Journal of Pharmacy and Pharmacology最新文献

Background: Preclinical studies have demonstrated that the edible arboreal medicinal mushroom Hericium erinaceus (HE) mitigates high corticosterone levels and enhances stress-coping strategies in rodents, with emerging evidence suggesting similar neuroprotective potential for Fomitopsis officinalis (FO) and Pleurotus djamor (PDJ). However, comparative dose-dependent effects, including comprehensive anxiety and depression assessments, remain underexplored.

Purpose: This study investigates the dose-dependent effects of dietary supplementation with HE, FO, or PDJ on anxiety-like behaviors and stress-coping strategies in rats, building on prior findings of their anxiolytic and antidepressant-like properties, and compares these effects to fluoxetine (FLX; 20 mg/kg), a standard treatment for stress-related psychiatric disorders.

Study design: Male Wistar rats received 0, 100, 250, or 500 mg/kg (per os) of HE, FO, or PDJ lyophilizate from in vitro cultures for 3 weeks.

Methods: Behavioral outcomes were assessed using the open field test (OFT), elevated plus maze (EPM), and forced swim test (FST). Pearson's correlations explored relationships between FST parameters.

Results: A middle dose of FO (250 mg/kg) increased rearing in the OFT, indicating reduced anxiety-like behavior. In the EPM, FO (100-250 mg/kg) and PDJ (100 mg/kg) increased open arm entries and time while reducing closed arm time, indicating anxiolytic-like effects consistent with prior studies on HE and extending novel insights to PDJ. In the FST, FO (250 mg/kg) reduced immobility, increased swimming, and decreased climbing, suggesting serotonergic-mediated antidepressant-like effects comparable or superior to FLX. HE and PDJ (250-500 mg/kg) reduced immobility and increased climbing or swimming, indicating dose-specific antidepressant effects. Immobility was strongly negatively correlated with swimming (r = -0.75, P < .0001) and moderately with climbing (r = -0.43, P < .001), with no significant correlation between swimming and climbing (r = -0.18, P = .06).

Conclusion: This study advances prior research by demonstrating that dietary supplementation with HE, FO, and PDJ exerts dose-dependent anxiolytic and antidepressant-like effects in rats, likely via serotonergic, noradrenergic, GABAergic, and anti-inflammatory pathways. The FST correlations highlight distinct coping mechanisms, supporting their potential as dietary interventions for stress-related disorders, comparable to FLX, warranting further investigation into underlying mechanisms and clinical applicability.

Objectives: To develop the orphan drug benznidazole (BNZ) in orally disintegrating tablets, for the neglected disease American Trypanosomiasis (Chagas disease) therapy. Although children are highly affected by this disease, there are no specific commercial pharmaceutical preparations for this age group in Argentina and in many other countries.

Methods: In the production process, co-milling in a ball mill was applied to enhance dissolution rates, followed by direct compression. Taste preference and taste masking experiments were conducted in a test panel of adult volunteers. The tablets were fully characterized and their stability and bioavailability determined.

Key findings: The tablets complied with all the quality control prerequisites, their disintegration time was 30 s, and as a consequence of the intimate mixture with hydrophilic excipients and particle size reduction, BNZ dissolution was improved, reaching 75% in 0.1 N hydrochloric acid and 62% in simulated salivary fluid, after 5 min. X-ray diffraction studies showed that BNZ maintained its original crystalline state (form I) in the tablets. The ODTs remained stable for at least 1 year. Oral bioavailability of BNZ of suspensions obtained from the prepared ODTs was comparable with that of pulverized commercial tablets.

Conclusions: The developed tablets may improve paediatric Chagas disease therapeutics.

Objectives: Myocardial infarction (MI) remains a leading cause of global mortality, and the inhibition of ferroptosis has cardioprotective potential. Taoren Honghua Jian (TRHHJ) has been used clinically to improve cardiovascular disorders. However, whether TRHHJ inhibits cardiomyocyte ferroptosis and ameliorates myocardial damage after MI requires further investigation. This study aimed to assess the ferroptosis-inhibiting effects of TRHHJ on post-MI myocardial injury and its underlying mechanisms.

Methods: In vivo MI models were established via left anterior descending coronary artery ligation, and the cardioprotective effects of TRHHJ were assessed by echocardiography and histopathology combined with ferroptosis biomarker detection and Nrf2 signaling protein analysis. In vitro, erastin induced ferroptosis in H9C2 cells, and the anti-ferroptotic effects of TRHHJ was evaluated using the MTT assay, ferroptosis markers, and Nrf2 signaling analysis. Mechanistically, Nrf2 inhibitor and knockout mice were used for validation.

Results: TRHHJ suppressed cardiomyocyte ferroptosis, reduced myocardial damage, and improved cardiac function in post-MI mice by activating the Nrf2 signaling pathway in vivo. TRHHJ enhanced cell viability and inhibited erastin-induced ferroptosis in H9C2 cells by increasing Nrf2 level and activating downstream signaling in vitro. Inhibition or knockout of Nrf2 partially abolished these protective effects.

Conclusions: TRHHJ inhibits cardiomyocyte ferroptosis and improves myocardial damage after MI through activation of Nrf2 signaling.

Cardiovascular diseases, such as arrhythmia and cardiomyopathy, are leading causes of mortality worldwide. Cardiomyopathy is often triggered by oxidative stress. Objective The current study aims to investigate the therapeutic potential of selenium and iron oxide (FeO) nanoparticles, individually and in combination, in treating doxorubicin (DOX)-induced cardiomyopathy in rats. Method Cardiomyopathy was induced in Wistar rats, where selenium, FeO nanoparticles, or both were formulated and tested on the rat model. Key findings DOX administration revealed a significant elevation in cardiac enzymes: creatinine kinase (CK-MB) and troponin-1 (cTn-1), and elevation of oxidative stress markers, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and malondialdehyde (MDA), together with a reduction in superoxide dismutase (SOD) and glutathione peroxidase (GPx). A significant elevation in inflammatory markers, protein kinase C (PKC), nuclear factor-kappa B (NF-kB), and metalloproteinase-9 (MMP-9), was obvious after DOX administration in rats for induction of cardiomyopathy together with histopathological alterations. Selenium and FeO nanoparticles groups significantly improved oxidative stress, inflammation, and apoptosis compared with the DOX group. Combined selenium and FeO nanoparticle groups showed better results compared with the other treatment groups. Conclusion Selenium and FeO nanoparticles showed potential anti-oxidant, anti-inflammatory and anti-apoptotic effects in the treatment of DOX-induced cardiomyopathy in rats.

Objectives: Natural products (NP) play a crucial role in the development of new compounds, due to their complex chemical structure and pharmacological diversity. Neurodegenerative diseases and other disorders in the central nervous system (CNS) have become a significant problem in the world due to the increase in life expectancy of the elderly population. This increases the risk of developing diseases, such as Parkinson's disease, Huntington's disease, Alzheimer's disease. Therefore, this exploratory review aims to show the applications of zebrafish for NP research and how they can be used in CNS's in vivo studies.

Methods: The present review covers the literature survey until 2023, including the descriptors for zebrafish, natural product and neurodegenerative diseases. The databases used were PubMed, Scopus, Cochrane and Lilacs.

Key findings: For the development of new medicines, an efficient animal model is required, and the zebrafish has stood out as a promising model due to its small size, low cost of maintenance, ease of handling, and transparency of embryos, which allows real-time observation of development and pathological processes. They possess conserved neurotransmission systems such as glutamatergic, cholinergic, dopaminergic, serotonergic, histaminergic, GABAergic, and purinergic pathways, making them especially relevant for modelling CNS disorders. From literature survey, flavonoids, alkaloids, and phenolic compounds were the most frequently studied, indicating that its influence the pathophysiological mechanisms associated with neurodegenerative diseases.

Conclusions: This current review offers data for further research work with natural products aiming treatment for CNS disorders.

Objectives: Ruxolitinib (Rux), an oral Janus tyrosine Kinase (JAK) tyrosine kinase inhibitor, has demonstrated anti-inflammatory properties and the ability to mitigate denervation-induced skeletal muscle atrophy. Here, we checked the potential efficacy of Rux on cancer cachexia and tried to clarified its mechanisms.

Methods: The in vitro cell models of C26 or LLC CM-induced C2C12 myotubes were used to check the influence of Rux on myotube atrophy. C26 tumour-bearing mice (male BALB/c mice) were applied as the animal model to examine the effects of Rux in attenuating cachexia symptoms. Western blot analysis was utilized to investigate the potential mechanisms of Rux.

Key findings: Rux significantly attenuated C2C12 myotube atrophy in vitro. Rux suppressed the interleukin-6 secretion by inhibiting STAT3 activation in tumour cells and macrophages. The administration of Rux prevented body weight loss and muscle wasting in C26 tumour-bearing mice without affecting tumour growth. At the end of the experiment, mice in the Rux treatment group exhibited a 6.7% increase in body weight compared to the C26 model group. Furthermore, Rux enhanced in gastrocnemius myofibres cross-sectional area and grip strength.

Conclusions: Rux ameliorates cancer cachexia muscle atrophy by inhibiting STAT3/Atrogin-1 signaling. Rux may represent a promising therapeutic candidate for the treatment of cancer cachexia.

Objectives: Ling Gui Zhu Gan (LGZG) Granules is a marketed traditional Chinese medicine compound granule, which is formulated to be consistent with the key quality attributes of the traditional LGZG Decoction. The volatile components are important parts of its preparation process.

Methods: A high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mouse model was established to evaluate the therapeutic effects of LGZG and preparation of LGZG's volatile components (IC-LGZG). Gut microbiota composition, Short-chain Fatty Acids (SCFA) levels, and intestinal parameters were assessed, and its correlations were analyzed. Lipopolysaccharide-induced RAW264.7 cells tested anti-inflammatory effects.

Key findings: LGZG and IC-LGZG significantly reduced HFD-induced body weight gain, improved lipid profiles and liver function, restored gut microbiota balance, increased beneficial bacteria (Akkermansia, Bacteroides, Parabacteroides, Dubosiella, and Bifidobacterium) that produce SCFAs, thereby enhancing SCFA concentrations (acetic acid, propionic acid, and butyric acid), decreased harmful bacteria abundance, and strengthened the intestinal barrier. In vitro studies showed that LGZG, IC-LGZG, and cinnamaldehyde exerted anti-inflammatory effects.

Conclusion: LGZG and its volatile components effectively alleviate the progression of NAFLD by modulating the gut microbiota homeostasis and SCFA levels, and can exert anti-inflammatory effects.

Objective: To evaluate the clinical efficacy of the topical application of vancomycin powder in the prevention of surgical site infection after total joint arthroplasty (TJA).

Method: Five English-language databases and four Chinese-language databases were systematically searched from the establishment of the database to 31 January 2024, and a meta-analysis was performed using Review Manager 5.3 software.

Results: A total of 34 314 patients from 17 studies were included in this meta-analysis. The results showed that, compared with the control group, the topical application of vancomycin powder in the experimental group reduced the overall incidence of prosthetic joint infection (PJI) after TJA surgery (P < .001). Within the subdivisions of the surgical field, in total knee arthroplasty, the incidence of PJI was significantly lower in the experimental group using vancomycin powder than in the control group not using this powder (P < .001). In total hip arthroplasty, the incidence of PJI was also significantly lower in the experimental group than in the control group (P = .004). However, 11 studies mentioned adverse reactions, and the results showed that the incidence of adverse reactions in the experimental group increased compared with the control group (P = .008).

Conclusion: The application of vancomycin powder appears to significantly reduce PJI risk in TJA patients; however, an increased incidence of postoperative wound complications warrants cautious clinical consideration.

Objectives: Chronic kidney disease (CKD) is a progressive medical condition marked by a gradual decline in kidney function, leading to an accumulation of waste products and fluids in the body. Drug-induced liver injury (DILI) poses a significant clinical challenge in CKD management, with paracetamol being a commonly used medication. Advanced oxidation protein products (AOPPs) are biomarkers of CKD progression and contributors to DILI. However, the mechanisms behind the increased incidence of DILI in CKD remain unclear.

Methods: We developed an adenine-induced CKD mice model, a paracetamol-induced DILI mice model, and an AOPPs-loaded mice model using intraperitoneal injections.

Key findings: Declining renal function in the CKD model was associated with a significant weight loss and increased the concentration of serum creatinine and blood urea nitrogen. Following paracetamol administration, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), and N-acetyl-p-benzoquinoneimine and liver tissue necrosis increased significantly in CKD groups. In addition, the expression of cytochrome P450 2E1 (CYP2E1) and thrombospondin receptor (CD36) were upregulated, while the adenylate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway showed significant changes in protein expression and phosphorylation. In AOPPs-loaded model, AOPPs upregulated AMPK and Akt protein expression, along with reduced mTOR levels. In HepG2 and L0-2 cell lines, AOPPs and paracetamol significantly increased the protein expression and phosphorylation of AMPK and Akt, alongside a decreased mTOR expression and phosphorylation. AOPPs and paracetamol significantly induced the apoptosis in HepG2 and L0-2 cells. Notably, the expression of CYP2E1 induced by AOPPs and paracetamol was inhibited by dorsomorphin and corynoxine B.

Conclusions: These findings suggest that the AMPK-mTOR signaling pathway mediates the worsening of paracetamol-induced liver injury in CKD, with AOPPs potentially serving as key endogenous factors. This study lays the groundwork for identifying crucial molecules involved in exacerbated paracetamol-induced liver injury in CKD, which may serve as new drug targets and improve the safety profile of paracetamol in patients with CKD.

Objectives: To investigate the antitumor effects of aucubin (AC) in non-small cell lung cancer (NSCLC) and uncover its plausible mechanism against lung cancer stem-like cells (LCSCs).

Methods: In vitro experiments included MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a reagent commonly used for cell viability assay) and colony formation assays to assess anti-proliferative effects on A549 and NCI-H1975 lung cancer cell lines, wound healing and Transwell invasion assays to evaluate inhibition of cell migration and invasion, tumorsphere-formation experiments to detect changes in NSCLC cell stemness, as well as Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses to measure the expression of LCSC markers (CD44, CD133, Oct4, and Nanog). In vivo experiments were conducted to observe the impact of AC on NSCLC metastasis and mouse survival rates. Further mechanistic studies involved transcriptomic gene set enrichment analysis, Western blot, qRT-PCR, molecular docking, and Surface Plasmon Resonance (SPR) methods to investigate how AC directly targets β-catenin and promotes its ubiquitin-mediated degradation.

Key findings: AC exerted significant anti-proliferative effects on A549 and NCI-H1975 cells, inhibited cancer cell migration and invasion, reduced the stemness of NSCLC cells, and markedly downregulated the expression of LCSC markers in vitro. In vivo, AC treatment significantly reduced NSCLC metastasis and improved mouse survival rates.Mechanistically, AC blocked the WNT (Wingless-related integration site, a family of secreted lipid-modified signaling glycoproteins that play crucial roles in embryonic development, tissue homeostasis, and regeneration) signaling pathway by downregulating β-catenin and c-Myc expression. It directly targeted β-catenin, promoting its degradation via the ubiquitin-proteasome pathway.

Conclusions: This study uncovers a novel anti-LCSC mechanism of AC, offers alternative strategies for NSCLC treatment, and provides innovative lead compounds for the development of drugs targeting lung cancer stem cells.