Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis

JCI Insight, Год журнала: 2023, Номер 8(3)

Опубликована: Фев. 7, 2023

Patients with progressive fibrosing interstitial lung diseases (PF-ILDs) carry a poor prognosis and have limited therapeutic options. A hallmark feature is fibroblast resistance to apoptosis, leading their persistence, accumulation, excessive deposition of extracellular matrix. complex balance the B cell lymphoma 2 (BCL-2) protein family controlling intrinsic pathway apoptosis reliance on antiapoptotic proteins has been hypothesized contribute this resistant phenotype. Examination tissue from patients PF-ILD (idiopathic pulmonary fibrosis silicosis) mice (repetitive bleomycin showed increased expression BCL-2 members in α–smooth muscle actin–positive fibroblasts, suggesting that fibroblasts fibrotic lungs may exhibit susceptibility inhibition BCL-2, BCL-XL, BCL-W BH3 mimetic ABT-263. We used murine models test efficacy ABT-263 reversing established persistent fibrosis. Treatment induced decreased numbers, reduced collagen levels, radiographic disease, histologically evident Our studies provide insight into how gain become sensitive proteins. By targeting profibrotic offers promising option for PF-ILDs.

Язык: Английский

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The pyruvate dehydrogenase complex: Life’s essential, vulnerable and druggable energy homeostat

Mitochondrion, Год журнала: 2023, Номер 70, С. 59 - 102

Опубликована: Март 1, 2023

Язык: Английский

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Cellular and Molecular Mechanisms in Idiopathic Pulmonary Fibrosis

Advances in respiratory medicine, Год журнала: 2023, Номер 91(1), С. 26 - 48

Опубликована: Янв. 31, 2023

The respiratory system is a well-organized multicellular organ, and disruption of cellular homeostasis or abnormal tissue repair caused by genetic deficiency exposure to risk factors lead life-threatening pulmonary disease including idiopathic fibrosis (IPF). Although there no clear etiology as the name reflected, its pathological progress closely related uncoordinated molecular signals. Here, we review advances in our understanding role lung cells IPF pathology epithelial cells, mesenchymal stem fibroblasts, immune endothelial cells. These summarize various cell components signaling pathways pathogenesis fibrosis, which helpful further study mechanism disease, provide new opportunities for prevention treatment, expected improve survival rate quality life patients.

Язык: Английский

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Unlocking the Mitochondria for Nanomedicine-based Treatments: Overcoming Biological Barriers, Improving Designs, and Selecting Verification Techniques

Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 207, С. 115195 - 115195

Опубликована: Фев. 5, 2024

Enhanced targeting approaches will support the treatment of diseases associated with dysfunctional mitochondria, which play critical roles in energy generation and cell survival. Obstacles to mitochondria-specific include presence distinct biological barriers need pass through (or avoid) various internalization mechanisms. A range studies have reported design mitochondrially-targeted nanomedicines that navigate complex routes required influence mitochondrial function; nonetheless, a significant journey lies ahead before become suitable for clinical use. Moving swiftly forward require safety studies, vivo assays confirming effectiveness, methodologies validate mitochondria-targeted nanomedicines' subcellular location/activity. From nanomedicine standpoint, we describe involved (from administration arrival within mitochondria), features influencing rational design, techniques used identify/validate successful targeting. Overall, rationally-designed mitochondria-targeted-based hold great promise precise therapeutic delivery.

Язык: Английский

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Unraveling the interplay between vital organelle stress and oxidative stress in idiopathic pulmonary fibrosis

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Год журнала: 2024, Номер 1871(3), С. 119676 - 119676

Опубликована: Янв. 21, 2024

Язык: Английский

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Immune cells crosstalk Pathways, and metabolic alterations in Idiopathic pulmonary fibrosis

International Immunopharmacology, Год журнала: 2024, Номер 135, С. 112269 - 112269

Опубликована: Май 22, 2024

Язык: Английский

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Targeting organ-specific mitochondrial dysfunction to improve biological aging

Pharmacology & Therapeutics, Год журнала: 2024, Номер 262, С. 108710 - 108710

Опубликована: Авг. 22, 2024

In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites key regulators programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, mitochondrial dysfunction pivotal factor progressive age-related decline cellular homeostasis organ function. The current review examines recent advances understanding interplay between organ-specific aging. Thereby, we dissect molecular mechanisms underlying impairment associated with deterioration exploring DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated patterns, biogenesis, turnover, dynamics. We also highlight emerging therapeutic preclinical clinical tests that supposed rejuvenate such as antioxidants, biogenesis stimulators, modulators turnover Furthermore, discuss potential benefits challenges use interventions, emphasizing need for approaches given unique characteristics different tissues. conclusion, this highlights addressing mitigate aging, focusing on skin, liver, lung, brain, skeletal muscle, well reproductive, immune, cardiovascular systems. Based comprehensive multifaceted roles mitochondria, innovative may be developed optimized biological promote healthy across diverse

Язык: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Язык: Английский

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Mitochondrial Dysfunction in Chronic Respiratory Diseases: Implications for the Pathogenesis and Potential Therapeutics

Oxidative Medicine and Cellular Longevity, Год журнала: 2021, Номер 2021(1)

Опубликована: Янв. 1, 2021

Mitochondria are indispensable for energy metabolism and cell signaling. Mitochondrial homeostasis is sustained with stabilization of mitochondrial membrane potential, balance calcium, integrity DNA, timely clearance damaged mitochondria via mitophagy. dysfunction featured by increased generation reactive oxygen species, reduced calcium imbalance, DNA damage, abnormal Accumulating evidence indicates that dysregulation causes oxidative stress, inflammasome activation, apoptosis, senescence, metabolic reprogramming. All these cellular processes participate in the pathogenesis progression chronic respiratory diseases, including obstructive pulmonary disease, fibrosis, asthma. In this review, we provide a comprehensive updated overview impact on involved development diseases. This not only implicates mechanisms lung diseases but also provides potential therapeutic approaches targeting dysfunctional mitochondria.

Язык: Английский

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Mitochondrial uncoupling protein‐2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age‐associated lung fibrosis

Aging Cell, Год журнала: 2022, Номер 21(9)

Опубликована: Авг. 7, 2022

Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in increased generation reactive oxygen species, altered redox state and cellular bioenergetics, impaired fatty acid oxidation, induction myofibroblast senescence. This pro-oxidant senescence reprogramming occurs concert conventional actions UCP2 as an uncoupler oxidative phosphorylation dissipation membrane potential. is highly expressed human IPF lung myofibroblasts aged fibroblasts. In aging murine model fibrosis, vivo silencing induces regression. These studies indicate a pro-fibrotic function disease support its therapeutic targeting diseases tissue regeneration organ fibrosis.

Язык: Английский

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