Towards natural mimetics of metformin and rapamycin

Aliper, Alexander; Jellen, Leslie C.; Cortese, Franco; Artemov, Artem V.; Karpinsky-Semper, Darla; Moskalev, Alexey; Swick, Andrew G.; Zhavoronkov, Alex

doi:10.18632/aging.101319

Cited by 67 publications

(61 citation statements)

References 186 publications

(227 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We performed an interaction-based similarity analysis and found that the genotoxic compounds cluster separately from the other drugs, suggesting that they have a similar mechanism of action (S2 text). Similarities were also identified regarding the mechanisms of action of sorafenib and regorafenib, bexarotene and GW-501516, and sirolimus and ECGC, in agreement with previous studies [36].…”

Section: Resultssupporting

confidence: 90%

Using the drug-protein interactome to identify anti-ageing compounds for humans

Valenzuela

Dönertaş

Williams

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…In the present study, we show that ISLQ treatment increases cellular ROS, and that this is involved in mediating the cytotoxic effects of ISLQ on human NB cells. It is also worth noting that a recent study identified ISLQ as a natural mimetic of rapamycin [68], which is an FDA-approved mTOR inhibitor that has anti-carcinogenic effects in NB cells [69]. Treatment of NB cells with rapamycin for 24 h has been shown to increase cellular levels of ROS [70], which is consistent with the increases in cellular oxidative stress in MYCN-amplified SK-N-BE(2) cells induced by ISLQ treatment for 24 h, found in our study.…”

Section: Discussionmentioning

confidence: 99%

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

et al. 2019

View full text Add to dashboard Cite

Neuroblastoma (NB) is the most common extracranial solid tumor of early childhood; it accounts for approximately 8-10% of all childhood cancers and is the most common cancer in children in the first year of life. Patients in the high-risk group have a poor prognosis, with relapses being common and often refractory to drug treatment in those that survive. Moreover, the drug treatment itself can lead to a range of long-term sequelae. Therefore, there is a critical need to identify new therapeutics for NB. Isoliquiritigenin (ISLQ) is a naturally-occurring, dietary chalcone-type flavonoid with a range of biological effects that depend on the cell type and context. ISLQ has potential as an anticancer agent. Here we show that ISLQ has potent cytotoxic effects on SK-N-BE(2) and IMR-32 human NB cells, which carry amplification of the MYCN gene, the main prognostic marker of poor survival in NB. ISLQ was found to increase cellular reactive oxygen species (ROS). The cytotoxic effect of ISLQ was blocked by small molecule inhibitors of oxidative stress-induced cell death, and by the antioxidant N-acetyl-L-cysteine (NAC). Combined treatment of either SK-N-B-E(2) or IMR-32 cells with ISLQ and the anticancer agent cisplatin resulted in loss of cell viability that was greater than that induced by cisplatin alone. This study provides proof-of-principle that ISLQ is a potent cytotoxin for MYCN-amplified human NB cells. This is an important first step in rationalizing the further study of ISLQ as a potential adjunct therapy for high-risk NB.

show abstract

“…One of the most impactful applications of DL in biomedicine was in the applications of generative models to de novo molecular design [32][33][34][35][36] . In the context of aging research, these new methods can be combined for geroprotector discovery [37][38][39][40][41] . Indeed, since 2013, many aging clocks have been developed in both humans and other model organisms.…”

Section: Introductionmentioning

confidence: 99%

Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects

Galkin

Putin

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

The human gut microbiome is a complex ecosystem that both affects and is affected by its host status. Previous analyses of gut microflora revealed associations between specific microbes and host health and disease status, genotype and diet. Here, we developed a method of predicting biological age of the host based on the microbiological profiles of gut microbiota using a curated dataset of 1,165 healthy individuals (3,663 microbiome samples). Our predictive model, a human microbiome clock, has an architecture of a deep neural network and achieves the accuracy of 3.94 years mean absolute error in cross-validation. The performance of the deep microbiome clock was also evaluated on several additional populations. We further introduce a platform for biological interpretation of individual microbial features used in age models, which relies on permutation feature importance and accumulated local effects. This approach has allowed us to define two lists of 95 intestinal biomarkers of human aging. We further show that this list can be reduced to 39 taxa that convey the most information on their host's aging. Overall, we show that (a) microbiological profiles can be used to predict human age; and (b) microbial features selected by models are age-related.

show abstract

“…Similarly, W. somnifera decreased MDA (a secondary product of LPO) levels in patients with type‐2 diabetes (Usharani, Fatima, et al, ; Usharani, Kishan, et al, ). The observed antioxidant activities of W. somnifera might be, majorly, attributed to its active constituent withaferin A—a steroidal lactone (Aliper et al, ; Lee et al, ) as well other bioactive elements—steroidal alkaloids/lactones such as withanine, somniferine, withanone sitoindosides VII–X and withanolide A, D and G (Durg et al, ; Mirjalili, Moyano, Bonfill, Cusido, & Palazón, ).…”

Section: Discussionmentioning

confidence: 99%

“…W. somnifera also showed glucose lowering activity through insulinotropic effects which improves insulin sensitivity by reducing hyperinsulinemia and insulin resistant besides improving glucose tolerance (Anwer et al, ). The recent in ‐ silico screening revealed that withaferin A mimics the anti‐aging properties of mTOR inhibitors, that is, metformin and rapamycin (Aliper et al, ); the two FDA‐approved drugs which tops the list of drugs mimicking caloric restriction (Ingram et al, ). Further, Lee et al demonstrated withaferin A as a potential leptin sensitizer with great anti‐diabetic effects in mice (Lee et al, ).…”

Section: Discussionmentioning

confidence: 99%

Withania somnifera(Indian ginseng) in diabetes mellitus: A systematic review and meta‐analysis of scientific evidence from experimental research to clinical application

Durg¹,

Bavage²,

Shivaram

2020

Phytotherapy Research

View full text Add to dashboard Cite

Withania somnifera Dunal, also known as Indian ginseng, has been in use since ancient times in the management of diabetes mellitus (DM). This systematic review and meta-analysis evaluated the efficacy/effectiveness, safety and tolerability of W. somnifera in managing DM. Literature search (published/unpublished) was performed from inception to April 2019 in guidelines recommended databases. A total of 6 in-vitro, 13 pre-clinical and 5 clinical studies were included for systematic evaluation. W. somnifera treatment in DM significantly restored the altered levels of blood glucose (experimental data; mean difference, −196.27; 95% confidence interval [−220.96, −171.58]; p < .00001) glycosylated haemoglobin (HbA1c), insulin, lipid profile, serum and oxidative stress markers with no safety concerns. The results suggest the potential role of W. somnifera in managing DM. However, the available clinical data are not considerably enough to provide novel and sufficiently robust evidence for the use of W. somnifera in managing DM. To further strength the antidiabetic profile of W. somnifera, well-designed randomized-controlled trial(s) with alarger sample size and longer duration is warranted with evaluation of its effect primarily on blood glucose, HbA1c and insulin. Future research also needs to elucidate the molecular mechanism(s) of W. somnifera including its active principles in DM. K E Y W O R D Sdiabetes mellitus, Indian ginseng, meta-analysis, oxidative stress, systematic review

show abstract

Towards natural mimetics of metformin and rapamycin

Cited by 67 publications

References 186 publications

Using the drug-protein interactome to identify anti-ageing compounds for humans

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects

Withania somnifera(Indian ginseng) in diabetes mellitus: A systematic review and meta‐analysis of scientific evidence from experimental research to clinical application

Contact Info

Product

Resources

About