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Current Molecular Pharmacology - Online First

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    • Thymol and Carvacrol as Potential Tocolytic and Anti-inflammatory Agents in Pregnant Rat Uterus

      https://doi.org/10.2174/0118761429342128241231163610
      Available online: 09 January 2025
      Introduction:

      This work aimed to evaluate the anti-inflammatory and myorelaxant effect of thymol (TM) and carvacrol (CAR) in the pregnant rat uterus. Both compounds exhibit considerable antimicrobial, antispasmodic, and anti-inflammatory effects and due to these properties, they were studied in this model of premature birth induced by infection.

      Method:

      All uterine tissues were studied in uterine contraction tests to determine the inhibitory effect of TM, CAR (10, 56, 100, 150, and 230 µM), and nifedipine (a calcium channel antagonist) on phasic and tonic contraction induced by electro- and pharmacomechanical stimuli. The quantitative determination of cyclic adenosine monophosphate (cAMP) induced by TM and CAR in the uterine lysate was carried out by ELISA. For the determination of the anti-inflammatory effect of TM, the pro-inflammatory cytokine, interleukin (IL)-1β, in uterine samples stimulated with lipopolysaccharide (LPS) was measured. Forskolin (FSK) was used as a positive control to evaluate the cAMP and cytokine levels. TM, CAR, and nifedipine inhibited the uterine contractions at the highest concentration level, however, nifedipine was the most equipotent (<0.05). In addition, TM and CAR did not increase the intracellular cAMP production in comparison with FSK (<0.05). However, both compounds were able to decrease the LPS-induced production in a concentration-dependent manner that was considered statistically significant (>0.05).

      Results:

      Finally, both the anti-inflammatory and uterine relaxing effects induced by TM and CAR were neither associated with the increase in cAMP levels nor with the production of IL-1β in pregnant rat uterine samples. Therefore, TM and CAR can be considered as alternative adjuvants for the treatment of infection-induced preterm labor. Before the experiments, an in-silico analysis was conducted using the Expaisy online server to evaluate the biological effects of thymol on uterine contraction.

      Conclusion:

      It is crucial to know the interaction and identification of genes encoding the Voltage-dependent L-type calcium channel subunit alpha-1C proteins, because of the functional relationship it may have in the inhibition of the uterine contraction. These properties place TM as a potentially safe and effective adjuvant agent in cases of preterm birth, an area of pharmacological treatment that requires urgent improvement.

    • Chrysin: A Potential Antiandrogen Ligand to Mutated Androgen Receptors in Prostate Cancer

      https://doi.org/10.2174/0118761429350210250102131611
      Available online: 09 January 2025
      Background:

      Androgen receptor mutations, particularly T877A and W741L, promote prostate cancer (PCa). The main therapies against PCa use androgen receptor (AR) antagonists, including Bicalutamide; but these drugs lose their effectiveness over time. Chrysin is a flavonoid with several biological activities, including antitumoral properties; however, its potential as an antiandrogen must be explored.

      Objective:

      The present study aimed to characterize and compare the molecular interactions of chrysin with wild-type and mutated ARs and their cytotoxic effect in an model of PCa.

      Methods:

      The affinities and molecular interactions of Bicalutamide and chrysin for the wild-type and mutated forms of AR were assessed by molecular docking. The MTT assay was used to evaluate the cytotoxic effect of these ligands on the DU-145 (T877A) and PC3 (W741L) PCa cell lines and on non-tumoral RWPE-1 cells.

      Results:

      The molecular dockings predicted a higher affinity of chrysin for the mutated AR than the wild-type AR (WT-AR); meanwhile, Bicalutamide presented a higher affinity for WT-AR. The amino acid residues involved in molecular interactions within the binding site of these receptors changed according to the ligands and AR variants, affecting their affinity scores. Chrysin exerted a specific cytotoxic effect against the PCa tumoral cells but none against the non-tumoral cells. In contrast, Bicalutamide showed potent cytotoxicity against all cell lines. Thus, the cytotoxic effect of chrysin against the DU-145 and PC3 cell line may be related to its strong and specific molecular interaction with the mutated ARs.

      Conclusion:

      This study evidences the potential antiandrogen effect of chrysin on mutated AR and specific cytotoxicity against PCa cells, suggesting that this flavonoid should be further studied to confirm its potential for therapy of advanced PCa.

    • Sirt1 Regulates Phenotypic Transformation of Diabetic Cardiac Fibroblasts through Akt/Α-SMA Pathway

      https://doi.org/10.2174/0118761429353519250106115016
      Available online: 09 January 2025
      Aims:

      Cardiac fibrosis causes most pathological alterations of cardiomyopathy in diabetes and heart failure patients. The activation and transformation of cardiac fibroblasts (CFs) are the main pathological mechanisms of cardiac fibrosis. It has been established that Sirtuin1 (Sirt1) plays a protective role in the pathogenesis of cardiovascular disorders. This study aimed to ascertain the Sirt1 effect on the phenotypic transformation of CFs in diabetes and its possible mechanisms.

      Methods:

      Type 1 diabetes was induced in 6-week-old male mice by subcutaneously injecting 50 mg/kg streptozotocin (STZ, i.p.). Western blotting, collagen staining, and echocardiography were performed to detect protein expression and assess cardiac fibrosis and function . We used high glucose (HG) to culture CFs prior to protein expression measurement .

      Results:

      Upregulation of Sirt1 expression effectively alleviated the degree of cardiac fibrosis by improving cardiac function in diabetic mice. experiments revealed that HG decreased the protein expression levels of Sirt1, but increased those of type I collagen and alpha-smooth muscle actin (α-SMA), as well as the transdifferentiation of fibroblasts into myofibroblasts. Further studies confirmed that downregulation of Sirt1 expression in the HG environment reduced the protein kinase-B (Akt) phosphorylation, thereby promoting the transdifferentiation of CFs into myofibroblasts coupled with the deterioration of cardiac function.

      Conclusion:

      Diabetes mellitus leads to downregulation of Sirt1 protein expression in CFs and decreased Akt phosphorylation, which promotes the transdifferentiation of CFs into myofibroblasts, the pathological process of cardiac fibrosis, and mediates the incidence and development of diabetic cardiomyopathy.

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