Combined carvacrol and cilostazol ameliorate ethanol-induced liver fibrosis in rats: Possible role of SIRT1/Nrf2/HO-1 pathway

Abu-Risha, Sally El-Sayed; Sokar, Samia Salem; Elbohoty, Heba R; El‐Sisi, Alaa E.

doi:10.1016/j.intimp.2023.109750

Cited by 10 publications

(3 citation statements)

References 65 publications

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“…The study illuminated a multifaceted mechanism wherein CAR exerted signi cant therapeutic effects by alleviating oxidative stress, downregulating the pro-brotic growth factor (TGF-β1), augmenting the anti-in ammatory cytokine interleukin-10 (IL-10), inhibiting collagen synthesis as evidenced by reduced 4hydroxyproline (4-HYP) levels, and attenuating hepatic stellate cell (HSC) activation, as manifested by the diminished expression of alpha-smooth muscle actin (α-SMA) in hepatocytes. These ndings underscore CAR's profound antioxidant, anti-in ammatory, and anti-brotic properties, providing valuable insights into its potential therapeutic utility 53 . Furthermore, CAR's capacity to impede the progression of liver brosis through its interaction with the TGF-β signaling pathway was substantiated by Mohseni et al 54 Their ndings echoed the multifaceted anti-brotic and anti-in ammatory attributes of CAR, further solidifying its potential as a therapeutic intervention against hepatic brosis.…”

Section: Discussionmentioning

confidence: 93%

Deciphering the Protective Effects of Carvacrol Against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo

Retnosari,

Ghani,

Alkharji

et al. 2024

Preprint

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Doxorubicin (DOX), a widely used chemotherapy, extends its impact beyond cancer cells, notably affecting the heart, leading to substantial concerns about DOX-induced cardiotoxicity (DIC). However, subclinical DIC remains unresolved, necessitating advanced cardio-protection strategies in cancer therapy. Recent research explores carvacrol (CAR), a natural substance with antioxidant and anti-inflammatory properties, as a potential shield against DIC. However, further exploration is warranted, particularly concerning hypertrophy and cardiac fibrosis. This study investigated CAR’s potential cardioprotective properties against DIC in H9c2 cardiomyocytes and rats. Induction with DOX reduced cardiomyocyte viability, while pretreatment with 0.01 µg/mL CAR enhanced the viability of DOX-induced cardiomyocytes. Meanwhile, administration of DOX induced adverse effects in rats, causing decreased total heart weight and left ventricular mass, and lowered blood pressure. DOX also caused cardiac dysfunction, lipid peroxidation, hypertrophy, and fibrosis. In rat models, CAR pretreatment effectively mitigated DOX-induced reductions in blood pressure, hypertrophy, and cardiac fibrosis. However, the pretreatment kept the heart function, oxidative stress, and antioxidant enzymes unaltered. In conclusion, the results show that CAR could be an adjuvant to reduce DIC by ameliorating cardiac fibrosis and hypertrophy.

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Section: Discussionmentioning

confidence: 93%

Deciphering the Protective Effects of Carvacrol Against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo

Retnosari,

Ghani,

Alkharji

et al. 2024

Preprint

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“…Salvianolic acid A Influences autophagosome-lysosome fusion, essential for cellular homeostasis in liver disease ( Shi et al, 2018 ). Carvacrol and Cilostazol combination demonstrate hepatoprotective effect against ALF through the SIRT1/Nrf2/HO-1 pathway, exhibiting antioxidant, anti-inflammatory, and anti-fibrotic features ( Abu-Risha et al, 2023 ).…”

Section: Survey Methodologymentioning

confidence: 99%

The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target

Wang,

Zhao,

Chen

et al. 2024

PeerJ

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Liver disease is a common and serious threat to human health. The progression of liver diseases is influenced by many physiologic processes, including oxidative stress, inflammation, bile acid metabolism, and autophagy. Various factors lead to the dysfunction of these processes and basing on the different pathogeny, pathology, clinical manifestation, and pathogenesis, liver diseases are grouped into different categories. Specifically, Sirtuin1 (SIRT1), a member of the sirtuin protein family, has been extensively studied in the context of liver injury in recent years and are confirmed the significant role in liver disease. SIRT1 has been found to play a critical role in regulating key processes in liver injury. Further, SIRT1 seems to cause divers outcomes in different types of liver diseases. Recent studies have showed some therapeutic strategies involving modulating SIRT1, which may bring a novel therapeutic target. To elucidate the mechanisms underlying the role of sirtuin1 in liver injury and its potentiality as a therapeutic target, this review outlines the key signaling pathways associated with sirtuin1 and liver injury, and discusses recent advances in therapeutic strategies targeting sirtuin1 in liver diseases.

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“…Elevated levels of cAMP and/or cGMP have been found to have antifibrotic effects by inhibiting the myofibroblast-driven ECM production. − Thus, several PDE inhibitors have been used to investigate the antifibrotic effects in different liver fibrosis animal models. For example, the PDE5 inhibitor tadalafil could improve portal hypertension and reduce liver fibrosis induced by bile duct ligation (BDL) in rats. , The PDE3 inhibitor cilostazol could protect rats from alcohol-induced liver fibrosis by suppressing the TGF-β/CTGF activation and the cAMP/EPAC1 signal. , Our group developed a PDE9 inhibitor 4a , which showed significant antifibrotic effects in a BDL-induced rat model …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis

Zhao,

Jiang,

Huang

et al. 2024

J. Med. Chem.

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Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/ 1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC 50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

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Combined carvacrol and cilostazol ameliorate ethanol-induced liver fibrosis in rats: Possible role of SIRT1/Nrf2/HO-1 pathway

Cited by 10 publications

References 65 publications

Deciphering the Protective Effects of Carvacrol Against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo

Deciphering the Protective Effects of Carvacrol Against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo

The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis

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