Current molecular pharmacology最新文献

Background: Ginkgetin, a flavonoid extracted from Ginkgo biloba, has been shown to exhibit broad anti-inflammatory, anticancer, and antioxidative bioactivity. Moreover, the extract of Ginkgo folium has been reported on attenuating bleomycin-induced pulmonary fibrosis, but the anti-fibrotic effects of ginkgetin are still unclear. This study was intended to investigate the protective effects of ginkgetin against experimental pulmonary fibrosis and its underlying mechanism.

Methods: In vivo, bleomycin (5 mg/kg) in 50 μL saline was administrated intratracheally in mice. One week after bleomycin administration, ginkgetin (25 or 50 mg/kg) or nintedanib (40 mg/kg) was administrated intragastrically daily for 14 consecutive days. In vitro, the AMPK-siRNA transfection in primary lung fibroblasts further verified the regulatory effect of ginkgetin on AMPK.

Results: Administration of bleomycin caused characteristic histopathology structural changes with elevated lipid peroxidation, pulmonary fibrosis indexes, and inflammatory mediators. The bleomycin- induced alteration was normalized by ginkgetin intervention. Moreover, this protective effect of ginkgetin (20 mg/kg) was equivalent to that of nintedanib (40 mg/kg). AMPK-siRNA transfection in primary lung fibroblasts markedly blocked TGF-β1-induced myofibroblasts transdifferentiation and abolished oxidative stress.

Conclusion: All these results suggested that ginkgetin exerted ameliorative effects on bleomycininduced oxidative stress and lung fibrosis mainly through an AMPK-dependent manner.

Background: Chronic kidney disease is a global health problem for which renal fibrogenesis is the final treatment target.

Objective: In our work, we have highlighted two new strategies, nicorandil and Bone marrow-derived mesenchymal stem cells (BM-MSCs), as effective in reversing renal fibrosis induced by partial unilateral ureteral obstruction (PUUO).

Methods: The current study included 96 male albino rats randomly divided into four groups, with 24 rats per group; Group I, the control group; Group II, PUUO, where two-thirds of the left ureter was entrenched in the psoas muscle; Group III, same surgical procedure as in Group II for 7 days, and then the rats received 15 mg/kg/day nicorandil once daily for 21 days; and Group IV, same surgical procedure as in Group II for 7 days, and then rats were given 3 × 106 of labeled MSCs injected intravenous, and left for 21 days. Blood and kidney tissues were collected for biochemical, histological, and molecular analyses.

Results: Both the nicorandil and BM-MSCs treatment groups could ameliorate kidney damage evidenced by inhibition of MDA elevation and total antioxidant capacity reduction caused by PUUO. Also, there was a significant reduction observed in TNF, TGF, IL6, collagen I, and α-SMA in addition to improvement in histological examination. However, a significant difference was found between the BM-MSCs and nicorandil-treated groups.

Conclusion: Our results suggest that BM-MSCs and nicorandil improved renal fibrosis progression through their antiapoptotic, anti-inflammatory, and antifibrotic effects in male albino rats subjected to PUUO, with BM-MSCs being more effective compared to nicorandil.

Background: Alzheimer's disease (AD), the primary cause of dementia, escalating worldwide, has no proper diagnosis or effective treatment. Neuronal cell death and impairment of cognitive abilities, possibly triggered by several brain mechanisms, are the most significant characteristic of this disorder.

Methods: A multitude of pharmacological targets have been identified for potential drug design against AD. Although many advances in treatment strategies have been made to correct various abnormalities, these often exhibit limited clinical significance because this disease aggressively progresses into different regions of the brain, causing severe deterioration.

Results: These biomarkers can be game-changers for early detection and timely monitoring of such disorders.

Conclusion: This review covers clinically significant biomarkers of AD for precise and early monitoring of risk factors and stages of this disease, the potential site of action and novel targets for drugs, and pharmacological approaches to clinical management.

Objective: Cardiac ischemia-related myocardial damage has been considered a major reason for heart failure. We aimed to investigate the role of levosimendan (LEVO) in comparison to ramipril and sacubitril/valsartan (Sac/Val) in preventing damage associated with isoproterenol (ISO) induced myocardial infarction.

Methods: Myocardial infarction was induced by injecting subcutaneous isoproterenol (5 mg/kg once for 7 consecutive days) to establish an experimental heart failure model. Simultaneously, LEVO (1 mg/kg/day), ramipril (3mg/kg/day) and Sac/Val (68 mg/kg/day) suspension were administered orally for four weeks.

Results: We observed a significant correlation between ISO-induced ischemia with cardiac remodeling and alterations in myocardial architecture. LEVO, ramipril, and Sac/Val significantly prevented lipid peroxidation and damaged antioxidant enzymes like superoxide dismutase, catalase, glutathione and thioredoxin reductase. We also observed their ameliorative effects in myocardium's cardiac hypertrophy, evidenced by reduced heart weight to body weight ratio and transforming growth factor β related collagen deposition. LEVO, ramipril, and Sac/Val also maintained cardiac biomarkers like lactate dehydrogenase, creatine kinase-MB, brain natriuretic peptide and cardiac Troponin-I, indicating reduced myocardial damage that was further demonstrated by histopathological examination. Decreased sarcoplasmic endoplasmic reticulum Ca2+ATPase2a and sodium-calcium exchanger-1 protein depletion after LEVO, ramipril, and Sac/Val administration indicated improved Ca2+ homeostasis during myocardial contractility.

Conclusion: Our findings suggest that LEVO has comparable effects to ramipril, and Sac/Val in preventing myocardial damage via balancing oxidant-antioxidant system, decreased collagen deposition, reduced myocardial stress as well as improved Ca2+ homeostasis during myocardial contractility.

Background: Increased exposure of humans to toxic metals and high-fat diet (HFD) consumption severely damages brain health. Natural plant extracts have shown huge potential to treat multiple human diseases.

Objective: The present study was designed to evaluate the protective effects of Shogaol (an active component of ginger) in neuroinflammation and behavioral paradigms in mice treated with metals and HFD.

Methods: 8-11 weeks old male mice model was developed by giving a combination of metals, i.e., Arsenic (As), Lead (Pb) and Aluminum (Al), 25mg/kg each mixed in drinking water with laboratory prepared HFD (40% fat) for a total duration of 72 days. Shogaol treated groups received two doses (2mg/kg & 12mg/kg) of Shogaol along with metals and HFD. The biochemical parameters, including body weights, blood glucose, and kidney and liver functions, were assessed along with the integrity of the blood-brain barrier (BBB). The expression analysis of neuroinflammatory genes (TNF-α, IL-1β & GFAP) was performed using q-PCR in the hippocampus and cortex. The exploratory and anxiety-like behavior was assessed using an open field test, and depressive behavior was assessed through the forced swim test, while learning and memory were assessed using the Morris water maze test and y-maze test.

Results: Shogaol (2mg/kg & 12mg/kg) treatment improved metabolic profile and reduced expression of neuroinflammatory genes in the cortex and the hippocampus. Shogaol treatment improved BBB integrity. Results of the behavioral analysis showed that Shogaol treatment (2mg/kg & 12mg/kg) rescued behavioral impairment and improved anxiety and depression.

Conclusion: Shogaol treatment showed strong therapeutic potential in metals & HFD induced neuroinflammation and improved cognitive functions; thus, can be considered a potential drug candidate in the future.

The increasing number of cases of diabetes mellitus (DM) and related diseases has become a global health concern. In this context, controlling blood glucose levels is critical to prevent and/or slow down the development of diabetes-related complications. Incretins, as gutderived hormones that trigger the post-meal secretion of insulin, are a well-known family of blood glucose modulators. Currently, incretin medications, including glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors, are extensively used to treat patients with type 2 diabetes mellitus (T2D). Several experimental and clinical studies illustrate that these metabolic hormones exert their antidiabetic effects through multiple molecular mechanisms. Accordingly, the current review aims to investigate key mechanisms and signaling pathways, such as the cAMP/PKA, Nrf2, PI3K/Akt, and AMPK pathways, associated with the antidiabetic effects of incretins. It also summarizes the outcomes of a group of clinical trials evaluating the incretins' antidiabetic potential in diabetic patients.

Magnolol and honokiol are natural lignans with good physiological effects. As the main active substances derived from Magnolia officinalis, their pharmacological activities have attracted extensive attention. It is reported that both of them can cross the blood-brain barrier (BBB) and exert neuroprotective effects through a variety of mechanisms. This suggests that these two ingredients can be used as effective therapeutic compounds to treat a wide range of neurological diseases. This article provides a review of the mechanisms involved in the therapeutic effects of magnolol and honokiol in combating diseases, such as cerebral ischemia, neuroinflammation, Alzheimer's disease, and brain tumors, as well as psychiatric disorders, such as anxiety and depression. Although magnolol and honokiol have the pharmacological effects described above, their clinical potential remains untapped. More research is needed to improve the bioavailability of magnolol and honokiol and perform experiments to examine the therapeutic potential of magnolol and honokiol.

Mycobacterium tuberculosis causes a contagious pulmonary disease with a high mortality rate in developing countries. However, the recommendation of DOTS (approved by WHO) was effective in treating tuberculosis, but nowadays, resistance from the first line (MDR-TB) and the second line (XDR-TB) drugs is highly common. Whereas, the resistance is a result of factors like poor patient constancy due to the long duration of therapy and co-infection with HIV. The approval of bedaquiline under an accelerated program for the treatment of MDR-TB has revealed its effectiveness in clinical trials as a therapeutic novel molecule. BDQ selectively inhibits the ATP synthase of bacterium and reduces ATP production. Additionally, the poor pharmacokinetic properties raised provocations in the MDR therapy, but the use of targeted drug delivery can solve the hurdles. While the preclinical and clinical studies included in this review are strongly suggesting the usefulness of BDQ in MDR-TB and XDR-TB, the repurposing of different drug classes in resistant TB is opening new opportunities to manage the disease conditions. In this review, we have summarized the examples of pipeline drugs and repurposed molecules with preclinical formulation developments.

Background: Acne is a chronic inflammatory disease mainly observed in adolescence, but it can also be seen during the neonatal, infantile, pre-pubertal, and adult periods. Isotretinoin (13-cis-retinoic acid) is a first-generation retinoid and is the most effective treatment for acne vulgaris.

Objective: The present study has been systematically designed to figure out the toxic, genotoxic, and carcinogenic activities of isotretinoin.

Methods: In this study, a systematic approach was followed by focusing on the possible links between these topics. The search of the databases was carried out author in accordance with the guidelines of the Centre for Reviews and Dissemination (2009) developed by York University National Institute of Health Research. The search was concentrated on the Web of Science, PubMed, Science Direct, Scopus, EBSCO Host, and Google Scholar databases.

Results: Isotretinoin was found as a toxic agent in all studies. All researchers proposed that apoptosis is the only pathway of adverse effects of isotretinoin. However, genotoxicity, teratogenicity, and carcinogenicity information of isotretinoin is very limited and controversial.

Conclusion: More detailed studies need to clarify the genotoxic and carcinogenic potential of isotretinoin. Patients should be informed correctly, the risks of treatment should be explained, and awareness should be raised.

Background: Migraine is a common neurological condition marked by frequent mild to extreme headaches that last 4 to 72 hours. A migraine headache may cause a pulsing or concentrated throbbing pain in one part of the brain. Nausea, vomiting, excessive sensitivity to light and sound, smell, feeling sick, vomiting, painful headache, and blurred vision are all symptoms of migraine disorder. Females are more affected by migraines in comparison to males.

Objective: The present review article summarizes preventive and therapeutic measures, including allopathic and herbal remedies for the treatment of migraine.

Results: This review highlights the current aspects of migraine pathophysiology and covers an understanding of the complex workings of the migraine state. Therapeutic agents that could provide an effective treatment have also been discussed.

Conclusion: It can be concluded that different migraines could be treated based on their type and severity.