Author: Jankowska, Elzbieta ; Chmielarz, Piotr ; Seelbach, Anna ; Domanskyi, Andrii ; Pasculli, Maria Samuela ; Er, Safak ; Parkkinen, Ilmari ; Trepczyk, Karolina ; Luk, Kelvin ; De Lorenzo, Francesca ; Airavaara, Mikko

Failures in protein homeostasis are linked to Parkinson's disease (PD) and other neurodegenerative diseases. Lewy bodies, proteinaceous inclusions rich in phosphorylated alpha-synuclein are a hallmark of PD. Glial cell line-derived neurotrophic factor (GDNF) can eliminate Lewy body-like inclusions in mouse dopamine neurons. This study explores whether GDNF has protective effects against alpha-synuclein protofibril toxicity under proteasome inhibition by lactacystin, both in vitro and in vivo. GDNF did not shield midbrain dopamine neurons from lactacystin-induced neurodegeneration, but still prevented phosphorylated alpha-synuclein accumulation. In vivo experiment with control or GDNF-expressing viral vectors assessed alpha-synuclein pathology spread in the nigrostriatal pathway and lactacystin-caused damage in the midbrain. GDNF overexpression reduced phosphorylated alpha-synuclein inclusions. Lactacystin-treated mice showed motor asymmetry and decreased spontaneous activity, exacerbated without AAV-GDNF pre-treatment. However, GDNF's neuroprotective effect could not be confirmed in vivo, due to side-effects from overexpression in the midbrain. Importantly, these findings show that GDNF continues to eliminate alpha-synuclein aggregation despite lactacystin-induced proteasome inhibition. Activating neurotrophic signaling pathways may protect against alpha-synuclein pathology in PD, even with impaired protein degradation mechanisms.

01 Jul 2024·International Immunopharmacology

A novel anti-inflammatory strategy for myocardial ischemia–reperfusion in rats with cinnamamide derivative compound 7

Article

Author: Zhao, Guangyuan ; Peng, Yajie ; Ji, Zhangyue ; Wei, Bo ; Wang, Diya ; Duan, Yusen ; Shi, Yangyang

Reperfusion after myocardial ischemia would aggravate myocardial structural and functional damage, known as myocardial ischemia-reperfusion (MI/R) injury. Cinnamamide derivatives have been reported to exert cardioprotective effects, and we have previously reported that compound 7 played a role in cardioprotection against MI/R via anti-inflammatory effect. However, exact mechanism underlying such beneficial action of compound 7 is still unclear. The protective effect of compound 7 was determined in H9c2 cells under H₂O₂ stimulation with or without nigerin (NLRP3 activator). Electrocardiogram, echocardiography, myocardial infarction size, histopathology and serum biochemical assay were performed in MI/R rats. Metabolomics in vivo and mRNA or protein levels of NLRP3, ASC, cleaved caspase-1 and its downstream IL-18 and IL-1β were detected both in vitro and in vivo. Compound 7 significantly ameliorate H₂O₂-induced cardiomyocyte damage, which was supported by in vivo data determined by improved left ventricular systolic function and histopathological changes, reduced myocardial infarction area and cellular apoptosis in heart tissue. Cardiac differential metabolites demonstrated that compound 7 indeed altered the cardiac reprogramming of inflammation-related metabolites, which was evidenced by down-regulated cardiac inflammation by compound 7. Additionally, compound 7 alleviated myocardial injury by inhibiting the NLRP3 pathway rather than other members of the inflammasome both in vitro and in vivo, which was further evidenced by CETSA assay. Whereas, nigerin blocked the inhibitory activity of compound 7 against NLRP3. Cinnamamide derivative compound 7 ameliorated MI/R injury by inhibiting inflammation via NLRP3.

01 Jun 2024·Bioorganic Chemistry

New meroterpenoids and polyketides from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1 and their anti-inflammatory and SARS-CoV-2 Mpro inhibitory activities

Article

Author: Li, Qi ; Gao, Lu ; Yang, Peng-Yun ; Peng, Chao ; Zhang, Xing-Jie ; Li, Yan-Ping ; Jiang, Yun-Tao

Seven new meroterpenoids, paraphaeones A-G (1-7), and two new polyketides, paraphaeones H-I (8-9), along with eight known compounds (10-17), were isolated from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1. The structures of 1-9 were identified through the analysis of ¹H, ¹³C, and 2D NMR spectra, assisted by HR-ESI-MS data. Compounds 1 and 7 exhibited a dose-dependent decrease in lactate dehydrogenase levels, with IC₅₀ values of 1.78 μM and 1.54 μM, respectively. Moreover, they inhibited the secretion of IL-1β and CASP-1, resulting in a reduction in the activity levels of NLRP3 inflammasomes. Fluorescence microscopy results indicated that compound 7 concentration-dependently attenuated cell pyroptosis. Additionally, compounds 4 and 7 showed potential inhibitory effects on the severe acute respiratory syndrome coronavirus-2 main protease (SARS-CoV-2 M^pro), with IC₅₀ values of 10.8 ± 0.9 μM and 12.9 ± 0.7 μM, respectively.

100 Deals associated with 20S proteasome inhibitors(Novartis Institutes for Biomedical Research)

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Indication	Highest Phase	Country/Location	Organization	Date
Trypanosomiasis, African	Preclinical	United States	Novartis Institutes for Biomedical Research, Inc.	28 Sep 2022

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