Rotating magnetic field inhibits Aβ protein aggregation and alleviates cognitive impairment in Alzheimer’s disease mice

Amyloid beta(Aβ)monomers aggregate to form fibrils and amyloid plaques,which are critical mechanisms in the pathogenesis of Alzheimer’s disease(AD).Given the important role of Aβ1-42 aggregation in plaque formation,leading to brain lesions and cognitive impairment,numerous studies have aimed to reduce Aβaggregation and slow AD progression.The diphenylalanine(FF)sequence is critical for amyloid aggregation,and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings.In this study,we examined the effects of a moderate-intensity rotating magnetic field(RMF)on Aβaggregation and AD pathogenesis.Results indicated that the RMF directly inhibited Aβamyloid fibril formation and reduced Aβ-induced cytotoxicity in neural cells in vitro.Using the AD mouse model APP/PS1,RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments,including exploration and spatial and non-spatial memory abilities.Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation,attenuated microglial activation,and reduced oxidative stress in the APP/PS1 mouse brain.These findings suggest that RMF holds considerable potential as a non-invasive,high-penetration physical approach for AD treatment.

Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field

Acetaminophen(APAP),the most frequently used mild analgesic and antipyretic drug worldwide,is implicated in causing 46%of all acute liver failures in the USA and between 40%and 70%in Europe.The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine(NAC);however,its efficacy is limited in cases of advanced liver injury or when administered at a late stage.In the current study,we discovered that treatment with a moderate intensity static magnetic field(SMF)notably reduced the mortality rate in mice subjected to high-dose APAP from 40%to 0%,proving effective at both the initial liver injury stage and the subsequent recovery stage.During the early phase of liver injury,SMF markedly reduced APAPinduced oxidative stress,free radicals,and liver damage,resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione(GSH).During the later stage of liver recovery,application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation.Moreover,the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery,even 24 h post overdose,when the effectiveness of NAC alone substantially declines.Overall,this study provides a noninvasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose.Of note,this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP,and potentially other toxic overdoses.

Study on the Effectiveness of Circulation Well for Remediation of Benzene and Toluene Contaminated Silt Sand Aquifer

In order to investigate the remediation effect of groundwater circulation well on benzene and toluene contaminated silt sand aquifer,a simulation remediation experiment was conducted in the laboratory using a two-dimensional simulation tank.The results showed that in the silt sand aquifer,the concentrations of benzene and toluene decreased from 179.210 mg/L and 327.520 mg/L to below the detection limit after 24 h of operation of the circulation well.The closer to the circulation well in the horizontal direction,the faster the removal efficiency of benzene and toluene.The study has shown that circulating wells have good remediation effects on both benzene-and toluene-contaminated chalk sand aquifers.

Effects of gradient high-field static magnetic fields on diabetic mice

Although 9.4 T magnetic resonance imaging(MRI) has been tested in healthy volunteers,its safety in diabetic patients is unclear.Furthermore,the effects of high static magnetic fields(SMFs),especially gradient vs.uniform fields,have not been investigated in diabetics.Here,we investigated the consequences of exposure to 1.0-9.4 T high SMFs of different gradients(>10 T/m vs.0-10 T/m)on type 1 diabetic(T1D) and type 2 diabetic(T2D) mice.We found that 14 h of prolonged treatment of gradient(as high as 55.5 T/m) high SMFs(1.0-8.6 T) had negative effects on T1D and T2D mice,including spleen,hepatic,and renal tissue impairment and elevated glycosylated serum protein,blood glucose,inflammation,and anxiety,while 9.4 T quasi-uniform SMFs at 0-10 T/m did not induce the same effects.In regular T1D mice(blood glucose>16.7 mmol/L),the>10 T/m gradient high SMFs increased malondialdehyde(P<0.01) and decreased superoxide dismutase(P<0.05).However,in the severe T1D mice(blood glucose≥30.0 mmol/L),the>10 T/m gradient high SMFs significantly increased tissue damage and reduced survival rate.In vitro cellular studies showed that gradient high SMFs increased cellular reactive oxygen species and apoptosis and reduced MS-1 cell number and proliferation.Therefore,this study showed that prolonged exposure to high-field(1.0-8.6 T)>10 T/m gradient SMFs(35-1 380 times higher than that of current clinical MRI)can have negative effects on diabetic mice,especially mice with severe T1D,whereas 9.4 T high SMFs at 0-10T/m did not produce the same effects,providing important information for the future development and clinical application of SMFs,especially high-field MRI.

房屋建筑工程中防渗漏施工技术的运用分析

房屋建筑防渗漏技术直接关系到人们的生活质量和安全,因此在房屋建筑工程施工中,应对造成房屋建筑渗漏的因素予以分析,并采取合理的防渗漏施工技术来提高建筑质量,延长建筑使用寿命。

Effects of All-trans Retinoic Acid (ATRA) against Bacterial Infection in Chickens

In order to investigate the effects of all-trans retinoic acid （ATRA） against bacterial infection in chickens, 35 3-day-old AA broiler chickens were fed adaptively for two days and randomly divided into five groups, including Escherichia coli experimental group （ group 1 ）, Escherichia coli control group （group 2）, blank control group （ group 3 ）, PasteureUa experimental group （ group 4）, and PasteureUa control group （ group 5 ）. At 5 days of age, the chickens in group 1 and group 4 were drenched with 5 p.mol/kg ATRA for seven consecutive days according to their weight; the chickens in group 2, group 3 and group 5 were drenched with an equal volume of dimethyl sulfoxlde （DMSO）. The clinical symptoms and weight changes in each group were observed and recorded. Seven days later, the chickens were euthanized and dissected to determine the immune organ indexes. The results showed that there were significant differences in body weight between ATRA-administrated chickens and non-administrated chickens after bacterial infection （P 〈 0.05 ） ; moreover, the immune organ indexes of ATRA-administrated chickens exhibited significant differences compared with control group （P 〈 0.05 ）, indicating that ATRA could promote the development of immune organs of poultry, thereby enhancing the body immunity against bacterial infection.

An Anomeric Base-Tolerant Ester of 8-Alkynyl-1-naphthoate for Gold(I)-Catalyzed Glycosylation Reaction

Given the extreme complexity and diversity of carbohydrates,efficient approaches to the homogeneous oligosaccharide remain limited.Chemical synthesis represents one of the most reliable methods to access homogeneous samples,which mainly relies on the key glycosylation reaction.Consistent with enormous efforts to develop leaving groups for establishing robust glycosylation protocols,we herein disclose a structurally novel leaving group of 8-phenylethynyl-1-naphthoate that is able to enable efficient glycosylation reactions under the extremely mild condition of gold(I)-catalysis.Notably,the anomeric naphthoate possesses the unprecedent character of base-stability in sharp contrast to the conventional ester groups at anomeric position of carbohydrates,which endows high compatibility with a variety of chemical transformations.Furthermore,the present glycosylation protocol with 8-phenylethynyl-1-naphthoate as leaving group is able to realize minimally protected glycosylation processes.Mechanistic studies reveal a unique structure of 8-phenylethynyl-1-naphthoate that accounts for the reason for these characteristics.

Total Synthesis of Starfish Cyclic Steroid Glycosides.Part 2,Model Synthesis via Intramolecular Etherification

Comprehensive Summary Sepositoside A(1)is a prototypical cyclic steroid glycoside bearing a hybrid 16-membered ring composed of the steroid skeleton and a 1,2-trans-linked trisaccharide.Herein,we report an expedient access toward two simplified analogues,in which the strained 16-membered ring is constructed via Au(I)-catalyzed intramolecular addition of alcohol to epoxide.A similar macroetherification in relevant steroid trisaccharides has been intensively examined,however,failed to furnish the macrocyclic skeleton of Sepositoside A.

Total Synthesis of Starfish Cyclic Steroid Glycosides.Part 3,Formal Total Synthesis of Luzonicosides A and D

Comprehensive Summary Luzonicosides A(1)and D(2)are the major saponins isolated from pacific starfish Echinaster Luzonicus,featuring a sterically congested 16-membered ring which is formed by bridging the C3 and C6 of a 3β,6β-dihydroxy-Δ7-ene steroid with a 1,2-trans-linked linear trisaccharide via glycosidic and ether bonds,respectively.Here,we describe a formal total synthesis of starfish cyclic steroid glycosides 1 and 2.The synthetic route is highly modular and versatile,involving construction of the 16-membered macrocycles via Au(I)-catalyzed intramolecular glycosylation,highly efficient installation of unsaturated sugar moieties with ortho-hexynylbenzoates,elaboration of glucuronic acid unit via post-oxidation,and a de novo synthesis of the ether-linked pyranose unit.

Magnetic Fields Affect Alcoholic Liver Disease by Liver Cell Oxidative Stress and Proliferation Regulation

It is well known that alcohol consumption leads to substantially increased free radical levels and health risks,which lacks effective treatment besides alcohol abstinence.Here,we compared different static magnetic field(SMF)settings and found that a downward quasi-uniform SMF of~0.1 to 0.2 T could effectively alleviate alcohol-induced liver damage and lipid accumulation and improve hepatic function.SMFs of two different directions can reduce the inflammation,reactive oxygen species levels,and oxidative stress in the liver,while the downward SMF had more obvious effects.Moreover,we found that the upward direction SMF of~0.1 to 0.2 T could inhibit DNA synthesis and regeneration in hepatocytes,which caused detrimental effects on the lifespan of"heavy drinking"mice.In contrast,the downward SMF prolongs survival of"heavy drinking"mice.On one hand,our study shows that~0.1 to 0.2 T moderate quasi-uniform SMFs with a downward direction have great promises to be developed into a physical method to reduce alcohol-induced liver damage;on the other hand,although the internationally recognized upper limit for SMF public exposure is 0.4 T,people should also pay extra attention to SMF strength,direction,and inhomogeneity that could generate harmful effects on specific severe pathological conditions.

The aromatic peptide protected gold nanoclusters with significant Stokes shift:Ligand-mediated two-step FRET

During the last decade,a great variety of ligand protected gold nanoclusters(AuNCs)have been synthesized,and their broad applications have been intensively reported.Although the spectroscopic properties of AuNCs have been comprehensively explored,the mechanism of the significant Stokes shift(>200 nm)and the specific role played by surface ligands have not been clearly explained yet.In this study,a series of fluorescent AuNCs with huge Stokes shift(up to 530 nm)were successfully prepared by employing the rationally designed tri-peptides as the protecting ligands,and their spectroscopic properties were systematically investigated.The detailed measurements on the example product,YCY-AuNCs(Tyr-Cys-Tyr liganded AuNCs),showed that the energy absorbed by the tyrosine(~250 nm)can be effectively transferred through the ligand-mediated two-step Förster resonance energy transfer(FRET)process and released as fluorescence emission in the near-infrared fluorescence(NIR)range(~780 nm),which resulted in the significant apparent Stokes shift.The YCY ligands play a critical role by offering the tyrosine groups(donor of the first FRET pair),generating the dityrosine-like structure on the AuNCs surface(acceptor of the first FRET pair and donor of the second FRET pair),and protecting the cores(acceptor of the second acceptor).The additional ligand exchange experiments and the investigation on the other AuNCs further demonstrated that the sufficient high density of the aromatic groups is also essential to mediate the two-step FRET and achieve the remarkable Stokes shift.We believe that the aromatic ligand-mediated FRET mechanism not only offers a new theoretical explanation for the huge Stokes shift exhibited in AuNCs,but also provides a general strategy for the construction of new materials with large Stokes shift.

Peptidomimetic-liganded gold nanoclusters for controlled iron delivery and synergistic suppression of tumor growth

A novel peptidomimetic-liganded gold nanocluster(CDp-AuNC)is proposed for the synergistic suppression of tumor growth.Taking advantages of the multi-capabilities offered by the surface ligands,including iron chelation,glutathione peroxidases-1(GPx-1)binding,and tumor cells recognition,CDp-AuNCs are able to function as the nanocarriers to deliver iron in a controlled manner for the ferroptosis therapy and as the inhibitors for GPx-1 to induce the apoptosis of tumor cells.The Fe2+@CDp-AuNC nanocomplexes are fabricated through a facile self-assembly method.The experimental data verify that the nanocomplexes are internalized specifically by tumor cells with high efficiency.The acidic microenvironment in endosomes triggers the collapse of the nanocomplexes and thereby releases Fe2+to induce ferroptosis and CDp-AuNCs to inhibit the enzyme activity of GPx-1.Benefiting from the H_(2)O_(2)-depleted pathway inhibition and ferroptosis acceleration,the intracellular reactive oxygen species(ROS)level could be enhanced significantly.As a consequence,the apoptosis/ferroptosis of 4T1 cells as well as the tumor elimination in vivo are observed after treatment with the Fe2+@CDp-AuNC nanocomplexes at a relatively low dose.The facile iron loading method,simple construction procedure,and outstanding tumor suppression performance,provide CDp-AuNCs great application promise.More importantly,the strategy of peptidomimetic ligands design provides a transferable approach to building multifunctional nanomaterials.

Total Synthesis of Starfish Cyclic Steroid Glycosides.Part 1,Synthesis of the Aglycone and Attempts at Installation of the Sugar Units

Comprehensive Summary Sepositoside A(1)is the major and first cyclic steroid glycoside isolated from starfishes,which features a strained 16-membered ring formed by tethering C3 and C6 of the steroid aglycone with a linear trisaccharide.We conceived a convergent synthetic plan in which sepositoside A was disconnected into a disaccharide and a steroid-glucose hybrid ether.The desired 3β,6β-dihydroxy-Δ7,8-23-one aglcyone was readily prepared from dehydroepiandrosterone in 12 steps.The etherification of the 6β-hydroxy-Δ7,8-steroid with a variety of hexopyranoside-C6-electrophiles and CO_(2)-extrusion of a steroid-pyranose hybrid carbonate were extensively studied;however,formation of the desired steroid-pyranose etherate linkage has not been successful.Model studies on theβ-selective installation of the(1→2)-linked disaccharide onto the steroidal C3β-OH with the corresponding disaccharideα-imidates were also examined,however,formation of theα-glycosides prevailed.The present results force us to explore alternative approaches to construct the steroid-pyranose etherate linkage and stepwise assembly of the glycans en route to the starfish cyclic steroid glycosides,which will be presented in two articles that follow.

Bioeffects of Microgravity and Hypergravity on Animals

Gravity alterations in space cause significant adaptive effects on the human body,including changes to the muscular,skeletal,and vestibular systems.However,multiple factors besides gravity exist in space;therefore,it is difficult to distinguish gravity-related bioeffects from those of the other factors,including radiation.Although everything on the Earth surface is subject to gravity,gravity-induced effects are not explicitly clear.Here,different research methods that have been used in gravity alterations,including parabolic flight,diamagnetic levitation,and centrifuge,are reviewed and compared.The bioeffects that are reported to be associated with altered gravity in animals are summarized,and the potential risks of hypergravity and microgravity are discussed,with a focus on microgravity,which has been studied more extensively.It should be noted that although various microgravity and hypergravity research methods have their limitations,such as the inevitable magnetic field effects in diamagnetic levitation and short duration of parabolic flight,it is evident that ground-based clinical,animal,and cellular experiments that simulate gravity alterations have served as important and necessary complements to space research.These researches not only provide critical and fundamental biological information on the effects of gravity from biomechanics and the biophysical perspectives,but also help in developing future countermeasures for astronauts.

Synthesis of the Diverse Glycosides in Traditional Chinese Medicine

CT Traditional Chinese medicine （TCM） is a huge treasure trove for the discovery and development of modern pharmaceuticals. Indeed, numerous biologically and pharmacologically significant molecules have been identified from TCM; among them, a considerable portion belongs to glycosides. These glycosides are extremely diverse in structures, consisting of a large variety of aglycones, glycans, as well as glycosidic linkages. In addition, these glycosides occur frequently as a complicated mixture of congeners in the nature sources. This micro-heterogeneity leads to the isolation of a ho- mogeneous glycoside in an appreciable amount a formidable task. Therefore, development of synthetic approaches toward these nature glycosides has received great attention. In this account, we summarize our twenty-year efforts spent on this topic. Fifty five representative TCM-relevant glycosides synthesized by our group are highlighted. Based on the aglycone structure, these glycosides are categorized into three groups, i.e., steroid glycosides, triterpene glycosides, and flavonoid and phenolic glycosides. Typical synthetic approaches are discussed, showing the demanding tactics for regio- and stereo-controlled installation of glycans and overall manipulation of protecting groups. These expedient and scalable synthetic approaches have provided practical alternatives to the accessibility of these TCM components and thus opportunities for their in depth biological and pharmacological studies.

Carbohydrate-based drugs launched during 2000-2021

Carbohydrates are fundamental molecules involved in nearly all aspects of lives,such as being involved in formating the genetic and energy materials,supporting the structure of organisms,constituting invasion and host defense systems,and forming antibiotics secondary metabolites.The naturally occurring carbohydrates and their derivatives have been extensively studied as therapeutic agents for the treatment of various diseases.During 2000 to 2021,totally 54 carbohydrate-based drugs which contain carbohydrate moities as the major structural units have been approved as drugs or diagnostic agents.Here we provide a comprehensive review on the chemical structures,activities,and clinical trial results of these carbohydrate-based drugs,which are categorized by their indications into antiviral drugs,antibacterial/antiparasitic drugs,anticancer drugs,antidiabetics drugs,cardiovascular drugs,nervous system drugs,and other agents.

Revealing Functional Significance of Interleukin-2 Glycopro-teoforms Enabled by Expressed Serine Ligation

Naturally occurring interleukin-2(IL-2)is a pleiotropic glycoprotein that regulates immune responses by controlling the differentia-tion and homeostasis of T cells.Non-glycosylated IL-2 has been used in clinical settings for three decades.However,the function of the O-glycan of native IL-2 remains elusive.Herein,to stress this issue,we report a highly efficient semi-synthesis of homogeneous glycosylated IL-2 with various glycoproteoforms on a multi-milligram scale.The glycopeptide fragment was prepared by chemical synthesis and then merged with recombinant fragment via a serine ligation to generate the desired glycoprotein in a single opera-tion.Biological evaluation of the homogenous glycoprotein library reveals that the activity of IL-2 in activating individual T cell subset is glycan dependent,thus highlighting the possibility of further improving current clinical medicine.

2-Diphenylphosphinoyl-acetyl as a Remote Directing Group for the Highly Stereoselective Synthesis ofβ-Glycosides

Comprehensive Summary The configuration of the anomeric glycosidic linkages is crucial for maintaining the biological functions and activities of carbohydrate molecules.However,their stereochemistry control in glycosylation represents one of the most challenging tasks in carbohydrate chemistry.

Synthesis of 4-（2-Phenylhydrazono）-l-（4-phenylthiazol-2-yl）- 1H-pyrazol-5（4H）-one Compounds and Characterization of Their Affinities to Anti-apoptotic Bcl-2 Family Proteins

Organic compounds containing the thiazol-2-yl-lH-pyrazol-5（4H）-one moiety are known to be associated with versatile pharmacological applications. In this study, we describe the methods for preparing 4-（2-phenylhydrazono）- l-（4-phenylthiazol-2-yl）-1H-pyrazol-5（4H）-one compounds. A set of 26 compounds were synthesized with overall yields ranging between 37%-92%. They were tested in a fluorescence polarization-based binding assay against three anti-apoptotic Bcl-2 family proteins, including Bcl-xL, Bcl-2, and Mcl-1. Our results indicate that this class of compounds are not effective inhibitors of these anti-apoptotic Bcl-2 family proteins. Their apoptosis-inducing ef- fects are possibly due to BAX activation as suggested by Gavathiotis et al. in their recent study. However, other possibilities should not be ignored. In addition, a crystal structure obtained by us reveals that the exocyclic double bond in the molecular structure of this class of compounds is in the （Z）-configuration.

Arabidopsis Acetyl-Amido Synthetase GH3.5 Involvement in Camalexin Biosynthesis through Conjugation of Indole-3-Carboxylic Acid and Cysteine and Upregulation of Camalexin Biosynthesis Genes

Camalexin （3-thiazol-2＇-yl-indole） is the major phytoalexin found in Arabidopsis thaliana. Several key intermediates and corresponding enzymes have been identified in camalexin biosynthesis through mutant screening and biochemical experiments. Camalexin is formed when indole-3-acetonitrile （IAN） is catalyzed by the cytochrome P450 monooxygenase CYP71A13. Here, we demonstrate that the Ara- bidopsis GH3.5 protein, a multifunctional acetyl-amido synthetase, is involved in camalexin biosynthesis via conjugating indole-3-carboxylic acid （ICA） and cysteine （Cys） and regulating camalexin biosynthesis genes. Camalexin levels were increased in the activation-tagged mutant gh3.5-1D in both Col-0 and cyp71A13-2 mutant backgrounds after pathogen infection. The recombinant GH3.5 protein catalyzed the conjugation of ICA and Cys to form a possible intermediate indole-3-acyl-cysteinate （ICA（Cys）） in vitro. In support of the in vitro reaction, feeding with ICA and Cys increased camalexin levels in Col-0 and gh3.5-1D. Dihydrocamalexic acid （DHCA）, the precursor of camalexin and the substrate for PAD3, was accumulated in gh3.5-1DIpad3-1, suggesting that ICA（Cys） could be an additional precursor of DHCA for camalexin biosynthesis. Furthermore, expression of the major camalexin biosynthesis genes CYP79B2, CYP71A12, CYP71A13 and PAD3 was strongly induced in gh3.5-1D. Our study suggests that GH3.5 is involved in camalexin biosynthesis through direct catalyzation of the formation of ICA（Cys）, and upregulation of the major biosynthetic pathway genes.