-
Frontiers in Bioscience (Landmark... Jun 2024Persistent hyperuricemia can lead to the generation and deposition of monosodium urate (MSU) crystals. This can trigger gouty arthritis (GA), which in turn induces...
BACKGROUND
Persistent hyperuricemia can lead to the generation and deposition of monosodium urate (MSU) crystals. This can trigger gouty arthritis (GA), which in turn induces inflammation. Activation of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the onset and progression of GA. Autophagy may have a dual effect on GA with regard to the NLRP3 inflammasome. Therefore, the present study aimed to gain a deeper comprehension of the interaction between autophagy and NLRP3 inflammasome activation is imperative for developing more efficacious treatments for GA.
METHODS
Peripheral blood monocytes (PBMCs) were first isolated from GA patients and healthy controls and underwent bulk RNA sequencing analysis. Overexpression and knockdown of dual specificity phosphatase 1 (DUSP1) was performed in THP-1 monocytes to investigate its role in the immune response and mitochondrial damage. The luciferase assay and Western blot analysis were used to study the interaction between autophagy and NLRP3 inflammasome activation.
RESULTS
Bulk RNA sequencing analysis showed significant upregulation of DUSP1 expression in PBMCs from GA patients compared to healthy controls. This result was subsequently verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). DUSP1 expression in human THP-1 monocytes was also shown to increase after MSU treatment. Downregulation of DUSP1 expression increased the secretion of inflammatory cytokines after MSU treatment, whereas the overexpression of DUSP1 decreased the secretion levels. Lipopolysaccharides (LPS) combined with adenosine-triphosphate (ATP) led to mitochondrial damage, which was rescued by overexpressing DUSP1. DUSP1 overexpression further increased the level of autophagy following MSU treatment, whereas downregulation of DUSP1 decreased autophagy. Treatment with the autophagy inhibitor 3-Methyladenine (3-MA) restored inflammatory cytokine secretion levels in the DUSP1 overexpression group. MSU caused pronounced pathological ankle swelling . However, DUSP1 overexpression significantly mitigated this phenotype, accompanied by significant downregulation of inflammatory cytokine secretion levels in the joint tissues.
CONCLUSIONS
This study revealed a novel function and mechanism for DUSP1 in promoting autophagy to mitigate the MSU-induced immune response in GA. This finding suggests potential diagnostic biomarkers and anti-inflammatory targets for more effective GA therapy.
Topics: Humans; Autophagy; Dual Specificity Phosphatase 1; Arthritis, Gouty; Uric Acid; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; THP-1 Cells; Male; Monocytes; Case-Control Studies; Female; Leukocytes, Mononuclear; Middle Aged
PubMed: 38940057
DOI: 10.31083/j.fbl2906222 -
Frontiers in Bioscience (Landmark... Jun 2024
Topics: Humans; Biomarkers; Dementia; Proteostasis Deficiencies; Protein Folding; Alzheimer Disease
PubMed: 38940055
DOI: 10.31083/j.fbl2906227 -
Frontiers in Bioscience (Landmark... Jun 2024This study aimed to elucidate the molecular mechanism through which C1q/tumor necrosis factor (TNF)-related protein 9 (CTRP9) acts in the formation and differentiation...
BACKGROUND
This study aimed to elucidate the molecular mechanism through which C1q/tumor necrosis factor (TNF)-related protein 9 (CTRP9) acts in the formation and differentiation of brown adipose tissue (BAT).
METHODS
Adenovirus particles encoding CTRP9 and green fluorescent protein were inoculated into the scapula of C57BL/6J mice and fed a high-fat diet for 8 weeks; the body weight, lipid droplet morphology, glucose tolerance, insulin tolerance, and protein expression levels were analyzed. In addition, CTRP9 adenovirus was transfected into brown preadipocytes, and differentiation was induced to identify the effect of CTRP9 overexpression on adipocyte differentiation.
RESULTS
CTRP9 overexpression significantly increased the weight gain of mice. Additionally, the CTRP9 overexpression group exhibited significantly increased adipose tissue weight and glucose clearance rates and decreased insulin sensitivity and serum triglyceride levels compared to the control group. Furthermore, CTRP9 overexpression significantly upregulated the adipose triglyceride lipase (ATGL) and perilipin 1 protein expression levels in BAT. The cell experiment results confirmed that CTRP9 overexpression significantly inhibited the adipogenesis of brown adipocytes as evidenced by the downregulation of uncoupling protein 1, beta-3 adrenergic receptor, ATGL, and hormone-sensitive lipase mRNA levels and the significant suppression of uncoupling protein 1, ATGL, and perilipin 1 protein levels in brown adipocytes.
CONCLUSIONS
The finding of this study demonstrated that CTRP9 promotes lipolysis by upregulating ATGL expression and inhibits the differentiation of brown preadipocytes .
Topics: Animals; Lipolysis; Diet, High-Fat; Adipose Tissue, Brown; Mice, Inbred C57BL; Male; Mice; Adiponectin; Insulin Resistance; Lipase; Cell Differentiation; Adipogenesis; Perilipin-1; Acyltransferases; Glycoproteins
PubMed: 38940054
DOI: 10.31083/j.fbl2906236 -
Frontiers in Bioscience (Landmark... Jun 2024Under fasting conditions, the pathway converting gluconeogenesis precursors into muscle glycogen becomes crucial due to reduced glycogen reserves. However, there is...
BACKGROUND
Under fasting conditions, the pathway converting gluconeogenesis precursors into muscle glycogen becomes crucial due to reduced glycogen reserves. However, there is limited research on skeletal muscle gluconeogenesis and the impact of fasting on gluconeogenic gene expression.
METHODS
Sheep fetal skeletal muscle cells cultured were used to study the effects of varying lactic acid concentrations (0 to 30 mM) and 2.5 mM glucose on the expression of gluconeogenesis-related genes after 6 h of fasting. The effects on mRNA and protein expression of key genes involved in skeletal muscle gluconeogenesis were measured by quantitative real time polymerase chain reaction (qRT-PCR), immunofluorescence, and western blotting at 48 h.
RESULTS
Fasting increased the expression of key gluconeogenic genes, fructose-1,6-bisphosphatase 2 (), glucose-6-phosphatase 3 (), pyruvate kinase M (), monocarboxylate transporter1 (), glucose transporter type 4 (), pyruvate carboxylase (), and lactate dehydrogenase A (). The mRNA levels of , , and significantly decreased with glucose addition. Additionally, 10 mM lactic acid significantly promoted the expression of , , , , , and while inhibiting phosphoenolpyruvate carboxykinase () expression. At the protein level, 10 mM lactic acid significantly increased FBP2 and PKM protein expression.
CONCLUSIONS
This study shows that fasting regulates key gluconeogenic gene expression in sheep skeletal muscle cells and highlights the role of lactic acid in inducing these gene expressions.
Topics: Animals; Gluconeogenesis; Sheep; Muscle, Skeletal; Gene Expression Regulation; Glucose; Cells, Cultured; Lactic Acid; Fructose-Bisphosphatase
PubMed: 38940053
DOI: 10.31083/j.fbl2906237 -
Frontiers in Bioscience (Landmark... Jun 2024Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the... (Review)
Review
Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the forkhead box (FOX) proteins, characterized by a conserved DNA-binding domain, play vital roles in various cellular processes, including cancer. The FOXA subfamily, encompassing FOXA1, FOXA2, and FOXA3, stands out for its pivotal role in mammalian development. FOXA1, initially identified in the liver, exhibits diverse expression across multiple organ tissues and plays a critical role in cell proliferation, differentiation, and tumor development. Its structural composition includes transactivation domains and a DNA-binding domain, facilitating its function as a pioneer factor, which is crucial for chromatin interaction and the recruitment of other transcriptional regulators. The involvement of FOXA1 in sex hormone-related tumors underscores its significance in cancer biology. This review provides an overview of multifaceted roles of FOXA1 in normal development and its implications in the pathogenesis of hormone-related cancers, particularly breast cancer and prostate cancer.
Topics: Humans; Hepatocyte Nuclear Factor 3-alpha; Male; Female; Breast Neoplasms; Prostatic Neoplasms; Gonadal Steroid Hormones; Neoplasms; Animals; Gene Expression Regulation, Neoplastic
PubMed: 38940052
DOI: 10.31083/j.fbl2906225 -
Frontiers in Bioscience (Landmark... Jun 2024Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal tau neurofibrillary tangles and excessive neurodegeneration. The mechanisms of...
BACKGROUND
Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal tau neurofibrillary tangles and excessive neurodegeneration. The mechanisms of neuron degeneration and the potential of these neurons to form new nerve fibers for compensation remain elusive. The present study aimed to evaluate the impact of beta-amyloid and tau on new formations of nerve fibers from mouse organotypic brain slices connected to collagen-based microcontact prints.
METHODS
Organotypic brain slices of postnatal day 8-10 wild-type mice were connected to established collagen-based microcontact prints loaded with polyornithine to enhance nerve fiber outgrowth. Human beta-amyloid(42) or P301S mutated aggregated tau was co-loaded to the prints. Nerve fibers were immunohistochemically stained with neurofilament antibodies. The physiological activity of outgrown neurites was tested with neurotracer MiniRuby, voltage-sensitive dye FluoVolt, and calcium-sensitive dye Rhod-4.
RESULTS
Immunohistochemical staining revealed newly formed nerve fibers extending along the prints derived from the brain slices. While collagen-only microcontact prints stimulated nerve fiber growth, those loaded with polyornithine significantly enhanced nerve fiber outgrowth. Beta-amyloid(42) significantly increased the neurofilament-positive nerve fibers, while tau had only a weak effect. MiniRuby crystals, retrogradely transported along these newly formed nerve fibers, reached the hippocampus, while FluoVolt and Rhod-4 monitored electrical activity in newly formed nerve fibers.
CONCLUSIONS
Our data provide evidence that intact nerve fibers can form along collagen-based microcontact prints from mouse brain slices. The Alzheimer's peptide beta-amyloid(42) stimulates this growth, hinting at a neuroprotective function when physiologically active. This "brain-on-chip" model may offer a platform for screening bioactive factors or testing drug effects on nerve fiber growth.
Topics: Animals; Amyloid beta-Peptides; Mice; Nerve Fibers; Brain; tau Proteins; Humans; Immunohistochemistry; Peptide Fragments; Alzheimer Disease; Mice, Inbred C57BL
PubMed: 38940051
DOI: 10.31083/j.fbl2906232 -
Frontiers in Bioscience (Landmark... Jun 2024Neuroinflammation has emerged as a shared molecular mechanism in epilepsy and cognitive impairment, offering new insights into the complex interplay between immune... (Review)
Review
Neuroinflammation has emerged as a shared molecular mechanism in epilepsy and cognitive impairment, offering new insights into the complex interplay between immune responses and brain function. Evidence reveals involvement of High mobility group box 1 (HMGB1) in blood-brain barrier disruption and correlations with epilepsy severity and drug resistance. While anti-inflammatory treatments show promise, translating these discoveries faces challenges in elucidating mechanisms and developing reliable biomarkers. However, strategically targeting neuroinflammation and HMGB1-mediated inflammation holds therapeutic potential. This review synthesises knowledge on HMGB1 and related biomarkers in epilepsy and cognitive impairment to shape future research and treatments targeting these intricate inflammatory processes.
Topics: HMGB1 Protein; Humans; Epilepsy; Cognitive Dysfunction; Neuroinflammatory Diseases; Animals; Blood-Brain Barrier; Biomarkers; Translational Research, Biomedical; Inflammation
PubMed: 38940048
DOI: 10.31083/j.fbl2906229 -
Frontiers in Bioscience (Landmark... Jun 2024Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of... (Comparative Study)
Comparative Study
BACKGROUND
Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of UCMSC transplantation, such as infusion routes and doses, need to be further optimized.
METHODS
In this study, we compared the therapeutic effects of UCMSCs transplanted via intravenous injection and intratracheal instillation on lipopolysaccharide-induced ALI using a rat model. Following transplantation, levels of inflammatory factors in serum; neutrophils, total white blood cells, and lymphocytes in bronchoalveolar lavage fluid (BALF); and lung damage levels were analyzed.
RESULTS
The results indicated that UCMSCs administered via both intravenous and intratracheal routes were effective in alleviating ALI, as determined by analyses of arterial blood gas, lung histopathology, BALF contents, and levels of inflammatory factors. Comparatively, the intratracheal instillation of UCMSCs was found to result in lower levels of lymphocytes and total proteins in BALF, whereas greater reductions in the serum levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) were detected in rats receiving intravenously injected stem cells.
CONCLUSIONS
Our findings in this study provide convincing evidence to indicate the efficacy of UCMSC therapy in the treatment of ALI mediated via different delivery routes, thereby providing a reliable theoretical basis for further clinical studies. Moreover, these findings imply that the effects obtained using the two assessed delivery routes for UCMSC transplantation are mediated via different mechanisms, which could be attributable to different cellular or molecular targets.
Topics: Animals; Acute Lung Injury; Lipopolysaccharides; Mesenchymal Stem Cell Transplantation; Umbilical Cord; Rats, Sprague-Dawley; Rats; Male; Bronchoalveolar Lavage Fluid; Mesenchymal Stem Cells; Tumor Necrosis Factor-alpha; Injections, Intravenous
PubMed: 38940047
DOI: 10.31083/j.fbl2906217 -
Frontiers in Bioscience (Landmark... Jun 2024has been used as a model system to identify and characterize genetic contributions to development, homeostasis, and to investigate the molecular determinants of... (Review)
Review
has been used as a model system to identify and characterize genetic contributions to development, homeostasis, and to investigate the molecular determinants of numerous human diseases. While there exist many differences at the genetic, structural, and molecular level, many signalling components and cellular machineries are conserved between and humans. For this reason, can and has been used extensively to model, and study human pathologies. The extensive genetic resources available make this model system a powerful one. Over the years, the sophisticated and rapidly expanding genetic toolkit has provided valuable novel insights into the contribution of genetic components to human diseases. The activity of Notch signalling is crucial during development and conserved across the Metazoa and has been associated with many human diseases. Here we highlight examples of mechanisms involving Notch signalling that have been elucidated from modelling human diseases in that include neurodegenerative diseases, congenital diseases, several cancers, and cardiac disorders.
Topics: Animals; Drosophila melanogaster; Receptors, Notch; Signal Transduction; Humans; Disease Models, Animal; Neoplasms; Neurodegenerative Diseases; Heart Diseases
PubMed: 38940046
DOI: 10.31083/j.fbl2906234 -
Frontiers in Bioscience (Landmark... Jun 2024Hormone receptors exert their function through binding with their ligands, which results in cellular signaling activation mediated by genomic or non-genomic mechanisms....
BACKGROUND
Hormone receptors exert their function through binding with their ligands, which results in cellular signaling activation mediated by genomic or non-genomic mechanisms. The intrinsic molecular communication of tick and its host comprises an endocrine regulation involving hormones. In the present study, we performed a molecular and analysis of a Membrane Associated Progesterone Receptor in (RmMAPRC).
METHODS
The RmMAPRC protein sequence was analyzed with bioinformatics tools, and its structure was characterized by three-dimensional (3D) modeling and molecular docking. A semi-quantitative reverse transcription and polymerase chain reaction (sqRT-PCR) assessed the gene presence and relative expression in tick organs and embryonic cells.
RESULTS
relative expression in salivary glands, ovaries, and embryonic cells showed overexpression of 3%, 13%, and 24%, respectively. Bioinformatic analysis revealed that RmMAPRC corresponded to a Progesterone Receptor Membrane Component 1 (RmPGRMC1) of ~23.7 kDa, with an N-terminal transmembrane domain and a C-terminal Cytochrome b5-like heme/steroid binding domain. The docking results suggest that RmPGRMC1 could bind to progesterone (P4), some progestins, and P4 antagonists. The phylogenetic reconstruction showed that spp. MAPRC receptors were clustered in a clade that includes , , and (RmMAPRC), and mammals and helminths MAPRC receptors clustered in two separated clades away from ticks.
CONCLUSIONS
The presence of RmPGRMC1 highlights the importance of transregulation as a conserved adaptive mechanism that has succeeded for arthropod parasites, making it a target for tick control.
Topics: Animals; Rhipicephalus; Receptors, Progesterone; Progesterone; Cattle; Molecular Docking Simulation; Host-Parasite Interactions; Female; Amino Acid Sequence; Protein Binding; Phylogeny
PubMed: 38940045
DOI: 10.31083/j.fbl2906238