Journal of Pharmacy and Pharmacology最新文献

Objectives: Tiaogan Jiejiu Tongluo formula (TJTF) is a traditional Chinese medicine formula for liver disease. The purpose of this study was to explore the protective effects and mechanisms of TJTF on nonalcoholic fatty liver disease (NAFLD) mice.

Methods: A NAFLD model of mice was established by a combination of a high-fat diet and CCL4 and then treated with TJTF. The damage to liver tissue was observed through histopathology, and the levels of AST, ALT, TG, TC, LDL-C, and HDL-C in the serum, as well as SOD, GSH, and MDA in the liver tissue were determined using biochemistry or ELISA kit. The expression of proteins related to the AMPK pathway was detected by western blotting.

Results: Biochemical indicators and pathological examination showed that TJTF could enhance the antioxidant capacity of liver tissue and significantly reduce liver lipid deposition. In addition, TJTF significantly increased levels of LKB1 and p-AMPK, and decreased the levels of HMGCR, SREBP-1c, FAS, and ACC.

Conclusion: TJTF can alleviate hepatic steatosis and effectively improve NAFLD by regulating AMPK signaling pathway in NAFLD mice.

Objective: This research studied two extracts from Treculia africana leaves for their potential against hyperglycaemia-related disorders.

Methods: The influence of the extracts on α-glucosidase activity and albumin glycation was investigated, and cell viability was estimated in HT-29 human colorectal cells. Phenolic and flavonoid contents and antiradical activity were also detected. The extracts were examined using HPLC-DAD analysis.

Key findings: The methanol and dichloromethane leaf extracts showed a significant concentration-dependent inhibition of α-glucosidase activity (IC50= 3.73 and 21.28 µg/ml, respectively). Both extracts also inhibited ribose-induced glycation of bovine serum albumin from 250 µg/ml. Phytochemical analysis revealed the presence of chlorogenic acid and α-mangostin in the extracts. The extracts did not change HT-29 cell viability up to 250 µg/ml, thus showing very low cytotoxicity.

Conclusions: The methanol leaf extract of T. africana inhibited α-glucosidase activity in a concentration-dependent manner, supporting the use of the leaves in traditional medicine to control hyperglycaemia. Chlorogenic acid and α-mangostin, the latter identified for the first time in this species, were found in the T. africana leaves. Further, in vivo studies and pilot clinical trials should be conducted using standardized T. africana leaf extracts to evaluate their potential effectiveness in diabetes mellitus.

Objectives: The purpose of this study was to explore the mechanism of naringin in atherosclerotic mice from the perspective of network pharmacology and non-targeted metabolomics.

Methods: ApoE-/- mice were induced to establish an atherosclerotic model to explore the pharmacodynamics and potential mechanism of naringin in atherosclerosis (AS). Pathological section and blood lipid levels were used to evaluate the intervention effects. The core targets, metabolites, and related pathways of naringin alleviating atherosclerotic were predicted through network pharmacology and metabolomics analysis. Furthermore, the inflammatory factors and pathway-related protein expression were detected using ELISA and Western blot methods.

Key findings: It turned out that compared with the model group, the naringin could reduce the development degree in atherosclerotic mice. The network pharmacology suggested that PI3K-AKT pathway was an important mechanism for naringin to interfere with AS. Serum metabolic data were collected and analyzed, and a total of 27 potential biomarkers were identified, involving vitamin B6 metabolism, arginine metabolism, and retinol metabolism. The experiment verified that naringin inhibited inflammation in AS through the PI3K-AKT/TLR4/NF-κB pathway.

Conclusions: This study provides a strategy combining metabolomics and network pharmacology to explore the alleviation of AS by naringin and offers a new idea for its application.

Objectives: This study aimed to investigate the role of dipeptidyl peptidase-8 and 9 (DPP-8/9) enzymes in inflammatory bone loss using a 4-vinylcyclohexene diepoxide (VCD)-induced model in Wistar rats. Additionally, we evaluated the therapeutic potential of inhibiting these enzymes with the flavonoid chrysin.

Methods: Inflammatory osteoporosis was induced by administering VCD that elevated interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) levels. DPP-8/9 enzyme expression and various bone markers were assayed using serum. Further analysis included bone microarchitecture, histology, and immunohistochemistry. Additionally, chrysin's potential to inhibit DPP-8/9 and mitigate VCD-induced inflammatory bone loss was also evaluated.

Key findings: VCD administration in rats caused ovotoxicity that increased IL-6 and TNF-α levels, resulting in significant bone loss. Serum analysis revealed elevated bone resorption markers and DPP-8/9 enzyme levels. Inhibiting DPP-8/9 with 1G244 reversed these effects, confirmed by histology, immunohistochemistry, and micro-CT scans. Moreover, chrysin significantly reduced DPP-8/9 levels compared with the untreated group, improved bone markers, and lower inflammatory cytokines, indicating reduced osteoclastogenesis.

Conclusion: This study highlights the role of DPP-8/9 in inflammation-induced osteoporosis. Following inhibition of DPP-8/9, we observed improved bone markers with preservation of trabecular bone mineral density in rats. Additionally, chrysin demonstrated potential as an anti-DPP-8/9 agent, suggesting its viability for future therapeutic interventions in DPP-8/9-related inflammatory diseases.

Purpose: The study aimed to evaluate the effect of roflumilast on modulating TNF-α/Caspase mediated cellular signals in cisplatin-induced nephrotoxicity in rats.

Methods: The rats (Male Wistar) were divided into five groups: normal control, disease control (cisplatin: 7 mg/kg i.p.), and cisplatin + roflumilast (0.25, 0.5, and 1 mg/kg b.w., p.o.). Cisplatin was administrated to rats on 0 day, and roflumilast treatment was started from the 6th-15th days. Blood and tissue were collected. Tissue was used to measure oxidative stress, such as malondialdehyde, superoxide dismutase, and catalase. Gene expression study involved real-time PCR of key genes linked with inflammation and apoptosis, i.e. Tnf-α, Tnfr1, Tnfr2, Fas, Nfkb, Casp3, Casp8, and Nrf2.

Findings: Cisplatin showed decreased serum creatinine and urea, high albumin, and total protein. Cisplatin elevated the malondialdehyde and reduced superoxide dismutase and catalase activity. Cisplatin also attributed an overexpression of Tnf-α, Tnfr1, Tnfr2, Nfkb, Fas, Casp3, and Casp8, and a decrease in the Nrf2 gene. Roflumilast decreased creatinine and urea and increased albumin and total protein levels. Roflumilast also downregulated the expression of Tnf-α, Tnfr1, Tnfr2, Nfkb, Fas, Casp3, and Casp8 and upregulated the Nrf2 gene expression.

Conclusion: Roflumilast manifested as a potential reno-protective agent against cisplatin-induced nephrotoxicity.

Context: Our clinical observation found that JiJiaoLiHuang Pill (JJLH), a classic traditional Chinese medicine (TCM) formulation, can significantly reduce the abdominal circumference of patients with malignant ascites, increase urine output, and improve the quality of life of patients, with preliminary efficacy. But, the exact mechanism is not yet clear.

Objective: Based on the above observations, the potential mechanism of action of the treatment was preliminarily explored.

Methods: We identified active ingredients by constructing a "Chinese medicine ingredient-key target-target" network, and verified them by molecular docking using AutoDock tools and PyMOL. Finally, we conducted preliminary verification of the validated pathways and targets using a mouse model of liver cancer ascites.

Results: Network pharmacology analysis obtained the top five active ingredients were quercetin, EUPATIN, kaempferol, Obtucarbamate B, and isorhamnetin and the top five key genes were SRC, HSP90AA1, MAPK1, STAT3, and PIK3CA. Molecular docking showed that all 5 active compounds were closely bound to key target genes (binding energy <-6). The animal experiment results showed that JJLH can significantly reduce abdominal circumference, increase urine output, and exhibit dose-dependent inhibition of the AQP-3/JAK-STAT-3 signaling pathway and the expression of related inflammatory factors.

Conclusions: The JJLH potentially inhibits the recurrence of liver cancer malignant ascites through the AQP-3/JAK-STAT-3 pathway and affects the prognosis of MA patients.

The incidence and mortality rate of atherosclerotic cardiovascular disease (ASCVD) is increasing yearly worldwide. Recently, a growing body of evidence has unveiled the anti-atherosclerotic properties of fisetin, a natural polyphenol compound. In this article, we reviewed the pharmacologic actions of fisetin on experimental atherosclerosis and its protective effects on disease-relevant cell types such as endothelial cells, macrophages, vascular smooth muscle cells, and platelets. Based on its profound cardiovascular actions, fisetin holds potential for clinical translation and could be developed as a potential therapeutic option for atherosclerosis and its related complications. Large-scale randomized clinical trials are warranted to ascertain the safety and efficacy of fisetin in patients with or high risk for ASCVD.

Objectives: Given the success of galanthamine in treating Alzheimer's disease, this study aims to establish an effective method to find drugs from Amaryllidaceae alkaloids and to clarify its mechanism in treating Alzheimer's disease.

Methods: The pharmacodynamic basis and mechanism of action between Amaryllidaceae alkaloids and Alzheimer's disease were explored by constructing a compound-target-disease network, targets protein-protein interaction, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and molecular docking verification.

Key findings: In total, a chemical library of 357 potential alkaloids was constructed. A total of 100 active alkaloid components were identified. Thirty-nine associated targets were yielded based on network construction, and the key targets were defined as HSP90AA1, ESR1, NOS3, PTGS2, and PPARG using protein-protein interaction network. Gene ontology items (490) and 68 Kyoto Encyclopedia of Genes and Genomes pathways were selected through the enrichment of target functions, including neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, Alzheimer disease, and serotonergic synapse that were related to Alzheimer's disease. Lastly, molecular docking demonstrated good stability in combining selected alkaloids with targets.

Conclusions: This study explained the mechanisms of Amaryllidaceae alkaloids in preventing and treating Alzheimer's disease and established a novel strategy to discover new drugs from biological chemical sources.

Objectives: This study aimed to develop a suitable osteomyelitis model for pharmacokinetic/pharmacodynamic (PK/PD) evaluation and to investigate the target PK/PD values of vancomycin and tedizolid against methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis.

Methods: An osteomyelitis model was established by implanting an MRSA-exposed sterilized suture in the tibia of normal mice and mice with cyclophosphamide-induced neutropenia. The suitability of the osteomyelitis mouse model for PK/PD evaluation was assessed using vancomycin as an indicator. The target PK/PD values for tedizolid were determined using this model.

Key findings: In neutropenic mice, to achieve a static effect and 1 log10 kill against MRSA, the ratios of the area under the free drug concentration-time curve for 24 h to the minimum inhibitory concentration (fAUC24/MIC) of vancomycin were 91.29 and 430.03, respectively, confirming the validity of the osteomyelitis model for PK/PD evaluation. In immunocompetent mice, the target fAUC24/MIC values of tedizolid for achieving a static effect and 1 log10 kill against MRSA were 2.40 and 49.20, respectively. Additionally, only a 0.28 log10 kill was achieved in neutropenic mice with 20 times the human equivalent dose of tedizolid.

Conclusions: In patients with restored immunity, tedizolid can potentially be used as an alternative to intravenous vancomycin therapy.

Objectives: Kratom preparation containing Mitragyna speciosa Korth plant is frequently used as a recreational drug. Mitragynine, a major alkaloid isolated from M. speciosa, is often detected concurrently with other drugs during forensic analysis, indicating a safety concern. P-glycoprotein (P-gp) is a multidrug transporter. Modulation of P-gp transport activity by drugs or herbal compounds in the brain may lead to drug-herb interactions, resulting in neurotoxicity. We aim to determine the effects of mitragynine on the P-gp regulation and possible neurotoxicity.

Methods: The effects of mitragynine on the P-gp regulation were investigated in human brain capillary endothelial cells (hCMEC/D3) using molecular docking and dynamic simulation and an optimized bidirectional transport assay, respectively. Repeated-dose treatment and neurotoxicity assessment were carried out using a blood-brain barrier model and polimerase chain reaction (PCR) array.

Key findings: Mitragynine inhibits the P-gp transport activity via binding onto the nucleotide-binding domain site and forms a stable interaction with the P-gp protein complex. Nontoxic concentrations of mitragynine (<4 μM) and substrate drugs (0.001 μM) in the cells significantly enhanced endothelial cell permeability and elicited signs of neurotoxicity in PC-12 cells.

Conclusions: Mitragynine is likely a P-gp inhibitor, hence concurrent administration of kratom products with P-gp substrates may lead to clinically significant interactions and neurotoxicity.