Melatonin Engineering M2 Macrophage‐Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy

Advanced Science, Journal Year: 2023, Volume and Issue: 10(27)

Published: July 14, 2023

Periodontitis is a chronic infectious disease caused by bacterial irritation. As an essential component of the host immunity, macrophages are highly plastic and play crucial role in inflammatory response. An appropriate timely transition from proinflammatory (M1) to anti-inflammatory (M2) indispensable for treating periodontitis. M2 macrophage-derived exosomes (M2-exos) can actively target sites modulate immune microenvironments, M2-exos effectively treat Excessive endoplasmic reticulum stress (ER stress) unfolded protein response (UPR) destructive pathological characteristics during periodontal bone loss. Although melatonin has antioxidant effects, studies focusing on ER modulation remain limited. This study fabricates engineered loading with (Mel@M2-exos) result, drive macrophage reprogramming M1 type, which resolves inflammation accelerated healing. Melatonin released Mel@M2-exos rescues osteogenic cementogenic differentiation capacity human ligament cells (hPDLCs) reducing excessive UPR. Injectable gelatin methacryloyl (GelMA) hydrogels sustained-release accelerate regeneration rats ligation-induced Taken together, engineering promising candidates tissue regeneration.

Language: Английский

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Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: March 20, 2024

Abstract The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads stress (ER stress). As ER ensues, protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, kinase R-like kinase, activating transcription factor 6 promptly activates enhance ER’s protein-folding capacity restore homeostasis. However, prolonged levels propels UPR towards cellular demise subsequent inflammatory cascade, contributing development human diseases, including cancer, neurodegenerative disorders, diabetes. Notably, increased expression all pathways has been observed in these pathologies, reduction molecule correlates with decreased proliferation disease-associated target cells. Consequently, therapeutic strategies targeting stress-related interventions have attracted significant research interest. In this review, we elucidate critical role metabolic, offering novel approaches for conditions.

Language: Английский

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Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4368 - 4368

Published: April 15, 2024

Dynamic regulation of the cellular proteome is mainly controlled in endoplasmic reticulum (ER). Accumulation misfolded proteins due to ER stress leads activation unfolded protein response (UPR). The primary role UPR reduce bulk damages and try drive back system former or a new homeostatic state by autophagy, while an excessive level results apoptosis. It has already been proven that proper order characteristic features both surviving self-killing mechanisms are negative positive feedback loops, respectively. suggest these loops found not only within but also between branches UPR, fine-tuning stress. In this review, we summarize recent knowledge dynamical mechanism using theoretical molecular biological techniques. addition, review pays special attention describing action controlling life-and-death decision upon Since appears diseases common worldwide, more detailed understanding behaviour medical importance.

Language: Английский

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GRINA alleviates hepatic ischemia‒reperfusion injury-induced apoptosis and ER-phagy by enhancing HRD1-mediated ATF6 ubiquitination

Journal of Hepatology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Applications and Enhancement Strategies of ROS-based Non-invasive Therapies in Cancer Treatment

Redox Biology, Journal Year: 2025, Volume and Issue: unknown, P. 103515 - 103515

Published: Jan. 1, 2025

Language: Английский

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Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: 234, P. 116799 - 116799

Published: Feb. 12, 2025

Language: Английский

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Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(12), P. 3937 - 3950

Published: Jan. 1, 2023

Ferroptosis, an iron-dependent cell death form, has recently been observed in the development of non-alcoholic fatty liver disease (NAFLD).Melatonin (Mel) shows potential benefits for preventing and treating diseases.Whether how Mel ameliorates hepatic ferroptosis NAFLD is not fully understood.Here we established a mouse model induced by long-term high-fat diet (HFD) feeding.We found that treatment ameliorated global metabolic abnormalities inhibited progression mice.Most importantly, supplementation significantly improved HFD-induced iron homeostasis disorders liver, including overload ferritin transport disorders.For another, lipid peroxidation.The recuperative role exogenous on hepatocyte was also PA-or Erastin-treated HepG2 cells.Mechanistically, MT2, but MT1, involved effect Mel.Furthermore, HFD or Erastin-activated ER stress activated PKA/IRE1 signaling pathway.Co-expression p-PKA p-IRE1 enhanced MT2 antagonist.Inhibitions PKA IRE1 respectively ferroptosis, activations cAMP/PKA reversed Mel's ferroptosis.Collectively, these findings suggest inhibits ameliorating through MT2/cAMP/PKA/IRE1 pathway, proving promising candidate drug NAFLD.

Language: Английский

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Unravelling the role of NFE2L1 in stress responses and related diseases

Redox Biology, Journal Year: 2023, Volume and Issue: 65, P. 102819 - 102819

Published: July 14, 2023

The nuclear factor erythroid 2 (NF-E2)-related 1 (NFE2L1, also known as Nrf1) is a highly conserved transcription that belongs to the CNC-bZIP subfamily. Its significance lies in its control over redox balance, proteasome activity, and organ integrity. Stress responses encompass series of compensatory adaptations utilized by cells organisms cope with extracellular or intracellular stress initiated stressful stimuli. Recently, extensive evidence has demonstrated NFE2L1 plays crucial role cellular adaptation 1) responding oxidative through induction antioxidative responses, 2) addressing proteotoxic endoplasmic reticulum (ER) regulating ubiquitin-proteasome system (UPS), unfolded protein response (UPR), ER-associated degradation (ERAD). It worth noting serves core adaptation, which been extensively studied cancer neurodegeneration associated enhanced proteasomal stress. In these contexts, utilization inhibitors attenuate "bounce-back" holds tremendous potential for enhancing efficacy inhibitors. Additionally, abnormal disturbances homeostasis contribute pathophysiological complications cardiovascular diseases, inflammatory autoimmune diseases. Therefore, comprehensive exploration molecular basis NFE2L1-mediated diseases related would not only facilitate identification novel diagnostic prognostic indicators but enable specific therapeutic targets NFE2L1-related

Language: Английский

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Gut microbiota contributes to bisphenol A-induced maternal intestinal and placental apoptosis, oxidative stress, and fetal growth restriction in pregnant ewe model by regulating gut-placental axis

Microbiome, Journal Year: 2024, Volume and Issue: 12(1)

Published: Feb. 17, 2024

Abstract Background Bisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed BPA exposure causes placental apoptosis and oxidative stress (OS) decreases efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum (ERS), OS maternal placenta intestine are unclear ovine model gestation. Results Two ewe groups ( n = 8/group) were given either a subcutaneous (sc) injection corn oil (CON group) or (5 mg/kg/day) dissolved (BPA once daily, from day 40 110 The colonic digesta ileum tissue samples collected measure biomarkers ERS, OS. To investigate link between BPA-induced FGR ewes, transplantation (GMT) was conducted two mice 10/group) 0 18 gestation after removing their intestinal by antibiotics. results indicated aggravates ERS function injury ileum, dysbiosis ewes. GMT attributed resulting exposure. Conclusions Our findings indicate underlying gut-placental axis behind OS, further provide novel insights into modulating balance through medication probiotics, functioning via axis, alleviate gut-derived impairment

Language: Английский

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Dual regulation of NEMO by Nrf2 and miR-125a inhibits ferroptosis and protects liver from endoplasmic reticulum stress-induced injury

Theranostics, Journal Year: 2024, Volume and Issue: 14(5), P. 1841 - 1859

Published: Jan. 1, 2024

Rationale:The surge of severe liver damage underscores the necessity for identifying new targets and therapeutic agents.Endoplasmic reticulum (ER) stress induces ferroptosis with Gα12 overexpression.NF-κB essential modulator (NEMO) is a regulator inflammation necroptosis.Nonetheless, regulatory basis NEMO de novo synthesis its impact on hepatocyte need to be established.This study investigated whether Nrf2 transcriptionally IKBKG (the gene) inhibition and, if so, how induction protects hepatocytes against ER stress-induced ferroptosis.Methods: Experiments were conducted using human tissues, hepatocytes, injury models, incorporating overexpression gene modulations.RNA sequencing, immunoblotting, immunohistochemistry, reporter assays, mutation analyses done.Results: downregulation connects closely oxidative stress, worsening via ferroptosis.NEMO from by promoting glutathione peroxidase 4 (GPX4) expression.This protective role extends stress.Similar shifts occur in nuclear factor erythroid-2-related factor-2 (Nrf2) expression alongside changes.Nrf2 newly identified as an (NEMO transactivator.Gα12 changes, apart Nrf2, expression, pointing post-transcriptional control.Gα12 reduction lowers miR-125a, inhibitor NEMO, while has opposite effect.NEMO also counters which triggers overexpression.Gα12's significance NEMO-dependent survival confirmed ROCK1 inhibition, downstream kinase, miR-125a.The verified alterations or associations within targeted entities are validated specimens datasets originating livers subjected exposure other injurious agents.Conclusions: Hepatic prompted leads suppression thereby facilitating through GPX4.IKBKG transactivated responsible increase unprecedented inhibitor, resulting GPX4 induction.Accordingly, mitigates ferroptotic injury.

Language: Английский

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