Despite converging epidemiological evidence for the inverse relationship of regular caffeine consumption and risk of developing Parkinson's disease (PD) with animal studies demonstrating protective effect of caffeine in various neurotoxin models of PD, whether caffeine can protect against mutant α-synuclein (α-Syn) A53T-induced neurotoxicity in intact animals has not been examined. Here, we determined the effect of chronic caffeine treatment using the α-Syn fibril model of PD by intra-striatal injection of preformed A53T α-Syn fibrils. We demonstrated that chronic caffeine treatment blunted a cascade of pathological events leading to α-synucleinopathy, including pSer129α-Syn-rich aggregates, apoptotic neuronal cell death, microglia, and astroglia reactivation. Importantly, chronic caffeine treatment did not affect autophagy processes in the normal striatum, but selectively reversed α-Syn-induced defects in macroautophagy (by enhancing microtubule-associated protein 1 light chain 3, and reducing the receptor protein sequestosome 1, SQSTM1/p62) and chaperone-mediated autophagy (CMA, by enhancing LAMP2A). These findings support that caffeine—a strongly protective environment factor as suggested by epidemiological evidence—may represent a novel pharmacological therapy for PD by targeting autophagy pathway.

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Despite the progress in deorphanization of G Protein-Coupled Receptors (GPCRs), ≈100 GPCRs are still classified as orphan receptors without identified endogenous ligands and with unknown physiological functions. The lack of endogenous ligands triggering GPCR signaling has hampered the study of orphan GPCR functions. Using GPR37 as an example, we provide here the first demonstration of the channelrhodopsin 2 (ChR2)-GPCR approach to bypass the endogenous ligand and selectively activate the orphan GPCR signal by optogenetics. Inspired by the opto-XR approach, we designed the ChR2-GPR37 chimera, in which the corresponding parts of GPR37 replaced the intracellular portions of ChR2. We showed that optogenetic activation of ChR2/opto-GPR37 elicited specific GPR37 signaling, as evidenced by reduced cAMP level, enhanced ERK phosphorylation and increased motor activity, confirming the specificity of opto-GPR37 signaling. Besides, optogenetic activation of opto-GPR37 uncovered novel aspects of GPR37 signaling (such as IP-3 signaling) and anxiety-related behavior. Optogenetic activation of opto-GPR37 permits the causal analysis of GPR37 activity in the defined cells and behavioral responses of freely moving animals. Importantly, given the evolutionarily conserved seven-helix transmembrane structures of ChR2 and orphan GPCRs, we propose that opto-GPR37 approach can be readily applied to other orphan GPCRs for their deorphanization in freely moving animals.

This study aimed to investigate the prevalence of age-related macular degeneration (AMD) in patients with diabetes mellitus (DM) and diabetic retinopathy (DR) and analyze whether DR is a risk factor for AMD. This population-based epidemiological study included 14,440 people from the Kailuan Eye Study in 2016, of whom 1,618 were patients with type 2 DM aged over 50 years, and 409 had DM with DR. We analyzed whether there were differences in the prevalence of AMD between DM with DR and DM without DR, and conducted a hierarchical statistical analysis according to different stages of DR. Using variable regression analysis, we explored whether DR constituted a risk factor for AMD. In the DM population, the prevalence of wet AMD in patients with DM with and without DR was 0. 3 and 0.2%, respectively, with no significant difference (P = 0.607). Meanwhile, the prevalence of dry AMD in patients with DM with and without DR was 20.8 and 16.0%, respectively, with a significant difference. In the subgroup analysis of dry AMD, the prevalence of early, middle, and late dry AMD in DM with DR was 14.4, 5.9, and 0.5%, respectively. In DM without DR, the prevalence of early, middle, and late dry AMD was 10.5, 4.8, and 0.7%, respectively (P = 0.031). In the subgroup analysis of DR staging, statistical analysis could not be performed because of the limited number of patients with PDR. In the variable regression analysis of risk factors for dry AMD, after adjusting for age, sex, body mass index, hypertension, and dyslipidemia, DR constituted the risk factor for dry AMD. In conclusion, DM did not constitute a risk factor for AMD, and the prevalence of wet AMD and dry AMD in patients with DM and DR was higher than that in patients with DM without DR (among which dry AMD was statistically significant). Multivariate regression analysis confirmed that DR is an independent risk factor for dry AMD. Reasonable control of DM and slowing down the occurrence and development of DR may effectively reduce the prevalence of AMD in patients with DM.

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Long noncoding RNAs (lncRNAs), a group of transcripts, have been revealed to be critical participants in regulating multiple biological processes of malignant tumors. The knowledge of NPPA‐AS1 (a new lncRNA) in cancer research is hardly known. Thus, it is of urgent need to study the underlying role of NPPA antisense RNA 1 (NPPA‐AS1) in cervical cancer (CC). In this study, NPPA‐AS1 was discovered to be lowly expressed and upregulation of it impaired cell proliferation and migration in CC. Besides, downregulation of it led to opposite results. Molecular mechanism assays uncovered that increased expression of NPPA‐AS1 could inactivate Wnt/β‐catenin signaling pathway in CC. In addition, NPPA‐AS1 was found to negatively interact with miR‐302e whereas positively correlate with dickkopf‐1 (DKK1, an inhibitor of Wnt pathway) in CC. Besides, loss of function assay illuminated that miR‐302e inhibition restrained cell proliferation and migration in CC. Subsequent rescue assays confirmed that NPPA‐AS1 acted as a competing endogenous RNA in CC by sponging miR‐302e to upregulate DKK1 expression. Finally, the RE‐1 silencing transcription factor (REST) was testified to function as a transcription suppressor of NPPA‐AS1 in CC. In brief, REST‐repressed NPPA‐AS1 regulates CC progression by modulating miR‐302e/DKK1/Wnt/β‐catenin signaling pathway.