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The Journal of Physiology Mar 2022The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, and new treatments are sorely needed. Nicotinamide adenine dinucleotide (NAD ) has... (Review)
Review
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, and new treatments are sorely needed. Nicotinamide adenine dinucleotide (NAD ) has been proposed as a potential target to prevent and reverse NAFLD. NAD is an important redox factor for energy metabolism and is used as a substrate by a range of enzymes, including sirtuins (SIRT), which regulates histone acetylation, transcription factor activity and mitochondrial function. NAD is also a precursor for reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is an important component of the antioxidant defense system. NAD precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are available as over-the-counter dietary supplements, and oral supplementation with these precursors increases hepatic NAD levels and prevents hepatic lipid accumulation in pre-clinical models of NAFLD. NAD precursors have also been found to improve hepatic mitochondrial function and decrease oxidative stress in pre-clinical NAFLD models. NAD repletion also prevents NAFLD progression to non-alcoholic steatohepatitis (NASH), as NAD precursor supplementation is associated with decreased hepatic stellate cell activation, and decreased fibrosis. However, initial clinical trials have only shown modest effects when NAD precursors were administrated to people with obesity. We review the available pre-clinical investigations of NAD supplementation for targeting NAFLD, and discuss how data from the first clinical trials can be reconciled with observations from preclinical research.
Topics: Animals; Dietary Supplements; Humans; Mice; Mice, Inbred C57BL; NAD; Non-alcoholic Fatty Liver Disease
PubMed: 33932956
DOI: 10.1113/JP280908 -
Bioscience Reports Mar 2023RNA is a fundamental biomolecule that has many purposes within cells. Due to its single-stranded and flexible nature, RNA naturally folds into complex and dynamic... (Review)
Review
RNA is a fundamental biomolecule that has many purposes within cells. Due to its single-stranded and flexible nature, RNA naturally folds into complex and dynamic structures. Recent technological and computational advances have produced an explosion of RNA structural data. Many RNA structures have regulatory and functional properties. Studying the structure of nascent RNAs is particularly challenging due to their low abundance and long length, but their structures are important because they can influence RNA processing. Precursor RNA processing is a nexus of pathways that determines mature isoform composition and that controls gene expression. In this review, we examine what is known about human nascent RNA structure and the influence of RNA structure on processing of precursor RNAs. These known structures provide examples of how other nascent RNAs may be structured and show how novel RNA structures may influence RNA processing including splicing and polyadenylation. RNA structures can be targeted therapeutically to treat disease.
Topics: Humans; RNA Precursors; RNA Splicing; RNA; Polyadenylation; Gene Expression
PubMed: 36689327
DOI: 10.1042/BSR20220149 -
Molecules (Basel, Switzerland) Mar 2024During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in... (Review)
Review
During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in clinical practice. In addition to exploring new antibiotics, this makes it one of the research priorities of to effectively increase the yield of antibiotics in production strains by various means. Most antibiotic-producing strains have a variety of functional regulatory factors that regulate their growth, development, and secondary metabolite biosynthesis processes. Through the study of precursor substances in antibiotic biosynthesis, researchers have revealed the precursor biosynthesis process and the mechanism by which precursor synthesis regulators affect the biosynthesis of secondary metabolites, which can be used to obtain engineered strains with high antibiotic production. This paper summarizes the supply of antibiotic biosynthesis precursors and the progress of research on the role of regulators in the process of precursors in biosynthesis. This lays the foundation for the establishment of effective breeding methods to improve antibiotic yields through the manipulation of precursor synthesis genes and related regulators.
Topics: Anti-Bacterial Agents; Actinobacteria; Actinomyces; Secondary Metabolism
PubMed: 38474644
DOI: 10.3390/molecules29051132 -
Substance Abuse and Rehabilitation 2022Recreational gamma-hydroxybutyrate (GHB) use, although less common than other substance use, is increasingly recognised and is over-represented in emergency toxicology... (Review)
Review
Recreational gamma-hydroxybutyrate (GHB) use, although less common than other substance use, is increasingly recognised and is over-represented in emergency toxicology presentations. This narrative review summarizes GHB pharmacology, current patterns of use, potential harms and management of GHB toxicity and withdrawal. There is a complex interplay between GHB and GABA as GHB is both a prodrug and metabolite of GABA and GHB activates both GHB and GABA receptors. GHB is rapidly absorbed, with effects seen within minutes of ingestion. Metabolism is non-linear at higher doses. While GHB is listed as a controlled substance, its precursor's gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are easily available as both have industrial applications. National surveys indicate low rates of GHB use, with identification of high-risk populations in men who have sex with men and polysubstance users. GHB is one of the three drugs most commonly used in chemsex. GHB is often co-ingested with other interacting psychoactive substances. Acute toxicity is dose-dependent, and management is supportive care. Withdrawal management is generally with benzodiazepines with addition of baclofen for more severe withdrawal. Barbiturates may have a role. Titration and tapering of pharmaceutical GHB is commonly used in the Netherlands. Complicated withdrawal with delirium may require intensive care and treatment with intravenous sedation. There are high rates of relapse after withdrawal and medications for longer-term management are currently being investigated. Chronic use is associated with poorer mental, physical and sexual health, social dysfunction and poor work performance. Laboratory detection is complicated as GHB is an endogenous substance with a short half-life, and therefore not often routinely assayed in the clinical setting. Future research should focus on improving GHB detection and management of GHB withdrawal and dependence. Interventions specific for high-risk groups should be developed and assessed.
PubMed: 35173515
DOI: 10.2147/SAR.S315720 -
Ground Water Jan 2022Groundwater professionals require tools to evaluate a variety of technical issues related to per- and polyfluoroalkyl substances (PFAS). These include the potential...
Groundwater professionals require tools to evaluate a variety of technical issues related to per- and polyfluoroalkyl substances (PFAS). These include the potential impact of PFAS precursors on groundwater plumes of perfluoroalkyl acids (PFAAs). Numerical modeling results show that, by adjusting the mass loading rate, source zones with or without a precursor can produce similar PFAA plumes. However, if a precursor is present, it can impact PFAA plume concentrations and extend PFAA plume durations by decades. Additional research regarding in situ precursor transformation rates-and improvements in source area characterization-will further advance the predictive value of modeling.
Topics: Fluorocarbons; Groundwater; Water Pollutants, Chemical
PubMed: 34850384
DOI: 10.1111/gwat.13152 -
Current Opinion in Plant Biology Oct 2022Post-translationally modified peptides (PMPs) are important regulators of plant growth and development. They are derived from larger inactive precursors by... (Review)
Review
Post-translationally modified peptides (PMPs) are important regulators of plant growth and development. They are derived from larger inactive precursors by post-translational modification (PTM) and proteolytic processing to result in the bioactive peptide signals. We discuss how and why these modifications contribute to the bioactivity of inflorescence deficient in abscission (IDA), phytosulfokine (PSK), and peptides of the Casparian strip integrity factor (CIF) family, as signaling molecules during reproductive development. The emerging picture suggests that PTMs evolved to increase the specificity of interaction of PMPs with cognate receptors and of PMP precursors with processing proteases. Cleavage sites in PMP precursors are recognized by subtilases (SBTs) in a highly specific manner. SBT-mediated processing results in the activation of PMP signals regulating stress-induced flower drop, the formation of the embryonic cuticle, and pollen development.
Topics: Flowers; Peptide Hormones; Peptide Hydrolases; Plant Development; Plants
PubMed: 35977439
DOI: 10.1016/j.pbi.2022.102274 -
Genomics, Proteomics & Bioinformatics May 2024Ribonuclease P (RNase P) was first described in the 1970's as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies,... (Review)
Review
Ribonuclease P (RNase P) was first described in the 1970's as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies, however, have uncovered non-canonical roles for RNase P and its components. Here, we review the recent progress of its involvement in chromatin assembly, DNA damage response, and maintenance of genome stability with implications in tumorigenesis. The possibility of RNase P as a therapeutic target in cancer is also discussed.
Topics: Ribonuclease P; Humans; RNA, Transfer; Neoplasms; RNA Precursors; Genomic Instability; Animals; DNA Damage; RNA Processing, Post-Transcriptional; Chromatin Assembly and Disassembly
PubMed: 38862431
DOI: 10.1093/gpbjnl/qzae016 -
Frontiers in Bioengineering and... 2022Food is essential for human survival. Nowadays, traditional agriculture faces challenges in balancing the need of sustainable environmental development and the rising... (Review)
Review
Food is essential for human survival. Nowadays, traditional agriculture faces challenges in balancing the need of sustainable environmental development and the rising food demand caused by an increasing population. In addition, in the emerging of consumers' awareness of health related issues bring a growing trend towards novel nature-based food additives. Synthetic biology, using engineered microbial cell factories for production of various molecules, shows great advantages for generating food alternatives and additives, which not only relieve the pressure laid on tradition agriculture, but also create a new stage in healthy and sustainable food supplement. The biosynthesis of food components (protein, fats, carbohydrates or vitamins) in engineered microbial cells often involves cellular central metabolic pathways, where common precursors are processed into different proteins and products. Quantitation of the precursors provides information of the metabolic flux and intracellular metabolic state, giving guidance for precise pathway engineering. In this review, we summarized the quantitation methods for most cellular biosynthetic precursors, including energy molecules and co-factors involved in redox-reactions. It will also be useful for studies worked on pathway engineering of other microbial-derived metabolites. Finally, advantages and limitations of each method are discussed.
PubMed: 35360389
DOI: 10.3389/fbioe.2022.849177 -
The American Journal of Surgical... Dec 2023Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We...
Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We analyzed the histologic and immunohistochemical characteristics of 70 peritumoral precursor lesions and correlated them with the histology and mutational profile of the adjacent HPV-negative invasive penile SCC. Atypical basal keratinocyte proliferation with variously elongated epithelial rete with premature squamatiziation, but regular superficial cornification, termed differentiated penile intraepithelial neoplasia (d-PeIN), were identified adjacent to 42/70 (60%) SCC (36/42 keratinizing ( P <0.001); 3 papillary, and 1 each verrucous, clear cell, sarcomatoid SCC). d-PeIN were associated with chronic inflammatory dermatoses (32/42; P <0.001), p53 overexpression (26/42; P <0.001), and hotspot mutations in TP53 (32/42; P <0.001), CDKN2A (26/42; P <0.001) or both (21/42; P =0.003) in the adjacent SCC. Cytoplasmic p16 ink4a overexpression in 5/42 d-PeIN correlated with CDKN2A missense mutations in the adjacent SCC. In all, 21/70 (30%) cornified verrucous or glycogenated verruciform precursors with minimal atypia and wild-type p53 (18/21; P <0.001) occurred adjacent to verrucous or papillary SCC (17/21; P <0.001) and keratinizing (4/21) SCC, which harbored mutations in HRAS and/or PIK3CA (12/21; P <0.004). Undifferentiated p16 ink4a -negative full-thickness precursors were identified in 7/70 (10%) SCC. Four histologically different HPV-independent penile precursor lesions can be assigned to 2 major genetic/biological pathways with characteristic highly differentiated precursors requiring different clinical management decisions. These include d-PeIN in chronic inflammatory dermatoses, with p53 overexpression and TP53/CDKN2A mutations, and the p53 wild-type verrucous and verruciform precursors unassociated with dermatoses, but with mutations in oncogenes PIK3CA and HRAS .
Topics: Male; Female; Humans; Papillomavirus Infections; Tumor Suppressor Protein p53; Human Papillomavirus Viruses; Skin Neoplasms; Carcinoma in Situ; Carcinoma, Squamous Cell; Penile Neoplasms; Penis; Papillomaviridae; Class I Phosphatidylinositol 3-Kinases; Vulvar Neoplasms
PubMed: 37768009
DOI: 10.1097/PAS.0000000000002130 -
Biochemical and Biophysical Research... Apr 2024Nicotinamide adenine dinucleotide (NAD) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis.... (Review)
Review
Nicotinamide adenine dinucleotide (NAD) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD decreases with age in certain tissues, and age-related NAD depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD precursor significantly elevates NAD levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD in animal studies, the efficacy of NAD precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD precursor treatment efficiently increases NAD levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD metabolism. Also, the reduced form of NAD precursor shows their potential to raise NAD, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD metabolism.
Topics: Mice; Animals; NAD; Dietary Supplements; Aging; Niacinamide; Nicotinamide Mononucleotide
PubMed: 38340651
DOI: 10.1016/j.bbrc.2024.149590