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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 -
Clinical and Experimental Medicine Feb 2024This review provides a concise overview of the cellular and clinical aspects of the role of zinc, an essential micronutrient, in human physiology and discusses... (Review)
Review
This review provides a concise overview of the cellular and clinical aspects of the role of zinc, an essential micronutrient, in human physiology and discusses zinc-related pathological states. Zinc cannot be stored in significant amounts, so regular dietary intake is essential. ZIP4 and/or ZnT5B transport dietary zinc ions from the duodenum into the enterocyte, ZnT1 transports zinc ions from the enterocyte into the circulation, and ZnT5B (bidirectional zinc transporter) facilitates endogenous zinc secretion into the intestinal lumen. Putative promoters of zinc absorption that increase its bioavailability include amino acids released from protein digestion and citrate, whereas dietary phytates, casein and calcium can reduce zinc bioavailability. In circulation, 70% of zinc is bound to albumin, and the majority in the body is found in skeletal muscle and bone. Zinc excretion is via faeces (predominantly), urine, sweat, menstrual flow and semen. Excessive zinc intake can inhibit the absorption of copper and iron, leading to copper deficiency and anaemia, respectively. Zinc toxicity can adversely affect the lipid profile and immune system, and its treatment depends on the mode of zinc acquisition. Acquired zinc deficiency usually presents later in life alongside risk factors like malabsorption syndromes, but medications like diuretics and angiotensin-receptor blockers can also cause zinc deficiency. Inherited zinc deficiency condition acrodermatitis enteropathica, which occurs due to mutation in the SLC39A4 gene (encoding ZIP4), presents from birth. Treatment involves zinc supplementation via zinc gluconate, zinc sulphate or zinc chloride. Notably, oral zinc supplementation may decrease the absorption of drugs like ciprofloxacin, doxycycline and risedronate.
Topics: Humans; Copper; Zinc; Intestines; Ions; Cation Transport Proteins; Acrodermatitis
PubMed: 38367035
DOI: 10.1007/s10238-024-01302-6 -
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 Apr 2024Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor...
Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.
Topics: Animals; Female; Humans; Male; Mice; Cell Line, Tumor; CRISPR-Cas Systems; Gene Editing; Mutation; Neoplasms; SMARCB1 Protein; Tumor Suppressor Proteins; Multiprotein Complexes; Proteolysis; Ubiquitin
PubMed: 38538798
DOI: 10.1038/s41586-024-07250-1 -
Advances in Kidney Disease and Health Nov 2023The use of peritoneal dialysis (PD) has been associated with improved quality of life, cost-effectiveness, and better outcomes for patients with kidney failure. However,... (Review)
Review
The use of peritoneal dialysis (PD) has been associated with improved quality of life, cost-effectiveness, and better outcomes for patients with kidney failure. However, many patients utilizing PD for replacement therapy face numerous nutritional hurdles. As the use of PD continues to increase worldwide, malnutrition has become an increasingly recognized concern for patients undergoing PD. The nephrology community needs to recognize and treat malnutrition to promote optimal nutritional states for our patients. In this review, we discuss several factors that contribute to malnutrition and protein-energy wasting and explore the benefits and limitations of nutritional parameters used to assess protein-calorie malnutrition. We also emphasize updated guidelines on daily caloric, protein, and micronutrient recommendations, as well as their effects on electrolyte homeostasis.
Topics: Humans; Quality of Life; Nutritional Status; Peritoneal Dialysis; Malnutrition; Protein-Energy Malnutrition
PubMed: 38453271
DOI: 10.1053/j.akdh.2023.12.008