Naunyn-Schmiedeberg's archives of pharmacology最新文献

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.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The "mild" clinical behavior of PTC often leads to underestimation of the complexity of its treatment. Ruminococcus (Rum) is a cancer-related intestinal flora. Further study on its functional mechanism is expected to provide a new direction for microbial targeted therapy of cancer. Therefore, the aim of this study was to investigate the therapeutic effect of Rum on PTC and its related mechanism. Rum upregulated the mRNA expression level of RBM15 in BCPAP and KTC-1 cells, decreased their cell viability, promoted pyroptotic signaling, and inhibited their invasion and migration, as well as reduced the volume and weight of tumor tissue and aggravated their pathological injuries. Moreover, Rum downregulated MMP2 and MMP9 mRNA and protein expression levels and upregulated IFN-γ, IL-1β, and IL-18 expression levels, as well as NLRP3, ASC, Caspase-1 mRNA and protein expression levels, the m6A methylation content, and the m6A methylation of NLRP3 in vivo and in vitro. In addition, knocking down RBM15 effectively reversed the effects of Rum mentioned above in vivo and in vitro. Mechanistically, Rum activates the NLRP3/ASC/Caspase-1 axis-mediated pyroptotic signaling in PTC by upregulating RBM15 to increase the N6-methyladenosine methylation modulation of NLRP3, thereby providing a novel strategy and target for the clinical treatment of PTC.

This study investigated lacosamide (LCM), a third-generation antiepileptic drug, as a potential gonadoprotective agent against cyclophosphamide (CP)-induced testicular injury. The research addressed the critical need for safer antiepileptic alternatives in cancer patients requiring concurrent chemotherapy and seizure control. Male Wistar rats underwent comprehensive biochemical and histopathological analyses including Western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, steroidogenic enzyme activity assessments, sexual hormone measurements, sperm quality evaluations, and molecular docking studies to evaluate LCM's protective mechanisms against CP-induced testicular damage. CP administration significantly elevated oxidative stress markers, pro-inflammatory mediators (Nuclear factor kappa B [NF-κB], Tumor necrosis factor-α [TNF-α], Interleukin-6 [IL-6], Interleukin-1β [IL-1β]), and apoptotic signaling (Bcl-2-associated x protein [Bax], caspase-3), while activating regulatory proteins c-jun N-terminal kinase 1 (JNK1) and Signal transducer and activator of transcription 3 (STAT-3) (identified as novel markers in CP-induced testicular injury). CP suppressed antioxidant defenses, steroidogenic factors (steroidogenic acute regulatory protein [StAR], 3β-hydroxysteroid dehydrogenase [3β-HSD], 17β-hydroxysteroid dehydrogenase [17β-HSD]), Heme oxygenase 1 (HO-1) expression, and androgen receptor (AR) functionality, resulting in decreased testosterone, gonadotropin levels, and compromised spermatogenesis. LCM treatment effectively mitigated these deleterious effects through multi-target protective mechanisms including c-jun N-terminal kinase 1(JNK1)-mediated apoptosis inhibition, HO-1 upregulation, IL-6/ signal transducer and activator of transcription 3 (STAT-3) signaling suppression, prevention of p-JNK1/STAT-3 crosstalk, and AR preservation. This study establishes LCM's multi-target protective efficacy, supporting its potential as a safer antiepileptic alternative providing dual benefits of seizure control and reproductive preservation during chemotherapy.

Obesity is a chronic disease caused by the accumulation of cholesterol, which often requires long-term management strategies, such as dietary changes, increased physical activity, and psychological support. Obesity associated neurobehavioral disorders are a growing global health concern, emphasizing the need for innovative therapeutic strategies. Our study evaluates the therapeutic efficacy of (Z)-1-(furan-2-yl)-N-(4-(2-nitrophenyl)-6-(p-tolyl)pyrimidin-2-yl)methanimine referred as BN3 derivative, in treating high-fat diet-induced metabolic and behavioral dysfunctions in a zebrafish model. The research focused on reducing oxidative stress, lipid accumulation, and neurobehavioral deficits, which are closely linked to obesity-related metabolic stress. In this study, zebrafish were divided into five separate experimental groups: control group, model of obesity caused by high-fat diets, BN3 (50 µM and 100 µM), and Positive Control (PC) Group treated with Lovastatin 100 µM. Initially, fish were fed a high-fat diet for 14 days and followed by 30 days of exercise and simultaneously administering BN3 treatments via oral gavage. Assessment of biochemical, histopathology, gene expression, and behavioral were carried out. The results indicated that BN3 treatment significantly decreased oxidative stress levels by enhancing the activity of four antioxidant enzymes (Superoxide Dismutase, Catalase, Glutathione Transferase and Glutathione Peroxidase). BN3 also decreased lipid accumulation as evidenced through histological staining analysis, and total cholesterol estimation. BN3 enhanced locomotion, social interaction, and exploratory behaviors, and reduced anxiety, with the 100 µM treatment group exhibiting the same results as the PC. Gene expression analysis indicates that BN3 is modulating pparγ, fas, pik3cd, src-3, and bdnf pathways (metabolic and neuroinflammation pathways). BN3 impacted these multiple metabolic and neurobehavioral impairments associated with obesity through a multisite treatment approach. BN3 demonstrates significant therapeutic potential, assuring further studies to explore its long-term safety, pharmacokinetics, and translational application in managing obesity and related disorders.

Przewaquinone A (PrA), a natural active substance extracted from Salvia przewalskii Maxim, has been shown to have antitumor activity and can act as a STAT3 inhibitor to modulate the Src/STAT3 pathway. However, its role in colorectal cancer (CRC), along with its related mechanisms, has not yet been clarified. This study aims to explore whether PrA inhibits the malignant advancement of CRC via the Src/STAT3 pathway, and to provide new drug candidates and molecular targets for CRC clinical treatment. The toxic effects of PrA on normal cells NCM460 and on CRC cells (SW480, HCT116, etc.) were explored by Cell Counting Kit-8 (CCK-8) assay. The malignant phenotype, cell cycle distribution, and apoptosis rate were analyzed with the help of Transwell assay, clone formation assay, and flow cytometry. The impact of PrA on autophagic flow in CRC cells was analyzed by GFP-RFP-LC3 dual fluorescent labeling. Plasmid transfection was used to modulate Src expression to verify whether PrA acts through the Src/STAT3 pathway. Finally, subcutaneous graft tumor and carcinoma in situ models were constructed in nude mice, and cell proliferation and apoptosis were detected by pathological staining, and the expression of indicator proteins and Src/STAT3 pathway-related proteins were evaluated via western blot. PrA at 1 ~ 4 µM did not markedly impact NCM460 cell viability, but it dose-dependently reduced CRC cell viability. PrA also diminished the migration and invasion ability of CRC cells, induced G0/G1 phase cycle block, apoptosis, and autophagy, and inhibited Src/STAT3 pathway activation and nuclear translocation of STAT3. Furthermore, overexpression of Src reversed the regulatory impacts of PrA described above. In vivo, PrA treatment hindered tumor growth in nude mice, inhibited cell proliferation, and promoted apoptosis, whereas Src overexpression attenuated the tumor-suppressive effects of PrA. By suppressing the Src/STAT3 pathway, PrA regulates cell cycle and autophagy in CRC cells, thereby inhibiting CRC malignant progression.