Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function

We discuss the article by Koizumi et al published in the World Journal of Gastroenterology.Our focus is on the therapeutic targets for fibrosis associated with alcohol-related liver disease(ALD)and the mechanism of action of elafibranor(EFN),a dual agonist of peroxisome proliferator-activated receptorα(PPARα)and peroxisome PPARδ(PPARδ).EFN is currently in phase III clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis.ALD progresses from alcoholic fatty liver to alcoholic steatohepatitis(ASH),with chronic ASH eventually leading to fibrosis,cirrhosis,and,in some cases,hepatocellular carcinoma.The pathogenesis of ALD is driven by hepatic steatosis,oxidative stress,and acetaldehyde toxicity.Alcohol consumption disrupts lipid metabolism by inactivating PPARα,exacerbating the progression of ALD.EFN primarily activates PPARα,promoting lipolysis andβ-oxidation in ethanol-stimulated HepG2 cells,which significantly reduces hepatic steatosis,apoptosis,and fibrosis in an ALD mouse model.Additionally,alcohol disrupts the gut-liver axis at several interconnected levels,contributing to a proinflammatory environment in the liver.EFN helps alleviate intestinal hyperpermeability by restoring tight junction protein expression and autophagy,inhibiting apoptosis and inflammatory responses,and enhancing intestinal barrier function through PPARδactivation.

红芪多糖“脱蛋白-大孔吸附树脂”的纯化富集工艺考察

目的研究红芪多糖(HPS)标准提取物,筛选优化其“脱蛋白-大孔吸附树脂纯化富集”的工艺方法与工艺参数。方法以蛋白脱除率和多糖损失率为指标,比较4种不同方法的脱蛋白效果,并对筛选出的方法进行工艺参数优化;以吸附量和吸附率为指标,考察4种型号大孔吸附树脂(AB-8、D-101、NKA-9、X-5)对HPS的纯化富集效果,并进行相关工艺参数优化;采用苯酚硫酸法和考马斯亮兰法分别测定多糖和蛋白质含量;采用紫外分光光度(UV)和红外光谱(IR)法比较纯化前后多糖的基本特征。结∶果筛选出的脱蛋白方法为Sevag法,优选的树脂为AB-8大孔吸附树脂。通过工艺参数优选,确定的纯化工艺为:10 mg·mL^(-1)粗多糖水溶液,以1/2倍体积氯仿^(-1),∶v/v)混合试剂进行脱蛋白操作2次;除去残留有机溶剂后,以质量浓度为1.5 mg·mL^(-1)的水溶液,上预处理好的AB-8大孔吸附树脂柱[树脂量(g)与上样体10]∶,以2.0 mL·min^(-1)流速循环上样2次,动态吸附后再静态吸附6~8 h,后以30%乙醇1.0 mL·min^(-1)进行洗脱,至洗脱液无明显碱性酒石酸铜反应,收集洗脱液浓缩至与原药1冲洗沉淀,即得HPS。结论验证试验表明,经本工艺纯化富集后,所得HPS样品纯度提高了1.27倍;UV在260,280 nm处未见蛋白质吸收峰;IR表现出更突出的多糖结构特征吸收峰,说明纯化过程有效且未对HPS主要结构产生影响。优选出的HPS脱蛋白和大孔树脂纯化工艺稳定可行,重复性较好,使多糖得到较好的纯化富集,为HPS标准提取物的形成以及其能成为制剂科学化原料药提供了研究基础。

A paradox:Insulin inhibits expression and secretion of resistin which induces insulin resistance

AIM: To confirm whether insulin regulates resistinexpression and secretion during differentiation of 3T3-L1preadipocytes and the relationship of resistin with insulinresistance both in vivo and in vitro.METHODS: Supernatant resistin was measured duringdifferentiation of 3T3-L1 preadipocytes. L6 rat myoblastsand hepatoma cell line H4IIE were used to confirm thecellular function of resistin. Diet-induced obese ratswere used as an insulin resistance model to study therelationship of resistin with insulin resistance.RESULTS: Resistin expression and secretion wereenhanced during differentiation 3T3-L1 preadipocytes.This cellular differentiation stimulated resistin expressionand secretion, but was suppressed by insulin. Resistinalso induced insulin resistance in H4IIE hepatocytes andL6 myoblasts. In diet-induced obese rats, serum resistinlevels were negatively correlated with insulin sensitivity,but not with serum insulin.CONCLUSION: Insulin can inhibit resistin expressionand secretion in vitro, but insulin is not a major regulatorof resistin in vivo . Fat tissue mass affects insulinsensitivity by altering the expression and secretion ofresistin.

An SBT-memristor-based crossbar memory circuit

Implementing memory using nonvolatile, low power, and nano-structure memristors has elicited widespread interest.In this paper, the SPICE model of Sr_(0.95)Ba_(0.05)TiO_(3)(SBT)-memristor was established and the corresponding characteristic was analyzed. Based on an SBT-memristor, the process of writing, reading, and rewriting of the binary and multi-value memory circuit was analyzed. Moreover, we verified the SBT-memristor-based 4×4 crossbar binary and multi-value memory circuits through comprehensive simulations, and analyzed the sneak-path current and memory density. Finally, we apply the 8×8 crossbar multi-value memory circuits to the images memory.

Artificial synaptic behavior of the SBT-memristor

The synapse of human brain neurons is not only the transmission channel of information,but also the basic unit of human brain learning and information storing.The artificial synapse is constructed based on the Sr_(0.97)Ba_(0.03)TiO_(3-x)(SBT)memristor,which realizes the short-term and long-term plasticity of the synapse.The experiential learning and non-associative learning behavior in accordance with human cognitive rules are realized by using the SBT-memristor-based synapse.The process of synaptic habituation and sensitization is analyzed.This study provides insightful guidance for realization of artificial synapse and the development of artificial neural network.

Dynamics of the two-SBT-memristor-based chaotic circuit

A two-SBT-memristor-based chaotic circuit was proposed. The stability of the equilibrium point was studied by theoretical analysis. The close dependence of the circuit dynamic characteristics on its initial conditions and circuit parameters was investigated by utilizing Lyapunov exponents spectra, bifurcation diagrams, phase diagrams, and Poincaré maps. The analysis showed that the circuit system had complex dynamic behaviors, such as stable points, period, chaos, limit cycles,and so on. In particular, the chaotic circuit produced the multistability phenomenon, such as coexisting attractors and coexisting periods.

Effects of Different Wall-breaking Methods on Extraction of Solanesol from Stems and Leaves of Potato

In order to extract solanesol from potato stems and leaves more effectively and improve the extraction rate of solanesol, the same batch of potato stems and leaves harvested from Guyuan, Ningxia was selected as a research object, cell wall of potato stems and leaves was broken by enzymolysis with cellulase and high- speed shearing, and then reflux-extracted with 95% ethanol. Solanesol content was determined by HPLC, and extract yield was calculated. Extract yield and solanesol extraction rate was used as an index for comparison of difference between the 2 wall-breaking methods, so as to select the optimal wall-breaking method. The results showed that enzymolysis with cellulase exhibited extraction rate and extract yield of solanesol of 91.38% and 8.02%, respectively, which were better than those under high-speed shear emulsification technique. The enzymolysis wall-breaking method has the advantages of simple operation and strong feasibility.

Verapamil inhibits 3T3-L1 preadipocyte differentiation

Objective： To investigate the effect of the calcium channel blocker verapamil on adipocyte differentiation and its mechanism of action. Methods： Preadipocytes from 3T3-L1 strain mouse embryos were cultured and differentiated into matured adipocytes in vitro. Verapamil was added to the culture medium in the concentration of 30 μmol/L on Day 0. Cell differentiation was determined by Oil Red O staining and marker gene mRNA expression was evaluated and compared by RT-PCR. The fluo-3/AM probe and laser scanning confocal microscopy were used to measure intracetlular calcium concentrations. Results： （1）The differentiation rate of 3T3-L1 preadipocytes exposed to verapamil was lower than that of untreated cells. （2）Verapamil promoted the retention of pref-1 gene expression. Lipoprotein lipase expression in the verapamil group was significantly lower than that in the control group on Day 4, Day 6 and Day 8 （P 〈 0.05） and resistin expression was significantly lower than that in the control group on Day 6, Day 8 and Day 10 （P 〈 0.05）. Fatty acid synthase expression in the verapamil group was significantly lower than that in the control group from Day 2 （P 〈 0.05）. （3） Intracellular concentrations of calcium [Ca^2＋]i in the verapamil group were significantly decreased compared with those in the control group on Day 2, Day 4 and Day 6 （P 〈 0.05）, while there was no obvious difference between the two groups on Day 0 （P 〉 0.05）. Conclusion： In 3T3-L1 preadipocytes verapamil significantly reduced adipocyte differentiation, down-regulated the mRNA expression of three marker genes for adipocytes differentiation, and prolonged the mRNA expression of an inhibitor of differentiation. The inhibitory effect of verapamil on differentiation may involve its role as a blocker of calcium influx in adipocytes.

Artesunate Induces Ferroptosis in Hepatic Stellate Cells and Alleviates Liver Fibrosis via the ROCK1/ATF3 Axis

Background and Aims:Development of fibrosis in chronic liver disease requires activation of hepatic stellate cells(HSCs)and leads to a poor outcome.Artesunate(Art)is an ester derivative of artemisinin that can induce ferroptosis in HSCs,and activated transcriptional factor 3(ATF3)is an ATF/CREB transcription factor that is induced in response to stress.In this study,we examined the role of the Rho-associated protein kinase 1(ROCK1)/ATF3 axis in Art-induced ferroptosis in HSCs.Methods:HSC activation and ferroptosis were studied in vitro by western blotting,polymerase chain reaction,immunofluorescence,and other assays.ATF3 electrophoretic mobility and ROCK1 protein stability were assayed by western blotting.Immunoprecipitation was used to detect the interaction of ROCK1 and ATF3,as well as ATF3 phosphorylation.A ubiquitination assay was used to verify ROCK1 degradation.Atf3-interfering and Rock1-overexpressing mice were constructed to validate the anti-hepatic fibrosis activity of Art in vivo.Results:Art induced ferroptosis in HSCs following glutathione-dependent antioxidant system inactivation resulting from nuclear accumulation of unphosphorylated ATF3 mediated by ROCK1-ubiquitination in vitro.Art also decreased carbon tetrachloride-induced liver fibrosis in mice,which was reversed by interfering with Atf3 or overexpressing Rock1.Conclusions:The ROCK1/ATF3 axis was involved in liver fibrosis and regulation of ferroptosis,which provides an experimental basis for further study of Art for the treatment of liver fibrosis.

单分子磁体研究的最新进展

宏观上表现出可测的慢磁弛豫行为的单个分子称为单分子磁体,它主要包括过渡金属单分子磁体和稀土单分子磁体,其在量子计算、高密度信息存储以及自旋器件等方面的潜在应用吸引了研究者的广泛关注.本文介绍了单分子磁体研究的最新进展,重点总结了构筑高性能单分子磁体的合成策略.

HLA-mismatched allogeneic adoptive immune therapy in severely immunosuppressed AIDS patients

Severely immunosuppressed AIDS patients with recurrent opportunistic infections(Ols)represent an unmet medical need even in the era of antiretroviral therapy(ART).Here we report the development of a human leukocyte antigen(HLA)-mismatched allogeneic adaptive immune therapy(AAIT)for severely immunosuppressed AIDS patients.Twelve severely immunosuppressed AIDS patients with severe Ols were enrolled in this single-arm study.Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis.Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients.Clinical,immunological,and virological parameters were monitored during a 12-month follow-up period.We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients.Improvements in clinical symptoms were evident throughout the study period.All patients exhibited a steady increase of peripheral CD4^(+)T cells from a median 10.5 to 207.5 cells/μl.Rapid increase in peripheral CD8^(+)T-cell count from a median 416.5 to 1206.5 cells/μl was found in the first 90 days since initiation of AAIT.In addition,their inflammatory cytokine levels and HIV RNA viral load decreased.A short-term microchimerism with donor cells was found.There were no adverse events associated with graft-versus-host disease throughout the study period.Overall,AAIT treatment was safe,and might help severely immunosuppressed AIDS patients to achieve a better immune restoration.A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

Phonon characteristics and dielectric properties of BaMoO_(4)ceramic

BaMoO_(4)ceramic was prepared using a conventional solid-sintering method.It was observed that the sample is a pure BaMoO_(4)with a tetragonal scheelite structure by analyzing X-ray diffraction data.Scanning electron microscopy characterized the dense sample with uniform grains.The phonon modes were analyzed by Raman and Far-infrared reflection spectra,and the phonon characteristics were studied.The intrinsic properties of the sample were calculated by the four-parameter semi-quantum model as well as the Clausius-Mosotti&damping equations,and the results were ofεr=9.388 and tanδ=4.760×10^(-4),εr=9.798 and tanδ=6.445×10^(-4),respectively,which agrees well with the experimental values(εr=9.84,tanδ=5.0×10^(-4)).The contributions to dielectric properties of each mode were investigated,and the results indicate that the external mode(Eu)yield greatest contribution to intrinsic permittivity and loss.

Tuning Magnetic Relaxation in Square-Pyramidal Dysprosium Single-Molecule Magnets Using Apical Alkoxide Ligands

Eight square-pyramidal dysprosium complexes of the type[Dy(X)(DBP)_(2){TMG(H)}_(2)]were synthesized,where TMG(H)denotes 1,1,3,3-tetramethylguanidine,X denotes an alkoxide ligand or anionic guanidinate in the apical position,and DBP denotes 2,6-di-tert-butylphenoxide.These complexes,expressed as 5-Dy-X,are single-molecule magnets(SMMs)with properties dependent on the nature of the apical X ligand.

强耦合氧化钼氮碳复合材料的制备及其锂离子存储性能研究

氧化钼(MoO_(3))是一种具有吸引力的锂离子电池(LIBs)负极材料;然而,其导电性低、锂化后体积膨胀大、锂离子扩散动力学缓慢等特点严重限制了其实际应用.本文中,我们利用高量Mo/N掺杂的碳前驱材料合成了超细的MoO_(3)纳米颗粒(NPs,10–15 nm),所合成的MoO_(3)NPs被限制在原位生成的N掺杂碳网络结构中.这种设计既促进了快速的电子传导,又缩短了锂离子扩散路径;同时,MoO_(3)表面丰富的氮物种和氧缺陷有助于降低锂离子的吸附能垒,这些共同支持了MoO_(3)NPs在高电流倍率下耐久储锂性能的提升.值得注意的是,所获得的NCMoO_(3)纳米复合材料表现出1362 mA h g^(−1)(0.1 A g^(−1))的较高容量,并在10.0 A g^(−1)时保持394 mA h g^(−1)的可逆容量.全电池测试表明:在大倍率5 C下,LiFePO_(4)//NC-MoO_(3)-400电池仍可以输出81 mA h g^(−1)的比容量.我们的工作有望启发其他嵌入导电碳网络的过渡金属氧化物的设计合成及其在LIBs中的实际应用.

Mismatched donor cell infusion-related syndrome following microtransplant in patients with acute myeloid leukemia

Background:Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment,and the concomitant symptoms,including cytokine release syndrome(CRS)or immune-related adverse events(irAEs),are frequently reported.However,clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell(GPBMC)infusion in patients receiving microtransplant(MST)have not yet been well depicted.Methods:We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison.Clinical symptoms and their correlation with clinical features,laboratory findings,and clinical response were explored.Results:Fever(58.0%[51/88])and chills(43.2%[38/88])were the significant early-onset symptoms after GPBMC infusion.Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills(3[2–5]loci vs.5[3–5]loci,P=0.043 and 66.7%[12/18]vs.37.1%[26/70],P=0.024).On the other hand,those with decreased CD4^(+)/CD8^(+)T-cell ratio developed more fever(0.8[0.7–1.2]vs.1.4[1.1–2.2],P=0.007).Multivariable analysis demonstrated that younger patients experienced more fever(odds ratio[OR]=0.963,95%confidence interval[CI]:0.932–0.995,P=0.022),while patients with younger donors experienced more chills(OR=0.915,95%CI:0.859–0.975,P=0.006).Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion,which indicated mild and transient inflammatory response.Although no predictive value of infusion-related syndrome to leukemia burden change was found,the proportion of host pre-treatment activated T cells was positively correlated with leukemia control.Conclusions:Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes,which were associated with donor-or recipient-derived risk factors,with less safety and tolerance concerns than reported CRS or irAEs.