-
Communications Biology Jun 2024Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary...
Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary Arterial Hypertension (PAH). Augmented expression and action of growth factors trigger these pathological changes. Endogenous factors opposing such alterations are barely known. Here, we examine whether and how the endothelial hormone C-type natriuretic peptide (CNP), signaling through the cyclic guanosine monophosphate (cGMP) -producing guanylyl cyclase B (GC-B) receptor, attenuates the pericyte dysfunction observed in PAH. The results demonstrate that CNP/GC-B/cGMP signaling is preserved in lung pericytes from patients with PAH and prevents their growth factor-induced proliferation, migration, and transdifferentiation. The anti-proliferative effect of CNP is mediated by cGMP-dependent protein kinase I and inhibition of the Phosphoinositide 3-kinase (PI3K)/AKT pathway, ultimately leading to the nuclear stabilization and activation of the Forkhead Box O 3 (FoxO3) transcription factor. Augmentation of the CNP/GC-B/cGMP/FoxO3 signaling pathway might be a target for novel therapeutics in the field of PAH.
Topics: Humans; Pericytes; Natriuretic Peptide, C-Type; Cyclic GMP; Signal Transduction; Forkhead Box Protein O3; Cell Proliferation; Male; Female; Pulmonary Arterial Hypertension; Middle Aged; Hypertension, Pulmonary; Adult; Receptors, Atrial Natriuretic Factor; Cells, Cultured
PubMed: 38844781
DOI: 10.1038/s42003-024-06375-3 -
Biomedical and Environmental Sciences :... May 2024Little is known about the association between whole-blood nicotinamide adenine dinucleotide (NAD ) levels and nabothian cysts. This study aimed to assess the association...
OBJECTIVE
Little is known about the association between whole-blood nicotinamide adenine dinucleotide (NAD ) levels and nabothian cysts. This study aimed to assess the association between NAD levels and nabothian cysts in healthy Chinese women.
METHODS
Multivariate logistic regression analysis was performed to analyze the association between NAD levels and nabothian cysts.
RESULTS
The mean age was 43.0 ± 11.5 years, and the mean level of NAD was 31.3 ± 5.3 μmol/L. Nabothian cysts occurred in 184 (27.7%) participants, with single and multiple cysts in 100 (15.0%) and 84 (12.6%) participants, respectively. The total nabothian cyst prevalence gradually decreased from 37.4% to 21.6% from Q1 to Q4 of NAD and the prevalence of single and multiple nabothian cysts also decreased across the NAD quartiles. As compared with the highest NAD quartile (≥ 34.4 μmol/L), the adjusted odds ratios with 95% confidence interval of the NAD Q1 was 1.89 (1.14-3.14) for total nabothian cysts. The risk of total and single nabothian cysts linearly decreased with increasing NAD levels, while the risk of multiple nabothian cysts decreased more rapidly at NAD levels of 28.0 to 35.0 μmol/L.
CONCLUSION
Low NAD levels were associated with an increased risk of total and multiple nabothian cysts.
Topics: Humans; Female; Adult; Middle Aged; NAD; Cysts; China
PubMed: 38843920
DOI: 10.3967/bes2024.052 -
Nature Jun 2024Histone acetylation regulates gene expression, cell function and cell fate. Here we study the pattern of histone acetylation in the epithelial tissue of the Drosophila...
Histone acetylation regulates gene expression, cell function and cell fate. Here we study the pattern of histone acetylation in the epithelial tissue of the Drosophila wing disc. H3K18ac, H4K8ac and total lysine acetylation are increased in the outer rim of the disc. This acetylation pattern is controlled by nuclear position, whereby nuclei continuously move from apical to basal locations within the epithelium and exhibit high levels of H3K18ac when they are in proximity to the tissue surface. These surface nuclei have increased levels of acetyl-CoA synthase, which generates the acetyl-CoA for histone acetylation. The carbon source for histone acetylation in the rim is fatty acid β-oxidation, which is also increased in the rim. Inhibition of fatty acid β-oxidation causes H3K18ac levels to decrease in the genomic proximity of genes involved in disc development. In summary, there is a physical mark of the outer rim of the wing and other imaginal epithelia in Drosophila that affects gene expression.
Topics: Animals; Acetate-CoA Ligase; Acetyl Coenzyme A; Acetylation; Biological Transport; Cell Nucleus; Chromatin; Drosophila melanogaster; Drosophila Proteins; Fatty Acids; Gene Expression Regulation; Histones; Imaginal Discs; Lysine; Oxidation-Reduction; Wings, Animal
PubMed: 38839952
DOI: 10.1038/s41586-024-07471-4 -
Frontiers in Endocrinology 2024Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in kidney disease, yet its regulation in diabetic kidney disease (DKD) remains inadequately...
BACKGROUND
Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in kidney disease, yet its regulation in diabetic kidney disease (DKD) remains inadequately understood.
OBJECTIVE
Therefore, we investigated the changes of NAD+ levels in DKD and the underlying mechanism.
METHODS
Alternations of NAD+ levels and its biosynthesis enzymes were detected in kidneys from streptozotocin-induced diabetic mouse model by real-time PCR and immunoblot. The distribution of NAD+ synthetic enzymes was explored via immunohistochemical study. NAD+ synthetic metabolite was measured by LC-MS. Human data from NephroSeq were analyzed to verify our findings.
RESULTS
The study showed that NAD+ levels were decreased in diabetic kidneys. Both mRNA and protein levels of kynurenine 3-monooxygenase (KMO) in NAD+ synthesis pathway were decreased, while NAD+ synthetic enzymes in salvage pathway and NAD+ consuming enzymes remained unchanged. Further analysis of human data suggested KMO, primarily expressed in the proximal tubules shown by our immunohistochemical staining, was consistently downregulated in human diabetic kidneys.
CONCLUSION
Our study demonstrated KMO of NAD+ synthesis pathway was decreased in diabetic kidney and might be responsible for NAD+ reduction in diabetic kidneys, offering valuable insights into complex regulatory mechanisms of NAD+ in DKD.
Topics: Animals; Diabetic Nephropathies; NAD; Humans; Mice; Diabetes Mellitus, Experimental; Male; Mice, Inbred C57BL; Disease Models, Animal; Kidney
PubMed: 38836233
DOI: 10.3389/fendo.2024.1384953 -
Cell Death & Disease Jun 2024Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between...
Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.
Topics: Animals; Humans; Mice; Acetyl Coenzyme A; Acetylation; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Fructose-Bisphosphatase; Glycolysis; Histones; Keratinocytes; Mice, Inbred C57BL; Psoriasis
PubMed: 38834617
DOI: 10.1038/s41419-024-06706-6 -
Biomedicine & Pharmacotherapy =... Jul 2024Depression is a prevalent psychiatric disorder with accumulating evidence implicating dysregulation of extracellular adenosine triphosphate (ATP) levels in the medial...
Depression is a prevalent psychiatric disorder with accumulating evidence implicating dysregulation of extracellular adenosine triphosphate (ATP) levels in the medial prefrontal cortex (mPFC). It remains unclear whether facilitating endogenous ATP production and subsequently increasing extracellular ATP level in the mPFC can exert a prophylactic effect against chronic social defeat stress (CSDS)-induced depressive-like behaviors and enhance stress resilience. Here, we found that nicotinamide mononucleotide (NMN) treatment effectively elevated nicotinamide adenine dinucleotide (NAD) biosynthesis and extracellular ATP levels in the mPFC. Moreover, both the 2-week intraperitoneal (i.p.) injection and 3-week oral gavage of NMN prior to exposure to CSDS effectively prevented the development of depressive-like behavior in mice. These protective effects were accompanied with the preservation of both NAD biosynthesis and extracellular ATP level in the mPFC. Furthermore, catalyzing ATP hydrolysis by mPFC injection of the ATPase apyrase negated the prophylactic effects of NMN on CSDS-induced depressive-like behaviors. Prophylactic NMN treatment also prevented the reduction in GABAergic inhibition and the increase in excitability in mPFC neurons projecting to the lateral habenula (LHb). Collectively, these findings demonstrate that the prophylactic effects of NMN on depressive-like behaviors are mediated by preventing extracellular ATP loss in the mPFC, which highlights the potential of NMN supplementation as a novel approach for protecting and preventing stress-induced depression in susceptible individuals.
Topics: Animals; Prefrontal Cortex; Male; Adenosine Triphosphate; Nicotinamide Mononucleotide; Depression; Stress, Psychological; Mice, Inbred C57BL; Mice; Behavior, Animal; Social Defeat; NAD; Disease Models, Animal
PubMed: 38834006
DOI: 10.1016/j.biopha.2024.116850 -
Biophysical Chemistry Aug 2024We propose a detailed computational beta cell model that emphasizes the role of anaplerotic metabolism under glucose and glucose-glutamine stimulation. This model goes...
We propose a detailed computational beta cell model that emphasizes the role of anaplerotic metabolism under glucose and glucose-glutamine stimulation. This model goes beyond the traditional focus on mitochondrial oxidative phosphorylation and ATP-sensitive K channels, highlighting the predominant generation of ATP from phosphoenolpyruvate in the vicinity of K channels. It also underlines the modulatory role of HO as a signaling molecule in the first phase of glucose-stimulated insulin secretion. In the second phase, the model emphasizes the critical role of anaplerotic pathways, activated by glucose stimulation via pyruvate carboxylase and by glutamine via glutamate dehydrogenase. It particularly focuses on the production of NADPH and glutamate as key enhancers of insulin secretion. The predictions of the model are consistent with empirical data, highlighting the complex interplay of metabolic pathways and emphasizing the primary role of glucose and the facilitating role of glutamine in insulin secretion. By delineating these crucial metabolic pathways, the model provides valuable insights into potential therapeutic targets for diabetes.
Topics: Glutamine; Glucose; Insulin; Insulin Secretion; Models, Biological; Humans; Insulin-Secreting Cells; Animals; Pyruvate Carboxylase; Hydrogen Peroxide; Adenosine Triphosphate
PubMed: 38833963
DOI: 10.1016/j.bpc.2024.107270 -
Biochemistry. Biokhimiia Apr 2024Accurate duplication and separation of long linear genomic DNA molecules is associated with a number of purely mechanical problems. SMC complexes are key components of... (Review)
Review
Accurate duplication and separation of long linear genomic DNA molecules is associated with a number of purely mechanical problems. SMC complexes are key components of the cellular machinery that ensures decatenation of sister chromosomes and compaction of genomic DNA during division. Cohesin, one of the essential eukaryotic SMC complexes, has a typical ring structure with intersubunit pore through which DNA molecules can be threaded. Capacity of cohesin for such topological entrapment of DNA is crucial for the phenomenon of post-replicative association of sister chromatids better known as cohesion. Recently, it became apparent that cohesin and other SMC complexes are, in fact, motor proteins with a very peculiar movement pattern leading to formation of DNA loops. This specific process has been called loop extrusion. Extrusion underlies multiple functions of cohesin beyond cohesion, but molecular mechanism of the process remains a mystery. In this review, we summarized the data on molecular architecture of cohesin, effect of ATP hydrolysis cycle on this architecture, and known modes of cohesin-DNA interactions. Many of the seemingly disparate facts presented here will probably be incorporated in a unified mechanistic model of loop extrusion in the not-so-distant future.
Topics: Cohesins; Chromosomal Proteins, Non-Histone; Cell Cycle Proteins; DNA; Humans; Animals; Adenosine Triphosphate; Chromatids
PubMed: 38831498
DOI: 10.1134/S0006297924040011 -
NPJ Systems Biology and Applications Jun 2024Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although...
Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although FN3Ks are present across the Tree of Life and share detectable sequence similarity to eukaryotic protein kinases, the biological processes regulated by these kinases are largely unknown. To address this knowledge gap, we leveraged the FN3K CRISPR Knock-Out (KO) HepG2 cell line alongside an integrative multi-omics study combining transcriptomics, metabolomics, and interactomics to place these enzymes in a pathway context. The integrative analyses revealed the enrichment of pathways related to oxidative stress response, lipid biosynthesis (cholesterol and fatty acids), and carbon and co-factor metabolism. Moreover, enrichment of nicotinamide adenine dinucleotide (NAD) binding proteins and localization of human FN3K (HsFN3K) to mitochondria suggests potential links between FN3K and NAD-mediated energy metabolism and redox balance. We report specific binding of HsFN3K to NAD compounds in a metal and concentration-dependent manner and provide insight into their binding mode using modeling and experimental site-directed mutagenesis. Our studies provide a framework for targeting these understudied kinases in diabetic complications and metabolic disorders where redox balance and NAD-dependent metabolic processes are altered.
Topics: Humans; Phosphotransferases (Alcohol Group Acceptor); Hep G2 Cells; Metabolic Networks and Pathways; Metabolomics; NAD; Oxidative Stress; Multiomics
PubMed: 38830903
DOI: 10.1038/s41540-024-00390-0 -
Annals of Medicine Dec 2024Literature on the safety of remdesivir in hospitalized COVID-19 patients with severe renal impairment is limited. We aimed to investigate the safety and effectiveness of...
BACKGROUND
Literature on the safety of remdesivir in hospitalized COVID-19 patients with severe renal impairment is limited. We aimed to investigate the safety and effectiveness of remdesivir in this population.
METHODS
We conducted a retrospective cohort study of adult hospitalized COVID-19 patients who received remdesivir between April 2022 and October 2022. Outcomes were compared between estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m and ≥30 mL/min/1.73 m groups. The primary safety outcomes were acute kidney injury (AKI) and bradycardia, while the primary effectiveness outcomes included mortality in COVID-19-dedicated wards and hospital mortality. Secondary outcomes included laboratory changes, disease progression, and recovery time.
RESULTS
A total of 1,343 patients were recruited, with 307 (22.9%) in the eGFR <30 group and 1,036 (77.1%) in the eGFR ≥30 group. Patients with an eGFR <30 had higher risks of AKI (adjusted hazard ratio [aHR] 2.92, 95% CI 1.93-4.44) and hospital mortality (aHR 1.47, 95% CI 1.06-2.05) but had comparable risks of bradycardia (aHR 1.15, 95% CI 0.85-1.56) and mortality in dedicated wards (aHR 1.43, 95% CI 0.90-2.28) than patients with an eGFR ≥30. Risk of disease progression was higher in the eGFR <30 group (adjusted odds ratio 1.62, 95% CI 1.16-2.26). No difference between the two groups in laboratory changes and recovery time.
CONCLUSIONS
Hospitalized COVID-19 patients receiving remdesivir with severe renal impairment had an increased risk of AKI, hospital mortality, and COVID-19 disease progression compared to patients without severe renal impairment.
Topics: Humans; Alanine; Adenosine Monophosphate; Male; Female; Retrospective Studies; COVID-19 Drug Treatment; Middle Aged; Aged; Antiviral Agents; Acute Kidney Injury; Hospital Mortality; Hospitalization; Glomerular Filtration Rate; SARS-CoV-2; COVID-19; Treatment Outcome; Renal Insufficiency; Bradycardia; Adult
PubMed: 38830017
DOI: 10.1080/07853890.2024.2361843