Physiological Role Research Articles

The (patho)physiological roles of the individual deacylase activities of a sirtuin

AbstractSince the discovery of the sirtuin family founding member (i.e., the yeast silent information regulator 2 (sir2) protein) in 2000, more and more sirtuin proteins have been identified and are currently known to be present in organisms from all the three kingdoms of life (i.e., bacteria, archaea, and eukarya). Seven sirtuin proteins have been identified in mammals including humans, that is, SIRT1/2/3/4/5/6/7. Sirtuin proteins are a class of enzymes with primary catalytic activity being the β‐nicotinamide adenine dinucleotide (β‐NAD+ or NAD+)‐dependent deacylation from the Nε‐acyl‐lysine residues on cellular proteins. Many sirtuins (e.g., human SIRT1/2/3/4/5/6/7) have been found to each possess multiple individual deacylase activities acting on Nε‐acyl‐lysine substrates with different acyl groups ranging from the simple formyl and acetyl to the more complex groups like succinyl and myristoyl; however, our current knowledge on the (patho)physiological roles of these individual deacylase activities is still limited, which could be due to the currently still thin research toolbox for investigation (i.e., the deacylase‐selective sirtuin mutant and inhibitor/activator). In this article, an updated account on the subject matter will be presented with biochemical and medicinal chemistry perspectives.

BmSLC7A5 is essential for silk protein synthesis and larval development in Bombyx mori.

Insects produce silk to form cocoons, nests, and webs, which are important for their survival and reproduction. However, little is known about the molecular mechanism of silk protein synthesis at the translation level. The solute carrier family7 (SLC7) genes are involved in activating the target of rapamycin complex1 (TORC1) signaling pathway and protein translation process, but the physiological roles of SLC7 genes in silk-producing insects have not been reported. Here, we found that amino acid signaling regulates silk protein synthesis and larval development via the L-type amino acid transporter1 (LAT1; also known as SLC7A5) in Bombyx mori. A total of 12 SLC7 homologs were identified in the silkworm genome, among which BmSLC7A5 was found to be a silk gland-enriched gene and may be involved in leucine transport. Bioinformatics analysis indicated that SLC7A5 displays high homology and a close phylogenetic relationship in silk-producing insects. Subsequently, we found that leucine treatment significantly increased silk protein synthesis by improving the transcription and protein levels of silk genes. Furthermore, systemic and silk gland-specific knockout of BmSLC7A5 led to decreased silk protein synthesis by inhibiting TORC1 signaling, and somatic mutation also resulted in arrested development from the 5th instar to the early pupal stage. Altogether, our study reveals that BmSLC7A5 is involved in regulating silk protein synthesis and larval development by affecting the TORC1 signaling pathway, which provides a new strategy and target for improving silk yield.

H2A.Z is involved in premature aging and DSB repair initiation in muscle fibers.

Histone variants are key epigenetic players, but their functional and physiological roles remain poorly understood. Here, we show that depletion of the histone variant H2A.Z in mouse skeletal muscle causes oxidative stress, oxidation of proteins, accumulation of DNA damages, and both neuromuscular junction and mitochondria lesions that consequently lead to premature muscle aging and reduced life span. Investigation of the molecular mechanisms involved shows that H2A.Z is required to initiate DNA double strand break repair by recruiting Ku80 at DNA lesions. This is achieved via specific interactions of Ku80 vWA domain with H2A.Z. Taken as a whole, our data reveal that H2A.Z containing nucleosomes act as a molecular platform to bring together the proteins required to initiate and process DNA double strand break repair.

Computational exploration of the genomic assignments, molecular structure, and dynamics of the ccdABXn 2 toxin-antitoxin homolog with its bacterial target, the DNA gyrase, in the entomopathogen Xenorhabdus nematophila

Toxin-antitoxin (TA) modules, initially discovered on bacterial plasmids and subsequently identified within chromosomal contexts, hold a pivotal role in the realm of bacterial physiology. Among these, the pioneering TA system, ccd (Control of Cell Death), primarily localized on the F-plasmid, is known for its orchestration of plasmid replication with cellular division. Nonetheless, the precise functions of such systems within bacterial chromosomal settings remain a compelling subject that demands deeper investigation. To bridge this knowledge gap, our study focuses on exploring ccdABXn2 , a chromosomally encoded TA module originating from the entomopathogenic bacterium Xenorhabdus nematophila. We meticulously delved into the system’s genomic assignments, structural attributes, and functional interplay. Our findings uncovered intriguing patterns—CcdB toxin homologs exhibited higher conservation levels compared to their CcdA antitoxin counterparts. Moreover, we constructed secondary as well as tertiary models for both the CcdB toxin and CcdA antitoxin using threading techniques and subsequently validated their structural integrity. Our exploration extended to the identification of key interactions, including the peptide interaction with gyrase for the CcdB homolog and CcdB toxin interactions for the CcdA homolog, highlighting the intricate TA interaction network. Through docking and simulation analyses, we unequivocally demonstrated the inhibition of replication via binding the CcdB toxin to its target, DNA gyrase. These insights provide valuable knowledge about the metabolic and physiological roles of the chromosomally encoded ccdABXn 2 TA module within the context of X. nematophila, significantly enhancing our comprehension of its functional significance within the intricate ecosystem of the bacterial host. Communicated by Ramaswamy H. Sarma

ARGINASE 2 AMELIORATES EXPERIMENTAL COLITIS THROUGH ANTIOXIDANT EFFECTS VIA SPERMIDINE PRODUCTION

Abstract BACKGROUND Spermidine which is a type of polyamine, shows elevated levels in patients with ulcerative colitis and is implicated in the pathogenesis of ulcerative colitis (UC). Arginase 2 (ARG2) plays a critical role in spermidine production. This study aimed to determine the role and mechanism of endogenous spermidine by using ARG2-deficient mice. METHODS The protective role of spermidine against oxidative stress was examined by intracellular reactive oxygen species levels and cell viability. The physiological role of spermidine was investigated using Arg2 knockdown cells with reduced spermidine. The importance of ARG2 in inflammation was examined in the dextran sulfate sodium-induced colitis model. Protein expression levels of ARG2 and accumulation of spermidine in patients with UC were evaluated by immunohistochemistry of the rectum. RESULTS ARG2 protein expression and the accumulation of spermidine were upregulated in the rectum of mice with dextran sulfate sodium colitis. Spermidine upregulated antioxidant genes in the cells. Arg2 knockdown cells showed reduced antioxidant activity. Dextran sulfate sodium colitis was more severe in Arg2-deficient mice, and organoids derived from Arg2-deficient mice showed diminished tolerance to oxidative stress. Furthermore, in the rectum of patients with UC, ARG2 and spermidine expression levels were higher in the active phase than in the remission phase. CONCLUSIONS Endogenous spermidine in the intestinal epithelium induced by ARG2 has a protective role in colitis. Spermidine may be a promising new therapeutic target for inflammatory bowel disease.

Revisiting the Role of Serotonin in Sleep-Disordered Breathing.

Serotonin or 5-hydroxytryptamine (5-HT) is a ubiquitous neuro-modulator-transmitter that acts in the central nervous system, playing a major role in the control of breathing and other physiological functions. The midbrain, pons, and medulla regions contain several serotonergic nuclei with distinct physiological roles, including regulating the hypercapnic ventilatory response, upper airway patency, and sleep-wake states. Obesity is a major risk factor in the development of sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA), recurrent closure of the upper airway during sleep, and obesity hypoventilation syndrome (OHS), a condition characterized by daytime hypercapnia and hypoventilation during sleep. Approximately 936 million adults have OSA, and 32 million have OHS worldwide. 5-HT acts on 5-HT receptor subtypes that modulate neural control of breathing and upper airway patency. This article reviews the role of 5-HT in SDB and the current advances in 5-HT-targeted treatments for SDB.

Moderate Elevation of Homocysteine Induces Endothelial Dysfunction through Adaptive UPR Activation and Metabolic Rewiring.

Elevation of the intermediate amino acid metabolite Homocysteine (Hcy) causes Hyperhomocysteinemia (HHcy), a metabolic disorder frequently associated with mutations in the methionine-cysteine metabolic cycle as well as with nutritional deficiency and aging. The previous literature suggests that HHcy is a strong risk factor for cardiovascular diseases. Severe HHcy is well-established to correlate with vascular pathologies primarily via endothelial cell death. Though moderate HHcy is more prevalent and associated with an increased risk of cardiovascular abnormalities in later part of life, its precise role in endothelial physiology is largely unknown. In this study, we report that moderate elevation of Hcy causes endothelial dysfunction through impairment of their migration and proliferation. We established that unlike severe elevation of Hcy, moderate HHcy is not associated with suppression of endothelial VEGF/VEGFR transcripts and ROS induction. We further showed that moderate HHcy induces a sub-lethal ER stress that causes defective endothelial migration through abnormal actin cytoskeletal remodeling. We also found that sub-lethal increase in Hcy causes endothelial proliferation defect by suppressing mitochondrial respiration and concomitantly increases glycolysis to compensate the consequential ATP loss and maintain overall energy homeostasis. Finally, analyzing a previously published microarray dataset, we confirmed that these hallmarks of moderate HHcy are conserved in adult endothelial cells as well. Thus, we identified adaptive UPR and metabolic rewiring as two key mechanistic signatures in moderate HHcy-associated endothelial dysfunction. As HHcy is clinically associated with enhanced vascular inflammation and hypercoagulability, identifying these mechanistic pathways may serve as future targets to regulate endothelial function and health.

The Role of Extracellular Vesicles in SARS-CoV-2-Induced Acute Kidney Injury: An Overview.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions worldwide since its outbreak in the winter of 2019. While extensive research has primarily focused on the deleterious respiratory effects of SARS-CoV-2 in recent years, its pan-tropism has become evident. Among the vital organs susceptible to SARS-CoV-2 infection is the kidney. Post SARS-CoV-2 infection, patients have developed coronavirus disease 19 (COVID-19), with reported incidences of COVID-19 patients developing acute kidney injury (AKI). Given COVID-19's multisystemic manifestation, our review focuses on the impact of SARS-CoV-2 infection within the renal system with an emphasis on the current hypotheses regarding the role of extracellular vesicles (EVs) in SARS-CoV-2 pathogenesis. Emerging studies have shown that SARS-CoV-2 can directly infect the kidney, whereas EVs are involved in the spreading of SARS-CoV-2 particles to other neighboring cells. Once the viral particles are within the kidney system, many proinflammatory signaling pathways are shown to be activated, resulting in AKI. Hence, clinical investigation of urinary proinflammatory components and total urinary extracellular vesicles (uEVs) with viral particles have been used to assess the severity of AKI in patients with COVID-19. Remarkedly, new emerging studies have shown the potential of mesenchymal stem cell-derived EVs (MSC-EVs) and ACE2-containing EVs as a hopeful therapeutic tool to inhibit SARS-CoV-2 RNA replication and block viral entry, respectively. Overall, understanding EVs' physiological role is crucial and hopefully will rejuvenate our therapeutic approach towards COVID-19 patients with AKI.

Ferredoxin 1 is essential for embryonic development and lipid homeostasis.

Mammalian ferredoxin 1 and 2 (FDX1/2) belong to an evolutionary conserved family of iron-sulfur cluster containing proteins and act as electron shutters between ferredoxin reductase (FDXR) and numerous proteins involved in critical biological pathways. FDX1 is involved in biogenesis of steroids and bile acids, Vitamin A/D metabolism, and lipoylation of tricarboxylic acid (TCA) cycle enzymes. FDX1 has been extensively characterized biochemically but its role in physiology and lipid metabolism has not been explored. In this study, we generated Fdx1-deficient mice and showed that knockout of both alleles of the Fdx1 gene led to embryonic lethality. We also showed that like Fdxr+/-+/-, Fdx1+/-+/- had a shorter life span and were prone to steatohepatitis. However, unlike Fdxr+/-+/-, Fdx1+/-+/- were not prone to spontaneous tumors. Additionally, we showed that FDX1 deficiency led to lipid droplet accumulation possibly via the ABCA1-SREBP1/2 pathway. Specifically, untargeted lipidomic analysis showed that FDX1 deficiency led to alterations in several classes of lipids, including cholesterol, triacylglycerides, acylcarnitines, ceramides, phospholipids and lysophospholipids. Taken together, our data indicate that FDX1 is essential for mammalian embryonic development and lipid homeostasis at both cellular and organismal levels.

Associations between maternal urinary kisspeptin in late pregnancy and decreased fetal growth: a pregnancy-birth cohort study.

Kisspeptin has been indicated to be a biomarker of fetal growth. Although some evidence suggested that maternal kisspeptin concentrations in early pregnancy were associated with increased fetal growth, studies are still limited and the effect of kisspeptin in late pregnancy remains unknown. This study aimed to investigate the associations between maternal kisspeptin in late pregnancy and fetal growth. Based on the Shanghai-Minhang Birth Cohort study, 724 mother-neonate pairs were included in this study. We measured maternal kisspeptin concentrations in the urine samples collected in late pregnancy and neonatal anthropometric indices at birth. The associations between maternal kisspeptin and neonatal anthropometry were investigated using multiple linear regression models. Higher maternal urinary kisspeptin concentrations were associated with lower neonatal birth weight, head circumference, upper arm circumference, abdominal skinfold thickness, triceps skinfold thickness, and back skinfold thickness. The inverse associations were more pronounced for the highest kisspeptin levels versus the lowest. These patterns were consistent in analyses stratified by neonatal sex, with notably stable associations between maternal kisspeptin concentrations and skinfold thickness. The present study suggested that maternal kisspeptin concentrations in late pregnancy might be inversely associated with fetal growth. The physiological mechanisms of maternal kisspeptin might differ from those in early pregnancy. Further studies are required to assess associations between maternal kisspeptin and energy homeostasis and explore the physiological roles of kisspeptin in late pregnancy.

Inhibition of vertebrate complement system by hematophagous arthropods: inhibitory molecules, mechanisms, physiological roles, and applications.

In arthropods, hematophagy has arisen several times throughout evolution. This specialized feeding behavior offered a highly nutritious diet obtained during blood feeds. On the other hand, blood-sucking arthropods must overcome problems brought on by blood intake and digestion. Host blood complement acts on the bite site and is still active after ingestion, so complement activation is a potential threat to the host's skin feeding environment and to the arthropod gut enterocytes. During evolution, blood-sucking arthropods have selected, either in their saliva or gut, anticomplement molecules that inactivate host blood complement. This review presents an overview of the complement system and discusses the arthropod's salivary and gut anticomplement molecules studied to date, exploring their mechanism of action and other aspects related to the arthropod-host-pathogen interface. The possible therapeutic applications of arthropod's anticomplement molecules are also discussed.

Aagab is required for zebrafish larval development by regulating neural activity

Clathrin-mediated endocytosis has been implicated in various physiological processes, including nutrient uptake, signal transduction, synaptic vesicle recycling, maintenance of cell polarity, and antigen presentation. Despite prior knowledge of its importance as a key regulator in promoting clathrin-mediated endocytosis, the physiological function of α- and γ-adaptin binding protein (aagab) remains elusive. In this study, we investigate the biological function of aagab during zebrafish development. We establish a loss-of-function mutant of aagab in zebrafish, revealing impaired swimming and early larval mortality. Given the high expression level of aagab in the brain, we probe into its physiological role in the nervous system. aagab mutants display subdued calcium responses and local field potential in the optic tectal neurons, aligning with reduced neurotransmitter release (e.g., norepinephrine) in the tectal neuropil of aagab mutants. Overexpressing aagab mRNA or nervous stimulant treatment in mutants restores neurotransmitter release, calcium responses, swimming ability, and survival. Furthermore, our observations show delayed release of FM 1–43 in AAGAB knockdown differentiated neuroblastoma cells, pointing towards a probable link to defective clathrin-mediated synaptic vesicle recycling. In conclusion, our study underscores the significance of Aagab in neurobiology and suggests its potential impacts on neurological disorders.

Decoding the nature and complexity of extracellular mtDNA: Types and implications for health and disease

The mitochondrial DNA (mtDNA) is replicated and canonically functions within intracellular mitochondria, but recent discoveries reveal that the mtDNA has another exciting extracellular life. mtDNA fragments and mitochondria-containing vesicular structures are detected at high concentrations in cell-free forms, in different biofluids. Commonly referred to as cell-free mtDNA (cf-mtDNA), the field is currently without a comprehensive classification system that acknowledges the various biological forms of mtDNA and whole mitochondria existing outside the cell. This absence of classification hampers the creation of precise and consistent quantification methods across different laboratories, which is crucial for unraveling the molecular and biological characteristics of mtDNA. In this article, we integrate recent findings to propose a classification for different types of Extracellular mtDNA [ex-mtDNA]. The major biologically distinct types include: Naked mtDNA [N-mtDNA], mtDNA within non-mitochondrial Membranes [M-mtDNA], Extracellular mitochondria [exM-mtDNA], and mtDNA within Mitochondria enclosed in a Membrane [MM-mtDNA]. We outline the challenges associated with accurately quantifying these ex-mtDNA types, suggest potential physiological roles for each ex-mtDNA type, and explore how this classification could establish a foundation for future research endeavors and further analysis and definitions for ex-mtDNA. By proposing this classification of circulating mtDNA forms, we draw a parallel with the clinically recognized forms of cholesterol, such as HDL and LDL, to illustrate potential future significance in a similar manner. While not directly analogous, these mtDNA forms may one day be as biologically relevant in clinical interpretation as cholesterol fractions are currently. We also discuss how advancing methodologies to reliably quantify distinct ex-mtDNA forms could significantly enhance their utility as health or disease biomarkers, and how their application may offer innovative therapeutic approaches.

Cell membrane-targeted surface enhanced Raman scattering nanoprobes for the monitoring of hydrogen sulfide secreted from living cells

Hydrogen sulfide (H2S), an important gas signal molecule, participates in intercellular signal transmission and plays a considerable role in physiology and pathology. However, in-situ monitoring of H2S level during the processes of material transport between cells remains considerably challenging. Herein, a cell membrane-targeted surface-enhanced Raman scattering (SERS) nanoprobe was designed to quantitatively detect H2S secreted from living cells. The nanoprobes were fabricated by assembling cholesterol-functionalized DNA strands and dithiobis(phenylazide) (DTBPA) molecules on core-shell gold nanostars embedded with 4-mercaptoacetonitrile (4-MBN) (AuNPs@4-MBN@Au). Thus, three functions including cell-membrane targeted via cholesterol, internal standard calibration, and responsiveness to H2S through reduction of azide group in DTBPA molecules were integrated into the nanoprobes. In addition, the nanoprobes can quickly respond to H2S within 90 s and sensitively, selectively, and reliably detect H2S with a limit of detection as low as 37 nM due to internal standard-assisted calibration and reaction specificity. Moreover, the nanoprobes can effectively target on cell membrane and realize SERS visualization of dynamic H2S released from HeLa cells. By employing the proposed approach, an intriguing phenomenon was observed: the other two major endogenous gas transmitters, carbon monoxide (CO) and nitric oxide (NO), exhibited opposite effect on H2S production in living cells stimulated by related gas release molecules. In particular, the introduction of CO inhibited the generation of H2S in HeLa cells, while NO promoted its output. Thus, the nanoprobes can provide a robust method for investigating H2S-related extracellular metabolism and intercellular signaling transmission.

Hybrid lineages of CD4+ T cells: a handbook update.

CD4+ T lymphocytes have been classified into several lineages, according to their gene expression profiles and their effector responses. Interestingly, recent evidence is showing that many lineages could yield hybrid phenotypes with unique properties and functions. It has been reported that such hybrid lineages might underlie pathologies or may function as effector cells with protection capacities against molecular threats. In this work, we reviewed the characteristics of the hybrid lineages reported in the literature, in order to identify the expression profiles that characterize them and the markers that could be used to identify them. We also review the differentiation cues that elicit their hybrid origin and what is known about their physiological roles.

Hydrogen Sulfide (H2S)/Polysulfides (H2Sn) Signalling and TRPA1 Channels Modification on Sulfur Metabolism.

Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) produced by enzymes play a role as signalling molecules regulating neurotransmission, vascular tone, cytoprotection, inflammation, oxygen sensing, and energy formation. H2Sn, which have additional sulfur atoms to H2S, and other S-sulfurated molecules such as cysteine persulfide and S-sulfurated cysteine residues of proteins, are produced by enzymes including 3-mercaptopyruvate sulfurtransferase (3MST). H2Sn are also generated by the chemical interaction of H2S with NO, or to a lesser extent with H2O2. S-sulfuration (S-sulfhydration) has been proposed as a mode of action of H2S and H2Sn to regulate the activity of target molecules. Recently, we found that H2S/H2S2 regulate the release of neurotransmitters, such as GABA, glutamate, and D-serine, a co-agonist of N-methyl-D-aspartate (NMDA) receptors. H2S facilitates the induction of hippocampal long-term potentiation, a synaptic model of memory formation, by enhancing the activity of NMDA receptors, while H2S2 achieves this by activating transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes, potentially leading to the activation of nearby neurons. The recent findings show the other aspects of TRPA1 channels-that is, the regulation of the levels of sulfur-containing molecules and their metabolizing enzymes. Disturbance of the signalling by H2S/H2Sn has been demonstrated to be involved in various diseases, including cognitive and psychiatric diseases. The physiological and pathophysiological roles of these molecules will be discussed.

A reaction-based bright red-emitting fluorescence probe for hypochlorite detection and its biological application

Monitoring the fluctuations of endogenous ClO−in vivo is very important to understand the physiological roles of ClO−and the mechanisms of ClO− relevant diseases. Herein, a new fluorescent probe, RhB-FL exhibited excellent sensitivity and anti-interference for ClO− detection, and the detection limit was as low as 4.8 × 10−7 M. Furthermore, RhB-FL was effectively applied to detect ClO− in cells.

Exploring the Hemostatic Effects of Platelet Lysate-Derived Vesicles: Insights from Mouse Models.

Platelet transfusion has various challenges, and platelet-derived extracellular vesicles have been reported to have more significant procoagulant activity than platelets themselves. Furthermore, platelet products derived from platelet-rich plasma and platelet lysates (PLs) have gained attention for their physiological activity and potential role as drug delivery vehicles owing to the properties of their membranes. We aimed to investigate the characteristics of the fractions isolated through ultracentrifugation from mouse-washed PLs and assess the potential clinical applications of these fractions as a therapeutic approach for bleeding conditions. We prepared PLs from C57BL/6 mouse-washed platelets and isolated three different fractions (20K-vesicles, 100K-vesicles, and PLwo-vesicles) using ultracentrifugation. There was a notable difference in particle size distribution between 20K-vesicles and 100K-vesicles, particularly in terms of the most frequent diameter. The 20K-vesicles exhibited procoagulant activity with concentration dependence, whereas PLwo-vesicles exhibited anticoagulant activity. PLwo-vesicles did not exhibit thrombin generation capacity, and the addition of PLwo-vesicles to Microparticle Free Plasma extended the time to initiate thrombin generation by 20K-vesicles and decreased the peak thrombin value. In a tail-snip bleeding assay, pre-administration of 20K-vesicles significantly shortened bleeding time. PL-derived 20K-vesicles exhibited highly potent procoagulant activity, making them potential alternatives to platelet transfusion.

Structural and accessibility studies highlight the differential binding of clemizole to TRPC5 and TRPC6

Transient Receptor Potential Canonical 5 (T RP C5) and T RP C6 channels play critical physiological roles in various cell types. Their involvement in numerous disease progression mechanisms has led to extensive searches for their inhibitors. Although several potent T RP C inhibitors have been developed and the structure of their binding sites were mapped using cryo electron microscopy, a comprehensive understanding of the molecular interactions within the inhibitor binding site of T RP Cs remains elusive. This study aimed to decipher the structural determinants and molecular mechanisms contributing to the differential binding of clemizole to T RP C5 and T RP C6, with a particular focus on the accessibility of binding site residues. This information can help better understand what molecular features allow for selective binding, which is a key characteristic of clinically effective pharmacological agents. Using computational methodologies, we conducted an in-depth molecular docking analysis of clemizole with T RP C5 and T RP C6 channels. The protein structures were retrieved from publicly accessible protein databases. Discovery Studio 2020 Client Visualizer and Chimera software facilitated our in-silico mutation experiments and enabled us to identify the critical structural elements influencing clemizole binding. Our study reveals key molecular determinants at the clemizole binding site, specifically outlining the role of residues' Accessible Surface Area (ASA) and Relative Accessible Surface Area (RASA) in differential binding. We found that lower accessibility of T RP C6 binding site residues, compared to those in T RP C5, could account for the lower affinity binding of clemizole to T RP C6. This work illuminates the pivotal role of binding site residue accessibility in determining the affinity of clemizole to T RP C5 and T RP C6. A nuanced understanding of the distinct binding properties between these homologous proteins may pave the way for the development of more selective inhibitors, promising improved therapeutic efficacy and fewer off-target effects. By demystifying the structural and molecular subtleties of T RP C inhibitors, this research could significantly accelerate the drug discovery process, offering hope to patients afflicted with T RP C-related diseases.

The chylomicron saga: time to focus on postprandial metabolism.

Since statins have had such tremendous therapeutic success over the last three decades, the field of atherosclerosis has become somewhat LDL-centric, dismissing the relevance of triglycerides (TG), particularly chylomicrons, in atherogenesis. Nonetheless, 50% of patients who take statins are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and are unable to achieve their goal LDL-C levels. This residual risk is mediated, in part by triglyceride rich lipoproteins (TRL) and their remnants. Following his seminal investigation on the subject, Zilversmit proposed that atherosclerosis is a postprandial event in 1979 (1-4). In essence, the concept suggests that remnant cholesterol-rich chylomicron (CM) and very-low density lipoprotein (VLDL) particles play a role in atherogenesis. Given the foregoing, this narrative review addresses the most recent improvements in our understanding of postprandial dyslipidemia. The primary metabolic pathways of chylomicrons are discussed, emphasizing the critical physiological role of lipoprotein lipase and apoCIII, the importance of these particles' fluxes in the postprandial period, their catabolic rate, the complexities of testing postprandial metabolism, and the role of angiopoietin-like proteins in the partition of CM during the fed cycle. The narrative is rounded out by the dysregulation of postprandial lipid metabolism in insulin resistance states and consequent CVD risk, the clinical evaluation of postprandial dyslipidemia, current research limits, and potential future study directions.