ACS Pharmacology and Translational Science最新文献_第10页

Curcumin: A Potential Weapon in the Prevention and Treatment of Head and Neck Cancer. 姜黄素：预防和治疗头颈癌的潜在武器。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-14 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00518

Kateřina Veselá, Zdeněk Kejík, Michal Masařík, Petr Babula, Petr Dytrych, Pavel Martásek, Milan Jakubek

{"title":"Curcumin: A Potential Weapon in the Prevention and Treatment of Head and Neck Cancer.","authors":"Kateřina Veselá, Zdeněk Kejík, Michal Masařík, Petr Babula, Petr Dytrych, Pavel Martásek, Milan Jakubek","doi":"10.1021/acsptsci.4c00518","DOIUrl":"10.1021/acsptsci.4c00518","url":null,"abstract":"Head and neck cancers (HNC) are aggressive, difficult-to-treat tumors that can be caused by genetic factors but mainly by lifestyle or infection caused by the human papillomavirus. As the sixth most common malignancy, it presents a formidable therapeutic challenge with limited therapeutic modalities. Curcumin, a natural polyphenol, is appearing as a promising multitarget anticancer and antimetastatic agent. Numerous studies have shown that curcumin and its derivatives have the potential to affect signaling pathways (NF-κB, JAK/STAT, and EGFR) and molecular mechanisms that are crucial for the growth and migration of head and neck tumors. Furthermore, its ability to interact with the tumor microenvironment and trigger the immune system may significantly influence the organism's immune response to the tumor. Combining curcumin with conventional therapies such as chemotherapy or radiotherapy may improve the efficacy of treatment and reduce the side effects of treatment, thereby increasing its therapeutic potential. This review is a comprehensive overview that discusses both the benefits and limitations of curcumin and its therapeutic effects in the context of tumor biology, with an emphasis on molecular mechanisms in the context of HNC. This review also includes possibilities to improve the limiting properties of curcumin both in terms of the development of new derivatives, formulations, or combinations with conventional therapies that have potential as a new type of therapy for the treatment of HNC and subsequent use in clinical practice.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3394-3418"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Covalent Modification of p53 by (E)-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one. (E)-1-(4-甲基哌嗪-1-基)-3-(5-硝基呋喃-2-基)丙-2-烯-1-酮对 p53 的共价修饰。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-14 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00447

Kate Brown, Marco Robello, Andrew J Perciaccante, Jerry C Dinan, Tapan K Maity, Gaelyn C Lyons, Jay P Kumar, Stewart R Durell, Harichandra D Tagad, Daniel Schilling, Herman Nikolayevskiy, Robert O'Connor, Ettore Appella, Daniel H Appella, Lisa M Jenkins

{"title":"Covalent Modification of p53 by (E)-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one.","authors":"Kate Brown, Marco Robello, Andrew J Perciaccante, Jerry C Dinan, Tapan K Maity, Gaelyn C Lyons, Jay P Kumar, Stewart R Durell, Harichandra D Tagad, Daniel Schilling, Herman Nikolayevskiy, Robert O'Connor, Ettore Appella, Daniel H Appella, Lisa M Jenkins","doi":"10.1021/acsptsci.4c00447","DOIUrl":"10.1021/acsptsci.4c00447","url":null,"abstract":"TP53 is commonly mutated in cancer, giving rise to loss of wild-type tumor suppressor function and increases in gain-of-function oncogenic roles. Thus, inhibition of mutant p53 and reactivation of wild-type function represents a potential means to target diverse tumor types. (E)-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984), first identified from a high-throughput screen, induces wild-type p53 signaling and antiproliferative effects while inhibiting mutant p53 gain-of-function activities. Here, we investigate the specific mechanism of action of NSC59984 against p53. We found that NSC59984 reacts with thiols via an unusual Michael addition at the α-carbon. Covalent modification of p53 Cys124 and Cys229 was observed both following in vitro reaction and upon treatment of cells. Finally, we used a biotinylated form of NSC59984 and, separately, thermal proteome profiling to examine off-target effects, identifying several metabolic proteins involved in cellular metabolism as potential targets. These results demonstrate that covalent modification of p53 by NSC59984 leads to increased wild-type activity and suggest that potential reaction with metabolic enzymes may contribute to antiproliferative function.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3559-3572"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical Perspectives and Novel Preclinical Models of Malignant Pleural Mesothelioma: A Critical Review. 恶性胸膜间皮瘤的临床前景和新型临床前模型：批判性评论。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-14 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00324

Aliakbar Ebrahimi, Güntülü Ak, Ceren Özel, Hüseyin İzgördü, Hamed Ghorbanpoor, Shabir Hassan, Huseyin Avci, Muzaffer Metintaş

{"title":"Clinical Perspectives and Novel Preclinical Models of Malignant Pleural Mesothelioma: A Critical Review.","authors":"Aliakbar Ebrahimi, Güntülü Ak, Ceren Özel, Hüseyin İzgördü, Hamed Ghorbanpoor, Shabir Hassan, Huseyin Avci, Muzaffer Metintaş","doi":"10.1021/acsptsci.4c00324","DOIUrl":"10.1021/acsptsci.4c00324","url":null,"abstract":"Pleural mesothelioma (PM), a rare malignant tumor explicitly associated with asbestos and erionite exposures, has become a global health problem due to limited treatment options and a poor prognosis, in which the median life expectancy varies depending on the method of treatment. However, the importance of early diagnosis is emphasized, and the practical methods have not matured yet. This study provides a critical overview of PM, addressing various aspects like epidemiology, etiology, diagnosis, treatment options, and the potential use of advanced technologies like microfluidic chip-based models for research and diagnosis. It initially begins with fundamentals of clinical aspects and then discusses the identification of disease-specific biomarkers in patients' serum or plasma samples, which could potentially be used for early diagnosis. A detailed investigation of the sophisticated preclinical models is highlighted. Recent three-dimensional (3D) model accomplishments, including microarchitecture modeling by transwell coculture, spheroids, organoids, 3D bioprinting constructs, and ex vivo tumor slices, are discussed comprehensively. On-chip models that imitate physiological processes, such as detection chips and therapeutic screening chips, are assessed as potential techniques. The review concludes with a critical and constructive discussion of the growing interest in the topic and its limitations and suggestions.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3299-3333"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparison of Protocols to Test Peptide Stability in Blood Plasma and Cell Culture Supernatants. 血浆和细胞培养上清液中多肽稳定性测试方案比较

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-14 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00503

Anna Kohler, Eva-Maria Jülke, Jan Stichel, Annette G Beck-Sickinger

{"title":"Comparison of Protocols to Test Peptide Stability in Blood Plasma and Cell Culture Supernatants.","authors":"Anna Kohler, Eva-Maria Jülke, Jan Stichel, Annette G Beck-Sickinger","doi":"10.1021/acsptsci.4c00503","DOIUrl":"10.1021/acsptsci.4c00503","url":null,"abstract":"Due to their high specificity, peptides are promising candidates in drug development, but fast degradation often limits their biological activity. Thus, a short half-life is one of the major challenges in the development of new peptide therapeutics. Moreover, the enzymatic cleavage of peptides can be a reason for misleading results in biological assays. Peptide stability assays typically consist of incubation, precipitation, and detection steps. However, the current methods differ greatly regarding these three steps, thus limiting the compatibility. Here, we systematically evaluate different parameters of peptide stability assays. First, we quantified and compared the analyte loss during the precipitation of plasma proteins. Especially, broadly used precipitation by strong acids was found to be unsuitable, while mixtures of organic solvents preserved more peptides for further analysis. Next, the stability of four fluorescently labeled model peptides was analyzed in blood plasma and two different cell culture supernatants. Strong variation in the degradation dynamics and patterns was found. Finally, we evaluated the role of fluorescent labeling on peptide stability and compared results to peptides with isotopic labels, underlining the individual advantages of both methods. Altogether, the data provide important parameters for analyzing and comparing the peptide stability.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3618-3625"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Cognitive Restoration Effects of Resveratrol: Insight Molecular through Behavioral Studies in Various Cognitive Impairment Models. 白藜芦醇的认知恢复效应：通过对各种认知障碍模型的行为研究洞察分子。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-10 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00373

Yingrak Boondam, Chaianan Saefoong, Natjanan Niltup, Arnaud Monteil, Worawan Kitphati

{"title":"The Cognitive Restoration Effects of Resveratrol: Insight Molecular through Behavioral Studies in Various Cognitive Impairment Models.","authors":"Yingrak Boondam, Chaianan Saefoong, Natjanan Niltup, Arnaud Monteil, Worawan Kitphati","doi":"10.1021/acsptsci.4c00373","DOIUrl":"10.1021/acsptsci.4c00373","url":null,"abstract":"Cognition is essential for daily activities and progressively deteriorates with age due to various factors leading to cognitive decline. This decline often begins with memory impairment and advances to broader cognitive dysfunctions. Resveratrol (RES), a natural phenolic compound found in red wine, has garnered significant attention for its potential to prevent cognitive decline. This review aims to synthesize the latest preclinical data on the cognitive restorative effects of RES. We highlight RES activities from cellular mechanisms to behavioral outcomes. Evidence from various cognitive impairment models demonstrates that RES exerts neuroprotective effects through multiple mechanisms, including anti-inflammatory, antioxidative, anti-apoptotic, and neurotrophic actions, all of which contribute to cognitive enhancement in behavioral studies. Despite the established role of RES in mitigating memory decline, our review identifies a critical gap in behavioral studies regarding cognitive flexibility. Further research in this domain is recommended. Additionally, species-specific pharmacokinetic differences may account for the inconsistencies between preclinical and clinical outcomes, particularly in rats and humans. We propose that formulations designed to delay gut metabolism through enterohepatic circulation could enhance the translational potential of RES. Furthermore, long-term studies are needed to determine the optimal dose capable of maximizing health benefits without raising toxicity during chronic use.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3334-3357"},"PeriodicalIF":4.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Melatonin Alleviates Albumin-Induced Tubular Cell Injury by Activating Clock-Controlled Nuclear Enriched Abundant Transcript 1-Mediated Proliferation. 褪黑素通过激活时钟控制的核富集丰度转录本 1 介导的增殖缓解白蛋白诱导的肾小管细胞损伤

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-10 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00495

Yen-Sung Huang, Kuo-Cheng Lu, Yu-Tien Chang, Shuk-Man Ka, Cheng-Yi Guo, Hsin-Yi Hsieh, Hsiu-Ming Shih, Huey-Kang Sytwu, Chia-Chao Wu

{"title":"Melatonin Alleviates Albumin-Induced Tubular Cell Injury by Activating Clock-Controlled Nuclear Enriched Abundant Transcript 1-Mediated Proliferation.","authors":"Yen-Sung Huang, Kuo-Cheng Lu, Yu-Tien Chang, Shuk-Man Ka, Cheng-Yi Guo, Hsin-Yi Hsieh, Hsiu-Ming Shih, Huey-Kang Sytwu, Chia-Chao Wu","doi":"10.1021/acsptsci.4c00495","DOIUrl":"10.1021/acsptsci.4c00495","url":null,"abstract":"The pleiotropic and protective effects of melatonin have been demonstrated in a variety of animal models of renal injury. While coding RNAs regulated by melatonin in renal tissues are well identified, the functional involvement of long noncoding RNAs (lncRNAs) in melatonin signaling remains undefined. This study identified nuclear enriched abundant transcript 1 (NEAT1), a clock-controlled lncRNA that was upregulated by melatonin through the BMAL1/CLOCK heterodimer in renal tubular epithelial cells (TECs). Mechanistic studies showed that melatonin enhanced NEAT1 expression via increasing BMAL1 stability and thereby the enrichment of BMAL1 on NEAT1's promoter. Further studies have revealed that NEAT1 promotes the proliferation of TECs by increasing levels of H3K27ac and H3K4me1 at the promoter regions of the proliferation gene MKI67. Treatment of albumin-injured TECs with melatonin promoted proliferation by transactivating NEAT1 and restoring the expression levels of core clock genes and MKI67. Moreover, melatonin treatment ameliorated proteinuria, hypoalbuminemia, and fibrotic lesions, which was correlated with increased levels of core clock genes, H3K27ac, Mki67, and Neat1 in experimental MN kidneys. Melatonin mediates a novel regulatory axis, BMAL1-NEAT1-MKI67, in TEC proliferation, establishing potential therapeutic targets for MN and other renal diseases.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3607-3617"},"PeriodicalIF":4.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Investigation of Programmed Death Ligand-1 as a New Prognostic Biomarker in Pancreatic Cancer Patients. 将程序性死亡配体-1作为胰腺癌患者新的预后生物标记物的研究

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-07 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00490

Abdul Salam, Asif Ali, Umar Nishan, Noaman Khan, Mohamed A Ibrahim, Zafar Iqbal, Nawshad Muhammad, Anum Fayyaz, Fawad Muhammad, Abdul Mateen, Zhiyuan Wu, Saifullah Afridi

{"title":"Investigation of Programmed Death Ligand-1 as a New Prognostic Biomarker in Pancreatic Cancer Patients.","authors":"Abdul Salam, Asif Ali, Umar Nishan, Noaman Khan, Mohamed A Ibrahim, Zafar Iqbal, Nawshad Muhammad, Anum Fayyaz, Fawad Muhammad, Abdul Mateen, Zhiyuan Wu, Saifullah Afridi","doi":"10.1021/acsptsci.4c00490","DOIUrl":"10.1021/acsptsci.4c00490","url":null,"abstract":"Pancreatic cancer is one of the most lethal and fast-growing cancers with a poor prognosis. Herein, we report the expression of programmed death ligand 1 (PD-L1) as a new prognostic biomarker in pancreatic cancer progression analysis at the clinical level. Immunohistochemistry was performed on 86 clinically proven cases of pancreatic cancer tissue microarrays (TMAs) using anti-PD-L1 antibodies. Histoscore was done, and a variety of cutoffs were identified for analyses of the results. The chi-square test and Kaplan-Meier method were used to find the association between pancreatic cancer and various clinicopathological variables and the overall survival of the patients. PD-L1 expression was associated with histological grade and recurrence of the disease for epithelial and stromal staining at 10 histoscores. In addition, PD-L1 expression was strongly associated with lymph node involvement at the stromal 20 histoscore. The tumor stage of pancreatic cancer had an association with PD-L1 expression with epithelial and stromal 20 histoscores for all comparisons. At a stromal 20 histoscore, overall survival in high-low expression of PD-L1 was 7-19 months, and at a nuclear/cytoplasmic 10 histoscore, it was 9-28 months (p = 0.0001), respectively. Overall, PD-L1 overexpression in subcellular compartments was associated with disease aggression phenotypes and poor patient survival. Overexpression of PD-L1 was directly linked to pancreatic cancer progression and a poor survival rate. Therefore, PD-L1 may be used as a prognostic biomarker in the diagnosis, treatment, and management of pancreatic cancer patients.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3585-3591"},"PeriodicalIF":4.9,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhalable Advanced Co-Spray Dried Microparticles/Nanoparticles of a Novel RhoA/Rho Kinase Inhibitor with Lung Surfactant Biomimetic Phospholipids for Targeted Lung Delivery. 新型 RhoA/Rho 激酶抑制剂与肺表面活性剂仿生磷脂的可吸入高级共喷雾干燥微颗粒/纳米颗粒用于肺部靶向递送

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-03 eCollection Date: 2024-10-11 DOI: 10.1021/acsptsci.4c00432

Victor H Ruiz, David Encinas-Basurto, Neftali Ortega-Alarcon, Basanth Babu Eedara, Jeffrey R Fineman, Stephen M Black, Heidi M Mansour

{"title":"Inhalable Advanced Co-Spray Dried Microparticles/Nanoparticles of a Novel RhoA/Rho Kinase Inhibitor with Lung Surfactant Biomimetic Phospholipids for Targeted Lung Delivery.","authors":"Victor H Ruiz, David Encinas-Basurto, Neftali Ortega-Alarcon, Basanth Babu Eedara, Jeffrey R Fineman, Stephen M Black, Heidi M Mansour","doi":"10.1021/acsptsci.4c00432","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00432","url":null,"abstract":"Co-spray dried inhalable powder formulations of fasudil monohydrochloride salt (FMCS) and inhalable lung surfactant-based nanocarriers composed of synthetic phospholipids, zwitterionic DPPC (1,2-palmitoyl-sn-glycero-3-phosphocholine) and anionic DPPG (1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]) sodium salt, were designed and optimized using organic solution advanced spray drying. FMCS can potentially be used for the treatment of various complex pulmonary diseases with this current work focusing on pulmonary arterial hypertension. Comprehensive physicochemical characterization, electron and optical microscopy imaging, thermal analysis, molecular fingerprinting spectroscopy, in vitro aerosol dispersion performance with human dry powder inhaler (DPI) devices, in vitro membrane permeation and drug release, and in vitro human cellular studies were conducted. Well-defined, small, and smooth nanoparticles/microparticles in the solid state were engineered at different molar ratios of FMCS/DPPC/DPPG (25:75, 50:50, and 75:25) and successfully produced as inhalable powders having the properties necessary for targeted pulmonary delivery as dry powder inhalers. In vitro aerosol performance demonstrated excellent aerosol dispersion with different DPI devices. The phospholipid bilayer biophysical properties were confirmed and retained following cospray drying. Sustained release of fasudil drug and in vitro biocompatibility were demonstrated on human lung cells from different airway regions.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 10","pages":"3241-3254"},"PeriodicalIF":4.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intricate Role of the Cyclic Guanosine Monophosphate Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway in Traumatic Brain Injury-Generated Neuroinflammation and Neuronal Death. 单磷酸环鸟苷腺苷合成酶-干扰素基因刺激器（cGAS-STING）通路在创伤性脑损伤引发的神经炎症和神经元死亡中的复杂作用

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-02 eCollection Date: 2024-10-11 DOI: 10.1021/acsptsci.4c00310

Deepali Kumari, Simranjit Kaur, Manoj P Dandekar

{"title":"Intricate Role of the Cyclic Guanosine Monophosphate Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway in Traumatic Brain Injury-Generated Neuroinflammation and Neuronal Death.","authors":"Deepali Kumari, Simranjit Kaur, Manoj P Dandekar","doi":"10.1021/acsptsci.4c00310","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00310","url":null,"abstract":"The secondary insult in the aftermath of traumatic brain injury (TBI) causes detrimental and self-perpetuating alteration in cells, resulting in aberrant function and the death of neuronal cells. The secondary insult is mainly driven by activation of the neuroinflammatory pathway. Among several classical pathways, the cGAS-STING pathway, a primary neuroinflammatory route, encompasses the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptor. Recently, the cGAS-STING research domain has gained exponential attention. The aberrant stimulation of cGAS-STING machinery and corresponding neuroinflammation have also been reported after TBI. In addition to the critical contribution to neuroinflammation, the cGAS-STING signaling also provokes neuronal cell death through various cell death mechanisms. This review highlights the structural and molecular mechanisms of the cGAS-STING machinery associated with TBI. We also focus on the intricate relationship and framework between cGAS-STING signaling and cell death mechanisms (autophagy, apoptosis, pyroptosis, ferroptosis, and necroptosis) in the aftermath of TBI. We suggest that the targeting of cGAS-STING signaling may open new therapeutic strategies to combat neuroinflammation and neurodegeneration in TBI.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 10","pages":"2936-2950"},"PeriodicalIF":4.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel Alkynylamide-Based Nonpeptidic Allosteric Inhibitors for SARS-CoV-2 3-Chymotrypsin-like Protease. 基于炔酰胺的新型非肽异构抑制剂，用于抑制 SARS-CoV-2 3-Chymotrypsin-like 蛋白酶。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-02 eCollection Date: 2024-10-11 DOI: 10.1021/acsptsci.4c00369

Jian Xue, Hongtao Li, Ruyu Wang, Meiting Wang, Xixiang Chen, Yaqi Deng, Jiani Lu, Yexi Li, Yuheng Song, Jianrong Xu, Tong Zhu, Lili Chen, Shunying Liu

{"title":"Novel Alkynylamide-Based Nonpeptidic Allosteric Inhibitors for SARS-CoV-2 3-Chymotrypsin-like Protease.","authors":"Jian Xue, Hongtao Li, Ruyu Wang, Meiting Wang, Xixiang Chen, Yaqi Deng, Jiani Lu, Yexi Li, Yuheng Song, Jianrong Xu, Tong Zhu, Lili Chen, Shunying Liu","doi":"10.1021/acsptsci.4c00369","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00369","url":null,"abstract":"Although the coronavirus disease 2019 (COVID-19) crisis has passed, there remains a necessity for continuous efforts toward developing more targeted drugs and preparing for potential future virus attacks. Currently, most of the drugs received authorization for the treatment of COVID-19 have exhibited several limitations, such as poor metabolic stability, formidable preparation, and uncertain effectiveness. It is still significant to develop novel, structurally diverse small-molecule antiviral drugs targeting SARS-CoV-2 3-chymotrypsin-like protease (3CLpro). Herein, we report a class of alkynylamide-based nonpeptidic 3CLpro inhibitors that can be prepared conveniently by our previously developed one-pot synthetic method. The structure-activity relationships of alkynylamides as SARS-CoV-2 3CLpro inhibitors have been carefully investigated and discussed in this study. The two stereoisomers of the resulting molecules exhibit stereoselective interaction with 3CLpro, and the optimized compound (S,R)-4y inhibits 3CLpro with high potency (IC50 = 0.43 μM), low cytotoxicity, and acceptable cell permeability. Compound (S,R)-4y presents as a noncovalent inhibitor of 3CLpro against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. The Lineweaver-Burk plots, binding energy, surface plasmon resonance, and molecular docking studies suggest that (S,R)-4y specifically binds to an allosteric pocket of the SARS-CoV-2 3CLpro. These findings provide a novel class of nonpeptidic alkynylamide-based allosteric inhibitors with high selectivity against SARS-CoV-2 3CLpro featured by a simplified one-pot synthesis at room temperature in air.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 10","pages":"3170-3191"},"PeriodicalIF":4.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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