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Medicina Clinica Apr 2024Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition caused by decreased plasma and tissue levels of alpha-1 antitrypsin (AAT) that can lead to serious... (Review)
Review
Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition caused by decreased plasma and tissue levels of alpha-1 antitrypsin (AAT) that can lead to serious lung and liver disease in children and adults. AATD patients face challenges such as under diagnosis, clinical variability, and limited treatment options for liver disease. Early detection and biomarkers for predicting outcomes are needed to improve patient outcome. Currently, the only approved pharmacological therapy is augmentation therapy, which can delay the progression of emphysema. However, alternative strategies such as gene therapy, induced pluripotent stem cells, and prevention of AAT polymerization inside hepatocytes are being investigated. This review aims to summarize and update current knowledge on AATD, identify areas of controversy, and formulate questions for further research.
Topics: Adult; Child; Humans; alpha 1-Antitrypsin Deficiency; Biomarkers; Lung; Pulmonary Disease, Chronic Obstructive
PubMed: 37993348
DOI: 10.1016/j.medcli.2023.10.014 -
Bioscience Reports Oct 2023Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a...
Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a special role in the body as a coenzyme necessary for the metabolism of carbohydrates, fats and proteins. In addition, it participates in the cellular respiration and oxidation of fatty acids: in malnourished people, high doses of glucose result in acute thiamine deficiency. It also participates in energy production in the mitochondria and protein synthesis. In addition, it is also needed to ensure the proper functioning of the central and peripheral nervous system, where it is involved in neurotransmitter synthesis. Its deficiency leads to mitochondrial dysfunction, lactate and pyruvate accumulation, and consequently to focal thalamic degeneration, manifested as Wernicke's encephalopathy or Wernicke-Korsakoff syndrome. It can also lead to severe or even fatal neurologic and cardiovascular complications, including heart failure, neuropathy leading to ataxia and paralysis, confusion, or delirium. The most common risk factor for thiamine deficiency is alcohol abuse. This paper presents current knowledge of the biological functions of thiamine, its antioxidant properties, and the effects of its deficiency in the body.
Topics: Humans; Thiamine; Thiamine Deficiency; Korsakoff Syndrome; Wernicke Encephalopathy; Vitamin B Complex; Malnutrition
PubMed: 37389565
DOI: 10.1042/BSR20230374 -
Nature Jul 2023In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle, when mitogen signalling engages a positive...
In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle, when mitogen signalling engages a positive feedback loop between cyclin A2/cyclin-dependent kinase 2 (CDK2) and the retinoblastoma protein. Contrary to this textbook model, here we show that the decision to proliferate is actually fully reversible. Instead, we find that all cycling cells will exit the cell cycle in the absence of mitogens unless they make it to mitosis and divide first. This temporal competition between two fates, mitosis and cell cycle exit, arises because cyclin A2/CDK2 activity depends upon CDK4/6 activity throughout the cell cycle, not just in G1 phase. Without mitogens, mitosis is only observed when the half-life of cyclin A2 protein is long enough to sustain CDK2 activity throughout G2/M. Thus, cells are dependent on mitogens and CDK4/6 activity to maintain CDK2 activity and retinoblastoma protein phosphorylation throughout interphase. Consequently, even a 2-h delay in a cell's progression towards mitosis can induce cell cycle exit if mitogen signalling is lost. Our results uncover the molecular mechanism underlying the restriction point phenomenon, reveal an unexpected role for CDK4/6 activity in S and G2 phases and explain the behaviour of all cells following loss of mitogen signalling.
Topics: Animals; Cell Cycle; Cyclin A2; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; G2 Phase; Mitogens; Mitosis; Phosphorylation; Retinoblastoma Protein; Cyclin-Dependent Kinase 6; S Phase; G1 Phase
PubMed: 37407814
DOI: 10.1038/s41586-023-06274-3 -
Redox Biology Aug 2023Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value is extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1...
OBJECTIVE
Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value is extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1 (LUZP1) plays critical roles in cardiovascular development, and this study is designed for determining its function and mechanism in DOX-induced cardiotoxicity.
METHODS
Cardiac-specific Luzp1 knockout (cKO) and transgenic (cTG) mice received a single or repeated DOX injections to establish acute and chronic cardiotoxicity. Biomarkers of inflammation, oxidative damage and cell apoptosis were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Meanwhile, primary cardiomyocytes were applied to confirm the beneficial effects of LUZP1 in depth.
RESULTS
LUZP1 was upregulated in DOX-injured hearts and cardiomyocytes. Cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated DOX-associated inflammation, oxidative damage, cell apoptosis and acute cardiac injury. Mechanistic studies revealed that LUZP1 ameliorated DOX-induced cardiotoxicity through activating 5'-AMP-activated protein kinase (AMPK) pathway, and AMPK deficiency abolished the cardioprotection of LUZP1. Further findings suggested that LUZP1 interacted with protein phosphatase 1 to activate AMPK pathway. Moreover, we determined that cardiac-specific LUZP1 overexpression could also attenuate DOX-associated chronic cardiac injury in mice.
CONCLUSION
LUZP1 attenuates DOX-induced inflammation, oxidative damage, cell apoptosis and ventricular impairment through regulating AMPK pathway, and gene therapy targeting LUZP1 may provide novel therapeutic approached to treat DOX-induced cardiotoxicity.
Topics: Mice; Animals; Cardiotoxicity; AMP-Activated Protein Kinases; Leucine Zippers; Doxorubicin; Myocytes, Cardiac; Oxidative Stress; Apoptosis; Heart Injuries; Inflammation; DNA-Binding Proteins
PubMed: 37354826
DOI: 10.1016/j.redox.2023.102780