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The enhancement of the toxic effect of microplastics (MPs) on heavy metals and its mechanism needs more in-depth and systematic research. In this study, the copper (Cu) accumulation, histological injury, and expression of genes involved in oxidative stress, inflammation, apoptosis, and autophagy of goldfish after single or combined exposure of MPs (1 mg/L) and Cu

Background: Type 2 diabetes is a persistent inflammatory response that impairs the healing process. We hypothesized that stimulation with high glucose following a pro-inflammatory signal would lead to autophagy inhibition, reactive oxygen species (ROS) production and eventually to the activation of the Nod-like receptor protein (NLRP) -3. Methods: Macrophages were isolated from human diabetic wound. We measured the expression of NLRP3, caspase1 and interleukin-1 beta (IL-1β) by western blot and real-time PCR, and the surface markers on cells by flow cytometry. THP-1-derived macrophages exposed to high glucose were applied to study the link between autophagy, ROS and NLRP3 activation. LC3-II, P62, NLRP3 inflammation and IL-1β expression were measured by western blot and real-time PCR. ROS production was measured with a Cellular Reactive Oxygen Species Detection Assay Kit. Results: Macrophages isolated from diabetic wounds exhibited a pro-inflammatory phenotype, including sustained NLRP3 inflammasome activity associated with IL-1β secretion. Our data showed that high glucose inhibited autophagy, induced ROS production, and activated NLRP3 inflammasome and cytokine secretion in THP-1-derived macrophages. To study high glucose-induced NLRP3 inflammasome signalling, we performed studies using an autophagy inducer, a ROS inhibitor and a NLRP3 inhibitor and found that all reduced the NLRP3 inflammasome activation and cytokine secretion. Conclusion: Sustained NLRP3 inflammasome activity in wound-derived macrophages contributes to the hyper-inflammation in human diabetic wounds. Autophagy inhibition and ROS generation play an essential role in high glucose-induced NLRP3 inflammasome activation and cytokine secretion in macrophages.

Stroke is a cerebrovascular disorder that affects many people worldwide. Pericytes play an important role in stroke progression and recovery. The sigma-1 receptor (σ-1R) signaling pathway has been suggested as having promising neuroprotective potential in treating stroke; however, whether σ-1R activation regulates pericyte function remains unknown. The aim of this study was to elucidate the role of σ-1R and a novel σ-1R agonist in pericytes following ischemic stroke. An ischemic stroke animal model was induced by photothrombotic middle cerebral artery occlusion (pMCAO) in σ-1R knockout (KO) and wild-type (WT) mice. After pMCAO, there was significant pericyte loss and coverage in σ-1R KO mice compared with WT mice as determined using transmission electron microscopy, immunofluorescence staining, and western blot. Interestingly, a novel σ-1R agonist decreased infarct volume and blood-brain barrier damage with a concomitant amelioration of pericyte loss, as determined by western blot. Further studies indicated that cell apoptosis and autophagy were induced in an in vivo pMCAO ischemic stroke animal model and an in vitro oxygen glucose deprivation-treatment group. Inhibition of autophagy using a pharmacological approach significantly mitigated pericyte apoptosis, suggesting that autophagy was upstream of apoptosis in pericytes. Both in vivo and in vitro studies indicated that the σ-1R agonist significantly decreased cell apoptosis via inhibition of autophagy with a subsequent enhancement of pericyte survival. This study identified the unique roles for σ-1R in mediating pericyte survival via the regulation of the interplay between apoptosis and autophagy, suggesting that a novel σ-1R agonist may be a promising therapeutic agent for the treatment of stroke patients.

As one of the most notorious of malignancies, glioblastoma multiforme (GBM), accounts for 45.2% of all malignant primary brain tumors.1 Despite aggressive surgery, radiation, and chemotherapy, the life expectancy of patients averages a mere 14 months after diagnosis.2 Soluble N-ethylmaleimide-sensitive factor (NSF) receptor (SNARE) is a superfamily of small proteins with more than 35 members in mammals, varying in size and primary structure.3 As an essential mechanism for cellular activities, SNARE has been observed in the progression of various tumors.4,5 Vesicle-associated membrane protein 8 (VAMP8) was first identified as an endosomal SNARE that participates in diverse biological functions including endosomal fusion,6–8 the exocytosis of GLUT4 and insulin,9,10 regulation of exocytosis in secretory cells,11 sequential granule-to-granule fusion,11 and autophagy.12,13 Nevertheless, nobody has reported its involvement in tumor progression. Temozolomide (TMZ) is the most commonly used chemotherapeutic drug in clinical trials for glioma. However, a large number of patients are resistant to TMZ, which greatly compromise the clinical treatment. Thus, research on TMZ resistance is of great importance for ameliorating the therapeutic efficacy and alleviating the suffering of patients. Autophagy is a dynamic process of protein degradation that is essential for survival, differentiation, development, and homeostasis.14 Despite evidence demonstrating the role of autophagy in modifying TMZ resistance in GBM,15–17 it remains incompletely understood, and clarification is needed. In this study, we first analyzed the expression and prognostic value of VAMP8 in The Cancer Genome Atlas (TCGA) and a cohort of 282 glioma patients, and then investigated its roles on tumorigenisis and TMZ resistance in glioma. Our findings revealed that the dysregulation of VAMP8 is a potential component of glioma pathogenesis and TMZ resistance, which might become a new therapeutic target for patients with glioma.