Maillard Reaction Inspired Microexplosion toward Fast Synthesis of Two-Dimensional Mesoporous Tin Oxides for Efficient Chemiresistive Gas Sensing.

Two-dimensional (2D) mesoporous transition metal oxides are highly desired in various applications, but their fast and low-cost synthesis remains a great challenge. Herein, a Maillard reaction inspired microexplosion approach is applied to rapidly synthesize ultrathin 2D mesoporous tin oxide (mSnO2). During the microexplosion between granular ammonia nitrate with melanoidin at high temperature, the organic species can be carbonized and expanded rapidly due to the instantaneous release of gases, thus producing ultrathin carbonaceous templates with rich functional groups to effectively anchor SnO2 nanoparticles on the surface. The subsequent removal of carbonaceous templates via calcination in air results in the formation of 2D mSnO2 due to the confinement effect of the templates. Pd nanoparticles are controllably deposited on the surface of 2D mSnO2 via in situ reduction, forming ultrathin 2D Pd/mSnO2 nanocomposites with thicknesses of 6-8 nm. Owing to the unique 2D mesoporous structure with rich oxygen defects and highly exposed metal-metal oxide interfaces, 2D Pd/mSnO2 exhibits excellent sensing performance toward acetone with high sensitivity, a short response time, and good selectivity under low working temperature (100 °C). This fast and convenient microexplosion synthesis strategy opens up the possibility of constructing 2D porous functional materials for various applications including high-performance gas sensors.

The arachidonic acid metabolome reveals elevation of prostaglandin E2 biosynthesis in colorectal cancer.

Arachidonic acid metabolites are a family of bioactive lipids derived from membrane phospholipids. They are involved in cancer progression, but arachidonic acid metabolite profiles and their related biosynthetic pathways remain uncertain in colorectal cancer (CRC). To compare the arachidonic acid metabolite profiles between CRC patients and healthy controls, quantification was performed using a liquid chromatography-mass spectrometry-based analysis of serum and tissue samples. Metabolomics analysis delineated the distinct oxidized lipids in CRC patients and healthy controls. Prostaglandin (PGE2)-derived metabolites were increased, suggesting that the PGE2 biosynthetic pathway was upregulated in CRC. The qRT-PCR and immunohistochemistry analyses showed that the expression level of PGE2 synthases, the key protein of PGE2 biosynthesis, was upregulated in CRC and positively correlated with the CD68+ macrophage density and CRC development. Our study indicates that the PGE2 biosynthetic pathway is associated with macrophage infiltration and progression of CRC tumors.

Cholesterol-Modified DNA Nanostructures Serve as Effective Non-Viral Carriers for Delivering siRNA to the Kidneys to Prevent Acute Kidney Injury.

With the emergence of gene therapy utilizing viral vectors, the potential risks associated with these vectors have prompted increased attention toward non-viral alternatives. DNA nanotechnology enables the assembly of specific oligonucleotide chains into nanostructures possessing defined spatial configurations. Due to their inherent characteristics, DNA nanostructures possess natural advantages as carriers for regulating gene expression in a non-viral manner. Cholesterol modification can convert DNA nanostructures from hydrophilic materials to amphiphilic materials, thereby extending their systemic circulation time. In this study, the high-dimensional design and cholesterol modification are shown to prolong the systemic circulation half-life of DNA nanostructures in mice. Specifically, the tetrahedron structure modified with three cholesterol molecules (TDN-3Chol) exhibit excellent circulation time and demonstrate a preference for renal uptake. The unique characteristics of TDN-3Chol can effectively deliver p53 siRNA to the mouse renal tubular tissue, resulting in successful knockdown of p53 and demonstrating its potential for preventing acute kidney injury. Furthermore, TDN-3Chol is not exhibited significant toxicity in mice, highlighting its promising role as a non-viral vector for targeted gene expression regulation in the kidneys. The designed non-viral vector as a prophylactic medication shows potential in addressing the current clinical challenges associated with nephrotoxic drugs.

Efficacy and safety of caffeic acid tablets in the treatment of thrombocytopenia: A systematic review and meta-analysis.

BACKGROUND: Caffeic acid tablets (CFA) are a proprietary Chinese medicine in treating thrombocytopenia. The efficacy and safety of CFA compared with other platelet-raising drugs for the treatment of thrombocytopenia have been widely reported in the literature, but there is no systematic evaluation. Therefore, we designed this meta-analysis to further establish the efficacy and safety of CFA in treating thrombocytopenia. METHODS: A computerized search was conducted in the Chinese biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, Chinese Scientific Journal Database (VIP), PubMed, and Web of Science databases using the keywords "caffeic acid tablets" and "thrombocytopenia." All randomized controlled trials were selected for the timeframe of build to 02/2023 and then screened and analyzed using RevMan 5.4 and stata17.0 software. RESULTS: A total of 35 publications with an overall 2533 patients were included in the study. The results of the meta-analysis showed that CFA were effective in the treatment of thrombocytopenia with a statistically significant difference [relative risk ratio (RR) = 1.24, 95% CI (1.17, 1.31), P < .00001] and in increasing platelet counts [standardized mean difference (SMD) = 1.50, 95% CI (1.09, 1.91), P < .00001], white blood cell count [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001], and neutrophil count [SMD = 0.73, 95% CI (0.19, 1.28), P = .009], and CFA reduced myelosuppression [RR = 0.19, 95% CI (0.1, 0.37), P < .00001] and adverse effects [RR = 0.75, 95% CI (0.58, 0.96), P = .02]. CONCLUSION: CFA can effectively improve the clinical outcome of patients with thrombocytopenia with a good safety profile and are worth promoting. However, due to the low quality and small sample size of the included literature, a larger sample size and more standardized, high-quality studies are needed to validate these results.

Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion.

Immunoregulatory B cells impede antitumor immunity through unknown features and mechanisms. We report the existence of leucine-tRNA-synthase-2 (LARS2)-expressing B cell (LARS B) subset with a transforming growth factor-ß1 (TGF-ß1)-dominant regulatory feature in both mouse and human progressive colorectal cancer (CRC). Of note, LARS B cells exhibited a leucine nutrient preference and displayed active mitochondrial aminoacyl-tRNA biosynthesis. They were located outside the tertiary lymphoid structure and correlated with colorectal hyperplasia and shortened survival in CRC patients. A leucine diet induced LARS B cell generation, whereas LARS B cell deletion by Lars2 gene ablation or leucine blockage repressed CRC immunoevasion. Mechanistically, LARS2 programmed mitochondrial nicotinamide adenine dinucleotide (NAD+) regeneration and oxidative metabolism, thus determining the regulatory feature of LARS B cells in which the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was involved. We propose a leucine-dieting scheme to inhibit LARS B cells, which is safe and useful for CRC therapy.

Diagnostic value of serum sphingolipids in patients with colorectal cancer.

Background: Abnormal lipid metabolism affects the regulation of tumor progression, though use of serum lipids and sphingolipids for disease progression identification is uncertain. Methods: Serum samples from 51 healthy volunteers and 76 patients were collected and analyzed by liquid chromatography tandem mass spectrometry. Results: Levels of serum total cholesterol and high-density lipoprotein were significantly lower in colorectal cancer patients. Multivariate analysis demonstrated distinct sphingolipid profiles between healthy individuals and patients. Of 106 sphingolipids, 15 metabolites that showed statistical significance were selected, and receiver operating characteristic analysis of these metabolites yielded an area under the curve of 0.868 to 0.9 by machine learning algorithms for distinguishing colorectal cancer from a healthy status. Conclusions: Healthy individuals, polyps patients and colorectal cancer patients have different serum sphingolipid signatures. Serum sphingolipids might be used as biomarkers for early detection or prediction of colorectal cancer.

Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis.

BACKGROUND & AIMS: The liver is a metabolically active organ and is also 'tolerogenic', exhibiting sophisticated mechanisms of immune regulation that prevent pathogen attacks and tumorigenesis. How metabolism impacts the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains understudied. METHODS: We investigated the role of the metabolic regulator SIRT5 in HCC development by conducting metabolomic analysis, gene expression profiling, flow cytometry and immunohistochemistry analyses in oncogene-induced HCC mouse models and human HCC samples. RESULTS: We show that SIRT5 is downregulated in human primary HCC samples and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, via hypersuccinylation and increased BA biosynthesis in the peroxisomes of hepatocytes. BAs act as a signaling mediator to stimulate their nuclear receptor and promote M2-like macrophage polarization, creating an immunosuppressive TME that favors tumor-initiating cells (TICs). Accordingly, high serum levels of taurocholic acid correlate with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in HCC patient samples. Finally, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency in promoting M2-like polarized TAMs and liver tumor growth. CONCLUSIONS: This study uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC development. Our results also suggest a potential strategy of using clinically proven BA sequestrants for the treatment of patients with HCC, especially those with decreased SIRT5 and abnormally high BAs. LAY SUMMARY: Hepatocellular caricinoma (HCC) development is closely linked to metabolic dysregulation and an altered tumor microenvironment. Herein, we show that loss of the metabolic regulator Sirt5 promotes hepatocarcinogenesis, which is associated with abnormally elevated bile acids and subsequently an immunosuppressive microenvironment that favors HCC development. Targeting this mechanism could be a promising clinical strategy for HCC.

FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for bacterial elimination.

Macrophages rapidly undergo glycolytic reprogramming in response to macroautophagy/autophagy, inflammasome activation and pyroptosis for the clearance of bacteria. Identification the key molecules involved in these three events will provide critical potential therapeutic applications. Upon S. typhimurium infection, FLT4/VEGFR3 and its ligand VEGFC were inducibly expressed in macrophages, and FLT4 signaling inhibited CASP1 (caspase 1)-dependent inflammasome activation and pyroptosis but enhanced MAP1LC3/LC3 activation for elimination of the bacteria. Consistently, FLT4 mutants lacking the extracellular ligand-binding domain increased production of the proinflammatory metabolites such as succinate and lactate, and reduced antimicrobial metabolites including citrate and NAD(P)H in macrophages and liver upon infection. Mechanistically, FLT4 recruited AMP-activated protein kinase (AMPK) and phosphorylated Y247 and Y441/442 in the PRKAA/alpha subunit for AMPK activation. The AMPK agonist AICAR could rescue glycolytic reprogramming and inflammasome activation in macrophages expressing the mutant FLT4, which has potential translational application in patients carrying Flt4 mutations to prevent recurrent infections. Collectively, we have elucidated that the FLT4-AMPK module in macrophages coordinates glycolytic reprogramming, autophagy, inflammasome activation and pyroptosis to eliminate invading bacteria.Abbreviations: 3-MA: 3-methyladenine; AICAR: 5-aminoimidazole-4-carboxamide1-ß-D-ribofuranoside; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; BMDM: bone marrow-derived macrophage; CASP1: caspase 1; CFUs: colony-forming units; FLT4/VEGFR3: FMS-like tyrosine kinase 4; GFP: green fluorescent protein; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PEM: peritoneal exudate macrophage; PRKAA1/AMPKα1: protein kinase, AMP-activated, alpha 1 catalytic subunit; PYCARD/ASC: PYD and CARD domain containing; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TLR4: toll-like receptor 4; ULK1: unc-51 like autophagy activating kinase 1; VEGFC: vascular endothelial growth factor C; WT: wild type.

Metabolomics analysis provides new insights into the medicinal value of flavonoids in tobacco leaves.

Tobacco is a traditional Chinese medicine containing a variety of biologically active substances. In addition to being used to make cigarettes, tobacco is also a vastly underdeveloped medicinal resource. In order to identify and clarify the biological activities and medicinal value of tobacco leaves, the metabolomes of tobacco leaves were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) based on multiple reaction monitoring (MRM). In total, 1169 metabolites were identified and quantified. The results showed that the metabolic profiles of the tobacco cultivars K326 and Yun87 are similar to each other but different from that of Hongda. Moreover, the curing process affects the metabolic profiles of tobacco leaves. Flavonoids are the largest class of metabolites in tobacco leaves. Flavonoids have multiple biological functions; for example, they can promote or inhibit inflammation. We found that quercetin provides anti-inflammatory activity by inhibiting the il-1ß mRNA expression, while glycitin and neohesperidin can promote il-1ß and il-6 production. Our results provide in-depth insights into the medical uses and biological mechanisms of tobacco leaves.

Microarray investigation of glycan remodeling during macrophage polarization reveals α2,6 sialic acid as an anti-inflammatory indicator.

Glycosylation is a widely occurring posttranslational modification. Here, we applied a quick, convenient and high-throughput strategy (lectin array) to investigate the variation in glycans on different macrophage subtypes derived from THP-1 and RAW264.7 cells. For THP-1 cells, there were more significant differences in the glycan on M2 macrophages compared to the other two subtypes. In contrast, M1 macrophages exhibited more significant glycan remodeling than the other subtypes for the RAW264.7 cell line. The response of the lectins which recogonize the N-glycan and α2,6 sialic acid was higher during polarization into anti-inflammatory phase (THP-1 derived M2 subtypes), and lower in pro-inflammatory phase (RAW264.7 M1 subtypes). The regulation of several α2,6 sialyltransferase genes was coincident with the regulation of the α2,6 sialic acid on the two cell lines. The lectin response and glycosyltranferase gene expression confirmed that α2,6 sialic acid showed higher expression in the anti-inflammatory phase. This indicated that α2,6 sialic acid was a potential indicator for the anti-inflammatory response.

SIRT5 Contributes to Colorectal Cancer Growth by Regulating T Cell Activity.

Over the past several years, SIRT5 has attracted considerable attention in metabolic regulation. However, the function of SIRT5 in tumorigenesis by regulating tumor microenvironment is poorly understood. In this work, we found that Sirt5 knockout mice were resistant to AOM and DSS-induced colitis-associated colorectal tumorigenesis and the level of IFN-γ in their tumor microenvironment was higher. Additionally, proteome and network analysis revealed that SIRT5 was important in the T cell receptor signaling pathway. Furthermore, we determined that a deficiency of Sirt5 induced stronger T cell activation and demonstrated that SIRT5 played a pivotal role in regulating the differentiation of CD4+ regulatory T (Treg) cells and T helper 1 (Th1) cells. An imbalance in the lineages of immunosuppressive Treg cells and the inflammatory Th1 subsets of helper T cells leads to the development of colon cancer. Our results revealed a regulatory role of SIRT5 in T cell activation and colorectal tumorigenesis.

Deceleration of glycometabolism impedes IgG-producing B-cell-mediated tumor elimination by targeting SATB1.

B lymphocytes, known as antibody producers, mediate tumor cell destruction in the manner of antibody-dependent cell-mediated cytotoxicity; however, their anti-tumor function seems to be weakened during tumorigenesis, while the underlying mechanisms remain unclear. In this study, we found that IgG mediated anti-tumor effects, but IgG-producing B cells decreased in various tumors. Considering the underlying mechanism, glycometabolism was noteworthy. We found that tumor-infiltrating B cells were glucose-starved and accompanied by a deceleration of glycometabolism. Both inhibition of glycometabolism and deprivation of glucose through tumor cells, or glucose-free treatment, reduced the differentiation of B cells into IgG-producing cells. In this process, special AT-rich sequence-binding protein-1 (SATB1) was significantly silenced in B cells. Down-regulating SATB1 by inhibiting glycometabolism or RNA interference reduced the binding of signal transducer and activator of transcription 6 (STAT6) to the promoter of germline Cγ gene, subsequently resulting in fewer B cells producing IgG. Our findings provide the first evidence that glycometabolic inhibition by tumorigenesis suppresses differentiation of B cells into IgG-producing cells, and altering glycometabolism may be promising in improving the anti-tumor effect of B cells.

mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells.

Immune cell activation occurs concurrently with metabolic reprogramming. As important components of the tumor microenvironment, monocytic myeloid-derived suppressor cells (M-MDSCs) are featured by their potent immunosuppressive abilities on anti-tumor effector cells. However, little is known about the contribution of metabolic adaptations to their suppressive roles. In this study, we found that tumor-infiltrating M-MDSCs had the same phenotype with splenic M-MDSCs. Compared with splenic M-MDSCs, tumor-infiltrating M-MDSCs exhibited stronger suppressive activities which was accompanied by higher glycolysis. Inhibition of glycolysis impaired the suppressive function of tumor M-MDSCs. Meanwhile, the results demonstrated that mTOR was responsible for this function regulation. mTOR inhibition by rapamycin decreased the glycolysis and reduced the suppressive activities of these cells. Furthermore, rapamycin treatment inhibited the tumor growth and reduced the percentage of M-MDSCs in 3LL tumor bearing mice. These results demonstrated that modulation of metabolism in immune cells can be an effective way to enhance anti-tumor effects.

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid ß-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

SIRT5 Desuccinylates and Activates Pyruvate Kinase M2 to Block Macrophage IL-1ß Production and to Prevent DSS-Induced Colitis in Mice.

LPS-activated macrophages undergo a metabolic shift from dependence on mitochondria-produced ATP to reliance on aerobic glycolysis, where PKM2 is a critical determinant. Here, we show that PKM2 is a physiological substrate of SIRT5 and that SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. Moreover, a succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. Furthermore, we show that SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1α is formed at the promoter of IL-1ß gene in LPS-stimulated macrophages. Activation of PKM2 using TEPP-46 attenuates Sirt5-deficiency-mediated IL-1ß upregulation in LPS-stimulated macrophages. Finally, we find that Sirt5-deficient mice are more susceptible to DSS-induced colitis, which is associated with Sirt5 deficiency prompted PKM2 hypersuccinylation and boosted IL-1ß production. In conclusion, our findings reveal a mechanism by which SIRT5 suppresses the pro-inflammatory response in macrophages at least in part by regulating PKM2 succinylation, activity, and function.

Quantitative profiling of glycerophospholipids during mouse and human macrophage differentiation using targeted mass spectrometry.

Macrophage lipid metabolism plays a pivotal role in innate and adaptive immune responses. Previous studies have shown that this process plays a role in infections and contributes to the pathogenesis of diabetes, atherosclerosis, and other immunometabolic diseases. M1 macrophages, or classically activated macrophages, are key players in the defense against bacterial infections. M2 macrophages, or alternatively activated macrophages, are involved in anti-inflammatory responses. Using the multiple reaction monitoring method, we identified changes in lipid composition during the differentiation of human and murine macrophages. We detected over 300 lipid molecules in mammalian macrophages, and we observed a striking shift in the composition of glycerophospholipids (GLs) from saturated and monounsaturated to polyunsaturated during human macrophage polarization. Moreover, M2 macrophages showed a higher level of lysophospholipids (lysoGLs) than did M1 macrophages. The lysoPI species increased in human and mouse M2 macrophages, suggesting that they may be involved in M2 macrophage polarization and anti-inflammatory processes. Collectively, these results indicate that lipids may play a role in the pro- and anti-inflammatory activities of macrophages and may be markers of the macrophage activation state.

Mapping and analyzing the human liver proteome: progress and potential.

INTRODUCTION: The liver is an important organ in humans. Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world. Progress in the Human Liver Proteome Project (HLPP) has improved understanding of the liver and the liver cancer proteome. AREAS COVERED: Here, we summarize the recent progress in liver proteome modification profiles, proteomic studies in liver cancer, proteomic study in the search for novel liver cancer biomarkers and drug targets, and progress of the Chromosome Centric Human Proteome Project (CHPP) in the past five years in the Institutes of Biomedical Sciences (IBS) of Fudan University. Expert commentary: Recent advances and findings discussed here provide great promise of improving the outcome of patients with liver cancer.

SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense.

Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5-dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation.

ASPP1/2-PP1 complexes are required for chromosome segregation and kinetochore-microtubule attachments.

Regulated interactions between kinetochores and spindle microtubules are critical for maintaining genomic stability during chromosome segregation. Defects in chromosome segregation are widespread phenomenon in human cancers that are thought to serve as the fuel for tumorigenic progression. Tumor suppressor proteins ASPP1 and ASPP2, two members of the apoptosis stimulating proteins of p53 (ASPP) family, are frequently down-regulated in human cancers. Here we report that ASPP1/2 are required for proper mitotic progression. In ASPP1/2 co-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in persistent spindle assembly checkpoint (SAC) activation. Using protein affinity purification methods, we searched for functional partners of ASPP1/2, and found that ASPP1/2 were associated with a subset of kinetochore proteins (Hec1, KNL-1, and CENP-F). It was found that ASPP1/2 act as PP1-targeting subunits to facilitate the interaction between PP1 and Hec1, and catalyze Hec1 (Ser165) dephosphorylation during late mitosis. These observations revealed a previously unrecognized function of ASPP1/2 in chromosome segregation and kinetochore-microtubule attachments that likely contributes to their roles in chromosome stability and tumor suppression.