Toxicology and applied pharmacology最新文献

{"title":"Alpha-Asarone attenuates alcohol-induced hepatotoxicity in a murine model by ameliorating oxidative stress, inflammation, and modulating apoptotic-Autophagic cell death","authors":"Nada A.M. Ali ,&nbsp;Amir Mohamed Abdelhamid ,&nbsp;Norhan M. El-Sayed ,&nbsp;Asmaa Radwan","doi":"10.1016/j.taap.2024.117041","DOIUrl":"10.1016/j.taap.2024.117041","url":null,"abstract":"<div><p>Alcoholic liver disease (ALD) is a major cause of chronic liver injury characterized by steatosis, inflammation, and fibrosis. This study explored the hepatoprotective mechanisms of alpha-asarone in a mouse model of chronic-binge alcohol feeding. Adult male mice were randomized into control, alcohol, and alcohol plus alpha-asarone groups. Serum aminotransferases and histopathology assessed liver injury. Oxidative stress was evaluated via malondialdehyde content, glutathione, superoxide dismutase, and catalase activities. Pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were quantified by ELISA. P53-mediated apoptosis was determined by immunohistochemistry. Key autophagy markers phospho-AMPK, AMPK, Beclin-1, LC3-I/LC3-II ratio, and LC3 were examined by immunoblotting. Alcohol administration increased serum ALT, AST and ALP, indicating hepatocellular damage. This liver dysfunction was associated with increased oxidative stress, inflammation, p53 expression and altered autophagy. Alpha-asarone treatment significantly decreased ALT, AST and ALP levels and improved histological architecture versus alcohol alone. Alpha-asarone also mitigated oxidative stress, reduced TNF-α, IL-1β and IL-6 levels, ameliorated p53 overexpression and favorably modulated autophagy markers. Our findings demonstrate that alpha-asarone confers protective effects against ALD by enhancing antioxidant defenses, suppressing hepatic inflammation, regulating apoptotic signaling, and restoring autophagic flux. This preclinical study provides compelling evidence for the therapeutic potential of alpha-asarone in attenuating alcohol-induced liver injury and warrants further evaluation as a pharmacotherapy for ALD.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117041"},"PeriodicalIF":3.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767432","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}

{"title":"The role of drug efflux and uptake transporters in the plasma pharmacokinetics and tissue disposition of morphine and its main metabolites","authors":"Margarida L. F. Martins ,&nbsp;Paniz Heydari ,&nbsp;Wenlong Li ,&nbsp;Alejandra Martínez-Chávez ,&nbsp;Malika el Yattouti ,&nbsp;Maria C. Lebre ,&nbsp;Jos H. Beijnen ,&nbsp;Alfred H. Schinkel","doi":"10.1016/j.taap.2024.117040","DOIUrl":"10.1016/j.taap.2024.117040","url":null,"abstract":"<div><p>Morphine is a widely used opioid for the treatment of pain. Differences in drug transporter expression and activity may contribute to variability in morphine pharmacokinetics and response. Using appropriate mouse models, we investigated the impact of the efflux transporters ABCB1 and ABCG2 and the OATP uptake transporters on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and M6G. Upon subcutaneous administration of morphine, its plasma exposure in <em>Abcb1a/1b</em>^{<em>−/−</em>}<em>;Abcg2</em>^{<em>−/</em>−‐}, A<em>bcb1a/1b</em>^{<em>−/−</em>}<em>;Abcg2</em>^{<em>−/−</em>}<em>;Oatp1a/1b</em>^{<em>−/−</em>}<em>;Oatp2b1</em>^{<em>−/−</em>} (<em>Bab12</em>), and <em>Oatp1a/1b</em>^{<em>−/−</em>}<em>;Oatp2b1</em>^{<em>−/−</em>} mice was similar to that found in wild-type mice. Forty minutes after dosing, morphine brain accumulation increased by 2-fold when mouse (m)Abcb1 and mAbcg2 were ablated. Relative recovery of morphine in small intestinal content was significantly reduced in all the knockout strains. In the absence of mOatp1a/1b and mOatp2b1, plasma levels of M3G were markedly increased, suggesting a lower elimination rate. Moreover, Oatp-deficient mice displayed reduced hepatic and intestinal M3G accumulation. Mouse Oatps similarly affected plasma and tissue disposition of subcutaneously administered M6G. Human OATP1B1/1B3 transporters modestly contribute to the liver accumulation of M6G. In summary, mAbcb1, in combination with mAbcg2, limits morphine brain penetration and its net intestinal absorption. Variation in ABCB1 activity due to genetic polymorphisms/mutations and/or environmental factors might, therefore, partially affect morphine tissue exposure in patients. The ablation of mOatp1a/1b increases plasma exposure and decreases the liver and small intestinal disposition of M3G and M6G. Since the contribution of human OATP1B1/1B3 to M6G liver uptake was quite modest, the risks of undesirable drug interactions or interindividual variation related to OATP activity are likely negligible.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117040"},"PeriodicalIF":3.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735052","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}

{"title":"Metformin augments major cytoplasmic organization except for spindle organization in oocytes cultured under hyperglycemic and hyperlipidemic conditions: An in vitro study","authors":"Amrutha Nedumbrakkad Kunnath ,&nbsp;Shravani Kanakadas Parker ,&nbsp;Daphne Norma Crasta ,&nbsp;Jyolsna Ponnaratta Kunhiraman ,&nbsp;Vanishree Vasave Madhvacharya ,&nbsp;Sandhya Kumari ,&nbsp;Guruprasad Nayak ,&nbsp;R. Vani Lakshmi ,&nbsp;Prashanth Kumar Modi ,&nbsp;Thottethodi Subrahmanya Keshava Prasad ,&nbsp;Anujith Kumar ,&nbsp;Ayush Khandelwal ,&nbsp;Nadeem Khan Ghani ,&nbsp;Shama Prasada Kabekkodu ,&nbsp;Satish Kumar Adiga ,&nbsp;Guruprasad Kalthur","doi":"10.1016/j.taap.2024.117039","DOIUrl":"10.1016/j.taap.2024.117039","url":null,"abstract":"<div><p>The present study aimed to investigate the role of antidiabetic drug metformin on the cytoplasmic organization of oocytes. Germinal vesicle (GV) stage oocytes were collected from adult female Swiss albino mice and subjected to <em>in vitro</em> maturation (IVM) in various experimental groups- control, vehicle control (0.3% ethanol), metformin (50 μg/mL), high glucose and high lipid (HGHL, 10 mM glucose; 150 μM palmitic acid; 75 μM stearic acid and 200 μM oleic acid in ethanol), and HGHL supplemented with metformin. The metaphase II (MII) oocytes were analyzed for lipid accumulation, mitochondrial and endoplasmic reticulum (ER) distribution pattern, oxidative and ER stress, actin filament organization, cortical granule distribution pattern, spindle organization and chromosome alignment. An early polar body extrusion was observed in the HGHL group. However, the maturation rate at 24 h did not differ significantly among the experimental groups compared to the control. The HGHL conditions exhibited significantly higher levels of oxidative stress, ER stress, poor actin filament organization, increased lipid accumulation, altered mitochondrial distribution, spindle abnormalities, and chromosome misalignment compared to the control. Except for spindle organization, supplementation of metformin to the HGHL conditions improved all the parameters (non-significant for ER and actin distribution pattern)<strong>.</strong> These results show that metformin exposure in the culture media helped to improve the hyperglycemia and hyperlipidemia-induced cytoplasmic anomalies except for spindle organization. Given the crucial role of spindle organization in proper chromosome segregation during oocyte maturation and meiotic resumption, the implications of metformin's limitations in this aspect warrant careful evaluation and further investigation.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117039"},"PeriodicalIF":3.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0041008X24002370/pdfft?md5=ce1dd83e1c451dd15a716d25f3b2e2e1&pid=1-s2.0-S0041008X24002370-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634620","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}

{"title":"Pirfenidone ameliorates ANIT-induced cholestatic liver injury via modulation of FXR, NF-кB/TNF-α, and Wnt/GSK-3β/β-catenin signaling pathways","authors":"Wesam H. Abdulaal ,&nbsp;Ulfat M. Omar ,&nbsp;Mustafa Zeyadi ,&nbsp;Dina S. El-Agamy ,&nbsp;Nabil A. Alhakamy ,&nbsp;Sabrin R.M. Ibrahim ,&nbsp;Naif A.R. Almalki ,&nbsp;Hani Z. Asfour ,&nbsp;Mohammed W. Al-Rabia ,&nbsp;Gamal A. Mohamed ,&nbsp;Mahmoud Elshal","doi":"10.1016/j.taap.2024.117038","DOIUrl":"10.1016/j.taap.2024.117038","url":null,"abstract":"<div><p>Cholestasis is a hepatobiliary disorder characterized by the excessive accumulation of toxic bile acids in hepatocytes, leading to cholestatic liver injury (CLI) through multiple pathogenic inflammatory pathways. Currently, there are limited therapeutic options for the management of cholestasis and associated CLI; therefore, new options are urgently needed. Pirfenidone (PF), an oral bioavailable pyridone analog, is used for the treatment of idiopathic pulmonary fibrosis. PF has recently demonstrated diverse potential therapeutic activities against different pathologies. Accordingly, the present study adopted the α-naphthyl isothiocyanate (ANIT)-induced CLI model in mice to explore the potential protective impact of PF and investigate the underlying mechanisms of action. PF intervention markedly reduced the serum levels of ALT, AST, LDH, total bilirubin, and total bile acids, which was accompanied by a remarkable amelioration of histopathological lesions induced by ANIT. PF also protected the mice against ANIT-induced redox imbalance in the liver, represented by reduced MDA levels and elevated GSH and SOD activities. Mechanistically, PF inhibited ANIT-induced downregulated expressions of the farnesoid X receptor (FXR), as well as the bile salt export pump (BSEP) and the multidrug resistance-associated protein 2 (MRP2) bile acid efflux channels. PF further repressed ANIT-induced NF-κB activation and TNF-α and IL-6 production. These beneficial effects were associated with its ability to dose-dependently inhibit Wnt/GSK-3β/β-catenin/cyclin D1 signaling. Collectively, PF protects against ANIT-induced CLI in mice, demonstrating powerful antioxidant and anti-inflammatory activities as well as an ability to oppose BA homeostasis disorder. These protective effects are primarily mediated by modulating the interplay between FXR, NF-κB/TNF-α/IL-6, and Wnt/β-catenin signaling pathways.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117038"},"PeriodicalIF":3.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634621","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}

{"title":"PM10 exposure induces bronchial hyperresponsiveness by upreguating acetylcholine muscarinic 3 receptor","authors":"Xue Xiao ,&nbsp;Yali Lei ,&nbsp;Tong Yao ,&nbsp;Tingting Huang ,&nbsp;Pingping Yan ,&nbsp;Lei Cao ,&nbsp;Yongxiao Cao","doi":"10.1016/j.taap.2024.117035","DOIUrl":"10.1016/j.taap.2024.117035","url":null,"abstract":"<div><p>Exposure to particulate matter (PM₁₀) can induce respiratory diseases that are closely related to bronchial hyperresponsiveness. However, the involved mechanism remains to be fully elucidated. This study aimed to demonstrate the effects of PM₁₀ on the acetylcholine muscarinic 3 receptor (CHRM3) expression and the role of the ERK1/2 pathway in rat bronchial smooth muscle. A whole-body PM₁₀ exposure system was used to stimulate bronchial hyperresponsiveness in rats for 2 and 4 months, accompanied by MEK1/2 inhibitor U0126 injection. The whole-body plethysmography system and myography were used to detect the pulmonary and bronchoconstrictor function, respectively. The mRNA and protein levels were determined by Western blotting, qPCR, and immunofluorescence. Enzyme-linked immunosorbent assay was used to detect the inflammatory cytokines. Compared with the filtered air group, 4 months of PM₁₀ exposure significantly increased CHRM3-mediated pulmonary function and bronchial constriction, elevated CHRM3 mRNA and protein expression levels on bronchial smooth muscle, then induced bronchial hyperreactivity. Additionally, 4 months of PM₁₀ exposure caused an increase in ERK1/2 phosphorylation and increased the secretion of inflammatory factors in bronchoalveolar lavage fluid. Treatment with the MEK1/2 inhibitor, U0126 inhibited the PM₁₀ exposure-induced phosphorylation of the ERK1/2 pathway, thereby reducing the PM₁₀ exposure-induced upregulation of CHRM3 in bronchial smooth muscle and CHRM3-mediated bronchoconstriction. U0126 could rescue PM₁₀ exposure-induced pathological changes in the bronchus. In conclusion, PM₁₀ exposure can induce bronchial hyperresponsiveness in rats by upregulating CHRM3, and the ERK1/2 pathway may be involved in this process. These findings could reveal a potential therapeutic target for air pollution induced respiratory diseases.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117035"},"PeriodicalIF":3.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634622","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}

{"title":"Effects of catechin on the malignant biological behavior of gastric cancer cells through the PI3K/Akt signaling pathway","authors":"Ye Ding ,&nbsp;Hao Li ,&nbsp;Saisai Cao ,&nbsp;Yong Yu","doi":"10.1016/j.taap.2024.117036","DOIUrl":"10.1016/j.taap.2024.117036","url":null,"abstract":"<div><p>Catechin is a kind of flavonoids, mainly derived from the plant <em>Camellia sinensis</em>. It has a strong antioxidant effect, and it also has significant therapeutic effects on anti-cancer, anti-diabetes, and anti-infection. This study was intended to look at how catechin affected the malignant biological activity of gastric cancer cells. We used databases to predict the targets of catechin and the pathogenic targets of gastric cancer. Venn diagram was used to find the intersection genes, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed on intersection genes. Using the STRING database, the Protein-Protein Interaction (PPI) network was built. The top 8 genes were screened by Cytoscape 3.9.1, then their binding was verified by molecular docking. The proliferation ability, cell cycle, apoptosis and migration of gastric cancer cells were detected, as well as the protein expression levels of PI3K, p-AKT, and AKT and the mRNA expression levels of AKT1, VEGFA, EGFR, HRAS, and HSP90AA1 in gastric cancer cells. Our research revealed that different concentrations of catechin could effectively inhibit the proliferation and migration of gastric cancer cells, regulate the cell cycle, and promote the death of these cells, and it's possible that the PI3K/Akt pathway was crucial in mediating this impact. Moreover, adding the PI3K/Akt pathway agonist significantly reduced the promoting effect of catechin on the apoptosis of gastric cancer cells. This study suggested that catechin was a potential drug for the treatment of gastric cancer.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117036"},"PeriodicalIF":3.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0041008X24002345/pdfft?md5=7ee54db16a528109a0a052860d1fa87b&pid=1-s2.0-S0041008X24002345-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620931","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}

{"title":"Can we do better with Mylotarg? Model-based assessment of opportunities to improve therapeutic index","authors":"Madison Stoddard ,&nbsp;Lin Yuan ,&nbsp;Jodi Cooper ,&nbsp;Christine Carcillo Neumar ,&nbsp;Barbara Hibner ,&nbsp;Humphrey Gardner ,&nbsp;Arijit Chakravarty","doi":"10.1016/j.taap.2024.117034","DOIUrl":"10.1016/j.taap.2024.117034","url":null,"abstract":"<div><p>Late-stage clinical trial failures increase the overall cost and risk of bringing new drugs to market. Determining the pharmacokinetic (PK) drivers of toxicity and efficacy in preclinical studies and early clinical trials supports quantitative optimization of drug schedule and dose through computational modeling. Additionally, this approach permits prioritization of lead candidates with better PK properties early in development. Mylotarg is an antibody-drug conjugate (ADC) that attained U.S. Food and Drug Administration (FDA) approval under a fractionated dosing schedule after 17 years of clinical trials, including a 10-year period on the market resulting in hundreds of fatal adverse events. Although ADCs are often considered lower risk for toxicity due to their targeted nature, off-target activity and liberated payload can still constrain dosing and drive clinical failure. Under its original schedule, Mylotarg was dosed infrequently at high levels, which is typical for ADCs because of their long half-lives. However, our PK modeling suggests that these regimens increase maximum plasma concentration (C_max)-related toxicities while producing suboptimal exposures to the target receptor. Our analysis demonstrates that the benefits of dose fractionation for Mylotarg tolerability should have been obvious early in the drug's clinical development and could have curtailed the proliferation of ineffective Phase III studies. We also identify schedules likely to be even more efficacious without compromising on tolerability. Alternatively, a longer-circulating Mylotarg formulation could obviate the need for dose fractionation, allowing superior patient convenience. Early-stage PK optimization through quantitative modeling methods can accelerate clinical development and prevent late-stage failures.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117034"},"PeriodicalIF":3.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620930","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}

{"title":"Ameliorative effect of nano-pregabalin in gastrocnemius muscle of gamma irradiated rats with an experimental model of fibromyalgia: Crosstalk of Sirt3, IL-1β and PARP1 pathways","authors":"Esraa M. Samy,&nbsp;Rasha R. Radwan,&nbsp;Farag M. Mosallam,&nbsp;Heba A. Mohamed","doi":"10.1016/j.taap.2024.117037","DOIUrl":"10.1016/j.taap.2024.117037","url":null,"abstract":"<div><h3>Background</h3><p>Fibromyalgia (FM) is a complex syndrome with somatic symptoms connected to the operational state of muscles. Although radiotherapy is a cornerstone in cancer treatment, it is implicated in the aggravation of FM. Lately, formulation of medicines in nano-forms become of great prominence due to their prospective applications in medicine. So, this study aimed to assess possible therapeutic benefits of formulating pregabalin in a nono-form (N-PG) for managing FM during exposure to gamma radiation.</p></div><div><h3>Methods</h3><p>Gamma rays administered in fractionated doses (2 Gy/day) to male rats after one hour of s.c. injection of reserpine (1 mL/kg per day) to induce FM, then treated with single daily dose of (30 mg/kg, p.o.) PG or N-PG for ten successive days. Rats were subjected to behavioral tests, then sacrificed to obtain serum and gastrocnemius muscles.</p></div><div><h3>Results</h3><p>N-PG significantly antagonized reserpine-induced FM as proved by; the immobility and performance times in forced swim and rotarod performance tests, respectively were restored near to the normal time, serum IL-8 and MCP-1 chemokines were nearby the normal levels, mitigated oxidative stress through increasing total thiol, Sirt3, CAT enzyme and decreasing COX-1, inhibition of inflammation via IL-1β and MIF significant reduction, it possessed anti-apoptotic effect verified by decreasing PARP-1 and increasing Bcl-X_L, gastrocnemius muscles had minimal fibrosis levels as seen after Masson trichrome staining. Histopathological results were coincidence with biochemical inspection.</p></div><div><h3>Conclusion</h3><p>This study identifies N-PG as a novel drug that could be of a value in the management of FM particularly in cancer patients undergoing radiotherapy.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117037"},"PeriodicalIF":3.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617162","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}

{"title":"Exploring the potentials of S4, a selective androgen receptor modulator, in glioblastoma multiforme therapy","authors":"","doi":"10.1016/j.taap.2024.117029","DOIUrl":"10.1016/j.taap.2024.117029","url":null,"abstract":"<div><p>Glioblastoma multiforme (GBM) ranks among the prevalent neoplastic diseases globally, presenting challenges in therapeutic management. Traditional modalities have yielded suboptimal response rates due to its intrinsic pathological resistance. This underscores the imperative for identifying novel molecular targets to enhance therapeutic efficacy. Literature indicates a notable correlation between androgen receptor (AR) signaling and GBM pathogenesis. To mitigate the adverse effects associated with androgenic modulation of AR, scientists have pivoted towards the synthesis of non-steroidal anabolic agents, selective androgen receptor modulators (SARMs). Among these, S4, used as a supplement by the bodybuilders to efficiently grow muscle mass with favourable oral bioavailability has emerged as a candidate of interest. This investigation substantiates the anti-oncogenic potential of S4 in temozolomide-responsive and -resistant GBM cells through cellular and molecular evaluations. We observed restriction in GBM cell growth, and motility, coupled with an induction of apoptosis, reactive oxygen species (ROS) generation, and cellular senescence. S4 exposure precipitated the upregulation of genes associated with apoptosis, cell-cycle arrest, DNA damage response, and senescence, while concurrently downregulating those involved in cellular proliferation. Future research endeavours are warranted to delineate the mechanisms underpinning S4's actions, assess its antineoplastic effects <em>in-vivo</em>, and its ability to penetrate the blood-brain barrier.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117029"},"PeriodicalIF":3.3,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601801","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}

{"title":"Gallic acid ameliorates synovial inflammation and fibrosis by regulating the intestinal flora and its metabolites","authors":"","doi":"10.1016/j.taap.2024.117033","DOIUrl":"10.1016/j.taap.2024.117033","url":null,"abstract":"<div><p>Gallic acid (GA) has been found by a large number of studies to have pharmacological effects such as antioxidant and anti-inflammatory properties. However, the underlying therapeutic mechanisms are not fully understood.. Studies have shown that altering the intestinal flora affects host metabolism and effectively mediates the development of synovitis. The aim of this study was to explore the pharmacological effects of GA in the treatment of synovial inflammation and anti-synovial fibrosis in knee osteoarthritis (KOA) and the underlying mechanisms by macrogenomics combined with off-target metabolomics. We established a synovitis model via in vivo <em>and</em> in vitro <em>experiments</em> to observe the effect of GA intervention on synovitis. Moreover, we collected serum and feces from rats and analyzed the changes in intestinal flora by macro-genome sequencing and the changes in metabolites in the serum by untargeted metabolomics. We found that GA reduced the levels of IL-1β, IL-6, and TNF-α, and decreased the protein expression levels of α-SMA, TGF-β, and Collagen I in synovial tissues and cells, and the composition and function of the intestinal flora were similarly altered. Combined with macrogenomic pathway enrichment analysis and metabolic pathway enrichment analysis, these findings revealed that GA impacts Bacteroidia and Muribaculaceae abundance, and via the following metabolic pathways: sphingolipid metabolism, glycerophospholipid metabolism, and arginine biology.to ameliorate synovial inflammation and fibrosis in KOA. The therapeutic effect of GA on KOA synovitis and fibrosis is partly attributed to the alleviation of metabolic disorder and the rebalancing of the intestinal flora. These results provides a rationale for the therapeutic application of GA in the treatment of synovitis.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"490 ","pages":"Article 117033"},"PeriodicalIF":3.3,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0041008X2400231X/pdfft?md5=be401887a9b00045b39590554b0512ae&pid=1-s2.0-S0041008X2400231X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601802","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}