α-synuclein abnormal accumulation and mitochondria dysfunction are involved in the pathogenesis of Parkinson’s disease. Selective autophagy of mitochondria (mitophagy) is a crucial component of the network controlling the mitochondrial homeostasis. However, the underlying mechanism that mutant α-synuclein induces mitochondrial abnormality through mitophagy impairment is not fully understood. Here, we showed that mutant A53T α-synuclein accumulation impaired mitochondrial function and Parkin-mediated mitophgy in α-synucleinA53T model. α-synucleinA53T overexpression caused p38 MAPK activation, then p38 MAPK directly phosphorylated Parkin at serine 131 to disrupt the Parkin’s protective function. The p38 MAPK inhibition significantly reduced cellular apoptosis, restored mitochondrial membrane potential as well as increased synaptic density both in SN4741 cells and primary midbrain neurons. These findings show that the p38 MAPK-Parkin signaling pathway regulates mitochondrial homeostasis and neuronal degeneration, which may be a potential therapeutic strategy of PD via enhancing mitochondrial turn-over and maintenance.

Excessive oxygen and its chemical derivatives, namely reactive oxygen species (ROS), produce oxidative stress that has been known to lead to cell injury in ischemic stroke. ROS can damage macromolecules such as proteins and lipids and leads to cell autophagy, apoptosis, and necrosis to the cells. This review describes studies on the generation of ROS, its role in the pathogenesis of ischemic stroke, and recent development in therapeutic strategies in reducing oxidative stress after ischemic stroke.

The SOCE (store-operated Ca2+ entry) pathway plays a key role in both normal cells and cancerous cells. However, its molecular mechanism remains a long-lasting puzzle of Ca2+ signalling. In this paper, we provide evidence that butyric acid, a dietary fibre-derived short-chain fatty acid, induces apoptosis of colon cancer cells via SOCE signalling networks. We found that sodium butyrate (NaB) induces Ca2+ release from endoplasmic reticulum, which in turn causes extracellular Ca2+ influx in HCT-116 cells. The Ca2+ release and influx are important, because the addition of chelators, EGTA or BAPTA/AM [1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] respectively blocked NaB-induced apoptosis. Furthermore, down-regulation of STIM1 (stromal interaction molecule 1) by RNA interference or pharmacological blockade of the SOCC (store-operated Ca2+ channel) by 2-APB (2-aminoethoxydiphenyl borate) or SKF-96365 inhibited NaB-induced extracellular Ca2+ influx and apoptosis in HCT-116 cells. Thus we conclude that NaB triggers colon cancer cell apoptosis in an SOCE-dependent manner. This finding provides new insights into how butyric acid suppresses colon carcinogenesis.

MTA1 protein overexpression is common in early-stage NSCLC and is significantly associated with tumor angiogenesis and poor survival. These findings suggest that MTA1 may have clinical potential as a promising predictor to identify individuals with poor prognostic potential and as a possible novel target molecule of antiangiogenic therapy for patients with early-stage NSCLC.

The aim of the present study was to investigate the potential protective effects of new Wenshen Shengjing Decoction (new WSSJD; including Cornu Cervi Nippon Parvum, Panax ginseng, Cynomorium songaricum, Cistanche deserticola, Radix Astragali, Epimedium brevicornum and Angelica sinensis) on cyclosporine-induced impairment of testosterone synthesis and spermatogenic apoptosis in mice. A total of 90 adult male Kunming mice were divided into the following 6 groups: Control (no intervention), dimethylsulfoxide (DMSO; received only DMSO), cyclosporine A (CsA), clomifene citrate (CC; CsA + CC, 15 mg/kg/day), WSSJD (CsA + WSSJD, crude drug 12 g/kg/day) and new WSSJD (CsA + new WSSJD, crude drug 12 g/kg/day). All mice were treated for 30 days via oral gavage. The testes were subsequently fixed and stained with hematoxylin & eosin to assess the development of seminiferous epithelia. Immunohistochemical techniques were used to detect the expression of luteinizing hormone receptor (LHR) and P450 side chain cleavage (P450scc) in testicular Leydig cells. In addition, the apoptosis of spermatogenic cells in the testes was detected using a terminal dexynucleotidyl transferase-mediated dUTP nick-end labeling assay, and flow cytometry was used to analyze the survival rate and early apoptosis of sperm in the epididymis. Compared with the CsA and CC groups, new WSSJD administration significantly increased levels of serum testosterone and the expressions of LHR and P450scc in testicular Leydig cells (P<0.05), while the apoptosis of spermatogenic cells in the seminiferous tubules and early apoptosis of mature sperm were significantly decreased (P<0.05). These results suggest that new WSSJD may ameliorate CsA-induced spermatogenic damage in male mice by enhancing testosterone synthesis and the secretion of testicular Leydig cells, and by reducing the apoptosis of spermatogenic cells.

No abstract

Impairment in autophagy-lysosomal pathway (ALP) results in accumulation of misfolded proteins and dysfunctional organelles, which is the hallmark of neurodegenerative diseases including Parkinson's disease (PD). Recent studies revealed activated nonreceptor tyrosine kinase Abelson (c-Abl) in PD models and brain specimen of PD patients. Inhibition of c-Abl through pharmacological inhibitors has been shown to enhance ALP function and provide neuroprotective effects in cells and animal models of PD. However, the molecular mechanisms of neuroprotective effects underlying c-Abl inhibition remain elusive. In this study, STI-571, a c-Abl inhibitor, rescued the ALP function through facilitating the nuclear translocation of TFEB and protected against MPP+-induced neuronal cell death. Furthermore, siRNA-mediated knock-down or pharmacological inhibition of GSK3β mitigated the MPP+-induced neuronal cell death, which was achieved through promoting TFEB nuclear localization and subsequently reversing the function of ALP. Intriguingly, either DPH, c-Abl activator, or MPP+ led to the activation of GSK3β, which is a negative regulator of TFEB. In addition, c-Abl directly interacted with GSK3β and catalyzed its phosphorylation at tyrosine 216, and their interaction was enhanced under MPP+ treatment. In contrast, STI-571 abrogated phosphorylation of GSK3β-Tyr216 induced by MPP+ in SN4741 cells and in primary midbrain neurons. Taken together, these results demonstrate that GSK3β is a novel c-Abl substrate, and c-Abl-GSk3β pathway mediates MPP+-induced ALP defects and neuronal cell death, which may represent a potential therapeutic target for PD.

SphK1 and SphK2 are involved in proliferation of glioma cells in hypoxic conditions through distinct signalling pathways. SphK1, but not SphK2, promotes cell population expansion in hypoxic conditions by activating ERK.