Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 28, 2023

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates dramatically increasing incidence worldwide. This study provides novel insights into capacity exogenous β-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated activity colon weight-to-length ratio, improved macro microstructures damaged colon. Importantly, KD curbed DSS-induced aberrant NLRP3 inflammasome activation as observed mRNA protein expression analysis. Additionally, inhibition NLRP3/NGSDMD-mediated pyroptosis was detected response regimens. In parallel, these modalities caspase-1 its associated consequences IL-1β IL-18 overproduction. They also mitigated apoptosis indicated by inactivation caspase-3. The anti-inflammatory effects BHB were confirmed reported decline levels markers including MPO, NFκB, IL-6, TNF-α. Moreover, exhibited antioxidative properties reducing ROS production improving enzymes. Their effectiveness mitigating evident renovation normal intestinal epithelial barrier function, shown correcting discrepancies tight junction proteins ZO-1, OCLN, CLDN5. Furthermore, their on microbiota homeostasis investigated. terms autophagy, upregulated BECN-1 downregulated p62, which may account for superiority over attenuating colonic damage. conclusion, this experimental evidence supporting potential therapeutic use or β-hydroxybutyrate-boosting regimens UC.

Language: Английский

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Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice

Journal of Biomedical Science, Journal Year: 2024, Volume and Issue: 31(1)

Published: Jan. 23, 2024

Abstract Background CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, persistently high level of promotes longevity and ameliorates an age-related skin phenotype transgenic mice. Here we translate the genetic evidence into pharmaceutical application using potent activator, hesperetin, which enhances expression HEK001 human keratinocytes from older person. We also treated naturally aged mice order to study activator’s anti-aging efficacy. Methods studied biological effects hesperetin on aging using, firstly, cell-based platform, namely keratinocyte cell line established Secondly, used mouse model, old at 21-month old. In latter case, investigate efficacy ultraviolet B (UVB)-induced photoaging skin. identify underlying mechanisms potential pathways involved this process carried out transcriptomic analysis. Finally, knockdown Cisd2 knockout were Cisd2-dependent Results Four findings are pinpointed. Firstly , skin, mainly expressed proliferating epidermal basal layer and, furthermore, sun-exposed epidermis. Secondly person, mitochondrial function protects against reactive oxygen species-induced oxidative stress via increased expression; enhancement CISD2-dependent. Additionally, alleviates UVB-induced damage suppresses matrix metalloproteinase-1 expression, being major indicator keratinocytes. Thirdly analysis revealed that modulates panel differentially genes associated with function, redox homeostasis, inflammation attenuate senescence. Intriguingly, activates two known longevity-associated regulators, FOXO3a FOXM1, suppress senescence-associated secretory phenotype. Finally ameliorate occurs mechanism involving CISD2. Most strikingly, late-life treatment started lasting for 5 months, able retard rejuvenate Conclusions Our results reveal pharmacological elevation stage feasible approach effectively mitigating both intrinsic extrinsic could act as functional food or skincare product fighting

Language: Английский

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Unraveling the Effects of Uric Acid on Endothelial Cells: A Global Proteomic Study

Redox Biology, Journal Year: 2025, Volume and Issue: unknown, P. 103625 - 103625

Published: April 1, 2025

This work aims to understand how normouricemic levels of uric acid can induce endothelial dysfunction seeking global proteomic alterations in Human Umbilical Vein cells (HUVEC). It reveals significant redox-sensitive and antioxidant proteins, chaperones, proteins associated with cell migration adhesion response exposure. Monitoring cellular oxidation the roGFP2-Grx1 probe proved increased induced by acid, which be attenuated peroxidasin (PXDN) inhibition, suggesting a regulatory role for PXDN mitigating oxidative stress acid. As consequence formation reactive intermediate, we identified adducts (+140 kDa) novel post-translation modification named uratylation. Increased misfolded protein p62 aggregation were also found, indicating disturbances proteostasis. Furthermore, promoted monocyte upregulated ICAM VCAM levels, implicating pro-inflammatory cells. These findings provide critical insights into molecular mechanisms underlying vascular damage

Language: Английский

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Exosomal miR‐122, miR‐128, miR‐200, miR‐298, and miR‐342 as novel diagnostic biomarkers in NAFL/NASH: Impact of LPS/TLR‐4/FoxO3 pathway

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(4)

Published: Jan. 22, 2024

Abstract Nonalcoholic fatty liver disease (NAFLD) is a common disorder affecting quarter of the global residents. Progression NAFL into nonalcoholic steatohepatitis (NASH) may cause cirrhosis, cancer, and failure. Gut microbiota imbalance causes microbial components translocation circulation, triggering inflammation NASH‐related fibrosis. MicroRNAs (miRNAs) regulate gene expression via repressing target genes. Exosomal miRNAs are diagnostic prognostic biomarkers for NASH damage. Our work investigated role gut in NAFLD pathogenesis lipopolysaccharide/toll‐like receptor 4/Forkhead box protein O3 (LPS/TLR‐4/FoxO3) pathway certain as noninvasive or its development to NASH. miRNA levels were measured using quantitative reverse transcription polymerase chain reaction (qRT‐PCR) 50 patients, normal controls. Plasma LPS, TLR‐4, adiponectin, peroxisome proliferator‐activated γ (PPAR‐γ), FoxO3 concentrations enzyme‐linked immunosorbent assay (ELISA). In miR‐122, miR‐128, FoxO3, PPAR‐γ upregulated while miR‐200, miR‐298, miR‐342, adiponectin downregulated compared with control. The examined might distinguish patients from control receiver operating characteristic analysis. study first examine these NAFLD. findings imply that potentially promising early diagnosis progression. Understanding LPS/TLR‐4/FoxO3 involvement NAFL/NASH aid management.

Language: Английский

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Tissue‐Adhesive, Antibacterial, and Antioxidant Hydrogel Sealant for Sealing Colorectal Anastomotic Leakage and Preventing Postoperative Adhesion

Advanced Healthcare Materials, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Abstract Surgical treatment of colorectal diseases typically involves excising the diseased portion bowel and anastomosing remaining sections to reestablish continuity. suturing has limitations in preventing anastomotic leakage postoperative adhesion. To address these challenges, a tissue‐adhesive, antibacterial, antioxidant hydrogel is designed cover seal wounds. The formed situ by simply mixing oxidized hyaluronic acid, adipic acid dihydrazide‐modified ε‐poly‐ l ‐lysine, tannic acid. exhibits rapid gelation rate self‐healing ability. Compared with commercial fibrin glue, superior tissue‐adhesive strength wound sealing performance. displays potent reactive oxygen species scavenging ability antibacterial activity against both Gram‐positive Gram‐negative bacteria. also good biodegradation biocompatibility. In cecum‐abdominal wall adhesion model rats, attaches firmly injured tissues serves as physical barrier prevent formation. models after colon resection rats rabbits, effectively seals leakage, prevents adhesion, promotes healing. Thus, this multifunctional strong clinical potential for formation surgery.

Language: Английский

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Meta-Analytical and Meta-Regression Evaluation of Subclinical Hyperthyroidism's Effect on Male Reproductive Health: Hormonal and Seminal Perspectives

Reproductive Sciences, Journal Year: 2024, Volume and Issue: 31(10), P. 2957 - 2971

Published: Aug. 21, 2024

Language: Английский

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Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway

Experimental Eye Research, Journal Year: 2024, Volume and Issue: 244, P. 109919 - 109919

Published: May 8, 2024

Age-related macular degeneration (AMD) is the leading cause of vision loss among elderly, which primarily attributed to oxidative stress-induced damage retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered be one most promising for clinical application due their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) exosomes (hAMSC-exo) derived from hAMSC, as mediators intercellular communication, play an important role in treatment diseases, but effect mechanism on are not explored. Here, we reported that hAMSC-CM alleviated H

Language: Английский

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Multi-System-Level Analysis with RNA-Seq on Pterygium Inflammation Discovers Association between Inflammatory Responses, Oxidative Stress, and Oxidative Phosphorylation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4789 - 4789

Published: April 27, 2024

A pterygium is a common conjunctival degeneration and inflammatory condition. It grows onto the corneal surface or limbus, causing blurred vision cosmetic issues. Ultraviolet well-known risk factor for development of pterygium, although its pathogenesis remains unclear, with only limited understanding hereditary basis. In this study, we collected RNA-seq from both pterygial tissues (as controls) six patients (a total twelve biological samples) retrieved publicly available data, including eight samples controls. We investigated intrinsic gene regulatory mechanisms closely linked to reactions pterygiums compared Asian (Korea) European (Germany) using multiple analysis approaches different perspectives. The increased expression antioxidant genes in response oxidative stress DNA damage implies an association between these factors development. Also, our comparative revealed similarities differences pterygiums. decrease expressions involved three primary signaling pathways—JAK/STAT, MAPK, NF-kappa B signaling—suggests connection pathway dysfunction also observed relatively higher activity autophagy antioxidants group, while group exhibited more pronounced responses against stress. These could potentially be necessitated by energy-associated pathways, specifically phosphorylation.

Language: Английский

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Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 18, 2024

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring significant unmet therapeutic need. BMS-477118, reversible inhibitor dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical clinical studies with minimal adverse effects compared other antidiabetic agents. However, potential benefits BMS-477118 UC have not yet been explored. In this study, we aimed investigate rats subjected dextran sodium sulfate (DSS) administration. Our findings indicate that activates interconnected positive feedback loop involving AMPK, SIRT1, FOXO3a, improving histological appearance injured rat colons. also reduced fibrotic changes associated nature animal model, alleviated macroscopic damage severity, improved colon weight-to-length ratio. Additionally, prevented DSS-induced weight loss enhanced tight junction proteins. These effects, conjunction oxidative stress its anti-inflammatory, antiapoptotic, autophagy-inducing properties, fostered prolonged survival UC. To conclude, activate AMPK/SIRT1/FOXO3a signaling pathway inflamed results suggest could be new target for Further research mandatory explore possibilities pathway. continued on DPP4 inhibitors are promising creating treatments conditions, including diabetic patients.

Language: Английский

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Gengnianchun Against H₂O₂‐Induced Oxidative Damage in KGN Cells via miR‐548m/FOXO3 Signaling

Journal of Cellular Biochemistry, Journal Year: 2025, Volume and Issue: 126(1)

Published: Jan. 1, 2025

ABSTRACT Gengnianchun (GNC) is a traditional remedy used for diminished ovarian reserve, but its underlying mechanisms remain unclear. This study aimed to explore these in human granulosa‐like cancer (KGN) cells pretreated with medicated rat serum (MRS) before H 2 O exposure. MRS pretreatment significantly alleviated ‐induced cell damage, including improvements viability, superoxide dismutase and GSH‐Px activities, Bcl‐2 expression. Conversely, treatment increased apoptosis, autophagosomes, IL‐1β, TNF‐α, reactive oxygen species, malondialdehyde levels, the expression of LC‐II/LC3‐I, Bax, Beclin‐1. GEO database analysis revealed significant differential several miRNAs, miR‐548m. qPCR confirmed that upregulated miR‐548m expression, which was downregulated by dose‐dependent manner. Preincubation prevented decline mitigated autophagy, oxidative stress. suppressed FOXO3 3'‐UTR luciferase activity, anti‐miR‐548m enhanced it. Transfection reduced mRNA protein while them. These findings suggest GNC protects against damage modulating miR‐548m/FOXO3 axis, triggering autophagy apoptosis.

Language: Английский

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