UFM1 inhibits hypoxia-induced angiogenesis via promoting proteasome degradation of HIF-1α.

Angiogenesis is crucial for blood flow recovery and ischemic tissue repair of peripheral artery disease (PAD). Exploration of new mechanisms underlying angiogenesis will shed light on the treatment of PAD. Ubiquitin-fold modifier 1 (UFM1), a newly identified ubiquitin-like molecule, has been discovered to be involved in various pathophysiological processes. However, the role of UFM1 in the pathogenesis of PAD, especially in endothelial angiogenesis remains obscure, and we aimed to clarify this issue in this study. We initially found UFM1 was significantly upregulated in gastrocnemius muscles of PAD patients and hind limb ischemia mice. And UFM1 was mainly colocalized with endothelial cells in ischemic muscle tissues. Further, elevated expression of UFM1 was observed in hypoxic endothelial cells. Subsequent genetic inhibition of UFM1 dramatically enhanced migration, invasion, adhesion, and tube formation of endothelial cells under hypoxia. Mechanistically, UFM1 reduced the stability of hypoxia-inducible factor-1α (HIF-1α) and promoted the von Hippel-Lindau-mediated K48-linked ubiquitin-proteasome degradation of HIF-1α, which in turn decreased angiogenic factor VEGFA expression and suppressed VEGFA related signaling pathway. Consistently, overexpression of UFM1 inhibited the angiogenesis of endothelial cells under hypoxic conditions, whereas overexpression of HIF-1α reversed this effect. Collectively, our data reveal that UFM1 inhibits the angiogenesis of endothelial cells under hypoxia through promoting ubiquitin-proteasome degradation of HIF-1α, suggesting UFM1 might serve as a potential therapeutic target for PAD.

Anti-inflammatory and antinociceptive effects, toxicity, and phytochemical analysis of Beaumontia grandiflora Wall.

Preliminary pharmacological studies revealed that the EtOAc fraction (BGEA) might be the main active fraction with anti-inflammatory and antinociceptive effects in Beaumontia grandiflora Wall. Further assays on BGEA at doses of 200, 400, and 800 mg/kg using four animal models showed that it could inhibit the xylene-induced ear edema, carrageenan-induced paw edema, and acetic acid-induced writhing and prolong the latency time in the hot-plate test. ELISA analysis revealed that the anti-inflammatory activity of BGEA might be associated with the decrease of TNF-α, IL-1ß, and IL-6 levels and the increase of the IL-10 level. The acute toxicity test showed that except for the n-BuOH fraction, the LD50 values of the extract and other three fractions were higher than 2000 mg/kg bw. Finally, 14 compounds were identified from BGEA by LC-MS. This research provides some basis for the folk use of B. grandiflora in the treatment of inflammation and pain-related diseases.

Hypolipidemic effect and gut microbiota regulation of Gypenoside aglycones in rats fed a high-fat diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynostemma pentaphyllum (Thunb.) Makino has traditional applications in Chinese medicine to treat lipid abnormalities. Gypenosides (GPs), the main bioactive components of Gynostemma pentaphyllum, have been reported to exert hypolipidemic effects through multiple mechanisms. The lipid-lowering effects of GPs may be attributed to the aglycone portion resulting from hydrolysis of GPs by the gut microbiota. However, to date, there have been no reports on whether gypenoside aglycones (Agl), the primary bioactive constituents, can ameliorate hyperlipidemia by modulating the gut microbiota. AIM OF THE STUDY: This study explored the potential therapeutic effects of gypenoside aglycone (Agl) in a rat model of high-fat diet (HFD)-induced hyperlipidemia. METHODS: A hyperlipidemic rat model was established by feeding rats with a high-fat diet. Agl was administered orally, and serum lipid levels were analyzed. Molecular techniques, including RT-polymerase chain reaction (PCR) and fecal microbiota sequencing, were used to investigate the effects of Agl on lipid metabolism and gut microbiota composition. RESULTS: Agl administration significantly reduced serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and mitigated hepatic damage induced by HFD. Molecular investigations have revealed the modulation of key lipid metabolism genes and proteins by Agl. Notably, Agl treatment enriched the gut microbiota with beneficial genera, including Lactobacillus, Akkermansia, and Blautia and promoted specific shifts in Lactobacillus murinus, Firmicutes bacterium CAG:424, and Allobaculum stercoricanis. CONCLUSION: This comprehensive study established Agl as a promising candidate for the treatment of hyperlipidemia. It also exhibits remarkable hypolipidemic and hepatoprotective properties. The modulation of lipid metabolism-related genes, along with the restoration of gut microbiota balance, provides mechanistic insights. Thus, Agl has great potential for clinical applications in hyperlipidemia management.

Genetic Insights into Glycine's Protective Role Against CAD - European and East Asia, 2015 and 2020.

Introduction: The purpose of this study is to examine the potential causal relationship between levels of circulating glycine and coronary artery disease (CAD) using a two-step Mendelian randomization (MR) analysis. Methods: We analyzed data from genome-wide association studies (GWAS) conducted on European and East Asian populations. To assess the causal effects of circulating glycine levels on the risk of CAD. We used the inverse-variance weighting (IVW), weighted median (WM), MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Furthermore, we conducted mediation analysis to investigate the contribution of blood pressure and other cardiovascular disease-related traits. Results: The two-step Mendelian randomization analysis revealed that higher levels of glycine in the blood were associated with a reduced risk of CAD in Europeans [odds ratio ( OR)=0.84, 95% confidence interval ( CI): 0.72, -0.98; P=0.029] and East Asians: ( OR=0.76, 95% CI: 0.66, -0.89; P=3.57×10 -4). Sensitivity analysis confirmed the robustness of these findings. Additionally, our results suggest that about 6.06% of the observed causal effect is mediated through genetically predicted systolic blood pressure (SBP) in the European population. Discussion: Our results contribute to the current knowledge regarding the involvement of glycine in the progression of CAD, and provide valuable methodological insights for the prevention and treatment of this condition.

Current scenario of chalcone hybrids with antibreast cancer therapeutic applications.

Breast cancer, an epithelial malignant tumor that occurs in the terminal ducts of the breast, is the most common female malignancy. Currently, approximately 70%-80% of breast cancer with early-stage, nonmetastatic disorder is curable, but the emergency of drug resistance often leads to treatment failure. Moreover, advanced breast cancer with distant organ metastases is incurable with the available therapeutics, creating an urgent demand to explore novel antibreast cancer agents. Chalcones, the precursors for flavonoids and isoflavonoids, exhibit promising activity against various breast cancer hallmarks, inclusive of proliferation, angiogenesis, invasion, metastasis, inflammation, stemness, and regulation of cancer epigenetics, representing useful scaffolds for the discovery of novel antibreast cancer chemotherapeutic candidates. In particular, chalcone hybrids could act on two or more different biological targets simultaneously with more efficacy, lower toxicity, and less susceptibility to resistance. Accordingly, there is a huge scope for application of chalcone hybrids to tackle the present difficulties in breast cancer therapy. This review outlines the chalcone hybrids with antibreast cancer potential developed from 2018. The structure-activity relationships as well as mechanisms of action are also discussed to shed light on the development of more effective and multitargeted chalcone candidates.

Biochar derived from rice husk: Impact on soil enzyme and microbial dynamics, lettuce growth, and toxicity.

This study was set to investigate the effects of rice husk biochar (RHB) on soil characteristics and growth of lettuce (Lactuca sativa). A comprehensive research approach was employed to examine the effect of different RHB concentrations (i.e., 0-1.5%) on soil pH, soil enzyme activities (i.e., alkaline phosphatase, beta-glucosidase, and dehydrogenase), soil microbial community, lettuce growth, and earthworm toxicity. The results showed that, within the studied RHB concentration range, the RHB application did not have significant effects on the soil pH. However, the enzyme activities were increased with increasing RHB concentration after the 28 d-lettuce growth period. The RHB application also increased the abundances of the bacterial genera Massilia and Bacillus and fungal genus Trichocladium having the plant growth promoting abilities. Furthermore, the study revealed that the root weight and number of lettuce leaves were significantly increased in the presence of the RHB, and the growth was dependent on the RHB concentration. The improved lettuce growth can be explained by the changes in the enzyme and microbial dynamics, which have resulted from the increased nutrient availability with the RHB application. Additionally, the earthworm toxicity test indicated that the tested RHB concentrations can be safely applied to soil without any significant ecotoxicity. In conclusion, this study underscores the potential of RHB as a soil amendment with positive effects on crop growth, highlighting the utilization of agricultural byproducts to enhance soil biological quality and plant growth through biochar application.

Feasibility of flattening filter free beams for hippocampal avoidance whole-brain radiotherapy: a dosimetric and radiobiological analysis.

Objectives: The purpose of this study is to evaluate the potential of the flattening filter free (FFF) mode of a linear accelerator for patients with hippocampal avoidance whole-brain radiotherapy (HA-WBRT) by comparison with flattened beams (FF) technique in the application of volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) using dosimetric and radiobiological indexes based on the volume of hippocampus and target. Methods: 2 VMAT- and 2 IMRT- plans were optimized in Eclipse planning system with 2 different delivery modes (6 MV standard vs. 6 MV FFF) for each of 25 patients. Dose distributions of the target and organs at risk (OARs), normal tissue complication probability (NTCP) of the hippocampus, monitor units, treatment time and quality assurance results were evaluated to compare the normal and FFF beam characteristics by Wilcoxon matched-pair signed-rank test with a significance level of 0.05. Results: VMAT-FFF provided the significantly best homogeneity and conformity of the target, delivered the lowest dose to hippocampus and the other OARs, and led to the lowest NTCP of the hippocampus among all modalities, which has the potential to alleviate neurocognitive decline after WBRT. IMRT-FFF reduced the dose to the lens with similar dose distributions of the target compared with IMRT-FF, whereas the lower dose to the hippocampus was achieved using the conventional beams. The monitor units were obviously increased by 19.2% for VMAT and 33.8% for IMRT, when FFF beams w ere used. The removal of flattening filter for IMRT resulted in a 26% reduction in treatment time, but VMAT had the similar treatment time for the two modes owing to the limitation of gantry rotation speed. Gamma analysis showed an excellent agreement for all plans at 3%/2 mm, and no statistical differences were found between FF and FFF. Conclusion: In conclusion, this study suggests that FFF mode is feasible and advantageous in HA-WBRT and VMAT-FFF is the optimal solution in terms of dose distribution of the target, OARs sparing, NTCP of the hippocampus and delivery efficiency compared to the other three techniques. Additionally, the advantages of the FFF technique for VMAT are more prominent in cases with small hippocampal volumes.

New dammarane-type triterpenoids from hydrolyzate of total Gynostemma pentaphyllum saponins with protein tyrosine phosphatase 1B inhibitory activity.

Protein tyrosine phosphatase 1B (PTP1B) is a key factor and regulator of glucose, lipid metabolism throughout the body, and a promising target for treatment of type 2 diabetes mellitus (T2DM). Gynostemma pentaphyllum is a famous oriental traditional medicinal herbal plant and functional food, which has shown many beneficial effects on glucose and lipid metabolism. The aim of the present study is to assess the inhibitory activity of five new and four known dammarane triterpenoids isolated from the hydrolysate product of total G. pentaphyllum saponins. The bioassay data showed that all the compounds exhibited significant inhibitory activity against PTP1B. The structure-activity relationship showed that the strength of PTP1B inhibitory activity was mainly related to the electron-donating group on its side chain. Molecular docking analysis suggested that its mechanism may be due to the formation of competitive hydrogen bonding between the electron-donating moiety and the Asp48 amino acid residues on the PTP1B protein.

Large-Scale Observations Support Aboveground Vegetation as an Important Biological Mercury Sink in the Tibetan Plateau.

Mercury, a pervasive global pollutant, primarily enters the atmosphere through human activities and legacy emissions from the land and oceans. A significant portion of this mercury subsequently settles on land through vegetation uptake. Characterizing mercury storage and distribution within vegetation is essential for comprehending regional and global mercury cycles. We conducted an unprecedented large-scale aboveground vegetation mercury survey across the expansive Tibetan Plateau. We find that mosses (31.1 ± 0.5 ng/g) and cushion plants (15.2 ± 0.7 ng/g) outstood high mercury concentrations. Despite exceptionally low anthropogenic mercury emissions, mercury concentrations of all biomes exceeded at least one-third of their respective global averages. While acknowledging the role of plant physiological factors, statistical models emphasize the predominant impact of atmospheric mercury on driving variations in mercury concentrations. Our estimations indicate that aboveground vegetation on the plateau accumulates 32-12+21 Mg (interquartile range) mercury. Forests occupy the highest biomass and store 82% of mercury, while mosses, representing only 3% of the biomass, disproportionally contribute 13% to mercury storage and account for 43% (2.5-1.4+3.0 Mg/year) of annual mercury assimilation by vegetation. Additionally, our study underscores that extrapolating aboveground vegetation mercury storage from lower-altitude regions to the Tibetan Plateau can lead to substantial overestimation, inspiring further exploration in alpine ecosystems worldwide.

Wintertime Formation of Large Sulfate Particles in China and Implications for Human Health.

Outdoor air pollution causes millions of premature deaths annually worldwide. Sulfate is a major component of particulate pollution. Winter sulfate observations in China show both high concentrations and an accumulation mode with a modal size >1 µm. However, we find that this observed size distribution cannot be simulated using classical gaseous and aqueous phase formation (CSF) or proposed aerosol-processing formation (APF) mechanisms. Specifically, the CSF simulation underestimates sulfate concentrations by 76% over megacities in China and predicts particle size distributions with a modal size of ∼0.35 µm, significantly smaller than observations. Although incorporating the APF mechanism in the atmospheric chemical model notably improves sulfate concentration simulation with reasonable parameters, the simulated sulfate particle size distribution remains similar to that using the CSF mechanism. We further conduct theoretical analyses and show that particles with diameters <0.3 µm grow rapidly (2-3 s) to 1 µm through the condensation of sulfuric acid in fresh high-temperature exhaust plumes, referred to as in-source formation (ISF). An ISF sulfate source equivalent to 15% of sulfur emissions from fossil fuel combustion largely explains both observed size distributions and mass concentrations of sulfate particles. The findings imply that ISF is a major source of wintertime micron-sized sulfate in China and underscore the importance of considering the size distribution of aerosols for accurately assessing the impacts of inorganic aerosols on radiative forcing and human health.

Riverine Discharge Fuels the Production of Methylmercury in a Large Temperate Estuary.

Estuaries are an important food source for the world's growing population, yet human health is at risk from elevated exposure to methylmercury (MeHg) via the consumption of estuarine fish. Moreover, the sources and cycling of MeHg in temperate estuarine ecosystems are poorly understood. Here, we investigated the seasonal and tidal patterns of mercury (Hg) forms in Long Island Sound (LIS), in a location where North Atlantic Ocean waters mix with the Connecticut River. We found that seasonal variations in Hg and MeHg in LIS followed the extent of riverine Hg delivery, while tides further exacerbated the remobilization of earlier deposited riverine Hg. The net production of MeHg near the river plume was significant compared to that in other locations and enhanced during high tide, possibly resulting from the enhanced microbial activity and organic carbon remineralization in the river plume. Statistical models, driven by our novel data, further support the hypothesis that the river-delivered organic matter and inorganic Hg drive net MeHg production in the estuarine water column. Our study sheds light on the significance of water column biogeochemical processes in temperate tidal estuaries in regulating MeHg levels and inspires new questions in our quest to understand MeHg sources and dynamics in coastal oceans.

Research Progress of Takeda G Protein-Coupled Receptor 5 in Metabolic Syndrome.

Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, recent preclinical studies also demonstrate that TGR5 plays a significant role in the generation and progression of metabolic syndrome, encompassing type 2 diabetes mellitus, obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). In this review, we discuss the role of TGR5 in metabolic syndrome, illustrating the underlying mechanisms and therapeutic targets.

Can red tourism lead to spiritual transformation? Evidence from tourists visiting the Red Army Long March Xiangjiang Battle Memorial Park.

The mechanism of spiritual transformation in red tourism plays a key role in facilitating the inheritance of red culture. A survey of 385 tourists of Chinese nationality was conducted to explore the path of red tourism's influence on tourists' spiritual transformation. Based on the stimulus-organism-response theory, this paper explores tourists' environmental perceptions of red tourism activities as special external stimuli, introduces a positive emotion factor, and constructs a path model of red tourism for tourists' positive emotions based on educational function and cultural identity, which ultimately leads to their spiritual transformation. The results of the empirical tests using structural equation modelling indicated that environmental perceptions had a significantly positive effect on the stimulation of positive emotions, while positive emotions had an indirect effect on spiritual transformation. The research results enhance people's understanding of the spiritual transformation brought by red tourism and provide management significance for red tourism planning.

A three-snoRNA signature: SNORD15A, SNORD35B and SNORD60 as novel biomarker for renal cell carcinoma.

BACKGROUND: Accumulating evidence has confirmed the role of snoRNAs in a variety of cancer, but rare in renal cell carcinoma (RCC). This study aims to clarify the role of snoRNAs in RCC tumorigenesis and their potential as novel tumor biomarkers. MATERIALS AND METHODS: The snoRNA expression matrix was obtained from the public TCGA and SNORic databases. SNORD15A, SNORD35B and SNORD60 were selected and validated by qPCR, then analyzed combined with related clinical factors using T-test and ROC curve. RESULTS: All three snoRNAs: SNORD15A, SNORD35B and SNORD60 were significantly upregulated in cancer tissues compared to adjacent tissues from TCGA or FFPE detection. These three snoRNAs were also increased in urinary sediment (US) of RCC as well as the early-stage RCC patients compared with the healthy controls. In addition, RNase stability experiments confirmed their stable existence in US. Meanwhile, the ROC curve shows that SNORD15A, SNORD35B and SNORD60 could effectively distinguish RCC (AUC = 0.7421) and early-stage RCC (AUC = 0.7465) from healthy individuals. CONCLUSION: SNORD15A, SNORD35B and SNORD60 were upregulated in tissues and US of RCC, serving as novel potential biomarkers for RCC diagnosis.

The protective role of Wnt3a in peroxynitrite-induced damage of cochlear hair cells in vitro.

OBJECTIVE: To investigate the effect of peroxynitrite on the cultured cochlear hair cells of C57BL/6 P3 mice in vitro as well as the role of Wnt3a, as an activator of the canonical Wnt signaling pathway, underlying the action of such an oxidative stress. METHODS: The in vitro primary cultured cochlear hair cells were subjected to l00 µM peroxynitrite and l00 µM peroxynitrite +25 ng/mL Wnt3a for 24 h, the cell survival and morphological changes were examined by immunofluorescence and transmission electron microscopy. RESULTS: The number of surviving hair cells was significantly reduced in the 100 µM peroxynitrite group, while it was significantly higher in the Wnt3a + peroxynitrite treated group compared with the peroxynitrite treated group. The transmission electron microscopy showed that exposure to peroxynitrite induced a dramatic decrease in the number of mitochondria and severely disrupted mitochondrial ultrastructure, while Wnt3a clearly diminished the disruption of mitochondrial structure and preserved a higher number of mitochondria. CONCLUSION: These results indicated that peroxynitrite could cause oxidative damage to the cochlear hair cells, and low concentrations of Wnt3a has a protective effect against oxidative damage. LEVEL OF EVIDENCE: Level 2.

Galactose-functionalized injectable thermosensitive microgels for target specific uptake in hepatoma cells.

Microgels acts as a potential candidate for responsive composite materials, which has been favored by scientists because of its excellent colloid stability, easy integration, and most of their surface area can be used as support after modification. Specififically, microgels are fascinating capable of maintaining good biocompatibility and controlled-release in vivo and making the possible for applications in biomaterials and biomedicines. Besides, in the process of microgel synthesis, some targeting factors can be combined to achieve the purpose of cell targeting and uptake. Therefore, how to fundamentally design microgels is an urgent problem to be solved. In this study, we design and synthesize an injectable microgel P(DEGMA-co-OVNGal) that is made of 2-methyl-2-acrylate-2-(2-methoxy ethoxy) ethyl ester (DEGMA) and glycopolymer (OVNGal) that is thermoresponsive and contains galactose. When the content of crosslinking agent is regulated, the microgel will realize the transformation from sol to gel at the temperature around human body, causing the controlled release of the loaded drugs. With the increase of crosslinker content from 1% to 7%, the appearance of microgel changed from loose and ordered to compact and hard morphology, the swelling ratio of microgel decreased from 187% to 142%, and the phase volume transition temperature decreased from 29.2°C to 28°C. The results indicated that when the monomer ratio (DEGMA: OVNGal) increased from 2:1 to 40:1 with the amount of crosslinking agent at 1%, the particle size of microgel increased from 460 nm to 660 nm. In vitro released studies confirmed that the cumulative released DOX (doxorubicin, as a selected model drug) from the microgel can reach 50% after 7 days. Furthermore, in vitro experiments demonstrated that the injectable microgel P(DEGMA-co-OVNGal) can target HepG2 cells effectively and meantime dispalys excellent biocompatibility. Therefore, the injected microgels based on P(DEGMA-co-OVNGal) have the potential to serve as a robust and promising drug delivery carrier for targeted cancer therapy.

ß-Glucan produced by Lentinus edodes suppresses breast cancer progression via the inhibition of macrophage M2 polarization by integrating autophagy and inflammatory signals.

BACKGROUND: ß-Glucan from Lentinus edodes (LNT), an edible mushroom, possesses strong anticancer activity. However, the therapeutic effects of LNT during the occurrence and progression of breast cancer and their underlying molecular mechanisms have not been elucidated. METHODS: Mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) transgenic mice were used as a breast cancer mouse model. Hematoxylin and eosin, immunohistochemical, and immunofluorescence staining were performed for histopathological analysis. Moreover, we developed an inflammatory cell model using tumor necrosis factor-α (TNF-α). Macrophage polarization was assessed using western blot analysis and immunofluorescence. RESULTS: Orphan nuclear receptor 77 (Nur77) and sequestosome-1 (p62) were highly expressed and positively correlated with each other in breast cancer tissues. LNT significantly inhibited tumor growth, ameliorated inflammatory cell infiltration, and induced tumor cell apoptosis in PyMT transgenic mice. Moreover, LNT attenuated the ability of tumors to metastasize to lung tissue. Mechanistically, LNT treatment restrained macrophage polarization from M1 to M2 phenotype and promoted autophagic cell death by inhibiting Nur77 expression, AKT/mTOR signaling, and inflammatory signals in breast tumor cells. However, LNT did not exhibit a direct pro-autophagic effect on tumor cell death, except for its inhibitory effect on Nur77 expression. LNT-mediated autophagic tumor cell death depends on M1 macrophage polarization. In in vitro experiments, LNT inhibited the upregulation of p62, autophagy activation, and inflammatory signaling pathways in Nur77 cells. CONCLUSION: LNT inhibited macrophage M2 polarization and subsequently blocked the AKT/mTOR and inflammatory signaling axes in breast cancer cells, thereby promoting autophagic tumor cell death. Thus, LNT may be a promising therapeutic strategy for breast cancer.

Contents in tumor-educated platelets as the novel biosource for cancer diagnostics.

Liquid biopsy, a powerful non-invasive test, has been widely used in cancer diagnosis and treatment. Platelets, the second most abundant cells in peripheral blood, are becoming one of the richest sources of liquid biopsy with the capacity to systematically and locally respond to the presence of cancer and absorb and store circulating proteins and different types of nucleic acids, thus called "tumor-educated platelets (TEPs)". The contents of TEPs are significantly and specifically altered, empowering them with the potential as cancer biomarkers. The current review focuses on the alternation of TEP content, including coding and non-coding RNA and proteins, and their role in cancer diagnostics.

Tumor-educated platelet SNORA58, SNORA68 and SNORD93 as novel diagnostic biomarkers for esophageal cancer.

Aim: The purpose of this study was to evaluate whether tumor-educated platelet (TEP) snoRNAs could be used as a diagnostic biomarker for esophageal cancer (ESCA). Methods: Platelet precipitates were obtained from platelet-rich plasma by low-speed centrifugation, and total RNA was extracted from platelets using Trizol™ reagent. RT-qPCR was used to detect snoRNA expression, and the receiver operating characteristic was used to assess its diagnostic potential. Results: SNORA58, SNORA68 and SNORD93 were significantly upregulated in TEPs from ESCA patients and early-stage patients compared with healthy controls. Importantly, the three snoRNAs were capable of serving as circulating biomarkers of diagnostics and early diagnosis of ESCA, possessing areas under the curve of 0.846 and 0.857, respectively. Conclusion: TEP SNORA58, SNORA68 and SNORD93 could potentially serve as noninvasive biomarkers for diagnosis and early diagnosis of ESCA.

Gypenosides ameliorate high-fat diet-induced nonalcoholic fatty liver disease in mice by regulating lipid metabolism.

Gypenosides (GP), extracted from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino, have been used to treat metabolic disorders, including lipid metabolism disorders and diabetes. Although recent studies have confirmed their beneficial effects in nonalcoholic fatty liver disease (NAFLD), the underlying therapeutic mechanism remains unclear. In this study, we explored the protective mechanism of GP against NAFLD in mice and provided new insights into the prevention and treatment of NAFLD. Male C57BL6/J mice were divided into three experimental groups: normal diet, high-fat diet (HFD), and GP groups. The mice were fed an HFD for 16 weeks to establish an NAFLD model and then treated with GP for 22 weeks. The transcriptome and proteome of the mice livers were profiled using RNA sequencing and high-resolution mass spectrometry, respectively. The results showed that GP decreased serum lipid levels, liver index, and liver fat accumulation in mice. Principal component and heatmap analyses indicated that GP significantly modulated the changes in the expression of genes associated with HFD-induced NAFLD. The 164 differentially expressed genes recovered using GP were enriched in fatty acid and steroid metabolism pathways. Further results showed that GP reduced fatty acid synthesis by downregulating the expression of Srebf1, Fasn, Acss2, Acly, Acaca, Fads1, and Elovl6; modulated glycerolipid metabolism by inducing the expression of Mgll; promoted fatty acid transportation and degradation by inducing the expression of Slc27a1, Cpt1a, and Ehhadh; and reduced hepatic cholesterol synthesis by downregulating the expression of Tm7sf2, Ebp, Sc5d, Lss, Fdft1, Cyp51, Nsdhl, Pmvk, Mvd, Fdps, and Dhcr7. The proteomic data further indicated that GP decreased the protein expression levels of ACACA, ACLY, ACSS2, TM7SF2, EBP, FDFT1, NSDHL, PMVK, MVD, FDPS, and DHCR7 and increased those of MGLL, SLC27A1, and EHHADH. In conclusion, GP can regulate the key genes involved in hepatic lipid metabolism in NAFLD mice, providing initial evidence for the mechanisms underlying the therapeutic effect of GP in NAFLD.