Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in a Macrophage-Specific and Liver-Specific Manner

Nonalcoholic steatohepatitis(NASH)may soon become the leading cause of end-stage liver disease worldwide with limited treatment options.Liver fibrosis,which is driven by chronic inflammation and hepatic stellate cell(HSC)activation,critically determines morbidity and mortality in patients with NASH.Pyruvate kinase M2(PKM2)is involved in immune activation and inflammatory liver diseases;however,its role and therapeutic potential in NASH-related fibrosis remain largely unexplored.Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells(NPCs),especially macrophages,in the livers of patients with fibrotic NASH.Macrophage-specific PKM2 knockout(PKM2^(FL/FL)LysM-Cre)significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine-and choline-deficient(MCD)diet,a high-fat high-cholesterol(HFHC)diet,and a western diet plus weekly carbon tetrachloride injection(WD/CCl_(4)).Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6C^(high) macrophage infiltration.Mechanistically,PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3(NLRP3)activation in proinflammatory macrophages,which induced HSC activation and fibrogenesis.A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo.Translationally,ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides,a novel oligonucleotide drug that preferentially accumulates in the liver,dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity.The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis.Thus,therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

左归复方对MKR转基因2型糖尿病鼠PPARγ表达的影响

目的观察左归复方(滋阴益气活血解毒组方)干预治疗MKR小鼠后,糖代谢及PPARγ在肝脏、骨骼肌和脂肪组织中的表达变化。方法取MKR小鼠40只,经鉴定后随机分为MKR模型组、左归复方高、低剂量组、文迪雅组(阳性药对照组),每组10只,C57野生鼠10只作为空白对照组。各药物组分别以相应剂量连续给药30d。末次给药后0.5h,空腹测定血糖;心脏取血,放射免疫法测定血清胰岛素,RT-PCR法检测PPARγmRNA在肝脏、骨骼肌中的表达,Western Blotting及免疫组化法检测PPARγ蛋白在肝脏、骨骼肌和脂肪组织中的表达。结果左归复方干预治疗后,其高剂量组具有显著的降低MKR小鼠空腹血糖、改善高胰岛素血症的作用(P<0.05或P<0.01)。与C57野生鼠组比较,MKR模型组小鼠肝脏和骨骼肌PPARγmRNA表达均显著下调(P<0.01),而其蛋白表达在骨骼肌和脂肪组织中也显著下调(P<0.05);经左归复方治疗后,与MKR模型组比较,左归复方高剂量组MKR鼠肝脏和骨骼肌PPARγmRNA表达均明显上调(P<0.05),PPARγ蛋白表达在三种组织中均显著上调(P<0.05或P<0.01)。左归复方上调各组织中PPARγmRNA及蛋白表达与阳性对照药文迪雅组作用相当(P>0.05)。结论左归复方具有显著的改善MKR鼠糖代谢的作用,其机制与上调肝脏、骨骼肌和脂肪组织中PPARγ表达,增强外周组织对胰岛素的敏感性,改善胰岛素抵抗有关。

Liposomes for systematic delivery of vancomycin hydrochloride to decrease nephrotoxicity:Characterization and evaluation

Vancomycin hydrochloride(VANH),the first glycopeptide antibiotic,is a water-soluble drug for the treatment of acute osteomyelitis.Liposomal formulations of VANH have already been manipulated and characterized,which was a mean of increasing their therapeutic index,reducing their toxicity and altering drug biodistribution.One of the challenges for preparing VANH-Lips is their low encapsulation efficiency(EE).In the present study,we aim to improve the liposomal formulation of VANH for higher EE,longer systemic circulation,reduced nephrotoxicity and enhanced antimicrobial activities.Vancomycin hydrochloride-loaded liposomes(VANH-Lips)were formulated by the method of modified reverse phase evaporation.Based on the optimization of formulation with orthogonal experimental design,the average drug encapsulation efficiency and the mean particle size of VANH-Lips were found to be 40.78±2.56%and 188.4±2.77 nm.In vitro drug release of VANH-Lips possessed a sustained release characteristic and their release behavior was in accordance with the Weibull equation.After intravenous injection to mice,the mean residence time(MRT)of VANH-Lips group was significantly prolonged in vivo and the AUC value was improved as well compared with the vancomycin hydrochloride solution(VANH-Sol)group.Furthermore,the biodistribution results in mice showed that VANH-Lips decreased the accumulation of VANH in kidney after intravenous injection.In conclusion,VANH-Lips may be a potential delivery system for VANH to decrease nephrotoxicity in the treatment of osteomyelitis.

Global stability for delay SIR epidemic model with vertical transmission

A SIR epidemic model with delay, saturated contact rate and vertical transmission is considered. The basic reproduction number is calculated. It is shown that this number characterizes the disease transmission dynamics: if, there only exists the disease-free equilibrium which is globally asymptotically stable;if, there is a unique endemic equilibrium and the disease persists, sufficient cond- itions are obtained for the global asymptotic stability of the endemic equilibrium.

Application of Three-dimensional Laser Scanning Technology in the Teaching Practice of Surveying and Mapping of Ancient Buildings

Based on the study of the application of three-dimensional laser scanning technology in ancient building surveying and mapping,this paper briefly describes the working principle and flow of three-dimensional laser scanning technology.Based on the practical application,this paper puts forward the discussion of related problems and matters needing attention.This has a certain reference significance for the study of new technology in surveying and mapping of ancient buildings.

Exploration on the Teaching Method for Surveying and Mapping Practice in Ancient Architecture

Since the introduction of the architecture course,the practice of surveying and mapping of ancient architecture has always been an important compulsory course in the professional course of architecture in colleges and universities in China. Against the background of the new era,the teaching methods used so far can no longer fully meet the needs of the development of the times and the construction of " Double FirstClass" initiative. This paper explores deeply from the aspects of organizational planning,technical support and achievement transformation,in order to enrich the teaching methods for ancient architecture surveying and mapping practice course in architecture major,and finally improve the teaching level and improve the teaching effect.

A predictive model for ethylene-mediated auxin and cytokinin patterning in the Arabidopsis root

The interaction between auxin and cytokinin is important in many aspects of plant development.Experimental measurements of both auxin and cytokinin concentration and reporter gene expression clearly show the coexistence of auxin and cytokinin concentration patterning in Arabidopsis root development.However,in the context of crosstalk among auxin,cytokinin,and ethylene,little is known about how auxin and cytokinin concentration patterns simultaneously emerge and how they regulate each other in the Arabidopsis root.This work utilizes a wide range of experimental observations to propose a mechanism for simultaneous patterning of auxin and cytokinin concentrations.In addition to revealing the regulatory relationships between auxin and cytokinin,this mechanism shows that ethylene signaling is an important factor in achieving simultaneous auxin and cytokinin patterning,while also predicting other experimental observations.Combining the mechanism with a realistic in silico root model reproduces experimental observations of both auxin and cytokinin patterning.Predictions made by the mechanism can be compared with a variety of experimental observations,including those obtained by our group and other independent experiments reported by other groups.Examples of these predictions include patterning of auxin biosynthesis rate,changes in PIN1 and PIN2 patterns in pin3,4,7 mutants,changes in cytokinin patterning in the pls mutant,PLS patterning,and various trends in different mutants.This research reveals a plausible mechanism for simultaneous patterning of auxin and cytokinin concentrations in Arabidopsis root development and suggests a key role for ethylene pattern integration.

Dynamics and functionalities of bacterial community during foxtail millet dough fermentation by metagenomic analysis

Sourdough flavors were closely related to microbial metabolism.The microbial diversity of foxtail millet dough during fermentation has never been studied.Here,the metabolic potential and diversity of the bactenial community were analyzed by metagenomic during dough fermentation.Firmicutes was the dominant phylum in the dough,within heterofementative lactic acid bacteria(e.g.Companilactobacillus,Limosilactobacillus,Pediococcus and Lactobacillus)as the most abundant bacteria.Proteobacteria was gradually inhibited after fermentation.Companilactobacillus_crustorum was notably found abundant during dough 1eavening.Limosilactobacillus_fermentum increased markedly during fermentation,while Companilactobacillus_cnustorum decreased significantly.For futher exploration,genes associated with metabolism were annotated through metagenomics.Limosilactobacillus,Companilactobacillus and Pediococcus were actively engaged in glycolysis(ko00010),starch and sucrose metabolism(ko00500),and pyruvate metabolism(ko00620),leading in part to 1actic and acetic acid acumulations and dough acidification.Limosilactobacillus and Lactiplantibacillus were the main contributors to key aninopeptidases ox/and transaminases involved in amino acid metabolism,which was nesponsible for flavor metabolite formation.This study will provide an enhanced understanding of the predominance and diversity of dough bactenial communities,and contribute to future strain screening in the dough for better flavor.

Investigation on the mechanism of structural reconstruction of biochars derived from lignin and cellulose during graphitization under high temperature

The structural reconstruction mechanism of lignin and cellulose-derived biochars during direct graphitization under ultra-high temperatures was intensively investigated.It was demonstrated that cellulose-derived char was almost composed of carbon microcrystallites,whereas lignin-derived char reserved some of its skeleton structures,and such structural difference played a vital role in the morphology of formed graphitic layers.The results illustrated that the graphitized lignin-derived sample under 2800℃had graphitic degree of 89.53%,interlayer spacing of 0.3363 nm and electronic conductivity of 104.6 S cm^(−1),while cellulose-derived sample had graphitic degree of 76.74%,layer distance of 0.3374 nm,and electronic conductivity of only 48.8 S cm^(−1).Combined with the results of structural analysis of the chars derived from lignin and cellulose,it was inferred that the stable and aromatic ring containing skeleton structure in lignin was beneficial to the ring-enlarging reconstruction and the formation of large areas of continuous graphitic layers during graphitizing process,leading to high electronic conductivity.Meanwhile,the interwoven microcrystallites in cellulose-derived char strongly restricted the expanding of continuous lamellar graphitic areas even at such ultra-high temperature,causing the formation of turbostratic structure with numerous structural defects as well,and finally resulting in relatively lower electronic conductivity.This work is expected to provide theoretical guidance for preparing high-performance functional carbon materials from lignocellulosic biomass.

Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

Nonalcoholic steatohepatitis(NASH)is a condition that progresses from nonalcoholic fatty liver disease(NAFLD)and is characterized by hepatic fat accumulation,inflammation,and fibrosis.It has the potential to develop into cirrhosis and liver cancer,and currently no effective pharmacological treatment is available.In this study,we investigate the therapeutic potential of targeting ceruloplasmin(Cp),a copper-containing protein predominantly secreted by hepatocytes,for treating NASH.Our result show that hepatic Cp is remarkedly upregulated in individuals with NASH and the mouse NASH model.Hepatocyte-specific Cp ablation effectively attenuates the onset of dietary-induced NASH by decreasing lipid accumulation,curbing inflammation,mitigating fibrosis,and ameliorating liver damage.By employing transcriptomics and metabolomics approaches,we have discovered that hepatic deletion of Cp brings about remarkable restoration of bile acid(BA)metabolism during NASH.Hepatic deletion of Cp effectively remodels BA metabolism by upregulating Cyp7a1 and Cyp8b1,which subsequently leads to enhanced BA synthesis and notable alterations in BA profiles.In conclusion,our studies elucidate the crucial involvement of Cp in NASH,highlighting its significance as a promising therapeutic target for the treatment of this disease.

Global dynamics in a model for anthrax transmission in animal populations

In this paper,we propose a deterministic model to study the transmission dynamics of anthrax disease,which includes live animals,carcasses,spores in the environment and vectors.We derive three biologically plausible and insightful quantities(reproduction numbers)that determine the stability of the equilibria.We carry out rigorous mathematical analysis on the model dynamics,the global stability of the disease-free and vector-free equilibrium,the disease-free equilibrium and the vector-free disease equilibrium is proved.The global stability of the endemic equilibrium as the basic reproduction number is greater than one is derived in the special case in which the disease-related death rate is zero.The possibility of backward bifurcation is briefly discussed.Numerical analyses are carried out to understand the transmission dynamics of anthrax and investigate effective control strategies for the outbreaks of the disease.Our studies suggest that the larval vector control measure should be taken as early as possible to control the vector population size,a vaccination policy and an animal carcass removal policy are useful methods to control the prevalence of the diseases in infected animal populations,the adult vector control measure is also necessary to prevent the transmission of anthrax.

Friend or foe for obesity: How hepatokines remodel adipose tissues and translational perspective

Due to excess energy intake and a sedentary lifestyle, the prevalence of obesity is rising steadily and has emerged as a global public health problem. Adipose tissue undergoes structural remodeling and dysfunction in the obese state. Secreted proteins derived from the liver, also termed as hepatokines, exert multiple effects on adipose tissue remodeling and the development of obesity, and has drawn extensive attention for their therapeutic potential in the treatment of obesity and related diseases. Several novel hepatokines and their functions on systemic metabolism have been interrogated recently as well. The drug development programs targeting hepatokines also have shown inspiring benefits in obesity treatment. In this review, we outline how adipose tissue changes during obesity. Then, we summarize and critically analyze the novel findings on the effects of metabolic “beneficial” and metabolic “harmful” hepatokines to adipose tissue. We also discuss the in-depth molecular mechanism that hepatokines may mediate the liver-adipose tissue crosstalk, the novel technologies targeting hepatokines and their receptors in vivo to explore their functions, and the potential application of these interventions in clinical practice.

Comments on‘Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1–AMPK–LKB1 complex’

Human health requires macronutrients,such as amino acids,glucose,and lipids,as well as micronutrients,including copper and iron.Copper is required for the assembly of various enzymes,such as copper/zinc superoxide dismutase and cytochrome c oxidase(Kim et al.,2008).It has been well documented that adenosine monophosphate-activated protein kinase(AMPK)senses intracellular glucose concentrations(Li et al.,2019),mTOR is responsible for monitoring intracellular amino acid levels(Liu and Sabatini,2020),and CD36 functions as a sensor for intracellular lipid amounts(Hao et al.,2020).However,it is still unclear how intracellular copper dynamic changes are sensed and whether copper plays a crucial messenger role in the regulation of metabolism of macronutrients.

猪丁型冠状病毒诱导的细胞线粒体凋亡

猪丁型冠状病毒(Porcine deltacoronavirus,PDCoV)是一种新型的猪肠道致病性冠状病毒,可引起猪群剧烈腹泻及呕吐,但致病机制尚不清楚。本研究检测了PDCoV感染诱导的细胞凋亡。Caspase酶活性检测显示,在PDCoV感染的细胞中,caspase 3、caspase 8和caspase 9的活性随病毒感染量的增多而显著提高,类似的现象未能在紫外灭活病毒感染的细胞中观察到,表明PDCoV感染可同时激活内源性与外源性细胞凋亡通路,并暗示细胞凋亡的诱导依赖于病毒复制。为深入探究PDCoV诱导的内源性细胞凋亡,分别检测胞浆和线粒体中细胞色素C与凋亡诱导因子。结果显示,与正常细胞相比,PDCoV感染细胞从线粒体释放到胞浆的细胞色素C显著增多,且其释放量随着感染时间的延长而增多,而凋亡诱导因子始终定位于线粒体,提示PDCoV感染通过促使线粒体膜间隙的细胞色素C进入胞浆而启动caspase依赖的线粒体凋亡通路。本研究初步揭示了PDCoV诱导细胞凋亡的机制。

Crosstalk Complexities between Auxin, Cytokinin, and Ethylene in Arabidopsis Root Development： From Experiments to Systems Modeling, and Back Again

Understanding how hormones and genes interact to coordinate plant growth in a changing environment is a major challenge in plant developmental biology. Auxin, cytokinin, and ethylene are three important hormones that regulate many aspects of plant development. This review critically evaluates the crosstalk between the three hormones in Arabidopsis root development. We integrate a variety of experimental data into a crosstalk network, which reveals multiple layers of complexity in auxin, cytokinin, and ethylene crosstalk. In particular, data integration reveals an additional, largely overlooked link between the ethylene and cytokinin pathways, which acts through a phosphorelay mechanism. This proposed link addresses outstanding questions on whether ethylene application promotes or inhibits receptor kinase activity of the ethylene receptors. Elucidating the complexity in auxin, cytokinin, and ethylene crosstalk requires a combined experimental and systems modeling approach. We evaluate important modeling efforts for establishing how crosstalk between auxin, cytokinin, and ethylene regulates patterning in root develop- ment. We discuss how a novel methodology that iteratively combines experiments with systems modeling analysis is essential for elucidating the complexity in crosstalk of auxin, cytokinin, and ethylene in root development. Finally, we discuss the future challenges from a combined experimental and modeling perspective.

Developing a bacteriophage cocktail for biocontrol of potato bacterial wilt

Bacterial wilt is a devastating disease of potato and can cause an 80% production loss. To control wilt using bacteriophage therapy, we isolated and characterized twelve lytic bacteriophages from different water sources in Kenya and China. Based on the lytic curves of the phages with the pathogen Ralstonia solanacearum, one optimal bacteriophage cocktail, P1, containing six phage isolations was formulated and used for studying wilt prevention and treatment efficiency in potato plants growing in pots. The preliminary tests showed that the phage cocktail was very effective in preventing potato bacterial wilt by injection of the phages into the plants or decontamination of sterilized soil spiked with R. solanacearum. Eighty percent of potato plants could be protected from the bacterial wilt(caused by R. solanacearum reference strain GIM1.74 and field isolates), and the P1 cocktail could kill 98% of live bacteria spiked in the sterilized soil at one week after spraying.However, the treatment efficiencies of P1 depended on the timing of application of the phages, the susceptibility of the plants to the bacterial wilt, as well as the virulence of the bacteria infected,suggesting that it is important to apply the phage therapy as soon as possible once there are early signs of the bacterial wilt. These results provide the basis for the development of bacteriophagebased biocontrol of potato bacterial wilt as an alternative to the use of antibiotics.

Preparation,thermal stability and biocompatibility studies of gelatin-induced hydroxyapatite co-substituted with essential physiological trace elements

Gelatin-induced hydroxyapatite with combined substitution of essential physiological trace elements(G-FAP)was prepared by a precipitation method.Pure hydroxyapatite(HAP)and ion-substituted hydroxyapatite(FAP)were also prepared for comparison.The characteristics of the precipitated powders were determined using X-ray diffraction(XRD),scanning electron microscopy(SEM),transmission electron microscopy(TEM),Fourier transform infrared spectroscopy(FT-IR),specific surface area measurement(SSA),X-ray fluorescence spectroscopy(XRF),and thermogravimetric(TG)analysis.The biocompatibility was also determined by an in vitro investigation with MC3T3-E1 cells.SEM and TEM results showed that the G-FAP powders were composed of dense aggregates of agglomerated whisker-like crystals of200–300 nm in length and 10–20 nm in width.XRD and FT-IR analyses indicated the formation of pure apatite phase,and the substituted ions and gelatin did not change the diffraction pattern of the precipitated powders.The SSAs of the precipitated powder were 64.741,72.492,and107.745 m2/g,for HAP,FAP,and G-FAP,respectively.XRF analysis showed that Na+,Mg2+,and F-were substituted into the crystal lattice.TG results showed a reduced thermal stability of the precipitated G-FAP powders,with an advanced phase transformation beginning at800°C and a serious phase transformation from hexagonal apatite phase to rhombohedral b-TCP phase at 1,200°C in comparison with HAP and FAP.In vitro biological tests showed non-cytotoxic effects for all powders.However,G-FAP stimulated the proliferation of MC3T3-E1 cells earlier than HAP and FAP.The present G-FAP will therefore be a promising primary biomaterial for bone regeneration,tooth filling,or as a coating for metal artificial limbs.

Tumor necrosis factor-α signaling in nonalcoholic steatohepatitis and targeted therapies

Nonalcoholic steatohepatitis(NASH),an inflammatory subtype of nonalcoholic fatty liver disease,is featured by significantly elevated levels of various proinflammatory cytokines.Among numerous proinflammatory factors that contribute to NASH pathogenesis,the secreted protein,tumor necrosis factoralpha(TNF-α),plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target.In this review,we will first systematically describe the preclinical studies on the biochemical function of TNF-αand its intracellular downstream signaling mechanisms through its receptors.Moreover,we extensively discuss its functions in regulating inflammation,cell death,and fibrosis of liver cells in the pathogenesis of NASH,and the molecular mechanism that TNF-αexpression is regulated by NF-κB and other upstream master regulators during NASH progression.As TNF-αis one of the causal factors that remarkably contributes to NASH progression,combination of therapeutic modalities,including TNF-α-based therapies may lead to the resolution of NASH via multiple pathways and thus generate clinical benefits.For translational studies,we summarize recent advances in strategies targeting TNF-αand its signaling pathway,which paves the way for potential therapeutic treatments for NASH in the future.

Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation

Excessive inflammatory responses contribute to the pathogenesis and lethality of highly pathogenic human coronaviruses,but the underlying mechanism remains unclear.In this study,the N proteins of highly pathogenic human coronaviruses,including severe acute respiratory syndrome coronavirus(SARS-CoV),middle east respiratory syndrome coronavirus(MERS-CoV)and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),were found to bind MASP-2,a key serine protease in the lectin pathway of complement activation,resulting in excessive complement activation by potentiating MBL-dependent MASP-2 activation,and the deposition of MASP-2,C4b,activated C3 and C5b-9.Aggravated inflammatory lung injury was observed in mice infected with adenovirus expressing the N protein.Complement hyperactivation was also observed in SARS-CoV-2-infected patients.Either blocking the N protein:MASP-2 interaction,MASP-2 depletion or suppressing complement activation can significantly alleviate N protein-induced complement hyperactivation and lung injury in vitro and in vivo.Altogether,these data suggested that complement suppression may represent a novel therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.

2020 Roadmap on two-dimensional nanomaterials for environmental catalysis

Environmental catalysis has drawn a great deal ofattention due to its clean ways to produce useful chemicals or carry out some chemical processes.Photocatalysis and electrocatalysis play important roles in these fields.They can decompose and remove organic pollutants from the aqueous environment,and prepare some fine chemicals.Moreover,they also can carry out some important reactions,such as 02 reduction reaction(ORR),O2 evolution reaction(OER),H2 evolution reaction(HER),CO2 reduction reaction(C02 RR),and N2 fixation(NRR).For catalytic reactions,it is the key to develop high-performance catalysts to meet the demand fortargeted reactions.In recentyears,two-dimensional(2 D) materials have attracted great interest in environmental catalysis due to their unique layered structures,which offer us to make use of their electronic and structural characteristics.Great progress has been made so far,including graphene,black phosphorus,oxides,layered double hydroxides(LDHs),chalcogenides,bismuth-based layered compounds,MXenes,metal organic frameworks(MOFs),covalent organic frameworks(COFs),and others.This content drives us to invite many famous groups in these fields to write the roadmap on two-dimensional nanomaterials for environmental catalysis.We hope that this roadmap can give the useful guidance to researchers in future researches,and provide the research directions.