Результаты поиска

NETosis in diabetic kidney disease: Molecular mechanisms and therapeutic opportunities.

Diabetic Kidney Disease (DKD) is a leading cause of end-stage renal failure, with limited therapeutic options beyond glycemic and blood pressure control. NETosis, is a unique form of neutrophil cell death where they extrude their nuclear material comprising of DNA-histone complexes and granular proteins such as myeloperoxidase (MPO) and neutrophil elastase (NE) in the form of Neutrophil Extracellular Traps (NETs). Hyperglycemia-induced reactive oxygen species (ROS), calcium influx, activation of Protein-arginine deiminase type-4 (PAD4) and NADPH oxidases contribute to NETs formation in the dia

Vascular Aging and Multi-Omic Regulation in Ischemic Stroke: Toward Precision Neurorepair.

Ischemic stroke (IS) remains a leading cause of disability and mortality in aging populations. Recovery trajectories are shaped not only by the acute vascular insult but also by pre-existing comorbidities, genetic predisposition, and age-dependent molecular remodeling. Common vascular risk factors, such as diabetes mellitus, atrial fibrillation, hypertension, and dyslipidemia, sustain systemic and cerebral inflammation, promote endothelial dysfunction, disrupt blood-brain barrier integrity, and impair neuroplasticity, collectively limiting neurovascular repair and recovery potential. Recent ad

Role of SIRT7 in Prostate Cancer Progression: New Insight Into Potential Therapeutic Target.

Prostate cancer (PCa) is the second most common cancer in men worldwide, and understanding its molecular mechanisms is crucial for developing effective treatment strategies. SIRT7, a NAD+-dependent histone deacetylase, has emerged as a key regulator in PCa progression due to its roles in chromatin remodeling, DNA repair, and transcriptional regulation. Analysis of 492 PCa samples from The Cancer Genome Atlas (TCGA) via cBioPortal revealed that high SIRT7 expression is associated with poor prognosis in PCa patients. Mechanistically, SIRT7 deacetylates histone H3 at lysine 18 (H3K18Ac), a marker

Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy.

Overexpression of protein lysine methyltransferase G9a, which catalyzes mono- and di-methylation of histone H3K9 and non-histone proteins, is closely associated with poor prognosis and metastasis of various cancers. Here, we designed and synthesized a series of novel G9a inhibitors bearing 2-tetrahydroisoquinoline substituted quinazoline scaffold. Among them, compound 31 with 2-dioxole fused tetrahydroisoquinoline exhibited the most potent inhibitory effects against G9a with an IC50 value of 0.032 μM and high selectivity against the other tested lysine/arginine methyltransferases. Molecular do

KDM6B induces demethylation of H3K27me3 in MFN1 to modulate aberrant mitophagy in sepsis-induced acute lung injury.

Acute lung injury (ALI) commonly occurs as a complication of sepsis, significantly increasing mortality rates in septic patients. Macrophages play a critical role in sepsis pathogenesis. KDM6B, a histone demethylase, has been reported to regulate macrophage death in ALI. In this study, we investigated the impact of KDM6B on macrophage processes during sepsis-induced ALI and elucidated the underlying molecular mechanisms. A cecal ligation and puncture (CLP)-induced septic mouse model was established to assess KDM6B's effects on lung injury severity and survival outcomes. Raw264.7 macrophages we

Inhibiting sirtuin-dependent DNA repair and oxidative stress responses impairs DIPG cell survival.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are universally fatal pediatric brain tumors often characterized by a H3 histone mutation (H3K27M) that leads to epigenetic alterations and gene dysregulation. Histone deacetylases (HDAC), key players in modulating epigenetic pathways in cancer, have emerged as potential therapeutic targets for DIPG. This study evaluates the class III HDAC inhibitor, sirtinol, as a potential therapeutic for DIPG. METHODS: Sirtinol's efficacy and cellular mechanism were investigated using two patient-derived DIPG cell lines and one immortalized normal human

Environmental pollutant SO₂ exposure affects trophoblast function involving an ER stress pathway.

Sulphur dioxide (SO₂) is a toxic air pollutant with deleterious effects on the respiratory, cardiovascular, endocrine and reproductive systems. SO₂, being freely diffusible, can cross the placenta and reach the fetal system. Previous studies have reported the association between SO₂ exposure and adverse pregnancy and fetal outcomes without much emphasis on its molecular aspects. The present study has investigated the adverse consequences of SO₂ derivatives on the two key trophoblast functions critical for placentation: invasion and fusion. SO₂ exposure inhibited the fusogenic potential of BeWo

IV Immunoglobulin Is Associated With Epigenetic, Ribosomal, and Immune Changes in Pediatric Acute-Onset Neuropsychiatric Syndrome.

OBJECTIVES: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by infection-provoked abrupt-onset obsessive compulsive disorder (OCD) and neurodevelopmental regression. Owing to the neuroimmune hypothesis, we investigated the effects of IV immunoglobulin (IVIg) on cell-specific gene expression. METHODS: Single-cell RNA sequencing of peripheral immune cells was performed in 5 children with PANS (median age 8 (5.5-16) years), before and after administering open-label IVIg, compared with 4 controls (median age 13.5 [IQR 12-15] years). RESULTS: The index PANS event (age 1.8-

The overview of lactylation in the placenta of preeclampsia.

BACKGROUND: Preeclampsia is a major challenge for obstetricians due to its severe impacts on maternal and fetal health. Lysine lactylation (Kla) derived from lactate is a novel type of post-translational modification which has been confirmed to affect the malignant progression of diseases as an epigenetic modifier. However, the systemic lactylome profiling of preeclampsia is still unclear. MATERIAL AND METHODS: Immunohistochemistry and protein immunoassay were performed on placenta tissues from preeclamptic patients and control pregnancies to compare lactylation levels between the groups. The

Citrate: a key signalling molecule and therapeutic target for bone remodeling disorder.

Bone remodeling is a continuous cyclic process that maintains and regulates bone structure and strength. The disturbance of bone remodeling leads to a series of bone metabolic diseases. Recent studies have shown that citrate, an intermediate metabolite of the tricarboxylic acid (TCA) cycle, plays an important role in bone remodeling. But the exact mechanism is still unclear. In this study, we focused on the systemic regulatory mechanism of citrate on bone remodeling, and found that citrate is involved in bone remodeling in multiple ways. The participation of citrate in oxidative phosphorylatio

Improved quantitative structure-activity relationship (QSAR) models to predict the activity of hydroxamic acids as HDAC inhibitors against malaria parasites.

There are ∼600,000 malaria-related deaths annually, predominantly due to Plasmodium falciparum infections. Malaria parasite drug resistance is driving the search for new antimalarials with novel modes of action to current options. Histone deacetylases (HDACs) modulate protein lysine acetylation, regulating a range of cellular processes and are prospective new antimalarial drug targets. To accelerate HDAC inhibitor discovery for malaria, we generated quantitative structure-activity relationship (QSAR) classification models B1-B9 using 572 hydroxamic acid-based structures and their paired P. fal

Prognostic Significance of EZH2-Related Gene Variants in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy.

BACKGROUND/AIM: Prostate cancer remains a major global health burden, with treatment resistance posing a significant challenge. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a histone methyltransferase, is frequently overexpressed in prostate cancer, contributing to tumor progression and castration resistance. Clinical trials of EZH2 inhibitors may have therapeutic benefits. This study aimed to evaluate the impact of genetic variants in EZH2-related genes on survival outcomes in prostate cancer. PATIENTS AND METHODS: We conducted a genetic association study evaluating 76 s

HKDC1 promotes the H3K18 lactylation of the promoter of ORMDL3 to induce the activation of hepatic stellate cells in liver cirrhosis.

PURPOSE: We aimed to investigate the role and possible mechanism of action of hexokinase domain containing 1 (HKDC1) in liver cirrhosis. METHODS: Hepatic stellate cell (HSC) activation model was established in LX-2 cells by transforming growth factor (TGF)-βl stimulation. A mouse model of hepatic fibrosis was established using carbon tetrachloride (CCl4) stimulation. HKDC1 expression was assessed using qRT-PCR, western blotting, and immunofluorescence. Hematoxylin and eosin (H&E) and Masson staining were used to assess liver injury and fibrosis. Changes in fibrosis markers were assessed using

Эпигенетика и метаболическая метаболическая дисфункция при многоразовом склерозе: обзор подходов к травяным лекарствам и текущих клинических испытаний.

Множественный склероз (MS) — сложная аутоиммунная болезнь, характеризующаяся воспалением, обезвоживанием и нейродегенерацией в центральной нервной системе (КНС). Хотя точные причины остаются неясными, недавние исследования подчеркивают важную роль эпигенетических изменений и митохондриальной дисфункции в начале и развитии болезни. Эпигенетические изменения, такие, как метилация ДНК, модификация гистона и регулирование микроРНК, влияют на генное выражение, не изменяя последовательности ДНК, что приводит к иммунной дисрегуляции и воспалению. Аналогичным образом, митохондриальная дисфункция, отме

Совпадение в полном тексте источника
… Histone Modifications Chromatin is made up of proteins called histones, around which DNA is wrapped. The structure of chromatin can be changed by chemical alterations to histones, such as methylation, acetylation, phosphorylation, and ubiquitination. … Histone methylation: According to the particular histone and location modified, histone methylation may produce a variety of effects. …

Genome-wide characterization of dynamic DNA 5-hydroxymethylcytosine and TET2-related DNA demethylation during breast tumorigenesis.

BACKGROUND: Breast tumorigenesis is a complex and multistep process accompanied by both genetic and epigenetic dysregulation. In contrast to the extensive studies on DNA epigenetic modifications 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in malignant breast tumors, their roles in the early phases of breast tumorigenesis remain ambiguous. RESULTS: DNA 5hmC and 5mC exhibited a consistent and significant decrease from usual ductal hyperplasia to atypical ductal hyperplasia and subsequently to ductal carcinoma in situ (DCIS). However, 5hmC showed a modest increase in invasive ducta

Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.

Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50 mg·kg-1·d-1, i.g.) for another 8 weeks. By co

The role of H3K27 acetylation in oxygen-glucose deprivation-induced spinal cord injury and potential for neuroprotective therapies.

OBJECTIVE: Spinal cord injury (SCI) is a debilitating condition that often results in paralysis and lifelong medical challenges. Research has shown that epigenetic modifications, particularly histone acetylation, play a role in neuroprotection following hypoxic-ischemic events in SCI. The objective of this study was to explore the effects of histone H3K27 acetylation, along with its underlying mechanisms, on the tolerance to hypoxia and ischemia in SCI. METHODS: This study employed an organotypic spinal cord slice culture model subjected to oxygen-glucose deprivation (OGD). We assessed cell a

Acute depletion of BRG1 reveals its primary function as an activator of transcription.

The mammalian SWI/SNF-like BAF complexes play critical roles during animal development and pathological conditions. Previous gene deletion studies and characterization of human gene mutations implicate that the complexes both repress and activate a large number of genes. However, the direct function of the complexes in cells remains largely unclear due to the relatively long-term nature of gene deletion or natural mutation. Here we generate a mouse line by knocking in the auxin-inducible degron tag (AID) to the Smarca4 gene, which encodes BRG1, the essential ATPase subunit of the BAF complexes

ASF1B is an essential prognostic indicator linked to the growth and resistance characteristics of bladder cancer.

BACKGROUND: Anti-silencing function 1 (ASF1) is a conserved histone H3-H4 chaperone protein. ASF1B (Anti-Silencing Function 1B Histone Chaperone), a paralog of ASF1, is involved in tumor metabolism and growth. The regulatory network of ASF1B in cancer is intricate and remains inadequately explored. The objective of this study was to examine the biological role of ASF1B in bladder cancer (BC). METHODS: The presence of ASF1B in BC was examined using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases. In addition, a correlation analysis was performed to evaluate th

The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species.

Although few resistance mechanisms for histone deacetylase inhibitors (HDACis) have been described, we recently demonstrated that TMT1A (formerly METTL7A) and TMT1B (formerly METTL7B) can mediate resistance to HDACis with a thiol as the zinc-binding group by methylating and inactivating the drug. TMT1A and TMT1B are poorly characterized, and their normal physiological role has yet to be determined. As animal model systems are often used to determine the physiological function of proteins, we investigated whether the ability of these methyltransferases to methylate thiol-based HDACis is conserv