Search

Emerging evidence suggests that both apoptosis and autophagy contribute to global cerebral ischemia‑reperfusion (GCIR)‑induced neuronal death, which results from cardiac arrest (CA). However, the mechanism of how GCIR may affect the balance between apoptosis and autophagy resulting from CA remains to be elucidated. Additionally, the role of adiponectin (APN) in reversing the apoptosis and autophagy induced by GCIR following cardiac arrest‑cardiopulmonary resuscitation (CA‑CPR) is unclear. Thus, the aim of the present study was to investigate how GCIR affect the apoptosis and autophagy in response to CA and to clarify whether APN may alter the apoptosis and autophagy of neuronal death in GCIR‑injured brain post‑CA‑CPR. Using normal controls (Sham group) and two experimental groups [CA‑CPR‑induced GCIR injury (PCAS) group and exogenous treatment with adiponectin post‑CA‑CPR (APN group)], it was demonstrated that both apoptosis and autophagy were observed simultaneously in the brain subjected to GCIR, but apoptosis appeared to be more apparent. Exogenous administration of APN significantly reduced the formation of malondialdehyde, a marker of oxidative stress and increased the expression of superoxide dismutase, an anti‑oxidative enzyme, resulting in the stimulation of autophagy, inhibition of apoptosis and reduced brain tissue injury (P<0.05 vs. PCAS). APN treatment increased the expression of APN receptor 1 (AdipR1) and the phosphorylation of AMP‑activated protein kinase (AMPK; Ser182) in brain tissues. In conclusion, GCIR induced apoptosis and inhibited autophagy, contributing to brain injury in CA‑CPR. By contrast, APN reduced the brain injury by reversing the changes of neuronal autophagy and apoptosis induced by GCIR. The possible mechanism might owe to its effects on the activation of AMPK after combining with AdipR1 on neurons, which suggests a novel intervention against GCIR injury in CA‑CPR conditions.

Sertoli cells (SCs) are necessary for proper germ cell development and viability. Unc-51 like autophagy activating kinase (ULK1) protein kinase is an important regulator of autophagy activation. This study aims to investigate the role of autophagy promoter ULK1 on cell viability of goat SCs. Our results showed that ULK1 knockdown in goat SCs decreased autophagy activation, which was confirmed by decreased expression of autophagy-related markers including LC3, Beclin1, Atg5, and Atg7 (P < 0.05). Meanwhile, lower ULK1 levels resulted in decreased expressions of goat SC marker genes ABP, AMH, FASL, and GATA4. However, a reverse trend of these parameters occurred when the goat SCs were transfected with ULK1 overexpression construct; higher ULK1 levels in goat SCs also decreased the ratio of Bax/Bcl-2. Moreover, ULK1 overexpression in goat SCs activated the autophagy levels when cells were exposed to an environmental contaminant bisphenol A (BPA). The above results indicated that ULK1 gene might play important roles in goat SC function by regulating cell viability.

Cisplatin remains the standard first-line chemotherapeutic agent in the treatment of many types of cancers, but its clinical application is hindered by its severe nephrotoxicity. Previous studies reported that scutellarin enhanced the anti-cancer activity of cisplatin in lung cancer cells, with no confirmation on cisplatin-induced renal damage. Here, we investigated the nephroprotective effect of scutellarin on cisplatin-induced renal injury and its underlying mechanisms. Renal function, histological change, inflammation, apoptosis, autophagy and involved pathways were investigated. Pretreatment with scutellarin prevented cisplatin-induced decline of renal function including BUN, CRE, and histological damage. Scutellarin also reduced renal inflammation by suppressing the levels of pro-inflammatory cytokine, TNF-α and IL-6. Similarly, scutellarin administration inhibited apoptosis triggered by cisplatin through reducing the expressions of Cleaved caspase-3, Cleaved PARP, p53, and the ratio of Bax/Bcl-2. Moreover, scutellarin prevented cisplatin-induced inhibition of autophagy via enhancing LC3-II/LC3-I and Atg7, and inhibition of p62. Of note, the activations of JNK, ERK, p38 and stat3 induced by cisplatin were strikingly attenuated in scutellarin-treated mice. Thus, these results provide compelling evidence that scutellarin is a novel nephroprotectant against cisplatin-induced renal toxicity., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aim: To investigate the effects of betulinic acid (BA) on apoptosis and autophagic flux in multiple myeloma cells and the relationship between the two processes., Methods: The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytometry (FCM) and Hoechst 33258 staining were used to analyze the cell apoptosis. Caspase 3, PARP, Beclin1, LC3-II, and P62 were detected using Western blotting., Results: Treatment of KM3 cells with BA (5-25 μg/mL) suppressed the cell proliferation in time- and dose-dependent manners. The IC(50) values at 12, 24, and 36 h were 22.29, 17.36, and 13.06 μg/mL, respectively. BA treatment dose-dependently induced apoptosis of KM3 cells, which was associated with the activation of caspase 3. However, Z-DEVD-FMK, a specific inhibitor of caspase 3, did not decrease, but rather sensitized the cells to BA-induced apoptosis, suggesting an alternative mechanism involved. On other hand, BA treatment dose-dependently increased the accumulation of LC3-II and P62 in KM3 cells, representing the inhibition of autophagic flux. Furthermore, BA treatment dose-dependently downregulated the expression of Beclin 1, an important inducer of autophagy, in KM3 cells. In the presence of BA, Z-DEVD-FMK induced autophagy and increased the amount of LC3-II in KM3 cells, which may occur via attenuating BA-induced decrease in the level of Beclin 1. Similarly, rapamycin, an autophagy inducer, increased the amount of LC3-II in KM3 cells. In the presence of BA, rapamycin caused further increase in the amount of LC3-II. Furthermore, rapamycin sensitized BA-treated KM3 cells to apoptosis., Conclusion: The results demonstrate that BA induces apoptosis and blocks autophagic flux in KM3 cells. Furthermore, in addition to activation of caspase 3, the inhibition of autophagic flux also contributes to the BA-mediated apoptosis of KM3 cells.

ATP is essential for mammalian sperm to maintain fertilizing capacity. Metformin (Met) can activate 5′-AMP-activated protein kinase (AMPK) to maintain energy homeostasis. Thus, the aim of the present study was to investigate whether Met can improve testis function, semen quality, antioxidant and autophagy capacity through AMPK mediation of energy metabolism in goats. Twelve adult goats were randomly divided into three dietary treatments. All goats were fed a basal diet for 3 weeks and then assigned to a Met supplementation diet containing 0, 150, or 300 mg/kg for 8 weeks. The results showed that sperm viability, sperm membranal functional integrity, and acrosome integrity increased (P < 0.05) relative to the other treatments in the 300 mg/kg Met group. Growth hormone (GH) and insulin-like growth factor (IGF-1) in the 300 mg/kg Met group significantly decreased (P < 0.05) relative to the control group. Estrogen levels (E 2) in the 300 mg/kg Met group remarkably improved (P < 0.05) compared with the control group. The activities of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GSH-px), and superoxide dismutase (SOD) significantly increased (P < 0.05) in the 300 mg/kg Met group relative to the control group. A significant increase in AMPK and p-AMPK protein expression in the 300 mg/kg Met group was observed relative to the control group (P < 0.05). Belicin-1 and LC3II/I protein expression was significantly increased by adding Met to the diet (P < 0.05) and reached a maximum in the 300 mg/kg Met group. In addition, differentially expressed genes (DEGs) of goat testis were confirmed by RNA-seq. GO enrichment analysis revealed that DEGs were enriched in testicular metabolism and sperm development-related functional pathways. Overall, the results indicate that Met may play an important role in the regulation of testis function, semen quality, antioxidant, and autophagy capacity. These findings will help elucidate the role of Met in goat testis development. • The addition of Met improves reproductive performance of goats, significantly improved semen acrosome integrity and plasma membrane integrity. • The expression of AMPK and p-AMPK proteins were significantly increased. • The autophagy marker proteins and the activities of antioxidant enzymes were significantly increased. [ABSTRACT FROM AUTHOR]

Prostaglandin pathway plays multiple roles in various physiological and pathological conditions. The present study aimed to investigate the effect of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in the degradation of prostaglandins, on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice. In this study, male C57BL/6J mice were injected intraperitoneally with LPS (10 mg/kg). SW033291, a potent small-molecule inhibitor of 15-PGDH, was used to investigate the therapeutic potential of 15-PGDH inhibition on LPS-induced AKI. We discovered that the expression of 15-PGDH protein was upregulated in kidneys of LPS-stimulated mice, and it was mainly localized in the cytoplasm of renal tubular epithelial cells in renal cortex and outer medulla. SW033291 administration improved the survival rates of mice and attenuated renal injury of mice that were challenged by LPS. Additionally, inhibition of 15-PGDH also reversed LPS-induced apoptosis of renal cells, increased expression of anti-apoptotic protein Bcl-2, and downregulated expression of Fas, caspase-3, and caspase-8. Pretreatment of SW033291 enhanced autophagy in kidney cells after LPS stimulation. Our data also showed that inhibition of 15-PGDH relieved the level of lipid peroxidation and downregulated NADPH oxidase subunits induced by LPS in mice kidneys but had no significant effect on the release of inflammatory factors, such as IL-6, IL-1β, TNF-α, and MCP-1. Our study demonstrated that inhibition of 15-PGDH could alleviate LPS-induced AKI by regulating the apoptosis, autophagy, and oxidative stress rather than inflammation in mice. [ABSTRACT FROM AUTHOR]

The present study explored the protective effect of exogenous hydrogen sulfide (H2S) on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and the underlying mechanisms. To establish an AKI injury mouse model, LPS (10 mg/kg) was intraperitoneally injected into mice pretreated with 0.8 mg/kg sodium hydrosulfide hydrate (NaHS), an H2S donor. The mouse survival rate and the degree of kidney injury were examined. To construct a cell damage model, HK-2 cells were pretreated with different concentrations (0.1, 0.3 and 0.5 mM) of NaHS, and then the cells were stimulated with LPS (1 µg/ml). The cell viability, autophagy, apoptosis levels and the release of inflammatory factors were examined in mouse kidney tissue and HK-2 renal tubular epithelial cells. It was found that pretreatment with NaHS significantly improved the survival rate of septic AKI mice, and reduced the renal damage, release of inflammatory factors and apoptosis. In HK-2 cells, NaHS protected cells from LPS caused damage via promoting autophagy and inhibiting apoptosis and the release of inflammatory factors. In order to clarify the relationship between autophagy and apoptosis and inflammatory factors, this study used 3-methyladenine (3-MA) to inhibit autophagy. The results revealed that 3-MA eliminated the protective effect of NaHS in HK-2 cells and AKI mice. Overall, NaHS can protect from LPS-induced AKI by promoting autophagy and inhibiting apoptosis and the release of inflammatory factors. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON), a type B trichothecene mycotoxin mainly affects the health status of pigs and reduced their growth. This study aimed to determine the effects of PI3K/Akt/mTOR pathway on DON-induced autophagy of piglet hippocampal nerve cells (PHNCs), and the relationship between autophagy and apoptosis. The effects of DON on autophagy of PHNCs were examined by cell morphology, cell viability, apoptosis rate, electron microscopy, transient transfection of GFP-LC3 plasmid, immunofluorescence and expression of autophagy-related genes and proteins. The relationship between autophagy and cell apoptosis was analyzed by western blotting, CCK-8 and flow cytometry. The results indicated that, DON inhibited the proliferation of PHNCs and significantly changed cell morphology, and induced apoptosis and autophagy. The expression levels of LC3 protein and gene increased, while the expression levels of PI3K/Akt/mTOR pathway-related genes and proteins decreased, when the concentration of DON increased. Activation of autophagy significantly increased cell viability, reduced apoptosis rate, inhibits autophagy significantly, reduced cell activity and increased apoptosis rate. This data demonstrated that DON exerts certain toxic effect on PHNCs, induced apoptosis and autophagy. PI3K/Akt/mTOR signaling pathway plays a negative regulatory role in DON-induced autophagy of PHNCs. At the same time, autophagy plays a protective role in DON-induced PHNCs injury. • DON exerts certain toxic effect on PHNCs, induced apoptosis. • DON can induce autophagy in PHNCs. • PI3K/Akt/mTOR signaling pathway plays a negative regulatory role in DON-induced autophagy of PHNCs. • Autophagy plays a protective role in DON-induced PHNCs injury. [ABSTRACT FROM AUTHOR]