Roles of 5-HT2 receptors in effects of DOM,ketamine and methamphetamine on prepulse inhibition in Sprague Dawley rats

OBJECTIVE Prepulse inhibition(PPI)of the acoustic startle response provides a measure of sensorimotor gating system mecha⁃nisms,which is known to be impaired in schizo⁃phrenia patients.We assessed the effects of the 5-HT2A/2C receptor agonist(±)2,5-dimethoxy-4-methylamphetamine(DOM),the NMDA receptor antagonist ketamine,the dopamine receptor ago⁃nist methamphetamine(Meth)on PPI and the startle magnitude in SD rats.METHODS AND RESULTS Systemic administration of the three compounds all dose-dependently reduced PPI.However,as far as startle magnitude,only DOM at the doses of 3 mg·kg-1 reduced that,while both ketamine and Meth did not change the startle magnitudes.Furthermore,to determine whether 5-HT2A receptor mediate this effect,the non-spe⁃cific 5-HT2 receptor antagonist cyproheptadine,specific 5-HT2A receptor antagonist ketanserin and specific 5-HT2C receptor antagonist SB242084 were tested.Cyproheptadine,ketan⁃serin and SB242084 did not alter startle ampli⁃tude by themselves in SD rats and only ketanserin slightly increased PPI at higher dose(3 mg·kg-1).PPI impairment induced by DOM was restored by pretreatment of cyproheptadine(1 mg·kg-1)and ketanserin(1 mg·kg-1),while not by pretreat⁃ment of SB242084(1 mg·kg-1).Damage of PPI induced by ketamine and Meth was not reversed by cyproheptadine(1 and 5 mg·kg-1).CONCLU⁃SION The receptor mechanisms underlying the disruption of PPI caused by DOM,ketamine and Meth were different from each other,at least 5-HT2A receptor was not the junction receptor for which the three chemicals acted.

Boosting ferroptosis and microtubule inhibition for antitumor therapy via a carrier-free supermolecule nanoreactor

Traditional microtubule inhibitors fail to significantly enhance+e effect of colorectal cancer;hence,new and efficient strategies are necessary.In+is study,a supramolecular nanoreactor(DOC@TA-Fe^(3+))based on tannic acid(TA),iron ion(Fe^(3+)),and docetaxel(DOC)wi+microtubule inhibition,reactive oxygen species(ROS)generation,and gluta+ione peroxidase 4(GPX4)inhibition,is prepared for ferroptosis/apoptosis treatment.After internalization by CT26 cells,+e DOC@TA-Fe^(3+)nanoreactor escapes from+e lysosomes to release payloads.+e subsequent Fe^(3+)/Fe^(2+)conversion mediated by TA reducibility can trigger+e Fenton reaction to enhance+e ROS concentration.Additionally,Fe^(3+)can consume gluta+ione to repress+e activity of GPX4 to induce ferroptosis.Meanwhile,+e released DOC controls microtubule dynamics to activate+e apoptosis pa+way.+e superior in vivo antitumor efficacy of DOC@TA-Fe^(3+)nanoreactor in terms of tumor grow+inhibition and improved survival is verified in CT26 tumor-bearing mouse model.+erefore,+e nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer+erapy.

Antidiabetic activity of Callicarpa nudiflora extract in type 2 diabetic rats via activation of the AMPK-ACC pathway

Objective:To evaluate the antidiabetic effect of Callicarpa nudiflora extract in streptozotoc-ininduced diabetic rats.Methods:The chemical constituents in Callicarpa nudiflora extract were identified by UPLCQ-TOF-MS.Callicarpa nudiflora extract(0.15 and 0.3 g/kg)was orally administered to streptozotocin-induced diabetic rats for 42 d.The effects of Callicarpa nudiflora extract on body weight,blood glucose,serum insulin,total cholesterol,triglyceride,LDL-C and HDL-C were investigated,and its effect on liver and pancreatic pathology was assessed by histopathological analysis.Moreover,the expression levels of adenosine 5’-monophosphate-activated protein kinase(AMPK),glucose transporter type 4(GLUT4),phospho-AMPK/AMPK,and p-acetylcoA carboxylase(P-ACC)/ACC in the skeletal muscles and liver were determined by reverse transcription-polymerase chain reaction,Western blotting,and immunohistochemistry.Results:A total of 34 compounds,including 8 iridoids,14 phenylpropanoids,and 12 flavonoids,were identified from Callicarpa nudiflora extract.Callicarpa nudiflora extract significantly reduced blood glucose and significantly restored all other biochemical parameters to near normal levels,including serum insulin,total cholesterol,triglyceride,LDL-C,and HDL-C.Callicarpa nudiflora extract improved insulin resistance and reversed the damage in the liver and pancreas caused by diabetes.Furthermore,Callicarpa nudiflora extract increased the expression levels of phospho-AMPK,GLUT4,P-ACC,and insulin receptor substrate-1 and decreased the expression level of PPAR r in diabetic rats.Conclusions:Callicarpa nudiflora extract improved oral glucose tolerance,lipid metabolism,insulin resistance,and reversed the diabetes-related damage in the liver and pancreas by activating the AMPK-ACC pathway.

Commonalities and characteristics of aqueous extracts from three Uighur medicines were analyzed by using three-stage infrared spectroscopy combined with ultra-performance liquid chromatography-time of flight-mass spectra

OBJECTIVE: To establish a method to analyze the commonalities and characteristics of the aqueous extracts from three Uighur medicines.METHODS: In this study, a combination method of three-stage infrared spectroscopy and ultra-performance liquid chromatography-time of flight-mass spectra(UPLC-TOF-MS) method was used to analyze the commonalities and characteristics of the aqueous extracts from Hezi(Fructus Chebulae),Maohezi(Terminalia Belliricae Fructus) and Xiqingguo(Chebulae Fructus Immaturus).RESULTS: In Fourier transform-infrared spectroscopy spectra, all three samples showed the characteristic absorption peaks of tannins similarly. According to UPLC-TOF-MS data analysis, the difference of the position and intensity of the peaks at 1713-1707 cm^(-1) in the three samples were related to the difference in the relative content of tannin and pentacyclic triterpenoids. In second derivative infrared spectroscopy spectra, further analysis of the differences in the infrared spectra of the three samples was performed by increasing the apparent resolution. In combination with UPLC-TOF-MS data, some features infrared absorption peaks were assigned.The absorption peaks at 1032-1030 cm^(-1) assigned to the stretching vibration of C-O-C(ether bond)groups of tannins; 1164-1163, 1063-1062, 1009-1005, 904 cm^(-1) attributed to the stretching vibration of C-O(ether bond) and C-O-C groups of glycosidic compounds. 1385-1383 cm^(-1) attributed to the bending vibration of C-H(alkyl hydrogen) of methoxyl group of pentacyclic triterpenoids. Peak 835 cm^(-1) was assigned to the characteristic absorption peak of bending vibration of = C-H groups of pentacyclic triterpenoids. The two dimensional correlation infrared spectroscopy could further quickly distinguish three samples through the dynamic structural information of their chemical components and discrepancy of auto-peaks and cross-peaks intuitively in the range of 1720-419 cm^(-1).CONCLUSION: By comparing the intensity of the infrared characteristic absorption peaks, the main chemical components were assigned, which significantly enriched and perfected the data analysis of the infrared spectra of three Uighur Medicines. It provided a rationale for the identification of medicinal materials with complex and similar chemical components using the three-stage infrared spectroscopy and UPLC-TOF-MS.

Analyses and identification of the chemical constituents of the Uighur formulation Baixuan Xiatare using three-stage infrared spectroscopy

OBJECTIVE:To identify,rapidly and accurately,the chemical composition of the traditional Uighur formulation Baixuan Xiatare(BXXTR-FU).METHODS:We investigated if application of three-stage infrared(IR)spectroscopy enabled identification of the main chemical constituents(and their origins)in BXXTR-FU.RESULTS:The characteristic peaks of herbal material(s)and BXXTR-FU were assigned.In Fourier transform-IR(FT-IR)spectroscopy of BXXTR-FU,peaks at1616 and 1605 cm-1 of BXXTR-FU were considered to denote anthraquinones and their derivatives;1066 cm-1 was regarded as the characteristic absorption peak of resin glycosides.In second-derivative IR(SD-IR)spectroscopy,the main carbonyl types of BXXTR-FU in the range 1743-1636 cm-1 were assigned:1651 cm-1 belonged to the carbonyl stretching vibrations of flavonoids and chromones;1717 cm-1 belonged to tannins;1699 cm-1 belonged to carboxylic acids;1636 cm-1 belonged to anthraquinones and their derivatives.SD-IR spectroscopy further confirmed that the characteristicabsorption peaks at 1636,1618 and 1603 cm-1 could be used as markers that BXXTR-FU contained anthraquinones and their derivatives.Synchronous2 D-IR correlation spectra of chemical groups further confirmed the results of FT-IR and SD-IR spectroscopy.CONCLUSION:Our study strongly supported the necessity and importance of three-stage IR spectroscopy owing to its rapid and accurate identification of herbal formulations.

Catalytic Asymmetric Cross-Dehydrogenative Coupling of 2H-Chromenes and Aldehydes

The first catalytic asymmetric cross-dehydrogenative coupling of 2H-chromenes with aldehydes using o-chloranil (3,4,5,6-tetrachloro-1,2- benzoquinone)as an oxidant has been described.The organocatalytic process is tolerated with a broad range of structurally and electronically varied 2H-chromenes and aldehydes with good yield and high enantiocontrol.

Recent advances in the development of nanomedicines for the treatment of ischemic stroke

Ischemic stroke is still a serious threat to human life and health,but there are few therapeutic options available to treat stroke because of limited blood-brain penetration.The development of nanotechnology may overcome some of the problems related to traditional drug development.In this review,we focus on the potential applications of nanotechnology in stroke.First,we will discuss the main molecular pathological mechanisms of ischemic stroke to develop a targeted strategy.Second,considering the important role of the blood-brain barrier in stroke treatment,we also delve mechanisms by which the blood-brain barrier protects the brain,and the reasons why the therapeutics must pass through the blood-brain barrier to achieve efficacy.Lastly,we provide a comprehensive review related to the application of nanomaterials to treat stroke,including liposomes,polymers,metal nanoparticles,carbon nanotubes,graphene,black phosphorus,hydrogels and dendrimers.To conclude,we will summarize the challenges and future prospects of nanomedicine-based stroke treatments.

Recent advances of two-dimensional materials in smart drug delivery nanosystems

Smart drug delivery nano-systems show significant changes in their physical or chemical properties in response to slight change in environmental physical and/or chemical signals,and further releasing drugs adjusted to the progression of the disease at the right target and rate intelligently.Two-dimensional materials possess dramatic status extend all over various scientific and technological disciplines by reason of their exceptional unique properties in application of smart drug delivery nano-systems.In this review,we summarized current progress to highlight various kinds of two-dimensional materials drug carriers which are widely explored in smart drug delivery systems as well as classification of stimuli responsive two-dimensional materials and the advantages and disadvantages of their applications.Consequently,we anticipate that this review might inspire the development of new two-dimensional materials with smart drug delivery systems,and deepen researchers’understanding of smart nano-carries based on two-dimensional materials.

Anti-cataract effects of Dajizhi(Euphorbium) eye drops on selenite-induced cataracts in rats

OBJECTIVE:To evaluate the effects of Dajizhi(Euphorbium)on selenite-induced cataracts.METHODS:Wistar rat pups were divided into 9 groups.Rats in group 1 were subcutaneously injected with saline,and rats in the other groups were injected with sodium-selenite.Every right eye was treated with 5μL eye drops 3 times per day,and the left eye received no treatment.The eyes of rats in group 3 were treated with pirenoxine;rats in groups 4,5,6,7,8 and 9 were respectively treated with Dajizhi(Euphorbium)(25 mg/m L),Dajizhi(Euphorbium)(5 mg/m L),Dajizhi(Euphorbium)methanol extract(25 mg/m L),Dajizhi(Euphorbium)methanol extract(5 mg/m L),euphol(25 mg/m L),euphol(5 mg/m L).Cataracts were observed by a slit lamp before and after treatment.Electroretinograms were acquired at set intervals.The morphological changes of the rat eyes were observed in vitro,and the levels of glutathione peroxidase(GSH-Px)and superoxide dismutase(SOD)in the lenses and aqueous humour were estimated at set intervals.RESULTS:Slit lamp examination showed decreased degrees of cataracts after administration of the different treatments.Morphological comparison showed that Dajizhi(Euphorbium)can reduce the turbidity of the lenses,meaning that Dajizhi(Euphorbium)has the anti-cataract effects.Low-concentration of Dajizhi(Euphorbium),its methanol extract and euphol treatment prevented the b-wave amplitudes of the electroretinograms from falling.Euphorbium treatment significantly restored GSH-Px and SOD levels in the lenses and aqueous humour,especially after 10 and 25 d of administration.Euphorbium may help lenses fight oxidative stress caused by selenite.CONCLUSION:The administration of Dajizhi(Euphorbium)can inhibit selenite-induced cataracts.

In sights into the antineoplastic mechanism of Chelidonium majus via systems pharmacology approach

Background: The antineoplastic activity of Chelidonium majus has been reported, but its mechanism of action (MoA) is unsuspected. The emerging theory of systems pharmacology may be a useful approach to analyze the complicated MoA of this multi-ingredient traditional Chinese medicine (TCM). Methods: We collected the ingredients and related compound-target interactions of C. majus from several databases. The bSDTNBI (balanced substructure-drug-target network-based inference) method was applied to predict each ingredienfs targets. Pathway enrichment analysis was subsequently conducted to illustrate the potential MoA, and prognostic genes were identified to predict the certain types of cancers that C. majus might be beneficial in treatment. Bioassays and literature survey were used to validate the in silico results? Results: Systems pharmacology analysis demonstrated that C. majus exerted experimental or putative interactions with 18 cancer-associated pathways, and might specifically act on 13 types of cancers. Chelidonine, sanguinarine, chelerythrine, berberine, and coptisine, which are the predominant components of C. majus, may suppress the cancer genes by regulating cell cycle, inducing cell apoptosis and inhibiting proliferation. Conclusions: The antineoplastic MoA of C. majus was investigated by systems pharmacology approach. C. majus exhibited promising pharmacological effect against cancer, and may consequently be useful material in further drug development. The alkaloids are the key components in C. majus that exhibit anticancer activity.

Multifunctional metal-polyphenol nanocomposite for melanoma targeted photo/chemodynamic synergistic therapy

Due to the hypoxic state of the tumor microenvironment(TME),photodynamic therapy(PDT)suffers from insufficient ROS production.The metal-polyphenol network-mediated Fenton reaction can generate reac-tive oxygen species(ROS)by consuming H_(2)O_(2) in TME,improving the inadequate ROS generation problem of PDT.Therefore,synergistic therapy combining PDT and Fenton response-based CDT is a promising ap-proach for cancer treatment.Herein,a metal-polyphenol nanocomposite was deposited with gallic acid grafted hyaluronic acid and Fe^(3+) to contrast a Ce6 nano-delivery system(Ce6@HSF NPs)for melanoma synergistic therapy.Ce6@HSF NPs could be used as a Fenton reagent to induce the·OH production and enhance the PDT effect of Ce6 to a certain extent.After 4 h of cellular uptake,the fluorescence intensity of Ce6 in the Ce6@HSF NPs group was higher than 3 times that in the Ce6 group.The intracellular ROS generation level of the Ce6@HSF NPs(L)group combining CDT and PDT was higher than that of the Ce6 group and Ce6@HSF NPs group.In vitro and in vivo anti-melanoma studies show that Ce6@HSF NPs(L)group exhibited better anti-melanoma than other groups.Together,Ce6@HSF NPs provide a promising synergistic treatment potential for melanoma.