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Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 μg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson’s disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson’s disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01018-5.

Glomerular mesangial cell (MC) proliferation is one of the main pathological changes in diabetic nephropathy (DN), but its mechanism needs further elaboration. The Hippo and PI3K/Akt signalling pathways are involved in the regulation of MC proliferation, but their relationship in hyperglycaemia-induced MC proliferation has not been reported. We used db/db mice and high-glucose-cultured mesangial cells to generate a diabetic nephropathy model. An MST1-knockdown plasmid was used to identify whether the PI3K/Akt pathway is linked to the Hippo pathway through MST1. LY294002 and SC79 were used to verify the role of the PI3K/Akt signalling pathway in MC cells. RNA silencing and overexpression were performed by using YAP and PTEN-expression/knockdown plasmids to investigate the function of YAP and PTEN, respectively, in the Hippo and PI3K/Akt signalling pathways. By examining a potential feedback loop, we found decreased phosphorylation of MST1 and Lats1 and increased PI3K/Akt activation in db/db mice and high glucose-treated MCs, along with increased MC proliferation. The results of our gene silencing experiment proved PI3K/Akt-mediated intervention in the Hippo pathway and the regulatory effect of YAP on PI3K/Akt through PTEN. The Hippo pathway is inhibited under diabetic conditions, leading to YAP activation and promoting MC proliferation. The PI3K/Akt pathway is activated through the inhibitory effect of YAP on its repressor, PTEN. Finally, activation of the PI3K/Akt pathway inhibits the Hippo pathway, resulting in nuclear YAP accumulation and accelerating MC proliferation and DN formation.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Early diagnosis is the key to treatment but is still a great challenge in the clinic now. The discovery of alpha-synuclein (α-syn) aggregates ligands has become an attractive strategy to meet the early diagnosis of PD. Herein, we designed and synthesized a series of styrylaniline derivatives as novel α-syn aggregates ligands. Several compounds displayed good potency to α-syn aggregates with Kd values less than 0.1 μM. The docking study revealed that the hydrogen bonds and cation-pi interaction between ligands and α-syn aggregates would be crucial for the activity. The representative compound 7–16 not only detected α-syn aggregates in both SH-SY5Y cells and brain tissues prepared from two kinds of α-syn preformed-fibrils-injected mice models but also showed good blood-brain barrier penetration characteristics in vivo with a brain/plasma ratio over 1.0, which demonstrates its potential as a lead compound for further development of in vivo imaging agents.

Podocyte injury following abnormal podocyte autophagy plays an indispensable role in diabetic nephropathy (DN), therefore, restoration of podocyte autophagy is considered as a feasible strategy for the treatment of DN. Here, we investigated the preventive effects of sarsasapogenin (Sar), the main active ingredient in Anemarrhena asphodeloides Bunge, on the podocyte injury in diabetic rats, and tried to illustrate the mechanisms underlying the effects in high glucose (HG, 40 mM)-treated podocytes (MPs). Diabetes model was established in rats with single streptozocin (60 mg· kg−1) intraperitoneal administration. The rats were then treated with Sar (20, 60 mg· kg−1· d−1, i.g.) or a positive control drug insulin (INS) (40 U· kg−1· d−1, i.h.) for 10 weeks. Our results showed that both Sar and insulin precluded the decreases of autophagy-related proteins (ATG5, Beclin1 and LC3B) and podocyte marker proteins (podocin, nephrin and synaptopodin) in the diabetic kidney. Furthermore, network pharmacology was utilized to assess GSK3β as the potential target involved in the action of Sar on DN and were substantiated by significant changes of GSK3β signaling in the diabetic kidney. The underlying protection mechanisms of Sar were explored in HG-treated MPs. Sar (20, 40 μM) or insulin (50 mU/L) significantly increased the expression of autophagy- related proteins and podocyte marker proteins in HG-treated MPs. Furthermore, Sar or insulin treatment efficiently regulated phosphorylation at activation and inhibition sites of GSK3β. To sum up, this study certifies that Sar meliorates experimental DN through targeting GSK3β signaling pathway and restoring podocyte autophagy.

Silent information regulator 1 (Sirt1) is a deacetylase, which plays an important role in the occurrence and development of diabetic nephropathy (DN). Our previous study shows that Yin yang 1 (YY1), a widely expressed zinc finger DNA/RNA-binding transcription factor, is a novel regulator of renal fibrosis in diabetic nephropathy. Since the activity of YY1 is regulated via acetylation and deacetylation modification, this study aimed to explore whether Sirt1-induced deacetylation of YY1 mediated high glucose (HG)-induced renal tubular epithelial–mesenchymal transition (EMT) and renal fibrosis in vivo and in vitro. We first confirmed that Sirt1 expression level was significantly decreased in the kidney of db/db mice and in HG-treated HK-2 cells. Diabetes-induced Sirt1 reduction enhanced the level of YY1 acetylation and renal tubular EMT. Then, we manipulated Sirt1 expression in vivo and in vitro by injecting resveratrol (50 mg·kg −1 ·d −1 . ip) to db/db mice for 2 weeks or application of SRT1720 (2.5 μM) in HG-treated HK-2 cells, we found that activation of Sirt1 reversed the renal tubular EMT and YY1 acetylation induced by HG condition. On the contrary, Sirt1 was knocked down in db/m mice or EX527 (1 μM) was added in HK-2 cells, we found that inhibition of Sirt1 exacerbated renal fibrosis in diabetic mice and enhanced level of YY1 acetylation in HK-2 cells. Furthermore, knockdown of YY1 inhibited the ameliorating effect of resveratrol on renal tubular EMT and renal fibrosis in db/db mice. In conclusion, this study demonstrates that Sirt1 plays an important role in renal tubular EMT of DN through mediating deacetylation of YY1.