Pharmacology & Therapeutics, Journal Year: 2019, Volume and Issue: 200, P. 27 - 41
Published: April 8, 2019
Language: Английский
Human Reproduction, Journal Year: 2018, Volume and Issue: 34(1), P. 69 - 78
Published: Nov. 1, 2018
Abstract STUDY QUESTION Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? SUMMARY ANSWER We found that approximately one-quarter of IE cases somatic-cancer mutations, which commonly affect components the MAPK/RAS or PI3K-Akt-mTor signaling pathways. WHAT IS KNOWN ALREADY Despite classification as a benign gynecological disease, it shares key features with cancers such resistance to apoptosis and stimulation angiogenesis is well-established precursor clear cell endometrioid ovarian carcinomas. Our group has recently shown deep infiltrating (DE), form rarely undergoes malignant transformation, harbors recurrent mutations. DESIGN, SIZE, DURATION In retrospective study comparing iatrogenically induced endogenously occurring forms unlikely progress cancer, we examined specimens from 40 women 36 DE. Specimens were collected between 2004 2017 five hospital sites in either Canada, Germany Netherlands. DE cohorts age-matched all presented histologically typical without known history malignancy. PARTICIPANTS/MATERIALS, SETTING, METHODS Archival tissue containing endometriotic lesions macrodissected and/or laser-capture microdissected enrich stroma epithelium hypersensitive cancer hotspot sequencing panel was used assess for presence Mutations subsequently validated using droplet digital PCR. PTEN ARID1A immunohistochemistry (IHC) performed surrogates events resulting functional loss respective proteins. MAIN RESULTS AND THE ROLE OF CHANCE Overall, detected 11 (27.5%) 13 (36.1%) cases, including mutations KRAS, ERBB2, PIK3CA CTNNB1. Heterogeneous occurred at similar rates (7/40 vs 5/36, respectively), whereas only single case While detectable are not statistically significant (P > 0.05), KRAS activating more prevalent LIMITATIONS, REASONS FOR CAUTION Detection limited hotspots analyzed our panel-based assay protein expression by IHC archival tissue. Whole genome exome sequencing, epigenetic analysis may uncover additional alterations. Moreover, because descriptive nature this study, roles identified within context remain unclear causality cannot be established. WIDER IMPLICATIONS FINDINGS The alterations report important driving growth survival ectopic regions body. Given frequency mutation surgically displaced endometrium (IE), examination eutopic endometrium, well clinically annotated other endometriosis, particular endometriomas most linked malignancy, warranted. FUNDING/COMPETING INTEREST(S) This funded Canadian Cancer Society Impact Grant [701603, PI Huntsman], Institutes Health Research Transitional Open Operating [MOP-142273, Yong], Foundation [FDN-154290, Project [PJT-156084, PIs Yong Anglesio], Janet D. Cottrelle through BC [PI Huntsman]. D.G. Huntsman co-founder shareholder Contextual Genomics Inc., profit company provides clinical reporting assist patient treatment. R. Aguirre-Hernandez, J. Khattra L.M. Prentice have patent MOLECULAR QUALITY ASSURANCE USE IN SEQUENCING pending current (or former) employees Inc. remaining authors no competing interests declare. TRIAL REGISTRATION NUMBER Not applicable.
Language: Английский
Citations
90
Cell Death and Disease, Journal Year: 2018, Volume and Issue: 10(1)
Published: Dec. 18, 2018
Abstract Mounting evidence has demonstrated that angiogenesis plays an important role in tumour progression. However, the key regulators remain unclear. Recently, emerging reports have indicated SIRT2 critical roles proliferation, metastasis and tumourigenesis diverse tumours. function of mechanism underlying regulation by are still unknown. Here, we found was upregulated colorectal cancer tissues compared to normal samples elevated associated with poor prognosis patients cancer. In addition, a series vitro vivo experiments were performed demonstrate angiogenesis. We showed silencing significantly suppressed Mechanistically, knockdown inhibited STAT3 phosphorylation, causing decreased secretion VEGFA. Notably, directly interacted affected phosphorylation translocation phosphorylated nucleus. Importantly, rescue suggested depends on STAT3/VEGFA signalling pathway. Our findings provide insight into colon suggest SIRT2/STAT3/VEGFA might be novel prognostic biomarker potential therapeutic target for
Language: Английский
Citations
90
Metabolites, Journal Year: 2020, Volume and Issue: 10(11), P. 450 - 450
Published: Nov. 7, 2020
There is a growing body of evidencethat indicates that the aging brain results from decline energy metabolism. In particular, neuronal metabolism glucose declines steadily, resulting in deficit adenosine triphosphate (ATP) production—which, turn, limits access. This vicious circle at cellular level evoked by rising deficiency nicotinamide adenine dinucleotide (NAD) mitochondrial salvage pathway and subsequent impairment Krebs cycle. A decreasing NAD also impoverishes activity NAD-dependent enzymes augments genetic errors initiate processes degeneration death.This sequence events characteristic several structures which neurons have highest Neurons cerebral cortex basal ganglia with long unmyelinated axons these numerous synaptic junctions are particularly prone to senescence neurodegeneration. Unfortunately, functional deficits neurodegeneration initially well-compensated, therefore, clinical symptoms recognized too late when damages already irreversible. Therefore, future treatment strategies neurodegenerative disorders should focus on compensation age-related neurons. review summarizes complex interrelationships between metabolic systemic levels provides directions how reduce risk protect elderly against diseases.
Language: Английский
Citations
89
Pharmacology & Therapeutics, Journal Year: 2020, Volume and Issue: 221, P. 107748 - 107748
Published: Nov. 24, 2020
Language: Английский
Citations
88
International Journal of Cancer, Journal Year: 2020, Volume and Issue: 147(12), P. 3297 - 3304
Published: May 25, 2020
Sirtuin 2 (SIRT2) belongs to the sirtuins family. It exists in many tissues and organs of human body regulates a wide range biological functions. Studies have found that abnormal expression SIRT2 was associated with variety malignant tumors. possesses an important role tumorigenesis, both tumor-promoting tumor-suppressing function. However, mechanisms which plays roles cancer are still controversial. This article reviews molecular mechanism tumor evolution, provides ideas for future research this field, guide targeted therapy drug development related malignancies.
Language: Английский
Citations
85
PROTEOMICS, Journal Year: 2020, Volume and Issue: 20(5-6)
Published: Feb. 18, 2020
Abstract Aging biology is intimately associated with dysregulated metabolism, which one of the hallmarks aging. Aging‐related pathways such as mTOR and AMPK, are major targets anti‐aging interventions including rapamcyin, metformin, exercise, either directly regulate or intersect metabolic pathways. In this review, numerous candidate bio‐markers aging that have emerged using metabolomics outlined. Metabolomics studies also reveal not all metabolites created equally. A set core “hub” emerging central mediators The hub reviewed here nicotinamide adenine dinucleotide, reduced dinucleotide phosphate, α‐ketoglutarate, β‐hydroxybutyrate. These signaling epigenetic roles along their canonical co‐factors intermediates carbon metabolism. Together these suggest a role TCA cycle in dysregulation
Language: Английский
Citations
76
Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(11)
Published: April 7, 2022
Type 2 alveolar epithelial cells (AEC2s) function as progenitor in the lung. We have shown previously that failure of AEC2 regeneration results progressive lung fibrosis mice and is a cardinal feature idiopathic pulmonary (IPF). In this study, we identified deficiency specific zinc transporter, SLC39A8 (ZIP8), AEC2s from both IPF lungs old mice. Loss ZIP8 expression was associated with impaired renewal capacity enhanced fibrosis. regulation dependent on SIRT1. Replenishment exogenous SIRT1 activation promoted self-renewal differentiation tissues patients Deletion Zip8 resulted renewal, increased susceptibility to bleomycin injury, development spontaneous Therapeutic strategies restore metabolism appropriate signaling could improve mitigate ongoing fibrogenesis.
Language: Английский
Citations
66
Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(19), P. 7175 - 7191
Published: May 8, 2023
Aging refers to the gradual physiological changes that occur in an organism after reaching adulthood, resulting senescence and a decline biological functions, ultimately leading death. Epidemiological evidence shows aging is driving factor developing of various diseases, including cardiovascular neurodegenerative immune system disorders, cancer, chronic low-grade inflammation. Natural plant polysaccharides have emerged as crucial food components delaying process. Therefore, it essential continuously investigate potential sources new pharmaceuticals for aging. Modern pharmacological research indicates can exert antiaging effects by scavenging free radicals, increasing telomerase activity, regulating apoptosis, enhancing immunity, inhibiting glycosylation, improving mitochondrial dysfunction gene expression, activating autophagy, modulating gut microbiota. Moreover, activity mediated one or more signaling pathways, IIS, mTOR, Nrf2, NF-κB, Sirtuin, p53, MAPK, UPR pathways. This review summarizes properties pathways participating polysaccharide-regulating Finally, we discuss structure-activity relationships polysaccharides.
Language: Английский
Citations
37
Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(1), P. 253 - 268
Published: Jan. 18, 2023
Abstract Mitochondrial dysfunction plays a major role in the development of intervertebral disc degeneration (IDD). Sirtuin 5 (SIRT5) participates maintenance mitochondrial homeostasis through its desuccinylase activity. However, it is still unclear whether succinylation or SIRT5 involved impairment mitochondria and IDD induced by excessive mechanical stress. Our 4D label-free quantitative proteomic results showed decreased expression rat nucleus pulposus (NP) tissues under loading. Overexpression Sirt5 effectively alleviated, whereas knockdown aggravated, apoptosis NP cells stress, consistent with more severe phenotype KO mice than wild-type that underwent lumbar spine instability (LSI) surgery. Moreover, immunoprecipitation-coupled mass spectrometry (IP-MS) suggested AIFM1 was downstream target SIRT5, which verified Co-IP assay. We further demonstrated reduced resulted increased AIFM1, turn abolished interaction between CHCHD4 thus led to electron transfer chain (ETC) complex subunits cells. Reduced ETC subsequent occurrence Finally, we validated efficacy treatments targeting disrupted protein importation upregulating methylene blue (MB) administration compression-induced model. In conclusion, our study provides new insights into offers promising therapeutic approaches for IDD.
Language: Английский
Citations
32
Aging and Disease, Journal Year: 2023, Volume and Issue: 14(5), P. 1651 - 1651
Published: Jan. 1, 2023
In cell transplantation therapy, mesenchymal stem cells(MSCs)are ideal seed cells due to their easy acquisition and cultivation, strong regenerative capacity, multi-directional differentiation abilities, immunomodulatory effects. Autologous MSCs are better applicable compared with allogeneic in clinical practice. The elderly the main population for but as donor aging, tissue show aging-related changes. When number of generations vitro expansion is increased, will also exhibit replicative senescence. quantity quality decline during which limits efficacy autologous therapy. this review, we examine changes MSC senescence a result discuss progress research on mechanisms signalling pathways senescence, possible rejuvenation strategies aged combat enhance health therapeutic potential MSCs.
Language: Английский
Citations
28