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.

Human mitochondrial DNA contains a distinctive guanine-rich motif denoted conserved sequence block II (CSB II) that stops RNA transcription, producing prematurely terminated transcripts to prime mitochondrial DNA replication. Recently, we reported a general phenomenon that DNA:RNA hybrid G-quadruplexes (HQs) readily form during transcription when the non-template DNA strand is guanine-rich and such HQs in turn regulate transcription. In this work, we show that transcription of mitochondrial DNA leads to the formation of a stable HQ or alternatively an unstable intramolecular DNA G-quadruplex (DQ) at the CSB II. The HQ is the dominant species and contributes to the majority of the premature transcription termination. Manipulating the stability of the DQ has little effect on the termination even in the absence of HQ; however, abolishing the formation of HQs by preventing the participation of either DNA or RNA abolishes the vast majority of the termination. These results demonstrate that the type of G-quadruplexes (HQ or DQ) is a crucial determinant in directing the transcription termination at the CSB II and suggest a potential functionality of the co-transcriptionally formed HQ in DNA replication initiation. They also suggest that the competition/conversion between an HQ and a DQ may regulate the function of a G-quadruplex-forming sequence.

Telomere extension by telomerase is essential for chromosome stability and cell vitality. Here, we report the identification of a splice variant of mammalian heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2), hnRNP A2*, which binds telomeric DNA and telomerase in vitro. hnRNP A2* colocalizes with telomerase in Cajal bodies and at telomeres. In vitro assays show that hnRNP A2* actively unfolds telomeric G-quadruplex DNA, exposes 5 nt of the 3′ telomere tail and substantially enhances the catalytic activity and processivity of telomerase. The expression level of hnRNP A2* in tissues positively correlates with telomerase activity, and overexpression of hnRNP A2* leads to telomere elongation in vivo. Thus, hnRNP A2* plays a positive role in unfolding telomere Gquadruplexes and in enhancing telomere extension by telomerase.H uman chromosome ends are protected by telomeres, which are composed of TTAGGG DNA repeats and associated proteins. Telomeres shorten with each cell division because of incomplete DNA-end replication (1). Cells compensate for telomere attrition through the action of telomerase, a specialized reverse transcriptase that adds telomeric repeats to the 3′ end of the telomere (2). Normal somatic cells do not express telomerase and undergo replicative senescence. The expression of telomerase is a hallmark of highly proliferative stem cells and most cancer cells. In budding yeast, the recruitment of telomerase to the telomere end is mediated by Cdc13 and Est1. Cdc13 is a singlestranded telomere DNA-binding protein that associates with Est1, a protein that interacts with the RNA component of yeast telomerase (3,4). Similarly, in Tetrahymena, Teb1 bridges the interaction between telomerase and the telomere, which promotes highly processive telomere extension by telomerase (5). However, the mechanism(s) and factors required to promote a similar interaction between the telomere and telomerase in mammalian cells are poorly understood.Telomere DNA can adopt a four-stranded G-quadruplex structure (6) that can be either intermolecular and intramolecular. Although an intermolecular G-quadruplex is an excellent substrate for ciliate telomerases (7), an intramolecular G-quadruplex is not. In vertebrates, intramolecular G-quadruplexes (hereinafter referred to as G-quadruplex) preferentially form at the furthest 3′ end of the telomeric DNA (8), rendering it inaccessible to telomerase. As a result, this structure inhibits telomere extension (9-11). Only a few proteins have been identified that can disrupt Gquadruplex. One such protein is protection of telomeres 1 (POT1) (12), a component of the telomere shelterin complex that binds telomere overhangs with high affinity (13). Despite its ability to disrupt G-quadruplex, POT1 actually inhibits telomere extension by binding to the telomere overhang and blocking telomerase access to the overhang (14-16).Some proteins of the hnRNP family are also able to unfold telomeric G-quadruplex (17, 18). These proteins interact with telomeric ssDNA (19) and telomerase in vitro (20...

DNA with four guanine tracts can fold into G-quadruplexes that are targets of transcription regulation. We recently found that hybrid DNA:RNA G-quadruplexes (HQs) can form during in vitro transcription. However, it is unclear whether they can form in cells. Evidence is presented supporting their formation in plasmids in bacterial cells. The formation of the HQs is indicated by a unique pattern of prematurely terminated transcripts under two conditions where the RNA transcripts do or do not participate in G-quadruplex assembly and further supported by a number of chemical and biochemical analysis. HQs dominate over the intramolecular DNA G-quadruplexes (DQ) in mediating the transcription termination when both structures are able to form. These findings provide the first evidence of HQ formation in cells and suggest that the competition/conversion between HQ and DQ may regulate transcription and serve as drug target in pharmaceutical applications.

To describe the measurement of anterior chamber area and anterior chamber volume by anteriorsegment optical coherence tomography and to investigate the association of these parameters with the presence of narrow angles. Methods: This was a cross-sectional study of subjects aged at least 50 years without ophthalmic symptoms recruited from a community clinic. All participants underwent standardized ocular examination and anterior-segment optical coherence tomography. Customized software was used to measure anterior chamber area (cross-sectional area bounded by the corneal endothelium, anterior surface of iris, and lens within the pupil) and anterior chamber volume (calculated by rotating the anterior chamber area 360°a round a vertical axis through the midpoint of the anterior chamber area). An eye was considered to have narrow angles if the posterior pigmented trabecular meshwork was not visible for at least 180°on gonioscopy with the eye in the primary position. Results: A total of 1922 subjects were included in the final analyses, 317 (16.5%) of whom had narrow angles. Mean anterior chamber area (15.6 vs 21.1 mm 2 ; PϽ.001) and anterior chamber volume (97.6 vs 142.1 mm 3 ; P Ͻ .001) were smaller in eyes with narrow angles compared with those in eyes without narrow angles. After adjusting for age, sex, anterior chamber depth, axial length, and pupil size, smaller anterior chamber area (odds ratio, 53.2; 95% confidence interval, 27.1-104.5) and anterior chamber volume (odds ratio, 40.2; 95% confidence interval, 21.5-75.2) were significantly associated with the presence of narrow angles. Conclusion: Smaller anterior chamber area and anterior chamber volume were independently associated with narrow angles in Singaporeans, even after controlling for other known ocular risk factors.

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

Oxidative stress occurs when cellular reactive oxygen species levels exceed the self-antioxidant capacity of the body. Oxidative stress induces many pathological changes, including inflammation and cancer. Chronic inflammation is believed to be strongly associated with the major stages of carcinogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating oxidative stress and inflammation by manipulating key antioxidant and detoxification enzyme genes via the antioxidant response element. Many dietary phytochemicals with cancer chemopreventive properties, such as polyphenols, isothiocyanates, and triterpenoids, exert antioxidant and anti-inflammatory functions by activating the Nrf2 pathway. Furthermore, epigenetic changes, including DNA methylation, histone post-translational modifications, and miRNA-mediated post-transcriptional alterations, also lead to various carcinogenesis processes by suppressing cancer repressor gene transcription. Using epigenetic research tools, including next-generation sequencing technologies, many dietary phytochemicals are shown to modify and reverse aberrant epigenetic/epigenome changes, potentially leading to cancer prevention/treatment. Thus, the beneficial effects of dietary phytochemicals on cancer development warrant further investigation to provide additional impetus for clinical translational studies.

Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NFE2L2/Nrf2) signaling pathway is a pivotal player in the antioxidant response to oxidative and electrophilic stress and can play a role in many human diseases. Activation or inhibition of Nrf2 has been an approach to treating many diseases such as cancer and regulation of this pathway has been thoroughly studied. Recently, epigenetics has emerged as another layer for regulating Keap1-Nrf2. Epigenetics modification is defined as heritable changes to gene expression without changing DNA sequence and various modifications have been found to be involved in regulating Keap1-Nrf2. Therefore, targeting these epigenetic changes on Keap1-Nrf2 provides a potential pathway for modulating Keap1-Nrf2 to treat disease. In this review, several important and recent findings on epigenetic regulation and perspectives on Keap1-Nrf2 are discussed and shared.