Integrating network pharmacology and experimental validation reveals therapeutic effects of D-mannose on NAFLD through mTOR suppression.

Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition and metabolic disorder, has emerged as a significant health issue worldwide. D-mannose, a natural monosaccharide widely existing in plants and animals, has demonstrated metabolic regulatory properties. However, the effect and mechanism by which D-mannose may counteract NAFLD have not been studied. In this study, network pharmacology followed by molecular docking analysis was utilized to identify potential targets of mannose against NAFLD, and the leptin receptor-deficient, genetically obese db/db mice was employed as an animal model of NAFLD to validate the regulation of D-mannose on core targets. As a result, 67 targets of mannose are predicted associated with NAFLD, which are surprisingly centered on the mechanistic target of rapamycin (mTOR). Further analyses suggest that mTOR signaling is functionally enriched in potential targets of mannose treating NAFLD, and that mannose putatively binds to mTOR as a core mechanism. Expectedly, repeated oral gavage of supraphysiological D-mannose ameliorates liver steatosis of db/db mice, which is based on suppression of hepatic mTOR signaling. Moreover, daily D-mannose administration reduced hepatic expression of lipogenic regulatory genes in counteracting NAFLD. Together, these findings reveal D-mannose as an effective and potential NAFLD therapeutic through mTOR suppression, which holds translational promise.

Development of a targeted method for DNA adductome and its application as sensitive biomarkers of ambient air pollution exposure.

DNA adducts are widely recognized as biomarkers of exposure to environmental carcinogens and associated health effects in toxicological and epidemiological studies. This study presents a targeted and sensitive method for comprehensive DNA adductome analysis using ultra-high-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UHPLC-QqQ-MS/MS). The method was developed using calf thymus DNA, with careful optimization of mass spectrometric parameters, chromatographic separation conditions, and pretreatment methods. Ultimately, a targeted method was established for 41 DNA adducts, which showed good linearity (R2 ≥0.992), recovery (80.1-119.4 %), accuracy (81.3-117.8 %), and precision (relative standard deviation <14.2 %). The established method was employed to analyze DNA adducts in peripheral blood cells from pregnant women in Shanxi and Beijing. Up to 23 DNA adducts were successfully detected in samples of varying sizes. From 2 µg of maternal DNA samples, seven specific adducts were identified: 5-methyl-2'-deoxycytidine (5-MedC), 5-hydroxymethyl-2'-deoxycytidine (5-HmdC), N6-methyl-2'-deoxyadenosine (N6-MedA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), 5-hydroxy-2'-deoxycytidine (5-OHdC), 1,N6-etheno-2'-deoxyadenosine (1,N6-εdA), and N2-methyl-2'-deoxyguanosine (N2-MedG). This study reveals that exposure to higher concentrations of ambient air pollutants may elevate the levels of DNA methylation and oxidative damage at different base sites, highlighting the application potential of DNA adducts as sensitive biomarkers of air pollution exposure.

[Spatio-temporal Evolution and Prediction of Carbon Storage in Huaibei City Based on InVEST-PLUS Model].

This study aimed to investigate the impact of spatiotemporal changes in land use on ecosystem carbon storage. The study analyzed the spatiotemporal changes in carbon storage in the study area based on land use data from five periods (1985, 1995, 2005, 2015, and 2020) using the InVEST model. The PLUS model was used to predict land use changes in the study area under four different scenarios (natural development, farmland protection, ecological protection, and double protection of farmland and ecology) in 2035, and the ecosystem carbon storage under different scenarios was estimated. The results of the study indicated that the farmland in the area under investigation had been decreasing consistently from 1985 to 2020, with a more rapid rate of change observed between 2015 and 2020. During this period, the overall dynamic attitude towards land use reached 34.62 %. Additionally, the carbon storage in the area showed a decreasing trend over the years, with a decrease of 1.55×105 t from 1985 to 2020. Between 2005 and 2015, the carbon storage showed a decrease of 1.22×105 t, with an average annual decrease of 1.22×104 t. The areas with higher carbon storage were located in the eastern part of the study area, whereas areas with lower carbon storage were found in the central and northwestern parts. Although the proportion of carbon storage in farmland decreased from 66.89 % to 57.73 %, farmland remained the most important carbon pool in the study area. The conversion of other land use types to grassland and forestland was advantageous for increasing ecosystem carbon storage. Finally, the study projected that by 2035, the carbon storage in the natural development scenario, the farmland protection scenario, the ecological protection scenario, and the dual protection scenario would be 81.77×105, 82.45×105, 82.82×105, and 82.51×105 t, respectively.

Glycemic control by umbilical cord-derived mesenchymal stem cells promotes effects of fasting-mimicking diet on type 2 diabetic mice.

BACKGROUND: Hepatic steatosis is a big hurdle to treat type 2 diabetes (T2D). Fasting-mimicking diet (FMD) has been shown to be an effective intervention in dyslipidemia of T2D. However, fasting may impair the normal glucose metabolism. Human umbilical cord-derived mesenchymal stem cell (UC-MSC) transplantation has been discovered to regulate immune reactions and reduce hyperglycemia in diabetes. However, the effect of UC-MSCs on improving the lipid metabolism disorder is not quite satisfactory. We have investigated the efficacy comparison and interaction between FMD and UC-MSC infusion, aiming to establish effective T2D therapies and explore its mechanism. METHODS: C57/BL6 mice were fed with high-fat diet (HFD) to induce a diet-induced obese (DIO) mouse model. Leptin receptor-deficient (db/db) mice were used for follow-up experiments. DIO or db/db mice were divided into 4 groups: phosphate buffer saline (PBS), UC-MSCs, FMD, and UC-MSCs + FMD. At the end of the study period, mice were fasted and sacrificed, with the measurement of physiological and biochemical indexes. In addition, the fresh liver, skin, and white adipose tissue were analyzed by histology. RESULTS: FMD restored the lipid metabolism in DIO mice, whereas its capacity to rescue hyperglycemia was uncertain. Infusion of UC-MSCs was effective in T2D glycemic control but the impact on dyslipidemia was insufficient. Furthermore, both the glucose and the lipid alterations of DIO and db/db mice recovered after UC-MSCs combined with FMD. It was proved that UC-MSCs promoted FMD effects on ameliorating hyperglycemia and restoring the lipid metabolism in T2D mice, while FMD had little promotion effect on UC-MSCs. Mechanistically, we discovered that UC-MSC infusion significantly modulated systematic inflammatory microenvironment, which contributed to concerted actions with FMD. CONCLUSIONS: We established a strategy that combined UC-MSC infusion and FMD and was effective in treating T2D, which provided potential approaches for developing novel clinical T2D therapies.

Dynamics expression of DmFKBP12/Calstabin during embryonic early development of Drosophila melanogaster.

BACKGROUND: Calcium signaling are conserved from invertebrates to vertebrates and plays critical roles in many molecular mechanisms of embryogenesis and postnatal development. As a critical component of the signaling pathway, the RyR medicated calcium-induced calcium release signaling system, has been well studied along with their regulator FK506-binding protein 12 (FKBP12/Calstabin). Lack of FKBP12 is known to result in lethal cardiac dysfunction in mouse. However, precisely how FKBP12 is regulated and effects calcium signaling in Drosophila melanogaster remains largely unknown. RESULTS: In this study, we identified both temporal and localization changes in expression of DmFKBP12, a translational and transcriptional regulator of Drosophila RyR (DmRyR) and FKBP12, through embryonic development. DmFKBP12 is first expressed at the syncytial blastoderm stage and undergoes increased expression during the cellular blastoderm and early gastrulation stages. At late gastrulation, DmFKBP12 expression begins to decline until it reaches homeostasis, which it then maintains throughout the rest of development. Throughout these described changes in expression, DmFKBP12 mRNA remain stable, which indicates that protein dynamics are attributed to regulation at the mRNA to protein translation level. In addition to temporal changes in expression, dynamic expression profiles during Drosophila development also revealed DmFKBP12 localization. Although DmFKBP12 is distributed evenly between the anterior to posterior poles of the blastoderm egg, the protein is expressed more strongly in the cortex of the early Drosophila gastrula with the highest concentration found in the basement membrane of the cellular blastoderm. Fertilized egg, through the profile as under-membrane cortex distribution concentering onto basement at cellular blastoderm, to the profile as three-gem layer localization in primitive neuronal and digestion architecture of early Drosophila gastrula. By late gastrulation, DmFKBP12 is no longer identified in the yolk or lumen of duct structures and has relocated to the future brain (suboesophageal and supraesophageal ganglions), ventral nervous system, and muscular system. Throughout these changes in distribution, in situ DmFKBP12 mRNA monitoring detected equal distribution of DmFKBP12 mRNA, once again indicating that regulation of DmFKBP12 occurs at the translational level in Drosophila development. CONCLUSION: As a critical regulator of the DmRyR-FKBP complex, DmFKBP12 expression in Drosophila fluctuates temporally and geographically with the formation of organ systems. These finding indicate that DmFKBP12 and RyR associated calcium signaling plays an essential role in the successful development of Drosophila melanogaster. Further study on the differences between mammalian RyR-FKBP12 and Drosophila DmRyR-FKBP12 can be exploited to develop safe pesticides.