Pub Date : 2025-04-11DOI: 10.1016/j.cbi.2025.111509
S. Aishwarya , Gabriela C. Torres , Jose A. Lopez-Saenz , Denisse A. Gutierrez , Sujeet Kumar , Ashok Madarakhandi , Basavaraj Metikurki , Nishith Teraiya , Renato J. Aguilera , Subhas S. Karki
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 7a and 8e. Compounds 7a and 8e were the most cytotoxic to acute lymphoblastic leukemia CEM cells, with CC50 values of 4.78 μM and 9.23 μM, respectively. Compound 8e was selected for further biological testing, whereas compound 7a was excluded from subsequent evaluations due to its poor solubility. To investigate the mechanism of action of 8e, 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 8e induced the intrinsic apoptosis pathway and arrested cells in the S phase of the cell cycle. Furthermore, in silico docking and molecular dynamic simulation revealed a strong affinity of 7a and 8e 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 8e is a promising anticancer agent.
{"title":"Synthesis of novel pyridazine and pyrimidine linked pyrazole derivatives as DNA ligase 1 and IV inhibitors that induce apoptosis","authors":"S. Aishwarya , Gabriela C. Torres , Jose A. Lopez-Saenz , Denisse A. Gutierrez , Sujeet Kumar , Ashok Madarakhandi , Basavaraj Metikurki , Nishith Teraiya , Renato J. Aguilera , 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 CC<sub>50</sub> 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}
Pub Date : 2025-04-11DOI: 10.1016/j.cbi.2025.111510
Sana Zafar , Maryam Jamil , Muhammad Ibrar Khan , Fakhar ud Din , Eun Kyoung Seo , Salman Khan
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.
{"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 , Maryam Jamil , Muhammad Ibrar Khan , Fakhar ud Din , Eun Kyoung Seo , 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}
Pub Date : 2025-04-10DOI: 10.1016/j.cbi.2025.111508
Lili Yang , Jialu Liu , Lei Di , Siming Tang, Ping Hu, Fang Wang, Zeng Li
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 hit12 demonstrating the most potent anti-inflammatory activity. Hit12 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 hit12 and MD2, particularly with Arg90. Cellular thermal shift analysis (CETSA) showed that hit12 enhanced the thermal stability of MD2, and molecular dynamics (MD) simulations and free energy calculations proposed the binding mode of hit12. In vivo experiments showed that hit12 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.
{"title":"Discovery of potent MD2 inhibitors by hierarchical virtual screening strategy and bioactivity evaluation","authors":"Lili Yang , Jialu Liu , Lei Di , Siming Tang, Ping Hu, Fang Wang, 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}
Pub Date : 2025-04-10DOI: 10.1016/j.cbi.2025.111500
Dieniffer Espinosa Janner , Andriele de Moura Brinck , Frâncelly Marquez de Figueiredo , Elize Aparecida Santos Musachio , Luana Barreto Meichtry , Eliana Jardim Fernandes , Pamela Piardi de Almeida , Carlos Borges Filho , Magali Kemmerich , Amarilis Santos De Carvalho , Odinei Hess Gonçalves , Fernanda Vitória Leimann , Rilton Alves de Freitas , Marina Prigol , Gustavo Petri Guerra
Considering that woman's health during pregnancy is crucial to well-being as much maternal and fetal as well as the child's future, supplementation with antioxidant compounds has emerged as a promising strategy to prevent the development of future diseases. Given this context, the study aimed to evaluate the effect of lutein carrier nanoparticles supplementation during the preconception period on the offspring of Drosophila melanogaster subjected to a neurodevelopmental disorder model. Female flies, were exposed to either a standard diet or a diet containing NPs LUT (6 μM) for 24 h. Following this period, the flies were transferred to new experimental vials, and eighteen males were added, resulting in a total of 53 flies per experimental group. The male and female flies were then subdivided into two groups and exposed to either a standard diet or imidacloprid (IMI), for 7 days, to induce the neurodevelopmental disorder model, creating four experimental groups: 1) Control; 2) IMI; 3) NPs LUT; 4) NPs LUT + IMI. The hatched offspring were then used for behavioral and biochemical evaluations. Our results showed that supplementation with lutein carrier nanoparticles was able to prevent decreased activity of enzyme tyrosine hydroxylase (TH), as did neurotransmitters dopamine (DA) and serotonin (5-HT) in the head of flies, and as a consequence it prevented behavioral damages such as hyperactivity, anxiety, social interaction, repetitive movements, learning and memory in the progeny of both sexes. Thus, these findings highlight the relevance of preconception supplementation with lutein carrier nanoparticles as an effective approach to prevent the emergence of symptoms associated with neuropsychiatric disorders, paving the way for future research aimed at investigating the best intervention period to prevent ASD and ADHD-type disorders.
{"title":"Modulation of dopamine, serotonin, and behavior by lutein carrier nanoparticles in a Drosophila melanogaster model of neurodevelopmental disorders","authors":"Dieniffer Espinosa Janner , Andriele de Moura Brinck , Frâncelly Marquez de Figueiredo , Elize Aparecida Santos Musachio , Luana Barreto Meichtry , Eliana Jardim Fernandes , Pamela Piardi de Almeida , Carlos Borges Filho , Magali Kemmerich , Amarilis Santos De Carvalho , Odinei Hess Gonçalves , Fernanda Vitória Leimann , Rilton Alves de Freitas , Marina Prigol , Gustavo Petri Guerra","doi":"10.1016/j.cbi.2025.111500","DOIUrl":"10.1016/j.cbi.2025.111500","url":null,"abstract":"<div><div>Considering that woman's health during pregnancy is crucial to well-being as much maternal and fetal as well as the child's future, supplementation with antioxidant compounds has emerged as a promising strategy to prevent the development of future diseases. Given this context, the study aimed to evaluate the effect of lutein carrier nanoparticles supplementation during the preconception period on the offspring of <em>Drosophila melanogaster</em> subjected to a neurodevelopmental disorder model. Female flies, were exposed to either a standard diet or a diet containing NPs LUT (6 μM) for 24 h. Following this period, the flies were transferred to new experimental vials, and eighteen males were added, resulting in a total of 53 flies per experimental group. The male and female flies were then subdivided into two groups and exposed to either a standard diet or imidacloprid (IMI), for 7 days, to induce the neurodevelopmental disorder model, creating four experimental groups: 1) Control; 2) IMI; 3) NPs LUT; 4) NPs LUT + IMI. The hatched offspring were then used for behavioral and biochemical evaluations. Our results showed that supplementation with lutein carrier nanoparticles was able to prevent decreased activity of enzyme tyrosine hydroxylase (TH), as did neurotransmitters dopamine (DA) and serotonin (5-HT) in the head of flies, and as a consequence it prevented behavioral damages such as hyperactivity, anxiety, social interaction, repetitive movements, learning and memory in the progeny of both sexes. Thus, these findings highlight the relevance of preconception supplementation with lutein carrier nanoparticles as an effective approach to prevent the emergence of symptoms associated with neuropsychiatric disorders, paving the way for future research aimed at investigating the best intervention period to prevent ASD and ADHD-type disorders.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111500"},"PeriodicalIF":4.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826044","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}
Pub Date : 2025-04-08DOI: 10.1016/j.cbi.2025.111507
Weiyong Chen , Peiwen Wang , Yan Xie , Daxiao Xie , Hailan Wang , Ning Bu , Jiaheng Lin , Meng Wu , Haibo Xia , Cheng Cheng , Yuanzhong Zhou , Qizhan Liu
Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4+ T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased global lactylation (Kla), H3K18la, interferon-regulatory factor 4 (IRF4), retinoic acid receptor-related orphan receptor gamma t (RORγt), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells (HSCs). These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of HSCs, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.
{"title":"Histone lactylation-augmented IRF4 is implicated in arsenite-induced liver fibrosis via modulating Th17 cell differentiation","authors":"Weiyong Chen , Peiwen Wang , Yan Xie , Daxiao Xie , Hailan Wang , Ning Bu , Jiaheng Lin , Meng Wu , Haibo Xia , Cheng Cheng , Yuanzhong Zhou , Qizhan Liu","doi":"10.1016/j.cbi.2025.111507","DOIUrl":"10.1016/j.cbi.2025.111507","url":null,"abstract":"<div><div>Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4<sup>+</sup> T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased global lactylation (Kla), H3K18la, interferon-regulatory factor 4 (IRF4), retinoic acid receptor-related orphan receptor gamma t (RORγt), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells (HSCs). These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of HSCs, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111507"},"PeriodicalIF":4.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828506","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}
Pub Date : 2025-04-02DOI: 10.1016/j.cbi.2025.111499
Lili Sun , Yanmei Zhu , Yuan Yuan
Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a numerous family of cytoplasmic proteins. Members of this family not only function as innate immune sensors, but also serve as transcriptional regulators of major histocompatibility complex class II (MHC II) and major histocompatibility complex class I (MHC I) genes to activate adaptive immunity. Furthermore, NLRs are involved in mediating various signaling pathways, including the inflammasome. To date, extensive research has been conducted on the contradictory roles and mechanisms of NLRs in the occurrence, development, invasion, and metastasis of tumors within the tumor microenvironment (TME). The double-edged sword effect (either positive or negative role) of NLRs in the treatment of malignant tumors has attracted increasing attention in recent years, making these a promising bidirectional therapeutic target for such tumors. Rational utilization of the double-edged sword nature of NLRs can provide a feasible solution for improving the efficacy of malignant tumor treatment and overcoming chemotherapy resistance. This article provides a systematic review of the influence of the NLR family on chemosensitivity in different malignant tumors and the regulatory mechanisms of their upstream and downstream signaling pathways. In doing do, we aim to elucidate the dual role of NLRs in promoting and combating tumor chemotherapy resistance, and elucidate their application value in tumor chemotherapy resistance.
{"title":"NLRs in tumor chemotherapy resistance: A double-edged sword","authors":"Lili Sun , Yanmei Zhu , Yuan Yuan","doi":"10.1016/j.cbi.2025.111499","DOIUrl":"10.1016/j.cbi.2025.111499","url":null,"abstract":"<div><div>Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a numerous family of cytoplasmic proteins. Members of this family not only function as innate immune sensors, but also serve as transcriptional regulators of major histocompatibility complex class II (MHC II) and major histocompatibility complex class I (MHC I) genes to activate adaptive immunity. Furthermore, NLRs are involved in mediating various signaling pathways, including the inflammasome. To date, extensive research has been conducted on the contradictory roles and mechanisms of NLRs in the occurrence, development, invasion, and metastasis of tumors within the tumor microenvironment (TME). The double-edged sword effect (either positive or negative role) of NLRs in the treatment of malignant tumors has attracted increasing attention in recent years, making these a promising bidirectional therapeutic target for such tumors. Rational utilization of the double-edged sword nature of NLRs can provide a feasible solution for improving the efficacy of malignant tumor treatment and overcoming chemotherapy resistance. This article provides a systematic review of the influence of the NLR family on chemosensitivity in different malignant tumors and the regulatory mechanisms of their upstream and downstream signaling pathways. In doing do, we aim to elucidate the dual role of NLRs in promoting and combating tumor chemotherapy resistance, and elucidate their application value in tumor chemotherapy resistance.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111499"},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768024","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}
Pub Date : 2025-03-31DOI: 10.1016/j.cbi.2025.111495
Qi Song , Zhiliang Jin , Han Zhang , Kunqiao Hong , Beibei Zhu , Haisen Yin , Baoping Yu
An increasing body of research indicates that Fusobacterium nucleatum (F. nucleatum) significantly influences the onset and progression of colorectal cancer (CRC). Our previous study has shown that F. nucleatum exerts pro-tumorigenic effects through aryl hydrocarbon receptor (AhR) activation. However, the role of its microbial metabolites in regulating immune responses remains unclear. Here, we report for the first time that F. nucleatum-derived 3-Indolepropionic acid (IPA) activates AhR in macrophages, driving M2 polarization and tumor-promoting immunosuppression. We discovered that culture supernatant of F. nucleatum (CSF) robustly activates AhR in macrophages. In co-culture systems, CSF upregulated the expression of the M2 marker CD206 and elevated mRNA levels of CD163, TGF-β, IL-10, and VEGF. In a subcutaneous allograft model, CSF induced an elevated number of CD206+ macrophages and decreased presence of CD8+ T cells within the tumor microenvironment, thereby promoting tumor growth. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed IPA as a novel major AhR-activating metabolite in CSF. Strikingly, IPA recapitulated CSF's effects in promoting tumor cell migration and immunosuppression, both in vitro and in vivo. Critically, the AhR inhibitor CH223191 abolished both IPA-mediated M2 polarization and tumor growth. Our study revealed a novel mechanism by which F. nucleatum-derived IPA reprograms macrophages through AhR activation to fuel CRC progression, providing potential therapeutic targets for CRC treatment and prognosis improvement.
{"title":"Fusobacterium nucleatum-derived 3-indolepropionic acid promotes colorectal cancer progression via aryl hydrocarbon receptor activation in macrophages","authors":"Qi Song , Zhiliang Jin , Han Zhang , Kunqiao Hong , Beibei Zhu , Haisen Yin , Baoping Yu","doi":"10.1016/j.cbi.2025.111495","DOIUrl":"10.1016/j.cbi.2025.111495","url":null,"abstract":"<div><div>An increasing body of research indicates that <em>Fusobacterium nucleatum</em> (<em>F. nucleatum</em>) significantly influences the onset and progression of colorectal cancer (CRC). Our previous study has shown that <em>F. nucleatum</em> exerts pro-tumorigenic effects through aryl hydrocarbon receptor (AhR) activation. However, the role of its microbial metabolites in regulating immune responses remains unclear. Here, we report for the first time that <em>F. nucleatum</em>-derived 3-Indolepropionic acid (IPA) activates AhR in macrophages, driving M2 polarization and tumor-promoting immunosuppression. We discovered that culture supernatant of <em>F. nucleatum</em> (CSF) robustly activates AhR in macrophages. In co-culture systems, CSF upregulated the expression of the M2 marker CD206 and elevated mRNA levels of CD163, TGF-β, IL-10, and VEGF. In a subcutaneous allograft model, CSF induced an elevated number of CD206<sup>+</sup> macrophages and decreased presence of CD8<sup>+</sup> T cells within the tumor microenvironment, thereby promoting tumor growth. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed IPA as a novel major AhR-activating metabolite in CSF. Strikingly, IPA recapitulated CSF's effects in promoting tumor cell migration and immunosuppression, both <em>in vitro</em> and <em>in vivo</em>. Critically, the AhR inhibitor CH223191 abolished both IPA-mediated M2 polarization and tumor growth. Our study revealed a novel mechanism by which <em>F. nucleatum</em>-derived IPA reprograms macrophages through AhR activation to fuel CRC progression, providing potential therapeutic targets for CRC treatment and prognosis improvement.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111495"},"PeriodicalIF":4.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775203","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}
Pub Date : 2025-03-31DOI: 10.1016/j.cbi.2025.111498
Wei Zhang , Linna Gao , Shuyuan Zhang , Jiaqing Luo , Ruoxuan Yu , Xiting Li , Zhili Lu , Baozhu Chi , Ying Guo , Xun Tuo
Tetrabromobisphenol S Dimethyl Ether (TBBPS-BME) serves as a substitute for Tetrabromobisphenol A (TBBPA). It exhibits a greater potential for bioaccumulation, potentially posing substantial risks to environmental health and human safety. This research utilized a variety of spectroscopic and computational modeling methods to investigate structural and functional alterations of human serum albumin (HSA) induced by TBBPS-BME. The findings revealed that TBBPS-BME induces fluorescence quenching in HSA by binding to site I. The predominant force in this binding process is hydrophobic interaction. The binding constant for this complex is 2.394 ± 0.032 × 104 M-1 at 298 K, suggesting that they can form complex in vivo. The interaction with TBBPS-BME causes structural alterations in HSA, leading to a decrease in α-helix proportion and an overall enhancement of protein structural flexibility. The esterase-like function of HSA was also impacted by the presence of TBBPS-BME. Computational simulation tests indicate that this may be through interactions with residues Lys199 and Lys195. Molecular dynamics simulations further validated the formation of stable TBBPS-BME-HSA binary complexes, highlighting the critical role of hydrogen bonds in this steadiness. Alanine scanning mutation analysis revealed that Trp214, Phe211, Arg218, Lys199, and His242 are necessary for the assembly of the TBBPS-BME-HSA complex. Overall, this study provides an exhaustive examination of the binding mechanisms between TBBPS-BME and HSA, elucidating the underlying health hazards that may arise from exposure to TBBPS-BME.
{"title":"Structural and Functional Alterations of Human Serum Albumin (HSA) Induced by TBBPS-BME: A Spectroscopic, Computational, and Molecular Dynamics Study","authors":"Wei Zhang , Linna Gao , Shuyuan Zhang , Jiaqing Luo , Ruoxuan Yu , Xiting Li , Zhili Lu , Baozhu Chi , Ying Guo , Xun Tuo","doi":"10.1016/j.cbi.2025.111498","DOIUrl":"10.1016/j.cbi.2025.111498","url":null,"abstract":"<div><div>Tetrabromobisphenol S Dimethyl Ether (TBBPS-BME) serves as a substitute for Tetrabromobisphenol A (TBBPA). It exhibits a greater potential for bioaccumulation, potentially posing substantial risks to environmental health and human safety. This research utilized a variety of spectroscopic and computational modeling methods to investigate structural and functional alterations of human serum albumin (HSA) induced by TBBPS-BME. The findings revealed that TBBPS-BME induces fluorescence quenching in HSA by binding to site I. The predominant force in this binding process is hydrophobic interaction. The binding constant for this complex is 2.394 ± 0.032 × 10<sup>4</sup> M<sup>-1</sup> at 298 K, suggesting that they can form complex <em>in vivo</em>. The interaction with TBBPS-BME causes structural alterations in HSA, leading to a decrease in α-helix proportion and an overall enhancement of protein structural flexibility. The esterase-like function of HSA was also impacted by the presence of TBBPS-BME. Computational simulation tests indicate that this may be through interactions with residues Lys199 and Lys195. Molecular dynamics simulations further validated the formation of stable TBBPS-BME-HSA binary complexes, highlighting the critical role of hydrogen bonds in this steadiness. Alanine scanning mutation analysis revealed that Trp214, Phe211, Arg218, Lys199, and His242 are necessary for the assembly of the TBBPS-BME-HSA complex. Overall, this study provides an exhaustive examination of the binding mechanisms between TBBPS-BME and HSA, elucidating the underlying health hazards that may arise from exposure to TBBPS-BME.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111498"},"PeriodicalIF":4.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767633","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}
Pub Date : 2025-03-28DOI: 10.1016/j.cbi.2025.111497
José Luis Marco-Contelles , María Jesús Oset-Gasque
Herein, we have summarized the most significant results that we have communicated from our laboratories in the last thirty years, highlighting the most potent and attractive ChEIs based hit(lead)-Multitarget Small Molecules, such as (S)-p-methoxytacripyrine (1), ASS234 (2), Contilisant (3), and Contilistat (4), that we have identified in the search for new chemical entities for the therapy of Alzheimer's disease.
{"title":"Cholinesterase-based inhibitors as multitarget small molecules for the therapy of Alzheimer's disease","authors":"José Luis Marco-Contelles , María Jesús Oset-Gasque","doi":"10.1016/j.cbi.2025.111497","DOIUrl":"10.1016/j.cbi.2025.111497","url":null,"abstract":"<div><div>Herein, we have summarized the most significant results that we have communicated from our laboratories in the last thirty years, highlighting the most potent and attractive ChEIs based hit(lead)-Multitarget Small Molecules, such as (<em>S</em>)<em>-p</em>-methoxytacripyrine (<strong>1</strong>), ASS234 (<strong>2</strong>), Contilisant (<strong>3</strong>), and Contilistat (<strong>4</strong>), that we have identified in the search for new chemical entities for the therapy of Alzheimer's disease.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111497"},"PeriodicalIF":4.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756465","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}
Pub Date : 2025-03-27DOI: 10.1016/j.cbi.2025.111494
Yi Liu , Yang Wang , Shengqi Cheng , Jie Mu , Guanchen Yin , Hang Gao
Osteoarthritis (OA) is a degenerative joint disease that is a major cause of deformity, swelling, pain and even loss of function in the knee joints of the elderly. Pantothenic acid (PA) plays a protective role in many organs due to its antioxidant and anti-inflammatory properties. Herein, we aimed to assess the protective role of PA on osteoarthritis and investigate the underlying molecular mechanism. The levels of inflammatory factors (IL-1β and TNF-α) in knee tissues were measured by ELISA. The Safranin O-Fast Green staining was used to assess the severity of OA and the H&E staining was used to assess the degree of synovitis. In vitro, the levels of iron, MDA, GSH were measured by the detection kits. Western blotting was used to assess the levels of signaling-related proteins. Our results showed that PA significantly attenuated the degree of cartilage degeneration in the MIA-induced osteoarthritis model. PA also reduced the expression of IL-1β, TNF-α, MMP1 and MMP3. In vitro, PA effectively reduced the concentrations of MMP1 and MMP3 in IL-1β-stimulated chondrocytes. PA decreased the levels of Fe2+ and MDA, while increasing GSH production and GPX4 and SLC7A11 expression in IL-1β-induced chondrocytes. Meanwhile, we found that PA was able to inhibit the phosphorylation level of p65, IκB protein in chondrocytes, which effectively blocked the NF-κB signaling pathway. Furthermore, PA also increased the level of SIRT1, Nrf2, and HO-1 protein expression. In addition, the inhibition of PA on IL-1β-induced MMPs production and ferroptosis were inhibited by the SIRT1 inhibitor EX-527. In conclusion, PA inhibited chondrocyte ferroptosis and cartilage destruction in osteoarthritis. The mechanism was through activating SIRT1/Nrf2 signaling pathway.
{"title":"Pantothenic acid alleviates osteoarthritis progression by inhibiting inflammatory response and ferroptosis through the SIRT1/Nrf2 signaling pathway","authors":"Yi Liu , Yang Wang , Shengqi Cheng , Jie Mu , Guanchen Yin , Hang Gao","doi":"10.1016/j.cbi.2025.111494","DOIUrl":"10.1016/j.cbi.2025.111494","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a degenerative joint disease that is a major cause of deformity, swelling, pain and even loss of function in the knee joints of the elderly. Pantothenic acid (PA) plays a protective role in many organs due to its antioxidant and anti-inflammatory properties. Herein, we aimed to assess the protective role of PA on osteoarthritis and investigate the underlying molecular mechanism. The levels of inflammatory factors (IL-1β and TNF-α) in knee tissues were measured by ELISA. The Safranin O-Fast Green staining was used to assess the severity of OA and the H&E staining was used to assess the degree of synovitis. In vitro, the levels of iron, MDA, GSH were measured by the detection kits. Western blotting was used to assess the levels of signaling-related proteins. Our results showed that PA significantly attenuated the degree of cartilage degeneration in the MIA-induced osteoarthritis model. PA also reduced the expression of IL-1β, TNF-α, MMP1 and MMP3. In vitro, PA effectively reduced the concentrations of MMP1 and MMP3 in IL-1β-stimulated chondrocytes. PA decreased the levels of Fe<sup>2+</sup> and MDA, while increasing GSH production and GPX4 and SLC7A11 expression in IL-1β-induced chondrocytes. Meanwhile, we found that PA was able to inhibit the phosphorylation level of p65, IκB protein in chondrocytes, which effectively blocked the NF-κB signaling pathway. Furthermore, PA also increased the level of SIRT1, Nrf2, and HO-1 protein expression. In addition, the inhibition of PA on IL-1β-induced MMPs production and ferroptosis were inhibited by the SIRT1 inhibitor EX-527. In conclusion, PA inhibited chondrocyte ferroptosis and cartilage destruction in osteoarthritis. The mechanism was through activating SIRT1/Nrf2 signaling pathway.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111494"},"PeriodicalIF":4.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738251","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}
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