Type 2 Diabetes Mellitus, Non-Alcoholic Fatty Liver Disease, and Metabolic Repercussions: The Vicious Cycle and Its Interplay with Inflammation

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9677 - 9677

Published: June 2, 2023

The prevalence of metabolic-related disorders, such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (DM2), has been increasing. Therefore, developing improved methods for the prevention, treatment, detection these two conditions is also necessary. In this study, our primary focus was on examining role chronic inflammation a potential link in pathogenesis diseases their interconnections. A comprehensive search PubMed database using keywords "non-alcoholic disease", "type mellitus", "chronic inflammation", "pathogenesis", "progression" yielded 177 relevant papers analysis. findings study revealed intricate relationships between NAFLD DM2, emphasizing crucial inflammatory processes. These connections involve various molecular functions, including altered signaling pathways, patterns gene methylation, expression related peptides, up- downregulation several genes. Our foundational platform future research into relationship allowing better understanding underlying mechanisms introducing new treatment standards.

Language: Английский

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Gallic Acid-Modified Polyethylenimine–Polypropylene Carbonate–Polyethylenimine Nanoparticles: Synthesis, Characterization, and Anti-Periodontitis Evaluation

ACS Omega, Journal Year: 2024, Volume and Issue: 9(12), P. 14475 - 14488

Published: March 15, 2024

The aim of the research was to develop novel gallic acid (GA)-modified amphiphilic nanoparticles polyethylenimine (PEI)–polypropylene carbonate (PPC)–PEI (PEPE) and comprehensively assess its properties as an antiperiodontitis nanoparticle targeting Toll-like receptor (TLR). first step is evaluate binding potential GA core trigger receptors TLR2 TLR4/MD2 for periodontitis using molecular docking techniques. Following this, we conducted NMR, transmission electron microscopy, dynamic light scattering analyses on synthesized PEPE nanoparticles. As final step, investigated synthetic results in vitro GA-PEPE investigation revealed that exhibits targeted complex. Furthermore, successfully developed 91.19 nm positively charged Spectroscopic analysis indicated successful synthesis GA-modified PEPE. Additionally, CCK8 demonstrated modification significantly reduced biotoxicity assessment illustrated 6.25 μM expression pro-inflammatory factors TNF-α, IL-1β, IL-6. nanoparticles, with their TLR capabilities, were found possess excellent biocompatibility properties. will provide highly innovative input into development anti-

Language: Английский

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Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 276, P. 116317 - 116317

Published: April 13, 2024

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism polarization is unclear. Recent studies TLR9 an important regulatory polarization. In present study, we demonstrated elevated levels oxidative stress hepatocytes mediate release mtDNA into bloodstream, leading to macrophages regulate vivo experiments revealed pretreatment with SS-31, mitochondria-targeting antioxidant peptide, reduced level hepatocytes, decrease release. Importantly, SS-31 inhibited macrophages, suggesting hepatocyte may activate macrophages. Further pharmacological inhibition by ODN2088 partially blocked activation, dependent on activation. vitro involving extraction from TCE-sensitized mice treated RAW264.7 cells further confirmed can mouse peritoneal summary, our study comprehensively released and regulating These findings reveal injury provide new perspectives therapeutic targets for treatment OMDT-induced injury.

Language: Английский

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Linking nutrient sensing, mitochondrial function, and PRR immune cell signaling in liver disease

Trends in Immunology, Journal Year: 2022, Volume and Issue: 43(11), P. 886 - 900

Published: Oct. 7, 2022

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic hepatic steatohepatitis (NASH) are on the rise, therapeutics to successfully target these detrimental conditions very limited.Nutrient-induced lipid overload across cells in mammalian contributes mitochondrial dysfunction, producing damage-associated molecular patterns (DAMPs) that initiate hepatosteatosis.Pattern recognition receptors (PRRs) integrate perturbations into proinflammatory cellular behavior parenchymal immune cells, supporting NAFLD pathogenesis progression NASH.Intracellular components of canonical PRR system, complement (the complosome), operate a range humans mice, may contribute NAFLD/NASH pathogenesis.Pharmacologically targeting nutrient–mitochondria–PRR pathways, including intracellularly active complement, might lead new putative treatments. The mechanistic understanding recently identified functional interplay between nutrient sensing, activity, classic PRR, intracellular activation cell populations help uncover novel therapeutic intervention targets treat disease. Caloric overconsumption vertebrates promotes adipose fat accumulation while perturbing gut microbiome. This triad triggers pattern receptor (PRR)-mediated signaling sterile inflammation. Moreover, system perpetuates metabolic consequences, (NASH). Recent findings show sensing overabundance disrupts activity homeostasis central energy-generating organelle, mitochondrion. In parallel, whether caloric excess-initiated coordinated amplify this inflammatory process NASH remains question. We hypothesize altered function, signaling, response together play an integrated role landscape, leading inflammation progression. Sustained excess leads syndrome, umbrella term incorporates at least four pathophysiological obesity, insulin resistance, hypercholesterolemia, hypertension. Metabolic turn, increases stroke, cardiovascular (CVD), type 2 diabetes mellitus (T2DM) risk [1.O'Neill S. O'Driscoll L. syndrome: closer look growing epidemic its associated pathologies.Obes. Rev. 2015; 16: 1-12Crossref PubMed Scopus (1017) Google Scholar]. (see Glossary) is further manifestation syndrome encompasses initial excessive infiltration (steatosis), which can progress reversible potential towards non-reversible cirrhosis, increasing hepatocellular carcinoma (HCC) development [2.Anstee Q.M. et al.From HCC: current concepts future challenges.Nat. Gastroenterol. Hepatol. 2019; 411-428Crossref (710) full spectrum constitutes most common chronic prevalence parallel with global rise obesity [3.Estes C. al.Modeling demonstrates exponential increase burden disease.Hepatology. 2018; 67: 123-133Crossref (1180) Although genetic susceptibility evident [4.Baker 2nd, P.R. Friedman J.E. Mitochondrial neonatal predisposition developing disease.J. Clin. Invest. 128: 3692-3703Crossref (37) Scholar], implicates environmental where load major driver. Under physiological conditions, hepatocyte deposition functions as dynamic storage site during eating fasting, concomitant regulated machinery controls droplet (LD) synthesis lipolysis [5.Kramer D.A. al.Fasting refeeding induces changes mouse proteome.J. Proteome. 181: 213-224Crossref (29) nutritional overwhelms regulatory programs, steatosis [6.Gluchowski N.L. al.Lipid droplets disease: from basic biology clinical implications.Nat. 2017; 14: 343-355Crossref (334) Subsequently, death promote systemic local (chronic) inflammation; induced fibrosis, liver-resident infiltrative (Box 1) – precursor exacerbated consequences [7.Schuster al.Triggering resolution NASH.Nat. 15: 349-364Crossref (452) For latter, contributors include elevated state vascular endothelium atherosclerosis [8.Fracanzani A.L. al.Carotid artery intima-media thickness disease.Am. J. Med. 2008; 121: 72-78Abstract Full Text PDF (188) Scholar] overconsumption-driven intestinal permeability microbe leakage [9.Henao-Mejia al.Inflammasome-mediated dysbiosis regulates obesity.Nature. 2012; 482: 179-185Crossref (1798) both provide additional sources signals.Box 1Liver cellsThe comprises multiple types distinct roles depending their localization around either portal (intestinal) venous or arterial supplies subsequent drainage through hepatobiliary sinusoidal systems [85.Jenne C.N. Kubes P. Immune surveillance by liver.Nat. Immunol. 2013; 996-1006Crossref (705) linked pathophysiology hepatocytes, LSECs, SCs (mediators fibrosis) also harbors large resident myeloid [e.g., macrophages called KCs dendritic (DCs)], innate T [γδ natural killer (NKTs), mucosa-associated invariant (MAIT cells)], well adaptive αβ B [86.MacParland S.A. al.Single RNA sequencing human reveals intrahepatic macrophage populations.Nat. Commun. 9: 4383Crossref (663) healthy liver, general landscape sustained mostly anti-inflammatory tolerogenic Scholar,85.Jenne During NASH, two principal events occur. First, repertoire reshaped activated state; second, marked influx almost all subtypes inflamed be seen, dominating recruited [87.Cai al.The steatohepatitis.Hepatology. 70: 1026-1037Crossref (120) Together sustain environment injury. various affect different aspects NAFLD, we currently know about contributions (specifically neutrophils, monocytes, macrophages) conventional Scholar,87.Cai therefore focus here nutrient–PRR–mitochondria axes latter types. generally have 'resting' phenotype [10.Dou al.Hepatic environment, disease.Semin. Liver Dis. 38: 170-180Crossref (40) However, transition danger signals mediators released injured and/or dying hepatocytes reshape signatures via engagement phenotypes [11.Zhou Z. al.Neutrophil–hepatic stellate interactions fibrosis experimental steatohepatitis.Cell. Mol. 5: 399-413Abstract (82) Scholar,12.Daemen al.Dynamic shifts composition influence tissue remodeling NASH.Cell Rep. 2021; 34108626Abstract (111) This, combination monocyte neutrophil periphery, augments dysfunction [13.Gadd V.L. infiltrate ductular reaction 2014; 59: 1393-1405Crossref (296) (Figure 1). Most studies assess single pathways isolation. opinion article, argue there significant recognized overload, PRR-mediated control programs benign NASH. Further, posit that, nutrient-sensing mitochondrion node initiates PRR-inflammatory programs. addition, suggest unexpected activities important constituent Identifying networks underlying for urgently needed interventions. succinct overview known PRRs such Toll-like (TLRs), inflammasomes, cyclic GMP-AMP synthase–stimulator interferon genes (cGAS–STING) discuss discovered how intersect steatohepatitis. highlight NASH/NAFLD pharmacological interventions proposed axes, limitations model key outstanding questions. One function triglycerides (TGs) LDs It not surprising augmented overload. themselves does induce injury because encapsulation form TGs neutralizes lipotoxic effects mitochondria, organelles, trigger retrograde often engagement, [14.Garcia-Martinez I. al.Hepatocyte DNA drives TLR9.J. 2016; 126: 859-864Crossref (327) Mitochondria highly abundant part supply energy intermediates cholesterol, steroid, bile acid, lipid, glycogen synthesis, ketone bodies [15.Legaki A.I. dynamics bioenergetics obesity-related non-alcoholic disease.Curr. Obes. 2022; 11: 126-143Crossref (17) progressive histological biochemical evidenced swelling, cristae disruption, impaired oxidative phosphorylation [16.Wei Y. al.Nonalcoholic dysfunction.World 193-199Crossref (279) Of note, obese subjects, loss respiratory capacity mass correlate [17.Koliaki al.Adaptation lost steatohepatitis.Cell Metab. 21: 739-746Abstract (604) mechanism whereby perturbed fidelity driven evolutionary formation organelles vestiges bacterial origins; indeed eukaryotic mitochondria retain numerous prokaryotic molecules, hypomethylated (mtDNA), formyl peptides, cardiolipin [18.Calfee C.S. Matthay M.A. Clinical immunology: culprits ties.Nature. 2010; 464: 41-42Crossref (46) Leakage extrusion outer membrane [19.Sack M.N. agility fate function.J. 3651-3661Crossref (21) Hence, disruption integrity NOD, LRR, pyrin domain-containing protein 3 (NLRP3) inflammasome STING–interferon factor (IRF3) extracellular TLR9-initiated signaling. Perturbed reactive oxygen species (ROS) production, another strong driver [20.Sorbara M.T. Girardin S.E. ROS fuel inflammasome.Cell Res. 2011; 558-560Crossref (193) Scholar,21.Liu T. al.Imbalanced GSH/ROS sequential death.J. Biochem. Toxicol. 36e22942Crossref (69) propose crosstalk infiltrating given emerging evidence dysfunction-initiated considerable triggered contribution progression, areas require study demonstrate our hypothesis module hypothetical consequence NAFLD-associated enlarged termed megamitochondria, become resistant engulfment autophagosomes, thereby preclude recycling/repair selective mitophagy [22.Yamada al.Prevention regression megamitochondria blocking fusion liver.iScience. 25103996Abstract (10) concept was explored methionine/choline-deficient dietary antisense knockdown optic atrophy 1 (OPA1) Preventing formation, assessed confocal immunofluorescence sections, inhibited reversed established quality (mitochondrial fidelity) attenuated OPA1 depletion blunted fibrosis. specific were model, observed downregulation Il1b gene transcript encoding interleukin IL-1β following inhibition NLRP3 mechanism, inflammasome-induced cytokine Because autophagy processes (and iterations, e.g., lipophagy) mechanisms removing intrinsic molecules it impairment context infidelity, 2).Box 2Autophagic inflammationAutophagy (self-digestion) homeostatic catabolic recycles content removes (pathogens, damaged unfolded proteins, etc.) them lysosomes destruction. Autophagosomes myriad roles, (mitophagy) catabolism stores (autophagy, lipophagy, lysosomal lipolysis). These essential building blocks more globally promote, context-specific manner, pro- [89.Das U.N. Essential acids metabolites pathobiology resolution.Biomolecules. 1873Crossref (28) inflammation, lipids, lipotoxicity, compromised engage combat disturbances reinstate [90.Czaja M.J. al.Functions normal diseased liver.Autophagy. 1131-1158Crossref (366) defined, beneficial autophagic flux gradually reduced consequently DAMPs, viability [91.Lavallard V.J. Gual Autophagy disease.Biomed. Int. 2014120179Crossref (102) Scholar, 92.Ueno Komatsu M. liver: health disease.Nat. 170-184Crossref (337) 93.Filali-Mouncef menage trois autophagy, disease.Autophagy. 18: 50-72Crossref (78) Similarly, DAMP-driven negative impact example, oxidant-stressed reducing expression activators [94.Sun Q. al.Inflammasome regulation two-way street.Mol. 23: 188-195Crossref (132) Furthermore, lipophagic) patients, several murine models HFD-induced [93.Filali-Mouncef attractive (based PRR–mitochondrion interface), approach needs evaluated carefully serves removal non-functional phases [95.Onishi al.Molecular mitophagy.EMBO 40e104705Crossref (367) Scholar,96.Saha al.Autophagy comprehensive review.Biomed. Pharmacother. 104: 485-495Crossref (338) primary Kupffer

Language: Английский

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Macrophage Functions in Psoriasis: Lessons from Mouse Models

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5306 - 5306

Published: May 13, 2024

Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal Langerhans cells and dermal involved innate immunity, orchestration of adaptive maintenance tissue homeostasis due to their ability constantly shift phenotype adapt the current microenvironment. Consequently, both macrophage populations play dual roles psoriasis. In some circumstances, pro-inflammatory activated trigger psoriatic inflammation, while other cases anti-inflammatory stimulation results amelioration disease. These features make interesting candidates for modern therapeutic strategies. Owing significant progress knowledge, our review article summarizes achievements indicates future research directions better understand function

Language: Английский

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Inhibition of the NLRP3 inflammasome attenuates spiral ganglion neuron degeneration in aminoglycoside-induced hearing loss

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(10), P. 3025 - 3039

Published: June 3, 2024

JOURNAL/nrgr/04.03/01300535-202510000-00031/figure1/v/2024-11-26T163120Z/r/image-tiff Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum. However, use leads to irreversible hearing damage by causing apoptosis hair cells as direct target. In addition, the caused aminoglycosides involves spiral ganglion neurons upon exposure. To investigate mechanisms underlying neuron degeneration induced aminoglycosides, we C57BL/6J mouse model treated with kanamycin. We found that mice exhibited auditory deficits following acute loss outer cells. Spiral displayed hallmarks pyroptosis progressive over time. Transcriptomic profiling these showed significant upregulation genes associated inflammation immune response, particularly those related NLRP3 inflammasome. Activation canonical pyroptotic pathway in was observed, accompanied infiltration macrophages release proinflammatory cytokines. Pharmacological intervention targeting using Mcc950 genetic knockout ameliorated injury model. These findings suggest inflammasome–mediated plays role aminoglycoside-induced degeneration. Inhibition this may offer potential therapeutic strategy treating sensorineural reducing

Language: Английский

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Mechanism of immune attack in the progression of obesity-related type 2 diabetes

World Journal of Diabetes, Journal Year: 2023, Volume and Issue: 14(5), P. 494 - 511

Published: May 15, 2023

Obesity and overweight are widespread issues in adults, children, adolescents globally, have caused a noticeable rise obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis T2DM. This proinflammatory activation occurs multiple organs tissues. Immune cell-mediated systemic attack considered to contribute strongly impaired insulin secretion, resistance, other metabolic disorders. review focused on highlighting recent advances underlying mechanisms immune cell infiltration inflammatory responses gut, islet, insulin-targeting (adipose tissue, liver, skeletal muscle) There current evidence that both innate adaptive systems development obesity

Language: Английский

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Cholesterol‐autoxidation metabolites in host defense against infectious diseases

European Journal of Immunology, Journal Year: 2023, Volume and Issue: 53(9)

Published: June 27, 2023

Abstract Cholesterol plays essential roles in biological processes, including cell membrane stability and myelin formation. can be metabolized to oxysterols by enzymatic or nonenzymatic ways. Nonenzymatic cholesterol metabolites, also called cholesterol‐autoxidation are formed dependent on the oxidation of reactive oxygen species (ROS) such as OH• nitrogen species, ONOO − . Cholesterol‐autoxidation metabolites abundantly produced diseases inflammatory bowel disease atherosclerosis, which associated with oxidative stress. Recent studies have shown that further regulate immune system. Here, we review literature summarize how 25‐hydroxycholesterol (25‐OHC), 7α/β‐OHC, 7‐ketocholesterol, deal occurrence development infectious through pattern recognition receptors, inflammasomes, ROS production, nuclear G‐protein‐coupled receptor 183, lipid availability. In addition, include research regarding these COVID‐19 infection discuss our viewpoints future directions.

Language: Английский

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Therapeutic Applications of Oxysterols and Derivatives in Age-Related Diseases, Infectious and Inflammatory Diseases, and Cancers

Advances in experimental medicine and biology, Journal Year: 2023, Volume and Issue: unknown, P. 379 - 400

Published: Dec. 1, 2023

Language: Английский

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Anti-Inflammatory Oxysterol, Oxy210, Inhibits Atherosclerosis in Hyperlipidemic Mice and Inflammatory Responses of Vascular Cells

Cells, Journal Year: 2024, Volume and Issue: 13(19), P. 1632 - 1632

Published: Sept. 30, 2024

Background and aims: We previously reported that Oxy210, an oxysterol-based drug candidate, exhibits antifibrotic anti-inflammatory properties. also showed that, in mice, it ameliorates hepatic hallmarks of non-alcoholic steatohepatitis (NASH), including inflammation fibrosis, reduces adipose tissue inflammation. Here, we aim to investigate the effects Oxy210 on atherosclerosis, inflammatory disease large arteries is linked NASH epidemiologic studies, shares many same risk factors, major cause mortality people with NASH. Methods: was studied vivo APOE*3-Leiden.CETP a humanized mouse model for both which symptoms are induced by consumption high fat, cholesterol “Western” diet (WD). vitro using two cell types important atherogenesis: human aortic endothelial cells (HAECs) macrophages treated atherogenic agents. Results: reduced atherosclerotic lesion formation more than 50% hyperlipidemic mice fed WD 16 weeks. This accompanied plasma levels lesions. In HAECs macrophages, expression key markers associated interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), vascular adhesion molecule-1 (VCAM-1), E-Selectin. addition, efflux significantly enhanced Oxy210. Conclusions: These findings suggest could be candidate targeting as well chronic manifestations metabolic syndrome.

Language: Английский

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