Metabolic Mechanisms Research Articles

Insight into the structure, oligomerization, and the role in drug resistance of human UDP-glucuronosyltransferases.

Human UDP-glucuronosyltransferases (UGTs) are pivotal phase II metabolic enzymes facilitating the transfer of glucuronic acid from UDP-glucuronic acid (UDPGA) to various substrates. UGTs are classic type I transmembrane glycoproteins, mainly localized in the endoplasmic reticulum (ER) membrane. This review comprehensively explores UGTs, encompassing gene expression, functional characteristics, substrate specificity, and metabolic mechanisms. A recent analysis of C-terminal structures, compared with original data, underscores the pivotal role of α3, α4, and β4 functional domains in selectively recognizing diverse glycosyl donors. Accumulating evidence suggests that UGTs function as homo- and heterodimers, with oligomers likely stabilizing UGTs and modulating their activity. The review sheds light on the implications of UGT oligomerization on substrate glucuronidation and the interplay between protein-protein interaction and glucuronidation activity. UGT-mediated drug resistance, often underestimated, emerges as a clinically relevant form of chemical resistance, with delineated outcomes in tumors and other diseases. This review provides a multifaceted exploration of the physiological significance of UGTs, spanning genetics, proteins, oligomerization, drug resistance, and more, offering insights into their metabolic mechanisms. Understanding interactions between UGT isoforms is crucial for predicting drug-drug interactions, preventing drug toxicity, and enabling precision treatment.

The molecular mechanisms of cuproptosis and its relevance to atherosclerosis

Atherosclerosis is a chronic inflammatory disease associated with lipid deposition in the vascular intima. Copper is a vital trace element implicated in the onset and progression of atherosclerosis. Excessive intracellular copper accumulation induces a unique form of cell death termed “cuproptosis.” The emergence of the concept of cuproptosis has highlighted the potential role of copper in atherosclerosis. This review explores the regulatory mechanisms of copper metabolism and cuproptosis, summarizes recent findings on the link between copper excess and atherosclerosis, and examines how cuproptosis may influence atherosclerosis progression. The goal is to propose novel diagnostic and therapeutic strategies for atherosclerosis through the lens of cuproptosis.

Two-photon NAD(P)H-FLIM reveals unperturbed energy metabolism of Ascaris suum larvae, in contrast to host macrophages upon artemisinin derivatives exposure

Abstract Soil-transmitted helminths (STH) are widespread, with Ascaris lumbricoides infecting millions globally. Malaria and STH co-infections are common in co-endemic regions. Artemisinin derivatives (ARTs)—artesunate, artemether, and dihydroartemisinin—are standard malaria treatments and are also known to influence the energy metabolism of parasites, tumors, and immune cells. Herein, we explore the potential of ARTs to influence ascariasis either by directly targeting larvae or indirectly by modifying macrophage responses. Ascaris suum third-stage larvae and porcine IL-4 polarized (M2-like) macrophages were exposed to ARTs in vitro, and their metabolism was evaluated using two-photon NAD(P)H-FLIM. Both larvae and M2-like macrophages exhibited a steady-state bioenergetic profile of high oxidative phosphorylation and low anaerobic glycolysis. In A. suum larvae, two metabolically distinct regions were identified, with particularly high DUOX activity in the pharynx compared to the midgut; however, ARTs did not alter these profiles. In contrast, exposure of M2-like macrophages to ARTs induced a metabolic shift towards high anaerobic glycolysis and reduced metabolic activity, suggesting a possible indirect effect of ARTs on the helminth infection. Overall, two-photon NAD(P)H-FLIM proved to be a powerful tool for studying specific metabolic pathways in Ascaris larvae and host macrophages, offering valuable insights into the metabolic mechanisms of drug action on both parasite and host.

13C-metabolic flux analysis of respiratory chain disrupted strain ΔndhF1 of Synechocystis sp. PCC 6803.

Cyanobacteria are advantageous hosts for industrial applications toward achieving sustainable society due to their unique and superior properties such as atmospheric CO2 fixation via photosynthesis. However, cyanobacterial productivities tend to be weak compared to heterotrophic microbes. To enhance them, it is necessary to understand the fundamental metabolic mechanisms unique to cyanobacteria. In cyanobacteria, NADPH and ATP regenerated by linear and cyclic electron transfers using light energy are consumed by CO2 fixation in a central metabolic pathway. The previous study demonstrated that the strain deleted a part of respiratory chain complex (ΔndhF1) perturbed NADPH levels and photosynthetic activity in Synechocystis sp. PCC 6803. It is expected that disruption of ndhF1 would result in a decrease in the function of cyclic electron transfer, which controls the ATP/NAD(P)H production ratio properly. In this study, we evaluated the effects of ndhF1 deletion on central metabolism and photosynthesis by 13C-metabolic flux analysis. As results of culturing the control and ΔndhF1 strains in a medium containing [1,2-13C] glucose and estimating the flux distribution, CO2 fixation rate by RuBisCO was decreased to be less than half in the ΔndhF1 strain. In addition, the regeneration rate of NAD(P)H and ATP by the photosystem, which can be estimated from the flux distribution, also decreased to be less than half in the ΔndhF1 strain, whereas no significant difference was observed in ATP/NAD(P)H production ratio between the control and the ΔndhF1 strains. Our result suggests that the ratio of utilization of cyclic electron transfer is not reduced in the ΔndhF1 strain unexpectedly.

Combined transcriptomic and metabolomic analyses reveal the pharmacognostic mechanism of the metabolism of flavonoids in different parts of Polygonum capitatum.

The plant Polygonum capitatum (P. capitatum) contains a variety of flavonoids that are distributed differently among different parts. Nevertheless, differentially expressed genes (DEGs) associated with this heterogeneous distribution have not been identified. In this study, combined with transcriptomic and metabonomic analysis, we identified significant DEGs related to variations in flavonoid composition among different parts of P. capitatum. Subsequently, transcriptomic and nontargeted metabolomic analyses revealed that flavonoids and phenolic acids in different parts of P. capitatum were significantly enriched in the phenylpropanoid biosynthesis, shikimic acid biosynthesis, and flavonoid biosynthesis pathways. The expression levels of genes encoding enzymes, including shikimate O-hydroxycinnamoyltransferase (HCT), chalcone synthase (CHS), flavonoid 3',5'-hydroxylase (CYP75A), flavones 3-hydroxylase (F3H), flavonol synthase (FLS), leucoanthocyanidin reductase (LAR), trans-cinnamate 4-monooxygenase (CYP73A), and shikimate kinase (SK), were found to be the lowest in the leaves of P. capitatum via quantitative PCR. Interestingly, these genes are involved in the biosynthesis of quality markers such as gallic acid, quercetin, and quercitrin in P. capitatum. Finally, the targeted metabolomic results reconfirmed that the gallic acid, quercetin, and quercitrin contents were the highest in the leaves of P. capitatum. This research provides a theoretical basis for further understanding the differential regulatory mechanism of flavonoid metabolism in different parts of P. capitatum, providing novel insights into the pharmacognostic basis of P. capitatum.

Neurosteroids and neurological disorders.

Neurosteroids play an important role as endogenous neuromodulators that are locally produced in the central nervous system and rapidly change the excitability of neurons and the activation of microglial cells and astrocytes. Here we review the mechanisms of synthesis, metabolism, and actions of neurosteroids in the central nervous system. Neurosteroids are able to play a variety of roles in the central nervous system under physiological conditions by binding to membrane ion channels and receptors such as gamma-aminobutyric acid type A receptors, Nmethyl- D-aspartate receptors, L- and T-type calcium channels, and sigma-1 receptors. In addition, numerous neurological disorders, including persistent neuropathic pain, multiple sclerosis, and seizures, have altered the levels of neurosteroids in the central nervous system. Thus, we review how local synthesis and metabolism of neurosteroids are modulated in the central nervous system and describe the role of neurosteroids under pathological conditions. Furthermore, we discuss whether neurosteroids may play a role as a new therapeutic for the treatment of neurological disorders.

Integrated Metabolome, Transcriptome, and Physiological Analysis of the Flavonoid and Phenylethanol Glycosides Accumulation in Wild Phlomoides rotata Roots from Different Habitats

Phlomoides rotata, a traditional medicinal plant, is commonly found on the Tibetan Plateau at altitudes of 3100–5200 m. Its primary active medicinal compounds, flavonoids and phenylethanol glycosides (PhGs), exhibit various pharmacological effects, including hemostatic, anti-inflammatory, antitumor, immunomodulatory, and antioxidant activities. This study analyzed flavonoid and PhG metabolites in the roots of P. rotata collected from Henan County (HN), Guoluo County (GL), Yushu County (YS), and Chengduo County (CD) in Qinghai Province. A total of differentially abundant metabolites (DAMs) including 38 flavonoids and 21 PhGs were identified. Six genes (UFGT1, CHS1, COMT2, C4H3, C4H8, and C4H5) and four enzymes (4CL, C4H, PPO, and ALDH) were found to play key roles in regulating flavonoid and PhG biosynthesis in P. rotata roots. With increasing altitude, the relative content of 15 metabolites, the expression of seven genes, and the activity of four enzymes associated with flavonoid and PhG metabolism increased. These findings enhance our understanding of the regulatory mechanisms of flavonoid and PhG metabolism in P. rotata and provide insights into the potential pharmaceutical applications of its bioactive compounds.

Metabolomic Profiling Reveals Potential Biomarkers and Prominent Features in HIV/AIDS Patients Co-Infected with SARS-CoV-2

The underlying mechanisms and diagnostic biomarkers for the progress of COVID-19 in HIV patients have not been fully elucidated. In this study, the aim is to analyze the metabolomic profiles of HIV/AIDS patients co-infected with SARS-CoV-2 and to identify biomarkers indicative of co-infection. In this study, we conducted a retrospective cohort analysis of peripheral blood samples collected from 30 HIV/AIDS patients co-infected with SARS-CoV-2 (pc group) and 30 patients without SARS-CoV-2 (nc group). In this study, through non-targeted metabolomics and lipidomics analysis, 77 differential metabolites were identified in the plasma of patients co-infected with HIV and SARS-CoV-2 compared to the nc group, with vitamin K1 emerging as a significant feature. Moreover, the plasma of the pc group showed disturbances in lipid metabolism, with elevated triglycerides (TG) and phosphatidylcholine (PC) and decreased phosphatidylglycerol (PG) compared to the control group. Vitamin K1 may be a biomarker for SARS-CoV-2 in HIV/AIDS patients, and changes in the levels of TG, PC, and PG molecules appear to be the main features following HIV co-infection with COVID-19. The emphasis in our study is on the power of using comprehensive metabolomics (lipidomics) approaches to identify metabolic biomarkers and potential mechanisms of COVID-19 in HIV/AIDS patients.

Integrated transcriptome and metabolome analysis of liver reveals unsynchronized growth mechanisms in blunt-snout bream (Megalobrama amblycephala)

BackgroundMegalobrama amblycephala presents unsynchronized growth, which affects its productivity and profitability. The liver is essential for substance exchange and energy metabolism, significantly influencing the growth of fish.ResultsTo investigate the differential metabolites and genes governing growth, and understand the mechanism underlying their unsynchronized growth, we conducted comprehensive transcriptomic and metabolomic analyses of liver from fast-growing (FG) and slow-growing (SG) M. amblycephala individuals. A total of 2,097 differentially expressed genes (DEGs) were identified between FG and SG, with 830 genes exhibiting significantly higher expression level in FG. KEGG and GO enrichment analysis indicated that the DEGs with higher expression level were significantly correlated with insulin signaling pathway, steroid hormone and lipid metabolism related pathway (PPAR signaling pathway and fatty acid degradation). In the metabolomic analysis, 224 differentially expressed metabolites (DEMs) were detected, of which 128 were significantly more abundant in FG. These more abundant DEMs were prominently enriched in pathways associated with cell proliferation and energy metabolism (Oxidative phosphorylation, mTOR signaling pathway and FoxO signaling pathway). In addition, DEGs and DEMs in adenosine diphosphate (ATP) hydrolysis activity and associate with fatty acid metabolism, glucose metabolism, and amino acid metabolism pathways were both found in the transcriptomic and metabolomic integrated data. These findings suggest that the large amounts of energy generated by fatty acid, glucose metabolism and other energy metabolism pathway promote the rapid growth of FG.ConclusionsThis research is the first to integrate metabolomic and transcriptomic analyses of liver to identify key genes, metabolites, and pathways to uncover the molecular and metabolic mechanisms of unsynchronized growth in M. amblycephala. The identified metabolic and genes can be potential targets for selective breeding programs to improve growth performance in aquaculture.

Effects of acteoside from Cistanche tubulosa on the plasma metabolome of cancer-related fatigue mice inoculated with colon cancer cells

ObjectiveTo elucidate the metabolic mechanisms by which acteoside (ACT) isolated from Cistanche tubulosa alleviates cancer-related fatigue (CRF) in a murine model of colon cancer with cachexia.MethodsBALB/c mice inoculated with C26 colon cancer cells were treated with paclitaxel (PTX, 10 mg/kg) and ACT (100 mg/kg) alone or in combination for 21 days. Fatigue-associated behaviors, tumor inhibition rate, and skeletal muscle morphology assessed by hematoxylin-eosin (H&E) staining and electron microscopy were evaluated. Finally, liquid chromatography-mass spectrometry (LC/MS) was employed to investigate alterations in the plasma metabolic profile of tumor-bearing mice with CRF in response to ACT treatment, and the affinity between metabolite-associated proteins and ACT was verified by Surface plasmon resonance (SPR) assay.ResultsOur study demonstrated the presence of CRF in the colon cancer mouse model, with the severity of fatigue increasing alongside tumor growth. Administration of ACT ameliorated both tumor burden and PTX-induced muscle fatigue-like behavior. LC/MS analysis identified a panel of differentially regulated metabolites, including trans-aconitine, citric acid, 3-coumaric acid, ephedrine, thymine, cytosine, indole-3-acetic acid, and pantothenol-9. These metabolites were primarily enriched in pathways associated with valine biosynthesis, tyrosine metabolism, tryptophan metabolism, and biosynthesis of pyridine alkaloids. Furthermore, several key enzymes, including CYP3A4, CYP19A1, CYP2E1, TNF, BCL-2, RYR2, and ATP2A1, were identified as potential targets underlying the anti-CRF effects of ACT.ConclusionThis study suggests that ACT derived from C. tubulosa harbors protective properties against cancer-related fatigue mediated by tumor cells.

Lipid metabolism and microbial regulation analyses provide insights into the energy-saving strategies of hibernating snakes

Hibernation is a necessary means for animals to maintain survival while coping with low temperatures and food shortages. While most studies have largely focused on mammalian hibernation, its reptilian equivalent has been less studied. In order to provide insights into the energy metabolism and potential microbial regulatory mechanisms in hibernating snakes, the serum, liver, gut content samples were measured by multi-omic methods. Here we show the active snakes have more vigorous lipid metabolism, whereas snakes in hibernation groups have higher sphingolipid metabolism. Furthermore, the results indicate that the potential energy supply pathway was gluconeogenesis. Microbial analysis reveals that Proteobacteria and Firmicutes showed dynamic changes with the transformation among active, pre-hibernation and hibernation periods. The correlation analysis reveals the potential role of Romboutsia, Providencia and Vagococcus in regulating above metabolism by producing certain metabolites. The results advance the understanding of the complex energy-saving strategy in hibernating poikilotherms.

Genomic insights into Thermomonas hydrothermalis: potential applications in industrial biotechnology.

Thermomonas hydrothermalis, a thermophilic bacterium isolated from hot springs, exhibits unique genomic features that underpin its adaptability to extreme environments and its potential in industrial biotechnology. In this study, we present a comparative genomic analysis of two strains, DSM 14834 and HOT.CON.106, revealing distinct metabolic pathways and stress response mechanisms. The genome annotation highlighted strain-specific variations, such as enhanced motility and chemotaxis capabilities in HOT.CON.106 and a stronger genomic stability emphasis in DSM 14834. Comparative analysis with other Thermomonas species demonstrated that T. hydrothermalis possesses a unique genomic architecture, including genes for thermostable enzymes (e.g., amylases and pullulanases) and secondary metabolite biosynthesis. These enzymes and metabolites have significant industrial potential in high-temperature processes such as bioenergy production, bioplastics synthesis, and bioremediation. The findings underscore the relative differentiation between the strains and their broader implications for sustainable biotechnology, offering a basis for further exploration of thermophilic microorganisms in industrial applications.

Analysis of growth physiological changes and metabolome of highland barley seedlings under cadmium (II) stress.

This study aims to investigate the physiological changes in growth and metabolic response mechanisms of highland barley under different concentrations of cadmium. To achieve this, cadmium stress was applied to green barley at levels of 20, 40, and 80 mg/L. The results revealed that, under Cd(II) stress, the chlorophyll content and photosynthesis in leaves of highland barley seedlings were inhibited to some extent. Additionally, the malondialdehyde (MDA) content and superoxide dismutase activity increased significantly, indicating that the seedlings were affected by oxidative stress. In addition, Cd(II) stress also significantly affected the accumulation of metabolites in highland barley seedlings, resulting in an increase in lipids and lipid molecules, organic heterocyclic compounds, and phenylpropanoids. Cd(II) stress also significantly interfered with phenylalanine metabolism, fructose and mannose metabolism, amino acid, sugar, and nucleotide sugar metabolism, and biosynthetic metabolic pathways of isoquinoline alkaloids. The increase in Cd(II) stress also resulted in elevated levels of soluble sugars, soluble proteins, and proline as defense mechanisms against the stress. Overall, barley has a very good ability to resist adversity, and the mechanism of barley's resistance to adversity has not been deeply investigated. Therefore, in this paper, we systematically investigated the stress resistance mechanism of barley to cadmium stress and found that the growth physiology and metabolism of barley seedlings were significantly affected by cadmium stress. Differential changes in metabolites and enrichment of metabolic pathways may be the main mechanisms for barley seedlings to cope with Cd(II) stress . This provides direction for selecting better varieties of barley.

Copper homeostasis and pregnancy complications: a comprehensive review.

Pregnancy complications pose challenges for both pregnant women and obstetricians globally, with the pathogenesis of many remaining poorly understood. Recently coined as a mode of cell death, cuproptosis has been proposed but remains largely unexplored. This process involves copper overload, resulting in the accumulation of fatty acylated proteins and subsequent loss of iron-sulfur cluster proteins. This cascade induces proteotoxic stress, leading to cell death. In recent years, studies have indicated a connection between abnormal copper metabolism and several pregnancy-related diseases, including maternal placental dysplasia, gestational diabetes mellitus (GDM), gestational hypertension (PIH), preterm birth or abortion, as well as conditions in offspring such as intrauterine growth restriction (IUGR), allergic disease, Menkes disease, and Wilson's disease. Investigating the mechanism of cuproptosis and abnormal copper metabolism in these pregnancy-related diseases emerges as a critical research area. This article provides a concise review of cuproptosis mechanisms and emphasizes the association between abnormal copper metabolism and pregnancy-related diseases. Nevertheless, the doubtful viewpoints were also discussed.

Exploration of Novel Metabolic Mechanisms Underlying Primary Biliary Cholangitis Using Hepatic Metabolomics, Lipidomics, and Proteomics Analysis.

Metabolic reprogramming is important in primary biliary cholangitis (PBC) development. However, studies investigating the metabolic signature within the liver of PBC patients are limited. In this study, liver biopsies from 31 PBC patients and 15 healthy controls were collected, and comprehensive metabolomics, lipidomics, and proteomics analysis were conducted to characterize the metabolic landscape in PBC. We observed distinct lipidome remodeling in PBC with increased polyunsaturated fatty acid levels and augmented fatty acid β-oxidation (FAO), evidenced by the increased acylcarnitine levels and upregulated expression of proteins involved in FAO. Notably, PBC patients exhibited an increase in glucose-6-phosphate (G6P) and purines, alongside a reduction in pyruvate, suggesting impaired glycolysis and increased purines biosynthesis in PBC. Additionally, the accumulation of bile acids as well as a decrease in branched chain amino acids and aromatic amino acids were observed in PBC liver. We also observed an aberrant upregulation of proteins associated with ductular reaction, apoptosis, and autophagy. In conclusion, our study highlighted substantial metabolic reprogramming in glycolysis, fatty acid metabolism, and purine biosynthesis, coupled with aberrant upregulation of proteins associated with apoptosis and autophagy in PBC patients. Targeting the specific metabolic reprogramming may offer potential targets for the therapeutic intervention of PBC.

Persistently high concentrations of β-hydroxybutyrate affect hepatic SOD2 expression and blood SOD activity in high-yielding dairy cows

BackgroundElevated BHB levels are hypothesized to influence hepatic antioxidant enzyme expression and activity, contributing to oxidative response. However, the impact of BHB between 0.8 and 1.2 mmol/L on these mechanisms remains unclear. We hypothesized that elevated serum BHB levels would influence the hepatic expression of antioxidant genes (SOD1, SOD2, SOD3, and GPX3) and blood antioxidant enzyme activity, contributing to oxidative response. The primary objective was to evaluate the correlation between serum BHB levels, hepatic antioxidant gene expression, and blood antioxidant enzyme activity in high-yielding dairy cows during the postpartum period. The study involved 23 healthy high-yielding Holstein-Friesian dairy cows, divided into experimental (EXP, n = 12) and control (CONT, n = 11) groups based on serum BHB levels during the first three weeks postpartum. The EXP group maintained BHB levels between 0.8 and 1.2 mmol/L, while the CONT group remained below 0.8 mmol/L. All animals were monitored up to 9 weeks postpartum. This cohort study utilized weekly blood samples from 7 days prepartum to 9 weeks postpartum and liver biopsy samples from 4 to 7 weeks postpartum. Serum BHB concentrations, blood SOD and GSH-Px activities, and hepatic expression of SOD1, SOD2, SOD3, and GPX3 genes were analyzed.ResultsThe EXP group exhibited a significant increase in hepatic SOD2 expression at 4 weeks postpartum (p < 0.05) and higher blood SOD activity at 6 and 7 weeks postpartum compared to controls. This suggests an oxidative activity response to elevated BHB levels. By week 7, hepatic SOD2 expression began to normalize, indicating a transient response or adaptation. No significant changes were observed in hepatic SOD1, SOD3, or GPX3 expression between groups.ConclusionPersistently high serum BHB levels in postparturient dairy cows significantly impact hepatic SOD2 expression and blood SOD activity. The specificity of this response, primarily involving SOD2, highlights the complex interplay between metabolic changes and oxidative mechanisms during the transition period. These findings underline the importance of BHB concentration monitoring and suggest potential reevaluation of current BHB thresholds for identifying at-risk cows. Furthermore, SOD2 could potentially serve as an early biomarker.

Circulating metabolomic biomarkers of 5-year body weight and composition change in a biracial cohort of community-dwelling older adults.

Unintentional weight loss in older populations is linked to greater mortality and morbidity risks. This study aims to understand the metabolic mechanisms of unintentional weight loss and their relationship with body composition changes in older adults. We investigated plasma metabolite associations with weight and body composition changes over 5years in 1335 participants (mean age 73.4years at Year 1, 51% women, and 33% Black) from the Health, Aging and Body Composition (Health ABC) study. Multinomial logistic regressions were used to examine associations of the 442 metabolites with weight loss > 5% over 5years with/without an intention, weight gain > 5%, and fluctuating weight relative to weight stability. Metabolite associations with unintentional weight loss differed from other weight change patterns. Lower levels of essential amino acids, phospholipids, long-chain polyunsaturated triglycerides, cholesterol esters, and uridine were associated with higher odds of unintentional weight loss versus weight stability after adjusting for age, sex, race, and Year 1 BMI categories. Losses in fat mass and muscle mass each attenuated > 20% of the associations between many metabolites, such as phospholipids and essential amino acids, and unintentional weight loss. DXA whole-body fat mass loss (mean 3% annually) further attenuated 9 metabolite associations by > 50% after CT muscle loss (mean 2% annually) adjustment. Lipids and amino acids related to energy and protein balance were associated with unintentional weight loss in older adults. Fat and muscle mass losses partially attenuated these associations, suggesting connections of these metabolic pathways with muscle, and particularly adiposity dynamics.

Bioanalysis, Analysis, Chemistry, and Pharmacological Aspects of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

The development of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIFPHIs), such as Roxadustat (ROX), Enarodustat (ENA), Desidustat (DES), Vadadustat (VAD), Molidustat (MOL), and Daprodustat (DAP), has significant effects on anemia in chronic kidney disease. This review presents comprehensive information about the synthesis, pharmacology, and analysis of HIF-PHIs across several matrices. The literature has presented several approaches for quantifying HIF-PHIs in diverse sample matrices. Furthermore, HIF-PHIs exhibit similar modes of action, demonstrating distinct pharmacokinetic parameters. The pharmacological insights encompass their half-life, mechanism of action, absorption, distribution, metabolism, excretion, and therapeutic uses. Research indicates that most studies concentrate on hyphenated methodologies for drug estimation in various biological fluids. Consequently, this study assesses the biological efficacy of HIF-PHIs and elucidates the analytical methodologies currently employed for measurement across various matrices.

Fisetin Alleviates d-Galactose-Induced Senescence in C2C12 Myoblasts: Metabolic and Gene Regulatory Mechanisms.

Skeletal muscle aging poses a major threat to the health and quality of life of elderly individuals. Fisetin, a natural polyphenolic compound, exhibits various biological activities; however, its role in preventing skeletal muscle cell aging is still unclear. This study aimed to elucidate the effects of fisetin on skeletal muscle aging using a d-galactose-induced C2C12 myoblast senescence model. Fisetin treatment effectively ameliorated d-galactose-induced aging damage and restored cellular functionality by improving cell viability, reducing the accumulation of the senescence marker enzyme SA-β-gal, and decreasing the expression of key aging marker proteins, p16 and p53. NMR-based metabolomics and RNA-seq transcriptomics analyses revealed that fisetin regulates several critical metabolic pathways, including glutathione metabolism, glycine, serine and threonine metabolism, as well as taurine and hypotaurine metabolism. This regulation led to the restoration of amino acid metabolism, stabilization of cellular energy homeostasis, and the preservation of membrane integrity. In addition, fisetin inhibited calcium signaling and JAK-STAT pathways, reduced cellular stress responses and reversed senescence-induced cell cycle arrest. Together, these findings highlight the potential of fisetin as a therapeutic agent to combat skeletal muscle aging and restore cellular homeostasis, offering a promising avenue for the development of antiaging treatments for skeletal muscle degeneration.

Idebenone Protects Photoreceptors Impaired by Oxidative Phosphorylation Disorder in Retinal Detachment.

Oxidative phosphorylation (OXPHOS) is an aerobic metabolic mechanism, and its dysfunction plays an important role in the pathological changes of ischemic diseases. However, systematic studies on the occurrence of retinal detachment (RD) are lacking. Single-cell RNA sequencing (scRNA-seq) of the human retina was performed to detect the metabolic changes of various retinal cells after RD. In this study, animal experiments were conducted to explore the OXPHOS activity after RD. In addition, idebenone, a coenzyme Q10 (CoQ10) analog currently used to treat Leber hereditary optic neuropathy (LHON), was used to improve the OXPHOS disorder in experimental RD model. ScRNA-seq revealed abnormal energy metabolism and OXPHOS pathways in retinal cells after RD. Adenosine triphosphate (ATP) and reactive oxygen species (ROS) are the main products of OXPHOS, the mouse RD model indicated that the rise in ROS levels may have a greater impact on photoreceptors in the early stage, whereas decreased ATP synthesis was observed in the later stage; these changes threaten the function and morphology of the retina. Idebenone was administered to model mice intragastrically, leading to reduced ROS levels in the early stage post-RD and improved ATP synthesis in the later stage, which was closely related to the maintenance of mitochondrial morphology. OXPHOS disorder leads to photoreceptor degeneration after RD, which can be alleviated by improving OXPHOS function.