Journal of Pharmacy and Pharmacology最新文献

Objectives: The primary aim was to characterize the influence of diet-induced obesity on the stereoselective pharmacokinetics of racemic bupivacaine in male and female rats.

Method: Rats were fed either a standard diet (StdD) or high-fat diet (HFD) for 12 weeks. A stereoselective assay was used to measure plasma concentrations after subcutaneous injection of racemic bupivacaine. A rich sampling protocol was initially employed for cannulated rats, while a sparse sampling in non-cannulated rats, coupled with Bayesian forecasting, was used in dietary assessment.

Key findings: Clearance (CL) of both enantiomers was significantly reduced in males fed HFD. StdD females had lower peak concentrations and longer elimination phases than StdD males. Stereoselectivity was modest, with the d-enantiomer displaying marginally higher CL than antipode. There was an apparent late-absorption peak with rich sampling.

Conclusion: Bupivacaine exhibits modest stereoselectivity in rats, with diet and sex influencing CL. The application of Bayesian forecasting in sparse sampling models in rats proved to be a robust tool for pharmacokinetic assessment, aligning with the goals of reducing numbers, refining experimental design and replacing invasiveness of procedures in the use of animals.

Objective: To investigate the mechanism and pharmacological activity of (Xiaoyaosan decoction) XYSD in the treatment of NAFL (nonalcoholic fatty liver) by proteomic techniques.

Methods: C57BL/6 mice NAFL model was induced by HFD (high fat diet), and observed biochemical indicators and histopathological changes. We employed TMT (tandem mass tag) quantitative proteomics and conducted bioinformatics analysis. Additionally, an in vitro model using unsaturated FFA (free fatty acid)-induced lipid accumulation was established to discover the effect of XYSD on lipid accumulation in HepG2 cells.

Results: The results showed that XYSD improved liver index and biochemical indexes, and reversed the characteristics of liver steatosis in NAFL mice. Based on the results of in vivo proteomic enrichment analysis, we hypothesize that the activation of the PPARα signaling pathway may be a potential mechanism underlying the therapeutic effect of XYSD in treating NAFL. XYSD remarkably improved protein and gene expression of Fads2 (fatty acid desaturase 2), Hmgcs2 (3-hydroxymethylglutaryl-CoA synthase 2), Fabp1 (fatty acid-binding protein 1) and PPARα. This hypothesis has been further confirmed in our in vitro experiments.

Conclusion: The study shows that XYSD improves lipid accumulation by activating PPARα signaling pathway, and finally achieves the effect of NAFL.

Objectives: Co-administration of multiple drugs typically induces drug-drug interactions (DDIs). DDIs have the potential to exert significant effects on the pharmacokinetics and therapeutic efficacy of the drugs employed. The treatment for estrogen receptor-positive (ER+) breast cancer is advancing with the incorporation of third-generation selective CDK4/6 inhibitors, such as abemaciclib. Honokiol, a bioactive phytochemical derived from Magnolia species, possesses broad anti-cancer actions. The study aimed to, in vitro and in vivo, investigate the impact of honokiol on the pharmacokinetics of abemaciclib.

Methods: To measure the IC50 values of honokiol on abemaciclib in vitro, rat liver microsomes (RLMs) were used. Eighteen Sprague-Dawley rats were randomly assigned to three groups: honokiol multiple-dose, honokiol single dose and control. All rats received a 10 mg/kg (high energy diet: 1.6 mg/kg) dose of abemaciclib. The plasma concentration of abemaciclib was measured utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS-MS) technique. Molecular docking was performed with AutoDock software to analyse the binding energies of honokiol and abemaciclib to CYP3A4.

Key findings: IC50 values for abemaciclib were determined in vitro in RLMs at 27.6 μM. The results showed that the values of area under the plasma concentration and mean residence time of abemaciclib were significantly increased and the values of Cmax and Tmax were significantly extended when rats were pretreated with honokiol. In contrast, our results revealed that CLz/F values were markedly decreased (P < .05). Honokiol and abemaciclib possess the amino acid residue ALA370 as their binding site, which may explain why they compete for metabolism via the CYP3A4 enzyme.

Conclusions: Honokiol and abemaciclib show significant DDIs in vitro and in vivo and more attention is required when administered synchronously.

Objectives: Formononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN.

‌methods: Antidepressant efficacy was evaluated in corticosterone (CORT)-induced depression models. In vivo, CORT-exposed mice received FMN to assess behavioral and hippocampal changes (dendritic spine density, synaptic markers: MAP-2/GAP-43). In silico, network pharmacology and molecular docking predicted FMN's binding affinity and enriched pathways. In vitro, HT22 cells pretreated with FMN (10 μM, 6 h) were subjected to CORT injury, with mechanistic validation via ERα antagonist (MPP) and ERK inhibitor (PD98059).

Key findings: FMN alleviated depressive-like behaviors and preserved hippocampal integrity in mice. Bioinformatics analysis revealed FMN's strong binding to ER subtypes and enrichment in estrogen/MAPK pathways. In vitro, FMN pretreatment activated the ERK-CREB-BDNF axis in CORT-injured HT22 cells, enhancing neuronal survival and synaptic function. The activation was ERα/ERK-dependent, as evidenced by the abolition of protective effects following pharmacological inhibition with MPP (ERα antagonist) or PD98059 (ERK inhibitor). Concomitantly, in vivo FMN treatment restored hippocampal p-ERK/ERK ratios in mice, directly corroborating the ERK-CREB-BDNF pathway activation and highlighting its efficacy in reversing CORT-induced signaling deficits.

Conclusion: FMN exerts antidepressant effects via ERα-mediated neurotrophic signaling (ERK-CREB-BDNF), offering a mechanistic foundation for natural antidepressant development.

Objectives: β-Caryophyllene (β-Cary) is known for its anti-inflammatory properties and offers a promising avenue for drug development. This study prepared a lipid-based self-emulsifying system containing clove oil-derived β-Cary and investigated its bioavailability and anti-inflammatory effects upon oral administration in rats.

Methods: The formulation (β-SNEDDS), composed of β-Cary, surfactant, and lipophilic phase, was evaluated as size, morphology, and rheology.

Key findings: β-SNEDDS exhibited Newtonian flow and formed spherical droplets (≈100 nm) in water and phosphate-buffered saline (pH 6.8), with a diameter ~15% higher in PBS, likely due to ionic strength affecting surfactant hydration and interfacial structure. Transmission electron microscopy confirmed spherical particles in simulated gastrointestinal medium. β-SNEDDS showed twice the oral bioavailability of β-Cary. This phenomenon allowed β-SNEDDS to reduce carrageenan-induced paw edema and pleural polymorphonuclear leukocyte recruitment in the pleural cavity of rats, showing greater efficacy than β-Cary. Furthermore, β-Cary reduced N-Formyl-Met-Leu-Phe (fMLP)-induced leukocyte chemotaxis in vitro, and oral β-SNEDDS or β-Cary reduced rolling and adherent leukocytes in situ in rat microvascular endothelium. Notably, β-SNEDDS exhibited a more pronounced effect on rolling behavior.

Conclusions: β-Cary showed significant anti-inflammatory activity by inhibiting leukocyte migration to the inflamed site. Its β-SNEDDS formulation improved oral bioavailability and additional anti-inflammatory parameters in vivo, beyond those achieved by β-Cary, supporting this approach as a promising oral strategy.

Objectives: This study investigated the effects of pigment epithelium-derived factor (PEDF) on bone homeostasis in a glucocorticoid-induced osteoporosis (GIOP) rat model, focusing on prostaglandin E2 receptors EP2 and EP4.

Methods: Male Sprague-Dawley rats were divided into six groups. Dexamethasone (DEX, 1 mg/kg) was administered intramuscularly twice weekly for 90 days to induce osteoporosis. PEDF (50, 100, 200 mg/kg) was then given subcutaneously for 30 days. Bone mineral density (BMD) and bone morphology were assessed by computed tomography. Bone turnover markers-C-terminal telopeptide of type I collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRAP-5b), and bone-specific alkaline phosphatase-as well as EP2/EP4 mRNA expressions were evaluated using qRT-PCR.

Key findings: Immunohistochemical analysis was performed for ALP, osteopontin, osteocalcin, and VEGFR1. PEDF partially mitigated DEX-induced weight loss and dose-dependently restored BMD. Histopathological analyses showed improved bone architecture in all PEDF-treated groups. PEDF increased bone formation markers, reduced bone resorption markers, and upregulated EP2/EP4 expression.

Conclusion: These findings indicate that PEDF exerts protective effects against GIOP and may modulate bone metabolism through EP2/EP4 signalling pathways. PEDF shows promise as a potential therapeutic agent for preventing bone loss in GIOP.

Objectives: Increased intraocular pressure (IOP) is a significant risk factor for primary open-angle glaucoma (POAG). Physiologically, the trabecular meshwork (TM) controls IOP and the secretion of aqueous humor. A change in resistance to aqueous outflow is related to the phagocytic ability of trabecular meshwork cells (TMCs); in addition, alterations in extracellular matrix can also affect the function of TMCs. However, their application has certain limitations due to the nondirected differentiation and tumorigenic effect of stem cells, while their exosomes can reduce side effects and exert the same effects.

Methods: The effects of mesenchymal stem cell exosomes on the extracellular environment and the function of human trabecular meshwork cells were observed, and glaucomato-related proteins as well as the NRF2 signaling pathway were detected.

Key findings and conclusions: The exosomes could improve the phagocytosis of TMCs, reduce the damage, and lead to some changes in the pathways related to oxidative stress.

Background: Kidney diseases affect over 850 million people globally and are a significant cause of morbidity and mortality. Traditional biomarkers like serum creatinine, blood urea nitrogen, and proteinuria have limited sensitivity and specificity, often detecting damage only after substantial renal function loss. Even U.S. Food and Drug Administration (FDA)-approved biomarkers, such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C, have limitations because their levels can be influenced by inflammation, infections, or disease stage. There is an urgent need for reliable, non-invasive biomarkers for early diagnosis and treatment guidance.

Objective: This review provides an updated overview of emerging biomarkers for early detection and monitoring of kidney diseases (acute kidney injury, chronic kidney disease, diabetic kidney disease, polycystic kidney disease, lupus nephritis, renal cell carcinoma).

Methods: A comprehensive literature review focused on studies from the past decade on urine and blood-based biomarkers that reflect key pathological processes, including inflammation, tubular injury, fibrosis, and immune activation.

Results: Promising biomarkers include collectrin, olfactomedin 4, activin A, follistatin, USP18, galectin-3, fetuin-A, sestrin-2, podocalyxin, copeptin, anti-C1q, p-cresol glucuronide, serum CD206, lncRNAs, and miRNAs.

Conclusions: These biomarkers may enhance early diagnosis, enable personalized therapy, and improve kidney disease outcomes. Their integration into clinical practice may bridge the gap between early detection and effective intervention, potentially improving long-term outcomes in patients with kidney disease.

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is a Gram-positive bacterium found in hospital-acquired infections, particularly in immunosuppressed individuals. Brazilian red propolis is a beekeeping product with antimicrobial and immunomodulatory properties. Its composition includes flavonoids and benzophenones, such as oblongifolin B (OBLB). This study investigated the antibacterial activity of OBLB isolated from Brazilian red propolis against MRSA in vitro and its modulatory effects on macrophages.

Methods: The activity of OBLB was assessed both alone and in combination with antimicrobials. The minimum inhibitory and minimum bactericidal concentrations were determined for the USA300 MRSA strain and for a clinical isolate. The interaction between OBLB and the antimicrobials against MRSA was analysed using the checkerboard method. The effects of OBLB on THP-1 cells differentiated into macrophages were analysed regarding cytokine and eicosanoid production, cell surface marker expression, bactericidal activity, and hydrogen peroxide production.

Key findings: OBLB exhibited anti-MRSA activity and had no synergistic effects with antimicrobials or cytotoxic effects on macrophages. It stimulated tumor necrosis factor-α and interleukin-1β production, CD80 expression, and increased the bactericidal activity of macrophages suppressed or not by dexamethasone against MRSA.

Conclusions: OBLB exerted anti-MRSA properties and modulated macrophage activity, suggesting it is a potential candidate in new therapeutic approaches for MRSA infections.

Objectives: Tamoxifen is an endocrine therapy for breast cancer that works by competing with estradiol for estrogen receptors, but continued use of tamoxifen by patients can lead to resistance and metastasis. Studies have shown that 4-hydroxytamoxifen (4-OH-TAM), the active product of tamoxifen, promotes the malignant biological behavior of breast cancer cells, but the mechanism is not fully understood.

Methods: We investigated the effects of 4-OH-TAM on breast cancer cell stemness, paclitaxel (PTX) resistance and metastasis. Molecular mechanism studies were used to investigate the pro-cancer effects of 4-OH-TAM.

Key findings: Treatment with low-dose 4-OH-TAM increased the resistance of ER-positive (MCF-7 and T47D cells) and triple-negative (4T1 and MDA-MB-231 cells) breast cancer cells to PTX. In vitro and in vivo experiments showed that 4-OH-TAM enhanced stemness in T47D and 4T1 cells by upregulating the stem cell markers CD44 and CD133. Mechanistically, 4-OH-TAM enhanced breast cancer cell stemness by upregulating estrogen-related receptor alpha (ERRα) protein expression via neuropilin-1 (NRP-1). Notably, inhibition of the NRP-1/ERRα signaling pathway reversed 4-OH-TAM-induced PTX resistance and tumor metastasis.

Conclusion: 4-hydroxytamoxifen enhances stemness through the NRP/ERRα pathway to enhance breast cancer cell PTX resistance and metastasis.