Aging is usually accompanied by mitochondrial dysfunction, reduced energy levels, and cell death in the brain and other tissues. Mitochondria play a crucial role in maintaining cellular energy through oxidative phosphorylation (OXPHOS). However, OXPHOS is impaired as the mitochondrial oxygen supply decreases with age. We explored whether pharmacologically increased oxygen diffusion by crocetin can restore OXPHOS and help delay the aging of the brain and other vital organs. We found that aged mice treated with crocetin for four months displayed significantly improved memory behavior, neuromuscular coordination, and ATP and NAD+ levels in the brain and other vital organs, leading to an increased median life span. The transcriptomic analysis of hippocampi from crocetin-treated mice revealed that enhanced brain energy level was caused by the upregulation of genes linked to OXPHOS, and their expression was close to that in young mice. The chronic treatment of aged astrocytes also showed improved mitochondrial membrane potential and energy state of the cells. Moreover, chronic treatment with crocetin did not cause any oxidative stress. Our data suggest that restoring OXPHOS and the normal energy state of the cell can delay aging and enhance longevity. Therefore, molecules such as crocetin should be further explored to treat age-related diseases.
衰老通常伴随着线粒体功能障碍、能量水平降低以及大脑和其他组织的细胞死亡。线粒体通过氧化磷酸化（OXPHOS）在维持细胞能量方面发挥着至关重要的作用。然而，随着年龄的增长，线粒体的供氧量减少，OXPHOS 的作用也随之减弱。我们探讨了通过药理学方法增加西番莲素的氧扩散是否能恢复 OXPHOS 并帮助延缓大脑和其他重要器官的衰老。我们发现，使用西西替酯治疗四个月的老年小鼠在记忆行为、神经肌肉协调性、大脑和其他重要器官的 ATP 和 NAD+ 水平等方面都有明显改善，从而延长了小鼠的中位寿命。克罗西汀治疗小鼠海马的转录组分析表明，大脑能量水平的提高是由与氧合磷酸酶相关的基因上调引起的，这些基因的表达与年轻小鼠接近。对老年星形胶质细胞的慢性治疗也显示出线粒体膜电位和细胞能量状态的改善。此外，用鳄梨素进行慢性治疗不会引起任何氧化应激。我们的数据表明，恢复细胞的 OXPHOS 和正常能量状态可以延缓衰老，延年益寿。因此，应该进一步探索用鳄梨素等分子来治疗与年龄有关的疾病。
{"title":"Crocetin Delays Brain and Body Aging by Increasing Cellular Energy Levels in Aged C57BL/6J Mice","authors":"Sushil Choudhary, Vishnu Kumar, Kuhu Sharma, Abhishek Gour, Ashish Sahrawat, Anshika Jotshi, Diksha Manhas, Utpal Nandi, Sandip B. Bharate, Zabeer Ahmed, Ajay Kumar","doi":"10.1021/acsptsci.4c00151","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00151","url":null,"abstract":"Aging is usually accompanied by mitochondrial dysfunction, reduced energy levels, and cell death in the brain and other tissues. Mitochondria play a crucial role in maintaining cellular energy through oxidative phosphorylation (OXPHOS). However, OXPHOS is impaired as the mitochondrial oxygen supply decreases with age. We explored whether pharmacologically increased oxygen diffusion by crocetin can restore OXPHOS and help delay the aging of the brain and other vital organs. We found that aged mice treated with crocetin for four months displayed significantly improved memory behavior, neuromuscular coordination, and ATP and NAD<sup>+</sup> levels in the brain and other vital organs, leading to an increased median life span. The transcriptomic analysis of hippocampi from crocetin-treated mice revealed that enhanced brain energy level was caused by the upregulation of genes linked to OXPHOS, and their expression was close to that in young mice. The chronic treatment of aged astrocytes also showed improved mitochondrial membrane potential and energy state of the cells. Moreover, chronic treatment with crocetin did not cause any oxidative stress. Our data suggest that restoring OXPHOS and the normal energy state of the cell can delay aging and enhance longevity. Therefore, molecules such as crocetin should be further explored to treat age-related diseases.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1021/acsptsci.4c00306
Mohamed Hemida, Rodell C. Barrientos, Caleb Kinsey, Nathan Kuster, Mayank Bhavsar, Armen G. Beck, Heather Wang, Andrew Singh, Pankaj Aggarwal, Arthur Arcinas, Malini Mukherjee, Emmanuel Appiah-Amponsah, Erik L. Regalado
The growing use of adjuvants in the fast-paced formulation of new vaccines has created an unprecedented need for meaningful analytical assays that deliver reliable quantitative data from complex adjuvant and adjuvant–antigen mixtures. Due to their complex chemical and physical properties, method development for the separation of vaccine adjuvants is considered a highly challenging and laborious task. Reversed-phase liquid chromatography (RPLC) is among the most important tests in the (bio)pharmaceutical industry for release and stability indicating measurements including adjuvant content, identity, and purity profile. However, the time constraints of developing “on-demand” robust quantitative methods prior to each change in formulation can easily lead to sample analysis becoming a bottleneck in vaccine development. Herein, a simple and efficient generic analytical framework capable of chromatographically resolving the most commonly used non-aluminum-based adjuvants across academic and industrial sectors is introduced. This was designed to seek a more proactive approach for fast-paced assay development endeavors that evolved from extensive stationary phase screening in conjunction with multifactorial in silico simulations of adjuvant retention time (RT) as a function of gradient time, temperature, organic modifier blending, and buffer concentration. The multifactorial retention models yield 3D resolution maps with excellent baseline separation of all adjuvants in a single run, which was found to be very accurate, with differences between experimental and simulated retention times of less than 1%. The analytical framework described here also includes the introduction of a more versatile approach to method development by introducing a dynamic RT database for adjuvants covering the entire library of adjuvants with broad mechanisms of action across numerous vaccine formulations with excellent linearity, accuracy, precision, and specificity. The power of this framework was also demonstrated with numerous analytical assays that can be generated rapidly from simulations guiding vaccine processes in the development of new adjuvant formulations. Analytical assay in this work covers content, purity profile by LC with diode array detector (DAD) and charged aerosol detector (CAD), and component identification by LC with mass spectrometry (MS) across complex vaccine formulations, including the use of surfactants (e.g., polysorbates) as well as their separation from adjuvant targets.
{"title":"Digitally Enabled Generic Analytical Framework Accelerating the Pace of Liquid Chromatography Method Development for Vaccine Adjuvant Formulations","authors":"Mohamed Hemida, Rodell C. Barrientos, Caleb Kinsey, Nathan Kuster, Mayank Bhavsar, Armen G. Beck, Heather Wang, Andrew Singh, Pankaj Aggarwal, Arthur Arcinas, Malini Mukherjee, Emmanuel Appiah-Amponsah, Erik L. Regalado","doi":"10.1021/acsptsci.4c00306","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00306","url":null,"abstract":"The growing use of adjuvants in the fast-paced formulation of new vaccines has created an unprecedented need for meaningful analytical assays that deliver reliable quantitative data from complex adjuvant and adjuvant–antigen mixtures. Due to their complex chemical and physical properties, method development for the separation of vaccine adjuvants is considered a highly challenging and laborious task. Reversed-phase liquid chromatography (RPLC) is among the most important tests in the (bio)pharmaceutical industry for release and stability indicating measurements including adjuvant content, identity, and purity profile. However, the time constraints of developing “on-demand” robust quantitative methods prior to each change in formulation can easily lead to sample analysis becoming a bottleneck in vaccine development. Herein, a simple and efficient generic analytical framework capable of chromatographically resolving the most commonly used non-aluminum-based adjuvants across academic and industrial sectors is introduced. This was designed to seek a more proactive approach for fast-paced assay development endeavors that evolved from extensive stationary phase screening in conjunction with multifactorial <i>in silico</i> simulations of adjuvant retention time (RT) as a function of gradient time, temperature, organic modifier blending, and buffer concentration. The multifactorial retention models yield 3D resolution maps with excellent baseline separation of all adjuvants in a single run, which was found to be very accurate, with differences between experimental and simulated retention times of less than 1%. The analytical framework described here also includes the introduction of a more versatile approach to method development by introducing a dynamic RT database for adjuvants covering the entire library of adjuvants with broad mechanisms of action across numerous vaccine formulations with excellent linearity, accuracy, precision, and specificity. The power of this framework was also demonstrated with numerous analytical assays that can be generated rapidly from simulations guiding vaccine processes in the development of new adjuvant formulations. Analytical assay in this work covers content, purity profile by LC with diode array detector (DAD) and charged aerosol detector (CAD), and component identification by LC with mass spectrometry (MS) across complex vaccine formulations, including the use of surfactants (<i>e.g.</i>, polysorbates) as well as their separation from adjuvant targets.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Varicose veins, a prevalent condition that primarily affects the lower limbs, present significant hurdles in diagnosis and treatment due to their diverse causes. This study dives into the complex hormonal, environmental, and molecular elements that influence varicose vein genesis, emphasizing the need for precise diagnostic methods and changing therapy approaches to improve patient outcomes. It investigates the epidemiology and demographic distribution of varicose veins, delves into their pathophysiology, and assesses diagnostic methods such as duplex ultrasonography and the CEAP classification system. In addition, the study discusses novel therapies such as sclerotherapy and endovenous thermal ablation, as well as the effectiveness of existing diagnostic methods in detecting chronic venous illnesses. By investigating venous wall remodeling and inflammatory pathways, it gives a thorough knowledge of varicose vein formation. The study calls for future research that focuses on patient-centered methods, bioengineering advances, digital health applications, and genetic and molecular studies to improve the accuracy and effectiveness of vascular therapy. As a result, a multidisciplinary literature analysis was done, drawing on insights from vascular medicine, epidemiology, genetics, and pharmacology, to consolidate existing knowledge and identify possibilities to enhance varicose vein diagnosis, treatment, and patient care outcomes.
{"title":"Innovative Approaches and Future Directions in the Management and Understanding of Varicose Veins: A Systematic Review","authors":"Aaqib Javaid, Abutwaibe KA, Sherilraj PM, Kanika Arora, Shyam Lal Mudavath","doi":"10.1021/acsptsci.4c00430","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00430","url":null,"abstract":"Varicose veins, a prevalent condition that primarily affects the lower limbs, present significant hurdles in diagnosis and treatment due to their diverse causes. This study dives into the complex hormonal, environmental, and molecular elements that influence varicose vein genesis, emphasizing the need for precise diagnostic methods and changing therapy approaches to improve patient outcomes. It investigates the epidemiology and demographic distribution of varicose veins, delves into their pathophysiology, and assesses diagnostic methods such as duplex ultrasonography and the CEAP classification system. In addition, the study discusses novel therapies such as sclerotherapy and endovenous thermal ablation, as well as the effectiveness of existing diagnostic methods in detecting chronic venous illnesses. By investigating venous wall remodeling and inflammatory pathways, it gives a thorough knowledge of varicose vein formation. The study calls for future research that focuses on patient-centered methods, bioengineering advances, digital health applications, and genetic and molecular studies to improve the accuracy and effectiveness of vascular therapy. As a result, a multidisciplinary literature analysis was done, drawing on insights from vascular medicine, epidemiology, genetics, and pharmacology, to consolidate existing knowledge and identify possibilities to enhance varicose vein diagnosis, treatment, and patient care outcomes.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It is widely said that a healthy intestinal environment plays an essential role in better mental condition. One known dietary nutrient that maintains the intestinal environment is dietary fiber. A recent study showed that maintaining the intestinal environment with dietary fiber alleviated symptoms of psychiatric disorders in animals. However, such effects have only been reported with soluble fiber, which is highly fermentable and promotes short-chain fatty acid (SCFA) production, and not with insoluble fiber. Therefore, we aimed to verify whether insoluble fiber, such as cellulose, can alter emotion via changes in the gut. We divided mice into two groups and fed either a standard diet (SD, which contains both insoluble and soluble dietary fibers) or a cellulose-rich diet (CRD, which contains cellulose alone as the dietary fibers). We found that CRD-fed mice display increased anxiety-like behavior. CRD-fed animals also showed decreased intestinal SCFA levels along with increased intestinal permeability, dysmotility, and hypersensitivity. This behavioral and physiological effect of CRD has been completely abolished in vagotomized mice, indicating the direct link between intestinal environment exacerbation to the emotion through the gut-brain axis. Additionally, we found that amygdalar dopamine signaling has been modified in CRD-fed animals, and the opioid antagonist abolished this dopaminergic modification as well as CRD-induced anxiety. Altogether, our findings indicate that consumption of cellulose alone as the dietary fiber may evoke intestinal abnormalities, which fire the vagus nerve, then the opioidergic system, and amygdalar dopamine upregulation, resulting in the enhancement of anxiety.
{"title":"A Cellulose-Rich Diet Disrupts Gut Homeostasis and Leads to Anxiety through the Gut-Brain Axis","authors":"Kaede Ito, Haruka Hosoki, Yuya Kasai, Hiroyuki Sasaki, Atsushi Haraguchi, Shigenobu Shibata, Chihiro Nozaki","doi":"10.1021/acsptsci.4c00270","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00270","url":null,"abstract":"It is widely said that a healthy intestinal environment plays an essential role in better mental condition. One known dietary nutrient that maintains the intestinal environment is dietary fiber. A recent study showed that maintaining the intestinal environment with dietary fiber alleviated symptoms of psychiatric disorders in animals. However, such effects have only been reported with soluble fiber, which is highly fermentable and promotes short-chain fatty acid (SCFA) production, and not with insoluble fiber. Therefore, we aimed to verify whether insoluble fiber, such as cellulose, can alter emotion via changes in the gut. We divided mice into two groups and fed either a standard diet (SD, which contains both insoluble and soluble dietary fibers) or a cellulose-rich diet (CRD, which contains cellulose alone as the dietary fibers). We found that CRD-fed mice display increased anxiety-like behavior. CRD-fed animals also showed decreased intestinal SCFA levels along with increased intestinal permeability, dysmotility, and hypersensitivity. This behavioral and physiological effect of CRD has been completely abolished in vagotomized mice, indicating the direct link between intestinal environment exacerbation to the emotion through the gut-brain axis. Additionally, we found that amygdalar dopamine signaling has been modified in CRD-fed animals, and the opioid antagonist abolished this dopaminergic modification as well as CRD-induced anxiety. Altogether, our findings indicate that consumption of cellulose alone as the dietary fiber may evoke intestinal abnormalities, which fire the vagus nerve, then the opioidergic system, and amygdalar dopamine upregulation, resulting in the enhancement of anxiety.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"97 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1021/acsptsci.4c00229
Ben Boyarko, Sonia Podvin, Barry Greenberg, Steven Arnold, Almudena Maroto Juanes, Rik van der Kant, Lawrence Goldstein, Jeremiah D. Momper, Anne Bang, James Silverman, Howard H. Feldman, Vivian Hook
Therapeutic research and development for Alzheimer’s disease (AD) has been an area of intense research to alleviate memory loss and neurodegeneration. There is growing interest in drug repositioning and repurposing strategies for FDA-approved medications as potential candidates that may further advance AD therapeutics. The FDA drug efavirenz has been investigated as a candidate drug for repurposing as an AD medication. The proposed mechanism of action of efavirenz (at low doses) is the activation of the neuron-specific enzyme CYP46A1 that converts excess brain cholesterol into 24-hydroxycholesterol (24-HC) that is exported to the periphery. Efavirenz at a low dose was found to improve memory deficit in the 5XFAD model of AD that was accompanied by elevated 24-HC and reduction in Aβ; furthermore, efavirenz reduced pTau and excess cholesterol levels in human iPSC-derived Alzheimer’s neurons. The low dose of efavirenz used in the AD mouse model to increase 24-HC contrasts with the use of more than 100-fold higher doses of efavirenz for clinical treatment of human immunodeficiency virus (HIV) through inhibition of reverse transcriptase. Low doses of efavirenz may avoid neurotoxic adverse effects that occur at high efavirenz doses used for HIV treatment. This review evaluates the drug properties of efavirenz with respect to its preclinical data on regulating memory deficit, pharmacokinetics, pharmacodynamics, metabolites, and genetic variabilities in drug metabolism as well as its potential adverse effects. These analyses discuss the challenges and questions that should be addressed in future studies to consider the opportunity for low dose efavirenz as a candidate for AD drug development.
{"title":"Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer’s Disease Therapeutics","authors":"Ben Boyarko, Sonia Podvin, Barry Greenberg, Steven Arnold, Almudena Maroto Juanes, Rik van der Kant, Lawrence Goldstein, Jeremiah D. Momper, Anne Bang, James Silverman, Howard H. Feldman, Vivian Hook","doi":"10.1021/acsptsci.4c00229","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00229","url":null,"abstract":"Therapeutic research and development for Alzheimer’s disease (AD) has been an area of intense research to alleviate memory loss and neurodegeneration. There is growing interest in drug repositioning and repurposing strategies for FDA-approved medications as potential candidates that may further advance AD therapeutics. The FDA drug efavirenz has been investigated as a candidate drug for repurposing as an AD medication. The proposed mechanism of action of efavirenz (at low doses) is the activation of the neuron-specific enzyme CYP46A1 that converts excess brain cholesterol into 24-hydroxycholesterol (24-HC) that is exported to the periphery. Efavirenz at a low dose was found to improve memory deficit in the 5XFAD model of AD that was accompanied by elevated 24-HC and reduction in Aβ; furthermore, efavirenz reduced pTau and excess cholesterol levels in human iPSC-derived Alzheimer’s neurons. The low dose of efavirenz used in the AD mouse model to increase 24-HC contrasts with the use of more than 100-fold higher doses of efavirenz for clinical treatment of human immunodeficiency virus (HIV) through inhibition of reverse transcriptase. Low doses of efavirenz may avoid neurotoxic adverse effects that occur at high efavirenz doses used for HIV treatment. This review evaluates the drug properties of efavirenz with respect to its preclinical data on regulating memory deficit, pharmacokinetics, pharmacodynamics, metabolites, and genetic variabilities in drug metabolism as well as its potential adverse effects. These analyses discuss the challenges and questions that should be addressed in future studies to consider the opportunity for low dose efavirenz as a candidate for AD drug development.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1021/acsptsci.4c00358
Bocheng Wu, Subhasish Tapadar, Zhiping Ruan, Carrie Q. Sun, Rebecca S. Arnold, Alexis Johnston, Jeremiah O. Olugbami, Uche Arunsi, David A. Gaul, John A. Petros, Tatsuya Kobayashi, Dan G. Duda, Adegboyega K. Oyelere
Hepatocellular carcinoma (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylase (HDAC) activation. However, inhibiting HDACs─an effective treatment for lymphomas─has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 (3) showed a favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53, showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8+ to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Transcriptomic analysis revealed that STR-V-53 primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.
{"title":"A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy","authors":"Bocheng Wu, Subhasish Tapadar, Zhiping Ruan, Carrie Q. Sun, Rebecca S. Arnold, Alexis Johnston, Jeremiah O. Olugbami, Uche Arunsi, David A. Gaul, John A. Petros, Tatsuya Kobayashi, Dan G. Duda, Adegboyega K. Oyelere","doi":"10.1021/acsptsci.4c00358","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00358","url":null,"abstract":"Hepatocellular carcinoma (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylase (HDAC) activation. However, inhibiting HDACs─an effective treatment for lymphomas─has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound <b>STR-V-53</b> (<b>3</b>) showed a favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, <b>STR-V-53</b>, showed greater in vivo efficacy. Moreover, <b>STR-V-53</b> combined with anti-PD1 therapy increased the CD8<sup>+</sup> to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Transcriptomic analysis revealed that <b>STR-V-53</b> primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACi <b>STR-V-53</b> is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1021/acsptsci.4c00419
Luca Digiacomo, Serena Renzi, Andrea Pirrottina, Heinz Amenitsch, Valentina De Lorenzi, Daniela Pozzi, Francesco Cardarelli, Giulio Caracciolo
Polyethylene glycol (PEG) is a common surface modification for lipid nanoparticles (LNPs) to improve their stability and in vivo circulation time. However, the impact of PEGylation on LNP cellular uptake remains poorly understood. To tackle this issue, we systematically compared plain and PEGylated LNPs by combining dynamic light scattering, electrophoretic light scattering, and synchrotron small-angle X-ray scattering (SAXS) that unveils a striking similarity in size and core structure but a significant reduction in surface charge. Upon administration to human embryonic kidney (HEK 293) cells, plain and PEGylated LNPs were internalized through different endocytic routes, as revealed by spatiotemporal correlation spectroscopy. An imaging-derived mean square displacement (iMSD) analysis shows that PEGylated LNPs exhibit a significantly stronger preference for caveolae-mediated endocytosis (CAV) and clathrin-mediated endocytosis (CME) pathways compared to plain LNPs, with these latter being better tailored to MCR-dependent internalization and trafficking. This suggests that PEG plays a crucial role in directing LNPs toward specific cellular uptake routes. Further studies should explore how PEG-mediated endocytosis impacts intracellular trafficking and ultimately translates to therapeutic efficacy, guiding the design of next-generation LNP delivery systems.
{"title":"PEGylation-Dependent Cell Uptake of Lipid Nanoparticles Revealed by Spatiotemporal Correlation Spectroscopy","authors":"Luca Digiacomo, Serena Renzi, Andrea Pirrottina, Heinz Amenitsch, Valentina De Lorenzi, Daniela Pozzi, Francesco Cardarelli, Giulio Caracciolo","doi":"10.1021/acsptsci.4c00419","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00419","url":null,"abstract":"Polyethylene glycol (PEG) is a common surface modification for lipid nanoparticles (LNPs) to improve their stability and in vivo circulation time. However, the impact of PEGylation on LNP cellular uptake remains poorly understood. To tackle this issue, we systematically compared plain and PEGylated LNPs by combining dynamic light scattering, electrophoretic light scattering, and synchrotron small-angle X-ray scattering (SAXS) that unveils a striking similarity in size and core structure but a significant reduction in surface charge. Upon administration to human embryonic kidney (HEK 293) cells, plain and PEGylated LNPs were internalized through different endocytic routes, as revealed by spatiotemporal correlation spectroscopy. An imaging-derived mean square displacement (iMSD) analysis shows that PEGylated LNPs exhibit a significantly stronger preference for caveolae-mediated endocytosis (CAV) and clathrin-mediated endocytosis (CME) pathways compared to plain LNPs, with these latter being better tailored to MCR-dependent internalization and trafficking. This suggests that PEG plays a crucial role in directing LNPs toward specific cellular uptake routes. Further studies should explore how PEG-mediated endocytosis impacts intracellular trafficking and ultimately translates to therapeutic efficacy, guiding the design of next-generation LNP delivery systems.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1021/acsptsci.4c00278
Arun Upadhyay, Vibhuti Joshi
Ubiquitin (Ub) is often considered a structurally conserved protein. Ubiquitination plays a prominent role in the regulation of physiological pathways. Since the first mention of Ub in protein degradation pathways, a plethora of nonproteolytic functions of this post-translational modification have been identified and investigated in detail. In addition, several other structurally and functionally related proteins have been identified and investigated for their Ub-like structures and functions. Ubiquitination and Ub-like modifications play vital roles in modulating the pathways involved in crucial biological processes and thus affect the global proteome. In this Review, we provide a snapshot of pathways, substrates, diseases, and novel therapeutic targets that are associated with ubiquitination or Ub-like modifications. In the past few years, a large number of proteomic studies have identified pools of ubiquitinated proteins (ubiquitylomes) involved or induced in healthy or stressed conditions. These comprehensive studies involving identification of new ubiquitination substrates and sites contribute enormously to our understanding of ubiquitination in more depth. However, with the current tools, there are certain limitations that need to be addressed. We review recent technological advancements in ubiquitylomic studies and their limitations and challenges. Overall, large-scale ubiquitylomic studies contribute toward understanding global ubiquitination in the contexts of normal and disease conditions.
{"title":"The Ubiquitin Tale: Current Strategies and Future Challenges","authors":"Arun Upadhyay, Vibhuti Joshi","doi":"10.1021/acsptsci.4c00278","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00278","url":null,"abstract":"Ubiquitin (Ub) is often considered a structurally conserved protein. Ubiquitination plays a prominent role in the regulation of physiological pathways. Since the first mention of Ub in protein degradation pathways, a plethora of nonproteolytic functions of this post-translational modification have been identified and investigated in detail. In addition, several other structurally and functionally related proteins have been identified and investigated for their Ub-like structures and functions. Ubiquitination and Ub-like modifications play vital roles in modulating the pathways involved in crucial biological processes and thus affect the global proteome. In this Review, we provide a snapshot of pathways, substrates, diseases, and novel therapeutic targets that are associated with ubiquitination or Ub-like modifications. In the past few years, a large number of proteomic studies have identified pools of ubiquitinated proteins (ubiquitylomes) involved or induced in healthy or stressed conditions. These comprehensive studies involving identification of new ubiquitination substrates and sites contribute enormously to our understanding of ubiquitination in more depth. However, with the current tools, there are certain limitations that need to be addressed. We review recent technological advancements in ubiquitylomic studies and their limitations and challenges. Overall, large-scale ubiquitylomic studies contribute toward understanding global ubiquitination in the contexts of normal and disease conditions.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1021/acsptsci.4c00418
Lisa Gould, Morteza Mahmoudi
Diabetic foot ulcers (DFUs) pose a significant challenge in wound care due to their chronic nature and impaired healing processes. This study examines the biogenic amines and small molecule metabolites present in DFU wound exudates to identify their potential roles in wound healing. Under an IRB-approved protocol, wound fluid samples were collected from 25 diabetic patients and analyzed using ultrahigh-pressure liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. The analysis identified 721 metabolites, with 402 confirmed through stringent criteria. Key metabolites significantly contributing to the wound exudates include betaine, lactic acid, carnitine, choline, creatine, and metformin (a widely used first-line treatment for type 2 diabetes). These molecules are known to influence wound healing processes, such as collagen synthesis, angiogenesis, inflammation modulation, and energy metabolism. Notably, the presence of drugs such as metformin and beclomethasone in the exudates suggests significant pharmacodynamic interactions that could influence wound healing. Specifically, we discovered that the combined use of insulin and metformin administered systemically significantly increased the concentration of metformin in the wound exudates (from 0.3% ± 0.0 to 3.1% ± 3.4; p = 0.00 49). This study highlights the complexity of DFU exudate composition and underscores the potential for targeted metabolic profiling to develop personalized wound care strategies.
{"title":"Analysis of Biogenic Amines and Small Molecule Metabolites in Human Diabetic Wound Ulcer Exudate","authors":"Lisa Gould, Morteza Mahmoudi","doi":"10.1021/acsptsci.4c00418","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00418","url":null,"abstract":"Diabetic foot ulcers (DFUs) pose a significant challenge in wound care due to their chronic nature and impaired healing processes. This study examines the biogenic amines and small molecule metabolites present in DFU wound exudates to identify their potential roles in wound healing. Under an IRB-approved protocol, wound fluid samples were collected from 25 diabetic patients and analyzed using ultrahigh-pressure liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. The analysis identified 721 metabolites, with 402 confirmed through stringent criteria. Key metabolites significantly contributing to the wound exudates include betaine, lactic acid, carnitine, choline, creatine, and metformin (a widely used first-line treatment for type 2 diabetes). These molecules are known to influence wound healing processes, such as collagen synthesis, angiogenesis, inflammation modulation, and energy metabolism. Notably, the presence of drugs such as metformin and beclomethasone in the exudates suggests significant pharmacodynamic interactions that could influence wound healing. Specifically, we discovered that the combined use of insulin and metformin administered systemically significantly increased the concentration of metformin in the wound exudates (from 0.3% ± 0.0 to 3.1% ± 3.4; <i>p</i> = 0.00 49). This study highlights the complexity of DFU exudate composition and underscores the potential for targeted metabolic profiling to develop personalized wound care strategies.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metastasis stands as a prime contributor to triple-negative breast cancer (TNBC) associated mortality worldwide, presenting heightened severity and significant challenges due to limited treatment options. Addressing TNBC metastasis necessitates innovative approaches and novel therapeutics to specifically target its propensity for dissemination to distant organs. Targeted therapies capable of reversing epithelial-to-mesenchymal transition (EMT) play a crucial role in suppressing metastasis and enhancing the treatment response. Beauvericin, a promising fungal secondary metabolite, exhibits significant potential in diminishing the viability of EMT-induced TNBC cells by triggering intracellular oxidative stress, as evidenced by an enhanced reactive oxygen species level and reduced mitochondrial transmembrane potential. In monolayer cultures, it has exhibited an IC50 of 2.3 μM in both MDA-MB-468 and MDA-MB-231 cells, while in 3D spheroids, the IC50 values are 9.7 and 7.1 μM, respectively. Beauvericin has also reduced the migratory capability of MDA-MB-468 and MDA-MB-231 cells by 1.5- and 1.7-fold, respectively. Both qRT-PCR and Western blot analysis have shown significant upregulation in the expression of epithelial marker (E-cadherin) and downregulation in the expression of mesenchymal markers (N-cadherin, vimentin, Snail, Slug, and β-catenin), following treatment, indicating reversal of EMT. Furthermore, beauvericin has suppressed the Notch signaling pathway by substantially downregulating Notch-1, Notch-3, Hes-1, and cyclinD3 expression and induced autophagy as observed by elevated expression of autophagy markers LC3 and Beclin-1. In conclusion, beauvericin has successfully downregulated TNBC cell survival by inducing oxidative stress and suppressed their migratory potential by reversing EMT through the inhibition of Notch signaling and activation of autophagy.
{"title":"Beauvericin Reverses Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer Cells through Regulation of Notch Signaling and Autophagy","authors":"Arupam Patra, Arisha Arora, Siddhartha Sankar Ghosh, Gurvinder Kaur Saini","doi":"10.1021/acsptsci.4c00370","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00370","url":null,"abstract":"Metastasis stands as a prime contributor to triple-negative breast cancer (TNBC) associated mortality worldwide, presenting heightened severity and significant challenges due to limited treatment options. Addressing TNBC metastasis necessitates innovative approaches and novel therapeutics to specifically target its propensity for dissemination to distant organs. Targeted therapies capable of reversing epithelial-to-mesenchymal transition (EMT) play a crucial role in suppressing metastasis and enhancing the treatment response. Beauvericin, a promising fungal secondary metabolite, exhibits significant potential in diminishing the viability of EMT-induced TNBC cells by triggering intracellular oxidative stress, as evidenced by an enhanced reactive oxygen species level and reduced mitochondrial transmembrane potential. In monolayer cultures, it has exhibited an IC<sub>50</sub> of 2.3 μM in both MDA-MB-468 and MDA-MB-231 cells, while in 3D spheroids, the IC<sub>50</sub> values are 9.7 and 7.1 μM, respectively. Beauvericin has also reduced the migratory capability of MDA-MB-468 and MDA-MB-231 cells by 1.5- and 1.7-fold, respectively. Both qRT-PCR and Western blot analysis have shown significant upregulation in the expression of epithelial marker (E-cadherin) and downregulation in the expression of mesenchymal markers (N-cadherin, vimentin, Snail, Slug, and β-catenin), following treatment, indicating reversal of EMT. Furthermore, beauvericin has suppressed the Notch signaling pathway by substantially downregulating Notch-1, Notch-3, Hes-1, and cyclinD3 expression and induced autophagy as observed by elevated expression of autophagy markers LC3 and Beclin-1. In conclusion, beauvericin has successfully downregulated TNBC cell survival by inducing oxidative stress and suppressed their migratory potential by reversing EMT through the inhibition of Notch signaling and activation of autophagy.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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