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Integrated bulk and single-cell transcriptomic analyses identify senescence-related hub genes and microenvironmental remodeling in sarcopenia.

Increasing evidence indicates that cellular senescence, metabolic dysfunction, stromal remodeling, and immune perturbation collectively cont … d pathways. GSEA revealed positive enrichment of NABA Core Matrisome and negative enrichment of the citric acid cycle and respiratory electron transport pathway in sarcopenia. Integrative machine learning analysis converged on PCK1, EGFR, and MAPKAPK3 as senescence-related hub genes. PCK1 and EGFR were significantly upregulated in sarcopenia, whereas MAPKAPK3 was s …

ATG7 regulates energy metabolism, differentiation and survival of Philadelphia-chromosome-positive cells.

A major drawback of tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is that primitive CML cells are able to survive TKI-mediated BCR-ABL inhibition, leading to disease persistence in patients. Investigation of strategies aiming to inhibit alternative survival pathways in CML is therefore critical. We have previously shown that a nonspecific pharmacological inhibition of autophagy potentiates TKI-induced death in Philadelphia chromosome-positive cells. Here we provide further understanding of how specific and pharmacological autophagy inhibition affects nonmitochondr

Metabolic gatekeeper function of B-lymphoid transcription factors.

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy d

AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.

AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial

mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells.

Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass producti

Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex.

The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL1/2 complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex w

Bortezomib alters sour taste sensitivity in mice.

Chemotherapy-induced taste disorder is one of the critical issues in cancer therapy. Bortezomib, a proteasome inhibitor, is a key agent in multiple myeloma therapy, but it induces a taste disorder. In this study, we investigated the characteristics of bortezomib-induced taste disorder and the underlying mechanism in mice. Among the five basic tastes, the sour taste sensitivity of mice was significantly increased by bortezomib administration. In bortezomib-administered mice, protein expression of PKD2L1 was increased. The increased sour taste sensitivity induced by bortezomib returned to the co

IDH Mutations in Glioma: Molecular, Cellular, Diagnostic, and Clinical Implications.

In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via i

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… Citric Acid Cycle Rewiring in IDH Mutant Cells The citric acid cycle is the cornerstone of cellular metabolism [ 101 ]. This pathway is directly involved in energy production and supplies metabolic intermediates for the generation of fatty acids, amino acids and nucleotides. … These findings are supported by studies showing that citric acid cycle intermediates downstream of IDH, including αKG, succinate and fumarate, are decreased [ 102 , 103 ]. Anaplerotic reactions serve to replenish citric acid cycle intermediates, maintaining cycle flux [ 101 ]. …

Research Hotspots and Trends in Global Cancer immunometabolism:A Bibliometric Analysis from 2000 to 2023.

BackgroundCancer poses a major global health challenge, and immunotherapy, known as the third revolution in cancer treatment, has brought new hope to patients. The emerging field of immunometabolism has further enhanced the safety and efficacy of immunotherapy. Over the past two decades, this field has rapidly evolved in oncology, leading to numerous significant findings. This review systematically examines the literature on immunometabolism in cancer, visualizing research trends and identifying future directions.MethodsA comprehensive literature search was conducted in the Web of Science, Pub

Iron deprivation in cancer--potential therapeutic implications.

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention i

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… Several proteins involved in metabolism have been implicated in a variety of malignancies, including enzymes of the citric acid cycle, the Myc family of proteins, and the hypoxia inducible factors 1 and 2. Iron regulates the activity of several enzymes involved in the citric acid cycle. … Iron-dependent changes in cellular energy metabolism: Influence on citric acid cycle and oxidative phosphorylation. Biochim. Biophys. Acta. 1999;1413:99–107. doi: 10.1016/s0005-2728(99)00088-2. 49. King A., Selak M.A., Gottlieb E. …

Иммунометаболизм в старении мозга и нейродегенерации: преодоление метаболических путей и иммунные ответные меры.

Сложный набор взаимодействий между иммунной системой и метаболизмом, известный как иммунометаболизм, стал критическим регулятором последствий заболеваний в центральной нервной системе. В ходе многочисленных исследований метаболические расстройства увязывались с ослабленной иммунной реакцией при старении мозга, нейродегенеративных расстройствах и травме мозга. В этом обзоре мы обсудим вопрос о том, как нарушения баланса иммунометаболизма мозга способствуют патофизиологии дисфункции мозга. В первой части обзора резюмируется вклад таких критических групп иммунной клетки, как микроглии, астроциты,

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… Sirt1 | Regulates the plasticity of helper T cells and Tregs α-ketoglutarate (αKG) | Citric acid cycle | CD4+ T cells | N/A | Promotes CD4(+) T cell differentiation | [ 152 ] Acetyl coenzyme A (acetyl-CoA) carboxylase 1 (ACC1) | Fatty acid synthesis | Th-17 T cells | N/A | Promotes Th17 cell development …

Targeted synthesis of a trimethoxyphenyltetrahydropyrimidine analogue designed as a DNA intercalator: in silico, multi-spectroscopic, thermodynamic, and in vitro approaches.

Based on the rational design of DNA intercalators and Topo-II inhibitors and taking into consideration the main pharmacophoric features of doxorubicin (Dox) as a reference standard, we theoretically designed novel substituted tetrahydropyrimidine analogues (T1-35). The designed analogues (T1-35) were investigated for their inhibitory potential towards the hybrid DNA and Topo-II target receptor using molecular docking. Interestingly, the theoretically designed analogue T30 with a 3,4,5-trimethoxy phenyl side chain was found to be the superior candidate, achieving a binding score of -7.06 kcal m

Тела эндогенных кетонов связаны с метаболической уязвимостью и инвалидностью при множественном склерозе.

Цель: Тела кетона могут быть полезными биомаркерами в множестве склероза (МС), поскольку патофизиологические процессы, лежащие в основе развития заболеваний MS, вызывают метаболический стресс. Цель заключалась в оценке связей кетоновых тел с биомаркерами метаболического, подстрекательского и окислительного стресса в MS. Методы: Образцы крови и неврологические оценки были получены от 153 здоровых контрольных приборов (HC), 187 релапсирующих излучающих веществ (RRMS) и 91 пациента с прогрессивным MS (PMS). AcAc, BHB и ацетон измерялись с помощью спектроскопии протонного ядерного магнитного резон

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… During ketolysis, energy is produced from ketone bodies by converting AcAc back to acetyl-CoA, which enters the citric acid cycle to generate adenosine triphosphate (ATP). The liver is a net exporter of ketone bodies because it lacks succinyl-CoA-3-oxaloacid CoA transferase (SCOT). … Leucine is a ketogenic amino acid that is catabolized into acetyl-CoA and acetoacetate to enter the citric acid cycle. Alanine and valine are glucogenic amino acids and are catabolized to glucose, and isoleucine is amphibolic. …

Saliva как матрица для терапевтического мониторинга наркотиков и биомаркеров заболеваний у детей и подростков.

Saliva — более доступная, менее напряженная и менее дорогостоящая биологическая матрица, чем кровь, и она может применяться в терапевтическом мониторинге лекарственных средств (ПТМ). Концентрации слюны отражают фармацевтический активный ненавязанный препарат. В этом обзоре содержится последняя информация о слюне в качестве матрицы для лечебного контроля за наркотиками и определения биомаркеров у младенцев, детей и подростков. К октябрю 2024 года по базе данных PubMed были проведены обыски литературы, 64 исследования были включены в TDM, стероиды, добавки, биомаркеры заболеваний, стоматология,

Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas.

Pediatric ependymomas are a type of malignant brain tumor that occurs in children. The overall 10-year survival rate has been reported as being 45-75%. Maximal safe surgical resection combined with adjuvant chemoradiation therapy is associated with the highest overall and progression-free survival rates. Despite aggressive treatment, one-third of ependymomas exhibit recurrence within 2 years of initial treatment. Therefore, this study aimed to find new agents to overcome chemoresistance and defer radiotherapy treatment since, in addition, radiation exposure may cause long-term side effects in

Transferrin-conjugated SNALPs encapsulating 2'-O-methylated miR-34a for the treatment of multiple myeloma.

Stable nucleic acid lipid vesicles (SNALPs) encapsulating miR-34a to treat multiple myeloma (MM) were developed. Wild type or completely 2'-O-methylated (OMet) MiR-34a was used in this study. Moreover, SNALPs were conjugated with transferrin (Tf) in order to target MM cells overexpressing transferrin receptors (TfRs). The type of miR-34a chemical backbone did not significantly affect the characteristics of SNALPs in terms of mean size, polydispersity index, and zeta potential, while the encapsulation of an OMet miR-34a resulted in a significant increase of miRNA encapsulation into the SNALPs.

Cardiovascular Biomarkers in Cardio-Oncology: Antineoplastic Drug Cardiotoxicity and Beyond.

Serum biomarkers represent a reproducible, sensitive, minimally invasive and inexpensive method to explore possible adverse cardiovascular effects of antineoplastic treatments. They are useful tools in risk stratification, the early detection of cardiotoxicity and the follow-up and prognostic assessment of cancer patients. In this literature review, we aim at describing the current state of knowledge on the meaning and the usefulness of cardiovascular biomarkers in patients with cancer; analyzing the intricate relationship between cancer and cardiovascular disease (especially HF) and how this

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… Changes in Citric Acid Cycle and Nucleoside Metabolism Are Associated with Anthracycline Cardiotoxicity in Patients with Breast Cancer J. Cardiovasc. Transl. Res. 2020 13 349 356 10.1007/s12265-019-09897-y 31278494 147. Cocco D. Ferro E. Ricci S. Deidda M. Noto A. Madeddu C. Atzori F. Scartozzi M. …

In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma.

Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are urgently awaited. A rising body of evidence supports the notion that microRNAs (miRNAs), master regulators of eukaryotic gene expression, may exert anti-MM activity. Here, we evaluated the activity of synthetic miR-34a in MM cells. We found that transfection of miR-34a mimics in MM cells induces a significant change of gene expression with relevant effects on multiple signal transduction pathways. We detected early inactivation of pro-survival and proliferative kinases Erk-2 and Akt followed at later

Multiplatform plasma fingerprinting in cancer cachexia: a pilot observational and translational study.

BACKGROUND: Cachexia is a metabolic syndrome that affects up to 50-80% of cancer patients. The pathophysiology is characterized by a variable combination of reduced food intake and abnormal metabolism, including systemic inflammation and negative protein and energy balance. Despite its high clinical significance, defined diagnostic criteria and established therapeutic strategies are lacking. The 'omics' technologies provide a global view of biological systems. We hypothesize that blood-based metabolomics might identify findings in cachectic patients that could provide clues to gain knowledge o

Clinical antitumor application and pharmacological mechanisms of Dahuang Zhechong Pill.

Cancer still has elevated morbidity and mortality, which undoubtedly impacts the life quality of affected individuals. Remarkable advances have been made in cancer therapy, although the toxicities of traditional therapies remain an obvious challenge. Dahuang Zhechong Pill (DHZCP), developed by Zhongjing Zhang in the Synopsis of the Golden Chamber, represents an effective anticancer traditional Chinese medicine (TCM). In this review, it was found that DHZCP is therapeutically utilized in liver, lung, gastric, pancreatic and other cancers in clinic. Pharmacological evidence showed that its anti-