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Toosendanin (TSN) is the main active component in the traditional herb Melia toosendan Siebold & Zucc, which exhibits promising potential for development due to its diverse pharmacological properties. However, the hepatotoxicity associated with TSN needs further investigation. Previous research has implicated autophagy dysregulation in TSN-induced hepatotoxicity, yet the underlying mechanisms remain elusive. In this study, the mechanisms of signal transducer and activator of transcription 3 (STAT3) in TSN-induced autophagy inhibition and liver injury were explored using Stat3 knockout C57BL/6 mice and HepG2 cells. TSN decreased cell viability, increased lactate dehydrogenase (LDH) production in vitro , and elevated serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels as well as liver lesions in vivo , suggesting TSN had significant hepatotoxicity. TSN inhibited Janus kinase 2 (JAK2)/STAT3 pathway and the expression of cathepsin C (CTSC). Inhibition of STAT3 exacerbated TSN-induced autophagy inhibition and hepatic injury, whereas activation of STAT3 attenuated these effects of TSN. Mechanistically, STAT3 transcriptionally regulated the level of CTSC gene, which in turn affected autophagy and the process of liver injury. TSN-administered Stat3 knockout mice showed more severe hepatotoxicity, CTSC downregulation, and autophagy blockade than wildtype mice. In summary, TSN caused hepatotoxicity by inhibiting STAT3/CTSC axis-dependent autophagy and lysosomal function. [Display omitted] • TSN inhibited JAK2/STAT3 pathway and autophagy in hepatocytes. • TSN inhibited autophagy by STAT3-mediated CTSC downregulation. • Stat3 KO mice were more susceptible to the hepatotoxicity of TSN. [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]

The present study aimed to increase the content of minor ginsenosides and enhance the anti-colorectal cancer activity of ginsenosides via biotransformation by Lactiplantibacillus plantarum MB11 screened from fermented foods. A subcutaneous transplantation tumor model of murine colorectal cancer CT26 cells was established in mice to study the anticarcinogenic activities and mechanism of fermented total ginsenosides (FTGs). The results showed that L. plantarum MB11 fermentation increased the content of minor ginsenosides and decreased that of major ginsenosides. FTGs reduced the tumor weight and size compared with the model group. Immunofluorescence and TdT-mediated dUTP nick end labeling (TUNEL) analysis showed that FTGs significantly increase the number of caspase-3 cells in tumor tissue and induce cell apoptosis. Mechanically, FTGs activate AMPK/mTOR autophagy pathway and regulate JAK2/STAT3 and Bax/Bcl-2/caspase-3 apoptosis pathway. Overall, fermentation with L. plantarum MB11 enhanced minor ginsenosides in total ginsenosides, and FTGs induced subcutaneous transplantation tumor autophagy and apoptosis in mice. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs), the predominant stromal cell of tumor microenvironment (TME), play an important role in tumor progression and immunoregulation by remodeling extracellular matrix (ECM) and secreting cytokines. However, little is known about the details of the underlying mechanism in bladder cancer. Methods: Bioinformatics analysis was performed to analyze the prognostic value of CAFs and CXCL12 using GEO, TCGA and SRA databases. The effects of CXCL12 on bladder cancer progression were investigated through in vitro and in vivo assays. The biological mechanism of the effect of CXCL12 on PDL1 were investigated using western blotting, immunoprecipitation, RT-PCR, immunofluorescence, mass spectrometry, protein stability, and flow cytometry. Results: The results demonstrated that CAFs-derived CXCL12 promoted cancer cell migration and invasion and upregulated PDL1. Mechanistically, upon binding to its specific receptor, CXCL12 activated the downstream JAK2/STAT3 pathway and rapidly up-regulated the expression of deubiquitinase CYLD. CYLD deubiquitinated P62 causing P62 accumulation, which in turn inhibited the autophagic degradation of PDL1. In vivo experiments demonstrated that blocking CXCL12 inhibited tumor growth, reduced tumor PDL1 expression and increased immune cell infiltration. Conclusions: This study revealed a novel mechanism for the role of CXCL12 in P62-mediated PDL1 autophagic regulation. Combined application of CXCL12 receptor blocker and PD1/PDL1 blocker can more effectively inhibit PDL1 expression and enhance antitumor immune response. Targeting CAFs-derived CXCL12 may provide an effective strategy for immunotherapy in bladder cancer. [ABSTRACT FROM AUTHOR]

Introduction. Diabetes mellitus (DM) is one of the most common chronic diseases worldwide, and diabetic nephropathy (DN) is the most significant complication of DM, which is highly prevalent and difficult to cure. This research project aims to investigate the role and mechanism of Nucleoporin 160kDa (NUP160)-regulated autophagy in the pathogenesis of DN. Methods. NUP160 levels in diabetic and non-diabetic kidney tissues were measured by Western blot, and the connection between NUP160 and renal function of DN patients was analyzed. The podocytes were divided into four groups, namely the standard group (culture medium: standard glucose solution), high glucose (HG) group (HG solution), HG+si-NUP160 group (HG solution+si-NUP160 transfection) and HG+si-NC group (HG solution+si-NUP 160 transfection) for the determination of apoptosis by flow cytometry and measurements of LC3B, Prostacyclin-62 (P62), Janus kinase 2 (JAK2) and Signal transducer and activator of transcription3 (STAT3) by Western blot. Results. In DN patients, NUP160 decreased in podocytes and was inversely proportional to Blood urea nitrogen (BUN), Serum creatinine (Scr) and β2-Microglobulin (β2-MG) (P < .05). Compared with a standard group, the apoptosis rate, P62 level, and the ratios of phosphorylation-JAK2 (p-JAK2)/JAK2, phosphorylation-STAT3 (p-STAT3)/STAT3, and LC3B-Ⅱ/LC3B-Ⅰ elevated in the other three groups (P < .05). Apoptosis rate and P62 level, p-JAK2/JAK2 and p-STAT3/STAT3 ratios increased, and LC3B-Ⅱ/LC3B-Ⅰ ratio decreased in the HG+si-NUP160 group (P < .05), while those in HG+si-NC group showed no evident changes, compared with HG group (P > .05). Conclusion. NUP160 is downregulated in DN and can affect cellular autophagy through the activation of JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Context: Cyanidin has been shown to have therapeutic potential in osteoarthritis. However, it is unclear whether cyanidin prevents the progression of intervertebral disc degeneration (IVDD). Objective: This study evaluates the effects of cyanidin on IVDD in vitro and in vivo. Materials and methods: Nucleus pulposus cells (NPCs) isolated from lumbar IVD of 4-week-old male Sprague-Dawley (SD) rats were exposed to 20 ng/mL IL-1b, and then treated with different doses (0-120 mM) of cyanidin for 24 h. SD rats were classified into three groups (n=8) and treated as follows: control (normal saline), IVDD (vehicle), IVDDþcyanidin (50mg/kg). Cyanidin was administered intraperitoneally for 8 weeks. Results: The IC50 of cyanidin for NPCs was 94.78 mM, and cyanidin had no toxicity at concentrations up to 500 mg/kg in SD rats. Cyanidin inhibited the apoptosis of NPCs induced by IL-1b (12.73 ± 0.61% vs. 18.54 ± 0.60%), promoted collagen II (0.82-fold) and aggrecan (0.81-fold) expression, while reducing MMP-13 (1.02-fold) and ADAMTS-5 (1.40-fold) expression. Cyanidin increased the formation of autophagosomes in IL-1b-induced NPCs, and promoted LC3II/LC3I (0.83-fold) and beclin-1 (0.85-fold) expression, which could be reversed by chloroquine. Cyanidin inhibited the phosphorylation of JAK2 (0.47-fold) and STAT3 (0.53-fold) in IL-1b-induced NPCs. The effects of cyanidin could be enhanced by AG490. Furthermore, cyanidin mitigated disc degeneration in IVDD rats in vivo. Discussion and conclusions: Cyanidin improved the function of NPCs in IVDD by regulating the JAK2/STAT3 pathway, which may provide a novel alternative strategy for IVDD. The mechanism of cyanidin improving IVDD still needs further work for in-depth investigation. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common allergic skin disease, and its pathogenesis involves genetic and environmental factors, as well as the immune response and skin barrier. PJ-001 is a small-molecule proteolysis-targeting chimera, which can degrade proteins related to the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. In the present study, 0.5% 2,4-dinitrofluorobenzene was used to induce a mouse model of AD. Following treatment with PJ-001, the number of scratches and the severity of skin damage in the AD mice were recorded. Pathological changes in skin lesions were observed with hematoxylin and eosin staining. The expression levels of JAK2/STAT3, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB), Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3) were detected using western blotting. Furthermore, reverse transcription-PCR was used to detect the mRNA expression levels of filaggrin (FLG) and keratin 17, and the change in interleukin-10 levels in the splenic tissue of the mice. Compared with in the control group, the model group exhibited severe skin lesions. Following treatment with PJ-001, the AD-like inflammation in mice decreased. The expression levels of LC3 II/LC3 I and Beclin 1 were significantly reduced (P<0.01), and the expression levels of JAK2, STAT3, TLR4 and NF-κB were significantly downregulated (P<0.001). Additionally, the mRNA expression levels of FLG were significantly upregulated (P<0.001). These results indicated that PJ-001 may alleviate the skin condition in a mouse model of AD. The underlying mechanism may involve inhibition of the JAK/STAT signaling pathway, thereby suppressing the release of inflammatory factors, reducing excessive autophagy at the site of skin lesions, and enhancing the skin barrier function. In conclusion, PJ-001 could be considered a potential therapeutic option for AD. [ABSTRACT FROM AUTHOR]

White spot syndrome virus (WSSV) is a fatal pathogen threatening global crustacean industry with no commercially available drugs to control. Herbal medicines have been widely used to treat a number of viral infections, which could offer a rich reserve for antiviral drug discovery. Here, we evaluated the inhibition activities of 30 herbal medicines against WSSV in Chinese mitten crab Eriocheir sinensis. A WSSV infection model in E. sinensis was firstly established in order to determine the antiviral effects of the plant extracts and to explore the potential action mechanisms. Results showed that the highest anti-WSSV activity was obtained by the treatment of Ophiopogon japonicus extract (93.03%, 100 mg/kg). O. japonicus treatment decreased viral loads in a dose-dependent manner and significantly improved the survival of WSSV-challenged crabs. O. japonicus reduced the expression of vital genes in viral life cycle in vivo , particularly for the immediate-early stage gene ie1. Further results indicated that O. japonicus could repress the JAK-STAT signaling pathway to block ie1 transcription. Moreover, O. japonicus could modulate certain immune genes such as the myosin , toll-like receptor , crustin , and prophenoloxidase in the interactions between WSSV and crabs. The up-regulated expression of pro-autophagic factors (Gabarap and Atg7) and elevated levels of antioxidant enzymes (SOD, CAT and GSH) suggested that O. japonicus may induce autophagy and attenuate WSSV-induced oxidative stress. Taken together, O. japonicus could inhibit WSSV proliferation and improve the survival of WSSV-challenged crabs. Thus, O. japonicus may have the potential to be developed as a preventive or therapeutic agent against WSSV, and its effective compounds merit further isolation and identification. • The WSSV infection model was established and evaluated in Eriocheir sinensis for the first time. • Ophiopogon japonicus restrains WSSV proliferation and improves survival of WSSV-challenged crabs. • O.japonicus represses the JAK/STAT signaling pathway to block the transcription of WSSV early gene. • Ophiopogon japonicus induces immune response in crabs. • O.japonicus induces apoptosis-related factors and enhances anti-oxidative activity in WSSV-challenged crabs. [ABSTRACT FROM AUTHOR]

Background: Trophoblast dysfunction during pregnancy is fundamentally involved in preeclampsia. Several studies have revealed that human chorionic villous mesenchymal stem cells (CV-MSCs) could regulate trophoblasts function. Results: To understand how human chorionic villous mesenchymal stem cells (CV-MSCs) regulate trophoblast function, we treated trophoblasts with CV-MSC supernatant under hypoxic conditions. Treatment markedly enhanced proliferation and invasion and augmented autophagy. Transcriptome and pathway analyses of trophoblasts before and after treatment revealed JAK2/STAT3 signalling as an upstream regulator. In addition, STAT3 mRNA and protein levels increased during CV-MSC treatment. Consistent with these findings, JAK2/STAT3 signalling inhibition reduced the autophagy, survival and invasion of trophoblasts, even in the presence of CV-MSCs, and blocking autophagy did not affect STAT3 activation in trophoblasts treated with CV-MSCs. Importantly, STAT3 overexpression increased autophagy levels in trophoblasts; thus, it positively regulated autophagy in hypoxic trophoblasts. Human placental explants also proved our findings by showing that STAT3 was activated and that LC3B-II levels were increased by CV-MSC treatment. Conclusion: In summary, our data suggest that CV-MSC-dependent JAK2/STAT3 signalling activation is a prerequisite for autophagy upregulation in trophoblasts. [ABSTRACT FROM AUTHOR]

Objective: Interleukin-17 (IL-17), produced by T helper (Th)-17 cells, is a potent regulator of bone homeostasis. Osteoblasts are key cells that orchestrate inflammatory bone destruction and bone remodeling. This study examines the effect of different concentrations of IL-17 on osteogenesis and receptor activator of nuclear factor-kappa B ligand (RANKL) expression of primary osteoblasts. Methods: First, the growth of primary osteoblasts was evaluated. Second, we assessed the effects of IL-17 on the level of autophagy and the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway. Next, osteogenic activity in different concentrations of IL-17 was tested. Finally, the specific JAK2/STAT3 signaling pathway inhibitor AG490 and autophagy inhibitor 3-MA were used to investigate the involvement of this pathway and autophagy in IL-17-induced regulation of RANKL expression. Results: Initially, we found that IL-17 treatment promoted growth of osteoblasts in a time- and dose-dependent manner. Next, we showed that low levels of IL-17 promoted autophagy activity, whereas the opposite was observed at high levels of IL-17. Moreover, high levels of IL-17 activated the JAK2/STAT3 signaling pathway, although this effect was reversed by upregulation of autophagy. Furthermore, our findings indicated that high concentrations of IL-17 promoted the differentiation, calcification, and RANKL expression of murine osteoblasts via activation of the JAK2/STAT3 pathway. Importantly, downregulation of autophagy at high IL-17 concentrations further enhanced RANKL expression via suppressing the JAK2/STAT3 cascade. Conclusion: Overall, our findings demonstrate, for the first time, that IL-17 modulates RANKL expression of osteoblasts through an autophagy–JAK2-STAT3 signaling pathway, thus affecting bone metabolism. [ABSTRACT FROM AUTHOR]

[Display omitted] • SBL triggers IL-6 activation through P2RX7 mediated signalling axis in dTHP-1 cells. • Akt/CREB pathway acts downstream to the P2RX7 receptor to facilitate IL-6 release in SBL-treated dTHP-1 cells. • The released IL-6, in turn, activates the JAK2/STAT3/Mcl-1 pathway upon interaction with IL-6Rα in an autocrine fashion. • Elevated Mcl-1 level downstream to the IL-6 signalling axis stimulates autophagy in SBL-treated dTHP-1 cells. • Mcl-1 stimulated autophagy in SBL-treated cells leads to inhibition of the intracellular survival of both fast- (M. smegmatis) and slow- (M. bovis BCG) growing mycobacteria. Cytokine therapy and cytokine-mediated autophagy have been used as prominent host-directed therapy (HDT) approaches to restrain M. tb growth in the host cell. In the present study, we have dissected the anti-tubercular activity of Soybean lectin (SBL) through cytokine-mediated autophagy induction in differentiated THP-1 (dTHP-1) cells. A significant increase in IL-6 expression was observed in both uninfected and mycobacteria infected dTHP-1 cells through the P2RX7 mediated pathway via PI3K/Akt/CREB-dependent signalling after SBL treatment. Inhibition of IL-6 level using IL-6 neutralizing antibody or associated signalling significantly enhanced the mycobacterial load in SBL-treated dTHP-1 cells. Further, autocrine signalling of IL-6 through its receptor-induced Mcl-1 expression activated autophagy via JAK2/STAT3 pathway, and inhibition of this pathway affected autophagy. Finally, blocking the IL-6-regulated autophagy through NSC 33994 (a JAK2 inhibitor) or S63845 (an Mcl-1 inhibitor) led to a notable increase in intracellular mycobacterial growth in SBL-treated cells. Taken together, these results indicate that SBL interacts with P2RX7 to regulate PI3K/Akt/CREB network to release IL-6 in dTHP-1 cells. The released IL-6, in turn, activates the JAK2/STAT3/Mcl-1 pathway upon interaction with IL-6Rα to modulate autophagy that ultimately controls mycobacterial growth in macrophages. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion injury (IRI) is an important factor limiting the success of cardiac reperfusion therapy. Curcumin has a significant cardioprotective effect against IRI, can inhibit ventricular remodeling induced by pressure load or MI, and improve cardiac function. However, the poor water solubility and low bioavailability of curcumin restrict its clinical application. Methods: In this study, we prepared and evaluated a curcumin-hydrogel (cur-hydrogel) to reduce cardiomyocyte apoptosis and reactive oxygen species formation induced by hypoxia-reoxygenation injury, promote autophagy, and reduce mitochondrial damage by maintaining the phosphorylation of Cx43. Results: Meanwhile, cur-hydrogel can restore cardiac function, inhibit myocardial collagen deposition and apoptosis, and activate JAK2/STAT3 pathway to alleviate myocardial ischemia-reperfusion injury in rats. Conclusions: The purpose of this study is to elucidate the protective effects of cur-hydrogel on myocardial ischemia-reperfusion injury by regulating apoptosis, autophagy, and mitochondrial injury in vitro and in vivo, which lays a new theoretical and experimental foundation for the prevention and reduction of IRI. [ABSTRACT FROM AUTHOR]

DIRAS family is a group of GTPases belonging to the RAS superfamily and shares homology with the pro‐oncogenic Ras GTPases. Currently, accumulating evidence show that DIRAS family members could be identified as putative tumor suppressors in various cancers. The either lost or reduced expression of DIRAS proteins play an important role in cancer development, including cell growth, migration, apoptosis, autophagic cell death, and tumor dormancy. This review focuses on the latest research regarding the roles and mechanisms of the DIRAS family members in regulating Ras function, cancer development, assessing potential challenges, and providing insights into the possibility of targeting them for therapeutic use. This review focuses on the latest research regarding the roles and mechanisms of the DIRAS family members in regulating Ras function, cancer development, assessing potential challenges, and providing insights into the possibility of targeting them for therapeutic use. Ingenuity signaling pathway analysis of cellular physiology (cell proliferation, migration, apoptosis, autophagy) by induction of DIRAS family members. DIRAS family members mainly regulate the PI‐3K/AKT/mTOR, RAS/RAF/MEK/ERK, NF‐κB, and JAK/STAT signaling pathways to inhibit cell proliferation and migration (light green ellipse) and induce apoptosis and autophagy (dark green ellipse). (Orange round represent DIRAS family members, pink round represent molecular upregulated by DIRAS family members, purple hexagon represent molecular downregulated by DIRAS family members, small yellow round represent molecular by phosphorylation, blue oval represent transmembrane receptor, and green square represent extracellular factor). [ABSTRACT FROM AUTHOR]

Abstract Death-associated protein kinase 2 (DAPK2) has indicated functional roles in cellular processes, including survival, apoptosis, and autophagy. This study is aimed to identify the effect of DAPK2 on oxidative damage and apoptosis of placental cells in hypertensive disorder complicating pregnancy (HDCP) through mTOR pathway. Microarray-based gene expression analysis was performed to predict the differentially expressed genes related to HDCP. To investigate the specific mechanism of DAPK2 in HDCP cells, placental microvascular endothelial cells were treated with mimic or siRNA of DAPK2 and mTOR to detect the expression of related genes, cell autophagy and apoptosis and oxidative damage. Finally, rats were modeled with HDCP to verify the cell experiment results. DAPK2 was downregulated in HDCP, and could activate mTOR. Besides, DAPK2 overexpression led to decreases in autophagy in HPVECs as well as apoptosis and oxidative damage in placental cells indicated by a substantial decrease in Beclin-1, LC3 II/LC3 I and Bax along with an increase in Bcl-2, 4EBP1 and p70S6K. It also ameliorates blood pressure elevation in HDCP rats. The study defined remission effect of DAPK2 on placental cell oxidative damage and apoptosis in HDCP via mTOR activation. Together, DAPK2 regulating mTOR pathway presents a promising therapy for HDCP treatment. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a clinically common and severe complication of ischemia-reperfusion (I/R), associated with high morbidity and mortality rates, and prolonged hospitalization. Rapamycin is a type of macrolide, primarily used for anti-rejection therapy following organ transplantation and the treatment of autoimmune diseases. Rapamycin has been identified to exert a protective effect against AKI induced by renal I/R as an autophagy inducer. However, whether rapamycin preconditioning may relieve AKI following cerebral I/R (CIR) remains to be fully elucidated. The purpose of the present study was to investigate the effects of CIR on the renal system of rats and the role of rapamycin in AKI following CIR. In the present study, a CIR model was established in Sprague-Dawley rats via a 90-min period of middle cerebral artery occlusion and 24 h reperfusion, and pretreatment with an intraperitoneal injection of rapamycin (dosage: 1 mg/kg; 0.5 h) prior to CIR. The levels of serum creatinine and blood urea nitrogen (BUN), and the expression of inflammation-, apoptosis- and autophagy-associated markers were subsequently measured. In addition to certain histopathological alterations to the kidney, it was identified that CIR significantly increased the levels of serum creatinine, BUN, tumor necrosis factor-α and interleukin-1β, and significantly induced apoptosis and autophagy. It was observed that rapamycin induced autophagy through the mammalian target of rapamycin complex 1/autophagy-related 13/unc-51 like autophagy activating kinase 1 signaling pathway, and that rapamycin pre-treatment significantly improved renal function and alleviated renal tissue inflammation and cell apoptosis in rats following CIR. In conclusion, the results suggested that rapamycin may alleviate AKI following CIR via the induction of autophagy. [ABSTRACT FROM AUTHOR]

Phosphodiesterase-5 inhibitors (PDE5Is) have been shown to modulate cell death/cell survival in different in vivo and in vitro models of disease by activating many signaling pathways. This review aimed at elucidating how PDE5Is can inhibit apoptosis. In this study, we describe many signaling pathways involved with the mechanism of action of PDE5Is that ultimately inhibit apoptosis and thus promote cell survival. [ABSTRACT FROM AUTHOR]

Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated. Moreover, trichothecenes may generate an 'immune evasion' milieu that allows pathogens to escape host and vaccine immune defenses. Some trichothecenes, especially macrocyclic trichothecenes, also potently kill cancer cells. T-2 toxin conjugated with anti-cancer monoclonal antibodies significantly suppresses the growth of thymoma EL-4 cells and colon cancer cells. The type B trichothecene diacetoxyscirpenol specifically inhibits the tumor-promoting factor HIF-1 in cancer cells under hypoxic conditions. Trichothecin markedly inhibits the growth of multiple cancer cells with constitutively activated NF-κB. The type D macrocyclic toxin Verrucarin A is also a promising therapeutic candidate for leukemia, breast cancer, prostate cancer, and pancreatic cancer. The anti-cancer activities of trichothecenes have not been comprehensively summarized. Here, we first summarize the data on the immunomodulatory effects of trichothecenes and discuss recent studies that shed light on the underlying cellular and molecular mechanisms. These mechanisms include autophagy and major signaling pathways and their crosstalk. Second, the anti-cancer potential of trichothecenes and the underlying mechanisms will be discussed. We hope that this review will show how trichothecene bioactivities can be exploited to generate therapies against pathogens and cancer. [ABSTRACT FROM AUTHOR]

The present study evaluated the retinoic acid (RA) enhancement of temozolomide (TMZ) effects on the human glioma cells U251 and explored its underlying molecular mechanism. The cell growth was detected using the MTT assay and the cell cycle was assessed by flow cytometry. Cell apoptosis was analyzed by Annexin V/propidium iodide staining, and the cell morphology was evaluated using transmission electron microscopy (TEM). Additionally, reverse transcription-PCR and western blot analysis were applied to detect the mRNA and protein levels. The RA treatment in combination with TMZ in the human U251 cells further inhibited cells growth, arresting cell cycle progression at the G0/G1 phase, and significantly induced apoptosis of U251 cells. After the RA+TMZ treatment of U251 cells, autophagy associated proteins Beclin 1 and LC3B were significantly increased, and the TEM analysis were consistent with autophagy protein levels. Moreover, Keap1/Nrf2/ARE expression was downregulated significantly, indicating the involvement in the mechanisms that RA treatment could enhance the TMZ effects on U251 cells. RA treatment in combination with TMZ may provide some experimental evidence for the possible effect of RA+TMZ against the growth and the proliferation of glioma cells. Therefore, the RA+TMZ administration may have potential utility for glioblastoma treatment. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are innate pattern recognition receptors that play a critical role in allergic inflammation, yet their contribution to autophagy in asthma remains poorly defined. Here, we investigate the role of Toll-like receptor 2 (TLR2) in phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway-mediated autophagy in ovalbumin-induced airway inflammation in mice. Wild-type (WT) and TLR2-knockout (TLR2) C57BL/6 mice were ovalbumin-sensitized and ovalbumin-challenged. In ovalbumin-challenged WT mice, enhanced expression of TLR2 in lung tissue, remarkable inflammatory cell infiltrates, goblet cell hyperplasia, and increased mucus production were observed. The number of inflammatory cells and interleukin-13 (IL-13) levels increased, while interferon-gamma (IFN-γ) levels decreased in bronchoalveolar lavage fluid. Expression of PI3K, phospho-Akt, Beclin-1 and LC3-II was enhanced significantly. These changes were mitigated dose-dependently in 3-methyl adenine-treated mice. In contrast, similar but weaker changes were found in ovalbumin-challenged TLR2 mice, and the changes were not significantly attenuated by 3-methyl adenine treatment. These results indicate that TLR2 confers a pivotal role in allergic airway inflammation via regulating the PI3K/Akt signaling pathway-related autophagy in mice. [ABSTRACT FROM AUTHOR]

Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P = 0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQB alone or in combination with cisplatin on the suppression of ovarian cancer via Atg-5-dependent autophagy. We believe these findings will be beneficial in the development of a novel anti-ovarian cancer therapeutic strategy. [ABSTRACT FROM AUTHOR]

Objective: This study aims to explore the effects of the exogenous hydrogen sulfide (H2S)- mediated scavenger receptor A (SR-A) signaling pathway on renal ischemia/reperfusion injury (IRI) by regulating endoplasmic reticulum (ER) stress-induced autophagy in rats. Methods: A total of 48 normal Sprague-Dawley (SD) rats and SR-A knockout rats were selected and divided into six groups (n = 8): wild-type (WT) + sham, WT + ischemia-reperfusion (I/R), WT + I/R + NaHS, SR-A-/- + sham, SR-A-/- + I/R and SR-A-/- + I/R + NaHS. The concentrations of urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), malondialdehyde (MDA) and H2S in renal tissue were detected. qRT-PCR and Western blotting were used to detect the mRNA and protein levels of IL-6, TGF-β, SR-A, LC3I, LC3II, P62, PERK, ATF6 and IRE1 pathway-related genes. A TUNEL assay was used to detect cell apoptosis. Electron microscopy was applied to observe the structure of renal autophagosomes. Results: Compared with the WT + sham group, in the rates of the WT + I/R group, the urine volume, urinary protein, BUN, SCR and MDA concentrations, the mRNA and protein expression of IL-6, TGF-β, LC3II/I, and ER stress pathway-related genes, the cell apoptosis index, and the number of autophagosomes were significantly increased 24 h after I/R, while P62 and SR-A protein expression and SOD and H2S concentrations were significantly decreased (all P < 0.05). The levels of renal injury, autophagy and ER stress pathway-related genes were decreased in the WT + I/R + NaHS group but were increased in the SR-A-/- + I/R group relative to the WT + I/R group. No significant differences were observed in the urine volume; the concentrations of urinary protein, BUN, SCR and MDA; the SOD activity; the mRNA and protein expression of IL-6, TGF-β, SR-A, GRP78, SR-A, GPR94, ATF4, IRE1, XBP1, ATF6, and eIF2α; the cell apoptosis index; or the number of autophagosomes in rats of the SR-A-/- + I/R and SR-A-/- + I/R + NaHS groups (all P > 0.05). Conclusion: These results demonstrate that the exogenous H2S-mediated SR-A signaling pathway reduces renal IRI injury by up-regulating ER stress-induced autophagy in rats. [ABSTRACT FROM AUTHOR]

The pathogenesis of acute lung injury (ALI) induced by lipopolysaccharide (LPS) involves excessive pulmonary inflammation and oxidative stress. In turn, autophagy is associated with inflammatory diseases and organ dysfunction, and studies have demonstrated that LPS treatment may trigger autophagy. Thus, excessive autophagy may stimulate the strong inflammatory response observed in the development of LPS-induced ALI. Saturated hydrogen saline may alleviate LPS-induced ALI by inhibiting autophagy, however its underlying mechanisms of action remain unknown. It has been suggested that saturated hydrogen saline may downregulate expression of nuclear factor (NF)-κB, leading to a decrease in Beclin-1 transcription and inhibition of autophagy. Inhibition of autophagy also occurs via the phosphorylation of Unc-51-like autophagy activating kinase 1 and autophagy-related protein-13 by mechanistic target of rapamycin, which in turn may be upregulated by saturated hydrogen saline. In addition, signaling pathways involving heme oxygenase-1 and p38 mitogen-activated protein kinase are associated with the alleviative effects of saturated hydrogen saline on LPS-induced autophagy. The present review focuses on potential molecular mechanisms regarding the effects of saturated hydrogen saline in the reduction of autophagy during LPS-induced ALI. [ABSTRACT FROM AUTHOR]

Hypoxia is widely accepted as a fundamental biological phenomenon, which is strongly associated with tissue damage and cell viability under stress conditions. Insulin-like growth factor-1 (IGF-1) is known to protect tissues from multiple types of damage, and protect cells from apoptosis. Hypoxia is a regulatory factor of the IGF system, however the role of the IGF-1 receptor (IGF-1R) in hypoxia-induced apoptosis remains unclear. The present study investigated the potential mechanisms associated with IGF-1R-associated apoptosis under hypoxic conditions. Mouse embryonic fibroblasts exhibiting disruption or overexpression of IGF-1R (R- cells and R+ cells) were used to examine the level of apoptosis, autophagy, and production of reactive oxygen species (ROS). The autophagy inhibitor 3-methyladenine was used to assess the effect of autophagy on ROS production and apoptosis under hypoxic conditions. A potential downstream signaling pathway involving phosphatidylinositol 3-kinase (PI3K)/threonine protein kinase B (Akt)/mammalian target of rapamycin (mTOR) was identified by western blot analysis. The results demonstrated that hypoxia induced apoptosis, increased ROS production, and promoted autophagy in a time-dependent manner relative to that observed under normoxia. R+ cells exhibited a lower percentage of apoptotic cells, lower ROS production, and higher levels of autophagy when compared to that of R- cells. In addition, inhibition of autophagy led to increased ROS production and a higher percentage of apoptotic cells in the two cell types. Furthermore, IGF-1R is related with PI3K/Akt/mTOR signaling pathway and enhanced autophagy-associated protein expression, which was verified following treatment with the PI3K inhibitor LY294002. These results indicated that IGF-1R may increase cell viability under hypoxic conditions by promoting autophagy and scavenging ROS production, which is closed with PI3K/Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Interferon stimulated (sensitive) genes (ISGs) are the effector molecules downstream of type I/III interferon (IFN) signaling pathways in host innate immunity. ISG12a can be induced by IFN-α. Although ISG12a has been reported to inhibit the replication of HCV, the exact mechanism remains to be determined. In this study, we investigated the possible mechanisms of ISG12a anti- HCV property by exploring the production of type I IFN and the activation of Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway, apoptosis and autophagy in Huh7.5.1 cells transiently transfected with ISG12a over-expression plasmid. Interestingly, we found that ISG12a inhibited HCV replication in both Con1b replicon and the HCV JFH1-based cell culture system and potentiated the anti-HCV activity of IFN-α. ISG12a promoted the production of IFN α/β and activated the type I IFN signaling pathway as shown by increased p-STAT1 level, higher Interferon sensitive response element (ISRE) activity and up-regulated ISG levels. However, ISG12a over-expression did not affect cell autophagy and apoptosis. Data from our current study collectively indicated that ISG12a inhibited HCV replication and potentiated the anti-HCV activity of IFN-α possibly through induced production of type I IFNs and activation of Jak/STAT signaling pathway independent of autophagy and cell apoptosis. [ABSTRACT FROM AUTHOR]

Activin A (Act A), a member of the transforming growth factor-beta (TGF-β), reduces neuronal apoptosis during cerebral ischemia through Act A/Smads signaling pathway. However, little is known about the effect of Act A/Smads pathway on autophagy in neurons. Here, we found that oxygen-glucose deprivation (OGD)-induced autophagy was suppressed by exogenous Act A in a concentration-dependent manner and enhanced by Act A/Smads pathway inhibitor (ActRIIA-Ab) in neuronal PC12 cells. These results indicate that Act A/Smads pathway negatively regulates autophagy in OGD-treated PC12 cells. In addition, we found that c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways are involved in the OGD-induced autophagy. The activation of JNK and p38 MAPK pathways in OGD-treated PC12 cells was suppressed by exogenous Act A and enhanced by ActRIIA-Ab. Together, our results suggest that Act A/Smads signaling pathway negatively regulates OGD-induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells. [ABSTRACT FROM AUTHOR]

Dysregulation of autophagy in endothelial cells plays a vital role in cardiovascular dysfunction and atherosclerosis. Accumulating evidence shows that miRNAs regulate autophagy in various cell types by targeting autophagy-related genes. In the present study, we found that a co-culture of human umbilical vein endothelial cells (HUVECs) with human aortic smooth muscle cells (HAoSMCs) inhibited autophagy activity in HUVECs. Furthermore, we isolated exosomes secreted by HAoSMCs, and confirmed that the exosomes contain miR-221/222. We investigated the role of miR-221/222 transferred by HAoSMC-derived exosomes in HUVECs. These exosomes induced an increase of miR-221/222 expression and a down-regulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in HUVECs. Dual luciferase reporter assays revealed that miR-221/222 could bind to the 3′UTR of PTEN, which implied that PTEN was a direct target of miR-221/222. The expression of PTEN could be down-regulated by miR-221/222 over-expression. Then, we detected the expression of PTEN, LC3, ATG5, SQSTM1/p62, Beclin-1, Akt, and phospho-Akt in HUVECs transfected with miR-221/222 mimics and inhibitors. Our results demonstrated that miR-221/222 overexpression inhibited the expression of PTEN and subsequently activated Akt signaling, and eventually down-regulated the expression of LC3II, ATG5 and Beclin-1, and elevated the expression of SQSTM1/p62. This phenomenon can be reversed by the transfection of miR-221/222 inhibitors. These data suggested that miR-221/222 from HAoSMC-derived exosomes inhibited autophagy in HUVECs by modulating PTEN/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

• JAK-STAT signaling pathway played an essential role in ICP progression. • EGF, GRIA1 and ESR1 etc. might be potential target for ICP therapy. • EGFR was mainly expressed in placenta and related to destroyed autophagy and ferroptosis. Intrahepatic cholestasis of pregnancy (ICP) was the most common liver disease specific to pregnancy. The symptoms of ICP were maternal pruritus and increased bile acid level in serum which was related to preterm birth, fetal distress, meconium-stained amniotic fluid and stillbirth. However, the mechanism of ICP progression on fetal development remained obscure. Sequencing data of 2 normal placenta samples and 4 intrahepatic cholestasis samples during pregnancy was analyzed by GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for analysis of differentially expressed genes. MCODE - A plug-in of Cytoscape was used for molecular complex detection. STRING, Cytoscape, GeneMANIA, NetworkAnalyst, TransmiR, JASPAR, DGIdb and DrugBank were used in this study. Furthermore, histopathological and cell experiments were used to verify our results. Our study identified the key KEGG pathway and four MCODEs which were closely with ICP development, further, sorted by degree centrality, we showed top 30 genes from 7209 differential genes, such as TP53, SRC, EGFR, ESR1, IL10, CD8A, MAPK3, PTPRC, EGF, KIT, ITGAM, LEP and CSF2, etc. Moreover, these hub genes participated in JAK-STAT3 signaling pathway and STAT1/3 regulated these genes expression in a direct way or miRNA-mediated manner. Drug-target analysis about up-regulated genes among hub genes showed that these genes contained multiple drug action site. Furthermore, hub gene-EGFR was associated with destroyed autophagy and ferroptosis. In conclusion, our study analyzed key genes and pathways in ICP development. JAK-STAT3 pathway and EGFR might be a potential target for ICP therapy. [ABSTRACT FROM AUTHOR]

Autophagy is a cellular process by which mammalian cells degrade and assist in recycling damaged organelles and proteins. This study aimed to ascertain the role of autophagy in remote ischemic preconditioning (RIPC)-induced cardioprotection. Sprague Dawley rats were subjected to RIPC at the hindlimb followed by a 30-min transient blockade of the left coronary artery to simulate ischemia reperfusion (I/R) injury. Hindlimb muscle and the heart were excised 24 h post reperfusion. RIPC prior to I/R upregulated autophagy in the rat heart at 24 h post reperfusion. In vitro, autophagy inhibition or stimulation prior to RIPC, respectively, either ameliorated or stimulated the cardioprotective effect, measured as improved cell viability to mimic the preconditioning effect. Recombinant interleukin-6 (IL-6) treatment prior to I/R increased in vitro autophagy in a dose-dependent manner, activating the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway without affecting the other kinase pathways, such as p38 mitogen-activated protein kinases (MAPK), and glycogen synthase kinase 3 Beta (GSK-3β) pathways. Prior to I/R, in vitro inhibition of the JAK-STAT pathway reduced autophagy upregulation despite recombinant IL-6 pre-treatment. Autophagy is an essential component of RIPC-induced cardioprotection that may upregulate autophagy through an IL-6/JAK-STAT-dependent mechanism, thus identifying a potentially new therapeutic option for the treatment of ischemic heart disease. [ABSTRACT FROM AUTHOR]

Pancreatic stellate cells (PSCs) are the main functional cells leading to pancreatic fibrosis. Nicotine is widely considered as an independent risk factor of pancreatic fibrosis, but the mechanism is still unclear. Our study was aimed to explore the effects of nicotine on human pancreatic stellate cells (hPSCs) and involved pathways. Primary human PSCs were cultured and treated with nicotine (0.1 μM and 1 μM). The proliferation, apoptosis, α-SMA expression, extracellular matrix metabolism and autophagy of hPSCs were detected by CCK-8 assay, flow cytometry, real-time PCR and Western blotting analysis. The α7nAChR-mediated JAK2/STAT3 signaling pathway was also examined, and an α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. The proliferation, α-SMA expression and autophagy of hPSCs were significantly promoted by 1 μM nicotine. Meanwhile, the apoptosis of hPSCs was significantly reduced. The extracellular matrix metabolism of hPSCs was also regulated by nicotine. Moreover, the α7nAChR-mediated JAK2/STAT3 signaling pathway was activated by nicotine, this pathway and effects of nicotine can be blocked by α-BTX. Our finding suggests that nicotine can promote activation of human pancreatic stellate cells (hPSCs) through inducing autophagy via α7nAChR-mediated JAK2/STAT3 signaling pathway, providing a new insight into the mechanisms by which nicotine affects pancreatic fibrosis. [ABSTRACT FROM AUTHOR]

Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities. [ABSTRACT FROM AUTHOR]