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In our previous multicenter study, we delineated the inherent metabolic features of colorectal cancer (CRC). Therein, we identified a member of the ectonucleotide pyrophosphatase/ phosphodiesterase family (ENPP2) as a significant differential metabolite of CRC. In this study, the role of ENPP2 in CRC has been demonstrated using established in vitro and in vivo models including ENPP2 gene knockdown, and use of the ENPP2 inhibitor, GLPG1690. We found that CRC proliferation was decreased after either ENPP2 gene knockdown or use of ENPP2 inhibitors. We further evaluated the role of GLPG1690 in AOM/DSS-induced CRC mice via intestinal barrier function, macrophage polarization, inflammatory response and microbial homeostasis. Results of immunofluorescence staining and Western blotting showed that GLPG1690 can restore gut-barrier function by increasing the expression of tight junction proteins, claudin-1, occludin and ZO-1. M2 tumor-associated macrophage polarization and colonic inflammation were attenuated after treatment with GLPG1690 using the Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) model. Moreover, 16 S rDNA pyrosequencing and metagenomic analysis showed that GLPG1690 could alleviate gut dysbiosis in mice. Furthermore, administration of GLPG1690 with antibiotics as well as fecal microbiota transplantation assays demonstrated a close link between the efficacy of GLPG1690 and the gut microbiota composition. Finally, results of metabolomic analysis implicated mainly the gut microbiota-derived metabolites of aromatic amino acids in CRC progression. These findings may provide novel insights into the development of small-molecule ENPP2 inhibitors for the treatment of CRC.

Acute skin injuries require timely and effective treatment. Injectable self-healing hydrogels are a very promising approach, but they face many challenges because of the complex microenvironments of skin wound. Although hydrogels have been extensively studied for multifunction, injectable self-healing hydrogels with both hemostatic and antioxidant properties are rare. In this paper, gelatin grafted protocatechuic acid (GT-PCA) and oxidized-dextran (Odex) were used to engineer GT-PCA/Odex composite hydrogels via Schiff base reaction. The in vitro experimental results show that the hydrogels not only are injectable, self-healing, hemostatic, antioxidant, but also have good degradability, adhesion and biocompatibility. Further, the hydrogels can promote wound healing in full-thickness mouse skin defect models by reducing inflammation and increasing angiogenesis, collagen deposition and granulation tissue formation. Notably, the preparation method of GT-PCA/Odex hydrogels is gentle and simple, the hydrogel system has bright prospects in the treatment of acute skin injury and is expected to be applied in clinical trials.

Injectable Hydrogels with adhesive, antioxidant and hemostatic properties are highly desired for promoting skin injury repair. In this study, we prepared a multi-functional carboxymethyl chitosan/hyaluronic acid-dopamine (CMC/HA-DA) hydrogel, which can be crosslinked by horseradish peroxidase and hydrogen peroxide. The antioxidation, gelation time, degradability, rheology and antihemorrhagic properties of hydrogels can be finely tuned by varying composition ratio. The cytocompatibility test and hemolysis test confirmed that the designed hydrogel holds good biocompatibility. More importantly, the repair effect of the hydrogel on full-thickness skin injury model in mice was studied. The results of wound healing, collagen deposition, immunohistochemistry and immunofluorescence showed that CMC/HA-DA hydrogel could significantly promote angiogenesis and cell proliferation at the injured site. Notably, the inflammatory response can also be regulated to promote the repair of full-thickness skin defect in mice. Results indicate that this injectable CMC/HA-DA hydrogel holds high application prospect for promising wound healing.

Background: Metabolic syndrome (MetS) is a cluster of multiple cardiometabolic risk factors that increase the risk of type 2 diabetes and cardiovascular diseases. Identifying novel biomarkers of MetS and their genetic associations could provide insights into the mechanisms of cardiometabolic diseases. Methods: Potential MetS-associated metabolites were screened and internally validated by untargeted metabolomics analyses among 693 patients with MetS and 705 controls. External validation was conducted using two well-established targeted metabolomic methods among 149 patients with MetS and 253 controls. The genetic associations of metabolites were determined by linear regression using our previous genome-wide SNP data. Causal relationships were assessed using a one-sample Mendelian Randomization (MR) approach. Findings: Nine metabolites were ultimately found to be associated with MetS or its components. Five metabolites, including LysoPC(14:0), LysoPC(15:0), propionyl carnitine, phenylalanine, and docosapentaenoic acid (DPA) were selected to construct a metabolite risk score (MRS), which was found to have a dose-response relationship with MetS and metabolic abnormalities. Moreover, MRS displayed a good ability to differentiate MetS and metabolic abnormalities. Three SNPs (rs11635491, rs7067822, and rs1952458) were associated with LysoPC(15:0). Two SNPs, rs1952458 and rs11635491 were found to be marginally correlated with several MetS components. MR analyses showed that a higher LysoPC(15:0) level was causally associated with the risk of overweight/obesity, dyslipidaemia, high uric acid, high insulin and high HOMA-IR. Interpretation: We identified five metabolite biomarkers of MetS and three SNPs associated with LysoPC(15:0). MR analyses revealed that abnormal LysoPC metabolism may be causally linked the metabolic risk. Funding: This work was supported by grants from the National Key Research and Development Program of China (2017YFC0907004).

This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) and its application to a pharmacokinetic study involving single and multiple intravenous infusions to healthy Chinese volunteers. After sample preparation of plasma by liquid–liquid extraction with ethyl acetate, the analyte and internal standard, urapidil, were separated by reversed phase chromatography in a run time of 4 min and detected by positive ion electrospray ionization followed by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 326.2→308.1 for ifenprodil and m/z 388.4→205.3 for IS. The assay was linear in the concentration range 0.2–50.0 ng/mL with recovery >76.4%. In the pharmacokinetic study of single intravenous infusions of 5, 10 and 15 mg ifenprodil, peak plasma concentrations and areas under the plasma concentration–time curve were both linearly related to dose. In the pharmacokinetic study of multiple once daily intravenous infusions of 10 mg ifenprodil for 7 days, pharmacokinetic parameters were similar to those after the single dose showing that ifenprodil does not accumulate on repeated administration.

α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions.

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5’-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection.

As a tool to deal with the phenomenon in layered or porous media, many theoretical problems need to be improved urgently. In this paper, the definitions of two kinds of fractal derivatives based on scale transformation are developed from the perspective of mathematics, and the four operation rules, chain rules, Rolle theorem, mean value theorem, Taylor formula, variable upper limit integral derivation rule, definite integral basic principle, partial integral formula and double partial integral formula of the fractal version are given. Better still, we derive the fractal Euler-Lagrangian equation by using the variational method, and demonstrate the steps and effectiveness of deriving the fractal nonlinear wave equation based on the fractal Euler-Lagrangian equation through the example of the functionally graded beam.

Epidemiologic studies have demonstrated a direct correlation between fine particulate matter (FPM) exposure and the high risk of respiratory diseases. FPM can penetrate deep into the lung and deposit in the alveoli with breath, where it directly interacts with alveolar epithelial cell (APC). However, we know little about the effects nor mechanisms of FPM on APC. Here, using human APC A549 cells, we found that FPM resulted in blockade of autophagic flux, redox imbalance and oxidative stress, mitochondrial fragmentation, increased mitophagy and impaired mitochondrial respiration. Further we showed that activation of JNK signaling (c-Jun N-terminal kinase) and excessive ROS (reactive oxygen species) release contribute to these adverse effects, with the former being upstream of the latter. More importantly, we found that scavenging ROS or inhibiting JNK activation could restore those effects as well as ameliorate FPM-induced inhibition of cell proliferation, and epithelial-mesenchymal transformation (EMT) in A549 cells. Taken together, our findings indicate that FPM leads to toxicity in alveolar type II cells via JNK activation, and JNK-targeting or antioxidant strategies might be beneficial for prevention or treatment of FPM-related pulmonary diseases.

Background: Angiogenesis constitutes a major mechanism responsible for exercise-induced beneficial effects. Our previous study identified a cluster of differentially expressed extracellular vesicle microRNAs (miRNAs) after exercise and found that some of them act as exerkines. However, whether these extracellular vesicle miRNAs mediate the exercise-induced angiogenesis remains unknown. Methods: A 9-day treadmill training was used as an exercise model in C57BL/6 mice. Liver-specific adeno-associated virus 8 was used to knock down microRNA-122-5p (miR-122-5p). Human umbilical vein endothelial cells were used in vitro. Results: Among these differentially expressed extracellular vesicle miRNAs, miR-122-5p was identified as a potent pro-angiogenic factor that activated vascular endothelial growth factor signaling and promoted angiogenesis both in vivo and in vitro. Exercise increased circulating levels of miR-122-5p, which was produced mainly by the liver and shuttled by extracellular vesicles in mice. Inhibition of circulating miR-122-5p or liver-specific knockdown of miR-122-5p significantly abolished the exercise-induced pro-angiogenic effect in skeletal muscles, and exercise-improved muscle performance in mice. Mechanistically, miR-122-5p promoted angiogenesis through shifting substrate preference to fatty acids in endothelial cells, and miR-122-5p upregulated endothelial cell fatty-acid utilization by targeting 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT1). In addition, miR-122-5p increased capillary density in perilesional skin tissues and accelerated wound healing in mice. Conclusion: These findings demonstrated that exercise promotes angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p, which enhances fatty acid utilization by targeting AGPAT1 in endothelial cells, highlighting the therapeutic potential of miR-122-5p in tissue repair.

The Horqin temperate steppe is the largest grassland in northern China. With the combined disturbance of multiple potential drivers, the native herbaceous vegetation has degraded with different intensity, and woody plants have transformed into the dominant vegetation in this area. On the one hand, woody plants play an important role in sand control, food/timber product provision, etc. On the other hand, this transformation process significantly affects the steppe ecosystem structure and function. It is necessary to clarify the patterns and determinants of woody plant cover changes. In view of the lack of high spatio-temporal resolution remote sensing data for woody cover. Here, based on high-resolution satellite images and the random forest model, the study reports the annual mean woody plant cover of the Horqin temperate steppe is 17.55 % over the past 35 years, and the significant increase area is approximately 43.7 % of the total area. Analysis of the boosted regression tree model showed potential drivers were mainly attributed to climate change (i.e., mean annual temperature, mean annual wind speed, and annual precipitation) and grazing intensity, with the cumulative contribution approaching 70 %. Furthermore, large-scale and high-density afforestation could also be responsible for the increase in woody plant cover. Against the background of frequent climate extremes, maintaining and improving steppe productivity, avoiding regional climate deterioration caused by blind afforestation, and developing a reasonable grazing management policy is the urgently needed to ensure the relative ecological stability of semi-arid temperate steppes and to achieve relatively sustainable development of the regional agro-pastoral economy.

Alzheimer's disease (AD) has become a major public health problem that affects the elderly population. Therapeutic compounds with curative effects are not available due to the complex pathogenesis of AD. Daphnetin, a natural coumarin derivative and inhibitor of various kinases, has anti-inflammatory and antioxidant activities. In this study, we found that daphnetin improved spatial learning and memory in an amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mouse model of AD. Daphnetin markedly decreased the levels of amyloid-β peptide 1–40 (Aβ40) and 1–42 (Aβ42) in the cerebral cortex, downregulated the expressions of enzymes involved in APP processing, e.g., beta-site APP-cleaving enzyme (BACE), nicastrin and presenilin enhancer protein 2 (PEN2). We further found the reduced serum levels of inflammatory factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and chemokine (C-C motif) ligand 3 (CCL3), while daphnetin increased total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels in the serum. Interestingly, daphnetin markedly decreased the expression of glial fibrillary acidic protein (GFAP) and the upstream regulatory molecule- phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in APP/PS1 mice, and mainly inhibited the phosphorylation of STAT3 at Ser727 to decrease GFAP expression evidenced in a LPS-activated glial cell model. These results suggest that daphnetin ameliorates cognitive deficits and that Aβ deposition in APP/PS1 mice is mainly correlated with astrocyte activation and APP processing.

Mitochondria harbor a unique fatty acid synthesis pathway (mtFAS) with mysterious functions gaining increasing interest, while its involvement in metabolic regulation is essentially unknown. Here we show that 3-Hydroxyacyl-ACP dehydratase (HTD2), a key enzyme in mtFAS pathway was primarily downregulated in adipocytes of mice under metabolic disorders, accompanied by decreased de novo production of lipoic acid, which is the byproduct of mtFAS pathway. Knockdown of Htd2 in 3T3-L1 preadipocytes or differentiated 3T3-L1 mature adipocytes impaired mitochondrial function via suppression of complex I activity, resulting in enhanced oxidative stress and impaired insulin sensitivity, which were all attenuated by supplement of lipoic acid. Moreover, lipidomic study revealed limited lipid alterations in mtFAS deficient cells which primarily presenting accumulation of triglycerides, attributed to mitochondrial dysfunction. Collectively, the present study highlighted the pivotal role of mtFAS pathway in regulating mitochondrial function and adipocytes insulin sensitivity, demonstrating supportive evidence for lipoic acid being potential effective nutrient for improving insulin resistance and related metabolic disorders.

Objective: Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum (ER). In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport. Methods: CRISPR/Cas9 gene editing was carried out to generate cell lines deficient in Aster-B expression. The effect of Aster-B deficiency on mitochondrial cholesterol transport was examined by both confocal imaging analysis and biochemical assays. Deletion mutational analysis was also carried out to identify the function of a putative mitochondrial targeting sequence (MTS) at the N-terminus of Aster-B for its role in targeting Aster-B to mitochondria and in mediating mitochondrial cholesterol trafficking. Results: Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction. Conclusions: We identified Aster-B as a key regulator of cholesterol transport from the ER to mitochondria. Aster-B also coordinates mitochondrial cholesterol trafficking with uptake of fatty acids derived from cholesterol esters, implicating the Aster-B protein as a novel regulator of steroidogenesis.

Increasing evidence demonstrates that hyperlipidemia plays a causal role in the development of cardiovascular diseases (CVDs) due to endothelial dysfunction. Houttuynia cordata aqueous extract (HAE), using as both medicine and food, whose effect and mechanism were investigated in endothelial dysfunction. In vivo, it profoundly attenuated hyperlipidemia-induced accumulation of serum metabolites, which in turn contributed to alleviating morphologic and functional damage in vascular endothelium. Moreover, the decrease expression of FoxO1/PGC-1α and mitochondrial complexes in thoracic vessels were ameliorated by HAE administration. Through in vitro cultures, consistently, the results showed that HAE predominantly activated PGC-1α for mitochondrial biogenesis via enhancing FoxO1 expression. Additionally, silencing of FoxO1 remarkably abolished the ability of HAE to augment PGC-1α expression, implying the imperative role of FoxO1 during protection. Besides, the anti-inflammation was mainly mediated via p38 MAPK pathway. Briefly, our study demonstrated that HAE ameliorated hyperlipidemia-induced endothelial injury via upregulating FoxO1/PGC-1α and suppressing p38 MAPK.

Background: Bitter gourd (BG) fruit powder was previously showed to prevent high-fat diet (HFD)-induced metabolic disorders in mice. In current study, we investigated the beneficial difference of the water soluble (S-BG) and insoluble fractions (IS-BG) of bitter gourd. Results: Compared to normal chow diet, the HFD induced greater body weight gain and increased fat mass accompanied by impaired insulin sensitivity, elevated serum lipids and inflammation. Supplementation of BG, S-BG, and IS-BG showed similar beneficial effects and restored the metabolic changes in mice. Interestingly, BG showed no effect on fat mass, which was decreased by both S-BG and IS-BG. Additionally, S-BG and IS-BG inhibited the SREBP-1/FAS pathway, thereby decreasing liver cholesterol accumulation, while only BG showed improvement on mitochondrial activity. Conclusion: These results further support the position that bitter gourd has multiple active ingredients and that both fractions have beneficial effects on metabolic disorders.

Apple polysaccharides have been previously demonstrated to have beneficial effects on hepatic metabolic functions. Approximately 1.9 million tons of young apples are thinned and abandoned annually in China, and whether the polysaccharide derived from these thinned young apples has metabolic benefits lacks evidence. Thinned young apple polysaccharide (TYAP) has been investigated in high fat diet (HFD)-induced obese mice for its effect on metabolic disorder. Water-soluble TYAP was isolated from thinned young apples and chemically characterized. TYAP administration at dosages of 400 mg/kg/day and 800 mg/kg/day significantly rescued HFD-induced hepatic metabolic impairment, reduced body weight gain, and ameliorated hepatic oxidative stress induced by HFD. In a palmitate-loaded HepG2 cell model, TYAP protected the cells from palmitate-induced insulin resistance and viability loss, suppressed mitochondrial ROS and improved the mitochondrial respiratory function impaired by palmitate. These findings suggest that TYAP could successfully attenuate obesity-associated hepatic metabolic disorder possibly by activating the hepatic mitochondrial respiratory function.

Olive oil, the primary source of dietary fat in the Mediterranean diet, is reported to have benefits on bone health, mechanisms of which remain obscure. Here we investigated the protective effects of hydroxytyrosol (HT), a major polyphenol in olive on preosteoblast toxicity induced by acrolein, the major component of cigarette smoke. Acrolein at 75 µM, induced significant oxidative stress which was attributed to the inhibition of Nrf2 nuclear translocation and suppression of phase II enzymes. And HT could efficiently promote Phase II enzymes activation and prevent the decrease of antioxidative enzymes, protect the autophagy pathway and maintain the normal level of mitochondrial complexes. These results indicated that cigarettes smoking could damage preosteoblast cells by inducing oxidative stress and mitochondrial dysfunction. While through activation of Keap1/Nrf2 pathway, olive component HT could contribute to cellular protection and potential bone health.