Boiogito Increases the Synthesis and Secretion of Adiponectin by Promoting Differentiation in Cultured Human Adipocytes

Boiogito (BOT) ameliorates insulin resistance and diabetes in several animal models;however, the underlying mechanisms for these in vivo effects remain unclear. Thiazolidine derivatives, which are peroxisome proliferator-activated receptor γ (PPARγ) agonists for the treatment of type II diabetes, promote adiponectin production by inducing adipocyte differentiation, thereby reducing insulin resistance. This study aimed to evaluate the effect of BOT on adipocyte differentiation using cultured human visceral preadipocytes (HVPAds) compared with the thiazolidine derivative troglitazone (TRG). We investigated the effects of BOT (0.125 - 1 mg/mL) and TRG (10 μM) on the differentiation of adipocytes treated with or without tumor necrosis factor-α (TNF-α: 5 ng/mL). On day 14 of culture, the following adipocyte differentiation marker levels were measured: intracellular lipids, extracellular (i.e., medium) adiponectin, and intracellular differentiation-related genes (PPARγ, CCAAT/enhancer binding protein, adiponectin, differentiation cluster 36, glucose transporter type 4). BOT and TRG increased factors associated with differentiation including lipid, adiponectin, and differentiation-related gene expression levels compared with the controls. The increases in these differentiation markers were inhibited by the PPARγ antagonist GW9662 (20 μM). Furthermore, TNF-α decreased all differentiation marker levels. The decreases in differentiation markers were inhibited by BOT and TRG;however, these inhibitory effects were blocked by GW9662. The results suggest that BOT increases the synthesis and secretion of adiponectin by promoting differentiation similar to TRG. This study is the first to demonstrate that adipocyte differentiation-promoting activity is a mechanism for the beneficial effects of BOT on diabetes and insulin resistance.

结直肠癌差异基因筛选及功能预测

目的基于美国癌症肿瘤基因图谱(TCGA)数据库分析结直肠癌组织及正常组织的差异表达基因,并探讨其相关分子机制。方法从TCGA数据库下载所有结直肠癌中mRNA转录组数据。共包含样本740例,其中,结直肠癌组织为571例,正常组织为169例。在R语言环境下,采用edge R工具包处理数据,得到差异表达基因。利用DAVID数据库对差异表达的前1000个基因进行GO分析及KEGG通路富集分析。对显著差异表达的前200个差异表达基因进行分析,基于Cysctoscape绘制蛋白互作网络图。比较关键基因在癌组织及正常组织中的表达水平。以关键基因的中位表达水平为界值,将关键基因分为高表达组与低表达组,比较高表达组与低表达组的生存情况。结果共筛选出5073个差异表达基因,其中,上调基因2136个,下调基因2937个。GO分析结果显示,其生物过程主要在细胞增殖、转运、rRNA加工、受体介导的内吞作用等功能富集。KEGG富集分析结果表明,差异表达基因的信号通路主要有细胞周期、转录失调、胆汁分泌、甲状腺激素信号通路、血小板活化等信号通路。筛选出的前7位关键基因为PLK1、BRD4、EHMT2、HIST2H4B、PRPF19、SUV39H1、TRIM28。进一步分析显示,癌组织中PLK1、PRPF19、SUV39H1表达均高于正常组织(P<0.05)。从生存分析曲线可知,PLK1和SUV39H1高表达组总生存时间与低表达组比较,差异无统计学意义(P>0.05);HIST2H4B低表达组总生存时间高于HIST2H4B高表达组(P<0.05)。结论基于TCGA数据库分析出PLK1在结直肠癌组织中高表达,其参与细胞增殖、有丝分裂细胞周期的G2/M转换等生物过程,通过P53信号通路发挥作用,在结直肠癌的发生、发展中起重要作用,有望成为诊断结直肠癌的肿瘤标志物。

Absolute bioavailability,dose proportionality,and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method

Rotundic acid(RA),an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb.(Aquifoliaceae),possesses diverse bioactivities.To further study its pharmacokinetics,a simple and sensitive liquid chromatography with triple quadrupole mass spectrometry(LC-QqQ-MS/MS)method was developed and validated to quantify RA concentration in rat plasma and tissue using etofesalamide as an internal standard(IS).Plasma and tissue samples were subjected to one-step protein precipitation.Chromatographic separation was achieved on a ZORBAX Eclipse XDB-C_(18) column(4.6mm×50mm,5μm)under gradient conditions with eluents of methanol:acetonitrile(1:1,V/V)and 5mM ammonium formate:methanol(9:1,V/V)at 0.5mL/min.Multiple reaction monitoring transitions were performed at m/z 487.30→437.30 for RA and m/z 256.10→227.10 for IS in the negative mode.The developed LC-QqQ-MS/MS method exhibited good linearity(2-500 ng/mL)and was fully validated in accordance with U.S.Food and Drug Administration bioanalytical guidelines.Dose proportionality and bioavailability in rats were determined by comparing pharmacokinetic data after single oral(10,20,and 40mg/kg)and intravenous(10mg/kg)administration of RA.Tissue distribution was studied following oral administration at 20mg/kg.The results showed that the absolute bioavailability of RA after administration at different doses ranged from 16.1%to 19.4%.RA showed good dose proportionality over a dose range of 10-40 mg/kg.RA was rapidly absorbed in a dose-dependent manner and highly distributed in the liver.In conclusion,this study is the first to systematically elucidate the absorption and distribution characteristics of RA in rats,which can provide additional information for further development and evaluation of RA in drug metabolism and pharmacokinetic studies.

Development of an LC–MS/MS method for the quantitation of deoxyglycychloxazol in rat plasma and its application in pharmacokinetic study

Deoxyglycychloxazol （TY501） is a glycyrrhetinic acid derivative which exhibits high anti-inflammatory activity and reduced pseudoaldosteronism compared to glycyrrhetinic acid. In this study, a sensitive and rapid liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was established for the quantitation of TY501 in rat plasma. Plasma samples were treated by precipitating protein with methanol and supernatants were separated by a Symmetry C8 column with the mobile phase consisting of methanol and 10 mM ammonium formate （containing 0.1% of formic acid） （90：10, v/v）. The selected reaction monitoring （SRM） transitions were performed at m/z 647.4→191.2 for TY501 and m/z 473.3→143.3 for astragaloside aglycone （IS） in the positive ion mode with atmospheric pressure chemical ionization （APCI） source. Calibration curve was linear over the concentration range of 5-5000 ng/mL. The lower limit of quantification was 5 ng/mL. The mean recovery was over 88%. The intra- and inter-day precisions were lower than 6.0% and 12.8%, respectively, and the accuracy was within ± 1.3%. TY501 was stable under usual storage conditions and handling procedure. The validated method has been successfully applied to a pharmacokinetic study after oral administration of TY501 to rats at a dosage of 10 mg/kg.

Discussion on compact mechanism of air-stream and synchro-formed clamp plate impact molding

Applying the air impact molding method to mold the complicated pattern with wider opening surface and deeper concave, there always exist vaulted phenomenon and lower compactibility of sand mold over the entrance and the concave regions. Using the air-stream and synchro-formed clamp plate impact molding, however, this problem will be preferably solved. In this paper, the compact mechanism of the new molding method and the effect of some configuration factors, such as the area flowed by compressed air and the highness of the protruding block displacement around the diffluent clamp plate, on the compactibility of sand mold were discussed.

Analytic Solutions of a Predator-Prey System

A predator prey interaction of both populations was treated by the Painlevé analysis method. The analytic solutions for the related equations was obtained using the truncated Painlevé expansion.

Galvanostatic method assembled ZIFs nanostructure as novel nanozyme for the glucose oxidation and biosensing

Recently,the composite of soft conductive substrates,such as carbon fiber(CF),with metal-organic frameworks(MOFs)has been employed in a myriad of applications.The composite material has demonstrated exceptional potential in the realm of electrochemical sensing platforms.However,the rapid growth of MOFs on the surface of CF remains a challenge.Herein,we propose a simple galvanostatic method as an effective strategy for rapidly growing zeolitic imidazolate frameworks(ZIFs)on CF,and obtain nanocaltrop-like ZIFs modified CF(NC-ZIFs/CF)glucose(Glu)sensor platform with distinctive morphology.The prepared NC-ZIFs/CF demonstrated significant electrocatalytic activity towards the oxidation of Glu in alkaline media,characterized by a pronounced augmentation in oxidation current density.At an applied potential of 0.4 V,NC-ZIFs/CF exhibited a remarkably broad detection range(3–30,000μmol/L)and demonstrated outstanding selectivity,repeatability and reproducibility.Additionally,the NC-ZIFs/CF was efficaciously employed for the detection of blood Glu levels in the serum of both normoglycemic and hyperglycemic patients,obtaining highly reliable results.This work demonstrates the feasibility of using galvanostatic method assembly to induce the growth of MOFs on conductive substrates,providing new ideas for electrocatalysis sensors and other electrochemical applications.

Time series models in prediction of severe fever with thrombocytopenia syndrome cases in Shandong province,China

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV). Predicting the incidence of this disease in advance is crucial for policymakers to develop prevention and control strategies. In this study, we utilized historical incidence data of SFTS (2013–2020) in Shandong Province, China to establish three univariate prediction models based on two time-series forecasting algorithms Autoregressive Integrated Moving Average (ARIMA) and Prophet, as well as a special type of recurrent neural network Long Short-Term Memory (LSTM) algorithm. We then evaluated and compared the performance of these models. All three models demonstrated good predictive capabilities for SFTS cases, with the predicted results closely aligning with the actual cases. Among the models, the LSTM model exhibited the best fitting and prediction performance. It achieved the lowest values for mean absolute error (MAE), mean square error (MSE), and root mean square error (RMSE). The number of SFTS cases in the subsequent 5 years in this area were also generated using this model. The LSTM model, being simple and practical, provides valuable information and data for assessing the potential risk of SFTS in advance. This information is crucial for the development of early warning systems and the formulation of effective prevention and control measures for SFTS.

Heterologous expression facilitates the discovery and characterization of marine microbial natural products

Microbial natural products and their derivatives have been developed as a considerable part of clinical drugs and agricultural chemicals.Marine microbial natural products exhibit diverse chemical structures and bioactivities with substantial potential for the development of novel pharmaceuticals.However,discovering compounds with new skeletons from marine microbes remains challenging.In recent decades,multiple approaches have been de-veloped to discover novel marine microbial natural products,among which heterologous expression has proven to be an effective method.Facilitated by large DNA cloning and comparative metabolomic technologies,a few novel bioactive natural products from marine microorganisms have been identified by the expression of their biosynthetic gene clusters(BGCs)in heterologous hosts.Heterologous expression is advantageous for character-izing gene functions and elucidating the biosynthetic mechanisms of natural products.This review provides an overview of recent progress in heterologous expression-guided discovery,biosynthetic mechanism elucidation,and yield optimization of natural products from marine microorganisms and discusses the future directions of the heterologous expression strategy in facilitating novel natural product exploitation.

Phosphorylation of NF2 at Serine-13 by MAP4K family kinases mediates pathological angiogenesis

Dear Editor,Angiogenesis is vital for the development and maintenance of functional organs,and also participates in diverse pathological processes,such as wound healing,oxygen tension,and tumorigenesis(Potente et al.,2011).Thus,understanding the molecular mechanisms responsible for angiogenesis has important clinical implications and may guide strategies for drug development.

Computational pharmacological studies on cardiovascular disease by Qishen Yiqi Diwan

Computational pharmacological methods were used to study the distribution of 1729 compounds contained in a Chinese medicine,Qishen Yiqi Diwan,in chemical space.The results show that most of these compounds have good drug-like properties.Molecular docking was used to study the interactions between 1729 compounds of Qishen Yiqi Diwan and 26 drug targets related to cardiovascular disease and the distribution of 1729 compounds in drug-target space.The results may shed light on the action mechanism and the search for the active compounds in Qishen Yiqi Diwan.

Effects of acute low temperature stress on the endocrine reactions of the Qinghai toad-headed lizard

Endoctinological action is generally thought to be a way for animals to respond to stress at low temperatures. To learn the role of hormones in ectotherms inhabiting alpine environments, we studied the effects of acute low temperature exposure on tile endocrinological reactions of Qinghai toad-headed lizards in the Qinghai-Tibetan Plateau. We monitored plasma corticos- terone and insulin concentration of the lizards under five low temperature treatments. We found no significant difference in plasma corticosterone or insulin in lizards among our five different treatments. For males and females the correlation between plasma corticosterone and insulin concentrations was not significant. In contrast to other studies on reptiles at low altitude, we suggest that due to the alpine environment （low temperature and low oxygen concentration） they inhabit, Qinghai toad-headed lizards respond to experimental cold stress slightly to mobilize energy and live their vivid life. In addition, corticosterone and insulin of Qinghai toad-headed lizards are secreted independently along with low temperature treatments

Visualizable Delivery of Nanodisc Antigen-Conjugated Adjuvant for Cancer Immunotherapy

Engineering synthetic vaccines is promising for improving the efficacy of cancer immunotherapy.One of the major challenges in the development of vaccines is achieving controllable codelivery of antigen and adjuvant to lymph nodes for maximizing the antitumor immune responses.To address this issue,we herein developed an innovative visualizable nanodisc vaccine based on ovalbumin(OVA)and short-stranded oligodeoxynucleotides containing unmethylated cytosine-phosphate-guanine(CpG)motifs.The nanovaccine was fabricated by covalently attaching CpG onto the surface of a nanodisc antigen formed upon self-assembly of amphiphilic molecular conjugates of OVA and cypate(Cy),a near-infrared(NIR)fluorescent dye,for noninvasively visualizing the delivery of the resulting nanovaccines.Systematic in vitro experiments demonstrated that the engineered nanovaccines can specifically locate to dendritic cells(DCs)via toll-like receptor 9 and membrane thiols,and then efficiently activate DCs.The animal experiments combining NIR fluorescence imaging with the lymphatic T-cell phenotype and key cytokine secretion analyses revealed that targeted lymphatic homing of the mature DCs and consequent priming of CD8^(+)T cells were enabled to initiate strong tumor-specific T-cell responses with robust immune memory effects.Thus,this study offers a visualizable platform for optimizing the efficacy of nanovaccines toward cancer immunotherapies.