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Individuals with Down syndrome (DS) have been characterized by greater postural sway in quiet stance and insufficient motor ability. However, there is a lack of studies to explore the properties of dynamic postural sway, especially under conditions of task-oriented movement. The purpose of this study was to investigate the relationships between task-oriented postural control and motor ability in children and adolescents with DS. The participants were 23 children and adolescents with DS (DS group, M plus or minus SD age, 14.4 plus or minus 2.8 years) and 18 age- and gender-matched peers (M plus or minus SD age, 13.8 plus or minus 3.6 years). A force plate was used to collect postural data represented by center of pressure (COP) parameters. Postural measurements were conducted for both groups in quiet standing with eyes open and with eyes closed, and also while throwing a ball at erect standing. Assessments of motor ability were only applied to the DS group by using two dimensions of the original version of Gross Motor Function Measure and 4 subtests of the Bruininks Oseretsky Test of Motor Proficiency, second edition. The results showed that while the participants with DS showed greater displacement and higher velocity of COP sways at quiet standing, they exhibited smaller COP displacement in anterior/posterior direction during throwing the ball. Three areas of motor ability, including standing motor skills, walk/run/jump motor skills and muscle strength, were found to make a significant contribution to the displacement and velocity of postural sway during the voluntary movement. It is suggested that future research should focus on investigating the definite underlying mechanism of postural sway during movement and the influence of increasing motor ability on the reactive postural sway in this population. (Contains 3 tables.)

Purpose: Metagenomic next-generation sequencing (mNGS) is a powerful yet unbiased method to identify pathogens in suspected infections. However, little is known about its clinical effectiveness. The present study aimed to assess the efficacy of mNGS in routine clinical practice. Patients and Methods: In this single-center retrospective cohort study, 518 patients with suspected infectious diseases were assessed for inclusion. Among them, each patient had undergone mNGS testing; 407 patients had undergone both microbial culture and mNGS testing. The result of mNGS testing was compared to microbial culture performed concurrently. The diagnostic performance of mNGS was evaluated using the comprehensive clinical diagnosis as the reference standard. Results: There was a significant difference in the positive detection rates of pathogens between mNGS and culture (331/407, 81.3% vs 79/407, 19.4%, P < 0.001). The sensitivity of mNGS was much higher than the culture method (79.5% vs 21.3%, P < 0.001), especially in sample types of sputum and bronchoalveolar lavage fluid (BALF). Notably, the sensitivity of blood mNGS was relatively lower than other sample types (67.4% vs 88.9– 93.8%). Pathogen cfDNA load based on standardized stringently mapped read number at the species level of microorganisms (SDSMRN) was significantly lower in blood than in other sample types from the same patient (P = 0.0003). Importantly, mNGS directly led to a change of treatment regimen in 142 (27.4%) cases, including antibiotic escalation (15.3%), antibiotic de-escalation (9.1%), and early definitive diagnosis to initiate appropriate treatment (3.1%). Conclusion: Our in-house mNGS platform significantly improved the sensitivity for the diagnosis of infectious diseases. mNGS has the potential to improve clinical outcomes by optimizing antimicrobial therapy. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive and selective death of dopaminergic neurons. Orexin-A is involved in many biological effects of the body. It has been reported that orexin-A has protective effects in cellular models of PD. However, little is known about the protective effects of orexin-A in animal parkinsonian models and the cellular mechanism has not yet been fully clarified. The aim of this study was to evaluate the effects of orexin-A in MPTP mice model of PD as well as the possible neuroprotective mechanisms of orexin-A on dopaminergic neurons. The results from animal experiments demonstrated that orexin-A attenuated the loss of dopaminergic neurons and the decrease of tyrosine hydroxylase (TH) expression in the substantia nigra, normalized the striatal dopaminergic fibers, and prevented the depletion of dopamine and its metabolites in the striatum. MPTP-treated mice showed cognitive impairments accompanied with significant motor deficiency. Orexin-A improved MPTP-induced impairments in both motor activity and spatial memory. Importantly, orexin-A increased the protein level of brain-derived neurotrophic factor (BDNF) in dopaminergic neurons of the substantia nigra. Furthermore, the protective effects of orexin-A on MPTP parkinsonian mice could be blocked by orexinergic receptor 1 (OX1R) antagonist, SB334867. In another set of experiments with SH-SY5Y dopaminergic cells, orexin-A significantly induced the expression of BDNF in a dose and time-dependent manner. The upregulation of BDNF is mainly concerned with PI3K and PKC signaling pathways via OX1R. The present study demonstrated that orexin-A exerted neuroprotective effects on MPTP parkinsonian mice, which may imply orexin-A as a potential therapeutic target for PD. [ABSTRACT FROM AUTHOR]

Orexin is a member of neuropeptides which is involved in the central motor control. The substantia nigra pars compacta (SNc) is an important nucleus participating in motor control under both physiological and pathological conditions. Morphological studies reveal that orexinergic neurons located in lateral hypothalamus innervate the SNc. Both orexin‐1 receptors (OX1R) and orexin‐2 receptors (OX2R) are expressed in the SNc. To investigate the effects of orexins on SNc, single unit in vivo extracellular recordings and behavioral tests were performed in this study. Micro‐pressure administration of orexin A and orexin B significantly increased the spontaneous firing rate of nigral DAergic neurons by 65.87 ± 7.73% and 90.49 ± 17.83%, respectively. The excitatory effects of orexin A on nigral DAergic neurons were mainly mediated by OX1R, while OX2R were involved in the increase in firing rate induced by orexin B. Selectively blocking OX1R and OX2R significantly decreased the firing rate of nigral DAergic neurons by 36.77 ± 6.26% and 32.04 ± 6.12%, respectively, which suggested that endogenous orexins modulated the spontaneous firing activity of nigral DAergic neurons. Finally, both elevated body swing test and haloperidol‐induced postural behavioral test showed that unilateral microinjection of orexin A and orexin B induced significantly contralateral‐biased swing and deflection behavior. Meanwhile, the specific OX1R and OX2R antagonists produced opposite effects. The present electrophysiological and behavioral studies suggested that orexins increased the firing activity of nigral DAergic neurons and participated in central motor control. Open Practices: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Orexin‐1 receptors (OX1R) and orexin‐2 receptors (OX2R) are expressed in DAergic neurons in the substantia nigra pars compacta (SNc). Orexin A increases the spontaneous firing activity of DAergic neurons mainly via OX1R, while orexin B increases the firing rate via OX2R. The orexins‐induced excitation of nigral DAergic neurons in turn increases the excitability of motor cortex through basal ganglia circuit. Therefore, microinjection of orexins into the SNc enhances motor performance in elevated body swing test (EBST) and improves haloperidol‐induced catalepsy. [ABSTRACT FROM AUTHOR]

This study examined chronic, isolated posterior cruciate ligament (PCL) rupture patients, dividing them into symptomatic and asymptomatic groups according to whether they displayed obvious symptoms in daily activities. Each group comprised 10 patients while 10 healthy, young individuals were adopted as the control group. Using a three-dimensional motion analysis system and force plates, the gait patterns of the PCL-deficient patients were analyzed from both kinematics and kinetics perspectives to identify whether they differed from the control group and to compare symmetry between the injured and uninjured sides. The results showed that the symptomatic PCL-deficient group was closer to "normal", and the asymptomatic PCL-deficient group showed less knee extension moment and lower power absorption in the terminal stance than the control group. Additionally, the symptomatic PCL-deficient group appeared to have a relatively symmetric gait while the asymptomatic PCL-deficient group primarily showed an asymmetric gait also occurring in the terminal stance, including less joint moment and lower power absorption of the hip and knee, and lower vertical ground reaction force (GRF). Regarding the gait adaptations of the asymptomatic PCL-deficient group these compensation mechanisms are most likely to have been produced in order to assist in joint stabilization and reduce symptoms in joints. [ABSTRACT FROM AUTHOR]

This study compares the effectiveness of alcohol, natural drying, and salicylic sugar powder on umbilical separation time of the neonate in our high-humidity region. From September 2007 to May 2008, a total of 143 neonates in a community hospital were divided into 3 groups according to their birth month in sequence. Each umbilical care regimen was randomly assigned to a 3-month period. Data on occurrence of omphalitis and cord separation time were collected by telephone follow-up until stump separation. The salicylic sugar powder group had the lowest rates of colonization and shortest cord separation time compared with the natural drying and alcohol groups. No omphalitis developed in any of the 3 groups. Natural drying and salicylic sugar powder are safe and effective ways to care for the umbilical cord stump in high-humidity regions. Nursing professionals should consider choosing a more effective umbilical care regimen and provide mothers with thorough instruction. [ABSTRACT FROM AUTHOR]

Two new rearranged patchoulane sesquiterpene glycosides, 3α-hydroxypatchoulol 3-O-β-d-glucopyranoside (1) and 15-hydroxypatchoulol 15-O-β-d-glucopyranoside (2) together with rubusoside, a known diterpene glycoside, were isolated from the ethanol extract of the whole plant of Pogostemon cablin (Blanco) Benth. The structures of 1 and 2 were elucidated by spectroscopic analysis. [ABSTRACT FROM AUTHOR]

Lu, Y-M, Lin, J-H, Hsiao, S-F, Liu, M-F, Chen, S-M, and Lue, Y-J. The relative and absolute reliability of leg muscle strength testing by a handheld dynamometer. J Strength Cond Res 25(4): 1065-1071, 2011-To examine the relative and absolute interrater reliability of handheld dynamometers (HHD) for assessing the lower extremity muscle strength, maximal voluntary contractions (MVCs) of 16 young adults for bilateral hip and knee muscles were tested using the break method. Three MVCs of each muscle group were required for obtaining the muscle strength. Participants' muscle strengths were tested by 2 raters. The intraclass correlation coefficients (ICCs) and the smallest real differences (SRD) were used to examine the relative and absolute reliabilities, and the Bland-Altman analyses were used to check whether systematic bias exists. The results showed that the relative reliabilities of all muscle groups were excellent (ICCs = 0.83-0.92) except for the knee extensors (ICC = 0.60). The SRD represents the smallest difference that indicates a real change for a single subject. The SRD% of all muscle groups was acceptable (ranging from 8.4 to 22.8 %), with the hip extensors being the smallest and knee extensors being the largest. The reliability of the knee extensors was unsatisfactory because of poor relative and absolute reliabilities and systematic bias. In addition to assessing the relative reliability in strength measurement, the absolute reliability provides the data of the measurement error, which is useful information in clinical practice to know whether the change in strength of a subject is real. Hand-held dynamometer is a reliable tool for quantifying most of the hip and knee strength except for the knee extensors. Modifying the measuring technique for knee extension is needed in future studies to improve the reliability. [ABSTRACT FROM AUTHOR]

Abstract: The reaction of 2-imidazolyl carbene-derived 2-arylthiocarbamoyl imidazolium salts with ethyl propiolate proceeded via the solvent dependent tandem [3+2] cycloaddition and subsequent ring transformation processes. While the reaction in butanone yielded 3-amino-2-vinylthiopyrroles as the major products, use of benzene as the solvent led to the predominant formation of pyrrolo[2,3-b][1,4]thiazines. This work disclosed a unique ring transformation of imidazoline-spiro-pyrrolines to pyrrolo[2,3-b][1,4]thiazines, which provides a simple route to both multifunctional pyrroles and pyrrolo[2,3-b][1,4]thiazines that are otherwise difficult to synthesize. [Copyright &y& Elsevier]

Purpose: This study aimed to examine the association between the systemic immune-inflammation index (SII) (ie, neutrophil count × platelet count/lymphocyte count), the age-adjusted Charlson comorbidity index (ACCI), and overall survival (OS) in non-small cell lung cancer (NSCLC) patients undergoing first-line platinum-based chemotherapy (PBC), with a particular emphasis on the role of SII in supporting ACCI., Patients and Methods: This retrospective study enrolled 353 cases treated between July 2013 and November 2020. Mann-Whitney U -test and Kruskal-Wallis test were employed to compare parameters between high and low SII groups. The cut-off values for SII and ACCI were determined using the X-tile software. Prognostic significance was evaluated through the utilization of Kaplan-Meier curves and Cox regression analysis., Results: In a univariate Cox regression analysis, sex, age, TNM, lymph node, therapy, SII, and ACCI were associated with OS. After adjusting for confounders in the multivariate analysis, TNM, SII, and ACCI remained independent prognostic factors for OS. Furthermore, within the ACCI subgroups (ACCI<5 or ACCI≥5), a high SII was significantly associated with an increased risk of death. Patients with both a high ACCI and a high SII had the highest risk of death ( p < 0.001), with a loss of approximately ten months of survival during the first three years after treatment., Conclusion: SII was proven to be valuable in predicting OS and, when complemented by ACCI, can help tailor prognostic assessment and treatment strategies in assessing the survival of NSCLC patients with first-line PBC., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Sheng et al.)

Background: Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment., Aim: To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model., Methods: The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice., Results: Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF., Conclusion: MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The emerging prevalence of drug-resistant Staphylococcus aureus isolates underscores the urgent need for alternative therapeutic strategies due to the declining effectiveness of traditional antibiotics in clinical settings. MgrA, a key virulence regulator in S. aureus , orchestrates the expression of numerous virulence factors. Here, we report the discovery of isorhapontigenin, a methoxylated analog of resveratrol, as a potential anti-virulence agent against S. aureus . Isorhapontigenin effectively inhibits the hemolytic activity of S. aureus in a non-bactericidal manner. Additionally, it significantly reduces the cytotoxicity of S. aureus and impairs its ability to survive in macrophages. Mechanistically, isorhapontigenin modulates the expression of virulence factors, dose-dependently downregulating hla and upregulating the MgrA-regulated gene spa . Electrophoretic mobility shift assays demonstrated that isorhapontigenin inhibits the binding of MgrA to the hla promoter in a dose-dependent manner. Thermal shift assays confirmed the direct interaction between isorhapontigenin and the MgrA protein. The in vivo experiments demonstrated that isorhapontigenin significantly reduced the area of skin abscesses and improved survival in a pneumonia model while decreasing bacterial burden and inflammation in the lungs. In conclusion, isorhapontigenin holds potential as a candidate drug for further development as an anti-virulence agent for treating S. aureus infections., Importance: The emergence of antibiotic-resistant Staphylococcus aureus strains presents a formidable challenge to public health, necessitating novel approaches in combating these pathogens. Traditional antibiotics are becoming increasingly ineffective, leading to a pressing need for innovative therapeutic strategies. In this study, targeting virulence factors that play a crucial role in the pathogenesis of bacterial infections offers a promising alternative to circumvent resistance mechanisms. The discovery of isorhapontigenin as an inhibitor of S. aureus virulence represents a significant advance in anti-virulence therapy., Competing Interests: The authors declare no conflict of interest.

Staphylococcus aureus readily forms biofilms on host tissues and medical devices, enabling its persistence in chronic infections and resistance to antibiotic therapy. The accessory gene regulator (Agr) quorum sensing system plays a key role in regulating S. aureus biofilm formation. This study reveals the widely used fluoroquinolone antibiotic, ciprofloxacin, strongly stimulates biofilm formation in methicillin-resistant S. aureus , methicillin-sensitive S. aureus , and clinical isolates with diverse genetic backgrounds. Crystal violet staining indicated that ciprofloxacin induced a remarkable 12.46- to 15.19-fold increase in biofilm biomass. Confocal laser scanning microscopy revealed that ciprofloxacin induced denser biofilms. Phenotypic assays suggest that ciprofloxacin may enhance polysaccharide intercellular adhesin production, inhibit autolysis, and reduce proteolysis during the biofilm development, thus promoting initial adhesion and enhancing biofilm stability. Mechanistically, ciprofloxacin significantly alters the expression of various biofilm-related genes ( icaA , icaD , fnbA , fnbB , eap , emp ) and regulators ( agrA , saeR ). Gene knockout experiments revealed that deletion of agrC , rather than saeRS , abolishes the ciprofloxacin-induced enhancement of biofilm formation, underscoring the key role of agrC . Thermal shift assays showed ciprofloxacin binds purified AgrC protein, thereby inhibiting the Agr system. Molecular docking results further support the potential interaction between ciprofloxacin and AgrC. In summary, subinhibitory concentrations of ciprofloxacin stimulate S. aureus biofilm formation via an agrC -dependent pathway. This inductive effect may facilitate local infection establishment and bacterial persistence, ultimately leading to therapeutic failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Li, Liu and Zhao.)

Context: Subacromial impingement syndrome (SIS) is associated with scapular dyskinesis, or imbalanced scapular muscle activity. Evidence has shown that feedback can improve scapular control in patients with SIS. However, it is unknown whether real-time video feedback or electromyography (EMG) biofeedback is optimal for improving scapular kinematics and muscle activity during a functional task., Objective: To compare the effects of video and EMG feedback sessions on absolute muscle activity (upper trapezius [UT], lower trapezius [LT], serratus anterior), muscle balance ratios (UT/LT, UT/serratus anterior), and scapular kinematics (anterior-posterior tilt, external-internal rotation, upward rotation) in SIS participants during arm elevation and lowering., Design: Randomized controlled clinical trial., Setting: Research laboratory., Patients or Other Participants: Overhead athletes who were diagnosed with SIS and who also exhibited scapular dyskinesis (N = 41)., Main Outcome Measure(s): Three-dimensional kinematics and EMG were recorded before and after feedback training., Results: Lower trapezius muscle activity increased (4.2%-18%, P < .011) and UT/LT decreased (0.56-1.17, P < .013) in the EMG biofeedback training group as compared with those in the video feedback training group. Scapular upward rotation during arm elevation was higher in the video group than in the EMG group after feedback training (2.3°, P = .024)., Conclusions: The EMG biofeedback improved muscle control and video feedback improved the correction of scapular upward rotation in patients with SIS., Trial Registration Number: ClinicalTrials.gov: NCT03252444.

Orexin is a peptide neurotransmitter released in the globus pallidus. Morphological evidence reveals that both orexin 1 receptor (OX 1 R) and orexin 2 receptor (OX 2 R) exist in the globus pallidus. Here we showed that bilateral microinjection of both orexin-A and orexin-B into the globus pallidus alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Further in vivo extracellular single-unit recording revealed that the basal spontaneous firing rate of the globus pallidus neurons in MPTP parkinsonian mice was slower than that of normal mice. Application of orexin-A or orexin-B significantly increased the spontaneous firing rate of pallidal neurons. The influx of Ca 2+ through the L-type Ca 2+ channel is the major mechanism involved in orexin-induced excitation in the globus pallidus. Orexin-A-induced increase in firing rate of pallidal neurons in MPTP parkinsonian mice was stronger than that of normal mice. Orexin-A exerted both electrophysiological and behavioral effects mainly via OX 1 R, and orexin-B exerted the effects via OX 2 R. Endogenous orexins modulated the excitability of globus pallidus neurons mainly through OX 1 R. The present behavioral and electrophysiological results suggest that orexins ameliorate parkinsonian motor deficits through increasing the spontaneous firing of globus pallidus neurons.

Adipose tissue is the main energy reserve of the body. When energy is required, adipocyte triglycerides stored in lipid droplets (LDs) are broken down by lipase, and free fatty acids are released to supply the physiological need. Intracellular LDs are active metabolic organelles in mammalian cells, particularly in adipocytes. The present study was aimed to investigate the morphological changes of LDs and the alternation of LD-associated perilipin family proteins during long-term lipolysis stimulated by forskolin. Primary differentiated adipocytes derived from epididymal fat pads of Sprague-Dawley (SD) rats were incubated in the presence or absence of 1 μmol/L forskolin for 24 h. Content of glycerol released to the culture medium was determined by a colorimetric assay and served as an index of lipolysis. Morphological changes of LDs were observed by Nile red staining. The mRNA level of perilipin family genes was detected by quantitative real-time PCR. The protein level and subcellular localization were examined by immunoblotting and immunofluorescence staining, respectively. The results showed that forskolin induced sustained lipolysis in differentiated adipocytes. The morphology of LDs changed in a time-dependent manner. Large clustered LDs became gradually smaller in size and eventually disappeared; in contrast, peripheral micro-LDs increased gradually in number until the cytoplasm was filled with numerous micro-LDs. The protein level of the perilipin family proteins showed obvious alternation. Mature adipocytes physiologically expressed a very low level of Plin2 protein, whereas in adipocytes stimulated with lipolytic forskolin, the protein and mRNA levels of Plin2 were significantly increased, and the increased Plin2 was specifically bound to the surface of LDs. During chronic stimulation of forskolin, the mRNA level of Plin3 was unchanged, but the mRNA levels of Plin1, Plin4 and Plin5 were significantly decreased. These results suggest that the morphology of LDs and perilipin family proteins on the surface of LDs are significantly altered during long-term lipolysis stimulated by forskolin, representing a dynamic process of the remodeling of LDs.

The interaction of 2-(phenylthiocarbamoyl) imidazolium inner salts with dimethyl acetylenedicarboxylate produced dimethyl 2-(imidazolin-2-ylidene)-3-thioxobutanedioates in moderate to good yields. The process involved a tandem reaction comprising a 1,3-dipolar cycloaddition and an unprecedented cheletropic elimination of the phenyl isonitrile from a 2-phenyliminodihydrothiophene moiety. NMR and X-ray diffraction studies confirmed that the 2-(imidazolin-2-ylidene)-3-thioxobutanedioates are novel push-pull olefins and have potential applications in nonlinear optical materials.

2-aryl thiocarbamoyl benzimidazolium and imidazolinium inner salts derived from benzimidazole and imidazoline carbenes are unique ambident C-C-S and C-C-N 1,3-dipolar systems, which undergo highly efficient and site-selective cycloaddition reactions with dimethyl acetylenedicarboxylate or dibenzoylacetylene to furnish spiro(imidazole-2,3'-thiophene) derivatives in excellent yields. When treated with ethyl propiolate, methyl acrylate or acrylonitrile, spiro(imidazole-2,3'-pyrrole) derivatives were formed in good yields. Theoretical studies revealed an asynchronous concerted mechanism for both the C-C-S and C-C-N 1,3-dipolar cycloaddition reactions. The site selectivity in the [3+2] cycloaddition reaction of ambident 1,3-dipoles was predictably regulated by both the electronic and steric effects of dipolarophiles.

Antiangiogenesis is a promising strategy of cancer treatment. Vascular endothelial growth factor receptor [fetal liver kinase/kinase-inserting domain-containing receptor (KDR)] is a tyrosine kinase receptor and has been strongly implicated in tumor angiogenesis. In this study, we report that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (ON-III), extracted from the dried flower Cleistocalyx operculatus, used in traditional Chinese medicine, reversibly inhibited KDR tyrosine kinase phosphorylation, but epidermal growth factor receptor tyrosine kinase phosphorylation was unaffected under the same concentrations of ON-III. ON-III also inhibited mitogen-activated protein kinase (MAPK) and AKT activation of KDR signal transduction in downstream molecules without reduced total MAPK and AKT. The results in vitro showed that ON-III inhibited growth of human vascular endothelial HDMEC cells in the presence of VEGF preferentially, compared with epidermal growth factor. Systemic administration of ON-III at nontoxic doses in nude mice resulted in inhibition of subcutaneous tumor growth of human hepatocarcinoma Bel7402 and lung cancer GLC-82 xenografts. The tumor vessel density decreased, as determined by immunohistochemical staining, for CD31 after ON-III treatment. These results indicated that ON-III inhibited KDR tyrosine kinase, shut down KDR-mediated signal transduction, and inhibited tumor growth of human xenografts in vivo.