Naunyn-Schmiedeberg's archives of pharmacology最新文献

Assessing the biological activities of some potential drugs and comparing their suitability for in vitro and in vivo combination therapy or in silico drug repositioning against important targets is essential for minimizing labor, costs, and time in drug development. Herein, dose- and time-dependent in vitro anticancer activity studies of anti-inflammatory drugs, including celecoxib (C), indomethacin (I), and meloxicam (M), in combination with natural products (taxifolin (T), quercetin (Q), and rutin (R)) and doxorubicin (Dox), were carried out in MDA-MB-231, BT-20, MCF-7, and HT-29 human cancer cell lines. Drug C demonstrated significant anticancer activity in cancer cells with natural products (< 40 µM) and Dox (< 5 µM). The antiulcerative effect of the most promising drug C in combination with T and R in rats was carried out. The histopathological analysis suggests that the substitution of R with T, when combined with drug C, leads to a statistically significant improvement in the amelioration of gastric mucosal injury. Additionally, in silico studies have been conducted against the important cancer drug target sphingosine kinase 1 (SphK1). The obtained results highlight that drug C and T may be potential inhibitor candidates as SphK1 inhibitors for targeted cancer therapy. Overall, the combination of drug C with T has shown promising results, anticancer effects in breast and colon cancer cells and antiulcerative effects in rats.

Gastric ulcer (GU) is primarily caused by Helicobacter pylori (H. pylori) infection, ethanol-induced oxidative stress, and excessive gastric acid secretion. This is a significant global health burden. Lifetime prevalence of peptic ulcer disease (including GU and duodenal ulcer) in the general population has been estimated to be about 5-10%, and incidence 0.1-0.3% per year. Kahweol (a coffee-derived diterpene) exhibits broad pharmacological effects. Although Kahweol has strong antioxidant, anti-inflammatory and cytoprotective effects, its gastroprotective potential against ethanol-induced GU has remained unexplored. This is the first study demonstrating the multifaceted gastroprotective effects of Kahweol using an integrated computational, in vitro, and in vivo approaches, including direct comparison with omeprazole and evidence of dual acid-suppressive and anti-H. pylori activity. Molecular docking and 100 ns molecular dynamics simulations demonstrated stable Kahweol binding to H⁺/K⁺-ATPase, nuclear factor-kappa B, NOD-like receptor protein 3, and cyclooxygenase-2. Kahweol exhibits inhibition of inflammatory pathways and acid secretion, having the highest affinity for H⁺/K⁺-ATPase (-7.92 kcal/mol). In vitro assays revealed that Kahweol has dose-dependent antibacterial activity against H. pylori clinical isolates. In vivo, Kahweol significantly decreased the ethanol-induced ulcer index in a dose-dependent manner. Kahweol pretreatment inhibited GU up to 80% with 10 mg/kg dose, which was comparable to that of omeprazole (85%). Histopathological analysis in Kahweol-treated groups confirmed preserved mucosal architecture, reduced vacuolation, and restored epithelial boundaries, which were comparable to those of omeprazole. Biochemical assays of Kahweol-treated groups showed enhanced antioxidant defenses, with increased levels of reduced glutathione, glutathione S-transferase, and catalase, along with decreased levels of nitric oxide and malondialdehyde. Results from the enzyme-linked immunosorbent assay of the Kahweol-treated group showed that the pro-inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha were suppressed, confirming anti-inflammatory effects. Quantitative real-time polymerase chain reaction verified that the expression of H⁺/K⁺-ATPase was downregulated by Kahweol, indicating the acid-inhibition effect of Kahweol. These findings suggest Kahweol is the potential natural agent for the prevention and treatment of ethanol-induced GU, highlighting the comprehensive gastroprotective effects of Kahweol through its antioxidant, anti-inflammatory, anti-secretory, and anti-H. pylori activity.

Complex systemic immune dysregulation and chronic inflammation in rheumatological diseases lead to long-term inflammation and morbidity, which are primarily controlled by systemic immunosuppressant agents with diverse effects, underscoring the need for more precise and innovative treatments. The unmatched specificity in targeting disease-driving genes and pathways makes small interfering RNA (siRNA) a transformative treatment approach. This review examines how siRNA can precisely transform the therapy of rheumatological diseases by targeting critical molecular pathways associated with inflammation, immunological dysregulation, and tissue damage. While this study elucidates siRNA therapies targeting inflammatory pathways to treat rheumatological diseases, it moves beyond the conventional therapeutic application of siRNAs targeting pro-inflammatory cytokines; it explicitly focuses on upstream signaling hubs within synovial fibroblasts, T cells, and plasma cells, as well as on non-inflammatory mechanisms that lead to bone damage. The review also integrates in vitro and in vivo, as well as preclinical siRNA studies, to identify the most promising targets and determine whether these siRNA modifications, combined with delivery systems, achieve body-wide and joint-specific immune-stromal network reprogramming through targeted delivery without causing total immune system breakdown.

Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder during pregnancy associated with adverse maternal and fetal outcomes, highlighting the urgent need for novel, genetically supported drug targets due to suboptimal glycemic control and safety concerns with existing therapies. This study integrated cis-expression quantitative trait loci (cis-eQTL) of druggable genes with genome-wide association data to identify putative causal genes for GDM through two-sample Mendelian randomization (MR), with significant associations further validated using multi-tissue summary data-based Mendelian randomization (SMR), colocalization analysis, cis-protein quantitative trait loci (cis-pQTL) MR, and single-cell RNA sequencing (scRNA-seq) to confirm tissue- and cell type specific expression. MR analysis identified 15 genes significantly associated with GDM risk after Bonferroni correction, with SMR and colocalization analyses confirming robust associations for five key genes: higher expression of NRBP1, LPL, and BTN3A2 was causally linked to reduced GDM risk, while elevated GSTM1 and GRINA levels were associated with increased risk. ScRNA-seq revealed distinct expression patterns in placental cell types, with NRBP1 and GRINA highly expressed in trophoblasts and certain immune cell populations. Phenome-wide association studies revealed no significant pleiotropic effects, and pharmacological drug-target databases identified several compounds with potential regulatory interactions. This multi-omics study successfully identifies several genetically supported, druggable targets for GDM, providing a robust foundation for developing mechanism-based therapeutics and precision prevention strategies in pregnancy metabolism.

Cocaine use disorder (CUD) remains a major public health challenge with limited effective therapeutic options. Cannabidiol (CBD) has been proposed as a potential treatment due to its neuroprotective and anti-craving properties. This scoping review aims to synthesize and map the existing evidence from clinical trials evaluating CBD's effects on craving reduction, relapse prevention, cognitive function, and emotional regulation in individuals with CUD. Although CBD was well tolerated and associated with fewer adverse events than conventional pharmacological treatments, clinical studies included in this review did not demonstrate significant efficacy over placebo in reducing cocaine craving, preventing relapse, or improving cognitive performance, despite promising preclinical outcomes. The review also highlights methodological limitations across studies, including variability in dosage, treatment duration, and study design. Although current evidence does not support CBD as a standalone treatment for CUD, its favorable safety profile suggests potential utility within a broader, multimodal therapeutic framework. Future research should prioritize standardized protocols and explore synergistic combinations with behavioral or pharmacological interventions to enhance treatment efficacy.

Hepatitis C virus remains a pressing global health issue that has driven extensive research for introducing advanced therapeutic regimens. Among these, the sofosbuvir (SFV)/ribavirin (RBV) drug regimen has had a profound effect on reducing the viral load. Nevertheless, this drug regimen has led to adverse testicular alterations. This study aimed to investigate the restorative effects of SFV/RBV over different durations to determine the possibility of restoring normal histological and histophotometrical testicular tissue. Swiss Albino mice were grouped as total n = 80 with subgroups of n = 5 per timepoint per group, into control group, SFV group received 41mg/kg once daily of SFV, RBV group administered with RBV 41 mg/kg twice daily, and SFV-RBV group received a combined dose of SFV + RBV, identical to those used separately. All drugs were administered by oral gavage for 5 successive days. Testicular tissue in the SFV, RBV, and SFV-RBV groups, at 5 and 70 days after administration, exhibited pronounced alterations, including spermatocyte degeneration, Leydig cell impairment, and disrupted spermatogenesis. Moreover, altered morphometric parameters were observed, characterized by a reduction in testicular area, a diminished seminiferous diameter, and a regression in spermatic epithelium thickness, which collectively contributed to a decline in the spermatogenic index and the conception index. Conversely, starting from day 140 and persisting through day 175 post-treatment, testicular architecture demonstrated substantial recovery, with restoration of spermatogenesis and improvements across morphometric parameters. The administration of SFV and/or RBV for 5 days induced significant testicular injury, which was reversed after 175 treatments. Restorative effects underscore the potential safety of SFV/RBV regimens in human males.

The present study aimed to formulate and evaluate, both in vitro and in vivo, enteric-coated mucoadhesive microspheres of pantoprazole using xanthan gum and Eudragit L100-55 in order to protect pantoprazole from gastric acid degradation and to create a temporary drug reservoir in the gastrointestinal tract, thereby achieving enhanced targeting. The goal was to assess their potential in preventing ketorolac-induced gastric ulcers in rats. Various formulations of pantoprazole microspheres were prepared and developed via an extrusion method using ionotropic gelation and dip coating. The formulations were evaluated for encapsulation efficiency, particle size, mucoadhesive properties, swelling percentage, resistance to gastric acid, and drug release over six hours in vitro. The optimized formulation (10 mg/kg) was subsequently tested in vivo on rats with ketorolac-induced (30 mg/kg) gastric ulcers, and the gastric tissue was examined for histopathological changes. The formulation containing 1% xanthan gum showed the highest drug release (80% w/w) and suitable loading (77.58% w/w), with a swelling index of 50.84% w/w, average particle size of 1.19 mm, an adhesion strength of 2.71 ± 0.87 N per 0.1 g and was fully resistant to acidic conditions. In vivo, it prevented gastric ulcers as effectively as the marketed product and, unlike the marketed product, also prevented vascular rupture in all ketorolac-induced ulcer rats. The optimized formulation performed well, suggesting its potential as an oral delivery alternative.

This study aimed to develop a pH-responsive polymeric hydrogel for the controlled delivery of cytarabine for the treatment of acute leukemia. The polymeric hydrogel was synthesized via free radical polymerization using pluronic acid F127, PEG-800, and agarose as a polymer, and crosslinked via methylene bis acrylamide. The optimized formulation (PPA12) was investigated for cytarabine loading (%), thermal analysis, compatibility of formulation ingredients, swelling trend, morphology, release kinetics, and toxicity in rabbits. Cytarabine loading increased with increase in ratio of polymer, monomer, and pH. The developed hydrogels exhibited excellent swelling behavior at pH 7.4. Cytarabine release occurred in a controlled fashion over a time period of 24 h. Based on the regression coefficient (R²), the best-fit model was of the zero order. Structural entanglement was confirmed by Fourier-transform infrared spectroscopy (FTIR) studies, which confirmed the formation of a hydrogel blend. Toxicity studies have revealed no signs of ocular, oral, or dermal toxicity, thereby ensuring safety and biocompatibility. Therefore, these findings strongly suggest that the developed and optimized polymeric hydrogel (PPA12) is biocompatible, capable of delivering cytarabine at a particular pH, and can be a carrier of choice for targeted drug delivery.

Aims: This study examined the renoprotective effect of Piribedil against cyclophosphamide (CP)-induced nephrotoxicity through modulation of adenosine monophosphate-activated protein kinase (AMPK)/sirtuin-1 (SIRT1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinases (MAPKs), and Toll-like receptor-4 (TLR4)/NOD-like receptor protein-3 (NLRP3) pathways, as well as renal injury markers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL).

Main methods: Male rats were divided into four groups (n = 8). Controls received distilled water plus saline; the CP group received a single CP dose (200 mg/kg, i.p.) on day 7; Piribedil groups received 15 or 40 mg/kg/day for 10 days with CP on day 7. Renal function, oxidative stress, inflammation, and injury markers (KIM-1 and NGAL) were assessed via biochemical assays, histopathology, immunohistochemistry, and quantitative real-time PCR (qRT-PCR).

Key findings: CP caused significant renal dysfunction, elevating blood urea nitrogen (BUN), serum creatinine (SCr), NGAL, and KIM-1, increasing oxidative stress (malondialdehyde [MDA], inducible nitric oxide synthase [iNOS]) and reducing nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione (GSH). CP also upregulated inflammatory mediators (interleukin-1β [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α], nuclear factor-κB p65 [NF-κB p65]) and enhanced TLR4, NLRP3, and MAPKs, while suppressing AMPK, SIRT1, and PI3K/Akt signaling. Piribedil reversed these changes, improving renal function, lowering oxidative and inflammatory markers, and normalizing BUN, SCr, KIM-1, and NGAL. Histology confirmed reduced renal damage.

Significance: Piribedil effectively protects against CP-induced nephrotoxicity by modulating AMPK/SIRT1 and related oxidative and inflammatory pathways, supporting its potential use in drug-induced kidney injury.

Benign prostatic hyperplasia (BPH) is a noncancerous prostate enlargement that significantly impacts the quality of life in aged men. Both oxidative stress and inflammation interplay to induce hyperplasia of prostatic epithelial cells as well as seminal vesicle tissues. Dihydromyricetin (DHM), extracted from Ampelopsis grossedentata, is used in traditional Chinese medicine for hundreds of years. It exhibited prominent anticancer, anti-inflammatory, and antioxidant activities in several models. To date, its potential protective effects for BPH have not been investigated. The aim of this study was to investigate the role of DHM in the management of testosterone-induced proliferation in prostate and seminal vesicle tissues. Male Wistar rats (200 to 250 g) were divided into three groups: a control group receiving sesame oil (the vehicle), a BPH group receiving testosterone oenanthate (3 mg/kg, subcutaneously) daily for 4 weeks to induce hyperplasia, and a DHM group receiving DHM (50 mg/kg) alongside testosterone oenanthate (3 mg/kg). DHM significantly reduced the prostate and seminal vesicle weights, ameliorated the histopathological changes induced by testosterone, and nearly normalized the serum testosterone, FSH, and LH levels. It also reduced the serum PSA level. Further, DHM reduced MDA levels while increasing GSH levels. Besides, it reduced the prostatic levels of 5-alpha reductase and attenuated TGF-β1/Smad-2 pathway. The anti-hyperproliferation and the anti-inflammatory effects of DHM were attributed to the attenuation of the expression of PCNA, procaspase-3, iNOS, TLR-4, and IL-1β in both the prostate and seminal vesicle tissues. DHM has potential protective effects against testosterone-induced BPH model via downregulation of inflammatory mediators, restoration of oxidative balance, and induction of cell apoptosis.