Effects of Maillard reaction and its product AGEs on aging and age-related diseases

Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction products(MRPs)found in some food for health and storage application have appeared,however,the MR occurring in human physiological environment can produce advanced glycation end products(AGEs)by non-enzymatic modification of macromolecules such as proteins,lipids and nucleic acid,which could change the structure and functional activity of the molecules themselves.In this review,we take AGEs as our main object,on the one hand,discuss physiologic aging,that is,age-dependent covalent cross-linking and modification of proteins such as collagen that occur in eyes and skin containing connective tissue.On the other hand,pathological aging associated with autoimmune and inflammatory diseases,neurodegenerative diseases,diabetes and diabetic nephropathy,cardiovascular diseases and bone degenerative diseases have been mainly proposed.Based on the series of adverse effects of accelerated aging and disease pathologies caused by MRPs,the possible harm caused by some MR can be slowed down or inhibited by artificial drug intervention,dietary pattern and lifestyle control.It also stimulates people's curiosity to continue to explore the potential link between the MR and human aging and health,which should be paid more attention to for the development of life sciences.

超临界CO_(2)大展身手的时代

超临界二氧化碳(scCO_(2))是二氧化碳的一种物态(临界温度及临界压力以上),超临界流体技术在我国已经成为了重要的研究领域和新学科生长点。本文通过拟人化的手法,介绍了超临界二氧化碳的定义、优点、应用以及发展前景,同时也介绍了部分物理化学原理,帮助读者学习超临界二氧化碳的相关知识。

Regulation of phenylpropanoid biosynthesis by MdMYB88 and MdMYB124 contributes to pathogen and drought resistance in apple

MdMYB88 and MdMYB124 have been demonstrated to be responsible for lignin accumulation in apple under drought stress.In this study,using a metabolomic approach,we identified differentially accumulated phenylpropanoid and flavonoid metabolites in MdMYB88/124 transgenic RNAi plants under control and long-term drought stress conditions in apple roots.We confirmed the regulation of phenylalanine by MdMYB88 and MdMYB124 via UPLC-MS in apple roots under both control and drought conditions.Using Electrophoretic Mobility Shift Assay(EMSA)and ChIPquantitative PCR(qPCR)analyses,we found that MdMYB88 positively regulates the MdCM2 gene,which is responsible for phenylalanine biosynthesis,through binding to its promoter region.Under long-term drought conditions,MdMYB88/124 RNAi plants consistently accumulated increased amounts of H2O2 and MDA,while MdMYB88 and MdMYB124 overexpression plants accumulated decreased amounts of H2O2 and MDA.We also examined the accumulation of metabolites in the phenylpropanoid biosynthesis pathway in the leaves of MdMYB88 and MdMYB124 transgenic apple plants after long-term drought stress.We found that metabolites responsible for plant defense,including phenylpropanoids and flavonoids,accumulated less in the RNAi plants but more in the overexpression plants under both control and drought conditions.We further demonstrated that MdMYB88/124 RNAi plants were more sensitive to Alternaria alternata f.sp.mali and Valsa mali,two pathogens that currently severely threaten apple production.In contrast,MdMYB88 and MdMYB124 overexpression plants were more tolerant to these pathogens.The cumulative results of this study provided evidence for secondary metabolite regulation by MdMYB88 and MdMYB124,further explained the molecular roles of MdMYB88 and MdMYB124 in drought resistance,and provided information concerning molecular aspects of their roles in disease resistance.

Ellagic acid ameliorates cisplatin-induced acute kidney injury by regulating inflammation and SIRT6/TNF-α signaling

De spite cisplatin has been widely used in the treatment of various cancers,the noteworthy nephrotoxicity greatly constrained its clinical value.For this reason,finding novel targeted therapies to attenuate the nephrotoxicity of cisplatin should be pretty significant.Our previous study found that histone deacetylase sirtuin 6(SIRT6)could be an ideal target for the treatment of cisplatin-induced acute kidney injury.In this study,we explored the protective effects of ellagic acid,a natural polyphenol compound that activates SIRT6,on cisplatin-induced nephrotoxicity.Pre-treatment of ellagic acid attenuated cytotoxicity of cisplatin in primary renal cells and TCMK-1 cells.Moreover,ellagic acid ameliorated renal dysfunction,apoptosis and fibrosis induced by cisplatin in mice.Furthermore,ellagic acid reduced nephrotoxicity-associated inflammatory factor interleukin(IL)-1βand IL-6 expression both in vitro and in vivo.Mechanistically,ellagic acid reversed cisplatin-reduced SIRT6 expression and diminished cisplatin-induced tumor necrosis factor(TNF)-αexpression.And SIRT6 knockdown abrogated the protective effects of ellagic acid on cisplatin-induced cell apoptosis,indicating the renal-protective effects of ellagic acid are mainly dependent on ellagic acid-mediated SIRT6 activation.Our results provide preclinical rationale for using ellagic acid as a feasible and promising agent to ameliorate cisplatin-induced acute kidney injury,and support ellagic acid as a potential adjunctive therapy for future cancer treatment.

High-starchy carbohydrate diet aggravates NAFLD by increasing fatty acids influx mediated by NOX2

Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.

Carbon-Based Electrode Materials for Supercapacitor： Progress, Challenges and Prospective Solutions

Carbon-based materials are typical and commercially active electrode for supercapacitors due to their advantages such as low cost, good stability and easy availability. In the light of energy storage, supercapacitors mechanism is classified into EDLCs （electrochemical double layer capacitors） and pseudocapacitors. Multidimensional carbon nanomaterials （active carbon, carbon nanotube, graphene, etc.）, carbon-based composite and corresponding electrolyte are the critical and important factor in the eyes of researcher. In this minireview, we will discuss the storage mechanism and summarize recent developed novel carbon and carbon-based materials in supercapacitors. The techniques to design the novel nanostructure and high performance electrodematerials that facilitate charge transfer to achieve high energy and power densities will also be discussed.

Multiple rapid-responsive probes for hypochlorite detection based on dioxetane luminophore derivatives

In recent years,various methods for detecting exogenous and endogenous hypochlorite have been studied,considering its essential role as a biomolecule.However,the existing technologies still pose obstacles such as their invasiveness,high costs,and complicated operation.In the current study,we developed a glow-type chemiluminescent probe,hypochlorite chemiluminescence probe(HCCL)-1,based on the scaffold of Schaap's 1,2-dioxetane luminophores.To better explore the physiological and pathological functions of hypochlorite,we modified the luminophore scaffold of HCCL-1 to develop several probes,including HCCL-2,HCCL-3,and HCCL-4,which amplify the response signal of hypochlorite.By comparing the luminescent intensities of the four probes using the IVIS®system,we determined that HCCL-2 with a limit of detection of 0.166 mM has enhanced sensitivity and selectivity for tracking hypochlorite both in vitro and in vivo.

Water quality characteristics and assessment of Yongding New River by improved comprehensive water quality identification index based on game theory

The Yongding New River is essential for the water supplies of Tianjin.To date,there is no comprehensive report that assesses the year-round water quality of the Yongding New River Main stream.Moreover,little attention has been given to determining a combined weight for improving the traditional comprehensive water quality identification index(ICWQII)by the game theory.Seven water quality parameters were investigated monthly along the main stream of the Yongding New River from May 2018 to April 2019.Organic contaminants and nitrogen pollution were mainly caused by point sources pollution,and the total phosphorus mainly by non-point source pollution.Dramatic spatio-temporal variations of water quality parameters were jointly caused by different pollutant sources and hydrometeorological factors.In terms of this study,an improved comprehensive water quality identification index(ICWQII)based on entropy weight or variation coefficient and traditional CWQII underestimated the water qualities,and an ICWQII based on the superstandard multiple method overvalued the assessments.By contrast,water qualities assessments done with an ICWQII based on the game theory matched perfectly with the practical situation.The ICWQII based on game theory proposed in this study takes into account not only the degree of disorder and variation of water quality data,but also the influence of standard-exceeded pollution indicators,whose results are relatively reasonable.All findings and the ICWQII based on game theory can provide scientific support for decisions related to the water environment management of the Yongding New River and other waters.

Zebrafish hhex-null mutant develops an intrahepatic intestinal tube due to de-repression of cdx1b and pdx1

The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder, and pancreatic duct. Haematopoietically expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD;however, the molecular mechanism remains elusive. Here, we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The hepatobiliary duct part of the mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty acid-binding protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 are expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 could restore the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis showed that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b, Pdx1, and Sox9b form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

Hepatocytes in a normal adult liver are derived solely from the embryonic hepatocytes

In vertebrates,body weight increases many folds as a consequence of body growth from the childhood to adulthood（e.g.,～20 folds for a mouse）.Considering the fact that the liver-to-body weight ratio（LBR）stays relatively constant within species（Weglarz and Sandgren,2000;Kan et al.,2009）,the cell number in a liver must therefore keep increasing along with the growth of an individual organism. For example, during the growth of the zebrafish from 5 days post-fertilization （dpf） to 1.5 years old, the number of liver cells increased -900 folds （Figs. 1A and S1 ）.

Ample dietary fat reduced the risk of primary vesical calculi by inducing macrophages to engulf budding crystals in mice

Although primary vesical calculi is an ancient disease,the mechanism of calculi formation remains unclear.In this study,we established a novel primary vesical calculi model with D,L-choline tartrate in mice.Compared with commonly used melamine and ethylene glycol models,our model was the only approach that induced vesical calculi without causing kidney injury.Previous studies suggest that proteins in the daily diet are the main contributors to the prevention of vesical calculi,yet the effect of fat is overlooked.To assay the relationship of dietary fat with the formation of primary vesical calculi,D,L-choline tartrate-treated mice were fed a high-fat,low-fat,or normal-fat diet.Genetic changes in the mouse bladder were detected with transcriptome analysis.A high-fat diet remarkably reduced the morbidity of primary vesical calculi.Higher fatty acid levels in serum and urine were observed in the high-fat diet group,and more intact epithelia in bladder were observed in the same group compared with the normal-and low-fat diet groups,suggesting the protective effect of fatty acids on bladder epithelia to maintain its normal histological structure.Transcriptome analysis revealed that the macrophage differentiation-related gene C-X-C motif chemokine ligand 14(Cxcl14)was upregulated in the bladders of high-fat diet-fed mice compared with those of normal-or low-fat diet-fed mice,which was consistent with histological observations.The expression of CXCL14 significantly increased in the bladder in the high-fat diet group.CXCL14 enhanced the recruitment of macrophages to the crystal nucleus and induced the transformation of M2 macrophages,which led to phagocytosis of budding crystals and prevented accumulation of calculi.In human bladder epithelia(HCV-29)cells,high fatty acid supplementation significantly increased the expression of CXCL14.Dietary fat is essential for the maintenance of physiological functions of the bladder and for the prevention of primary vesical calculi,which provides new ideas for the reduction of morbidity of primary vesical calculi.

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH treatment.The crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.

Spatiotemporal optical properties of dissolved organic matter in a sluice-controlled coastal plain river with both salinity and trophic gradients

Due to the combined effect of sluices and sea tide,the sluice-controlled coastal plain river would be characterized by both trophic state and salinity gradients,affecting the spatiotemporal optical properties of dissolved organicmatter(DOM).In this study,we investigated the spatiotemporal variation of water quality parameters and optical properties of DOM in the Haihe River,a representative sluice-controlled coastal plain river in Tianjin,China.A significant salinity gradient and four trophic states were observed in the water body of the Haihe River.Two humic-and one protein-like substances were identified from the DOM by the three-dimensional fluorescence spectra combined with the parallel factor(PARAFAC)analysis.Pearson’s correlation analysis and redundancy analysis(RDA)showed that the salinity significantly affected the abundance of chromophoric DOM(CDOM)but did not cause significant changes in the fluorescence optical characteristics.In addition,the effect of Trophic state index(TSI)on the CDOM abundance was greater than that on the fluorescence intensity of fluorescent dissolved organic matter(FDOM).In the water body with both salinity and trophic state gradients,TSI posed a greater influence than salinity on the CDOM abundance.Our results fill the research gap in spatiotemporal DOM characteristics and water quality variation in water bodies with both salinity and trophic state gradients.These results are beneficial for clarifying the joint influence of saline intrusion and sluices on the DOM characteristics and water quality in sluice-controlled coastal plain rivers.

Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore,overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment.Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicininduced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice.These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

Cdx1b protects intestinal cell fate by repressing signaling networks for liver specification

In mammals,the expression of the homeobox family member Cdx2/CDX2 is restricted within the intestine.Conditional ablation of the mouse Cdx2 in the endodermal cells causes a homeotic transformation of the intestine towards the esophagus or gastric fate.In this report,we show that null mutants of zebrafish cdx1b,encoding the counterpart of mammalian CDX2,could survive more than 10 days post fertilization,a stage when the zebrafish digestive system has been well developed.Through RNA sequencing(RNA-seq)and single-cell sequencing(sc RNA-seq)of the dissected intestine from the mutant embryos,we demonstrate that the loss-of-function of the zebrafish cdx1b yields hepatocyte-like intestinal cells,a phenotype never observed in the mouse model.Further RNA-seq data analysis,and genetic double mutants and signaling inhibitor studies reveal that Cdx1b functions to guard the intestinal fate by repressing,directly or indirectly,a range of transcriptional factors and signaling pathways for liver specification.Finally,we demonstrate that heat shock-induced overexpression of cdx1b in a transgenic fish abolishes the liver formation.Therefore,we demonstrate that Cdx1b is a key repressor of hepatic fate during the intestine specification in zebrafish.

A specific and selective chemiluminescent probe for Pd^(2+) detection

As an important transition metal catalyst, palladium is extensively used in many areas including electronics industry, petroleum industry, automobile industry and fine chemicals engineering. However,it brings harm to the environment as well as people's health. Herein, we managed to introduce a butynyl group to 1,2-dioxetane developing a reaction-based chemiluminescent probe as well as an imaging approach for monitoring palladium(II). Exhibiting enhanced total flux in Pd2+enriched areas, palladium chemiluminescent probe(PCL) may afford potential utility for detecting Pd2+in vitro, in cellulo and in vivo.

A lightweight cryptographic algorithm for the transmission of images from road environments in self-driving

With the large-scale application of 5G in industrial production,the Internet of Things has become an important technology for various industries to achieve efficiency improvement and digital transformation with the help of the mobile edge computing.In the modern industry,the user often stores data collected by IoT devices in the cloud,but the data at the edge of the network involves a large of the sensitive information,which increases the risk of privacy leakage.In order to address these two challenges,we propose a security strategy in the edge computing.Our security strategy combines the Feistel architecture and short comparable encryption based on sliding window(SCESW).Compared to existing security strategies,our proposed security strategy guarantees its security while significantly reducing the computational overhead.And our GRC algorithm can be successfully deployed on a hardware platform.

FAP senescence:a critical event in muscle regeneration

In a recent study published in Nature,Moiseeva and colleagues examined senescent cells,including fibro/adipogenic progenitors(FAPs),muscle stem cells(MuSCs)and macrophages,which generate an inflammatory and fibrotic niche,thus inhibiting the activation of MuSCs and muscle regeneration.1 The researchers developed a method to distinguish endogenous senescent cells and showed the importance of cellular senescence as a potential target for improving muscle regeneration and repair(Fig.1).^(1)

A lightweight cryptographic algorithm for the transmission of images from road environments in self-driving

With the large-scale application of 5G in industrial production,the Internet of Things has become an important technology for various industries to achieve efficiency improvement and digital transformation with the help of the mobile edge computing.In the modern industry,the user often stores data collected by IoT devices in the cloud,but the data at the edge of the network involves a large of the sensitive information,which increases the risk of privacy leakage.In order to address these two challenges,we propose a security strategy in the edge computing.Our security strategy combines the Feistel architecture and short comparable encryption based on sliding window(SCESW).Compared to existing security strategies,our proposed security strategy guarantees its security while significantly reducing the computational overhead.And our GRC algorithm can be successfully deployed on a hardware platform.