Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.
- MeSH
- autofagie * genetika MeSH
- běloši genetika MeSH
- duktální karcinom slinivky břišní * genetika patologie MeSH
- forkhead transkripční faktory MeSH
- genetická predispozice k nemoci * MeSH
- hepatocytární jaderný faktor 3-alfa genetika metabolismus MeSH
- jednonukleotidový polymorfismus * MeSH
- kohortové studie MeSH
- lidé MeSH
- nádorové biomarkery * genetika MeSH
- nádorové supresorové proteiny * genetika MeSH
- nádory slinivky břišní * genetika patologie MeSH
- studie případů a kontrol MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
Lysosomes are crucial in the tumour immune microenvironment, which is essential for the survival and homeostasis in multiple myeloma (MM). Here, we aimed to identify lysosome-related genes for the prognosis of MM and predicted their regulatory mechanisms. Gene expression profiles of MM from the GSE2658 and GSE57317 datasets were analysed. Lysosome-related differentially expressed genes (DEGs) were identified and used for molecular subtyping of MM patients. A prognostic model was constructed using univariate Cox regression and LASSO regression analyses. The relationship between prognostic genes, immune cell types, and autophagy pathways was assessed through correlation analysis. RT-qPCR was performed to validate the expression of prognostic genes in MM cells. A total of 9,954 DEGs were identified between high and low immune score groups, with 213 intersecting with lysosomal genes. Molecular subtyping revealed two distinct MM subtypes with significant differences in immune cell types and autophagy pathway activities. Five lysosome-related DEGs (CORO1A, ELANE, PSAP, RNASE2, and SNAPIN) were identified as significant prognostic markers. The prognostic model showed moderate predictive accuracy with AUC values up to 0.723. Prognostic genes demonstrated significant correlations with various immune cell types and autophagy pathways. Additionally, CORO1A, PSAP and RNASE2 expression was up-regulated in MM cells, while ELANE and SNAPIN were down-regulated. Five lysosomal genes in MM were identified, and a new risk model for prognosis was developed using these genes. This research could lead to discovering important gene markers for the treatment and prognosis of MM.
- MeSH
- autofagie genetika MeSH
- lidé MeSH
- lyzozomy * metabolismus genetika MeSH
- mnohočetný myelom * genetika imunologie MeSH
- nádorové biomarkery genetika MeSH
- nádorové mikroprostředí genetika imunologie MeSH
- prognóza MeSH
- regulace genové exprese u nádorů MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Ginsenoside Rb2 is beneficial in cardiovascular disease treatment, yet its role in heart failure (HF) is obscure. This study aimed to investigate the effect and mechanism of ginsenoside Rb2 on HF. METHODS: The left anterior descending branch-ligated HF rat model and oxygen-glucose deprivation/reoxygenation (OGD/R) H9c2 cell model were constructed. Ginsenoside Rb2 were applied for intervention. Heart function indexes, miR-216a-5p expression, autophagy, oxidative stress, apoptosis, cell morphology, and proliferation were detected to explore the effect of ginsenoside Rb2 on HF. Overexpression of miR-216a-5p was employed to explore the specific mechanism of ginsenoside Rb2 on HF. RESULTS: Ginsenoside Rb2 improved the heart function of HF rats, including the reduction of heart rate, LVEDP, and heart weight/body weight ratio, and the increase of LVSP, +dP/dtmax, -dP/dtmax, LVEF, and LVFS. It also down-regulated miR-216a-5p expression and enhanced OGD/R-induced cardiomyocyte viability. Ginsenoside Rb2 up-regulated Bcl2, LC3B II/I, and Beclin1, and down-regulated Bax, Caspase-3, and p62 in the myocardium of HF rats and OGD/R-induced H9c2 cells. Moreover, ginsenoside Rb2 increased the levels of SOD and CAT, but decreased the levels of MDA and ROS in the myocardium of HF rats and OGD/R-induced H9c2 cells. However, overexpression of miR-216a-5p promoted the apoptosis and oxidative stress of cardiomyocytes and inhibited autophagy, thus reversing the therapeutic effect of ginsenoside Rb2 on HF in vivo and in vitro. CONCLUSION: Ginsenoside Rb2 demonstrated potential as a therapeutic intervention for HF by enhancing autophagy and reducing apoptosis and oxidative stress through miR-216a-5p downregulation. Further research could explore its application in clinical trials and investigate the complex mechanism networks underlying its effects.
- MeSH
- apoptóza genetika MeSH
- autofagie genetika MeSH
- krysa rodu rattus MeSH
- mikro RNA * genetika MeSH
- oxidační stres genetika MeSH
- srdeční selhání * farmakoterapie genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
- MeSH
- autofagie genetika MeSH
- fibróza MeSH
- homeostáza MeSH
- lidé MeSH
- myši MeSH
- neurotrofní faktory genetika MeSH
- polycystická choroba ledvin * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The apicomplexan Toxoplasma gondii (Nicolle et Manceaux, 1908) secretes a group of serine/threonine kinases from rhoptries, which play vital roles in boosting intracellular infection. Toxoplasma gondii rhoptry organelle protein 17 (ROP17) is one of these important kinase proteins. Nevertheless, its function remains unclear. Here, we showed that ROP17 induced autophagy in vitro and in vivo. The autophagy of small intestine tissues of T. gondii tachyzoite (RH strain)-infected mice was detected by the immunohistochemistry staining of LC3B, Beclin 1 and P62. ROP17 overexpression augmented starvation-induced autophagy in HEK 293T cells as measured by MDC staining, transmission electron microscopy (TEM), fluorescence microscopy and Western blot analysis. Moreover, the interaction of ROP17 and Bcl-2 was confirmed using co-immunoprecipitation analysis, and the data demonstrated that ROP17 had an autophagic role dependent on the Beclin 1-Bcl-2 pathway, which was also revealed in an in vivo model through immunohistochemical staining. Pearson coefficient analysis showed that there existed strong positive correlations between the expression of ROP17 and LC3B, Beclin 1 and phosphorylation of Bcl-2, while strong negative correlations between the expression of ROP17 and p62 and Bcl-2. Collectively, our findings indicate that ROP17 plays a pivotal role in maintaining T. gondii proliferation in host cells via the promotion of autophagy-dependent survival.
- MeSH
- autofagie genetika MeSH
- beclin 1 metabolismus MeSH
- faktory virulence genetika metabolismus MeSH
- HEK293 buňky MeSH
- lidé MeSH
- myši MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus MeSH
- protozoální proteiny genetika metabolismus MeSH
- Toxoplasma genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Iron oxide-based nanoparticles have been repeatedly shown to affect lysosomal-mediated signaling. Recently, nanoparticles have demonstrated an ability to modulate autophagic flux via lysosome-dependent signaling. However, the precise underlying mechanisms of such modulation as well as the impact of cellular genetic background remain enigmatic. In this study, we investigated how lysosomal-mediated signaling is affected by iron oxide nanoparticle uptake in three distinct hepatic cell lines. We found that nanoparticle-induced lysosomal dysfunction alters sub-cellular localization of pmTOR and p53 proteins. Our data indicate that alterations in the sub-cellular localization of p53 protein induced by nanoparticle greatly affect the autophagic flux. We found that cells with high levels of Bcl-2 are insensitive to autophagy initiated by nanoparticles. Altogether, our data identify lysosomes as a central hub that control nanoparticle-mediated responses in hepatic cells. Our results provide an important fundamental background for the future development of targeted nanoparticle-based therapies.
- MeSH
- autofagie genetika MeSH
- buněčné linie MeSH
- hepatocyty metabolismus MeSH
- lidé MeSH
- lyzozomy metabolismus MeSH
- magnetické nanočástice oxidů železa * MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound.
- MeSH
- apoptóza účinky léků genetika MeSH
- ATM protein * antagonisté a inhibitory metabolismus MeSH
- autofagie účinky léků genetika MeSH
- buňky A549 MeSH
- G-kvadruplexy * MeSH
- HeLa buňky MeSH
- lidé MeSH
- ligandy MeSH
- myši inbrední NOD MeSH
- myši knockoutované MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory genetika patologie MeSH
- poškození DNA účinky léků MeSH
- signální transdukce účinky léků genetika MeSH
- stárnutí buněk účinky léků genetika MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- apoptóza MeSH
- autofagie genetika imunologie účinky léků MeSH
- buněčná smrt * fyziologie genetika imunologie účinky léků MeSH
- lidé MeSH
- nekróza MeSH
- protinádorové látky farmakologie imunologie terapeutické užití MeSH
- pyroptóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Autophagy is a major catabolic process whereby autophagosomes deliver cytoplasmic content to the lytic compartment for recycling. Autophagosome formation requires two ubiquitin-like systems conjugating Atg12 with Atg5, and Atg8 with lipid phosphatidylethanolamine (PE), respectively. Genetic suppression of these systems causes autophagy-deficient phenotypes with reduced fitness and longevity. We show that Atg5 and the E1-like enzyme, Atg7, are rate-limiting components of Atg8-PE conjugation in Arabidopsis. Overexpression of ATG5 or ATG7 stimulates Atg8 lipidation, autophagosome formation, and autophagic flux. It also induces transcriptional changes opposite to those observed in atg5 and atg7 mutants, favoring stress resistance and growth. As a result, ATG5- or ATG7-overexpressing plants exhibit increased resistance to necrotrophic pathogens and oxidative stress, delayed aging and enhanced growth, seed set, and seed oil content. This work provides an experimental paradigm and mechanistic insight into genetic stimulation of autophagy in planta and shows its efficiency for improving plant productivity.
- MeSH
- Arabidopsis genetika fyziologie MeSH
- Atg5 genetika metabolismus MeSH
- autofagie genetika MeSH
- genetická zdatnost * MeSH
- proteiny huseníčku genetika metabolismus MeSH
- rodina proteinů Atg8 genetika metabolismus MeSH
- signální transdukce genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.
- MeSH
- acetylkoenzym A metabolismus MeSH
- Aspirin farmakologie MeSH
- autofagie účinky léků genetika MeSH
- kalorická restrikce * MeSH
- lidé MeSH
- metabolom účinky léků MeSH
- metabolomika MeSH
- myši inbrední C57BL MeSH
- nádorové buněčné linie MeSH
- protein p300 asociovaný s E1A metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH