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Autophagy Jun 2023Each protein must be synthesized with the correct amino acid sequence, folded into its native structure, and transported to a relevant subcellular location and protein...
Each protein must be synthesized with the correct amino acid sequence, folded into its native structure, and transported to a relevant subcellular location and protein complex. If any of these steps fail, the cell has the capacity to break down aberrant proteins to maintain protein homeostasis (also called proteostasis). All cells possess a set of well-characterized protein quality control systems to minimize protein misfolding and the damage it might cause. Autophagy, a conserved pathway for the degradation of long-lived proteins, aggregates, and damaged organelles, was initially characterized as a bulk degradation pathway. However, it is now clear that autophagy also contributes to intracellular homeostasis by selectively degrading cargo material. One of the pathways involved in the selective removal of damaged and misfolded proteins is chaperone-assisted selective autophagy (CASA). The CASA complex is composed of three main proteins (HSPA, HSPB8 and BAG3), essential to maintain protein homeostasis in muscle and neuronal cells. A failure in the CASA complex, caused by mutations in the respective coding genes, can lead to (cardio)myopathies and neurodegenerative diseases. Here, we summarize our current understanding of the CASA complex and its dynamics. We also briefly discuss how CASA complex proteins are involved in disease and may represent an interesting therapeutic target. ALP: autophagy lysosomal pathway; ALS: amyotrophic lateral sclerosis; AMOTL1: angiomotin like 1; ARP2/3: actin related protein 2/3; BAG: BAG cochaperone; BAG3: BAG cochaperone 3; CASA: chaperone-assisted selective autophagy; CMA: chaperone-mediated autophagy; DNAJ/HSP40: DnaJ heat shock protein family (Hsp40); DRiPs: defective ribosomal products; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK1/HRI: eukaryotic translation initiation factor 2 alpha kinase 1; GABARAP: GABA type A receptor-associated protein; HDAC6: histone deacetylase 6; HSP: heat shock protein; HSPA/HSP70: heat shock protein family A (Hsp70); HSP90: heat shock protein 90; HSPB8: heat shock protein family B (small) member 8; IPV: isoleucine-proline-valine; ISR: integrated stress response; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LATS1: large tumor suppressor kinase 1; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOC: microtubule organizing center; MTOR: mechanistic target of rapamycin kinase; NFKB/NF-κB: nuclear factor kappa B; NFE2L2: NFE2 like bZIP transcription factor 2; PLCG/PLCγ: phospholipase C gamma; polyQ: polyglutamine; PQC: protein quality control; PxxP: proline-rich; RAN translation: repeat-associated non-AUG translation; SG: stress granule; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; STK: serine/threonine kinase; SYNPO: synaptopodin; TBP: TATA-box binding protein; TARDBP/TDP-43: TAR DNA binding protein; TFEB: transcription factor EB; TPR: tetratricopeptide repeats; TSC1: TSC complex subunit 1; UBA: ubiquitin associated; UPS: ubiquitin-proteasome system; WW: tryptophan-tryptophan; WWTR1: WW domain containing transcription regulator 1; YAP1: Yes1 associated transcriptional regulator.
Topics: Autophagy; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Heat-Shock Proteins; Molecular Chaperones; Intracellular Signaling Peptides and Proteins; Ubiquitins
PubMed: 36594740
DOI: 10.1080/15548627.2022.2160564 -
Clinical Nutrition (Edinburgh, Scotland) Dec 2023Studies have suggested a possible relevance between branched-chain amino acid (BCAA) catabolic enzymes and cancers. However, few studies have explored the variation in...
BACKGROUND
Studies have suggested a possible relevance between branched-chain amino acid (BCAA) catabolic enzymes and cancers. However, few studies have explored the variation in circulating concentrations of BCAAs. Our study used bi-directional, two-sample Mendelian randomization (MR) analysis for predicting the causality between the BCAA levels and 9 types of cancers.
METHODS
The largest genome-wide association studies (GWAS) provided data for total BCAAs, valine, leucine, and isoleucine from the UK Biobank. Data on multiple cancer endpoints were collected from various sources, such as the International Lung Cancer Consortium (ILCCO), the Pancreatic Cancer Cohort Consortium 1 (PanScan1), the Breast Cancer Association Consortium (BCAC), the FinnGen Biobank, and the Ovarian Cancer National Alliance (OCAC). The mainly analysis method was the inverse-variance-weighted (IVW). For assessing horizontal pleiotropy, the researchers performed MR-Egger regression and MR-PRESSO global test. Finally, the Cochran's Q test served for evaluating the heterogeneity.
RESULTS
Circulating total BCAAs levels (OR 1.708, 95%CI 1.168, 2.498; p = 0.006), valine levels (OR 1.747, 95%CI 1.217, 2.402; p < 0.001), leucine levels (OR 1.923, 95%CI 1.279, 2.890; p = 0.002) as well as isoleucine levels (OR 1.898, 95%CI 1.164, 3.094; p = 0.010) positively correlated with the squamous cell lung cancer risk. Nevertheless, no compelling evidence was found to support a causal link between BCAAs and any other examined cancers.
CONCLUSIONS
Increased circulating total-BCAAs levels, leucine levels, isoleucine levels and valine levels had higher hazard of squamous cell lung cancer. No such associations were found for BCAAs with other cancers.
Topics: Humans; Female; Isoleucine; Mendelian Randomization Analysis; Leucine; Genome-Wide Association Study; Amino Acids, Branched-Chain; Valine; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Lung Neoplasms
PubMed: 37922693
DOI: 10.1016/j.clnu.2023.10.019 -
Metabolites Sep 2023Jasmonates (JAs), including jasmonic acid (JA), its precursor 12-oxo-phytodienoic acid (OPDA) and its derivatives jasmonoyl-isoleucine (JA-Ile), methyl jasmonate (MeJA),... (Review)
Review
Jasmonates (JAs), including jasmonic acid (JA), its precursor 12-oxo-phytodienoic acid (OPDA) and its derivatives jasmonoyl-isoleucine (JA-Ile), methyl jasmonate (MeJA), -jasmone (CJ) and other oxylipins, are important in the regulation of a range of ecological interactions of plants with their abiotic and particularly their biotic environments. Plant secondary/specialized metabolites play critical roles in implementing these ecological functions of JAs. Pathway and transcriptional regulation analyses have established a central role of JA-Ile-mediated core signaling in promoting the biosynthesis of a great diversity of secondary metabolites. Here, we summarized the advances in JAs-induced secondary metabolites, particularly in secondary metabolites induced by OPDA and volatile organic compounds (VOCs) induced by CJ through signaling independent of JA-Ile. The roles of JAs in integrating and coordinating the primary and secondary metabolism, thereby orchestrating plant growth-defense tradeoffs, were highlighted and discussed. Finally, we provided perspectives on the improvement of the adaptability and resilience of plants to changing environments and the production of valuable phytochemicals by exploiting JAs-regulated secondary metabolites.
PubMed: 37755288
DOI: 10.3390/metabo13091008 -
Annual Review of Microbiology Sep 2023Amino acids are indispensable substrates for protein synthesis in all organisms and incorporated into diverse aspects of metabolic physiology and signaling. However,... (Review)
Review
Amino acids are indispensable substrates for protein synthesis in all organisms and incorporated into diverse aspects of metabolic physiology and signaling. However, animals lack the ability to synthesize several of them and must acquire these essential amino acids from their diet or perhaps their associated microbial communities. The essential amino acids therefore occupy a unique position in the health of animals and their relationships with microbes. Here we review recent work connecting microbial production and metabolism of essential amino acids to host biology, and the reciprocal impacts of host metabolism of essential amino acids on their associated microbes. We focus on the roles of the branched-chain amino acids (valine, leucine, and isoleucine) and tryptophan on host-microbe communication in the intestine of humans and other vertebrates. We then conclude by highlighting research questions surrounding the less-understood aspects of microbial essential amino acid synthesis in animal hosts.
Topics: Animals; Humans; Host Microbial Interactions; Amino Acids, Essential; Amino Acids, Branched-Chain; Leucine; Isoleucine
PubMed: 37339735
DOI: 10.1146/annurev-micro-032421-111819 -
Metabolites Aug 2023This review analyzed 21 scientific papers on the determination of amino acids in various types of cancer in saliva. Most of the studies are on oral cancer (8/21), breast... (Review)
Review
This review analyzed 21 scientific papers on the determination of amino acids in various types of cancer in saliva. Most of the studies are on oral cancer (8/21), breast cancer (4/21), gastric cancer (3/21), lung cancer (2/21), glioblastoma (2/21) and one study on colorectal, pancreatic, thyroid and liver cancer. The amino acids alanine, valine, phenylalanine, leucine and isoleucine play a leading role in the diagnosis of cancer via the saliva. In an independent version, amino acids are rarely used; the authors combine either amino acids with each other or with other metabolites, which makes it possible to obtain high values of sensitivity and specificity. Nevertheless, a logical and complete substantiation of the changes in saliva occurring in cancer, including changes in salivary amino acid levels, has not yet been formed, which makes it important to continue research in this direction.
PubMed: 37623893
DOI: 10.3390/metabo13080950 -
Journal of Cerebral Blood Flow and... Sep 2023Cerebral venous thrombosis (CVT) is a special and easily misdiagnosed or undiagnosed subtype of stroke. To identify specific biomarkers with a high predictive ability...
Cerebral venous thrombosis (CVT) is a special and easily misdiagnosed or undiagnosed subtype of stroke. To identify specific biomarkers with a high predictive ability for the diagnosis of acute CVT, we performed metabolomic analysis in plasma samples from acute CVT patients and healthy controls and confirmed the results in validation cohorts. In the discovery stage, there were 343 differential metabolites, and the caffeine metabolism pathway and the biosynthesis pathway for the branched chain amino acids (BCAAs) valine, leucine, and isoleucine were two significant pathways between the CVT and healthy cohorts. The area under the curve (AUC) for metabolites associated with valine, leucine, and isoleucine biosynthesis was 0.934. In the validation stage, the BCAA concentrations demonstrated an AUC of 0.935 to differentiate patients with acute CVT from the control cohort. In addition, BCAAs combined with D-dimer levels were used to establish a diagnostic model for CVT, and the AUC was 0.951, showing good diagnostic efficacy of separating CVT patients from the control cohort. BCAAs as plasma biomarkers deserve to be further studied and even developed in clinical CVT management.
Topics: Humans; Amino Acids, Branched-Chain; Leucine; Isoleucine; Diagnosis, Differential; Valine; Biomarkers; Venous Thrombosis
PubMed: 37066688
DOI: 10.1177/0271678X231170037 -
Frontiers in Nutrition 2023As a terminal stage of various cardiovascular diseases, heart failure is of great concern due to its high mortality rate and limited treatment options. Researchers are... (Review)
Review
As a terminal stage of various cardiovascular diseases, heart failure is of great concern due to its high mortality rate and limited treatment options. Researchers are currently focusing their efforts on investigating the metabolism of carbohydrates, fatty acids, and amino acids to enhance the prognosis of cardiovascular diseases. Simultaneously, branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, play significant roles in blood glucose regulation, protein synthesis, and insulin sensitivity. However, disrupted BCAAs metabolism has been associated with conditions such as hypertension, obesity, and atherosclerosis. This article explores intricate metabolic pathways, unveiling the connection between disrupted BCAAs metabolism and the progression of heart failure. Furthermore, the article discusses therapeutic strategies, assesses the impact of BCAAs on cardiac dysfunction, and examines the potential of modulating BCAAs metabolism as a treatment for heart failure. BCAAs and their metabolites are also considered as biomarkers for evaluating cardiac metabolic risk. In conclusion, this article elucidates the multifaceted roles of BCAAs in heart failure and cardiovascular health, providing guidance for future research and intervention measures.
PubMed: 38075219
DOI: 10.3389/fnut.2023.1279066 -
Cell Reports May 2023Understanding the axis of the human microbiome and physiological homeostasis is an essential task in managing deep-space-travel-associated health risks. The NASA-led...
Understanding the axis of the human microbiome and physiological homeostasis is an essential task in managing deep-space-travel-associated health risks. The NASA-led Rodent Research 5 mission enabled an ancillary investigation of the gut microbiome, varying exposure to microgravity (flight) relative to ground controls in the context of previously shown bone mineral density (BMD) loss that was observed in these flight groups. We demonstrate elevated abundance of Lactobacillus murinus and Dorea sp. during microgravity exposure relative to ground control through whole-genome sequencing and 16S rRNA analyses. Specific functionally assigned gene clusters of L. murinus and Dorea sp. capable of producing metabolites, lactic acid, leucine/isoleucine, and glutathione are enriched. These metabolites are elevated in the microgravity-exposed host serum as shown by liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis. Along with BMD loss, ELISA reveals increases in osteocalcin and reductions in tartrate-resistant acid phosphatase 5b signifying additional loss of bone homeostasis in flight.
Topics: Humans; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Chromatography, Liquid; Travel; Tandem Mass Spectrometry; Space Flight
PubMed: 37080202
DOI: 10.1016/j.celrep.2023.112299