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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 -
Biochemical Pharmacology Feb 2022Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids... (Meta-Analysis)
Meta-Analysis
Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs. In cancer, this provides rapid access to cholesterol to maintain continual synthesis of the plasma membrane. In this systematic review and meta-analysis, we summarise the current depth of understanding of the role of this metabolic pathway in pan-cancer development. A systematic search of PubMed, Scopus, Web of Science, and Cochrane Library for preclinical studies identified eight studies where cholesteryl ester concentrations were compared between tumour and adjacent-normal tissue, and 24 studies where cholesterol esterification was blocked by pharmacological or genetic approaches. Tumour tissue had a significantly greater concentration of cholesteryl esters than non-tumour tissue (p < 0.0001). Pharmacological or genetic inhibition of SOAT was associated with significantly smaller tumours of all types (p ≤ 0.002). SOAT inhibition increased tumour apoptosis (p = 0.007), CD8 + lymphocyte infiltration and cytotoxicity (p ≤ 0.05), and reduced proliferation (p = 0.0003) and metastasis (p < 0.0001). Significant risk of publication bias was found and may have contributed to a 32% overestimation of the meta-analysed effect size. Avasimibe, the most frequently used SOAT inhibitor, was effective at doses equivalent to those previously reported to be safe and tolerable in humans. This work indicates that SOAT inhibition should be explored in clinical trials as an adjunct to existing anti-neoplastic agents.
Topics: Animals; Anticholesteremic Agents; Antineoplastic Agents; Cholesterol; Clinical Trials as Topic; Esterification; Humans; Organic Anion Transporters; Tumor Burden; Urea; Xenograft Model Antitumor Assays
PubMed: 34407453
DOI: 10.1016/j.bcp.2021.114731 -
European Journal of Physical and... Aug 2023Muscle changes after stroke cannot be explained solely on the basis of corticospinal bundle damage. Muscle-specific changes contribute to limited functional recovery but...
INTRODUCTION
Muscle changes after stroke cannot be explained solely on the basis of corticospinal bundle damage. Muscle-specific changes contribute to limited functional recovery but have been poorly characterized.
EVIDENCE ACQUISITION
We conducted a systematic review of muscular changes occurring at the histological, neuromuscular and functional levels during the first year after the onset of post-stroke hemiplegia. A literature search was performed on PubMed, Embase and CINHAL databases up to November 2022 using a keyword combination comprising cerebral stroke, hemiplegic, atrophy, muscle structure, paresis, skeletal muscle fiber type, motor unit, oxidative stress, strength, motor control.
EVIDENCE SYNTHESIS
Twenty-seven trial reports were included in the review, out of 12,798 articles screened. Structural modifications described on the paretic side include atrophy, transformation of type II fibers into type I fibers, decrease in fiber diameter and apparent myofilament disorganization from the first week post-stroke up to the fourth month. Reported biochemical changes comprise the abnormal presence of lipid droplets and glycogen granules in the subsarcolemmal region during the first month post-stroke. At the neurophysiological level, studies indicate an early decrease in the number and activity of motor units, correlated with the degree of motor impairment. All these modifications were present to a lesser degree on the non-paretic side. Although only sparse data concerning the subacute stage are available, these changes seem to appear during the first two weeks post-stroke and continue up to the third or fourth month.
CONCLUSIONS
Considering these early pathophysiological changes on both the paretic and non-paretic sides, it seems crucial to promptly stimulate central and also peripheral muscular activation after stroke through specific rehabilitation programs focused on the maintenance of muscle capacities associated with neurological recovery or plasticity.
Topics: Humans; Hemiplegia; Muscles; Databases, Factual; Paresis; PubMed; Stroke
PubMed: 37695037
DOI: 10.23736/S1973-9087.23.07844-9 -
Cellular and Molecular Life Sciences :... Mar 2024Reputable evidence from multiple studies suggests that excessive and uncontrolled inflammation plays an indispensable role in mediating, amplifying, and protracting...
Reputable evidence from multiple studies suggests that excessive and uncontrolled inflammation plays an indispensable role in mediating, amplifying, and protracting acute lung injury (ALI). Traditionally, immunity and energy metabolism are regarded as separate functions regulated by distinct mechanisms, but recently, more and more evidence show that immunity and energy metabolism exhibit a strong interaction which has given rise to an emerging field of immunometabolism. Mammalian lungs are organs with active fatty acid metabolism, however, during ALI, inflammation and oxidative stress lead to a series metabolic reprogramming such as impaired fatty acid oxidation, increased expression of proteins involved in fatty acid uptake and transport, enhanced synthesis of fatty acids, and accumulation of lipid droplets. In addition, obesity represents a significant risk factor for ALI/ARDS. Thus, we have further elucidated the mechanisms of obesity exacerbating ALI from the perspective of fatty acid metabolism. To sum up, this paper presents a systematical review of the relationship between extensive fatty acid metabolic pathways and acute lung injury and summarizes recent advances in understanding the involvement of fatty acid metabolism-related pathways in ALI. We hold an optimistic believe that targeting fatty acid metabolism pathway is a promising lung protection strategy, but the specific regulatory mechanisms are way too complex, necessitating further extensive and in-depth investigations in future studies.
Topics: Animals; Acute Lung Injury; Fatty Acids; Inflammation; Lipopolysaccharides; Lung; Obesity; Humans
PubMed: 38456906
DOI: 10.1007/s00018-024-05131-4 -
Frontiers in Neuroscience 2022Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may...
Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism are commonly observed in early preclinical stages of major NDs, including Parkinson's disease (PD) and Alzheimer's disease (AD). Among the multitude of underlying defective molecular mechanisms that have been suggested in the past decades, dysregulation of inter-organellar communication through the so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type of subcellular organelle, to date, most focus has been put on defective communication between the ER and mitochondria in NDs, given these compartments are critical in neuronal survival. Contributions of other MCSs, notably those with endolysosomes and lipid droplets are emerging, supported as well by genetic studies, identifying genes functionally involved in lysosomal homeostasis. In this review, we summarize the molecular identity of the organelle interactome in yeast and mammalian cells, and critically evaluate the evidence supporting the contribution of disturbed MCSs to the general disrupted inter-organellar homeostasis in NDs, taking PD and AD as major examples.
PubMed: 35801175
DOI: 10.3389/fnins.2022.900338 -
Nutrients Feb 2021(1) Background: Milk fat globule membrane (MFGM), composing fat droplets responsible for lipid transport in breast milk, has been shown to possess immunological and... (Meta-Analysis)
Meta-Analysis
(1) Background: Milk fat globule membrane (MFGM), composing fat droplets responsible for lipid transport in breast milk, has been shown to possess immunological and antimicrobial effects. Standard formulas (SF) are devoid of MFGMs during the production process. The study's aim was to evaluate the safety and benefits of MFGMs supplementation in children. (2) Methods: We searched four databases for randomized controlled trials evaluating the supplementation of MFGMs in children. Growth parameters were chosen as the primary outcome. (3) Results: Twenty-four publications of seventeen studies were included. Meta-analyses assessing the primary outcomes at the age of 4 months included four studies (814 children) comparing the MFGM-supplemented formulas and SF, and two trials (549 children) comparing the MFGM-supplemented formulas and breastfeeding. The primary outcomes were non-inferior in all the experimental MFGM formulas compared to SF, or even represented more similar results to breastfed infants. The promising effects, including a lower incidence of acute otitis media and improved cognitive development, cannot be firmly confirmed due to the small amount of existing evidence. No significant adverse effects were reported in any of the assessed products. (4) Conclusions: The available data signaled beneficial effects and a good safety profile, requiring future research with well-designed trials.
Topics: Breast Feeding; Child Development; Cognition; Dietary Supplements; Female; Glycolipids; Glycoproteins; Humans; Infant; Infant Formula; Lipid Droplets; Male; Milk, Human; Randomized Controlled Trials as Topic
PubMed: 33668227
DOI: 10.3390/nu13030714 -
Pharmacology & Therapeutics Sep 2020Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its...
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
Topics: Cyclin-Dependent Kinases; Drug Resistance; E2F4 Transcription Factor; Holoenzymes; Humans; Lipid Droplets; Molecular Chaperones; Muscle Proteins; NF-kappa B; Neoplasms; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteostasis; Tumor Suppressor Protein p53; Ubiquitin
PubMed: 32442437
DOI: 10.1016/j.pharmthera.2020.107579 -
European Review For Medical and... Jun 2020Intravenous lipid emulsions (ILE) were developed many decades ago to supply nutritional requirements to patients unable to obtain adequate enteral nutrition. The utility...
OBJECTIVE
Intravenous lipid emulsions (ILE) were developed many decades ago to supply nutritional requirements to patients unable to obtain adequate enteral nutrition. The utility of ILE was extended to therapeutics, facilitating the delivery of drugs. More recently, the potential for ILE to act as an antidote for inversion of drug toxicity has been recognized. This review aims to summarize the literature on ILE therapy as an antidote. Suggested mechanisms of action, safety profile, and recommendations on the administration of ILE in cases of drug intoxication are highlighted.
MATERIALS AND METHODS
A complete literature survey was performed using the PubMed database search to collect available information regarding mechanisms of ILE action as an antidote, ILE administration for drug toxicity, and presentation of adverse events.
RESULTS
A total of 102 studies met the selection criteria for inclusion in the review. Mainly used for local anesthetics toxicity, ILE therapy has been expanded in clinical toxicology involving overdose treatment of drugs other than local anesthetics. Partitioning in a lipid phase of fat droplets is a mechanism named the lipid sink phenomenon that has primarily been described to explain this action of ILE and remains the most widely accepted. At the same time, recent research has also revealed several molecular mechanisms that may contribute to ILE efficacy.
CONCLUSIONS
ILE therapy comprises a recognized approach in clinical toxicology. Due to the lack of randomized clinical trials, recommendations on administration are based on animal studies and published cases. Thus, the constantly increased knowledge about ILE therapy supports the need for a detailed appraisal.
Topics: Anesthetics, Local; Animals; Antidotes; Drug-Related Side Effects and Adverse Reactions; Fat Emulsions, Intravenous; Humans
PubMed: 32633409
DOI: 10.26355/eurrev_202006_21708