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中华医学杂志(英文版) 2024年第8期137卷 2024 Mar 19页

作者： Wang Xiaoshuang Wang Jing Cheng Tao institute of Basic medical sciences Chinese Academy of medical sciences & Peking Union medical College Beijing 100005 China

Suspended particulate matter promotes epithelial-to-mesenchymal transition in alveolar epithelial cells via TGF-β1-mediated ROS/IL-8/SMAD3 axis

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Journal of Environmental sciences 2024年第7期141卷 139-150页

作者： Shahrzad Molavinia Dian Dayer Mohammad Javad Khodayar Gholamreza Goudarzi Maryam Salehcheh Cellular and Molecular Research Center Medical Basic Sciences Research InstituteAhvaz Jundishapur University of Medical SciencesAhvazIran Department of Toxicology School of PharmacyAhvaz Jundishapur University of Medical SciencesAhvazIran Student Research Committee Ahvaz Jundishapur University of Medical SciencesAhvazIran Toxicology Research Center Medical Basic Sciences Research InstituteAhvaz Jundishapur University of Medical SciencesAhvazIran Air Pollution and Respiratory Diseases Research Center Ahvaz Jundishapur University of Medical SciencesAhvazIran Iranian Scientific Association of Clean Air TehranIran

Epidemiological evidence presents that dust storms are related to respiratory diseases,such as pulmonary fibrosis(PF).However,the precise underlying mechanisms of SPM-elicited adverse effects still need to be investigated.Epithelial-mesenchymal transition(EMT)process is a characteristic of PF.We discussed whether suspended particulate matter(SPM)is involved in EMT induction via transforming growth factor-β1(TGF-β1).In this study,a detailed elemental analysis(55 elements),particle size,and morphology were determined.To investigate the toxicity of SPM,an MTT test was performed to detect cell viability.Next,A549cells were exposed to selected concentrations of SPM(20 and 40μg/mL)for single and repeated exposures.The DCFH-DA assay showed that exposure to SPM could produce reactive oxygen species(ROS).The ELISA assay demonstrated increased levels of interleukin-8(IL-8)and TGF-β1 in the supernatant.Western blot was used to detect the expression of proteins associated with EMT and the SMAD3-dependent pathway.Results of western blot demonstrated that E-cadherin was reduced,whereas p-SMAD3,vimentin,andα-smooth muscle actin were elevated.Our findings indicated that SPM triggered EMT by induction of oxidative stress,inflammation,and the TGF-β1/SMAD3 pathway activation.

关键词： Particulate matter TGF-β1 Oxidative stress Epithelial-mesenchymal transition Pulmonary fibrosis Cells

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Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

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Signal Transduction and Targeted Therapy 2024年第1期9卷 173-210页

作者： Md Entaz Bahar Hyun Joon Kim Deok Ryong Kim Department of Biochemistry and Convergence medical sciences and institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea Department of Anatomy and Convergence medical sciences and institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea

Metastatic dissemination of solid tumors,a leading cause of cancer-related mortality,underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis,chemoresistance,and the mechanistic backgrounds of individuals whose cancers are prone to migration.The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase(MAPK)pathway,encompassing the RAS–RAF–MAPK kinase(MEK)–extracellular signal-related kinase(ERK)pathway.RAF kinase is a primary mediator of the MAPK pathway,responsible for the sequential activation of downstream targets,such as MEK and the transcription factor ERK,which control numerous cellular and physiological processes,including organism development,cell cycle control,cell proliferation and differentiation,cell survival,and death.Defects in this signaling cascade are associated with diseases such as cancer.RAF inhibitors(RAFi)combined with MEK blockers represent an FDAapproved therapeutic strategy for numerous RAF-mutant cancers,including melanoma,non-small cell lung carcinoma,and thyroid cancer.However,the development of therapy resistance by cancer cells remains an important barrier.Autophagy,an intracellular lysosome-dependent catabolic recycling process,plays a critical role in the development of RAFi resistance in cancer.Thus,targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers.In this review,we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance.Furthermore,we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles.Additionally,this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

关键词： RAF insight mechanism

Metabolic plasticity of T cell fate decision

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中华医学杂志(英文版) 2024年第7期137卷 762-775页

作者： Pan Xiaoli Wang Jiajia Zhang Lianjun Li Guideng Huang Bo institute of Basic medical sciences Chinese Academy of medical sciences (CAMS) & Beijing 100005 National Key Laboratory of Immunity and Inflammation Suzhou institute of Systems Medicine Chinese Academy of medical sciences & Peking Union medical College Suzhou Jiangsu 215123 China Department of Immunology & National Key Laboratory of medical Molecular Biology

The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells. Upon antigen exposure, T cells undergo metabolic reprogramming, leading to the development of functional effectors or memory populations. However, within the tumor microenvironment (TME), metabolic stress impairs CD8+ T cell anti-tumor immunity, resulting in exhausted differentiation. Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy. In this review, we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions. Furthermore, we delved into the different metabolic switches that occur during T cell exhaustion, exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion, ultimately leading to a persistently exhausted state. Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.

关键词： T cell immunotherapy T cell differentiation T cell exhaustion Metabolic reprogramming Tumor microenvironment

Microglial response to aging and neuroinflammation in the development of neurodegenerative diseases

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Neural Regeneration Research 2024年第6期19卷 1241-1248页

作者： Tingting Han Yuxiang Xu Lin Sun Makoto Hashimoto Jianshe Wei institute for Brain sciences Research School of Life Sciences Henan University College of Chemistry and Molecular sciences Henan University Department of Basic Technology Tokyo Metropolitan Institute of Medical Science

Cellular senescence and chronic inflammation in response to aging are considered to be indicators of brain aging; they have a great impact on the aging process and are the main risk factors for neurodegeneration. Reviewing the microglial response to aging and neuroinflammation in neurodegenerative diseases will help understand the importance of microglia in neurodegenerative diseases. This review describes the origin and function of microglia and focuses on the role of different states of the microglial response to aging and chronic inflammation on the occurrence and development of neurodegenerative diseases, including Alzheimer’s disease, Huntington’s chorea, and Parkinson’s disease. This review also describes the potential benefits of treating neurodegenerative diseases by modulating changes in microglial states. Therefore, inducing a shift from the neurotoxic to neuroprotective microglial state in neurodegenerative diseases induced by aging and chronic inflammation holds promise for the treatment of neurodegenerative diseases in the future.

关键词： aging Alzheimer’s disease cytokines Huntington’s disease microglia neurodegenerative diseases neuroinflammation neuroprotection neurotoxicity Parkinson’s disease

Signaling pathways governing the behaviors of leukemia stem cells

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Genes & Diseases 2024年第2期11卷 830-846页

作者： Shirin Azizidoost Ava Nasrolahi Mohadeseh Sheykhi-Sabzehpoush Amir Anbiyaiee Seyed Esmaeil Khoshnam Maryam Farzaneh Shahab Uddin Atherosclerosis Research Center Ahvaz Jundishapur University of Medical SciencesAhvaz ***Iran Infectious Ophthalmologic Research Center Ahvaz Jundishapur University of Medical SciencesAhvaz ***Iran Department of Laboratory Imam Khomeini Hospital ComplexTehran University of Medical SciencesTehran ***Iran Department of Surgery School of MedicineAhvaz Jundishapur University of Medical SciencesAhvaz ***Iran Persian Gulf Physiology Research Center Medical Basic Sciences Research InstituteAhvaz Jundishapur University of Medical SciencesAhvaz ***Iran Fertility Infertility and Perinatology Research CenterAhvaz Jundishapur University of Medical SciencesAhvaz ***Iran Translational Research institute and Dermatology institute Academic Health SystemHamad Medical CorporationDoha 3050Qatar

Leukemia is a malignancy in the blood that develops from the lymphatic system and bone marrow.Although various treatment options have been used for different types of leukemia,understanding the molecular pathways involved in the development and progression of leukemia is necessary.Recent studies showed that leukemia stem cells(LSCs)play essential roles in the pathogenesis of leukemia by targeting several signaling pathways,including Notch,Wnt,Hedgehog,and STAT3.LSCs are highly proliferative cells that stimulate tumor initiation,migration,EMT,and drug resistance.This review summarizes cellular pathways that stimulate and prevent LSCs'self-renewal,metastasis,and tumorigenesis.

关键词： Leukemia Leukemia stem cells Pathogenesis Signaling pathways Stem cells

Perspective of Calcium Imaging Technology Applied to Acupuncture Research

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Chinese Journal of Integrative Medicine 2024年第1期30卷 3-9页

作者： LI Sha LIU Yun ZHANG Nan LI Wang XU Wen-jie XU Yi-qian CHEN Yi-yuan CUI Xiang ZHU Bing GAO Xin-yan institute of Acupuncture and Moxibustion China Academy of Chinese Medical SciencesBeijing(100700)China

Acupuncture, a therapeutic treatment defined as the insertion of needles into the body at specific points(ie, acupoints), has growing in popularity world-wide to treat various diseases effectively, especially acute and chronic pain. In parallel, interest in the physiological mechanisms underlying acupuncture analgesia, particularly the neural mechanisms have been increasing. Over the past decades, our understanding of how the central nervous system and peripheral nervous system process signals induced by acupuncture has developed rapidly by using electrophysiological methods. However, with the development of neuroscience, electrophysiology is being challenged by calcium imaging in view field, neuron population and visualization in vivo. Owing to the outstanding spatial resolution, the novel imaging approaches provide opportunities to enrich our knowledge about the neurophysiological mechanisms of acupuncture analgesia at subcellular, cellular, and circuit levels in combination with new labeling, genetic and circuit tracing techniques. Therefore, this review will introduce the principle and the method of calcium imaging applied to acupuncture research. We will also review the current findings in pain research using calcium imaging from in vitro to in vivo experiments and discuss the potential methodological considerations in studying acupuncture analgesia.

关键词： acupuncture research calcium imaging optical imaging nervous system

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Movement Trend Alterations in the Periaqueductal Gray(PAG)-Employed Ratbot Navigation Are Correlated with Stimulation Parameters

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Journal of Bionic Engineering 2024年第2期21卷 866-876页

作者： Sina Khajei Abed Khorasani Mohammad Reza Afarinesh Vahid Sheibani Neuroscience Research Center Institute of NeuropharmacologyKerman University of Medical SciencesKerman***Iran Cognitive Neuroscience Research Center Institute of NeuropharmacologyKerman University of Medical SciencesKerman***Iran

In previous studies,Periaqueductal Gray(PAG)stimulation was used to stop ratbots from moving.Due to the homology between the PAG and the intercollicular nucleus,which has been used for forward movement in birds,we investigated the possibility of PAG application to induce forward locomotion for the first time.Using a corridor maze,the traveled distances via PAG electrical stimulation were examined in nine Wistar male rats during three sessions.A custom-designed stimulator was developed to apply the stimulation.The results showed reductions in responses to stimulation over time.Accordingly,the traveled distances had negative slopes during the consecutive trials(in 8 out of the 9 rats),and the slope mean was significantly different from zero.There was a strong correlation between the stimulation parameters(electric Charge per Phase(CPP)and the Number of Pulses(NP))and the observed slopes.The negative Movement Slopes(MS)were highly correlated with the CPP and the NP,as the Pearson's linear correlation coefficients were−0.87 and−0.79,respectively.The MS-CPP coefficients of determination(R-squared)were also between 0.76 and 0.95.In addition,the MS-NP coefficients of determination were between 0.63 and 0.87.Thus,it is concluded that the electrical stimulation parameters influence the behavioral outcomes directly.Furthermore,the PAG area may be considered a suitable candidate for forward locomotion control in the future if the area is harnessed effectively to prevent undesirable chaotic behaviors.

关键词： Periaqueductal Gray(PAG) Navigation Ratbot Animal-robot Forward locomotion Movement slope

Amebic liver abscess: An update

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World Journal of Hepatology 2024年第3期16卷 316-330页

作者： Ramesh Kumar Rishabh Patel Rajeev Nayan Priyadarshi Ruchika Narayan Tanmoy Maji Utpal Anand Jinit R Soni Department of Gastroenterology All India Institute of Medical SciencesPatna 801507India Department of Radiodiagnosis All India Institute of Medical SciencesPatna 801507India Department of Surgical Gastroenterology All India Institute of Medical SciencesPatna 801507India

Amebic liver abscess(ALA)is still a common problem in the tropical world,where it affects over three-quarters of patients with liver abscess.It is caused by an anaerobic protozoan Entamoeba hystolytica,which primarily colonises the cecum.It is a non-suppurative infection of the liver consisting primarily of dead hepatocytes and cellular debris.People of the male gender,during their reproductive years,are most prone to ALA,and this appears to be due to a poorly mounted immune response linked to serum testosterone levels.ALA is more common in the right lobe of the liver,is strongly associated with alcohol consumption,and can heal without the need for drainage.While majority of ALA patients have an uncomplicated course,a number of complications have been described,including rupture into abdomino-thoracic structures,biliary fistula,vascular thrombosis,bilio-vascular compression,and secondary bacterial infection.Based on clinico-radiological findings,a classification system for ALA has emerged recently,which can assist clinicians in making treatment decisions.Recent research has revealed the role of venous thrombosis-related ischemia in the severity of ALA.Recent years have seen the development and refinement of newer molecular diagnostic techniques that can greatly aid in overcoming the diagnostic challenge in endemic area where serology-based tests have limited accuracy.Metronidazole has been the drug of choice for ALA patients for many years.However,concerns over the resistance and adverse effects necessitate the creation of new,safe,and potent antiamebic medications.Although the indication of the drainage of uncomplicated ALA has become more clear,high-quality randomised trials are still necessary for robust conclusions.Percutaneous drainage appears to be a viable option for patients with ruptured ALA and diffuse peritonitis,for whom surgery represents a significant risk of mortality.With regard to all of the aforementioned issues,this article intends to present an updated review of ALA.

关键词： Amebic liver abscess Amebiasis Ruptured liver abscess Percutaneous drainage Metronidazole

Targeting nuclear receptors for NASH/MASH:From bench to bedside

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Liver Research 2024年第1期8卷 34-45页

作者： Rohit A.Sinha Department of Endocrinology Sanjay Gandhi Postgraduate Institute of Medical SciencesLucknowIndia

The onset of metabolic dysfunction-associated steatohepatitis(MASH)or non-alcoholic steatohepatitis(NASH)represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD).With no pharmacological treat-ment currently available for MASH/NASH,the race is on to develop drugs targeting multiple facets of hepatic metabolism,inflammation,and pro-fibrotic events,which are major drivers of MASH.Nuclear receptors(NRs)regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation.Ligands of NRs may include hormones,lipids,bile acids,and synthetic ligands,which upon binding to NRs regulate the transcriptional activities of target genes.NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH.This review aims to cover the current understanding of NRs,including nuclear hormone receptors,non-steroid hormone receptors,circadian NRs,and orphan NRs,which are currently undergoing clinical trials for MASH treatment,along with NRs that have shown promising results in preclinical studies.

关键词： Nuclear receptor(NR) Metabolic dysfunction-associated steatohepatitis(MASH) Metabolic dysfunction-associated steatotic liver disease(MASLD) Transcription factor Liver Drug