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Discovery of a Promising Hydroxyamino-Piperidine HDAC6 Inhibitor via Integrated Virtual Screening and Experimental Validation in Multiple Myeloma.

Background: Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC isozyme characterized by two catalytic domains and a zinc finger ubiquitin-binding domain. It plays critical roles in various cellular processes, including protein degradation, autophagy, immune regulation, and cytoskeletal dynamics. Due to its multifunctional nature and overexpression in several cancer types, HDAC6 has emerged as a promising therapeutic target. Methods: In this study, we employed a ligand-based pharmacophore modeling approach using a structurally diverse set of known HDAC6 inhibitors. This was followed by th

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… They function by removing acetyl groups from lysine residues on both histone and non-histone proteins, thereby modulating intracellular acetylation levels in concert with histone acetyltransferases [ 1 , 2 ]. …

Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma.

The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumo

The BE (2)-M17 neuroblastoma cell line: revealing its potential as a cellular model for Parkinson's disease.

Parkinson's disease is a pathology with a wide range of in vivo and in vitro models available. Among these, the SH-SY5Y neuroblastoma cell line is one of the most employed. This model expresses catecholaminergic markers and can differentiate and acquire various neuronal phenotypes. However, challenges persist, primarily concerning the variability of growth media, expression of dopaminergic markers, and a wide variety of differentiation protocols have been reported in the literature without direct comparison between them. This lack of standardized differentiation conditions impacts result repro

Epigenetic Modifiers as Novel Therapeutic Targets and a Systematic Review of Clinical Studies Investigating Epigenetic Inhibitors in Head and Neck Cancer.

The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and di

HDAC Inhibitors: Therapeutic Potential in Fibrosis-Associated Human Diseases.

Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypo

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… Histone acetylation is mediated by histone acetyltransferases (HATs), whereas histone deacetylation is carried out by histone deacetylases (HDACs). HATs and HDACs finely regulate the histone acetylation status and thereby transcription. …

IRF4 is a novel mediator for neuronal survival in ischaemic stroke.

Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibit

Роль ядерных рецепторов в развитии множественного склероза: обзор.

Множественный склероз (MS) является следствием раннего возбудительного демиэлирования и прогрессивных нейродегенеративных повреждений в центральной нервной системе (КНС). Несмотря на неясный патогенез MS, происходят два основных процесса: ремонт олигодендроцита и липидный метаболизм. Было отмечено, что ядерные рецепторы играют роль линейных датчиков, регуляторов транскрипционных факторов и модуляторов генного выражения. Один из членов этой семьи, ретиноид X-рецептор (RXR), который образует гетеродимерный комплекс с рецептором печени X (LXR), был замешан в патофизиологии MS. Кроме того, было вы

Enhanced Antitumor Activity and Induction of Immunogenic Cell Death in NUT Carcinoma Cells by Combining Oncolytic Viruses with the Dual Inhibitor NEO2734.

NUT carcinoma (NC) is a rare exceptionally aggressive malignancy, defined by NUTM1 gene translocations, most commonly generating a BRD4::NUTM1 fusion that results in a poor prognosis and limited therapeutic options. Oncolytic virotherapy has emerged as a promising strategy for NC, and the dual bromodomain and extra-terminal domain (BET) and p300/CBP inhibitor NEO2734 has demonstrated potent antiproliferative activity. To investigate multimodal therapeutic approaches that combine epigenetic modulation with immunogenic and cytotoxic effects of oncolytic viruses (OVs), we evaluated two recombinan

LncRNA Gas5, a Target of the Nonsense-Mediated Decay Pathway in the Brain, Regulates Neuroinflammation and Neurodegenerative Disease Pathways in a Tauopathy Mouse Model.

Dysregulation of target genes of nonsense-mediated decay (NMD) in the brain remains sparsely known in tauopathies. PS19 transgenic mice expressing human mutant P301S tau were evaluated for levels of lncRNA Gas5, a target of NMD. The results show Gas5 decreased in the brains of PS19 mice as they aged. We evaluated the consequences of blocking the NMD-mediated turnover of Gas5 using a small molecule administered intranasally to PS19 mice. The results show NPC86 disassociated Upf1 and Gas5, thereby hindering NMD. NPC86 treatment increased Gas5 levels in the cortex of male PS19 mice concurrent wit

Nanovesicular Drug Delivery Systems for Overcoming Antibiotic Resistance.

Despite the early success of treating bacterial infections with antibiotics, resistance development has become a global problem. Treatment of organisms that have become resistant to common antibacterial agents is challenging and can cause severe and extended illness, longer hospital stays, and increased medical costs. Bacteria may develop antibiotic resistance by multiple biochemical pathways, including target-site gene mutations, decreased permeability, drug uptake or efflux mechanisms that remove the drug from the host cells, and alterations in metabolic pathways. Several strategies to overc

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… In the case of aminoglycosides (AGs), the most common mechanism is enzymatic deactivation by AG acetyltransferases, AG nucleotidyltransferases, and AG phosphotransferases. AG resistance also occurs by modification of the ribosome target by a family of ribosomal methyltransferase enzymes. …

Combined spatial metabolomics and 4D-DIA quantitative proteomics approaches to explore the relationship between lung cancer and the heart.

Lung cancer and cardiovascular disease pose persistent threats to human health, despite advancements in targeted therapy, percutaneous coronary intervention, and drug treatments. Challenges such as side effects, drug resistance, hospitalization rates, and mortality remain high. These diseases are closely linked, sharing common risk factors and intricately influencing each other. This study aims to investigate the interplay between lung disease and cardiovascular disease by examining changes in cardiac metabolites and protein expression using spatial metabolomics and 4D-DIA quantitative proteom

Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities.

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new tr

Effects of three flavonoids from an ancient traditional Chinese medicine Radix puerariae on geriatric diseases.

As the worldwide population ages, the morbidity of neurodegenerative, cardiovascular, cerebrovascular, and endocrine diseases, such as diabetes and osteoporosis, continues to increase. The etiology of geriatric diseases is complex, involving the interaction of genes and the environment, which makes effective treatment challenging. Traditional Chinese medicine, unlike Western medicine, uses diverse bioactive ingredients to target multiple signaling pathways in geriatric diseases. Radix puerariae is one of the most widely used ancient traditional Chinese medicines and is also consumed as food. T

Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis.

BACKGROUND: In spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug-resistant clones. We previously showed that MM cells upregulate the transcriptional repressor, growth factor independence 1 (Gfi1), in bone marrow stromal cells (BMSCs) that induces prolonged inhibition of osteoblast differentiation. However, the role of Gfi1 in MM cells is unknown. METHODS: Human primary CD138+ and BMSC were purified from normal donors and MM patients' bone marrow aspirates. Gfi1 knockdown and overexpressing cells were generated by lent

NAD+‒circadian rhythm coupling in dementia.

The circadian rhythm system and sleep coordinate whole-body functions across the 24-h cycle, yet these rhythms progressively deteriorate with neurodegenerative diseases, including dementia. Growing evidence indicates that nicotinamide adenine dinucleotide (NAD+) interacts with the circadian system through multiple molecular pathways and that NAD+ levels decline with dementia. In this review, we synthesize current evidence on the bidirectional relationship between NAD+ metabolism and circadian regulation in several dementia disorders, emphasizing the key circadian pathways, the nicotinamide pho

PPAR-γ in Melanoma and Immune Cells: Insights into Disease Pathogenesis and Therapeutic Implications.

Changes in skin pigmentation, like hyperpigmentation or moles, can affect appearance and social life. Unlike locally containable moles, malignant melanomas are aggressive and can spread rapidly, disproportionately affecting younger individuals with a high potential for metastasis. Research has shown that the peroxisome proliferator-activated receptor gamma (PPAR-γ) and its ligands exhibit protective effects against melanoma. As a transcription factor, PPAR-γ is crucial in functions like fatty acid storage and glucose metabolism. Activation of PPAR-γ promotes lipid uptake and enhances sensitivi

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer.

Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been i

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… Histone acetyltransferases (HATs) attach acetyl groups to DNA and loosen the histone wrap allowing the transcription factors to communicate the DNA and regulate the gene expressions. … Dehydroepiandrosterone DHT | Dihydrotestosterone DRE | Digital rectal examination ECM | Extracellular matrix EMT | Epithelial–mesenchymal transition EMC | Epithelial-mesenchymal cell ER | Endoplasmic reticulum GM-CSF | Granulocyte-macrophage colony-stimulating factor G-CSF | Granulocyte CSF HAT | Histone acetyltransferase …

Множественная миелома: сказка о дерегулированных факторах транскрипции.

Всеобъемлющее понимание молекулярных механизмов, лежащих в основе множественных миэломных (ММ) патогенеза, крайне важно для разработки терапевтических стратегий, позволяющих преодолеть гетерогенность заболеваний и рецидив лечения. В этом обзоре мы сосредоточимся на коэффициентах транскрипции (TF), ключевых регуляторах генного экспрессия, которые играют важнейшую роль в обычной гематопоизисе и биологии MM. Сначала мы обсудим физиологические функции ТФ в составе лимфоидной линии и конечной дифференциации В-клеток на плазменные клетки. Это позволяет получить представление о вкладе ключевых ЦГ, та

Animal Models in Rheumatoid Arthritis: Is There a Correlation Between Autoantibodies in Human Pathology and Animal Models?

RA is a chronic autoimmune disease characterized by synovial inflammation and joint damage, driven by autoantibodies such as ACPA, anti-CarP and RF. These autoantibodies, influenced by genetic and environmental factors, play a crucial role in RA pathogenesis through post-translational modifications like citrullination, carbamylation, and acetylation. The early detection of ACPA provides a potential window for intervention, while anti-CarP antibodies correlate with severe disease progression and RF aids in diagnosis. Translating these findings from human pathology to animal models presents sign

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… This process, facilitated by various N-terminal and lysine acetyltransferases, is reversible and can significantly impact protein function [ 34 ]. …

Alcohol Consumption and Autoimmune Diseases.

Alcohol is the second-most misused substance after tobacco. It has been identified as a causal factor in more than 200 diseases and 5.3% of all deaths and is associated with significant behavioral, social, and economic difficulties. As alcohol consumption may modulate the immune system's regulatory mechanisms to avoid attacking the body's tissues, it has been proven to play a dichotomic role in autoimmune diseases (ADs) based on the quantity of consumption. In this review, we report updated evidence on the role of alcohol in ADs, with a focus on alcohol addiction and the human biological immun