Dietary regulation in health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 23, 2022

Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan delaying ageing various species such as yeast, drosophila, rodent, primate human. It emerges develop precision-nutrition therapeutics slow age-related biological processes treat diverse diseases. However, nutritive advantages frequently diversify among individuals well organs tissues, which brings challenges this field. In review, we summarize different forms of dietary interventions extensively prescribed improvement disease treatment pre-clinical or clinical. We discuss nutrient-mediated mechanisms including metabolic regulators, metabolism pathways, epigenetic circadian clocks. Comparably, describe diet-responsive effectors by influence endocrinic, immunological, microbial neural states responsible improving health preventing multiple diseases humans. Furthermore, expatiate patterns dietotheroapies, fasting, calorie-restricted diet, ketogenic high-fibre plants-based protein restriction diet with specific reduction amino acids microelements, potentially affecting morbid states. Altogether, emphasize profound nutritional therapy, highlight crosstalk explored critical factors individualized therapeutic approaches predictors.

Language: Английский

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Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: May 27, 2022

Inflammation contributes to the poor prognosis of intracerebral hemorrhage (ICH). Intermittent fasting (IF) has been shown be protective against inflammation in multiple pathogenic processes. In present study, we aimed investigated beneficial effects IF attenuating neuroinflammation and neurological deficits a mouse model ICH investigate underlying mechanism.ICH was modeled by intrastriatal injection autologous blood every-other-day feeding male control mice (C57BL/6), with microglia specific knockout Sirt3f/f;Cx3cr1-Cre (Sirt3 cKO), Sirt3f/f (wild-type) mice. Brain tissues arterial were harvested at 1, 3, 7 28 days after for immunohistochemistry analysis Iba-1, DARPP-32 HO-1, morphological HE staining inflammatory factor release tests ELISA. Neurological functions approached corner test cylinder test. Fluorescent double-labeled Iba-1 CD16, Arg1 or Sirt3 used provide direct image co-expression these molecules microglia. TUNEL, cleaved caspase-3 Nissl performed evaluate cellular injuries.IF alleviated both acute chronic phases ICH. Morphologically, enhanced hematoma clearance, reduced brain edema phase attenuated striatum atrophy phase. addition, decreased numbers TUNEL+ cells increased Nissl+ neuron number day 3 suppressed CD16+Iba-1+ activation releases, such as IL-1β TNF-α. The above deletion partly because an inhibition Nrf2/HO-1 signaling pathway. Interestingly, Iba-1+ which mainly expressed while proinflammatory levels. microglia-specific deletion, on anti-inflammatory expressions when compared wild-type mice.IF protects suppressing responses via Sirt3/Nrf2/HO-1

Language: Английский

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Tubular cell senescence promotes maladaptive kidney repair and chronic kidney disease after cisplatin nephrotoxicity

JCI Insight, Journal Year: 2023, Volume and Issue: 8(8)

Published: March 14, 2023

Cisplatin is a widely used chemotherapy drug but it induces both acute and chronic kidney diseases (CKD) in cancer patients. The pathogenesis of cisplatin-induced CKD unclear effective renoprotective approaches are not available. Here, we report that repeated low-dose cisplatin (RLDC) treatment C57BL/6 mice induced cellular senescence tubules, accompanied with tubular degeneration pro-fibrotic phenotype transformation culminated maladaptive repair renal fibrosis. Suppression by senolytic drugs ABT-263 Fisetin attenuated fibrosis improved as indicated restoration regeneration function. In vitro, RLDC also mouse proximal BUMPT cells. eliminated senescent cells following treatment, reversed the increased their clonogenic activity. Moreover, alleviated paracrine effect RLDC-treated on fibroblasts for Consistently, knockdown p16 suppressed post-RLDC fibrotic changes cells, effects fibroblast proliferation. These results indicate persistent induction plays an important role promoting CKD. Targeting may be efficient to improve prevention

Language: Английский

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Efficacy and Safety of Phase 1 of Very Low Energy Ketogenic Therapy (VLEKT) in Subjects with Obesity and Mild Renal Impairment

Nutrients, Journal Year: 2025, Volume and Issue: 17(4), P. 721 - 721

Published: Feb. 18, 2025

Background: Obesity impairs renal function through direct mechanisms, such as proinflammatory adipocytokine production, and indirect including obesity-related comorbidities. Despite the increasing prevalence of obesity chronic kidney disease (CKD), clinical guidelines for their combined management remain lacking. Very Low Energy Ketogenic Therapy (VLEKT) has demonstrated efficacy in weight loss, but evidence on its safety individuals with mild impairment is limited. This study aimed to assess Phase 1 VLEKT impairment. Methods: cross-sectional included 73 overweight or (mean age 53.7 ± 8.8 years; BMI 35.3 4.2 kg/m2) an estimated glomerular filtration rate (eGFR) at least 60 mL/min/1.73 m2 (evaluated using CKD-EPI equation). Anthropometric (weight, BMI, waist circumference) biochemical parameters (fasting plasma glucose, insulin, cholesterol profile, triglycerides, AST, ALT, urea) were collected baseline after 45 (±2) days VLEKT. Results: At baseline, 54.8% participants had eGFR <90 m2, while 45.2% ≥ 90 no significant differences sex distribution. After VLEKT, both groups showed reductions (p < 0.001), circumference fasting glucose ≤ 0.004), insulin HOMA-IR total LDL LDL/HDL ratio 0.002), triglycerides 0.009), AST 0.034), ALT 0.009). Notably, significantly increased changes observed those m2. Conclusions: could effectively promote loss metabolic improvements without compromising function, even Further research warranted confirm outcomes across all protocol phases.

Language: Английский

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Podocyte Injury in Diabetic Kidney Disease: A Focus on Mitochondrial Dysfunction

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: March 7, 2022

Podocytes are a crucial cellular component in maintaining the glomerular filtration barrier, and their injury is major determinant development of albuminuria diabetic kidney disease (DKD). rich mitochondria heavily dependent on them for energy to maintain normal functions. Emerging evidence suggests that mitochondrial dysfunction key driver pathogenesis podocyte DKD. Impairment function results an crisis, oxidative stress, inflammation, cell death. In this review, we summarize recent advances molecular mechanisms cause damage illustrate impact podocytes. The related pathways involved DKD include dynamics mitophagy, biogenesis, phosphorylation protein quality control. Furthermore, discuss role mitochondria-associated membranes (MAMs) formation, which intimately linked with Finally, examine experimental exploring targeting treating conclude discussion potential directions future research field podocytes

Language: Английский

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Astragaloside IV attenuates podocyte apoptosis through ameliorating mitochondrial dysfunction by up-regulated Nrf2-ARE/TFAM signaling in diabetic kidney disease

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 203, P. 45 - 57

Published: April 6, 2023

Defective antioxidant system as well mitochondrial dysfunction contributes to the pathogenesis and progression of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related 2 (Nrf2)-mediated signaling is central defensive mechanism against oxidative stress therefore pharmacological activation Nrf2 a promising therapeutic strategy. In this study, using molecular docking we found that Astragaloside IV (AS-IV), an active ingredient from traditional formula Huangqi decoction (HQD), exerted higher potential promote escape Keap1-Nrf2 interaction via competitively bind amino acid sites in Keap1. When podocyte exposed high glucose (HG) stimulation, morphological alterations apoptosis were presented accompanied by transcription A (TFAM) downregulation. Mechanistically, HG promoted decrease mitochondria-specific electron transport chain (ETC) complexes, ATP synthesis mtDNA content increased ROS production. Conversely, all these defects dramatically alleviated AS-IV, but suppression with inhibitor or siRNA TFAM simultaneously AS-IV efficacy. Moreover, experimental mice exhibited significant renal injury disorder, corresponding decreased expression TFAM. On contrary, reversed abnormality also restored. Taken together, present findings demonstrate improvement on function, thereby resistance stress-induced apoptosis, process closely associated Nrf2-ARE/TFAM signaling.

Language: Английский

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The redox-sensitive GSK3β is a key regulator of glomerular podocyte injury in type 2 diabetic kidney disease

Redox Biology, Journal Year: 2024, Volume and Issue: 72, P. 103127 - 103127

Published: March 16, 2024

Emerging evidence suggests that GSK3β, a redox-sensitive transducer downstream of insulin signaling, acts as convergent point for myriad pathways implicated in kidney injury, repair, and regeneration. However, its role diabetic disease remains controversial. In cultured glomerular podocytes, exposure to milieu type 2 diabetes elicited prominent signs podocyte injury degeneration, marked by loss homeostatic marker proteins like synaptopodin, actin cytoskeleton disruption, oxidative stress apoptosis, stress-induced premature senescence, shown increased staining senescence-associated β-galactosidase activity, amplified formation γH2AX foci, elevated expression mediators senescence p21 p16INK4A. These degenerative changes coincided with GSK3β hyperactivity, evidenced overexpression reduced inhibitory phosphorylation were averted tideglusib, highly-selective small molecule inhibitor GSK3β. agreement, post-hoc analysis publicly-available transcriptomics dataset from patients nephropathy revealed the curated nephropathy-related gene set was enriched high group. Mechanistically, GSK3β-modulated nuclear factor Nrf2 signaling is involved podocytopathy, because knockdown reinforced antioxidant response suppressed stress, resulting an improvement senescence. Conversely, ectopic constitutively active mutant impaired augmented culminating exacerbated Moreover, IRS-1 found be cognate substrate at IRS-1S332, which negatively regulates activity. hyperactivity promoted phosphorylation, denoting desensitized signaling. Consistently, vivo db/db mice nephropathy, hyperactive associated hyperphosphorylation, Our finding likely novel therapeutic target treating injury.

Language: Английский

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Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes

Redox Biology, Journal Year: 2024, Volume and Issue: 71, P. 103104 - 103104

Published: Feb. 28, 2024

Spinal cord injury (SCI) is a devastating neurological disease that often results in tremendous loss of motor function. Increasing evidence demonstrates diabetes worsens outcomes for patients with SCI due to the higher levels neuronal oxidative stress. Mammalian sterile 20-like kinase (MST1) key mediator stress central nervous system; however, mechanism its action still not clear. Here, we investigated role MST1 activation induced both and diabetes. Diabetes was established mice by diet induction combined intraperitoneal injection streptozotocin (STZ). performed at T10 level through weight dropping. Advanced glycation end products (AGEs) were applied mimic diabetic conditions PC12 cell line vitro. We employed HE, Nissl staining, footprint assessment Basso mouse scale evaluate functional recovery after SCI. Moreover, immunoblotting, qPCR, immunofluorescence protein-protein docking analysis used detect mechanism. Regarding vivo experiments, resulted up-regulation MST1, excessive apoptosis weakened function mice. Furthermore, impeded NRF2-mediated antioxidant defense neurons damaged spinal cord. Treatment AAV-siMST1 could restore properties facilitate reactive oxygen species (ROS) clearance, which subsequently promoted survival improve locomotor recovery. In vitro model found AGEs worsened mitochondrial dysfunction increased cellular While inhibition chemical inhibitor XMU-MP-1 or MST1-shRNA infection restored NRF2 nuclear accumulation transcription downstream enzymes, therefore preventing ROS generation. However, these effects reversed knockdown. Our in-depth studies showed over-activation directly hindered neuroprotective AKT1, fostered ubiquitination degradation via GSK3β/β-TrCP pathway. significantly restores preexisting diabetes, largely attributed GSK3β(Ser 9)/β-TrCP/NRF2 may be promising pharmacological target effective treatment

Language: Английский

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The therapeutic potential of ketones in cardiometabolic disease: impact on heart and skeletal muscle

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 326(2), P. C551 - C566

Published: Jan. 9, 2024

β-Hydroxybutyrate (βOHB) is the major ketone in body, and it recognized as a metabolic energy source an important signaling molecule. While oxidation essential brain during prolonged fasting/starvation, other organs such skeletal muscle heart also use ketones substrates. Additionally, βOHB-mediated molecular events occur cells, via metabolism and/or signaling, may contribute to optimal health cardiac function. Of importance, when of for ATP production molecules becomes disturbed presence underlying obesity, type 2 diabetes, cardiovascular diseases, these changes cardiometabolic disease. As result disturbances disease, multiple approaches have been used elevate circulating with goal optimizing either or ketone-mediated signaling. These produced significant improvements disease wide range benefits that include improved metabolism, weight loss, better glycemic control, vascular function, well reduced inflammation oxidative stress. Herein, we present evidence indicates therapy could be approach help treat diseases by targeting muscles.

Language: Английский

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Cellular senescence and kidney aging

Clinical Science, Journal Year: 2023, Volume and Issue: 137(24), P. 1805 - 1821

Published: Dec. 1, 2023

Abstract Life expectancy is increasing worldwide, and by 2050 the proportion of world’s population over 65 years age estimated to surpass 1.5 billion. Kidney aging associated with molecular physiological changes that cause a loss renal function regenerative potential. As grows, it crucial understand mechanisms underlying these changes, as they increase susceptibility developing acute kidney injury (AKI) chronic disease (CKD). Various cellular processes pathways take part in complex process aging. In this review, we will focus on phenomenon senescence one involved at crossroad aging, age-related disease, CKD. We highlight experimental clinical findings about role addition, review challenges research emerging therapeutic aspects. great potential senolytic strategies for elimination harmful senescent cells promote healthy avoid This aims give insight into recent discoveries future developments, providing comprehensive overview current knowledge anti-senescent therapies field.

Language: Английский

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