knockdown suppressed proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. Moreover, it prompted apoptosis and autophagy. On the other hand, SLC25A17 knockdown promoted autophagy through triggering ROS accumulation, which was counteracted by N-acetyl-l-cysteine (NAC). Furthermore, the pro-apoptotic effect of SLC25A17 knockdown was reversed when treated with autophagy inhibitor 3-MA in TNBC cells, suggesting that SLC25A17 knockdown-induced autophagic cell death. Mechanistically, SLC25A17 performed its function through regulation JAK2/STAT3 signaling in TNBC. In a nude mice xenograft study, SLC25A17 knockdown markedly decreased breast tumor growth and metastasis. Conclusion: SLC25A17 up-regulation may be a critical factor driving TNBC progression by modulating ROS production and autophagy. Consequently, targeting SLC25A17 could be an effective therapeutic strategy against TNBC. [ABSTRACT FROM AUTHOR]

This study aimed to explore the molecular mechanism of LCN2 regulating aerobic glycolysis on abnormal proliferation of HCC cells. Based on the prediction of GEPIA database, the expression levels of LCN2 in hepatocellular carcinoma tissues were detected by RT-qPCR analysis, western blot, and immunohistochemical staining, respectively. In addition, CCK-8 kit, clone formation, and EdU staining were used to analyze the effect of LCN2 on the proliferation of hepatocellular carcinoma cells. Glucose uptake and lactate production were detected using kits. In addition, western blot was used to detect the expressions of aerobic glycolysis-related proteins. Finally, western blot was used to detect the expressions of phosphorylation of JAK2 and STAT3. We found LCN2 was upregualted in hepatocellular carcinoma tissues. CCK-8 kit, clone formation, and EdU staining results showed that LCN2 could promote the proliferation in hepatocellular carcinoma cells (Huh7 and HCCLM3 cells). Western blot results and kits confirmed that LCN2 significantly promotes aerobic glycolysis in hepatocellular carcinoma cells. Western blot results showed that LCN2 could significantly upregulate the phosphorylation of JAK2 and STAT3. Our results indicated that LCN2 activated the JAK2/STAT3 signaling pathway, promoted aerobic glycolysis, and accelerated malignant proliferation of hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a relapsing inflammatory disease with a unique aetiology. The treatment of UC is challenging, and the current clinical therapeutics for colitis have limited efficacy. Thus, finding new and effective treatment options remains urgent. Baricitinib, an inhibitor of Janus kinase (JAK), has been clinically used to treat rheumatoid arthritis (RA). However, its potential effects on UC have not been fully elucidated. In this study, we aimed to explore the effects of baricitinib on UC and its underlying mechanism. Dextran sulphate sodium (DSS)-induced murine model of chronic colitis was used to investigate the intervention efficacy following oral administration of baricitinib. The levels of key cytokines, such as IL-6, IFN-γ and IL-17A, were determined. Moreover, western blotting for IκBα, p-IκBα, JAK2, p-JAK2, STAT3 and p-STAT3 protein expression was performed to investigate the associated signalling pathways. Our findings demonstrated that baricitinib can significantly relieve DSS-induced UC in mice. After baricitinib intervention, IL-6, IFN-γ and IL-17A levels were decreased both in vitro and in vivo. Moreover, the elevated expression levels of p-IκBα, p-JAK2, and p-STAT3 were significantly reduced after treatment. Collectively, these results suggest that baricitinib is a potential therapeutic agent for alleviation of DSS-induced colitis. This study provides a method for subsequent investigations on potential curative drugs development of the for colitis. [ABSTRACT FROM AUTHOR]

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. Here, we show that K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway. Collectively, this study may provide a preliminary basis for further cancer treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition. The search for multi-target traditional Chinese medicines or ingredients for treating AD has attracted much attention. Corydalis rhizome (CR) is a traditional Chinese medicine. Its main components are alkaloids, which have therapeutic effects that can potentially be used for treating AD. However, no systematic study has been conducted to explore the anti-AD efficacy of CR, as well as its active compounds and mechanisms of action. Objective: The present study aimed to clarify CR’s active constituents and its pharmacological mechanisms in treating AD. Methods: A D-galactose & scopolamine hydrobromide-induced AD mouse model was used and CR was administered orally. The prototypical alkaloid components were identified in the serum. The core components, key targets, and possible mechanisms of action of these alkaloids were revealed through network pharmacology. Molecular docking of the key target was performed. Finally, the mechanism was validated by lipopolysaccharide (LPS)-induced activation of BV2 microglia. Results: The results showed that CR improved anxiety-like behavior, spatial and non-spatial recognition, and memory capacity in AD mice. It also achieved synergistic AD treatment by modulating neurotransmitter levels, antineuroinflammation, and anti-oxidative stress. The core components that enhance CR’s efficacy in treating AD are protoberberine-type alkaloids. The CR may induce the polarization of LPS-activated BV2 microglia from phenotype M1 to M2. This is partially achieved by modulating the IL-6/JAK2/STAT3 signaling pathway, which could be the mechanism by which CR treats AD through anti-inflammation. Conclusion: The present study provided a theoretical and experimental basis for the clinical application of CR in treating AD. It also provides information that aids the secondary development, and precise clinical use of CR. [ABSTRACT FROM AUTHOR]

Purpose: Tingli Dazao Xiefei Decoction (TDXD) is a Traditional Chinese Medicine (TCM) formula used to treat acute lung injury (ALI). However, the precise mechanism of TDXD in treating ALI remains unclear. We investigated the therapeutic mechanism of TDXD against ALI using a complementary approach combining network pharmacology, molecular docking, and in vitro and in vivo experiments.Material and Methods: Potential drug targets of TDXD and relevant target genes associated with ALI were retrieved from Chinese medicines and disease genes databases. Bioinformatics technology was employed to screen potential active ingredients and core targets. Validation experiments were conducted using a lipopolysaccharide (LPS)-induced ALI mouse (C57BL/6J) model, LPS-induced inflammatory RAW264.7 cells, and molecular docking between active compounds of TDXD and potential targets.Results: Network pharmacology suggested that the mechanism of TDXD against ALI involved phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) / phosphatase and tensin homolog (PTEN) and Janus kinase 2 (JAK2) / signal transducer and activator of transcription 3 (STAT3) pathways. Quercetin, β-sitosterol, kaempferol, isorhamnetin, and L-stepholidine were identified as the main active compounds of TDXD that exerted anti-ALI effects. Molecular docking indicated that these compounds exhibited good binding capabilities (≤ − 5kcal/mol) to key targets in PI3K/AKT/PTEN and JAK2/STAT3 signaling pathways. In the animal model, TDXD alleviated injuries and inflammatory responses in lung tissues, accompanied by inhibition of expression of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), STAT3, and Suppressor of Cytokine Signaling 3 (SOCS3) mRNA, and key proteins in PI3K/AKT/PTEN and JAK2/STAT3 pathways (all P values < 0.05). Cell based experiments showed that TDXD dose-dependently inhibited the expression of essential proteins in PI3K/AKT/PTEN and JAK2/STAT3 pathways (P < 0.05).Conclusion: This study revealed that the mechanism of TDXD in ALI treatment might involve simultaneous regulation of PI3K/AKT/PTEN and JAK2/STAT3 pathways. [ABSTRACT FROM AUTHOR]

Retinoblastoma (RB) is an intraocular tumor in children. Accumulated evidence confirms that microRNAs (miRNAs) exert critical functions in RB. This research aimed to investigate the miR‐452‐5p function in RB. MiR‐452‐5p expressions in RB were tested with quantitative real‐time polymerase chain reaction (PCR). MiR‐452‐5p functions in RB were evaluated via Cell Counting Kit‐8, 5‐Ethynyl‐2′‐deoxyuridine assay, flow cytometry, Western blot, and Transwell. MiR‐452‐5p mechanism in RB was assessed using bioinformatics software Starbase and dual‐luciferase reporter gene assay. Meanwhile, miR‐452‐5p function in RB in vivo was examined by constructing tumor xenografts in nude mice, immunohistochemistry, and Western blot assays. MiR‐452‐5p was overexpressed in RB tissues and cells, and miR‐452‐5p expression was positively correlated with RB clinicopathology including the Largest tumor base (mm) and Differentiation. Functionally, miR‐452‐5p knockdown restrained RB cell proliferation, invasion, epithelial–mesenchymal transition (EMT), and facilitated cell apoptosis. Mechanistically, suppressors of cytokine signaling (SOCS3) knockdown restored the inhibitory effects of miR‐452‐5p knockdown on RB cells. Meanwhile, in vivo studies further corroborated that miR‐452‐5p knockdown reduced RB tumor growth, EMT, and accelerated apoptosis in vivo. Also, miR‐452‐5p knockdown increased SOCS3 protein levels, and decreased phosphorylated Janus kinase 2/Janus kinase 2 (JAK2), phosphorylated signal transducer and activator of transcription 3/signal transducer and activator of transcription 3 (STAT3) in vivo. MiR‐452‐5p accelerated RB cell growth and invasion by SOCS3/JAK2/STAT3. [ABSTRACT FROM AUTHOR]

Objective(s): Ovarian ischemia/reperfusion (I/R) is an extremely complex pathological problem that begins with oxygen deprivation, progresses to excessive free radical production, and intensifies inflammation. The JAK2/STAT3 signaling pathway is a multipurpose signaling transcript channel that plays a role in several biological functions. Trimetazidine (TMZ) is a cellular anti-ischemic agent. This study aims to investigate the effects of TMZ on ovarian I/R injury in rats. Materials and Methods: sixty four rats were divided into 8 groups at random: healthy(group1); healthy+TMZ20(group2); ischemia (I) (group 3); I+TMZ10(group4); I+ TMZ20(group5); I/R(group6); I/R+TMZ10(group7); I/R+TMZ20(group8). Vascular clamps were placed just beneath the ovaries and over the uterine horns for 3 hr to induce ischemia. The clamps were removed for the reperfusion groups, and the rats were reperfused with care to ensure that the blood flowed into the ovaries, subjecting them to reperfusion for 3 hr. TMZ was administered orally by gavage 6 and 1 hr before operations. At the end of the experiment, ovarian tissues were removed for biochemical, molecular, and histopathological investigation. Results: TMZ administration ameliorated ischemia/reperfusion-induced disturbances in GSH and MDA levels. TMZ treatment inhibited I/R-induced JAK2/STAT3 signaling pathway activation in ovarian tissues. TMZ administration also improved the increase in the mRNA expressions of IL-1β, TNF-α, and NF-κB caused by ischemia/reperfusion injury. Moreover, TMZ treatment improved histopathologic injury in ovarian tissues caused by ischemia/reperfusion. Conclusion: TMZ treatment protected rats against ovarian ischemia/reperfusion injury by alleviating oxidative stress and inflammatory cascades. These findings may provide a mechanistic basis for using TMZ to treat ovarian ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo Zuzhi Gongcheng Yanjiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Butyrate (BU), a gut microbiota‐derived metabolite, has been reported to play a neuroprotective role in Parkinson's disease (PD). However, the specific molecular mechanism of BU has not been fully interpreted. This work aimed to verify the protective effects of BU against MPTP/MPP+‐induced neurotoxicity and explore the mechanisms involved. The results showed that BU protected against MPTP‐induced motor dysfunction and decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels. Additionally, BU pretreatment improved PC12 cell viability and reduced MPP+‐induced PC12 cell apoptosis. BU treatment also attenuated MPP+‐stimulated oxidative stress and inflammatory response in PC12 cells. Furthermore, BU inhibited MPTP/MPP+‐induced hyperactivation of the JAK2/STAT3 signaling in mice and PC12 cells. Besides, a JAK2 agonist, Coumermycin A1 (C‐A1), substantially reversed BU‐mediated inhibition on JAK2/STAT3 phosphorylation in MPP+‐challenged PC12 cells and abated BU‐induced repression on MPP+‐triggered apoptosis, oxidative stress, and inflammatory response in PC12 cells. To sum up, BU might exert neuroprotective effects against MPP+/MPTP‐induced neurotoxicity by inactivating the JAK2/STAT3 signaling. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) implicates oxidative stress, apoptosis, and inflammation, all of which may contribute liver injury. Aerobic exercise is assured to positively regulate metabolism in the liver. This project was designed to investigate whether and how aerobic exercise improves DM-induced liver injury.Methods: Seven-week-old male db/db mice and age-matched m/m mice were randomly divided into a rest control group or a group that received 12 weeks of aerobic exercise by treadmill training (10 m/min). Haematoxylin and eosin (HE) staining, electron microscopy, Oil Red O staining and TUNEL assays were used to evaluate the histopathological changes in mouse liver. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TRIG), cholesterol (CHOL) were analyzed by serum biochemical analysis. Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed via ELISA. Nuclear factor E2-associated factor-2 (Nrf2), nuclear factor κB (NF-κB) and JAK2/STAT3 pathway-related proteins were measured by immunofluorescence, Western blotting and q-PCR. F4/80 expression in liver tissues was assessed by immunohistochemistry.Results: In diabetic mice, exercise training significantly decreased the levels of serum TRIG, CHOL, IL-6, TNF-α, ALT and AST; prevented weight gain, hyperglycaemia, and impaired glucose and insulin tolerance. Morphologically, exercise mitigated the diabetes-induced increase in liver tissue microvesicles, inflammatory cells, F4/80 (macrophage marker) levels, and TUNEL-positive cells. In addition, exercise reduced the apoptosis index, which is consistent with the results for caspase-3 and Bax. Additionally, exercise significantly increased SOD activity, decreased MDA levels, activated Nrf2 and decreased the expression of NF-kB, phosphorylated JAK2 and STAT3 proteins in the livers of diabetic mice.Conclusion: This study demonstrated that aerobic exercise reversed liver dysfunction in db/db mice with T2DM by reducing oxidative stress, apoptosis and inflammation, possibly by enhancing Nrf2 expression and inhibiting the JAK2/STAT3 cascade response. [ABSTRACT FROM AUTHOR]

The male reproductive system requires the pleiotropic activity of JAK/STAT to maintain its function, especially spermatogenesis. The study aims to investigate the effect of JAK2 signaling on the expression of the Keap1/Nrf2 axis, spermatogenesis, and the Sertoli cells (Sc) junctions in an animal model of testicular ischemia reperfusion injury (tIRI). Testes subjected to tIRI exhibited increased JAK2/STAT3 activity associated with spermatogenic arrest and reduced expression of the Sc junctions. In addition, there was an increased protein expression of Keap1 and decreased Nrf2., which was coupled with the downregulation of gene expression of antioxidant enzymes. Reduced SOD and CAT activities were accompanied by increased lipid peroxidation and protein carbonylation during tIRI. Increased caspase 9 activity and Bax/Bcl2 ratio indicated initiation of apoptosis. Inhibition of JAK2 activity by AG490 maintained the integrity of spermatogenesis and SC junctions, normalized the expression of the Keap1/Nrf2 axis and its downstream antioxidant enzymes, and prevented germ cell apoptosis. The results further emphasized the regulatory role of JAK2/STAT3 on spermatogenesis, Keap1/Nrf2 signaling, and maintenance of the testicular redox balance to combat testicular dysfunction and male infertility. [ABSTRACT FROM AUTHOR]

Background: The development and prognosis of breast cancer are intricately linked to psychological stress. In addition, depression is the most common psychological comorbidity among breast cancer survivors, and reportedly, Fang-Xia-Dihuang decoction (FXDH) can effectively manage depression in such patients. However, its pharmacological and molecular mechanisms remain obscure. Methods: Public databases were used for obtaining active components and related targets. Main active components were further verified by ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). Protein-protein interaction and enrichment analyses were taken to predict potential hub targets and related pathways. Molecule docking was used to understand the interactions between main compounds and hub targets. In addition, an animal model of breast cancer combined with depression was established to evaluate the intervention effect of FXDH and verify the pathways screened by network pharmacology. Results: 174 active components of FXDH and 163 intersection targets of FXDH, breast cancer, and depression were identified. Quercetin, methyl ferulate, luteolin, ferulaldehyde, wogonin, and diincarvilone were identified as the principal active components of FXDH. Protein-protein interaction and KEGG enrichment analyses revealed that the phosphoinositide-3-kinase-protein kinase B (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK2/STAT3) signaling pathways played a crucial role in mediating the efficacy of FXDH for inhibiting breast cancer progression induced by depression. In addition, in vivo experiments revealed that FXDH ameliorated depression-like behavior in mice and inhibited excessive tumor growth in mice with breast cancer and depression. FXDH treatment downregulated the expression of epinephrine, PI3K, AKT, STAT3, and JAK2 compared with the control treatment (p < 0.05). Molecular docking verified the relationship between the six primary components of FXDH and the three most important targets, including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT, and STAT3. Conclusion: This study provides a scientific basis to support the clinical application of FXDH for improving depression-like behavior and inhibiting breast cancer progression promoted by chronic stress. The therapeutic effects FXDH may be closely related to the PI3K/AKT and JAK2/STAT3 pathways. This finding helps better understand the regulatory mechanisms underlying the efficacy of FXDH. [ABSTRACT FROM AUTHOR]

Daphnetin is a natural coumarin compound with anti‐inflammatory, anti‐oxidant, and anti‐apoptotic effects, which has been previously demonstrated to ameliorate DSS‐induced ulcerative colitis (UC). However, the molecular mechanism involved in the daphnetin‐mediated pathological process of UC remains unclarified. The current study used DSS‐induced mice and LPS‐challenged Caco‐2 cells as UC models. Bodyweight, disease activity index (DAI) score, and colon length were used to evaluate the severity of colitis. The histological changes in colon tissues were observed using H&E and PAS staining. Protein levels were detected by western blot. The malondialdehyde (MDA) and superoxide dismutase (SOD) activities were used to assess oxidative stress. Inflammatory responses were evaluated by detecting the levels of inflammatory cytokines (IFN‐r, IL‐1β, IL‐6, and TNF‐α) using flow cytometry. CCK‐8 and TUNEL assay were employed to determine cell growth and cell death, respectively. The results showed that daphnetin could ameliorate the severity of colitis and attenuate the damage to intestinal structure in DSS‐induced mice. Compared with the DSS group, the expression of ZO‐1, occludin, and anti‐apoptotic protein (BCL‐2) was increased while the level of pro‐apoptotic proteins (Bax and cleaved caspase 3) was decreased in DSS + daphnetin group. The activity of MDA and SOD, as well as the levels of inflammatory cytokines were substantially suppressed by daphnetin. In consistency, in vitro assays indicated that daphnetin protected Caco‐2 cells from LPS‐stimulated viability impairment, apoptosis, oxidative stress, and inflammation. Furthermore, daphnetin suppressed the activity of JAK2/STAT signaling in LPS‐induced Caco‐2 cells in a REG3A‐dependent manner. REG3A overexpression abated the ameliorative effects of daphnetin while JAK2/STAT signaling inhibition functioned synergically with daphnetin in LPS‐stimulated Caco‐2 cells. Collectively, this study deepened the understanding of the therapeutic effects of daphnetin on UC and uncovered for the first time that daphnetin functioned through REG3A‐activated JAK2/STAT3 signaling in UC, which may provide novel insights for the treatment of UC. [ABSTRACT FROM AUTHOR]

Endocannabinoids act as a stress response system; simultaneously, the modulation of this system has emerged a novel approach for the therapy of cardiovascular disorders. We investigated the protective effects of the chronic administration of the fatty acid amide hydrolase inhibitor URB597 on morphology, pro-inflammatory and anti-inflammatory cytokine, the cytoplasm-nuclear distribution of JAK2/STAT3, and NF-κB and Nrf2/HO-1 signaling in the left ventricle of female and male rats exposed to chronic unpredictable stress. Our results show that URB597 treatment exhibits an antidepressant-like effect, decreases the heart/body weight ratio, prevents the hypertrophy of cardiomyocytes, and reduces the increased level of IL-6 in the wall of the left ventricle of stressed female and male rats. The phosphorylation levels of JAK2 and STAT3 in the ventricle of male rats treated with URB597 were declined, whereas in female rats the decrease of STAT3 was observed. In addition, URB597 reduced increased NF-κB in both females and males and increased the expression of Nrf2 and HO-1 protein in the cytosol of male rats, whereas did not affect their levels in females. Cardioprotective effects of URB597 could be linked to the ability to inhibit the JAK2 in males and the STAT3 inflammatory signaling pathways in both females and males. [ABSTRACT FROM AUTHOR]

Optic nerve injury is a type of neurodegenerative disease. Physcion is an anthraquinone that exerts a protective role against various diseases. However, its function in regulating optic nerve injury remains largely unknown. An in vitro model of optic nerve injury was established in HAPI cells treated with IFN-ß. Functional assays were used to detect HAPI cell viability and apoptosis. The levels of inflammation and the expression levels of oxidative stress-related genes were measured in HAPI cells. In addition, western blot analysis was used to detect the expression levels of Janus kinase 2 (JAK2)/STAT3-linked genes in HAPI cells. Treatment of the cells with physcion prevented cells against IFN-ß-induced neuronal injury. Physcion restrained IFN-ß-induced inflammatory response and oxidative stress in HAPI cells. In addition, it improved IFN-ß-induced injury in HAPI cells by suppressing the JAK2/STAT3 pathway. In conclusion, the present study revealed that physcion improved optic nerve injury in vitro by inhibiting the JAK2/STAT3 pathway. Physcion may be a promising therapeutic target for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Background: Hepatic ischemia–reperfusion injury (IRI) in donation after cardiac death (DCD) donors is a major determinant of transplantation success. Endoplasmic reticulum (ER) stress plays a key role in hepatic IRI, with potential involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and the antiapoptotic protein hematopoietic-lineage substrate-1-associated protein X-1 (HAX1). In this study, we aimed to investigate the effects of hypothermic oxygenated perfusion (HOPE), an organ preservation modality, on ER stress and apoptosis during hepatic IRI in a DCD rat model. Methods: To investigate whether HOPE could improve IRI in DCD livers, levels of different related proteins were examined by western blotting and quantitative real-time polymerase chain reaction. Further expression analyses, immunohistochemical analyses, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and transmission electron microscopy were conducted to analyze the effects of HOPE on ER stress and apoptosis. To clarify the role of the JAK2/STAT3 pathway and HAX1 in this process, AG490 inhibitor, JAX1 plasmid transfection, co-immunoprecipitation (CO-IP), and flow cytometry analyses were conducted. Results: HOPE reduced liver injury and inflammation while alleviating ER stress and apoptosis in the DCD rat model. Mechanistically, HOPE inhibited unfolded protein responses by activating the JAK2/STAT3 pathway, thus reducing ER stress and apoptosis. Moreover, the activated JAK2/STAT3 pathway upregulated HAX1, promoting the interaction between HAX1 and SERCA2b to maintain ER calcium homeostasis. Upregulated HAX1 also modulated ER stress and apoptosis by inhibiting the inositol-requiring enzyme 1 (IRE1) pathway. Conclusions: JAK2/STAT3-mediated upregulation of HAX1 during HOPE alleviates hepatic ER stress and apoptosis, indicating the JAK2/STAT3/HAX1 pathway as a potential target for IRI management during DCD liver transplantation. [ABSTRACT FROM AUTHOR]

The progression of hepatocellular carcinoma (HCC) involves multifactor, multistep interactions. High expression of interleukin‐6 receptor (IL‐6R) plays an important role in the occurrence and development of tumours, but the regulatory mechanism of IL‐6R expression and its function in HCC have not been fully defined. Western blot was used to evaluate the phosphorylation of key kinases in the JAK2/STAT3 pathway and the protein expression levels of related proliferation molecules, migration molecules and apoptotic molecules. The antiapoptosis, migration and proliferation of cells of each group were analysed with JC‐1 to judge the cell apoptosis rate, the EdU method to determine the proliferation vitality of the cells, clone formation experiments and Transwell experiments. High expression of IL‐6R in cell lines, lower protein levels of the apoptotic molecules c‐Caspase7 and c‐Caspase3 and higher protein levels of the proliferative molecules p‐P70S6K and migration molecules MMP9 and MMP2 were consistent with stronger antiapoptosis, proliferation and migration. Interestingly, IL‐6 upregulated the expression of IL‐6R by activating the JAK2/STAT3 signalling pathway. Also, the expression of IL‐6R protein was downregulated after lentivirus knockdown of STAT3. In nude mice bearing subcutaneous tumours, upregulation of IL‐6R expression after activation of the JAK2/STAT3 signalling pathway by IL‐6 significantly increased tumour growth. Moreover, the expression of IL‐6R protein was downregulated, and the terminal tumour volume was significantly downregulated in the lentiviral STAT3 knockdown group. IL‐6 regulated the transcription of IL‐6R through the activation of the JAK2/STAT3 signalling pathway. [ABSTRACT FROM AUTHOR]

Copyright of Mycosystema is the property of Mycosystema Editorial Board and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Osteoarthritis (OA) is a multifactorial chronic disease primarily characterized by the degeneration of articular cartilage. Currently, there is a lack of effective treatments for OA other than surgery. The exploration of the mechanisms of occurrence is important in exploring other new and effective treatments for OA. The current evidence shows that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a vital role in cytogenesis and is involved in OA progression. The terms "JAK2", "STAT3", and "Osteoarthritis"were used in a comprehensive literature search in PubMed to further investigate the relationship between the JAK2/STAT3 signaling pathway and OA. This review focuses on the role and mechanism of JAK2/STAT3 signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation. In addition, this review summarizes recent evidence of therapeutic approaches to treat OA by targeting the JAK2/STAT3 pathway to accelerate the translation of evidence into the progression of strategies for OA treatment. Aq2kuF8RhmhLRVBTwsgJsc Video abstract [ABSTRACT FROM AUTHOR]

Purpose: Sepsis is an aggressive and life-threatening organ dysfunction induced by infection. Excessive inflammation and coagulation contribute to the negative outcomes for sepsis, resulting in high morbidity and mortality. In this study, we explored whether Eupatilin could alleviate lung injury, reduce inflammation and coagulation during sepsis. Methods: We constructed an in vitro sepsis model by stimulating RAW264.7 cells with 1 μg/mL lipopolysaccharide (LPS) for 6 hours. The cells were divided into control group, LPS group, LPS+ Eupatilin (Eup) group, and Eup group to detect their cell activity and inflammatory cytokines and coagulation factor levels. Cells in LPS+Eup and Eup group were pretreated with Eupatilin (10μM) for 2 hours. In vivo, mice were divided into sham operation group, cecal ligation and puncture (CLP) group and Eup group. Mice in the CLP and Eup groups were pretreated with Eupatilin (10mg/kg) for 2 hours by gavage. Lung tissue and plasma were collected and inflammatory cytokines, coagulation factors and signaling were measured. Results: In vitro, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and tissue factor (TF) expression in LPS-stimulated RAW264.7 cells was downregulated by Eupatilin (10μM). Furthermore, Eupatilin inhibited phosphorylation of the JAK2/STAT3 signaling pathway and suppressed p-STAT3 nuclear translocation. In vivo, Eupatilin increased the survival rate of the mice. In septic mice, plasma concentrations of TNF-α, IL-1β and IL-6, as well as TF, plasminogen activator inhibitor 1 (PAI-1), D-dimer, thrombin-antithrombin complex (TAT) and fibrinogen were improved by Eupatilin. Moreover, Eupatilin alleviated lung injury by improving the expression of inflammatory cytokines and TF, fibrin deposition and macrophage infiltration in lung tissue. Conclusion: Our results revealed that Eupatilin may modulate inflammation and coagulation indicators as well as improve lung injury in sepsis via the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. At present, the mortality rate of the deadly disease is still very high, while the existing treatments only delay the progression of the disease and improve the quality of life of patients. Lung cancer (LC) is the most fatal disease in the world. In recent years, IPF has been considered to be an independent risk factor for the development of LC. The incidence of lung cancer is increased in the patients with IPF and the mortality is also significantly increased in the patients inflicted with the two diseases. In this study, we evaluated an animal model of pulmonary fibrosis complicated with LC by implanting LC cells orthotopically into the lungs of mice several days after bleomycin induction of the pulmonary fibrosis in the same mice. In vivo studies with the model showed that exogenous recombinant human thymosin beta 4 (exo-rhTβ4) alleviated the impairment of lung function and severity of damage of the alveolar structure by the pulmonary fibrosis and inhibited the proliferation of LC tumor growth. In addition, in vitro studies showed that exo-rhTβ4 inhibited the proliferation and migration of A549 and Mlg cells. Furthermore, our results also showed that rhTβ4 could effectively inhibit the JAK2-STAT3 signaling pathway and this might exert an anti-IPF-LC effect. The establishment of the IPF-LC animal model will be helpful for the development of drugs for the treatment of IPF-LC. Exogenous rhTβ4 can be potentially used for the treatment of IPF and LC. [ABSTRACT FROM AUTHOR]

Retinal fibrosis was a key characteristic of diabetes retinopathy (DR). Apelin was found to be a candidate for tissue fibrosis. Nevertheless, the role of Apelin in the Müller cells in DR remains unclear. This study identified the function and mechanism of Apelin in Müller cells and the fibrosis of retinal tissue. Western blot was carried out to detect the Apelin, GFAP, Collagen I, α-SMA, JAK2 and STAT3 protein levels. Masson staining was performed to display the histopathological changes in retinal tissue of diabetic mellitus (DM) rats. The immunofluorescence staining was conducted to evaluate the Apelin levels in the retinal tissue. The levels of GFAP, Collagen I and α-SMA in the retinal tissue of DM rats was visualised by the immunohistochemistry staining. The results showed that Apelin, GFAP, Collagen I andα-SMA expression was prominently elevated in the retinal tissue of DM rats and high glucose (HG)-exposed Müller cells. The results of Masson staining showed that the epiretinal fibrotic membrane was observed in DM rats. Apelin knockdown declined the GFAP, Collagen I andα-SMA levels. Besides, the protein levels of p-JAK2 and p-STAT3 were elevated in the HG-treated Müller cells, while Apelin knockdown declined them. FLLL32 treatment neutralised the role of Apelin. In conclusion, Apelin facilitated the fibrogenic activity of Müller cells through activating the JAK2/STAT3 signalling pathway, and thus inducing the retinal fibrosis in DR. [ABSTRACT FROM AUTHOR]

Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1/2/total ERK1/2, phosphorylated STAT3/total STAT3, and phosphorylated AKT1/2/3/total AKT1/2/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2/STAT3, MAPK/ERK, and PI3K/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFNγ, IL-8, IL-6, GM-CSF, MCP-1, and TNF-α), fibrotic (TGF-β1, TGF-β2, and TGF-β3), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-α, TGF-β3, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways. [ABSTRACT FROM AUTHOR]

Zinc (Zn) has been reported to mediate leptin secretion, and thus leptin can be an important candidate molecule linking Zn with bone formation. The present study investigated whether zinc deficiency induces leptin secretion by activating a JAK2/STAT3 signaling pathway and leads to osteoblastic apoptosis. MC3T3-E1 cells were incubated for 24 h in normal osteogenic differentiation medium (OSM) or OSM treated with either 1 μM (Low Zn) or 15 μM (High Zn) of ZnCl2 containing 5 μM TPEN (Zn chelator). Our results demonstrated that low Zn stimulated extracellular leptin secretion and increased mRNA and protein expression of leptin in osteoblastic MC3T3-E1 cells. The OB-Rb (long isoform of leptin receptor) expressions were also elevated in osteoblasts under depletion of Zn. Leptin-signaling proteins, JAK2 and p-JAK2 in the cytosol of low Zn osteoblast conveyed leptin signaling, which ultimately induced higher p-STAT3 expression in the nucleus. Apoptotic effects of JAK2/STAT3 pathway were shown by increased caspase-3 in low Zn osteoblasts as well as apoptotic morphological features observed by TEM. Together, these data suggest that low Zn modulates leptin secretion by activating JAK2/STAT3 signaling pathway and induces apoptosis of osteoblastic MC3T3-E1 cells. [ABSTRACT FROM AUTHOR]

Objectives: Esculetin is a coumarin derivative, which is extracted from the dried barks of fraxinus chinensis Roxb. Although it is reported esculetin possesses multiple pharmacological activities, its associated regulatory mechanism on ovarian cancer isn't well investigated. Methods: Cytotoxicity is evaluated by MTT, clonogenic and living/dead cells staining assays. Migration and invasion effects are investigated by wound healing, and transwell assays. The effect of cell cycle and apoptosis are analyzed by flow cytometry and western blotting. Mitochondrial membrane potential and intracellular reactive oxygen species (ROS) is assessed by fluorescence microscope. Analysis of animal experiments are carried out by various pathological section assays. Key findings: Esculetin exerts an anti- ovarian cancer effect. It is found that apoptosis induction is promoted by the accumulation of excessive ROS and inhibition of JAK2/STAT3 signalling pathway. In addition, exposure to esculetin leads to the cell viability reduction, migration and invasion capability decrease and G0/G1 phase cell cycle arrest induced by down-regulating downstream targets of STAT3. In vivo experimental results also indicate esculetin can inhibit tumour growth of mice. Conclusions: Our study provides some strong evidences to support esculetin as a potential anti-cancer agent in ovarian cancer. [ABSTRACT FROM AUTHOR]

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Atopic dermatitis (AD) is a chronic inflammatory skin disease with a profound negative impact on patients' quality of life. Four known secondary fungal metabolites were found in the chemical study of the Antarctic fungus Pleosporales sp. SF-7343, including 14-methoxyalternate C (1), 5′-methoxy-6-methyl-biphenyl-3,4,3′-triol (2), 3,8,10-trihydroxy-4-methoxy-6-methylbenzocoumarin (3), and alternariol monomethyl ether (4). Additionally, we identified the skin anti-inflammatory composition from the SF-7343 strain. Interleukin-8 and -6 Screening results showed that compound 1 inhibited IL-8 and IL-6 in tumor necrosis factor-α/interferon-γ stimulated HaCaT cells. Compound 1 showed inhibitory effects on MDC and RANTES. It also downregulated the expression of intercellular adhesion molecule-1 (ICAM-1) and upregulated the expression of involucrin. The results of the mechanistic study showed that compound 1 inhibited the nuclear translocation of nuclear factor-kappa B p65 and STAT3. In conclusion, this study demonstrates the potential of the Antarctic fungal strain SF-7343 as a bioactive resource to inhibit skin inflammation, such as AD. [ABSTRACT FROM AUTHOR]

Background: Cibotii rhizoma (CR) is a famous traditional Chinese medicine (TCM) used to treat bleeding, rheumatism, lumbago, etc. However, its therapeutic effects and mechanism against thrombocytopenia are still unknown so far. In the study, we investigated the effects of aqueous extracts of Cibotii rhizoma (AECRs) against thrombocytopenia and its molecular mechanism.Methods: Giemsa staining, phalloidin staining, and flow cytometry were performed to measure the effect of AECRs on the megakaryocyte differentiation in K562 and Meg-01 cells. A radiation-induced thrombocytopenia mouse model was constructed to assess the therapeutic actions of AECRs on thrombocytopenia. Network pharmacology and experimental verification were carried out to clarify its mechanism against thrombocytopenia. Results: AECRs promoted megakaryocyte differentiation in K562 and Meg-01 cells and accelerated platelet recovery and megakaryopoiesis with no systemic toxicity in radiation-induced thrombocytopenia mice. The PI3K/AKT, MEK/ERK, and JAK2/STAT3 signaling pathways contributed to AECR-induced megakaryocyte differentiation. The suppression of the above signaling pathways by their inhibitors blocked AERC-induced megakaryocyte differentiation. Conclusions: AECRs can promote megakaryopoiesis and thrombopoiesis through activating PI3K/AKT, MEK/ERK, and JAK2/STAT3 signaling pathways, which has the potential to treat radiation-induced thrombocytopenia in the clinic. [ABSTRACT FROM AUTHOR]

Atropine is an anticholinergic drug widely used in the field of ophthalmology, but its abuse can cause cytotoxicity to the cornea, resulting in blurred vision. This study used cultured human corneal epithelial cells (HCECs) to investigate the mechanism of high‐concentration atropine‐induced cytotoxicity. HCECs were treated with different concentrations of atropine. The expression levels of microRNA (miR)‐30c‐1 and suppressor of cytokine signaling 3 (SOCS3) were manipulated in HCECs treated with 0.1% atropine. Cell counting kit‐8 assay and flow cytometry were used to assess the viability and apoptosis of HCECs. The relationship between miR‐30c‐1 and SOCS3 was obtained from an online database and validated using a dual‐luciferase reporter assay and RNA immunoprecipitation method. The effect of atropine on the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway was also investigated. High‐concentration atropine inhibited the viability of HCECs and promoted their apoptosis. Moreover, atropine reduced miR‐30c‐1 expression and increased SOCS3 expression in a dose‐dependent manner. It was found that miR‐30c‐1 targeted SOCS3. Overexpression of miR‐30c‐1‐reduced atropine‐induced HCEC cytotoxicity, whereas upregulation of SOCS3 reversed the effects of miR‐30c‐1 overexpression. High‐concentration atropine inhibited activation of the JAK2/STAT3 signaling pathway via miR‐30c‐1/SOCS3. High‐concentration atropine induces HCEC apoptosis by regulating the miR‐30c‐1/SOCS3 axis and JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a multisystemic and placental inflammatory disease that causes maternal and infant health issues. As one of the active components in peony root extract, paeonol (Pae) exerts anti‐apoptosis and anti‐inflammatory effects. Nonetheless, the protective role of Pae in PE has not yet been characterized. A mouse model of PE was constructed through tail vein injection of 1 mg/d phosphatidylserine/dioleoyl‐phosphatidycholine suspension. The levels of inflammatory cytokines in the placenta were examined via enzyme‐linked immunosorbent assay (ELISA). The mRNA levels of inflammatory cytokines (TNF‐α, IL‐6, IFN‐γ, and IL‐4) and apoptosis markers (Bax, Bcl‐2, and caspase‐3) were tested using quantitative reverse transcription‐polymerase chain reaction (qRT–PCR). Western blot analysis was performed to detect the protein levels of apoptosis markers and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway‐related molecules. Here, Pae repressed the inflammatory response in the placenta of PE‐like mouse models, as demonstrated by the decreased concentrations and mRNA levels of TNF‐α, IL‐6, and IFN‐γ and the increased concentrations and mRNA levels of IL‐4. Apoptosis in the placentas of PE‐like mouse models was attenuated by Pae, as manifested by the downregulated mRNA and protein levels of Bax and cleaved‐caspase‐3 and the upregulated Bcl‐2. Administration of Pae inhibited the phosphorylation of JAK2 and STAT3 in the placental tissues of PE mice. The JAK2/STAT3 pathway agonist (SC‐39100) reversed Pae treatment‐mediated suppression of placental inflammation and apoptosis in PE mice. Overall, Pae inhibits the JAK2/STAT3 signaling pathway to attenuate placental inflammation and apoptosis in PE mice. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is a common cancer type, especially among men. Although cucurbitacin I (CuI), widely found in plants belonging to the Ecballium elaterium (E. L) plant family, has been shown to have antitumorigenic properties in many cancer types, its anticancer effect, molecular mechanism, and apoptotic effect mediated by signal pathways on hepatocellular carcinoma have not been fully clarified. In the present study, we investigated the anticancer effect of CuI treated at different doses on the HepG2 cell line and the underlying mechanism in vitro. High‐purity CuI was obtained from the E. elaterium plant with the aid of HPLC. The effects of this substance on the viability of cells were studied by the MTT assay. The effects of CuI on cell cycle progression and apoptosis were studied with flow cytometry. DNA breaks were analyzed by the Comet assay method. The proteins and genes involved in the JAK/STAT3, MAPK/ERK, and AKT/mTOR signaling pathways were investigated using Western blot and qRT‐PCR, respectively. The results of this study demonstrated that CuI significantly reduced HepG2 cell growth in vitro, induced antiproliferation, and G2/M phase of the cell cycle was interrupted. Practical applications: CuI administration was shown to downregulate the levels of proteins in the PI3K/AKT/mTOR, MAPK, and JAK2/STAT3 cascades in HepG2 cells. CuI also reduced the expression of MAPK, STAT3, mTOR, JAK2, and Akt genes in different concentrations. DNA breaks are formed as a result of this effect. CuI, by reducing cell proliferation and promoting apoptosis, was found to have potential as a chemotherapeutic agent of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

How to use bioinformatics methods to quickly and accurately locate the effective targets of traditional Chinese medicine monomer (TCM) is still an urgent problem needing to be solved. Here, we used high-throughput sequencing to identify the genes that were up-regulated after cells were treated with TCM monomers and used bioinformatics methods to analyze which transcription factors activated these genes. Then, the binding proteins of these transcription factors were analyzed and cross-analyzed with the docking proteins predicted by small molecule reverse docking software to quickly and accurately determine the monomer's targets. Followeding this method, we predicted that the TCM monomer Daphnoretin (DT) directly binds to JAK2 with a binding energy of −5.43 kcal/mol, and activates the JAK2/STAT3 signaling transduction pathway. Subsequent Western blotting and in vitro binding and kinase experiments further validated our bioinformatics predictions. Our method provides a new approach for quickly and accurately locating the effective targets of TCM monomers, and we also have discovered for the first time that TCM monomer DT is an agonist of JAK2. [ABSTRACT FROM AUTHOR]