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Hossain MT, Hossain MA. Targeting PI3K in cancer treatment: A comprehensive review with insights from clinical outcomes. Eur J Pharmacol 2025; 996:177432. [PMID: 40020984 DOI: 10.1016/j.ejphar.2025.177432] [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: 11/16/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.
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Affiliation(s)
- Md Takdir Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
| | - Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
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Lee T, Kim CJ, Lim DH, Lee YS. microRNA miR-315-5p regulates developmental growth in Drosophila wings by targeting S6k. INSECT SCIENCE 2025. [PMID: 40166978 DOI: 10.1111/1744-7917.70027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 02/12/2025] [Accepted: 02/18/2025] [Indexed: 04/02/2025]
Abstract
Tissue growth in Drosophila is regulated by various factors, with microRNAs (miRNAs) emerging as key players over the past decade. However, the precise roles of miRNAs in growth regulation remain incompletely understood. In this study, we explored the biological role of miR-315 in wing growth regulation. Inhibition of miR-315-5p activity using a miR-315 sponge led to an increase in wing size, whereas its overexpression resulted in reduced wing size, primarily through a decrease in wing cell size. We identified ribosomal protein kinase p-70-S6k (S6k) as a target of miR-315-5p in relation to wing growth control. Overexpression of miR-315 reduced both total S6k and phosphorylated S6k protein levels in Drosophila S2 cells and wing discs. Additionally, a luciferase reporter assay confirmed that miR-315-5p directly binds to the 3'-untranslated region of S6k. Consistently, RNAi-mediated depletion of S6k led to smaller wings, primarily due to a reduction in cell size. Notably, co-overexpression of active S6k rescued the wing defects caused by miR-315 overexpression. Overall, these findings demonstrate that miR-315 regulates wing growth by suppressing S6k expression.
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Affiliation(s)
- Taeheon Lee
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Chae Jeong Kim
- School of Systems Biomedical Science, Soongsil University, Seoul, Republic of Korea
| | - Do-Hwan Lim
- School of Systems Biomedical Science, Soongsil University, Seoul, Republic of Korea
| | - Young Sik Lee
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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Tashkandi AJ, Gorman A, McGoldrick Mathers E, Carney G, Yacoub A, Setyaningsih WAW, Kuburas R, Margariti A. Metabolic and Mitochondrial Dysregulations in Diabetic Cardiac Complications. Int J Mol Sci 2025; 26:3016. [PMID: 40243689 PMCID: PMC11988959 DOI: 10.3390/ijms26073016] [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: 02/01/2025] [Revised: 03/16/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
The growing prevalence of diabetes highlights the urgent need to study diabetic cardiovascular complications, specifically diabetic cardiomyopathy, which is a diabetes-induced myocardial dysfunction independent of hypertension or coronary artery disease. This review examines the role of mitochondrial dysfunction in promoting diabetic cardiac dysfunction and highlights metabolic mechanisms such as hyperglycaemia-induced oxidative stress. Chronic hyperglycaemia and insulin resistance can activate harmful pathways, including advanced glycation end-products (AGEs), protein kinase C (PKC) and hexosamine signalling, uncontrolled reactive oxygen species (ROS) production and mishandling of Ca2+ transient. These processes lead to cardiomyocyte apoptosis, fibrosis and contractile dysfunction. Moreover, endoplasmic reticulum (ER) stress and dysregulated RNA-binding proteins (RBPs) and extracellular vesicles (EVs) contribute to tissue damage, which drives cardiac function towards heart failure (HF). Advanced patient-derived induced pluripotent stem cell (iPSC) cardiac organoids (iPS-COs) are transformative tools for modelling diabetic cardiomyopathy and capturing human disease's genetic, epigenetic and metabolic hallmarks. iPS-COs may facilitate the precise examination of molecular pathways and therapeutic interventions. Future research directions encourage the integration of advanced models with mechanistic techniques to promote novel therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | - Refik Kuburas
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
| | - Andriana Margariti
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
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Huang D, Gu J, Liang H, Ren M, Xue C. Effects of Seaweed Polysaccharide on the Growth and Physiological Health of Largemouth Bass, Micropterus salmoides. Antioxidants (Basel) 2025; 14:52. [PMID: 39857386 PMCID: PMC11763202 DOI: 10.3390/antiox14010052] [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: 11/25/2024] [Revised: 12/17/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
A seven-week trial was designed to evaluate the effects of dietary seaweed polysaccharide (SP) supplementation on the growth performance and physiological health of largemouth bass. The results reveal that the 0.05SP group showed the best growth performance. The mRNA expression levels of tor, 4ebp1, and igf1 genes were remarkably down-regulated in the 0.15SP and 0.2SP groups compared to the control group. The CAT activities were significantly increased in the 0.05SP and 0.1SP groups, and the GSH-Px activity was increased in the 0.15SP group. The expression of the immune response-related gene nfκb was significantly down-regulated in the 0.1SP group, and those of tnfα and il-8 were at the maximum in the control group. Moreover, the expression of il-10 in the 0.15SP and 0.2SP groups was significantly down-regulated. Furthermore, endoplasmic reticulum stress (ERS)-related expression of atf6 was the highest in the control group. Furthermore, the chopα and bax expression levels in the 0.15SP and 0.2SP groups were significantly down-regulated compared with other groups. In addition, the highest expression level of bcl-xl was observed in the 0.15SP group. Finally, the quadratic regression analysis of antioxidant, immune, and ERS core parameters (CAT, nf-κb, and bcl-xl) determined 0.06-0.11% to be the optimal SP supplemental level in largemouth bass diets.
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Affiliation(s)
- Dongyu Huang
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Jiaze Gu
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China
| | - Hualiang Liang
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Mingchun Ren
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Chunyu Xue
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China
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Huang H, Qin J, Wen Z, Wang C, Chen C, Liu Y, Li H, Cao S, Yang X. Association of branched-chain amino acids and risk of three urologic cancers: a Mendelian randomization study. Transl Cancer Res 2024; 13:6709-6720. [PMID: 39816560 PMCID: PMC11729756 DOI: 10.21037/tcr-24-1142] [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: 07/04/2024] [Accepted: 10/31/2024] [Indexed: 01/18/2025]
Abstract
Background Multiple studies suggest a plausible connection between urologic cancers and branched-chain amino acids (BCAAs) breakdown metabolic enzymes. Nevertheless, there is scarce exploration into the variations in circulating BCAAs. In our research, we utilize bidirectional, two-sample Mendelian randomization (MR) analysis to predict the link between BCAAs levels and three distinct types of urological tumors. Methods The study examined data from the UK Biobank, including a comprehensive genome-wide association study (GWAS) of total BCAAs, leucine, isoleucine, and valine, alongside three urological system tumors [prostate cancer (PCa), kidney cancer, and bladder cancer] sourced from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) and FinnGen Consortium databases. The primary analytical approach involved the use of the inverse variance weighted (IVW) method, complemented by MR-PRESSO global testing and MR-Egger regression to identify potential horizontal pleiotropy. Heterogeneity was evaluated using the Cochran Q test. Results The levels of circulating total BCAAs [odds ratio (OR) =1.002688, 95% confidence interval (CI): 1.000, 1.005, P=0.03], leucine (OR =1.0038, 95% CI: 1.001, 1.007, P=0.008), isoleucine (OR =1.003352, 95% CI: 1.000, 1.007, P=0.04), and valine (OR =1.00279, 95% CI: 1.001, 1.005, P=0.009) showed positive associations with PCa risk. However, there was inadequate evidence to establish a link between BCAAs and bladder or kidney cancer. Conclusions In summary, an association existed between elevated levels of circulating total BCAAs, leucine, isoleucine, and valine, and an increased risk of PCa. However, no correlation was detected between BCAAs and kidney or bladder cancer.
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Affiliation(s)
- Haotian Huang
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Jiao Qin
- Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Zhi Wen
- Department of Urology, Langzhong People’s Hospital, Langzhong, China
| | - Chongjian Wang
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Caixia Chen
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Yang Liu
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Hongyuan Li
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Song Cao
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Xuesong Yang
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Health Management Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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Chen H, Wang W, Chang S, Huang X, Wang N. A useful mTORC1 signaling-related RiskScore model for the personalized treatment of osteosarcoma patients by using the bulk RNA-seq analysis. Discov Oncol 2024; 15:418. [PMID: 39251459 PMCID: PMC11383908 DOI: 10.1007/s12672-024-01301-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024] Open
Abstract
AIMS This research developed a prognostic model for OS patients based on the Mechanistic Target of Rapamycin Complex 1 (mTORC1) signature. BACKGROUND The mTORC1 signaling pathway has a critical role in the maintenance of cellular homeostasis and tumorigenesis and development through the regulation of cell growth, metabolism and autophagy. However, the mechanism of action of this signaling pathway in Osteosarcoma (OS) remains unclear. OBJECTIVE The datasets including the TARGET-OS and GSE39058, and 200 mTORC1 genes were collected. METHODS The mTORC1 signaling-related genes were obtained based on the Molecular Signatures Database (MSigDB) database, and the single sample gene set enrichment analysis (ssGSEA) algorithm was utilized in order to calculate the mTORC1 score. Then, the WGCNA were performed for the mTORC1-correlated gene module, the un/multivariate and lasso Cox regression analysis were conducted for the RiskScore model. The immune infiltration analysis was performed by using the ssGSEA method, ESTIMATE tool and MCP-Count algorithm. KM survival and Receiver Operating Characteristic (ROC) Curve analysis were performed by using the survival and timeROC package. RESULTS The mTORC1 score and WGCNA with β = 5 screened the mTORC1 positively correlated skyblue2 module that included 67 genes, which are also associated with the metabolism and hypoxia pathways. Further narrowing of candidate genes and calculating the regression coefficient, we developed a useful and reliable RiskScore model, which can classify the patients in the training and validation set into high and low-risk groups based on the median value of RiskScore as an independent and robust prognostic factor. High-risk patients had a significantly poor prognosis, lower immune infiltration level of multiple immune cells and prone to cancer metastasis. Finally, we a nomogram model incorporating the metastasis features and RiskScore showed excellent prediction accuracy and clinical practicability. CONCLUSION We developed a useful and reliable risk prognosis model based on the mTORC1 signaling signature.
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Affiliation(s)
- Hongxia Chen
- Department of Hematology, Chongqing University Three Gorges Hospital, Chongqing, 404000, China
| | - Wei Wang
- Department of Oncology, Chongqing University Three Gorges Hospital, Chongqing, 404000, China
| | - Shichuan Chang
- Department of Oncology, Chongqing University Three Gorges Hospital, Chongqing, 404000, China
| | - Xiaoping Huang
- Department of Oncology, Chongqing University Three Gorges Hospital, Chongqing, 404000, China.
| | - Ning Wang
- Department of Oncology, Chongqing University Three Gorges Hospital, Chongqing, 404000, China.
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Abstract
Myelination has evolved as a mechanism to ensure fast and efficient propagation of nerve impulses along axons. Within the central nervous system (CNS), myelination is carried out by highly specialized glial cells, oligodendrocytes. The formation of myelin is a prolonged aspect of CNS development that occurs well into adulthood in humans, continuing throughout life in response to injury or as a component of neuroplasticity. The timing of myelination is tightly tied to the generation of oligodendrocytes through the differentiation of their committed progenitors, oligodendrocyte precursor cells (OPCs), which reside throughout the developing and adult CNS. In this article, we summarize our current understanding of some of the signals and pathways that regulate the differentiation of OPCs, and thus the myelination of CNS axons.
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Affiliation(s)
- Ben Emery
- Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, Oregon 97239, USA
| | - Teresa L Wood
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, New Jersey 07103, USA
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Kharouf N, Flanagan TW, Alamodi AA, Al Hmada Y, Hassan SY, Shalaby H, Santourlidis S, Hassan SL, Haikel Y, Megahed M, Brodell RT, Hassan M. CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance. Cells 2024; 13:240. [PMID: 38334632 PMCID: PMC10854812 DOI: 10.3390/cells13030240] [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: 11/29/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.
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Affiliation(s)
- Naji Kharouf
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France; (N.K.); (Y.H.)
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
| | - Thomas W. Flanagan
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA;
| | | | - Youssef Al Hmada
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA; (Y.A.H.); (R.T.B.)
| | - Sofie-Yasmin Hassan
- Department of Pharmacy, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany;
| | - Hosam Shalaby
- Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA;
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany;
| | - Sarah-Lilly Hassan
- Department of Chemistry, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany;
| | - Youssef Haikel
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France; (N.K.); (Y.H.)
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
- Pôle de Médecine et Chirurgie Bucco-Dentaire, Hôpital Civil, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France
| | - Mossad Megahed
- Clinic of Dermatology, University Hospital of Aachen, 52074 Aachen, Germany;
| | - Robert T. Brodell
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA; (Y.A.H.); (R.T.B.)
| | - Mohamed Hassan
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France; (N.K.); (Y.H.)
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
- Research Laboratory of Surgery-Oncology, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
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Wu X, Xin Y, Ma Y, Ping K, Li Q, Sun Y, Hu Z, Dong J. Abamectin induced brain and liver toxicity in carp: The healing potential of silybin and potential molecular mechanisms. FISH & SHELLFISH IMMUNOLOGY 2023; 142:109152. [PMID: 37821005 DOI: 10.1016/j.fsi.2023.109152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 10/04/2023] [Accepted: 10/08/2023] [Indexed: 10/13/2023]
Abstract
Abamectin (ABM) abuse contaminated aquatic environment and posed a potential threat to fish health as well as public safety. Silybin (SIL), a flavonoid, has been widely used as a novel feed additive to promote fish health. This research was to explore the potential antagonistic mechanism between ABM and SIL on brain and liver toxicity was investigated in common carp. Sixty carp were divided into four groups at random: the Control group, the SIL group, the ABM group, and ABM + SIL group. This experiment lasted for 30 d. According to behavioral observation, the detection of levels of acetylcholinesterase (AchE), iron, and mRNA expression levels of blood-brain barrier (BBB) related tight junction proteins (ZO-1, Claudin7, Occludin, MMP2, MMP9, and MMP13) in brain tissues, it was found that SIL relieved neurobehavioral disorders caused by ABM-induced BBB destruction in carp. H&E staining showed SIL mitigated nerve injury and liver injury caused by ABM. Oil Red O staining and liver-related parameters showed that SIL alleviated hepatotoxicity and lipid metabolism disorder caused by ABM exposure. Furthermore, this work also explored the specific molecular mechanism of SIL in liver protection and neuroprotection. It was shown that SIL lowered ROS levels in liver and brain tissues via the GSK-3β/TSC2/TOR pathway. Simultaneously, SIL inhibited NF-κB signaling pathway and played an anti-inflammatory role. In conclusion, we believed that SIL supplementation has a protective effect on the brain and liver by regulating oxidative stress and inflammation.
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Affiliation(s)
- Xinyu Wu
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Yue Xin
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Yeyun Ma
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Kaixin Ping
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Qiulu Li
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Ying Sun
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Zunhan Hu
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Jingquan Dong
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China.
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Muñoz-Muñoz PLA, Mares-Alejandre RE, Meléndez-López SG, Ramos-Ibarra MA. Structural Insights into the Giardia lamblia Target of Rapamycin Homolog: A Bioinformatics Approach. Int J Mol Sci 2023; 24:11992. [PMID: 37569368 PMCID: PMC10418948 DOI: 10.3390/ijms241511992] [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: 06/02/2023] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
TOR proteins, also known as targets of rapamycin, are serine/threonine kinases involved in various signaling pathways that regulate cell growth. The protozoan parasite Giardia lamblia is the causative agent of giardiasis, a neglected infectious disease in humans. In this study, we used a bioinformatics approach to examine the structural features of GTOR, a G. lamblia TOR-like protein, and predict functional associations. Our findings confirmed that it shares significant similarities with functional TOR kinases, including a binding domain for the FKBP-rapamycin complex and a kinase domain resembling that of phosphatidylinositol 3-kinase-related kinases. In addition, it can form multiprotein complexes such as TORC1 and TORC2. These results provide valuable insights into the structure-function relationship of GTOR, highlighting its potential as a molecular target for controlling G. lamblia cell proliferation. Furthermore, our study represents a step toward rational drug design for specific anti-giardiasis therapeutic agents.
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Affiliation(s)
| | - Rosa E. Mares-Alejandre
- Biotechnology and Biosciences Research Group, School of Chemical Sciences and Engineering, Autonomous University of Baja California, Tijuana 22390, Mexico; (P.L.A.M.-M.); (S.G.M.-L.); (M.A.R.-I.)
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Alhaddad A, Radwan A, Mohamed NA, Mehanna ET, Mostafa YM, El-Sayed NM, Fattah SA. Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway. Biomedicines 2023; 11:biomedicines11030860. [PMID: 36979839 PMCID: PMC10046017 DOI: 10.3390/biomedicines11030860] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/18/2023] Open
Abstract
Major depressive disorder (MDD) is a common, complex disease with poorly understood pathogenesis. Disruption of glucose metabolism is implicated in the pathogenesis of depression. AMP-activated protein kinase (AMPK) has been shown to regulate the activity of several kinases, including pAKT, p38MAPK, and mTOR, which are important signaling pathways in the treatment of depression. This study tested the hypothesis that rosiglitazone (RGZ) has an antidepressant impact on dexamethasone (DEXA)-induced depression by analyzing the function of the pAKT/p38MAPK/mTOR pathway and NGF through regulation of AMPK. MDD-like pathology was induced by subcutaneous administration of DEXA (20 mg/kg) for 21 days in all groups except in the normal control group, which received saline. To investigate the possible mechanism of RGZ, the protein expression of pAMPK, pAKT, p38MAPK, and 4EBP1 as well as the levels of hexokinase, pyruvate kinase, and NGF were assessed in prefrontal cortex and hippocampal samples. The activities of pAMPK and NGF increased after treatment with RGZ. The administration of RGZ also decreased the activity of mTOR as well as downregulating the downstream signaling pathways pAKT, p38MAPK, and 4EBP1. Here, we show that RGZ exerts a potent inhibitory effect on the pAKT/p38MAPK/mTOR/4EBP1 pathway and causes activation of NGF in brain cells. This study has provided sufficient evidence of the potential for RGZ to ameliorate DEXA-induced depression. A new insight has been introduced into the critical role of NGF activation in brain cells in depression. These results suggest that RGZ is a promising antidepressant for the treatment of MDD.
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Affiliation(s)
- Aisha Alhaddad
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah 30078, Saudi Arabia
| | - Asmaa Radwan
- Department of Pharmacology &Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Noha A. Mohamed
- Department of Forgery & Counterfeiting, Forensic Medicine, Ministry of Justice, Ismailia 41522, Egypt
| | - Eman T. Mehanna
- Department of Biochemistry & Molecular Biology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
- Correspondence: (E.T.M.); (N.M.E.-S.)
| | - Yasser M. Mostafa
- Department of Pharmacology &Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo, Badr 11829, Egypt
| | - Norhan M. El-Sayed
- Department of Pharmacology &Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
- Correspondence: (E.T.M.); (N.M.E.-S.)
| | - Shaimaa A. Fattah
- Department of Biochemistry & Molecular Biology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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12
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Mierke F, Brink DP, Norbeck J, Siewers V, Andlid T. Functional genome annotation and transcriptome analysis of Pseudozyma hubeiensis BOT-O, an oleaginous yeast that utilizes glucose and xylose at equal rates. Fungal Genet Biol 2023; 166:103783. [PMID: 36870442 DOI: 10.1016/j.fgb.2023.103783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 02/10/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023]
Abstract
Pseudozyma hubeiensis is a basidiomycete yeast that has the highly desirable traits for lignocellulose valorisation of being equally efficient at utilization of glucose and xylose, and capable of their co-utilization. The species has previously mainly been studied for its capacity to produce secreted biosurfactants in the form of mannosylerythritol lipids, but it is also an oleaginous species capable of accumulating high levels of triacylglycerol storage lipids during nutrient starvation. In this study, we aimed to further characterize the oleaginous nature of P. hubeiensis by evaluating metabolism and gene expression responses during storage lipid formation conditions with glucose or xylose as a carbon source. The genome of the recently isolated P. hubeiensis BOT-O strain was sequenced using MinION long-read sequencing and resulted in the most contiguous P. hubeiensis assembly to date with 18.95 Mb in 31 contigs. Using transcriptome data as experimental support, we generated the first mRNA-supported P. hubeiensis genome annotation and identified 6540 genes. 80% of the predicted genes were assigned functional annotations based on protein homology to other yeasts. Based on the annotation, key metabolic pathways in BOT-O were reconstructed, including pathways for storage lipids, mannosylerythritol lipids and xylose assimilation. BOT-O was confirmed to consume glucose and xylose at equal rates, but during mixed glucose-xylose cultivation glucose was found to be taken up faster. Differential expression analysis revealed that only a total of 122 genes were significantly differentially expressed at a cut-off of |log2 fold change| ≥ 2 when comparing cultivation on xylose with glucose, during exponential growth and during nitrogen-starvation. Of these 122 genes, a core-set of 24 genes was identified that were differentially expressed at all time points. Nitrogen-starvation resulted in a larger transcriptional effect, with a total of 1179 genes with significant expression changes at the designated fold change cut-off compared with exponential growth on either glucose or xylose.
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Affiliation(s)
- Friederike Mierke
- Food and Nutrition Science, Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden; Systems and Synthetic Biology, Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Daniel P Brink
- Systems and Synthetic Biology, Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden; Applied Microbiology, Department of Chemistry, Lund University, Lund, Sweden
| | - Joakim Norbeck
- Systems and Synthetic Biology, Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Verena Siewers
- Systems and Synthetic Biology, Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden.
| | - Thomas Andlid
- Food and Nutrition Science, Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden
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13
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Farley JH, Brady WE, O'Malley D, Fujiwara K, Yonemori K, Bonebrake A, Secord AA, Stephan JM, Walker JL, Nam JH, Birrer MJ, Gershenson DM. A phase II evaluation of temsirolimus with carboplatin and paclitaxel followed by temsirolimus consolidation in clear cell ovarian cancer: An NRG oncology trial. Gynecol Oncol 2022; 167:423-428. [PMID: 36244829 PMCID: PMC9789681 DOI: 10.1016/j.ygyno.2022.10.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVE The primary objective of the study was to estimate the 12-month progression-free survival (PFS) for carboplatin/paclitaxel + temsirolimus in women with newly diagnosed clear cell ovarian cancer (CCOC), compared to historical controls in this patient population. METHODS Patients with Stage III or IV CCOC were treated with Paclitaxel 175 mg/m2 on Day 1, Carboplatin AUC 6 Day 1, and temsirolimus (CCI-779) 25 mg IV Days 1 and 8 every 3 weeks for Cycles 1-6 or disease progression, followed by consolidation therapy with temsirolimus 25 mg Days 1, 8, and 15 every 3 weeks cycles 7-17 or until disease progression. RESULTS Ninety patients were accrued to the study: 45 in the US and Korea (US/Korea) and 45 in Japan. Twenty-two percent received ≤6 cycles of therapy while 28% completed all 17 cycles of chemotherapy. Median PFS (OS) was 11 (23) months for US/Korea and 12 (26) months for Japan. In the US, none of suboptimally debulked patients had PFS >12 months, and 49% of optimal patients did, compared to 25% and 59% in Japan. Most common grade 3-4 adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, hypertension, hypertriglyceridemia, and oral mucositis. CONCLUSION The carboplatin/paclitaxel + temsirolimus regimen was well tolerated. In optimally debulked patients, 54% had a PFS >12 months. This regimen did not statistically significantly increase PFS at 12 months compared to historical controls. No statistically significant differences in PFS or OS were observed between US/Korea vs Japan, or Asians vs non-Asians.
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Affiliation(s)
- John H Farley
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
| | - William E Brady
- NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | | | - Kan Yonemori
- National Cancer Center Hospital, 5 Chome-1 - 1 Tsukiji, Chuo City, Tokyo 104-0045, Japan.
| | - Albert Bonebrake
- Cancer Research for the Ozarks-Cox Health, Springfield, MO, USA.
| | | | | | - Joan L Walker
- University of Oklahoma, Oklahoma City, OK 73104, USA.
| | - Joo-Hyun Nam
- Asan Medical Center, University of Ulsan, Seoul 13876 05505, KR, Republic of Korea.
| | | | - David M Gershenson
- Dept. of Gynecologic Oncology, University of Texas, MD, USA; Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, TX 77230-1439, USA.
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14
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Liu X, Oh S, Kirschner MW. The uniformity and stability of cellular mass density in mammalian cell culture. Front Cell Dev Biol 2022; 10:1017499. [PMID: 36313562 PMCID: PMC9597509 DOI: 10.3389/fcell.2022.1017499] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/23/2022] [Indexed: 12/04/2022] Open
Abstract
Cell dry mass is principally determined by the sum of biosynthesis and degradation. Measurable change in dry mass occurs on a time scale of hours. By contrast, cell volume can change in minutes by altering the osmotic conditions. How changes in dry mass and volume are coupled is a fundamental question in cell size control. If cell volume were proportional to cell dry mass during growth, the cell would always maintain the same cellular mass density, defined as cell dry mass dividing by cell volume. The accuracy and stability against perturbation of this proportionality has never been stringently tested. Normalized Raman Imaging (NoRI), can measure both protein and lipid dry mass density directly. Using this new technique, we have been able to investigate the stability of mass density in response to pharmaceutical and physiological perturbations in three cultured mammalian cell lines. We find a remarkably narrow mass density distribution within cells, that is, significantly tighter than the variability of mass or volume distribution. The measured mass density is independent of the cell cycle. We find that mass density can be modulated directly by extracellular osmolytes or by disruptions of the cytoskeleton. Yet, mass density is surprisingly resistant to pharmacological perturbations of protein synthesis or protein degradation, suggesting there must be some form of feedback control to maintain the homeostasis of mass density when mass is altered. By contrast, physiological perturbations such as starvation or senescence induce significant shifts in mass density. We have begun to shed light on how and why cell mass density remains fixed against some perturbations and yet is sensitive during transitions in physiological state.
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Affiliation(s)
| | | | - Marc W. Kirschner
- Department of Systems Biology, Harvard Medical School, Boston, MA, United States
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15
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Yang Y, Huang P, Ma Y, Jiang R, Jiang C, Wang G. Insights into intracellular signaling network in Fusarium species. Int J Biol Macromol 2022; 222:1007-1014. [PMID: 36179869 DOI: 10.1016/j.ijbiomac.2022.09.211] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/23/2022] [Indexed: 11/27/2022]
Abstract
Fusarium is a large genus of filamentous fungi including numerous important plant pathogens. In addition to causing huge economic losses of crops, some Fusarium species produce a wide range of mycotoxins in cereal crops that affect human and animal health. The intracellular signaling in Fusarium plays an important role in growth, sexual and asexual developments, pathogenesis, and mycotoxin biosynthesis. In this review, we highlight the recent advances and provide insight into signal sensing and transduction in Fusarium species. G protein-coupled receptors and other conserved membrane receptors mediate recognition of environmental cues and activate complex intracellular signaling. Once activated, the cAMP-PKA and three well-conserved MAP kinase pathways activate downstream transcriptional regulatory networks. The functions of individual signaling pathways have been well characterized in a variety of Fusarium species, showing the conserved components with diverged functions. Furthermore, these signaling pathways crosstalk and coordinately regulate various fungal development and infection-related morphogenesis.
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Affiliation(s)
- Yang Yang
- State Key Laboratory of Crop Stress Biology for Arid areas, Northwestern A&F University, Yangling, Shaanxi 712100, China
| | - Panpan Huang
- State Key Laboratory of Crop Stress Biology for Arid areas, Northwestern A&F University, Yangling, Shaanxi 712100, China
| | - Yutong Ma
- State Key Laboratory of Crop Stress Biology for Arid areas, Northwestern A&F University, Yangling, Shaanxi 712100, China
| | - Ruoxuan Jiang
- State Key Laboratory of Crop Stress Biology for Arid areas, Northwestern A&F University, Yangling, Shaanxi 712100, China
| | - Cong Jiang
- State Key Laboratory of Crop Stress Biology for Arid areas, Northwestern A&F University, Yangling, Shaanxi 712100, China.
| | - Guanghui Wang
- State Key Laboratory of Crop Stress Biology for Arid areas, Northwestern A&F University, Yangling, Shaanxi 712100, China.
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16
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Wagner ND, Simmons DBD, Prater C, Frost PC. Proteome changes in an aquatic invertebrate consumer in response to different nutritional stressors. Oecologia 2022; 199:329-341. [PMID: 35661252 DOI: 10.1007/s00442-022-05198-5] [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: 08/16/2021] [Accepted: 05/21/2022] [Indexed: 11/26/2022]
Abstract
Nutrient imbalances in zooplankton are caused by the differences in elemental content of producers and the demand for elements in consumers, which alter the life-history traits in consumers. Changes in life-history traits are mediated through metabolic pathways that affect gene expression and the metabolome. However, less is known about proteomic changes to elemental-limitation in zooplankton. Here, we grew Daphnia pulex under high food quantity and quality (HF), low food quantity (LF), and phosphorus (P)-limited (PL) diets for six days and measured growth, elemental composition, and the proteome. Daphnids in both LF and PL diets grew less. Animals in LF diets had less carbon (C), while daphnids in PL diets had less P compared to HF fed animals. In total, we identified 1719 proteins that were used in a partial least squares regression discriminant analysis (PLS-DA). Focusing on a subset of the proteome, the PLS-DA resulted in a clear separation between animals fed HF diets and PL and LF diets. Many proteome changes in nutrient-limited diets are associated with growth, reproduction, lipid metabolism, and nutrient assimilation. Regardless of the limiting nutrient, there were less hemoglobin and small subunit processome component proteins compared to HF fed animals. Daphnids fed LF diets had less vitellogenin fused superoxide dismutase and more lipid-droplet hydrolase, whereas Daphnia fed PL diets had higher abundances of cytochrome P450 and serine protease. Our proteome results compliment other "omic" studies that could be used to study Daphnia physiology in lakes.
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Affiliation(s)
- Nicole D Wagner
- Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas, USA.
| | | | - Clay Prater
- Department of Integrative Biology, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Paul C Frost
- Department of Biology, Tent University, Peterborough, ON, Canada
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17
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Gutiérrez-Santiago F, Cintas-Galán M, Martín-Expósito M, del Carmen Mota-Trujillo M, Cobo-Huesa C, Perez-Fernandez J, Navarro Gómez F. A High-Copy Suppressor Screen Reveals a Broad Role of Prefoldin-like Bud27 in the TOR Signaling Pathway in Saccharomyces cerevisiae. Genes (Basel) 2022; 13:genes13050748. [PMID: 35627133 PMCID: PMC9141189 DOI: 10.3390/genes13050748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/18/2022] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
Bud27 is a prefoldin-like, a member of the family of ATP-independent molecular chaperones that associates with RNA polymerases I, II, and III in Saccharomyces cerevisiae. Bud27 and its human ortholog URI perform several functions in the cytoplasm and the nucleus. Both proteins participate in the TOR signaling cascade by coordinating nutrient availability with gene expression, and lack of Bud27 partially mimics TOR pathway inactivation. Bud27 regulates the transcription of the three RNA polymerases to mediate the synthesis of ribosomal components for ribosome biogenesis through the TOR cascade. This work presents a high-copy suppression screening of the temperature sensitivity of the bud27Δ mutant. It shows that Bud27 influences different TOR-dependent processes. Our data also suggest that Bud27 can impact some of these TOR-dependent processes: cell wall integrity and autophagy induction.
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Affiliation(s)
- Francisco Gutiérrez-Santiago
- Departamento de Biología Experimental-Genética, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain; (F.G.-S.); (M.C.-G.); (M.M.-E.); (M.d.C.M.-T.); (C.C.-H.); (J.P.-F.)
| | - María Cintas-Galán
- Departamento de Biología Experimental-Genética, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain; (F.G.-S.); (M.C.-G.); (M.M.-E.); (M.d.C.M.-T.); (C.C.-H.); (J.P.-F.)
| | - Manuel Martín-Expósito
- Departamento de Biología Experimental-Genética, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain; (F.G.-S.); (M.C.-G.); (M.M.-E.); (M.d.C.M.-T.); (C.C.-H.); (J.P.-F.)
| | - Maria del Carmen Mota-Trujillo
- Departamento de Biología Experimental-Genética, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain; (F.G.-S.); (M.C.-G.); (M.M.-E.); (M.d.C.M.-T.); (C.C.-H.); (J.P.-F.)
| | - Cristina Cobo-Huesa
- Departamento de Biología Experimental-Genética, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain; (F.G.-S.); (M.C.-G.); (M.M.-E.); (M.d.C.M.-T.); (C.C.-H.); (J.P.-F.)
| | - Jorge Perez-Fernandez
- Departamento de Biología Experimental-Genética, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain; (F.G.-S.); (M.C.-G.); (M.M.-E.); (M.d.C.M.-T.); (C.C.-H.); (J.P.-F.)
| | - Francisco Navarro Gómez
- Departamento de Biología Experimental-Genética, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain; (F.G.-S.); (M.C.-G.); (M.M.-E.); (M.d.C.M.-T.); (C.C.-H.); (J.P.-F.)
- Centro de Estudios Avanzados en Aceite de Oliva y Olivar, Universidad de Jaén, Paraje de las Lagunillas, s/n, E-23071 Jaén, Spain
- Correspondence: ; Tel.: +34-953-212771; Fax: +34-953-211875
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18
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Chen SY, Wang J, Jia F, Shen ZD, Zhang WB, Wang YX, Ren KF, Fu GS, Ji J. Bioinspired NO release coating enhances endothelial cells and inhibits smooth muscle cells. J Mater Chem B 2022; 10:2454-2462. [PMID: 34698745 DOI: 10.1039/d1tb01828k] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Thrombus and restenosis after stent implantation are the major complications because traditional drugs such as rapamycin delay the process of endothelialization. Nitric oxide (NO) is mainly produced by endothelial nitric oxide synthase (eNOS) on the membrane of endothelial cells (ECs) in the cardiovascular system and plays an important role in vasomotor function. It strongly inhibits the proliferation of smooth muscle cells (SMCs) and ameliorates endothelial function when ECs get hurt. Inspired by this, introducing NO to traditional stent coating may alleviate endothelial insufficiency caused by rapamycin. Here, we introduced SNAP as the NO donor, mimicking how NO affects in vivo, into rapamycin coating to alleviate endothelial damage while inhibiting SMC proliferation. Through wicking effects, SNAP was absorbed into a hierarchical coating that had an upper porous layer and a dense polymer layer with rapamycin at the bottom. Cells were cultured on the coatings, and it was observed that the injured ECs were restored while the growth of SMCs further diminished. Genome analysis was conducted to further clarify possible signaling pathways: the effect of cell growth attenuated by NO may cause by affecting cell cycle and enhancing inflammation. These findings supported the idea that introducing NO to traditional drug-eluting stents alleviates incomplete endothelialization and further inhibits the stenosis caused by the proliferation of SMCs.
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Affiliation(s)
- Sheng-Yu Chen
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
| | - Jing Wang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Fan Jia
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Zhi-da Shen
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
| | - Wen-Bin Zhang
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
| | - You-Xiang Wang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Ke-Feng Ren
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Guo-Sheng Fu
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
| | - Jian Ji
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
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Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia. Biomolecules 2022; 12:biom12020247. [PMID: 35204748 PMCID: PMC8961589 DOI: 10.3390/biom12020247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic inflammation is characterized by the production of reactive oxygen species (ROS), reactive nitrogen species, and inflammatory cytokines in myeloproliferative neoplasms (MPNs). In addition to these parameters, the aim of this study was to analyze the influence of ROS on the proliferation-related AKT/mTOR signaling pathway and the relationship with inflammatory factors in chronic myelogenous leukemia (CML). The activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase is reduced in erythrocytes while levels of the oxidative stress markers malondialdehyde and protein carbonyl are elevated in the plasma of patients with CML. In addition, nitrogen species (nitrotyrosine, iNOS, eNOS) and inflammation markers (IL-6, NFkB, and S100 protein) were increased in granulocytes of CML while anti-inflammatory levels of IL-10 were decreased in plasma. CML granulocytes exhibited greater resistance to cytotoxic H2O2 activity compared to healthy subjects. Moreover, phosphorylation of the apoptotic p53 protein was reduced while the activity of the AKT/mTOR signaling pathway was increased, which was further enhanced by oxidative stress (H2O2) in granulocytes and erythroleukemic K562 cells. IL-6 caused oxidative stress and DNA damage that was mitigated using antioxidant or inhibition of inflammatory NFkB transcription factor in K562 cells. We demonstrated the presence of oxidative and nitrosative stress in CML, with the former mediated by AKT/mTOR signaling and stimulated by inflammation.
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20
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Karagianni F, Pavlidis A, Malakou LS, Piperi C, Papadavid E. Predominant Role of mTOR Signaling in Skin Diseases with Therapeutic Potential. Int J Mol Sci 2022; 23:ijms23031693. [PMID: 35163615 PMCID: PMC8835793 DOI: 10.3390/ijms23031693] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/30/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
The serine/threonine kinase mechanistic target of rapamycin (mTOR) plays a pivotal role in the regulation of cell proliferation, survival, and motility in response to availability of energy and nutrients as well as mitogens. The mTOR signaling axis regulates important biological processes, including cellular growth, metabolism, and survival in many tissues. In the skin, dysregulation of PI3K/AKT/mTOR pathway may lead to severe pathological conditions characterized by uncontrolled proliferation and inflammation, including skin hyperproliferative as well as malignant diseases. Herein, we provide an update on the current knowledge regarding the pathogenic implication of the mTOR pathway in skin diseases with inflammatory features (such as psoriasis, atopic dermatitis, pemphigus, and acne) and malignant characteristics (such as cutaneous T cell lymphoma and melanoma) while we critically discuss current and future perspectives for therapeutic targeting of mTOR axis in clinical practice.
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Affiliation(s)
- Fani Karagianni
- National Center of Rare Diseases—Cutaneous Lymphoma, Second Department of Dermatology and Venereal Diseases, Attikon University General Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece; (F.K.); (A.P.); (E.P.)
| | - Antreas Pavlidis
- National Center of Rare Diseases—Cutaneous Lymphoma, Second Department of Dermatology and Venereal Diseases, Attikon University General Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece; (F.K.); (A.P.); (E.P.)
| | - Lina S. Malakou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Correspondence:
| | - Evangelia Papadavid
- National Center of Rare Diseases—Cutaneous Lymphoma, Second Department of Dermatology and Venereal Diseases, Attikon University General Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece; (F.K.); (A.P.); (E.P.)
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21
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Ma T, Zhang L, Wang M, Li Y, Jian Y, Wu L, Kistler HC, Ma Z, Yin Y. Plant defense compound triggers mycotoxin synthesis by regulating H2B ub1 and H3K4 me2/3 deposition. THE NEW PHYTOLOGIST 2021; 232:2106-2123. [PMID: 34480757 PMCID: PMC9293436 DOI: 10.1111/nph.17718] [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] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/30/2021] [Indexed: 05/05/2023]
Abstract
Fusarium graminearum produces the mycotoxin deoxynivalenol (DON) which promotes its expansion during infection on its plant host wheat. Conditional expression of DON production during infection is poorly characterized. Wheat produces the defense compound putrescine, which induces hypertranscription of DON biosynthetic genes (FgTRIs) and subsequently leads to DON accumulation during infection. Further, the regulatory mechanisms of FgTRIs hypertranscription upon putrescine treatment were investigated. The transcription factor FgAreA regulates putrescine-mediated transcription of FgTRIs by facilitating the enrichment of histone H2B monoubiquitination (H2B ub1) and histone 3 lysine 4 di- and trimethylations (H3K4 me2/3) on FgTRIs. Importantly, a DNA-binding domain (bZIP) specifically within the Fusarium H2B ub1 E3 ligase Bre1 othologs is identified, and the binding of this bZIP domain to FgTRIs depends on FgAreA-mediated chromatin rearrangement. Interestingly, H2B ub1 regulates H3K4 me2/3 via the methyltransferase complex COMPASS component FgBre2, which is different from Saccharomyces cerevisiae. Taken together, our findings reveal the molecular mechanisms by which host-generated putrescine induces DON production during F. graminearum infection. Our results also provide a novel insight into the role of putrescine during phytopathogen-host interactions and broaden our knowledge of H2B ub1 biogenesis and crosstalk between H2B ub1 and H3K4 me2/3 in eukaryotes.
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Affiliation(s)
- Tianling Ma
- State Key Laboratory of Rice BiologyInstitute of BiotechnologyZhejiang University866 Yuhangtang RoadHangzhou310058China
| | - Lixin Zhang
- State Key Laboratory of Rice BiologyInstitute of BiotechnologyZhejiang University866 Yuhangtang RoadHangzhou310058China
| | - Minhui Wang
- State Key Laboratory of Rice BiologyInstitute of BiotechnologyZhejiang University866 Yuhangtang RoadHangzhou310058China
| | - Yiqing Li
- State Key Laboratory of Rice BiologyInstitute of BiotechnologyZhejiang University866 Yuhangtang RoadHangzhou310058China
| | - Yunqing Jian
- State Key Laboratory of Rice BiologyInstitute of BiotechnologyZhejiang University866 Yuhangtang RoadHangzhou310058China
| | - Liang Wu
- Institute of Crop ScienceZhejiang University866 Yuhangtang RoadHangzhou310058China
| | - Harold Corby Kistler
- United States Department of AgricultureAgricultural Research Service1551 Lindig StreetSt PaulMN55108USA
| | - Zhonghua Ma
- State Key Laboratory of Rice BiologyInstitute of BiotechnologyZhejiang University866 Yuhangtang RoadHangzhou310058China
| | - Yanni Yin
- State Key Laboratory of Rice BiologyInstitute of BiotechnologyZhejiang University866 Yuhangtang RoadHangzhou310058China
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22
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Liu M, Li C, Tang H, Gong M, Yue Z, Zhao M, Liu L, Li F. Dietary lysine supplementation improves growth performance and skeletal muscle development in rabbits fed a low protein diet. J Anim Physiol Anim Nutr (Berl) 2021; 106:1118-1129. [PMID: 34496098 DOI: 10.1111/jpn.13632] [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: 07/02/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022]
Abstract
The purpose of this study was to investigate the effects on growth of Lysine (Lys) supplementation in a low protein diet. We also investigated the gene or protein expression related to skeletal muscle development and intestinal amino acid transporters, and determined the major signalling associated with Lys-regulating skeletal muscle development. 1000 healthy, weights averaging 938.6 ± 6.54 g weaned rabbits were randomly divided into five groups (five replicates in each group and 40 rabbits in each replicate). These groups consisted of the normal protein group (NP group, consuming a diet containing 16.27% protein), the low protein group (LP group, 14.15%-14.19% protein) and the LP group with an addition of 0.15%, 0.3% or 0.45% Lys. The trial included 7 d of pre-feeding and 28 d of exposure to the treatment. Compared with NP diet and LP diet, LP+0.3% Lys group improved growth performance (p < 0.05), full-bore weight and half-bore weight of rabbits (p < 0.05). The LP+0.3% Lys group also resulted in a decrease in the excretion of faecal nitrogen and urinary nitrogen (FN; UN; p < 0.05), and an increase in nitrogen utilisation rate (NUR; p < 0.05). LP diet increased the mRNA expression of MSTN and WWP1, and decreased the mRNA expression of IGF1 (p < 0.05). LP diet decreased the protein expression of P-P70S6K1, P-4EBP1 and P-S6 (p < 0.05). LP+0.3% Lys group attenuated the effects of LP diet on the expression of MSTN, WWP1, IGF1, P-P70S6K1, P-4EBP1 and P-S6 (p < 0.05). LP+0.3% Lys group resulted in an increase in mRNA expression of MyoD and protein expression of P-mTOR relative to the NP and LP groups (p < 0.05). In summary, the addition of Lys to a LP diet provides a theoretical basis for the popularisation and application of Lys in rabbit production.
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Affiliation(s)
- Mengqi Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
| | - Chenyang Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
| | - Haojia Tang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
| | - Maohua Gong
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
| | - Zhengkai Yue
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
| | - Man Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
| | - Lei Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
| | - Fuchang Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science, Shandong Agricultural University, Taian, Shandong, China
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23
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Muñoz-Muñoz PLA, Mares-Alejandre RE, Meléndez-López SG, Ramos-Ibarra MA. Bioinformatic Analysis of Two TOR (Target of Rapamycin)-Like Proteins Encoded by Entamoeba histolytica Revealed Structural Similarities with Functional Homologs. Genes (Basel) 2021; 12:genes12081139. [PMID: 34440318 PMCID: PMC8391992 DOI: 10.3390/genes12081139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 01/04/2023] Open
Abstract
The target of rapamycin (TOR), also known as FKBP-rapamycin associated protein (FRAP), is a protein kinase belonging to the PIKK (phosphatidylinositol 3-kinase (PI3K)-related kinases) family. TOR kinases are involved in several signaling pathways that control cell growth and proliferation. Entamoeba histolytica, the protozoan parasite that causes human amoebiasis, contains two genes encoding TOR-like proteins: EhFRAP and EhTOR2. To assess their potential as drug targets to control the cell proliferation of E. histolytica, we studied the structural features of EhFRAP and EhTOR2 using a biocomputational approach. The overall results confirmed that both TOR amoebic homologs share structural similarities with functional TOR kinases, and show inherent abilities to form TORC complexes and participate in protein-protein interaction networks. To our knowledge, this study represents the first in silico characterization of the structure-function relationships of EhFRAP and EhTOR2.
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24
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Kaur K, Anant A, Asati V. Structural Aspects of mTOR Inhibitors: In Progress to Search Potential Compounds. Anticancer Agents Med Chem 2021; 22:1037-1055. [PMID: 34288843 DOI: 10.2174/1871520621666210720121403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/01/2021] [Accepted: 06/05/2021] [Indexed: 11/22/2022]
Abstract
mTOR (mammalian target of rapamycin) is a catalytic subunit composed of two multi-protein complexes that indicate mTORC1, mTORC2. It plays a crucial role in various fundamental cell processes like cell proliferation, metabolism, survival, cell growth, etc. Various first line mTOR inhibitors such as Rapamycin, Temsirolimus, Everolimus, Ridaforolimus, Umirolimus, Zotarolimus have been used popularly. Whereas, several mTOR inhibitors such as Gedatolisib (PF-05212384) are under phase 2 clinical trials studies for the treatment of triple-negative breast cancer. The mTOR inhibitors bearing heterocyclic moieties such as quinazoline, thiophene, morpholine, imidazole, pyrazine, furan, quinoline are under investigation against various cancer cell lines (U87MG, PC-3, MCF-7, A549, MDA-231). In this review, we summarized updated research related to mTOR inhibitors, their structure-activity relationship which may help scientists for the development of potent inhibitors against cancer.
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Affiliation(s)
- Kamalpreet Kaur
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
| | - Arjun Anant
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
| | - Vivek Asati
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
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25
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Huwatibieke B, Yin W, Liu L, Jin Y, Xiang X, Han J, Zhang W, Li Y. Mammalian Target of Rapamycin Signaling Pathway Regulates Mitochondrial Quality Control of Brown Adipocytes in Mice. Front Physiol 2021; 12:638352. [PMID: 34335285 PMCID: PMC8317026 DOI: 10.3389/fphys.2021.638352] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 05/26/2021] [Indexed: 01/13/2023] Open
Abstract
The mammalian target of rapamycin (mTOR) is an important protein kinase that senses changes in extracellular and intracellular energy levels and plays a key role in regulating energy metabolism. Brown adipose tissue, which can be converted to white adipose tissue, contains a large number of mitochondria and regulates energy expenditure through thermogenesis. Because obesity is a process of fat accumulation due to chronic excessive energy intake, we attempted to determine whether the mTOR signaling pathway can affect the mitochondrial quality control of brown adipocytes through sensing energy status, thereby regulating brown/white adipocyte transformation. In the present study, through activation or inhibition of mTOR signaling, we detected mitochondrial biogenesis, dynamics, and autophagy-related markers in brown adipocytes. We found that activation of mTOR signaling downregulated the expression of mitochondrial biogenesis, dynamics, and autophagy-relevant markers and inhibited the mitochondrial quality control of brown adipocytes, indicating a phenotypic transformation of brown to white adipocytes. In contrast, inhibition of mTOR signaling upregulated the expression of mitochondrial biogenesis, dynamics, and mitophagy-relevant markers and strengthened mitochondrial quality control, suggesting an inhibition of the phenotypic transformation of brown to white adipocytes. In conclusion, the mTOR signaling pathway plays an important role in modulating the transformation of adipocytes by regulating mitochondrial quality control.
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Affiliation(s)
- Bahetiyaer Huwatibieke
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Wenzhen Yin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Lingchao Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yuxin Jin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.,Department of Integration of Chinese and Western Medicine, Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
| | - Xinxin Xiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.,Department of Pathology, Central Hospital of Zibo, Zibo, China
| | - Jingyan Han
- Department of Integration of Chinese and Western Medicine, Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yin Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.,Department of Integration of Chinese and Western Medicine, Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
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26
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Altschuler RA, Kabara L, Martin C, Kanicki A, Stewart CE, Kohrman DC, Dolan DF. Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice. Front Cell Neurosci 2021; 15:658972. [PMID: 33897373 PMCID: PMC8058174 DOI: 10.3389/fncel.2021.658972] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/11/2021] [Indexed: 01/30/2023] Open
Abstract
Our previous study demonstrated rapamycin added to diet at 4 months of age had significantly less age-related outer hair cell loss in the basal half of the cochlea at 22 months of age compared to mice without rapamycin. The present study tested adding rapamycin to diet later in life, at 14 months of age, and added a longitudinal assessment of auditory brain stem response (ABR). The present study used UMHET4 mice, a 4 way cross in which all grandparental strains lack the Cdh23753A allele that predisposes to early onset, progressive hearing loss. UMHET4 mice typically have normal hearing until 16-17 months, then exhibit threshold shifts at low frequencies/apical cochlea and later in more basal high frequency regions. ABR thresholds at 4, 12, 24, and 48 kHz were assessed at 12, 18, and 24 months of age and compared to baseline ABR thresholds acquired at 5 months of age to determine threshold shifts (TS). There was no TS at 12 months of age at any frequency tested. At 18 months of age mice with rapamycin added to diet at 14 months had a significantly lower mean TS at 4 and 12 kHz compared to mice on control diet with no significant difference at 24 and 48 kHz. At 24 months of age, the mean 4 kHz TS in rapamycin diet group was no longer significantly lower than the control diet group, while the 12 kHz mean remained significantly lower. Mean TS at 24 and 48 kHz in the rapamycin diet group became significantly lower than in the control diet group at 24 months. Hair cell counts at 24 months showed large loss in the apical half of most rapamycin and control diet mice cochleae with no significant difference between groups. There was only mild outer hair cell loss in the basal half of rapamycin and control diet mice cochleae with no significant difference between groups. The results show that a later life addition of rapamycin can decrease age-related hearing loss in the mouse model, however, it also suggests that this decrease is a delay/deceleration rather than a complete prevention.
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Affiliation(s)
- Richard A Altschuler
- Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.,VA Ann Arbor Health Care System, Ann Arbor, MI, United States.,Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
| | - Lisa Kabara
- Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Catherine Martin
- Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Ariane Kanicki
- Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Courtney E Stewart
- Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.,VA Ann Arbor Health Care System, Ann Arbor, MI, United States
| | - David C Kohrman
- Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - David F Dolan
- Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
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27
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Saud A, Luiz RS, Leite APO, Muller CR, Visona I, Reinecke N, Silva WH, Gloria MA, Razvickas CV, Casarini DE, Schor N. Resistance exercise training ameliorates chronic kidney disease outcomes in a 5/6 nephrectomy model. Life Sci 2021; 275:119362. [PMID: 33741414 DOI: 10.1016/j.lfs.2021.119362] [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: 11/12/2020] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 11/15/2022]
Abstract
Chronic kidney disease (CKD) is defined by decreased glomerular filtration rate (GFR) or increased albumin excretion leading to renal injury. However, exercise training is an important non-pharmacological intervention that ameliorates and protects against Diabetes Mellitus, cardiovascular disease, and CKD. AIM Our aim was to evaluate the capability of resistance exercise training (RET) to improve CKD outcomes and the contribution of the renal and muscular Akt/mTOR signaling pathway for RET beneficial effects on a CKD model. MAIN METHODS Male Wistar rats were subjected to RET, followed for 10 weeks, and randomly divided into 5 groups: Sham: Sham-operated; sedentary and nephrectomy (5/6Nx) (SNS); exercising post-5/6Nx (SNE); exercising pre-5/6Nx (ENS); exercising pre- and post-5/6Nx (ENE). The systolic blood pressure (BP) was measured. Creatinine, proteinuria, and blood urea nitrogen (BUN) were evaluated. After euthanasia Renal and muscular Akt/mTOR signaling pathways were analyzed. KEY FINDING Our study showed that the SNS presented renal injury, hypertension, weight and muscular mass loss and a higher mortality rate. SNS group also decreased renal IL-10 and increased TNF-alfa and TGF-Beta. Renal AKT, mTOR, and rpS6 pathway were increased, PTEN was decreased on SNS. And muscular Akt and mTOR were decreased on SNS. SIGNIFICANCE The RET before and after the 5/6Nx ameliorates all these parameters mentioned above, suggesting that RET is a good non-pharmacological approach to diminish complications frequently found in CKD. We also suggest that the AKT-m-TOR pathway can play an important role in these beneficial outcomes of RET on the CKD animal model.
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Affiliation(s)
- A Saud
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | - R S Luiz
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | - A P O Leite
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil; Tulane University, Department of Physiology & Medicine, New Orleans, LA, United States
| | - C R Muller
- Department of Bioengineering, University of California San Diego, La Jolla, CA, United States
| | - I Visona
- Departamento de Patologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | - N Reinecke
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | - W H Silva
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | - M A Gloria
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | - C V Razvickas
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | - D E Casarini
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil.
| | - N Schor
- Departamento de Medicina, Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brazil
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28
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Stępień Ł, Lalak-Kańczugowska J. Signaling pathways involved in virulence and stress response of plant-pathogenic Fusarium species. FUNGAL BIOL REV 2021. [DOI: 10.1016/j.fbr.2020.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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A highly annotated database of genes associated with platinum resistance in cancer. Oncogene 2021; 40:6395-6405. [PMID: 34645978 PMCID: PMC8602037 DOI: 10.1038/s41388-021-02055-2] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 09/21/2021] [Accepted: 09/30/2021] [Indexed: 01/10/2023]
Abstract
Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org .
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30
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Zhang DM, Chen S. In-Stent Restenosis and a Drug-Coated Balloon: Insights from a Clinical Therapeutic Strategy on Coronary Artery Diseases. Cardiol Res Pract 2020; 2020:8104939. [PMID: 33163230 PMCID: PMC7605950 DOI: 10.1155/2020/8104939] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 09/29/2020] [Accepted: 10/10/2020] [Indexed: 12/14/2022] Open
Abstract
Coronary heart disease is a major cause of death and disability in developed countries. Stent implantation has become an efficacious treatment for a culprit lesion vessel of the coronary artery. However, 10%-20% restenosis is still an important complication that restricts the clinical safety and efficacy of drug-eluting stents. In-stent restenosis may lead to the recurrence of major cardiovascular adverse events, including angina pectoris, acute myocardial infarction, and even sudden cardiac death. These events are currently serious problems that occur after coronary stent implantation. Clinical physicians face a difficult choice for in-stent restenosis treatment. Recent studies indicate that a drug-coated balloon has promising clinical efficacy similar to the drug-eluting stents for treating coronary in-stent restenosis. Therefore, in this study, we highlight the progress of coronary intervention and the use of drug-coated balloons in the treatment of in-stent restenosis (ISR).
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Affiliation(s)
- Dai-Min Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Shaoliang Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
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31
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Cai Y, Xue F, Qin H, Chen X, Liu N, Fleming C, Hu X, Zhang HG, Chen F, Zheng J, Yan J. Differential Roles of the mTOR-STAT3 Signaling in Dermal γδ T Cell Effector Function in Skin Inflammation. Cell Rep 2020; 27:3034-3048.e5. [PMID: 31167146 PMCID: PMC6617524 DOI: 10.1016/j.celrep.2019.05.019] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 04/04/2019] [Accepted: 05/02/2019] [Indexed: 02/06/2023] Open
Abstract
Dermal γδT cells play critical roles in skin homeostasis and inflammation. However, the underlying molecular mechanisms by which these cells are activated have not been fully understood. Here, we show that the mechanistic or mammalian target of rapamycin (mTOR) and STAT3 pathways are activated in dermal γδT cells in response to innate stimuli such as interleukin-1β (IL-1β) and IL-23. Although both mTOR complex 1 (mTORC1) and mTORC2 are essential for dermal γδT cell proliferation, mTORC2 deficiency leads to decreased dermal γδT17 cells. It appears that mitochondria-mediated oxidative phosphorylation is critical in this process. Notably, although the STAT3 pathway is critical for dermal Vγ4T17 effector function, it is not required for γδ6T17 cells. Transcription factor IRF-4 activation promotes dermal γδT cell IL-17 production by linking IL-1β and IL-23 signaling. The absence of mTORC2 in dermal γδT cells, but not STAT3, ameliorates skin inflammation. Taken together, our results demonstrate that the mTOR-STAT3 signaling differentially regulates dermal γδT cell effector function in skin inflammation. Cai et al. demonstrate that the mTOR and STAT3 signaling pathways differentially regulate dermal Vγ4 and Vγ6 T cell effector function, leading to distinct outcomes in skin inflammation.
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Affiliation(s)
- Yihua Cai
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Feng Xue
- Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Hui Qin
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Xu Chen
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Laboratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Na Liu
- Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Chris Fleming
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Xiaoling Hu
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Huang-Ge Zhang
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Fuxiang Chen
- Department of Laboratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Jie Zheng
- Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Jun Yan
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
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32
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Annett S, Moore G, Robson T. FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention. Pharmacol Ther 2020; 215:107623. [PMID: 32622856 DOI: 10.1016/j.pharmthera.2020.107623] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/24/2020] [Indexed: 02/07/2023]
Abstract
FK506 binding (FKBP) proteins are part of the highly conserved immunophilin family and its members have fundamental roles in the regulation of signalling pathways involved in inflammation, adaptive immune responses, cancer and developmental biology. The original member of this family, FKBP12, is a well-known binding partner for the immunosuppressive drugs tacrolimus (FK506) and sirolimus (rapamycin). FKBP12 and its analog, FKBP12.6, function as cis/trans peptidyl prolyl isomerases (PPIase) and they catalyse the interconversion of cis/trans prolyl conformations. Members of this family uniquely contain a PPIase domain, which may not be functional. The larger FKBPs, such as FKBP51, FKBP52 and FKBPL, contain extra regions, including tetratricopeptide repeat (TPR) domains, which are important for their versatile protein-protein interactions with inflammation-related signalling pathways. In this review we focus on the pivotal role of FKBP proteins in regulating glucocorticoid signalling, canonical and non-canonical NF-κB signalling, mTOR/AKT signalling and TGF-β signalling. We examine the mechanism of action of FKBP based immunosuppressive drugs on these cell signalling pathways and how off target interactions lead to the development of side effects often seen in the clinic. Finally, we discuss the latest advances in the role of FKBPs as therapeutic targets and the development of novel agents for a range of indications of unmet clinical need, including glucocorticoid resistance, obesity, stress-induced inflammation and novel cancer immunotherapy.
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Affiliation(s)
- Stephanie Annett
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Gillian Moore
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
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33
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Wang M, Jia L, Wu X, Sun Z, Xu Z, Kong C, Ma L, Zhao R, Lu S. Deep Brain Stimulation Improves Motor Function in Rats with Spinal Cord Injury by Increasing Synaptic Plasticity. World Neurosurg 2020; 140:e294-e303. [PMID: 32407911 DOI: 10.1016/j.wneu.2020.05.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/03/2020] [Accepted: 05/04/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To investigate the effect of deep brain stimulation (DBS) on rats with spinal cord injury (SCI) and its possible molecular mechanism. METHODS A rat SCI model was prepared using a modified Allen method. The animals were randomly divided into 3 groups (n = 12 per group): the sham group, the SCI group, and the SCI + DBS group. Then, DBS was applied to the rats in the SCI + DBS group for half an hour per day for 4 weeks. Basso, Beattie, and Bresnahan scores were used to assess spinal function. RESULTS DBS significantly improved hindlimb motor function in SCI rats, and the protein expression levels of brain-derived neurotrophic factor, the mammalian target of rapamycin, tropomyosin-related kinase B, protein kinase B, p70 ribosomal S6 protein kinase, postsynaptic density protein 95, and synaptophysin increased correspondingly. CONCLUSIONS DBS improves motor function in rats with SCI by increasing synaptic plasticity via tropomyosin-related kinase B-protein kinase B-mammalian target of rapamycin pathway.
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Affiliation(s)
- Min Wang
- Department of Orthopedics, Xuanwu Hospital Capital Medical University, Beijing, China; The fourth Department of Orthopedics, Jincheng General Hospital, Jincheng, Shanxi Province, China
| | - Lina Jia
- Beijing Key Laboratory of Mental Disorders & The National Clinical Research Center for Mental Disorder, Beijing Anding Hospital, Capital Medical University, Beijing, China; Department of Neurology, Jincheng General Hospital, Jincheng, Shanxi Province, China
| | - Xiaobo Wu
- The fourth Department of Orthopedics, Jincheng General Hospital, Jincheng, Shanxi Province, China
| | - Zuoli Sun
- Beijing Key Laboratory of Mental Disorders & The National Clinical Research Center for Mental Disorder, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Zheng Xu
- The fourth Department of Orthopedics, Jincheng General Hospital, Jincheng, Shanxi Province, China
| | - Chao Kong
- Department of Orthopedics, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Lin Ma
- The fourth Department of Orthopedics, Jincheng General Hospital, Jincheng, Shanxi Province, China
| | - Ruifeng Zhao
- The fourth Department of Orthopedics, Jincheng General Hospital, Jincheng, Shanxi Province, China
| | - Shibao Lu
- Department of Orthopedics, Xuanwu Hospital Capital Medical University, Beijing, China.
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Kordowitzki P, Hamdi M, Derevyanko A, Rizos D, Blasco M. The effect of rapamycin on bovine oocyte maturation success and metaphase telomere length maintenance. Aging (Albany NY) 2020; 12:7576-7584. [PMID: 32339158 PMCID: PMC7202508 DOI: 10.18632/aging.103126] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 03/30/2020] [Indexed: 12/18/2022]
Abstract
Maternal aging-associated reduction of oocyte viability is a common feature in mammals, but more research is needed to counteract this process. In women, the first aging phenotype appears with a decline in reproductive function, and the follicle number gradually decreases from menarche to menopause. Cows can be used as a model of early human embryonic development and reproductive aging because both species share a very high degree of similarity during follicle selection, cleavage, and blastocyst formation. Recently, it has been proposed that the main driver of aging is the mammalian target of rapamycin (mTOR) signaling rather than reactive oxygen species. Based on these observations, the study aimed to investigate for the first time the possible role of rapamycin on oocyte maturation, embryonic development, and telomere length in the bovine species, as a target for future strategies for female infertility caused by advanced maternal age. The 1nm rapamycin in vitro treatment showed the best results for maturation rates (95.21±4.18%) of oocytes and was considered for further experiments. In conclusion, rapamycin influenced maturation rates of oocytes in a concentration-dependent manner. Our results also suggest a possible link between mTOR, telomere maintenance, and bovine blastocyst formation.
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Affiliation(s)
- Pawel Kordowitzki
- Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Poland.,Institute of Veterinary Medicine, Nicolaus Copernicus University, Torun, Poland
| | - Meriem Hamdi
- Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Department of Animal Reproduction, Madrid, Spain
| | - Aksinya Derevyanko
- Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Dimitrios Rizos
- Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Department of Animal Reproduction, Madrid, Spain
| | - Maria Blasco
- Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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Yao K, Rochman ND, Sun SX. CTRL - a label-free artificial intelligence method for dynamic measurement of single-cell volume. J Cell Sci 2020; 133:jcs.245050. [PMID: 32094267 DOI: 10.1242/jcs.245050] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 02/10/2020] [Indexed: 12/27/2022] Open
Abstract
Measuring the physical size of a cell is valuable in understanding cell growth control. Current single-cell volume measurement methods for mammalian cells are labor intensive, inflexible and can cause cell damage. We introduce CTRL: Cell Topography Reconstruction Learner, a label-free technique incorporating the deep learning algorithm and the fluorescence exclusion method for reconstructing cell topography and estimating mammalian cell volume from differential interference contrast (DIC) microscopy images alone. The method achieves quantitative accuracy, requires minimal sample preparation, and applies to a wide range of biological and experimental conditions. The method can be used to track single-cell volume dynamics over arbitrarily long time periods. For HT1080 fibrosarcoma cells, we observe that the cell size at division is positively correlated with the cell size at birth (sizer), and there is a noticeable reduction in cell size fluctuations at 25% completion of the cell cycle in HT1080 fibrosarcoma cells.
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Affiliation(s)
- Kai Yao
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.,Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Nash D Rochman
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.,Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Sean X Sun
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA .,Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.,Physical Sciences in Oncology Center (PSOC), Johns Hopkins University, Baltimore, MD 21218, USA
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36
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Akalu Y, Molla MD, Dessie G, Ayelign B. Physiological Effect of Ghrelin on Body Systems. Int J Endocrinol 2020; 2020:1385138. [PMID: 32565790 PMCID: PMC7267865 DOI: 10.1155/2020/1385138] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 02/08/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.
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Affiliation(s)
- Yonas Akalu
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Meseret Derbew Molla
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Gashaw Dessie
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Birhanu Ayelign
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Science, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Steidle EA, Morrissette VA, Fujimaki K, Chong L, Resnick AC, Capaldi AP, Rolfes RJ. The InsP 7 phosphatase Siw14 regulates inositol pyrophosphate levels to control localization of the general stress response transcription factor Msn2. J Biol Chem 2019; 295:2043-2056. [PMID: 31848224 DOI: 10.1074/jbc.ra119.012148] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Indexed: 12/28/2022] Open
Abstract
The environmental stress response (ESR) is critical for cell survival. Yeast cells unable to synthesize inositol pyrophosphates (PP-InsPs) are unable to induce the ESR. We recently discovered a diphosphoinositol pentakisphosphate (PP-InsP5) phosphatase in Saccharomyces cerevisiae encoded by SIW14 Yeast strains deleted for SIW14 have increased levels of PP-InsPs. We hypothesized that strains with high inositol pyrophosphate levels will have an increased stress response. We examined the response of the siw14Δ mutant to heat shock, nutrient limitation, osmotic stress, and oxidative treatment using cell growth assays and found increased resistance to each. Transcriptional responses to oxidative and osmotic stresses were assessed using microarray and reverse transcriptase quantitative PCR. The ESR was partially induced in the siw14Δ mutant strain, consistent with the increased stress resistance, and the mutant strain further induced the ESR in response to oxidative and osmotic stresses. The levels of PP-InsPs increased in WT cells under oxidative stress but not under hyperosmotic stress, and they were high and unchanging in the mutant. Phosphatase activity of Siw14 was inhibited by oxidation that was reversible. To determine how altered PP-InsP levels affect the ESR, we performed epistasis experiments with mutations in rpd3 and msn2/4 combined with siw14Δ. We show that mutations in msn2Δ and msn4Δ, but not rpd3, are epistatic to siw14Δ by assessing growth under oxidative stress conditions and expression of CTT1 Msn2-GFP nuclear localization was increased in the siw14Δ. These data support a model in which the modulation of PP-InsPs influence the ESR through general stress response transcription factors Msn2/4.
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Affiliation(s)
| | | | - Kotaro Fujimaki
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721
| | - Lucy Chong
- Division of Neurosurgery, Colket Translational Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104
| | - Adam C Resnick
- Division of Neurosurgery, Colket Translational Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104
| | - Andrew P Capaldi
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721
| | - Ronda J Rolfes
- Department of Biology, Georgetown University, Washington, D. C. 20057.
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Abstract
Some amino acids (AA) act through several signalling pathways and mechanisms to mediate the control of gene expression at the translation level, and the regulation occurs, specifically, on the initiation and the signalling pathways for translation. The translation of mRNA to protein synthesis proceeds through the steps of initiation and elongation, and AA act as important feed-forward activators that are involved in many pathways, such as the sensing and the transportation of AA by cells, in these steps in many tissues of mammals. For the translation, phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a critical molecule that controls the translation initiation and its functions can be regulated by some AA. Another control point in the mRNA binding step in the translation initiation is at the regulation by mammalian target of rapamycin, which requires a change of phosphorylation status of ribosomal protein S6. In fact, the change of phosphorylation status of ribosomal protein S6 might be involved in global protein synthesis. The present review summarises recent work on the molecular mechanisms of the regulation of protein synthesis by AA and highlights new findings.
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Han C, He X, Xia X, Guo J, Liu A, Liu X, Wang X, Li C, Peng S, Zhao W, Zhou M, Shi X, Li Y, Li Y, Shan Z, Teng W. Sphk1/S1P/S1PR1 Signaling is Involved in the Development of Autoimmune Thyroiditis in Patients and NOD.H-2 h4 Mice. Thyroid 2019; 29:700-713. [PMID: 30963819 DOI: 10.1089/thy.2018.0065] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background: There is growing evidence that sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite synthesized intracellularly by two closely related sphingosine kinases (SphKs), SphK1 and SphK2, is involved in inflammation. However, the role of SphKs/S1P/S1P receptors (S1PRs) in autoimmune thyroiditis (AIT) has not been studied to date. Methods: This study examined whether SphK1/S1P/S1PR1 signaling is aberrantly altered in thyroid tissues and serum of both AIT patients and a spontaneously autoimmune thyroiditis (SAT) mouse model. Murine CD4+T cells were employed to further investigate the downstream signaling of SphK1/S1P/S1PR1. Furthermore, a total of 102 NOD.H-2h4 mice, randomly divided into different groups, were used to investigate the therapeutic effect of S1PR1 blockade and its potential mechanism. Results: We found that components of the SphK1/S1P/S1PR1 pathway were abnormally expressed in patients with Hashimoto thyroiditis and in a SAT mouse model. In addition, S1P could activate signal transducer and activator of transcription 3 (STAT3) through S1PR1 and its downstream signaling pathways in CD4+T cells of NOD.H-2h4 mice. Furthermore, an in vivo study demonstrated that blocking S1PR1 by FTY720 administration could reduce the incidence and severity of thyroiditis and goiter in SAT mice in a time-dependent manner. The proportions of STAT3-related and inflammation-related cell subtypes, such as T helper 1, T helper 17, and follicular T helper cells, were elevated in the SAT group when compared to the control group, and these cell subtypes decreased after FTY720 administration. Furthermore, the downstream inflammatory cytokines of STAT3 were also downregulated after FTY720 administration. Conclusion: The present study shows that blocking Sphk1/S1P/S1PR1 signaling can ameliorate the severity of AIT, providing evidence of a promising therapeutic target for AIT.
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Affiliation(s)
- Cheng Han
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
- 2 Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York
| | - Xue He
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xinghai Xia
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
- 3 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Jiahui Guo
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Aihua Liu
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xin Liu
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xinyi Wang
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chengyan Li
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Shiqiao Peng
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Wei Zhao
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
- 4 Department of Endocrinology, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
| | - Mi Zhou
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
- 3 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Xiaoguang Shi
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yushu Li
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongze Li
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhongyan Shan
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Weiping Teng
- 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, China
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Szatkowska R, Garcia-Albornoz M, Roszkowska K, Holman SW, Furmanek E, Hubbard SJ, Beynon RJ, Adamczyk M. Glycolytic flux in Saccharomyces cerevisiae is dependent on RNA polymerase III and its negative regulator Maf1. Biochem J 2019; 476:1053-1082. [PMID: 30885983 PMCID: PMC6448137 DOI: 10.1042/bcj20180701] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 03/11/2019] [Accepted: 03/15/2019] [Indexed: 02/07/2023]
Abstract
Protein biosynthesis is energetically costly, is tightly regulated and is coupled to stress conditions including glucose deprivation. RNA polymerase III (RNAP III)-driven transcription of tDNA genes for production of tRNAs is a key element in efficient protein biosynthesis. Here we present an analysis of the effects of altered RNAP III activity on the Saccharomyces cerevisiae proteome and metabolism under glucose-rich conditions. We show for the first time that RNAP III is tightly coupled to the glycolytic system at the molecular systems level. Decreased RNAP III activity or the absence of the RNAP III negative regulator, Maf1 elicit broad changes in the abundance profiles of enzymes engaged in fundamental metabolism in S. cerevisiae In a mutant compromised in RNAP III activity, there is a repartitioning towards amino acids synthesis de novo at the expense of glycolytic throughput. Conversely, cells lacking Maf1 protein have greater potential for glycolytic flux.
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Affiliation(s)
- Roza Szatkowska
- Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland
| | - Manuel Garcia-Albornoz
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, U.K
| | - Katarzyna Roszkowska
- Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland
| | - Stephen W Holman
- Centre for Proteome Research, Institute of Integrative Biology, University of Liverpool, Liverpool, U.K
| | - Emil Furmanek
- Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland
| | - Simon J Hubbard
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, U.K
| | - Robert J Beynon
- Centre for Proteome Research, Institute of Integrative Biology, University of Liverpool, Liverpool, U.K
| | - Malgorzata Adamczyk
- Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland
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Sajiki K, Tahara Y, Villar-Briones A, Pluskal T, Teruya T, Mori A, Hatanaka M, Ebe M, Nakamura T, Aoki K, Nakaseko Y, Yanagida M. Genetic defects in SAPK signalling, chromatin regulation, vesicle transport and CoA-related lipid metabolism are rescued by rapamycin in fission yeast. Open Biol 2019; 8:rsob.170261. [PMID: 29593117 PMCID: PMC5881033 DOI: 10.1098/rsob.170261] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 02/19/2018] [Indexed: 12/20/2022] Open
Abstract
Rapamycin inhibits TOR (target of rapamycin) kinase, and is being used clinically to treat various diseases ranging from cancers to fibrodysplasia ossificans progressiva. To understand rapamycin mechanisms of action more comprehensively, 1014 temperature-sensitive (ts) fission yeast (Schizosaccharomyces pombe) mutants were screened in order to isolate strains in which the ts phenotype was rescued by rapamycin. Rapamycin-rescued 45 strains, among which 12 genes responsible for temperature sensitivity were identified. These genes are involved in stress-activated protein kinase (SAPK) signalling, chromatin regulation, vesicle transport, and CoA- and mevalonate-related lipid metabolism. Subsequent metabolome analyses revealed that rapamycin upregulated stress-responsive metabolites, while it downregulated purine biosynthesis intermediates and nucleotide derivatives. Rapamycin alleviated abnormalities in cell growth and cell division caused by sty1 mutants (Δsty1) of SAPK. Notably, in Δsty1, rapamycin reduced greater than 75% of overproduced metabolites (greater than 2× WT), like purine biosynthesis intermediates and nucleotide derivatives, to WT levels. This suggests that these compounds may be the points at which the SAPK/TOR balance regulates continuous cell proliferation. Rapamycin might be therapeutically useful for specific defects of these gene functions.
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Affiliation(s)
- Kenichi Sajiki
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Yuria Tahara
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Alejandro Villar-Briones
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Tomáš Pluskal
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Takayuki Teruya
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Ayaka Mori
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Mitsuko Hatanaka
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Masahiro Ebe
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Takahiro Nakamura
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
| | - Keita Aoki
- Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yukinobu Nakaseko
- Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Mitsuhiro Yanagida
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
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Zhang Z, Zhang X, Zhao D, Liu B, Wang B, Yu W, Li J, Yu X, Cao F, Zheng G, Zhang Y, Liu Y. TGF‑β1 promotes the osteoinduction of human osteoblasts via the PI3K/AKT/mTOR/S6K1 signalling pathway. Mol Med Rep 2019; 19:3505-3518. [PMID: 30896852 PMCID: PMC6471541 DOI: 10.3892/mmr.2019.10051] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 03/06/2019] [Indexed: 12/22/2022] Open
Abstract
Transforming growth factor β1 (TGF-β1) has been suggested to be a candidate cytokine in the field of bone tissue engineering. Cytokines serve important roles in tissue engineering, particularly in the repair of bone damage; however, the underlying molecular mechanisms remain unclear. In the present study, the effects of TGF-β1 on the osteogenesis and motility of hFOB1.19 human osteoblasts were demonstrated via the phenotype and gene expression of cells. Additionally, the role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/S6 kinase 1 (PI3K/AKT/mTOR/S6K1) signalling pathway in the effects of TGF-β1 on osteoblasts was investigated. It was demonstrated using Cell Counting Kit-8 and flow cytometry assays that the proliferation of human osteoblasts was promoted by 1 ng/ml TGF-β1. In addition, alkaline phosphatase activity, Alizarin red staining, scratch-wound and Transwell assays were conducted. It was revealed that osteogenesis and the migration of cells were regulated by TGF-β1 via the upregulation of osteogenic and migration-associated genes. Alterations in the expression of osteogenesis- and migration-associated genes were evaluated following pre-treatment with a PI3K/AKT inhibitor (LY294002) and an mTOR/S6K1 inhibitor (rapamycin), with or without TGF-β1. The results indicated that TGF-β1 affected the osteogenesis and mineralisation of osteoblasts via the PI3K/AKT signalling pathway. Furthermore, TGF-β1 exhibited effects on mTOR/S6K1 downstream of PI3K/AKT. The present study demonstrated that TGF-β1 promoted the proliferation, differentiation and migration of human hFOB1.19 osteoblasts, and revealed that TGF-β1 affected the biological activity of osteoblasts via the PI3K/AKT/mTOR/S6K1 signalling pathway. Our findings may provide novel insight to aid the development of bone tissue engineering methods for the treatment of bone injury.
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Affiliation(s)
- Zhaodong Zhang
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Xiuzhi Zhang
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Dewei Zhao
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Baoyi Liu
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Benjie Wang
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Weiting Yu
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Junlei Li
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Xiaobing Yu
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Fang Cao
- Department of Biomedical Engineering, Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian, Liaoning 116024, P.R. China
| | - Guoshuang Zheng
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Yao Zhang
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Yupeng Liu
- Department of Orthopaedics, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
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Li Z, Yu R, Yin W, Qin Y, Ma L, Mulholland M, Zhang W. mTOR Signaling in X/A-Like Cells Contributes to Lipid Homeostasis in Mice. Hepatology 2019; 69:860-875. [PMID: 30141265 PMCID: PMC6351211 DOI: 10.1002/hep.30229] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 08/19/2018] [Indexed: 01/02/2023]
Abstract
Gastric mechanistic target of rapamycin (mTOR) signaling is inversely associated with the expression and secretion of ghrelin, a 28-aa peptide hormone produced by gastric X/A-like cells. Ghrelin contributes to obesity and hepatic steatosis. We sought to control global lipid metabolism via the manipulation of gastric mTOR signaling in X/A-like cells. We established a ghrl-cre transgene in which the Cre enzyme is expressed in X/A-like cells under the control of the ghrelin-promoter. mTORflox/flox and tuberous sclerosis 1 (TSC1)flox/flox mice were separately bred with ghrl-cre mice to generate mTOR-ghrl-cre or TSC1-ghrl-cre mice, within which mTOR signaling was suppressed or activated, respectively. Lipid metabolism in liver and adipose depots was analyzed. Under the control of the ghrelin-promoter, the Cre enzyme was exclusively expressed in stomach X/A-like cells in adult animals. Knockout of mTOR in X/A-like cells increased circulating acyl-ghrelin and promoted hepatic lipogenesis with effects on adipose depots. Activation of mTOR signaling by deletion of its upstream inhibitor, TSC1, decreased ghrelin expression and secretion, altering lipid metabolism as evidenced by resistance to high-fat diet-induced obesity and hepatic steatosis. Both ghrelin administration and injection of rapamycin, an inhibitor of mTOR, altered the phenotypes of TSC1-ghrl-cre mice. Conclusion: Gastric mTOR signaling in X/A-like cells contributes to organism lipid homeostasis by regulating hepatic and adipose lipid metabolism. Gastric mTOR signaling may provide an alternative strategy for intervention in lipid disorders.
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Affiliation(s)
- Ziru Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China,Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0346, USA
| | - Ruili Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Wenzhen Yin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yan Qin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Liangxiao Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Michael Mulholland
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0346, USA,Corresponding author. Contact information: Michael W. Mulholland, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Tel: 1-734-936-3236; ; Or. Weizhen Zhang, NCRC 26-241N, 2800 Plymouth Rd, Ann Arbor, MI 48105, United State, Tel: 1-734-615-0360; Fax: 1-734-763-4135;
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China,Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0346, USA,Corresponding author. Contact information: Michael W. Mulholland, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Tel: 1-734-936-3236; ; Or. Weizhen Zhang, NCRC 26-241N, 2800 Plymouth Rd, Ann Arbor, MI 48105, United State, Tel: 1-734-615-0360; Fax: 1-734-763-4135;
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Kumar P, Kundu D, Mondal AK, Nain V, Puria R. Inhibition of TOR signalling in lea1 mutant induces apoptosis in Saccharomyces cerevisiae. ANN MICROBIOL 2019. [DOI: 10.1007/s13213-018-1422-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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Clatici VG, Voicu C, Voaides C, Roseanu A, Icriverzi M, Jurcoane S. Diseases of Civilization - Cancer, Diabetes, Obesity and Acne - the Implication of Milk, IGF-1 and mTORC1. MAEDICA 2018; 13:273-281. [PMID: 30774725 PMCID: PMC6362881 DOI: 10.26574/maedica.2018.13.4.273] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nutrition and food are one of the most complex aspects of human lives, being influenced by biochemical, psychological, social and cultural factors. The Western diet is the prototype of modern dietary pattern and is mainly characterized by the intake of large amounts of red meat, dairy products, refined grains and sugar. Large amounts of scientific evidence positively correlate Western diet to acne, obesity, diabetes, heart disease and cancer, the so-called "diseases of civilization". The pathophysiological common ground of all these pathologies is the IGF-1 and mTORC pathways, which will be disscussed further in this paper.
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Affiliation(s)
| | | | | | - Anca Roseanu
- Department of Ligand-Receptor Interaction, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Madalina Icriverzi
- Department of Ligand-Receptor Interaction, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
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Liang S, Medina EA, Li B, Habib SL. Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer. Mol Oncol 2018; 12:1917-1934. [PMID: 30107094 PMCID: PMC6210038 DOI: 10.1002/1878-0261.12370] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 07/19/2018] [Accepted: 07/26/2018] [Indexed: 12/31/2022] Open
Abstract
Loss of Von Hippel-Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia-inducible factor (HIF-α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5-aminoimidazole-4-carboxamide-riboside (AICAR) as AMPK activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and HIF-2α expression in renal cell carcinoma cells, including primary cells isolated from kidney cancer patients. Significant decreases in cell migration and invasion were detected using drug combinations. Drug combinations effectively abolished binding of HIF-2α to the Akt promoter and effected formation of the DNA-protein complex in nuclear extracts from 786-O cells, as demonstrated using electromobility shift assay and examination of Akt promoter activity. Importantly, we tested the effect of each drug and the combined drugs on kidney tumor size in the nude mouse model. Our data show that treatment with rapamycin, AICAR, and rapamycin+AICAR decreased tumor size by 38%, 36%, and 80%, respectively, suggesting that drug combinations have an additive effect in reducing tumor size compared with use of each drug alone. Drug combinations effectively decreased cell proliferation, increased apoptotic cells, and significantly decreased p-Akt, HIF-2α, and vascular endothelial growth factor expression in tumor kidney tissues from mice. These results show for the first time that drug combinations are more effective than single drugs in reducing kidney tumor progression. This study provides important evidence that may lead to the initiation of pre-clinical trials in patients with kidney cancer.
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Affiliation(s)
- Sitai Liang
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX, USA
| | - Edward A Medina
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, TX, USA
| | - Boajie Li
- Bio-X Institutes, Shanghai Jiao Tong University, China
| | - Samy L Habib
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX, USA.,South Texas Veterans Health Care System, San Antonio, TX, USA
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The PP2A-like Protein Phosphatase Ppg1 and the Far Complex Cooperatively Counteract CK2-Mediated Phosphorylation of Atg32 to Inhibit Mitophagy. Cell Rep 2018; 23:3579-3590. [DOI: 10.1016/j.celrep.2018.05.064] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 05/07/2018] [Accepted: 05/17/2018] [Indexed: 12/13/2022] Open
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Kimbrough-Allah MN, Millena AC, Khan SA. Differential role of PTEN in transforming growth factor β (TGF-β) effects on proliferation and migration in prostate cancer cells. Prostate 2018; 78:377-389. [PMID: 29341212 PMCID: PMC5820153 DOI: 10.1002/pros.23482] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 12/21/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Transforming growth factor-β (TGF-β) acts as a tumor suppressor in normal epithelial cells but as a tumor promoter in advanced prostate cancer cells. PI3-kinase pathway mediates TGF-β effects on prostate cancer cell migration and invasion. PTEN inhibits PI3-kinase pathway and is frequently mutated in prostate cancers. We investigated possible role(s) of PTEN in TGF-β effects on proliferation and migration in prostate cancer cells. METHODS Expression of PTEN mRNA and proteins were determined using RT-PCR and Western blotting in RWPE1 and DU145 cells. We also studied the role of PTEN in TGF-β effects on cell proliferation and migration in DU145 cells after transient silencing of endogenous PTEN. Conversely, we determined the role of PTEN in cell proliferation and migration after over-expression of PTEN in PC3 cells which lack endogenous PTEN. RESULTS TGF-β1 and TGF-β3 had no effect on PTEN mRNA levels but both isoforms increased PTEN protein levels in DU145 and RWPE1 cells indicating that PTEN may mediate TGF-β effects on cell proliferation. Knockdown of PTEN in DU145 cells resulted in significant increase in cell proliferation which was not affected by TGF-β isoforms. PTEN overexpression in PC3 cells inhibited cell proliferation. Knockdown of endogenous PTEN enhanced cell migration in DU145 cells, whereas PTEN overexpression reduced migration in PC3 cells and reduced phosphorylation of AKT in response to TGF-β. CONCLUSION We conclude that PTEN plays a role in inhibitory effects of TGF-β on cell proliferation whereas its absence may enhance TGF-β effects on activation of PI3-kinase pathway and cell migration.
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Affiliation(s)
| | - Ana C Millena
- Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Shafiq A Khan
- Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
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Liu D, Gao L, Zhang Z, Tao S, Pang Q, Li A, Deng H, Yu H. Lithium promotes the production of reactive oxygen species via GSK-3β/TSC2/TOR signaling in the gill of zebrafish (Danio rerio). CHEMOSPHERE 2018; 195:854-863. [PMID: 29291576 DOI: 10.1016/j.chemosphere.2017.12.130] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/20/2017] [Accepted: 12/21/2017] [Indexed: 06/07/2023]
Abstract
In this study, the mechanism that lithium (Li) promotes the production of reactive oxygen species (ROS) via the glycogen synthase kinase-3β (GSK-3β)/tuberous sclerosis complex 2 (TSC2)/target of rapamycin (TOR) signaling was investigated in the gill of zebrafish (Danio rerio). After the zebrafish were treated by 25 and 50 mg/L Li+, the mRNA expression of GSK-3β and TSC2 was inhibited, but the expression of TOR was induced in the gill of zebrafish. The levels of hydrogen peroxide (H2O2), superoxide anion (O2·-), and hydroxy radical (·OH) as well as the activity of superoxide dismutase (SOD) were increased, while the activities of catalase (CAT), glutathione peroxidase (GSH-PX), and peroxidase (POD) were decreased by 25 and 50 mg/L Li+ treatments. In the ZF4 cells, the mRNA expression of GSK-3β and TSC2 was inhibited, but TOR expression was induced by 1, 5, and 10 mmol/L Li+ treatments. To further confirm that lithium promoted ROS production via GSK-3β inhibition, GSK-3β RNA was interfered. It was found that the interference of GSK-3β RNA induced the TSC2/TOR signaling. The levels of H2O2, O2·-, and ·OH were increased, but the activities of CAT, GSH-PX, and POD were decreased by GSK-3β RNA interference. In addition, lithium decreased the mitochondrial membrane potential (MMP) with Rhodamine-123 assay, but increased the levels of ROS by 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The present results indicated that lithium promoted the ROS production through the GSK-3β/TSC2/TOR signaling in the gill of zebrafish.
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Affiliation(s)
- Dongwu Liu
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China
| | - Lili Gao
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China
| | - Zhuangzhuang Zhang
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China
| | - Shiyi Tao
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China
| | - Qiuxiang Pang
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China.
| | - Ao Li
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China
| | - Hongkuan Deng
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China
| | - Hairui Yu
- College of Biological and Agricultural Engineering, Weifang Bioengineering Technology Research Center, Weifang University, Weifang 261061, China
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Abstract
Lymphangioleiomyomatosis (LAM) is a rare, low-grade, metastasizing neoplasm that arises from an unknown source, spreads via the lymphatics, and targets the lungs. All pulmonary structures become infiltrated with benign-appearing spindle and epithelioid cells (LAM cells) that express smooth-muscle and melanocyte-lineage markers, harbor mTOR-activating mutations in tuberous sclerosis complex (TSC) genes, and recruit abundant stromal cells. Elaboration of lymphangiogenic growth factors and matrix remodeling enzymes by LAM cells enables their access to lymphatic channels and likely drives the cystic lung remodeling that often culminates in respiratory failure. Dysregulated cellular signaling results in a shift from oxidative phosphorylation to glycolysis as the preferred mode of energy generation, to allow for the accumulation of biomass required for cell growth and tolerance of nutrient-poor, anaerobic environments. Symptomatic LAM occurs almost exclusively in females after menarche, highlighting the central but as yet poorly understood role for sex-restricted anatomical structures and/or hormones in disease pathogenesis. LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell-metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism and the pathogenesis of cancer.
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Affiliation(s)
- Vera P Krymskaya
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Francis X McCormack
- Department of Internal Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267;
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