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Parolini C. Pathophysiology of bone remodelling cycle: Role of immune system and lipids. Biochem Pharmacol 2025; 235:116844. [PMID: 40044049 DOI: 10.1016/j.bcp.2025.116844] [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: 11/28/2024] [Revised: 01/31/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
Osteoporosis is the most common skeletal disease worldwide, characterized by low bone mineral density, resulting in weaker bones, and an increased risk of fragility fractures. The maintenance of bone mass relies on the precise balance between bone synthesis and resorption. The close relationship between the immune and skeletal systems, called "osteoimmunology", was coined to identify these overlapping "scientific worlds", and its function resides in the evaluation of the mutual effects of the skeletal and immune systems at the molecular and cellular levels, in both physiological and pathological states. Lipids play an essential role in skeletal metabolism and bone health. Indeed, bone marrow and its skeletal components demand a dramatic amount of daily energy to control hematopoietic turnover, acquire and maintain bone mass, and actively being involved in whole-body metabolism. Statins, the main therapeutic agents in lowering plasma cholesterol levels, are able to promote osteoblastogenesis and inhibit osteoclastogenesis. This review is meant to provide an updated overview of the pathophysiology of bone remodelling cycle, focusing on the interplay between bone, immune system and lipids. Novel therapeutic strategies for the management of osteoporosis are also discussed.
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Affiliation(s)
- Cinzia Parolini
- Department of Pharmacological and Biomolecular Sciences, 'Rodolfo Paoletti', via Balzaretti 9 - Università degli Studi di Milano 20133 Milano, Italy.
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Sgarra L, Desantis V, Matteucci A, Caccavo VP, Troisi F, Di Monaco A, Mangini F, Katsouras G, Guaricci AI, Dadamo ML, Fortunato F, Nacci C, Potenza MA, Montagnani M, Grimaldi M. Non-Anticoagulation Strategies Aimed at Primary Stroke Prevention in Nascent Atrial Fibrillation. Biomedicines 2025; 13:660. [PMID: 40149635 PMCID: PMC11939867 DOI: 10.3390/biomedicines13030660] [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: 01/16/2025] [Revised: 02/23/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
At its earliest appearance, atrial fibrillation (AF) is often unnoticed, asymptomatic, and/or merely device-detected. Widespread use of heart-rate monitoring technologies has facilitated such "nascent atrial fibrillation (nAF)" recognition. Consequently, clinicians face a growing number of patients affected by new-onset AF in the absence of a definite indication for anticoagulation due to several counterarguments: (1) a CHA2DS2-VA score ≤ 1 in otherwise apparently healthy subjects; (2) an uncertain embolic/hemorrhagic benefit/risk ratio with anticoagulation; (3) EKG demonstration and confirmation of AF; and (4) existence of a pathogenic mechanism other than atrial hypercoagulability. In this frustrating limitation of pharmacological options, cardiologists may miss a complete comprehension of drugs with proven anti-ictal potential, whose administration may serve both as a bridge strategy toward future anticoagulation and as a consolidative strategy paralleling anticoagulation. This review aims to summarize and elucidate such therapeutic strategies and their preventative mechanisms.
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Affiliation(s)
- Luca Sgarra
- Cardiology Unit, Medicine Department, General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
| | - Vanessa Desantis
- Pharmacology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro Medical School, 70124 Bari, Italy (M.M.)
| | - Andrea Matteucci
- Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, ASL Rome 1, 00135 Rome, Italy
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Vincenzo Paolo Caccavo
- Cardiology Unit, Medicine Department, General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
| | - Federica Troisi
- Cardiology Unit, Medicine Department, General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
| | - Antonio Di Monaco
- Cardiology Unit, Medicine Department, General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
| | - Francesco Mangini
- Cardiology Unit, Medicine Department, General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
| | - Grigorios Katsouras
- Cardiology Unit, Medicine Department, General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
| | - Andrea Igoren Guaricci
- Cardiology Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Michele Luca Dadamo
- Cardiology Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Fabrizio Fortunato
- Department of Cardiology, Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, 90127 Palermo, Italy
| | - Carmela Nacci
- Pharmacology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro Medical School, 70124 Bari, Italy (M.M.)
| | - Maria Assunta Potenza
- Pharmacology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro Medical School, 70124 Bari, Italy (M.M.)
| | - Monica Montagnani
- Pharmacology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro Medical School, 70124 Bari, Italy (M.M.)
| | - Massimo Grimaldi
- Cardiology Unit, Medicine Department, General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
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Simons P, Bondu V, Shevy L, Young S, Wandinger-Ness A, Bologa CG, Buranda T. A model for predicting bacteremia species based on host immune response. Front Cell Infect Microbiol 2025; 15:1451293. [PMID: 40041147 PMCID: PMC11876111 DOI: 10.3389/fcimb.2025.1451293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 01/29/2025] [Indexed: 03/06/2025] Open
Abstract
Introduction Clinicians encounter significant challenges in quickly and accurately identifying the bacterial species responsible for patient bacteremia and in selecting appropriate antibiotics for timely treatment. This study introduces a novel approach that combines immune response data from routine blood counts with assessments of immune cell activation, specifically through quantitative measurements of Rho family GTPase activity. The combined data were used to develop a machine-learning model capable of distinguishing specific classes of bacteria and their associations. Methods We aimed to determine whether different classes of bacteria elicit distinct patterns of host immune responses, as indicated by quantitative differences in leukocyte populations from routine complete blood counts with differential. Concurrently, we conducted quantitative measurements of activated Rac1 (Rac1•GTP) levels using a novel 'G-Trap assay' we developed. With the G-Trap, we measured Rac1•GTP in peripheral blood monocytes (PBMC) and polymorphonuclear (PMN) cells from blood samples collected from 28 culture-positive patients and over 80 non-infected patients used as controls. Results Our findings indicated that 18 of the 28 patients with bacteremia showed an increase of ≥ 3-fold in Rac1•GTP levels compared to the controls. The remaining ten patients with bacteremia exhibited either neutrophilia or pancytopenia and displayed normal to below-normal Rac1 GTPase activity, which is consistent with bacteria-induced immunosuppression. To analyze the data, we employed partial least squares discriminant analysis (PLS-DA), a supervised method that optimizes group separation and aids in building a novel machine-learning model for pathogen identification. Discussion The results demonstrated that PLS-DA effectively differentiates between specific pathogen groups, and external validation confirmed the predictive model's utility. Given that bacterial culture confirmation may take several days, our study underscores the potential of combining routine assays with a machine-learning model as a valuable clinical decision-support tool. This approach could enable prompt and accurate treatment on the same day that patients present to the clinic.
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Affiliation(s)
- Peter Simons
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Virginie Bondu
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Laura Shevy
- Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico, Health Sciences Center, Albuquerque, NM, United States
| | - Stephen Young
- Tricore Research Laboratories, Albuquerque, NM, United States
| | - Angela Wandinger-Ness
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Cristian G. Bologa
- Translational Informatics Division, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Tione Buranda
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
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Liu JC, Lei SY, Zhang DH, He QY, Sun YY, Zhu HJ, Qu Y, Zhou SY, Yang Y, Li C, Guo ZN. The pleiotropic effects of statins: a comprehensive exploration of neurovascular unit modulation and blood-brain barrier protection. Mol Med 2024; 30:256. [PMID: 39707228 DOI: 10.1186/s10020-024-01025-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
The blood-brain barrier (BBB) is the most central component of the neurovascular unit (NVU) and is crucial for the maintenance of the internal environment of the central nervous system and the regulation of homeostasis. A multitude of neuroprotective agents have been developed to exert neuroprotective effects and improve the prognosis of patients with ischemic stroke. These agents have been designed to maintain integrity and promote BBB repair. Statins are widely used as pharmacological agents for the treatment and prevention of ischemic stroke, making them a cornerstone in the pharmacological armamentarium for this condition. The primary mechanism of action is the reduction of serum cholesterol through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which results in a decrease in low-density lipoprotein cholesterol (LDL-C) and an increase in cholesterol clearance. Nevertheless, basic and clinical research has indicated that statins may exert additional pleiotropic effects beyond LDL-C reduction. Previous studies on ischemic stroke have demonstrated that statins can enhance neurological function, reduce inflammation, and promote angiogenic and synaptic processes following ischemic stroke. The BBB has been increasingly recognized for its role in the development and progression of ischemic stroke. Statins have also been found to play a potential BBB protective role by affecting members of the NVU. This review aimed to provide a comprehensive theoretical basis for the clinical application of statins by systematically detailing how statins influence the BBB, particularly focusing on the regulation of the function of each member of the NVU.
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Affiliation(s)
- Jia-Cheng Liu
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Shuang-Yin Lei
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Dian-Hui Zhang
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Qian-Yan He
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Ying-Ying Sun
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Hong-Jing Zhu
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Yang Qu
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Sheng-Yu Zhou
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Yi Yang
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
- Jilin Provincial Key Laboratory of Cerebrovascular Disease, Xinmin Street 1#, Changchun, 130021, China
| | - Chao Li
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China.
| | - Zhen-Ni Guo
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China.
- Jilin Provincial Key Laboratory of Cerebrovascular Disease, Xinmin Street 1#, Changchun, 130021, China.
- Neuroscience Research Center, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China.
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Martinez Barrera S, Hatchell E, Byrum SD, Mackintosh SG, Kozubowski L. Quantitative analysis of septin Cdc10 & Cdc3-associated proteome during stress response in the fungal pathogen Cryptococcus neoformans. PLoS One 2024; 19:e0313444. [PMID: 39689097 DOI: 10.1371/journal.pone.0313444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 10/23/2024] [Indexed: 12/19/2024] Open
Abstract
Cryptococcus neoformans is a pathogenic basidiomycetous yeast that primarily infects immunocompromised individuals. Fatal outcome of cryptococcosis depends on the ability of C. neoformans to sense and adapt to 37°C. A complex of conserved filament forming GTPases, called septins, composed of Cdc3, Cdc10, Cdc11, and Cdc12, assembles at the mother-bud neck in C. neoformans. Septins Cdc3 and Cdc12 are essential for proliferation of C. neoformans at 37°C and for virulence in the Galleria mellonella model of infection, presumably due to their requirement for septin complex formation, and the involvement in cytokinesis. However, how exactly Cdc3, and Cdc12 contribute to C. neoformans growth at 37°C remains unknown. Based on studies investigating roles of septins in Saccharomyces cerevisiae, septin complex at the mother-bud neck of C. neoformans is predicted to interact with proteins involved in cell cycle control, morphogenesis, and cytokinesis, but the septin-associated proteome in C. neoformans has not been investigated. Here, we utilized tandem mass spectrometry to define C. neoformans proteins that associate with either Cdc3 or Cdc10 at ∼25°C or after the shift to 37°C. Our findings unveil a diverse array of septin-associated proteins, highlighting potential roles of septins in cell division, and stress response. Two proteins, identified as associated with both Cdc3 and Cdc10, the actin-binding protein profilin, which was detected at both temperatures, and ATP-binding multi-drug transporter Afr1, which was detected exclusively at 37°C, were further confirmed by co-immunoprecipitation. We also confirmed that association of Cdc3 with Afr1 was enhanced at 37°C. Upon shift to 37°C, septins Cdc3 and Cdc10 exhibited altered localization and Cdc3 partially co-localized with Afr1. In addition, we also investigated changes to levels of individual C. neoformans proteins upon shift from ∼25 to 37°C in exponentially grown culture and when cells entered stationary phase at ∼25°C. Our study reveals changes to C. neoformans proteome associated with heat and nutrient deprivation stresses and provides a landscape of septin-associated C. neoformans proteome, which will facilitate elucidating the biology of septins and mechanisms of stress response in this fungal pathogen.
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Affiliation(s)
- Stephani Martinez Barrera
- Department of Genetics and Biochemistry, Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, SC, United States of America
| | - Emma Hatchell
- Department of Genetics and Biochemistry, Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, SC, United States of America
| | - Stephanie D Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Samuel G Mackintosh
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Lukasz Kozubowski
- Department of Genetics and Biochemistry, Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, SC, United States of America
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Solano E, Foksinska A, Crowder CM. Variants in RHOBTB2 associated with cancer and rare developmental and epileptic encephalopathy. Front Pediatr 2024; 12:1448793. [PMID: 39736890 PMCID: PMC11683136 DOI: 10.3389/fped.2024.1448793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 11/29/2024] [Indexed: 01/01/2025] Open
Abstract
RHOBTB2 is a member of the Rho GTPases subfamily of signaling proteins, known tumor suppressors whose loss of function and decreased expression is associated with cancer onset. Beyond its cancer-related role, RHOBTB2 is implicated in rare neurodevelopmental disorders, specifically RHOBTB2-related disorders, recognized in 2018 as a subtype of developmental and epileptic encephalopathies (DEE). Common symptoms of these disorders include early-onset epilepsy, severe intellectual disability, microcephaly, and movement disorders. Few studies have investigated patient variants associated with RHOBTB2-related disorders, and the impact of these variants on protein function remains unclear. Limited research suggests that the accumulation of RHOBTB2 in neural tissues contributes to the development of DEE. Similarly, preclinical studies indicate that missense variants near or in the BTB domain of RHOBTB2 result in decreased degradation of RHOBTB2 and the onset of DEE, whereas variants in the GTPase domain cause more variable neurodevelopmental symptoms, but do not impair proteasomal degradation of RHOBTB2. However, the exact pathophysiological mechanisms are unclear and may differ across variants. Current treatment approaches for individuals with RHOBTB2-related DEE involve the use of antiseizure medications to decrease seizures; however, no treatments have been identified that address the other symptoms or the underlying pathophysiological mechanisms associated with these disorders. Overall, RHOBTB2 remains an understudied protein with limited information on its function and how it contributes to disease mechanisms. This review provides an overview of the current knowledge of RHOBTB2 function, with an emphasis on its association with neurodevelopmental disorders through an analysis of preclinical studies and case reports that link individual variants with clinical features.
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Affiliation(s)
- Elaina Solano
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Aleksandra Foksinska
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Camerron M. Crowder
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL, United States
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Seabaugh JA, Anderson DM. Pathogenicity and virulence of Yersinia. Virulence 2024; 15:2316439. [PMID: 38389313 PMCID: PMC10896167 DOI: 10.1080/21505594.2024.2316439] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 02/04/2024] [Indexed: 02/24/2024] Open
Abstract
The genus Yersinia includes human, animal, insect, and plant pathogens as well as many symbionts and harmless bacteria. Within this genus are Yersinia enterocolitica and the Yersinia pseudotuberculosis complex, with four human pathogenic species that are highly related at the genomic level including the causative agent of plague, Yersinia pestis. Extensive laboratory, field work, and clinical research have been conducted to understand the underlying pathogenesis and zoonotic transmission of these pathogens. There are presently more than 500 whole genome sequences from which an evolutionary footprint can be developed that details shared and unique virulence properties. Whereas the virulence of Y. pestis now seems in apparent homoeostasis within its flea transmission cycle, substantial evolutionary changes that affect transmission and disease severity continue to ndergo apparent selective pressure within the other Yersiniae that cause intestinal diseases. In this review, we will summarize the present understanding of the virulence and pathogenesis of Yersinia, highlighting shared mechanisms of virulence and the differences that determine the infection niche and disease severity.
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Affiliation(s)
- Jarett A. Seabaugh
- Department of Veterinary Pathobiology, University of Missouri, Columbia, USA
| | - Deborah M. Anderson
- Department of Veterinary Pathobiology, University of Missouri, Columbia, USA
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Carvajal JA, Galaz J, Villagrán S, Astudillo R, Garmendia L, Delpiano AM. The role of the RHOA/ROCK pathway in the regulation of myometrial stages throughout pregnancy. AJOG GLOBAL REPORTS 2024; 4:100394. [PMID: 39434813 PMCID: PMC11491706 DOI: 10.1016/j.xagr.2024.100394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2024] Open
Abstract
Background Controlling uterine contractile activity is essential to regulate the duration of pregnancy. During most of the pregnancy, the uterus does not contract (i.e., myometrial quiescence). The myometrium recovers its contractile phenotype at around 36 weeks (i.e., myometrial activation) through several mechanisms. The RHOA/ROCK pathway plays a vital role in facilitating muscular contractions by calcium sensitization in humans. Yet, the role of this pathway during different myometrial stages, including quiescence, has not been elucidated. Objective we aimed to study the role of the RHOA/ROCK pathway in the regulation of the different myometrial stages throughout pregnancy. Specifically, we hypothesized that the inhibition of the components of the RHOA/ROCK pathway play an important role in maintaining uterine quiescence. Study design Myometrial samples were obtained from pregnant individuals who underwent cesarean section. Pregnant individuals who delivered preterm without labor (myometrial quiescence), preterm with labor (nonphysiological myometrial stimulation), term not in labor (activation), and term in labor (physiological myometrial stimulation) were included. The mRNA and protein expression of RHOA, ROCK I, ROCK II, RND1-3, and ROCK activity through pMYTP1 were evaluated. Results We found that the human myometrium constitutively expressed RHOA/ROCK pathway components throughout pregnancy. No changes in the components of the RHOA/ROCK pathway were found during quiescence. Moreover, the RHOA protein and ROCK activity increased in the myometrium during labor, supporting the hypothesis that this pathway participates in maintaining the contractile activity of the myometrium. This study provides insight into the role of the RHOA/ROCK pathway in controlling myometrial contractile activity during pregnancy.
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Affiliation(s)
- Jorge A. Carvajal
- Departamento de Obstetricia, Escuela de Medicina, Unidad de Medicina Materno Fetal, Pontificia Universidad Católica de Chile, Santiago, Chile (All authors)
| | - Jose Galaz
- Departamento de Obstetricia, Escuela de Medicina, Unidad de Medicina Materno Fetal, Pontificia Universidad Católica de Chile, Santiago, Chile (All authors)
| | - Sofía Villagrán
- Departamento de Obstetricia, Escuela de Medicina, Unidad de Medicina Materno Fetal, Pontificia Universidad Católica de Chile, Santiago, Chile (All authors)
| | - Rocío Astudillo
- Departamento de Obstetricia, Escuela de Medicina, Unidad de Medicina Materno Fetal, Pontificia Universidad Católica de Chile, Santiago, Chile (All authors)
| | - Liliana Garmendia
- Departamento de Obstetricia, Escuela de Medicina, Unidad de Medicina Materno Fetal, Pontificia Universidad Católica de Chile, Santiago, Chile (All authors)
| | - Ana María Delpiano
- Departamento de Obstetricia, Escuela de Medicina, Unidad de Medicina Materno Fetal, Pontificia Universidad Católica de Chile, Santiago, Chile (All authors)
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Anselmino LE, Malizia F, Avila A, Cesatti Laluce N, Mamberto M, Zanotti LC, Farré C, Sauzeau V, Menacho Márquez M. Overcoming Therapy Resistance in Colorectal Cancer: Targeting the Rac1 Signaling Pathway as a Potential Therapeutic Approach. Cells 2024; 13:1776. [PMID: 39513883 PMCID: PMC11545287 DOI: 10.3390/cells13211776] [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: 08/25/2024] [Revised: 10/10/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide and is responsible for numerous deaths. 5-fluorouracil (5-FU) is an effective chemotherapy drug commonly used in the treatment of CRC, either as monotherapy or in combination with other drugs. However, half of CRC cases are resistant to 5-FU-based therapies. To contribute to the understanding of the mechanisms underlying CRC resistance or recurrence after 5-FU-based therapies, we performed a comprehensive study integrating in silico, in vitro, and in vivo approaches. We identified differentially expressed genes and enrichment of pathways associated with recurrence after 5-FU-based therapies. Using these bioinformatics data as a starting point, we selected a group of drugs that restored 5-FU sensitivity to 5-FU resistant cells. Interestingly, treatment with the novel Rac1 inhibitor, 1A-116, reversed morphological changes associated with 5-FU resistance.. Moreover, our in vivo studies have shown that 1A-116 affected tumor growth and the development of metastasis. All our data allowed us to postulate that targeting Rac1 represents a promising avenue for the development of new treatments for patients with CRC resistant to 5-FU-based therapies.
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Affiliation(s)
- Luciano E. Anselmino
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 2000, Argentina; (L.E.A.); (F.M.); (N.C.L.); (M.M.); (L.C.Z.); (C.F.)
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 2000, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
| | - Florencia Malizia
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 2000, Argentina; (L.E.A.); (F.M.); (N.C.L.); (M.M.); (L.C.Z.); (C.F.)
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 2000, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
| | - Aylén Avila
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
| | - Nahuel Cesatti Laluce
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 2000, Argentina; (L.E.A.); (F.M.); (N.C.L.); (M.M.); (L.C.Z.); (C.F.)
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 2000, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
| | - Macarena Mamberto
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 2000, Argentina; (L.E.A.); (F.M.); (N.C.L.); (M.M.); (L.C.Z.); (C.F.)
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 2000, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
| | - Lucía C. Zanotti
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 2000, Argentina; (L.E.A.); (F.M.); (N.C.L.); (M.M.); (L.C.Z.); (C.F.)
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 2000, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
| | - Cecilia Farré
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 2000, Argentina; (L.E.A.); (F.M.); (N.C.L.); (M.M.); (L.C.Z.); (C.F.)
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 2000, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
| | - Vincent Sauzeau
- Institut du Thorax, Inserm, CNRS, Université de Nantes, 44000 Nantes, France;
| | - Mauricio Menacho Márquez
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 2000, Argentina; (L.E.A.); (F.M.); (N.C.L.); (M.M.); (L.C.Z.); (C.F.)
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 2000, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina;
- Centro de Investigación del Cáncer de Rosario (CIC-R), Red de Investigación del Cáncer de Rosario (RICaR), Rosario 2000, Argentina
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10
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Popov IK, Tao J, Chang C. The RhoGEF protein Plekhg5 self-associates via its PH domain to regulate apical cell constriction. Mol Biol Cell 2024; 35:ar134. [PMID: 39196644 PMCID: PMC11481697 DOI: 10.1091/mbc.e24-04-0179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 08/12/2024] [Accepted: 08/19/2024] [Indexed: 08/30/2024] Open
Abstract
RhoGEFs are critical activators of Rho family small GTPases and regulate diverse biological processes, such as cell division and tissue morphogenesis. We reported previously that the RhoGEF gene plekhg5 controls apical constriction of bottle cells at the blastopore lip during Xenopus gastrulation, but the detailed mechanism of plekhg5 action is not understood in depth. In this study, we show that localization of Plekhg5 in the apical cortex depends on its N-terminal sequences and intact guanine nucleotide exchange activity, whereas the C-terminal sequences prevent ectopic localization of the protein to the basolateral compartment. We also reveal that Plekhg5 self-associates via its PH domain, and this interaction leads to functional rescue of two mutants that lack the N-terminal region and the guanine nucleotide exchange factor activity, respectively, in trans. A point mutation in the PH domain corresponding to a variant associated with human disease leads to loss of self-association and failure of the mutant to induce apical constriction. Taken together, our results suggest that PH-mediated self-association and N-terminal domain-mediated subcellular localization are both crucial for the function of Plekhg5 in inducing apical constriction.
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Affiliation(s)
- Ivan K. Popov
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Jiahui Tao
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Chenbei Chang
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294
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11
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Katsura Y, Shigenobu S, Satta Y. Adaptive Evolution and Functional Differentiation of Testis-Expressed Genes in Theria. Animals (Basel) 2024; 14:2316. [PMID: 39199849 PMCID: PMC11350913 DOI: 10.3390/ani14162316] [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: 07/02/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 09/01/2024] Open
Abstract
Gene expression patterns differ in different tissues, and the expression pattern of genes in the mammalian testis is known to be extremely variable in different species. To clarify how the testis transcriptomic pattern has evolved in particular species, we examined the evolution of the adult testis transcriptome in Theria using 10 species: two marsupials (opossum and Tasmanian devil), six eutherian (placental) mammals (human, chimpanzee, bonobo, gorilla, rhesus macaque, and mouse), and two outgroup species (platypus and chicken). We show that 22 testis-expressed genes are marsupial-specific, suggesting their acquisition in the stem lineage of marsupials after the divergence from eutherians. Despite the time length of the eutherian stem lineage being similar to that of the marsupial lineage, acquisition of testis-expressed genes was not found in the stem lineage of eutherians; rather, their expression patterns differed by species, suggesting rapid gene evolution in the eutherian ancestors. Fifteen testis-expressed genes are therian-specific, and for three of these genes, the evolutionary tempo is markedly faster in eutherians than in marsupials. Our phylogenetic analysis of Rho GTPase-activating protein 28 (ARHGAP28) suggests the adaptive evolution of this gene in the eutherians, probably together with the expression pattern differentiation.
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Affiliation(s)
- Yukako Katsura
- Center for the Evolutionary Origins of Human Behavior, Kyoto University, Inuyama 484-8506, Japan
| | - Shuji Shigenobu
- NIBB Core Research Facilities, National Institute for Basic Biology, Okazaki 444-0867, Japan;
| | - Yoko Satta
- Research Center for Integrative Evolutionary Science, SOKENDAI (The Graduate University for Advanced Studies), Hayama 240-0193, Japan;
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12
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Hoisington ZW, Salvi A, Laguesse S, Ehinger Y, Shukla C, Phamluong K, Ron D. The Small G-Protein Rac1 in the Dorsomedial Striatum Promotes Alcohol-Dependent Structural Plasticity and Goal-Directed Learning in Mice. J Neurosci 2024; 44:e1644232024. [PMID: 38886056 PMCID: PMC11255432 DOI: 10.1523/jneurosci.1644-23.2024] [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: 08/28/2023] [Revised: 04/04/2024] [Accepted: 04/10/2024] [Indexed: 06/20/2024] Open
Abstract
The small G-protein Ras-related C3 botulinum toxin substrate 1 (Rac1) promotes the formation of filamentous actin (F-actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an adeno-associated virus (AAV) expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning.
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Affiliation(s)
- Zachary W Hoisington
- Alcohol and Addiction Research Group, Department of Neurology, University of California San Francisco, San Francisco, California 94107
| | - Alexandra Salvi
- Alcohol and Addiction Research Group, Department of Neurology, University of California San Francisco, San Francisco, California 94107
| | - Sophie Laguesse
- GIGA-Stem Cells and GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, Liège 4000, Belgium
| | - Yann Ehinger
- Alcohol and Addiction Research Group, Department of Neurology, University of California San Francisco, San Francisco, California 94107
| | - Chhavi Shukla
- Alcohol and Addiction Research Group, Department of Neurology, University of California San Francisco, San Francisco, California 94107
| | - Khanhky Phamluong
- Alcohol and Addiction Research Group, Department of Neurology, University of California San Francisco, San Francisco, California 94107
| | - Dorit Ron
- Alcohol and Addiction Research Group, Department of Neurology, University of California San Francisco, San Francisco, California 94107
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13
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Hoisington ZW, Salvi A, Laguesse S, Ehinger Y, Shukla C, Phamluong K, Ron D. The small G-protein Rac1 in the dorsomedial striatum promotes alcohol-dependent structural plasticity and goal-directed learning in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.08.30.555562. [PMID: 37693512 PMCID: PMC10491244 DOI: 10.1101/2023.08.30.555562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
The small G-protein Rac1 promotes the formation of filamentous actin (F-Actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice, or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an AAV expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning. Significance Statement Addiction, including alcohol use disorder, is characterized by molecular and cellular adaptations that promote maladaptive behaviors. We found that Rac1 was activated by alcohol in the dorsomedial striatum (DMS) of male mice. We show that alcohol-mediated Rac1 signaling is responsible for alterations in actin dynamics and neuronal morphology. We also present data to suggest that Rac1 is important for alcohol-associated learning processes. These results suggest that Rac1 in the DMS is an important contributor to adaptations that promote alcohol use disorder.
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14
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Hernández-Toledano DS, Vega L. Methylated dialkylphosphate metabolites of the organophosphate pesticide malathion modify actin cytoskeleton arrangement and cell migration via activation of Rho GTPases Rac1 and Cdc42. Chem Biol Interact 2023; 382:110593. [PMID: 37270087 DOI: 10.1016/j.cbi.2023.110593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/08/2023] [Accepted: 06/01/2023] [Indexed: 06/05/2023]
Abstract
The non-cholinergic molecular targets of organophosphate (OP) compounds have recently been investigated to explain their role in the generation of non-neurological diseases, such as immunotoxicity and cancer. Here, we evaluated the effects of malathion and its dialkylphosphate (DAP) metabolites on the cytoskeleton components and organization of RAW264.7 murine macrophages as non-cholinergic targets of OP and DAPs toxicity. All OP compounds affected actin and tubulin polymerization. Malathion, dimethyldithiophosphate (DMDTP) dimethylthiophosphate (DMTP), and dimethylphosphate (DMP) induced elongated morphologies and the formation of pseudopods rich in microtubule structures, and increased filopodia formation and general actin disorganization in RAW264.7 cells and slightly reduced stress fibers in the human fibroblasts GM03440, without significantly disrupting the tubulin or vimentin cytoskeleton. Exposure to DMTP and DMP increased cell migration in the wound healing assay but did not affect phagocytosis, indicating a very specific modification in the organization of the cytoskeleton. The induction of actin cytoskeleton rearrangement and cell migration suggested the activation of cytoskeletal regulators such as small GTPases. We found that DMP slightly reduced Ras homolog family member A activity but increased the activities of Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) from 5 min to 2 h of exposure. Chemical inhibition of Rac1 with NSC23766 reduced cell polarization and treatment with DMP enhanced cell migration, but Cdc42 inhibition by ML-141 completely inhibited the effects of DMP. These results suggest that methylated OP compounds, especially DMP, can modify macrophage cytoskeleton function and configuration via activation of Cdc42, which may represent a potential non-cholinergic molecular target for OP compounds.
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Affiliation(s)
- David Sebastián Hernández-Toledano
- Department of Toxicology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico. Av. Instituto Politécnico Nacional 2508, San Pedro Zacatenco, C.P. 07360, Gustavo A. Madero, Ciudad de México, Mexico
| | - Libia Vega
- Department of Toxicology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico. Av. Instituto Politécnico Nacional 2508, San Pedro Zacatenco, C.P. 07360, Gustavo A. Madero, Ciudad de México, Mexico.
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15
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Wang H, Yamahashi Y, Riedl M, Amano M, Kaibuchi K. The Evaluation of Rac1 Signaling as a Potential Therapeutic Target of Alzheimer's Disease. Int J Mol Sci 2023; 24:11880. [PMID: 37569255 PMCID: PMC10418761 DOI: 10.3390/ijms241511880] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 07/06/2023] [Accepted: 07/22/2023] [Indexed: 08/13/2023] Open
Abstract
The Small GTPase Rac1 is critical for various fundamental cellular processes, including cognitive functions. The cyclical activation and inactivation of Rac1, mediated by Rac guanine nucleotide exchange factors (RacGEFs) and Rac GTPase-activating proteins (RacGAPs), respectively, are essential for activating intracellular signaling pathways and controlling cellular processes. We have recently shown that the Alzheimer's disease (AD) therapeutic drug donepezil activates the Rac1-PAK pathway in the nucleus accumbens (NAc) for enhanced aversive learning. Also, PAK activation itself in the NAc enhances aversive learning. As aversive learning allows short-term preliminary AD drug screening, here we tested whether sustained Rac1 activation by RacGAP inhibition can be used as an AD therapeutic strategy for improving AD-learning deficits based on aversive learning. We found that the RacGAP domain of breakpoint cluster region protein (Bcr) (Bcr-GAP) efficiently inhibited Rac1 activity in a membrane ruffling assay. We also found that, in striatal/accumbal primary neurons, Bcr knockdown by microRNA mimic-expressing adeno-associated virus (AAV-miRNA mimic) activated Rac1-PAK signaling, while Bcr-GAP-expressing AAV inactivated it. Furthermore, conditional knockdown of Bcr in the NAc of wild-type adult mice enhanced aversive learning, while Bcr-GAP expression in the NAc inhibited it. The findings indicate that Rac1 activation by RacGAP inhibition enhances aversive learning, implying the AD therapeutic potential of Rac1 signaling.
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Affiliation(s)
- Huanhuan Wang
- Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan; (H.W.); (M.A.)
| | - Yukie Yamahashi
- Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake 470-1192, Japan; (Y.Y.); (M.R.)
| | - Marcel Riedl
- Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake 470-1192, Japan; (Y.Y.); (M.R.)
| | - Mutsuki Amano
- Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan; (H.W.); (M.A.)
| | - Kozo Kaibuchi
- Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake 470-1192, Japan; (Y.Y.); (M.R.)
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16
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Su WP, Li CJ, Lin LT, Lin PH, Wen ZH, Sheu JJC, Tsui KH. Boosting mitochondrial function and metabolism in aging female germ cells with dual ROCK/ROS inhibition. Biomed Pharmacother 2023; 163:114888. [PMID: 37196543 DOI: 10.1016/j.biopha.2023.114888] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/07/2023] [Accepted: 05/12/2023] [Indexed: 05/19/2023] Open
Abstract
The decline in oocyte quality with age is an irreversible process that results in low fertility. Reproductive aging causes an increase in oocyte aneuploidy leading to a decrease in embryo quality and an increase in the incidence of miscarriage and congenital defects. Here, we show that the dysfunction associated with aging is not limited to the oocyte, as oocyte granulosa cells also show a range of defects related to mitochondrial activity. The addition of Y-27632 and Vitamin C combination drugs to aging germ cells was effective in enhancing the quality of aging cells. We observed that supplement treatment significantly decreased the production of reactive oxygen species (ROS) and restored the balance of mitochondrial membrane potential. Supplementation treatment reduces excessive mitochondrial fragmentation in aging cells by upregulating mitochondrial fusion. Moreover, it regulated the energy metabolism within cells, favoring oxygen respiration and reducing anaerobic respiration, thereby increasing cellular ATP production. In an experiment with aged mice, supplement treatment improved the maturation of oocytes in vitro and prevented the buildup of ROS in aging oocytes in culture. Additionally, this treatment resulted in an increased concentration of anti-mullerian hormone (AMH) in the culture medium. By improving mitochondrial metabolism in aging females, supplement treatment has the potential to increase quality of oocytes during in vitro fertilization.
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Affiliation(s)
- Wan-Ping Su
- Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Chia-Jung Li
- Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Li-Te Lin
- Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan; Department of Obstetrics and Gynaecology, National Yang-Ming University School of Medicine, Taipei 112, Taiwan
| | - Pei-Hsuan Lin
- Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Jim Jinn-Chyuan Sheu
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
| | - Kuan-Hao Tsui
- Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan; Department of Obstetrics and Gynaecology, National Yang-Ming University School of Medicine, Taipei 112, Taiwan; Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan; Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung County 907, Taiwan; Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
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17
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Kounoupa Z, Tivodar S, Theodorakis K, Kyriakis D, Denaxa M, Karagogeos D. Rac1 and Rac3 GTPases and TPC2 are required for axonal outgrowth and migration of cortical interneurons. J Cell Sci 2023; 136:286920. [PMID: 36744839 DOI: 10.1242/jcs.260373] [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: 06/24/2022] [Accepted: 01/31/2023] [Indexed: 02/07/2023] Open
Abstract
Rho GTPases, among them Rac1 and Rac3, are major transducers of extracellular signals and are involved in multiple cellular processes. In cortical interneurons, the neurons that control the balance between excitation and inhibition of cortical circuits, Rac1 and Rac3 are essential for their development. Ablation of both leads to a severe reduction in the numbers of mature interneurons found in the murine cortex, which is partially due to abnormal cell cycle progression of interneuron precursors and defective formation of growth cones in young neurons. Here, we present new evidence that upon Rac1 and Rac3 ablation, centrosome, Golgi complex and lysosome positioning is significantly perturbed, thus affecting both interneuron migration and axon growth. Moreover, for the first time, we provide evidence of altered expression and localization of the two-pore channel 2 (TPC2) voltage-gated ion channel that mediates Ca2+ release. Pharmacological inhibition of TPC2 negatively affected axonal growth and migration of interneurons. Our data, taken together, suggest that TPC2 contributes to the severe phenotype in axon growth initiation, extension and interneuron migration in the absence of Rac1 and Rac3.
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Affiliation(s)
- Zouzana Kounoupa
- Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion 71110, Greece.,Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion 71110, Greece
| | - Simona Tivodar
- Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion 71110, Greece.,Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion 71110, Greece
| | - Kostas Theodorakis
- Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion 71110, Greece.,Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion 71110, Greece
| | - Dimitrios Kyriakis
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4365 Esch-sur-Alzette, Luxembourg
| | - Myrto Denaxa
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Centre 'Al. Fleming', Vari, 16672, Greece
| | - Domna Karagogeos
- Institute of Molecular Biology and Biotechnology (IMBB, FORTH), Heraklion 71110, Greece.,Department of Basic Science, Faculty of Medicine, University of Crete, Heraklion 71110, Greece
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18
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Morishita J, Nurse P. Identification of a small RhoA GTPase inhibitor effective in fission yeast and human cells. Open Biol 2023; 13:220185. [PMID: 36854376 PMCID: PMC9974304 DOI: 10.1098/rsob.220185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
The Rho GTPase family proteins are key regulators of cytoskeletal dynamics. Deregulated activity of Rho GTPases is associated with cancers and neurodegenerative diseases, and their potential as drug targets has long been recognized. Using an economically effective drug screening workflow in fission yeast and human cells, we have identified a Rho GTPase inhibitor, O1. By a suppressor mutant screen in fission yeast, we find a point mutation in the rho1 gene that confers resistance to O1. Consistent with the idea that O1 is the direct inhibitor of Rho1, O1 reduced the cellular amount of activated, GTP-bound Rho1 in wild-type cells, but not in the O1-resistant mutant cells, in which the evolutionarily conserved Ala62 residue is mutated to Thr. Similarly, O1 inhibits activity of the human orthologue RhoA GTPase in tissue culture cells. Our studies illustrate the power of yeast phenotypic screens in the identification and characterization of drugs relevant to human cells and have identified a novel GTPase inhibitor for fission yeast and human cells.
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Affiliation(s)
- Jun Morishita
- Laboratory of Yeast Genetics and Cell Biology, Rockefeller University, New York, NY 10065, USA
| | - Paul Nurse
- Laboratory of Yeast Genetics and Cell Biology, Rockefeller University, New York, NY 10065, USA
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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19
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Lin J, de Rezende VL, de Aguiar da Costa M, de Oliveira J, Gonçalves CL. Cholesterol metabolism pathway in autism spectrum disorder: From animal models to clinical observations. Pharmacol Biochem Behav 2023; 223:173522. [PMID: 36717034 DOI: 10.1016/j.pbb.2023.173522] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/18/2022] [Accepted: 01/24/2023] [Indexed: 01/29/2023]
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a persistent impairment of social skills, including aspects of perception, interpretation, and response, combined with restricted and repetitive behavior. ASD is a complex and multifactorial condition, and its etiology could be attributed to genetic and environmental factors. Despite numerous clinical and experimental studies, no etiological factor, biomarker, and specific model of transmission have been consistently associated with ASD. However, an imbalance in cholesterol levels has been observed in many patients, more specifically, a condition of hypocholesterolemia, which seems to be shared between ASD and ASD-related genetic syndromes such as fragile X syndrome (FXS), Rett syndrome (RS), and Smith- Lemli-Opitz (SLO). Furthermore, it is known that alterations in cholesterol levels lead to neuroinflammation, oxidative stress, impaired myelination and synaptogenesis. Thus, the aim of this review is to discuss the cholesterol metabolic pathways in the ASD context, as well as in genetic syndromes related to ASD, through clinical observations and animal models. In fact, SLO, FXS, and RS patients display early behavioral markers of ASD followed by cholesterol disturbances. Several studies have demonstrated the role of cholesterol in psychiatric conditions and how its levels modulate brain neurodevelopment. This review suggests an important relationship between ASD pathology and cholesterol metabolism impairment; thus, some strategies could be raised - at clinical and pre-clinical levels - to explore whether cholesterol metabolism disturbance has a generally adverse effect in exacerbating the symptoms of ASD patients.
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Affiliation(s)
- Jaime Lin
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Victória Linden de Rezende
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Maiara de Aguiar da Costa
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Jade de Oliveira
- Laboratory for Research in Metabolic Disorders and Neurodegenerative Diseases, Graduate Program in Health Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Cinara Ludvig Gonçalves
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil.
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Dandamudi A, Akbar H, Cancelas J, Zheng Y. Rho GTPase Signaling in Platelet Regulation and Implication for Antiplatelet Therapies. Int J Mol Sci 2023; 24:ijms24032519. [PMID: 36768837 PMCID: PMC9917354 DOI: 10.3390/ijms24032519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/16/2023] [Accepted: 01/21/2023] [Indexed: 01/31/2023] Open
Abstract
Platelets play a vital role in regulating hemostasis and thrombosis. Rho GTPases are well known as molecular switches that control various cellular functions via a balanced GTP-binding/GTP-hydrolysis cycle and signaling cascade through downstream effectors. In platelets, Rho GTPases function as critical regulators by mediating signal transduction that drives platelet activation and aggregation. Mostly by gene targeting and pharmacological inhibition approaches, Rho GTPase family members RhoA, Rac1, and Cdc42 have been shown to be indispensable in regulating the actin cytoskeleton dynamics in platelets, affecting platelet shape change, spreading, secretion, and aggregation, leading to thrombus formation. Additionally, studies of Rho GTPase function using platelets as a non-transformed model due to their anucleated nature have revealed valuable information on cell signaling principles. This review provides an updated summary of recent advances in Rho GTPase signaling in platelet regulation. We also highlight pharmacological approaches that effectively inhibited platelet activation to explore their possible development into future antiplatelet therapies.
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Affiliation(s)
- Akhila Dandamudi
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
- Department of Pathology, University of Cincinnati Graduate School, Cincinnati, OH 45267, USA
| | - Huzoor Akbar
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Jose Cancelas
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
- Hoxworth Blood Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA
| | - Yi Zheng
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
- Department of Pathology, University of Cincinnati Graduate School, Cincinnati, OH 45267, USA
- Correspondence: ; Tel.: +1-513-636-0595
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21
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Tian X, Nanding K, Dai X, Wang Q, Wang J, Morigen, Fan L. Pattern recognition receptor mediated innate immune response requires a Rif-dependent pathway. J Autoimmun 2023; 134:102975. [PMID: 36527784 DOI: 10.1016/j.jaut.2022.102975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 12/02/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022]
Abstract
Small GTPases play critical roles in cell morphology, movement, and adhesion by dynamic regulation of actin cytoskeleton. The small Rho GTPase Rif/RhoF (Rho in filopodia) regulates the formation of filopodia and stress fibers in cells. Rif is highly expressed in a number of cell types in the immune system; however, it's role in immune system function is unclear. In this research, we found that Rif expression is necessary for NF-κB activation in primary immune cells, and mature dendritic cell (mature DCs) induced from Bone Marrow-Derived Dendritic Cells (BMDCs) isolated from Rif knock out (Rif KO) mice displayed impaired degradation of I-κBα, as well as reduced TNF-α secretion and p38 MAPK phosphorylation under LPS stimulation. Interestingly, we revealed that TLR agonists, such as LPS and poly (I:C), as well as bacterial virulence factor SopE could induce a transient increase in Rif activation in monocytes THP-1 cells. Furthermore, Rif was found to be an integral part of the TLR4, TLR3 and nodosome signaling complex. We further identified Src tyrosine kinases as upstream activator of Rif in both bacterial and viral induced immune responses. Moreover, activated Rif induces activation of transcription factors, such as NF-κB, AP-1 and IRF-3, and mediates inflammation through secretion of IL-6, IL-8 or TNFα. Rif activation by PRRs contributes in a variety of ways to protective host responses against invading microbes. Taken together, this study reveals that Rif is indispensable for both extracellular and intracellular pattern-recognition receptor-mediated innate immune responses. Rif possess broad anti-pathogenic effect and understanding of the molecular mechanisms by which this small Rho GTPase interferes with innate immune system will be beneficial to develop therapies against infectious agents.
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Affiliation(s)
- Xiaoxia Tian
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China; The Laboratory for Tumor Molecular Diagnosis, Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Kathleen Nanding
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Xueyao Dai
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Qian Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Junyu Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Morigen
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China.
| | - Lifei Fan
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China.
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22
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Phuphisut O, Poodeepiyasawat A, Yoonuan T, Watthanakulpanich D, Chotsiri P, Reamtong O, Mousley A, Gobert GN, Adisakwattana P. Transcriptome profiling of male and female Ascaris lumbricoides reproductive tissues. Parasit Vectors 2022; 15:477. [PMID: 36539906 PMCID: PMC9768952 DOI: 10.1186/s13071-022-05602-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Ascaris lumbricoides causes human ascariasis, the most prevalent helminth disease, infecting approximately 1 billion individuals globally. In 2019 the global disease burden was estimated to be 754,000 DALYs and resulted in 2090 deaths. In the absence of a vaccination strategy, treatment of ascariasis has relied on anthelminthic chemotherapy, but drug resistance is a concern. The propensity for reinfection is also a major challenge to disease control; female worms lay up to 200,000 eggs daily, which contaminate surrounding environments and remain viable for years, resulting in high transmission rates. Understanding the molecular mechanisms of reproductive processes, including control of egg production, spermatogenesis, oogenesis and embryogenesis, will drive the development of new drugs and/or vaccine targets for future ascariasis control. METHODS Transcriptome profiles of discrete reproductive and somatic tissue samples were generated from adult male and female worms using Illumina HiSeq with 2 × 150 bp paired-end sequencing. Male tissues included: testis germinal zone, testis part of vas deferens, seminal vesicle and somatic tissue. Female tissues included: ovary germinal zone, ovary part of the oviduct, uterus and somatic tissue. Differentially expressed genes (DEGs) were identified from the fragments per kilobases per million reads (FPKM) profiles. Hierarchical analysis was performed to identify tissue-specific genes. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to identify significant terms and pathways for the DEGs. RESULTS DEGs involved in protein phosphorylation and adhesion molecules were indicated to play a crucial role in spermatogenesis and fertilization, respectively. Those genes associated with the G-protein-coupled receptor (GPCR) signaling pathway and small GTPase-mediated signal transduction pathway play an essential role in cytoskeleton organization during oogenesis. Additionally, DEGs associated with the SMA genes and TGF-β signaling pathway are crucial in adult female embryogenesis. Some genes associated with particular biological processes and pathways that were identified in this study have been linked to defects in germline development, embryogenesis and reproductive behavior. In the enriched KEGG pathway analysis, Hippo signaling, oxytocin signaling and tight junction pathways were identified to play a role in Ascaris male and female reproductive systems. CONCLUSIONS This study has provided comprehensive transcriptome profiles of discrete A. lumbricoides reproductive tissue samples, revealing the molecular basis of these functionally important tissues. The data generated from this study will provide fundamental knowledge on the reproductive biology of Ascaris and will inform future target identification for anti-ascariasis drugs and/or vaccines.
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Affiliation(s)
- Orawan Phuphisut
- Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
| | - Akkarin Poodeepiyasawat
- Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
| | - Tippayarat Yoonuan
- Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
| | - Dorn Watthanakulpanich
- Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
| | - Palang Chotsiri
- Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, 10400, Thailand
| | - Onrapak Reamtong
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
| | - Angela Mousley
- School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK
| | - Geoffrey N Gobert
- School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK
| | - Poom Adisakwattana
- Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand.
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Lee PH, Choi SM, An MH, Hwang DY, Park S, Baek AR, Jang AS. Nectin4 is a potential therapeutic target for asthma. Front Immunol 2022; 13:1049900. [PMID: 36457999 PMCID: PMC9707334 DOI: 10.3389/fimmu.2022.1049900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/26/2022] [Indexed: 10/31/2023] Open
Abstract
BACKGROUND Nectins comprise a family of cellular adhesion molecules involved in Ca2+-independent cellular adhesion. Neither the biological significance nor clinical potential of Nectin4 for asthma has been investigated. OBJECTIVES The aims of this study were to elucidate the role of Nectin4 in airway inflammation and to determine the relationship between Nectin4 and clinical variables in patients with asthma. METHODS The relationship between Nectin4 levels in the blood of asthmatic patients and clinical variables was examined. Dermatophagoides pteronyssinus 1 (Der p1)-exposed normal human bronchial epithelial (NHBE) cells, and Nectin4-deficient (Nectin4-/-) and wild-type (WT) mice sensitized/challenged with ovalbumin (OVA), were used to investigate the involvement of Nectin4 in the pathogenesis of bronchial asthma via the Src/Rac1 pathway. RESULTS Plasma Nectin4 levels were significantly higher in asthmatic patients than controls and correlated with specific IgE D1, D2, lung function. The ROC curves for Nectin4 levels differed between asthma patients and controls. Nectin4/Afadin and Src/Rac1 levels were significantly increased in NHBE cells exposed to Der p1, but decreased in NHBE cells treated with Nectin4 siRNA. Airway obstruction and inflammation, as well as the levels of Th2 cytokines, Nectin4, and Src/Rac1, were increased in WT OVA/OVA mice compared with WT sham mice. Nectin4 knockdown resulted in lower levels of Afadin and Src/Rac1 in Nectin4-/-OVA/OVA than WT OVA/OVA mice. CONCLUSION These results suggest that Nectin4 is involved in airway inflammation and may be a therapeutic target in patients with asthma.
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Affiliation(s)
- Pureun-Haneul Lee
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School of Soonchunhyang University, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea
| | - Seon Muk Choi
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School of Soonchunhyang University, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea
| | - Min Hyeok An
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School of Soonchunhyang University, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea
| | - Da Yeon Hwang
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School of Soonchunhyang University, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea
| | - Shinhee Park
- Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, South Korea
| | - Ae Rin Baek
- Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, South Korea
| | - An-Soo Jang
- Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, South Korea
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24
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Liu X, Lu Y, Huang J, Xing Y, Dai H, Zhu L, Li S, Feng J, Zhou B, Li J, Xia Q, Li J, Huang M, Gu Y, Su S. CD16 + fibroblasts foster a trastuzumab-refractory microenvironment that is reversed by VAV2 inhibition. Cancer Cell 2022; 40:1341-1357.e13. [PMID: 36379207 DOI: 10.1016/j.ccell.2022.10.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 05/16/2022] [Accepted: 10/17/2022] [Indexed: 11/16/2022]
Abstract
The leukocyte Fcγ receptor (FcγR)-mediated response is important for the efficacy of therapeutic antibodies; however, little is known about the role of FcγRs in other cell types. Here we identify a subset of fibroblasts in human breast cancer that express CD16 (FcγRIII). An abundance of these cells in HER2+ breast cancer patients is associated with poor prognosis and response to trastuzumab. Functionally, upon trastuzumab stimulation, CD16+ fibroblasts reduce drug delivery by enhancing extracellular matrix stiffness. Interaction between trastuzumab and CD16 activates the intracellular SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A pathway, leading to elevated contractile force and matrix production. Targeting of a Rho family guanine nucleotide exchange factor, VAV2, which is indispensable for the function of CD16 in fibroblasts rather than leukocytes, reverses desmoplasia provoked by CD16+ fibroblasts. Collectively, our study reveals a role for the fibroblast FcγR in drug resistance, and suggests that VAV2 is an attractive target to augment the effects of antibody treatments.
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Affiliation(s)
- Xinwei Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Breast Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Yiwen Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jingying Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yue Xing
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Huiqi Dai
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Liling Zhu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Shunrong Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jingwei Feng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Boxuan Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jiaqian Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Qidong Xia
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jiang Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Min Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yuanting Gu
- Department of Breast Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Shicheng Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China; Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Biotherapy Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
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25
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González B, Cullen PJ. Regulation of Cdc42 protein turnover modulates the filamentous growth MAPK pathway. J Cell Biol 2022; 221:213675. [PMID: 36350310 PMCID: PMC9811999 DOI: 10.1083/jcb.202112100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 05/25/2022] [Accepted: 09/19/2022] [Indexed: 11/11/2022] Open
Abstract
Rho GTPases are central regulators of cell polarity and signaling. How Rho GTPases are directed to function in certain settings remains unclear. Here, we show the protein levels of the yeast Rho GTPase Cdc42p are regulated, which impacts a subset of its biological functions. Specifically, the active conformation of Cdc42p was ubiquitinated by the NEDD4 ubiquitin ligase Rsp5p and HSP40/HSP70 chaperones and turned over in the proteasome. A GTP-locked (Q61L) turnover-defective (TD) version, Cdc42pQ61L+TD, hyperactivated the MAPK pathway that regulates filamentous growth (fMAPK). Cdc42pQ61L+TD did not influence the activity of the mating pathway, which shares components with the fMAPK pathway. The fMAPK pathway adaptor, Bem4p, stabilized Cdc42p levels, which resulted in elevated fMAPK pathway signaling. Our results identify Cdc42p turnover regulation as being critical for the regulation of a MAPK pathway. The control of Rho GTPase levels by stabilization and turnover may be a general feature of signaling pathway regulation, which can result in the execution of a specific developmental program.
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Affiliation(s)
- Beatriz González
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY
| | - Paul J. Cullen
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY,Correspondence to Paul J. Cullen:
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Wang T, Rao D, Yu C, Sheng J, Luo Y, Xia L, Huang W. RHO GTPase family in hepatocellular carcinoma. Exp Hematol Oncol 2022; 11:91. [DOI: 10.1186/s40164-022-00344-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractRHO GTPases are a subfamily of the RAS superfamily of proteins, which are highly conserved in eukaryotic species and have important biological functions, including actin cytoskeleton reorganization, cell proliferation, cell polarity, and vesicular transport. Recent studies indicate that RHO GTPases participate in the proliferation, migration, invasion and metastasis of cancer, playing an essential role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). This review first introduces the classification, structure, regulators and functions of RHO GTPases, then dissects its role in HCC, especially in migration and metastasis. Finally, we summarize inhibitors targeting RHO GTPases and highlight the issues that should be addressed to improve the potency of these inhibitors.
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27
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Roberts E, Xu T, Assoian RK. Cell contractility and focal adhesion kinase control circumferential arterial stiffness. VASCULAR BIOLOGY (BRISTOL, ENGLAND) 2022; 4:28-39. [PMID: 36222505 PMCID: PMC9782408 DOI: 10.1530/vb-22-0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/12/2022] [Indexed: 11/07/2022]
Abstract
Arterial stiffening is a hallmark of aging and cardiovascular disease. While it is well established that vascular smooth muscle cells (SMCs) contribute to arterial stiffness by synthesizing and remodeling the arterial extracellular matrix, the direct contributions of SMC contractility and mechanosensors to arterial stiffness, and particularly the arterial response to pressure, remain less well understood despite being a long-standing question of biomedical importance. Here, we have examined this issue by combining the use of pressure myography of intact carotid arteries, pharmacologic inhibition of contractility, and genetic deletion of SMC focal adhesion kinase (FAK). Biaxial inflation-extension tests performed at physiological pressures showed that acute inhibition of cell contractility with blebbistatin or EGTA altered vessel geometry and preferentially reduced circumferential, as opposed to axial, arterial stiffness in wild-type mice. Similarly, genetic deletion of SMC FAK, which attenuated arterial contraction to KCl, reduced vessel wall thickness and circumferential arterial stiffness in response to pressure while having minimal effect on axial mechanics. Moreover, these effects of FAK deletion were lost by treating arteries with blebbistatin or by inhibiting myosin light-chain kinase. The expression of arterial fibrillar collagens, the integrity of arterial elastin, or markers of SMC differentiation were not affected by the deletion of SMC FAK. Our results connect cell contractility and SMC FAK to the regulation of arterial wall thickness and directionally specific arterial stiffening.
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Affiliation(s)
- Emilia Roberts
- Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tina Xu
- Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Richard K Assoian
- Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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28
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Li Q, Chen X, Lin L, Zhang L, Wang L, Bao J, Zhang D. Transcriptomic Dynamics of Active and Inactive States of Rho GTPase MoRho3 in Magnaporthe oryzae. J Fungi (Basel) 2022; 8:jof8101060. [PMID: 36294629 PMCID: PMC9605073 DOI: 10.3390/jof8101060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 11/17/2022] Open
Abstract
The small Rho GTPase acts as a molecular switch in eukaryotic signal transduction, which plays a critical role in polar cell growth and vesicle trafficking. Previous studies demonstrated that constitutively active (CA) mutant strains, of MoRho3-CA were defective in appressorium formation. While dominant-negative (DN) mutant strains MoRho3-DN shows defects in polar growth. However, the molecular dynamics of MoRho3-mediated regulatory networks in the pathogenesis of Magnaporthe oryzae still needs to be uncovered. Here, we perform comparative transcriptomic profiling of MoRho3-CA and MoRho3-DN mutant strains using a high-throughput RNA sequencing approach. We find that genetic manipulation of MoRho3 significantly disrupts the expression of 28 homologs of Saccharomyces cerevisiae Rho3-interacting proteins, including EXO70, BNI1, and BNI2 in the MoRho3 CA, DN mutant strains. Functional enrichment analyses of up-regulated DEGs reveal a significant enrichment of genes associated with ribosome biogenesis in the MoRho3-CA mutant strain. Down-regulated DEGs in the MoRho3-CA mutant strains shows significant enrichment in starch/sucrose metabolism and the ABC transporter pathway. Moreover, analyses of down-regulated DEGs in the in MoRho3-DN reveals an over-representation of genes enriched in metabolic pathways. In addition, we observe a significant suppression in the expression levels of secreted proteins suppressed in both MoRho3-CA and DN mutant strains. Together, our results uncover expression dynamics mediated by two states of the small GTPase MoRho3, demonstrating its crucial roles in regulating the expression of ribosome biogenesis and secreted proteins.
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Affiliation(s)
- Qian Li
- Meishan Vocational Technical College, Ministerial and Provincial Joint Innovation Centre for Safety Production of Cross-Strait Crops, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- Correspondence: (Q.L.); (D.Z.)
| | - Xi Chen
- State Key Laboratory for Ecological Pest Control of Fujian and Taiwan Crops, College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Lianyu Lin
- State Key Laboratory for Ecological Pest Control of Fujian and Taiwan Crops, College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Lianhu Zhang
- State Key Laboratory for Ecological Pest Control of Fujian and Taiwan Crops, College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- College of Agronomy, Jiangxi Agricultural University, Nanchang 330045, China
| | - Li Wang
- Meishan Vocational Technical College, Ministerial and Provincial Joint Innovation Centre for Safety Production of Cross-Strait Crops, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Jiandong Bao
- State Key Laboratory for Ecological Pest Control of Fujian and Taiwan Crops, College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Dongmei Zhang
- State Key Laboratory for Ecological Pest Control of Fujian and Taiwan Crops, College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- Correspondence: (Q.L.); (D.Z.)
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Zhou X, Franklin RA, Adler M, Carter TS, Condiff E, Adams TS, Pope SD, Philip NH, Meizlish ML, Kaminski N, Medzhitov R. Microenvironmental sensing by fibroblasts controls macrophage population size. Proc Natl Acad Sci U S A 2022; 119:e2205360119. [PMID: 35930670 PMCID: PMC9371703 DOI: 10.1073/pnas.2205360119] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Animal tissues comprise diverse cell types. However, the mechanisms controlling the number of each cell type within tissue compartments remain poorly understood. Here, we report that different cell types utilize distinct strategies to control population numbers. Proliferation of fibroblasts, stromal cells important for tissue integrity, is limited by space availability. In contrast, proliferation of macrophages, innate immune cells involved in defense, repair, and homeostasis, is constrained by growth factor availability. Examination of density-dependent gene expression in fibroblasts revealed that Hippo and TGF-β target genes are both regulated by cell density. We found YAP1, the transcriptional coactivator of the Hippo signaling pathway, directly regulates expression of Csf1, the lineage-specific growth factor for macrophages, through an enhancer of Csf1 that is specifically active in fibroblasts. Activation of YAP1 in fibroblasts elevates Csf1 expression and is sufficient to increase the number of macrophages at steady state. Our data also suggest that expression programs in fibroblasts that change with density may result from sensing of mechanical force through actin-dependent mechanisms. Altogether, we demonstrate that two different modes of population control are connected and coordinated to regulate cell numbers of distinct cell types. Sensing of the tissue environment may serve as a general strategy to control tissue composition.
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Affiliation(s)
- Xu Zhou
- aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
| | - Ruth A. Franklin
- aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
| | - Miri Adler
- bBroad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Trevor S. Carter
- cDepartment of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Emily Condiff
- aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
| | - Taylor S. Adams
- dPulmonary Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06510
| | - Scott D. Pope
- aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
- eHHMI, Yale University School of Medicine, New Haven, CT 06510
| | - Naomi H. Philip
- aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
| | - Matthew L. Meizlish
- aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
| | - Naftali Kaminski
- dPulmonary Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06510
| | - Ruslan Medzhitov
- aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
- eHHMI, Yale University School of Medicine, New Haven, CT 06510
- 5To whom correspondence may be addressed.
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30
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Ahangar P, Strudwick XL, Cowin AJ. Wound Healing from an Actin Cytoskeletal Perspective. Cold Spring Harb Perspect Biol 2022; 14:a041235. [PMID: 35074864 PMCID: PMC9341468 DOI: 10.1101/cshperspect.a041235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Wound healing requires a complex cascade of highly controlled and conserved cellular and molecular processes. These involve numerous cell types and extracellular matrix molecules regulated by the actin cytoskeleton. This microscopic network of filaments is present within the cytoplasm of all cells and provides the shape and mechanical support required for cell movement and proliferation. Here, an overview of the processes of wound healing are described from the perspective of the cell in relation to the actin cytoskeleton. Key points of discussion include the role of actin, its binding proteins, signaling pathways, and events that play significant roles in the phases of wound healing. The identification of cytoskeletal targets that can be used to manipulate and improve wound healing is included as an emerging area of focus that may inform future therapeutic approaches to improve healing of complex wounds.
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Affiliation(s)
- Parinaz Ahangar
- Future Industries Institute, UniSA STEM, University of South Australia, South Australia, Adelaide 5000, Australia
| | - Xanthe L Strudwick
- Future Industries Institute, UniSA STEM, University of South Australia, South Australia, Adelaide 5000, Australia
| | - Allison J Cowin
- Future Industries Institute, UniSA STEM, University of South Australia, South Australia, Adelaide 5000, Australia
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31
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Zhao SK, Yeung EH, Ouidir M, Hinkle SN, Grantz KL, Mitro SD, Wu J, Stevens DR, Chatterjee S, Tekola-Ayele F, Zhang C. Recreational physical activity before and during pregnancy and placental DNA methylation-an epigenome-wide association study. Am J Clin Nutr 2022; 116:1168-1183. [PMID: 35771992 PMCID: PMC9535520 DOI: 10.1093/ajcn/nqac111] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 04/22/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Physical activity (PA) prior to and during pregnancy may have intergenerational effects on offspring health through placental epigenetic modifications. We are unaware of epidemiologic studies on longitudinal PA and placental DNA methylation. OBJECTIVES We evaluated the association between PA before and during pregnancy and placental DNA methylation. METHODS Placental tissues were obtained at delivery and methylation was measured using HumanMethylation450 Beadchips for participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons among 298 participants. Using the Pregnancy Physical Activity Questionnaire, women recalled periconception PA (past 12 mo) at 8-13 wk of gestation and PA since last visit at 4 follow-up visits at 16-22, 24-29, 30-33, and 34-37 wk. We conducted linear regression for associations of PA at each visit with methylation controlling for false discovery rate (FDR). Top 100 CpGs were queried for enrichment of functional pathways using Ingenuity Pathway Analysis. RESULTS Periconception PA was significantly associated with 1 CpG site. PA since last visit for visits 1-4 was associated with 2, 2, 8, and 0 CpGs (log fold changes ranging from -0.0319 to 0.0080, after controlling for FDR). The largest change in methylation occurred at a site in TIMP2 , which is known to encode a protein critical for vasodilation, placentation, and uterine expansion during pregnancy (log fold change: -0.05; 95% CI: -0.06, -0.03 per metabolic equivalent of task-h/wk at 30-33 wk). Most significantly enriched pathways include cardiac hypertrophy signaling, B-cell receptor signaling, and netrin signaling. Significant CpGs and enriched pathways varied by visit. CONCLUSIONS Recreational PA in the year prior and during pregnancy was associated with placental DNA methylation. The associated CpG sites varied based on timing of PA. If replicated, the findings may inform the mechanisms underlying the impacts of PA on placenta health. This study was registered at clinicaltrials.gov as NCT00912132.
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Affiliation(s)
- Sifang Kathy Zhao
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | | | - Marion Ouidir
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Stefanie N Hinkle
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA,Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Katherine L Grantz
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Susanna D Mitro
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Jing Wu
- Glotech, Inc, Rockville, MD, USA
| | - Danielle R Stevens
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Suvo Chatterjee
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Fasil Tekola-Ayele
- Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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Nsaibia MJ, Devendran A, Goubaa E, Bouitbir J, Capoulade R, Bouchareb R. Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail? J Clin Med 2022; 11:jcm11123331. [PMID: 35743402 PMCID: PMC9225514 DOI: 10.3390/jcm11123331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 12/12/2022] Open
Abstract
Calcific Aortic Valve Disease (CAVD) is a fibrocalcific disease. Lipoproteins and oxidized phospholipids play a substantial role in CAVD; the level of Lp(a) has been shown to accelerate the progression of valve calcification. Indeed, oxidized phospholipids carried by Lp(a) into the aortic valve stimulate endothelial dysfunction and promote inflammation. Inflammation and growth factors actively promote the synthesis of the extracellular matrix (ECM) and trigger an osteogenic program. The accumulation of ECM proteins promotes lipid adhesion to valve tissue, which could initiate the osteogenic program in interstitial valve cells. Statin treatment has been shown to have the ability to diminish the death rate in subjects with atherosclerotic impediments by decreasing the serum LDL cholesterol levels. However, the use of HMG-CoA inhibitors (statins) as cholesterol-lowering therapy did not significantly reduce the progression or the severity of aortic valve calcification. However, new clinical trials targeting Lp(a) or PCSK9 are showing promising results in reducing the severity of aortic stenosis. In this review, we discuss the implication of lipids in aortic valve calcification and the current findings on the effect of lipid-lowering therapy in aortic stenosis.
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Affiliation(s)
- Mohamed J. Nsaibia
- Department of Cell Biology and Molecular Medicine, Rutgers University, Newark, NJ 07103, USA;
| | - Anichavezhi Devendran
- Department of Medicine, Cardiovascular Research Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Eshak Goubaa
- Thomas Jefferson University East Falls, Philadelphia, PA 19144, USA;
| | - Jamal Bouitbir
- Department of Pharmaceutical Sciences, Division of Molecular and Systems Toxicology, University of Basel, 4056 Basel, Switzerland;
| | - Romain Capoulade
- L’institut Du Thorax, Nantes Université, CNRS, INSERM, F-44000 Nantes, France;
| | - Rihab Bouchareb
- Department of Medicine, Division of Nephrology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Correspondence: or ; Tel.: +1-(212)-241-8471
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Zhao Y, Lykov N, Tzeng C. Talin‑1 interaction network in cellular mechanotransduction (Review). Int J Mol Med 2022; 49:60. [PMID: 35266014 PMCID: PMC8930095 DOI: 10.3892/ijmm.2022.5116] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/23/2022] [Indexed: 11/16/2022] Open
Abstract
The mechanical signals within the extracellular matrix (ECM) regulate cell growth, proliferation and differentiation, and integrins function as the hub between the ECM and cellular actin. Focal adhesions (FAs) are multi‑protein, integrin‑containing complexes, acting as tension‑sensing anchoring points that bond cells to the extracellular microenvironment. Talin‑1 serves as the central protein of FAs that participates in the activation of integrins and connects them with the actin cytoskeleton. As a cytoplasmic protein, Talin‑1 consists of a globular head domain and a long rod comprised of a series of α‑helical bundles. The unique structure of the Talin‑1 rod domain permits folding and unfolding in response to the mechanical stress, revealing various binding sites. Thus, conformation changes of the Talin‑1 rod domain enable the cell to convert mechanical signals into chemical through multiple signaling pathways. The present review discusses the binding partners of Talin‑1, their interactions, effects on the cellular processes, and their possible roles in diseases.
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Affiliation(s)
- Ye Zhao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, Jiangsu 211800, P.R. China
| | - Nikita Lykov
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, Jiangsu 211800, P.R. China
| | - Chimeng Tzeng
- Translational Medicine Research Center-Key Laboratory for Cancer T-Cell Theragnostic and Clinical Translation, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, P.R. China
- Xiamen Chang Gung Hospital Medical Research Center, Xiamen, Fujian 361005, P.R. China
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Merenich D, Nakos K, Pompan T, Donovan SJ, Gill A, Patel P, Spiliotis ET, Myers KA. Septins guide noncentrosomal microtubules to promote focal adhesion disassembly in migrating cells. Mol Biol Cell 2022; 33:ar40. [PMID: 35274967 PMCID: PMC9282018 DOI: 10.1091/mbc.e21-06-0334] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 02/07/2022] [Accepted: 03/04/2022] [Indexed: 11/30/2022] Open
Abstract
Endothelial cell migration is critical for vascular angiogenesis and is compromised to facilitate tumor metastasis. The migratory process requires the coordinated assembly and disassembly of focal adhesions (FA), actin, and microtubules (MT). MT dynamics at FAs deliver vesicular cargoes and enhance actomyosin contractility to promote FA turnover and facilitate cell advance. Noncentrosomal (NC) MTs regulate FA dynamics and are sufficient to drive cell polarity, but how NC MTs target FAs to control FA turnover is not understood. Here, we show that Rac1 induces the assembly of FA-proximal septin filaments that promote NC MT growth into FAs and inhibit mitotic centromere-associated kinesin (MCAK)-associated MT disassembly, thereby maintaining intact MT plus ends proximal to FAs. Septin-associated MT rescue is coupled with accumulation of Aurora-A kinase and cytoplasmic linker-associated protein (CLASP) localization to the MT between septin and FAs. In this way, NC MTs are strategically positioned to undergo MCAK- and CLASP-regulated bouts of assembly and disassembly into FAs, thereby regulating FA turnover and cell migration.
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Affiliation(s)
- Daniel Merenich
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104
| | | | - Taylor Pompan
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104
| | - Samantha J. Donovan
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104
| | - Amrik Gill
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104
| | - Pranav Patel
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104
| | | | - Kenneth A. Myers
- Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104
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Apte A, Manich M, Labruyère E, Datta S. PI Kinase-EhGEF2-EhRho5 axis contributes to LPA stimulated macropinocytosis in Entamoeba histolytica. PLoS Pathog 2022; 18:e1010550. [PMID: 35594320 PMCID: PMC9173640 DOI: 10.1371/journal.ppat.1010550] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/07/2022] [Accepted: 04/26/2022] [Indexed: 12/04/2022] Open
Abstract
Entamoeba histolytica is a protozoan responsible for several pathologies in humans. Trophozoites breach the intestinal site to enter the bloodstream and thus traverse to a secondary site. Macropinocytosis and phagocytosis, collectively accounting for heterophagy, are the two major processes responsible for sustenance of Entamoeba histolytica within the host. Both of these processes require significant rearrangements in the structure to entrap the target. Rho GTPases play an indispensable role in mustering proteins that regulate cytoskeletal remodelling. Unlike phagocytosis which has been studied in extensive detail, information on machinery of macropinocytosis in E. histolytica is still limited. In the current study, using site directed mutagenesis and RNAi based silencing, coupled with functional studies, we have demonstrated the involvement of EhRho5 in constitutive and LPA stimulated macropinocytosis. We also report that LPA, a bioactive phospholipid present in the bloodstream of the host, activates EhRho5 and translocates it from cytosol to plasma membrane and endomembrane compartments. Using biochemical and FRAP studies, we established that a PI Kinase acts upstream of EhRho5 in LPA mediated signalling. We further identified EhGEF2 as a guanine nucleotide exchange factor of EhRho5. In the amoebic trophozoites, EhGEF2 depletion leads to reduced macropinocytic efficiency of trophozoites, thus phenocopying its substrate. Upon LPA stimulation, EhGEF2 is found to sequester near the plasma membrane in a wortmannin sensitive fashion, explaining a possible mode for activation of EhRho5 in the amoebic trophozoites. Collectively, we propose that LPA stimulated macropinocytosis in E. histolytica is driven by the PI Kinase-EhGEF2-EhRho5 axis.
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Affiliation(s)
- Achala Apte
- Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh, India
| | - Maria Manich
- Bioimage Analysis Unit, Institut Pasteur, Paris, France
| | | | - Sunando Datta
- Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh, India
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Vadakumchery A, Faraidun H, Ayoubi OE, Outaleb I, Schmid V, Abdelrasoul H, Amendt T, Khadour A, Setz C, Göhring K, Lodd K, Hitzing C, Alkhatib A, Bilal M, Benckendorff J, Al Shugri AK, Brakebusch CH, Engels N, Datta M, Hobeika E, Alsadeq A, Jumaa H. The Small GTPase RHOA Links SLP65 Activation to PTEN Function in Pre B Cells and Is Essential for the Generation and Survival of Normal and Malignant B Cells. Front Immunol 2022; 13:842340. [PMID: 35371049 PMCID: PMC8965026 DOI: 10.3389/fimmu.2022.842340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/18/2022] [Indexed: 11/13/2022] Open
Abstract
The generation, differentiation, survival and activation of B cells are coordinated by signals emerging from the B cell antigen receptor (BCR) or its precursor, the pre-BCR. The adaptor protein SLP65 (also known as BLNK) is an important signaling factor that controls pre-B cell differentiation by down-regulation of PI3K signaling. Here, we investigated the mechanism by which SLP65 interferes with PI3K signaling. We found that SLP65 induces the activity of the small GTPase RHOA, which activates PTEN, a negative regulator of PI3K signaling, by enabling its translocation to the plasma membrane. The essential role of RHOA is confirmed by the complete block in early B cell development in conditional RhoA-deficient mice. The RhoA-deficient progenitor B cells showed defects in activation of immunoglobulin gene rearrangement and fail to survive both in vitro and in vivo. Reconstituting the RhoA-deficient cells with RhoA or Foxo1, a transcription factor repressed by PI3K signaling and activated by PTEN, completely restores the survival defect. However, the defect in differentiation can only be restored by RhoA suggesting a unique role for RHOA in B cell generation and selection. In full agreement, conditional RhoA-deficient mice develop increased amounts of autoreactive antibodies with age. RHOA function is also required at later stage, as inactivation of RhoA in peripheral B cells or in a transformed mature B cell line resulted in cell loss. Together, these data show that RHOA is the key signaling factor for B cell development and function by providing a crucial SLP65-activated link between BCR signaling and activation of PTEN. Moreover, the identified essential role of RHOA for the survival of transformed B cells offers the opportunity for targeting B cell malignancies by blocking RHOA function.
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Affiliation(s)
| | - Hemin Faraidun
- Department of Molecular Immunology, Faculty of Biology, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Omar El Ayoubi
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Issame Outaleb
- Department of Molecular Immunology, Faculty of Biology, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Vera Schmid
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Hend Abdelrasoul
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Timm Amendt
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Ahmad Khadour
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Corinna Setz
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Katharina Göhring
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Karoline Lodd
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Christoffer Hitzing
- Institute of Cellular & Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
| | - Alabbas Alkhatib
- Department of Molecular Immunology, Faculty of Biology, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Mayas Bilal
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | | | | | - Cord Herbert Brakebusch
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Niklas Engels
- Institute of Cellular & Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
| | - Moumita Datta
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Elias Hobeika
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Ameera Alsadeq
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany
| | - Hassan Jumaa
- Institute of Immunology, Ulm University Medical Center, Ulm, Germany.,Department of Molecular Immunology, Faculty of Biology, Albert Ludwigs University of Freiburg, Freiburg, Germany
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Abstract
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used worldwide to manage dyslipidaemia and thus limit the development of atherosclerotic disease and its complications. These atheroprotective drugs are now known to exert pleiotropic actions outside of their cholesterol-lowering activity, including altering immune cell function. Macrophages are phagocytic leukocytes that play critical functional roles in the pathogenesis of atherosclerosis and are directly targeted by statins. Early studies documented the anti-inflammatory effects of statins on macrophages, but emerging evidence suggests that these drugs can also enhance pro-inflammatory macrophage responses, creating an unresolved paradox. This review comprehensively examines the in vitro, in vivo, and clinical literature to document the statin-induced changes in macrophage polarization and immunomodulatory functions, explore the underlying mechanisms involved, and offer potential explanations for this paradox. A better understanding of the immunomodulatory actions of statins on macrophages should pave the way for the development of novel therapeutic approaches to manage atherosclerosis and other chronic diseases and conditions characterised by unresolved inflammation.
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Yuan Y, Xiong R, Wu Y, Ha J, Wang W, Han X, He M. Associations of statin use with the onset and progression of open-angle glaucoma: A systematic review and meta-analysis. EClinicalMedicine 2022; 46:101364. [PMID: 35399812 PMCID: PMC8987630 DOI: 10.1016/j.eclinm.2022.101364] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 02/23/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Background Statins, the first-line therapy for hyperlipidemia, have received considerable attention as candidates for glaucoma treatments given its neuroprotective effects. In this systematic review and meta-analysis, we intended to assess the association of statin use with the onset and progression of open-angle glaucoma (OAG). Methods Databases including PubMed, Embase and Web of Science Core Collection were searched for longitudinal studies reporting the association between statin use and OAG onset or progression on Feb 3, 2021. A meta-analysis was performed for the association between statin use and OAG onset. Relative risks (RRs) with 95% confidential intervals (CIs) were retrieved from included studies and pooled using random-effects models. Potential risks of bias were evaluated by the Newcastle-Ottawa Quality Assessment Scale for all eligible studies. This study had been registered on PROSPERO (CRD 42021232172). Findings 515,788 participants (mean age 68.7 years, 62.3% female) from ten studies were included in the systematic review of the association between statin use and OAG onset, and 26,347 OAG patients (mean age 67.3 years, 52.2% female) from seven studies were included for the association between statin use and OAG progression. Potential risks of bias were detected in 12 studies, which were mainly attributed to selection and confounding bias. In addition, 515,600 participants from eight studies were included in the meta-analysis which collectively showed that statin use was associated with a reduced risk of OAG onset (Pooled RR: 0.95; 95%CI: 0.93-0.98; I2=0.199;). No significant heterogeneity or publication bias was found for studies included in the meta-analysis. There were inconsistent evidences for the association between statin use and OAG progression. Interpretation Statin use is associated with a slightly lower risk of OAG onset based on existing evidences from longitudinal observational studies, the association between statin use and OAG progression remains inconclusive. The included evidences were typically weak due to poor study design and under-powered studies. Current findings should be interpreted cautiously and still need to be validated in further research. Funding The National Key R&D Program of China (2018YFC0116500), Science and Technology Planning Project of Guangdong Province (2013B20400003), the China Postdoctoral Science Foundation (2019TQ0365), the National Natural Science Foundation of China (82000901 and 82101171).
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Key Words
- 3‑hydroxy‑3-methyl glutaryl coenzyme a (hmg-coa) reductase inhibitors
- CIS, confidential intervals
- HMG-COA, 3‑hydroxy‑3-methyl glutaryl coenzyme a
- HRS, hazard ratios
- ICD, international classification of diseases
- IOP, intraocular pressure
- NSLCM, non-statin lipid-controlling medications
- OAG, open-angle glaucoma
- ORS, odds ratios
- Open-angle glaucoma
- PRS, relative risks
- RGC, retinal ganglion cell
- VF, visual field
- WOS, web of science core collection
- meta-analysis
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Affiliation(s)
- Yixiong Yuan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| | - Ruilin Xiong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| | - Yi Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| | - Jason Ha
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
| | - Wei Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| | - Xiaotong Han
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| | - Mingguang He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Department of Surgery, Ophthalmology, University of Melbourne, Melbourne, Australia
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Artemisinin derivative TPN10466 suppresses immune cell migration and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis. Cell Immunol 2022; 373:104500. [DOI: 10.1016/j.cellimm.2022.104500] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/21/2022] [Accepted: 03/02/2022] [Indexed: 11/20/2022]
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The Relationship between Cadherin Polymorphisms and the Risk of Delayed Encephalopathy after Acute Carbon Monoxide Poisoning in the Chinese Han Population. Behav Neurol 2022; 2022:3155703. [PMID: 35140817 PMCID: PMC8818434 DOI: 10.1155/2022/3155703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/15/2022] [Indexed: 11/17/2022] Open
Abstract
Objective The purpose of this study was to analyze the relationship between cadherin gene single-nucleotide polymorphisms (SNPs) and the risk of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Materials and Methods A total of 416 patients with DEACMP and 754 patients with acute carbon monoxide poisoning (ACMP) were recruited. We used the Sequenom MassARRAY® system to detect cadherin gene SNPs related to DEACMP. Using different genetic analysis models, we evaluated the relationship between the cadherin gene polymorphisms and risk of DEACMP. Results We found that rs1944294 in the N-cadherin (CDH2) gene showed significant differences in genotype frequencies between the two groups under codominant and dominant inheritance models. Similarly, rs2513796 in the cadherin-17 (CDH17) gene showed significant differences under the codominant, dominant, and overdominant genetic models. And the T allele frequency of rs1944294 in the DEACMP group was significantly higher than that in the ACMP group (P = 0.023). Conclusions Cadherin gene SNPs (rs1944294, rs2513796) are associated with an increased risk of DEACMP in the Chinese population.
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Allam VSRR, Paudel KR, Gupta G, Singh SK, Vishwas S, Gulati M, Gupta S, Chaitanya MVNL, Jha NK, Gupta PK, Patel VK, Liu G, Kamal MA, Hansbro PM, Oliver BGG, Chellappan DK, Dua K. Nutraceuticals and mitochondrial oxidative stress: bridging the gap in the management of bronchial asthma. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:62733-62754. [PMID: 35796922 PMCID: PMC9477936 DOI: 10.1007/s11356-022-21454-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 06/10/2022] [Indexed: 02/05/2023]
Abstract
Asthma is a chronic inflammatory disease primarily characterized by inflammation and reversible bronchoconstriction. It is currently one of the leading causes of morbidity and mortality in the world. Oxidative stress further complicates the pathology of the disease. The current treatment strategies for asthma mainly involve the use of anti-inflammatory agents and bronchodilators. However, long-term usage of such medications is associated with severe adverse effects and complications. Hence, there is an urgent need to develop newer, novel, and safe treatment modalities for the management of asthma. This has therefore prompted further investigations and detailed research to identify and develop novel therapeutic interventions from potent untapped resources. This review focuses on the significance of oxidative stressors that are primarily derived from both mitochondrial and non-mitochondrial sources in initiating the clinical features of asthma. The review also discusses the biological scavenging system of the body and factors that may lead to its malfunction which could result in altered states. Furthermore, the review provides a detailed insight into the therapeutic role of nutraceuticals as an effective strategy to attenuate the deleterious effects of oxidative stress and may be used in the mitigation of the cardinal features of bronchial asthma.
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Affiliation(s)
| | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, NSW, 2007, Australia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, India
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, P.O. Box: 123 Broadway, Ultimo, NSW, 2007, Australia
| | - Sukriti Vishwas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, P.O. Box: 123 Broadway, Ultimo, NSW, 2007, Australia
| | - Saurabh Gupta
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | | | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research (SBSR), Sharda University, Greater Noida, Uttar Pradesh, Australia
| | - Vyoma K Patel
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, 2052, Australia
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, 2007, Australia
| | - Gang Liu
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, NSW, 2007, Australia
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, 21589, Saudi Arabia
- Institutes for Systems Genetics, Frontiers Science Center for Disease related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- Enzymoics, Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW, 2770, Australia
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, NSW, 2007, Australia
| | - Brian Gregory George Oliver
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia
- Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, 57000, Malaysia
| | - Kamal Dua
- Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, P.O. Box: 123 Broadway, Ultimo, NSW, 2007, Australia.
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
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Scott F, Fala AM, Takarada JE, Ficu MP, Pennicott LE, Reuillon TD, Couñago RM, Massirer KB, Elkins JM, Ward SE. Development of dihydropyrrolopyridinone-based PKN2/PRK2 chemical tools to enable drug discovery. Bioorg Med Chem Lett 2022; 60:128588. [DOI: 10.1016/j.bmcl.2022.128588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/14/2022] [Accepted: 01/22/2022] [Indexed: 11/02/2022]
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Li W, Li F, Zhang X, Lin HK, Xu C. Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment. Signal Transduct Target Ther 2021; 6:422. [PMID: 34924561 PMCID: PMC8685280 DOI: 10.1038/s41392-021-00825-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 12/11/2022] Open
Abstract
More and more in-depth studies have revealed that the occurrence and development of tumors depend on gene mutation and tumor heterogeneity. The most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment (TME) heterogeneity. This depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor network. TME has resulted in novel therapeutic interventions as a place beyond tumor beds. The malignant cancer cells, tumor infiltrate immune cells, angiogenic vascular cells, lymphatic endothelial cells, cancer-associated fibroblastic cells, and the released factors including intracellular metabolites, hormonal signals and inflammatory mediators all contribute actively to cancer progression. Protein post-translational modification (PTM) is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological homeostasis. Advances in quantitative transcriptomics, proteomics, and nuclease-based gene editing are now paving the global ways for exploring PTMs. In this review, we focus on recent developments in the PTM area and speculate on their importance as a critical functional readout for the regulation of TME. A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies.
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Affiliation(s)
- Wen Li
- Integrative Cancer Center & Cancer Clinical Research Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, 610042, Chengdu, P. R. China
| | - Feifei Li
- Integrative Cancer Center & Cancer Clinical Research Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, 610042, Chengdu, P. R. China
- Guangxi Collaborative Innovation Center for Biomedicine (Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment), Guangxi Medical University, 530021, Nanning, Guangxi, China
| | - Xia Zhang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Hui-Kuan Lin
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA
| | - Chuan Xu
- Integrative Cancer Center & Cancer Clinical Research Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, 610042, Chengdu, P. R. China.
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA.
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Mei Q, Li H, Liu Y, Wang X, Xiang W. Advances in the study of CDC42 in the female reproductive system. J Cell Mol Med 2021; 26:16-24. [PMID: 34859585 PMCID: PMC8742232 DOI: 10.1111/jcmm.17088] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 11/08/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
CDC42 is a member of the Rho‐GTPase family and is involved in a variety of cellular functions including regulation of cell cycle progression, constitution of the actin backbone and membrane transport. In particular, CDC42 plays a key role in the establishment of polarity in female vertebrate oocytes, and essential to this major regulatory role is its local occupation of specific regions of the cell to ensure that the contractile ring is assembled at the right time and place to ensure proper gametogenesis. The multifactor controlled ‘inactivation‐activation’ process of CDC42 also allows it to play an important role in the multilevel signalling network, and the synergistic regulation of multiple genes ensures maximum precision during gametogenesis. The purpose of this paper is to review the role of CDC42 in the control of gametogenesis and to explore its related mechanisms, with the aim of further understanding the great research potential of CDC42 in female vertebrate germ cells and its future clinical translation.
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Affiliation(s)
- Qiaojuan Mei
- Institute of Reproductive Health and Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiying Li
- Institute of Reproductive Health and Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Liu
- Institute of Reproductive Health and Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaofei Wang
- Institute of Reproductive Health and Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenpei Xiang
- Institute of Reproductive Health and Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lee NH, Fu T, Shin JH, Song YW, Jang DC, Kim KS. The Small GTPase CsRAC1 Is Important for Fungal Development and Pepper Anthracnose in Colletotrichum scovillei. THE PLANT PATHOLOGY JOURNAL 2021; 37:607-618. [PMID: 34897252 PMCID: PMC8666242 DOI: 10.5423/ppj.oa.09.2021.0140] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/27/2021] [Accepted: 10/31/2021] [Indexed: 06/14/2023]
Abstract
The pepper anthracnose fungus, Colletotrichum scovillei, causes severe losses of pepper fruit production in the tropical and temperate zones. RAC1 is a highly conserved small GTP-binding protein in the Rho GTPase family. This protein has been demonstrated to play a role in fungal development, and pathogenicity in several plant pathogenic fungi. However, the functional roles of RAC1 are not characterized in C. scovillei causing anthracnose on pepper fruits. Here, we generated a deletion mutant (ΔCsrac1) via homologous recombination to investigate the functional roles of CsRAC1. The ΔCsrac1 showed pleiotropic defects in fungal growth and developments, including vegetative growth, conidiogenesis, conidial germination and appressorium formation, compared to wild-type. Although ΔCsrac1 was able to develop appressoria, it failed to differentiate appressorium pegs. However, ΔCsrac1 still caused anthracnose disease with significantly reduced rate on wounded pepper fruits. Further analyses revealed that ΔCsrac1 was defective in tolerance to oxidative stress and suppression of host-defense genes. Taken together, our results suggest that CsRAC1 plays essential roles in fungal development and pathogenicity in C. scovillei-pepper fruit pathosystem.
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Affiliation(s)
- Noh-Hyun Lee
- Division of Bio-Resource Sciences, BioHerb Research Institute, and Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon 24341,
Korea
| | - Teng Fu
- Division of Bio-Resource Sciences, BioHerb Research Institute, and Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon 24341,
Korea
| | - Jong-Hwan Shin
- Division of Bio-Resource Sciences, BioHerb Research Institute, and Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon 24341,
Korea
| | - Yong-Won Song
- Division of Bio-Resource Sciences, BioHerb Research Institute, and Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon 24341,
Korea
| | - Dong-Cheol Jang
- Department of Horticulture, Kangwon National University, Chuncheon 24341,
Korea
| | - Kyoung Su Kim
- Division of Bio-Resource Sciences, BioHerb Research Institute, and Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon 24341,
Korea
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Pagliazzo L, Caby S, Lancelot J, Salomé-Desnoulez S, Saliou JM, Heimburg T, Chassat T, Cailliau K, Sippl W, Vicogne J, Pierce RJ. Histone deacetylase 8 interacts with the GTPase SmRho1 in Schistosoma mansoni. PLoS Negl Trop Dis 2021; 15:e0009503. [PMID: 34843489 PMCID: PMC8670706 DOI: 10.1371/journal.pntd.0009503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 12/14/2021] [Accepted: 10/23/2021] [Indexed: 12/15/2022] Open
Abstract
Background Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has elicited considerable interest as a target for drug discovery. Invalidation of its transcripts by RNAi leads to impaired survival of the worms in infected mice and its inhibition causes cell apoptosis and death. To determine why it is a promising therapeutic target the study of the currently unknown cellular signaling pathways involving this enzyme is essential. Protein partners of SmHDAC8 were previously identified by yeast two-hybrid (Y2H) cDNA library screening and by mass spectrometry (MS) analysis. Among these partners we characterized SmRho1, the schistosome orthologue of human RhoA GTPase, which is involved in the regulation of the cytoskeleton. In this work, we validated the interaction between SmHDAC8 and SmRho1 and explored the role of the lysine deacetylase in cytoskeletal regulation. Methodology/principal findings We characterized two isoforms of SmRho1, SmRho1.1 and SmRho1.2. Co- immunoprecipitation (Co-IP)/Mass Spectrometry (MS) analysis identified SmRho1 partner proteins and we used two heterologous expression systems (Y2H assay and Xenopus laevis oocytes) to study interactions between SmHDAC8 and SmRho1 isoforms. To confirm SmHDAC8 and SmRho1 interaction in adult worms and schistosomula, we performed Co-IP experiments and additionally demonstrated SmRho1 acetylation using a Nano LC-MS/MS approach. A major impact of SmHDAC8 in cytoskeleton organization was documented by treating adult worms and schistosomula with a selective SmHDAC8 inhibitor or using RNAi followed by confocal microscopy. Conclusions/significance Our results suggest that SmHDAC8 is involved in cytoskeleton organization via its interaction with the SmRho1.1 isoform. The SmRho1.2 isoform failed to interact with SmHDAC8, but did specifically interact with SmDia suggesting the existence of two distinct signaling pathways regulating S. mansoni cytoskeleton organization via the two SmRho1 isoforms. A specific interaction between SmHDAC8 and the C-terminal moiety of SmRho1.1 was demonstrated, and we showed that SmRho1 is acetylated on K136. SmHDAC8 inhibition or knockdown using RNAi caused extensive disruption of schistosomula actin cytoskeleton. Schistosoma mansoni is the major parasitic platyhelminth species causing intestinal schistosomiasis. Currently one drug, praziquantel, is the treatment of choice but its use in mass treatment programs means that the development of resistance is likely and renders imperative the development of new therapeutic agents. As new potential targets we have focused on lysine deacetylases, and in particular S. mansoni histone deacetylase 8 (SmHDAC8). Previous studies showed that reduction in the level of transcripts of SmHDAC8 by RNAi led to the impaired survival of the worms after the infection of mice. The analysis of the 3D structure of SmHDAC8 by X-ray crystallography showed that the catalytic domain structure diverges significantly from that of human HDAC8 and this was exploited to develop novel potential anti-schistosomal drugs. The biological roles of SmHDAC8 are unknown. For this reason, we previously characterized its protein binding partners and identified the schistosome orthologue of the human RhoA GTPase, suggesting the involvement of SmHDAC8 in the modulation of cytoskeleton organization. Here we investigated the interaction between SmHDAC8 and SmRho1 and identified two SmRho1 isoforms (SmRho1.1 and SmRho1.2). Our study showed that SmHDAC8 is involved in schistosome cytoskeleton organization.
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Affiliation(s)
- Lucile Pagliazzo
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, - Centre d’Infection et d’Immunité de Lille, Lille, France
| | - Stéphanie Caby
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, - Centre d’Infection et d’Immunité de Lille, Lille, France
| | - Julien Lancelot
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, - Centre d’Infection et d’Immunité de Lille, Lille, France
| | | | - Jean-Michel Saliou
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France
| | - Tino Heimburg
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Thierry Chassat
- Institut Pasteur de Lille - PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale), Lille, France
| | - Katia Cailliau
- Univ. Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
| | - Wolfgang Sippl
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Jérôme Vicogne
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, - Centre d’Infection et d’Immunité de Lille, Lille, France
- * E-mail: (JV); (RJP)
| | - Raymond J. Pierce
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, - Centre d’Infection et d’Immunité de Lille, Lille, France
- * E-mail: (JV); (RJP)
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Wu L, Chatla S, Lin Q, Chowdhury FA, Geldenhuys W, Du W. Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia. Nat Commun 2021; 12:6936. [PMID: 34836965 PMCID: PMC8626516 DOI: 10.1038/s41467-021-27300-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 11/11/2021] [Indexed: 01/30/2023] Open
Abstract
Chemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of Cdc42 Activity Specific Inhibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.
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Affiliation(s)
- Limei Wu
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA
| | - Srinivas Chatla
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Qiqi Lin
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA
| | - Fabliha Ahmed Chowdhury
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA
- Molecular Pharmacology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, USA
| | - Werner Geldenhuys
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA
| | - Wei Du
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA.
- Molecular Pharmacology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, USA.
- UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
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Broken detailed balance and entropy production in the human brain. Proc Natl Acad Sci U S A 2021; 118:2109889118. [PMID: 34789565 PMCID: PMC8617485 DOI: 10.1073/pnas.2109889118] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2021] [Indexed: 12/03/2022] Open
Abstract
To perform biological functions, living systems must break detailed balance by consuming energy and producing entropy. At microscopic scales, broken detailed balance enables a suite of molecular and cellular functions, including computations, kinetic proofreading, sensing, adaptation, and transportation. But do macroscopic violations of detailed balance enable higher-order biological functions, such as cognition and movement? To answer this question, we adapt tools from nonequilibrium statistical mechanics to quantify broken detailed balance in complex living systems. Analyzing neural recordings from hundreds of human subjects, we find that the brain violates detailed balance at large scales and that these violations increase with physical and cognitive exertion. Generally, we provide a flexible framework for investigating broken detailed balance at large scales in complex systems. Living systems break detailed balance at small scales, consuming energy and producing entropy in the environment to perform molecular and cellular functions. However, it remains unclear how broken detailed balance manifests at macroscopic scales and how such dynamics support higher-order biological functions. Here we present a framework to quantify broken detailed balance by measuring entropy production in macroscopic systems. We apply our method to the human brain, an organ whose immense metabolic consumption drives a diverse range of cognitive functions. Using whole-brain imaging data, we demonstrate that the brain nearly obeys detailed balance when at rest, but strongly breaks detailed balance when performing physically and cognitively demanding tasks. Using a dynamic Ising model, we show that these large-scale violations of detailed balance can emerge from fine-scale asymmetries in the interactions between elements, a known feature of neural systems. Together, these results suggest that violations of detailed balance are vital for cognition and provide a general tool for quantifying entropy production in macroscopic systems.
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Song LJ, Zhang H, Qu XP, Jin JG, Wang C, Jiang X, Gao L, Li G, Wang DL, Shen LL, Liu B. Increased expression of Rho-associated protein kinase 2 confers astroglial Stat3 pathway activation during epileptogenesis. Neurosci Res 2021; 177:25-37. [PMID: 34740726 DOI: 10.1016/j.neures.2021.10.013] [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: 07/21/2021] [Revised: 10/28/2021] [Accepted: 10/31/2021] [Indexed: 10/19/2022]
Abstract
Patients with TLE are prone to tolerance to antiepileptic drugs. Based on the perspective of molecular targets for drug resistance, it is necessary to explore effective drug resistant genes and signaling pathways for the treatment of TLE. We performed gene expression profiles in hippocampus of patients with drug-resistant TLE and identified ROCK2 as one of the 20 most significantly increased genes in hippocampus. In vitro and in vivo experiments were performed to identify the potential role of ROCK2 in epileptogenesis. In addition, the activity of Stat3 pathway was tested in rat hippocampal tissues and primary cultured astrocytes. The expression levels of ROCK2 in the hippocampus of TLE patients were significantly increased compared with the control group, which was due to the hypomethylation of ROCK2 promoter. Fasudil, a specific Rho-kinase inhibitor, alleviated epileptic seizures in the pilocarpine rat model of TLE. Furthermore, ROCK2 activated the Stat3 pathway in pilocarpine-treated epilepsy rats, and the spearman correlation method confirmed that ROCK2 is associated with Stat3 activation in TLE patients. In addition, ROCK2 was predominantly expressed in astrocytes during epileptogenesis, and induced epileptogenesis by activating astrocyte cell cycle progression via Stat3 pathway. The overexpressed ROCK2 plays an important role in the pathogenesis of drug-resistant epilepsy. ROCK2 accelerates astrocytes cell cycle progression via the activation of Stat3 pathway likely provides the key to explaining the process of epileptogenesis.
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Affiliation(s)
- Li-Jia Song
- Department of Pediatrics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Hua Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiao-Peng Qu
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jun-Gong Jin
- Department of Neurosurgery, Xi'an International Medical Center, Xi'an, China
| | - Chao Wang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xue Jiang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Li Gao
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Gang Li
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Da-Li Wang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Liang-Liang Shen
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
| | - Bei Liu
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
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Khamko R, Daduang J, Settasatian C, Limpaiboon T. OPCML Exerts Antitumor Effects in Cholangiocarcinoma via AXL/STAT3 Inactivation and Rho GTPase Down-regulation. Cancer Genomics Proteomics 2021; 18:771-780. [PMID: 34697068 DOI: 10.21873/cgp.20296] [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: 08/11/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/AIM Opioid-binding protein/cell adhesion molecule-like (OPCML) plays a crucial role in the suppression of tumor progression in several cancer types. Nevertheless, the association between OPCML functions and cholangiocarcinoma (CCA) progression remains unknown. We aimed to investigate biological functions of OPCML and related signaling pathways in CCA cell lines. MATERIALS AND METHODS Methylation status and ectopic expression of OPCML were determined in CCA cell lines using methylation-specific polymerase chain reaction and pcDNA3.1+/C-(K)DYK-OPCML, respectively. Cell proliferation, migration and invasion were investigated. RESULTS OPCML was found to be epigenetically silenced by DNA methylation. Ectopic expression of OPCML inhibited CCA proliferation by inducing apoptosis via AXL receptor tyrosine kinase/signal transducer and activator of transcription 3 (AXL/STAT3) inactivation. It also suppressed cell migration and invasion via down-regulation of Rho GTPases, ras homolog family member A (RHOA), Rac family small GTPase 1 (RAC1) and cell division cycle 42 (CDC42). CONCLUSION We are the first to unravel the antitumor effects and the related signaling pathways of OPCML in CCA. The loss of OPCML expression due to promoter hypermethylation can cause a decrease in cell death but increase in cell migration and invasion, which may at least in part contribute to CCA progression.
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Affiliation(s)
- Ricuphan Khamko
- Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand.,Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Jureerut Daduang
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Chatri Settasatian
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Temduang Limpaiboon
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand; .,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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