Lactate metabolism in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 1, 2022

Abstract The current understanding of lactate extends from its origins as a byproduct glycolysis to role in tumor metabolism, identified by studies on the Warburg effect. shuttle hypothesis suggests that plays an important bridging signaling molecule coordinates among different cells, organs and tissues. Lactylation is posttranslational modification initially reported Professor Yingming Zhao’s research group 2019. Subsequent confirmed lactylation vital component function involved proliferation, neural excitation, inflammation other biological processes. An indispensable substance for various physiological cellular functions, regulatory aspects energy metabolism signal transduction. Therefore, comprehensive review summary presented clarify disease provide reference direction future research. This offers systematic overview homeostasis roles pathological processes, well effects diseases, particularly cancer.

Language: Английский

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Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

Nature Reviews Clinical Oncology, Journal Year: 2022, Volume and Issue: 20(1), P. 49 - 62

Published: Nov. 23, 2022

Language: Английский

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Targeting the tumor stroma for cancer therapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Nov. 2, 2022

Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part the tumor microenvironment, stroma is highly dynamic, heterogeneous commonly tumor-type specific, it mainly includes noncellular compositions such as extracellular matrix unique cancer-associated vascular system well a wide variety cellular components including activated fibroblasts, mesenchymal cells, pericytes. All these elements operate with each other in coordinated fashion collectively promote initiation, progression, metastasis therapeutic resistance. Over past few decades, numerous studies have been conducted to study interaction crosstalk between neoplastic cells. Meanwhile, we also witnessed exponential increase investigation recognition critical roles solid tumors. A series clinical trials targeting launched continually. In this review, introduce discuss current advances understanding various their cancers. We elaborate on potential novel approaches for tumor-stroma-based targeting, aim leap from bench bedside.

Language: Английский

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Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(12), P. 6434 - 6434

Published: June 16, 2021

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk increased in patients with metabolic syndrome (MetS) its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least part increase colon via insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, underlying mechanisms linking IGF-1 MetS are still poorly understood. Hyperactivated glucose uptake aerobic glycolysis (the Warburg effect) considered as a six hallmarks cancer, including CRC. role insulin/IGF-1 during acquisition phenotypes cells It likely results from interaction multiple processes, directly or indirectly regulated IGF-1, such activation PI3K/Akt/mTORC, Raf/MAPK pathways, transporters GLUT1), key glycolytic enzymes LDHA, LDH5, HK II, PFKFB3), aberrant expression oncogenes MYC, KRAS) and/or overexpression proteins HIF-1, TGF-β1, PI3K, ERK, Akt, mTOR). This review describes metabolism physiology colorectal carcinogenesis, insulin/IGF system effect. Furthermore, current therapeutic strategies aimed repairing impaired indicated.

Language: Английский

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Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(20), P. 11047 - 11047

Published: Oct. 13, 2021

Until recently, radiation effects have been considered to be mainly due nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures ionizing (IR) highly depend on activation regulation through other components organelles determine cell survival proliferation capacities. As typical epigenetic-regulated central power stations cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply homeostasis as well radiation-induced signaling, death, immunological This review is focused how energy, dose quality IR affect mitochondria-dependent epigenetic functional control at tissue level. Low-dose appear associated with non-targeted involved genomic instability adaptive responses, whereas high-dose (>1 Gy) concern therapeutic long-term involving mitochondria-mediated innate immune Both quality. For example, increased efficacy high linear transfer particle radiotherapy, e.g., C-ion relies reduction anastasis, enhanced apoptosis immunogenic (antitumor)

Language: Английский

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Hypoxia: The Cornerstone of Glioblastoma

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(22), P. 12608 - 12608

Published: Nov. 22, 2021

Glioblastoma is the most aggressive form of brain tumor in adults and characterized by presence hypervascularization necrosis, both caused a hypoxic microenvironment. In this review, we highlight that hypoxia-induced factor 1 (HIF-1), main activated hypoxia, an important driver progression GB patients. HIF-1α transcription regulated or absence O2. The expression HIF-1 has been related to high-grade gliomas behavior. promotes via activation angiogenesis, immunosuppression, metabolic reprogramming, promoting cell invasion survival. Moreover, GB, not solely modulated oxygen but also oncogenic signaling pathways, such as MAPK/ERK, p53, PI3K/PTEN. Therefore, inhibition hypoxia pathway could represent treatment alternative disease with very few therapy options. Here, review roles inhibitors have studied thus far, aim shedding light on devastating disease.

Language: Английский

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Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(9), P. 1248 - 1263.e6

Published: Aug. 19, 2022

The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly converted induced neurons (iNs) from AD-patient-derived fibroblasts, we identified a metabolic switch to aerobic glycolysis in AD iNs. Pathological isoform switching the glycolytic enzyme pyruvate kinase M (PKM) toward cancer-associated PKM2 conferred and transcriptional changes These alterations occurred via PKM2's lack activity nuclear translocation association with STAT3 HIF1α promote neuronal fate loss vulnerability. Chemical modulation prevented translocation, restored mature metabolism, reversed AD-specific gene expression changes, re-activated resilience against cell death.

Language: Английский

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Mitochondria: It is all about energy

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: April 25, 2023

Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron calcium homeostasis the of hormones neurotransmitters, such as melatonin. They enable influence communication at all physical levels through interaction with other organelles, nucleus, outside environment. The literature suggests crosstalk between mitochondria circadian clocks, gut microbiota, immune system. might even be hub supporting integrating activity across these domains. Hence, they (missing) link Mitochondrial dysfunction related metabolic syndrome, neuronal diseases, cancer, cardiovascular infectious inflammatory disorders. In this regard, diseases Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), pain are discussed. This review focuses on understanding mitochondrial action that allow for maintenance pathways toward dysregulated mechanisms. Although have allowed us adapt changes over course evolution, turn, evolution has shaped mitochondria. Each evolution-based intervention influences its own way. use physiological stress triggers tolerance stressor, achieving adaptability resistance. describes strategies could recover functioning providing comprehensive, root-cause-focused, integrative approach recovering treating people suffering diseases.

Language: Английский

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Tumor acidity: From hallmark of cancer to target of treatment

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Aug. 29, 2022

Tumor acidity is one of the cancer hallmarks and associated with metabolic reprogramming use glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid stress major by activation expression proton lactate transporters exchangers have an inverted pH gradient (extracellular pHs are alkaline, respectively). The shift tumor acid-base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, treatment resistance. For example, weak-base chemotherapeutic agents may substantially reduced cellular uptake capacity due to "ion trapping". Lactic negatively affects functions activated effector T cells, stimulates regulatory them express programmed cell death receptor 1. On other hand, inversion could be weakness that will allow development new promising therapies, such as tumor-targeted pH-sensitive antibodies pH-responsible nanoparticle conjugates anticancer drugs. regulation levels pharmacological inhibition proteins (monocarboxylate transporters, H

Language: Английский

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An Epigenetic Role of Mitochondria in Cancer

Cells, Journal Year: 2022, Volume and Issue: 11(16), P. 2518 - 2518

Published: Aug. 13, 2022

Mitochondria are not only the main energy supplier but also cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which substrates for DNA methylation histone post-translation modifications, essential gene transcriptional regulation fate determination. Tumorigenesis is attributed to many factors, including mutations tumor microenvironment. initiation, evolution, metastasis, recurrence. Targeting mitochondrial metabolism promising therapeutic strategies treatment. In this review, we summarize of mitochondria required modification discuss current strategy cancer therapies via targeting epigenetic modifiers related enzymes This review an important contribution understanding metabolic-epigenetic-tumorigenesis concept.

Language: Английский

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