Pharmaceutical Science Advances最新文献

{"title":"Delayed treatment with hydro-ethanolic extract of Khaya grandifoliola protects mice from acetaminophen-hepatotoxicity through inhibition of c-Jun N-terminal kinase phosphorylation and mitochondrial dysfunction","authors":"Arnaud Fondjo Kouam ,&nbsp;Ibrahim Njingou ,&nbsp;Nina Jeannette Pekam Magoudjou ,&nbsp;Hamed Bechir Ngoumbe ,&nbsp;Philipe Herman Nfombouot Njitoyap ,&nbsp;Elisabeth Menkem Zeuko'o ,&nbsp;Frédéric Nico Njayou ,&nbsp;Paul Fewou Moundipa","doi":"10.1016/j.pscia.2024.100049","DOIUrl":"10.1016/j.pscia.2024.100049","url":null,"abstract":"<div><p>The use of N-acetylcysteine against acetaminophen(APAP)-induced hepatotoxicity, a leading cause of liver injury, has several drawbacks, including short therapeutic windows. <em>Khaya grandifoliola</em> (Meliaceae) has been traditionally used to manage liver-related diseases, and many reports have confirmed its hepatoprotective properties. However, its therapeutic potential as an antidote against APAP-induced hepatotoxicity has yet to be proven in a clinically relevant model. This study aimed to verify the efficacy of delayed treatment with the hydroethanolic extract of <em>K. grandifoliola</em> (KgE) in suppressing the early injury phase of APAP pathophysiology. KgE was analyzed using HPLC/UV. Acute oral toxicity tests were conducted in mice to determine the therapeutic dose of KgE. Mice were treated with 300 ​mg/kg APAP; 1h and 12h later, they were treated with either predetermined doses of KgE or 20 ​mg/kg c-Jun N-Terminal Kinase (JNK) inhibitor SP600125, which served as a reference antidote. At 6h and 24h after APAP treatment, the parameters of liver damage and mitochondrial dysfunction, phosphorylation of JNK, and mitochondrial translocation were assessed. KgE at a dose of 5000 ​mg/kg was safe for mice. Accordingly, 100, 200, and 400 ​mg/kg were selected as curative treatments. Delayed administration of KgE reversed the histopathological changes in the liver, inhibited serum levels of alanine aminotransferase, reduced the liver content of nitric oxide and malondialdehyde, and restored hepatic glutathione pools and superoxide dismutase and catalase activities in APAP-intoxicated mice. Moreover, KgE prevented APAP-induced JNK phosphorylation and p-JNK mitochondrial translocation and rescued the activities of mitochondrial enzyme complexes II and V. HPLC/UV analysis revealed the presence of gallic acid, Quercetin and Silibinin, with retention times of 3.77, 11.63 and 11.95 ​min as the major active ingredients present in KgE. Our findings demonstrate that post-treatment with KgE protects the mouse liver from APAP-hepatotoxicity through the inhibition of JNK activation and mitochondrial dysfunction<strong>.</strong></p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100049"},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000151/pdfft?md5=5d0d9d2a2dcad48b981b9abb76c4d105&pid=1-s2.0-S2773216924000151-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142088789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted drug conjugates in cancer therapy: Challenges and opportunities","authors":"Geng Jia,&nbsp;Yuqi Jiang,&nbsp;Xiaoyang Li","doi":"10.1016/j.pscia.2024.100048","DOIUrl":"10.1016/j.pscia.2024.100048","url":null,"abstract":"<div><div>Traditional chemotherapy is often accompanied by off-target toxicity, resulting in adverse side effects and driving the development of targeted therapies. Targeted drug conjugates (TDCs) typically comprise targeting ligands, such as specific antibodies, peptides, or small molecules, attached to a cytotoxic agent via a chemical linker. In this study, we briefly discussed the molecular aspects of the key components of TDCs and the mechanisms by which these key factors exert their activity. Moreover, we reviewed FDA-approved TDCs and promising candidates in clinical trials and discussed current challenges and future directions for TDC development, providing insights for the research and development of novel cancer therapeutics using TDCs. TDCs combine the advantages of highly specific targeting and a potent killing effect, enabling accurate and efficient cancer cell elimination. Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) have shown good efficacy in treating various cancers; however, they still present limitations such as immunogenicity, hematotoxicity, and complex pharmacokinetics. Smaller peptide-drug conjugates (PDCs) and small molecule-drug conjugates (SMDCs) may combine the advantages of ADCs while overcoming some of their limitations, thereby presenting more efficacious and safer alternatives. TDCs enhance the therapeutic effects of cytotoxic agents and reduce their adverse effects. However, tumor heterogeneity, limited transmembrane permeability, and drug resistance pose significant challenges for TDCs, potentially affecting their therapeutic efficacy. Nevertheless, TDCs are a promising therapeutic approach for cancer treatment, achieving precise drug delivery while minimizing toxicity and side effects on normal cells.</div></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100048"},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S277321692400014X/pdfft?md5=846700d9b5859bfcc716e905e2620342&pid=1-s2.0-S277321692400014X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142314135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting active RAS with molecular glue","authors":"Wenjing Su ,&nbsp;Xuben Hou","doi":"10.1016/j.pscia.2024.100047","DOIUrl":"10.1016/j.pscia.2024.100047","url":null,"abstract":"<div><p>Activating mutations in RAS genes, notably KRASG12C, are pervasive in numerous cancers, presenting formidable challenges to therapy due to their elusive druggability. The landmark discovery of KRASG12C allosteric inhibitors marked a transformative milestone in cancer treatment, resulting in the approval of sotorasib and adagrasib. However, limitations in the depth and duration of response prompted the quest for alternative strategies. Recently, Holderfield et al., Wasko et al., and Jiang et al. reported on tri-complex inhibitors, namely RMC-7977 and RMC-6236, targeting activated RAS variants, demonstrating promising preclinical efficacy surpassing adagrasib. These advancments signify a paradigm shift in RAS oncology, promising enduring therapeutic benefits and warranting further clinical exploration.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100047"},"PeriodicalIF":0.0,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000138/pdfft?md5=acdbb72e8561efb2719e3f80e8eeec17&pid=1-s2.0-S2773216924000138-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141622985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-targeting liposomal delivery of sorafenib and docetaxel for enhanced synergistic therapy in advanced hepatocellular carcinoma","authors":"Yawen Yao ,&nbsp;Yue Hu ,&nbsp;Xinwang Meng ,&nbsp;Fenyan Feng ,&nbsp;Feng Xu ,&nbsp;Guangji Wang ,&nbsp;Hua Yu ,&nbsp;Juan Li","doi":"10.1016/j.pscia.2024.100046","DOIUrl":"10.1016/j.pscia.2024.100046","url":null,"abstract":"<div><p>Patients with advanced hepatocellular carcinoma (HCC) are not sensitive to sorafenib (SOR), therefore, combination therapy is required. In this study, an improved thin-film dispersion and post-insertion anchoring technique was utilized to construct a dual-targeted co-delivery SOR and docetaxel (DTX) liposome drug delivery system, folate/chondroitin sulfate with SOR/DTX-modified liposomes (FA/CS@SDLP), to jointly enhance the anti-recurrence and metastasis of HCC. FA/CS@SDLP can establish the gradual release of the two drugs because of successful lysosomal escape in the condensed hyaluronidase environment. The results indicated that modification with folate (FA) and chondroitin sulfate (CS) significantly enhanced the cellular uptake of FA/CS@SDLP and the internalization of SOR/DTX in HepG2 cells through FA and CD44 receptor-mediated endocytosis. Compared to free drugs or the mono-targeted liposomal system (FA@SDLP), FA/CS@SDLP presented higher potency against HepG2 cells regarding pro-apoptosis, anti-proliferation, and anti-metastasis (migration and invasion). Moreover, a more satisfactory antitumor efficacy was observed for FA/CS@SDLP in the pulmonary metastasis of HCC in a mouse model. In summary, dual-targeted co-delivery of liposomes can synergistically treat HCC recurrence and metastasis, providing a new approach for the clinically accurate treatment of HCC.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100046"},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000126/pdfft?md5=ea9c0c8c42b198b328305e7f15c725ed&pid=1-s2.0-S2773216924000126-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141697484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progresses in the study of polysaccharide from medicinal plants of the Asclepiadaceae family","authors":"He Xiao ,&nbsp;Ziqing Zeng ,&nbsp;Wenjie Jiang","doi":"10.1016/j.pscia.2024.100045","DOIUrl":"https://doi.org/10.1016/j.pscia.2024.100045","url":null,"abstract":"<div><p>Medicinal plants from the Asclepiadaceae family, such as Luo Mo (<em>Metaplexis japonica</em> Makino), Xu Changqing (<em>Cynanchum paniculatum</em>), and Bai Wei (<em>Cynanchum atratum</em> Bge.), have long been staples in Traditional Chinese Medicine (TCM) due to their wide range of pharmacological activities (Su et al., 2021) [1]. These beneficial properties are largely attributed to compounds like saponins, alkaloids, and polysaccharides. Polysaccharides, in particular, are vital components in TCM and have garnered increasing attention for their diverse therapeutic effects. Polysaccharides from Asclepiadaceae plants are reported to exhibit a variety of pharmacological activities, including anti-radiation, anti-tumor, anti-fatigue, antioxidant, anti-hyperlipidemic, immune-boosting, and liver-protective effects. These polysaccharides have complex structures made up of different monosaccharides, contributing to their wide range of activities. In this review, we provide a comprehensive summary of the isolation, purification, structural characterization, and pharmacological activities of polysaccharides from medicinal plants in the Asclepiadaceae family. We begin by outlining the methods used for the extraction, isolation, and purification of these polysaccharides. Next, we delve into the pharmacological activities of the isolated polysaccharides. Finally, we discuss the potential clinical applications of these polysaccharides in treating various diseases and highlight areas that require further investigation.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100045"},"PeriodicalIF":0.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000114/pdfft?md5=d3e3439805917f3195d27ad1e679cd87&pid=1-s2.0-S2773216924000114-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141594753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fuel-propelled nanomotors for acute kidney injury applications","authors":"Weixin Wang ,&nbsp;Rui Gao ,&nbsp;Lin Zhang ,&nbsp;Zhongchao Wang ,&nbsp;Jiahui Sun ,&nbsp;Lei Luo ,&nbsp;Min Pan ,&nbsp;Miaofang Hong ,&nbsp;Jianming Wu ,&nbsp;Qibing Mei ,&nbsp;Ke Tong ,&nbsp;Yini Wang ,&nbsp;Lingyan Qiao ,&nbsp;Fei Tong","doi":"10.1016/j.pscia.2024.100044","DOIUrl":"https://doi.org/10.1016/j.pscia.2024.100044","url":null,"abstract":"<div><p>Acute kidney injury (AKI) is characterized by a rapid loss of renal metabolic function and a high mortality rate. Although significant progress has been made in developing targeted drugs for AKI treatment, issues such as inadequate antioxidant effects and poor renal enrichment efficiency remain. Nanomotors can enhance drug delivery efficiency in AKI treatments through self-propulsion in the microenvironment or via external stimuli. We reviewed recent progress in the targeted treatment of AKI with nanomotors, focusing on their contribution to targeted drug delivery at different stages and combined treatments. Current limitations and future development directions are also discussed.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100044"},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000102/pdfft?md5=4504c164042e6d4a1599cfcc3339045c&pid=1-s2.0-S2773216924000102-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141594752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Possible hemoglobin enhancing effect of phytol in methotrexate-induced folate deficient Swiss albino mice: In vivo and in silico studies","authors":"Muhammad Torequl Islam ,&nbsp;Raihan Chowdhury ,&nbsp;Md Sakib Al Hasan ,&nbsp;Salehin Sheikh ,&nbsp;Md Shimul Bhuia ,&nbsp;Sumaya Akter Bithi ,&nbsp;Most Israt Jahan Oni ,&nbsp;Mehedi Hasan Bappi ,&nbsp;Siddique Akber Ansari ,&nbsp;Elaine C.P. Lucetti ,&nbsp;Catarina M. Tahim ,&nbsp;Henrique Douglas Melo Coutinho ,&nbsp;Irfan Aamer Ansari","doi":"10.1016/j.pscia.2024.100043","DOIUrl":"10.1016/j.pscia.2024.100043","url":null,"abstract":"<div><p>The diterpenoid phytol is evidently acting against anemia in experimental animals. However, the molecular mechanisms behind this issue are yet to be discovered. This study aimed to evaluate phytol's effect on methotrexate-induced folate-deficient animals through in vivo and in silico studies. For this, a total of thirty adult male Swiss albino mice were randomly divided into six different groups, namely the normal control (vehicle), the negative control (folate deficiency inducer, methotrexate 3 ​mg/kg), the standard (folic acid 1.5 ​mg/kg), two test groups comprising phytol 25 and 50 ​mg/kg, and a combined group composed of the standard and highest test doses of phytol. Except for the vehicle, all groups were treated with methotrexate for the first 3 days (once/day) to induce folate deficiency. Then followed by the respective treatment once a day for 3 days. Hemoglobin (Hb) level was measured from the peripheral blood (by tail cutting) on days 1st (before treatment), 4th (after methotrexate treatment), and 7th (after treatment). On the other hand, the computational studies were performed by PyMol, PyRex, Discovery Studio, and other complementary tools. Findings suggest that phytol significantly (<em>p</em> ​&lt; ​0.05) augmented Hb levels that are altered by methotrexate-induced reduction of Hb levels in animals dose-dependently. The combination also augmented Hb levels in animals; however, its effect was slightly lower than the individual groups (standard and test). In the in silico study, phytol showed good binding capacity (binding energy: −7.0 ​kcal/mol) with dihydrofolate reductase (DHFR). In conclusion, phytol may act against folate deficiency by altering methotrexate's impacts in animals, possibly through interacting with DHFR. Further validated research is necessary to develop phytol as an anti-anemia drug in the near future.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100043"},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000096/pdfft?md5=bfaea545e629e34b31944f3178097e2e&pid=1-s2.0-S2773216924000096-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141407753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytochemical analysis and evaluation of the antibacterial and antibiotic potentiation activities of the aqueous extract of Cordia oncocalyx Allemão (Boraginaceae)","authors":"José Thyalisson da Costa Silva ,&nbsp;José Jailson Lima Bezerra ,&nbsp;Talysson Felismino Moura ,&nbsp;Rafael Pereira da Cruz ,&nbsp;Maraiza Gregorio de Oliveira ,&nbsp;Adrielle Rodrigues Costa ,&nbsp;Felicidade Caroline Rodrigues ,&nbsp;João Arthur de Oliveira Borges ,&nbsp;Terezinha Raila Ramos de Sousa ,&nbsp;Maria Flaviana Bezerra Morais-Braga ,&nbsp;Henrique Douglas Melo Coutinho ,&nbsp;José Weverton Almeida-Bezerra","doi":"10.1016/j.pscia.2024.100042","DOIUrl":"https://doi.org/10.1016/j.pscia.2024.100042","url":null,"abstract":"<div><p>The global antibiotic resistance crisis highlights the inappropriate use of medicines by the population and the lack of development of new antimicrobial agents. According to various studies, natural products are promising alternatives for combating bacterial resistance and treating infectious diseases. Accordingly, the present study aimed to analyze the chemical composition and evaluate the antibacterial and antibiotic potential of an aqueous extract of <em>Cordia oncocalyx</em> Allemão (AECO). Phytochemical analyses were performed using high-performance liquid chromatography equipped with a diode array detector (HPLC-DAD). The minimum inhibitory concentration (MIC) was used to evaluate the antibacterial activity of <em>C. oncocalyx</em> against conventional and multidrug-resistant (MDR) bacterial strains (<em>Escherichia coli, Pseudomonas aeruginosa</em>, and <em>Staphylococcus aureus</em>). According to HPLC-DAD analysis, the following compounds could be identified in the aqueous extract of <em>C. oncocalyx</em>: luteolin (3.07 ± 0.04 mg/g), caffeic acid (1.05 ± 0.03 mg/g), ellagic acid (0.62 ± 0.05 mg/g), and quercetin (0.58 ± 0.01). AECO did not exhibit antibacterial activity when administered alone (MIC &gt;512 μg/mL). However, when combined with gentamicin, ampicillin, and norfloxacin, AECO potentiated the action of these antibiotics against the multi-resistant strains of <em>P. aeruginosa</em> and <em>S. aureus</em>. Although clinical relevance was not revealed by the <em>in vitro</em> tests against pathogenic bacteria, AECO can combined with commercial antibiotics to improve their antibacterial effects. Future studies focusing on the mechanisms of action of the compounds isolated from <em>C. oncocalyx</em> and toxicological tests are fundamental.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100042"},"PeriodicalIF":0.0,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000084/pdfft?md5=3b5fd055b0939ece2db4bd95252fb6b5&pid=1-s2.0-S2773216924000084-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141083449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design of siRNA-based delivery systems for effective treatment of brain diseases","authors":"Dailin Lu ,&nbsp;Yonghang Sun ,&nbsp;Yuxia Luan,&nbsp;Wenxiu He","doi":"10.1016/j.pscia.2024.100041","DOIUrl":"https://doi.org/10.1016/j.pscia.2024.100041","url":null,"abstract":"<div><p>Effective clinical methods are urgently required to treat brain diseases. Small interfering RNAs (siRNAs) are promising in the treatment of brain diseases because of their ability to target and specifically silence genes associated with disease progression. However, their effectiveness is hindered by physiological barriers such as enzymatic degradation, the blood-brain barrier, and the blood-brain tumor barrier, severely restricting them from reaching the desired target sites. The development of nanotechnology has made the effective delivery of siRNAs to the brain possible. This is accomplished by encapsulating siRNAs in cationic polymers, liposomes, or micelles to improve their stability and targeting efficiency. In this review, we first analyzed the limitations of siRNA delivery in brain diseases such as brain tumors, stroke, and neurodegenerative diseases. Next, we summarized how nanotechnology can offer a solution by enabling effective siRNA delivery to the brain and improving the intracellular transfection efficiency of siRNA. Finally, we discussed the challenges and future advances of siRNA-based delivery systems to facilitate their clinical translation. This review emphasizes the importance of overcoming physiological barriers associated with siRNA delivery and highlights recent advances in the rational design of siRNA-based delivery systems for the effective treatment of brain diseases.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100041"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000072/pdfft?md5=8c06ff13b971cd909de39b050bf76bc3&pid=1-s2.0-S2773216924000072-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140558411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WN1703 alleviates gout symptoms via inflammatory signaling pathways in an acute gout rat model","authors":"Fuyao Liu,&nbsp;Xiaodan Lu,&nbsp;Lei Zhang,&nbsp;Jing Li","doi":"10.1016/j.pscia.2024.100039","DOIUrl":"10.1016/j.pscia.2024.100039","url":null,"abstract":"<div><p>We previously synthesized the xanthine oxidoreductase (XOR) inhibitor WN1703. In addition to showing XOR inhibitory effects, WN1703 also showed anti-inflammatory effects in a rat hyperuricemia model. Here, we studied WN1703's anti-inflammatory effects on gout and explored the underlying mechanisms. Tohoku Hospital Pediatrics-1 (THP-1) cells were stimulated by lipopolysaccharide/interferon-γ/monosodium urate (MSU). The levels of inflammatory cytokines in the supernatant and protein expression in THP-1 cells were detected using enzyme-linked immunosorbent assay (ELISA) kits and western blotting, respectively, to verify the inhibitory effects of WN1703 and its mechanism. Potassium oxonate, hypoxanthine, and MSU were administered to establish a hyperuricemia rat model complicated by acute gouty arthritis. At 1–24 h after MSU injection, the degree of ankle swelling was recorded to compare the anti-inflammatory effects at each time point. The potential mechanism was further explored using immunohistochemistry and ELISA. WN1703 significantly downregulated expression of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, toll-like receptor-4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), nuclear factor-kappa B (NF-κB), and relevant cytokine levels in THP-1 cells. Identical doses of WN1703 and febuxostat had comparable effects on these proteins and cytokines. In the gout rats, the same dose of WN1703 and febuxostat showed equivalent inhibitory effects on NLRP3, ASC, and NF-κB; however, WN1703 showed weaker impacts on alleviating ankle swelling than febuxostat showed. In conclusion, WN1703 showed significant anti-inflammatory effects in hyperuricemic rats with acute gout. Such effects were related to the inhibition of the NLRP3/ASC/Caspase-1 and TLR4/MyD88/NF-κB signaling pathways, thereby downregulating inflammation-related protein expression and decreasing inflammatory cytokine secretion.</p></div>","PeriodicalId":101012,"journal":{"name":"Pharmaceutical Science Advances","volume":"2 ","pages":"Article 100039"},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773216924000059/pdfft?md5=827dd9ffb0fdf9527799da1e715215a1&pid=1-s2.0-S2773216924000059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140401673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}