Chemico-Biological Interactions最新文献

{"title":"Assessment of CYP2D6 gene expression in liver tissue: Variability in CYP2D6 mRNA levels within genotype-predicted metabolizer phenotype groups","authors":"Erika L. Meaddough ,&nbsp;Sara M. Sarasua ,&nbsp;Deborah Kunkel ,&nbsp;Luigi Boccuto ,&nbsp;Satishkumar R. Ganakammal ,&nbsp;Matt Moersen ,&nbsp;Christopher L. Farrell","doi":"10.1016/j.cbi.2025.111526","DOIUrl":"10.1016/j.cbi.2025.111526","url":null,"abstract":"<div><div>Pharmacogenetic (PGx) testing can be used to help guide drug therapy and decrease or avoid the risk of adverse drug reactions. <em>CYP2D6</em> is an important pharmacogene in pharmacogenomics testing panels. However, phenoconversion, whereby an individual's ability to metabolize a drug does not match the genotype-predicted metabolizer status, is a confounding factor to the accurate application of PGx testing results to patient care. To address this issue, <em>CYP2D6</em> expression between and within genotype-predicted CYP2D6 metabolizer phenotype groups was compared using WGS and RNA-Seq data from 134 normal liver tissue donors obtained from the GTEx program. Wide variability in <em>CYP2D6</em> mRNA levels was observed within metabolizer phenotype groups. The median expression level for ultrarapid metabolizers (UMs) was 738.9 TPM (transcripts per million; 196.8–778.9 TPM), 212.5 TPM (32.1–666.5 TPM) for normal metabolizers (NMs), 219.6 TPM for intermediate metabolizers (IMs) (22–389.8 TPM), and 121.2 TPM for poor metabolizers (PMs) (9.3–298.2 TPM). The PM and UM phenotypes were significant predictors of <em>CYP2D6</em> expression (<em>p</em> = 0.0004 and <em>p</em> = 0.019, respectively). Interestingly, expression of the gene encoding human serum albumin (<em>ALB</em>) was also a significant predictor of <em>CYP2D6</em> expression (<em>p</em> = 0.0003). Data from 50 patients with hepatocellular carcinoma obtained from the TCGA program showed no significant difference in expression between tumor tissue (median = 119.7 TPM, range 0.16–817.7 TPM) and normal matched tissue (median = 143.3 TPM, range 26.2–810.7 TPM). Transcriptional regulation of <em>CYP2D6</em> expression may contribute to differences in drug response and risk for CYP2D6 phenoconversion. Efforts to understand the role of gene expression to predict CYP2D6 phenoconversion may inform the use of PGx testing in the clinical setting.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111526"},"PeriodicalIF":4.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective effect of copper on neurotoxicity of TOCP in vivo","authors":"Brenda Rosales-Castro ,&nbsp;Isabel Bravo-Ontiveros ,&nbsp;Keyla Betanzos-Rau ,&nbsp;Kenia Nava-Aparicio ,&nbsp;Laura Ramírez-González ,&nbsp;Elizabeth Undiano ,&nbsp;Iván Flores-Pérez ,&nbsp;Eugenio Vilanova ,&nbsp;Antonio Monroy-Noyola","doi":"10.1016/j.cbi.2025.111527","DOIUrl":"10.1016/j.cbi.2025.111527","url":null,"abstract":"<div><div>A single or repeated dose of tri-ortho-cresyl phosphate (TOCP) induces in humans and animals a known neuropathy as organophosphorus-induced delayed polyneuropathy (OPIDP). This syndrome is related to the inhibition of neuropathy target esterase (NTE), causing signs and symptoms in the nervous system, such as ataxia and paralysis. Currently, there is no antidotal treatment for OPIDP. In the present study, the neuroprotective effect of Cu(II) on the acute <em>in vivo</em> neurotoxicity of TOCP is characterized. Adult hens (27 and 65 weeks old) were administered a single dose of 380, 500, 750, or 1000 mg/kg of TOCP dissolved in vegetable oil. One hour before, the animals were administered a single dose of 160 mg/kg of Cu(II) or vehicle by the same route. Twenty-four hours later, half of the animals (n = 5) in each group were decapitated to obtain the brain and blood (serum) for measuring NTE, acetylcholinesterase (AChE), cholinesterases (ChEs), and kidney and hepatic biochemical parameters (ALT, AST, creatinine, urea). The other half of the animals in each group were kept under observation for 21 days for clinical evaluation of OPIDP using a scale from 1 to 4. The 24-h brain NTE residual activity of all TOCP-treated groups was around 5 % (∼95 % inhibition) compared to the control group (vehicles). However, the group of hens treated with 380 mg/kg TOCP (27 weeks old) pre-treated with Cu(II) presented significantly higher brain NTE activity (p &lt; 0.05), which was around 55 %. This activity value correlated with the OPIDP clinical score over 21 days. Hens treated with TOCP showed an OPIDP score of 3, whereas those pre-treated with Cu(II) showed no signs of OPIDP. The protective effect of Cu(II) on brain NTE and serum ChEs inhibition levels was associated with the degree of OPIDP. The levels of both activities decreased with the increase in OPIDP score (1–4) due to higher TOCP doses and the age of the hens. Brain AChE inhibition ranged from 16 % to 43 %, and hens showed no cholinergic signs in any group. The dose of Cu(II) used in this <em>in vivo</em> study demonstrated a neuroprotective effect and did not induce adverse effects in the liver and kidneys. However, it will be necessary to carry out specific experimental studies to investigate the neuroprotective mechanism of Cu(II).</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111527"},"PeriodicalIF":4.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guanylhydrazone and semicarbazone derivatives as potential prototypes for the design of cholinesterase inhibitors against Alzheimer's disease: biological evaluation and molecular modeling studies","authors":"Denise Cristian Ferreira Neto ,&nbsp;Joyce Sobreiro Francisco Diz ,&nbsp;Sulayne Janayna Araújo Guimarães ,&nbsp;Eduardo Mendes dos Santos ,&nbsp;Maria do Desterro Soares Brandão Nascimento ,&nbsp;Ana Paula Silva de Azevedo-Santos ,&nbsp;Tanos Celmar Costa França ,&nbsp;Steven R. LaPlante ,&nbsp;Claudia Jorge do Nascimento ,&nbsp;Josélia Alencar Lima","doi":"10.1016/j.cbi.2025.111515","DOIUrl":"10.1016/j.cbi.2025.111515","url":null,"abstract":"<div><div>Despite being present in many drugs, guanylhydrazones and semicarbazones are two functional groups that have been little investigated as potential therapeutic strategies for the treatment of Alzheimer's disease (AD). For this reason, we initiated the synthesis and evaluation of these compounds as potential anticholinesterase agents, aiming to offer new alternatives for drug development against AD. In the severe phase of AD butyrylcholinesterase (BChE) becomes the main enzyme responsible for the hydrolysis of acetylcholine (ACh). Therefore, in this project, we present the results of BChE inhibitory activity, enzyme kinetics, cytotoxicity, and molecular modeling studies for three guanylhydrazone and two semicarbazone derivatives that were previously synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Among the compounds tested, guanylhydrazones (<strong>1</strong>, <strong>2</strong>, and <strong>3</strong>) showed inhibitory activity against BChE, exhibiting a mixed non-competitive inhibition profile. Specifically, compound <strong>2</strong> (phenanthrenequinone) demonstrated superior inhibitory potency with an IC₅₀ of 0.68 μM, compared to compound <strong>1</strong> (acridinone) with an IC₅₀ of 3.87 μM, and compound <strong>3</strong> (benzodioxole) with an IC₅₀ of 101.7 μM. In contrast, semicarbazones (<strong>4</strong> and <strong>5</strong>) showed no BChE inhibition up to the highest concentration tested (300 μM). Importantly, all five compounds were found to be non-cytotoxic. Our results suggest that these compounds have potential as drug prototypes targeting different phases of AD. Compounds <strong>3</strong>, <strong>4</strong>, and <strong>5</strong> may be more effective in the early phase, when AChE activity remains high; compound <strong>1</strong> could be useful in the intermediate phase; and compound <strong>2</strong> appears particularly promising for the severe phase, when BChE plays a more dominant role.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111515"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental and organ toxicity of fenpropimorph in zebrafish: Involvement of apoptosis and inflammation","authors":"Junhun Kweon ,&nbsp;Hojun Lee ,&nbsp;Junho Park ,&nbsp;Taeyeon Hong ,&nbsp;Garam An ,&nbsp;Gwonhwa Song ,&nbsp;Whasun Lim ,&nbsp;Wooyoung Jeong","doi":"10.1016/j.cbi.2025.111512","DOIUrl":"10.1016/j.cbi.2025.111512","url":null,"abstract":"<div><div>Pesticides are increasingly the focus as a prominent factor in environmental pollution. Fenpropimorph, a widely utilized morpholine fungicide, is a significant water pollutant. Because of its extensive usage, fenpropimorph is readily detected in diverse aquatic ecosystems. Despite its well-known toxicity to aquatic organisms, its toxicity to zebrafish development and accompanying mechanics remain unexplored. To assess fenpropimorph's toxicity and potential mechanism, we employed the zebrafish model, a representative tool in toxicological studies. Our results showed that exposure to fenpropimorph reduced embryonic viability during the early stages of development and reduced head and body size. Moreover, fenpropimorph triggered apoptosis, DNA fragmentation, and inflammation. Aberrations in the vascular network were observed in the <em>fli1:eGFP</em> transgenic zebrafish model. Additionally, neurotoxic impacts were further assessed using transgenic <em>olig2:dsRed</em> zebrafish, accompanied by a reduction of liver size and fluorescence intensity of <em>fabp10a:dsRed</em> zebrafish. mRNA expression analysis related to corresponding organ development further supported our data. Overall, our research suggests that fenpropimorph may cause aberrations in aquatic organisms.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111512"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The use of Galleria mellonella in metal nanoparticle development: A systematic review","authors":"Razvan Vlad Opris ,&nbsp;Alina Mihaela Baciu ,&nbsp;Gabriela Adriana Filip ,&nbsp;Adrian Florea ,&nbsp;Carmen Costache","doi":"10.1016/j.cbi.2025.111511","DOIUrl":"10.1016/j.cbi.2025.111511","url":null,"abstract":"<div><div>Research on metal nanoparticles is crucial for their application in diverse fields, requiring detailed assessments of their effects and potential. <em>Galleria mellonella</em> larvae have emerged as a valuable model for studying the impacts of metal nanoparticles, offering ethical and logistical advantages over traditional models. This systematic review synthesizes evidence on the application of <em>Galleria mellonella</em> in evaluating the toxicity, distribution, and therapeutic potential of metal nanoparticles. Adhering to PRISMA guidelines, a comprehensive database search (MEDLINE, Embase, Cochrane, Scopus, Google Scholar, Science Citation Index Expanded) was conducted using keywords related to <em>Galleria mellonella</em> and metal nanoparticles. The SYRCLE's risk of bias tool (adapted for <em>G. mellonella</em>) was used for risk of bias assessment. Out of 1696 initially identified studies, 31 met the inclusion criteria, encompassing research from 2011 to 2024. The included studies effectively demonstrate <em>G. mellonella</em>'s capacity to model the toxicity of metal nanoparticles, their therapeutic potential in treating infections, and the impact on the innate immune response, bridging the gap between simpler <em>in vitro</em> assays and more complex mammalian models. <em>Galleria mellonella</em> stands out as a critical model for the early-stage development and evaluation of metal nanoparticles, particularly in assessing toxicity, therapeutic efficacy in infection treatment, and interaction with immune systems. This review underscores the larvae's role in metal nanoparticle research, advocating for its broader use to streamline development processes while minimizing ethical concerns.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111511"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyridoxine exerts antioxidant effects on kidney injury manifestations in high-fat diet-induced obese rats","authors":"Onanong Jaruan ,&nbsp;Sasivimon Promsan ,&nbsp;Laongdao Thongnak ,&nbsp;Nattavadee Pengrattanachot ,&nbsp;Nichakorn Phengpol ,&nbsp;Prempree Sutthasupha ,&nbsp;Anusorn Lungkaphin","doi":"10.1016/j.cbi.2025.111513","DOIUrl":"10.1016/j.cbi.2025.111513","url":null,"abstract":"<div><div>The modern diet contains a substantial level of fat which is believed to be one of the leading causes of the progression of kidney disease. Several studies have already demonstrated that consumption of a high-fat diet (HFD) induces inflammation and oxidative stress, causing activation of upstream mechanisms associated with kidney injury. For the prevention of such pathological events, a change in diet or the taking of nutritional supplements are recommended as alternative treatments. One of the forms of vitamin B6, pyridoxine (PN), has been shown to be an effective antioxidant and can also inhibit the formation of advanced-glycation end products (AGEs). In this study, the protective effects of PN (100 mg/kg/day for a period of eight weeks) against HFD-induced complications in obese rats were investigated. Rats fed on a HFD developed obesity which promoted inflammation, glucose intolerance, AGE receptor upregulation, oxidative stress, and kidney dysfunction. Intervention using PN mitigated obesity-related events and the impairment of kidney function by markedly reducing oxidative stress and also restoring the activity of antioxidant enzymes. Other studies have shown that some vitamin B6 derivatives inhibit the formation of AGEs but our study shows for the first time that PN exerted an antiglycative effect in this HFD-induced obesity model. Consequently, PN could potentially be a novel supplement for obese individuals to avoid kidney injury.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111513"},"PeriodicalIF":4.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel benzofuran derivative of β-elemene (ZT-22) inhibits hepatocellular carcinoma cell growth via directly targeting HSPA6","authors":"Zhiqiang Luo ,&nbsp;Huixia Fan ,&nbsp;Tao Zhang ,&nbsp;Jing Wang ,&nbsp;Jingqi Zheng ,&nbsp;Ruofan Guo ,&nbsp;Junhui Zhou ,&nbsp;Bin Yang ,&nbsp;Luqi Huang ,&nbsp;Guodu Liu ,&nbsp;Jian Yang","doi":"10.1016/j.cbi.2025.111514","DOIUrl":"10.1016/j.cbi.2025.111514","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and is associated with a poor prognosis. Current therapies for HCC have limited efficacy and require improvement. In our study, the benzofuran derivative of <em>β</em>-elemene (ZT-22) demonstrated enhanced anti-HCC efficacy compared to <em>β</em>-elemene, both <em>in vitro</em> and <em>in vivo</em>. Using network pharmacology, RNA sequencing, and western blot analysis, the crucial role of the p38 MAPK signaling pathway in the anti-HCC activity of ZT-22 cells was highlighted. Using drug affinity-responsive target stability (DARTS) combined with mass spectrometry (MS), HSPA6 was identified as the target for ZT-22. Techniques such as the cellular thermal shift assay (CETSA), surface plasmon resonance (SPR) analysis, microscale thermophoresis (MST), molecular docking and molecular dynamics (MD) simulations were used for further validation, confirming that ZT-22 directly binds to HSPA6. Knocking down HSPA6 diminished p38 MAPK signaling and reversed the anti-HCC effects of ZT-22. These findings suggest that ZT-22 exerts its anti-HCC activity by targeting HSPA6, which in turn activated the p38-MAPK signaling pathway. Our results support the development of ZT-22 as a potential therapeutic agent for HCC and highlight HSPA6 as a promising therapeutic target for HCC treatment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111514"},"PeriodicalIF":4.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of novel pyridazine and pyrimidine linked pyrazole derivatives as DNA ligase 1 and IV inhibitors that induce apoptosis","authors":"S. Aishwarya ,&nbsp;Gabriela C. Torres ,&nbsp;Jose A. Lopez-Saenz ,&nbsp;Denisse A. Gutierrez ,&nbsp;Sujeet Kumar ,&nbsp;Ashok Madarakhandi ,&nbsp;Basavaraj Metikurki ,&nbsp;Nishith Teraiya ,&nbsp;Renato J. Aguilera ,&nbsp;Subhas S. Karki","doi":"10.1016/j.cbi.2025.111509","DOIUrl":"10.1016/j.cbi.2025.111509","url":null,"abstract":"<div><div>Human ligase I and ligase IV have recently been recognized as potential targets and regulators of cancer. Novel pyrazole analogues were synthesized and evaluated for their anti-proliferation effects against lymphoma, breast and other cancer cell lines. The initial biological investigation resulted in the identification of lead compounds <strong>7a</strong> and <strong>8e</strong>. Compounds <strong>7a</strong> and <strong>8e</strong> were the most cytotoxic to acute lymphoblastic leukemia CEM cells, with CC₅₀ values of 4.78 μM and 9.23 μM, respectively. Compound <strong>8e</strong> was selected for further biological testing, whereas compound <strong>7a</strong> was excluded from subsequent evaluations due to its poor solubility. To investigate the mechanism of action of <strong>8e,</strong> it was tested for phosphatidylserine externalization, caspase-3 activation, mitochondrial membrane depolarization, reactive oxygen species generation (ROS) and its effects on the cell cycle. Results from these assays indicated that <strong>8e</strong> induced the intrinsic apoptosis pathway and arrested cells in the S phase of the cell cycle. Furthermore, <em>in silico</em> docking and molecular dynamic simulation revealed a strong affinity of <strong>7a</strong> and <strong>8e</strong> for ligase I and ligase IV suggesting that the induction of apoptosis is likely due to direct inhibition of these ligases. Collectively, these findings indicate that <strong>8e</strong> is a promising anticancer agent.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111509"},"PeriodicalIF":4.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN) attenuates inflammation and oxidative stress via MAPK, and Nrf2/HO-1 signaling in Traumatic brain injury","authors":"Sana Zafar ,&nbsp;Maryam Jamil ,&nbsp;Muhammad Ibrar Khan ,&nbsp;Fakhar ud Din ,&nbsp;Eun Kyoung Seo ,&nbsp;Salman Khan","doi":"10.1016/j.cbi.2025.111510","DOIUrl":"10.1016/j.cbi.2025.111510","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is an acquired neurological insult that has become a major cause of mortality.Hence, immediate and appropriate medical attention is essential. The present study investigated the neuroprotective effect of 7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid against a weight drop model of traumatic brain injury (TBI). During the in-vitro analysis, ECN demonstrated neuroprotective potential by remarkably improving the cell viability and also provided significant protection in case of nitric oxide-evoked oxidative stress in HT22 cells. The administration of ECN significantly improved the neurological severity score, and mechanical/periorbital allodynia following TBI, when compared with the TBI-group. The level of brain edema and blood-brain barrier (BBB) disruption were also significantly reduced by ECN treatment. ECN also restored constitutional changes in the protein/lipid profile; simultaneous with histological changes in the brain in contrast to the TBI-group. It significantly ameliorated neuronal loss and also minimized the intracerebral hemorrhages arising from traumatic insult. ECN exhibited potent anti-inflammatory effects, by altering the expression of extracellular-signal-regulated kinase (ERK), p38, and activating protein-1 (AP-1) proteins. It also exhibited antioxidant effects by increasing the production levels of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Furthermore, ECN also produced an anti-apoptotic effect by downregulation of caspase3 and upregulation of B-cell lymphoma 2 (Bcl-2). It also increased the levels of antioxidants while reducing the levels of oxidative stress and inflammatory markers in comparison to the TBI-group. In short, it was concluded that ECN exhibited protective anti-inflammatory, antioxidant, and anti-apoptotic effects against trauma-induced brain injury.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111510"},"PeriodicalIF":4.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of potent MD2 inhibitors by hierarchical virtual screening strategy and bioactivity evaluation","authors":"Lili Yang ,&nbsp;Jialu Liu ,&nbsp;Lei Di ,&nbsp;Siming Tang,&nbsp;Ping Hu,&nbsp;Fang Wang,&nbsp;Zeng Li","doi":"10.1016/j.cbi.2025.111508","DOIUrl":"10.1016/j.cbi.2025.111508","url":null,"abstract":"<div><div>Myeloid differentiation 2 (MD2), an accessory protein of Toll-like receptor 4 (TLR4), plays a crucial role in inflammation and represents a promising target for the development of anti-inflammatory drugs. This study used a hierarchical virtual screening strategy based on ligand and receptor pharmacophore models and docking to identify potential MD2 inhibitors. From an initial library of 257,706 compounds, 15 candidates were selected, with <strong>hit12</strong> demonstrating the most potent anti-inflammatory activity. <strong>Hit12</strong> inhibited the lipopolysaccharide (LPS)-induced formation of the TLR4/MD2 complex and blocked the NF-κB and MAPK signaling pathways. Molecular docking studies revealed hydrogen bonds between <strong>hit12</strong> and MD2, particularly with Arg90. Cellular thermal shift analysis (CETSA) showed that <strong>hit12</strong> enhanced the thermal stability of MD2, and molecular dynamics (MD) simulations and free energy calculations proposed the binding mode of <strong>hit12</strong>. In <em>vivo</em> experiments showed that <strong>hit12</strong> significantly reduced foot swelling in the adjuvant-induced arthritis (AIA) model rats. These results highlight the potential of MD2 as a target for the development of anti-inflammatory therapies.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111508"},"PeriodicalIF":4.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}