Journal of Pharmacy and Pharmacology最新文献

Objectives: The objective of this research was to enhance the bioavailability of ursolic acid (UA) by preparing multielement amorphous solid dispersion (ASD) systems comprising excipients.

Methods: The ASDs were prepared via the solvent evaporation method, characterized by a range of techniques, and investigated with respect to permeability of human colorectal adenocarcinoma cell line (Caco-2) cells monolayers and pharmacokinetics, with comparisons made to the physical mixture and the pure drug.

Key findings: The (UA-choline)-Polyethylcaprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer (Soluplus)-Vitamin E polyethylene glycol succinate (TPGS) ASD demonstrated superior dissolution properties compared to the corresponding binary solid dispersions and ternary solid dispersions (P < .05). The permeability studies of Caco-2 cell monolayers revealed that the ASD exhibited moderate permeability, with an efflux rate that was significantly lower than that of the UA raw material (P < .05). Pharmacokinetic studies in rats demonstrated that the oral bioavailability of the ASD was 19.0 times higher than that of UA (P < .01).

Conclusions: The research indicated that the multielement ASD could be employed as an efficacious drug delivery system for UA. Furthermore, the Soluplus/TPGS/choline combination represents a promising candidate for the fabrication of ASDs that can load weakly acidic and poorly soluble drugs.

Objectives: Rhein is one of the main bioactive compounds in the Polygonaceae plant, and has been proven to have anti-cancer activity in some reports. But the mechanism of Rhein in the treatment of gastric cancer (GC) is limited reported. In this research, network pharmacology combined with in vitro experiments was used for systematically studying the mechanism of Rhein.

Methods: Network pharmacology confirmed the major effect signaling pathway and key targets of Rhein in the treatment of GC. Cell viability assay, colony formation assay, fluorescence probe assay, apoptosis assay, western blot and qRT-PCR verified the mechanism of Rhein in the treatment of GC cells (AGS and MGC803 cells).

Key findings: The results showed that Rhein significantly induced the apoptosis process of AGS and MGC803 cells by regulating the Ras/phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) and the p38/mitogen-activated protein kinase signaling pathways. The AKT activator (SC79) and p38 inhibitor (SB202190) inhibited Rhein-induced apoptosis.

Conclusions: All results proved that Rhein could be recognized as a potential natural drug for the treatment of GC.

Objectives: Lipid nanoparticles (LNPs) play a crucial role in RNA-based therapies, and their production is generally based on nanoprecipitation and coalescence of lipids around an RNA core. This study investigated crossflow micromixing to prepare LNPs across various mixing ratios and production speeds.

Methods: A range of LNPs were prepared using crossflow micromixing across production speeds of 10-500 ml/min, and their physico-chemical characteristics (size, polydispersity index (PDI), zeta potential, and mRNA encapsulation), in vitro mRNA expression and in vitro efficacy (protein expression and antibody and cytokine responses).

Key findings: Our results demonstrate the reproducible production of mRNA-LNPs with controlled critical quality attributes, including high mRNA encapsulation from the initial screening scale through to GMP-scale production, where the same mixing ratio can be adopted across all product speeds from 30 to 500 ml/min used.

Conclusions: We confirm the applicability of stainless-steel crossflow membrane micromixing for the entire spectrum of mRNA-LNP production, ranging from initial discovery volumes to GMP-production scale.

Purpose: Investigate the protective effect and mechanism of Puerarin (PU) against Dioscorea bulbifera L. (DB)-induced liver injury.

Materials and methods: The protective effect of PU against DB-induced liver injury was evaluated by the present animal experiment, which assessed the pathological changes in the liver of mice and detected Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (AKP), as well as inflammation and oxidative stress-related indexes. Finally, the transcription and expression of related proteins were detected using western blot and quantitative reverse transcription (PCR) techniques.

Results: PU significantly increased body weight, reduced liver index, and attenuated pathological changes in the liver compared to the DB group. It also decreased levels of AST, ALT, AKP, tumor necrosis factor-α, interleukin-1β, and malondialdehyde while increasing interleukin-10 levels and superoxide dismutase activity. Additionally, it upregulated inhibitor of NF-κB (IκB-α), B-cell lymphoma-2 (Bcl-2), Nuclear respiratory factor 2 (Nrf2), and Heme oxygenase 1 (HO-1) expression while down-regulating p-NF-κB p65 and bcl2-associated x (Bax) expression in the liver. Furthermore, PU upregulated protein and gene expression levels of Multidrug resistance-associated protein2, bile salt export pump, p-glycoprotein, and UDP-glucuronyltransferase 1A1 (UGT1A1) as well.

Conclusion: PU mitigates DB-induced liver injury by regulating the expression of drug transporters and modulating the Nrf2/NF-κB/Bcl-2 signaling pathway.

Background: Agastache mexicana is used in traditional medicine to treat anxiety, insomnia, pain, among others. In a previous study, the methanolic extract exerted anxiolytic and sedative effects, as observed behaviorally, associated with one of its major components, tilianin.

Objective: To assess the effect produced by the extracts and tilianin obtained from Agastache mexicana on depressive-induced behavior model and on the activity of monoamine oxidases (MAOs).

Methods: The depression experimental model consisted of the forced swimming test in rats. MAOs activity was evaluated in cortex and hippocampus from the tilianin and Agastache extracts treated rats using specific inhibitors for each isoform. The quantification of monoamines was carried out using an High Performance Liquid Chromatography method.

Results: An increase in the swimming time was observed in rodents treated with doses of 16 (226.6 ± 5.5 seconds) and 50 mg/kg (237.8 ± 5.7 seconds) of tilianin, methanolic (260.4 ± 3 seconds), and hydroalcoholic extracts (249.6 ± 2.6 seconds) at 100 mg/kg. MAOs activity was significantly decreased in brain tissue from animals treated with 16 and 50 mg/kg of tilianin, methanolic, and hydroalcoholic extracts at 100 mg/kg.

Conclusions: The tilianin effect on monoamine oxidases inhibition is confirmed, suggesting its potential use in the treatment of certain neurological disorders.

Objective: To investigate the effects of Alogliptin in chemical-induced post-menopausal osteoporosis.

Methodology: The binding affinity of alogliptin with osteogenic proteins was analysed in silico. The effect of alogliptin on osteogenic proteins and mineralization of osteoblastic cells was evaluated in UMR-106 cells. Further, in vivo anti-osteoporotic activity of alogliptin was evaluated in postmenopausal osteoporosis. Various bone turnover markers were assayed in serum. This followed the analysis of microarchitecture of bone, histology, and immunohistochemistry (IHC) of bone tissue.

Results: Docking scores showed that alogliptin has binding affinity for bone alkaline phosphatase (BALP), osteocalcin, and bone morphogenic protein (BMP-2). Alogliptin also enhanced mineralization of osteoblast cells, evidenced with increased ALP, osteocalcin, and BMP-2. Animal studies revealed significant elevation of bone formation markers, bone ALP, osteocalcin and BMP-2, and decreased bone resorption markers, receptor activator of NF-κβ (RANKL), cathepsin K (CTSK), tartrate resistant acid phosphatase (TRAcP5b) in VCD-induced post-menopausal osteoporosis. Micro computed tomography (μCT) analysis and histology of femur bone and lumbar vertebrae demonstrated decrease in trabecular separation and improved bone density. IHC of femur showed reduced DPP4 enzyme.

Conclusions: Alogliptin increased mineralization in osteoblast cells. It had beneficial effects also altered bone turnover markers, repaired the trabecular microstructure, improved bone mineral density, and exhibited bone forming capacity targeting DPP-4 enzyme in postmenopausal osteoporosis.

Objective: To investigate the effects of Araucaria sp. brown propolis (ABP) against trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats.

Methods: Animals received vehicle (1% DMSO, 1 ml/kg) or hydroalcoholic extract of ABP (hydroalcoholic extract of Araucaria sp. brown propolis (HEABP), 30, 100, and 300 mg/kg) orally, or dexamethasone (25 mg/kg, s.c.) for 5 days. On day 4, the animals received intracolonic TNBS (150 mg/kg), on day 6 they were euthanized. The weight of the animals, the macroscopic and microscopic colonic damage, reduced glutathione (GSH) and malondialdehyde (MDA) levels, and the activity of glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) were measured in colon homogenate. The action of HEABP and two isolated compounds in neutrophil migration was recorded.

Key findings: HEABP (100 and 300 mg/kg), but not dexamethasone, decreased colonic lesion, and increased colonic mucin staining. In parallel, HEABP decreased MDA and restored GSH levels and the activity of SOD, CAT, and GST in the colon. A dose-dependent inhibition of MPO activity was observed (LogIC50 = 1.9). Moreover, HEBPA and the junicedric and abietic acids inhibited the neutrophil chemotaxis in vitro and HEBPA reduced neutrophil migration in vivo.

Conclusion: HEABP may be promising in the therapies for inflammatory bowel diseases, reducing oxidative and inflammatory damage, especially mediated by neutrophils.

Objective: To explore the effect and anxiolytic mechanism of a natural remedy called Fructus gardeniae (FG).

Methods: The elevated-plus maze (EPM) test was used to confirm the anxiolytic effect of FG. The potential and anxiolytic components, targets, and route processes of FG were investigated using the network pharmacology method in conjunction with metabolomics and molecular docking technologies.

Results: FG could greatly enhance the proportion of time and times of opening arms, according to the EPM data. As to the metabolomics findings, a total of 61 distinct metabolites were found, mainly involved in glycine, serine, and threonine metabolism as well as alanine, aspartate, and glutamate metabolism. The primary active ingredients of FG, nicotiflorin, jasminodiol, and crocetin, demonstrated substantial binding affinities with monoamine oxidase A (MAOA), monoamine oxidase A (ACHE), malate dehydrogenase 2 (MDH2), glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), and nitric oxide synthase (NOS1), according to the findings of network pharmacology and molecular docking.

Conclusion: FG exerts an anxiolytic action via targeting MAOA, ACHE, MDH2, GAD2, GAD1, and NOS1, and regulating the metabolism of glycine, serine, and threonine as well as alanine, aspartic acid, and glutamic acid.

Objectives: Poly(amidoamine) dendrimers have been widely investigated as potential nanomaterials that can enhance the skin permeation of topically applied drugs. This article reviews the studies that have used dendrimers as penetration enhancers and examines the mechanisms by which enhancement is claimed.

Key findings: A wide range of studies have demonstrated that, in certain circumstances and for certain drugs, the incorporation of dendrimers into a topically applied formulation can significantly increase the amount of drug passing into and through the skin. In some cases, dendrimers offered little or no enhancement of skin permeation, suggesting that the drug-dendrimer interaction and the selection of a specific dendrimer were central to ensuring optimal enhancement of skin permeation. Significant interactions between dendrimers and other formulation components were also reported in some cases.

Summary: Dendrimers offer substantial potential for enhancing drug delivery into and across the skin, putatively by mechanisms that include occlusion and changes to surface tension. However, most of these studies are conducted in vitro and limited progress has been made beyond such laboratory studies, some of which are conducted using membranes of limited relevance to humans, such as rodent skin. Thus, the outcomes and claims of such studies should be treated with caution.

Objectives: To unveil the mechanism of the Bufei Huoxue formula (BHF) for chronic obstructive pulmonary disease (COPD) through integrated network pharmacology (NP) and experimental verification.

Methods: LC-MS was first applied to the analysis of both in vitro and in vivo samples from BHF for chemical profiling. Then a ligand library was prepared for NP to reveal the mechanism of BHF against COPD. Finally, verification was performed using an animal model related to the results from the NP.

Key findings: A ligand library containing 170 compounds from BHF was obtained, while 357 targets related to COPD were filtered to construct a PPI network. GO and KEGG analysis demonstrated that bavachin, paeoniflorin, and demethylation of formononetin were the major compounds for BHF against COPD, which mainly by regulating the PI3K/Akt pathway. The experiments proved that BHF could alleviate lung injury and attenuate the release of TNF-α and IL-6 in the lung and BALF in a dose-dependent manner. Western blot further demonstrated the down-regulated effect of BHF on p-PI3K.

Conclusion: BHF provides a potent alternative for the treatment of COPD, and the mechanism is probably associated with regulating the PI3K/AKT pathway to alleviate inflammatory injury by bavachin, paeoniflorin, and demethylation of formononetin.