Pub Date : 2024-08-01DOI: 10.1016/j.apsb.2024.04.034
Tumor metastasis, the apex of cancer progression, poses a formidable challenge in therapeutic endeavors. Circulating tumor cells (CTCs), resilient entities originating from primary tumors or their metastases, significantly contribute to this process by demonstrating remarkable adaptability. They survive shear stress, resist anoikis, evade immune surveillance, and thwart chemotherapy. This comprehensive review aims to elucidate the intricate landscape of CTC formation, metastatic mechanisms, and the myriad factors influencing their behavior. Integral signaling pathways, such as integrin-related signaling, cellular autophagy, epithelial-mesenchymal transition, and interactions with platelets, are examined in detail. Furthermore, we explore the realm of precision nanomedicine design, with a specific emphasis on the anoikis‒platelet interface. This innovative approach strategically targets CTC survival mechanisms, offering promising avenues for combatting metastatic cancer with unprecedented precision and efficacy. The review underscores the indispensable role of the rational design of platelet-based nanomedicine in the pursuit of restraining CTC-driven metastasis.
{"title":"Advancements in precision nanomedicine design targeting the anoikis-platelet interface of circulating tumor cells","authors":"","doi":"10.1016/j.apsb.2024.04.034","DOIUrl":"10.1016/j.apsb.2024.04.034","url":null,"abstract":"<div><p>Tumor metastasis, the apex of cancer progression, poses a formidable challenge in therapeutic endeavors. Circulating tumor cells (CTCs), resilient entities originating from primary tumors or their metastases, significantly contribute to this process by demonstrating remarkable adaptability. They survive shear stress, resist anoikis, evade immune surveillance, and thwart chemotherapy. This comprehensive review aims to elucidate the intricate landscape of CTC formation, metastatic mechanisms, and the myriad factors influencing their behavior. Integral signaling pathways, such as integrin-related signaling, cellular autophagy, epithelial-mesenchymal transition, and interactions with platelets, are examined in detail. Furthermore, we explore the realm of precision nanomedicine design, with a specific emphasis on the anoikis‒platelet interface. This innovative approach strategically targets CTC survival mechanisms, offering promising avenues for combatting metastatic cancer with unprecedented precision and efficacy. The review underscores the indispensable role of the rational design of platelet-based nanomedicine in the pursuit of restraining CTC-driven metastasis.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001771/pdfft?md5=02dd6a13aa3311e047ad1f8463a34c1e&pid=1-s2.0-S2211383524001771-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141040873","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.03.018
Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q cell. The most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS assays. In the H460R231Q OE cell-derived xenograft (CDX) model, 37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks (TGI = 54.38%), without obvious toxicities. A pharmacokinetic study revealed that 37 possessed tolerable properties (t1/2 = 1.93 ± 0.91 h, F = 97.2%) after intraperitoneal administration in rats. Mechanism study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway. Moreover, analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the “Induced-fit” allosteric model in favor to the discovery of potent DOT1L candidates.
{"title":"Discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer","authors":"","doi":"10.1016/j.apsb.2024.03.018","DOIUrl":"10.1016/j.apsb.2024.03.018","url":null,"abstract":"<div><p>Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1L<sup>R231Q</sup> inhibition through antiproliferation assay and Western blot analysis in the H460<sup>R231Q</sup> cell. The most promising compound <strong>37</strong> significantly reduced DOT1L<sup>R231Q</sup> mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of <strong>37</strong> were verified by both CETSA and DARTS assays. In the H460<sup>R231Q OE</sup> cell-derived xenograft (CDX) model, <strong>37</strong> displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks (TGI = 54.38%), without obvious toxicities. A pharmacokinetic study revealed that <strong>37</strong> possessed tolerable properties (<em>t</em><sub>1/2</sub> = 1.93 ± 0.91 h, <em>F</em> = 97.2%) after intraperitoneal administration in rats. Mechanism study confirmed that <strong>37</strong> suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation <em>via</em> the MAPK/ERK signaling pathway. Moreover, analysis of the binding modes between molecules and DOT1L<sup>WT/R231Q</sup> proteins put forward the “Induced-fit” allosteric model in favor to the discovery of potent DOT1L candidates.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524000996/pdfft?md5=7409d9594a0368167ad66f0f09ac63e7&pid=1-s2.0-S2211383524000996-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140182152","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.04.021
Amino acid metabolic remodeling is a hallmark of cancer, driving an increased nutritional demand for amino acids. Amino acids are pivotal for energetic regulation, biosynthetic support, and homeostatic maintenance to stimulate cancer progression. However, the role of phenylalanine in multiple myeloma (MM) remains unknown. Here, we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow (BM) cells. After the treatment, phenylalanine levels increase in plasma and decrease in BM. This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression. The requirement for phenylalanine by MM cells exhibits a similar pattern. Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib (BTZ) treatment in vitro and murine models. Mechanistically, phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3–CHOP–DR5 pathway. Interference with ATF3 significantly affects phenylalanine deprivation therapy. In conclusion, we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling. Phenylalanine is necessary for MM proliferation, and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.
氨基酸代谢重塑是癌症的一大特征,促使对氨基酸的营养需求增加。氨基酸在能量调节、生物合成支持和平衡维持方面起着关键作用,从而刺激癌症的发展。然而,苯丙氨酸在多发性骨髓瘤(MM)中的作用仍然未知。在这里,我们证明 MM 患者血浆中的苯丙氨酸水平降低,但骨髓(BM)细胞中的苯丙氨酸水平升高。治疗后,血浆中的苯丙氨酸水平升高,而骨髓中的苯丙氨酸水平降低。这表明苯丙氨酸的变化具有诊断价值,而且骨髓微环境中的苯丙氨酸是 MM 病程进展的重要营养来源。MM 细胞对苯丙氨酸的需求也表现出类似的模式。抑制苯丙氨酸的利用可抑制 MM 细胞的生长,并与硼替佐米(BTZ)治疗和小鼠模型产生协同效应。从机理上讲,苯丙氨酸剥夺会诱导过度的内质网应激,并通过ATF3-CHOP-DR5途径导致MM细胞凋亡。干扰 ATF3 会明显影响苯丙氨酸剥夺疗法。总之,我们发现苯丙氨酸代谢是 MM 代谢重塑的一个特征。苯丙氨酸是MM增殖所必需的物质,其异常需求凸显了低苯丙氨酸饮食作为MM辅助治疗的重要性。
{"title":"Phenylalanine deprivation inhibits multiple myeloma progression by perturbing endoplasmic reticulum homeostasis","authors":"","doi":"10.1016/j.apsb.2024.04.021","DOIUrl":"10.1016/j.apsb.2024.04.021","url":null,"abstract":"<div><p>Amino acid metabolic remodeling is a hallmark of cancer, driving an increased nutritional demand for amino acids. Amino acids are pivotal for energetic regulation, biosynthetic support, and homeostatic maintenance to stimulate cancer progression. However, the role of phenylalanine in multiple myeloma (MM) remains unknown. Here, we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow (BM) cells. After the treatment, phenylalanine levels increase in plasma and decrease in BM. This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression. The requirement for phenylalanine by MM cells exhibits a similar pattern. Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib (BTZ) treatment <em>in vitro</em> and murine models. Mechanistically, phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3–CHOP–DR5 pathway. Interference with ATF3 significantly affects phenylalanine deprivation therapy. In conclusion, we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling. Phenylalanine is necessary for MM proliferation, and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221138352400162X/pdfft?md5=4b419060b041027996b20700822930b3&pid=1-s2.0-S221138352400162X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140842493","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.04.028
Due to the insufficient Cu+ accumulation, Cu+ efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu2+, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu+ efflux protein ATP7B and forming toxic Cu+, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.
{"title":"Inhalable nanoparticles with enhanced cuproptosis and cGAS–STING activation for synergistic lung metastasis immunotherapy","authors":"","doi":"10.1016/j.apsb.2024.04.028","DOIUrl":"10.1016/j.apsb.2024.04.028","url":null,"abstract":"<div><p>Due to the insufficient Cu<sup>+</sup> accumulation, Cu<sup>+</sup> efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu<sup>2+</sup>-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu<sup>2+</sup>, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu<sup>+</sup> efflux protein ATP7B and forming toxic Cu<sup>+</sup>, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001692/pdfft?md5=9e446719e44027e7fac0982dff7a7383&pid=1-s2.0-S2211383524001692-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140938819","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.04.016
Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPKα was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPKα and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.
{"title":"Mechanical regulation of lipid and sugar absorption by Piezo1 in enterocytes","authors":"","doi":"10.1016/j.apsb.2024.04.016","DOIUrl":"10.1016/j.apsb.2024.04.016","url":null,"abstract":"<div><p>Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPK<em>α</em> was decreased when compared to normal-weight individuals. Under high-fat diet condition, the <em>Piezo1</em><sup><em>iKO</em></sup> mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPK<em>α</em> and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221138352400145X/pdfft?md5=18a1417a4f2aeecb2a7f5ebf177873b9&pid=1-s2.0-S221138352400145X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140776113","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.04.022
Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.
嵌合抗原受体 T(CAR-T)细胞疗法作为一种领养细胞疗法(ACT),在癌症治疗中显示出了巨大的前景,美国食品及药物管理局批准的以 CD19 或 B 细胞成熟抗原(BCMA)为靶点的 CAR-T 细胞疗法治疗血液恶性肿瘤就证明了这一点,尽管这种疗法在实体瘤中的疗效一般。然而,尽管取得了这些进展,CAR-T疗法的疗效却常常因T细胞衰竭而大打折扣,这种现象阻碍了CAR-T细胞的持久性和效应功能,导致使用CD19或CD22 CAR-T细胞治疗血液恶性肿瘤的患者复发率高达75%。克服 CAR-T 衰竭的策略采用了最先进的基因组工程工具和单细胞测序技术。在这篇综述中,我们将全面介绍 T 细胞衰竭的最新机理及其对当前优化 CAR-T 细胞疗法的影响。这些见解与近期临床试验中基于 CAR-T 产品的基准测试所获得的经验教训相结合,旨在解决 T 细胞衰竭带来的挑战,为开发量身定制的下一代癌症治疗方法奠定基础。
{"title":"Unlocking T cell exhaustion: Insights and implications for CAR-T cell therapy","authors":"","doi":"10.1016/j.apsb.2024.04.022","DOIUrl":"10.1016/j.apsb.2024.04.022","url":null,"abstract":"<div><p>Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001631/pdfft?md5=28c821d03803398a737e8a7cae3eca5b&pid=1-s2.0-S2211383524001631-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140795624","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.04.010
The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8+ T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo. Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.
针对内质网(ER)的化疗免疫疗法为扩大化疗和免疫疗法的协同效应提供了机会。在这项研究中,我们通过促进结直肠癌(CRC)细胞的ER应激和自噬,初步验证了芹甾醇(CEL)是免疫原性细胞死亡(ICD)的诱导剂。随后,研究人员提出了一种ER靶向策略,即利用从牛奶中提取的KDEL肽修饰外泌体(KME)将CEL与PD-L1小干扰RNA(siRNA)进行编码传递,以提高化疗免疫疗法的效果。我们的研究结果表明,KME能通过高尔基体到ER途径高效地运输到ER。与非靶向性外泌体相比,KME能显著增强CEL诱导的ICD效应。此外,它还促进了危险信号分子(DAMPs)的释放,从而刺激了树突状细胞的抗原递呈功能,并促进了 T 细胞向肿瘤的浸润。同时,ER靶向递送PD-L1 siRNA能下调细胞内和细胞膜上PD-L1蛋白的表达,从而促进CD8+ T细胞的增殖和活性。最终,ER靶向制剂显示出更强的抗肿瘤疗效,并在体内激发了针对正位结直肠肿瘤的抗肿瘤免疫反应。总之,强大的ER靶向给药策略为实现有效的癌症化疗免疫疗法提供了一种令人鼓舞的方法。
{"title":"Endoplasmic reticulum-targeted delivery of celastrol and PD-L1 siRNA for reinforcing immunogenic cell death and potentiating cancer immunotherapy","authors":"","doi":"10.1016/j.apsb.2024.04.010","DOIUrl":"10.1016/j.apsb.2024.04.010","url":null,"abstract":"<div><p>The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER <em>via</em> the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8<sup>+</sup> T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors <em>in vivo</em>. Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001394/pdfft?md5=43664af8e2a3f8afd1bb04aa4797e0a5&pid=1-s2.0-S2211383524001394-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140769880","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.04.001
Glycosylation is an important post-modification reaction in plant secondary metabolism, and contributes to structural diversity of bioactive natural products. In plants, glycosylation is usually catalyzed by UDP-glycosyltransferases. Flavonoid 2′-O-glycosides are rare glycosides. However, no UGTs have been reported, thus far, to specifically catalyze 2′-O-glycosylation of flavonoids. In this work, UGT71AP2 was identified from the medicinal plant Scutellaria baicalensis as the first flavonoid 2′-O-glycosyltransferase. It could preferentially transfer a glycosyl moiety to 2′-hydroxy of at least nine flavonoids to yield six new compounds. Some of the 2′-O-glycosides showed noticeable inhibitory activities against cyclooxygenase 2. The crystal structure of UGT71AP2 (2.15 Å) was solved, and mechanisms of its regio-selectivity was interpreted by pKa calculations, molecular docking, MD simulation, MM/GBSA binding free energy, QM/MM, and hydrogen‒deuterium exchange mass spectrometry analysis. Through structure-guided rational design, we obtained the L138T/V179D/M180T mutant with remarkably enhanced regio-selectivity (the ratio of 7-O-glycosylation byproducts decreased from 48% to 4%) and catalytic efficiency of 2′-O-glycosylation (kcat/Km, 0.23 L/(s·μmol), 12-fold higher than the native). Moreover, UGT71AP2 also possesses moderate UDP-dependent de-glycosylation activity, and is a dual function glycosyltransferase. This work provides an efficient biocatalyst and sets a good example for protein engineering to optimize enzyme catalytic features through rational design.
{"title":"Functional characterization, structural basis, and protein engineering of a rare flavonoid 2′-O-glycosyltransferase from Scutellaria baicalensis","authors":"","doi":"10.1016/j.apsb.2024.04.001","DOIUrl":"10.1016/j.apsb.2024.04.001","url":null,"abstract":"<div><p>Glycosylation is an important post-modification reaction in plant secondary metabolism, and contributes to structural diversity of bioactive natural products. In plants, glycosylation is usually catalyzed by UDP-glycosyltransferases. Flavonoid 2′-<em>O</em>-glycosides are rare glycosides. However, no UGTs have been reported, thus far, to specifically catalyze 2′-<em>O</em>-glycosylation of flavonoids. In this work, UGT71AP2 was identified from the medicinal plant <em>Scutellaria baicalensis</em> as the first flavonoid 2′-<em>O</em>-glycosyltransferase. It could preferentially transfer a glycosyl moiety to 2′-hydroxy of at least nine flavonoids to yield six new compounds. Some of the 2′-<em>O</em>-glycosides showed noticeable inhibitory activities against cyclooxygenase 2. The crystal structure of UGT71AP2 (2.15 Å) was solved, and mechanisms of its regio-selectivity was interpreted by p<em>K</em><sub>a</sub> calculations, molecular docking, MD simulation, MM/GBSA binding free energy, QM/MM, and hydrogen‒deuterium exchange mass spectrometry analysis. Through structure-guided rational design, we obtained the L138T/V179D/M180T mutant with remarkably enhanced regio-selectivity (the ratio of 7-<em>O</em>-glycosylation byproducts decreased from 48% to 4%) and catalytic efficiency of 2′-<em>O</em>-glycosylation (<em>k</em><sub>cat</sub>/<em>K</em><sub>m</sub>, 0.23 L/(s·μmol), 12-fold higher than the native). Moreover, UGT71AP2 also possesses moderate UDP-dependent de-glycosylation activity, and is a dual function glycosyltransferase. This work provides an efficient biocatalyst and sets a good example for protein engineering to optimize enzyme catalytic features through rational design.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001291/pdfft?md5=7a8a1e5c48c8fcb596d744fd4b086287&pid=1-s2.0-S2211383524001291-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589047","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.04.004
Rheumatoid arthritis (RA) is an inflammatory disease accompanied by abnormal synovial microenvironment (SM). Sesquiterpene lactones (SLs) are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment. α-Methylene-γ-butyrolactone (α-M-γ-B) is a core moiety that widely exists in natural SLs. This study was designed to investigate the anti-arthritic potential of α-M-γ-B as an independent small molecule in vitro and in vivo. α-M-γ-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs. α-M-γ-B inhibited the production of pro-inflammatory mediators via repolarizing M1 macrophages into M2 macrophages. The transcriptome sequencing suggested that α-M-γ-B regulated the immune system pathway. Consistently, α-M-γ-B attenuated collagen type II-induced arthritic (CIA) phenotype, restored the balance of Tregs-macrophages and remodeled SM via repolarizing the synovial-associated macrophages in CIA mice. Mechanistically, although α-M-γ-B did not prevent the trans-nucleus of NF-κB it interfered with the DNA binding activity of NF-κB via direct interaction with the sulfhydryl in cysteine residue of NF-κB p65, which blocked the activation of NF-κB. Inhibition of NF-κB reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis. α-M-γ-B failed to ameliorate CIA in the presence of N-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of Rela. In conclusion, α-M-γ-B significantly attenuated the CIA phenotype by directly targeting NF-κB p65 and inhibiting its DNA binding ability. These results suggest that α-M-γ-B has the potential to serve as an alternative candidate for treating RA. The greater electrophilicity of α-M-γ-B, the basis for triggering strong anti-inflammatory activity, accounts for the reason why α-M-γ-B is evolutionarily conserved in the SLs by medical plants.
{"title":"Small molecule α-methylene-γ-butyrolactone, an evolutionarily conserved moiety in sesquiterpene lactones, ameliorates arthritic phenotype via interference DNA binding activity of NF-κB","authors":"","doi":"10.1016/j.apsb.2024.04.004","DOIUrl":"10.1016/j.apsb.2024.04.004","url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is an inflammatory disease accompanied by abnormal synovial microenvironment (SM). Sesquiterpene lactones (SLs) are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment. <em>α</em>-Methylene-<em>γ</em>-butyrolactone (<em>α</em>-M-<em>γ</em>-B) is a core moiety that widely exists in natural SLs. This study was designed to investigate the anti-arthritic potential of <em>α</em>-M-<em>γ</em>-B as an independent small molecule <em>in vitro</em> and <em>in vivo</em>. <em>α</em>-M-<em>γ</em>-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs. <em>α</em>-M-<em>γ</em>-B inhibited the production of pro-inflammatory mediators <em>via</em> repolarizing M1 macrophages into M2 macrophages. The transcriptome sequencing suggested that <em>α</em>-M-<em>γ</em>-B regulated the immune system pathway. Consistently, <em>α</em>-M-<em>γ</em>-B attenuated collagen type II-induced arthritic (CIA) phenotype, restored the balance of Tregs-macrophages and remodeled SM <em>via</em> repolarizing the synovial-associated macrophages in CIA mice. Mechanistically, although <em>α</em>-M-<em>γ</em>-B did not prevent the trans-nucleus of NF-<em>κ</em>B it interfered with the DNA binding activity of NF-<em>κ</em>B <em>via</em> direct interaction with the sulfhydryl in cysteine residue of NF-<em>κ</em>B p65, which blocked the activation of NF-<em>κ</em>B. Inhibition of NF-<em>κ</em>B reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis. <em>α</em>-M-<em>γ</em>-B failed to ameliorate CIA in the presence of <em>N</em>-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of <em>Rela</em>. In conclusion, <em>α</em>-M-<em>γ</em>-B significantly attenuated the CIA phenotype by directly targeting NF-<em>κ</em>B p65 and inhibiting its DNA binding ability. These results suggest that <em>α</em>-M-<em>γ</em>-B has the potential to serve as an alternative candidate for treating RA. The greater electrophilicity of <em>α</em>-M-<em>γ</em>-B, the basis for triggering strong anti-inflammatory activity, accounts for the reason why <em>α</em>-M-<em>γ</em>-B is evolutionarily conserved in the SLs by medical plants.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001321/pdfft?md5=8f8b8f0fb27d11def58e396ce288b705&pid=1-s2.0-S2211383524001321-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140613665","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 : 2024-08-01DOI: 10.1016/j.apsb.2024.05.021
{"title":"SOX17-mediated immune evasion in early colorectal cancer: From pre-malignant adaptation to tumor progression","authors":"","doi":"10.1016/j.apsb.2024.05.021","DOIUrl":"10.1016/j.apsb.2024.05.021","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001990/pdfft?md5=12d9a97b077ac3db4e4645ea4d474f0b&pid=1-s2.0-S2211383524001990-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528598","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}