Pharmacological effects of volatile oil from chrysanthemum and its associated mechanisms:a review

Volatile oil(VO)is the main chemical component of common plants in Chrysanthemum genus,and it possesses several beneficial pharmacological properties,including bacteriostatic,antioxidant,anti-tumor,anti-inflammatory,antipyretic,analgesic,antiosteoporotic,antihypertensive,sedative,and hypnotic effects.To date,research on the effective components of Chrysanthemum extract has mainly focused on flavonoids,whereas limited data are available on the chemical constituents and underlying mechanisms of action of the VO components.In this review,the pharmacological activities and mechanisms of VO are comprehensively reviewed with the aim of providing a foundation for further development for medicinal,aromatherapy,and diet therapy applications.

Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of most common and deadliest malignancies.Celastrol(Cel),a natural product derived from the Tripterygium wilfordii plant,has been extensively researched for its potential effectiveness in fighting cancer.However,its clinical application has been hindered by the unclear mechanism of action.Here,we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and antitumor capacity by developing a Cel-based liposomes in HCC.We demonstrated that Cel selectively targets the voltage-dependent anion channel 2(VDAC2).Cel directly binds to the cysteine residues of VDAC2,and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore(mPTP)function.We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells.Moreover,coencapsulation of Cel into alkyl glucoside-modified liposomes(AGCL)improved its antitumor efficacy and minimized its side effects.AGCL has been shown to effectively suppress the proliferation of tumor cells.In a xenograft nude mice experiment,AGCL significantly inhibited tumor growth and promoted apoptosis.Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death,while the Cel liposomes enhance its targetability and reduces side effects.Overall,Cel shows promise as a therapeutic agent for HCC.

Cytokines Activation kinetics in lung due to COVID-19 infection

COVID-19,as a concern in the world,can lead to death with a wide range of symptoms.Coronavirus,like other viral diseases,leads to the activation of inflammatory responses such as triggering the cytokine cascade.During the contact of the surface of the virus and its internal components with the human immune system,the path of expression and activation of cytokines begins.The body fights the virus through this operation and sometimes cell apoptosis.In the current review study,PubMed,Scopes,and Google Scholar were searched to provide information have shown the inflammasomes of COVID-19.In a review study,we examine the evidence that shows that COVID-19 activates inflammasomes;inflammasomes are cytosolic receptors that can identify microbial pathogens and endogenous signals resulting from stress or cell damage,including NLRP3(NLR Family Pyrin Domain Containing 3)type,NLRP4(NLR Family Pyrin Domain Containing 4),NLRP3.Through the activation of ASC and caspase 1,inflammasomes lead to the secretion of cytokines IL-1β(Interleukin-1 beta),IL-18(Interleukin-18),and IL6(Interleukin-6),TNF-α(Tumor Necrosis Factor-alpha).They can lead to the activation of inflammatory pathways.The results of this research can be useful in clarifying the relationship between the inflammatory pathways caused by the COVID-19 virus in people and the discovery of drugs in infected people.

Improved anti-tumor efficacy and pharmacokinetics of bufalin via PEGylated liposomes

OBJECTIVE To determine the characterization,anti-tumor efficacy and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity.METHODS Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high pressure homogenization method.The particle size and zeta potential of the liposomes were determined by dynamic light scattering technique.The direct imaging of morphology of liposomes was charactered by transmission electron microscope.The content of bufalin in liposomes was analysed by HPLC method.The entrapment efficiency and the particle size was applied to assess the stability profile,after storage at 4℃ on day 0,7,15,30 and 90.The in-vitro release behaviours of bufalin from liposomes were conducted using dialysis bag technique at 37℃.In-vitro cytotoxicity studies were carried out using MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]assay on several kinds of tumor cel lines including SW620,PC-3,MDA-MB-231,A549,U251,U87 and HepG2.In-vivo pharmacokinetic study of bufalin liposomes was evaluated by HPLC method.RESULTS Their mean particle sizes were 127.6 nm and 155.0 nm,mean zeta potentials were 2.24 m V and-18.5 m V,entrapment efficiencies were 76.31%and 78.40%,respectively.In-vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that of bufalin-loaded liposomes.The cytotoxicity of blank liposomes has been found within acceptable range,whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity.In-vivo pharmacokinetics indicated that bufalinloaded PEGylated liposomes could extend eliminate half-life time of bufalin in plasma in rats.CONCLUSION The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.

A new flavonoid glucoside from Cassia angustifolia

A new flavonoid glucoside with a known one was isolated from the leaves of Cassia angustifolia. Based on the spectral analysis, including MS, ^1H NMR, ^13C NMR, DEPT, ^1H-1HCOSY, HMQC, HMBC and NOSEY, their chemical structures were determined as kaempferol-3-O-[（6＇＇＇-O-trans-sinnapoyt）-β-D-glucopyranosyl （1 → 6）]-β-D-glucopyranoside 1 and apigenin-6,8-di-C-glycoside 2.

Synthesis, Crystal Structure and Cytotoxic Activity of a New NAN-190 Analogue

The NAN-190 analogue 2-(2-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethoxy)ethyl)isoindoline-1,3-dione(1, C23H27N3O4, Mr = 409.48) was synthesized via a three-step reaction and characterized by 1H NMR, 13 C NMR, ESIMS and single-crystal X-ray diffraction. The crystal belongs to orthorhombic, space group Pna21 with a = 7.6445(15), b = 38.851(8), c = 7.1316(14) A, V = 2118.0(7) A3, Z = 4, Dc = 1.2840 mg/mm3, μ = 0.089 mm-1, F(000) = 872.4, R = 0.0545 and w R = 0.1681. The single-crystal X-ray structural analysis reveals that the piperazine ring in compound 1 presents a stable and minimum energy chair conformation. In addition, the preliminary cytotoxic assay shows that the title compound exhibits strong and selective inhibitory activity against DU145 cells(IC50 = 5.88 ± 1.02 μM).

PEPT1-mediated prodrug strategy for oral delivery of peramivir

Peramivir was a novel and highly potent neuraminidase(NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability(only 3%) due to the high polarity(log P of-1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH_2)_2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine(gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC 50 was 1.34 ± 0.31 m M and 1.78 ± 0.48 m M, respectively. The direct uptake of Peramivir-(CH_2)_2-l-Val and Peramivirl-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile(0.01 to 50 m M) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH_2)_2-l-Val was rapid and extensive, and no Peramivir-(CH_2)_2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH_2)_2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug.

Polylactic Acid Nanoparticles Targeted to Brain Microvascular Endothelial Cells

In this work, blank polylactic acid （PLA） nanoparticles with unstained surface were prepared by the nano-deposition method. On the basis of the preparation, the effect of surface modification on brain microvascular endothelial cells （BMECs） targeting was examined by in vivo experiments and fluorescence microscopy. The results showed that PLA nanoparticles are less toxic than PACA nanoparticles but their BMECs targeting is similar to PACA nanoparticles. The experiments suggest that drugs can he loaded onto the particles and become more stable through adsorption on the surface of PLA nanoparticles with high surface activity. The surface of PLA nanoparticles was obviously modified and the hydrophilicity was increased as well in the presence of non-ionic surfactants on PLA nanoparticles. As a targeting moiety, polysobate 80 （T-80） can facilitate BMECs targeting of PLA nanoparticles.

Protective role of FoxO transcription factors against oxidative stress-induced chondrocyte dysfunction:a new therapeutic target for osteoarthritis

Chondrocyte dysfunction has been demonstrated to be a major inducer of osteoarthritis(OA).The pathological mechanism of chondrocyte dysfunction is definitely multifactoral,but oxidative stressis regarded as one of the leading causes of apoptosis,autophagy,senescence,and mitochondrial dysfunctionin chondrocytes.Strategies for arresting oxidative stress-induced chondrocyte dysfunction have been considered as potential therapeutic targets for OA.Recently,fork head box O(Fox O)transcription factors have been determined to play a protective role in chondrocytes through the regulation of autophagy and defense against oxidative stress;they also regulate growth,maturation,and matrix synthesis.To explore Fox O′s potential role in the treatment of OA,we first discussed the recent advances in the field of oxidative stress-induced chondrocyte dysfunction and then emphasized the protective role of fox otranscription factors as a potential molecular target for the treatment of OA.Understanding the function of fox otranscription factors will be important in designing next-generation therapies to prevent or reverse the development of OA.

Magnetic resonance imaging-guided and targeted theranostics of colorectal cancer

Colorectal cancer(CRC)is the most common gastrointestinal tract cancer worldwide and is associated with high morbidity and mortality.The development of nanosized drug delivery systems has provided a new direction in CRC treatment.Among these systems,magnetic nanoparticle(MNP)-based multifunctional platforms provide a novel strategy for magnetic resonance imaging(MRI)-related cancer theranostics.At the beginning o f this original review,the carcinogenesis and treatment status o f CRC are summarized.Then,diversified preparation and functionalization methods of MNPs are systematically analyzed,followed by MRIinvolved theranostic strategies.The latest progress in MRI-mediated multimode diagnosis and image-guided targeted therapy in CRC management is the main focus.Finally,the major challenges in promoting MRI-induced precise theranostics of CRC in clinical practice are discussed.

Silkworm Extract Ameliorates Type 2 Diabetes Mellitus and Protects Pancreaticβ-cell Functions in Rats

Objective The aim of the present study was to investigate the hypoglycemic effects of silkworm extract(SE)on experimental type 2 diabetes mellitus(T2DM)rats.Methods SE was prepared by dissolving freeze-dried silkworm powder in 70%(v/v)aqueous ethanol.T2DM rats were induced by feeding them a high fat diet and an intraperitoneal injection of streptozotocin(STZ).The blood glucose,free fatty acid(FFA),malondialdehyde(MDA),tumor necrosis factor alpha(TNF-α)and superoxide dismutase(SOD)levels were detected by enzyme-linked immunosorbent assay(ELISA).The quality of SE was controlled by high performance liquid chromatography(HPLC;Agilent 1260,Agilent,USA).Hematoxylin-eosin(HE)staining was performed for histological evaluation.Antibody expression was assessed via immunohistochemistry(IHC)staining.Results SE could improve insulin resistance and islet cell function by reducing FFA,MDA and TNF-αlevels and increasing SOD level.In addition,pancreatic HE staining analysis revealed that SE has a protective effect on isletβ-cells.Conclusions The present study indicates that SE has hypoglycemic as well as pancreatic protective effects in T2DM model rats.

Liquid Chromatography Tandem Mass Spectrometry Method for Determination of Anti-Diabetic Drug Repaglinide in Human Plasma

A highly sensitive, accurate and rapid analytical method based on reversed-phase liquid chromatography/electrospray ionization tandem mass spectrometry (RP-LC-ESI-MS/MS) has been developed and validated for the determination of repaglinide in human plasma using cetirizine as an internal standard (IS). The method was validated over a linear range of 0.5 - 100 ng/ml. After addition of IS, analytes were extracted from the plasma samples by liquid-liquid extraction using tert-butyl methyl ether as. The dried residue was reconstituted with 500 μL of mobile phase consisting of water/methanol/acetonitrile (62.5:20:17.5, v/v/v) and 0.2% formic acid. Chromatographic separations were achieved on a C18 analytical column. The analytes were detected with a triple quadrupole mass spectrometer using turbo V? ion spray source with positive ionization in multiple reaction monitoring (MRM) mode using MRM transitions m/z 453.3 > 162.2 and m/z 389.0 > 201.1 for the drug and IS, respectively. The proposed method was fully validated in terms of linearity, accuracy, precision, specificity, sensitivity, recovery and stability, giving results within the acceptable range. This method was successfully applied for a large number of authentic human plasma samples from a bioequivalence study.

Administration frequency as well as dosage of PTH are associated with development of cortical porosity in ovariectomized rats

To investigate whether the administration frequency of parathyroid hormone(PTH) is associated with the development of cortical porosity, this study established 15 dosage regimens of teriparatide [human PTH(1–34), TPTD] with four distinct concentrations and four distinct administration frequencies of TPTD to 16-week-old ovariectomized rats. Our analyses demonstrated that the bone mineral density, mechanical properties, and bone turnover were associated with the total amount of TPTD administered. Our observations further revealed that the cortical porosity was markedly developed as a result of an increased administration frequency with a lower concentration of total TPTD administration in our setting, although the highest concentration also induced cortical porosity. Deconvolution fluorescence tiling imaging on calcein-labeled undecalcified bone sections also demonstrated the development of cortical porosity to be closely associated with the bone site where periosteal bone formation took place. This site-specific cortical porosity involved intracortical bone resorption and an increased number and proximity of osteocytic lacunae,occasionally causing fused lacunae. Taken together, these findings suggested the involvement of local distinctions in the rate of bone growth that may be related to the site-specific mechanical properties in the development of cortical porosity induced by frequent and/or high doses of TPTD.

Empirical Prescriptions Used in Treatment of Epigastralgia due to Blood Stasis of Deficiency Type

Epigastralgia,a commonly-seen symptom inchronic gastritis or gastric ulcer,and usually causesinjury of the vital-qi and thereby deficiency of thehuman body due to its chronicity.The deficiency isdivided into deficiency of yin,yang,qi,and blood.Asis said in A Guide to Clinical Practice with MedicalRecords(临证指南医案),illnesses at the early stageaffect channels which dominate qi while at the latestage collaterals which dominate blood,and

Synthesis,Crystal Structure and Bioactivity of 1-(3-((Benzo[d][1,3]dioxol-5-yloxy)methyl)-phenethyl)-4-phenylpiperidin-4-ol

The title compound 1-（3-（（benzo[d][1,3]dioxol-5-yloxy）methyl）phenethyl）-4- phenylpiperidin-4-ol （4, C27H29NO4, Mr = 431.51） was synthesized by a four-step reaction and characterized by 1H NMR, 13C NMR, elemental analysis and single-crystal X-ray diffraction. The crystal is of triclinic, space group P1 with a = 5.8033（12）, b = 10.705（2）, c = 18.393（4）A, a = 83A4（3）, β = 82.71（3）, γ = 88.88 （3）°, V= 1126.0（4） A3, Z= 1, Dc= 1.273 g/cm3, S = 1.070, p = 0.681 mm^-1, F（000） = 460, R = 0.0618 and wR = 0.1619 for 6452 observed reflections with I 〉 2σ（I） Geometry conformations revealed that the dihedral angle between benzodioxole and aromatic planes contributed to the formation of C-H…π interactions. Hydrogen bonds and van der waals interactions were observed to stabilize the three-dimensional packing structure. The compound showed a moderate inhibitory activity against the prostate cancer cells.

Synthesis, Crystal Structure and Biological Activity of N-(2-hydroxy-3-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl)quinoxaline-2-methanamide

The title compound N-（2-hydroxy-3-（4-（2-methoxyphenyl）piperazin-l-yl）propyl）- quinoxaline-2-methanamide （4, C23H27N5O3, Mr = 421.50） was synthesized via a four-step reaction and characterized by ^1H NMR, ^13C NMR, ESIMS and single-crystal X-ray diffraction. The crystal is of monoclinic, space group P21/n with a = 12.108（2）, b = 12.639（3）, c = 14.601（3）A, fl = 104.87（3）°, V= 2159.6（8） A^3, Z = 4, Dc= 1.296 g/cm^3, S = 1.023,μ = 0.088 mm^-1, F（000） = 896, R = 0.0392 and wR = 0.0983 for 2836 observed reflections with I 〉 20（/）. The single-crystal X-ray structural analysis reveals that 4 is stabilized by intramolecular and intermolecular hydrogen bonds together with π-π interactions. The bioassay showed that 4 exhibited high selective activity for alAID VS. am-adrenoceptors subtype.

Stereoselective High-Performance Liquid Chromatography Tandem Mass Spectrometry Method for Determination of R- and S-Acenocoumarol in Human Plasma and Its Application in a Pharmacokinetics Study

A stereoselective, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MSMS) method for the determination of R-acenocoumarol and S-acenocoumarol in human plasma was developed and validated at IPRC bioanalytical labs. The procedure involved solid phase extraction of both enantiomers and their corresponding internal standard. The chromatographic separation was accomplished employing a chiral column and proper mobile phase. Detection was carried out using Waters Micromass®Quattro Premier mass spectrometer in multiple reaction monitoring (MRM) mode using turbo ion spray with negative ionization. The method was validated over a linear range of 0.40 - 40.00 ng/ml for R-acenocoumarol and 0.20 - 20.00 ng/ml for the S-acenocoumarol. Method validation covered different parameters such as linearity, accuracy, precision and stability. The method was successfully applied for the determination of R and S-acenocoumarol in plasma samples of 28 healthy subjects who participated in a pharmacokinetics study.

Modular Hydrogels for Drug Delivery

The development of novel drug delivery systems is an essential step toward controlled site-specific administration of therapeutics within the body. It is desirable for delivery vehicles to be introduced into the body through minimally invasive means and, these vehicles should be capable of releasing drug to their intended location at a controlled rate. Furthermore, it is desirable to develop drug delivery systems that are capable of in vivo to suffer degradation and to deliver the drug completely, avoiding the need to surgically remove the vehicle at the end of its useful lifetime. Hydrogels are of particular interest for drug delivery applications due to their ability to address these needs in addition to their good biocompatibility, tunable network structure to control the diffusion of drugs and, tunable affinity for drugs. However, hydrogels are also limited for drug delivery applications due to the often quick elution of drug from their highly swollen polymer matrices as well as the difficulty inherent in the injection of macroscopic hydrogels into the body. This paper presents an overview to the advances in hydrogels based drug delivery. Different types of hydrogels can be used for drug delivery to specific sites in the gastrointestinal tract ranging from the oral cavity to the colon. These novel systems exhibit a range of several peculiar properties which make them attractive as controlled drug release formulations. Moreover, such materials are biocompatible and can be formulated to give controlled, pulsed, and triggered drug release profiles in a variety of tissues.

α-Hederin inhibits growth of lung cancer A549 cells in vitro and in vivo by decreasing c-Myc and HIF-1α dependent glycolysis

OBJECTIVEα-Hederin is an effective component of the traditional Chinese medicine Pulsatilla chinensis,which has been reported to exert many pharmacological activities.However,the effect ofα-hederin on metabolism is still unclear.This study aimed to illuminate the role ofα-hederin in glucose metabolism in lung cancer cells and investigate the molecular mechanism ofα-hederin.METHODS CCK8 and colony formation assays were employed to assess the anti-proliferative effects induced byα-hederin.Glucose uptake,ATP generation,and reduced lactate production were measured using kits,and an A549 tumor xenograft mouse model of lung cancer was used to assess the in vivo antitumor effect ofα-hederin(5,10 mg·kg^-1).Glycolytic-related key enzymes were detected by Western blotting and immunohisto⁃chemical staining.RESULTS Cell proliferation was significantly inhibited byα-hederin in a dose-dependent manner and thatα-hederin inhibited glucose uptake and ATP generation and reduced lactate production.Furthermore,α-hederin remarkably inhibited hexokinase 2(HK2),glucose transporters 1(GLUT1),pyruvate kinase M2(PKM2),lactate dehydro⁃genase A(LDHA),monocarboxylate transporter(MCT4),c-Myc,and hypoxia inducible factor-1α(HIF-1α)protein expres⁃sion.Using inhibitors,we proved thatα-hederin inhibits glycolysis by inhibiting glycolytic regulators.Moreover,a tumor xenograft mouse model of lung cancer further confirmed thatα-hederin inhibits lung cancer growth via inhibiting glycolysis in vivo.CONCLUSIONα-Hederin inhibits the growth of non-small cell lung cancer A549 cells by inhibiting glycolysis.The mechanism of glycolysis inhibition includesα-hederin inhibiting the expression of the glycolytic regulatory factors HIF-1α and c-Myc.

Anti-Ulcerogenic Activity of the Pomegranate Peel (<i>Punica granatum</i>) Methanol Extract

Pomegranate (Punica granatum L.) belongs to genera Punica and family Punicaceae. It is a herbal preparation that has been suggested as useful in the treatment of gastrointestinal disorders. However, to our knowledge, no study has been conducted to evaluate this therapeutic property. In the present study the antiulcerogenic effects of pomegranate peel methanol extract, was tested on male Wistar albino rats. Oral pretreatment with peel extracts (25, 50 and 100 mg/kg) for 15 days protected the gastric mucosa against the damage induced by indomethacin (50 mg/kg). The incidence of ulceration in the control group was 100%. The best results were found in a dosage of 50 mg/kg in sour summer cultivar which inhibited the peptic ulcerin comparison with indomethacin induced gastric ulcer group. Lowest ulcer index (5.4 ± 0.55), an apparent decrease in the infiltration of polymorphonuclear leukocytes and hemorrhage were observed after administration of sour summer extracts (50 mg/kg). In conclusion present study showed that pomegranate peel extract, especially sour summer, has curative potential as an antiulcer, possibly via its high antioxidant activity. These results from pomegranate peel extract can provide an extra income and may contribute about good nutritional values of this product.