Abstract
Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 ...in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.
Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase, and the target of immunosuppressive agent tacrolimus (TAC). The dysfunction of calcineurin, or clinical ...applications of tacrolimus, have been reported to be associated with dyslipidemia. The underlying mechanisms of calcineurin and tacrolimus in lipid metabolism are largely unknown. Here, we showed that mutations of
and
, which respectively encode the catalytic subunit and the regulatory subunit of calcineurin, together with tacrolimus treatment, consistently led to decreased fat accumulation and delayed growth in the nematode
. In contrast, disruption of the AMP-activated protein kinase (AMPK) encoded by
and
reversed the above effects in worms. Moreover, calcineurin deficiency and tacrolimus treatment consistently activated the transcriptional expression of the lipolytic gene
, encoding triglyceride lipase. Furthermore, RNAi knockdown of
recovered the decreased fat accumulation in both calcineurin deficient and tacrolimus treated worms. Collectively, our results reveal that immunosuppressive agent tacrolimus and their target calcineurin may antagonize AMPK to regulate ATGL and lipolysis, thereby providing potential therapy for the application of immunosuppressive agents.
Sirtuins are pro-longevity genes with chromatin modulation potential, but how these properties are connected is not well understood. Here, we generated a panel of isogeneic human stem cell lines with ...SIRT1–SIRT7 knockouts and found that any sirtuin deficiency leads to accelerated cellular senescence. Through large-scale epigenomic analyses, we show how sirtuin deficiency alters genome organization and that genomic regions sensitive to sirtuin deficiency are preferentially enriched in active enhancers, thereby promoting interactions within topologically associated domains and the formation of de novo enhancer-promoter loops. In all sirtuin-deficient human stem cell lines, we found that chromatin contacts are rewired to promote aberrant activation of the placenta-specific gene PAPPA, which controls the pro-senescence effects associated with sirtuin deficiency and serves as a potential aging biomarker. Based on our survey of the 3D chromatin architecture, we established connections between sirtuins and potential target genes, thereby informing the development of strategies for aging interventions.
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•Deficiency of any sirtuin accelerates senescence in human stem cells•Epigenomic profiling links sirtuin depletion to chromatin reorganization during aging•Enhancer-promoter contacts are rewired in genomic regions sensitive to sirtuin deficiency•Activation of the placenta-specific gene PAPPA mediates aging resulting from sirtuin-deficiency
Bi et al. elucidated the effects of sirtuin deficiency on chromatin dynamics that drive the senescence program of human stem cells. They identified the upregulation of the PAPPA gene, triggered by chromatin contacts rewired by sirtuin deficiency and acting as both a biomarker and a driver of aging.
The lipid droplet (LD)-associated protein adipose differentiation-related protein (ADRP or PLIN2) is required for the formation and stability of the LD organelle, whereas its biological roles are ...still obscure. Herein, we show that PLIN2 is the most abundant protein on the lipid droplets (LDs) of mouse myoblast cell line C2C12. Both the expression of PLIN2 and the accumulation of LDs were up-regulated in a time- and dose-dependent manner when the cells were treated with oleate (OA). The protein level of PLIN2 was positively correlated with the formation of LDs, suggesting that LDs stabilize PLIN2. Furthermore, knocking out PLIN2 in C2C12 cells led to enlarged LDs and higher triacylglycerol hydrolysis activity. The isolated PLIN2 null LDs became closely contact with mitochondria and other cellular organelles. Additionally, mitochondrial activity was suppressed by OA in PLIN2 null cells. Our results reveal the pivotal roles of PLIN2 in governing LD dynamics and their relationship to mitochondria, and suggest a reciprocal stabilization between PLIN2 and LDs.
Background： As a organic acid, benzoic acid has become one of the most important alternatives for antibiotics,and its beneficial effect on performance in animals has been proven for a decade. ...However, knowledge of the effects of benzoic acid on jejunal digestive physiology, especially the antioxidant capacity and mucosal glucagon-like peptide2（GLP-2） concentrations is lacking.Methods： A total of 20 barrows Duroc ×（Yorkshire × Landrace） with an average body weight（BW） of 18.75 ± 0.2 kg were used in a 14-d trial to determine the potential mechanisms of benzoic acid supplementation on the performance,nutrient digestibility and jejunal digestive physiology in young pigs. All pigs were randomly allotted to 1 of 2 diets supplemented with 0 or 5000 mg/kg benzoic acid.Results： Relative to the control, benzoic acid supplementation increased the average daily feed intake（ADFI）, and average daily gain（ADG） in young pigs（P 〈 0.05）, improved the apparent total tract digestibility of dry matter（DM）,crude protein（CP）, ether extract（EE）, gross energy（GE） and crude ash（P 〈 0.05）, and enhanced the activities of trypsin,lipase and amylase in the jejunum（P 〈 0.05）. Similarly, relative to the control, supplementing benzoic acid in the diet resulted in a trend to reduce the p H values of the digesta（P = 0.06）, decreased crypt depth and increased the villus height to crypt depth ratio（P 〈 0.05） in the jejunum of pigs. Finally, benzoic acid supplementation increased the mR NA expression and concentration of glucagon-like peptide 2 and the activities of glutathione peroxidase and superoxide dismutase in the jejunal mucosa of young pigs（P 〈 0.05）.Conclusions： In conclusion, supplementation with 5000 mg/kg benzoic acid improved the performance of young pigs through promoting nutrient digestion, improving jejunal antioxidant capacity, and maintaining the jejunal morphology in young pigs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As a organic acid, benzoic acid has become one of the most important alternatives for antibiotics, and its beneficial effect on performance in animals has been proven for a decade. However, knowledge ...of the effects of benzoic acid on jejunal digestive physiology, especially the antioxidant capacity and mucosal glucagon-like peptide 2 (GLP-2) concentrations is lacking.
A total of 20 barrows Duroc × (Yorkshire × Landrace) with an average body weight (BW) of 18.75 ± 0.2 kg were used in a 14-d trial to determine the potential mechanisms of benzoic acid supplementation on the performance, nutrient digestibility and jejunal digestive physiology in young pigs. All pigs were randomly allotted to 1 of 2 diets supplemented with 0 or 5000 mg/kg benzoic acid.
Relative to the control, benzoic acid supplementation increased the average daily feed intake (ADFI), and average daily gain (ADG) in young pigs (P < 0.05), improved the apparent total tract digestibility of dry matter (DM), crude protein (CP), ether extract (EE), gross energy (GE) and crude ash (P < 0.05), and enhanced the activities of trypsin, lipase and amylase in the jejunum (P < 0.05). Similarly, relative to the control, supplementing benzoic acid in the diet resulted in a trend to reduce the pH values of the digesta (P = 0.06), decreased crypt depth and increased the villus height to crypt depth ratio (P < 0.05) in the jejunum of pigs. Finally, benzoic acid supplementation increased the mRNA expression and concentration of glucagon-like peptide 2 and the activities of glutathione peroxidase and superoxide dismutase in the jejunal mucosa of young pigs (P < 0.05).
In conclusion, supplementation with 5000 mg/kg benzoic acid improved the performance of young pigs through promoting nutrient digestion, improving jejunal antioxidant capacity, and maintaining the jejunal morphology in young pigs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Serous ovarian cancer (SOC) is a main histological subtype of ovarian cancer, in which cancer stem cells (CSC) are responsible for its chemoresistance. However, the underlying modulation mechanisms ...of chemoresistance led by cancer stemness are still undefined. We aimed to investigate potential drug-response indicators among stemness-associated biomarkers in advanced SOC samples. The mRNA expression-based stemness index (mRNAsi) of The Cancer Genome Atlas (TCGA) was evaluated and corrected by tumor purity. Weighted gene co-expression network analysis (WGCNA) was utilized to explore the gene modules and key genes involved in stemness characteristics. We found that mRNAsi and corrected mRNAsi scores were both greater in tumors of Grade 3 and 4 than that of Grade 1 and 2. Forty-two key genes were obtained from the most significant mRNAsi-related gene module. Functional annotation revealed that these key genes were mainly involved in the mitotic division. Thirteen potential platinum-response indicators were selected from the genes enriched to platinum-response associated pathways. Among them, we identified 11 genes with prognostic value of progression-free survival (PFS) in advanced SOC patients treated with platinum and 7 prognostic genes in patients treated with a combination of platinum and taxol. The expressions of the 13 key genes were also validated between platinum-resistant and -sensitive SOC samples of advanced stages in two Gene Expression Omnibus (GEO) datasets. The results revealed that CDC20 was a potential platinum-sensitivity indicator in advanced SOC. These findings may provide a new insight for chemotherapies in advanced SOC patients clinically.
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