Impaired Metabolism Research Articles

Comparison of silver nanoparticles and AgNO<sub>3</sub> toxic effects on <i>Caenorhabditis elegans</i> with a genetic disorder of copper metabolism

BACKGROUND: Silver nanoparticles are widely used in various types of industry, but their safety for humans has not been strictly proven. The experimental data currently available on the comparison of the toxic effect of silver nanoparticles and AgNO3 are contradictory and the question of the priority use of silver nanoparticles remains open, especially for organisms with impaired copper metabolism. AIM: The main aim of this study is to compare the effects of silver nanoparticles and AgNO3 on the nematode with normal and impaired copper metabolism and draw conclusions about their toxicity. MATERIALS AND METHODS: In this work, we determined the sublethal concentration (LC50) of AgNPs and AgNO3 for H828Q nematode strain. Using the results obtained, we performed the development assay, thrashing assay and lifespan analysis of the animals. RESULTS: It has been shown that LC50 of silver nanoparticles is lower than the one for AgNO3. Caenorhabditis elegans with impaired copper metabolism treated with silver nanoparticles have a statistically significant reduction in development, level of mobility and lifespan, comparing to animals treated with AgNO3. CONCLUSIONS: The results obtained allow us to conclude that the toxic effect of silver nanoparticles on C. elegans with a genetic defect in copper metabolism is higher comparing to ionic silver.

Management of Glucocorticoid-Induced Hyperglycemia in Cancer Patients: A Feasibility Study.

Glucocorticoids are commonly used in the management of patients with hematological and solid malignancies. However, their use may be associated with impaired glycemic metabolism and increased treatment-related morbidity and mortality. This study aimed to examine the feasibility and acceptability of a nurse-led model of care (MOC) for screening and managing glucocorticoid-induced hyperglycemia (GIH) in non-diabetic patients requiring high-dose glucocorticoid (HDG) therapies, as well as patients' and health professionals' experiences with the MOC. This study was a single-site feasibility study. Patients with hematological or oncological malignancies who were >18 years of age, receiving a chemotherapy regimen including HDGs, had no prior diagnosis of diabetes or prediabetes, and were not at the end of life were considered eligible for this study. Participants were recruited from a district hospital's Cancer Centre in Australia. All consenting participants were screened for diabetes and were provided with a blood glucose meter to monitor their blood glucose levels (BGLs) four times a day on the days of glucocorticoid therapy (GT) plus one extra day following GT, for the first four cycles of their treatment, to screen for the presence of GIH. Feasibility and acceptability were assessed using rates of consent, study completion, and staff and patient surveys. Forty-eight percent (35/74) of patients approached consented to participate in the study and had screening tests for preexisting diabetes. None were diagnosed with diabetes. Six out of 35 patients withdrew, and 10/29 patients did not complete the recommended BGL monitoring. Thirteen percent (4/29) of patients developed GIH. The most common reasons for non-participation and study withdrawal were related to the self-monitoring of BGLs. While clinical stakeholders found the MOC feasible and acceptable, the results of this study suggest that alternative methods for encouraging self-monitoring of BGL and monitoring the presence of GIH during high-dose chemotherapy need to be explored to address issues associated with adherence and sustainability.

Impact of allogenic Fecal Microbiota Transplantation (FMT) on lipid parameters in patients with metabolic syndrome (MetS): a meta-analysis

Abstract Background Metabolic Syndrome (MetS) has long been considered a formidable global health concern, and impaired lipid metabolism has been one of its crucial clinical manifestations. Fecal Microbiota Transplantation (FMT) has emerged as a potential therapeutic strategy for MetS, nevertheless, prior meta-analyses have not only yielded conflicting outcomes, but as well predominantly centered on glycemic parameters, leaving the potential impact of FMT on lipid metabolism remained unexplored. Purpose This meta-analysis systematically assessed the influence of allogenic FMT on lipid parameters in MetS patients, unraveling its potential as an innovative therapeutic modality for MetS. Methods A meta-analysis was performed to explore the impact of allogenic FMT on lipid parameters (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TCHO] and triglycerides [TG]) in patients with MetS. Terms regarding FMT and metabolic syndrome were searched in PubMed/Medline, EMBASE, Web of Science, the Cochrane Library, and Scopus from the inception of the databases until 31 August 2023. Ten randomized controlled trials (RCTs) were included and mean difference (MD) of parameters were pooled using a fixed effects model. Subgroup analyses according to follow-up durations were performed, and this study was registered in PROSPERO. Results A total of 532 patients in 10 studies were included. Patients undergoing allogenic FMT manifested significantly higher HDL-c level compared with control group (receiving placebo or autologous FMT, pooled MD 0.06 [95% CI: 0.02, 0.10]), and the result remained consistent in the subgroup with 4 to 6 weeks of follow-up (MD 0.07 [95% CI: 0.02, 0.10]). Though overall pooled result did not manifest a significant LDL lowering effect (MD -0.08 [95% CI: -0.21, 0.05]), in subgroup analyses, a significantly lowered LDL level was observed at 12 weeks of follow-up (MD -0.34 [95% CI: -0.60, -0.08]). No significant difference was observed between allogenic FMT and control group concerning TCHO ant TG levels regardless of lengths of follow-up. Conclusions An overall higher level of HDL-C and lowered LDL-C at 12 weeks of follow-up was observed in MetS patients receiving allogenic FMT. The results indicated that gut microbiota from lean, healthy donors may display a beneficial effect on modulating lipid metabolism in patients with MetS. Allogenic FMT manifested promising therapeutic impact and could serve as a viable intervention for MetS patients. Future large-scale RCTs are required for further validation.

Fenofibrate modulates cardiac energy metabolism in moderate-severe aortic stenosis: a mechanistic double-blinded randomised controlled MR trial

Abstract Background Aortic stenosis (AS) is associated with impaired cardiac metabolism and high-energy phosphate production which can further exacerbate the progression to HF. Myocardial lipid accumulation and reduced production of high-energy phosphates have important implications for both systolic and diastolic heart function in AS. Peroxisome proliferator-activated receptor alpha (PPAR-alpha agonist, has the potential to optimise cardiac substrate metabolism, thereby, may be effective in improving cardiac dysfunction and functional capacity in AS. Methods In this prospective, randomized, double-blind, placebo-controlled study, patients with moderate-to-severe asymptomatic AS (n=72) were randomly assigned to Fenofibrate 200 mg daily or matching placebo for 6 months in 4:1 fashion. Of the total 72 participants, 59 received Fenofibrate and 13 received placebo. All subjects underwent cardiac magnetic resonance (CMR) and exercise testing at 0 and 6 months, with follow-up data available in 47 patients. The primary end point was change in myocardial triglyceride content (MTG) determined by proton magnetic resonance spectroscopy (1H-MRS). Secondary outcome measures included change in cardiac energetics (PCr/ATP) determined by phosphorus magnetic resonance spectroscopy (31P-MRS), left ventricular strain determined by myocardial tagging and exercise capacity i.e. peak VO2 assessment via cardiopulmonary exercise testing. Results Cardiac energetics (PCr/ATP) showed statistically significant improvement in the Fenofibrate group (0.14 ± 0.48; CI: - 0.03, 0.30; p=0.05) vs placebo group (0.11 ± 0.75; CI -0.42, 0.65; p=0.64). There was also significant reduction in MTG in the Fenofibrate group (mean change -0.40 ± 0.97; 95% CI -0.74, -0.06; p=0.02). MTG content also reduced in the placebo group (mean change -0.41 ± 0.26, 95% CI -1.10, 0.18, p 0.13), but the reduction was not statistically significant. Though no significant changes were seen in the systolic function parameters, there was a significant improvement in diastolic function in the fenofibrate group only (peak diastolic longitudinal strain rate 9.6, 95% CI: 1.13, 18.1; p = 0.02). Peak VO2 did not show any significant improvement in either group. Conclusions Fenofibrate works as a metabolic modulator upregulating fatty acid metabolism in pressure overload AS hearts. Such modulation is associated with an improvement in cardiac energetics and diastolic function in moderate-severe AS.Main results from baseline to 6 monthsBaseline demographic and CMR parameters

Functional analysis of the extraplastidial TRX system in germination and early stages of development of Arabidopsis thaliana

A series of processes occur during seed formation, including remarkable metabolic changes that extend from early seed development to seedling establishment. The changes associated with processes initiated mainly after seed imbibition are usually characterized by extensive modification in the redox state of seed storage proteins and of pivotal enzymes for reserve mobilization and usage. Such changes in the redox state are often mediated by thioredoxins (TRXs), oxidoreductase capable of catalyzing the reduction of disulfide bonds in target proteins to regulate its structure and function. Here, we analyzed the previously characterized Arabidopsis mutants of NADPH-dependent TRX reductase types A and B (ntra ntrb), two independent mutant lines of mitochondrial thioredoxin o1 (trxo1) and two thioredoxin h2 (trxh2) mutant lines. Our results indicate that plants deficient in the NADPH dependent thioredoxin system are able to mobilize their reserves, but, at least partly, fail to use these reserves during germination. TRX mutants also show decreased activity of regulatory systems required to maintain redox homeostasis. Moreover, we observed reduced respiration in mutant seeds and seedlings, which in parallel with an impaired energy metabolism affects core biological processes responsible for germination and early development of TRX mutants. Together, these findings suggest that the lack of TRX system induces significant change in the respiration of seeds and seedlings, which undergo metabolic reprogramming to adapt to the new redox state.

Dual inhibition of SGLT 1 and 2 alleviates intracellular sodium overload in uraemic cardiomyopathy

Abstract Background Chronic kidney disease (CKD) is a leading cause of mortality with the risk of developing cardiovascular disease higher than progression to kidney failure. The aetiology of uraemic cardiomyopathy is multifactorial and includes metabolic derangement. It was previously shown that elevated intracellular sodium (Nai) is causally linked to cardiac metabolic impairment and that targeting sodium homeostasis can reprogramme cardiac metabolism. Dual inhibition of sodium-glucose co-transporters (SGLT) 1 and 2 is an emerging therapy for CKD, however the impact on intracellular sodium and cardiac metabolism is yet to be elucidated. Purpose This study aimed to assess whether dual SGLT1/2 inhibitor sotagliflozin impacts cardiometabolic phenotype in CKD. Methods CKD was surgically induced by 5/6 nephrectomy in Wistar rats (n=46) for a period of 4 weeks, with chronic sotagliflozin treatment (5mg/kg) given for the last 3 weeks. Upon termination, hearts were Langendorff-perfused and studied using 31P and 23Na NMR spectroscopy (Sham n=7, CKD n=6, CKD+sotagliflozin n=5). To assess the cardiac-specific effect of the drug, acute sotagliflozin treatment (30mM) was delivered in the Langendorff perfusate to an additional group of CKD hearts (n=5). Furthermore, the effect of chronic sotagliflozin treatment on in vivo cardiac function (echocardiography n=23) and metabolic profile (1H NMR spectroscopy n=15) was assessed. Results CKD animals were characterized by significant renal dysfunction (2-fold increase in urea and creatinine vs sham, p<0.05), and HFpEF (EF(%) sham 82±2 vs CKD 80±1 p>0.05; diastolic dysfunction (E/A) sham 1.39±0.03 vs CKD 1.11±0.01, p=0.0018). Myocardial Nai was significantly elevated in CKD animals compared to sham controls (TQF 23Na 3.04±0.18 vs 2.01±0.32 arb units, p=0.03). Chronic sotagliflozin treatment didn’t impact renal or cardiac dysfunction. Neither chronic nor acute drug treatment impacted baseline CKD cardiac energetics (PCr/ATP sham 1.53±0.22, CKD 1.25±0.13, chronic 1.16±0.14, acute 1.18±0.13, p>0.05; ΔGATP (kJ/mol) sham -64±4, CKD -66±8, chronic -56±1, acute -59±3, p>0.05). However, both chronic and acute sotagliflozin treatment normalised the increased myocardial Nai (TQF 23Na chronic 2.17±0.12, acute 2.23±0.14 arb units, p>0.05 vs sham). Chronic drug dosing altered the systemic metabolic profile of CKD animals reducing the levels of circulating triglycerides and FFA (p<0.05) as well as altering metabolomic profile of liver, muscle and kidneys. Conclusion(s) We have shown that uraemic cardiomyopathy is characterised by HFpEF, elevated myocardial Nai and altered systemic metabolic profile. Both chronic and acute treatment with dual SGLT1/2 inhibitor sotagliflozin normalised myocardial Nai. The alleviation of Nai load could lead to improved cardiometabolic outcomes in CKD.

The Relationship Between Ghrelin and Iron Metabolism In Beta Thalassemia Major Patients

IntroductionStudies in beta thalassemia major (β-TM) patients have shown that the responses of HIF2α, hepcidin and ferroportin molecules to high iron levels are impaired. In recent years, studies conducted in patients with iron deficiency anemia have investigated the relationship between ghrelin hormone and iron metabolism. In this study, we aimed to contribute to the etiopathogenesis of this disease by examining the changes in ghrelin hormone levels in patients with β-TM.Material and methodsFifty-two β-TM and 23 controls were included in our study. Blood counts, routine biochemical parameters, HIF2α, hepcidin and ghrelin levels were studied in blood samples taken from the volunteers.ResultsErythrocyte indexes, serum bilirubin, iron, unsaturated iron binding capacity, total iron binding capacity and ferritin levels showed significant differences between two groups (p<0.05) . There was no significant difference between two groups for serum HIF2α and hepcidin levels. When two groups were compared, ghrelin levels were found to be significantly higher in patients (p<0.05). When the correlation between parameters was examined in all subjects, a weak positive correlation was found between ghrelin and HIF2α (r=0.263) (p<0.05) and a significant positive correlation was found between ghrelin and ferritin (r=0.417) (p<0.05).ConclusionsOur study showed that there is a positive correlation between ghrelin and ferritin levels. Elevated ghrelin levels in patients with β-TM may have an important role in regulating impaired iron metabolism. Molecular level studies are needed to determine synthesis pathways.

Evaluation of metabolic and haematological impacts of light-at-night exposure on adult male Wistar rats under sleep restriction condition.

Health implications of shift work could not be completely due to exposure to light-at-night (LAN). This study evaluated metabolic and haematological impacts of LAN exposure on adult male Wistar rats under sleep restriction condition. The animals were grouped into control (n=8) and LAN exposed (n=8) groups. The controls were sleep restricted (SR) by gentle handling. In addition to SR, the LAN exposed group were exposed to LAN during the first five hours of scotophase for six weeks. Body weight, fasting blood glucose, lipid profile, full blood counts, CD4+ cells, malondialdehyde, superoxide dismutase and catalase were all assessed using their respective protocols. Statistical Package for Social Sciences (SPSS Version 20) was used to analyze and Mean±SEM was used to analyze and summarize the data. Intergroup differences were investigated using Student’s t-test and p≤ 0.05 was considered statistically significant. The results have shown that LAN-exposed rats eat less and have gained more body weight than controls. LAN-exposed rats also had higher fasting blood glucose. On the contrary, there is no statistical difference between the two groups for markers of oxidative stress, triglyceride-glucose index, high-density lipoprotein, and atherogenic index of plasma. In conclusion, the present study has shown that LAN exposure could cause metabolic and hematological impairments in sleep-restricted, Wistar rats. Hence, it might predispose exposed subjects to obesity, diabetes mellitus and adverse cardiovascular events.

Ferroptosis Inhibition Combats Metabolic Derangements and Improves Cardiac Function in Pulmonary Artery Banded Pigs.

Right heart failure (RHF) is a leading cause of mortality in multiple cardiovascular diseases and preclinical and human data suggest impaired metabolism is a significant contributor to right-sided cardiac dysfunction. Ferroptosis is a nonapopotic form of cell death driven by impaired metabolism. Rodent data suggests ferroptosis inhibition can restore mitochondrial electron transport chain function and enhance cardiac contractility in left heart failure models, but the effects of ferroptosis inhibition in translational large animal models of RHF are unknown. Here, we showed ferrostatin-1 mediated ferroptosis antagonism improve right heart structure and function in pulmonary artery banded pigs. Molecularly, ferrostatin-1 restored mitochondrial cristae structure and combatted downregulation of electron transport chain proteins. Metabolomics and lipidomics analyses revealed ferrostatin-1 improved fatty acid metabolism. Thus, these translational data suggest ferroptosis may be a therapeutic target for RHF.

Metabolic dysfunction-associated steatotic liver disease-induced changes in the antioxidant system: a review.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

Influence of major hepatectomy on gemcitabine-based chemotherapy for recurrent biliary tract cancer after surgery: a subgroup analysis of JCOG1113.

Major hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC. Of the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed. Grade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms. The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring

Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females. These findings underscore the persistent influence of maternal obesity on the offspring's health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.

Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover

Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic signatures are indicative of defects in lysosomal function and abnormal lipid metabolism. Consistent with these findings, CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Accordingly, we also observe impaired myelin integrity in aged Cln3∆ex7/8 mouse brain. Autophagy inducers and cholesterol-lowering drugs correct the observed microglial phenotypes. Taken together, these data implicate a cell-autonomous defect in CLN3-deficient microglia that impacts their ability to support neuronal cell health, suggesting microglial targeted therapies should be considered for CLN3 disease.

Liver damage in galactosemia type I: a literary review

Galactosemia is a rare hereditary disease associated with impaired galactose metabolism, which is characterized by a wide range of clinical syndromes. Most long-term observations are devoted to the study of neurological, ophthalmological and reproductive disorders. Liver damage in galactosemia is one of the central manifestations of the disease, determining the severity and prognosis of the disease, mainly in the neonatal period. The lack of timely dietary correction in the neonatal period leads to severe liver damage with the development of cirrhosis, portal hypertension and liver failure. An information search has shown that prolonged and catamnestic studies on the condition of the liver in children with various variants of galactosemia, in particular, against the background of dietary correction, are few. Most studies show significant reversibility of hepatopathy on the background of diet (even with severe manifestation), however, the number of such publications is not large and the issue requires further research.

The risks and benefits of managing obesity in older adults.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. This review discusses weight loss considerations in overweight and obese older adults. Current US guidelines do not address weight loss in older adults. Waist circumference rather than body mass index (BMI) may be a more accurate assessment tool for obesity in older adults. Weight loss interventions are not recommended in overweight older adults due to the decreased mortality in this population (known as the "obesity paradox"). While weight loss in obese older adults may be beneficial, it is not without risks. The greatest risks include loss of muscle mass, decline in bone mineral density, and development of sarcopenic obesity. Weight loss interventions may be considered in older adults with a BMI of greater than 30kg/m2 who have metabolic derangements, cardiovascular disease, and/or functional impairments after carefully weighing the risks against the benefits of weight loss and the impact of interventions on the patient's quality of life. Medicare provides limited benefits for weight loss interventions. In older adults, there is no consensus on which lifestyle interventions are best for weight loss and there is a paucity of data on the use of weight loss medications. Careful consideration should be given before utilizing medications for weight loss in older adults given the enhanced adverse effect profiles, interactions, contraindications, and costs. Weight loss in older adults should be approached differently from that in the general adult population. More data are needed on the efficacy and safety of weight loss medications in older adults.

Retinal pigment epithelium-specific ablation of GPx4 in adult mice recapitulates key features of geographic atrophy in age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population, particularly the late-stage of dry AMD known as geographic atrophy (GA), lacks effective treatment options. Genetic mouse models of AMD have revealed the significance of impaired lipid metabolism and anti-oxidative capacity in early/intermediate stage of AMD, but remains unclear in GA that severely damages visual function. Here, to investigate the potential relevance of peroxidized lipids in RPE for late-stage dry AMD, GPx4fl/fl mice underwent subretinal injections of RPE-specific AAV-Cre vector or control AAV vector. RPE-specific GPx4 deficiency led to rapid RPE degeneration resembling key features of late-stage dry AMD, including preceding loss of RPE cell polarity, accumulation of acrolein, malondialdehyde, and 4-hydroxynonenal, photoreceptor loss, lipofuscin-laden subretinal melanophage infiltration, and complement activation. Treatment with α-tocopherol and ferrostatin-1 mitigated RPE degeneration, and shrunk mitochondria were observed in GPx4 deficient mice, suggesting involvement of ferroptosis. Unexpectedly, necrostatin-1s, an inhibitor of necroptosis, also ameliorated RPE degeneration, and activation of RIP3 and MLKL along with inactivation of caspase-8 was observed, indicating crosstalk between ferroptosis and necroptosis pathways. Our findings shed light on the intricate mechanisms underlying RPE degeneration in AMD and highlight GPx4/lipid peroxidation as potential therapeutic targets. RPE-specific ablation of GPx4 in mice provides a valuable tool for further elucidating the interplay between lipid peroxidation, cell death pathways, and AMD pathogenesis, offering new insights for preclinical research and therapeutic development targeting GA.

Nr-CWS regulates METTL3-mediated m6A modification of CDS2 mRNA in vascular endothelial cells and has prognostic significance

Metabolic memory (MM) is a major factor in the delayed wound healing observed in diabetic patients. While “Nocardia rubrum cell wall skeleton” (Nr-CWS) is utilized to enhance macrophage proliferation in immune diseases, its impact on MM wounds in diabetes is unclear. This study demonstrates that transient hyperglycemia leads to prolonged damage in vascular endothelial cells by decreasing METTL3 expression, leading to decreased RNA methylation and impaired cellular metabolism. Remarkably, Nr-CWS application increases METTL3 levels in these cells, facilitating the recovery of cell function. Further in vivo and in vitro analyses demonstrate that transient hyperglycemia-induced reduction in METTL3 hinders RNA methylation of the downstream gene Cds2, impacting mitochondrial function and energy metabolism and consequently reducing angiogenic capacity in endothelial cells. This impairment significantly influences diabetic wound healing. Our findings highlight the profound impact of transient hyperglycemia on wound healing, establishing METTL3 as a significant role in vascular complications of diabetes. This study not only elucidates the pathophysiological mechanisms behind MM in diabetic wounds but also suggests Nr-CWS as a potential therapeutic agent, offering a novel approach for treating diabetic wounds.

Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension.

Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined. Multiomics and physiological analyses evaluated how ferroptosis inhibition-modulated preclinical PAH. The impact of adeno-associated virus 1-mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension. Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage-associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1-Acsl4 induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository. Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.

Selenium nanoparticles ameliorate lumbar disc degeneration by restoring GPX1-mediated redox homeostasis and mitochondrial function of nucleus pulposus cells

Intervertebral disc degeneration (IVDD) is a prevalent musculoskeletal disorder that involves the excessive accumulation of reactive oxygen species (ROS), resulting in mitochondrial dysfunction and matrix metabolism imbalance in nucleus pulposus cells (NPCs). Selenium, an indispensable trace element, plays a crucial role in maintaining mitochondrial redox homeostasis by being incorporated into antioxidant selenoproteins as selenocysteine. In this study, we employed a straightforward synthesis method to produce selenium nanoparticles (SeNPs) with consistent size and distribution, and evaluated their potential protective effects in ameliorating IVDD. In a simulated inflammatory environment induced by interleukin-1beta (IL-1β) in vitro, SeNPs demonstrated a protective effect on the matrix synthesis capacity of NPCs through the up-regulation of aggrecan and type II collagen, while concurrently suppressing the expression of matrix degradation enzymes including MMP13 and ADAMTS5. Additionally, SeNPs preserved mitochondrial integrity and restored impaired mitochondrial energy metabolism by activating glutathione peroxidase1 (GPX1) to rebalance redox homeostasis. In a rat lumbar disc model induced by puncture, the local administration of SeNPs preserved the hydration of nucleus pulposus tissue, promoted matrix deposition, and effectively mitigated the progression of IVDD. Our results indicate that the enhancement of GPX1 by SeNPs may offer a promising therapeutic approach for IVDD by restoring mitochondrial function and redox homeostasis.

Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice.

Aging, an independent risk factor for cardiometabolic diseases, refers to a progressive deterioration in physiological function, characterized by 12 established hallmarks. Vascular aging is driven by endothelial dysfunction, telomere dysfunction, oxidative stress, and vascular inflammation. This study investigated whether aged gut microbiome promotes vascular aging and metabolic impairment. Fecal microbiome transfer (FMT) was conducted from aged (>75 weeks old) to young C57BL/6 mice (8 weeks old) for 6 weeks. Wire myography was used to evaluate endothelial function in aortas and mesenteric arteries. ROS levels were measured by dihydroethidium (DHE) staining and lucigenin-enhanced chemiluminescence. Vascular and intestinal telomere function, in terms of relative telomere length, telomerase reverse transcriptase expression and telomerase activity, were measured. Systemic inflammation, endotoxemia and intestinal integrity of mice were assessed. Gut microbiome profiles were studied by 16S rRNA sequencing. Some middle-aged mice (40-42 weeks old) were subjected to chronic metformin treatment and exercise training for 4 weeks to evaluate their anti-aging benefits. Six-week FMT impaired glucose homeostasis and caused vascular dysfunction in aortas and mesenteric arteries in young mice. FMT triggered vascular inflammation and oxidative stress, along with declined telomerase activity and shorter telomere length in aortas. Additionally, FMT impaired intestinal integrity, and triggered AMPK inactivation and telomere dysfunction in intestines, potentially attributed to the altered gut microbial profiles. Metformin treatment and moderate exercise improved integrity, AMPK activation and telomere function in mouse intestines. Our data highlight aged microbiome as a mechanism that accelerates intestinal and vascular aging, suggesting the gut-vascular connection as a potential intervention target against cardiovascular aging and complications.