Pub Date : 2024-09-19DOI: 10.1016/j.bcp.2024.116547
Wenqin Yu , Yuzhen Lv , Ruirui Xuan , Peipei Han , Haihuan Xu , Xiaowei Ma
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are accompanied by high mortality rates and few effective treatments. Transplantation of human placental mesenchymal stem cells (hPMSCs) may attenuate ALI and the mechanism is still unclear. Our study aimed to elucidate the potential protective effect and therapeutic mechanism of hPMSCs against lipopolysaccharide (LPS)-induced ALI, An ALI model was induced by tracheal instillation of LPS into wild-type (WT) and angiotensin-converting enzyme 2 (ACE2) knockout (KO) male mice, followed by injection of hPMSCs by tail vein. Treatment with hPMSCs improved pulmonary histopathological injury, reduced pulmonary injury scores, decreased leukocyte count and protein levels in bronchoalveolar lavage fluid(BALF), protected the damaged alveolar epithelial barrier, and reversed LPS-induced upregulation of pro-inflammatory factors Interleukin-6 (IL-6) and Tumor necrosis factor-α(TNF-α) and downregulation of anti-inflammatory factor Interleukin-6(IL-10) in BALF. Moreover, administration of hPMSCs inhibited Angiotensin (Ang)II activation and promoted the expression levels of ACE2 and Ang (1–7) in ALI mice. Pathological damage, inflammation levels, and disruption of alveolar epithelial barrier in ALI mice were elevated after the deletion of ACE2 gene, and the Renin angiotensin system (RAS) imbalance was exacerbated. The therapeutic effect of hPMSCs was significantly reduced in ACE2 KO mice. Our findings suggest that ACE2 plays a key role in hPMSCs repairing the alveolar epithelial barrier to protect against ALI, laying a new foundation for the clinical treatment of ALI.
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的死亡率很高，而有效的治疗方法却很少。移植人胎盘间充质干细胞（hPMSCs）可减轻急性肺损伤，但其机制尚不清楚。我们的研究旨在阐明人胎盘间充质干细胞（hPMSCs）对脂多糖（LPS）诱导的ALI的潜在保护作用和治疗机制。使用 hPMSCs 治疗可改善肺组织病理学损伤，降低肺损伤评分，减少支气管肺泡灌洗液（BALF）中的白细胞数量和蛋白质水平，保护受损的肺泡上皮屏障、并逆转了 LPS 诱导的白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）在 BALF 中的上调，以及抗炎因子白细胞介素-6（IL-10）的下调。此外，给 ALI 小鼠注射 hPMSCs 可抑制血管紧张素（Ang）II 的激活，促进 ACE2 和 Ang (1-7) 的表达水平。ACE2基因缺失后，ALI小鼠的病理损伤、炎症水平和肺泡上皮屏障破坏程度升高，肾素血管紧张素系统（RAS）失衡加剧。在 ACE2 KO 小鼠中，hPMSCs 的治疗效果明显降低。我们的研究结果表明，ACE2 在 hPMSCs 修复肺泡上皮屏障以防止 ALI 中发挥了关键作用，为 ALI 的临床治疗奠定了新的基础。
{"title":"Human placental mesenchymal stem cells transplantation repairs the alveolar epithelial barrier to alleviate lipopolysaccharides-induced acute lung injury","authors":"Wenqin Yu , Yuzhen Lv , Ruirui Xuan , Peipei Han , Haihuan Xu , Xiaowei Ma","doi":"10.1016/j.bcp.2024.116547","DOIUrl":"10.1016/j.bcp.2024.116547","url":null,"abstract":"<div><div>Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are accompanied by high mortality rates and few effective treatments. Transplantation of human placental mesenchymal stem cells (hPMSCs) may attenuate ALI and the mechanism is still unclear. Our study aimed to elucidate the potential protective effect and therapeutic mechanism of hPMSCs against lipopolysaccharide (LPS)-induced ALI, An ALI model was induced by tracheal instillation of LPS into wild-type (WT) and angiotensin-converting enzyme 2 (ACE2) knockout (KO) male mice, followed by injection of hPMSCs by tail vein. Treatment with hPMSCs improved pulmonary histopathological injury, reduced pulmonary injury scores, decreased leukocyte count and protein levels in bronchoalveolar lavage fluid(BALF), protected the damaged alveolar epithelial barrier, and reversed LPS-induced upregulation of pro-inflammatory factors Interleukin-6 (IL-6) and Tumor necrosis factor-α(TNF-α) and downregulation of anti-inflammatory factor Interleukin-6(IL-10) in BALF. Moreover, administration of hPMSCs inhibited Angiotensin (Ang)II activation and promoted the expression levels of ACE2 and Ang (1–7) in ALI mice. Pathological damage, inflammation levels, and disruption of alveolar epithelial barrier in ALI mice were elevated after the deletion of ACE2 gene, and the Renin angiotensin system (RAS) imbalance was exacerbated. The therapeutic effect of hPMSCs was significantly reduced in ACE2 KO mice. Our findings suggest that ACE2 plays a key role in hPMSCs repairing the alveolar epithelial barrier to protect against ALI, laying a new foundation for the clinical treatment of ALI.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116547"},"PeriodicalIF":5.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279982","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}
Rosiglitazone, a full PPARγ agonist and a classical insulin sensitizer, was once used as a powerful weapon in the treatment of T2DM. However, its applications have been restricted recently because of its multiple side effects. Here, a natural compound, flavokawain B (FKB), which was screened in our previous experiments, was investigated for its potential as a preferable insulin sensitizer because it has no or few side effects. Using the surface plasmon resonance (SPR) technique, we confirmed that FKB is a natural ligand for PPARγ with high binding affinity. In in vitro experiments, FKB significantly increased 2-NBDG uptake in HepG2 and 3T3-L1 cells, which partially stimulated PPARγ transcriptional activity. Compared with rosiglitazone, FKB had little effect on the adipose differentiation of 3T3-L1 cells, and all of these features suggest that FKB is a selective modulator of PPARγ (SPPARγM). Moreover, FKB increased the mRNA expression levels of most genes related to insulin sensitivity and glucose metabolism but had no obvious effect on those related to adipose differentiation. In vivo experiments confirmed that FKB effectively decreased abnormal fasting blood glucose and postprandial blood glucose levels and reduced glycated hemoglobin levels, similar to rosiglitazone, in HFD-fed/STZ-treated and db/db mice, two T2DM animal models, but did not cause side effects, such as weight gain or liver or kidney damage. Further investigation revealed that FKB could inhibit PPARγ-Ser273 phosphorylation, which is the key mechanism involved in improving insulin resistance. Together, FKB is a well-performing SPPARγM that exerts a powerful glucose-lowering effect without causing the same side effects as rosiglitazone, and it may have great potential for development.
{"title":"Flavokawain B is an effective natural peroxisome proliferator-activated receptor γ-selective agonist with a strong glucose-lowering effect","authors":"Qixin Wu, Yue Jiao, Jingzhe Li, Yanyan Ma, Jingyi Wang, Mingzhu Luo, Yiting Wang, Xinrong Fan, Changzhen Liu","doi":"10.1016/j.bcp.2024.116548","DOIUrl":"10.1016/j.bcp.2024.116548","url":null,"abstract":"<div><div>Rosiglitazone, a full PPARγ agonist and a classical insulin sensitizer, was once used as a powerful weapon in the treatment of T2DM. However, its applications have been restricted recently because of its multiple side effects. Here, a natural compound, flavokawain B (FKB), which was screened in our previous experiments, was investigated for its potential as a preferable insulin sensitizer because it has no or few side effects. Using the surface plasmon resonance (SPR) technique, we confirmed that FKB is a natural ligand for PPARγ with high binding affinity. In <em>in vitro</em> experiments, FKB significantly increased 2-NBDG uptake in HepG2 and 3T3-L1 cells, which partially stimulated PPARγ transcriptional activity. Compared with rosiglitazone, FKB had little effect on the adipose differentiation of 3T3-L1 cells, and all of these features suggest that FKB is a selective modulator of PPARγ (SPPARγM). Moreover, FKB increased the mRNA expression levels of most genes related to insulin sensitivity and glucose metabolism but had no obvious effect on those related to adipose differentiation. <em>In vivo</em> experiments confirmed that FKB effectively decreased abnormal fasting blood glucose and postprandial blood glucose levels and reduced glycated hemoglobin levels, similar to rosiglitazone, in HFD-fed/STZ-treated and db/db mice, two T2DM animal models, but did not cause side effects, such as weight gain or liver or kidney damage. Further investigation revealed that FKB could inhibit PPARγ-Ser273 phosphorylation, which is the key mechanism involved in improving insulin resistance. Together, FKB is a well-performing SPPARγM that exerts a powerful glucose-lowering effect without causing the same side effects as rosiglitazone, and it may have great potential for development.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116548"},"PeriodicalIF":5.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279988","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 : 2024-09-18DOI: 10.1016/j.bcp.2024.116546
Ziyu Yang , Tao Sun , Pengli Wang , Lina Bai , Ye Wu , Tongtong Wang , Xiaoyan Li , Yutong Cheng , Suli Zhang , Huirong Liu
Recently, the identification of autoantibodies (AT1-AA) targeting the second extracellular loop of angiotensin II type 1 receptor (AT1R-ECII) in patients with coronary heart disease (CHD) offers a novel perspective on the interplay between immunity and cardiovascular disease. However, much remains unknown regarding the functional diversity of AT1-AA. In this study, we measured the levels of AT1-AA in the sera of 306 CHD patients and purified AT1-AA from patient’s sera (n = 127). The subclasses of AT1-AA were categorized based on their impact on intracellular calcium ([Ca2+]i) levels in mouse arterial smooth muscle cells (MASMCs). Our findings revealed 4 distinct [Ca2+]i response patterns indicating the existence of 4 functional subclasses named H1-, H2-, H3-, and H4-AT1-AA. The correlation analysis demonstrated a positive association between H1-AT1-AA and endogenous coagulation, as well as between H2-AT1-AA and exogenous coagulation; no significant correlation was observed between H3-AT1-AA and the indicators we analyzed. Conversely, H4-AT1-AA exhibited a negative correlation with both leukocyte number and bile acid levels. Logistic regression analysis showed that H2-AT1-AA possessed predictive value for severe CHD. Furthermore, in vitro experiments indicated that both H1- and H2-AT1-AA exerted cytotoxic effects on MASMCs, while H4-AT1-AA increased cell viability. Additionally, an AT1-AA-positive rat model was established by subcutaneously injecting with AT1R-ECII peptide, which produced four similar functional subclasses of rat AT1-AA upon active immunization. This study suggested that classifying different functional subclasses of AT1-AAs can facilitate more accurate evaluation of the condition and prognosis in patients with CHD, thereby providing a novel basis for clinical diagnosis and treatment.
{"title":"The functional subclasses of AT1 receptor autoantibody in patients with coronary heart disease","authors":"Ziyu Yang , Tao Sun , Pengli Wang , Lina Bai , Ye Wu , Tongtong Wang , Xiaoyan Li , Yutong Cheng , Suli Zhang , Huirong Liu","doi":"10.1016/j.bcp.2024.116546","DOIUrl":"10.1016/j.bcp.2024.116546","url":null,"abstract":"<div><p>Recently, the identification of autoantibodies (AT1-AA) targeting the second extracellular loop of angiotensin II type 1 receptor (AT1R-ECII) in patients with coronary heart disease (CHD) offers a novel perspective on the interplay between immunity and cardiovascular disease. However, much remains unknown regarding the functional diversity of AT1-AA. In this study, we measured the levels of AT1-AA in the sera of 306 CHD patients and purified AT1-AA from patient’s sera (n = 127). The subclasses of AT1-AA were categorized based on their impact on intracellular calcium ([Ca<sup>2+</sup>]<sub>i</sub>) levels in mouse arterial smooth muscle cells (MASMCs). Our findings revealed 4 distinct [Ca<sup>2+</sup>]<sub>i</sub> response patterns indicating the existence of 4 functional subclasses named H1-, H2-, H3-, and H4-AT1-AA. The correlation analysis demonstrated a positive association between H1-AT1-AA and endogenous coagulation, as well as between H2-AT1-AA and exogenous coagulation; no significant correlation was observed between H3-AT1-AA and the indicators we analyzed. Conversely, H4-AT1-AA exhibited a negative correlation with both leukocyte number and bile acid levels. Logistic regression analysis showed that H2-AT1-AA possessed predictive value for severe CHD. Furthermore, <em>in vitro</em> experiments indicated that both H1- and H2-AT1-AA exerted cytotoxic effects on MASMCs, while H4-AT1-AA increased cell viability. Additionally, an AT1-AA-positive rat model was established by subcutaneously injecting with AT1R-ECII peptide, which produced four similar functional subclasses of rat AT1-AA upon active immunization. This study suggested that classifying different functional subclasses of AT1-AAs can facilitate more accurate evaluation of the condition and prognosis in patients with CHD, thereby providing a novel basis for clinical diagnosis and treatment.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116546"},"PeriodicalIF":5.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S000629522400546X/pdfft?md5=e6d0c89b13fb97544107aacc2703f6b1&pid=1-s2.0-S000629522400546X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272006","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}
Pub Date : 2024-09-16DOI: 10.1016/j.bcp.2024.116544
Chiara Sfogliarini , Lien Hong Tran , Candida Maria Cesta , Marcello Allegretti , Massimo Locati , Elisabetta Vegeto
Beyond their clinical use as selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen have attracted recent attention for their favorable activity against a broad range of dangerous human pathogens. While consistently demonstrated to occur independently on classic estrogen receptors, the mechanisms underlying SERMs antimicrobial efficacy remain still poorly elucidated, but fundamental to benefit from repurposing strategies of these drugs. Macrophages are innate immune cells that protect from infections by rapidly reprogramming their metabolic state, particularly cholesterol disposal, which is at the center of an appropriate macrophage immune response as well as of the anabolic requirements of both the pathogen and the host cells. The microsomal antiestrogen binding site (AEBS) comprises enzymes involved in the last stages of cholesterol biosynthesis and is a high affinity off-target site for SERMs. We review here recent findings from our laboratory and other research groups in support of the hypothesis that AEBS multiprotein complex represents the candidate pre-genomic target of SERMs immunomodulatory activity. The cholesterol restriction resulting from SERMs-mediated AEBS inhibition may be responsible for boosting inflammatory and antimicrobial pathways that include inflammasome activation, modulation of Toll-like receptors (TLRs) responses, induction of interferon regulatory factor (IRF3) and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcriptional programs and, noteworthy, the mitigation of excessive inflammatory and proliferative responses, leading to the overall potentiation of the macrophage response to infections.
{"title":"AEBS inhibition in macrophages: Augmenting reality for SERMs repurposing against infections","authors":"Chiara Sfogliarini , Lien Hong Tran , Candida Maria Cesta , Marcello Allegretti , Massimo Locati , Elisabetta Vegeto","doi":"10.1016/j.bcp.2024.116544","DOIUrl":"10.1016/j.bcp.2024.116544","url":null,"abstract":"<div><p>Beyond their clinical use as selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen have attracted recent attention for their favorable activity against a broad range of dangerous human pathogens. While consistently demonstrated to occur independently on classic estrogen receptors, the mechanisms underlying SERMs antimicrobial efficacy remain still poorly elucidated, but fundamental to benefit from repurposing strategies of these drugs. Macrophages are innate immune cells that protect from infections by rapidly reprogramming their metabolic state, particularly cholesterol disposal, which is at the center of an appropriate macrophage immune response as well as of the anabolic requirements of both the pathogen and the host cells. The microsomal antiestrogen binding site (AEBS) comprises enzymes involved in the last stages of cholesterol biosynthesis and is a high affinity off-target site for SERMs. We review here recent findings from our laboratory and other research groups in support of the hypothesis that AEBS multiprotein complex represents the candidate pre-genomic target of SERMs immunomodulatory activity. The cholesterol restriction resulting from SERMs-mediated AEBS inhibition may be responsible for boosting inflammatory and antimicrobial pathways that include inflammasome activation, modulation of Toll-like receptors (TLRs) responses, induction of interferon regulatory factor (IRF3) and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcriptional programs and, noteworthy, the mitigation of excessive inflammatory and proliferative responses, leading to the overall potentiation of the macrophage response to infections.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116544"},"PeriodicalIF":5.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224005446/pdfft?md5=8425ce9b6c0edadc03a58455e229d33c&pid=1-s2.0-S0006295224005446-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272112","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}
Pub Date : 2024-09-16DOI: 10.1016/j.bcp.2024.116545
Koushik Sen , Sanjib Kumar Das , Nabanita Ghosh , Krishnendu Sinha , Parames C. Sil
Lupeol, a triterpene derived from various plants, has emerged as a potent dietary supplement with extensive therapeutic potential. This review offers a comprehensive examination of lupeol’s applications across diverse health conditions. By meticulously analyzing current scientific literature, we have synthesized findings that underscore lupeol’s impact on cancer, diabetes, gastrointestinal disorders, neurological diseases, dermatological conditions, nephrological issues, and cardiovascular health. The review delves into molecular studies that reveal lupeol’s ability to modulate disease pathways and alleviate symptoms, positioning it as a promising therapeutic agent. Moreover, we discuss the potential role of lupeol in clinical practice and public health strategies, emphasizing its substantial benefits as a natural compound. This thorough analysis serves as a critical resource for researchers, providing insights into the multifaceted therapeutic properties of lupeol and its potential to significantly enhance health outcomes.
{"title":"Lupeol: A dietary and medicinal triterpene with therapeutic potential","authors":"Koushik Sen , Sanjib Kumar Das , Nabanita Ghosh , Krishnendu Sinha , Parames C. Sil","doi":"10.1016/j.bcp.2024.116545","DOIUrl":"10.1016/j.bcp.2024.116545","url":null,"abstract":"<div><div>Lupeol, a triterpene derived from various plants, has emerged as a potent dietary supplement with extensive therapeutic potential. This review offers a comprehensive examination of lupeol’s applications across diverse health conditions. By meticulously analyzing current scientific literature, we have synthesized findings that underscore lupeol’s impact on cancer, diabetes, gastrointestinal disorders, neurological diseases, dermatological conditions, nephrological issues, and cardiovascular health. The review delves into molecular studies that reveal lupeol’s ability to modulate disease pathways and alleviate symptoms, positioning it as a promising therapeutic agent. Moreover, we discuss the potential role of lupeol in clinical practice and public health strategies, emphasizing its substantial benefits as a natural compound. This thorough analysis serves as a critical resource for researchers, providing insights into the multifaceted therapeutic properties of lupeol and its potential to significantly enhance health outcomes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116545"},"PeriodicalIF":5.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279984","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}
An uncontrolled activity of neutrophil serine proteases (NSPs) contributes to inflammatory diseases. Cathepsin C (CatC) is known to activate NSPs during neutrophilic differentiation and represents a promising pharmacological target in NSP-mediated diseases. In humans, Papillon-Lefèvre syndrome (PLS) patients have mutations in their CTSC gene, resulting in the complete absence of CatC activity. Despite this, low residual NSP activities are detected in PLS neutrophils (<10% vs healthy individuals), suggesting the involvement of CatC-independent proteolytic pathway(s) in the activation of proNSPs. This prompted us to characterize CatC-independent NSP activation pathways by blocking proCatC maturation. In this study, we show that inhibition of intracellular CatS almost completely blocked CatC maturation in human promyeloid HL-60 cells. Despite this, NSP activation was not significantly reduced, confirming the presence of a CatC-independent activation pathway involving a CatC-like protease that we termed NSPs-AAP-1. Similarly, when human CD34+ progenitor cells were treated with CatS inhibitors during neutrophilic differentiation in vitro, CatC activity was nearly abrogated but ∼30% NSP activities remained, further supporting the existence of NSPs-AAP-1. Our data indicate that NSPs-AAP-1 is a cysteine protease that is inhibited by reversible nitrile compounds designed for CatC inhibition. We further established a proof of concept for the indirect, although incomplete, inhibition of NSPs by pharmacological targeting of CatC maturation using CatS inhibitors. This emphasizes the potential of CatS as a therapeutic target for inflammatory diseases. Thus, preventing proNSP maturation using a CatS inhibitor, alone or in combination with a CatC/NSPs-AAP-1 inhibitor, represents a promising approach to efficiently control the extent of tissue injury in neutrophil-mediated inflammatory diseases.
{"title":"Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)","authors":"Roxane Domain , Seda Seren , Uwe Jerke , Manousos Makridakis , Kuan-Ju Chen , Jérôme Zoidakis , Moez Rhimi , Xian Zhang , Tillia Bonvent , Cécile Croix , Loïc Gonzalez , Dedong Li , Jessica Basso , Christophe Paget , Marie-Claude Viaud-Massuard , Gilles Lalmanach , Guo-Ping Shi , Ali Aghdassi , Antonia Vlahou , Patrick P. McDonald , Brice Korkmaz","doi":"10.1016/j.bcp.2024.116114","DOIUrl":"10.1016/j.bcp.2024.116114","url":null,"abstract":"<div><div>An uncontrolled activity of neutrophil serine proteases (NSPs) contributes to inflammatory diseases. Cathepsin C (CatC) is known to activate NSPs during neutrophilic differentiation and represents a promising pharmacological target in NSP-mediated diseases. In humans, Papillon-Lefèvre syndrome (PLS) patients have mutations in their<!--> <em>CTSC</em> gene, resulting in the complete absence of CatC activity. Despite this, low residual NSP activities are detected in PLS neutrophils (<10% vs healthy individuals)<em>,</em> suggesting the involvement of CatC-independent proteolytic pathway(s) in the activation of proNSPs. This prompted us to characterize CatC-independent NSP activation pathways by blocking proCatC maturation. In this study, we show that inhibition of intracellular CatS almost completely blocked CatC maturation in human promyeloid HL-60 cells. Despite this, NSP activation was not significantly reduced, confirming the presence of a CatC-independent activation pathway involving a CatC-like protease that we termed NSPs-AAP-1. Similarly, when human CD34<sup>+</sup> progenitor cells were treated with CatS inhibitors during neutrophilic differentiation <em>in vitro</em>, CatC activity was nearly abrogated but ∼30% NSP activities remained, further supporting the existence of NSPs-AAP-1. Our data indicate that NSPs-AAP-1 is a cysteine protease that is inhibited by reversible nitrile compounds designed for CatC inhibition. We further established a proof of concept for the indirect, although incomplete, inhibition of NSPs by pharmacological targeting of CatC maturation using CatS inhibitors. This emphasizes the potential of CatS as a therapeutic target for inflammatory diseases. Thus, preventing proNSP maturation using a CatS inhibitor, alone or in combination with a CatC/NSPs-AAP-1 inhibitor, represents a promising approach to efficiently control the extent of tissue injury in neutrophil-mediated inflammatory diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116114"},"PeriodicalIF":5.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493926","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}
Pub Date : 2024-09-14DOI: 10.1016/j.bcp.2024.116542
Xiaoyi Zhang , Yachuan Tao , Zhongli Xu , Biao Jiang , Xiaobao Yang , Taomin Huang , Wenfu Tan
The overexpression of BCL-xL is closely associated with poor prognosis in hepatocellular carcinoma (HCC). While the strategy of combination of BCL-xL and MCL-1 for treating solid tumors has been reported, it presents significant hepatotoxicity. SIAIS361034, a novel proteolysis targeting chimera (PROTAC) agent, selectively induces the ubiquitination and subsequent proteasomal degradation of BCL-xL through the CRBN-E3 ubiquitin ligase. When combined with sorafenib, SIAIS361034 showed a potent synergistic effect in inhibiting hepatocellular carcinoma development both in vitro and in vivo. Since SIAIS361034 exhibits a high degree of selectivity for degrading BCL-xL in hepatocellular carcinoma, the hepatotoxicity typically associated with the combined inhibition of BCL-xL and MCL-1 is significantly reduced, thereby greatly enhancing safety. Mechanistically, BCL-xL and MCL-1 sequester the BH3-only protein BIM on mitochondria at baseline. Treatment with SIAIS361034 and sorafenib destabilizes BIM/BCL-xL and BIM/MCL1 association, resulting in the liberation of more BIM proteins to trigger apoptosis. Additionally, we discovered a novel compensatory regulation mechanism in hepatocellular carcinoma cells. BIM can rapidly respond to changes in the balance between BCL-xL and MCL-1 through their co-transcription factor MEF2C to maintain apoptosis resistance. In summary, the combination therapy of SIAIS361034 and sorafenib represents an effective and safe approach for inhibiting hepatocellular carcinoma progression. The novel balancing mechanism may also provide insights for combination and precision therapies in the treatment of hepatocellular carcinoma.
{"title":"Sorafenib and SIAIS361034, a novel PROTAC degrader of BCL-xL, display synergistic antitumor effects on hepatocellular carcinoma with minimal hepatotoxicity","authors":"Xiaoyi Zhang , Yachuan Tao , Zhongli Xu , Biao Jiang , Xiaobao Yang , Taomin Huang , Wenfu Tan","doi":"10.1016/j.bcp.2024.116542","DOIUrl":"10.1016/j.bcp.2024.116542","url":null,"abstract":"<div><div>The overexpression of BCL-x<sub>L</sub> is closely associated with poor prognosis in hepatocellular carcinoma (HCC). While the strategy of combination of BCL-x<sub>L</sub> and MCL-1 for treating solid tumors has been reported, it presents significant hepatotoxicity. SIAIS361034, a novel proteolysis targeting chimera (PROTAC) agent, selectively induces the ubiquitination and subsequent proteasomal degradation of BCL-x<sub>L</sub> through the CRBN-E3 ubiquitin ligase. When combined with sorafenib, SIAIS361034 showed a potent synergistic effect in inhibiting hepatocellular carcinoma development both in vitro and in vivo. Since SIAIS361034 exhibits a high degree of selectivity for degrading BCL-x<sub>L</sub> in hepatocellular carcinoma, the hepatotoxicity typically associated with the combined inhibition of BCL-x<sub>L</sub> and MCL-1 is significantly reduced, thereby greatly enhancing safety. Mechanistically, BCL-x<sub>L</sub> and MCL-1 sequester the BH3-only protein BIM on mitochondria at baseline. Treatment with SIAIS361034 and sorafenib destabilizes BIM/BCL-x<sub>L</sub> and BIM/MCL1 association, resulting in the liberation of more BIM proteins to trigger apoptosis. Additionally, we discovered a novel compensatory regulation mechanism in hepatocellular carcinoma cells. BIM can rapidly respond to changes in the balance between BCL-x<sub>L</sub> and MCL-1 through their co-transcription factor MEF2C to maintain apoptosis resistance. In summary, the combination therapy of SIAIS361034 and sorafenib represents an effective and safe approach for inhibiting hepatocellular carcinoma progression. The novel balancing mechanism may also provide insights for combination and precision therapies in the treatment of hepatocellular carcinoma.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116542"},"PeriodicalIF":5.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279987","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 : 2024-09-14DOI: 10.1016/j.bcp.2024.116541
Kun Wang , Yang Zhou , Cong Wen , Linqin Du , Lan Li , Yangyang Cui , Hao Luo , Yanxu Liu , Lang Zeng , Shikang Li , Lijuan Xiong , Rongchuan Yue
Tetramethylpyrazine (TMP) belongs to the active ingredients of the traditional Chinese medicine Chuanxiong, which has a certain protective effect in myocardial ischemia–reperfusion (I/R) injury. It can improve postoperative cardiac function and alleviate ventricular remodeling in acute myocardial infarction patients. However, its specific protective mechanism is still unclear. In this study, a certain concentration of TMP was introduced into I/R mice or H9C2 cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment to observe the effects of TMP on cardiomyocyte activity, cytotoxicity, apoptosis, autophagy, pyroptosis, and NLRP3 inflammasome activation. The results displayed that TMP intervention could reduce OGD/R and I/R-induced cardiomyocyte apoptosis, accelerate cellular activity and autophagy levels, and ameliorate myocardial tissue necrosis in I/R mice in a dose-dependent manner. Further, TMP prevented the formation of NLRP3 inflammasomes to suppress pyroptosis by increasing the level of cardiomyocyte autophagy after I/R and OGD/R modelling, the introduction of chloroquine to suppress autophagic activity in vivo and in vitro was further analyzed to confirm whether TMP inhibits NLRP3 inflammasome activation and pyroptosis by increasing autophagy, and we found the inhibitory effect of TMP on NLRP3 inflammasomes and its protective effect against myocardial injury were blocked when autophagy was inhibited with chloroquine. In conclusion, this experiment demonstrated that TMP unusually attenuated I/R injury in mice, and this protective effect was achieved by inhibiting the activation of NLRP3 inflammasomes through enhancing autophagic activity.
{"title":"Protective effects of tetramethylpyrazine on myocardial ischemia/reperfusion injury involve NLRP3 inflammasome suppression by autophagy activation","authors":"Kun Wang , Yang Zhou , Cong Wen , Linqin Du , Lan Li , Yangyang Cui , Hao Luo , Yanxu Liu , Lang Zeng , Shikang Li , Lijuan Xiong , Rongchuan Yue","doi":"10.1016/j.bcp.2024.116541","DOIUrl":"10.1016/j.bcp.2024.116541","url":null,"abstract":"<div><p>Tetramethylpyrazine (TMP) belongs to the active ingredients of the traditional Chinese medicine Chuanxiong, which has a certain protective effect in myocardial ischemia–reperfusion (I/R) injury. It can improve postoperative cardiac function and alleviate ventricular remodeling in acute myocardial infarction patients. However, its specific protective mechanism is still unclear. In this study, a certain concentration of TMP was introduced into I/R mice or H9C2 cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment to observe the effects of TMP on cardiomyocyte activity, cytotoxicity, apoptosis, autophagy, pyroptosis, and NLRP3 inflammasome activation. The results displayed that TMP intervention could reduce OGD/R and I/R-induced cardiomyocyte apoptosis, accelerate cellular activity and autophagy levels, and ameliorate myocardial tissue necrosis in I/R mice in a dose-dependent manner. Further, TMP prevented the formation of NLRP3 inflammasomes to suppress pyroptosis by increasing the level of cardiomyocyte autophagy after I/R and OGD/R modelling, the introduction of chloroquine to suppress autophagic activity <em>in vivo</em> and <em>in vitro</em> was further analyzed to confirm whether TMP inhibits NLRP3 inflammasome activation and pyroptosis by increasing autophagy, and we found the inhibitory effect of TMP on NLRP3 inflammasomes and its protective effect against myocardial injury were blocked when autophagy was inhibited with chloroquine. In conclusion, this experiment demonstrated that TMP unusually attenuated I/R injury in mice, and this protective effect was achieved by inhibiting the activation of NLRP3 inflammasomes through enhancing autophagic activity.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116541"},"PeriodicalIF":5.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243323","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 : 2024-09-13DOI: 10.1016/j.bcp.2024.116533
Tzu-Hsiung Huang , Chieh-Mo Lin , Chin-Kuo Lin , Shun-Fu Chang , Chung-Sheng Shi
Ventilator-induced lung injury is a serious complication in mechanically ventilated patients. Neddylation, the post-translational modification of neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) conjugation, regulates numerous biological functions. However, its involvement and therapeutic significance in ventilator-induced lung injury remains unknown. Therefore, this study aimed to examine the kinetics and contribution of activated neddylation and the impact of neddylation inhibition in mice subjected to high tidal volume (HTV) ventilation in vivo and human pulmonary alveolar epithelial cells stimulated through cyclic stretching (CS) in vitro. The neddylation and expression of ubiquitin conjugating enzyme 3 (UBA3), a NEDD8-activating enzyme (NAE) catalytic subunit, were time-dependently upregulated in HTV-ventilated mice. Additionally, the NAE inhibitor MLN4924 considerably attenuated acute lung injury induced by HTV ventilation, manifesting as reduced inflammation and oxidative stress. Furthermore, MLN4924 effectively reduced the secretion of inflammatory cytokines from Ly6Chigh monocytes and neutrophils, subsequently decreasing endothelial permeability. Moreover, our study revealed an upregulation of the neddylation pathway, oxidative stress, and apoptosis during CS of alveolar epithelial cells. However, blockade of neddylation via MLN4924 or through UBA3 knockdown suppressed this upregulation. Overall, the inhibition of neddylation may alleviate HTV-induced acute lung injury by preventing CS-induced damage to alveolar epithelial cells. This indicates that the neddylation pathway plays a critical role in the progression of ventilator-induced lung injury. These findings may provide a new therapeutic target for treating ventilator-induced lung injury.
{"title":"The blockade of neddylation alleviates ventilator-induced lung injury by reducing stretch-induced damage to pulmonary epithelial cells","authors":"Tzu-Hsiung Huang , Chieh-Mo Lin , Chin-Kuo Lin , Shun-Fu Chang , Chung-Sheng Shi","doi":"10.1016/j.bcp.2024.116533","DOIUrl":"10.1016/j.bcp.2024.116533","url":null,"abstract":"<div><p>Ventilator-induced lung injury is a serious complication in mechanically ventilated patients. Neddylation, the post-translational modification of neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) conjugation, regulates numerous biological functions. However, its involvement and therapeutic significance in ventilator-induced lung injury remains unknown. Therefore, this study aimed to examine the kinetics and contribution of activated neddylation and the impact of neddylation inhibition in mice subjected to high tidal volume (HTV) ventilation in vivo and human pulmonary alveolar epithelial cells stimulated through cyclic stretching (CS) in vitro. The neddylation and expression of ubiquitin conjugating enzyme 3 (UBA3), a NEDD8-activating enzyme (NAE) catalytic subunit, were time-dependently upregulated in HTV-ventilated mice. Additionally, the NAE inhibitor MLN4924 considerably attenuated acute lung injury induced by HTV ventilation, manifesting as reduced inflammation and oxidative stress. Furthermore, MLN4924 effectively reduced the secretion of inflammatory cytokines from Ly6C<sup>high</sup> monocytes and neutrophils, subsequently decreasing endothelial permeability. Moreover, our study revealed an upregulation of the neddylation pathway, oxidative stress, and apoptosis during CS of alveolar epithelial cells. However, blockade of neddylation via MLN4924 or through UBA3 knockdown suppressed this upregulation. Overall, the inhibition of neddylation may alleviate HTV-induced acute lung injury by preventing CS-induced damage to alveolar epithelial cells. This indicates that the neddylation pathway plays a critical role in the progression of ventilator-induced lung injury. These findings may provide a new therapeutic target for treating ventilator-induced lung injury.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116533"},"PeriodicalIF":5.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224005288/pdfft?md5=9cc77bbff9d693d05872498036c2c5c4&pid=1-s2.0-S0006295224005288-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243324","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}
Pub Date : 2024-09-11DOI: 10.1016/j.bcp.2024.116532
Jingjing Zhang , Jiacheng Sun , Xiaosong Gu , Yuntian Shen , Hualin Sun
The pathogenesis of myocardial hypertrophy remains incompletely understood, highlighting the critical need for in-depth investigation into its pathogenesis and pathophysiology to develop innovative strategies for preventing and treating heart diseases. In this study, a model of angiotensin II (Ang II)-induced myocardial hypertrophy was established using subcutaneous administration with a micropump. Echocardiography, wheat germ agglutinin staining, and western blot analysis were used to evaluate the myocardial hypertrophy model after 5, 10, and 15 days of Ang II treatment. RNA-seq was employed to analyze the differential expression profile of mRNA, followed by bioinformatics analysis. Subsequently, the anti-inflammatory drug meloxicam was utilized to explore its impact on cardiac hypertrophy in mice. The findings demonstrated that mice developed myocardial hypertrophy following subcutaneous administration of Ang II. Transcriptomic analysis revealed significant changes in gene expression in the myocardium induced by Ang II, with the most pronounced differences observed at day 10. Functional analysis and verification of differentially expressed genes indicated that Ang II triggered an inflammatory response in the myocardium, leading to up-regulation of genes associated with fibrosis and apoptosis while decreasing energy metabolism; alterations were also observed in genes related to oxidative stress and calcium ion binding. Treatment with meloxicam improved Ang II-induced myocardial hypertrophy. This study not only elucidated the molecular regulatory mechanism underlying mouse myocardial hypertrophy at a transcriptional level but also provided new insights into clinical prevention and treatment strategies for cardiac diseases such as dilated cardiomyopathy and heart failure.
心肌肥厚的发病机理至今仍不完全清楚，因此亟需对其发病机理和病理生理学进行深入研究，以开发预防和治疗心脏病的创新策略。本研究利用微型泵皮下注射血管紧张素 II（Ang II），建立了血管紧张素 II（Ang II）诱导的心肌肥厚模型。利用超声心动图、小麦胚芽凝集素染色和 Western 印迹分析来评估血管紧张素 II 治疗 5 天、10 天和 15 天后的心肌肥厚模型。采用 RNA-seq 分析 mRNA 的差异表达谱，然后进行生物信息学分析。随后，利用抗炎药物美洛昔康探讨其对小鼠心肌肥厚的影响。研究结果表明，小鼠皮下注射 Ang II 后会出现心肌肥厚。转录组分析显示，Ang II 诱导的心肌基因表达发生了显著变化，在第 10 天观察到的差异最为明显。功能分析和差异表达基因的验证表明，Ang II引发了心肌的炎症反应，导致与纤维化和细胞凋亡相关的基因上调，同时降低了能量代谢；与氧化应激和钙离子结合相关的基因也发生了变化。使用美洛昔康治疗可改善 Ang II 诱导的心肌肥厚。这项研究不仅在转录水平上阐明了小鼠心肌肥厚的分子调控机制，还为扩张型心肌病和心力衰竭等心脏疾病的临床预防和治疗策略提供了新的见解。
{"title":"Transcriptome sequencing analysis reveals the molecular regulatory mechanism of myocardial hypertrophy induced by angiotensin II","authors":"Jingjing Zhang , Jiacheng Sun , Xiaosong Gu , Yuntian Shen , Hualin Sun","doi":"10.1016/j.bcp.2024.116532","DOIUrl":"10.1016/j.bcp.2024.116532","url":null,"abstract":"<div><p>The pathogenesis of myocardial hypertrophy remains incompletely understood, highlighting the critical need for in-depth investigation into its pathogenesis and pathophysiology to develop innovative strategies for preventing and treating heart diseases. In this study, a model of angiotensin II (Ang II)-induced myocardial hypertrophy was established using subcutaneous administration with a micropump. Echocardiography, wheat germ agglutinin staining, and western blot analysis were used to evaluate the myocardial hypertrophy model after 5, 10, and 15 days of Ang II treatment. RNA-seq was employed to analyze the differential expression profile of mRNA, followed by bioinformatics analysis. Subsequently, the anti-inflammatory drug meloxicam was utilized to explore its impact on cardiac hypertrophy in mice. The findings demonstrated that mice developed myocardial hypertrophy following subcutaneous administration of Ang II. Transcriptomic analysis revealed significant changes in gene expression in the myocardium induced by Ang II, with the most pronounced differences observed at day 10. Functional analysis and verification of differentially expressed genes indicated that Ang II triggered an inflammatory response in the myocardium, leading to up-regulation of genes associated with fibrosis and apoptosis while decreasing energy metabolism; alterations were also observed in genes related to oxidative stress and calcium ion binding. Treatment with meloxicam improved Ang II-induced myocardial hypertrophy. This study not only elucidated the molecular regulatory mechanism underlying mouse myocardial hypertrophy at a transcriptional level but also provided new insights into clinical prevention and treatment strategies for cardiac diseases such as dilated cardiomyopathy and heart failure.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116532"},"PeriodicalIF":5.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243322","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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