Pharmacology最新文献

Introduction: Membrane-associated guanylate kinase with an inverted domain structure-1 (MAGI1) is dysregulated in diabetes; however, its role in diabetic nephropathy (DN) remains unclear. In this study, we determined the function and associated mechanisms of MAGI1 in DN.

Methods: Serum samples from 28 patients with DN and 28 normal volunteers were collected. High-glucose (HG)-treated human renal mesangial cells (HRMCs) and streptozotocin-treated rats were used as cell and animal models of DN, respectively. MAGI1 mRNA expression was measured by quantitative reverse transcription polymerase chain reaction. An 5-Ethynyl-2'-deoxyuridine assay was used to assess cell proliferation, whereas Western blot analysis was performed to quantitate the levels of markers associated with proliferation, the extracellular matrix (ECM), and inflammation. These included collagens I, collagen IV, cyclin D1, AKT, phosphorylated-AKT (p-AKT), PI3K, and phosphorylated-PI3K (p-PI3K). The predicted binding of miR-205-5p with the MAGI1 3'UTR was verified using a luciferase assay.

Results: MAGI1 expression was increased in serum samples from DN patients and in HRMCs treated with HG. MAGI1 knockdown attenuated excessive proliferation, ECM accumulation, and inflammation in HG-induced HRMCs as well as injury to DN rats. MiR-205-5p potentially interacted with the 3'UTR of MAGI1 and binding was verified using a dual-luciferase reporter assay. Moreover, miR-205-5p repression offset the inhibitory influence of MAGI1 knockdown on proliferation, collagen deposition, and inflammation in HG-treated HRMCs.

Conclusion: MAGI1 contributes to injury caused by DN. Furthermore, miR-205-5p binds to MAGI1 and suppresses MAGI1 function. These findings suggest that miR-205-5p-mediates MAGI1 inhibition, which represents a potential treatment for DN.

Background: Hypoactive sexual desire disorder (HSDD) in premenopausal women involves biological, psychological, and social aspects. In the European Society for Sexual Medicine meeting in Rotterdam in February 2023, several leading experts in the field discussed the multifaceted nature of this disorder and the state of the art regarding treatment at a round table. This review reflects the information discussed at this event and further discusses current controversies.

Summary: HSDD is the most prevalent female-estimated sexual disorder reported by 28% of the 40% premenopausal women with sexual dysfunction. Flibanserin and bremelanotide are the only approved medications to treat HSDD in the USA, and none are approved in Europe. Lybrido, Lybridos, and Lorexys are under development. There are several psychological factors with impact in sexual desire, including depression and sexual abuse. Feminine sexual scripts, the pleasure gap, and structural inequalities also affect sexual desire. Evidence strongly supports the value of combining medical and psychological approaches in the treatment of HSDD, but there is ongoing controversy regarding the pharmacological treatment of young women with HSDD. However, some women seem open and would like to have access to drug treatment.

Key messages: The treatment of HSDD in young women requires a mixed treatment approach that addresses the disorder's complexity. Despite clinicians seeming to be divided between using pharmacological and/or psychosocial approaches, some women might respond better to one type of intervention over the others. This calls for the development of tools that assess the best approach for each person, including their will and informed choice.

Introduction: We investigated the potential of LPS (10-300 µg/rat) administered intratracheally (i.t.) to induce reproducible features of acute lung injury (ALI) and compared the pharmacological efficacy of anti-inflammatory glucocorticoids and antifibrotic drugs to reduce the disease. Additionally, we studied the time-dependent progression of ALI in this LPS rat model.

Methods: We conducted (1) dose effect studies of LPS administered i.t. at 10, 30, 100, and 300 μg/rat on ALI at 4 h timepoint; (2) pharmacological interventions using i.t. fluticasone (100 and 300 μg/rat), i.t. pirfenidone (4,000 μg/rat), and peroral dexamethasone (1 mg/kg) at 4 h timepoint; (3) kinetic studies at 0, 2, 4, 6, 8, 10, and 24 h post-LPS challenge. Phenotype or pharmacological efficacy was assessed using predetermined ALI features such as pulmonary inflammation, edema, and inflammatory mediators.

Results: All LPS doses induced a similar increase of inflammation, edema, and inflammatory mediators, e.g., IL6, IL1β, TNFα, and CINC-1. In pharmacological intervention studies, we showed fluticasone and dexamethasone ameliorated ALI by inhibiting inflammation (>60-80%), edema (>70-100%), and the increase of cytokines IL6, IL1β, and TNFα (≥70-90%). We also noticed some inhibition of CINC-1 (25-35%) and TIMP1 (57%) increase with fluticasone and dexamethasone. Conversely, pirfenidone failed to inhibit inflammation, edema, and mediators of inflammation. Last, in ALI kinetic studies, we observed progressive pulmonary inflammation and TIMP1 levels, which peaked at 6 h and remained elevated up to 24 h. Progressive pulmonary edema started between 2 and 4 h and was sustained at later timepoints. On average, levels of IL6 (peak at 6-8 h), IL1β (peak at 2-10 h), TNFα (peak at 2 h), CINC-1 (peak at 2-6 h), and TGFβ1 (peak at 8 h) were elevated between 2 and 10 h and declined toward 24 h post-LPS challenge.

Conclusion: Our data show that 10 μg/rat LPS achieved a robust, profound, and reproducible experimental ALI phenotype. Glucocorticoids ameliorated key ALI features at the 4-h timepoint, but the antifibrotic pirfenidone failed. Progressive inflammation and sustained pulmonary edema were present up to 24 h, whereas levels of inflammatory mediators were dynamic during ALI progression. This study's data might be helpful in designing appropriate experiments to test the potential of new therapeutics to cure ALI.

Background: Cholesterol homeostasis in the human body is a crucial process that involves a delicate balance between dietary cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver. Both pathways contribute significantly to the overall pool of cholesterol in the body, influencing plasma cholesterol levels and impacting cardiovascular health. Elevated absorption of cholesterol in the intestines has a suppressive impact on the synthesis of cholesterol in the liver, serving to preserve cholesterol balance. Nonetheless, the precise mechanisms driving this phenomenon remain largely unclear.

Summary: This review aimed to discuss the previously unrecognized role of cholesin and GPR146 in the regulation of cholesterol biosynthesis, providing a novel conceptual framework for understanding cholesterol homeostasis.

Key messages: The discovery of cholesin, a novel protein implicated in the regulation of cholesterol homeostasis, represents a significant advancement in our understanding of cholesterol biosynthesis and its associated pathways. The cholesin-GPR146 axis could have profound implications across various therapeutic areas concerning abnormal cholesterol metabolism, offering new hope for patients and improving overall healthcare outcomes.

Introduction: There is still no effective treatment for heart failure with preserved left ventricular ejection fraction (HFpEF), and therapies to improve prognosis are urgently needed. Clinical studies in patients with HFpEF have shown that statins and HMG-CoA reductase inhibitors may reduce their mortality rate. However, the mechanisms underlying the effects of statins on HFpEF remain unknown. In the present study, we examined whether simvastatin administration inhibits the development of cardiac fibrosis in HFpEF model mice. We further examined the contribution of the Smad and mitogen-activated protein (MAP) kinase pathways to the transforming growth factor-β (TGF-β) signaling pathway in the development of HFpEF.

Methods: HFpEF animals were prepared by feeding C57BL/6 N mice a high-fat diet and providing water containing N[w]-nitro-l-arginine methyl ester hydrochloride (l-NAME) for 15 weeks. Simvastatin (30 mg/kg/day) or vehicle was administered orally daily during the experimental period. Cardiac function was measured by echocardiography, and cardiac fibrosis was evaluated by Masson's trichrome staining. Changes in the TGF-β signaling proteins in myocardial tissue were examined by Western blotting.

Results: A high-fat diet and l-NAME solution load induced cardiac diastolic dysfunction with cardiac fibrosis. Simvastatin treatment markedly attenuated cardiac fibrosis and reduced cardiac diastolic dysfunction. In addition, simvastatin prevented the increase in phosphorylation levels of Smad (Smad2 and Smad3) and MAPK (c-Raf, Erk1/2) pathway proteins downstream of the TGF-β receptor in cardiac tissue.

Conclusions: Our present study demonstrated that simvastatin attenuated diastolic dysfunction by reducing cardiac fibrosis in HFpEF hearts. Furthermore, our findings suggest that the mechanisms by which simvastatin attenuates HFpEF development involve, at least in part, inhibition of the TGF-β signaling pathway, which is activated in the HFpEF heart.