Clinical Implication of Phosphodiesterase-4-Inhibition

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1209 - 1209

Published: Jan. 21, 2022

The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development pharmacological phosphodiesterase inhibitors (PDE-I) attenuate cAMP degradation. While there are many isotypes PDE, a predominant role PDE4 is regulate fundamental functions, including endothelial epithelial barrier stability, modulation inflammatory responses cognitive and/or mood functions. This makes use PDE4-I an interesting tool for various therapeutic approaches. However, due presence tissues, significant danger serious side effects. Based on this, aim this review provide comprehensive overview approaches effects different applications. In summary, despite obstacles approaches, current data warrant future research utilize potential 4 inhibition.

Language: Английский

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Molecular Mechanisms of Kidney Injury and Repair

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1542 - 1542

Published: Jan. 28, 2022

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing need to better understand molecular mechanisms damage and regeneration in kidney. CKD predisposes acute injury (AKI) which, turn, promotes progression. This implies that or AKI-to-CKD transition are associated with dysfunctional repair mechanisms. Current therapeutic options slow progression but fail treat accelerate recovery from AKI unable promote regeneration. Unraveling cellular involved repair, including failure this process, may provide novel biomarkers tools. We now review contribution different events transition, focusing on role macrophages injury, forms regulated cell necroinflammation, senescence senescence-associated secretory phenotype (SAPS), polyploidization, podocyte activation parietal epithelial cells. Next, we discuss key contributors opportunities for their manipulation, a focus resident renal progenitor cells, stem cells reparative secretome, certain macrophage subphenotypes within M2 senescent clearance.

Language: Английский

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A Review of Medicinal Plants with Renoprotective Activity in Diabetic Nephropathy Animal Models

Life, Journal Year: 2023, Volume and Issue: 13(2), P. 560 - 560

Published: Feb. 16, 2023

Diabetic nephropathy (DN), also recognized as diabetic kidney disease, is a malfunction caused by diabetes mellitus. A possible contributing factor to the onset of DN hyperglycemia. Poorly regulated hyperglycemia can damage blood vessel clusters in kidneys, leading damage. Its treatment difficult and expensive because its causes are extremely complex poorly understood. Extracts from medicinal plants be an alternative for DN. The bioactive content inhibits progression This work explores renoprotective activity mechanisms various plant extracts administered animal models. Research articles published 2011 2022 were gathered several databases including PubMed, Scopus, ProQuest, ScienceDirect ensure up-to-date findings. Results showed that ameliorated via reduction oxidative stress suppression inflammation, advanced glycation end-product formation, cell apoptosis, tissue injury-related protein expression.

Language: Английский

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Diosmin ameliorates renal fibrosis through inhibition of inflammation by regulating SIRT3-mediated NF-κB p65 nuclear translocation

BMC Complementary Medicine and Therapies, Journal Year: 2024, Volume and Issue: 24(1)

Published: Jan. 9, 2024

Abstract Background Renal fibrosis is considered an irreversible pathological process and the ultimate common pathway for development of all types chronic kidney diseases renal failure. Diosmin a natural flavonoid glycoside that has antioxidant, anti-inflammatory, antifibrotic activities. However, whether protects kidneys by inhibiting unknown. We aimed to investigate role in interstitial explore underlying mechanisms. Methods The UUO mouse model was established gavaged with (50 mg/kg·d 100 mg/kg·d) 14 days. HE staining, Masson immunohistochemistry, western blotting PCR were used assess tissue injury fibrosis. Elisa kits detect expression levels IL-1β, IL-6, TNF-α activity SIRT3 tissues. In addition, enrichment maps RNA sequencing analyzed changes signaling pathways. vitro, human tubular epithelial cells (HK-2) stimulated TGF-β1 then treated diosmin (75 μM). protein mRNA detected cells. 3-TYP (selective inhibitor SIRT3) small interfering (siRNA) reduce HK-2. Results attenuated UUO-induced TGF-β1-induced HK-2 reduced tissues supernatants medium. Interestingly, administration increased enzymatic kidneys. significantly vitro vivo. Inhibition using or siRNA abolished anti-inflammatory effects Enrichment map analysis indicates nuclear factor-kappa B (NF-κB) inhibited intervention group. Furthermore, we found NF-κB p65 but had little significant effect on total intracellular p65. Additionally, TGF-β1-caused translocation. Knockdown inhibition expression. Conclusions reduces inflammation fibrosis, which contributed translocation P65 through activating SIRT3.

Language: Английский

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Hypoxic mesenchymal stem cell-derived extracellular vesicles ameliorate renal fibrosis after ischemia–reperfusion injure by restoring CPT1A mediated fatty acid oxidation

Stem Cell Research & Therapy, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 7, 2022

Abstract Background Renal fibrosis is a common pathological process of chronic kidney diseases induced by multiple factors. Hypoxic pretreatment mesenchymal stem cells can enhance the efficacy secreted extracellular vesicles (MSC-EVs) on various diseases, but it not clear whether they better improve renal fibrosis. The latest research showed that recovery fatty acid oxidation (FAO) reduce In this study, we aimed to examine hypoxic with MSC (Hypo-EVs) FAO restore and investigate underlying mechanism. Methods Hypo-EVs were isolated from hypoxia-pretreated human placenta-derived (hP-MSC), Norm-EVs hP-MSC cultured under normal conditions. We used ischemia–reperfusion (I/R)-induced model in vivo. mice injected PBS, Hypo-EVs, or immediately after surgery day 1 postsurgery. function, pathology, assessed for damage evaluation. For mechanistic exploration, (FAO), mitochondrial morphological alterations, ATP production mass proteins detected Mitochondrial membrane potential reactive oxygen species (ROS) investigated vitro. Results found confer superior therapeutic effect structure damage, restoration function reduction Meanwhile, enhanced restoring expression key rate-limiting enzyme carnitine palmitoyl-transferase 1A (CPT1A). Mechanistically, improvement homeostasis, characterized repaired structure, production, inhibition oxidative stress, increased potential, partially explains improving thus attenuating I/R damage. Conclusions suppress CPT1A-mediated FAO, which effects may be achieved through regulation homeostasis. Our findings provide further mechanism support development cell-free therapy

Language: Английский

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A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 10014 - 10014

Published: Sept. 2, 2022

Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on development selective HDAC8is. addition, polypharmacological approaches been explored achieve synergistic action multi-factorial diseases or enhance drug efficacy. this frame, proteolysis-targeting chimeras (PROTACs) might be regarded dual-targeting approach attaining proteasomal degradation. This review highlights most relevant advances relative validation providing snapshot current HDAC8is, focus polyfunctional modulators.

Language: Английский

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Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis

Journal of Pharmaceutical Analysis, Journal Year: 2024, Volume and Issue: 14(8), P. 100933 - 100933

Published: Jan. 4, 2024

Renal fibrosis is a devastating consequence of progressive chronic kidney disease, representing major public health challenge worldwide. The underlying mechanisms in the pathogenesis renal remain unclear, and effective treatments are still lacking. tubular epithelial cells (RTECs) maintain function, their dysfunction has emerged as critical contributor to fibrosis. Cellular quality control comprises several components, including telomere homeostasis, ubiquitin-proteasome system, autophagy, mitochondrial homeostasis (mitophagy metabolism), endoplasmic reticulum (unfolded protein response), lysosomes. Failures cellular RTECs, deoxyribonucleic acid (DNA), protein, organelle damage, exert profibrotic functions by leading senescence, defective stress, lysosomal dysfunction, apoptosis, fibroblast activation, immune cell recruitment. In this review, we summarize recent advances understanding role components intercellular crosstalk networks within context

Language: Английский

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ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5

Experimental & Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Abstract Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in hydrolysis thioesters into free acids and CoA, key regulator lipid metabolism fibrotic kidneys. A significantly decreased level ACOT12 was observed kidney samples from human patients with chronic disease as well mice injuries. Acot12 deficiency induces accumulation fibrosis subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce −/− UUO. Moreover, restoration peroxisome proliferator-activated receptor α (PPARα) Pparα kidneys UUO exacerbated fibrosis, whereas reduced suggesting that, mechanistically, exacerbates independently PPAR . In UUO, reduction selective autophagic degradation peroxisomes pexophagy ACBD5 observed. conclusion, our study demonstrates functional role mechanistic details progression provides preclinical rationale for regulating expression presents novel means preventing

Language: Английский

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Diosmin Attenuates UUO-induced Renal Ferroptosis and Fibrosis by Inhibiting the HIF-1α/FABP4 Signaling Axis

Phytomedicine, Journal Year: 2025, Volume and Issue: unknown, P. 156738 - 156738

Published: April 1, 2025

Language: Английский

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Rosmarinic acid ameliorates renal interstitial fibrosis by inhibiting the phosphorylated-AKT mediated epithelial–mesenchymal transition in vitro and in vivo

Food & Function, Journal Year: 2022, Volume and Issue: 13(8), P. 4641 - 4652

Published: Jan. 1, 2022

Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via renal fibrosis. Epithelial-mesenchymal transition (EMT) is crucial feature of Rosmarinic acid (RA) an ester caffeic and 3,4-dihydroxyphenylacetic with wide range desirable biological activities. In this study, we investigated whether RA exerted anti-renal fibrosis effects its related mechanisms in unilateral ureteral obstruction (UUO) mouse model. C57BL/6 mice were orally administered (10 20 mg kg-1 d-1) for 7 consecutive days before after UUO surgery. The then sacrificed to collect the blood kidneys. Hematoxylin eosin (H&E) Masson's trichrome staining used evaluate injury function. Immunohistochemical analysis, reverse transcription-polymerase chain reaction (RT-PCR), western blotting detect expression levels EMT markers. vitro studies performed using IS-stimulated NRK-52E cell line. Here, pathological changes, collagen deposition, mRNA protein profibrotic factors fibrotic markers found be significantly elevated kidneys mice. We that administration ameliorated UUO-induced damage by reversing abnormal serum creatinine urea nitrogen levels. It was treatment decreased alpha-smooth muscle actin (α-SMA), I, fibronectin, transforming growth factor (TGF)-β1, vimentin phosphorylated AKT (p-AKT) while increasing E-cadherin both IS-treated cells. Our results demonstrate may promising therapeutic agent interstitial

Language: Английский

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