Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, ...detoxification and support of rapid proliferation. The pentose phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
Cellular senescence both protects multicellular organisms from cancer and contributes to their ageing. The pre-eminent tumour suppressor p53 has an important role in the induction and maintenance of ...senescence, but how it carries out this function remains poorly understood. In addition, although increasing evidence supports the idea that metabolic changes underlie many cell-fate decisions and p53-mediated tumour suppression, few connections between metabolic enzymes and senescence have been established. Here we describe a new mechanism by which p53 links these functions. We show that p53 represses the expression of the tricarboxylic-acid-cycle-associated malic enzymes ME1 and ME2 in human and mouse cells. Both malic enzymes are important for NADPH production, lipogenesis and glutamine metabolism, but ME2 has a more profound effect. Through the inhibition of malic enzymes, p53 regulates cell metabolism and proliferation. Downregulation of ME1 and ME2 reciprocally activates p53 through distinct MDM2- and AMP-activated protein kinase-mediated mechanisms in a feed-forward manner, bolstering this pathway and enhancing p53 activation. Downregulation of ME1 and ME2 also modulates the outcome of p53 activation, leading to strong induction of senescence, but not apoptosis, whereas enforced expression of either malic enzyme suppresses senescence. Our findings define physiological functions of malic enzymes, demonstrate a positive-feedback mechanism that sustains p53 activation, and reveal a connection between metabolism and senescence mediated by p53.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Conflicting reconstructions of Holocene variability of the East Asian summer monsoon (EASM) from speleothem versus other types of proxy records have yielded widely divergent estimates of its phase ...relationship with the Indian summer monsoon (ISM) and Northern Hemisphere summer insolation (NHSI). This apparent discrepancy has been partly attributed to the uncertainties in the climatic representation of Chinese speleothem oxygen isotope (δ18O) records. Here we present a composite speleothem δ18O record of the last ∼14 kyr from Shennong Cave in southeastern China and model-simulated data of rainfall and meteoric δ18O over eastern China. Our synthesis of the proxy-model data suggests that the spatial patterns in both speleothem δ18O and paleo-rainfall over eastern China during the Holocene are diverse at orbital and multi-millennial scales. Our findings imply that: 1) speleothem δ18O in the EASM regime is largely controlled by the large-scale circulation and concomitant latitudinal shifts of the monsoon rain belt; notwithstanding the heterogeneous spatiotemporal pattern of Holocene rainfall as inferred from various proxy records, a coherent orbital-scale speleothem δ18O variability across most Asian monsoon regions (except southeastern China) indeed stems from the NHSI-forced changes in overall monsoon intensity; overall monsoon intensity is not equivalent to monsoon rainfall amount but a manifestation of the large-scale atmospheric circulation; 2) divergent phase relationships with NHSI between speleothem δ18O and other proxy records are consistent with—rather than contradictory to—the NHSI forcing mechanism. Speleothem δ18O and rainfall records reflect two different aspects of the monsoon dynamics. These results may thus, largely help to reconcile the divergent views of the Holocene Asian monsoon variability.
•Holocene speleothem δ18O and rainfall show heterogeneous pattern in eastern China.•East Asian speleothem δ18O reflects large-scale circulation and monsoon rain belt shift.•Divergent phases between speleothem and other proxy records are not contradictory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer cells consume large quantities of glucose and primarily use glycolysis for ATP production, even in the presence of adequate oxygen. This metabolic signature (aerobic glycolysis or the Warburg ...effect) enables cancer cells to direct glucose to biosynthesis, supporting their rapid growth and proliferation. However, both causes of the Warburg effect and its connection to biosynthesis are not well understood. Here we show that the tumour suppressor p53, the most frequently mutated gene in human tumours, inhibits the pentose phosphate pathway (PPP). Through the PPP, p53 suppresses glucose consumption, NADPH production and biosynthesis. The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. Tumour-associated p53 mutants lack the G6PD-inhibitory activity. Therefore, enhanced PPP glucose flux due to p53 inactivation may increase glucose consumption and direct glucose towards biosynthesis in tumour cells.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cholesterol is essential for membrane biogenesis, cell proliferation, and differentiation. The role of cholesterol in cancer development and the regulation of cholesterol synthesis are still under ...active investigation. Here we show that under normal‐sterol conditions, p53 directly represses the expression of SQLE, a rate‐limiting and the first oxygenation enzyme in cholesterol synthesis, in a SREBP2‐independent manner. Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression. Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency. Conversely, SQLE overexpression or cholesterol addition promotes cell proliferation, particularly in p53 wild‐type cells. More importantly, pharmacological inhibition or shRNA‐mediated silencing of SQLE restricts nonalcoholic fatty liver disease (NAFLD)‐induced liver tumorigenesis in p53 knockout mice. Therefore, our findings reveal a role for p53 in regulating SQLE and cholesterol biosynthesis, and further demonstrate that downregulation of SQLE is critical for p53‐mediated tumor suppression.
Synopsis
This study reveals a SREBP2‐independent role for p53 in regulating SQLE and cholesterol biosynthesis under normal sterol conditions, and further demonstrate that downregulation of SQLE is critical for p53‐mediated tumor suppression.
Under normal‐sterol conditions, p53 directly represses the expression of SQLE in a SREBP2‐independent manner.
Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression.
Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency.
Pharmacological inhibition of SQLE by terbinafine represses NAFLD‐HCC tumorigenesis caused by p53 loss in vivo.
This study reveals a SREBP2‐independent role for p53 in regulating SQLE and cholesterol biosynthesis under normal sterol conditions, and further demonstrate that downregulation of SQLE is critical for p53‐mediated tumor suppression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cancer cells exhibit altered and usually increased metabolic processes to meet their high biogenetic demands
. Under these conditions, ammonia is concomitantly produced by the increased metabolic ...processing. However, it is unclear how tumour cells dispose of excess ammonia and what outcomes might be caused by the accumulation of ammonia. Here we report that the tumour suppressor p53, the most frequently mutated gene in human tumours, regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1, OTC and ARG1, p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumour growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC, thereby inhibiting the biosynthesis of polyamine and cell proliferation. Together, these findings link p53 to ureagenesis and ammonia metabolism, and further reveal a role for ammonia in controlling polyamine biosynthesis and cell proliferation.
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IJS, KISLJ, NUK, UL, UM, UPUK
Pulmonary fibrosis is a manifestation of the progression of interstitial pulmonary disease. Icariin (ICA) has been found to exhibit protective effects on multiple chronic diseases like diabetes, ...liver, heart, and renal fibrosis. Here, a systemic pharmacological study was designed to investigate whether ICA treatment alleviates bleomycin (BLM)-induced pulmonary fibrosis. The rat pulmonary fibrosis model was constructed by non-invasive endotracheal intubation instillation of BLM to observe the intervention effects of ICA on pulmonary fibrosis in the whole process of inflammation and fibrosis. ICA reduced the collagen deposition and inflammation induced by BLM in rat. The comparative RNA-sequencing was conducted to analyze the lung gene expression profiles in rat. KEGG analysis indicated that most of the genes were enriched in Hippo pathway, NF-κB pathway, and B-cell receptor signaling pathway, etc. Immunohistochemistry staining showed that the expression of YAP was significantly elevated in the model group and decreased in the ICA treatment group. Taken together, the anti-fibrotic effect of ICA appears to be mediated by its inhibitory of YAP, which is the core transcriptional regulator of Hippo pathway.
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•Bleomycin-induced histopathological and fibrotic changes is attenuated by treatment of ICA in lung tissues.•ICA reduces bleomycin-induced lung inflammatory response.•ICA reduces the expression of fibrotic mediators, leading to prevent and reverse pulmonary fibrosis.•ICA protects against bleomycin-induced pulmonary fibrosis at least partially through Hippo/YAP pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Astragaloside IV alleviated liver dysfunction during alcohol-induced liver injury.
Astragaloside IV inhibited LPS, LBP, and DAO translocation in the intestine.
Astragaloside IV attenuated liver ...dysfunction in mice by modulating gut microbiota and inhibiting NLRP3/Caspase-1 signaling pathway.
Astragaloside IV (AS-IV) is a natural saponin substance extracted from the plant Radix Astragali with anti-inflammatory, antioxidant, anti-apoptotic, and liver-protecting effects. This study was to evaluate the liver protection effect of AS-IV on mice after acute alcohol stimulation.
Mice were orally administrated with AS-IV (50, 150, and 500 mg/kg, respectively), and sodium carboxymethyl cellulose (CMC, 50 mg/kg) daily for 7 days, before giving five alcohol-intragastric injections.
Results suggested that the levels of serum ALT and AST, liver SOD, GSH-PX, 4-HNE, and MDA, serum and liver TNF-α, IL-1β, and IL-6, serum lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), diamine oxidase (DAO) and Myeloperoxidase (MPO), the mRNA and protein expression of hepatic NLRP3, Caspase-1, IL-1β, and IL-18 were significantly decreased in AS-IV-treated mice compared with the model group. Moreover, the effect of AS-IV on histopathology of liver tissue confirmed its protective function. Furthermore, AS-IV ameliorated the gut microbiota imbalance and adjusted the abundance of the following dysfunctional bacteria closer to the control group: Butyricicoccus, Turicibacter, Akkermansia, Anaerotruncus, and Mucispirillum. A strong correlation between intestinal bacteria and potential biomarkers was found.
Together, our findings indicated that AS-IV exert the hepatoprotective effect by modulating the gut microbiota imbalance and regulating NLRP3/Caspase-1 signaling pathway.
Ferroptosis is a newly generated regulatory cell death promoted by the accumulated lipid-based reactive oxygen species (ROS). Solute carrier family 7 member 11 (SLC7A11), the cystine/glutamate ...antiporter, is known as a ferroptosis executor that exhibits a positive correlation with carcinoma progression because of antioxidant function. Nonetheless, it is yet unclear on the understanding of ferroptosis regulation in lung cancer.
Database, qRT-PCR, Western-blot (WB), and immunohistochemistry were utilized to determine SLC7A11 expression and function, as well as gene iron related to necrosis in clinical tissue specimens and cells; a ferroptosis inducer, inhibitors, and SLC7A11 lentivirus were used to confirm SLC7A11's biological activity in cell viability, oxidative stress, lipid peroxidation, and iron ion enrichment in non-small cell lung cancer (NSCLC) in different cells; lentivirus was used to infect lung adenocarcinoma cell lines to acquire miR-27a-3p overexpression and knockdown cell lines, and to detect SLC7A11 level through qRT-PCR and WB. The influence of upregulated/downregulated miR-27a-3p on ferroptosis and other related biological characteristics of lung adenocarcinoma cell lines was detected.
Upregulated SLC7A11 was shown in NSCLC patients and cells, and increased SLC7A11 had a relation to the poorly prognostic status of NSCLC patients. Besides, a novel miRNA, miR-27a-3p, was an essential modulator of ferroptosis
directly targeting SLC7A11 in NSCLC cells. Overexpressing miR-27a-3p led to SLC7A11 suppression
directly binding to its 3'-UTR, followed by the reduction of erastin-caused ferroptosis. In contrast, inhibited miR-27a-3p resulted in an increase in NSCLC cells' sensitivity to erastin. Of importance, the accumulated lipid ROS and cell death of iron peptide mediated by anti-miR-27a-3p can be eliminated by impeding the glutamylation process. Our literature collectively uncovered that miR-27a-3p modulated ferroptosis by targeting SLC7A11 in NSCLC cells, illustrating the important role of miRNA in ferroptosis.
MiR-27a-3p modulates ferroptosis
targeting SLC7A11 in NSCLC cells, implying the significant role of miR-27a-3p/SLC7A11 in ferroptosis.
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