Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

Li, Xiaokang; Lu, Jian; Xu, Yixiang; Wang, Jiaying; Qiu, Xiaoxia; Fan, Lei; Li, Baoli; Liu, Wenwen; Mao, Fei; Zhu, Jin; Shen, Xu; Li, Jian

doi:10.1016/j.apsb.2019.07.006

Cited by 21 publications

(8 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Autophagy maintains cellular homeostasis and regulates apoptosis by degrading proteins with long half-lives or damaging organelles (39,40). The complexes formed by ATG5 and Beclin-1 proteins are the core molecular machinery for activation of the autophagy pathway (41).…”

Section: Discussionmentioning

confidence: 99%

Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

et al. 2021

View full text Add to dashboard Cite

Myocardial hypertrophy is an independent risk factor of cardiovascular diseases and is closely associated with the incidence of heart failure. In the present study, we hypothesized that difluoromethylornithine (DFMO) could attenuate cardiac hypertrophy through mitochondria-associated membranes (MAM) and autophagy. Cardiac hypertrophy was induced in male rats by intravenous administration of isoproterenol (ISO; 5 mg/kg/day) for 1, 3,7 and 14 days. For DFMO treatment group, rats were given ISO (5 mg/kg/day) for 14 days and 2% DFMO in their water for 4 weeks. The expression of atrial natriuretic peptide (ANP) mRNA,heart parameters, apoptosis rate, fibrotic area and protein expressions of cleaved caspase3/9, GRP75, Mfn2, CypD and VDAC1 were measured to confirm the development of cardiac hypertrophy, apoptosis and autophagy induced by ISO. ANP mRNA and MAM protein expression levels were assessed by reverse transcription-quantitative PCR and western blotting to evaluate hypertrophy and the effects of DFMO oral administration. The results demonstrated that heart parameters, ANP mRNA levels, fibrotic area and apoptosis rate were significantly increased in the heart tissue for ISO 7 and 14 day groups compared with the control group. Furthermore, treatment with DFMO significantly inhibited these indicators, and DFMO downregulated the MAM signaling pathway and upregulated the autophagy pathway in heart tissue compared with the ISO 14 day group. Overall, all ISO-induced changes analyzed in the present study were attenuated following treatment with DFMO. The findings form this study suggested that DFMO treatment may be considered as a potential strategy for preventing ISO-induced cardiac hypertrophy.

show abstract

Section: Discussionmentioning

confidence: 99%

Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These conventional antibiotics were not found to inhibit autophagosome formation stimulated by nitazoxanide ( Lam et al, 2012 ). Nitazoxanide has been previously explored as an autophagy agonist for treating multiple disease states such as Alzheimer’s and cancer ( Di Santo and Ehrisman, 2014 ; Li et al, 2020 ). It has also been examined as a potential treatment option against several mycobacteria including M. leprae ( Bailey et al, 2017 ) and MAC ( Rossignol, 1999 ).…”

Section: Harnessing Autophagy To Fight Mycobacteriamentioning

confidence: 99%

Targeting Autophagy as a Strategy for Developing New Vaccines and Host-Directed Therapeutics Against Mycobacteria

Strong

Lee

2021

Front. Microbiol.

View full text Add to dashboard Cite

Mycobacterial disease is an immense burden worldwide. This disease group includes tuberculosis, leprosy (Hansen’s disease), Buruli Ulcer, and non-tuberculous mycobacterial (NTM) disease. The burden of NTM disease, both pulmonary and ulcerative, is drastically escalating globally, especially in developed countries such as America and Australia. Mycobacteria’s ability to inhibit or evade the host immune system has contributed significantly to its continued prevalence. Pre-clinical studies have highlighted promising candidates that enhance endogenous pathways and/or limit destructive host responses. Autophagy is a cell-autonomous host defense mechanism by which intracytoplasmic cargos can be delivered and then destroyed in lysosomes. Previous studies have reported that autophagy-activating agents, small molecules, and autophagy-activating vaccines may be beneficial in restricting intracellular mycobacterial infection, even with multidrug-resistant strains. This review will examine how mycobacteria evade autophagy and discusses how autophagy could be exploited to design novel TB treatment strategies, such as host-directed therapeutics and vaccines, against Mycobacterium tuberculosis and NTMs.

show abstract

“…With respect to the structure activity relationship of the thiazolides, substitution of the nitro group on the 5-position of the thiazole ring with a chloride substituent diminished activity of the derivative (RM-5038) against bacteria and anaerobic protozoa but enhanced its activity against Hepatitis B and C viruses (Korba et al, 2008;. Also, replacement of the Nitro group on the thiazole heterocycle and changing the position of the ethanoate group from the 2 to 3 position of the Benzene ring led to a change in activity of the derivative which demonstrated enhanced anti-alzheimers activity (Li et al, 2020). Recently, a series of amino-acid ester thiazolide prodrugs were synthesized and tested with the aim of improving bioavailablity of the compound class.…”

Section: Nitazoxanidementioning

confidence: 99%

A review of the structure-activity relationships (SAR) of selected drugs with potential to be repurposed against SARS-COV-2

Ajima¹,

Kolawole²,

Falang³

et al. 2021

Asian J Pharm Pharmacol

View full text Add to dashboard Cite

Background: The pandemic caused by the novel SARS-CoV-2 virus has escalated rapidly and impacted human health worldwide, in addition to causing severe disruptions to socioeconomic life. There is presently no effective treatment for the disease and this underscores the urgent need for new therapeutic options against this life threatening disease. The traditional strategy for the development of new drugs is a slow and expensive process. Drug repurposing is a valuable alternative strategy that can be used to bypass some of the limitations of traditional drug discovery in order to rapidly develop new therapeutic agents for the management of Covid-19.The present review x-rays recent efforts to re-purpose some antiviral drugs for the treatment Objectives: of SARS-Cov-2 with an emphasis on the structure activity relationships (SAR) of the compounds.A systematic internet Methods: search of three academic databases of published literature was undertaken using relevant keywords and search terms which focused on drug re-purposing against SARS-CoV-2.A total of 853 results were generated and evaluated. The results of the search Results: were screened and relevant articles identified, yielding a total of 83 articles. Some of the drugs identified with potential for repurposing against SARS-CoV-2 include: Arbidol, Favipiravir, Ribavirin, Nitazoxanide etc.It is hoped that the Conclusion: information generated in this review will help deepen understanding of the potential mechanism of anti-SARS-CoV-2 action of the compounds and also draw attention to opportunities that exist for structural modification of these molecules with the aim of improving and enhancing their selectivity and efficacy against SARS-CoV-2.

show abstract

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

Cited by 21 publications

References 48 publications

Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

Targeting Autophagy as a Strategy for Developing New Vaccines and Host-Directed Therapeutics Against Mycobacteria

A review of the structure-activity relationships (SAR) of selected drugs with potential to be repurposed against SARS-COV-2

Contact Info

Product

Resources

About