Integrated causal inference modeling uncovers novel causal factors and potential therapeutic targets of Qingjin Yiqi granules for chronic fatigue syndrome

Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a clinically approved formula for treating post-COVID-19;however,its potential as a drug target for treating CFS remains largely unknown.This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS.Methods:This prospective cohort analysis included 4,212 adults aged≥65 years who were followed up for 7 years with 435 incident CFS cases.Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS.A proteome-wide,two-sample Mendelian randomization(MR)analysis was employed to explore the proteins associated with the identified causal factors of CFS,which may serve as potential drug targets.Furthermore,we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins.Results:Among 4,212 participants(47.5%men)with a median age of 69 years(interquartile range:69–70 years)enrolled in 2004,435 developed CFS by 2011.Causal graph analysis with multivariate logistic regression identified frequent cough(odds ratio:1.74,95%confidence interval[CI]:1.15–2.63)and insomnia(odds ratio:2.59,95%CI:1.77–3.79)as novel causal factors of CFS.Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule(ESAM)was causally linked to both chronic cough(odds ratio:1.019,95%CI:1.012–1.026,P=2.75 e^(−05))and insomnia(odds ratio:1.015,95%CI:1.008–1.022,P=4.40 e^(−08))in CFS.The major bioactive compounds of QJYQ,ginsenoside Rb2(docking score:−6.03)and RG4(docking score:−6.15),bound to ESAM with high affinity based on virtual screening.Conclusions:Our integrated analytical framework combining epidemiological,genetic,and in silico data provides a novel strategy for elucidating complex disease mechanisms,such as CFS,and informing models of action of traditional Chinese medicines,such as QJYQ.Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.

丹红注射液及其组分抗心肌缺血再灌注损伤作用机制的研究

心肌梗死在外科手术治疗中常伴随着心肌缺血再灌注损伤(MI/RI),影响术后患者的正常生活。丹红注射液(DHI)已在临床中被广泛用来治疗冠心病和心绞痛等疾病,但其对MI/RI的治疗效果仍需进一步研究。本研究旨在探讨DHI抗MI/RI的药效作用成分及其作用机制。通过化学分离的方法,从DHI中得到其中的初生代谢物组分(PM)和次生代谢物组分(SM),通过建立大鼠心肌缺血再灌注损伤模型并分别给药,验证DHI、PM和SM的药效作用。实验结果表明DHI、PM和SM能够纠正扩张的心脏结构,还可以下调补体C2的表达以减轻炎症反应,通过上调环氧合酶(COX)的表达减少活性氧(ROS)的产生以及通过抑制脂肪酸代谢和刺激糖代谢恢复正常能量供应来改善心脏功能。此外,DHI和SM还可以通过下调Ca^(2+)/钙调素依赖性蛋白激酶II(CaMKII)的表达来减轻因钙超载引起的炎症反应和氧化应激。这些发现可能为中药注射剂的质量控制和安全性评价提供依据,并为心血管疾病的预防和治疗提供新思路。

The“Top 50 High Impact Researches of Traditional Medicine”published in 2021

In recent years,significant progress has been achieved in both basic and clinical research within the field of traditional medicine,garnering increasing attention worldwide.To further promote a high-quality and international development of traditional medicine,the editorial board of Acupuncture and Herbal Medicine provided a collection of the“Top 50 High-impact Researches of Traditional Medicine”published in 2021 through objective indicators and a strict selection process.The findings of the selected articles have a significant academic influence and possess considerable academic value both nationally and internationally.The selected articles cover a wide range of topics,including clinical research,acupuncture,pharmacology,chemistry,biosynthesis,medicinal plant resources,and new formulation and drug delivery system research on traditional medicine.Therefore,this article outlines the selection process of the top 50 high-impact research articles,analyzes their research characteristics,and provides a brief summary of their new findings and perspectives in the field of traditional medicine.

Verbascoside exerts an anti-atherosclerotic effect by regulating liver glycerophospholipid metabolism

Verbascoside,abundant in olive mill wastewater,is a phenylethanolic glycoside with a wide range of pharmacological activities.Atherosclerosis(AS)is a common metabolic disease and abnormal lipid metabolism in liver is inseparable from its formation and development.In this study,the anti-atherosclerotic effect of verbascoside was evaluated by establishing an atherosclerosis model based on western diet feeding of apolipoprotein E-defi cient mice for 16 weeks.After 12 weeks of administration during the feeding period,the levels of total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C)in the plasma of mice were signifi cantly decreased,the formation of arterial plaques was delayed,and the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST)and lactate dehydrogenase(LDH)in plasma were alleviated,showing the hepatoprotective effect.In addition,based on untargeted lipidomic analysis,verbascoside stabilized glycerophospholipid metabolism,modulated lipid metabolism disorders and reduced lipid deposition in the liver to achieve the therapeutic effi cacy against atherosclerosis by regulating cardiolipin(CL),ether-linked phosphatidylcholine(ether-PC),lysophophatidylcholine(LPC),phosphatidylcholine(PC),oxidized phosphatidylcholine(OxPC),oxidized phosphatidylethanolamine(OxPE),triacylglycerol(TG),sphingomyelin(SM)back to normal levels.

Preparation and photodetection performance of high crystalline quality and large size β-Ga_(2)O_(3)microwires

Ultrawide band gap semiconductors are promising solar-blind ultraviolet(UV)photodetector materials due to their suitable bandgap,strong absorption and high sensitivity.Here,β-Ga_(2)O_(3)microwires with high crystal quality and large size were grown by the chemical vapor deposition(CVD)method.The microwires reach up to 1 cm in length and were single crystalline with low defect density.Owing to its high crystal quality,a metal–semiconductor–metal photodetector fabricated from a Ga_(2)O_(3)microwire showed a responsivity of 1.2 A/W at 240 nm with an ultrahigh UV/visible rejection ratio(R_(peak)/R_(400 nm))of 5.8×10^(5),indicating that the device has excellent spectral selectivity.In addition,no obvious persistent photoconductivity was observed in the test.The rise and decay time constants of the device were 0.13 and 0.14 s,respectively.This work not only provides a growth method for high-quality Ga_(2)O_(3)microwires,but also demonstrates the excellent performance of Ga_(2)O_(3)microwires in solar-blind ultraviolet detection.

The exciting and magical journey of components from compound formulae to where they fight

With its long-term empirical clinical practice and increasing number of health benefits reported,Chinese Materia Medica(CMM)is gaining increasing global acceptance.Importantly,the identification of chemical constituents in vitro and exposed forms in vivo is a prerequisite for understanding how CMM formulae prevent and treat diseases.This review systematically summarizes the exciting and magical journey of CMM components from compound formulae to where they fight,the possible structural transformation of CMM components in vitro and in vivo,and their pharmacological contribution.When a decoction is prepared,significant chemical reactions are observed,including degradation and production of polymers and self-assembling supramolecules,leading to the construction of a component library with diverse decoction structures.After ingestion,compounds pass through the intestinal and blood-brain barriers and undergo a more wonderful journey involving the gut microbiota,microbial enzymes,and endogenous drug-metabolizing enzymes(mainly liver enzymes).At this stage,they are modified and assembled into novel and complex compounds,such as newly generated metabolites,conjugates,and self-assembling superamolecules.This review might provide a strategic orientation to explore the active compounds of CMM formulae in vivo.

High-Efficiency Preparation of 2,5-Diformylfuran with a Keto-ABNO Catalyst Under Mild Conditions

In this paper, we report a new catalytic system for realizing the rapid and efficient oxidation of 5-hydroxymethylfurfural(HMF). First, we used 9-azabicyclo [3.3.1]nonan-3-one-N-oxyl(keto-ABNO) as a catalyst for the aerobic oxidation of 5-hydroxymethylfurfural(HMF) to 2,5-diformylfuran(DFF) in acetic acid. Then, we systematically studied the important reaction parameters, including the solvent, co-catalyst, and temperature. The results demonstrate that the acidic solvent used is crucial for the efficient oxidation of HMF to DFF. Under optimal conditions, we achieved a 93.4% yield of DFF within half an hour at room temperature. We also proposed the possible mechanism for this system.

CONFORMAL RESTRICTION MEASURES ON LOOPS SURROUNDING AN INTERIOR POINT

A conformal restriction measure is a probability measure which is used to describe the law of a random connected subset in a simply connected domain that satisfies a certain conformal restriction property. Usually there are three kinds of conformal restriction measures: one (called the chordal restriction measure) has two given boundary points of the random set, the second (called the radial restriction measure) has one boundary point and one interior point in the random set, and the third (called the tri-chordal restriction measure) has three boundary points in the random set. In this article, we will define a new probability measure such that the random set associated to it contains one given interior point and does not intersect with the boundary. Furthermore, we will show that this measure can be characterized by one parameter;we will also construct this one-parameter family of measures in two ways and obtain several properties.

ON THE DISTRIBUTION OF JULIA SETS OF HOLOMORPHIC MAPS

In 1965 Baker first considered the distribution of Julia sets of transcendental entire maps and proved that the Julia set of an entire map cannot be contained in any finite set of straight lines.In this paper we shall consider the distribution problem of Julia sets of meromorphic maps.We shall show that the Julia set of a transcendental meromorphic map with at most finitely many poles cannot be contained in any finite set of straight lines.Meanwhile,examples show that the Julia sets of meromorphic maps with infinitely many poles may indeed be contained in straight lines.Moreover,we shall show that the Julia set of a transcendental analytic self-map of C*can neither contain a free Jordan arc nor be contained in any finite set of straight lines.

PERIODIC POINTS AND NORMALITY CONCERNING MEROMORPHIC FUNCTIONS WITH MULTIPLICITY

In this article,two results concerning the periodic points and normality of meromorphic functions are obtained:(i)the exact lower bound for the numbers of periodic points of rational functions with multiple fixed points and zeros is proven by let ting R(z)be a nonpolynomial rational function,and if all zeros and poles of R(z)—z are multiple,then Rk(z)has at least k+1 fixed points in the complex plane for each integer k≥2;(ii)a complete solution to the problem of normality of meromorphic functions with periodic points is given by let ting F be a family of meromorphic functions in a domain D,and let ting k≥2 be a positive integer.If,for each f∈F,all zeros and poles of f(z)-z are multiple,and its iteration fk has at most k distinct fixed points in D,then F is normal in D.Examples show that all of the conditions are the best possible.

Tea as a natural gift for discovering antiviral candidates

Coronavirus disease(COVID-19)remains rampant worldwide and poses a serious threat to human health.Tea is a medicinal and edible homologous plant that exhibits potential anti-SARS-CoV-2 properties via the prevention of virus entry into host cells,inhibition of virus replication,and enhancement of the innate and cellular immune responses.In this review,the properties of six major types of tea were systematically summarized,including green tea,yellow tea,white tea,oolong tea,black tea,and dark tea.We focused on the primary components of tea exhibiting antiviral activities,which included(–)-epigallocatechin-3-gallate,(–)-gallocatechin gallate,tannic acid,oolonghomobisflavan A,theaflavins,and white-tip silver needle flavonoids.Among them,(–)-epigallocatechin-3-gallate is proposed to be an antiviral compound that interferes with the entire life cycle of SARS-CoV-2 by balancing inflammation and immunity.Thus,this compound can serve as a promising lead structure for the development of SARS-CoV-2 inhibitors.

Identification of prototype compounds and their metabolites in rats’ serum from Xuefu Zhuyu Decoction by UPLC-Q-TOF/MS

Objective: As a classic prescription in traditional Chinese medicine, Xuefu Zhuyu Decoction(XFZYD) has been widely used in the clinical treatment of cardiovascular and cerebrovascular diseases. In order to unveil the potentially effective compounds, a rapid ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS) method was established to identify prototype compounds and their metabolites from XFZYD in rats’ serum.Methods: The serum from rats after intragastric administration of XFZYD aqueous extract was analyzed by UPLC-Q-TOF/MS method. The prototype compounds and their metabolites were identified by comparison with the reference standards and tentatively characterized by comprehensively analyzing the retention time, MS data, characteristic MS fragmentation pattern and retrieving literatures.Results: A total of 175 compounds(24 prototype compounds and 151 metabolites) were identified and tentatively characterized. The metabolic pathways of prototype compounds in vivo were also summarized, including glucuronidation, hydrolyzation, sulfation, demethylation, and hydroxylation, and so on.Conclusion: In this study, a UPLC-Q-TOF/MS technique was developed to analyze prototype compounds and their metabolites from XFZYD in serum, which would provide the evidence for further studying the effective compounds of XFZYD.

具有双功能酶活性的Au/Cu多级组装颗粒的构建

纳米酶被定义为具有独特纳米结构和催化活性的模拟酶.受天然酶的启发,我们报道了一种具有仿多酚氧化酶和过氧化物酶活性的双功能Au/Cu多级组装颗粒(Hops).它不但能够快速氧化难降解的有毒酚类污染物,还可以用于灵敏检测生物供能物质.Au/Cu Hops纳米酶表现出优异的催化活性和可回收性,并且可在极端条件下保持稳定.值得注意的是,与天然漆酶相比,在相同质量浓度下,Au/Cu Hops纳米酶催化对苯二酚氧化反应具有更高的底物亲和力和6.37倍的Vmax.此外,基于Au/Cu Hops的仿过氧化物酶活性,我们构建了级联反应系统用于检测葡萄糖浓度,检测限低至5μmol L^(-1).最后,通过分子动力学模拟,我们证明了Cu-S簇在Au/Cu Hops表面形成双催化活性位点,并通过密度泛函理论计算揭示了纳米酶的催化途径.该工作对双功能纳米酶的构建和应用具有重要意义.

Supramolecular chiral polymeric aggregates: Construction and applications

Inspired by the mystery of natural homochirality,the design and construction of artificial chiral systems with special functions including mechanics,chiroptical devices,and chiral separation have aroused the great interest of scientists.Due to its diverse conformations and components,polymers become an excellent candidate to construct artificial chiral aggregates,which provides an opportunity to fabricate advanced chiral materials.Herein,in this review,we summarized not only the different strategies for construction and regulation of supramolecular chirality in chiral or achiral polymer systems,mainly including post-assembly and polymerizationinduced chiral self-assembly in chiral polymer systems and several chirality transfer and induction strategies in achiral polymer systems,but also the formation mechanisms of chiral aggregates by the chirality amplification from the molecular level to supramolecular level.Furthermore,we present the typical applications of chiral polymeric aggregates in circularly polarized light emission,chiral recognition and separation,and chiral elastomer.Finally,the current challenges and future directions of chiral polymeric aggregates are also elaborated.

肽基多孔材料及其应用

多肽自组装形成的多孔结构是新一代多孔材料,在催化、传感、分离和药物递送等领域具有很好的应用前景.肽基多孔材料的孔内充满氨基酸侧链,因此可以通过合理设计或修改肽序列来调节其孔径大小和性能.功能基团和金属离子的引入进一步扩展了多肽基多孔材料的结构与性能.在这篇综述中,我们讨论了肽基多孔材料的设计、合成、组装及其性能,并综述了近年来其在不同领域的应用.

Hierarchical metal-peptide assemblies with chirality-encoded spiral architecture and catalytic activity

We report the coordination assembly of the ferrocene-diphenylalanine(Fc-FF)with divalent copper ions(Cu^(2+))into metalpeptide assemblies(MPAs)with hierarchical spiral architectures.The MPA particles are composed of helically organized nanofibers which can be correlated to the logarithmic spirals.The MPAs are hierarchically porous with abundant Fc and Cu2+active sites and show much higher catalytic activity than natural laccase toward the decolorization reaction.Moreover,a series of hierarchical structures of the MPAs can be synthesized by controlling the temperature and enantiomeric excess(ee).The peptide enantiomers with higher ee values will self-assemble into highly complex and ordered structures,which show higher surface area and porosity and thus enhanced catalytic activity compared with those assembled by peptides with lower ee values.The results provide new insights into the vital role of chirality in directing the self-assembly of biomolecules into highly ordered complex functional structures.

随机Loewner演化介绍

本文对随机Loewner演化(stochastic Loewner evolution, SLE)这一新的研究方向做一个综述性的介绍.随机Loewner演化是Oded Schramm于2000年前后创立的曲线上的单参数共形不变测度族理论.它与复分析、共形几何、分形几何和随机分析有非常紧密的联系,特别是在统计物理中有十分重要的应用.

多肽超分子手性自组装与应用

多肽分子作为一类重要的生物手性小分子,能够通过分子自组装形成包括纳米螺旋、纳米管、手性凝胶等在内的有着独特生物效应和光学活性的手性纳米材料。这类材料具有易于功能化修饰的优点,在化学、生物、医药、材料科学等领域有着广泛应用,成功对多肽手性自组装结构进行精准多级调控,是进一步实现其功能化应用的基础。本文重点介绍了多肽分子氨基酸序列组成与构型等内部因素,以及溶液pH、溶剂、添加剂等外界因素对多肽分子手性自组装行为的影响,并归纳得出其关键作用机制;同时,还介绍了多肽手性自组装材料在手性催化、手性检测、模板合成、手性光学等领域的应用。

DNA-多肽复合分子的设计、组装与应用

DNA-多肽复合分子作为一类新型的自组装分子受到研究人员的广泛关注。DNA分子具有可编程性、高特异性、功能多样等优点,多肽分子是一类重要的生物小分子,能够通过分子自组装形成具有不同结构的纳米材料,因此,将二者通过共价交联,可以获得具有多级自组装行为的DNA-多肽复合分子,能够实现两类重要生物分子功能的集成优化,合成具有不同结构与功能的超分子自组装材料。此外,通过酶催化、DNA杂化、DNA链置换反应等,还可实现对多肽-DNA复合分子自组装行为的动态调控,进而模拟生命系统中复杂动态的自组装结构,强化相关材料在生物、化学、材料等领域的应用。本文讨论了DNA-多肽复合分子的设计、组装与应用方面的最新进展,最后基于目前DNA-多肽复合分子存在的一些问题对DNA-多肽复合分子的研究做了展望。

The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure,myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns(mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism.Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.