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Theranostics 2021Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and...
Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, . In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, . Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
Topics: Autophagy; Humans; Macroautophagy; Mitophagy; Organelles
PubMed: 33391472
DOI: 10.7150/thno.49860 -
Frontiers in Endocrinology 2023Insulin resistance (IR) plays a crucial role in the development and progression of metabolism-related diseases such as diabetes, hypertension, tumors, and nonalcoholic...
Insulin resistance (IR) plays a crucial role in the development and progression of metabolism-related diseases such as diabetes, hypertension, tumors, and nonalcoholic fatty liver disease, and provides the basis for a common understanding of these chronic diseases. In this study, we provide a systematic review of the causes, mechanisms, and treatments of IR. The pathogenesis of IR depends on genetics, obesity, age, disease, and drug effects. Mechanistically, any factor leading to abnormalities in the insulin signaling pathway leads to the development of IR in the host, including insulin receptor abnormalities, disturbances in the internal environment (regarding inflammation, hypoxia, lipotoxicity, and immunity), metabolic function of the liver and organelles, and other abnormalities. The available therapeutic strategies for IR are mainly exercise and dietary habit improvement, and chemotherapy based on biguanides and glucagon-like peptide-1, and traditional Chinese medicine treatments (e.g., herbs and acupuncture) can also be helpful. Based on the current understanding of IR mechanisms, there are still some vacancies to follow up and consider, and there is also a need to define more precise biomarkers for different chronic diseases and lifestyle interventions, and to explore natural or synthetic drugs targeting IR treatment. This could enable the treatment of patients with multiple combined metabolic diseases, with the aim of treating the disease holistically to reduce healthcare expenditures and to improve the quality of life of patients to some extent.
Topics: Insulin Resistance; Humans; Chronic Disease; Signal Transduction; Metabolic Diseases; Receptor, Insulin
PubMed: 37056675
DOI: 10.3389/fendo.2023.1149239 -
International Journal of Surgery... Sep 2016Hepatic ischemia reperfusion injury (IRI) is not only a pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues... (Review)
Review
Hepatic ischemia reperfusion injury (IRI) is not only a pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues and organs. Hepatic IRI can seriously impair liver function, even producing irreversible damage, which causes a cascade of multiple organ dysfunction. Many factors, including anaerobic metabolism, mitochondrial damage, oxidative stress and secretion of ROS, intracellular Ca(2+) overload, cytokines and chemokines produced by KCs and neutrophils, and NO, are involved in the regulation of hepatic IRI processes. Matrix Metalloproteinases (MMPs) can be an important mediator of early leukocyte recruitment and target in acute and chronic liver injury associated to ischemia. MMPs and neutrophil gelatinase-associated lipocalin (NGAL) could be used as markers of I-R injury severity stages. This review explores the relationship between factors and inflammatory pathways that characterize hepatic IRI, MMPs and current pharmacological approaches to this disease.
Topics: Animals; Antioxidants; Biomarkers; Cytokines; Genetic Therapy; Hepatectomy; Kupffer Cells; Leukocytes; Liver; Liver Diseases; Liver Transplantation; Male; Matrix Metalloproteinases; Mitochondria, Liver; Oxidative Stress; Prognosis; Reperfusion Injury; Risk Assessment
PubMed: 27255130
DOI: 10.1016/j.ijsu.2016.05.050 -
Nutrients Aug 2023Sarcopenia is an age-related disease characterized by loss of muscle strength, mass and performance. Malnutrition contributes to sarcopenia pathogenesis. The aim of this... (Review)
Review
The Role of Nutrition in the Treatment of Sarcopenia in Old Patients: From Restoration of Mitochondrial Activity to Improvement of Muscle Performance, a Systematic Review.
Sarcopenia is an age-related disease characterized by loss of muscle strength, mass and performance. Malnutrition contributes to sarcopenia pathogenesis. The aim of this systematic review is to analyze existing evidence on the efficacy of nutritional supplementation on muscle and mitochondrial health among sarcopenic or malnourished older adults. We included randomized controlled trials (RCTs) assessing the effect of branched-chain amino acid (BCAA), vitamin D and/or omega-3 polyunsaturated fatty acid (PUFA) on muscle mass, strength and performance and/or on mitochondrial activity and redox state in older sarcopenic and/or malnourished adults. The literature search was on MEDLINE, Embase and Cochrane Central, restricted to articles published in the last 10 years (2012-2022). Twelve RCTs with a total of 1337 subjects were included. BCAA with vitamin D significantly ameliorates appendicular muscle mass (4 RCTs), hand grip strength (4 RCTs), gait speed (3 RCTs), short physical performance battery (3 RCTs) or chair stand test (3 RCTs) among six out of nine RCTs. BCAA alone (2 RCTs) or PUFA (1 RCT) were not effective in improving muscle health. Mitochondrial function was significantly improved by the administration of BCAA alone (1 RCT) or in association with vitamin D (1 RCT). In conclusion, BCAA in association with vitamin D may be useful in the treatment of sarcopenia and boost mitochondrial bioenergetic and redox activity. PROSPERO CRD42022332288.
Topics: Humans; Aged; Sarcopenia; Muscles; Nutritional Status; Malnutrition; Vitamin D; Vitamins; Amino Acids, Branched-Chain; Mitochondria
PubMed: 37686735
DOI: 10.3390/nu15173703 -
Journal of the International Society of... May 2021Endurance athletes typically consume carbohydrate-rich diets to allow for optimal performance during competitions and intense training. However, acute exercise studies... (Meta-Analysis)
Meta-Analysis
Endurance athletes typically consume carbohydrate-rich diets to allow for optimal performance during competitions and intense training. However, acute exercise studies have revealed that training or recovery with low muscle glycogen stimulates factors of importance for mitochondrial biogenesis in addition to favourable metabolic adaptations in trained athletes. Compromised training quality and particularly lower intensities in peak intervals seem to be a major drawback from dietary interventions with chronic carbohydrate (CHO) restriction. Therefore, the concept of undertaking only selected training sessions with restricted CHO availability (periodized CHO restriction) has been proposed for endurance athletes. However, the overall performance effect of this concept has not been systematically reviewed in highly adapted endurance-trained athletes. We therefore conducted a meta-analysis of training studies that fulfilled the following criteria: a) inclusion of females and males demonstrating a VOmax ≥ 55 and 60 ml · kg · min, respectively; b) total intervention and training periods ≥ 1 week, c) use of interventions including training and/or recovery with periodized carbohydrate restriction at least three times per week, and d) measurements of endurance performance before and after the training period. The literature search resulted in 407 papers of which nine studies fulfilled the inclusion criteria. The subsequent meta-analysis demonstrated no overall effect of CHO periodization on endurance performance compared to control endurance training with normal (high) CHO availability (standardized mean difference = 0.17 [- 0.15, 0.49]; P = 0.29). Based on the available literature, we therefore conclude that periodized CHO restriction does not per se enhance performance in endurance-trained athletes. The review discusses different approaches to CHO periodization across studies with a focus on identifying potential physiological benefits.
Topics: Adaptation, Physiological; Diet, Carbohydrate-Restricted; Endurance Training; Female; Glycogen; Humans; Male; Muscle, Skeletal; Organelle Biogenesis; Physical Endurance
PubMed: 34001184
DOI: 10.1186/s12970-021-00435-3 -
Journal of Assisted Reproduction and... Jun 2023The storage and release of calcium ions (Ca2 +) in oocyte maturation and fertilization are particularly noteworthy features of the endoplasmic reticulum (ER). The ER... (Review)
Review
The storage and release of calcium ions (Ca2 +) in oocyte maturation and fertilization are particularly noteworthy features of the endoplasmic reticulum (ER). The ER is the largest organelle in the cell composed of rough ER, smooth ER, and nuclear envelope, and is the main site of protein synthesis, transport and folding, and lipid and steroid synthesis. An appropriate calcium signaling response can initiate oocyte development and embryogenesis, and the ER is the central link that initiates calcium signaling. The transition from immature oocytes to zygotes also requires many coordinated organelle reorganizations and changes. Therefore, the purpose of this review is to generalize information on the function, structure, interaction with other organelles, and spatiotemporal localization of the ER in mammalian oocytes. Mechanisms related to maintaining ER homeostasis have been extensively studied in recent years. Resolving ER stress through the unfolded protein response (UPR) is one of them. We combined the clinical problems caused by the ER in in vitro maturation (IVM), and the mechanisms of ER have been identified by single-cell RNA-seq. This article systematically reviews the functions of ER and provides a reference for assisted reproductive technology (ART) research.
Topics: Animals; Oocytes; Unfolded Protein Response; Endoplasmic Reticulum Stress; Oogenesis; Endoplasmic Reticulum; Mammals
PubMed: 37171741
DOI: 10.1007/s10815-023-02782-3 -
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins.Theranostics 2021Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence... (Review)
Review
Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
Topics: Animals; Cellular Microenvironment; Drug Delivery Systems; Drug Discovery; Humans; Lysosomes; Membrane Proteins; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 34373745
DOI: 10.7150/thno.62686 -
Traffic (Copenhagen, Denmark) Dec 2021Endoplasmic reticulum (ER)-to-Golgi trafficking is an essential and highly conserved cellular process. The coat protein complex-II (COPII) arm of the trafficking... (Review)
Review
Endoplasmic reticulum (ER)-to-Golgi trafficking is an essential and highly conserved cellular process. The coat protein complex-II (COPII) arm of the trafficking machinery incorporates a wide array of cargo proteins into vesicles through direct or indirect interactions with Sec24, the principal subunit of the COPII coat. Approximately one-third of all mammalian proteins rely on the COPII-mediated secretory pathway for membrane insertion or secretion. There are four mammalian Sec24 paralogs and three yeast Sec24 paralogs with emerging evidence of paralog-specific cargo interaction motifs. Furthermore, individual paralogs also differ in their affinity for a subset of sorting motifs present on cargo proteins. As with many aspects of protein trafficking, we lack a systematic and thorough understanding of the interaction of Sec24 with cargoes. This systematic review focuses on the current knowledge of cargo binding to both yeast and mammalian Sec24 paralogs and their ER export motifs. The analyses show that Sec24 paralog specificity of cargo (and cargo receptors) range from exclusive paralog dependence or preference to partial redundancy. We also discuss how the Sec24 secretion system is hijacked by viral (eg, VSV-G, Hepatitis B envelope protein) and bacterial (eg, the enteropathogenic Escherichia coli type III secretion system effector NleA/EspI) pathogens.
Topics: Animals; COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Mammals; Membrane Proteins; Protein Transport; Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Secretory Pathway
PubMed: 34533884
DOI: 10.1111/tra.12817 -
Mitochondrion Jul 2021Cell-free mitochondrial DNA (cf-mtDNA) is a marker of inflammatory disease and a predictor of mortality, but little is known about cf-mtDNA in relation to psychobiology.... (Review)
Review
Cell-free mitochondrial DNA (cf-mtDNA) is a marker of inflammatory disease and a predictor of mortality, but little is known about cf-mtDNA in relation to psychobiology. A systematic review of the literature reveals that blood cf-mtDNA varies in response to common real-world stressors including psychopathology, acute psychological stress, and exercise. Moreover, cf-mtDNA is inducible within minutes and exhibits high intra-individual day-to-day variation, highlighting the dynamic regulation of cf-mtDNA levels. We discuss current knowledge on the mechanisms of cf-mtDNA release, its forms of transport ("cell-free" does not mean "membrane-free"), potential physiological functions, putative cellular and neuroendocrine triggers, and factors that may contribute to cf-mtDNA removal from the circulation. A review of in vitro, pre-clinical, and clinical studies shows conflicting results around the dogma that physiological forms of cf-mtDNA are pro-inflammatory, opening the possibility of other physiological functions, including the cell-to-cell transfer of whole mitochondria. Finally, to enhance the reproducibility and biological interpretation of human cf-mtDNA research, we propose guidelines for blood collection, cf-mtDNA isolation, quantification, and reporting standards, which can promote concerted advances by the community. Defining the mechanistic basis for cf-mtDNA signaling is an opportunity to elucidate the role of mitochondria in brain-body interactions and psychopathology.
Topics: Brain; Cell-Free Nucleic Acids; DNA, Mitochondrial; Humans; Mitochondria; Signal Transduction
PubMed: 33839318
DOI: 10.1016/j.mito.2021.04.002 -
Cell Proliferation Oct 2023The liver is a common secondary metastasis site of many malignant tumours, such as the colorectum, pancreas, stomach, breast, prostate, and lung cancer. The clinical... (Review)
Review
The liver is a common secondary metastasis site of many malignant tumours, such as the colorectum, pancreas, stomach, breast, prostate, and lung cancer. The clinical management of liver metastases is challenging because of their strong heterogeneity, rapid progression, and poor prognosis. Now, exosomes, small membrane vesicles that are 40-160 nm in size, are released by tumour cells, namely, tumour-derived exosomes (TDEs), and are being increasingly studied because they can retain the original characteristics of tumour cells. Cell-cell communication via TDEs is pivotal for liver pre-metastatic niche (PMN) formation and liver metastasis; thus, TDEs can provide a theoretical basis to intensively study the potential mechanisms of liver metastasis and new insights into the diagnosis and treatment of liver metastasis. Here, we systematically review current research progress about the roles and possible regulatory mechanisms of TDE cargos in liver metastasis, focusing on the functions of TDEs in liver PMN formation. In addition, we discuss the clinical utility of TDEs in liver metastasis, including TDEs as potential biomarkers, and therapeutic approaches for future research reference in this field.
Topics: Humans; Exosomes; Liver Neoplasms; Cell Communication; Pancreas; Biomarkers, Tumor; Tumor Microenvironment; Neoplasm Metastasis
PubMed: 36941028
DOI: 10.1111/cpr.13452