Treatment of Acute Liver Injury through Selective Tropism of High Mobility Group Box 1 Gene-Silenced Large Peritoneal Macrophages

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

Tissue-resident macrophages (TRMs) are attractive cells to therapeutically deliver oligonucleotide and other gene-expression modifying modalities treat a wide array of diseases ranging from inflammatory autoimmune, even cancer. Here, we focus on TRMs located inside the peritoneal cavity lining abdomen that selectively express transcription factor GATA6 called large (GLPMs) successfully demonstrate functional GLPM-selective delivery Cy5-fluorophore-labeled siRNA encapsulated in C12–200 cationic-lipidoid-based nanoparticles (siRNA-Cy5 (C12–200)). Despite being TRMs, GLPMs possess specific migratory ability peritoneally liver tissue upon injury incited by acetaminophen (APAP) overdose mice. A rapid, injury-driven tropism carrying siRNA-Cy5 (C12–200) was seen via systemic circulation, which elegantly demonstrated using noninvasive live-cell tracking technique diffuse vivo flow cytometry (DiFC). Finally, RNAi-mediated silencing well-known pro-inflammatory damage-associated molecular pattern (DAMP) High Mobility Group Box-1 (HMGB1) gene led mitigation inflammation prevention GLPM modulation state, further translated into significant protection APAP-driven reduction circulating cytokines owing muted response acute injury. Moreover, HMGB1 GalNAc-conjugated hepatocyte-targeting did not reciprocate findings, solidifying our results. Together, data suggested act as carriers rapidly bringing lipid nanoparticle-encapsulated RNAi injured have emerged viable strategy address diseases, especially those more nature.

Язык: Английский

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NEDD4 E3 ligase-catalyzed NAMPT ubiquitination and autophagy activation are essential for pyroptosis-independent NAMPT secretion in human monocytes

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Март 30, 2025

Abstract NAMPT is an important intracellular metabolic enzyme (iNAMPT) regulating the NAD + salvage pathway. However, increased cellular stress (infection, inflammation, hypoxia) promotes secretion of extracellular (eNAMPT), a TLR4 ligand and damage-associated molecular pattern protein (DAMP) that directly drives amplification innate immune-mediated inflammatory, fibrotic, neoplastic responses to influence disease severity. We sought examine mechanisms underlying pyroptotic eNAMPT release from human monocytic THP-1 cells, evoked by Nigericin, non-pyroptotic elicited lipopolysaccharide (LPS). Our data indicate secretion/release requires NLRP3 inflammasome activation with substantial attenuation either inhibition (MCC-950) or targeted genetic deletion key components, including NLRP3, caspase-1, gasdermin D (GSDMD). Pyroptosis-associated involved cleavage pore-forming GSDMD resulting in plasma membrane rupture (PMR) whereas LPS-induced neither nor PMR, verified utilizing non-cleavable mutant constructs. secretion, however, was highly dependent upon ubiquitination catalyzed complex containing NEDD4 E3 ligase, Hsp90 (a selective chaperone), intact enzymatic silencing NEDD4, GSDMD, Hsp90. involves autophagy as super-resolution microscopy analyses demonstrate co-localization autophagosome marker LC3B significantly reduced ATG5 ATG7 inhibition, critical components E3-like complex. These studies provide insights into may accelerate development therapeutic strategies address unmet needs fibrotic disorders.

Язык: Английский

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HMGB1: new biomarker and therapeutic target of autoimmune and autoinflammatory skin diseases

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 16, 2025

High-mobility group box 1 (HMGB1) is expressed in almost all human cells. During cell activation and death, the nucleoprotein HMGB1 can translocate to extracellular space, thus mediating early inflammatory response as an alarmin or damage-associated molecular pattern (DAMP). Extracellular interacts with immune cells by binding recognition Toll-like receptors (TLRs), including TLR2 TLR4, receptor for advanced glycation end products (RAGE), protect host against pathogens maintain balance. reportedly upregulated a critical biomarker monitoring disease activity several chronic autoimmune disorders, multiple sclerosis, rheumatoid arthritis, bowel disease, systemic lupus erythematosus vitiligo. Additionally, inhibition of expression its has beneficial effects on animal models diseases. Thus, indispensable important therapeutic target This review provides detailed summary biological function comprehensive outlook terms HMGB-focused diagnostic applications skin

Язык: Английский

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Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor Alpha and Gamma Agonists on Myocardial Damage: Molecular Mechanisms and Clinical Evidence—A Narrative Review

Cells, Год журнала: 2024, Номер 13(17), С. 1488 - 1488

Опубликована: Сен. 5, 2024

Cardiovascular diseases remain the leading cause of death in world, and that is why finding an effective multi-functional treatment alternative to combat these has become more important. Fibrates thiazolidinediones, peroxisome proliferator-activated receptors alpha gamma are pharmacological therapies used treat dyslipidemia type 2 diabetes, respectively. New mechanisms action drugs have been found, demonstrating their pleiotropic effects, which contribute preserving heart by reducing or even preventing myocardial damage. Here, we review underlying cardioprotective effects PPAR agonists regulating morphological physiological alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, inflammation). Moreover, clinical evidence regarding effect also addressed.

Язык: Английский

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Snhg14/miR-181a-5p axis-mediated “M1” macrophages aggravate LPS-induced myocardial cell injury

Heliyon, Год журнала: 2024, Номер 10(18), С. e37104 - e37104

Опубликована: Авг. 28, 2024

An increasing number of studies have suggested that macrophages participate in sepsis-induced myocardial injury. Our study highlights the function and mechanism lncRNA Snhg14 "M1" polarized macrophage-mediated cell damage. Lipopolysaccharide (LPS) was used to treat H9c2 cells construct an

Язык: Английский

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Extraction, Detection, Bioactivity, and Product Development of Luteolin: A Review

Heliyon, Год журнала: 2024, Номер 10(24), С. e41068 - e41068

Опубликована: Дек. 1, 2024

Luteolin is a kind of natural flavonoid, widely existing in variety plants, has been revealed to have wide range biological activities. In recent years, the research results luteolin are abundant. Here we review latest order provide new ideas for further and development luteolin. this paper, focus search was published between 2010 2024 on extraction determination luteolin, activities, application products. A comprehensive using keyword "luteolin" conducted PubMed, Web Science WIPO databases. Through collection related literature, paper summarized techniques including immersion extraction, solvent ultrasonic-assisted supercritical fluid so on. The methods include: thin layer chromatography (TLC), high performance liquid (HPLC), capillary electrophoresis (CE), electrochemical method (ED) addition, activities antioxidant, anti-inflammatory, anti-tumor, antibacterial, analgesic on, were described. And as main component product being gradually developed, used field food, medicine cosmetics. This provides reference study

Язык: Английский

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