Search

Breast cancer is a leading cause of cancer‐related death worldwide, and chemoresistance often leads to poor patient outcomes. In this study, we investigated the anticancer activity of synthetic diphenyl disulfide (DPDS) in breast cancer cell lines. DPDS inhibited cellular proliferation and viability in a dose‐dependent manner and reduced colony formation, an index of clonogenicity. Annexin‐V and 7‐AAD double staining showed that DPDS could induce the apoptosis of breast cancer cells. Western blotting of the expression of Bax p21 and its cleaved form p18 suggested the activation of p18 Bax‐induced apoptosis. Furthermore, the increased expression of the autophagy marker LC3B‐II indicated autophagic lysosome accumulation induced by DPDS. Our findings suggest that DPDS has potential as a candidate for treating breast cancer, and further modifications and optimizations are warranted. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with increasing occurrence, high death rates and unfavorable treatment regimens. In the current study, we identified the expression of microRNA‐9 (miR‐9) and anoctamin‐1 (ANO1) in IPF mouse models induced by bleomycin, and their effects on inflammation and fibroblast proliferation through the transforming growth factor‐β (TGF‐β)–Smad3 pathway. To verify the targeting relationship between miR‐9 and ANO1, we used bioinformatics prediction and conducted a dual‐luciferase reporter gene assay. The underlying regulatory mechanisms of miR‐9 and the target gene ANO1 were investigated mainly with the treatment of miR‐9 mimic, miR‐9 inhibitor, or siRNA against ANO1 in fibroblasts isolated from IPF mice. Enzyme‐linked immunosorbent assay was performed to investigate the effect of miR‐9 or ANO1 on inflammatory factors. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and flow cytometry were used to detect fibroblast proliferation and apoptosis. Reverse transcription quantitative polymerase chain reaction and western blot analysis were applied to measure the expression of the TGF‐β–Smad3 pathway‐related genes. The determination of luciferase activity suggested that miR‐9 targets ANO1. Upregulation of miR‐9 or silencing of ANO1 intensified inflammation in IPF, promoted proliferation and inhibited apoptotic ability of lung fibroblasts. MiR‐9 negatively modulated ANO1, and thus activated the TGF‐β–Smad3 pathway. These findings suggest that miR‐9 can indirectly activate the TGF‐β–Smad3 pathway by inhibiting the expression of ANO1, thereby aggravating inflammation, promotes proliferation and suppressing apoptosis of lung fibroblasts in mice models of IPF. miR‐9 can indirectly activate the TGF‐β–Smad3 pathway by inhibiting the expression of ANO1, thereby aggravating inflammation, promotes proliferation and suppressing apoptosis of lung fibroblasts in mice models of IPF. [ABSTRACT FROM AUTHOR]

Melatonin induces apoptosis in many different cancer cell lines, including colorectal cancer. However, the precise mechanisms involved remain largely unresolved. In this study, we provide evidence to reveal a new mechanism by which melatonin induces apoptosis of colorectal cancer LoVo cells. Melatonin at pharmacological concentrations significantly suppressed cell proliferation and induced apoptosis in a dose-dependent manner. The observed apoptosis was accompanied by the melatonin-induced dephosphorylation and nuclear import of histone deacetylase 4 ( HDAC4). Pretreatment with a HDAC4-specific si RNA effectively attenuated the melatonin-induced apoptosis, indicating that nuclear localization of HDAC4 is required for melatonin-induced apoptosis. Moreover, constitutively active Ca2+/calmodulin-dependent protein kinase II alpha ( Ca MKII α) abrogated the melatonin-induced HDAC4 nuclear import and apoptosis of LoVo cells. Furthermore, melatonin decreased H3 acetylation on bcl-2 promoter, leading to a reduction of bcl-2 expression, whereas constitutively active Ca MKII α(T286D) or HDAC4-specific si RNA abrogated the effect of melatonin. In conclusion, the present study provides evidence that melatonin-induced apoptosis in colorectal cancer LoVo cells largely depends on the nuclear import of HDAC4 and subsequent H3 deacetylation via the inactivation of Ca MKII α. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore if cell autophagy is activated by Ang II before aging using human umbilical vascular endothelial cells ( HUVECs). The ultrastructural analysis of HUVECs was performed to observe autophagosomes. The LC3- II/ LC3-I ratio was determined by western blot assay. The β-gal staining was used to identify cell senescence. The flow cytometry was performed to evaluate cell apoptosis. The BH3 domain analog ABT737 or Beclin-1 knockdown by specific sh RNA or valsartan was applied to investigate their effects on cell autophagy, senescence, and apoptosis induced by Ang II. Cell autophagy was initiated after Ang II treatment at 24 h. And cell senescence and apoptosis were observed in Ang II-treated cells at 48 h. The significant interaction of Beclin-1 and Bcl-2 was detected at 48 h after Ang II treatment. Beclin-1 was indispensable to Ang II-induced autophagy, and its BH3 domain was required for the interaction with Bcl-2 to attenuate autophagy. Pretreated with valsartan, cells were present with less autophagic, senescent, and apoptotic cells after Ang II stimulation. In conclusion, Ang II induced autophagy, senescence, and apoptosis of HUVECs progressively, and autophagy presented an early protective effect on vascular endothelial damage due to Ang II. [ABSTRACT FROM AUTHOR]

Objective: Withaferin A (WA) is a bioactive compound with a remarkable anti‐cancer effect derived from Withania somnifera, commonly known as ashwagandha. However, the anti‐cancer mechanisms of WA in glioblastoma multiforme (GBM) are still unclear. Materials and Methods: Cell viability assays and xenografted nude mice were used to evaluate the effects of WA, along with flow cytometry to detect apoptosis and cell cycle of GBM. RNA‐seq analysis, Western blotting, immunofluorescence staining, qRT‐PCR and siRNA gene silencing were carried out to determine the signalling pathways affected by WA. Results: Withaferin A significantly inhibited the growth of GBM in vitro and in vivo and triggered the intrinsic apoptosis of GBM cells by up‐regulating expression of Bim and Bad. WA arrested GBM cells at the G2/M phase of the cell cycle through dephosphorylating Thr161 of CDK1 by activating p53‐independent p21 up‐regulation. Knockdown of p21 restored cell cycle progression and cell viability by down‐regulating the expression of Bad rather than Bim. We demonstrated that endoplasmic reticulum (ER) stress induced by WA through the ATF4‐ATF3‐CHOP axis, initiated apoptosis and G2/M arrest in GBM cells. Conclusion: We revealed a novel pathway that elucidated WA activation of apoptosis and G2/M arrest in GBM cells through the ATF4‐ATF3‐CHOP axis. This discovery is important for optimization of WA‐based regimens for prevention and/or treatment of GBM. [ABSTRACT FROM AUTHOR]