Quercetin, a natural flavonoid compound with a widespread occurrence throughout the plant kingdom, exhibits a variety of pharmacological activities. Because of the wide spectrum of health-promoting ...effects, quercetin has attracted much attention of dietitians and medicinal chemists. An updated review of the literature on quercetin was performed using PubMed, Embase, and Science Direct databases. This article presents an overview of recent developments in pharmacological activities of quercetin including anti-SARS-CoV-2, antioxidant, anticancer, antiaging, antiviral, and anti-inflammatory activities as well as the mechanism of actions involved. The biological activities of quercetin were evaluated both in vitro and in vivo, involving a number of cell lines and animal models, but metabolic mechanisms of quercetin in the human body are not clear. Therefore, further large sample clinical studies are needed to determine the appropriate dosage and form of quercetin for the treatment of the disease.
Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) as a result of accumulated drugs in the human body metabolized into toxic agents and helps generate heavy oxidative ...stress, inflammation, and apoptosis, which induces necrosis in hepatocytes and ultimately damages the liver. Sirtuin 1 (SIRT1) is said to have multiple vital roles in cell proliferation, aging, and antistress systems of the human body. The levels of SIRT1 and its activation precisely modulate its critical role in the interaction between multiple step procedures of DILI. The nuclear factor kappa-light-chain-enhancer of activated B cell- (NF-κB-) mediated inflammation signaling pathway, reactive oxygen species (ROS), DNA damage, mitochondrial membrane potential collapse, and endoplasmic reticulum (ER) stress also contribute to aggravate DILI. Apoptosis is regarded as the terminal reaction followed by multiple signaling cascades including caspases, p53, and mitochondrial dysfunction which have been said to contribute in DILI. The SIRT1 activator is regarded as a potential candidate for DILI, because the former could inhibit signaling of p53, NF-κB, and ER stress. On the other hand, overexpression of SIRT1 also enhances the activation of antioxidant responses via Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor- (erythroid-derived 2-) like 2 (Nrf2) signaling. The current manuscript will highlight the mechanism of DILI and the interaction of SIRT1 with various cytoplasmic factors leading to DILI along with the summary of potent SIRT1 agonists.
Sirtuin 3 (SIRT3) is a deacetylase involved in the development of many inflammation-related diseases including liver fibrosis. Withaferin A (WFA) is a bioactive constituent derived from the Withania ...somnifera plant, which has extensive pharmacological activities; however, little is known about the regulatory role of SIRT3 in the WFA-induced antifibrogenic effect. The current study is aimed at investigating the role of SIRT3 in WFA-induced antioxidant effects in liver fibrosis. Our study verified that WFA attenuated platelet-derived growth factor BB- (PDGF-BB-) induced liver fibrosis and promoted PDGF-BB-induced SIRT3 activity and expression in JS1 cells. SIRT3 silencing attenuated the antifibrogenic and antioxidant effects of WFA in activated JS1 cells. Moreover, WFA inhibited carbon tetrachloride- (CCl4-) induced liver injury, collagen deposition, and fibrosis; increased the SIRT3 expression; and suppressed the CCl4-induced oxidative stress in fibrotic livers of C57/BL6 mice. Furthermore, the antifibrogenic and antioxidant effects of WFA could be available in CCl4-induced WT (129S1/SvImJ) mice but were unavailable in CCl4-induced SIRT3 knockout (KO) mice. Our study suggested that WFA inhibited liver fibrosis through the inhibition of oxidative stress in a SIRT3-dependent manner. WFA could be a potential compound for the treatment of liver fibrosis.
Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker ...for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5'-TTAGGG-3')n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.
Eriodictyol is a flavonoid that belongs to a subclass of flavanones and is widespread in citrus fruits, vegetables, and medicinally important plants. Eriodictyol has been anticipated to explain the ...method of its activity via multiple cellular signaling cascades. Eriodictyol is an effective natural drug source to maintain higher health standards due to its excellent therapeutic roles in neuroprotection, cardioprotective activity, hepatoprotective activity, antidiabetes and obesity, and skin protection and having highly analgesic, antioxidant, and anti-inflammatory effects, antipyretic and antinociceptive actions, antitumor activity, and much more. This review aims to highlight the modes of action of eriodictyol against various diseases via multiple cellular signaling pathways.
This study sought to explore the anticancer mechanism of Picrorhizae Rhizoma (PR) extract based on network pharmacology and molecular docking. The potential chemicals of PR were screened through the ...Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and relevant literatures. Corresponding targets of active ingredients were found with the help of the UniProtKB database, and therapeutic targets for cancer action were screened with the help of the GeneCards database. We used Cytoscape software to construct the compound-target-pathway network of PR extract. We utilized the STRING database to obtain the protein-protein interaction (PPI) network. We used DAVID database combining Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, molecular docking was employed for initial efficacy checking. We have identified 16 potential active components of PR through screening, involving 112 disease action targets. Utilizing the GeneCards database, 112 intersecting targets between PR extract and cancer were found, which mainly exerts anticancer effects by regulating tumor necrosis factor (TNF), recombinant caspase 3 (CASP3), c-Jun NH2-terminal kinase (JNK)/JUN, epidermal growth factor receptor (EGFR), and estrogen receptor-1 (ESR1) with some other target genes and pathways associated with cancer. The major anticancer species are prostate cancer, colorectal cancer, small cell lung cancer, etc. In the molecular docking study, herbactin had a strong affinity for TNF. Based on network pharmacology and molecular docking studies, PR and their compounds have demonstrated potential anticancer activities against several key targets. Our preliminary findings provide a strong foundation for further experiments with PR constituents.
Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of ...S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro. In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC.
Abstract
KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in
KRAS
oncogene promoter (
KRAS
...-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available
KRAS
-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of
KRAS
-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing
KRAS
-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a “quasi-triad plane” that stacks over the two external G-tetrads. The binding involves both
π
-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the
KRAS
mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with
KRAS
-G4 and is beneficial for the design of specific
KRAS
-G4-interactive drugs.
Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that
is specifically overexpressed in GC and functionally required for GC development. In this study, we ...investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes.
We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of
and
relevance. To investigate mechanistic roles of
and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments.
Gene expression analysis across 19 tumour types revealed
to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top
-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (
) emerged as a convergent
direct target gene regulating GC metabolism. We show that wild-type
is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors.
Our results highlight a role for
in sustaining GC oncogenic metabolism, through the regulation of
. Drugs targeting wild-type
may thus have clinical utility in GCs exhibiting
overexpression, expanding the role of
in cancer beyond
mutated malignancies.
Naringin is a dihydroflavone which was found in citrus fruits. Previous studies have indicated the antiapoptotic, antioxidative stress, and anti-inflammatory effects of naringin. It can improve many ...common diseases, including fibrosis or hepatotoxicity, cardiovascular disease, and diabetes. Acetaminophen (APAP) is a frequently used painkiller, and hepatotoxic side effects limit its use. The purpose of the current examination is to find the impact of naringin on APAP-induced hepatic injury. Firstly, we pretreated mice model groups with naringin. Then, the liver injury model was established by injecting intraperitoneally into mice with APAP. After the mice were euthanized, we obtained serum and liver tissue samples from the mice. Finally, these samples were analyzed using a metabolomics approach to find the underlying mechanism of the effects of naringin on APAP-induced liver injury and provide a new treatment strategy for APAP-induced liver injury. Our data indicate that naringin significantly improves APAP-induced liver injury in mice and reduces the expression levels of liver injury markers in a dose-dependent manner. Furthermore, analysis of differential metabolites in mice with liver injury showed that naringin reduced APAP-induced hepatotoxicity due to reversing multiple metabolite expression levels and the rescue of energy, amino acid, and purine metabolism.
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