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IKKβ inhibits cognitive memory and adult hippocampal neurogenesis by modulating the β-catenin pathway IKKβ通过调节β-catenin通路抑制认知记忆和成人海马神经发生

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123490

Kyung-Joo Seong , Bo-Ram Mun , Shintae Kim , Won-Seok Choi , Sung Joong Lee , Ji-Yeon Jung , Won-Jae Kim

Aim

The IKKβ signaling pathway regulates NF-κB, influencing inflammation and cell survival in the brain. Radial glia cells are crucial for hippocampal neurogenesis and cognition. However, the role and mechanisms of IKKβ in modulating radial glia behavior and its impact on memory and neurogenesis remain unclear. Further studies are needed to understand how alterations in this pathway affect hippocampal function.

Main methods

The role of IKKβ in memory and hippocampal neurogenesis was examined using GFAP-CreERT2/IKKβ^flox/flox mice with IKKβ knockdown in radial glia cells. IKKβ expression, NSC proliferation, and differentiation were assessed by immunohistochemistry. NF-κB and β-catenin interactions were evaluated by immunoprecipitation. Cultured adult hippocampal NSCs, with IKKβ or β-catenin shRNA transfection, were analyzed by flow cytometry and western blot to examine stem cell characteristics, NF-κB signaling, cell cycle, and β-catenin pathways.

Key findings

Our results showed IKKβ cKD increased exploratory activity in the open-field and hyperactivity in the Y-maze, as well as enhanced spatial memory in the object location and Morris water maze tests. It also promoted adult hippocampal NSC proliferation by upregulating positive and inhibiting negative cell cycle regulators. Neuronal differentiation was enhanced, affecting β-catenin signaling and NeuroD1 expression. Additionally, IKKβ cKD promoted NSC survival, as shown by decreased cleaved caspase-3 and reduced Bax and cytochrome c in the hippocampus.

Significance

These findings suggest that in hippocampal NSCs, IKKβ inhibits locomotion, cognitive function, and adult hippocampal neurogenesis by suppressing the β-catenin signaling, highlighting its key role in decreasing hippocampal neurogenesis and cognitive function through NF-κB signaling in adult NSCs.

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引用次数: 0

Therapeutic targets in aging-related osteoarthritis: A focus on the extracellular matrix homeostasis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-18 DOI: 10.1016/j.lfs.2025.123487

Wan Hao , Minnan Chang , Di Shi , Chenxi Yun , Jun Li , Haitao Guo , Xiao Lin

Osteoarthritis (OA) represents a globally prevalent degenerative bone diseases and is the primary contributors to pain and disability among middle-aged and elderly people, thereby imposing significant social and economic burdens. When articular cartilage is in the aging environment, epigenetic modifications, DNA damage and mitochondrial dysfunction lead to cell senescence. Chondrocyte senescence has been identified as a pivotal event in this metabolic dysregulation of the extracellular matrix (ECM). It can affect the composition and structure of ECM, and the mechanical and biological signals transmitted by ECM to senescent chondrocytes affect their physiology and pathology. Over the past few decades, the role of ECM in aging-related OA has received increasing attention. In this review, we summarize the changes of cartilage's major ECM (type II collagen and aggrecan) and the interaction between aging and ECM in OA, and explore therapeutic strategies targeting cartilagae ECM, such as noncoding RNAs, small-molecule drugs, and mesenchymal stem cell (MSC)-derived extracellular vesicles for OA. The aim of this study was to elucidate the potential benefits of ECM-based therapies as novel strategies for the management of OA diseases.

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引用次数: 0

Targeting autophagy in premature ovarian failure: Therapeutic strategies from molecular pathways to clinical applications

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-17 DOI: 10.1016/j.lfs.2025.123473

Ziwen Ding, Genbao Shao, Mingyang Li

Premature ovarian failure (POF) is a condition where the ovaries lose their function before the age of 40, leading to significant impacts on reproductive health and overall well-being. Current treatment options are limited and often ineffective at restoring ovarian function. This review explores the role of autophagy— a cellular process that helps maintain homeostasis by recycling damaged components—in the development and potential treatment of POF. Autophagy is crucial for the survival of follicle cells and can be disrupted by various stressors associated with POF, such as oxidative damage and mitochondrial dysfunction. We review several key molecular pathways involved in autophagy, including the PI3K/AKT/mTOR, PINK1-Parkin, JAK2/STAT3, MAPK and AMPK/FOXO3a pathways, which have been implicated in POF. Each pathway offers unique insights into how autophagy can be modulated to counteract POF-related damage. Additionally, we discuss emerging therapeutic strategies that target these pathways, including chemical compounds, peptides, hormones, RNA therapy, extracellular vesicles and traditional Chinese medicine. These approaches aim to restore autophagic balance, promote follicle survival and improve ovarian function. By targeting autophagy, new treatments may offer hope for better management and potential reversal of POF, thus improving the quality of life for affected individuals.

{"title":"Targeting autophagy in premature ovarian failure: Therapeutic strategies from molecular pathways to clinical applications","authors":"Ziwen Ding, Genbao Shao, Mingyang Li","doi":"10.1016/j.lfs.2025.123473","DOIUrl":"10.1016/j.lfs.2025.123473","url":null,"abstract":"<div><div>Premature ovarian failure (POF) is a condition where the ovaries lose their function before the age of 40, leading to significant impacts on reproductive health and overall well-being. Current treatment options are limited and often ineffective at restoring ovarian function. This review explores the role of autophagy— a cellular process that helps maintain homeostasis by recycling damaged components—in the development and potential treatment of POF. Autophagy is crucial for the survival of follicle cells and can be disrupted by various stressors associated with POF, such as oxidative damage and mitochondrial dysfunction. We review several key molecular pathways involved in autophagy, including the PI3K/AKT/mTOR, PINK1-Parkin, JAK2/STAT3, MAPK and AMPK/FOXO3a pathways, which have been implicated in POF. Each pathway offers unique insights into how autophagy can be modulated to counteract POF-related damage. Additionally, we discuss emerging therapeutic strategies that target these pathways, including chemical compounds, peptides, hormones, RNA therapy, extracellular vesicles and traditional Chinese medicine. These approaches aim to restore autophagic balance, promote follicle survival and improve ovarian function. By targeting autophagy, new treatments may offer hope for better management and potential reversal of POF, thus improving the quality of life for affected individuals.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123473"},"PeriodicalIF":5.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiomyocyte-specific deletion of STING improves cardiac function, glucose homeostasis, and wound healing in diabetic mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-15 DOI: 10.1016/j.lfs.2025.123470

Xiaorong Li , Kai Guo , Qingju Zhou , Felycia Fernanda Hosyanto , Guoxiang Zhou , Yiying Zhang , Yuanjing Li , Shenglan Yang

Aims

The present study aimed to investigate the effects and underling mechanisms of cardiomyocyte-specific STING knockout on cardiac function and wound healing in diabetes.

Materials and methods

In this study, type 2 diabetes was induced in cardiomyocyte-specific STING knockout mice using a combination of a high-fat diet and streptozotocin. Cardiac function and remodeling were assessed by echocardiography and histopathological analysis. Glucose homeostasis was evaluated through insulin sensitivity tests and intraperitoneal glucose tolerance tests. Wound healing was quantified by measuring the wound area in diabetic mice.

Key findings

The results demonstrated that STING deletion in cardiomyocytes improved cardiac function in diabetic mice, which was accompanied by enhanced insulin sensitivity and improved glucose tolerance. Furthermore, the deletion of STING partially mitigated mitochondrial dysfunction in the myocardium. STING knockout in cardiomyocytes also facilitated angiogenesis and wound healing in diabetic mice.

Significance

Our findings suggest that cardiomyocyte-specific STING deletion enhances cardiac function, glucose homeostasis, and wound healing, indicating that targeting STING in the heart may serve as a promising therapeutic strategy for managing diabetes mellitus.

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引用次数: 0

Unravelling exosome paradigm: Therapeutic, diagnostic and theranostics application and regulatory consideration

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-15 DOI: 10.1016/j.lfs.2025.123472

Reetika Tandon, Nidhi Srivastava

In the recent decade, extracellular vesicles (EVs) have been released from nearly all the kingdoms, modulating intercellular communication and maintaining the human body's homeostasis by regulating different cellular processes. Among EVs, exosomes are the emerging field in biopharmaceuticals. They have lipid bilayer ranging from 30 to 150 nm in size and encompass DNA, RNA, protein lipids, etc. Their sources are widespread, easy to acquire, and cost-effective in manufacturing. This review focuses on the detailed classification of exosomes existing in nature, knowledge and application of omics, therapeutic, diagnostic and theranostic application of exosomes. It covers diseases such as cancer, infectious diseases (viral, bacterial, fungal infections), neurodegenerative diseases, metabolic diseases, lifestyle diseases (diabetes, cardiovascular, gastric disorder (IBD)), autoimmune disorders and their biodistribution. This article unfolds the recent progress in the exosomes arena and covers all the regulatory considerations (FDA, EMA, and other nations) involved with it. Moreover, a detailed discussion about clinical trials and its manifestation with exosomes and challenges associated with their isolation procedures, reproducibility, and safety concerns.

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引用次数: 0

Stress hyperglycemia in acute pancreatitis: From mechanisms to prognostic implications

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-15 DOI: 10.1016/j.lfs.2025.123469

Yuting Guan , Guoqing Liu , Feimin Tang , Xiangmin Wu , Jian Shi , Qiongguang Huang

Acute pancreatitis (AP) is an inflammatory reaction of the pancreas. When the disease is severe, it is often accompanied by destruction of the pancreatic islets, resulting in dysfunction of the endocrine system of the pancreas. Stress hyperglycemia is a transient increase in glucose during a critical illness, and its possible mechanism is related to abnormal glucose metabolism and insulin resistance due to the increased release of counterregulatory hormones and cytokines, such as glucagon, cortisol, and catecholamines. Numerous studies have shown that stress hyperglycemia is strongly associated with morbidity, mortality, and increased risk of post-acute pancreatitis diabetes in AP patients. Therefore, stress hyperglycemia may be a significant independent risk factor for poor clinical outcomes and prognosis in patients with AP. This article reviews the clinical features, risk factors, and mechanisms of action of stress hyperglycemia in AP and its influence on adverse clinical outcomes and the prognosis of inpatients with AP. For AP patients with stress hyperglycemia, it is necessary to comprehensively consider their blood glucose levels, daily habits, and complications to develop an appropriate treatment plan for hyperglycemia. Limited evidence indicates that in the case of acute hyperglycemia in critically ill patients, especially during the first 3 days of hospitalization, insulin therapy should not be undertaken if the blood glucose level does not exceed 10 mmol/L. However, some important questions related to clinical practice remain to be answered. More clinical trials and studies are needed in the future to provide a sufficient basis for clinical practice.

{"title":"Stress hyperglycemia in acute pancreatitis: From mechanisms to prognostic implications","authors":"Yuting Guan , Guoqing Liu , Feimin Tang , Xiangmin Wu , Jian Shi , Qiongguang Huang","doi":"10.1016/j.lfs.2025.123469","DOIUrl":"10.1016/j.lfs.2025.123469","url":null,"abstract":"<div><div>Acute pancreatitis (AP) is an inflammatory reaction of the pancreas. When the disease is severe, it is often accompanied by destruction of the pancreatic islets, resulting in dysfunction of the endocrine system of the pancreas. Stress hyperglycemia is a transient increase in glucose during a critical illness, and its possible mechanism is related to abnormal glucose metabolism and insulin resistance due to the increased release of counterregulatory hormones and cytokines, such as glucagon, cortisol, and catecholamines. Numerous studies have shown that stress hyperglycemia is strongly associated with morbidity, mortality, and increased risk of post-acute pancreatitis diabetes in AP patients. Therefore, stress hyperglycemia may be a significant independent risk factor for poor clinical outcomes and prognosis in patients with AP. This article reviews the clinical features, risk factors, and mechanisms of action of stress hyperglycemia in AP and its influence on adverse clinical outcomes and the prognosis of inpatients with AP. For AP patients with stress hyperglycemia, it is necessary to comprehensively consider their blood glucose levels, daily habits, and complications to develop an appropriate treatment plan for hyperglycemia. Limited evidence indicates that in the case of acute hyperglycemia in critically ill patients, especially during the first 3 days of hospitalization, insulin therapy should not be undertaken if the blood glucose level does not exceed 10 mmol/L. However, some important questions related to clinical practice remain to be answered. More clinical trials and studies are needed in the future to provide a sufficient basis for clinical practice.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"365 ","pages":"Article 123469"},"PeriodicalIF":5.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MiRNA-21-loaded chitosan nanoparticles ameliorate pancreatic apoptosis and oxidative stress in diabetic rats

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-14 DOI: 10.1016/j.lfs.2025.123471

Eman H. Thabet , Nehal A. Khalil , Marwa M. Essawy , Sahar A. Harby , Amany A. Solaiman , Hanaa M. El Gazaerly , Yassmin H. Khalifa

Background

Accelerated Pancreatic β-cell apoptosis and oxidative stress are the mainstays of type-1 diabetes. MicroRNA-21's (miRNA-21) role in regulating pancreatic β-cell function remains indefinable.

Material and methods

Five groups of rats were used in this study (healthy controls (Ia), controls that received only chitosan (CS) nanoparticles (NPs)(Ib), streptozotocin (STZ)-induced diabetics rats (II),STZ-induced diabetic rats that received only CS-NPs(III), and STZ-induced diabetic rats treated with mi-RNA-21-CS-NPs(IV). Sera were collected for measurement of fasting blood glucose levels (FBG), insulin, oxidative stress, and intraperitoneal glucose intolerance tests. Pancreatic tissue was collected after sacrifice partly for histological examination and for oxidative stress assessment and evaluation of PTEN/ AKT using qRT-PCR.

Key findings

We showed over-expression of cleaved-caspase-3 indicating accelerated apoptosis in the β-cell of STZ-induced diabetic rats. Apoptosis was significantly ameliorated by miRNA-21-CS. MiRNA-21-CS-NPs faithfully restored serum fasting insulin, and FBG, and reduced serum and pancreatic oxidative stress markers while enhancing the total antioxidant capacity. Histological examination revealed that miRNA-21 restored healthy β-cell architecture, decreased cleaved-caspase-3, and increased insulin secretion. Transmission electron microscopy revealed increased mitochondrial circularity that significantly correlated with an exaggerated oxidative stress profile as shown by high serum and pancreatic malondialdehyde (MDA), low glutathione peroxidase, and total antioxidant capacity in STZ-induced diabetes. This oxidative profile was reversed using miRNA-21-CS-NPs. Mi-RNA-21 therapy downregulated PTEN but increased AKT and pAKT expression. Altogether, we show that miRNA-21 restored normal islet β-cell structure and insulin secretion through PTEN inhibition.

Significance

miRNA-21- CS-NPs are promising targeted therapeutics that may effectively decrease the global burden of diabetes.

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引用次数: 0

Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-13 DOI: 10.1016/j.lfs.2025.123468

Kiran S. Satao, Gaurav M. Doshi

Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.

{"title":"Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders","authors":"Kiran S. Satao, Gaurav M. Doshi","doi":"10.1016/j.lfs.2025.123468","DOIUrl":"10.1016/j.lfs.2025.123468","url":null,"abstract":"<div><div>Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"365 ","pages":"Article 123468"},"PeriodicalIF":5.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oral microbiota in colorectal cancer: Unraveling mechanisms and application potential

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-11 DOI: 10.1016/j.lfs.2025.123462

Xinran Zhang , Yixin Chen , Yuwei Xia , Shenghao Lin , Xinlei Zhou , Xi Pang , Jieru Yu , Leitao Sun

Colorectal cancer (CRC), with a rising prevalence, is the third most commonly diagnosed cancer and the third leading cause of cancer-related death. Studies have shown that a complex interplay between the development of CRC and alterations in the oral microbiome. Recent advancements in genomics and metagenomics have highlighted the significant roles of certain oral microbes, particularly Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum), in the progression of CRC. However, the detailed mechanisms by which the oral microbiota influence CRC development remain unclear. This review aims to elucidate the role of oral microbiota in CRC progression, evaluate their potential as biomarkers, and explore therapeutic strategies targeting these microbes. This review offers insights into the mechanisms underlying the interaction between oral microbiota and CRC, underscoring the potential of oral microbes as diagnostic and prognostic biomarkers, as well as therapeutic targets. Future research should focus on clarifying the exact pathways and developing innovative therapeutic strategies to enhance the diagnosis and treatment.

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引用次数: 0

Neuronal calcium sensor 1: A key factor in the development of diseases

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-11 DOI: 10.1016/j.lfs.2025.123461

Duo Liu , Lingzhi Wang , Zhen Huang , Linxi Chen

Neuronal calcium sensor 1 (NCS1) belongs to the family of neuronal calcium sensing proteins, which are distributed in various tissues of the human body, mainly in nerve tissues. NCS1 has multiple functions, including participating in the transduction of intracellular calcium signals, neuronal morphology, development and exocytosis. NCS1 performs related functions by interacting with a variety of proteins, including inositol 1,4,5-trisphosphate receptors (InsP3Rs), voltage-gated K⁺ and Ca²⁺ channels, phosphatidylinositol 4-kinase IIIβ (PI (4) KIIIβ). Over the years, researches on NCS1 and diseases have mostly focused on the nervous system and cardiovascular system, it is found that the abnormal expression of NCS1 is also related to cancer. Starting from the structure of NCS1 and the proteins that interact with it, this review expounds the mechanism or potential mechanism of NCS1 imbalance leading to various diseases.

引用次数: 0

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