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PloS One 2024Recent studies suggest a shared genetic architecture between muscle and bone, yet the underlying molecular mechanisms remain elusive. This study aims to identify the...
Recent studies suggest a shared genetic architecture between muscle and bone, yet the underlying molecular mechanisms remain elusive. This study aims to identify the functionally annotated genes with shared genetic architecture between muscle and bone using the most up-to-date genome-wide association study (GWAS) summary statistics from bone mineral density (BMD) and fracture-related genetic variants. We employed an advanced statistical functional mapping method to investigate shared genetic architecture between muscle and bone, focusing on genes highly expressed in muscle tissue. Our analysis identified three genes, EPDR1, PKDCC, and SPTBN1, which are highly expressed in muscle tissue and previously unlinked to bone metabolism. About 90% and 85% of filtered Single-Nucleotide Polymorphisms were in the intronic and intergenic regions for the threshold at P≤5×10-8 and P≤5×10-100, respectively. EPDR1 was highly expressed in multiple tissues, including muscles, adrenal glands, blood vessels, and the thyroid. SPTBN1 was highly expressed in all 30 tissue types except blood, while PKDCC was highly expressed in all 30 tissue types except the brain, pancreas, and skin. Our study provides a framework for using GWAS findings to highlight functional evidence of crosstalk between multiple tissues based on shared genetic architecture between muscle and bone. Further research should focus on functional validation, multi-omics data integration, gene-environment interactions, and clinical relevance in musculoskeletal disorders.
Topics: Humans; Bone and Bones; Bone Density; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Spectrin
PubMed: 38683846
DOI: 10.1371/journal.pone.0300535 -
Developmental Cell Apr 2024For an organ to maintain correct architecture and function, its diverse cellular components must coordinate their size and shape. Although cell-intrinsic mechanisms...
For an organ to maintain correct architecture and function, its diverse cellular components must coordinate their size and shape. Although cell-intrinsic mechanisms driving homotypic cell-cell coordination are known, it is unclear how cell shape is regulated across heterotypic cells. We find that epithelial cells maintain the shape of neighboring sense-organ glia-neuron units in adult Caenorhabditis elegans (C. elegans). Hsp co-chaperone UNC-23/BAG2 prevents epithelial cell shape from deforming, and its loss causes head epithelia to stretch aberrantly during animal movement. In the sense-organ glia, amphid sheath (AMsh), this causes progressive fibroblast growth factor receptor (FGFR)-dependent disruption of the glial apical cytoskeleton. Resultant glial cell shape alteration causes concomitant shape change in glia-associated neuron endings. Epithelial UNC-23 maintenance of glia-neuron shape is specific both spatially, within a defined anatomical zone, and temporally, in a developmentally critical period. As all molecular components uncovered are broadly conserved across central and peripheral nervous systems, we posit that epithelia may similarly regulate glia-neuron architecture cross-species.
PubMed: 38670103
DOI: 10.1016/j.devcel.2024.04.005 -
Urologiia (Moscow, Russia : 1999) Mar 2024To determine the effect of standard treatment on changes in the structural and functional properties of erythrocytes in obstructive and non-obstructive acute...
[Influence of standard treatment on changes in the structural and functional properties of circulation red blood cells in obstructive and non-obstructive acute pyelonephritis].
AIM
To determine the effect of standard treatment on changes in the structural and functional properties of erythrocytes in obstructive and non-obstructive acute pyelonephritis.
MATERIALS AND METHODS
The structural and functional properties of erythrocytes and their intracellular metabolism in 78 patients with a diagnosis of primary non-obstructive and secondary obstructive acute pyelonephritis, randomized by age, gender, and the minimum number of concomitant diseases were investigated.
RESULTS AND DISCUSSION
In acute non-obstructive pyelonephritis, changes of the content of proteins in circulating erythrocytes responsible for the structure formation and stabilization of the plasma membrane (-spectrin, anion transport protein, pallidin, protein 4.1), intracellular metabolism (anion transport protein, glutathione-S-transferase), membrane flexibility and shape (actin, tropomyosin) are insignificant, alike from acute obstructive pyelonephritis. In addition, processes of lipid peroxidation inside red blood cells are intensified, and oxidative stress develops with a decrease in the sorption capacity of erythrocytes, as well as the content and ratio of lipid fractions in the plasma membrane, which form the basis of the lipid components and play the main role in the sequencing of protein macromolecules and the normal metabolism of red blood cells.
CONCLUSION
In acute obstructive pyelonephritis, changes in the content and ratio of proteins and lipids in the erythrocyte membrane lead to functional rearrangements that are not corrected by standard treatment.
Topics: Humans; Pyelonephritis; Erythrocytes; Female; Male; Acute Disease; Adult; Middle Aged; Erythrocyte Membrane
PubMed: 38650402
DOI: No ID Found -
Biochemical and Biophysical Research... Jun 2024βIV-spectrin is a membrane-associated cytoskeletal protein that maintains the structural stability of cell membranes and integral proteins such as ion channels and...
βIV-spectrin is a membrane-associated cytoskeletal protein that maintains the structural stability of cell membranes and integral proteins such as ion channels and transporters. Its biological functions are best characterized in the brain and heart, although recently we discovered a fundamental new role in the vascular system. Using cellular and genetic mouse models, we reported that βIV-spectrin acts as a critical regulator of developmental and tumor-associated angiogenesis. βIV-spectrin was shown to selectively express in proliferating endothelial cells (EC) and suppress VEGF/VEGFR2 signaling by enhancing receptor internalization and degradation. Here we examined how these events impact the downstream kinase signaling cascades and target substrates. Based on quantitative phosphoproteomics, we found that βIV-spectrin significantly affects the phosphorylation of epigenetic regulatory enzymes in the nucleus, among which DNA methyltransferase 1 (DNMT1) was determined as a top substrate. Biochemical and immunofluorescence results showed that βIV-spectrin inhibits DNMT1 function by activating ERK/MAPK, which in turn phosphorylates DNMT1 at S717 to impede its nuclear localization. Given that DNMT1 controls the DNA methylation patterns genome-wide, and is crucial for vascular development, our findings suggest that epigenetic regulation is a key mechanism by which βIV-spectrin suppresses angiogenesis.
Topics: DNA (Cytosine-5-)-Methyltransferase 1; Animals; Proteomics; MAP Kinase Signaling System; Mice; Phosphorylation; Humans; Neovascularization, Physiologic; Spectrin; Phosphoproteins; Neovascularization, Pathologic; Human Umbilical Vein Endothelial Cells; Endothelial Cells; Angiogenesis
PubMed: 38613866
DOI: 10.1016/j.bbrc.2024.149916 -
Infection, Genetics and Evolution :... Jun 2024Sepsis and multidrug resistance comprise a complex of factors attributable to mortality among intensive care unit (ICU) patients globally. Pathogens implicated in sepsis...
A sophisticated virulence repertoire and colistin resistance of Citrobacter freundii ST150 from a patient with sepsis admitted to ICU in a tertiary care hospital in Uganda, East Africa: Insight from genomic and molecular docking analyses.
Sepsis and multidrug resistance comprise a complex of factors attributable to mortality among intensive care unit (ICU) patients globally. Pathogens implicated in sepsis are diverse, and their virulence and drug resistance remain elusive. From a tertiary care hospital ICU in Uganda, we isolated a Citrobacter freundii strain RSM030 from a patient with sepsis and phenotypically tested it against a panel of 16 antibiotics including imipenem levofloxacin, cotrimoxazole and colistin, among others. We sequenced the organism's genome and integrated multilocus sequencing (MLST), PathogenFinder with Virulence Factor analyzer (VFanalyzer) to establish its pathogenic relevance. Thereafter, we combined antiSMASH and PRISM genome mining with molecular docking to predict biosynthetic gene clusters (BGCs), pathways, toxin structures and their potential targets in-silico. Finally, we coupled ResFinder with comprehensive antibiotic resistance database (CARD) to scrutinize the genomic antimicrobial resistance profile of the isolate. From PathogenFinder and MLST, this organism was confirmed to be a human pathogen (p = 0.843), sequence type (ST)150, whose virulence is determined by chromosomal type III secretion system (T3SS) (the injectosome) and plasmid-encoded type IV secretion system (T4SS), the enterobactin biosynthetic gene cluster and biofilm formation through the pgaABCD operon. Pathway and molecular docking analyses revealed that the shikimate pathway can generate a toxin targeting multiple host proteins including spectrin, detector of cytokinesis protein 2 (Dock2) and plasmalemma vesicle-associated protein (PLVAP), potentially distorting the host cell integrity. From phenotypic antibiotic testing, we found indeterminate results for amoxicillin/clavulanate and levofloxacin, with resistance to cotrimoxazole and colistin. Detailed genome analysis revealed chromosomal beta lactam resistance genes, i.e. blaCMY-79, blaCMY-116 and blaTEM-1B, along with multiple mutations of the lipopolysaccharide modifying operon genes PmrA/PmrB, pmrD, mgrA/mgrB and PhoP/PhoQ, conferring colistin resistance. From these findings, we infer that Citrobacter freundii strain RSM030 is implicated in sepsis and resistance to standard antibiotics, including colistin, the last resort.
Topics: Humans; Sepsis; Molecular Docking Simulation; Anti-Bacterial Agents; Citrobacter freundii; Tertiary Care Centers; Uganda; Enterobacteriaceae Infections; Intensive Care Units; Colistin; Virulence; Microbial Sensitivity Tests; Genomics; Drug Resistance, Bacterial; Genome, Bacterial; Multilocus Sequence Typing; Drug Resistance, Multiple, Bacterial; Virulence Factors
PubMed: 38604286
DOI: 10.1016/j.meegid.2024.105591 -
Biochimica Et Biophysica Acta. General... Jun 2024Deregulation of cell death is a common characteristic of cancer, and resistance to this process often occurs in lung cancer. Understanding the molecular mechanisms...
BACKGROUND
Deregulation of cell death is a common characteristic of cancer, and resistance to this process often occurs in lung cancer. Understanding the molecular mechanisms underlying an aberrant cell death is important. Recent studies have emphasized the involvement of calmodulin-regulated spectrin-associated protein 3 (CAMSAP3) in lung cancer aggressiveness, its influence on cell death regulation remains largely unexplored.
METHODS
CAMSAP3 was knockout in lung cancer cells using CRISPR-Cas9 system. Cell death and autophagy were evaluated using MTT and autophagic detection assays. Protein interactions were performed by proteomic analysis and immunoprecipitation. Protein expressions and their cytoplasmic localization were analyzed through immunoblotting and immunofluorescence techniques.
RESULTS
This study reveals a significant correlation between low CAMSAP3 expression and poor overall survival rates in lung cancer patients. Proteomic analysis identified high mobility group box 1 (HMGB1) as a candidate interacting protein involved in the regulation of cell death. Treatment with trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs) resulted in increased HMGB1 acetylation and its translocation to the cytoplasm and secretion, thereby inducing autophagic cell death. However, this process was diminished in CAMSAP3 knockout lung cancer cells. Mechanistically, immunoprecipitation indicated an interaction between CAMSAP3 and HMGB1, particularly with its acetylated form, in which this complex was elevated in the presence of TSA.
CONCLUSIONS
CAMSAP3 is prerequisite for TSA-mediated autophagic cell death by interacting with cytoplasmic acetylated HMGB1 and enhancing its release.
SIGNIFICANT
This finding provides molecular insights into the role of CAMSAP3 in regulating cell death, highlighting its potential as a therapeutic target for lung cancer treatment.
Topics: Humans; HMGB1 Protein; Lung Neoplasms; Acetylation; Autophagy; Cell Line, Tumor; Cell Death; A549 Cells; Hydroxamic Acids
PubMed: 38598971
DOI: 10.1016/j.bbagen.2024.130614 -
Brain & NeuroRehabilitation Mar 2024Traumatic brain injury (TBI) is a complex condition characterized by a multifaceted pathophysiology. It presents significant diagnostic and prognostic challenges in... (Review)
Review
Traumatic brain injury (TBI) is a complex condition characterized by a multifaceted pathophysiology. It presents significant diagnostic and prognostic challenges in clinical settings. This narrative review explores the evolving role of biofluid biomarkers as essential tools in the diagnosis, prognosis, and treatment of TBI. In recent times, preclinical and clinical trials utilizing these biofluid biomarkers have been actively pursued internationally. Among the biomarkers for nerve tissue proteins are neuronal biomarkers like neuronal specific enolase and ubiquitin C-terminal hydrolase L1; astroglia injury biomarkers such as S100B and glial fibrillary acidic protein; axonal injury and demyelination biomarkers, including neurofilaments and myelin basic protein; new axonal injury and neurodegeneration biomarkers like total tau and phosphorylated tau; and others such as spectrin breakdown products and microtubule-associated protein 2. The interpretation of these biomarkers can be influenced by various factors, including secretion from organs other than the injury site and systemic conditions. This review highlights the potential of these biomarkers to transform TBI management and emphasizes the need for continued research to validate their efficacy, refine testing platforms, and ultimately improve patient care and outcomes.
PubMed: 38585027
DOI: 10.12786/bn.2024.17.e8 -
Annals of Neurosciences Jan 2024Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain and is a non-proteinogenic amino acid. Doxorubcin (DOX) or adriamycin is...
BACKGROUND
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain and is a non-proteinogenic amino acid. Doxorubcin (DOX) or adriamycin is one of the most potent chemotherapy drugs for breast cancer.
PURPOSE
This study focused on diminishing the brain injury and neurotoxicity of doxorubicin (DOX) by GABA administration.
METHODS
Rats were randomly divided into four groups (8 rats each), which were the control group, DOX group (3 mg/kg for 4 weeks, then 2 mg/kg for 2 weeks), GABA group (2 mg/kg for 21 days), and DOX + GABA group (treated as the second and third groups). Neurotoxicity and brain injury were assessed by determining CSF biomarkers, serum inflammatory markers, and histopathological evaluation of the cerebral cortex.
RESULTS
DOX treatment significantly increased the levels of all CSF biomarkers (S100B, IL-1β, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), spectrin breakdown products (SBDP145), and C-C motif chemokine ligand 2 (CCL2) and all inflammatory markers (IL-6, TNF-α, and IFN-γ), causing extensive neutrophilic infiltration and great alteration in the cerebral cortex architecture as evidence of neurotoxicity. The oral administration of GABA significantly reduced the levels of all CSF biomarkers and inflammatory markers and restored the normal architecture of the cerebral cortex, with observed ameliorations in neutrophilic infiltration.
CONCLUSION
GABA administration can ameliorate neurotoxicity and protect the brain against the negative effects of DOX treatment.
PubMed: 38584977
DOI: 10.1177/09727531231161911 -
The Journal of Biological Chemistry May 2024Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the...
Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study, we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localize to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52 to 53, localized to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four-and-half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in the maintenance and/or regulation of sarcomeric organization and function.
Topics: Animals; Humans; Mice; Rats; Connectin; Cytoskeletal Proteins; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; LIM-Homeodomain Proteins; Microfilament Proteins; Muscle Proteins; Myocytes, Cardiac; Nerve Tissue Proteins; Nuclear Proteins; Protein Binding; Sarcomeres; Transcription Factors
PubMed: 38569934
DOI: 10.1016/j.jbc.2024.107254 -
NPJ Microgravity Mar 2024Exercise-induced mechanical loading can increase bone strength whilst mechanical unloading enhances bone-loss. Here, we investigated the role of lncRNA NONMMUT004552.2...
Exercise-induced mechanical loading can increase bone strength whilst mechanical unloading enhances bone-loss. Here, we investigated the role of lncRNA NONMMUT004552.2 in unloading-induced bone-loss. Knockout of lncRNA NONMMUT004552.2 in hindlimb-unloaded mice caused an increase in the bone formation and osteoblast activity. The silencing of lncRNA NONMMUT004552.2 also decreased the osteoblast apoptosis and expression of Bax and cleaved caspase-3, increased Bcl-2 protein expression in MC3T3-E1 cells. Mechanistic investigations demonstrated that NONMMUT004552.2 functions as a competing endogenous RNA (ceRNA) to facilitate the protein expression of spectrin repeat containing, nuclear envelope 1 (Syne1) by competitively binding miR-15b-5p and subsequently inhibits the osteoblast differentiation and bone formation in the microgravity unloading environment. These data highlight the importance of the lncRNA NONMMUT004552.2/miR-15b-5p/Syne1 axis for the treatment of osteoporosis.
PubMed: 38521778
DOI: 10.1038/s41526-024-00382-8