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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.

Background & Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis even cancer, antiviral therapy can reverse liver fibrosis with limited effect, thus we aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with ETV.Methods: Treatment naïve patients with CHB from Oct 1st, 2013 to Dec 31st, 2020 were randomly treated with ETV alone or combined with ALHX (ETV+ALHX). Patients’ demographic, laboratory and liver histology data before and after 78 weeks of treatment were collected. Ishak fibrosis score (F) was used and fibrosis regression means F decreased ≥1 after treatment.Results: In total, 394 patients with a second liver biopsy after treatment were included in per-protocol population: 132 patients in ETV group and 262 patients in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group were significantly higher than ETV group in baseline F≥3 patients: 124/211 (58.8%) verse 45/98 (45.9%), p=0.035. The degradation rate of liver stiffness measurement (LSM) is also consistent with it: 154/262 (73.0%) in ETV+ALHX group and 60/132 (61.2%) in ETV group, p=0.037. Logistic regression analysis showed that combined with ALHX was related to fibrosis regression (OR=1.94, p=0.018), and family history of hepatocellular carcinoma was on the contrary (OR=0.41, p=0.031).Conclusions: ETV combined with ALHX can significantly increase liver fibrosis regression in CHB patients.

α-Synuclein (α-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson’s disease (PD). Studies have shown that α-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro α-syn aggregation, and the amplified fibrils are more potent in inducing endogenous α-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of α-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD α-syn aggregation and suggests potential alteration of α-syn fibrils during the progression of PD clinical phases.Significance StatementIncreasing evidence support different conformational α-syn fibrils in patients with different α-synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is unknown. Here, we show that α-syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous α-syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of α-syn fibrils along with PD progression.

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.

Background Objective motor ratings and subjective motor complaints are both widely used in Parkinson's disease (PD). However, the objective basis to the self-perceived mobility quality is still not well elucidated. Purposes We aimed to figure out the relevancy between the UPDRS motor scores and PDQ39 mobility sub-scores, and further explore whether physician-assessed motor dysfunctions and patients-reported mobility deficits have some shared mechanisms. Methods 49 patients with PD who completed the PDQ39 scale were retrospectively included. The relevancy between mobility quality and UPDRS scores was assessed, as well as the related presynaptic dopaminergic binding (11C-CFT) and glucose metabolism (18F-FDG) in this dual-tracer PET imaging study. Results Modest correlation was found between UPDRS motor score and the PDQ39 mobility sub-score (r = 0.440, p = 0.002). No correlation was found between PDQ39 mobility SI and the dopaminergic lesions in putamen; however, the strict correlation was found with the UPDRS motor scores. In terms of global PD related pattern (PDRP) scores, the two motor scores both correlated strictly. In the further regional metabolism exploration, cerebellum correlated positively with PDQ39 mobility sub-scores, and the frontal and parietal regions mainly correlated negatively with the motor quality scores. Conclusion UPDRS motor scores and PDQ39 mobility scores were only modestly correlated. The mechanisms involved under mobility quality were beyond dopaminergic deficiency, including motor related cerebellum hyper-metabolism and non-motor related frontal hypo-metabolism. Conclusively, the self-reported mobility experience may have the neurophysiological basis related to both motor and non-motor manifestations in PD.

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.

The migration behavior of silicone molecules including octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane (denoted as D4, D5, D6, respectively) for silicone rubber baking mold (SRBM) under two different baking methods into food simulants and to cakes were investigated. Meantime, different daily used oils including corn, peanut, sunflower and butter were used to investigate the effects of oil property on migration of D4, D5 and D6, respectively where cakes were baked using SRMB at 175 °C for 30 min. Results showed that for olive oil, the migration of D4, D5 and D6 reached maximum in 240 min at 175°C under electric baking condition and reached maximum in 20 min at 800 W under microwaving baking. Unlike olive oil, the migration rate of D4, D5 and D6 into Tanex® decreased significantly with used times under both electric baking and microwaving methods. Importantly, results also showed that the amounts of D4, D5 and D6 in cakes baked with peanut oil and corn oil were significantly higher (p