Toxicology and applied pharmacology最新文献_第2页

Berberine attenuates ECM accumulation and the progression of acute liver failure through inhibition of NLRP3 inflammasome signalling 小檗碱通过抑制 NLRP3 炎性体信号传导，减轻 ECM 积累和急性肝衰竭的进展。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-18 DOI: 10.1016/j.taap.2024.117129

{"title":"Berberine attenuates ECM accumulation and the progression of acute liver failure through inhibition of NLRP3 inflammasome signalling","authors":"","doi":"10.1016/j.taap.2024.117129","DOIUrl":"10.1016/j.taap.2024.117129","url":null,"abstract":"<div><div>Acute liver failure (ALF) is a life-threatening disease, characterized by upregulated extracellular matrix deposition and inflammatory signalling, with no effective treatment options and targets. The present study was designed to investigate the preventive and therapeutic effects of berberine (BBR) and its underlying mechanism in thioacetamide (TAA)-induced ALF. Male SD rats were administered with TAA 300 mg/kg, <em>i.p.,</em> thrice to induce ALF and pre- or post-treated with BBR. To decipher the effects of BBR LFT markers, histopathological analysis of key fibrotic and inflammatory proteins was performed. In addition, the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α were assessed by ELISA. Our work showed TAA-induced ALF animals were associated with increased ALT, AST, bilirubin (LFT markers) and histopathological alterations with profuse infiltration of inflammatory cells in the liver tissue. Treatment with BBR has significantly inhibited LFT markers and histological alterations triggered by TAA. In addition, TAA animals demonstrated increased collagen accumulation and upregulated expression of TGF-β1, vimentin, and α-SMA compared to control. The excessive accumulation of collagen, TGF-β1, vimentin, and α-SMA were significantly modulated with BBR treatment. Further, the fluorescence intensity of ROS an activator of NLRP3 including the NLRP3 inflammasome, and its downstream signalling ASC, cleaved IL-1β, and other pro-inflammatory cytokines like TNF-α and IL-6 stimulated by TAA were attenuated by BBR treatment. The current work indicated that BBR significantly ameliorated TAA-induced ALF by inhibiting the extracellular matrix accumulation associated with the NLRP3/IL-1β signalling pathway and could be a viable therapeutic option to treat ALF and other fibroinflammatory diseases.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sappanone A ameliorates acute lung injury through inhibiting the activation of the NF-κB signaling pathway 萨帕酮 A 可通过抑制 NF-κB 信号通路的激活来改善急性肺损伤。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-16 DOI: 10.1016/j.taap.2024.117127

{"title":"Sappanone A ameliorates acute lung injury through inhibiting the activation of the NF-κB signaling pathway","authors":"","doi":"10.1016/j.taap.2024.117127","DOIUrl":"10.1016/j.taap.2024.117127","url":null,"abstract":"<div><div>Acute lung injury (ALI) is a serious respiratory disease characterized by diffuse alveolar injury, and it has emerged as a major concern in clinical practice due to limited treatments. This study aimed to explore the pharmacological effects and regulatory mechanism of sappanone A (SA) on ALI. In vivo, mice were administered with SA followed by intratracheal injection of lipopolysaccharide (LPS) to establish an animal model of ALI. We observed that SA exerted comparable anti-inflammatory effects to dexamethasone, as evidenced by effectively mitigating histopathological abnormalities and suppressing the inflammatory response in the lung tissues of mice with ALI. RNA sequencing analysis revealed that SA significantly inhibited the activation of the nuclear factor kappa B (NF-κB) signaling pathway. In vitro, we found that SA protected BEAS-2B cells against LPS-induced cellular injury and reduced inflammatory cytokine generation. Furthermore, both in vivo and in vitro experiments demonstrated that SA effectively prevented LPS-induced oxidative stress and apoptosis. Consistent with the results of the RNA sequencing analysis, SA significantly inhibited the increased protein expressions of p105, p50, c-REL, as well as the ratios of p-p65/p65 and p-IκBα/IκBα in the lung tissues of mice with ALI and LPS-stimulated BEAS-2B cells. Additionally, SA inhibited the nuclear translocation of p65 in BEAS-2B cells stimulated with LPS. Importantly, specific blockade of the NF-κB signaling pathway using BAY11–7082 was identified to alleviate LPS-induced cellular injury in BEAS-2B cells. Collectively, these findings suggest that SA can ameliorate ALI, at least in part, through the inhibition of NF-κB signaling pathway activation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the impact of sEH inhibition on intestinal cell differentiation and Colon Cancer: Insights from TPPU treatment 探索抑制 sEH 对肠细胞分化和结肠癌的影响：TPPU治疗的启示

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-15 DOI: 10.1016/j.taap.2024.117128

{"title":"Exploring the impact of sEH inhibition on intestinal cell differentiation and Colon Cancer: Insights from TPPU treatment","authors":"","doi":"10.1016/j.taap.2024.117128","DOIUrl":"10.1016/j.taap.2024.117128","url":null,"abstract":"<div><div>Inhibition of soluble epoxide hydrolase (sEH) appears to be promising for the treatment of many diseases. Studies have focused on the beneficial effects of epoxyeicosatrienoic acids (EETs), which are sEH substrates. However, our recent studies have shown that the sEH activity is crucial for the proper intestinal cell differentiation. In this recent study, we investigated the impact of TPPU, an inhibitor of sEH, on the colon cancer cell lines Caco2 and HT-29. We analysed the changes in the expression of the cytoskeletal protein ezrin and the phosphorylated protein kinase p38 (p-p38). Our results showed a decrease in ezrin expression in differentiated cells and an increase in p-p38 expression after TPPU treatment. Immunocytochemical staining revealed a higher staining intensity of p-p38 in the nuclei of HT-29 cells following TPPU treatment. Immunohistochemical staining was performed on human samples of normal colon tissue, grade 2 tumours, and embryonal/foetal tissues. The staining intensity of ezrin in tumours was reduced in the surface area compared to the crypts. Additionally, we observed the translocation of p-p38 expression from the cytoplasm to the nucleus during differentiation. The tumour samples exhibited higher levels of p-p38 in the cytoplasm, similar to normal undifferentiated tissue. To observe the disruption of the cytoskeleton after TPPU treatment, confocal microscopy was used. It was found that β-actin associated with ezrin forms clusters under the plasma membranes. All of these results are significant because sEH inhibitors are being tested in clinical trials, but they could cause an unexpected adverse effects.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of different gastric acid suppressants on chronic unpredictable mild stress-induced cognitive impairment in rats: A possible involvement of gut dysbiosis 不同胃酸抑制剂对慢性不可预测轻度应激诱发的大鼠认知障碍的影响：肠道菌群失调的可能参与

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-13 DOI: 10.1016/j.taap.2024.117126

{"title":"Impact of different gastric acid suppressants on chronic unpredictable mild stress-induced cognitive impairment in rats: A possible involvement of gut dysbiosis","authors":"","doi":"10.1016/j.taap.2024.117126","DOIUrl":"10.1016/j.taap.2024.117126","url":null,"abstract":"<div><div>Recently, clinical evidence indicates that gastric acid suppressants are associated with an increased risk of the development of cognitive impairment and dementia, especially in elderly patients and those with mild cognitive impairment. Therefore, the aim of this research was to explore the impact of different gastric acid suppressants use, famotidine (Famo), esomeprazole (Esome) and vonoprazan (Vono) in the absence or the presence of chronic unpredictable mild stress (CUMS) on several memory tasks with examination of the role of gut dysbiosis. In the present study, rats received famotidine (3.7 mg/kg/day, p.o.) or esomeprazole (3.7 mg/kg/day, p.o.) or vonoprazan (1.85 mg/kg/day, p.o.) for 7 weeks with or without exposure to CUMS. Remarkably, CUMS with different acid suppressants caused a significant decrease in all memory tasks in late CUMS in the current investigation. CUMS with acid suppressants also revealed a marked alteration in the fecal <em>Firmicutes</em>/<em>Bacteroidetes</em> ratio compared to CUMS alone. This gut microbiome alteration was associated with an alteration in gut membrane integrity, as revealed by colonic histopathology and an elevation of systemic inflammatory markers. Besides, upregulation of hippocampal amyloid β and p-tau proteins and modification of brain histopathology were noticed. Our findings support the detrimental effect of gastric acid suppressants, especially proton pump inhibitors, on cognitive impairment in the presence of stress, with the possible involvement of gut dysbiosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates 新型 GLP-1 受体偏性激动剂--SAL0112 在非人灵长类动物中的毒理学概况。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-10 DOI: 10.1016/j.taap.2024.117125

{"title":"Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates","authors":"","doi":"10.1016/j.taap.2024.117125","DOIUrl":"10.1016/j.taap.2024.117125","url":null,"abstract":"<div><div>Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both <em>in vitro</em> and <em>in vivo</em> preclinical toxicity investigations were conducted to explore the safety profile of SAL0112. The HTRF assay and TR-FRET assay were utilized for cAMP detection. Patch clamp assay was employed for hERG potassium ion channel determination. Cynomolgus monkeys were used in a cardiovascular safety pharmacology study and a 13-week repeated dose toxicity study. The telemetry system was employed to detect cardiovascular indicators such as ECG, HR, and BP. During the repeated dose toxicity study, body weight, food intake, hematology, coagulation function test, serum biochemistry tests, and urine analysis were measured. Macroscopic and microscopic observations were conducted at the end of the study. TK studies were conducted on Day 1 and Day 91. SAL0112 exhibited a high degree of potency in activating the monkey GLP-1 receptor whereas had no effect on the rodent GLP-1 receptor. In contrast to Danuglipron, which demonstrated high potency on hERG with an IC<sub>50</sub> value of 6.9 μM, the IC<sub>50</sub> of SAL0112 on hERG was greater than 100 μM. Compared to the Vehicle Control group, no significant changes in cardiovascular indicators were observed in the cardiovascular safety pharmacology study after a single dose of SAL0112 up to 250 mg/kg (<em>P</em> > 0.05). A repeated dose toxicity study revealed moderate anorexigenic effects and a reduction in body weight, effects that were found to be reversible and not associated with any pathological changes. The NOAEL of SAL0112 is 150 mg/kg, providing an approximate safety margin of threefold. SAL0112 demonstrated a favorable safety profile in cynomolgus monkeys, with a substantial therapeutic window that supports the progression of this compound into clinical studies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacology and molecular modeling studies of sulfoxaflor, flupyradifurone and neonicotinoids on the human neuronal α7 nicotinic acetylcholine receptor 磺胺草醚、氟吡菌脲和新烟碱类药物对人类神经元α7烟碱乙酰胆碱受体的药理学和分子模型研究。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-10 DOI: 10.1016/j.taap.2024.117123

{"title":"Pharmacology and molecular modeling studies of sulfoxaflor, flupyradifurone and neonicotinoids on the human neuronal α7 nicotinic acetylcholine receptor","authors":"","doi":"10.1016/j.taap.2024.117123","DOIUrl":"10.1016/j.taap.2024.117123","url":null,"abstract":"<div><div>We conducted electrophysiological and molecular docking studies using a heterologous expression system (Xenopus oocytes) to compare the effects of four neonicotinoids (acetamiprid, imidacloprid, clothianidin and thiamethoxam), one sulfoximine, (sulfoxaflor), and one butenolide (flupyradifurone), on human α7 neuronal nicotinic acetylcholine receptors (nAChRs). All neonicotinoids (except thiamethoxam), as well as the recently introduced nAChR competitive modulators, flupyradifurone and sulfoxaflor, appear to be weaker agonists than acetylcholine. Two mutations in loop C (E211N and E211P) and one mutation in loop D (Q79K), known to be involved in the binding properties of neonicotinoids were introduced to the α7 wild type. Interestingly, the acetylcholine and nicotine-evoked activation was not modified in human α7 mutated receptors, but the net charge was enhanced for clothianidin and imidacloprid, respectively. Flupyradifurone responses strongly increased under the Q79K mutation. The molecular docking investigations demonstrated that the orientations and interactions of the ligands considered were in accordance with those observed experimentally. Specifically, the charged fragments of acetylcholine and nicotine, used as reference ligands, and their neonicotinoid homologs were found to be surrounded by aromatic residues, with key interactions with Trp171 and Y210. Furthermore, the molecular docking investigations predicted the water-mediated interaction between the carbonyl oxygen of acetylcholine and the Nsp<sup>2</sup> nitrogen of the pyridine ring for nicotine (as well as for the majority of the corresponding neonicotinoid fragments) and main chain NH of L141. The docking scores, extending over a significant range of 6 kcal/mol, showed that most neonicotinoids were poorly stabilized in the α7 nAChR compared to acetylcholine, except sulfoxaflor.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circ_0049979 ameliorates myocardial infarction through improving Cx43-mediated endothelial functions Circ_0049979通过改善Cx43介导的内皮功能来改善心肌梗死。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-09 DOI: 10.1016/j.taap.2024.117121

{"title":"Circ_0049979 ameliorates myocardial infarction through improving Cx43-mediated endothelial functions","authors":"","doi":"10.1016/j.taap.2024.117121","DOIUrl":"10.1016/j.taap.2024.117121","url":null,"abstract":"<div><div>Endothelial injury is a fundamental pathogenesis of coronary atherosclerotic heart disease (CHD). Circular RNAs (circRNAs) are important post-transcriptional regulators in many human major diseases, including CHD. The aim of the present study was to explore the role of circ_0049979, a novel identified circRNA from ANO8 gene locus, in endothelial injury during CHD. We found that expression of circ_0049979 was reduced by ox-LDL treatment in HUVECs in a dose-dependent manner. Loss- and gain-of-function experiments demonstrated that knockdown of circ_0049979 decreased the capacities of proliferation, migration and tube formation in normal HUVECs. While, overexpression of circ_0049979 improved these capacities in both normal and ox-LDL-incubated HUVECs. Then, the online bioinformatic tool Circinteractome was used to predicted the target miRNAs of circ_0049979, and miR-653 was selected as the candidate. We demonstrated that miR-653 directly interacted with and was negatively regulated by circ_0049979, and played a negative role in regulating proliferation, migration and tube formation of HUVECs. In terms of the mechanism, miR-653 post-transcriptionally suppressed the expression of the gap junction protein 43 (Cx43), a key protein of endothelial tight junction. Finally, we verified that overexpression of circ_0049979 was able to alleviate plaque formation, lipid deposition, and endothelial cell apoptosis, as well as myocardial infarction, in coronary atherosclerotic mice <em>in vivo</em>. In conclusion, circ_0049979 plays a protective role in coronary atherosclerotic myocardial infarction by improving miR-653/Cx43-mediated endothelial functions.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PM10 dysregulates epithelial barrier function in human corneal epithelial cells that is restored by antioxidant SKQ1 PM10 可使人类角膜上皮细胞的上皮屏障功能失调，而抗氧化剂 SKQ1 可使其恢复正常。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-09 DOI: 10.1016/j.taap.2024.117122

{"title":"PM10 dysregulates epithelial barrier function in human corneal epithelial cells that is restored by antioxidant SKQ1","authors":"","doi":"10.1016/j.taap.2024.117122","DOIUrl":"10.1016/j.taap.2024.117122","url":null,"abstract":"<div><div>Exposure to airborne particulate <10 μm (PM<sub>10</sub>) adversely affects the ocular surface. This study tested PM<sub>10</sub> on epithelial barrier integrity in immortalized human corneal epithelial cells (HCE-2) and mouse cornea, and whether antioxidant SKQ1 is restorative. HCE-2 were exposed to 100 μg/ml PM<sub>10</sub> ± SKQ1 for 24 h. An Electric Cell-Substrate Impedance Sensing (ECIS) system monitored the impact of PM<sub>10</sub>. RT-PCR, western blotting and immunofluorescence measured levels of barrier and associated proteins, stanniocalcin 2 (STC2), and a kit measured total calcium. In vivo, female C57BL/6 mice were exposed to either control air or PM<sub>10</sub> (±SKQ1) in a whole-body exposure chamber, and barrier associated proteins tested. Tight junction and mucins proteins in the cornea were tested. In HCE-2, PM<sub>0</sub> vs control significantly reduced mRNA and protein levels of tight junction and adherence proteins, and mucins. ECIS data demonstrated that PM<sub>10</sub> vs control cells exhibited a significant decrease in epithelial barrier strength at 4000 Hz indicated by reduced impedance and resistance. PM<sub>10</sub> also upregulated STC2 protein and total calcium levels. In vivo, PM<sub>10</sub> vs control reduced zonula occludens 1 and mucins. SKQ1 pre-treatment reversed PM<sub>10</sub> effects both in vitro and in vivo. In conclusion, PM<sub>10</sub> exposure reduced tight junction and mucin proteins, and compromised the seal between cells in the corneal epithelium leading to decreased epithelial barrier strength. This effect was reversed by SKQ1. Since the corneal epithelium forms the first line of defense against air pollutants, including PM<sub>10</sub>, preserving its integrity using antioxidants such as SKQ1 is crucial in reducing the occurrence of ocular surface disorders.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes 西他列汀和左旋茶氨酸联合疗法对实验性糖尿病大鼠睾丸组织的影响

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-06 DOI: 10.1016/j.taap.2024.117119

{"title":"Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes","authors":"","doi":"10.1016/j.taap.2024.117119","DOIUrl":"10.1016/j.taap.2024.117119","url":null,"abstract":"<div><div>This study examines the impact of the combination of sitagliptin and L-theanine on the testis tissue of rats with experimental diabetes. Diabetes mellitus, a chronic metabolic illness, significantly reduces quality of life and can cause male infertility by decreasing sperm count, motility, and testosterone levels. Rats were allocated to five separate groups: control, diabetes, L-theanine, sitagliptin, and combination therapy. The measurements encompassed blood glucose levels, body weight, serum insulin levels, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The histological examination of testicular tissue was conducted using H&E, PAS<img>H, caspase-12, and PCNA staining techniques, in addition to a TUNEL assay to detect apoptosis. Levels of oxidative stress indicators, including glutathione peroxidase (GPX), malondialdehyde (MDA), and catalase, were also evaluated. The results showed that the group of individuals with diabetes had significantly higher levels of blood glucose, apoptotic indices, GPX, catalase, and MDA levels and activities in comparison with the control group. Although both the L-theanine and sitagliptin groups exhibited some improvement, the combination therapy demonstrated the most significant decrease in histopathological damage and apoptotic markers. These results indicate that the combination of sitagliptin and L-theanine may significantly decrease testicular damage caused by diabetes, making it a promising therapeutic strategy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fosaprepitant improves cyclophosphamide-induced bladder damage by alleviating inflammatory response in mice 福沙匹坦通过减轻炎症反应改善环磷酰胺诱发的小鼠膀胱损伤。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-06 DOI: 10.1016/j.taap.2024.117120

{"title":"Fosaprepitant improves cyclophosphamide-induced bladder damage by alleviating inflammatory response in mice","authors":"","doi":"10.1016/j.taap.2024.117120","DOIUrl":"10.1016/j.taap.2024.117120","url":null,"abstract":"<div><div>Inhibition of inflammatory process is a key therapeutic target for the treatment of interstitial cystitis (IC). Recent reports indicate that neurokinin 1 receptor (NK1R) antagonists have beneficial roles in inflammatory-based diseases. Herein, we investigate the protective effects of fosaprepitant (FOS), a NK1R antagonist, in cyclophosphamide (CP)-induced cystitis. The cystitis model was established multiple CP (80 mg/kg; i.p.) injection one day apart, and mice were treated with FOS (20 and 60 mg/kg/day; i.p.) for seven consecutive days. Detrusor contractility, vesical vascular permeability, myeloperoxidase (MPO) activity and protein expression levels of the TLR4 pathway were evaluated in mice bladder. Carbachol and electric field stimulation-evoked contractions of detrusor strips were significantly increased in CP-treated mice, which was significantly attenuated by FOS (60 mg/kg/day) treatment (p<0.001, p<0.05). Notably, vesical vascular permeability was markedly impaired in CP-induced cystitis, that was restored by FOS (60 mg/kg/day) treatment (p<0.01). MPO activity was significantly increased in cystitis group whereas FOS (20 and 60 mg/kg/day) treatment remarkably suppressed MPO activity in bladder tissue (p<0.001). Although TLR4 expression increased with cystitis, MyD88 and p-NFκB<sup>Ser536</sup>/total NFκB did not change, FOS (20 and 60 mg/kg/day) treatment caused a dramatic decrease in TLR4 expression (p<0.001), indicating the anti-inflammatory effect of FOS. In conclusion, FOS improved detrusor overactivity and inflammatory response by inhibiting MPO activity and TLR4 expression, resulting in functional and histological recovery in CP-induced cystitis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0