Prashar, A. | bioRxiv Science

bioRxiv2023

Network Pharmacology and molecular docking approach to unveil the mechanism of Hypericum perforatum in the management of Alzheimer's disorder

The pathogenesis of Alzheimers disease (AD) is not fully understood which limits the availability of safer and more efficient therapeutic strategies for the management of AD. There has been growing interest in recent years in exploring the potential of herbal medicines as a source of safer and alternative therapeutic strategies for the management of AD. This study aims to discover the mechanism of Hypericum perforatum in the management of AD using network pharmacology and molecular docking approach. The results of network pharmacology suggest that 39 bioactive molecules of H. perforatum target 127 genes associated with AD, amongst which ATP-dependent translocase, acetylcholinesterase, amyloid-{beta} precursor protein, {beta}-secretase 1, carbonic anhydrase 2, dipeptidyl peptidase 4, epidermal growth factor receptor, tyrosine-protein phosphatase non-receptor type 1, -synuclein, and vascular endothelial growth factor A seems to be the prominent target of these molecules. Further, the results of molecular docking predicted amentoflavone, I3,II8-biapigenin, rutin, miquelianin, quercetin, luteolin, and nicotiflorin as a promising modulator of target proteins which were determined from network pharmacology to be associated with AD. Our findings suggest that H. perforatum could be a safer and more promising alternative therapeutic strategy for the management of AD by targeting multiple pathways of AD pathogenesis.

pharmacology and toxicology↗

bioRxiv2021

The Hypoxia Response Pathway Promotes PEP Carboxykinase Expression And Gluconeogenesis

Actively dividing cells, including some cancers, rely on aerobic glycolysis rather than oxidative phosphorylation to generate energy, a phenomenon termed "the Warburg effect1." Constitutive activation of the Hypoxia Inducible Factor (HIF-1), a transcription factor known for mediating an adaptive response to oxygen deprivation (hypoxia), is a hallmark of the Warburg effect2. HIF-1 is thought to promote glycolysis and suppress oxidative phosphorylation. Here, we show instead that HIF-1 can promote gluconeogenesis. Using a multiomics approach, we determined the genomic, transcriptomic, and metabolomic landscapes regulated by constitutively active HIF-1 in C. elegans. We performed RNA-seq and ChIP-seq under aerobic conditions in mutants lacking EGL-9, a key negative regulator of HIF-1, and then integrated these approaches to identify over a hundred genes directly and functionally upregulated by HIF-1. We show that HIF-1 directly promotes the expression of PCK-1, a PEP carboxykinase that is a rate-limiting mediator of gluconeogenesis3. This activation of PCK-1 by HIF-1 promotes survival in response to both oxidative and hypoxic stress. Our work is the first to identify functional direct targets of HIF-1 in vivo, and it describes the first complete metabolome induced by constitutive HIF-1 activation in any organism.

genetics↗