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Faris A, Ibrahim IM, Alnajjar R, Hadni H, Bhat MA, Yaseen M, Chakraborty S, Alsakhen N, Shamkh IM, Mabood F, M Naglah A, Ullah I, Ziedan N, Elhallaoui M. QSAR-driven screening uncovers and designs novel pyrimidine-4,6-diamine derivatives as potent JAK3 inhibitors. J Biomol Struct Dyn 2025; 43:757-786. [PMID: 38059345 DOI: 10.1080/07391102.2023.2283168] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/08/2023] [Indexed: 12/08/2023]
Abstract
This study presents a robust and integrated methodology that harnesses a range of computational techniques to facilitate the design and prediction of new inhibitors targeting the JAK3/STAT pathway. This methodology encompasses several strategies, including QSAR analysis, pharmacophore modeling, ADMET prediction, covalent docking, molecular dynamics (MD) simulations, and the calculation of binding free energies (MM/GBSA). An efficacious QSAR model was meticulously crafted through the employment of multiple linear regression (MLR). The initial MLR model underwent further refinement employing an artificial neural network (ANN) methodology aimed at minimizing predictive errors. Notably, both MLR and ANN exhibited commendable performance, showcasing R2 values of 0.89 and 0.95, respectively. The model's precision was assessed via leave-one-out cross-validation (CV) yielding a Q2 value of 0.65, supplemented by rigorous Y-randomization. , The pharmacophore model effectively differentiated between active and inactive drugs, identifying potential JAK3 inhibitors, and demonstrated validity with an ROC value of 0.86. The newly discovered and designed inhibitors exhibited high inhibitory potency, ranging from 6 to 8, as accurately predicted by the QSAR models. Comparative analysis with FDA-approved Tofacitinib revealed that the new compounds exhibited promising ADMET properties and strong covalent docking (CovDock) interactions. The stability of the new discovered and designed inhibitors within the JAK3 binding site was confirmed through 500 ns MD simulations, while MM/GBSA calculations supported their binding affinity. Additionally, a retrosynthetic study was conducted to facilitate the synthesis of these potential JAK3/STAT inhibitors. The overall integrated approach demonstrates the feasibility of designing novel JAK3/STAT inhibitors with robust efficacy and excellent ADMET characteristics that surpass Tofacitinib by a significant margin.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Abdelmoujoud Faris
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ibrahim M Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Radwan Alnajjar
- Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya
| | - Hanine Hadni
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Mashooq Ahmad Bhat
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Muhammad Yaseen
- Institute of Chemical Sciences, University of Swat, Main Campus, Charbagh, Swat, Pakistan
| | - Souvik Chakraborty
- Department of Physiology, Bhairab Ganguly College, Belghoria, Kolkata, West Bengal, India
| | - Nada Alsakhen
- Department of Chemistry, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Israa M Shamkh
- Botany and Microbiology Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Fazal Mabood
- Institute of Chemical Sciences, University of Swat, Main Campus, Charbagh, Swat, Pakistan
| | - Ahmed M Naglah
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ihsan Ullah
- Institute of Chemical Sciences, University of Swat, Main Campus, Charbagh, Swat, Pakistan
| | - Noha Ziedan
- Department of Physical, Mathematical and Engineering Science, Faculty of Science, Business and Enterprise, University of Chester, Chester, UK
| | - Menana Elhallaoui
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
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Yamane T, Kitayama M. Successful treatment of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapidly progressive interstitial lung disease complicated by bilateral breast cancer following the additional tofacitinib: A case report. Mod Rheumatol Case Rep 2025; 9:93-99. [PMID: 39330992 DOI: 10.1093/mrcr/rxae060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/08/2024] [Accepted: 09/14/2024] [Indexed: 09/28/2024]
Abstract
Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody-positive dermatomyositis (MDA5-DM) often causes rapidly progressive interstitial lung disease (RP-ILD). Although cancer complications in MDA5-DM are less frequently reported compared to other forms of DM, they do occur. For MDA5-DM patients with cancer, particularly in paraneoplastic settings, the primary treatment strategy often targets the malignancy first. However, surgery, chemotherapy, and radiotherapy carry significant risks of exacerbating ILD, especially in patients with respiratory failure. Despite improved prognosis with initial immunosuppressive combination therapy, some cases of MDA5-DM with RP-ILD remain refractory to treatment. Recent studies have shown the potential benefit of Janus kinase (JAK) inhibitors for refractory cases, though their impact on cancer progression remains a concern. We report a 48-year-old woman with MDA5-DM, RP-ILD, and bilateral breast cancer. Due to her respiratory condition, radical surgery and chemotherapy were initially not possible. Endocrine therapy and immunosuppressive therapy were administered, but the disease remained refractory. Tofacitinib, combined with plasma exchange, improved her ILD, allowing for bilateral mastectomy. One year later, MDA5 antibody titers became negative, and glucocorticoids were discontinued after two years. Three years later, neither MDA5-DM nor breast cancer has recurred. This is the first report of MDA5-DM complicated by breast cancer, and the first use of JAK inhibitors in such a case. Effective treatment requires close collaboration with oncologists to balance the risks and benefits of therapy in cases of MDA5-DM with RP-ILD and cancer.
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Affiliation(s)
- Takashi Yamane
- Department of Rheumatology, Kakogawa Central City Hospital, Kakogawa, Hyogo, Japan
| | - Midori Kitayama
- Department of Rheumatology, Kakogawa Central City Hospital, Kakogawa, Hyogo, Japan
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Chen G, Li W, Liu Y, Li T, Zhu W, Liu Y, Jin X, Mei Q, Ye L. Design, Synthesis, Anticancer Evaluation and In Silico Studies of Imidazole Pyrazine Compounds. Chem Biodivers 2025; 22:e202401553. [PMID: 39513628 DOI: 10.1002/cbdv.202401553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/23/2024] [Indexed: 11/15/2024]
Abstract
The present study focused on design and synthesis novel imidazolopyrazine derivatives, investigate the effect of them on the proliferation and migration of several human cancer cell lines by CCK-8 method, and interactions with the JAKs by reverse molecular docking. It was found that most of the synthesized imidazolopyrazin derivatives exhibited excellent inhibitory effects towards three tested tutor cells in vitro. Among them, three compounds have IC50 values much lower than Fluorouracil while show low toxicity to normal cells L-02. The migration ability assay have proved that A6 and A9 effectively inhibit the migration of tumor cells. Reverse molecular docking studies indicated that the potent targets of these derivatives are JAKs as they well docked into kinases with low energy. These finding suggest that imidazo[1,5-a]pyrazin derivatives may be lead compounds for developing potent JAK targeted anticancer candidates.
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Affiliation(s)
- Gong Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Weiwei Li
- Department of Laboratory Medicine, Guiyang Maternity and Child Health Hospital, Guiyang, 550003, People's Republic of China
| | - Yuanhui Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Tong Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Wenrun Zhu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Ying Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Xiaobao Jin
- Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Qinghua Mei
- Guangdong Second Provincial General Hospital, Guangzhou, 510317, People's Republic of China
| | - Lianbao Ye
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
- Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
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Zhao M, Zhang H, Ma S, Gong S, Wei C, Miao L, Zhao W. Clinical pharmacokinetic characteristics of Jaktinib in subjects with hepatic impairment in a phase I trial. Drug Metab Pharmacokinet 2024; 59:101030. [PMID: 39442386 DOI: 10.1016/j.dmpk.2024.101030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 06/20/2024] [Accepted: 07/17/2024] [Indexed: 10/25/2024]
Abstract
Jaktinib is a novel Janus kinase (JAK) inhibitor, and a phase I clinical trial of single-dose Jaktinib was conducted in a population of subjects with hepatic impairment to assess the safety, tolerability, and pharmacokinetic characteristics of Jaktinib. The patients were administered orally with 100 mg Jaktinib on day 1 in all the mild hepatic impairment group (mild group, n = 8), moderate hepatic impairment group (moderate group, n = 8) and normal hepatic function group (normal group, n = 8), and the blood samples were collected for later analysis. The mild to moderate hepatic impairment affected the metabolism of Jaktinib, which may lead to accumulation of original Jaktinib. The pharmacokinetic characteristics of the metabolites (ZG0244 and ZG0245) of Jaktinib were also analyzed. The exposure of Jaktinib is approximately 2-fold in patients with mild and moderate hepatic impairment than normal hepatic function. No serious adverse events occurred. In summary, a dosage reduction is recommended for patients with mild or moderate hepatic impairment. Further investigations for the dose adjustment in mild/moderate hepatic impairment will be considered. Trial registration number: NCT04993404.
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Affiliation(s)
- Manna Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, PR China.
| | - Hua Zhang
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, PR China.
| | - Sheng Ma
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, PR China.
| | - Shuqing Gong
- Department of Zelgen Medicine and Writing, Suzhou Zelgen Biopharmaceutical Co., Ltd, Suzhou, Jiangsu Province, 215000, PR China.
| | - Cheng Wei
- Project Department, Suzhou Zelgen Biopharmaceutical Co., Ltd, Suzhou, Jiangsu Province, 215000, PR China.
| | - Liyan Miao
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, PR China.
| | - Weifeng Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, PR China.
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Kulma M, Hofman B, Szostakowska-Rodzoś M, Dymkowska D, Serwa RA, Piwowar K, Belczyk-Ciesielska A, Grochowska J, Tuszyńska I, Muchowicz A, Drzewicka K, Zabłocki K, Zasłona Z. The ubiquitin-specific protease 21 is critical for cancer cell mitochondrial function and regulates proliferation and migration. J Biol Chem 2024; 300:107793. [PMID: 39305962 PMCID: PMC11513602 DOI: 10.1016/j.jbc.2024.107793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/13/2024] [Accepted: 08/26/2024] [Indexed: 10/20/2024] Open
Abstract
Ubiquitin-specific proteases (USPs) are the main members of deubiquitinases (DUBs) that catalyze removing ubiquitin chains from target proteins, thereby modulating their half-life and function. Enzymatic activity of USP21 regulates protein degradation which is critical for maintaining cell homeostasis. USP21 determines the stability of oncogenic proteins and therefore is implicated in carcinogenesis. In this study, we investigated the effect of USP21 deletion on cancer cell metabolism. Transcriptomic and proteomic analysis of USP21 KO HAP-1 cells revealed that endogenous USP21 is critical for the expression of genes and proteins involved in mitochondrial function. Additionally, we have found that the deletion of USP21 reduced STAT3 activation and STAT3-dependent gene and protein expression in cancer cells. Genetic deletion of USP21 impaired mitochondrial respiration and disturbed ATP production. This resulted in cellular consequences such as inhibition of cell proliferation and migration. Presented results provide new insights into the biology of USP21, suggesting novel mechanisms for controlling STAT3 activity and mitochondrial function in tumor cells. Taken together, our findings indicate that targeting USP21 dysregulates the energy status of cancer cells offering new perspectives for anticancer therapy.
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Affiliation(s)
| | | | | | - Dorota Dymkowska
- Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Remigiusz A Serwa
- IMol, Polish Academy of Sciences, Warsaw, Poland; ReMedy International Research Agenda Unit, IMol, Polish Academy of Sciences, Warsaw, Poland
| | | | | | | | | | | | | | - Krzysztof Zabłocki
- Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
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Khan K, Zahid M, Ali N, Attaullah S, Ullah M, Khan K, Muhammad I, Abusharha A, Aschner M, Khan H. STAT3 single-nucleotide variants in autoimmune thyroid disease in the Pakhtun population of Khyber Pakhtunkhwa, Pakistan. GENE REPORTS 2024; 36:101950. [PMID: 39385969 PMCID: PMC11463997 DOI: 10.1016/j.genrep.2024.101950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
The current study was conducted to assess the relationship between the STAT3 gene variants rs744166 and rs2293152 and autoimmune thyroid disorder in the Pakhtun population of the province, of Khyber Pakhtunkhwa, Pakistan. Blood was collected from 100 healthy individuals and 400 thyroid-disordered patients. Of these, one hundred were diagnosed with Hashimoto's thyroiditis (HT), while 32 were confirmed as Grave's disease (GD) patients. T3, T4, and TSH serum levels were checked to diagnose thyroid disorders. The blood was analyzed for anti-thyroid peroxidase antibodies (Anti-TPOAb) (AESKULISA- ATPO - elisa kit), (Germany), and thyroid stimulating hormone receptor antibodies (TSHRAb), TSHR Ab elisa kit (Diametra Italy), respectively. PCR was used to amplify the targeted STAT3 gene polymorphisms from rs744166 (301 bp) and rs2293152 (365 bp) sequences and then digested by specific restriction endonucleases (AluI) and AciI respectively. The disease displayed a female predominance. The genotype TC and CC of rs744166 showed a significant relationship with Grave's disease (p = 0.002, OR = 0.28, 95 % CI = 0.11-0.77) in patients. The C allele contributed significantly to the disease in GD patients. The SNP rs2293152 significantly differed between GD patients and control (p = 0.032, OR = 0.29, 95 % CI = 0.09-0.86). Similarly, the G and C alleles showed a significant (p = 0.02) difference between GD patients and the control. No significant association was found for both SNPs in Hashimoto's thyroiditis disease. It is concluded that the STAT3 gene (rs744166 and rs2293152) was found to have a potential role in autoimmunity in GD patients. Still, it needs further studies with larger sample sizes in the Pakhtun population to understand this relationship.
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Affiliation(s)
- Khayyam Khan
- Department of Zoology, Islamia College University, 25120 Peshawar, Pakistan
| | - Muhammad Zahid
- Department of Zoology, Islamia College University, 25120 Peshawar, Pakistan
| | - Niaz Ali
- Institute of Basic Medical Sciences Khyber Medical University, 25120 Peshawar, Pakistan
| | - Sobia Attaullah
- Department of Zoology, Islamia College University, 25120 Peshawar, Pakistan
| | - Mujeeb Ullah
- Department of Zoology, Islamia College University, 25120 Peshawar, Pakistan
| | - Khalid Khan
- Department of Zoology, Islamia College University, 25120 Peshawar, Pakistan
| | - Ijaz Muhammad
- Department of Zoology, Abdul Wali Khan University Mardan, 23200 Mardan, Pakistan
| | - Ali Abusharha
- Optometry Department, Applied Medical Sciences Collage, King Saud University, P. O. Box 145111, Riyadh, Saudi Arabia
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200 Mardan, Pakistan
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Lv Y, Qi J, Babon JJ, Cao L, Fan G, Lang J, Zhang J, Mi P, Kobe B, Wang F. The JAK-STAT pathway: from structural biology to cytokine engineering. Signal Transduct Target Ther 2024; 9:221. [PMID: 39169031 PMCID: PMC11339341 DOI: 10.1038/s41392-024-01934-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/12/2024] [Accepted: 07/16/2024] [Indexed: 08/23/2024] Open
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway serves as a paradigm for signal transduction from the extracellular environment to the nucleus. It plays a pivotal role in physiological functions, such as hematopoiesis, immune balance, tissue homeostasis, and surveillance against tumors. Dysregulation of this pathway may lead to various disease conditions such as immune deficiencies, autoimmune diseases, hematologic disorders, and cancer. Due to its critical role in maintaining human health and involvement in disease, extensive studies have been conducted on this pathway, ranging from basic research to medical applications. Advances in the structural biology of this pathway have enabled us to gain insights into how the signaling cascade operates at the molecular level, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced comprehension of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed us to engineer cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. In this review, we outline the structural basis that governs key nodes in this pathway, offering a comprehensive overview of the signal transduction process. Furthermore, we explore recent advances in cytokine engineering for therapeutic development in this pathway.
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Affiliation(s)
- You Lv
- Center for Molecular Biosciences and Non-communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi, 710054, China
- Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China
| | - Jianxun Qi
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100080, China
| | - Jeffrey J Babon
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Longxing Cao
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China
| | - Guohuang Fan
- Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai, 201112, China
| | - Jiajia Lang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jin Zhang
- Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China
| | - Pengbing Mi
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Bostjan Kobe
- School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, 4072, Australia.
| | - Faming Wang
- Center for Molecular Biosciences and Non-communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi, 710054, China.
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Faris A, Cacciatore I, Alnajjar R, Aouidate A, AL Mughram MH, Elhallaoui M. Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3). Front Chem 2024; 12:1425220. [PMID: 39189018 PMCID: PMC11345245 DOI: 10.3389/fchem.2024.1425220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/12/2024] [Indexed: 08/28/2024] Open
Abstract
The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition.
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Affiliation(s)
- Abdelmoujoud Faris
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ivana Cacciatore
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Radwan Alnajjar
- CADD Unit, PharmD, Faculty of Pharmacy, Libyan International Medical University, Benghazi, Libya
| | - Adnane Aouidate
- School of Applied Sciences of Ait Melloul, Ibn Zohr University, Agadir, Morocco
| | - Mohammed H. AL Mughram
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Menana Elhallaoui
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
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Wang X, Chen J, Shen Y, Zhang H, Xu Y, Zhang J, Cheng L. Baricitinib protects ICIs-related myocarditis by targeting JAK1/STAT3 to regulate Macrophage polarization. Cytokine 2024; 179:156620. [PMID: 38701735 DOI: 10.1016/j.cyto.2024.156620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/13/2024] [Indexed: 05/05/2024]
Abstract
PURPOSE The emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis. METHODS To establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis. RESULTS Baricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings. CONCLUSION Baricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related myocarditis.
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Affiliation(s)
- Xuejun Wang
- Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China
| | - Jiahui Chen
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China
| | - Yihui Shen
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China
| | - Hui Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China
| | - Yuchen Xu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China
| | - Jian Zhang
- Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China
| | - Leilei Cheng
- Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China.
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10
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Lv Y, Mi P, Babon JJ, Fan G, Qi J, Cao L, Lang J, Zhang J, Wang F, Kobe B. Small molecule drug discovery targeting the JAK-STAT pathway. Pharmacol Res 2024; 204:107217. [PMID: 38777110 DOI: 10.1016/j.phrs.2024.107217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/05/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.
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Affiliation(s)
- You Lv
- Center for Molecular Biosciences and Non-Communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi 710054, China; Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi 710026, China
| | - Pengbing Mi
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Jeffrey J Babon
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Guohuang Fan
- Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai 201112, China
| | - Jianxun Qi
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China
| | - Longxing Cao
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Jiajia Lang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Jin Zhang
- Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi 710026, China
| | - Faming Wang
- Center for Molecular Biosciences and Non-Communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi 710054, China.
| | - Bostjan Kobe
- School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia.
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11
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Hossain A, Rahman ME, Faruqe MO, Saif A, Suhi S, Zaman R, Hirad AH, Matin MN, Rabbee MF, Baek KH. Characterization of Plant-Derived Natural Inhibitors of Dipeptidyl Peptidase-4 as Potential Antidiabetic Agents: A Computational Study. Pharmaceutics 2024; 16:483. [PMID: 38675143 PMCID: PMC11053753 DOI: 10.3390/pharmaceutics16040483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetes, characterized by elevated blood sugar levels, poses significant health and economic risks, correlating with complications like cardiovascular disease, kidney failure, and blindness. Dipeptidyl peptidase-4 (DPP-4), also referred to as T-cell activation antigen CD26 (EC 3.4.14.5.), plays a crucial role in glucose metabolism and immune function. Inhibiting DPP-4 was anticipated as a potential new therapy for diabetes. Therefore, identification of plant-based natural inhibitors of DPP-4 would help in eradicating diabetes worldwide. Here, for the identification of the potential natural inhibitors of DPP-4, we developed a phytochemicals library consisting of over 6000 phytochemicals detected in 81 medicinal plants that exhibited anti-diabetic potency. The library has been docked against the target proteins, where isorhamnetin, Benzyl 5-Amino-5-deoxy-2,3-O-isopropyl-alpha-D-mannofuranoside (DTXSID90724586), and 5-Oxo-7-[4-(trifluoromethyl) phenyl]-4H,6H,7H-[1,2]thiazolo[4,5-b]pyridine 3-carboxylic acid (CHEMBL3446108) showed binding affinities of -8.5, -8.3, and -8.3 kcal/mol, respectively. These compounds exhibiting strong interactions with DPP-4 active sites (Glu205, Glu206, Tyr547, Trp629, Ser630, Tyr662, His740) were identified. ADME/T and bioactivity predictions affirmed their pharmacological safety. Density functional theory calculations assessed stability and reactivity, while molecular dynamics simulations demonstrated persistent stability. Analyzing parameters like RMSD, RG, RMSF, SASA, H-bonds, MM-PBSA, and FEL confirmed stable protein-ligand compound formation. Principal component analysis provided structural variation insights. Our findings suggest that those compounds might be possible candidates for developing novel inhibitors targeting DPP-4 for treating diabetes.
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Affiliation(s)
- Alomgir Hossain
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (A.H.); (M.E.R.); (R.Z.); (M.N.M.)
| | - Md Ekhtiar Rahman
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (A.H.); (M.E.R.); (R.Z.); (M.N.M.)
| | - Md Omar Faruqe
- Department of Computer Science and Engineering, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Ahmed Saif
- Department of Pharmacy, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Suzzada Suhi
- Department of Zoology, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Rashed Zaman
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (A.H.); (M.E.R.); (R.Z.); (M.N.M.)
| | - Abdurahman Hajinur Hirad
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;
| | - Mohammad Nurul Matin
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (A.H.); (M.E.R.); (R.Z.); (M.N.M.)
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Republic of Korea
| | - Muhammad Fazle Rabbee
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Republic of Korea
| | - Kwang-Hyun Baek
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Republic of Korea
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12
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Faris A, Cacciatore I, Alnajjar R, Hanine H, Aouidate A, Mothana RA, Alanzi AR, Elhallaoui M. Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses. Front Mol Biosci 2024; 11:1348277. [PMID: 38516192 PMCID: PMC10956358 DOI: 10.3389/fmolb.2024.1348277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 01/17/2024] [Indexed: 03/23/2024] Open
Abstract
The heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between their complex structures and biological activities for the development of new drugs for the treatment of rheumatoid arthritis (RA) and cancer. In this study, a diverse set of 28 heterocyclic compounds selective for JAK1 and JAK3 was employed to construct quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR). Artificial neural network (ANN) models were employed in the development of QSAR models. The robustness and stability of the models were assessed through internal and external methodologies, including the domain of applicability (DoA). The molecular descriptors incorporated into the model exhibited a satisfactory correlation with the receptor-ligand complex structures of JAKs observed in X-ray crystallography, making the model interpretable and predictive. Furthermore, pharmacophore models ADRRR and ADHRR were designed for each JAK1 and JAK3, proving effective in discriminating between active compounds and decoys. Both models demonstrated good performance in identifying new compounds, with an ROC of 0.83 for the ADRRR model and an ROC of 0.75 for the ADHRR model. Using a pharmacophore model, the most promising compounds were selected based on their strong affinity compared to the most active compounds in the studied series each JAK1 and JAK3. Notably, the pharmacokinetic, physicochemical properties, and biological activities of the selected compounds (As compounds ZINC79189223 and ZINC66252348) were found to be consistent with their therapeutic effects in RA, owing to their non-toxic, cholinergic nature, absence of P-glycoprotein, high gastrointestinal absorption, and ability to penetrate the blood-brain barrier. Furthermore, ADMET properties were assessed, and molecular dynamics and MM/GBSA analysis revealed stability in these molecules.
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Affiliation(s)
- Abdelmoujoud Faris
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ivana Cacciatore
- Department of Pharmacy, University ‘G. d’Annunzio’ of Chieti-Pescara, Chieti, Italy
| | - Radwan Alnajjar
- CADD Unit, PharmD, Faculty of Pharmacy, Libyan International Medical University, Benghazi, Libya
| | - Hadni Hanine
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Adnane Aouidate
- School of Applied Sciences of Ait Melloul, Ibn Zohr University, Fez, Morocco
| | - Ramzi A. Mothana
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdullah R. Alanzi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Menana Elhallaoui
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
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13
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Pessino G, Scotti C, Maggi M, Immuno-Hub Consortium. Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets. Cancers (Basel) 2024; 16:901. [PMID: 38473265 DOI: 10.3390/cancers16050901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.
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Affiliation(s)
- Greta Pessino
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Claudia Scotti
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maristella Maggi
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Immuno-Hub Consortium
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
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14
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Pădureanu V, Drăgoescu AN, Pădureanu R, Rośu MM, Rădulescu D, Dop D, For£ofoiu MC. Treatment approaches in autoimmune pancreatitis (Review). Biomed Rep 2024; 20:26. [PMID: 38259589 PMCID: PMC10801350 DOI: 10.3892/br.2023.1714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Autoimmune pancreatitis (AIP) is a rare disease. There are two distinct types of AIP: AIP type 1 (AIP-1), a pancreatic manifestation of a multi-organ disease linked to immunoglobulin (Ig)G4, and AIP type 2 (AIP-2), a pancreas-specific disease unrelated to IgG4. The usual course of treatment for AIP is oral corticosteroid medication. Rituximab has also been recommended for recurrent AIP-1 in order to initiate remission and provide ongoing treatment. Immunomodulators such as azathioprine are used to keep certain patients in remission. Evaluation also takes into account a number of pharmacological alternatives, including biologic drugs like anti-tumor necrosis factor therapy, a safe and efficient second-line treatment for AIP-2 relapse or steroid dependence. Corticosteroids and immunosuppressants, which are poorly tolerated due to considerable side effects, are being replaced by other biologic drugs, which may offer a beneficial therapeutic alternative.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Alice Nicoleta Drăgoescu
- Department of Anaesthesiology and Intensive Care, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Maria Magdalena Rośu
- Department of Diabetes, Nutrition and Metabolic Diseases, County Clinical Emergency Hospital of Craiova, Craiova 200642, Romania
| | - Dumitru Rădulescu
- Department of Pediatrics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dalia Dop
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mircea Cătălin For£ofoiu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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15
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Westermann R, Cordtz RL, Duch K, Mellemkjaer L, Hetland ML, Burden AM, Dreyer L. Cancer risk in patients with rheumatoid arthritis treated with janus kinase inhibitors: a nationwide Danish register-based cohort study. Rheumatology (Oxford) 2024; 63:93-102. [PMID: 37052534 DOI: 10.1093/rheumatology/kead163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/01/2023] [Accepted: 03/24/2023] [Indexed: 04/14/2023] Open
Abstract
OBJECTIVES We aimed to investigate the risk of first primary cancer in patients with RA treated with janus kinase inhibitors (JAKi) compared with those who received biologic DMARDs (bDMARDs) in a real-world setting. METHODS We performed an observational cohort study using the nationwide registers in Denmark. Patients with RA aged 18+ years, without a previous cancer diagnosis, and who initiated treatment with JAKi or bDMARDs from 1 January 2017 to 31 December 2020 were followed for any cancer (except non-melanoma skin cancer). We applied inverse probability of treatment weighting (IPTW) to account for covariate differences between treatment groups. IPTW-generated weights were used with cause-specific Cox (CSC) models to calculate hazard ratios (HRs) for cancer incidence in JAKi-treated compared with bDMARD-treated patients with RA. RESULTS We identified 875 and 4247 RA patients treated with JAKi and bDMARDs, respectively. The JAKi group contributed 1315 person years (PYRS) and 19 cancers, the bDMARD group contributed 8597 PYRS and 111 cancers, with corresponding crude incidence rates per 1000 PYRS of 14.4 and 12.9. Comparing the two groups using weighted CSC models, a HR of 1.41 (95% CI 0.76, 2.37, 95% CIs) was seen for JAKi- vs bDMARD-treated patients with RA. CONCLUSION JAKi treatment in real-world patients with RA was not associated with a statistically significant increased risk of first primary cancer compared with those who received bDMARDs. However, several numerically increased risk estimates were detected, and a clinically important excess risk of cancer among JAKi recipients cannot be dismissed.
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Affiliation(s)
- Rasmus Westermann
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg University, Denmark
- Clinical Cancer Research Unit, Aalborg University Hospital, Aalborg, Denmark
| | - René Lindholm Cordtz
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg University, Denmark
| | - Kirsten Duch
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg University, Denmark
- Unit of Clinical Biostatistics, Aalborg University Hospital, Denmark
| | - Lene Mellemkjaer
- Danish Cancer Society Research Center (DCRC), Copenhagen, Denmark
| | - Merete Lund Hetland
- The DANBIO Registry, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup, Denmark
- Department of Clinical Medicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
- Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup, Denmark
| | - Andrea Michelle Burden
- Pharmacoepidemiology Group, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Lene Dreyer
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg University, Denmark
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16
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Panuganti BA, Carico C, Jeyarajan H, Flagg M, Tamayo P. Transcriptional subtypes of glottic cancer characterized by differential activation of canonical oncogenic programming. Head Neck 2023; 45:2851-2861. [PMID: 37682073 PMCID: PMC10901072 DOI: 10.1002/hed.27514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 08/31/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND There is a paucity of data concerning molecular heterogeneity among glottic squamous cell carcinoma, and the clinical implications thereof. METHODS Data corresponding to glottic squamous cell carcinoma were derived from The Cancer Genome Atlas. The Onco-GPS computational methodology was levied to derive four patterns of transcriptional activity and three functional subtypes of glottic cancer. RESULTS Thirty glottic cancer samples stratified to three distinct oncogenic states (S0-S2) based on a Onco-GPS model containing four transcriptional components (F0-F3). Membership in S2 and association with transcriptional component F0 conveyed an invasive phenotype, with transcriptional activity strongly reflecting EMT programming (including TGF-B and NF-KB signaling). S2 membership also correlated with inferior disease-specific survival (HR 9.027, 95% CI 1.021-79.767), and higher incidences of extracapsular spread and perineural invasion. CONCLUSIONS We present a functional taxonomy of glottic cancer, with subtypes demonstrating differential upregulation of canonical oncogenic networks and survival implications.
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Affiliation(s)
- Bharat A Panuganti
- Department of Otolaryngology - Head and Neck Surgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Birmingham Veteran Affairs Health Care System, Birmingham, Alabama, USA
- The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | - Christine Carico
- The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | - Harishanker Jeyarajan
- Department of Otolaryngology - Head and Neck Surgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | - Mitchell Flagg
- University of California-San Diego School of Medicine, San Diego, California, USA
| | - Pablo Tamayo
- University of California-San Diego School of Medicine, San Diego, California, USA
- Moores Cancer Center, Center for Novel Therapeutics and Division of Genomics and Precision Medicine, University of California-San Diego School of Medicine, San Diego, California, USA
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17
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Kim Y, Yang HI, Kim KS. Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease. Int J Mol Sci 2023; 24:14509. [PMID: 37833957 PMCID: PMC10572849 DOI: 10.3390/ijms241914509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 09/19/2023] [Accepted: 09/23/2023] [Indexed: 10/15/2023] Open
Abstract
Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and ethnicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast-myofibroblast transition, epithelial-mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the histopathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.
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Affiliation(s)
- Yerin Kim
- Department of Medicine, Catholic Kwandong University College of Medicine, Gangneung 25601, Republic of Korea;
| | - Hyung-In Yang
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea;
| | - Kyoung-Soo Kim
- East-West Bone & Joint Disease Research Institute, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
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18
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Faris A, Ibrahim IM, Al kamaly O, Saleh A, Elhallaoui M. Computer-Aided Drug Design of Novel Derivatives of 2-Amino-7,9-dihydro-8H-purin-8-one as Potent Pan-Janus JAK3 Inhibitors. Molecules 2023; 28:5914. [PMID: 37570884 PMCID: PMC10473238 DOI: 10.3390/molecules28155914] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Rheumatoid arthritis (RA) remains one of the most prevalent autoimmune diseases worldwide. Janus kinase 3 (JAK3) is an essential enzyme for treating autoimmune diseases, including RA. Molecular modeling techniques play a crucial role in the search for new drugs by reducing time delays. In this study, the 3D-QSAR approach is employed to predict new JAK3 inhibitors. Two robust models, both field-based with R2 = 0.93, R = 0.96, and Q2 = 87, and atom-based with R2 = 0.94, R = 0.97, and Q2 = 86, yielded good results by identifying groups that may readily direct their interaction. A reliable pharmacophore model, DHRRR1, was provided in this work to enable the clear characterization of chemical features, leading to the design of 13 inhibitors with their pIC50 values. The DHRRR1 model yielded a validation result with a ROC value of 0.87. Five promising inhibitors were selected for further study based on an ADMET analysis of their pharmacokinetic properties and covalent docking (CovDock). Compared to the FDA-approved drug tofacitinib, the pharmaceutical features, binding affinity and stability of the inhibitors were analyzed through CovDock, 300 ns molecular dynamics simulations, free energy binding calculations and ADMET predictions. The results show that the inhibitors have strong binding affinity, stability and favorable pharmaceutical properties. The newly predicted molecules, as JAK3 inhibitors for the treatment of RA, are promising candidates for use as drugs.
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Affiliation(s)
- Abdelmoujoud Faris
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez 30000, Morocco;
| | - Ibrahim M. Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Cairo 12613, Egypt;
| | - Omkulthom Al kamaly
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (O.A.k.); (A.S.)
| | - Asmaa Saleh
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (O.A.k.); (A.S.)
| | - Menana Elhallaoui
- LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez 30000, Morocco;
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19
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Kciuk M, Alam M, Ali N, Rashid S, Głowacka P, Sundaraj R, Celik I, Yahya EB, Dubey A, Zerroug E, Kontek R. Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications. Molecules 2023; 28:5246. [PMID: 37446908 PMCID: PMC10343677 DOI: 10.3390/molecules28135246] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Cellular signaling pathways involved in the maintenance of the equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most abundant phenolic compound found in green tea. It has been shown to regulate multiple crucial cellular signaling pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, and others. Deregulation of the abovementioned pathways is involved in the pathophysiology of cancer. It has been demonstrated that EGCG may exert anti-proliferative, anti-inflammatory, and apoptosis-inducing effects or induce epigenetic changes. Furthermore, preclinical and clinical studies suggest that EGCG may be used in the treatment of numerous disorders, including cancer. This review aims to summarize the existing knowledge regarding the biological properties of EGCG, especially in the context of cancer treatment and prophylaxis.
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Affiliation(s)
- Mateusz Kciuk
- Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland; (M.K.); (R.K.)
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India;
| | - Nemat Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | - Pola Głowacka
- Department of Medical Biochemistry, Medical University of Lodz, Mazowiecka 6/8, 90-001 Lodz, Poland;
- Doctoral School of Medical University of Lodz, Hallera 1 Square, 90-700 Lodz, Poland
| | - Rajamanikandan Sundaraj
- Department of Biochemistry, Centre for Drug Discovery, Karpagam Academy of Higher Education, Coimbatore 641021, India;
| | - Ismail Celik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38280, Turkey;
| | - Esam Bashir Yahya
- Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, Penang 11800, Malaysia;
| | - Amit Dubey
- Computational Chemistry and Drug Discovery Division, Quanta Calculus, Greater Noida 201310, India;
- Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College and Hospital, Chennai 600077, India
| | - Enfale Zerroug
- LMCE Laboratory, Group of Computational and Pharmaceutical Chemistry, University of Biskra, Biskra 07000, Algeria;
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland; (M.K.); (R.K.)
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Herrmann I, Mamo LB, Holmes J, Mohammed JP, Murphy KM, Bizikova P. Long-term effects of ciclosporin and oclacitinib on mediators of tolerance, regulatory T-cells, IL-10 and TGF-β, in dogs with atopic dermatitis. Vet Dermatol 2023; 34:107-114. [PMID: 36482868 DOI: 10.1111/vde.13140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 10/07/2022] [Accepted: 10/16/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Atopic dogs often are managed with allergen-specific immunotherapy (AIT) and concurrent dosages of ciclosporin (CSA) or oclacitinib to alleviate their clinical signs. Both drugs might affect proper tolerance induction by inhibiting regulatory T-cell (Treg) induction. HYPOTHESIS/OBJECTIVES We evaluated Treg cell numbers and serum interleukin (IL)-10 and transforming growth factor-beta (TGF-β)1 levels in dogs diagnosed with atopic dermatitis (AD) and successfully treated with either CSA or oclacitinib for nine or more months. ANIMALS We included 15 dogs receiving oclacitinib, 14 dogs treated with CSA, 15 healthy dogs, 13 dogs with untreated moderate-to-severe AD and 15 atopic dogs controlled with AIT. MATERIALS AND METHODS Peripheral blood CD4+CD25+FOXP3+ T-cell percentages were determined using flow cytometry. Serum concentrations of IL-10 and TGF-β1 were measured by enzyme-linked immunosorbent assay. RESULTS The percentage of Treg cells in the CSA group was significantly lower in comparison with the healthy group (p = 0.0003), the nontreated AD group (p = 0.0056) or the AIT group (p = 0.0186). There was no significant difference in Treg cell percentages between the CSA and oclacitinib groups, nor between the oclacitinib and the healthy, nontreated AD or AIT-treated dogs. No significant differences were detected in IL-10 and TGF-β1 serum concentrations between the five groups. CONCLUSIONS AND CLINICAL RELEVANCE Lower Treg cell percentages in the CSA-treated dogs suggest an impact of this drug on this cell population; however, it does not necessarily mean that it diminishes tolerance. Functionality and cytokine production may be more important than the number of Treg cells. Further studies evaluating the treatment outcome of dogs receiving AIT and concurrent drugs are needed to show clinical relevance.
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Affiliation(s)
- Ina Herrmann
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - Lisa B Mamo
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - Jenny Holmes
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - Javid P Mohammed
- Flow Cytometry & Cell Sorting Core, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - K Marcia Murphy
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - Petra Bizikova
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.,Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
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21
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Strzelec M, Detka J, Mieszczak P, Sobocińska MK, Majka M. Immunomodulation—a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system. Front Immunol 2023; 14:1127704. [PMID: 36969193 PMCID: PMC10033545 DOI: 10.3389/fimmu.2023.1127704] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/23/2023] [Indexed: 03/11/2023] Open
Abstract
In recent years, there has been a tremendous development of biotechnological, pharmacological, and medical techniques which can be implemented in the functional modulation of the immune system components. Immunomodulation has attracted much attention because it offers direct applications in both basic research and clinical therapy. Modulation of a non-adequate, amplified immune response enables to attenuate the clinical course of a disease and restore homeostasis. The potential targets to modulate immunity are as multiple as the components of the immune system, thus creating various possibilities for intervention. However, immunomodulation faces new challenges to design safer and more efficacious therapeutic compounds. This review offers a cross-sectional picture of the currently used and newest pharmacological interventions, genomic editing, and tools for regenerative medicine involving immunomodulation. We reviewed currently available experimental and clinical evidence to prove the efficiency, safety, and feasibility of immunomodulation in vitro and in vivo. We also reviewed the advantages and limitations of the described techniques. Despite its limitations, immunomodulation is considered as therapy itself or as an adjunct with promising results and developing potential.
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22
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Wu D, Luo Y, Li T, Zhao X, Lv T, Fang G, Ou P, Li H, Luo X, Huang A, Pang Y. Systemic complications of rheumatoid arthritis: Focus on pathogenesis and treatment. Front Immunol 2022; 13:1051082. [PMID: 36618407 PMCID: PMC9817137 DOI: 10.3389/fimmu.2022.1051082] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
As a systemic autoimmune disease, rheumatoid arthritis (RA) usually causes damage not only to joints, but also to other tissues and organs including the heart, kidneys, lungs, digestive system, eyes, skin, and nervous system. Excessive complications are closely related to the prognosis of RA patients and even lead to increased mortality. This article summarizes the serious complications of RA, focusing on its incidence, pathogenesis, clinical features, and treatment methods, aiming to provide a reference for clinicians to better manage the complications of RA.
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Affiliation(s)
- Di Wu
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yehao Luo
- School of Second Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Tong Li
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xinyi Zhao
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Ting Lv
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Gang Fang
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Peiqi Ou
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Hongyi Li
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xiaofan Luo
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - An Huang
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China,*Correspondence: An Huang, ; Yuzhou Pang,
| | - Yuzhou Pang
- Zhuang Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China,*Correspondence: An Huang, ; Yuzhou Pang,
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23
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Scarini JF, Lavareze L, Lima-Souza RAD, Emerick C, Gonçalves MT, Figueiredo-Maciel T, Vieira GDS, Kimura TDC, de Sá RS, Aquino IG, Fernandes PM, Kowalski LP, Altemani A, Mariano FV, Egal ESA. Head and neck squamous cell carcinoma: Exploring frontiers of combinatorial approaches with tyrosine kinase inhibitors and immune checkpoint therapy. Crit Rev Oncol Hematol 2022; 180:103863. [DOI: 10.1016/j.critrevonc.2022.103863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 10/20/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
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24
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Zhu Z, McGray AJR, Jiang W, Lu B, Kalinski P, Guo ZS. Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Mol Cancer 2022; 21:196. [PMID: 36221123 PMCID: PMC9554963 DOI: 10.1186/s12943-022-01664-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.
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Affiliation(s)
- Zhi Zhu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - A J Robert McGray
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Weijian Jiang
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Binfeng Lu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Pawel Kalinski
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
| | - Zong Sheng Guo
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA. .,Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
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25
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Dinakar YH, Kumar H, Mudavath SL, Jain R, Ajmeer R, Jain V. Role of STAT3 in the initiation, progression, proliferation and metastasis of breast cancer and strategies to deliver JAK and STAT3 inhibitors. Life Sci 2022; 309:120996. [PMID: 36170890 DOI: 10.1016/j.lfs.2022.120996] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/13/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Breast cancer (BC) accounts for the majority of cancers among the female population. Anomalous activation of various signaling pathways has become an issue of concern. The JAK-STAT signaling pathway is activated in numerous cancers, including BC. STAT3 is widely involved in BCs, as 40 % of BCs display phosphorylated STAT3. JAK-STAT signaling is crucial for proliferation, survival, metastasis and other cellular events associated with the tumor microenvironment. Hence, targeting this pathway has become an area of interest among researchers. KEY FINDINGS This review article focuses on the role of STAT3 in the initiation, proliferation, progression and metastasis of BC. The roles of various phytochemicals, synthetic molecules and biologicals against JAK-STAT and STAT3 in various cancers have been discussed, with special emphasis on BC. SIGNIFICANCE JAK and STAT3 are involved in various phases from initiation to metastasis, and targeting this pathway is a promising approach to inhibit the various stages of BC development and to prevent metastasis. A number of phytochemicals and synthetic and biological molecules have demonstrated potential inhibitory effects on JAK and STAT3, thereby paving the way for the development of better therapeutics against BC.
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Affiliation(s)
- Yirivinti Hayagreeva Dinakar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - Hitesh Kumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - Shyam Lal Mudavath
- Infectious Disease Biology Laboratory, Chemical Biology Unit, Institute of Nano Science and Technology, Mohali 140306, Punjab, India
| | - Rupshee Jain
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - Ramkishan Ajmeer
- Central Drugs Standard Control Organization, East Zone, Kolkata 700020, West Bengal, India
| | - Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India.
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26
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Xing Q, Zhang Z, Zhu B, Lin Q, Shen L, Li F, Xia Z, Zhao Z. Case Report: Treatment for steroid-refractory immune-related myocarditis with tofacitinib. Front Immunol 2022; 13:944013. [PMID: 36189247 PMCID: PMC9521497 DOI: 10.3389/fimmu.2022.944013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 08/30/2022] [Indexed: 12/19/2022] Open
Abstract
Introduction Immune therapy has ushered in a new era of tumor treatment, at the expense of immune-related adverse events, including rare but fatal adverse cardiovascular events, such as myocarditis. Steroids remain the cornerstone of therapy for immune-related myocarditis, with no clear consensus on additional immunosuppressive treatment for steroid-refractory cases yet. Case report Here, we report a patient with stage IV nasopharyngeal carcinoma who developed immune-related myocarditis in the fourth course of therapy with immune checkpoint inhibitors. The patient presented with precordial discomfort with elevation of cardiac enzymes and interleukin-6, atypical electrocardiographic abnormalities, and reduced left ventricular ejection fraction. Coronary computed tomography angiography excluded the possibility of acute coronary syndrome. The therapy with tofacitinib targeting the Janus kinase-signal transducer and activator of transcription signal pathway was successfully conducted, since there was no significant improvement in troponin under high-dose steroid and intravenous immunoglobulin treatment. The patient recovered without major adverse cardiac events during hospitalization. Discussion The safety and efficacy of tofacitinib in a patient with steroid-refractory immune-related myocarditis were investigated, hoping to provide a basis for prospective therapeutic strategies. Tofacitinib led to remarkable remissions in primary autoimmune disease by blocking the inflammatory cascade, indicating its potential therapeutic use in immune-related adverse events.
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Affiliation(s)
- Qian Xing
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhongwei Zhang
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Zhongwei Zhang, ; Biao Zhu,
| | - Biao Zhu
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Zhongwei Zhang, ; Biao Zhu,
| | - Qionghua Lin
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lihua Shen
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fangfang Li
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhili Xia
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiyong Zhao
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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27
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Cancer stem cell markers interplay with chemoresistance in triple negative breast cancer: A therapeutic perspective. Bull Cancer 2022; 109:960-971. [DOI: 10.1016/j.bulcan.2022.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/18/2022] [Accepted: 05/03/2022] [Indexed: 11/19/2022]
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28
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Benucci M, Damiani A, Infantino M, Manfredi M, Lari B, Grossi V, Gobbi FL, Sarzi-Puttini P. Cardiovascular safety, cancer and Jak-inhibitors: Differences to be highlighted. Pharmacol Res 2022; 183:106359. [PMID: 35907434 DOI: 10.1016/j.phrs.2022.106359] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 07/07/2022] [Accepted: 07/15/2022] [Indexed: 11/29/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease whose natural history leads to articular and extra-articular damage. Both cardiovascular risk and malignancy risk results higher in RA patients, compared to general population. Janus kinase inhibitors (JAKis) are oral targeted synthetic disease modifying antirheumatic drugs (tsDMARDs) that disrupt cytokine cascade and exert anti-inflammatory effects by interfering with signaling through the JAK-STAT intracellular pathways. A recent RCT comparing tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily and anti-TNF in rheumatoid arthritis demonstrated an increased risk of MACE HR 1.33 and cancer HR 1.49 at a follow-up of 4 years. This has led the FDA to class warnings for tofacitinib, baricitinib and upadacitinib. Cumulative RCT data, RCT extension data demonstrated a safety profile for Jak inhibitors. Conflicting data results from real life registries; the different selectivity for JAKs (JAK1, JAK2, JAK3 and Tyk2) probably determines differences in efficacy and safety profiles among the members of this group which should actually be evaluated. In order to better understand the cardiovascular and neoplastic risk linked to these class of drugs, we aim to provide a literature review on existing evidence of the safety of Jak-Inhibitors in rheumatoid arthritis.
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Affiliation(s)
- Maurizio Benucci
- Rheumatology Unit, S.Giovanni di Dio Hospital, Azienda USL-Toscana Centro Florence, Italy.
| | - Arianna Damiani
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy
| | - Maria Infantino
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Mariangela Manfredi
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Barbara Lari
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Valentina Grossi
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Francesca Li Gobbi
- Rheumatology Unit, S.Giovanni di Dio Hospital, Azienda USL-Toscana Centro Florence, Italy.
| | - Piercarlo Sarzi-Puttini
- Rheumatology Unit, ASST-Fatebenefratelli L. Sacco University Hospital, University of Milan, Italy
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29
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Glanville AR, Benden C, Bergeron A, Cheng GS, Gottlieb J, Lease ED, Perch M, Todd JL, Williams KM, Verleden GM. Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions. ERJ Open Res 2022; 8:00185-2022. [PMID: 35898810 PMCID: PMC9309343 DOI: 10.1183/23120541.00185-2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/18/2022] [Indexed: 11/05/2022] Open
Abstract
Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host-disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, that are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies, and (in patients with BOS after lung transplantation) B-cell–directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required.
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30
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Knitz MW, Darragh LB, Bickett TE, Bhatia S, Bukkapatnam S, Gadwa J, Piper M, Corbo S, Nguyen D, Van Court B, Oweida A, Karam SD. Loss of cancer cell STAT1 improves response to radiation therapy and promotes T cell activation in head and neck squamous cell carcinoma. Cancer Immunol Immunother 2022; 71:1049-1061. [PMID: 34559306 PMCID: PMC9987617 DOI: 10.1007/s00262-021-03059-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 09/10/2021] [Indexed: 10/20/2022]
Abstract
Resistance to radiation therapy (RT) remains an obstacle in HPV-negative head and neck squamous cell carcinomas (HNSCCs)-even with a combined RT-immunotherapy approach. Jak-Stat proteins have long been studied for both their immune regulatory role in the host immune response as well as their cancer cell signaling role in shaping the tumor microenvironment (TME). Here, we identify STAT1 as a mediator of radioresistance in HPV-negative preclinical mouse models of HNSCC, by which knockout of STAT1 in the cancer cell (STAT1 KO)-but not in the host-resulted in decreased tumor growth alongside increased immune activation. We show that RT increases STAT1/pSTAT1 expression, which may act as a marker of radioresistance. Whereas RT increased JAK-STAT and interferon (IFN) signaling, transcriptomic analysis revealed that STAT1 KO in the cancer cell resulted in decreased expression of IFN-associated genes of resistance. In vitro experiments showed that STAT1 KO increased T cell chemoattraction and decreased baseline growth. These results indicate that STAT1 may serve a tumor-promoting role in the cancer cell and will inform biomarker development and treatment regimens for HNSCC incorporating RT.
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Affiliation(s)
- Michael W Knitz
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Laurel B Darragh
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Thomas E Bickett
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Shilpa Bhatia
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Sanjana Bukkapatnam
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Jacob Gadwa
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Miles Piper
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Sophia Corbo
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Diemmy Nguyen
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Benjamin Van Court
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA
| | - Ayman Oweida
- Départment de Médecine Nucléaire et Radiobiologie, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Sana D Karam
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, Colorado, 80045, USA.
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Karati D, Mahadik KR, Trivedi P, Kumar D. The Emerging Role of Janus Kinase Inhibitors in the Treatment of Cancer. Curr Cancer Drug Targets 2022; 22:221-233. [PMID: 35232350 DOI: 10.2174/1568009622666220301105214] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/15/2021] [Accepted: 12/24/2021] [Indexed: 11/22/2022]
Abstract
Cancer is a leading cause of death worldwide. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signalling pathway is activated abnormally, which promotes carcinogenesis. Several cytokines are important cancer drivers. These proteins bind to receptors and use the Janus kinase (JAK) and STAT pathways to communicate their responses. Cancer risks are linked to genetic differences in the JAK-STAT system. JAK inhibitors have shown to reduce STAT initiation, tissue propagation, and cell existence in preclinical investigations in solid tumour cell line models. JAK inhibitors, notably ruxolitinib, a, JAK1 or 2 blockers, make cell lines and mouse models more susceptible to radiotherapy, biological response modifier therapy, and oncolytic viral treatment. Numerous JAK antagonists have been or are now being evaluated in cancerous patients as monotherapy or by combining with other drugs in clinical studies. In preclinical investigations, certain JAK inhibitors showed promise anticancer effects; however, clinical trials explicitly evaluating their effectiveness against the JAK/STAT system in solid tumours have yet to be completed. JAK inhibition is a promising strategy to target the JAK/STAT system in solid tumours, and it deserves to be tested further in clinical studies. The function of directing Janus kinases (JAKs), an upstream accelerator of STATs, as a technique for lowering STAT activity in various malignant circumstances is summarized in this article, which will help scientists to generate more specific drug molecules in future.
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Affiliation(s)
- Dipanjan Karati
- Poona college of Pharmacy, Bharati Vidyapeeth (Deemed to be Unoiversity), Erandwane, Pune- 411038, Maharashtra, India
| | - Kakasaheb Ramoo Mahadik
- Centre of Innovation and Translational Research, Poona College of Pharmacy, Bharati Vidyapeeth, Pune 411038, India
| | - Piyush Trivedi
- Centre of Innovation and Translational Research, Poona College of Pharmacy, Bharati Vidyapeeth, Pune 411038, India
| | - Dileep Kumar
- Poona college of Pharmacy, Bharati Vidyapeeth (Deemed to be Unoiversity), Erandwane, Pune- 411038, Maharashtra, India
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32
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Anbar HS, Shehab NG, El-Rouby NM, Ansari MA, Chenoth H, Majeed M, Naeem K, Hersi F, Omar HA. Upadacitinib protects against cisplatin-induced renal and hepatic dysfunction without impairing its anticancer activity. Eur J Pharm Sci 2022; 172:106149. [PMID: 35189270 DOI: 10.1016/j.ejps.2022.106149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 01/03/2022] [Accepted: 02/17/2022] [Indexed: 11/26/2022]
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Wang C, Lin J, Wang Y, Hsi DH, Chen J, Liu T, Zhou Y, Ren Z, Zeng Z, Cheng L, Ge J. Case Series of Steroid-Resistant Immune Checkpoint Inhibitor Associated Myocarditis: A Comparative Analysis of Corticosteroid and Tofacitinib Treatment. Front Pharmacol 2021; 12:770631. [PMID: 34938185 PMCID: PMC8685452 DOI: 10.3389/fphar.2021.770631] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 11/10/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Immune checkpoint inhibitor (ICI)–associated myocarditis is an uncommon and potentially fatal immune-related adverse event (irAE). Although corticosteroids are recommended as the first-line treatment by current guidelines, patients still have variable responses to it, and the guidelines vary significantly in terms of treatment strategies. Objectives: In this study, we performed a retrospective analysis of ICI-associated myocarditis in our hospital to propose a new comparative analysis to aid individualized treatment. Methods: We reviewed detailed records of 24 patients with confirmed ICI-associated myocarditis in our hospital from July 1, 2019, to April 1, 2021. Although all the cases in our study received recommended initial corticosteroid treatment according to the guidelines, different responses to corticosteroid were observed during the process of subsequent corticosteroid tapering. Basing on troponin cardiac troponin T rebound during corticosteroid tapering, we propose a new classification analysis of ICI-associated myocarditis that included two subgroups: corticosteroid-sensitive (n = 8) and corticosteroid-resistant group (n = 16). Results: Compared with corticosteroid-sensitive patients, larger doses of corticosteroid, longer period of treatment, and higher mortality rate were found in corticosteroid-resistant patients. Corticosteroid-resistant patients were characterized by more prominent ptosis, muscle weakness, elevated cardiac biomarkers, creatine kinase, and hepatic enzymes levels than that in the corticosteroid-sensitive patients. Tofacitinib (5 mg twice a day) was used in 11 corticosteroid-resistant patients, with seven patients recovered from ICI-associated myocarditis, showing a promising therapeutic effect. Conclusion: Our group analysis of corticosteroid responsiveness in patients with ICI-associated myocarditis may help clinicians to apply individualized treatment in this high-risk cohort. In addition, tofacitinib could provide clinical benefits when used early in the corticosteroid-resistant patients and may provide a new option for the treatment of ICI-associated myocarditis.
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Affiliation(s)
- Cong Wang
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China
| | - Jinyi Lin
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China
| | - Yan Wang
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - David H Hsi
- Department of Cardiology, Stamford Hospital, Stamford, CT, United States
| | - Jiahui Chen
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuhong Zhou
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenggang Ren
- Department of Liver Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaochong Zeng
- Department of Radiotherapy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Leilei Cheng
- Department of Echocardiography, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, Fudan University, Shanghai, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China
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Lashgari NA, Roudsari NM, Momtaz S, Sathyapalan T, Abdolghaffari AH, Sahebkar A. The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease. J Neuroimmunol 2021; 361:577758. [PMID: 34739911 DOI: 10.1016/j.jneuroim.2021.577758] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 10/13/2021] [Accepted: 10/25/2021] [Indexed: 11/29/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder in which inflammation and oxidative stress play key etiopathological role. The pathology of PD brain is characterized by inclusions of aggregated α-synuclein (α-SYN) in the cytoplasmic region of neurons. Clinical evidence suggests that stimulation of pro-inflammatory cytokines leads to neuroinflammation in the affected brain regions. Upon neuroinflammation, the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway, and other transcription factors such as nuclear factor κB (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), mammalian target of rapamycin (mTOR), and toll-like receptors (TLRs) are upregulated and induce the microglial activation, contributing to PD via dopaminergic neuron autophagy. Aberrant activation or phosphorylation of the components of JAK/STAT signaling pathway has been implicated in increased transcription of the inflammation-associated genes and many neurodegenerative disorders such as PD. Interferon gamma (IFN-γ), and interleukine (IL)-6 are two of the most potent activators of the JAK/STAT pathway, and it was shown to be elevated in PD. Stimulation of microglial cell with aggregated α-SYN results in production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and IL-1β in PD. Dysregulation of the JAK/STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. So far, a variety of synthetic or natural small-molecule JAK inhibitors (Jakinibs) have been found promising in managing a spectrum of ailments, many of which are in preclinical research or clinical trials. Herein, we provided a perspective on the function of the JAK/STAT signaling pathway in PD progression and gathered data that describe the rationale evidence on the potential application of Jakinibs to improve neuroinflammation in PD.
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Affiliation(s)
- Naser-Aldin Lashgari
- Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran; Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, United Kingdom
| | - Amir Hossein Abdolghaffari
- Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran; Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Thapa K, Verma N, Singh TG, Kaur Grewal A, Kanojia N, Rani L. COVID-19-Associated acute respiratory distress syndrome (CARDS): Mechanistic insights on therapeutic intervention and emerging trends. Int Immunopharmacol 2021; 101:108328. [PMID: 34768236 PMCID: PMC8563344 DOI: 10.1016/j.intimp.2021.108328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 02/07/2023]
Abstract
AIMS The novel Coronavirus disease 2019 (COVID-19) has caused great distress worldwide. Acute respiratory distress syndrome (ARDS) is well familiar but when it happens as part of COVID-19 it has discrete features which are unmanageable. Numerous pharmacological treatments have been evaluated in clinical trials to control the clinical effects of CARDS, but there is no assurance of their effectiveness. MATERIALS AND METHODS A systematic review of the literature of the Medline, Scopus, Bentham, PubMed, and EMBASE (Elsevier) databases was examined to understand the novel therapeutic approaches used in COVID-19-Associated Acute Respiratory Distress Syndrome and their outcomes. KEY FINDINGS Current therapeutic options may not be enough to manage COVID-19-associated ARDS complications in group of patients and therefore, the current review has discussed the pathophysiological mechanism of COVID-19-associated ARDS, potential pharmacological treatment and the emerging molecular drug targets. SIGNIFICANCE The rationale of this review is to talk about the pathophysiology of CARDS, potential pharmacological treatment and the emerging molecular drug targets. Currently accessible treatment focuses on modulating immune responses, rendering antiviral effects, anti-thrombosis or anti-coagulant effects. It is expected that considerable number of studies conducting globally may help to discover effective therapies to decrease mortality and morbidity occurring due to CARDS. Attention should be also given on molecular drug targets that possibly will help to develop efficient cure for COVID-19-associated ARDS.
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Affiliation(s)
- Komal Thapa
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India; Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Nitin Verma
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | | | | | - Neha Kanojia
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Lata Rani
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India
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Djediai S, Gonzalez Suarez N, El Cheikh-Hussein L, Rodriguez Torres S, Gresseau L, Dhayne S, Joly-Lopez Z, Annabi B. MT1-MMP Cooperates with TGF-β Receptor-Mediated Signaling to Trigger SNAIL and Induce Epithelial-to-Mesenchymal-like Transition in U87 Glioblastoma Cells. Int J Mol Sci 2021; 22:13006. [PMID: 34884812 PMCID: PMC8657819 DOI: 10.3390/ijms222313006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/25/2021] [Accepted: 11/28/2021] [Indexed: 12/27/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) recapitulates metastasis and can be induced in vitro through transforming growth factor (TGF)-β signaling. A role for MMP activity in glioblastoma multiforme has been ascribed to EMT, but the molecular crosstalk between TGF-β signaling and membrane type 1 MMP (MT1-MMP) remains poorly understood. Here, the expression of common EMT biomarkers, induced through TGF-β and the MT1-MMP inducer concanavalin A (ConA), was explored using RNA-seq analysis and differential gene arrays in human U87 glioblastoma cells. TGF-β triggered SNAIL and fibronectin expressions in 2D-adherent and 3D-spheroid U87 glioblastoma cell models. Those inductions were antagonized by the TGF-β receptor kinase inhibitor galunisertib, the JAK/STAT inhibitors AG490 and tofacitinib, and by the diet-derived epigallocatechin gallate (EGCG). Transient gene silencing of MT1-MMP prevented the induction of SNAIL by ConA and abrogated TGF-β-induced cell chemotaxis. Moreover, ConA induced STAT3 and Src phosphorylation, suggesting these pathways to be involved in the MT1-MMP-mediated signaling axis that led to SNAIL induction. Our findings highlight a new signaling axis linking MT1-MMP to TGF-β-mediated EMT-like induction in glioblastoma cells, the process of which can be prevented by the diet-derived EGCG.
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Affiliation(s)
- Souad Djediai
- Laboratoire d’Oncologie Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC H3C 3P8, Canada; (S.D.); (N.G.S.); (L.E.C.-H.); (S.R.T.); (L.G.)
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
| | - Narjara Gonzalez Suarez
- Laboratoire d’Oncologie Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC H3C 3P8, Canada; (S.D.); (N.G.S.); (L.E.C.-H.); (S.R.T.); (L.G.)
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
| | - Layal El Cheikh-Hussein
- Laboratoire d’Oncologie Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC H3C 3P8, Canada; (S.D.); (N.G.S.); (L.E.C.-H.); (S.R.T.); (L.G.)
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
| | - Sahily Rodriguez Torres
- Laboratoire d’Oncologie Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC H3C 3P8, Canada; (S.D.); (N.G.S.); (L.E.C.-H.); (S.R.T.); (L.G.)
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
| | - Loraine Gresseau
- Laboratoire d’Oncologie Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC H3C 3P8, Canada; (S.D.); (N.G.S.); (L.E.C.-H.); (S.R.T.); (L.G.)
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
| | - Sheraz Dhayne
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
| | - Zoé Joly-Lopez
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
| | - Borhane Annabi
- Laboratoire d’Oncologie Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC H3C 3P8, Canada; (S.D.); (N.G.S.); (L.E.C.-H.); (S.R.T.); (L.G.)
- Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3P8, Canada; (S.D.); (Z.J.-L.)
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Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 2021; 6:402. [PMID: 34824210 PMCID: PMC8617206 DOI: 10.1038/s41392-021-00791-1] [Citation(s) in RCA: 1157] [Impact Index Per Article: 289.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/09/2021] [Accepted: 09/21/2021] [Indexed: 02/08/2023] Open
Abstract
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.
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Affiliation(s)
- Xiaoyi Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, 610041, Chengdu, P. R. China
| | - Jing Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
| | - Maorong Fu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
| | - Xia Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China.
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, 610041, Chengdu, P. R. China.
| | - Wei Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China.
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Lokau J, Kespohl B, Kirschke S, Garbers C. The role of proteolysis in interleukin-11 signaling. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119135. [PMID: 34624437 DOI: 10.1016/j.bbamcr.2021.119135] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/26/2021] [Accepted: 09/06/2021] [Indexed: 12/14/2022]
Abstract
Although interleukin-11 (IL-11) was discovered more than 30 years ago, it remains an understudied member of the IL-6 family of cytokines. While it was originally discovered as a secreted factor that could foster megakaryocyte maturation and was therefore used as a recombinant protein to increase platelet production in patients with thrombocytopenia, recent research has established important roles for IL-11 in inflammation, fibrosis and cancer. In order to initiate signal transduction, IL-11 binds first to a non-signaling membrane-bound IL-11 receptor (IL-11R, classic signaling), which subsequently induces the formation of a heterodimer of the signal-transducing receptor gp130 that is shared with the other family members. Complex formation initiates several intracellular signaling cascades, most notably the Janus kinase/Signal Transducer and Activator of Transcription (Jak/STAT) pathway. We have recently identified a trans-signaling mechanism, in which IL-11 binds to soluble forms of the IL-11R (sIL-11R) and the agonistic IL-11/sIL-11R complex can activate cells that do not express the IL-11R and would usually not respond to IL-11. The generation of sIL-11R and thus the initiation of IL-11 trans-signaling is mediated by proteolytic cleavage. In this review, we summarize the current state of knowledge regarding IL-11R cleavage, highlight recent developments in IL-11 biology and discuss therapeutic opportunities and challenges in the light of IL-11 classic and trans-signaling.
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Affiliation(s)
- Juliane Lokau
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
| | - Birte Kespohl
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
| | - Sophia Kirschke
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
| | - Christoph Garbers
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany.
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Xu Y, Xu W, Lu Z, Cheung MH, Lin M, Liang C, Lou J, Chen Y. Anti-Gastric Cancer Effect of Purified Omphalia lapidescens Protein via Regulating the JAK/STAT3 Signaling Pathway. Nutr Cancer 2021; 74:1780-1791. [PMID: 34601984 DOI: 10.1080/01635581.2021.1960385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Gastric cancer is the leading cause of cancer-related death worldwide. The aim of present study was to investigate the anti-tumor effect of purified Omphalia lapidescens protein (pPeOp) in gastric cancer. Microarray analysis was performed to find out differentially expressed genes in pPeOp-treated MC-4 gastric cancer cells. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) three signaling pathway was most likely to be altered based on bioinformatics analysis. Interleukin-6 (IL-6) and NSC74859 were used as the agonist and inhibitor of the JAK/STAT3 signaling pathway, respectively. Flow cytometry and MTS assay were used for cell proliferation and viability analysis in pPeOp-treated gastric cancer cell lines with IL-6 or NSC74859. The anti-tumor effect was increased when pPeOp were co-treated with IL-6, while decreased in inhibitor treatment. The expression of the crucial members in the pathway of MC-4 cells, including glycoprotein 130 (GP130), JAK1, JAK2, STAT3, p-STAT3, suppressor of cytokine signaling SOCS1 and SOCS3, was detected by western blotting. pPeOp exhibited promising anticancer effect in the xenograft nude mice model, established by STAT3 knock down gastric cancer cells.Thus, JAK/STAT3 inhibition partially contributed to the anticancer effect of pPeOp, which may serve as a novel strategy for gastric cancer.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1960385.
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Affiliation(s)
- Yuqin Xu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wenjun Xu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhongxia Lu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China.,School of Medicine and Pharmacy, Ocean University of China, QingDao, China
| | - Man Hei Cheung
- Division of Life Science, Center for Cancer Research and State Key Lab for Molecular Neural Science, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Meiai Lin
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chun Liang
- School of Medicine and Pharmacy, Ocean University of China, QingDao, China.,EnKang Pharmaceuticals (Guangzhou), Ltd., Guangzhou, China
| | - Jianshu Lou
- Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province, Holistic Integrative Pharmacy Institutes, School of medicine, Hangzhou Normal University, Hangzhou, China
| | - Yitao Chen
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China.,Division of Life Science, Center for Cancer Research and State Key Lab for Molecular Neural Science, The Hong Kong University of Science and Technology, Hong Kong, China
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Velmurugan BK, Lin JT, Mahalakshmi B, Lin CC, Chuang YC, Lo YS, Ho HY, Hsieh MJ, Chen MK. Dehydrocrenatidine inhibits head and neck cancer cells invasion and migration by modulating JNK1/2 and ERK1/2 pathway and decreases MMP-2 expression. ENVIRONMENTAL TOXICOLOGY 2021; 36:1848-1856. [PMID: 34076342 DOI: 10.1002/tox.23305] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/14/2021] [Accepted: 05/24/2021] [Indexed: 06/12/2023]
Abstract
Head and neck cancer is associated with poor prognosis because of its highly metastatic nature. For the better management of head and neck cancer patients, it is very important to diagnose the cancer at an early stage, as well as to prevent the rapid spread of cancer either through direct invasion or lymphatic metastasis. In present study, the effect of dehydrocrenatidine, which is a beta-carboline alkaloid found in the medicinal plant Picrasma quassioides, on human head and neck cancer metastasis was investigated. The study results revealed the treatment of FaDu, SCC9, and SCC47 cells with 5, 10, and 20 μM of dehydrocrenatidine significantly decreased the motility, migration, and invasion of head and neck cancer cells. Moreover, the dehydrocrenatidine treatment significantly decreased the expression of MMP-2 and phosphorylation of ERK1/2 and JNK1/2. Additional experiments revealed that the cotreatment of dehydrocrenatidine with either ERK1/2 or JNK1/2 inhibitor caused further reduction in cancer cell motility and migration compared to that in dehydrocrenatidine treatment alone. Moreover, similar trend was observed in case of ERK1/2 and JNK1/2 phosphorylation and MMP-2 expression after the cotreatment. Taken together, the mechanism by which dehydrocrenatidine can decrease the phosphorylation of ERK1/2 and JNK1/2, follow decrease the expression of MMP-2 and inhibits head and neck cancer cells invasion and migration. This present study identifies dehydrocrenatidine as a potent antimetastatic agent that can be used clinically to improve head and neck cancer prognosis.
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Affiliation(s)
| | - Jen-Tsun Lin
- Division of Hematology and Oncology, Department of Medicine, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Post Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan
| | - B Mahalakshmi
- Department of Research and Development, Vels Publishers, Tamilnadu, India
| | - Chia-Chieh Lin
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ching Chuang
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yu-Sheng Lo
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsin-Yu Ho
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Ju Hsieh
- Post Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Mu-Kuan Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
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de Castro CPM, Cadefau M, Cuartero S. The Mutational Landscape of Myeloid Leukaemia in Down Syndrome. Cancers (Basel) 2021; 13:4144. [PMID: 34439298 PMCID: PMC8394284 DOI: 10.3390/cancers13164144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/30/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators-such as cohesin, CTCF or EZH2-and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.
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Affiliation(s)
| | - Maria Cadefau
- Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; (C.P.M.d.C); (M.C.)
- Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain
| | - Sergi Cuartero
- Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; (C.P.M.d.C); (M.C.)
- Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain
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Nerve growth factor orchestrates NGAL and matrix metalloproteinases activity to promote colorectal cancer metastasis. Clin Transl Oncol 2021; 24:34-47. [PMID: 34255268 DOI: 10.1007/s12094-021-02666-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE Colorectal cancer (CRC) is one most cancer type of high incidence and high mortality rate. Metastasis play an important role in survival rate and life quality of colorectal cancer patients. Nerve growth factor (NGF) has been shown to be involved in the metastasis and deterioration in many cancers, but the detail mechanisms in promoting the metastasis of colorectal cancer remain unknown. In this study, we aimed to explore the mechanism of NGF promoting colorectal cancer metastasis to provide new insights for developing NGF anti-colorectal cancer drugs. METHODS We examined the expression of NGF in human colorectal cancer by immunohistochemical staining, and Western blot to evaluate the relationship between NGF and colorectal cancer metastasis. Using biochemical experiments including wound healing assay, transwell migration and invasion assay, RT-PCR, Western blot and ELISA to explore the relative mechanism of NGF promoting colorectal cancer cells metastasis in vivo. RESULTS Our results found that the high expression of NGF was related with high incidence of metastasis. The binding of NGF to TrkA phosphorylated TrkA, which activated MAPK/Erk signaling pathway increasing the expression NGAL to enhance the activity of MMP2 and MMP9, promoted colorectal cancer metastasis. CONCLUSION Our finding demonstrated that NGF increased NGAL expression to enhance MMPs activity to promoted colorectal cancer cell metastasis by TrkA-MAPK/Erk axis.
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Zhirnov VV, Velihina YS, Mitiukhin OP, Brovarets VS. Intrinsic drug potential of oxazolo[5,4-d]pyrimidines and oxazolo[4,5-d]pyrimidines. Chem Biol Drug Des 2021; 98:561-581. [PMID: 34148293 DOI: 10.1111/cbdd.13911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/12/2021] [Accepted: 06/15/2021] [Indexed: 12/19/2022]
Abstract
The oxazole and pyrimidine rings are widely displayed in natural products and synthetic molecules. They are known as the prime skeletons for drug discovery. On the account of structural and chemical diversity, oxazole and pyrimidine-based molecules, as central scaffolds, not only provide different types of interactions with various receptors and enzymes, showing broad biological activities, but also occupy a core position in medicinal chemistry, showing their importance for development and discovery of newer potential therapeutic agents (Curr Top Med Chem, 16, 2016, 3133; Int J Pharm Pharm Sci, 8, 2016, 8; BMC Chem, 13, 2019, 44). For a long time, relatively little attention has been paid to their fused rings that are oxazolopyrimidines, whose chemical structure is similar to that of natural purines because probably none of these compounds were found in natural products or their biological activities turned out to be unexpressed (Bull Chem Soc Jpn, 43, 1970, 187). Recently, however, a significant number of studies have been published on the biological properties of oxazolo[5,4-d]pyrimidines, showing their significant activity as agonists and antagonists of signaling pathways involved in the regulation of the cell life cycle, whereas oxazolo[4,5-d]pyrimidines, on the contrary, represent a poorly studied class of compounds. Limited access to this scaffold has resulted in a corresponding lack of biological research (Eur J Organ Chem, 18, 2018, 2148). Actually, oxazolo[5,4-d]pyrimidine is a versatile scaffold used for the design of bioactive ligands against enzymes and receptors. This review focuses on biological targets and associated pathogenetic mechanisms, as well as pathological disorders that can be modified by well-known oxazolopyrimidines that have been proven to date. Many molecular details of these processes are omitted here, which the interested reader will find in the cited literature. This work also does not cover the methods for the synthesis of the oxazolopyrimidines, which are exhaustively described by De Coen et al. (Eur J Organ Chem, 18, 2018, 2148). The review as well does not discuss the structure-activity relationship, which is described in detail in the original works and deliberately, whenever possible, cites not primary sources, but mostly relevant review articles, so that the reader who wants to delve into a particular problem will immediately receive more complete information. It is expected that the information presented in this review will help readers better understand the purpose of the development of oxazolopyrimidines and the possibility of their development as drugs for the treatment of a wide range of diseases.
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Affiliation(s)
- Victor V Zhirnov
- Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv, Ukraine
| | - Yevheniia S Velihina
- Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv, Ukraine
| | - Oleg P Mitiukhin
- Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv, Ukraine
| | - Volodymyr S Brovarets
- Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv, Ukraine
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Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q, Deng S, Zhou H. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther 2021; 6:218. [PMID: 34108441 PMCID: PMC8190181 DOI: 10.1038/s41392-021-00641-0] [Citation(s) in RCA: 363] [Impact Index Per Article: 90.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/20/2021] [Accepted: 05/06/2021] [Indexed: 02/05/2023] Open
Abstract
To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial-mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.
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Affiliation(s)
- Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jin Yang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Junjiang Liu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ye Wang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jingtian Mu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qingxiang Zeng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shuzhi Deng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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Campochiaro C, Allanore Y. An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years. Arthritis Res Ther 2021; 23:155. [PMID: 34074331 PMCID: PMC8168022 DOI: 10.1186/s13075-021-02536-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 05/19/2021] [Indexed: 11/10/2022] Open
Abstract
New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.
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Affiliation(s)
- Corrado Campochiaro
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
| | - Yannick Allanore
- Service de Rhumatologie, Hôpital Cochin, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.
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Wang S, Zhang RH, Zhang H, Wang YC, Yang D, Zhao YL, Yan GY, Xu GB, Guan HY, Zhou YH, Cui DB, Liu T, Li YJ, Liao SG, Zhou M. Design, synthesis, and biological evaluation of 2,4-diamino pyrimidine derivatives as potent FAK inhibitors with anti-cancer and anti-angiogenesis activities. Eur J Med Chem 2021; 222:113573. [PMID: 34091209 DOI: 10.1016/j.ejmech.2021.113573] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/15/2021] [Accepted: 05/20/2021] [Indexed: 01/18/2023]
Abstract
A series of 2,4-diamino pyrimidine (DAPY) derivatives were designed, synthesized, and evaluated as inhibitors of focal adhesion kinase (FAK) with antitumor and anti-angiogenesis activities. Most compounds effectively suppressed the enzymatic activities of FAK, and the IC50s of 11b and 12f were 2.75 and 1.87 nM, respectively. 11b and 12f exhibited strong antiproliferative effects against seven human cancer cells, with IC50 values against two FAK-overexpressing pancreatic cancer cells (PANC-1 and BxPC-3) of 0.98 μM, 0.55 μM, and 0.11 μM, 0.15 μM, respectively. Moreover, 11b and 12f obviously suppressed the colony formation, migration, and invasion of PANC-1 cells in a dose-dependent manner. Meanwhile, these two compounds could induce the apoptosis of PANC-1 cells and arrest the cell cycle in G2/M phase according to the flow cytometry assay. Western blot revealed that 11b and 12f effectively inhibited the FAK/PI3K/Akt signal pathway and significantly decreased the expression of cyclin D1 and Bcl-2. In addition, compounds 11b and 12f potently inhibited the antiproliferative of HUVECs and obviously altered the cell morphology. 11b and 12f also significantly inhibited the migration, tube formation of HUVECs and severely impaired the angiogenesis in the zebrafish model. Overall, these results revealed the potential of compounds 11b and 12f as promising candidates for further preclinical studies.
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Affiliation(s)
- Shan Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang, 550004, PR China; School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Rong-Hong Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang, 550004, PR China; Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine of Guizhou Province, Guizhou Medical University, Guiyang, 550004, PR China
| | - Hong Zhang
- School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Yu-Chan Wang
- School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Dan Yang
- School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Yong-Long Zhao
- School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Guo-Yi Yan
- Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, Henan University, Zhengzhou, PR China
| | - Guo-Bo Xu
- School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Huan-Yu Guan
- School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Yan-Hua Zhou
- Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine of Guizhou Province, Guizhou Medical University, Guiyang, 550004, PR China
| | - Dong-Bing Cui
- Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine of Guizhou Province, Guizhou Medical University, Guiyang, 550004, PR China
| | - Ting Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang, 550004, PR China; School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Yong-Jun Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang, 550004, PR China; School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China
| | - Shang-Gao Liao
- School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China.
| | - Meng Zhou
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang, 550004, PR China; School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou, PR China.
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Solipuram V, Mohan A, Patel R, Ni R. Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. AUTOIMMUNITY HIGHLIGHTS 2021; 12:8. [PMID: 33910632 PMCID: PMC8080865 DOI: 10.1186/s13317-021-00153-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/25/2021] [Indexed: 12/14/2022]
Abstract
Background Rheumatoid arthritis (RA) is a systemic autoimmune disease. The combination therapy of methotrexate (MTX) and Janus kinase inhibitor (JAKi) is commonly used. Patients with RA are at increased risk of malignancy, however, it remains unclear whether the combination therapy is associated with a higher risk. Objective To assess the malignancy risk among patients with RA receiving combination therapy of JAKi and MTX compared to MTX alone. Methods PubMed, Cochrane and Embase were thoroughly searched for randomized controlled trials (RCTs) in patients with RA receiving JAKi and MTX, from inception to July 2020. Primary endpoints were malignancy events, Non melanomatous skin cancer (NMSC) and malignancy excluding NMSC and secondary endpoints were serious adverse events (SAE), deaths. Risk ratio (RR) and 95% CI were calculated using the Mantel–Haenszel random-effect method. Results 659 publications were screened and 13 RCTs with a total of 6911 patients were included in the analysis. There was no statistically significant difference in malignancy [RR = 1.42; 95% CI (0.59, 3.41)], neither NMSC [RR = 1.44 (0.36, 5.76)] nor malignancies excluding NMSC [RR = 1.12 (0.40, 3.13)]. No statistically significant difference between the two groups for SAE [RR = 1.15 (0.90, 1.47)] and deaths [RR = 1.99 (0.75, 5.27)] was found. Conclusion The adjunction of JAKi to MTX is not associated with an increased risk of malignancy when compared to MTX alone. There is no increased risk of SAE and deaths when compared to MTX alone in patients with RA. Supplementary Information The online version contains supplementary material available at 10.1186/s13317-021-00153-5.
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Affiliation(s)
- Vinod Solipuram
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA
| | - Akhila Mohan
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA
| | - Roshniben Patel
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA
| | - Ruoning Ni
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA.
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Wang X, Ge Y, Shi M, Dai H, Liu W, Wang P. Protein kinase N1 promotes proliferation and invasion of liver cancer. Exp Ther Med 2021; 21:651. [PMID: 33968181 PMCID: PMC8097187 DOI: 10.3892/etm.2021.10083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 03/22/2021] [Indexed: 12/24/2022] Open
Abstract
Protein kinase (PK) N1, also called PKC-related protein 1, participates in the proliferation, invasion and metastasis of various malignant tumors. However, the role of PKN1 in liver cancer remains to be elucidated. The present study investigated the expression of PKN1 using immunohistochemistry in surgical specimens from 36 patients and analyzed the correlation with VEGF, microvascular density (MVD), cell proliferation index (Ki67) and clinicopathological parameters. PKN1 was highly expressed in hepatocellular carcinoma (HCC) and was positively correlated with histological grading of HCC, Ki67 expression and MVD. PKN1 expression in moderately and poorly differentiated HCC was significantly higher compared with highly differentiated HCC. Expression of PKN1 was positively correlated with Ki67 and MVD, and Ki67 expression was positively correlated with MVD. The effects of PKN1 on proliferation, invasion and apoptosis of liver cancer cells were detected in vitro. Cell viability, migration and invasion were reduced and the apoptosis rate was significantly improved when PKN1 expression was silenced in liver cancer cells. Thus, PKN1 serves an important role in the development and progression of liver cancer. Inhibition of PKN1 activity may provide a promising therapeutic target for liver cancer.
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Affiliation(s)
- Xia Wang
- Department of Pathology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Yansong Ge
- Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Mingqi Shi
- Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Hanhan Dai
- Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Wei Liu
- Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Peiyuan Wang
- Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
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JAK/STAT inhibitor therapy partially rescues the lipodystrophic autoimmune phenotype in Clec16a KO mice. Sci Rep 2021; 11:7372. [PMID: 33795715 PMCID: PMC8016875 DOI: 10.1038/s41598-021-86493-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
CLEC16A is implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout (KO), Clec16aΔUBC mice to address the role of CLEC16A loss of function. KO mice exhibited loss of adipose tissue and severe weight loss in response to defective autophagic flux and exaggerated endoplasmic reticulum (ER) stress and robust cytokine storm. KO mice were glucose tolerant and displayed a state of systemic inflammation with elevated antibody levels, including IgM, IgA, Ig2b and IgG3, significantly reduced circulating insulin levels in the presence of normal food consumption. Metabolic analysis revealed disturbances in the lipid profile, white adipose decreasing concomitantly with enhanced inflammatory response, and energy wasting. Mechanistically, endoplasmic reticulum (ER) stress triggers excessive hormone sensitive lipases (HSL) mediated lipolysis which contributes to adipose inflammation via activation of JAK-STAT, stress kinases (ERK1/2, P38, JNK), and release of multiple proinflammatory mediators. Treatment with a JAK-STAT inhibitor (tofacitinib) partially rescued the inflammatory lipodystrophic phenotype and improved survival of Clec16aΔUBC mice by silencing cytokine release and modulating ER stress, lipolysis, mitophagy and autophagy. These results establish a mechanistic link between CLEC16A, lipid metabolism and the immune system perturbations. In summary, our Clec16aΔUBC mouse model highlights multifaceted roles of Clec16a in normal physiology, including a novel target for weight regulation and mutation-induced pathophysiology.
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Hosseini A, Gharibi T, Mohammadzadeh A, Ebrahimi-Kalan A, Jadidi-Niaragh F, Babaloo Z, Shanehbandi D, Baghbani E, Baradaran B. Ruxolitinib attenuates experimental autoimmune encephalomyelitis (EAE) development as animal models of multiple sclerosis (MS). Life Sci 2021; 276:119395. [PMID: 33781828 DOI: 10.1016/j.lfs.2021.119395] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 01/07/2023]
Abstract
AIMS STAT3 signaling is critical for Th17 development that plays an important role in multiple sclerosis pathogenesis. To evaluate the anti-inflammatory and regulatory T cells effects of JAK1/2 and STAT3 inhibition, we assessed the JAK 1/2 inhibitor ruxolitinib effects on Th17 cell/Tregs balance. MAIN METHODS Ruxolitinib was administered to experimental autoimmune encephalomyelitis (EAE) mice via oral gavage, and its effects were assessed. The expression of pro-inflammatory and anti-inflammatory cytokines, including IL-17A and IL-10, were analyzed by real-time PCR. The frequency of Th17 cells and Tregs were evaluated by flow cytometry. KEY FINDING Ruxolitinib ameliorated the EAE severity and decreased the proportion of Th17 cells and inflammatory markers levels. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine were increased in ruxolitinib-treated mice. Furthermore, ruxolitinib markedly decreased the expression of Th17 related transcription factor, RORɣt, whereas FOXP3 expression associated with Treg differentiation was increased. SIGNIFICANCE Our results show that ruxolitinib may be a promising therapeutic strategy for multiple sclerosis.
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Affiliation(s)
- Arezoo Hosseini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Adel Mohammadzadeh
- Department of Immunology and Genetics, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Abbas Ebrahimi-Kalan
- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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