Targeting ferroptosis opens new avenues for the development of novel therapeutics

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 21, 2023

Abstract Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, involving tissue and/or organ injury, inflammatory infectious diseases. Although precise regulatory networks underlie are largely unknown, particularly respect to initiation progression diseases, recognized bona fide target for further development treatment prevention strategies. Over past decade, considerable progress has been made developing pharmacological agonists antagonists these ferroptosis-related conditions. Here, we provide detailed overview our current knowledge regarding ferroptosis, its pathological roles, regulation during disease progression. Focusing on use chemical tools preclinical studies, also summarize recent advances targeting across growing spectrum ferroptosis-associated Finally, discuss new challenges opportunities potential strategy treating

Язык: Английский

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Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(23), С. 14959 - 14959

Опубликована: Ноя. 29, 2022

Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to architecture disruption and respiratory failure. The development of pulmonary mostly the result previous acute inflammation, caused by wide variety etiological factors, not resolved over time causing deposition fibrotic tissue in lungs. Despite long history study good coverage problem scientific literature, effective therapeutic approaches for treatment are currently lacking. Thus, molecular mechanisms underlying transition from inflammation fibrosis, search new markers promising targets prevent development, remain highly relevant tasks. This review focuses on etiology, pathogenesis, morphological characteristics outcomes as precursor fibrosis; pathomorphological changes lungs during development; known key players signaling pathways mediating well most common vivo models these processes. Moreover, prognostic injury severity approved potential suppressing discussed.

Язык: Английский

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Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)

Respiratory Research, Год журнала: 2024, Номер 25(1)

Опубликована: Янв. 13, 2024

Abstract Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advances, the mortality of ARDS remains unacceptably high, and there are still no effective targeted pharmacotherapeutic agents. With outbreak coronavirus disease 19 worldwide, has increased correspondingly. Comprehending pathophysiology underlying molecular mechanisms may thus be essential developing therapeutic strategies reducing mortality. To facilitate further understanding its pathogenesis exploring novel therapeutics, this review provides comprehensive information from presents therapeutics. We first describe that involve dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance oxidative stress. Next, we summarize signaling pathways related above four aspects pathophysiology, along latest research progress. Finally, discuss emerging show exciting promise in ARDS, including several pharmacologic therapies, microRNA-based therapies mesenchymal stromal cell highlighting pathophysiological basis influences on signal transduction for their use.

Язык: Английский

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Nrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 821 - 821

Опубликована: Янв. 9, 2024

Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads these of which increased oxidative stress in diabetic patients has strongly implicated. Limited knowledge antioxidative antidiabetic drugs substances can address comorbidities through the nuclear factor erythroid 2-related 2 (Nrf2) pathway calls for detailed investigation. This review will describe increases stress, general impact primarily contributes comorbidities. It also treatments diabetes, especially focusing on their effects Nrf2 pathway, shown similarly affect heart, kidney, systems. demonstrates common pathogenic component its associated potentially identifying this target guide future treatments.

Язык: Английский

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Lipid peroxidation products’ role in autophagy regulation

Free Radical Biology and Medicine, Год журнала: 2024, Номер 212, С. 375 - 383

Опубликована: Янв. 4, 2024

Autophagy, which is responsible for removing damaged molecules, prevents their accumulation in cells, thus maintaining intracellular homeostasis. It also the effects of oxidative stress, so its activation takes place during increased reactive oxygen species (ROS) generation and lipid peroxidation. Therefore, aim this review was to summarize all available knowledge about effect protein modifications by peroxidation products on autophagy impact interaction functioning cells. This shows that aldehydes (including 4-hydroxynonenal malondialdehyde), either directly or formation adducts with autophagic proteins, can activate prevent autophagy, depending concentration. relates not only initial stages when malondialdehyde affect levels proteins involved initiation phagophore formation, but final stage, degradation, aldehydes, binding active center cathepsins, inactivate proteolytic functions. Moreover, how little research exists analyzing autophagy. Such could be used therapy diseases related disorders.

Язык: Английский

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The gut-lung axis in severe acute Pancreatitis-associated lung injury: The protection by the gut microbiota through short-chain fatty acids

Pharmacological Research, Год журнала: 2022, Номер 182, С. 106321 - 106321

Опубликована: Июнь 22, 2022

The role of gut microbiota in regulating the intestinal homeostasis, as well pathogenesis severe acute pancreatitis-associated lung injury (PALI) is widely recognized. bioactive functions metabolites with small molecule weight and detail molecular mechanisms PALI mediated by "gut-lung axis" have gradually raised attentions researchers. Several studies proved that short-chain fatty acids (SCFAs) produced microbiome play crucial roles varied activities process PALI. However, relevant reviews reporting SCFAs involvement lacking. In this review, we firstly introduced synthetic metabolic pathways SCFAs, transport signal transduction routes brief. Afterwards, focused on possible clues to participate fight against which referred inhibition pathogen proliferation, anti-inflammatory effects, enhancement barrier functions, maintenance regulation immune homeostasis via pathogen-associated patterns (PAMPs) damage-associated (DAMPs). addition, latest reported pathological physiological gut-lung axis involved were reviewed. Finally, summarized potential therapeutic interventions targeting including dietary fiber supplementation, direct supplementation SCFAs/prebiotics/probiotics, drugs administration, expected provide new sights for clinical use future.

Язык: Английский

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Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment

Molecules, Год журнала: 2022, Номер 27(10), С. 3055 - 3055

Опубликована: Май 10, 2022

In recent years, important changes have occurred in the field of diabetes treatment. The focus treatment diabetic patients has shifted from control blood glucose itself to overall management risk factors, while adjusting goals according individualization. addition, regulators need approve new antidiabetic drugs which been tested for cardiovascular safety. Thus, newest class shown reduce major adverse events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they a prominent place hyperglycemia algorithms. role DPP4 inhibitors (DPP4i) modified. DPP4i favorable safety profile anti-inflammatory profile, do not cause hypoglycemia or weight gain, require dose escalation. it can also be applied types chronic kidney disease elderly with diabetes. Overall, DPP4i, as safe oral hypoglycemic agents, patients, there is extensive experience their use.

Язык: Английский

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Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke

Journal of Pharmaceutical Analysis, Год журнала: 2023, Номер 13(2), С. 156 - 169

Опубликована: Янв. 7, 2023

Stroke is the second leading cause of death worldwide, and oxidative stress plays a crucial role. Celastrol exhibits strong antioxidant properties in several diseases; however, whether it can affect oxidation cerebral ischemic-reperfusion injury (CIRI) remains unclear. This study aimed to determine celastrol could reduce damage during CIRI elucidate underlying mechanisms. Here, we found that attenuated by upregulating nuclear factor E2-related 2 (Nrf2). Using alkynyl-tagged liquid chromatography-tandem mass spectrometry, showed directly bound neuronally expressed developmentally downregulated 4 (Nedd4) then released Nrf2 from Nedd4 astrocytes. promoted degradation through K48-linked ubiquitination thus contributed astrocytic reactive oxygen species production CIRI, which was significantly blocked celastrol. Furthermore, inhibiting astrocyte activation, effectively rescued neurons axon apoptosis. Our uncovered as direct target celastrol, exerts an antioxidative effect on astrocytes interaction between reducing CIRI.

Язык: Английский

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Mechanisms of Qingyi Decoction in Severe Acute Pancreatitis-Associated Acute Lung Injury via Gut Microbiota: Targeting the Short-Chain Fatty Acids-Mediated AMPK/NF-κB/NLRP3 Pathway

Microbiology Spectrum, Год журнала: 2023, Номер 11(4)

Опубликована: Июнь 20, 2023

The pivotal roles of gut microbiota in severe acute pancreatitis-associated lung injury (SAP-ALI) are increasingly revealed, and recent discoveries the gut-lung axis have provided potential approaches for treating SAP-ALI. Qingyi decoction (QYD), a traditional Chinese medicine (TCM), is commonly used clinical to treat However, underlying mechanisms remain be fully elucidated. Herein, by using caerulein plus lipopolysaccharide (LPS)-induced SAP-ALI mice model antibiotics (Abx) cocktail-induced pseudogermfree model, we tried uncover administration QYD explored its possible mechanisms. Immunohistochemical results showed that severity intestinal barrier functions could affected relative depletion bacteria. composition was partially recovered after treatment with decreased Firmicutes/Bacteroidetes ratio increased abundance short-chain fatty acids (SCFAs)-producing Correspondingly levels SCFAs (especially propionate butyrate) feces, gut, serum, lungs were observed, generally consistent changes microbes. Western-blot analysis RT-qPCR indicated AMPK/NF-κB/NLRP3 signaling pathway activated oral QYD, which found possibly related regulatory effects on intestine lungs. In conclusion, our study provides new insights into through modulating has prospective practical value use future. IMPORTANCE Gut affects function. During SAP, significant increase pathogens (Escherichia, Enterococcus, Enterobacter, Peptostreptococcus, Helicobacter) observed. At same time, pathogenic bacteria SCFAs-producing (Bacteroides, Roseburia, Parabacteroides, Prevotella, Akkermansia). addition, mediated along may play an essential role preventing pathogenesis SAP-ALI, allows reduced systemic inflammation restoration barrier.

Язык: Английский

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Cyclosporine-induced kidney damage was halted by sitagliptin and hesperidin via increasing Nrf2 and suppressing TNF-α, NF-κB, and Bax

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Март 28, 2024

Abstract Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity a serious side effect that hampers the therapeutic use of CsA. Hesperidin sitagliptin were investigated their antioxidant, anti-inflammatory, tissue-protective properties. We aimed to investigate compare possible nephroprotective effects hesperidin sitagliptin. Male Wistar rats utilized induction CsA nephrotoxicity (20 mg/kg/day, intraperitoneally 7 days). Animals treated with (10 orally 14 days) or (200 Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), glucose measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, SOD estimated. Renal TNF-α protein expression was evaluated. Histopathological examination immunostaining study Bax, Nrf-2, NF-κB performed. Sitagliptin attenuated CsA-mediated elevations blood CYS-C, glucose, MDA, MPO, preserved SOD, GSH. They reduced expressions TNF-α, NF-κB, pathological kidney damage. Nrf2 in raised. could protect against through mitigation oxidative stress, apoptosis, inflammation. proved be more beneficial than hesperidin.

Язык: Английский

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