Biochemical pharmacology最新文献

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Carbon monoxide alleviates endotoxin-induced acute lung injury via NADPH oxidase inhibition in macrophages and neutrophils

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-27 DOI: 10.1016/j.bcp.2025.116782

Yuki Watabe , Victor Tuan Giam Chuang , Hiromi Sakai , Chihiro Ito , Yuki Enoki , Mitsutomo Kohno , Masaki Otagiri , Kazuaki Matsumoto , Kazuaki Taguchi

Sepsis is a life-threatening condition caused by severe infection and often complicates acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) due to the collapse of the oxidative and inflammatory balance induced by microbial pathogens, including lipopolysaccharides (LPS). In sepsis-related ARDS/ALI, NADPH oxidase (NOX) and toll-like receptors (TLR) in neutrophils and macrophages are key players in initiating oxidative and inflammatory imbalances. Although NOX and TLR activation has been linked to carbon monoxide (CO), the mechanism by which CO affects sepsis-related ARDS/ALI through NOX and TLR remains unknown. Here, we demonstrate that CO reduces sepsis-related ARDS/ALI by inhibiting NOX in neutrophils and macrophages, which in turn suppresses the production of reactive oxygen species (ROS), TLR4-associated inflammatory responses, and macrophage polarization toward M1-like macrophages. CO-bound hemoglobin vesicle (CO-HbV) therapy, a hemoglobin-based CO donor, exerts a protective effect against LPS-induced ALI by suppressing exaggerated oxidative and inflammatory responses and neutrophil and M1-like macrophage infiltration in the bronchoalveolar lavage fluid (BALF). Through suppression of NOX activity, CO decreased ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization toward M1-like macrophages, according to cellular experiments conducted with peripheral neutrophils, BALF cells, and Raw264.7 cells. Moreover, ALI was found to be more severe in Hmox1^+/- mice (mice with decreased endogenous CO production) than in the wild-type mice. Our findings suggest that both endogenously generated and exogenously supplied CO inhibit NOX-associated ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization, thereby eliciting antioxidant and anti-inflammatory responses that prevent the onset and progression of LPS-induced ALI.

{"title":"Carbon monoxide alleviates endotoxin-induced acute lung injury via NADPH oxidase inhibition in macrophages and neutrophils","authors":"Yuki Watabe , Victor Tuan Giam Chuang , Hiromi Sakai , Chihiro Ito , Yuki Enoki , Mitsutomo Kohno , Masaki Otagiri , Kazuaki Matsumoto , Kazuaki Taguchi","doi":"10.1016/j.bcp.2025.116782","DOIUrl":"10.1016/j.bcp.2025.116782","url":null,"abstract":"<div><div>Sepsis is a life-threatening condition caused by severe infection and often complicates acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) due to the collapse of the oxidative and inflammatory balance induced by microbial pathogens, including lipopolysaccharides (LPS). In sepsis-related ARDS/ALI, NADPH oxidase (NOX) and toll-like receptors (TLR) in neutrophils and macrophages are key players in initiating oxidative and inflammatory imbalances. Although NOX and TLR activation has been linked to carbon monoxide (CO), the mechanism by which CO affects sepsis-related ARDS/ALI through NOX and TLR remains unknown. Here, we demonstrate that CO reduces sepsis-related ARDS/ALI by inhibiting NOX in neutrophils and macrophages, which in turn suppresses the production of reactive oxygen species (ROS), TLR4-associated inflammatory responses, and macrophage polarization toward M1-like macrophages. CO-bound hemoglobin vesicle (CO-HbV) therapy, a hemoglobin-based CO donor, exerts a protective effect against LPS-induced ALI by suppressing exaggerated oxidative and inflammatory responses and neutrophil and M1-like macrophage infiltration in the bronchoalveolar lavage fluid (BALF). Through suppression of NOX activity, CO decreased ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization toward M1-like macrophages, according to cellular experiments conducted with peripheral neutrophils, BALF cells, and Raw264.7 cells. Moreover, ALI was found to be more severe in <em>Hmox1<sup>+/-</sup></em> mice (mice with decreased endogenous CO production) than in the wild-type mice. Our findings suggest that both endogenously generated and exogenously supplied CO inhibit NOX-associated ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization, thereby eliciting antioxidant and anti-inflammatory responses that prevent the onset and progression of LPS-induced ALI.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116782"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Variable peptide processing of a Conus (Asprella) neocostatus α-conotoxin generates bioactive toxiforms that are potent against distinct nicotinic acetylcholine receptor subtypes

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-27 DOI: 10.1016/j.bcp.2025.116781

Cydee Marie V. Ramones , Ryoichi S. Taguchi , Ella Mae E. Gamba , Abe Ernest Johann E. Isagan , Maren Watkins , Meljune O. Chicote , Michael C. Velarde , Aaron Joseph L. Villaraza , Eizadora T. Yu , Baldomero M. Olivera , Gisela P. Concepcion , Arturo O. Lluisma

Conus venoms are composed of peptides that are commonly post-translationally modified, increasing their chemical diversity beyond what is encoded in the genome and enhancing their potency and selectivity. This study describes how PTMs alter an α-conotoxin’s selectivity for specific nAChR subtypes. Venom from the cone snail Conus (Asprella) neocostatus was fractionated using high-performance liquid chromatography and tested using a behavioral intracranial mouse bioassay and a cholinergic calcium imaging assay using SH-SY5Y neuroblastoma cells. Four peptides were isolated from three HPLC fractions and found to have similar amino acid sequences using tandem mass spectrometry; they all contain C-terminal amidation. The four peptides appear to be encoded by a single gene as indicated by transcriptomic analysis. One of these, NcIA, contains no additional PTM. NcIB lacked the two glycine residues found in the N-terminus of NcIA and contained two hydroxylated prolines. Analogs of both peptides containing a ɣ-carboxylated glutamic residue (NcIA[E15γ] and NcIB[E13γ]) were also isolated. Functional assays revealed distinct receptor selectivity: NcIA inhibited nicotine-evoked responses by over 70 %, while NcIA[E15γ] did not. Conversely, NcIB[E13γ] was inhibitory (∼60 %), but NcIB was not. Against choline-evoked responses, NcIA was weakly inhibitory (∼40 %), whereas the other three were nearly fully inhibitory. The IC₅₀ values for NcIB and NcIB[E13γ] were 91.0 nM and 64.7 nM, respectively. These findings indicate that PTMs and N-terminal modifications influence peptide potency and receptor specificity, suggesting that cone snails use variable peptide processing not only to generate chemical diversity in their venom but also to fine-tune the pharmacology of its components.

{"title":"Variable peptide processing of a Conus (Asprella) neocostatus α-conotoxin generates bioactive toxiforms that are potent against distinct nicotinic acetylcholine receptor subtypes","authors":"Cydee Marie V. Ramones , Ryoichi S. Taguchi , Ella Mae E. Gamba , Abe Ernest Johann E. Isagan , Maren Watkins , Meljune O. Chicote , Michael C. Velarde , Aaron Joseph L. Villaraza , Eizadora T. Yu , Baldomero M. Olivera , Gisela P. Concepcion , Arturo O. Lluisma","doi":"10.1016/j.bcp.2025.116781","DOIUrl":"10.1016/j.bcp.2025.116781","url":null,"abstract":"<div><div><em>Conus</em>  <em>Conus</em>  <em>neocostatus</em>  values for NcIB and NcIB[E13γ] were 91.0 nM and 64.7 nM, respectively. These findings indicate that PTMs andN-terminal modifications influence peptide potency and receptor specificity, suggesting that cone snails use variable peptide processing not only to generate chemical diversity in their venom but also to fine-tune the pharmacology of its components.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116781"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063552","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}

引用次数: 0

A novel amino-pyrimidine inhibitor suppresses tumor growth via microtubule destabilization and Bmi-1 down-regulation

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-27 DOI: 10.1016/j.bcp.2025.116783

Lijie Gao , Jiawei Liu , Rui Zhang , Xi Chen , Mo Wang , Yujia Dong , Mykhaylo S. Frasinyuk , Wen Zhang , David Watt , Wenxiang Meng , Jun Xue , Chunming Liu , Yu Cheng , Xifu Liu

Colorectal cancer (CRC), one of the diseases posing a threat to global health, according to the latest data, is the third most common cancer globally and the second leading cause of cancer-related deaths. The development and refinement of novel structures of small molecular compounds play a crucial role in tumor treatment and overcoming drug resistance. In this study, our objective was to screen and characterize novel compounds for overcoming drug resistance via the B Lymphoma Mo-MLV insertion region 1 (Bmi-1) reporter screen assay. The stable cell line harboring the Bmi-1 reporter gene was utilized to screen 300 compounds, leading to the identification of an amino-pyrimidine compound, APD-94. In vitro, APD-94 markedly inhibited cancer cell proliferation and decreased Bmi-1 expression at both the RNA and protein levels. In vivo, APD-94 repressed the growth of HT29 cell xenografts in NOD/SCID mice without notable side effects. Flow cytometry results demonstrated that APD-94 induced G2/M phase arrest and apoptosis in cells. APD-94 was identified as a novel inhibitor of microtubule polymerization by directly targeting the tubulin. Furthermore, APD-94 was more effective in overcoming the resistance to paclitaxel in paclitaxel-resistant A549/Tax cells. This bifunctional inhibitor is a promising candidate drug for CRC treatment.

{"title":"A novel amino-pyrimidine inhibitor suppresses tumor growth via microtubule destabilization and Bmi-1 down-regulation","authors":"Lijie Gao , Jiawei Liu , Rui Zhang , Xi Chen , Mo Wang , Yujia Dong , Mykhaylo S. Frasinyuk , Wen Zhang , David Watt , Wenxiang Meng , Jun Xue , Chunming Liu , Yu Cheng , Xifu Liu","doi":"10.1016/j.bcp.2025.116783","DOIUrl":"10.1016/j.bcp.2025.116783","url":null,"abstract":"<div><div>Colorectal cancer (CRC), one of the diseases posing a threat to global health, according to the latest data, is the third most common cancer globally and the second leading cause of cancer-related deaths. The development and refinement of novel structures of small molecular compounds play a crucial role in tumor treatment and overcoming drug resistance. In this study, our objective was to screen and characterize novel compounds for overcoming drug resistance <em>via</em> the B Lymphoma Mo-MLV insertion region 1 (Bmi-1) reporter screen assay. The stable cell line harboring the Bmi-1 reporter gene was utilized to screen 300 compounds, leading to the identification of an amino-pyrimidine compound, <strong>APD-94</strong>. <em>In vitro</em>, <strong>APD-94</strong> markedly inhibited cancer cell proliferation and decreased Bmi-1 expression at both the RNA and protein levels. <em>In vivo</em>, <strong>APD-94</strong> repressed the growth of HT29 cell xenografts in NOD/SCID mice without notable side effects. Flow cytometry results demonstrated that <strong>APD-94</strong> induced G2/M phase arrest and apoptosis in cells. <strong>APD-94</strong> was identified as a novel inhibitor of microtubule polymerization by directly targeting the tubulin. Furthermore, <strong>APD-94</strong> was more effective in overcoming the resistance to paclitaxel in paclitaxel-resistant A549/Tax cells. This bifunctional inhibitor is a promising candidate drug for CRC treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116783"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063540","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}

引用次数: 0

GRHL3 drives radiotherapy resistance and blocks the anti-tumor response of NK and CD4+ T cells in lung squamous cell carcinoma via RNF2

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-27 DOI: 10.1016/j.bcp.2025.116784

Haijun Wang , Changjiang Liu , Chao Jiang , Yunjie Zhang , Xin Zhao , Zhongfei Jia , Jingchen Huo , Jie Yang

Grainyhead-like protein 3 homolog (GRHL3) has been identified as a top transcription factor associated with keratinization in lung squamous cell carcinoma (LUSC). We designed this study to elucidate the function of GRHL3 in radioresistance in LUSC and the mechanism involved. Transcriptome differences between radioresistant and parental cells were analyzed to identify the hub transcription factor. GRHL3 expression was overexpressed in radioresistant cells relative to parental cells, and the knockdown of GRHL3 conferred sensitivity to radioresistant LUSC cells, induced DNA damage, inhibited cell survival, and reduced tumor load in mice. GRHL3 promoted ring finger protein 2 (RNF2) transcription by binding to the RNF2 promoter. GRHL3 induced a radioresistant phenotype in parental cells and led to compromised anti-tumor immune responses of CD4⁺ T cells and NK cells. The GRHL3-promoted tumor progression was reversed by the knockdown of RNF2. The DNA methylation of GRHL3 was reduced in radioresistant cells. All in all, as GRHL3, helps LUSC cells escape from the immune surveillance and mediates radioresistance, it might be an attractive target for therapy-resistant LUSC.

{"title":"GRHL3 drives radiotherapy resistance and blocks the anti-tumor response of NK and CD4+ T cells in lung squamous cell carcinoma via RNF2","authors":"Haijun Wang , Changjiang Liu , Chao Jiang , Yunjie Zhang , Xin Zhao , Zhongfei Jia , Jingchen Huo , Jie Yang","doi":"10.1016/j.bcp.2025.116784","DOIUrl":"10.1016/j.bcp.2025.116784","url":null,"abstract":"<div><div>Grainyhead-like protein 3 homolog (GRHL3) has been identified as a top transcription factor associated with keratinization in lung squamous cell carcinoma (LUSC). We designed this study to elucidate the function of GRHL3 in radioresistance in LUSC and the mechanism involved. Transcriptome differences between radioresistant and parental cells were analyzed to identify the hub transcription factor. GRHL3 expression was overexpressed in radioresistant cells relative to parental cells, and the knockdown of GRHL3 conferred sensitivity to radioresistant LUSC cells, induced DNA damage, inhibited cell survival, and reduced tumor load in mice. GRHL3 promoted ring finger protein 2 (RNF2) transcription by binding to the RNF2 promoter. GRHL3 induced a radioresistant phenotype in parental cells and led to compromised anti-tumor immune responses of CD4<sup>+</sup> T cells and NK cells. The GRHL3-promoted tumor progression was reversed by the knockdown of RNF2. The DNA methylation of GRHL3 was reduced in radioresistant cells. All in all, as GRHL3, helps LUSC cells escape from the immune surveillance and mediates radioresistance, it might be an attractive target for therapy-resistant LUSC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116784"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063549","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}

引用次数: 0

Acute myeloid leukemia with t(8;21) translocation: Molecular pathogenesis, potential therapeutics and future directions

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-27 DOI: 10.1016/j.bcp.2025.116774

Pei Han Yu , Ze Yan Zhang , Yuan Yuan Kang , Ping Huang , Chang Yang , Hua Naranmandura

Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive blood cancer. Genetic abnormalities, such as the t(8;21) rearrangement, play a significant role in AML onset. This rearrangement leads to the formation of the RUNX1/RUNX1T1 fusion protein, disrupting gene regulation and genomic stability, ultimately causing full-blown leukemia. Despite a generally favorable prognosis, t(8;21) patients face relapse and chemotherapy resistance, particularly when harboring cooperating mutations. While advances in cellular genetics and molecular biology have improved AML treatment, there are currently no specific targeted therapies against RUNX1/RUNX1T1. Therefore, investigating targeted therapies for this AML subtype holds promise for patients. This review explores the complex landscape of t(8;21) AML, unravels the molecular mechanisms of RUNX1/RUNX1T1-driven leukemogenesis, and discusses recent advancements in target therapies including small molecule drugs and PROTAC. Our goal is to develop more effective and less toxic strategies for managing t(8;21) AML patients.

{"title":"Acute myeloid leukemia with t(8;21) translocation: Molecular pathogenesis, potential therapeutics and future directions","authors":"Pei Han Yu , Ze Yan Zhang , Yuan Yuan Kang , Ping Huang , Chang Yang , Hua Naranmandura","doi":"10.1016/j.bcp.2025.116774","DOIUrl":"10.1016/j.bcp.2025.116774","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive blood cancer. Genetic abnormalities, such as the t(8;21) rearrangement, play a significant role in AML onset. This rearrangement leads to the formation of the RUNX1/RUNX1T1 fusion protein, disrupting gene regulation and genomic stability, ultimately causing full-blown leukemia. Despite a generally favorable prognosis, t(8;21) patients face relapse and chemotherapy resistance, particularly when harboring cooperating mutations. While advances in cellular genetics and molecular biology have improved AML treatment, there are currently no specific targeted therapies against RUNX1/RUNX1T1. Therefore, investigating targeted therapies for this AML subtype holds promise for patients. This review explores the complex landscape of t(8;21) AML, unravels the molecular mechanisms of RUNX1/RUNX1T1-driven leukemogenesis, and discusses recent advancements in target therapies including small molecule drugs and PROTAC. Our goal is to develop more effective and less toxic strategies for managing t(8;21) AML patients.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116774"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045483","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}

引用次数: 0

Spinal ADAM17 contributes to the pathogenesis of painful diabetic neuropathy in leptin receptor-deficient mice

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-27 DOI: 10.1016/j.bcp.2025.116780

Wataru Nemoto, Ryota Yamagata , Osamu Nakagawasai, Tomohiro Hoshi, Ruka Kobayashi, Mizuki Watanabe, Koichi Tan-No

The pathogenesis of painful diabetic neuropathy (PDN) is complicated and remains not fully understood. A disintegrin and metalloprotease 17 (ADAM17) is an enzyme that is responsible for the degradation of membrane proteins. ADAM17 is known to be activated under diabetes, but its involvement in PDN is ill defined. Thus, we studied the role of spinal ADAM17 in PDN. Leptin receptor-deficient db/db mice were used as a mouse model of type 2 diabetes. To inhibit ADAM17, we used DNA-modified siRNA against ADAM17 (siADAM17) or TAPI-1, an ADAM17 inhibitor. The number of ADAM17-positive neurons was increased in the spinal dorsal horn (lamina I-V) in db/db mice, while ADAM17-positive microglia were increased only in lamina I-II. Inhibition of spinal ADAM17 by siADAM17 or TAPI-1 significantly attenuated PDN observed in db/db mice. Among several substrates of ADAM17, angiotensin (Ang)-converting enzyme 2 (ACE2) expression was significantly decreased in the spinal plasma membrane of db/db mice. Intrathecal administration of Ang (1–7), a peptide generated by ACE2, to db/db mice produced an anti-hyperalgesic effect, which was abolished by the MAS1 receptor antagonist A779. Our findings reveal a critical role for spinal ADAM17 in the pathogenesis of PDN mediated by the degradation of ACE2, and suggest a novel pain control mechanism acting through the degradation of plasma membrane proteins in the cause of pathological pain.

{"title":"Spinal ADAM17 contributes to the pathogenesis of painful diabetic neuropathy in leptin receptor-deficient mice","authors":"Wataru Nemoto, Ryota Yamagata , Osamu Nakagawasai, Tomohiro Hoshi, Ruka Kobayashi, Mizuki Watanabe, Koichi Tan-No","doi":"10.1016/j.bcp.2025.116780","DOIUrl":"10.1016/j.bcp.2025.116780","url":null,"abstract":"<div><div>The pathogenesis of painful diabetic neuropathy (PDN) is complicated and remains not fully understood. A disintegrin and metalloprotease 17 (ADAM17) is an enzyme that is responsible for the degradation of membrane proteins. ADAM17 is known to be activated under diabetes, but its involvement in PDN is ill defined. Thus, we studied the role of spinal ADAM17 in PDN. Leptin receptor-deficient <em>db/db</em> mice were used as a mouse model of type 2 diabetes. To inhibit ADAM17, we used DNA-modified siRNA against ADAM17 (siADAM17) or TAPI-1, an ADAM17 inhibitor. The number of ADAM17-positive neurons was increased in the spinal dorsal horn (lamina I-V) in <em>db/db</em> mice, while ADAM17-positive microglia were increased only in lamina I-II. Inhibition of spinal ADAM17 by siADAM17 or TAPI-1 significantly attenuated PDN observed in <em>db/db</em> mice. Among several substrates of ADAM17, angiotensin (Ang)-converting enzyme 2 (ACE2) expression was significantly decreased in the spinal plasma membrane of <em>db/db</em> mice. Intrathecal administration of Ang (1–7), a peptide generated by ACE2, to <em>db/db</em> mice produced an anti-hyperalgesic effect, which was abolished by the MAS1 receptor antagonist A779. Our findings reveal a critical role for spinal ADAM17 in the pathogenesis of PDN mediated by the degradation of ACE2, and suggest a novel pain control mechanism acting through the degradation of plasma membrane proteins in the cause of pathological pain.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116780"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063551","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}

引用次数: 0

The novel use of the CFTR corrector C17 in muscular dystrophy: pharmacological profile and in vivo efficacy

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-24 DOI: 10.1016/j.bcp.2025.116779

Alberto Benetollo , Sofia Parrasia , Martina Scano , Lucia Biasutto , Andrea Rossa , Leonardo Nogara , Bert Blaauw , Francesco Dalla Barba , Paola Caccin , Marcello Carotti , Alessandro Parolin , Eylem Emek Akyürek , Roberta Sacchetto , Dorianna Sandonà

Sarcoglycanopathies are rare forms of severe muscular dystrophies currently without a therapy. Mutations in sarcoglycan (SG) genes cause the reduction or absence of the SG-complex, a tetramer located in the sarcolemma that plays a protective role during muscle contraction. Missense mutations in SGCA, which cause α-sarcoglycanopathy, otherwise known as LGMD2D/R3, lead to folding defective forms of α-SG that are discarded by the cell quality control. Recently, we demonstrated how a small molecule called C17, initially identified as a CFTR corrector, can be re-used to ameliorate the dystrophic phenotype of a mouse model of α-sarcoglycanopathy. Here, we have examined the pharmacological profile of C17 by performing ADME (absorption, distribution, metabolism, and elimination) studies. Our data show that C17 is well-distributed to relevant organs like heart and skeletal muscle, and likely metabolized in the small intestine into hydrophilic and hydrophobic derivatives. Elimination occurs through faeces (unmodified and modified C17) and urine (modified forms). Interestingly, we detected a quantifiable amount of C17 in treated muscles 48 h after an acute parenteral administration. This led to design a regimen of chronic treatment with a reduced dosing frequency. The result was the recovery of muscle strength, thanks to the rescue of the SG-complex, despite containing a mutated subunit, at the level of the sarcolemma. Thus, we can conclude that CFTR corrector C17 has a reasonable pharmacological profile and great potential to become a valuable therapeutic option for LGMD2D/R3 and other forms of muscular dystrophy caused by folding defective but potentially functional proteins.

{"title":"The novel use of the CFTR corrector C17 in muscular dystrophy: pharmacological profile and in vivo efficacy","authors":"Alberto Benetollo , Sofia Parrasia , Martina Scano , Lucia Biasutto , Andrea Rossa , Leonardo Nogara , Bert Blaauw , Francesco Dalla Barba , Paola Caccin , Marcello Carotti , Alessandro Parolin , Eylem Emek Akyürek , Roberta Sacchetto , Dorianna Sandonà","doi":"10.1016/j.bcp.2025.116779","DOIUrl":"10.1016/j.bcp.2025.116779","url":null,"abstract":"<div><div>Sarcoglycanopathies are rare forms of severe muscular dystrophies currently without a therapy. Mutations in sarcoglycan (SG) genes cause the reduction or absence of the SG-complex, a tetramer located in the sarcolemma that plays a protective role during muscle contraction. Missense mutations in <em>SGCA</em>, which cause α-sarcoglycanopathy, otherwise known as LGMD2D/R3, lead to folding defective forms of α-SG that are discarded by the cell quality control. Recently, we demonstrated how a small molecule called C17, initially identified as a CFTR corrector, can be re-used to ameliorate the dystrophic phenotype of a mouse model of α-sarcoglycanopathy. Here, we have examined the pharmacological profile of C17 by performing ADME (absorption, distribution, metabolism, and elimination) studies. Our data show that C17 is well-distributed to relevant organs like heart and skeletal muscle, and likely metabolized in the small intestine into hydrophilic and hydrophobic derivatives. Elimination occurs through faeces (unmodified and modified C17) and urine (modified forms). Interestingly, we detected a quantifiable amount of C17 in treated muscles 48 h after an acute parenteral administration. This led to design a regimen of chronic treatment with a reduced dosing frequency. The result was the recovery of muscle strength, thanks to the rescue of the SG-complex, despite containing a mutated subunit, at the level of the sarcolemma. Thus, we can conclude that CFTR corrector C17 has a reasonable pharmacological profile and great potential to become a valuable therapeutic option for LGMD2D/R3 and other forms of muscular dystrophy caused by folding defective but potentially functional proteins.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116779"},"PeriodicalIF":5.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An introduction to the special issue “9th International Conference on Relaxin and Related Peptides”

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-23 DOI: 10.1016/j.bcp.2025.116775

Robert G. Bennett, Sabine Hombach-Klonisch, Thomas Klonisch, Brian C. Wilson

引用次数: 0

The natural product micheliolide promotes the nuclear translocation of GAPDH via binding to Cys247 and induces glioblastoma cell death in combination with temozolomide.

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-23 DOI: 10.1016/j.bcp.2025.116759

Jian-Shuang Guo, Ji-Yan Wang, Sheng-Hua Chen, Yang-Ping Deng, Qian-Yu Gao, Zi-Xiao Liu, Ju Liu, Ke Lv, Ning Liu, Gui-Ying Bai, Chang-Liang Shan, Xue-Quan Feng, Jing Li, Yue Chen

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is significantly upregulated in glioblastoma (GBM) and plays a crucial role in cell apoptosis and drug resistance. Micheliolide (MCL) is a natural product with a variety of antitumour activities, and the fumarate salt form of dimethylamino MCL (DMAMCL; commercial name ACT001) has been tested in clinical trials for recurrent GBM; this compound suppresses the proliferation of GBM cells by rewiring aerobic glycolysis. Herein, we demonstrated that MCL directly targets GAPDH through covalent binding to the cysteine 247 (Cys247) residue. Intriguingly, MCL does not affect the enzyme activity of GAPDH but facilitates the nuclear translocation of the GAPDH/Siah1 (E3 ligase) complex. Furthermore, MCL/DMAMCL can exacerbate temozolomide (TMZ)-induced DNA damage. This treatment synergistically induced GBM cell death and suppressed tumour growth in a GBM xenograft mouse model. Collectively, our results reveal that MCL triggers non-glycolysis-related functions of GAPDH and that MCL promotes GBM cell death, especially when combined with TMZ, thus providing a novel strategy for clinical GBM treatment.

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引用次数: 0

The AHR-NRF2-JDP2 gene battery: Ligand-induced AHR transcriptional activation.

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-01-22 DOI: 10.1016/j.bcp.2025.116761

Kenly Wuputra, Wen-Hung Hsu, Chia-Chen Ku, Ya-Han Yang, Kung-Kai Kuo, Fang-Jung Yu, Hsin-Su Yu, Kyosuke Nagata, Deng-Chyang Wu, Chao-Hung Kuo, Kazunari K Yokoyama

Aryl hydrocarbon receptor (AHR) and nuclear factor-erythroid 2-related factor 2 (NRF2) can regulate a series of genes encoding the detoxifying phase I and II enzymes, via a signaling crosstalk known as the "AHR-NRF2 gene battery". The chromatin transcriptional regulator Jun dimerization protein 2 (JDP2) plays a central role in thetranscription of AHR gene in response to the phase I enzyme ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. It forms a transcriptional complex with AHR-AHR nuclear translocator (ARNT) and NRF2-small musculoaponeurotic fibrosarcoma proteins (sMAF), which are then recruited to the respective cis-elements, such as dioxin response elements and antioxidant response elements, respectively, in the AHR promoter. Here, we present a revised description of the AHR-NRF2 gene battery as the AHR-NRF2-JDP2 gene battery for transactivating the AHR promoter by phase I enzyme ligands. The chromatin regulator JDP2 was found to be involved in the movement of AHR-NRF2 complexes from the dioxin response element to the antioxidant response element in the AHR promoter, during its activation in a spatiotemporal manner. This new epigenetic and chromatin remodeling role of AHR-NRF2-JDP2 axis is useful for identifying new therapeutic targets for various diseases, including immunological response, detoxification, development, and cancer-related diseases.

{"title":"The AHR-NRF2-JDP2 gene battery: Ligand-induced AHR transcriptional activation.","authors":"Kenly Wuputra, Wen-Hung Hsu, Chia-Chen Ku, Ya-Han Yang, Kung-Kai Kuo, Fang-Jung Yu, Hsin-Su Yu, Kyosuke Nagata, Deng-Chyang Wu, Chao-Hung Kuo, Kazunari K Yokoyama","doi":"10.1016/j.bcp.2025.116761","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116761","url":null,"abstract":"<p><p>Aryl hydrocarbon receptor (AHR) and nuclear factor-erythroid 2-related factor 2 (NRF2) can regulate a series of genes encoding the detoxifying phase I and II enzymes, via a signaling crosstalk known as the \"AHR-NRF2 gene battery\". The chromatin transcriptional regulator Jun dimerization protein 2 (JDP2) plays a central role in thetranscription of AHR gene in response to the phase I enzyme ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. It forms a transcriptional complex with AHR-AHR nuclear translocator (ARNT) and NRF2-small musculoaponeurotic fibrosarcoma proteins (sMAF), which are then recruited to the respective cis-elements, such as dioxin response elements and antioxidant response elements, respectively, in the AHR promoter. Here, we present a revised description of the AHR-NRF2 gene battery as the AHR-NRF2-JDP2 gene battery for transactivating the AHR promoter by phase I enzyme ligands. The chromatin regulator JDP2 was found to be involved in the movement of AHR-NRF2 complexes from the dioxin response element to the antioxidant response element in the AHR promoter, during its activation in a spatiotemporal manner. This new epigenetic and chromatin remodeling role of AHR-NRF2-JDP2 axis is useful for identifying new therapeutic targets for various diseases, including immunological response, detoxification, development, and cancer-related diseases.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116761"},"PeriodicalIF":5.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036280","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}

引用次数: 0

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