Archives of Pharmacal Research最新文献

{"title":"Engineered fibrotic liver-targeted truncated transforming growth factor β receptor type II variant for superior anti-liver fibrosis therapy","authors":"Manman Ma,&nbsp;Xiaohua Wang,&nbsp;Xiaohui Liu,&nbsp;Yang Han,&nbsp;Yanhui Chu,&nbsp;Yanzhong Guan,&nbsp;Haifeng Liu","doi":"10.1007/s12272-023-01435-4","DOIUrl":"10.1007/s12272-023-01435-4","url":null,"abstract":"<div><p>Truncated transforming growth factor β receptor type II (tTβRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-β1 by means of competing with wild type TβRII (wtTβRII). However, the widespread application of tTβRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTβRII variant Z-tTβRII by fusing the platelet-derived growth factor β receptor (PDGFβR)-specific affibody Z_PDGFβR to the N-terminus of tTβRII. The target protein Z-tTβRII was produced using <i>Escherichia coli</i> expression system. In vitro and in vivo studies showed that Z-tTβRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFβR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTβRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-β1/Smad pathway-related protein levels in TGF-β1-stimiluated HSC-T6 cells. Furthermore, Z-tTβRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-β1/Smad signaling pathway in CCl₄-induced liver fibrotic mice. More importantly, Z-tTβRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTβRII or former variant BiPPB-tTβRII (PDGFβR-binding peptide BiPPB modified tTβRII). In addition, Z-tTβRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTβRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 3","pages":"177 - 191"},"PeriodicalIF":6.7,"publicationDate":"2023-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9238736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cathepsin B maturation plays a critical role in leptin-induced hepatic cancer cell growth through activation of NLRP3 inflammasomes","authors":"ThiKem Nguyen,&nbsp;Raut Pawan Kumar,&nbsp;Pil-Hoon Park","doi":"10.1007/s12272-023-01437-2","DOIUrl":"10.1007/s12272-023-01437-2","url":null,"abstract":"<div><p>Leptin, an adipose tissue-derived hormone, exhibits potent tumor promoting effects through various mechanisms. Cathepsin B, a member of the lysosomal cysteine proteases, has been shown to modulate the growth of cancer cells. In this study, we have investigated the role of cathepsin B signaling in leptin-induced hepatic cancer growth. Leptin treatment caused significant increase in the levels of active cathepsin B through the axis of endoplasmic reticulum stress and autophagy induction without significant effects on pre- and pro-forms of cathepsin B. Interestingly, inhibition of cathepsin B signaling by gene silencing or treatment with a selective pharmacological inhibitor (CA-074) prevented leptin-enhanced viability of hepatic cancer cell and suppressed progression of cell cycle, indicating the critical role of cathepsin B in leptin-induced hepatic cancer growth. We have further observed that maturation of cathepsin B is required for NLRP3 inflammasomes activation, which is implicated in the growth of hepatic cancer cell. The crucial roles of cathepsin B maturation in leptin-induced hepatic cancer growth and NLRP3 inflammasomes activation were confirmed in an in vivo HepG2 tumor xenograft model. Taken together, these results demonstrate that cathepsin B signaling plays a pivotal role in leptin-induced hepatic cancer cell growth by activating NLRP3 inflammasomes.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 3","pages":"160 - 176"},"PeriodicalIF":6.7,"publicationDate":"2023-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9238737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-fibrotic effect of aurocyanide, the active metabolite of auranofin","authors":"Hyun Young Kim,&nbsp;Undarmaa Otgontenger,&nbsp;Jun-Woo Kim,&nbsp;Young Joo Lee,&nbsp;Sang-Bum Kim,&nbsp;Sung Chul Lim,&nbsp;Young-Mi Kim,&nbsp;Keon Wook Kang","doi":"10.1007/s12272-023-01438-1","DOIUrl":"10.1007/s12272-023-01438-1","url":null,"abstract":"<div><p>Drug repositioning has gained significant attention over the past several years. The anti-rheumatoid arthritis drug auranofin has been investigated for the treatment of other diseases, including liver fibrosis. Because auranofin is rapidly metabolized, it is necessary to identify the active metabolites of auranofin that have detectable levels in the blood and reflect its therapeutic effects. In the present study, we investigated whether aurocyanide as an active metabolite of auranofin, can be used to evaluate the anti-fibrotic effects of auranofin. Incubation of auranofin with liver microsomes showed that auranofin was susceptible to hepatic metabolism. Previously, we found that the anti-fibrotic effects of auranofin are mediated via system x_c^–-dependent inhibition of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Therefore, we tried to identify active metabolites of auranofin based on their inhibitory effects on system x_c^– and NLRP3 inflammasome in bone marrow-derived macrophages. Among the seven candidate metabolites, 1-thio-β-D-glycopyrano-sato-S-(triethyl-phosphine)-gold(I) and aurocyanide potently inhibited system x_c^– and NLRP3 inflammasome. A pharmacokinetics study on mice detected significant plasma levels of aurocyanide after auranofin administration. Oral administration of aurocyanide significantly prevented thioacetamide-induced liver fibrosis in mice. Moreover, the in vitro anti-fibrotic effects of aurocyanide were assessed in LX-2 cells, where aurocyanide significantly decreased the migratory ability of the cells. In conclusion, aurocyanide is metabolically stable and detectable in plasma, and has inhibitory effects on liver fibrosis, suggesting that it is a potential marker of the therapeutic effects of auranofin.\u0000</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 3","pages":"149 - 159"},"PeriodicalIF":6.7,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-023-01438-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9180772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: The multifaceted role of STAT3 pathway and its implication as a potential therapeutic target in oral cancer","authors":"Elina Khatoon,&nbsp;Mangala Hegde,&nbsp;Aviral Kumar,&nbsp;Uzini Devi Daimary,&nbsp;Gautam Sethi,&nbsp;Anupam Bishayee,&nbsp;Ajaikumar B. Kunnumakkara","doi":"10.1007/s12272-023-01434-5","DOIUrl":"10.1007/s12272-023-01434-5","url":null,"abstract":"","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 3","pages":"206 - 206"},"PeriodicalIF":6.7,"publicationDate":"2023-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9175026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody–drug conjugates and bispecific antibodies targeting cancers: applications of click chemistry","authors":"Yeji Hong,&nbsp;Su-Min Nam,&nbsp;Aree Moon","doi":"10.1007/s12272-023-01433-6","DOIUrl":"10.1007/s12272-023-01433-6","url":null,"abstract":"<div><p>Engineering approaches using antibody drug conjugates (ADCs) and bispecific antibodies (bsAbs) are designed to overcome the limitations of conventional chemotherapies and therapeutic antibodies such as drug resistance and non-specific toxicity. Cancer immunotherapies have been shown to be clinically successful with checkpoint blockade and chimeric antigen receptor T cell therapy; however, overactive immune systems still represent a major problem. Given the complexity of a tumor environment, it would be advantageous to have a strategy targeting two or more molecules. We highlight the necessity and importance of a multi-target platform strategy against cancer. Approximately 400 ADCs and over 200 bsAbs are currently being clinically developed for several indications, with promising signs of therapeutic activity. ADCs include antibodies that recognize tumor antigens, linkers that stably connect drugs, and powerful cytotoxic drugs, also known as payloads. ADCs have direct therapeutic effects by targeting cancers with a strong payload. Another type of drug that uses antibodies are bsAbs, targeting two antigens by linking to antigen recognition sites or bridging cytotoxic immune cells to tumor cells, resulting in cancer immunotherapy. Three bsAbs and one ADC have been approved for use by the FDA and the EMA in 2022. Among these, two of the bsAbs and the one ADC are used for cancers. We introduced that bsADC, a combination of ADC and bsAbs, has yet to be approved and several candidates are in the early stages of clinical development in this review. bsADCs technology helps increase the specificity of ADCs or the internalization and killing ability of bsAbs. We also briefly discuss the application of click chemistry in the efficient development of ADCs and bsAbs as a conjugation strategy. The present review summarizes the ADCs, bsAbs, and bsADCs that have been approved for anti-cancer or currently in development. These strategies selectively deliver drugs to malignant tumor cells and can be used as therapeutic approaches for various types of cancer.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 3","pages":"131 - 148"},"PeriodicalIF":6.7,"publicationDate":"2023-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9180745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dapagliflozin attenuates myocardial remodeling in hypertension by activating the circadian rhythm signaling pathway","authors":"Jing Wang,&nbsp;Qiang She,&nbsp;Jianlin Du","doi":"10.1007/s12272-023-01430-9","DOIUrl":"10.1007/s12272-023-01430-9","url":null,"abstract":"<div><p>Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a new kind of antidiabetic drug which has shown beneficial effects in reducing heart failure-related hospitalization and cardiovascular-related mortality. The mechanisms are complicated. Our study aimed to investigate the effects of dapagliflozin on the myocardium of spontaneously hypertensive rats (SHRs) without heart failure. Wistar-Kyoto rats were used as normal controls. SHRs were randomly divided into the SHR group and the -treated group. After 8 weeks of dapagliflozin treatment, the morphology of heart tissues was examined. The mRNA expression profiles were identified via RNA sequencing (RNA-Seq). Various analysis methods were used to find the differentially expressed genes (DEGs) to predict gene function and coexpression. After dapagliflozin treatment, systolic blood pressure was significantly reduced compared with that in the SHR group. Myocardial remodeling was ameliorated compared with that in the SHR group. After dapagliflozin intervention, 75 DEGs (|log2<i>-fold change</i> | &gt; 0 and <i>Q value</i> &lt; 0.05) were identified in the heart tissues compared to the SHR group. Quantitative real-time PCR analysis confirmed that the expression of the circadian rhythm genes <i>Per3</i>, <i>Bhlhe41</i>, and <i>Nr1d1</i> was significantly upregulated, while the results were coincident with the RNA-Seq results. Dapagliflozin may effectively inhibit myocardial remodeling and regulate blood pressure. The mechanisms may be related to the activation of the circadian rhythm signaling pathway.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 2","pages":"117 - 130"},"PeriodicalIF":6.7,"publicationDate":"2023-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10781356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor lactic acid: a potential target for cancer therapy","authors":"Jun-Kyu Byun","doi":"10.1007/s12272-023-01431-8","DOIUrl":"10.1007/s12272-023-01431-8","url":null,"abstract":"<div><p>Tumor development is influenced by circulating metabolites and most tumors are exposed to substantially elevated levels of lactic acid and low levels of nutrients, such as glucose and glutamine. Tumor-derived lactic acid, the major circulating carbon metabolite, regulates energy metabolism and cancer cell signaling pathways, while also acting as an energy source and signaling molecule. Recent studies have yielded new insights into the pro-tumorigenic action of lactic acid and its metabolism. These insights suggest an anti-tumor therapeutic strategy targeting the oncometabolite lactic acid, with the aim of improving the efficacy and clinical safety of tumor metabolism inhibitors. This review describes the current understanding of the multifunctional roles of tumor lactic acid, as well as therapeutic approaches targeting lactic acid metabolism, including lactate dehydrogenase and monocarboxylate transporters, for anti-cancer therapy.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 2","pages":"90 - 110"},"PeriodicalIF":6.7,"publicationDate":"2023-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9326166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate immune sensing of pathogens and its post-transcriptional regulations by RNA-binding proteins","authors":"Ka Man Tse,&nbsp;Osamu Takeuchi","doi":"10.1007/s12272-023-01429-2","DOIUrl":"10.1007/s12272-023-01429-2","url":null,"abstract":"<div><p> Innate immunity is one of the most ancient and conserved aspect of the immune system. It is responsible for an anti-infective response and has been intrinsically linked to the generation of inflammation. While the inflammatory response entails signaling to the adaptive immune system, it can be self-perpetuating and over-exaggerated, resulting in deleterious consequences, including cytokine storm, sepsis, and the development of inflammatory and autoimmune diseases. Cytokines are the defining features of the immune system. They are critical to mediation of inflammation and host immune defense, and are tightly regulated at several levels, including transcriptional and post-transcriptional levels. Recently, the role of post-transcriptional regulation in fine-tuning cytokine expression has become more appreciated. This interest has advanced our understanding of how various mechanisms are integrated and regulated to determine the amount of cytokine production in cells during inflammatory responses. Here, we would like to review how innate immunity recognizes and responds to pathogens by pattern-recognition receptors, and the molecular mechanisms regulating inflammatory responses, with a focus on the post-transcriptional regulations of inflammatory mediators by RNA-binding proteins, especially Regnase-1. Finally, we will discuss the regulatory mechanisms of Regnase-1 and highlight therapeutic strategies based on targeting Regnase-1 activity and its turnover as potential treatment options for chronic and autoimmune diseases.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 2","pages":"65 - 77"},"PeriodicalIF":6.7,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-023-01429-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10762546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinctive role of inflammation in tissue repair and regeneration","authors":"Bokeum Choi,&nbsp;Changjun Lee,&nbsp;Je-Wook Yu","doi":"10.1007/s12272-023-01428-3","DOIUrl":"10.1007/s12272-023-01428-3","url":null,"abstract":"<div><p>Inflammation is an essential host defense mechanism in response to microbial infection and tissue injury. In addition to its well-established role in infection, inflammation is actively involved in the repair of damaged tissues and restoration of homeostatic conditions after tissue injury. The intensity of the inflammatory response and types of cells involved in inflammation have a significant impact on the quality of tissue repair. Numerous immune cell subtypes participate in tissue repair and regeneration. In particular, immune cell-derived secretants, including cytokines and growth factors, can actively modulate the proliferation of resident stem cells or progenitor cells to facilitate tissue regeneration. These findings highlight the importance of inflammation during tissue repair and regeneration; however, the precise role of immune cells in tissue regeneration remains unclear. In this review, we summarize the current knowledge on the contribution of specific immune cell types to tissue repair and regeneration. We also discuss how inflammation affects the final outcome of tissue regeneration.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 2","pages":"78 - 89"},"PeriodicalIF":6.7,"publicationDate":"2023-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10763785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isolation, structure elucidation, total synthesis, and biosynthesis of dermazolium A, an antibacterial imidazolium metabolite of a vaginal bacterium Dermabacter vaginalis","authors":"Hye Ryeong Kim,&nbsp;Jonghwan Kim,&nbsp;Jae Sik Yu,&nbsp;Bum Soo Lee,&nbsp;Ki Hyun Kim,&nbsp;Chung Sub Kim","doi":"10.1007/s12272-022-01424-z","DOIUrl":"10.1007/s12272-022-01424-z","url":null,"abstract":"<div><p><i>Dermabacter vaginalis</i> is a human-derived bacterium isolated from vaginal fluid of a Korean female in 2016. Although several human-related species in <i>Dermabacter</i> genus have been reported there are few studies on their bioactive metabolites. Dermazolium A (<b>1</b>), a rare imidazolium metabolite, was isolated from <i>D. vaginalis</i> along with five known metabolites (<b>2–6</b>) and their chemical structures were determined by NMR, HRMS, and MS/MS data analysis. Feeding experiments using predicted precursors and biomimetic total synthesis of <b>1</b> corroborated its structure and led to suggestion of biosynthetic pathway of <b>1</b>. Antibacterial tests on the isolated compounds showed that <b>1</b> is a mild antibacterial agent with MIC values of 41 µg/mL against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) USA300, <i>Lacticaseibacillus paracasei</i> subsp. <i>paracasei</i> KCTC 3510 and <i>Brevibacterium epidermidis</i> KCTC 3090.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 1","pages":"35 - 43"},"PeriodicalIF":6.7,"publicationDate":"2023-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-022-01424-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10583373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}