The current pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.
Exposure to ultraviolet B (UVB) irradiation results in multitude of cellular responses including generation of reactive oxygen species and DNA damage and is responsible for non-melanoma skin cancers (NMSCs). Although genetic mutation is well documented, the epi-mutation, the alteration in epigenetics, remains elusive. In this study, we utilized CpG Methyl-seq to identify a genomewide DNA CpG methylation, to profile the DNA methylation in UVB-irradiated SKH-1 mouse skin epidermis and non-melanoma skin papillomas at various stages. Methyl-seq and RNA-seq were performed to examine the methylation and corresponding transcriptome alterations. The methylation profiles in mouse epidermis were altered by UVB-irradiation as time progresses. Ingenuity Pathways Analysis (IPA) identified many cancer related pathways including PTEN, p53, Nrf2 and inflammatory signaling in UVB-irradiation induced carcinogenesis. Additionally, some novel genes involved in skin carcinogenesis that were not previously reported were differentially methylated, including Enf2, Mgst2, Vegfa, and Cdk4. Taken together, the current study provides novel profiles and insights of methylation and transcriptomic changes at different stages of
Curcumin is a major component of the spice, turmeric (Curcuma longa) often used in food or as a dietary supplement. Many preclinical studies on curcumin suggests benefit in many diseases due to its antioxidant and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received 4 g of curcumin capsules with standard breakfast. Plasma samples were collected at specified timepoints and analyzed for curcumin levels. RNA was extracted and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were not detected by HPLC‐ITMS/MS/MS. However, curcumin glucuronide, a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and low levels of metabolite are in line with previous studies. Antioxidant genes Nrf2, HO‐1, NQO1, and HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. Curcumin glucuronide pharmacokinetics are well‐described by a one‐compartment model and the PK/PD of curcumin glucuronide and its effect on antioxidant and epigenetic gene expression are explained by indirect response model (IDR). Increasing AUC or exposure to curcumin glucuronide was correlated with overall PD response. Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with our observed data in the human volunteers. In vitro experiments on curcumin glucuronide in HepG2C8 cells also show that Nrf2‐ARE luciferase activity increases after 24‐hour treatment. These results show that poor bioavailability of curcumin remains a challenge but that oral administration of curcumin delivers detectable levels of curcumin glucuronide and may mediate the antioxidant and epigenetic effects of curcumin. Support or Funding Information Grant: This work was supported in part by institutional funds and R01AT007065 from the National Center for Complementary and Alternative Medicines (NCCAM) and the Office of Dietary Supplements (ODS). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Colorectal cancer (CRC) is associated with significant morbidity and mortality in the US and worldwide. CRC is the second most common cancer related death in both men and women globally. Chronic inflammation has been identified as one of the major risk factors of CRC. It may drive genetic and epigenetic/epigenomic alterations such as DNA methylation, histone modification, and noncoding RNA regulation. Current prevention modalities for CRC are limited and some treatment regimens such as use the NSAID aspirin may have severe side effects, namely gastrointestinal ulceration and bleeding. Therefore, there is an urgent need of developing alternative strategies. Recently, increasing evidence suggests that several dietary cancer chemopreventive phytochemicals possess anti-inflammation and anti-oxidative stress activities, and may prevent cancers including CRC. Curcumin is the yellow pigment that is found in the rhizomes of turmeric (Curcuma longa). Many studies have demonstrated that curcumin exhibits strong anticancer, anti-oxidative stress and anti-inflammatory activities by regulating signaling pathways such as Nrf2, NF-κB, and epigenetics/epigenomics pathways of histones modifications, and DNA methylation. In this review, we will discuss the latest evidence in epigenetics/ epigenomics alterations by curcumin in CRC and their potential contribution in the prevention of CRC.
Nonmelanoma skin cancers (NMSCs) are the most common type of skin cancers. Major risk factors for NMSCs include exposure to ultraviolet (UV) irradiation. Ursolic acid (UA) is a natural triterpenoid enriched in blueberries and herbal medicinal products, and possess anticancer activities. This study focuses on the impact of UA on epigenomic, genomic mechanisms and prevention of UVB‐mediated NMSC. CpG methylome and RNA transcriptome alterations of early, promotion and late stages of UA treated on UVB‐induced NMSC in SKH‐1 hairless mice were conducted using CpG methyl‐seq and RNA‐seq. Samples were collected at weeks 2, 15, and 25, and integrated bioinformatic analyses were performed to identify key pathways and genes modified by UA against UVB‐induced NMSC. Morphologically, UA significantly reduced NMSC tumor volume and tumor number. DNA methylome showed inflammatory pathways IL‐8, NF‐κB, and Nrf2 pathways were highly involved. Antioxidative stress master regulator Nrf2, cyclin D1, DNA damage, and anti‐inflammatory pathways were induced by UA. Nrf2, cyclin D1, TNFrsf1b, and Mybl1 at early (2 weeks) and late (25 weeks) stages were identified and validated by quantitative polymerase chain reaction. In summary, integration of CpG methylome and RNA transcriptome studies show UA alters antioxidative, anti‐inflammatory, and anticancer pathways in UVB‐induced NMSC carcinogenesis. Particularly, UA appears to drive Nrf2 and its upstream/downstream genes, anti‐inflammatory (at early stages) and cell cycle regulatory (both early and late stages) genes, of which might contribute to the overall chemopreventive effects of UVB‐induced MNSC. This study may provide potential biomarkers/targets for chemoprevention of early stage of UVB‐induced NMSC in human.
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