Biochemical and biophysical research communications最新文献_第8页

Multi-omics profiles reveal immune microenvironment alterations associated with PD-L1 checkpoint in acute pancreatitis in the early phase

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-05 DOI: 10.1016/j.bbrc.2025.151451

Di Wu , Wenhao Cai , Zehao Wu , Yilin Huang , Rajarshi Mukherjee , Jie Peng , Wei Huang , Qiang Li , Qing Xia , Kuirong Jiang

Background

Acute pancreatitis (AP) initiates as primarily sterile local inflammation that triggers pro-inflammatory response, which is subsequently counterbalanced by an anti-inflammatory response. Immune checkpoints, such as PD-1/PD-L1, play a pivotal role in modulating these responses to prevent excessive immune activation and associated inflammatory damage. This study aimed to investigate the underlying mechanisms of these processes in both murine and human AP.

Methods

We conducted a comprehensive integration of data from cerulein-induced AP mouse models (CER-AP), utilizing single-cell RNA sequencing and digital spatial profiling for pancreatic samples, as well as single-cell Cytometry by Time Of Flight (CyTOF) for blood samples. Additionally, bulk-RNA sequencing performed on blood samples from AP patients was employed to investigate innate and adaptive immune changes at early stage of the disease.

Results

Across the four analytical approaches, we observed consistent immune cell type distributions. Our integrative analysis revealed a significant imbalance between increased innate immune cells, including neutrophils, macrophages, and monocytes, and decreased adaptive immune cells, including CD4⁺ and CD8⁺ T cells, in early-stage AP. Notably, the PD-1/PD-L1 related pathway exhibited substantial alterations, especially in the acinar cells, T cells, B cells, macrophages, and neutrophils at the early stage of disease. Moreover, we observed a significant reduction in PD-L1 expression in the blood and regulatory T cells of CyTOF mice at the CyTOF level.

Conclusion

This multi-omics analysis deciphers a distinct imbalance between increased innate immunity and decreased adaptive immunity during the early phase of AP. The PD-L1 checkpoint emerges as a key regulator of immune homeostasis and a critical factor in the pathogenesis of AP.

{"title":"Multi-omics profiles reveal immune microenvironment alterations associated with PD-L1 checkpoint in acute pancreatitis in the early phase","authors":"Di Wu , Wenhao Cai , Zehao Wu , Yilin Huang , Rajarshi Mukherjee , Jie Peng , Wei Huang , Qiang Li , Qing Xia , Kuirong Jiang","doi":"10.1016/j.bbrc.2025.151451","DOIUrl":"10.1016/j.bbrc.2025.151451","url":null,"abstract":"<div><h3>Background</h3><div>Acute pancreatitis (AP) initiates as primarily sterile local inflammation that triggers pro-inflammatory response, which is subsequently counterbalanced by an anti-inflammatory response. Immune checkpoints, such as PD-1/PD-L1, play a pivotal role in modulating these responses to prevent excessive immune activation and associated inflammatory damage. This study aimed to investigate the underlying mechanisms of these processes in both murine and human AP.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive integration of data from cerulein-induced AP mouse models (CER-AP), utilizing single-cell RNA sequencing and digital spatial profiling for pancreatic samples, as well as single-cell Cytometry by Time Of Flight (CyTOF) for blood samples. Additionally, bulk-RNA sequencing performed on blood samples from AP patients was employed to investigate innate and adaptive immune changes at early stage of the disease.</div></div><div><h3>Results</h3><div>Across the four analytical approaches, we observed consistent immune cell type distributions. Our integrative analysis revealed a significant imbalance between increased innate immune cells, including neutrophils, macrophages, and monocytes, and decreased adaptive immune cells, including CD4<sup>+</sup> and CD8<sup>+</sup> T cells, in early-stage AP. Notably, the PD-1/PD-L1 related pathway exhibited substantial alterations, especially in the acinar cells, T cells, B cells, macrophages, and neutrophils at the early stage of disease. Moreover, we observed a significant reduction in PD-L1 expression in the blood and regulatory T cells of CyTOF mice at the CyTOF level.</div></div><div><h3>Conclusion</h3><div>This multi-omics analysis deciphers a distinct imbalance between increased innate immunity and decreased adaptive immunity during the early phase of AP. The PD-L1 checkpoint emerges as a key regulator of immune homeostasis and a critical factor in the pathogenesis of AP.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151451"},"PeriodicalIF":2.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Salusin-α attenuates lipid accumulation of C57BL/6 mice with Non-alcoholic fatty liver

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-05 DOI: 10.1016/j.bbrc.2025.151452

Ke-qian Chen , Tao Zeng , Wen-rui Tang , Shu-zhi Wang

With the development of society and economy, Non-alcoholic fatty liver disease (NAFLD) has gradually affected people's health. It is very important to find an effective treatment for NAFLD. Salusin-α is a kind of cardiovascular active peptide that can reduce blood pressure and slow down the heart rate. Studies have shown that Salusin-α can inhibit the development of atherosclerosis by regulating lipid metabolism. However, whether Salusin-α can inhibit the lipid accumulation of C57BL/6 mice with NAFLD has not been reported. Our study found that Salusin-α ameliorated lipid accumulation of NAFLD mice. Salusin-α has a good prospect in the treatment of NAFLD.

引用次数: 0

Lactobacillus rhamnosus GG ameliorates atherosclerosis via suppression of oxidative stress and inflammation by reshaping the gut microbiota

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-05 DOI: 10.1016/j.bbrc.2025.151417

Yajuan Liu , Zhixia Bai , Ru Yan , Junbai Ma , Liting Wang , Yiwei Li , Yuanyuan Liu , Huiyan Ma , Ting Wang , Libo Yang , Jian Liu , Wenke Shen , Xiaoxia Zhang , Shaobin Jia , Hao Wang

Objective

With growing awareness of probiotics' benefits, more studies are exploring their efficacy and mechanisms in reducing atherosclerosis (AS). This study aimed to investigate the potential therapeutic effects of Lactobacillus rhamnosus GG (LGG) on atherosclerotic mice and underlying mechanisms.

Design

ApoE^−/− mice were gavaged with a dose of 2 × 10⁹ CFU LGG per mouse once daily, while both ApoE^−/− and C57BL/6J mice received normal saline as controls. After 15 weeks, en face Oil Red O staining and aortic sinus morphometry were used to assess the effects of LGG intervention on AS. The expression of the Nrf2/HO-1 pathway, along with oxidative stress and inflammation, was measured in the aortic sinus, aortas, or plasma. Immune cells were analyzed by flow cytometry. 16S rRNA gene sequencing analysis evaluated structural changes in the intestinal microbiota.

Results

LGG-treated ApoE^−/− mice showed a significant reduction of AS progression by suppressing oxidative stress and inflammation. Mechanistically, LGG intervention significantly increased the levels of Nrf2/HO-1 in the aortic sinus of ApoE^−/− mice. Moreover, decreased aortic macrophages and elevated blood regulatory T cells (Tregs) were found with LGG intervention in the murine AS model. Moreover, compared to C57BL/6J mice, ApoE^−/− mice exhibited disrupted intestinal flora. Nonetheless, LGG intervention restored their intestinal flora to a composition resembling that of C57BL/6J mice, thereby increasing the abundance of beneficial bacteria.

Conclusion

LGG significantly attenuates AS by reducing oxidative stress and inflammation probably via activating the Nrf2/HO-1 pathway. Remarkably, LGG modulates gut microbiota, further enhancing its protective efficacy against AS.

{"title":"Lactobacillus rhamnosus GG ameliorates atherosclerosis via suppression of oxidative stress and inflammation by reshaping the gut microbiota","authors":"Yajuan Liu , Zhixia Bai , Ru Yan , Junbai Ma , Liting Wang , Yiwei Li , Yuanyuan Liu , Huiyan Ma , Ting Wang , Libo Yang , Jian Liu , Wenke Shen , Xiaoxia Zhang , Shaobin Jia , Hao Wang","doi":"10.1016/j.bbrc.2025.151417","DOIUrl":"10.1016/j.bbrc.2025.151417","url":null,"abstract":"<div><h3>Objective</h3><div>With growing awareness of probiotics' benefits, more studies are exploring their efficacy and mechanisms in reducing atherosclerosis (AS). This study aimed to investigate the potential therapeutic effects of <em>Lactobacillus rhamnosus</em> GG (LGG) on atherosclerotic mice and underlying mechanisms.</div></div><div><h3>Design</h3><div><em>ApoE</em><sup><em>−/−</em></sup> mice were gavaged with a dose of 2 × 10<sup>9</sup> CFU LGG per mouse once daily, while both <em>ApoE</em><sup>−/−</sup> and C57BL/6J mice received normal saline as controls. After 15 weeks, en face Oil Red O staining and aortic sinus morphometry were used to assess the effects of LGG intervention on AS. The expression of the Nrf2/HO-1 pathway, along with oxidative stress and inflammation, was measured in the aortic sinus, aortas, or plasma. Immune cells were analyzed by flow cytometry. 16S rRNA gene sequencing analysis evaluated structural changes in the intestinal microbiota.</div></div><div><h3>Results</h3><div>LGG-treated <em>ApoE</em><sup><em>−/−</em></sup> mice showed a significant reduction of AS progression by suppressing oxidative stress and inflammation. Mechanistically, LGG intervention significantly increased the levels of Nrf2/HO-1 in the aortic sinus of <em>ApoE</em><sup><em>−/−</em></sup> mice. Moreover, decreased aortic macrophages and elevated blood regulatory T cells (Tregs) were found with LGG intervention in the murine AS model. Moreover, compared to C57BL/6J mice, <em>ApoE</em><sup><em>−/−</em></sup> mice exhibited disrupted intestinal flora. Nonetheless, LGG intervention restored their intestinal flora to a composition resembling that of C57BL/6J mice, thereby increasing the abundance of beneficial bacteria.</div></div><div><h3>Conclusion</h3><div>LGG significantly attenuates AS by reducing oxidative stress and inflammation probably via activating the Nrf2/HO-1 pathway. Remarkably, LGG modulates gut microbiota, further enhancing its protective efficacy against AS.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151417"},"PeriodicalIF":2.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulation of NaCl on Bi-functionality of a chimeric enzyme for aromatic amino acid biosynthesis in Prevotella and Porphyromonas bacteria

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-04 DOI: 10.1016/j.bbrc.2025.151430

Yu Bai, Chenwei Dai

3-Deoxy-D-arabino heptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM) are key enzymes in the shikimate pathway responsible for aromatic amino acid biosynthesis in bacteria. This study investigated the functional interplay between the DAH7PS and CM domains within the bifunctional enzyme PniDAH7PS-CM from Prevotella nigrescens, a representative of the chimeric enzyme group DAH7PS-CM that is primarily distributed in the Prevotella and Porphyromonas genera. Analysis of the surface polarity demonstrated that DAH7PS and CM domains rely on hetero-domain polar interactions for their catalytic functions, rather than hydrophobic contacts. We evaluated the effects of NaCl on the catalytic activity, conformation, thermal stability, and molecular aggregation of PniDAH7PS-CM at varying NaCl concentrations (0, 150, and 300 mM). Results demonstrated that increasing NaCl concentrations significantly reduced the enzymatic activities of both DAH7PS and CM, with a complete loss of DAH7PS function at 300 mM NaCl. Notably, high NaCl concentrations promoted a more extended conformation of PniDAH7PS-CM and interfere with enzyme aggregation, suggesting that NaCl modulates the inter-domain interactions. Our findings suggest that Na⁺ ions, as kosmotropic agents, likely via enhancing the hydration layer on the enzyme's surface, stabilizes PniDAH7PS-CM structure but disrupting essential polar interactions for catalysis. Conversely, Cl⁻ ions may act as chaotropic agents, further impairing these interactions. This study illuminates the balance between salt ion concentration and enzyme functionality, offering insights for developing therapeutic strategies targeting bacterial metabolism and growth in the context of periodontal diseases.

{"title":"Regulation of NaCl on Bi-functionality of a chimeric enzyme for aromatic amino acid biosynthesis in Prevotella and Porphyromonas bacteria","authors":"Yu Bai, Chenwei Dai","doi":"10.1016/j.bbrc.2025.151430","DOIUrl":"10.1016/j.bbrc.2025.151430","url":null,"abstract":"<div><div>3-Deoxy-D-<em>arabino</em> heptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM) are key enzymes in the shikimate pathway responsible for aromatic amino acid biosynthesis in bacteria. This study investigated the functional interplay between the DAH7PS and CM domains within the bifunctional enzyme <em>Pni</em>DAH7PS-CM from <em>Prevotella nigrescens</em>, a representative of the chimeric enzyme group DAH7PS-CM that is primarily distributed in the <em>Prevotella</em> and <em>Porphyromonas</em> genera. Analysis of the surface polarity demonstrated that DAH7PS and CM domains rely on hetero-domain polar interactions for their catalytic functions, rather than hydrophobic contacts. We evaluated the effects of NaCl on the catalytic activity, conformation, thermal stability, and molecular aggregation of <em>Pni</em>DAH7PS-CM at varying NaCl concentrations (0, 150, and 300 mM). Results demonstrated that increasing NaCl concentrations significantly reduced the enzymatic activities of both DAH7PS and CM, with a complete loss of DAH7PS function at 300 mM NaCl. Notably, high NaCl concentrations promoted a more extended conformation of <em>Pni</em>DAH7PS-CM and interfere with enzyme aggregation, suggesting that NaCl modulates the inter-domain interactions. Our findings suggest that Na⁺ ions, as kosmotropic agents, likely via enhancing the hydration layer on the enzyme's surface, stabilizes <em>Pni</em>DAH7PS-CM structure but disrupting essential polar interactions for catalysis. Conversely, Cl⁻ ions may act as chaotropic agents, further impairing these interactions. This study illuminates the balance between salt ion concentration and enzyme functionality, offering insights for developing therapeutic strategies targeting bacterial metabolism and growth in the context of periodontal diseases.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151430"},"PeriodicalIF":2.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Arabidopsis root-type ferredoxin:NADP(H) oxidoreductases are crucial for root growth and ferredoxin-dependent processes

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-04 DOI: 10.1016/j.bbrc.2025.151448

Kota Monden , Daisuke Otomaru , Takamasa Suzuki , Tsuyoshi Nakagawa , Takushi Hachiya

Root-type ferredoxin:NADP(H) oxidoreductase (RFNR) is believed to reduce ferredoxin using NADPH in nonphotosynthetic tissues, facilitating ferredoxin-dependent biological processes. However, the physiological functions of RFNR remain unclear due to the difficulty in obtaining mutants lacking redundant RFNR isoproteins. The present study successfully generated Arabidopsis homozygous rnfr1;2 double mutants by traditional crossing and selection. However, they displayed severely stunted roots, challenging subsequent growth and abundant seed recovery. Notably, grafted plants combining mutant scions with wild-type rootstocks exhibited normal growth and produced abundant mutant seeds. Growth analysis employing reciprocal grafts with the wild-type and mutant plants showed that primary root growth was inhibited only when the rootstock was derived from the mutants. Meanwhile, the absence of RFNR1 and 2 in the scion had no apparent impact on shoot and root growth. Root transcriptome analysis revealed that RFNR1 and 2 deficiency upregulated genes encoding ferredoxin-dependent enzymes and root-type ferredoxin, leading to genome-wide reprogramming associated with cell walls, lipids, photosynthesis, secondary metabolism, and biotic/abiotic stress responses. Thus, Arabidopsis RFNR1 and 2 are crucial for root growth and various ferredoxin-dependent biological processes.

{"title":"Arabidopsis root-type ferredoxin:NADP(H) oxidoreductases are crucial for root growth and ferredoxin-dependent processes","authors":"Kota Monden , Daisuke Otomaru , Takamasa Suzuki , Tsuyoshi Nakagawa , Takushi Hachiya","doi":"10.1016/j.bbrc.2025.151448","DOIUrl":"10.1016/j.bbrc.2025.151448","url":null,"abstract":"<div><div>Root-type ferredoxin:NADP(H) oxidoreductase (RFNR) is believed to reduce ferredoxin using NADPH in nonphotosynthetic tissues, facilitating ferredoxin-dependent biological processes. However, the physiological functions of RFNR remain unclear due to the difficulty in obtaining mutants lacking redundant RFNR isoproteins. The present study successfully generated <em>Arabidopsis</em> homozygous <em>rnfr1</em>;<em>2</em> double mutants by traditional crossing and selection. However, they displayed severely stunted roots, challenging subsequent growth and abundant seed recovery. Notably, grafted plants combining mutant scions with wild-type rootstocks exhibited normal growth and produced abundant mutant seeds. Growth analysis employing reciprocal grafts with the wild-type and mutant plants showed that primary root growth was inhibited only when the rootstock was derived from the mutants. Meanwhile, the absence of RFNR1 and 2 in the scion had no apparent impact on shoot and root growth. Root transcriptome analysis revealed that RFNR1 and 2 deficiency upregulated genes encoding ferredoxin-dependent enzymes and root-type ferredoxin, leading to genome-wide reprogramming associated with cell walls, lipids, photosynthesis, secondary metabolism, and biotic/abiotic stress responses. Thus, <em>Arabidopsis</em> RFNR1 and 2 are crucial for root growth and various ferredoxin-dependent biological processes.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151448"},"PeriodicalIF":2.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143312237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Notch signaling modulation enhances porcine muscle stem cell proliferation and differentiation

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-04 DOI: 10.1016/j.bbrc.2025.151456

Guanyu Qin , Zheng Liu , Hao Lu , Yumeng Zhang , Shijie Ding , Guanghong Zhou , Chunbao Li , Renpeng Guo

Muscle stem cells (MuSCs) represent a promising starting material for the production of cultured meat. However, MuSCs exhibit impaired proliferative capabilities when cultured at high-density, with the underlying signaling pathways yet to be fully characterized. In this study, we revealed that Notch signaling was activated in response to high-density conditions in porcine MuSCs. Consistently, treatment with DAPT, a specific inhibitor of Notch signaling, significantly improved the proliferation of MuSCs cultivated at high-density. Further, Notch signaling was gradually repressed during MuSC differentiation. Notably, DAPT accelerated this downregulation process, thereby significantly promoting the myogenic differentiation potential of MuSCs. In summary, this study highlights the critical role of Notch signaling in regulating the proliferation and differentiation of MuSCs. Through modulating the activity of Notch signaling, we have identified a strategy to achieve extensive expansion of MuSCs and to enhance their myogenic differentiation.

{"title":"Notch signaling modulation enhances porcine muscle stem cell proliferation and differentiation","authors":"Guanyu Qin , Zheng Liu , Hao Lu , Yumeng Zhang , Shijie Ding , Guanghong Zhou , Chunbao Li , Renpeng Guo","doi":"10.1016/j.bbrc.2025.151456","DOIUrl":"10.1016/j.bbrc.2025.151456","url":null,"abstract":"<div><div>Muscle stem cells (MuSCs) represent a promising starting material for the production of cultured meat. However, MuSCs exhibit impaired proliferative capabilities when cultured at high-density, with the underlying signaling pathways yet to be fully characterized. In this study, we revealed that Notch signaling was activated in response to high-density conditions in porcine MuSCs. Consistently, treatment with DAPT, a specific inhibitor of Notch signaling, significantly improved the proliferation of MuSCs cultivated at high-density. Further, Notch signaling was gradually repressed during MuSC differentiation. Notably, DAPT accelerated this downregulation process, thereby significantly promoting the myogenic differentiation potential of MuSCs. In summary, this study highlights the critical role of Notch signaling in regulating the proliferation and differentiation of MuSCs. Through modulating the activity of Notch signaling, we have identified a strategy to achieve extensive expansion of MuSCs and to enhance their myogenic differentiation.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"752 ","pages":"Article 151456"},"PeriodicalIF":2.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143376432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of LAT1 in AOM/DSS-induced colorectal tumorigenesis

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-04 DOI: 10.1016/j.bbrc.2025.151446

Yunlong Sui , Namiko Hoshi , Norihiro Okamoto , Yuta Inoue , Takumi Funatsu , Yuna Ku , Makoto Ooi , Daisuke Watanabe , Haruka Miyazaki , Misaki Agawa , Hirotaka Nakamura , Ryuichi Ohgaki , Yoshikatsu Kanai , Hui Yang , Yuzo Kodama

Amino acid transporters are essential for supplying nutrients to cells and are implicated in tumor progression. L-type amino acid transporter 1 (LAT1) is reported to be overexpressed in various cancers, affecting tumor development. However, the exact mechanisms by which LAT1 affects colorectal cancer (CRC) arising from a chronic inflammatory background are not yet fully understood. This study aimed to explore the role of LAT1 in CRC. Mice with intestinal epithelium-specific deletions of LAT1 (LAT1^fl/fl; vil-cre) were treated with azoxymethane (AOM)/dextran sulfate sodium (DSS) in a colitis-associated cancer (CAC) model. Our results demonstrated that LAT1 was detected in normal colon crypts and highly expressed in AOM/DSS-induced tumor tissue. During the chronic colitis phase, weight loss was more prominent in LAT1^fl/fl; vil-cre mice, compared with that in LAT1^fl/fl mice. IL-1β and IL-6 expressions significantly increased in LAT1-deleted tumors; however, no overall difference in colon tumor number or size was observed between LAT1^fl/fl and LAT1^fl/fl; vil-cre mice. Accordingly, cell proliferation and apoptotic cell number were similar when comparing LAT1-deleted tumors with those with sufficient LAT1. Our findings indicated that LAT1 might not phenotypically affect overall colonic tumor development in this model; however, it affected the chronic colitis phase and inflammatory status within the tumors. These findings suggest that severe inflammation in tumors might have compensated for tumor growth in defects of amino acid supplementation through LAT1 deficiency, and provide insights into the potential of LAT1-targeted therapies for clinical CRC treatment.

{"title":"The role of LAT1 in AOM/DSS-induced colorectal tumorigenesis","authors":"Yunlong Sui , Namiko Hoshi , Norihiro Okamoto , Yuta Inoue , Takumi Funatsu , Yuna Ku , Makoto Ooi , Daisuke Watanabe , Haruka Miyazaki , Misaki Agawa , Hirotaka Nakamura , Ryuichi Ohgaki , Yoshikatsu Kanai , Hui Yang , Yuzo Kodama","doi":"10.1016/j.bbrc.2025.151446","DOIUrl":"10.1016/j.bbrc.2025.151446","url":null,"abstract":"<div><div>Amino acid transporters are essential for supplying nutrients to cells and are implicated in tumor progression. L-type amino acid transporter 1 (LAT1) is reported to be overexpressed in various cancers, affecting tumor development. However, the exact mechanisms by which LAT1 affects colorectal cancer (CRC) arising from a chronic inflammatory background are not yet fully understood. This study aimed to explore the role of LAT1 in CRC. Mice with intestinal epithelium-specific deletions of LAT1 (LAT1<sup>fl/fl</sup>; vil-cre) were treated with azoxymethane (AOM)/dextran sulfate sodium (DSS) in a colitis-associated cancer (CAC) model. Our results demonstrated that LAT1 was detected in normal colon crypts and highly expressed in AOM/DSS-induced tumor tissue. During the chronic colitis phase, weight loss was more prominent in LAT1<sup>fl/fl</sup>; vil-cre mice, compared with that in LAT1<sup>fl/fl</sup> mice. <em>IL-1β</em> and <em>IL-6</em> expressions significantly increased in LAT1-deleted tumors; however, no overall difference in colon tumor number or size was observed between LAT1<sup>fl/fl</sup> and LAT1<sup>fl/fl</sup>; vil-cre mice. Accordingly, cell proliferation and apoptotic cell number were similar when comparing LAT1-deleted tumors with those with sufficient LAT1. Our findings indicated that LAT1 might not phenotypically affect overall colonic tumor development in this model; however, it affected the chronic colitis phase and inflammatory status within the tumors. These findings suggest that severe inflammation in tumors might have compensated for tumor growth in defects of amino acid supplementation through LAT1 deficiency, and provide insights into the potential of LAT1-targeted therapies for clinical CRC treatment.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151446"},"PeriodicalIF":2.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143312208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Python-derived 16α-Hydroxylated Bile Acid, Pythocholic Acid is a ligand for TGR5, not farnesoid X receptors and vitamin D receptors

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-04 DOI: 10.1016/j.bbrc.2025.151453

Nicole Kiaei , Afsin Malik , Sydney O. Idahosa , Kevin K. Lee , Kaori Endo-Umeda , Makoto Makishima , Akira Kawamura , Sei Higuchi

Bile acids (BAs) are signaling molecules involved in energy expenditure, glucose homeostasis, and immune system regulation via activation of BA receptors, such as Takeda G-Protein-Coupled Receptor 5 (TGR5), Farnesoid X Receptor (FXR), and Vitamin D Receptor (VDR). The structure of BA, especially the hydroxyl group position, plays an important role in exerting its function. Previously, we reported that 16α-hydroxylated BA, also known as pythocholic acid (PCA), has beneficial effects on metabolic function and lipid metabolism in mammals. However, the molecular mechanism of PCA in mammals is yet to be explored because 16α-hydroxylated BA has not been seen in mammals. This study aims to investigate the binding interaction of PCA to human bile acid receptors, TGR5, FXR, and VDR, using a luciferase reporter assay. Luciferase reporter assay showed that PCA and tauro-conjugated-PCA (TPCA) activated TGR5, but did not activate FXR or VDR. Additionally, PCA and TPCA did not show an antagonistic effect on any of the BA receptors. TPCA treatment significantly decreased lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) expression in mouse peritoneal macrophages, and inhibition of TGR5 by SBI-115 canceled the anti-inflammatory effect of TPCA. Our data suggests that PCA and TPCA are ligands for mammalian TGR5 receptors.

{"title":"Python-derived 16α-Hydroxylated Bile Acid, Pythocholic Acid is a ligand for TGR5, not farnesoid X receptors and vitamin D receptors","authors":"Nicole Kiaei , Afsin Malik , Sydney O. Idahosa , Kevin K. Lee , Kaori Endo-Umeda , Makoto Makishima , Akira Kawamura , Sei Higuchi","doi":"10.1016/j.bbrc.2025.151453","DOIUrl":"10.1016/j.bbrc.2025.151453","url":null,"abstract":"<div><div>Bile acids (BAs) are signaling molecules involved in energy expenditure, glucose homeostasis, and immune system regulation via activation of BA receptors, such as Takeda G-Protein-Coupled Receptor 5 (TGR5), Farnesoid X Receptor (FXR), and Vitamin D Receptor (VDR). The structure of BA, especially the hydroxyl group position, plays an important role in exerting its function. Previously, we reported that 16α-hydroxylated BA, also known as pythocholic acid (PCA), has beneficial effects on metabolic function and lipid metabolism in mammals. However, the molecular mechanism of PCA in mammals is yet to be explored because 16α-hydroxylated BA has not been seen in mammals. This study aims to investigate the binding interaction of PCA to human bile acid receptors, TGR5, FXR, and VDR, using a luciferase reporter assay. Luciferase reporter assay showed that PCA and tauro-conjugated-PCA (TPCA) activated TGR5, but did not activate FXR or VDR. Additionally, PCA and TPCA did not show an antagonistic effect on any of the BA receptors. TPCA treatment significantly decreased lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) expression in mouse peritoneal macrophages, and inhibition of TGR5 by SBI-115 canceled the anti-inflammatory effect of TPCA. Our data suggests that PCA and TPCA are ligands for mammalian TGR5 receptors.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151453"},"PeriodicalIF":2.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dab1 expression level controls Reelin-induced PI3K-Akt activation in early GABAergic neurons

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-04 DOI: 10.1016/j.bbrc.2025.151444

Kavitha Sajukumar , Prabhakar Yadav , Gum Hwa Lee

Disabled-1 (Dab1) is a key regulator of the Reelin signaling cascades and controls many neurodevelopmental processes, including pyramidal neuron migration, dendrite growth, and spine formation. Dab1 is phosphorylated upon the binding of Reelin to Very low density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2) receptors, resulting in activation of a series of downstream signaling pathways, including Phosphoinositide 3-kinase (PI3K)/Akt, Lissencephaly 1 (Lis1), Crks/C3G, and Extracellular signal-regulated kinase 1/2 (Erk1/2). Dab1 is then rapidly degraded via the proteasome pathway. In humans, REELIN and DAB1 are genetically associated with several psychiatric disorders, such as schizophrenia and autism spectrum disorder. Although a subset of GABAergic neurons express Reelin and are continuously exposed to Reelin from early developmental stages through adulthood, most studies have only investigated the role of Reelin in the development and function of pyramidal neurons; as such the role of Reelin in GABAergic neurons remains poorly understood. In this study, we isolated primary neurons from mouse medial ganglionic eminence (MGE) at embryonic day 14.5 that 98–99 % were composed of GABAergic neurons. Using MGE-isolated GABAergic neurons, we studied the quantitative differences in Reelin signaling and expression of related genes in these neurons for the first time. Reelin supplementation did not activate PI3K-Akt signaling in most GABAergic neurons, but it did activate the signaling pathway in Somatostatin-positive GABAergic neurons. Dab1 was transcriptionally repressed in early GABAergic neurons, demonstrating the selective activation of Reelin signaling between subsets of neurons. This study provides quantitative evidence and contributes insights into the molecular mechanisms underlying the limited effects of Reelin on Dab1-related developmental activities in the majority of GABAergic neurons during brain development.

{"title":"Dab1 expression level controls Reelin-induced PI3K-Akt activation in early GABAergic neurons","authors":"Kavitha Sajukumar , Prabhakar Yadav , Gum Hwa Lee","doi":"10.1016/j.bbrc.2025.151444","DOIUrl":"10.1016/j.bbrc.2025.151444","url":null,"abstract":"<div><div>Disabled-1 (Dab1) is a key regulator of the Reelin signaling cascades and controls many neurodevelopmental processes, including pyramidal neuron migration, dendrite growth, and spine formation. Dab1 is phosphorylated upon the binding of Reelin to Very low density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2) receptors, resulting in activation of a series of downstream signaling pathways, including Phosphoinositide 3-kinase (PI3K)/Akt, Lissencephaly 1 (Lis1), Crks/C3G, and Extracellular signal-regulated kinase 1/2 (Erk1/2). Dab1 is then rapidly degraded via the proteasome pathway. In humans, REELIN and DAB1 are genetically associated with several psychiatric disorders, such as schizophrenia and autism spectrum disorder. Although a subset of GABAergic neurons express Reelin and are continuously exposed to Reelin from early developmental stages through adulthood, most studies have only investigated the role of Reelin in the development and function of pyramidal neurons; as such the role of Reelin in GABAergic neurons remains poorly understood. In this study, we isolated primary neurons from mouse medial ganglionic eminence (MGE) at embryonic day 14.5 that 98–99 % were composed of GABAergic neurons. Using MGE-isolated GABAergic neurons, we studied the quantitative differences in Reelin signaling and expression of related genes in these neurons for the first time. Reelin supplementation did not activate PI3K-Akt signaling in most GABAergic neurons, but it did activate the signaling pathway in Somatostatin-positive GABAergic neurons. Dab1 was transcriptionally repressed in early GABAergic neurons, demonstrating the selective activation of Reelin signaling between subsets of neurons. This study provides quantitative evidence and contributes insights into the molecular mechanisms underlying the limited effects of Reelin on Dab1-related developmental activities in the majority of GABAergic neurons during brain development.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151444"},"PeriodicalIF":2.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143312204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The catalytic action of enzymes exposed to charged substrates outperforms the activity exerted on their neutral counterparts

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2025-02-03 DOI: 10.1016/j.bbrc.2025.151436

Alessandra Stefan , Alejandro Hochkoeppler

Enzymes perform their catalytic action according to mechanisms featuring exquisite specificity, up to the selection of substrate conformers. However, regardless of this high specificity enzymes are able to deal with a repertoire of substrates, whose conversion into reaction products can occur with markedly different rates. Among the factors affecting the velocity of enzyme-catalyzed reactions, the presence in the substrate of an electrostatic charge could be of importance. Here we report on the kinetic parameters of four enzymes (bovine carbonic anhydrase and α-chymotrypsin, Escherichia coli β-galactosidase, and sweet almond β-glucosidase) determined using a NO₂-containing charged substrate or its neutral counterpart. Remarkably, all the considered enzymes were found more effective when exposed to the charged substrates, featuring K_m and k_cat values respectively lower and higher than those determined using the neutral substrates. Furthermore, by means of ultrafiltration experiments we detected the binding of o-nitrophenyl-β-d-galactopyranoside to a multiplicity of sites in E. coli β-galactosidase. Overall, our observations suggest that the unspecific binding of substrate to enzyme surface aids the cycling of subsequent catalytic turnovers.

{"title":"The catalytic action of enzymes exposed to charged substrates outperforms the activity exerted on their neutral counterparts","authors":"Alessandra Stefan , Alejandro Hochkoeppler","doi":"10.1016/j.bbrc.2025.151436","DOIUrl":"10.1016/j.bbrc.2025.151436","url":null,"abstract":"<div><div>Enzymes perform their catalytic action according to mechanisms featuring exquisite specificity, up to the selection of substrate conformers. However, regardless of this high specificity enzymes are able to deal with a repertoire of substrates, whose conversion into reaction products can occur with markedly different rates. Among the factors affecting the velocity of enzyme-catalyzed reactions, the presence in the substrate of an electrostatic charge could be of importance. Here we report on the kinetic parameters of four enzymes (bovine carbonic anhydrase and α-chymotrypsin, <em>Escherichia coli</em> β-galactosidase, and sweet almond β-glucosidase) determined using a NO<sub>2</sub>-containing charged substrate or its neutral counterpart. Remarkably, all the considered enzymes were found more effective when exposed to the charged substrates, featuring <em>K</em><sub>m</sub> and <em>k</em><sub>cat</sub> values respectively lower and higher than those determined using the neutral substrates. Furthermore, by means of ultrafiltration experiments we detected the binding of <em>o</em>-nitrophenyl-β-<span>d</span>-galactopyranoside to a multiplicity of sites in <em>E. coli</em> β-galactosidase. Overall, our observations suggest that the unspecific binding of substrate to enzyme surface aids the cycling of subsequent catalytic turnovers.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151436"},"PeriodicalIF":2.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143312240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0