Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) is a major driver of docetaxel resistance in prostate cancer. Thus, identifying effective agents that specifically target ABCB1 is essential for overcoming chemoresistance. Objectives: This study aimed to determine whether reserpine, a lipophilic indole alkaloid derived from Rauwolfia, could reverse docetaxel resistance in prostate cancer by modulating ABCB1. Methods: Network pharmacology analysis was used to identify potential targets of Rauwolfia-derived compounds. Molecular docking, cellular thermal shift assay and molecular dynamics simulation were performed to evaluate the interaction between reserpine and ABCB1. Cytotoxicity and reversal assays were conducted in docetaxel-resistant prostate cancer cells and ABCB1-overexpressing cells. Colony formation, 3D spheroid, doxorubicin accumulation/efflux, ATPase, apoptosis and cell-cycle assays were used to investigate the functional effects and underlying mechanism. Results: Reserpine was identified as a candidate Rauwolfia-derived compound associated with ABCB1. Computational and target-engagement analyses supported direct interaction between reserpine and ABCB1. At minimally cytotoxic concentrations, reserpine significantly restored docetaxel sensitivity in DU145-DTX, LNCaP-DTX and HEK293-ABCB1 cells, while showing little effect in parental control cells. Reserpine did not alter ABCB1 expression or subcellular localization, but increased intracellular accumulation of doxorubicin, inhibited drug efflux and stimulated ABCB1 ATPase activity. In addition, reserpine enhanced docetaxel-induced apoptosis and G₂/M arrest in resistant prostate cancer cells. Conclusion: Our Reserpine was identified as a promising natural small molecule capable of overcoming ABCB1-dependent docetaxel resistance, warranting further evaluation for prostate cancer therapy.

Abstract: Background: Many essential genes in different signaling pathways are significantly expressed in a stress- and time-dependent manner after acute kidney injury (AKI). Despite their traditional role in driving inflammation, TLR activation is increasingly recognized to promote renal epithelial repair by inducing the secretion of specific interleukins and growth factors. Objectives: This study explored the effects of TLR4 inhibition at early and late time points of cisplatin-mediated AKI. Methods: A mouse kidney injury model was developed using a single dose of cisplatin (10 mg/kg) and treated with the TLR4 inhibitor TAK-242 at either the initial or a later time point after cisplatin induction. Kidney tissues were analyzed for histopathological and gene expression changes by HE staining and qRT-PCR, respectively. Renal functional analysis was performed by estimating serum creatinine levels in the control and all treated groups. Results: Elevated biochemical markers and serum creatinine levels correlated with histological findings of tubular damage in all groups. Compared with the late intervention group, we observed prominent tubular cell injury in the cisplatin AKI model and the TAK242-early groups. Cisplatin significantly increased TLR4 expression in the AKI model, which was abrogated in both TAK242-treated AKI groups. Compared to the TAK242-early group, the late intervention group showed upregulation of Sod1 (p≤0.05), Hsp25 (p≤0.05), Nf-ĸb, Fzd8 and c-Met genes and downregulation of Il22 (p ≤0.001), Lcn2, and hsp70 gene expression. Other genes, such as Hgf1, Wnt4 and Lc3 II, showed no notable difference between the two intervention groups. Conclusion: The TLR4 pathway may be involved in immediate cell survival mechanisms after injury, as massive necrosis and elevated serum creatinine were observed following early inhibition of the TLR4 pathway, whereas late inhibition preserved tissue architecture and function. Understanding the optimal timing of TLR inhibition to achieve significant tissue protection can help underscore the role of this pathway in AKI repair and its associated pathological processes.

Abstract: Background: Serum squamous cell carcinoma antigen (SCC-Ag) and vascular endothelial growth factor (VEGF) may predict recurrence in patients with uterine fibroids after laparoscopic myomectomy (LM) and mifepristone treatment, but evidence is limited. Objectives: This retrospective cohort study aimed to evaluate whether preoperative serum SCC-Ag and VEGF levels can predict 2-year recurrence in patients with uterine fibroids receiving postoperative mifepristone after LM. Objectives: This study aimed to evaluate whether preoperative serum SCC-Ag and VEGF levels can predict 2-year recurrence in UF patients receiving postoperative mifepristone after LM. Methods: This retrospective study included 110 patients with uterine fibroids who underwent LM followed by 3 months of mifepristone. After a 2-year follow-up, 12 patients (recurrence group) had a recurrence and 98 (non-recurrence group) did not. Serum SCC-Ag, VEGF, estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured. Logistic regression, ROC analysis, decision curve analysis (DCA) and subgroup analysis were performed. Results: The recurrence group had significantly higher levels of E2, FSH, LH, SCC-Ag and VEGF (all P<0.05). The largest fibroid diameter (OR=3.142), SCC-Ag (OR=2.338), VEGF (OR=2.461) and E2 (OR=2.457) were independent risk factors. The AUCs for predicting recurrence were 0.796, 0.811, 0.843 and 0.767, respectively. DCA showed positive net benefits across risk thresholds. Subgroup analysis indicated stronger correlations with recurrence in patients with a largest fibroid diameter ≥10 cm, SCC-Ag ≥2.56 ng/mL, VEGF ≥275.34 ng/mL or E2 ≥345.12 pmol/L. Conclusion: Serum SCC-Ag, VEGF, largest fibroid diameter and E2 show good predictive value for early (2-year) recurrence in uterine fibroid patients after LM and mifepristone treatment. Owing to the single-center, retrospective design, small sample size (12 recurrences) and lack of molecular validation, these findings are exploratory and require validation in multicenter, prospective cohorts.

Abstract: Background: Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has preclinical anti-inflammatory and barrier-protective effects, but its safety profile and potential favorable reporting associations in ulcerative colitis (UC) remain uncertain. Objectives: To characterize liraglutide-associated reports in patients with UC and explore biological pathways that may contextualize the observed pharmacovigilance signals. Methods: Reports submitted to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) from January 1, 2013, to December 31, 2025, were analyzed in which liraglutide was recorded as the primary suspected drug and UC as the indication. Disproportionality was assessed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS). Network pharmacology identified shared targets, constructed a protein-protein interaction network and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Results: Among 5,903 unique cases and 28,607 preferred-term event entries, the most frequent categories were general disorders and administration-site conditions, gastrointestinal disorders, injury or medication-related complications, infections and investigations. The term “condition aggravated” was reported in 1,512 cases. Medication management, metabolic, infectious, neuropsychiatric and gastrointestinal signals were also detected. Herpes zoster was reported in 154 cases and pneumonia-related reports included eight fatal outcomes, although concomitant immunosuppressive therapy substantially limited attribution. The reporter-coded term “pre-existing condition improved” occurred in 38 cases (ROR 25.63; 95% confidence interval 16.48-39.85) and was interpreted only as an exploratory favorable reporting association. Network pharmacology identified 84 shared candidate targets and prioritized 10 hub genes. Enriched pathways included phosphoinositide 3-kinase/protein kinase B, tumor necrosis factor and Janus kinase/signal transducer and activator of transcription signaling.  Conclusion: FAERS findings generated safety and favorable-reporting hypotheses but did not establish incidence, causality, or therapeutic efficacy. The predicted pathways provide biological context only and require confirmation in comparator-based longitudinal studies, prospective clinical investigations and targeted experimental models.

Abstract: Background: Preoperative bowel preparation is a crucial perioperative step in gastrointestinal surgery. Traditional mannitol combined with soap enema regimens can easily damage the intestinal mucosa and disrupt the intestinal barrier. Compound polyethylene glycol electrolyte powder (PGEP) has the potential to protect the intestinal barrier; however, multidimensional clinical evidence remains limited. Objectives: From the perspective of intestinal barrier protection, this study compares the effects of PGEP and traditional regimens in elective gastrointestinal surgery, analyzing their influence on the intestinal barrier, microecology, stress, intestinal function and anastomotic healing. Methods: In this retrospective controlled study, 100 patients undergoing elective surgery at the Department of Gastrointestinal Surgery, Wenzhou Central Hospital, from June 2021 to June 2024 were allocated into an observation group (PGEP group, n=50;28 males, 22 females) and a control group (traditional regimen group, n=50;26 males, 24 females;) Patients were assigned to groups according to the bowel preparation regimen used in routine clinical practice. Relevant laboratory indicators were measured and clinical outcomes were recorded. Results: The primary endpoint, serum diamine oxidase (DAO) level on the 1st day after surgery, was significantly lower in the observation group than in the control group (p < 0.05). For the secondary endpoints, the observation group also showed superior bowel preparation quality (assessed by BBPS), better preservation of intestinal barrier function, greater gut microbiota stability (higher fecal short-chain fatty acids and more stable pH), a reduced stress response, faster recovery of intestinal function, reduced anastomotic edema, a higher primary healing rate and a lower overall postoperative complication rate (all p < 0.05). Conclusion: PGEP is clinically superior to traditional methods for preoperative bowel preparation in elective gastrointestinal surgeries. It effectively protects the intestinal mucosal barrier, stabilizes the gut microbiota and reduces stress, aligning with the principles of enhanced recovery after surgery (ERAS) and these results suggest potential clinical value.