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Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).

Cisplatin resistance remains a primary obstacle in oncology, leading to therapeutic failure and disease recurrence. While resistance mechanisms are multifactorial, metabolic reprogramming has emerged as a critical adaptive strategy for cancer cells to evade cisplatin-induced cytotoxicity. This review synthesizes current evidence on how altered metabolism drives cisplatin resistance, with a particular emphasis on the pivotal role of pyruvate dehydrogenase kinases (PDKs). PDKs act as metabolic gatekeepers by inhibiting the pyruvate dehydrogenase complex (PDHC), diverting glucose flux away from m

SETD2 and EZH2: Two epigenetic drivers of prostate cancer.

Prostate cancer is a prevalent malignancy among men, characterized by complex mechanisms underlying metastasis and treatment resistance. Epigenetic modifications play a crucial role in regulating prostate cancer progression, particularly involving histone methyltransferases such as SET-domain containing 2 (SETD2) and Enhancer of Zeste homolog 2 (EZH2). SETD2 contributes to chromatin stability by catalyzing the trimethylation of histone H3 lysine 36 (H3K36me3), and its downregulation is strongly correlated with increased invasiveness and epithelial-mesenchymal transition in prostate cancer. Con

Pro-inflammatory cytokine-mediated anemia: regarding molecular mechanisms of erythropoiesis.

Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway,

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… 2008-06-161117 64 Zhao W Kitidis C Fleming MD Lodish HF Ghaffari S Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway Blood 2006 107 3 907 915 16204311 10.1182/blood-2005-06-2516 PMC1895894 65 Blobel GA Nakajima T Eckner R Montminy M Orkin SH CREB-binding … of the transcription factor GATA-1 by acetylation Nature 1998 396 6711 594 598 9859997 10.1038/25166 67 Hung H-L Lau J Kim AY Weiss MJ Blobel GA CREB-Binding protein acetylates hematopoietic transcription factor GATA- 1 at functionally important sites Molecular and Cellular Biology 1999 19 5 3496 3505 …

NF-κB in biology and targeted therapy: new insights and translational implications.

NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other importa

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy.

Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and

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… Aside from phosphorylation, histone acetyltransferase p300/CREB-binding protein (CBP) can bind and acetylate the N-terminus of SREBP-2 to enhance its expression and transcriptional activity ( 52 ), while sirtuin-1 (SIRT1) deacetylates SREBP-2 to decrease the abundance of SREBP-2 in the nucleus ( 53 ) …

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

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… Abbreviations The following abbreviations are used in this manuscript: ANOVA | Analysis of variance ATP | Adenosine triphosphate BET | Bromodomain and extra-terminal domain BRD3/4 | Bromodomain containing protein 3 or 4 CALR | Calreticulin Cas9 | CRISPR-associated protein 9 CBP | CREB-binding protein …

Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen meta

Epigenetic modification in diabetic kidney disease.

Diabetic kidney disease (DKD) is a common microangiopathy in diabetic patients and the main cause of death in diabetic patients. The main manifestations of DKD are proteinuria and decreased renal filtration capacity. The glomerular filtration rate and urinary albumin level are two of the most important hallmarks of the progression of DKD. The classical treatment of DKD is controlling blood glucose and blood pressure. However, the commonly used clinical therapeutic strategies and the existing biomarkers only partially slow the progression of DKD and roughly predict disease progression. Therefor

Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2.

Osteolytic bone lesions are one of the central features of multiple myeloma (MM) and lead to bone pain, fractures, decreased quality of life, and decreased survival. Dysfunction of the osteoclast (OC)/osteoblast (OB) axis plays a key role in the development of myeloma-associated osteolytic lesions. Many signaling pathways and factors are associated with myeloma bone diseases (MBDs), including the RANKL/OPG and NF-κB pathways. NRF2, a master regulator of inflammatory signaling, might play a role in the regulation of bone metabolism via anti-inflammatory signaling and decreased reactive oxygen s

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… The Neh4 and Neh5 form the transactivation domain of NRF2 that recruits CREB-binding protein (CBP) and receptor-associated coactivator 3 (RAC 3). Neh7 domain interacts with retinoid X receptor alpha (RXRα), which represses the transactivation activity of NRF2. … Abbreviations ARE | antioxidant response elements bZIP | basic leucine zipper protein family β-TrCP | β-transducin repeat-containing protein BMSCs | bone marrow stromal cells CCL3 | chemokine C-C motif 3 CBP | CREB-binding protein CUL1-RBX1 | Cullin 1-RING Box 1 CUL3-RBX1 | Cullin 3-RING Box 1 DDK- …

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect.

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC pat

Obesity: pathophysiology and therapeutic interventions.

Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutr

Primary Osteoporosis Induced by Androgen and Estrogen Deficiency: The Molecular and Cellular Perspective on Pathophysiological Mechanisms and Treatments.

Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption throug

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing.

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the 'guardian of the genome' and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni syndrome (LFS), the inherited cance

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… Transcription activity of the longest form of p73, TAp73α, similarly to p53, is induced by acetylation by p300 and CREB-binding protein (CBP) acetyltransferases [ 86 ]. … The N-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding protein and mediates transcriptional activation and apoptosis. Mol. Cell. Biol. 2000;20:1299–1310. doi: 10.1128/MCB.20.4.1299-1310.2000. 87. Zuckerman V., Lenos K., Popowicz G.M., Silberman I., Grossman T., Marine J. …

Breaking into HIV-1's Epigenetic Vault: Cure Strategies to Eliminate the Viral Reservoir.

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that integrates into the host cell's DNA as a provirus. Transcription from the provirus is regulated in large part by cellular proteins and epigenetic factors. These may be repressive or permissive to productive infection. The host factors that regulate this balance are therefore attractive targets for HIV-1 therapeutics. Indeed, proviral chromatin is the focus of two of the current HIV-1 cure strategies. "Shock and Kill" uses latency reversal agents to open the provirus's chromatin, promoting high levels of gene expression that induc

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… This is additionally associated with enrichment of histone acetyltransferases (HATs) like p300/CREB-binding protein (CBP) [ 108 , 109 , 110 ] and the H3K27 demethylase UTX-1 [ 111 ], which work together to “loosen” the interaction between DNA and histone by neutralizing the charge of the histone core …

Окисляющий/нетрозирующий стресс, апоптоз и сигнализация " Redox " : основные игроки в нейродегенеративных заболеваниях.

Нейродегенеративные заболевания представляют собой серьезную проблему для здоровья, которая оказывает глубокое воздействие на качество и продолжительность жизни миллионов людей. Эти заболевания характеризуются патологическими изменениями в различных областях мозга, конкретными генетическими мутациями, связанными с болезнью, залежами аномальных белков и дегенерацией неврологических клеток. Поскольку нейродегенеративные расстройства различаются по своим эпидемиологическим характеристикам и степени уязвимости нейронов, лечение этих заболеваний обычно направлено на замедление развития заболеваний.

Crosstalk of the Wnt/β-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells.

The Wnt/β-catenin signaling pathway plays a major role in cell survival and proliferation, as well as in angiogenesis, migration, invasion, metastasis, and stem cell renewal in various cancer types. However, the modulation (either up- or downregulation) of this pathway can inhibit cell proliferation and apoptosis both through β-catenin-dependent and independent mechanisms, and by crosstalk with other signaling pathways in a wide range of malignant tumors. Existing studies have reported conflicting results, indicating that the Wnt signaling can have both oncogenic and tumor-suppressing roles, d

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… The hyperactivation of Wnt signaling by butyrate is influenced by the CREB-binding protein (CBP) and p300, histone acetylases that associate with β-catenin [ 136 ]. …

Спасение гиппокампальной синаптической пластичности и эффективности памяти Финголимода (FTY720) в модели APP/PS1 болезни Альцгеймера сопровождается коррекцией метаболизма финголипидов, полиаминов и фосфолипидного насыщенного состава.

Ранее, наши метаболомические, транскриптомные и геномные исследования характеризовали путь церамида/шфингомилена как терапевтическую цель в болезни Альцгеймера, и мы показали, что FTY720, фингозин-1-фосфахатный рецептор, утвержденный для лечения множественных склерозов, восстанавливает синаптическая пластичность и память в мышах APP/PS1. Для дальнейшего изучения того, как FTY720 спасает патологию, мы провели метаболический анализ мозга, плазмы и печени обученных APP/PS1 и диких мышей. APP/PS1 мыши продемонстрировали локальные нарушения мозга в полиаминах, фосфолипидах и сфинголипидах. Большинс

Targeting vascular endothelial growth receptor-2 (VEGFR-2): structural biology, functional insights, and therapeutic resistance.

Angiogenesis, the process of new blood vessel formation, is a fundamental physiological process implicated in several pathological disorders. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for angiogenesis and vasculogenesis. Among them, the tyrosine kinase receptor VEGFR-2 is primarily expressed in endothelial cells (ECs). These cells regulate various physiological responses, including differentiation, cell proliferation, migration, and survival, by binding to VEGF mitogens. Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key regulator of

Модуляторные эффекты традиционной китайской медицины и производные активных метаболитов на аутоиммунально-воспалительных путях сигнала при множестве склерозов: обзор повествования.

Множественный склероз (MS) — нервно-воспалительное заболевание с иммунной помощью, характеризующееся обезвоживанием, аксоновой травмой и обширным разрушением целостности центральной нервной системы. Экспериментальный аутоиммунный энцефаломиэлит (EAE) — наиболее часто применяемая модель для имитации патологических особенностей человека. В настоящее время еще многое предстоит сделать для совершенствования стратегии лечения MS. Все больше исследований показывают, что традиционная китайская медицина (TCM) и связанные с ней активные метаболиты полезны для лечения MS и умело регулируют уровни подстр

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreat

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… cancer Histone acetylation Acetylation and deacetylation of lysine residues within histone tails represents a crucial mechanism within a plethora of epigenetic regulatory mechanisms controlling gene expression. 10 While histone acetylation mediated by histone acetyltransferases (HATs), for example, CREB-binding … ACS Chem Biol 2016 ; 11 : 598 – 608 . 10.1021/acschembio.5b00831 26596782 PMC7295032 14 Balasubramanyam K , Varier RA , Altaf M , et al Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent …