Correction: Fan et al. Progress in the Preclinical and Clinical Study of Resveratrol for Vascular Metabolic Disease. Molecules 2022, 27, 7524.

Text Correction [...].

CH4 Synthesis from CO2 and H2O of an Electron Source over Rh-Ru Cocatalysts Loaded on NaTaO3:Sr Photocatalysts.

CO2 reduction as an artificial photosynthetic system is a promising technology to produce green energies and chemicals because it uses light energy to convert H2O and CO2 into valuable products such as CO, HCOOH, CH3OH, CH4, and preferably higher hydrocarbons. In photocatalytic reduction, water should be used as hydrogen and electron sources for CO2 reduction. Moreover, CH4 formation is an attractive and challenging topic because of the eight-electron-reducing product of CO2. Herein, we report the development of a new Rh-Ru cocatalyst decorated on an alkaline earth-doped NaTaO3 surface for the photocatalytic CO2 reduction to form CH4 using water as an electron donor. CH4 was obtained by a photocatalytic "uphill" reaction of CO2 reduction using Rh-Ru cocatalyst-loaded NaTaO3:Sr, water, and CO2 in an aqueous suspension system. About 10% of a selectivity (electronic efficiency) was obtained for CH4 formation under ambient conditions accompanied with O2 evolution of the oxidation product of H2O.

Progress in the Preclinical and Clinical Study of Resveratrol for Vascular Metabolic Disease.

Vascular metabolic dysfunction presents in various diseases, such as atherosclerosis, hypertension, and diabetes mellitus. Due to the high prevalence of these diseases, it is important to explore treatment strategies to protect vascular function. Resveratrol (RSV), a natural polyphenolic phytochemical, is regarded as an agent to regulate metabolic pathways. Many studies have proven that RSV has beneficial effects on improving metabolism in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), which provide new directions to treat vascular metabolic diseases. Herein, we overviewed that RSV could regulate cell metabolism activity by inhibiting glucose uptake, suppressing glycolysis, preventing cells from fatty acid-related damages, reducing lipogenesis, increasing fatty acid oxidation, enhancing lipolysis, elevating uptake and synthesis of glutamine, and increasing NO release. Furthermore, in clinical trials, although the results from different studies remain controversial, we proposed that RSV had better therapeutic effects at high concentrations and for patients with metabolic disorders.

Resveratrol Promotes Angiogenesis in a FoxO1-Dependent Manner in Hind Limb Ischemia in Mice.

Critical limb ischemia (CLI) is a severe form of peripheral artery diseases (PAD) and seriously endangers the health of people. Therapeutic angiogenesis represents an important treatment strategy for CLI; various methods have been applied to enhance collateral circulation. However, the current development drug therapy to promote angiogenesis is limited. Resveratrol (RSV), a polyphenol compound extracted from plants, has various properties such as anti-oxidative, anti-inflammatory and anti-cancer effects. Whether RSV exerts protective effects on CLI remains elusive. In the current study, we demonstrated that oral intake of RSV significantly improved hind limb ischemia in mice, and increased the expression of phosphorylated Forkhead box class-O1 (FoxO1). RSV treatment in human umbilical vein endothelial cells (HUVECs) could increase the phosphorylation of FoxO1 and its cytoplasmic re-localization to promote angiogenesis. Then we manipulated FoxO1 in HUVECs to further verify that the effect of RSV on angiogenesis is in a FoxO1-dependent manner. Furthermore, we performed metabolomics to screen the metabolic pathways altered upon RSV intervention. We found that the pathways of pyrimidine metabolism, purine metabolism, as well as alanine, aspartate and glutamate metabolism, were highly correlated with the beneficial effects of RSV on the ischemic muscle. This study provides a novel direction for the medical therapy to CLI.

17ß-Estradiol on the Expression of G-Protein Coupled Estrogen Receptor (GPER/GPR30) Mitophagy, and the PI3K/Akt Signaling Pathway in ATDC5 Chondrocytes In Vitro.

BACKGROUND Osteoarthritis is a progressive inflammatory joint disease resulting in damage to articular cartilage. G-protein coupled estrogen receptor (GPER/GPR30) activates cell signaling in response to 17ß-estradiol, which can be blocked by the GPR30 agonist, G15, an analog of G-1. The aims of this study were to investigate the effects of 17ß-estradiol on the expression of G-protein coupled estrogen receptor (GPER/GPR30) on mitophagy and the PI3K/Akt signaling pathway in ATDC5 chondrocytes in vitro. MATERIAL AND METHODS Cultured ATDC5 chondrocytes were treated with increasing concentrations of 17ß-estradiol with and without G15, p38 inhibitor (SB203580), JNK inhibitor (SP600125), PI3K inhibitor (LY294002, S1737), and mTOR inhibitor (S1842). Expression of GPER/GPR30 and components of the PI3K/Akt pathway in cultured ATDC5 chondrocytes were detected by immunofluorescence (IF) staining, Western blot, and real-time polymerase chain reaction (RT-PCR). Transmission electron microscopy (TEM) and IF were used to detect mitophagosomes. Expression of LC-3, LAMP2, TOM20, Hsp60, p-Akt, p-mTOR, p-p38, and p-JNK was investigated by Western blot. Proliferation and viability of the ATDC5 chondrocytes were determined using BrdU and MTT assays. RESULTS In 17ß-estradiol-treated ATDC5 chondrocytes, increased expression of GPER/GPR30 was found, but fewer mitophagosomes were observed, and decreased numbers of TOM20-positive granules were co-localized with decreased LAMP2 and increased expression levels of TOM20, Hsp60, p-Akt, and p-mTOR, and reduced expression of LC3-II, were found. In 17ß-estradiol-treated ATDC5 chondrocytes, the proliferation and viability of the 17ß-estradiol-treated ATDC5 chondrocytes were significantly elevated. CONCLUSIONS Treatment with 17ß-estradiol protected ATDC5 chondrocytes against mitophagy via the GPER/GPR30 and the PI3K/Akt signaling pathway.

Ultrashort Lipopeptides Self-Assembled with Gold Nanoparticles as Potent Antimicrobial Agents.

To develop new antimicrobial synthetic lipopeptides with optimizing peptide length, cationic tripeptides RWR/WRR were N-terminal fatty acylated, and self-assembled with 1-dodecanethiol-anchored gold nanoparticles (Au-DT NPs) via hydrophobic interaction. The ultrashort lipopeptides and their nano-assemblies were effective against a variety of microorganisms, with minimal inhibitory concentrations ranging from 0.5 to 8 µg/mL. Hemolysis analysis and in vitro cytotoxicity assay revealed that self-assembling with Au-DT NPs would improve biological toxicity of lipopeptides, especially for the most active lipopeptides (Palmitoyl-RWR, Palmitoyl-WRR) with long lipid tails. As lipopeptides/ Au-DT NPs displayed slower bactericidal kinetics compared with free lipopeptides, the mode of action was further investigated. Difference in membrane targeting mechanism between lipopeptides and their nano-assemblies may be attributed to the structural architecture. The simple composition and diverse specificities of lipopeptides/Au-DT NPs, as well as their biocompatibility could make them as economically available potent antimicrobial agents for various applications.

Modification of Visible-Light-Responsive Pb2Ti2O5.4F1.2 with Metal Oxide Cocatalysts to Improve Photocatalytic O2 Evolution toward Z-Scheme Overall Water Splitting.

The development of a highly active photocatalyst for visible-light water splitting requires a high-quality semiconductor material and a cocatalyst, which promote both the migration of photogenerated charge carriers and surface redox reactions. In this work, a cocatalyst was loaded onto an oxyfluoride photocatalyst, Pb2Ti2O5.4F1.2, to improve the water oxidation activity. Among the metal oxides examined as cocatalysts, RuO2 was found to be the most suitable, and the O2 evolution activity depended on the preparation conditions for Ru/Pb2Ti2O5.4F1.2. The highest activity was obtained with RuCl3-impregnated Pb2Ti2O5.4F1.2 heated under a flow of H2 at 523 K. The H2-treated Ru/Pb2Ti2O5.4F1.2 showed an O2 evolution rate an order of magnitude higher than those for the analogues without the H2 treatment (e. g., RuO2/Pb2Ti2O5.4F1.2). Physicochemical analyses by X-ray absorption fine-structure spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, and time-resolved microwave conductivity measurements indicated that the optimized photocatalyst contained partially reduced RuO2 species with a particle size of ~5 nm. These partially reduced species effectively trapped the photogenerated charge carriers and promoted the oxidation of water into O2. The optimized Ru/Pb2Ti2O5.4F1.2 could function as an O2-evolving photocatalyst in Z-scheme overall water splitting, in combination with an Ru-loaded, Rh-doped SrTiO3 photocatalyst.

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

Celastrol directly binds with VAMP7 and RAB7 to inhibit autophagy and induce apoptosis in preadipocytes.

Obesity is one of the most prevalent chronic metabolic diseases, and induction of apoptosis in preadipocytes and adipocytes is a potential strategy to treat obesity. Celastrol represents one of the most robust anti-obesity phytochemicals so far, yet its direct binding target remains elusive. Here, we determined that celastrol could induce apoptosis in preadipocytes via mitochondrial mediated pathway. Further study clarified that celastrol inhibited the fusion of autophagosome and lysosome to prohibit autophagy, leading to cell apoptosis. By conducting virtual screening and genetic manipulation, we verified that overexpression of VAMP7 and RAB7 could block the effects of celastrol on inhibiting autophagy and inducing apoptosis. The Surface Plasmon Resonance study confirmed the direct binding of celastrol with VAMP7 and RAB7. The functional study illustrated the inhibition of RAB7 GTPase activity after celastrol treatment. Moreover, celastrol induced comparable apoptosis in murine epididymal adipose tissue, human preadipocytes and adipocytes, but not in human hepatocytes. An inhibitory effect on differentiation of human primary visceral preadipocytes was also observed. In conclusion, celastrol exhibited inhibitory effect of autophagy via direct binding with VAMP7 and RAB7, leading to an increase in preadipocytes apoptosis. These results advance our understanding in the potential application of celastrol in treating obesity.

Screening plasma metabolites as potential biomarkers for type B aortic dissection.

Background: Aortic dissection (AD) is a serious aortic disease. Although current imaging methods can provide accurate diagnosis for AD, they do not include essential biological information. The aim of this study is to identify plasma metabolites for the risk and severity of type B AD (TBAD). Methods: In this cross-sectional study, we enrolled 16 hypertensive patients with TBAD and 7 hypertensive patients without TBAD in Jieyang People's Hospital between December 2021 and April 2022. After plasma metabolomics analysis, a metabolites risk score (MRS) model was conducted through logistic regression and least absolute shrinkage and selection operator (LASSO) regression to predict the risk of TBAD. Subsequently, TBAD group was divided into uncomplicated and complicated TBAD subgroups for further screening for metabolites related to the severity of TBAD. Results: Three metabolites, including 1,5-anhydro-D-glucitol, D-(+)-sucrose and PC(O-16:0/0:0) were related to the risk of TBAD. Compared to hypertensive patients without TBAD, the abundance of 1,5-anhydro-D-glucitol and D-(+)-sucrose were significantly increased while PC(O-16:0/0:0) was significantly reduced in hypertensive patients with TBAD (P<0.001). We subsequently built an MRS model based on these three metabolites. Furthermore, we found that hydrocinnamic acid (r=0.741, P<0.001) was independently correlated with the TBAD severity, while glycine deoxycholic acid (r=-0.538, P=0.008) and glycochenodeoxycholic acid (r=-0.538, P=0.008) were inversely correlated with the TBAD severity independently. Conclusions: The present study screened out three plasma metabolites associated with the risk of TBAD, constructed an MRS model, and identified three metabolites that were independently associated with the severity of TBAD. These findings may serve to identify more TBAD-related biomarkers and shed light on exploring potential mechanisms of TBAD.

Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry.

Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.

COVID-19 induces new-onset insulin resistance and lipid metabolic dysregulation via regulation of secreted metabolic factors.

Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism. In this study, we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases, and found new-onset insulin resistance, hyperglycemia, and decreased HDL-C in these patients. Mechanistically, SARS-CoV-2 infection increased the expression of RE1-silencing transcription factor (REST), which modulated the expression of secreted metabolic factors including myeloperoxidase, apelin, and myostatin at the transcriptional level, resulting in the perturbation of glucose and lipid metabolism. Furthermore, several lipids, including (±)5-HETE, (±)12-HETE, propionic acid, and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation, especially in insulin resistance. Taken together, our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19, and further illustrated the underlying mechanisms, providing potential therapeutic targets for COVID-19-induced metabolic complications.

Photoluminescence mechanism of self-activated titanate phosphors investigated by x-ray absorption spectroscopy under UV irradiation.

The electronic states of self-activated titanate phosphors (Ba2TiSi2O8, Sr2TiSi2O8, and Na2TiSiO5) were investigated by Ti K-edge x-ray absorption spectroscopy under ultraviolet (UV) irradiation in order to unveil the photoluminescence mechanism in the absence of particular atomic color centers. The overall spectral features of all samples were identical, main edges and large pre-edges corresponding to the Ti 4p and Ti 3d states, respectively. The pre-edge peak of Sr2TiSi2O8 shifted toward lower energy by 0.2 eV compared with the other two samples, corresponding to a red shift of the photoluminescence spectrum. In the region between these features, a small hump was observed for each sample, which gradually diminishes as a function of UV power. The hump can be attributed to the Ti 4p state based on the calculated electron density of states determined by multiple scattering theory, and this hump serves as a trap for UV-excited electrons.

Gadolinium Retention and Clearance in the Diabetic Brain after Administrations of Gadodiamide, Gadopentetate Dimeglumine, and Gadoterate Meglumine in a Rat Model.

PURPOSE: To evaluate gadolinium (Gd) retention and clearance in the brain of diabetic rats after administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. MATERIALS AND METHODS: Both diabetic rats (n = 52) and normal rats (n = 52) intravenously received 20 injections of 0.6 mmol Gd/kg gadodiamide, gadopentetate dimeglumine, gadoterate meglumine, or saline. Both diabetic rats and normal rats were divided into 2 subgroups of 24 and 28 rats for the 7-day and 42-day evaluations (i.e., they were sacrificed at 7 days (n = 6 per group) and 42 days (n = 7 per group)), respectively, after the last injection. For the 7-day subgroup, 6 rats were euthanized for inductively coupled plasma mass spectrometry (ICP-MS) analysis. For the 42-day subgroup, 6 rats underwent T1-weighted magnetic resonance imaging (MRI) and ICP-MS, and 1 rat was analyzed by transmission electron microscopy (TEM). RESULTS: The T1 enhancements in the deep cerebellar nuclei (DCNs) of diabetic rats were lower than those of normal rats in both linear Gd-based contrast agent (GBCA) groups (p < 0.05). The average Gd concentrations in the brains of diabetic rats were significantly lower than those of healthy rats in both the short-term groups and long-term groups (p < 0.05). The highest Gd retentions were in the olfactory bulb, DCN, and striatum with gadodiamide. Compared with the results obtained 7 days after the last injection, the residual Gd concentrations of the 42-day subgroups in the brains of diabetic rats showed no significant difference in both linear GBCA groups (p>0.05). CONCLUSIONS: Compared with normal rats, the diabetic status decreased the residual Gd concentrations in the brain after multiple administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. The clearable fraction of Gd in the brain was eliminated faster in diabetic rats than in normal rats.

Orexin A affects HepG2 human hepatocellular carcinoma cells glucose metabolism via HIF-1α-dependent and -independent mechanism.

Orexins are hypothalamic neuropeptides that regulate feeding, reward, wakefulness and energy homeostasis. The present study sought to characterize the involvement of orexin A in glucose metabolism in HepG2 human hepatocellular carcinoma cells, and investigated the role of hypoxia-inducible factor-1α (HIF-1α) in the response. HepG2 cells were exposed to different concentrations of orexin A (10-9 to 10-7 M) in vitro, without or with the orexin receptor 1 (OX1R) inhibitor (SB334867), HIF-1α inhibitor (YC-1) or a combination of both inhibitors. Subsequently, OX1R, HIF-1α expression and localization, glucose uptake, glucose transporter 1 (GLUT1) expression and ATP content were measured. We further investigated the intracellular fate of glucose by measuring the gene expression of pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase (LDHA) and pyruvate dehydrogenase B (PDHB), as well as metabolite levels including lactate generation and mitochondrial pyruvate dehydrogenase (PDH) activity. The activity of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was also assessed. Our results showed that the expression of OX1R was predominantly located in the nucleus in HepG2 cells. Orexin A oxygen-independently promoted the mRNA and protein expression of HIF-1α as well as its nuclear accumulation in HepG2 cells and the elevated HIF-1α protein was associated, at least partly, with the activation of the PI3K/Akt/mTOR pathway. Orexin A stimulated GLUT1 expression, glucose uptake as well as ATP generation in HepG2 cells via OX1R acting through the HIF-1α pathway. Moreover, orexin A inhibited LDHA, PDK1 expression and lactate production, stimulated PDHB expression and PDH enzyme activity independent of HIF-1α. Our results indicated that orexin signaling facilitated the glucose flux into mitochondrial oxidative metabolism rather than glycolysis in HepG2 cells. These findings provide new insight into the regulation of glucose metabolism by orexin A in hepatocellular carcinoma cells.