Frontiers in Pharmacology最新文献

Purpose: Diabetic cardiomyopathy (DCM), which is diabetes mellitus-induced cardiomyopathy, significantly elevates the risk of heart failure and sudden cardiac death. No specific treatments for DCM are currently available. Gallic acid (GA) is a polyhydroxyphenolic compound that has been shown to inhibit ferroptosis and maintain mitochondrial homeostasis, with potential therapeutic effects in various cardiac diseases. However, its specific role and underlying mechanisms in DCM remain unexplored.

Methods: An in vitro model was established using H9C2 cells pretreated with high glucose plus palmitate, and an in vivo type 2 diabetes mellitus model generated by treating rats with streptozotocin-induced and feeding a high-fat diet. The protective effects of GA and its mechanism of action were evaluated using various methods, including flow cytometry, Western blotting (WB), and transmission electron microscopy. Bioinformatics analysis identified potential target genes for GA's cardioprotection, which were subsequently validated using pAD/TSPO (for overexpression) and pAD/FTMT-shRNA (for silencing) constructs.

Results: GA treatment decreased PTGS2, lactate dehydrogenase, malondialdehyde, ferrous iron, ROS, and oxidized glutathione disulfide (GSSG) levels and increased cell viability, glutathione (GSH) levels, the GSH/GSSG ratio, and GPX4 protein levels in the injury models. GA markedly attenuated mitochondrial ultrastructural damage and promoted mitochondrial homeostasis. These protective effects were abrogated by TSPO overexpression and FTMT silencing.

Conclusion: GA was shown to attenuate diabetic cardiomyopathy by inhibiting ferroptosis and protecting mitochondria via the TSPO/FTMT signaling pathway.

Aim: This study aims to explore the impact of the distance between the tumor and the main trunk or first branch of the portal vein on the prognosis of hepatocellular carcinoma (HCC) patients undergoing radical resection.

Methods: This study retrospectively evaluated HCC patients who underwent radical resection between 1 January 2018 and 30 September 2024. Tumors were classified into two categories based on their location: central tumors and peripheral tumors. Central tumors were defined as those located within 2 cm of the main trunk or first branch of the portal vein, while the remaining tumors were classified as peripheral tumors. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups. Univariate and multivariate COX analyses were conducted to identify factors associated with RFS and OS. Propensity score matching (PSM) was employed to eliminate intergroup differences for further validation.

Results: A total of 667 HCC patients undergoing radical resection were initially enrolled. Through PSM, 247 patients were successfully matched in each comparative group. In the PSM cohort, the median RFS (mRFS) for patients with central tumors was 23.00 months (95% CI, 18.01-27.99 months), while the mRFS for those with peripheral tumors was 30.50 months (95% CI, 26.17-34.83 months) (p = 0.004). The median OS was 56.00 months (95% CI, 52.10-59.90 months) for central tumors and 72.00 months (95% CI, 67.37-76.63 months) for peripheral tumors (p = 0.043). Multivariate COX analysis confirmed that the distance of less than 2 cm between the tumor and the main trunk or first branch of the portal vein was an independent risk factor for RFS and OS in patients undergoing radical resection for HCC (HR: 1.744, p < 0.001; 1.728, p < 0.001, respectively).

Conclusion: The distance between the tumor and the main portal vein trunk or first branch correlates with the prognosis of hepatocellular carcinoma patients undergoing radical resection.

Background: Darolutamide, a novel androgen receptor inhibitor, significantly improved outcomes in the ARASENS trial when combined with androgen deprivation therapy (ADT) and docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer (mHSPC). In China, the regimen has been reimbursed since December 2023, expanding real-world accessibility. PSMA imaging-guided focal therapy enables precise localization of residual or oligometastatic lesions and may complement systemic control.

Objective: To evaluate the real-world efficacy and safety of darolutamide-based triplet therapy combined with PSMA imaging-guided focal treatment in patients with mHSPC.

Methods: This multicenter, retrospective study included 17 patients treated across three tertiary hospitals between June 2023 and June 2024. All patients received darolutamide (600 mg twice daily), ADT, and docetaxel (75 mg/m² every 3 weeks for 4-6 cycles), followed 4-6 weeks later by focal therapy (surgery or radiotherapy) based on multidisciplinary team (MDT) assessment and PSMA IMAGING findings. Data collection followed STROBE recommendations. The primary endpoint was PSA90 response; secondary endpoints included PSA ≤0.2 ng/mL, PSA progression-free survival (PSA-PFS), radiographic PFS (rPFS), and safety.

Results: Seventeen patients with predominantly low- to intermediate-volume metastatic disease were analyzed. The PSA90 response rate was 94.1%, and 82.4% achieved PSA ≤0.2 ng/mL. Median PSA-PFS and rPFS were not reached at a median follow-up of 16 months. The 12-/18-month PSA-PFS rates were 88% and 65%, while the corresponding rPFS rates were 94% and 76%. Grade 1-2 myelosuppression (64.7%) and fatigue (47.1%) were most common; grade 3 neutropenia occurred in two patients (11.8%) without grade ≥4 events. Focal therapy was well tolerated, with no severe complications.

Conclusion: Darolutamide-based triplet therapy combined with PSMA-guided focal intervention achieved deep biochemical responses and durable disease control with manageable toxicity in real-world Chinese patients with mHSPC. The multicenter design and standardized methodology support the feasibility of this multimodal approach, which warrants validation in larger prospective studies.

Background: CP/CPPS is characterized by pain, the primary symptom, which significantly affects QoL and disrupts lower urinary tract function. Conventional monotherapies are often ineffective, necessitating multimodal treatments targeting key symptoms.

Methods: This multicenter, prospective, randomized, parallel, positive-controlled trial enrolled 323 men aged 18-60 years with CP/CPPS across 14 centers in China. Participants were randomly assigned to three groups: tamsulosin 0.2 mg daily, Ningmitai capsule (NMT) 1.52 g thrice daily, or a combination of both, for 8 weeks. The primary endpoint was the change in the total NIH-CPSI score from baseline to week 8. Secondary endpoints included changes in pain, urinary, QoL subdomains, the percentage of patients achieving a ≥25% reduction in NIH-CPSI total score, and pain scores. Safety was monitored through adverse events and liver function tests.

Results: Of the 323 patients, 108 received tamsulosin, 109 NMT, and 106 combination therapy. After 8 weeks, both NMT and combination therapy demonstrated significantly greater reductions in total NIH-CPSI scores compared to tamsulosin (-11.44 vs. -8.58, P < 0.001; -11.94 vs. -8.58, P < 0.001). Combination therapy also significantly reduced pain (P = 0.001) and improved QoL (P < 0.001) compared to tamsulosin. The NMT group showed greater improvements in pain scores at both 4 and 8 weeks compared to tamsulosin (P < 0.05). At week 8, the percentage of patients achieving a ≥25% reduction in NIH-CPSI total score was significantly higher in the NMT (78.64% vs. 55.91%, P < 0.001) and combination groups (82.83% vs. 55.91%, P < 0.001). Subgroup analyses indicated that NMT was most effective in patients with mild to moderate CP/CPPS, younger age (18-34 years), and disease duration of <12 months. No serious adverse events occurred, and NMT was well-tolerated across all groups.

Conclusion: NMT demonstrated superior efficacy over tamsulosin in reducing pain and improving QoL in CP/CPPS patients. Combination therapy provided enhanced symptom relief, particularly in micturition and QoL domains, supporting a multimodal approach for more effective CP/CPPS management. These findings validate NMT as a promising treatment, either alone or in combination, for CP/CPPS. Further long-term studies are needed to optimize its use.

Clinical trial registration: ClinicalTrials.gov, identifier NCT05890235.

Introduction: Toxoplasmosis is a disease caused by the protozoan Toxoplasma gondii. Infection during pregnancy can lead to congenital toxoplasmosis, which is associated with severe outcomes such as fetal abnormalities, stillbirths, and miscarriage. Current treatment options for congenital toxoplasmosis have several limitations, including low efficacy in the chronic phase of the disease and concerns about potential fetal toxicity, such as bone marrow suppression and teratogenic effects. Therefore, there is an urgent need for more effective and safer therapeutic alternatives. The Medicines for Malaria Venture (MMV) offers a collection of bioactive compounds with antiparasitic potential for drug repurposing.

Methods: In this study, we evaluated three MMV Pathogen Box compounds-MMV675968, MMV022478, and MMV021013-for their ability to control T. gondii infection in human trophoblastic cells (BeWo) and third-trimester placental villous explants. We assessed compound toxicity, effects on the parasite's lytic cycle (including adhesion and infection), alterations in parasite morphology, and the host immune response through cytokine quantification.

Results: Nontoxic concentrations of all the three compounds irreversibly inhibited parasite proliferation and interfered with early stages of the lytic cycle, including adhesion and infection. Moreover, treated T. gondii tachyzoites exhibited membrane disruption, cytoplasmic degradation, and organelle disorganization. The cytokine profile indicated that compound treatment promoted an anti-inflammatory immune response, primarily by reducing IL-8 levels. Importantly, these compounds also effectively controlled T. gondii infection in human placental explants without inducing cytotoxicity.

Conclusion: Taken together, our findings support the potential of MMV675968, MMV022478, and MMV021013 as promising drug candidates for the treatment of congenital toxoplasmosis. MMV021013 stands out as the most promising compound, combining high predicted gastrointestinal (GI) absorption and blood-brain barrier (BBB) permeability, with no predicted mutagenic, tumorigenic, irritant, or reproductive effects.

Background: Cryptocarya alba (Mol.) Looser [Lauraceae], known as peumo, is an endemic species of the central Chilean landscape. C. alba has an essential ecological role in the threatened sclerophyllous forest, with traditional uses of leaves, bark, and fruits, and the biotechnological and pharmacological potential of its phytochemicals.

Purpose: The aim is to present the first comprehensive review of the current state of knowledge regarding traditional uses, ethnopharmacology, chemical composition, pharmacokinetic profile, and biological activities of C. alba.

Methodology: Literature data on the traditional uses, ethnopharmacology, chemistry, and bioactivity of C. alba were primarily obtained from digital databases, including Scopus®, ScienceDirect®, SciFinder®, PubMed®, SciELO, and Google Scholar®, as well as from the scientific journal publishers' platforms associated with these databases.

Results and discussion: Traditional uses include its role as a food source for prehistoric populations and ethnomedicinal applications for liver diseases, rheumatism, and infections. The aerial parts are rich in polyphenols, including chlorogenic acid, epicatechin, procyanidins, quercitrin, rutin, and hyperoside, as well as essential oils derived from the leaves. While it contains various alkaloids, only reticuline is present in significant amounts, contributing to the species' highly variable chemical composition. Studies evaluating the biological and pharmacological properties of its extracts and constituents are limited to a few in vitro and in vivo studies; to date, no preliminary or clinical studies are available.

Conclusion: The review highlights the entire existing ethnographic and cultural context of C. alba, revealing a significant gap in information about the species. Although there is a strong historical component, it supports the bioactivity of its main secondary metabolites, given its chemical and pharmacological profile. Given the limited nature of current biological and pharmacological evaluation studies, future research should focus on advancing preclinical and clinical trials, as well as toxicology studies, to ensure the safe and effective use of this approach.

Common kidney diseases include acute kidney injury, diabetic kidney disease, kidney cancer, and other related conditions. Ginsenosides, the principal bioactive constituents of ginseng, have been widely reported as therapeutic agents against these disorders. However, recent advances regarding their efficacy in kidney diseases have not been comprehensively synthesized. This review addresses this gap by summarizing current findings on the mechanisms and therapeutic targets of ginsenosides. Literature from PubMed, Web of Science, and other databases was systematically retrieved using keywords such as ginsenosides, acute kidney injury, diabetic nephropathy, renal cell carcinoma, lupus nephritis, and aging-related kidney injury. Evidence from cell-based and animal studies demonstrates that ginsenoside compound K, Rg1, Rg3, Rh2, Rb1, Rb3, Rg2, and Rg5 are the most frequently reported for kidney protection. Mechanistically, ginsenosides modulate multiple signalling networks, including NF-κB, PI3K/AKT, MAPK, TGF-β/Smads, PPAR, SIRT1, NLRP3, and Nrf2, to mitigate inflammation, oxidative stress, apoptosis, epithelial-mesenchymal transition, pyroptosis, autophagy, and endoplasmic reticulum stress. Taken together, these findings provide valuable insights into the therapeutic potential of ginsenosides and underscore their promise as candidates for the prevention and treatment of kidney diseases.

Objective: Although farrerol exhibits promising antitumor properties against various cancers, its potential therapeutic effects on colorectal cancer (CRC) remain unexplored, and the underlying mechanisms are still unclear. Based on network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experiments, this study aims to investigate the molecular mechanisms of farrerol in the treatment of CRC, thereby providing new research directions for CRC therapy.

Methods: This study employed network pharmacology to screen for potential therapeutic targets and pathways of farrerol in CRC, followed by preliminary validation of target validity through molecular docking and molecular dynamics simulations. Finally, in vitro experiments were conducted to verify the antitumor effects of farrerol against CRC.

Results: Network pharmacology identified 12 key targets: CCNA1, CCNA2, CCNE1, CDC25B, CDK2, CYP19A1, ESR1, ESR2, HSP90AA1, PTPN1, RAF1, and SRC. The molecular docking results revealed that the binding energies of farrerol with all target proteins were as follows: farrerol-CCNA1 (-8.6 kcal·mol^-1), farrerol-CCNA2 (-7.0 kcal·mol^-1), farrerol-CCNE1 (-7.4 kcal·mol¹), farrerol-CDC25B (-7.3 kcal·mol^-1), farrerol-CDK2 (-10.1 kcal·mol^-1), farrerol-CYP19A1 (-8.4 kcal·mol^-1), farrerol-ESR1 (-3.3 kcal·mol^-1), farrerol-ESR2 (-8.9 kcal·mol^-1), farrerol-HSP90AA1 (-10.4 kcal·mol^-1), farrerol-PTPN1 (-7.6 kcal·mol^-1), farrerol-RAF1 (-4.5 kcal·mol^-1), farrerol-SRC (-9.9 kcal·mol^-1), farrerol-VEGFA (-8.5 kcal·mol^-1), and farrerol-KDR (-9.0 kcal·mol^-1). These data indicate that farrerol can spontaneously bind to the target proteins. Molecular dynamics simulations demonstrated favorable interactions within the KDR-Farrerol and VEGFA-Farrerol complexes. In vitro experimental results demonstrated that farrerol could inhibit the proliferation and migration of CRC cells, induce cell cycle arrest at the G0/G1 phase, and suppress the protein expression of VEGFA, VEGFR2, and p-VEGFR2.

Conclusion: This study, for the first time, validated the antitumor effect of farrerol against CRC through network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experiments. The findings indicate that the ability of farrerol to inhibit the proliferation and migration of colorectal cancer cells may be associated with the induction of G0/G1 phase cell cycle arrest and the regulation of VEGF signaling pathway activation via binding to VEGFA and KDR.

Objective: Obesity disrupts intestinal homeostasis, leading to increased permeability ("leaky gut"), mucosal inflammation, and systemic metabolic dysfunction. Mitochondrial impairment in intestinal epithelial cells (IECs) is a central driver of this process. Essential amino acids (EAAs) improve mitochondrial function in metabolic tissues, but their impact on intestinal health remains underexplored. Here, we investigated whether dietary EAAs preserve gut barrier integrity through mitochondrial protection in obesity and inflammation.

Methods: Male C57BL/6N mice were fed a high-fat diet (HFD) or an isocaloric, isonitrogenous EAA-substituted HFD (HFD-EAA) for 33 weeks to assess metabolic outcomes, intestinal barrier function, inflammation, and mitochondrial biogenesis. Parallel, in vitro studies in differentiated Caco-2 cells tested an EAA formula enriched with Krebs cycle intermediates (E7), under basal and pro-inflammatory conditions (IL-1β, TNF-α, LPS).

Results: HFD-EAA supplementation prevented and reversed obesity, improved glucose tolerance, reduced mesenteric fat expansion, and preserved intestinal barrier integrity while attenuating inflammation. EAAs restored intestinal length and weight, lowered plasma calprotectin, and normalized citrulline, a biomarker of enterocyte mass. Tight and adherens junction proteins (zonulin-1, occludin, E-cadherin, claudins) were maintained, while pore-forming claudin-2 was reduced. EAAs also upregulated PGC-1α and mitochondrial electron transport chain genes in intestinal epithelial cells (IECs). Their direct effects were confirmed in vitro in Caco-2 cells, where E7 increased transepithelial electrical resistance (TEER), enhanced mitochondrial respiration, suppressed inflammation-induced glycolytic reprogramming, activated antioxidant defenses, and reduced IL8 secretion. Mechanistically, E7 promoted eNOS phosphorylation and inhibited mTORC1 signaling.

Conclusion: EAAs protect gut barrier integrity by sustaining mitochondrial biogenesis and function in IECs, thereby reducing obesity- and stress-induced inflammation. These findings highlight EAAs as a promising nutritional strategy to counteract mitochondrial dysfunction and prevent or reverse gut barrier disruption in obesity-related and inflammatory disorders.

Dapansutrile, an orally active and selective NLRP3 inflammasome inhibitor, exerts its effects by directly binding to the NLRP3 NACHT domain. This action disrupts inflammasome assembly and caspase-1 activation, thereby inhibiting the maturation and release of the pro-inflammatory cytokines IL-1β and IL-18. Beyond this core inhibition, dapansutrile modulates immune cell chemotaxis and inhibits pyroptosis. Preclinical and clinical studies demonstrate its efficacy in mitigating pathology in diverse conditions, including gouty arthritis, cardiovascular diseases, neurodegenerative disorders, inflammatory bowel disease, and periodontitis. A favorable safety profile distinguishes it from other NLRP3 inhibitors like MCC950, with no significant hepatotoxicity reported in trials. Furthermore, dapansutrile exhibits synergistic effects when combined with agents such as lonafarnib or immune checkpoint inhibitors, enhancing anti-inflammatory and anti-tumor responses. This review consolidates evidence on dapansutrile's molecular mechanisms, therapeutic applications, and biosafety, highlighting its potential as a novel, well-tolerated, and versatile anti-inflammatory agent. Future research should focus on optimizing its delivery, particularly to the central nervous system, and leveraging artificial intelligence to predict effective drug combinations.