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Simple Summary: DNA polymerases are essential enzymes for the growth and survival of a cell. These enzymes replicate and/or repair the cellular genome. Some DNA polymerases have been associated with specific diseases. For example, Y-family DNA polymerases have been associated with cancer. Family A polymerases (typified by E. coli DNA polymerase I) have been extensively studied, primarily to understand the mechanism of DNA replication. Human mitochondrial DNA polymerase γ and DNA polymerase θ are exceptions as they have roles in genetic diseases and cancer, respectively. However, recent studies have uncovered novel roles of Family A polymerases. Thus, polymerase θ has been shown to conduct reverse transcriptase activity, an activity displayed by retroviruses' (such as HIV) reverse transcriptases. The association of these polymerases with diseases makes them attractive therapeutic targets against diseases such as cancer and bacterial/parasitic infections. This perspective is focused on Family A polymerases as potential therapeutic targets for the development of new classes of antibiotics, antimalarial, and anticancer drugs. These new drugs could be used either alone or in combination with current interventions to circumvent drug-resistance. Modern techniques, such as artificial intelligence and docking of millions of drug-like compounds, can expedite the discovery of new interventions targeting Family A polymerases. DNA polymerases replicate cellular genomes and/or participate in the maintenance of genome integrity. DNA polymerases sharing high sequence homology with E. coli DNA polymerase I (pol I) have been grouped in Family A. Pol I participates in Okazaki fragment maturation and in bacterial genome repair. Since its discovery in 1956, pol I has been extensively studied, primarily to gain deeper insights into the mechanism of DNA replication. As research on DNA polymerases advances, many novel functions of this group of polymerases are being uncovered. For example, human DNA polymerase θ (a Family A DNA pol) has been shown to synthesize DNA using RNA as a template, a function typically attributed to retroviral reverse transcriptase. Increased interest in drug discovery against pol θ has emerged due to its roles in cancer. Likewise, Pol I family enzymes also appear attractive as drug-development targets against microbial infections. Development of antimalarial compounds targeting apicoplast apPOL, an ortholog of Pol I, further extends the targeting of this family of enzymes. Here, we summarize reported drug-development efforts against Family A polymerases and future perspective regarding these enzymes as antibiotic targets. Recently developed techniques, such as artificial intelligence, can be used to facilitate the development of new drugs. [ABSTRACT FROM AUTHOR]

Gut microbiota plays a crucial role in inflammatory bowel diseases (IBD) and can potentially prevent IBD through microbial-derived metabolites, making it a promising therapeutic avenue. Recent evidence suggests that despite an unclear underlying mechanism, red cabbage juice (RCJ) alleviates Dextran Sodium Sulfate (DSS)-induced colitis in mice. Thus, the study aims to unravel the molecular mechanism by which RCJ modulates the gut microbiota to alleviate DSS-induced colitis in mice. Using C57BL/6J mice, we evaluated RCJ's protective role in DSS-induced colitis through two cycles of 3% DSS. Mice were daily gavaged with PBS or RCJ until the endpoint, and gut microbiota composition was analyzed via shotgun metagenomics. RCJ treatment significantly improved body weight (p ≤ 0.001), survival in mice (p < 0.001) and reduced disease activity index (DAI) scores. Further, RCJ improved colonic barrier integrity by enhancing the expression of protective colonic mucins (p < 0.001) and tight junction proteins (p ≤ 0.01) in RCJ + DSS-treated mice compared to the DSS group. Shotgun metagenomic analysis revealed an enrichment of short-chain fatty acids (SCFAs)-producing bacteria (p < 0.05), leading to increased Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) activation (p ≤ 0.001). This, in turn, resulted in repression of the nuclear factor κB (NFκB) signaling pathway, causing decreased production of inflammatory cytokines and chemokines. Our study demonstrates colitis remission in a DSS-induced mouse model, showcasing RCJ as a potential modulator for gut microbiota and metabolites, with promising implications for IBD prevention and treatment. [ABSTRACT FROM AUTHOR]

Individual limb muscles have characteristic representation and spatial distribution of muscle fiber types (one slow and up to three fast isoforms) appropriate to their unique anatomical location and function. This distribution can be altered by physiological stimuli such as training (i.e., for increased endurance or force) or pathological conditions such as aging. Our group previously showed that ephrin-A3 is expressed only on slow myofibers, and that adult mice lacking ephrin-A3 have dramatically reduced numbers of slow myofibers due to postnatal innervation of previously slow myofibers by fast motor neurons. In this study, fiber type composition of hindlimb muscles of aged and denervated/reinnervated C57BL/6 and ephrin-A3-/- mice was analyzed to determine whether the loss of slow myofibers persists across the lifespan. Surprisingly, fiber-type composition of ephrin-A3-/- mouse muscles at two years of age was nearly indistinguishable from age-matched C57BL/6 mice. After challenge with nerve crush, the percentage of IIa and I/IIa hybrid myo- fibers increased significantly in aged ephrin-A3-/- mice. While EphA8, the receptor for ephrin-A3, is present at all neuromuscular junctions (NMJs) on fast fibers in 3-6 mo old C57BL/6 and ephrin-A3-/- mice, this exclusive localization is lost with aging, with EphA8 expression now found on a subset of NMJs on some slow muscle fibers. This return to appropriate fiber-type distribution given time and under use reinforces the role of activity in determining fiber-type representation and suggests that, rather than being a passive baseline, the developmentally and evolutionarily selected fiber type pattern may instead be actively reinforced by daily living. [ABSTRACT FROM AUTHOR]