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Purpose of the Study: Induction of endogenous antioxidants is one of the key molecular mechanisms of cell resistance to hypoxia/ischemia. Thioredoxin1 (Trx1) is a small multifunctional ubiquitous antioxidant with redox-active dithiol and plays an important role in cell apoptosis through mitochondrial apoptosis pathways. The specific role of Trx1 in ischemia-reperfusion induced astrocyte apoptosis, however, remains unclear., Materials and Methods: In this study, we investigated the effect of Trx1 on apoptosis of astrocyte using an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model which mimics ischemic/reperfusion conditions in vivo. The astrocytes prepared from newborn Sprague-Dawley rats were exposed to OGD for 4 h followed by reoxygenation for 24 h. Next, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to assess cell viability while cell damage was assessed by lactate dehydrogenase (LDH)., Results: We found that OGD/R increased cell death as well as the expression of Trx1 and that the interference of Trx1 further aggravated astrocyte damage under OGD/R condition. Furthermore, we detected an increase in the intracellular expressions of Ras2, cAMP, and PKA under OGD/R condition, which paralleled cell injury., Conclusions: Notably, the deletion of Trx1 exacerbated astrocyte apoptosis via the Ras2-cAMP-PKA signaling pathway. We concluded that Trx1 protects astrocytes against apoptotic injury induced by OGD/R, and this protective effect may be partly related to the Ras2-cAMP-PKA signaling pathway.

Apoptosis is critical for the development of cerebral ischemia/reperfusion injury. Thioredoxin-1(Trx-1) protein has been reported to have anti-apoptotic effects in a variety of cell types, and it has been implicated in brain injury after middle cerebral artery occlusion (MCAO). Thus, we studied the effects of Trx1 silencing after MCAO in rats and examined whether inhibition of endogenous Trx1 could increase tissue levels of apoptosis. Male Sprague-Dawley rats (N=170) were subjected to 1h of middle cerebral arterial occlusion followed by 24h of reperfusion. Trx1 siRNAs were injected into rat brains 24h prior to MCAO. Then, 24h after MCAO, brains were collected from euthanized rats for investigation. Treatment with Trx1 siRNA significantly increased mortality, behavioral deficits, and cerebral infarction volume and exacerbated neuronal cell apoptotic death after MCAO injury. Western blot revealed increased expression of apoptotic proteins such as P-ASK1, P-JNK, P-p38, cleaved caspase-3 and increased the level of cytochrome c in the cytosolic fraction in the Trx1 siRNA-treated group. Co-immunoprecipitation assay suggested an interaction between Trx1 and ASK1 in normal rat brains and Trx1 siRNA dissociated ASK1-Trx1 binding complex. Our data suggest that Trx1 siRNA increases apoptotic stress-induced ASK1 activation and this represents further evidence that Trx1 is an endogenous anti-apoptotic molecule that diminishes focal cerebral ischemia/reperfusion injury. Its mechanism of action is likely related to attenuation of the ASK1-JNK/p38 signaling pathway., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Simple Summary: In the present study, we aimed to explore the potential local regulatory role of the cocaine- and amphetamine-regulated transcript (CART) signaling pathway in granulosa cell (GC) apoptosis, which is a key mechanism promoting follicular atresia in several animal species, including buffalo. Our results showed how CART activity adversely influences buffalo GC viability by affecting estradiol production and enhancing apoptosis. The regulatory mechanism by which CART can affect GC apoptosis entails the modulation of the AKT/GSK3β/β-catenin pathway, a key intracellular signaling pathway essential for cell viability. In conclusion, this study provides valuable insights into the intricate mechanisms governing ovarian follicle development and granulosa cell function. These findings have implications for reproductive biology not only for buffalo but also for different species. Atresia is a process in ovarian follicles that is regulated by hormone-induced apoptosis. During atresia, granulosa cell (GC) apoptosis is a key mechanism orchestrated through diverse signaling pathways. Cocaine- and amphetamine-regulated transcript (CART) signaling within ovarian GCs has been demonstrated to play a key role in the regulation of follicular atresia in cattle, pigs, and sheep. The present work aimed to investigate the potential local regulatory role of CART in GC apoptosis-induced follicular atresia in buffalo, focusing on the modulation of the AKT/GSK3β/β-catenin signaling pathways, which are the intracellular signaling pathways involved in cell viability. Our findings revealed increased expression of CARTPT and BAX and decreased levels of AKT, β-catenin, and CYP19A1 genes in atretic follicles compared to healthy follicles. Subsequently, CART treatment in the presence of FSH inhibited the FSH-induced increase in GC viability by reducing estradiol production and increasing apoptosis. This change was accompanied by an increase in the gene expression levels of both CARTPT and BAX. At the protein level, treatment with CART in the presence of FSH negatively affected the activity of AKT, β-catenin, and LEF1, while the activity of GSK3β was enhanced. In conclusion, our study shows how CART negatively influences buffalo GC viability, underlying the modulation of the AKT/GSK3β/β-catenin pathway and promoting apoptosis—a key factor in follicular atresia. [ABSTRACT FROM AUTHOR]

An acid-labile dextran–bortezomib conjugate (Dex–BTZ), i.e., a macromolecularized proteasome inhibitor, is synthesized by a boron esterification reaction. The prodrug exhibits intracellular acidity-accelerated BTZ release, and up-regulated inhibition efficacies toward hypoxic tumor in vitro and in vivo through both NF-κB- and ERS-mediated apoptosis signaling pathways. [ABSTRACT FROM AUTHOR]

Twenty-five sophora alkaloids-cinnamic acid hybrids (including matrine-cinnamic acid hybrids, sophoridine-cinnamic acid hybrids, and sophocarpine-cinnamic acid hybrids) were designed, synthesized, and evaluated in vitro against three human tumor cell lines (HeLa, HepG2 and A549) with cisplatin as a positive control. Some matrine-cinnamic acid and sophoridine-cinnamic acid compounds exhibited potent effect against all three cancer cell lines, such as compounds 5b, 5e, 5g, and 6d. The structure-activity relationship study of the synthesized compounds was also performed. Preliminary mechanistic studies indicated that compounds 5e and 6d could induce apoptosis in HepG2 cell line. Further, compounds 5e and 6d altered mitochondrial membrane potential and produced ROS leading to cell apoptosis of HepG2 cells. Overall, our findings suggested that these compounds may provide promising lead compounds for further development as antitumor agents by structural modification. [ABSTRACT FROM AUTHOR]

Clavipyrrine A (1), a novel polycyclic nitrogenous meroterpenoid with a pyrrolo[1,2- a ]imidazole and a 10-membered carbocycle fused with an α,β-epoxy-γ-lactone, was isolated from Clitocybe clavipes , a basidiomycete. X-ray crystallography and spectroscopic analysis were used to fully elucidate its structure. The biosynthetic origin of the pyrrole unit in this nitrogenous meroterpenoid was identified by incorporating 15N-labeled γ-aminobutyric acid. Compound 1 displayed promising anti-glioma activities and induced glioma cell apoptosis through inhibiting the JAK/STAT3 pathway and reinforcing SOCS1/3. [Display omitted] • One polycyclic nitrogenous meroterpenoid was isolated from Clitocybe clavipes. • The pyrrolo[1,2- a ]benziimidazole skeleton was biosynthetically postulated. • Compound 1 displayed promising anti-glioma activities. • Compound 1 induced glioma cell apoptosis through inhibiting JAK/STAT3 pathway. Clavipyrrine A (1), a novel polycyclic nitrogenous meroterpenoid with a pyrrolo[1,2- a ]imidazole and a 10-membered carbocycle fused with an α,β-epoxy-γ-lactone, was isolated from Clitocybe clavipes , a basidiomycete. X-ray crystallography and spectroscopic analysis were used to fully elucidate its structure. The biosynthetic origin of the pyrrole unit in this nitrogenous meroterpenoid was identified by incorporating 15N-labeled γ-aminobutyric acid. Compound 1 displayed promising anti-glioma activities and induced glioma cell apoptosis through inhibiting the JAK/STAT3 pathway and reinforcing SOCS1/3. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) lacks a recognized therapeutic molecular target and has an unfavorable prognosis. (20S)-Protopanaxatriol (g-PPT, PPT) is an active metabolite extracted from ginseng. Accumulating evidence suggests that it has good anti-cancer activity in vivo and in vitro. In this study, we aimed to elucidate the anti-tumor effects of PPT in TNBC cells and tumor-bearing mice, as well as the relevant molecular mechanisms of autophagy and apoptosis. In vitro , we have found that PPT is capable of inducing non-protective autophagy and apoptosis, thus exerting some anti-proliferative and anti-migration activity in TNBC cells. And in vivo , the therapeutic effects of PPT were evaluated by xenograft mouse models. The potential binding mode of PPT and Akt was predicted by molecular docking. Our findings indicated that PPT treatment induced non-protective autophagy in TNBC cells by inhibiting the Akt/mTOR signaling pathway. Therefore, PPT may be a potential treatment for TNBC in the future. • PPT exerted anti-cancer effect in TNBC cells both in vitro and in vivo. • PPT activates apoptosis and non-protective autophagy in TNBC cells. • PPT activates apoptosis and autophagy by inhibiting Akt/mTOR pathway in TNBC cells. [ABSTRACT FROM AUTHOR]

Inactivated Sendai virus (HVJ-E) has shown potential anticancer efficacy in various cancer cells. However, the ability of HVJ-E to regulate cancer cell survival and death remains largely unknown. In the present study we first found that HVJ-E exhibited cytotoxic effects in the non-small cell lung cancer cell (NSCLC) line A549 and cisplatin-resistant A549 cells (A549/DDP). The suppression of cell viability was due to both the activation of caspases and the JNK and p38 MAPK signaling pathways in A549 and A549/DDP human lung cancer cells. In addition, we demonstrated that HVJ-E could induce autophagy in NSCLC cells via the PI3K/Akt/mTOR/p70S6K signaling pathway for the first time. Inhibiting autophagy in A549/DDP cells and inducing autophagy in A549 cells enhanced HVJ-E-induced apoptosis. These findings provide a molecular basis of HVJ-E-mediated cell death and support the notion that combination treatment with autophagy modulators is an effective strategy to augment the cytotoxic effects of HVJ-E in NSCLC cells. [ABSTRACT FROM AUTHOR]