TCA-phospholipid-glycolysis targeted triple therapy effectively suppresses ATP production and tumor growth in glioblastoma

Theranostics, Journal Year: 2022, Volume and Issue: 12(16), P. 7032 - 7050

Published: Jan. 1, 2022

Rationale: Glioblastoma (GBM) displays a complex metabolic reprogramming in cancer cells.Adenosine triphosphate (ATP) is one of the central mediators cell metabolism and signaling.GBM cells generate ATP by glycolysis tricarboxylic acid (TCA) cycle associated with oxidative phosphorylation (OXPHOS) through breaking-down pyruvate or fatty acids to meet growing energy demand cells.Therefore, it's urgent develop novel treatments targeting hinder tumor proliferation GBM.Methods: Non-targeted metabolomic profiling analysis was utilized evaluate using small molecule inhibitor (SMI) EPIC-0412 treatment.Cellular oxygen consumption rate (OCR) total proton efflux (PER), as well concentration, were tracked study responses specifically targeted inhibitors, including EPIC-0412, arachidonyl trifluoromethyl ketone (AACOCF3), 2 deoxy-D-glucose (2-DG).Cancer assessed CCK-8 measurements colony formation assay.Additionally, flow cytometry, immunoblotting (IB), immunofluorescence (IF) analyses performed GBM understand their tumorigenic properties under treatments.Finally, anticancer effects this combination therapy evaluated mouse model convection-enhanced delivery (CED).Results: We found that SMI could effectively perturb TCA cycle, which participated cytosolic phospholipase A2 (cPLA2)-inhibitor AACOCF3, hexokinase II (HK2)-inhibitor 2-DG disrupt for treatments.ATP production significantly declined glioma when treated monotherapy (EPIC-0412 AACOCF3), dual + triple AACOCF3 +2-DG) regimen.Our experiments revealed these therapies hindered growth, leading reduction G0/G1 arrest.We demonstrated extended survival cerebral tumor-bearing mice. Conclusion:Our findings indicate TCA-phospholipid-glycolysis axis can be blocked specific inhibitors suppress Ivyspring

Language: Английский

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Application of calcium overload-based ion interference therapy in tumor treatment: strategies, outcomes, and prospects

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 15, 2024

Low selectivity and tumor drug resistance are the main hinderances to conventional radiotherapy chemotherapy against tumor. Ion interference therapy is an innovative anti-tumor strategy that has been recently reported induce metabolic disorders inhibit proliferation of cells by reordering bioactive ions within cells. Calcium cation (Ca2+) indispensable for all physiological activities In particular, calcium overload, characterized abnormal intracellular Ca2+ accumulation, causes irreversible cell death. Consequently, overload-based ion potential overcome traditional treatment strategies holds promise clinical application. this review, we 1) Summed up current employed in therapy; 2) Described outcome death resulting from 3) Discussed its application synergistic with immunotherapy.

Language: Английский

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Pancreatic Ductal Adenocarcinoma: Molecular Pathology and Predictive Biomarkers

Cells, Journal Year: 2022, Volume and Issue: 11(19), P. 3068 - 3068

Published: Sept. 29, 2022

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance conventional treatment modalities, targeted therapies, immunotherapies. PDACs are a heterogenous group malignant epithelial neoplasms with various histomorphological patterns complex, genetic/molecular landscapes. The newly proposed molecular classifications PDAC based on extensive genomic, transcriptomic, proteomic epigenetic data have provided significant insights into heterogeneity aggressive biology this deadly disease. Recent studies characterizing tumor microenvironment (TME) shed light dynamic interplays between cells immunosuppressive TME PDAC, which is essential disease progression, as well chemotherapy, developed therapy immunotherapy. There critical need development predictive markers that can be clinically utilized select effective personalized therapies patients. In review, we provide overview histological subtypes precursor lesions, TME, currently available

Language: Английский

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Damage associated molecular patterns and neutrophil extracellular traps in acute pancreatitis

Frontiers in Cellular and Infection Microbiology, Journal Year: 2022, Volume and Issue: 12

Published: Aug. 12, 2022

Previous researches have emphasized a trypsin-centered theory of acute pancreatitis (AP) for more than century. With additional studies into the pathogenesis AP, new mechanisms been explored. Among them, role immune response bears great importance. Pro-inflammatory substances, especially damage-associated molecular patterns (DAMPs), play an essential in activating, signaling, and steering inflammation. Meanwhile, activated neutrophils attach importance to defense by forming neutrophil extracellular traps (NETs), which cause ductal obstruction, premature trypsinogen activation, modulate In this review, we discuss latest advances understanding pathological DAMPs NETs AP shed light on flexible crosstalk between these vital inflammatory mediators. We, then highlight potentially promising treatment targeting NETs, with focus novel insights mechanism, diagnosis, management AP.

Language: Английский

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When healing turns into killing – the pathophysiology of pancreatic and hepatic fibrosis

The Journal of Physiology, Journal Year: 2022, Volume and Issue: 600(11), P. 2579 - 2612

Published: April 17, 2022

Abstract Disorders such as pancreatic or hepatic fibrosis are a cruel reminder that disruption of the delicate physiological balance could result in severe pathological consequences. Fibrosis is usually associated with chronic diseases and manifests itself excessive deposition extracellular matrix, which gradually leads to replacement cellular components by fibrotic lesions, significantly compromising normal tissue functions. The main mediators different populations fibroblasts, predominantly stellate cells liver pancreas, respectively. These undergo phenotypic switch response (bio)chemical physical stimuli acquire myofibroblast‐like phenotype characterised increased contractile adhesive properties, elevated expression certain cytoskeletal membrane proteins, prominent production matrix components. In past few decades, substantial scientific effort has been undertaken investigate pathogenesis fibrosis. Here, mechanisms fibrosis, their aetiological factors, prospective therapies discussed. New against likely be focused on regulation hepatic/pancreatic cell physiology well normalisation organ mechanostasis. image

Language: Английский

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OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(7)

Published: March 31, 2024

Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which effectively prevented when the cell at rest. Here we showed that of zymogen granules acinar cells was driven directly released from acidic stores including through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded Tmem63a) as an organellar regulator protein integral membrane controlled release via inhibition TPC1 and TPC2 currents. Deletion led extensive NAADP-responsive under basal conditions well upon stimulation GPCR receptors. Moreover, deletion exacerbated disease phenotype murine models severe chronic pancreatitis. Our findings a gatekeeper endows NAADP-sensitive with autoregulatory mechanism preventing uncontrolled pancreatic tissue damage.

Language: Английский

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The role of mitochondrial damage-associated molecular patterns in acute pancreatitis

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 175, P. 116690 - 116690

Published: May 7, 2024

Acute pancreatitis (AP) is one of the most common gastrointestinal tract diseases with significant morbidity and mortality. Current treatments remain unspecific supportive due to severity clinical course AP, which can fluctuate rapidly unpredictably. Mitochondria, cellular power plant produce energy, are involved in a variety physiological or pathological activities human body. There growing evidence indicating that mitochondria damage-associated molecular patterns (mtDAMPs) play an important role pathogenesis progression AP. With pro-inflammatory properties, released mtDAMPs may damage pancreatic cells by binding receptors, activating downstream molecules releasing inflammatory factors. This review focuses on possible interaction between AP mtDAMPs, include cytochrome c (Cyt c), mitochondrial transcription factor A (TFAM), DNA (mtDNA), cardiolipin (CL), adenosine triphosphate (ATP) succinate, focus experimental research potential therapeutic targets practice. Preventing diminishing release targeting receptors might have progression.

Language: Английский

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Potential role of endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity-an update

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 12, 2024

As a chemotherapy agent, doxorubicin is used to combat cancer. However, cardiotoxicity has limited its use. The existing strategies fail eliminate doxorubicin-induced cardiotoxicity, and an in-depth exploration of pathogenesis in urgent need address the issue. Endoplasmic reticulum stress (ERS) occurs when Reticulum (ER) dysfunction results accumulation unfolded or misfolded proteins. Adaptive ERS helps regulate protein synthesis maintain cellular homeostasis, while prolonged stimulation may induce cell apoptosis, leading damage tissue organs. Numerous studies on strongly link excessive activation mechanisms including oxidative stress, calcium imbalance, autophagy, ubiquitination, apoptosis. researchers also found several clinical drugs, chemical compounds, phytochemicals, miRNAs inhibited by targeting ERS. present review aims outline interactions between other summarize ERS’s role this type cardiotoxicity. Additionally, enumerates for considering therapeutic regimens that

Language: Английский

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Activation and Regulation of Pancreatic Stellate Cells in Chronic Pancreatic Fibrosis: A Potential Therapeutic Approach for Chronic Pancreatitis

Biomedicines, Journal Year: 2024, Volume and Issue: 12(1), P. 108 - 108

Published: Jan. 4, 2024

In the complex progression of fibrosis in chronic pancreatitis, pancreatic stellate cells (PSCs) emerge as central figures. These cells, initially a dormant state characterized by storage vitamin A lipid droplets within pancreatitis microenvironment, undergo profound transformation into an activated state, typified secretion abundant extracellular matrix, including α-smooth muscle actin (α-SMA). This review delves myriad factors that trigger PSC activation context pancreatitis. encompass alcohol, cigarette smoke, hyperglycemia, mechanical stress, acinar cell injury, and inflammatory with focus on elucidating their underlying mechanisms. Additionally, we explore regulatory play significant roles during activation, such TGF-β, CTGF, IL-10, PDGF, among others. The investigation these pathways involved holds promise identifying potential therapeutic targets for ameliorating We provide summary recent research findings pertaining to modulation covering essential genes innovative mediators designed counteract activation. anticipate this will stimulate further insights mechanisms fibrosis, ultimately leading discovery groundbreaking therapies targeting cellular molecular responses processes.

Language: Английский

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Epithelial Anoctamins

Cell Calcium, Journal Year: 2024, Volume and Issue: 120, P. 102885 - 102885

Published: April 15, 2024

When activated by increase in intracellular Ca2+, anoctamins (TMEM16 proteins) operate as phospholipid scramblases and ion channels. Anoctamin 1 (ANO1) is the Ca2+-activated epithelial anion-selective channel that coexpressed together with abundant scramblase ANO6 additional anoctamins. In salivary pancreatic glands, ANO1 tightly packed apical membrane secretes Cl−. Epithelia of airways gut use cystic fibrosis transmembrane conductance regulator (CFTR) an Cl− exit pathway while supports secretion mainly facilitating activation luminal CFTR basolateral K+ Under healthy conditions modulates Ca2+ signals tethering endoplasmic reticulum, except glands its direct secretory contribution might be small, compared to CFTR. kidneys proximal tubular acid protein absorption probably helps excrete HCO3− collecting duct epithelium. However, under pathological polycystic kidney disease, strongly upregulated may cause enhanced proliferation cyst growth. condition, are channel/phospholipid scramblase, partly supporting Ca2+-dependent processes. Much less known about role other whose potential functions discussed this review.

Language: Английский

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