Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects
. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a ...major role in its mechanism of action
; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation
. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase
, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase
, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
Dysregulated expression of specific microRNAs (miRNAs) in serum has been recognised as promising diagnostic biomarkers for colorectal cancer (CRC). In the initial screening phase, a total of 32 ...differentially expressed miRNAs were selected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel with 3 CRC pool samples and 1 normal control (NC) pool. Using qRT-PCR, selected serum miRNAs were further confirmed in training (30 CRC VS. 30 NCs) and testing stages (136 CRC VS. 90 NCs). We identified that serum levels of miR-19a-3p, miR-21-5p and miR-425-5p were significantly higher in patients with CRC than in NCs. The areas under the receiver operating characteristic (ROC) curve of the three-miRNA panel were 0.86, 0.74 and 0.87 for the training, testing and the external validation stages (30 CRC VS. 18 NCs), respectively. Significantly, elevated expression of the three miRNAs was also observed in CRC tissues (n = 24). Furthermore, the expression levels of the three miRNAs were significantly elevated in exosomes from CRC serum samples (n = 10). In conclusion, we identified a serum three-miRNA panel for the diagnosis of CRC.
Intramuscular fat (IMF) is an important factor affecting meat quality, but lipid and metabolic profiles of donkey meat remain unclear. The present study was conducted to investigate lipid ...characteristics in different parts of Dezhou donkey using lipidomics. The results show that IMF was more abundant in longissimus dorsi muscle (LDM) than rump muscle (RM) and hamstring muscle (HM), and mainly composed of triglycerides (TGs) rich in saturated fatty acid (SFAs) and monounsaturated fatty acid (MUFAs). A total of 1143 lipids belonging to 14 subclasses were identified in donkey meat, of which 73 lipids (23 upregulated and 50 downregulated) including glycerolipids (GLs), glycerophospholipids (GPs) and sphingolipids (SPs) were significantly different and are therefore potential biomarkers in LDM versus RM versus HM analyses (variable importance in projection >1, p < 0.05). Notably, 21 TGs upregulated in LDM were rich in MUFAs at sn‐1 and SFAs at 2 and 3 positions of TG. Donkey muscle accumulated far more SFAs at the sn‐3 position of TG, while more SFAs were present at the sn‐1 positions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE), and the percentages of SFAs at the three positions in TG, PC, and PE in the LDM group were much higher. The abundance of MUFAs at the sn‐2 positions of TG, PC, and PE was significantly greater than in sn‐1 or 3 positions, and the percentages of 18:1n‐9 at the sn‐1 and 2 position of TGs in LDM were significantly higher than in RM and HM groups. Polyunsaturated fatty acids (e.g.,18:2n‐6, 18:3n‐3, and 20:4n‐6) tended to occur at the sn‐1 position in TG, but at the sn‐2 position in PC and PE. Significantly differential lipids were mainly enriched in GP, GL, and SP pathways, all considered key pathways for regulating IMF. The results reveal the components, structures and metabolic pathways of lipid molecules in donkey meat, and provide novel insight into the development of donkey meat products and accurate regulation of IMF.
Practical Application
Intramuscular fat (IMF) is an important factor affecting meat quality, which is directly related to meat flavor, juiciness, and tenderness, but lipid and metabolic profiles of IMF remain unclear. The current results provide basic information for the development of donkey meat products, and broaden our understanding of the regulation of IMF.
The study was conducted to investigate the effects of copper sources and levels on lipid profiles, immune parameters, antioxidant defenses, and trace element contents of meat and liver in Arbor Acres ...broilers. A total of 504 male broilers were randomly divided into 7 groups with 6 replicates per group and 12 broilers per replicate. The experiment was used in a 3 × 2 + 1 factorial experiment design; broilers in the control group were fed a basal diet, and broilers in the other six groups were fed basal diets supplemented with 3 sources (copper sulfate, tribasic copper chloride, and copper methionate) and 2 levels (10 and 20 mg/kg). The results showed that the levels of cholesterol and low-density lipoprotein cholesterol in broilers were significantly decreased with the increase of dietary copper level (
P <
0.05). Serum IL-6 and IgA contents, ceruloplasmin and GSH-Px activities, and liver copper contents of broilers increased significantly with dietary copper levels (
P <
0.05). Compared with the control group, dietary copper supplementation significantly decreased serum cholesterol (
P <
0.05) and significantly increased serum IL-6, ceruloplasmin, SOD, GSH-Px, and liver copper (
P <
0.05). Dietary supplementation of basic copper chloride and copper methionate significantly decreased low-density lipoprotein cholesterol content and liver iron content (
P
< 0.05). In conclusion, dietary copper supplementation can effectively reduce serum cholesterol content and improve immune and antioxidant functions in broilers. Adding 20 mg/kg copper to broiler diet can increase the copper content in the liver, but it will not affect the copper content in the chicken.
Wulong geese (Anser cygnoides orientalis) are known for their excellent egg-laying performance. However, they show considerable population differences in egg-laying behavior. This study combined ...genome-wide selection signal analysis with transcriptome analysis (RNA-seq) to identify the genes related to high egg production in Wulong geese. A total of 132 selected genomic regions were screened using genome-wide selection signal analysis, and 130 genes related to high egg production were annotated in these regions. These selected genes were enriched in pathways related to egg production, including oocyte meiosis, the estrogen signaling pathway, the oxytocin signaling pathway, and progesterone-mediated oocyte maturation. Furthermore, a total of 890 differentially expressed genes (DEGs), including 340 up-regulated and 550 down-regulated genes, were identified by RNA-seq. Two genes -- GCG and FAP -- were common to the list of selected genes and DEGs. A non-synonymous single nucleotide polymorphism was identified in an exon of FAP. Based on genome-wide selection signal analysis and transcriptome data, GCG and FAP were identified as candidate genes associated with high egg production in Wulong geese. These findings could promote the breeding of Wulong geese with high egg production abilities and provide a theoretical basis for exploring the mechanisms of reproductive regulation in poultry.
Filial piety, as a major traditional norm in Chinese culture and in Chinese families, affects the attitudes and behaviors of adult children toward their parents and impacts their end-of-life ...decision-making and the quality of death of their parents. Death literacy is a novel concept aimed at promoting palliative care in the context of public health.
To understand attitudes and behaviors related to filial piety and to examine the role of death literacy in filial behaviors toward dying parents among residents in the Guangdong-Hong Kong-Macao Greater Bay Area of China.
A cross-sectional online survey that employed the convenient and snowball sampling methods was adopted. Filial Piety Representations at Parents' End of Life Scale and Death Literacy Index were used.
This study identified a significant gap between the filial piety attitudes and behaviors of Chinese adult children. Gender, caregiving experience and death literacy were predictors of filial behaviors in an end-of-life context.
Providing truth disclosure support, offering guidance to young adult children and caregivers of terminally ill fathers, and strengthening factual and community knowledge of death are necessary to enhance the reciprocal comfort of both adult children and dying parents in the context of Chinese filiality.
Objective
We compared the diagnostic values of mammography and magnetic resonance imaging (MRI) for evaluating breast masses.
Methods
We retrospectively analyzed mammography, MRI, and ...histopathological data for 377 patients with breast masses on mammography, including 73 benign and 304 malignant masses.
Results
The sensitivities and negative predictive values (NPVs) were significantly higher for MRI compared with mammography for detecting breast cancer (98.4% vs. 89.8% and 87.8% vs. 46.6%, respectively). The specificity and positive predictive values (PPV) were similar for both techniques. Compared with mammography alone, mammography plus MRI improved the specificity (67.1% vs. 37.0%) and PPV (91.8% vs. 85.6%), but there was no significant difference in sensitivity or NPV. Compared with MRI alone, the combination significantly improved the specificity (67.1% vs. 49.3%), but the sensitivity (88.5% vs. 98.4%) and NPV (58.3% vs. 87.8%) were reduced, and the PPV was similar in both groups. There was no significant difference between mammography and MRI in terms of sensitivity or specificity among 81 patients with breast masses with calcification.
Conclusion
Breast MRI improved the sensitivity and NPV for breast cancer detection. Combining MRI and mammography improved the specificity and PPV, but MRI offered no advantage in patients with breast masses with calcification.
Fatty acid uptake is the first step in fatty acid utilization, but it remains unclear how the process is regulated. Protein palmitoylation is a fatty acyl modification that plays a key regulatory ...role in protein targeting and trafficking; however, its function in regulating fatty acid metabolism is unknown. Here, we show that two of the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC4 and DHHC5, regulate fatty acid uptake. DHHC4 and DHHC5 function at different subcellular localizations to control the palmitoylation, plasma membrane localization, and fatty acid uptake activity of the scavenger receptor CD36. Depletion of either DHHC4 or DHHC5 in cells disrupts CD36-dependent fatty acid uptake. Furthermore, both Dhhc4−/− and adipose-specific Dhhc5 knockout mice show decreased fatty acid uptake activity in adipose tissues and develop severe hypothermia upon acute cold exposure. These findings demonstrate a critical role of DHHC4 and DHHC5 in regulating fatty acid uptake.
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•CD36 is a physiological substrate of palmitoyl acyltransferases DHHC4/5•Palmitoylation of CD36 targets it to the plasma membrane•DHHC4/5 are required for the cellular fatty acid uptake activity of CD36•DHHC4/5 regulate fatty acid uptake activity in adipose tissues
Regulation of fatty acid uptake remains unclear. Wang et al. show that palmitoylation of CD36 by DHHC4 and DHHC5 is required for its plasma membrane localization and fatty acid uptake activity. Deficiency in DHHC4 or DHHC5 leads to decreased fatty acid uptake and increased susceptibility to cold.
In donkeys, the gestation period is a dynamic and precisely coordinated process involving systemic and local alterations. Both the gut microbiota and its link with blood metabolites are thought to ...play significant roles in maintaining maternal health and supporting fetal development during the gestation period. This study was conducted to evaluate gut microbiota changes and the correlation with plasma metabolites in Dezhou donkeys during the gestation period. The donkeys were divided into the four following groups according to their pregnancy stages: the non-pregnant (NP), early stage of pregnancy (P1), middle stage of pregnancy (P2), and late stage of pregnancy (P3) groups. A total of 24 (
n
= 6 per group) samples of donkey feces and plasma were collected. The results showed that the diversity (Shannon index) of fecal bacteria significantly increased throughout the gestation period. The phyla Spirochaetota and Fibrobacterota varied significantly according to the stages of pregnancy (
p
< 0.05). At the genus level, the abundance of
Treponema
in pregnant donkeys was greater than that in non-pregnant donkeys (
p
< 0.05), and the genus
Streptococcus
reached its maximum abundance in the P2 period (
p
< 0.05). The abundance of
Ruminococcaceae
_NK4A214_group and norank_f_norank_o_WCHB1-41 linearly increased with the progression of pregnancy (
p
< 0.05). In addition, the host plasma metabolome was altered significantly during the gestation period. Testolic acid, estradiol-17beta 3-sulfate, equol 7’-o-glucuronide, equol 4’-o-glucuronide, estrone, estrone 3-glucuronide, and estradiol were the most significant differential enriched metabolites, and they increased gradually as gestation progressed. The altered metabolites were mainly enriched in pathways matched to bile secretion, ABC transporters, amino acid metabolism, protein digestion and absorption, mineral absorption, fatty acid degradation, glycerophospholipid metabolism, and steroid hormone biosynthesis. We also found a significant correlation between the shifts in donkey fecal bacteria and changes in the host metabolism. In summary, this study provided systematic data on the fecal bacterial changes and host plasma metabolism of donkeys throughout pregnancy. The results indicated that host–bacteria interactions during the gestation period influence the host metabolism. These interactions benefit the pregnant donkeys by providing a sufficient supply of nutrients and energy for fetal growth and maternal health.
Donkey meat is extremely popular in China owing to its high nutritional value and unique flavour. However, the physical and chemical properties of meat from the Dezhou black donkey have seldom been ...reported. This study aimed to compare differences in the physical characteristics, intramuscular fat (IMF) content, fatty acid profile, and antioxidant capacity of meat from Dezhou black donkey. The results showed that the L* and ΔE values of longissimus dorsi (LD) were significantly lower than those of gluteus maximus (GM) and biceps femoris (BF), while the b* value of LD was significantly higher than that of GM (p < 0.05). The shear force, hardness, adhesiveness, and elasticity values of LD and BF were significantly lower than those of GM (p < 0.05). The IMF content in LD was significantly higher than those in GM and BF (p < 0.05). The contents of fatty acids 15:0, 14:1, 18:2n-6, 20:4n-6, and polyunsaturated fatty acids in LD were significantly lower than those in GM and BF, while the 18:0, 18:1n-9, and monounsaturated fatty acid contents showed the opposite trend (p < 0.05). The superoxide dismutase activity of LD was significantly higher than those of GM and BF (p < 0.05), while the malonaldehyde content showed the opposite trend (p < 0.05). Overall, LD is an ideal edible part of Dezhou black donkey, owing to its higher IMF, tenderness, 18:1n-9, and antioxidant capacity levels, and lower 18:2n-6 and ΔE levels. This study provides novel insight into the development of donkey meat products.
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