Journal of Pharmacy and Pharmacology最新文献

Objectives: Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM's effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase.

Methods: We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect.

Results: Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient's final time point matched the observed effects in 9 of the 11 patients.

Conclusion: This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.

Objective: The study was aimed at the synthesis and pharmacological investigation of (4Z)-4-(2-hydroxybenzylidine)-5-methyl-2-(pyridine-3-ylcarbonyl)-2, 4-dihydro-3H-pyrazole-3-one (IIc) in mice model of scopolamine-induced neurodegeneration and cognition impairment.

Methods: The behavioural studies included Y-Maze Test, Water Morris Test, and Novel Object Recognition Test in Albino mice (20-25 g). Scopalamine was used as an inducing agent. The acetylcholinesterase (AChE) inhibitory assay was used to assess the role of the test compounds in vitro. The Crystal Violet Staining (Nissl staining) was used to assess the neuroprotective and antiapoptotic effect through quantifying the number of neurons and viability. The expression of the anti-inflammatory enzyme cyclooxygenase-2 (COX-2), cytokine tumour necrotic factor (TNF-α), key transcription factor producing pro-inflammatory signals nuclear factor kappa B (P-NFkB), and apoptosis marker p-JNK was validated through enzyme-linked immunosorbent assay (ELISA) and immunohistochemical (IHC) analysis. The tested compound reverted cognitive and behavioural impairment through inhibiting scopolamine-induced inflammation and oxidative stress.

Key findings: We found that the compound IIc improved the short-term memory and learning behaviour of the experimental animals. Further investigation into molecular mechanisms showed that this effect was the manifestation of immunomodulatory, antioxidant, and consequently, of downsizing of inflammatory cytokines. These results were further validated through docking analysis.

Conclusion: Finally, we conclude that the pyrazolone-nicotinic acid derivative IIc reversed the scopolamine-induced cognitive and behavioural deficits, attributed to acetylcholinesterase inhibition, neuronal recovery, antioxidant potential, and through downregulating the neuroinflammatory mediators p-NF-kB, cytokine TNF-α, and anti-inflammatory enzyme COX-2.

Objectives: Copaiba essential oil (CEO) is obtained through the distillation of copaiba balsam and has been used in the traditional medicine to treat inflammatory conditions. However, the highly lipophilic nature of CEO restricts its pharmaceutical use. This study evaluated the effect of CEO, carried in a self-nanoemulsifying drug delivery system (SNEDDS), on articular and systemic inflammation and liver changes in Holtzman rats with Freund's adjuvant-induced arthritis.

Methods: Healthy and arthritic rats received orally for 18 days the non-formulated CEO and the one carried in a self-nanoemulsifying drug delivery system (FSNEDDS), both at doses of 50 and 100 mg/kg. The oral bioavailability of FSNEDDS was determined in healthy rats by quantifying the levels of β-caryophyllene in the plasma.

Key findings: FSNEDDS exhibited more than three times greater oral bioavailability compared to non-formulated CEO. This phenomenon allowed FSNEDDS (100 mg/kg) to effectively reduce adjuvant-induced articular and systemic inflammation and oxidative stress in arthritic rats at a dose four times lower than copaiba balsam and β-caryophyllene. Furthermore, FSNEDDS did not alter the serum markers of liver damage, hepatic morphometry, and liver gluconeogenesis in healthy rats.

Conclusion: FSNEDDS was effective against arthritis in rats, and unlike copaiba balsam, it does not exhibit hepatotoxicity, suggesting it could serve as a phytotherapeutic alternative in the treatment of rheumatoid arthritis.

Objectives: PD15, a novel natural steroidal saponin extracted from the rhizomes of Paris delavayi Franchet, has demonstrated a strong cytotoxic effect against HepG2 and U87MG cells. However, its therapeutic effects on colorectal cancer (CRC) and the underlying molecular mechanisms remain unclear.

Methods: MTT assay, clonogenic assay, Hoechst 33258 staining, flow cytometry, molecular docking, and western blot were used to investigate the mechanism of PD15 in HCT116 cell lines. Additionally, the anti-CRC effects of PD15 were evaluated in vivo using HCT116 xenograft models.

Key findings: PD15 significantly inhibited cell proliferation and induced G0/G1 phase arrest in HCT116 cells. Furthermore, PD15 upregulated cleaved Caspase 3 and 9, cleaved PARP, and Bax expression levels while downregulating Bcl-2, leading to apoptosis. Further experiments revealed that PD15 downregulated the protein expression of p-Akt and p-GSK3β, with LY294002 (a PI3K/Akt inhibitor) enhancing PD15-induced apoptosis and its effects on Akt/GSK3β-associated proteins. In addition, molecular docking demonstrated that PD15 exhibited strong binding affinity with Akt and GSK3β. Critically, PD15 inhibited CRC growth in vivo without causing apparent toxicity in mice.

Conclusions: These findings indicate that PD15 could trigger apoptosis by suppressing the Akt/GSK3β signaling pathway in HCT116 cells.

Background: Methylcinnamate (MC), a safe flavoring agent naturally found in Occimum basilicum L. is reported to have an anti-inflammatory responses in various disease models. Acetaminophen (APAP) toxicity is a significant contributor to acute liver injury, which leads to oxidative stress and inflammation. The transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulated the cellular defense mechanisms aid to antioxidant response facilitation and reduction in inflammation against various disorders.

Methodology: This study evaluated the protective effects of MC in APAP-induced hepatotoxicity in mice and its anti-oxidant, anti-inflammatory, and Nrf2 mechanisms were studied. In-vitro 2,2-diphenyl-1-picrylhydrazyl assay showed the antioxidant capacity of MC. Mice were pretreated with MC (25, 50, 75, and 100 mg/kg) orally for 7 days. After a fasting period of 16 h, hepatotoxicity was induced by injecting APAP 300 mg/kg intraperitoneal on day 7. Liver profile, oxidative test, and histopathological changes were studied. Gene expression of interlukin-1β (IL-1β), interlukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cytochrome P450 2E1 (CYP2E1), Nrf2, and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were estimated by real time quantitative polymerase chain reaction (RT-qPCR). IL-1β, IL-6, and TNF-α concentrations were also analyzed by enzyme-linked immunosorbent assay (ELISA).

Results: The MC treatment showed a notable reduction in alanine transaminase, aspartate aminotransferase and alkaline phosphatase activities, and total bilirubin level of serum. Moreover, MC significantly attenuated oxidative stress by rising the antioxidant enzymes catalase, glutathione, and superoxide dismutase and reducing the malondialdehyde and nitric oxide levels in the liver. Furthermore, MC successfully mitigated the levels of IL-1β, IL-6, and TNF-α, which were estimated through RT-qPCR and ELISA. The RT-qPCR revealed a CYP2E1 enzyme inhibition and significant upregulation of hepatic Nrf2 and NQO-1 levels after MC therapy. Histopathological analysis showed improvement in liver injury within the MC treatment groups.

Conclusion: It was concluded from this study that pretreatment of MC had successfully protected the liver through anti-inflammatory, anti-oxidant activity upon subsequent activation of Nrf2.

Objectives: Pancreatic cancer, a highly invasive and prognostically unfavorable malignant tumor, consistently exhibits resistance to conventional chemotherapy, leading to substantial side effects and diminished patient quality of life. This highlights the critical need for the discovery of novel, effective, and safe chemotherapy drugs. This study aimed to explore bioactive compounds, particularly natural products, as an alternative for JAK2 protein inhibitor in cancer treatment.

Methods: Molecular docking, molecular dynamics, and Western blot experiments were conducted to verify the binding of Calothrixin B to JAK2 and its inhibitory effect on the JAK2-STAT3 signaling axis.

Key findings: Recognizing the significant impact of JAK-STAT3 signaling pathway in pancreatic cancer, we screened the Zinc database to discover potential JAK2 inhibitors, and identified the small molecule Calothrixin B as a promising drug. Molecular simulations revealed stable interactions and the formation of hydrogen bonds between Calothrixin B and specific amino acids (Asp 994, Leu 855, and Arg 980) after a 100 ns simulation. Furthermore, we show that Calothrixin B inhibited the activity of the JAK2-STAT3 signaling pathway, arrested pancreatic cancer cells in the G1 phase, induced apoptosis, and significantly inhibited cell migration. Moreover, in vivo on a subcutaneous tumor model in nude mice confirmed that Calothrixin B effectively inhibited tumor growth in nude mice. In addition, the combination of Carlothrixin B and gemcitabine had a better inhibitory effect on pancreatic cancer cells.

Conclusion: These findings introduce new avenues for Calothrixin B as promising therapy for pancreatic cancer.

Objectives: Chronic kidney disease (CKD) is a serious health issue with rising morbidity and mortality rates. Despite advances in understanding its pathophysiology, effective therapeutic options are limited, necessitating innovative treatment approaches. Also, current frontline treatments that are available against CKD are not uniformly effective and often come with significant side effects. Therefore, identifying new therapeutic targets or improving existing treatments for CKD is crucial. Drug repurposing is a promising strategy in the drug discovery process that involves screening existing approved drugs for new therapeutic applications.

Key findings: This review discusses the pharmacological mechanisms and clinical evidence that support the efficacy of these repurposed drugs. Various drugs classes such as inodilators, endothelin-1 type A (ET-1A) receptor antagonists, bisphosphonates, mineralocorticoid receptor (MR) antagonists, DNA demethylating agents, nuclear factor erythroid 2-related factor 2 (NRF2) activators, P2X7 inhibitors, autophagy modulators, hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) are discussed that could remarkably contribute against CKD.

Summary: The review critically examines the potential for repurposing well-established drugs to slow the progression of CKD and enhance patient outcomes. This review emphasizes the importance of a multidisciplinary approach in advancing the field of drug repurposing, ultimately paving the way for innovative and effective therapies for patients suffering from CKD.

Background: Schistosomiasis is a neglected tropical disease caused by Schistosoma sp., and praziquantel (PZQ) is the first-line treatment. However, traditional PZQ formulations have low solubility and fast metabolism, limiting its effectiveness. Thus, nanoparticles have been proposed to improve the bioavailability and efficacy of poorly soluble antischistosomal drugs.

Aims: This systematic review used in vivo preclinical studies to map the available evidence and compare the efficacy of free PZQ and PZQ-based nanostructured formulations (N-PZQ) for schistosomiasis treatment.

Methods: PubMed, Embase, Scopus, and Web of Science were searched, and 1186 experimental studies published between 1974 and 2024 were screened. Parasitological, histopathological, pharmacokinetic, and toxicological outcomes were evaluated.

Results: Twelve relevant studies were identified exploring N-PZQ formulations based on liposomes, nanoliposomes, and nanocrystals. N-PZQ demonstrated better therapeutic efficacy than free PZQ, reducing parasite load, modifying oogram profiles, and down-regulating liver granuloma development (number and size). N-PZQ also exhibited improved pharmacokinetic profile, with enhanced bioavailability and longer half-life, as well as reduced toxicity (cytotoxicity, genotoxicity, and hepatotoxicity) compared to free PZQ.

Conclusion: PZQ-based nanostructured formulations represent a promising strategy to enhance schistosomiasis treatment by improving chemotherapy efficacy, optimizing antiparasitic responses, pharmacokinetics, and reducing drug toxicity.

Objectives: Platinum-based anticancer chemotherapy (PAC) represents a cornerstone in cancer treatment, retaining its status as the gold standard therapy. However, PAC's efficacy is countered by significant toxicities, such as nephrotoxicity, ototoxicity, and neurotoxicity. Recent studies have linked these toxicities to ferroptosis, characterized by iron accumulation, reactive oxygen species generation, and lipid peroxidation. This review explores the mechanisms underlying PAC-induced toxicities, focusing on the involvement of ferroptosis with three major PAC drugs-cisplatin, carboplatin, and oxaliplatin. Further, we provide a comprehensive analysis of the natural product mitigation of PAC-induced ferroptotic toxicity.

Key findings: The mechanistic role of ferroptosis in cisplatin- and oxaliplatin-induced toxicities has been investigated, while studies on carboplatin-induced ferroptotic toxicities are lacking. Natural compounds targeting molecular pathways of ferroptosis have been explored to mitigate PAC-induced ferroptotic toxicity.

Conclusion: While ferroptosis in cisplatin- and oxaliplatin-induced toxicities has been investigated, there remains a notable dearth of studies examining its involvement in carboplatin-induced toxicities. Hence, further exploration is warranted to define the role of ferroptosis in carboplatin-induced toxicities, and its further mitigation. Moreover, in-depth mechanistic evaluation is necessary to establish natural products evaluated against PAC-induced ferroptosis, as PAC adjuvants.

Background: Liver cancer is highly heterogeneous with poor drug response. Usenamine A has anticancer activity. Usnic acid has hepatocytotoxicity.

Objectives: As a derivative of usnic acid, if usenamine A can be safely used in treatment for liver cancer is unknown.

Methods: MTT and clone formation assays assessed cell viability and proliferation. Tumor growth was determined using a xenograft model. Flow cytometry was used to detect the cell cycle. mRNA transcriptome sequencing investigated differential gene expression. Safety was evaluated in mice.

Key findings: Usenamine A inhibited proliferation and clone formation of HepG2 cells and xenograft tumor growth through cell cycle arrest at G0/G1. Usenamine A altered gene expression in a direction supporting anticancer activity. IL24, JUN, DUSP4, and DUSP5 were upregulated while PRKACA, PRKCB, TP53, WNT6, E2F3, LGR4, GPR78, and MAPK4 were downregulated. Ten of above genes overlapped in the KEGG enriched non-small cell lung cancer/glioma/cytokine-cytokine receptor interaction/Wnt/MAPK pathway network. Usenamine A has a strong binding affinity for PRKACA and PRKCB proteins. Usenamine A showed minimal toxicity in mice.

Conclusions: Usenamine A is a safe anticancer agent against hepatocellular carcinoma. Regulation of 12 cancer-associated genes and the correlated pathway network are its therapeutic targets.