Pub Date : 2024-09-01DOI: 10.1016/j.apsb.2024.06.002
The intestinal mucus barrier is an important line of defense against gut pathogens. Damage to this barrier brings bacteria into close contact with the epithelium, leading to intestinal inflammation. Therefore, its restoration is a promising strategy for alleviating intestinal inflammation. This study showed that Abelmoschus manihot polysaccharide (AMP) fortifies the intestinal mucus barrier by increasing mucus production, which plays a crucial role in the AMP-mediated amelioration of colitis. IL-10-deficient mouse models demonstrated that the effect of AMP on mucus production is dependent on IL-10. Moreover, bacterial depletion and replenishment confirmed that the effects of AMP on IL-10 secretion and mucus production were mediated by Akkermansia muciniphila. These findings suggest that plant polysaccharides fortify the intestinal mucus barrier by maintaining homeostasis in the gut microbiota. This demonstrates that targeting mucus barrier is a promising strategy for treating intestinal inflammation.
{"title":"Abelmoschus manihot polysaccharide fortifies intestinal mucus barrier to alleviate intestinal inflammation by modulating Akkermansia muciniphila abundance","authors":"","doi":"10.1016/j.apsb.2024.06.002","DOIUrl":"10.1016/j.apsb.2024.06.002","url":null,"abstract":"<div><p>The intestinal mucus barrier is an important line of defense against gut pathogens. Damage to this barrier brings bacteria into close contact with the epithelium, leading to intestinal inflammation. Therefore, its restoration is a promising strategy for alleviating intestinal inflammation. This study showed that <em>Abelmoschus manihot</em> polysaccharide (AMP) fortifies the intestinal mucus barrier by increasing mucus production, which plays a crucial role in the AMP-mediated amelioration of colitis. IL-10-deficient mouse models demonstrated that the effect of AMP on mucus production is dependent on IL-10. Moreover, bacterial depletion and replenishment confirmed that the effects of AMP on IL-10 secretion and mucus production were mediated by <em>Akkermansia muciniphila.</em> These findings suggest that plant polysaccharides fortify the intestinal mucus barrier by maintaining homeostasis in the gut microbiota. This demonstrates that targeting mucus barrier is a promising strategy for treating intestinal inflammation.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 3901-3915"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002338/pdfft?md5=5ba5a7b277b00c9229e10b37cbbc64ec&pid=1-s2.0-S2211383524002338-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141400012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.apsb.2024.06.012
{"title":"Decoding the chromatin accessibility in Andrographis paniculata genome, a case study of genome-wide investigation of the cis-regulatory elements in medicinal plants","authors":"","doi":"10.1016/j.apsb.2024.06.012","DOIUrl":"10.1016/j.apsb.2024.06.012","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4179-4182"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002430/pdfft?md5=c9fb85ab990286125c9f132a4aa954d9&pid=1-s2.0-S2211383524002430-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rapid turnover of the intestinal epithelium is a critical strategy to balance the uptake of nutrients and defend against environmental insults, whereas inappropriate death promotes the spread of inflammation. PPAR is highly expressed in the small intestine and regulates the absorption of dietary lipids. However, as a key mediator of inflammation, the impact of intestinal PPAR signaling on cell death pathways is unknown. Here, we show that deficiency of intestinal epithelium up-regulates necroptosis signals, disrupts the gut vascular barrier, and promotes LPS translocation into the liver. Intestinal deficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet (HFHS). PPAR levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPAR up-regulates necroptosis signals in the intestinal organoids triggered by TNF- and LPS stimuli TRIM38/TRIF and CREB3L3/MLKL pathways. Butyric acid ameliorates hepatic steatosis induced by intestinal deficiency through the inhibition of necroptosis. Our data suggest that intestinal PPAR is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation the gut–liver axis.
{"title":"PPARα affects hepatic lipid homeostasis by perturbing necroptosis signals in the intestinal epithelium","authors":"Shufang Na, Yanjie Fan, HongLei Chen, Ling Li, Guolin Li, Furong Zhang, Rongyan Wang, Yafei Yang, Zixia Shen, Zhuang Peng, Yafei Wu, Yong Zhu, Zheqiong Yang, Guicheng Dong, Qifa Ye, Jiang Yue","doi":"10.1016/j.apsb.2024.08.021","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.021","url":null,"abstract":"Rapid turnover of the intestinal epithelium is a critical strategy to balance the uptake of nutrients and defend against environmental insults, whereas inappropriate death promotes the spread of inflammation. PPAR is highly expressed in the small intestine and regulates the absorption of dietary lipids. However, as a key mediator of inflammation, the impact of intestinal PPAR signaling on cell death pathways is unknown. Here, we show that deficiency of intestinal epithelium up-regulates necroptosis signals, disrupts the gut vascular barrier, and promotes LPS translocation into the liver. Intestinal deficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet (HFHS). PPAR levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPAR up-regulates necroptosis signals in the intestinal organoids triggered by TNF- and LPS stimuli TRIM38/TRIF and CREB3L3/MLKL pathways. Butyric acid ameliorates hepatic steatosis induced by intestinal deficiency through the inhibition of necroptosis. Our data suggest that intestinal PPAR is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation the gut–liver axis.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"59 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the Cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation and . Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.
诱导KRAS降解是抗击KRAS突变癌症的一种新策略。在这项研究中，我们发现泛素特异性蛋白酶2（USP2）是多发性骨髓瘤（MM）中KRAS的一种新型去泛素化酶。具体而言，我们证明甘草酸（GA）通过一个异构口袋与 USP2 的半胱氨酸 284 残基形成共价键，从而抑制其去泛素活性。USP2 失活或被敲除会导致 KRAS 降解，从而抑制 MM 细胞的增殖和死亡。相反，过量表达 USP2 会稳定 KRAS，并部分抑制 GA 诱导的 MM 细胞凋亡。此外，USP2 水平升高可能与 MM 患者预后较差有关。这些发现凸显了 USP2/KRAS 轴作为 MM 治疗靶点的潜力，表明战略性地诱导 KRAS 降解 USP2 抑制可能是治疗 KRAS 突变癌症的一种有前途的方法。
{"title":"Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells","authors":"Yingying Wang, Youping Zhang, Hao Luo, Wei Wei, Wanting Liu, Weiwei Wang, Yunzhao Wu, Cheng Peng, Yanjie Ji, Jianfang Zhang, Chujiao Zhu, Wenhui Bai, Li Xia, Hu Lei, Hanzhang Xu, Leimiao Yin, Wei Weng, Li Yang, Ligen Liu, Aiwu Zhou, Yueyue Wei, Qi Zhu, Weiliang Zhu, Yongqing Yang, Zhijian Xu, Yingli Wu","doi":"10.1016/j.apsb.2024.08.019","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.019","url":null,"abstract":"Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the Cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation and . Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"22 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody–drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity and . Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.
{"title":"A novel shark VNAR antibody-based immunotoxin targeting TROP-2 for cancer therapy","authors":"Xiaozhi Xi, Yanqing Wang, Guiqi An, Shitao Feng, Qiumei Zhu, Zhongqiu Wu, Jin Chen, Zhicheng Zuo, Qiang Wang, Ming-Wei Wang, Yuchao Gu","doi":"10.1016/j.apsb.2024.08.023","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.023","url":null,"abstract":"TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody–drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity and . Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"160 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy , improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives’ inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.
{"title":"Targeting toll-like receptor 7 as a therapeutic development strategy for systemic lupus erythematosus","authors":"Meng Wang, Hekai Chen, Tuan Zhang, Zhikuan Zhang, Xuwen Xiang, Meng Gao, Yilan Guo, Shuangshuang Jiang, Kejun Yin, Mintao Chen, Jian Huang, Xincheng Zhong, Umeharu Ohto, Jing Li, Toshiyuki Shimizu, Hang Yin","doi":"10.1016/j.apsb.2024.08.016","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.016","url":null,"abstract":"Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy , improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives’ inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.apsb.2024.08.020
Yuqi Yang, Nan Liu, Likun Gong
The APOBEC3 (A3) family plays a pivotal role in the immune system by performing DNA/RNA single-strand deamination. Cancers mostly arise from the accumulation of chronic mutations in somatic cells, and recent research has highlighted the A3 family as a major contributor to tumor-associated mutations, with A3A being a key driver gene leading to cancer-related mutations. A3A helps to defend the host against virus-induced tumors by editing the genome of cancer-associated viruses that invade the host. However, when it is abnormally expressed, it leads to persistent, chronic mutations in the genome, thereby fueling tumorigenesis. Notably, A3A is prominently expressed in innate immune cells, particularly macrophages, thereby affecting the functional state of tumor-infiltrating immune cells and tumor growth. Furthermore, the expression of A3A in tumor cells may directly affect their proliferation and migration. A growing body of research has unveiled that A3A is closely related to various cancers, which signifies the potential significance of A3A in cancer therapy. This paper mainly classifies and summarizes the evidence of the relationship between A3A and tumorigenesis based on the potential mechanisms, aiming to provide valuable references for further research on the functions of A3A and its development in the area of cancer therapy.
{"title":"An overview of the functions and mechanisms of APOBEC3A in tumorigenesis","authors":"Yuqi Yang, Nan Liu, Likun Gong","doi":"10.1016/j.apsb.2024.08.020","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.020","url":null,"abstract":"The APOBEC3 (A3) family plays a pivotal role in the immune system by performing DNA/RNA single-strand deamination. Cancers mostly arise from the accumulation of chronic mutations in somatic cells, and recent research has highlighted the A3 family as a major contributor to tumor-associated mutations, with A3A being a key driver gene leading to cancer-related mutations. A3A helps to defend the host against virus-induced tumors by editing the genome of cancer-associated viruses that invade the host. However, when it is abnormally expressed, it leads to persistent, chronic mutations in the genome, thereby fueling tumorigenesis. Notably, A3A is prominently expressed in innate immune cells, particularly macrophages, thereby affecting the functional state of tumor-infiltrating immune cells and tumor growth. Furthermore, the expression of A3A in tumor cells may directly affect their proliferation and migration. A growing body of research has unveiled that A3A is closely related to various cancers, which signifies the potential significance of A3A in cancer therapy. This paper mainly classifies and summarizes the evidence of the relationship between A3A and tumorigenesis based on the potential mechanisms, aiming to provide valuable references for further research on the functions of A3A and its development in the area of cancer therapy.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"13 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/j.apsb.2024.08.022
Xinyu Zhao, Jie Shan, Hanying Qian, Xu Jin, Yiwei Sun, Jianghao Xing, Qingrong Li, Xu-Lin Chen, Xianwen Wang
Ischemia-reperfusion (I/R) injury following skin flap transplantation is a critical factor leading to flap necrosis and transplant failure. Antagonizing inflammatory responses and oxidative stress are regarded as crucial targets for mitigating reperfusion injury and enhancing flap survival. In this study, caffeic acid-vanadium metal polyphenol nanoparticles (CA-V NPs) were prepared for the treatment of skin flap ischemia and reperfusion. This study was conducted using a one-step method to prepare new types of CA-V NPs with uniform sizes and stable structures. , the CA-V NPs exhibited CAT-like and SOD-like activities and could effectively scavenge ROS, generate oxygen, and alleviate oxidative stress. In the HO-induced cellular oxidative stress model, CA-V NPs effectively reduced ROS levels and inhibited apoptosis through the XIAP/Caspase-3 pathway. In the cellular inflammation model induced by LPS combined with IFN-, CA-V NPs reprogrammed macrophage polarization toward the M2 phenotype and reduced inflammatory responses by reducing the expression of the chemokines CCL4 and CXCL2. In addition, animal experiments have shown that CA-V NPs can alleviate oxidative stress in skin flap tissues, inhibit apoptosis, promote angiogenesis, and ultimately improve the survival rate of skin flaps. CA-V NPs provide a new target and strategy for the treatment of flap I/R injury.
{"title":"Caffeic acid-vanadium nanozymes treat skin flap ischemia-reperfusion injury through macrophage reprogramming and the upregulation of X-linked inhibitors of apoptotic proteins","authors":"Xinyu Zhao, Jie Shan, Hanying Qian, Xu Jin, Yiwei Sun, Jianghao Xing, Qingrong Li, Xu-Lin Chen, Xianwen Wang","doi":"10.1016/j.apsb.2024.08.022","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.022","url":null,"abstract":"Ischemia-reperfusion (I/R) injury following skin flap transplantation is a critical factor leading to flap necrosis and transplant failure. Antagonizing inflammatory responses and oxidative stress are regarded as crucial targets for mitigating reperfusion injury and enhancing flap survival. In this study, caffeic acid-vanadium metal polyphenol nanoparticles (CA-V NPs) were prepared for the treatment of skin flap ischemia and reperfusion. This study was conducted using a one-step method to prepare new types of CA-V NPs with uniform sizes and stable structures. , the CA-V NPs exhibited CAT-like and SOD-like activities and could effectively scavenge ROS, generate oxygen, and alleviate oxidative stress. In the HO-induced cellular oxidative stress model, CA-V NPs effectively reduced ROS levels and inhibited apoptosis through the XIAP/Caspase-3 pathway. In the cellular inflammation model induced by LPS combined with IFN-, CA-V NPs reprogrammed macrophage polarization toward the M2 phenotype and reduced inflammatory responses by reducing the expression of the chemokines CCL4 and CXCL2. In addition, animal experiments have shown that CA-V NPs can alleviate oxidative stress in skin flap tissues, inhibit apoptosis, promote angiogenesis, and ultimately improve the survival rate of skin flaps. CA-V NPs provide a new target and strategy for the treatment of flap I/R injury.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"5 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS and drug efficacy, suggesting that RS could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from and experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.
{"title":"GSFM: A genome-scale functional module transformation to represent drug efficacy for in silico drug discovery","authors":"Saisai Tian, Xuyang Liao, Wen Cao, Xinyi Wu, Zexi Chen, Jinyuan Lu, Qun Wang, Jinbo Zhang, Luonan Chen, Weidong Zhang","doi":"10.1016/j.apsb.2024.08.017","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.017","url":null,"abstract":"Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS and drug efficacy, suggesting that RS could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from and experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"40 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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