Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces. But known drugs for IPF are far from meeting clinical demands, validation of drug targets against pulmonary fibrosis is in urgent demand. Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling. In this study we designed and synthesized a new indazole derivative XBLJ-13, and identified XBLJ-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities. We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients. Then we showed that XBLJ-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM, respectively. Among a panel of 34 kinases tested, XBLJ-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1, as well as Abl kinase that had high homology with DDRs. Extensive profiling of XBLJ-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice. Furthermore, pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBLJ-13 (30, 60, 90 mg·kg-1·d-1, i.g.) for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis. Together, this study confirms that DDRs kinase is a potential target for PF, Particularly, compound XBLJ-13 is a highly potent and specific DDRs inhibitor, along with good pharmacokinetics profiles, and preferable in vivo efficacy, suggesting that it is a potential candidate for the treatment of PF.

Congenital absence of left atrial appendage combined with type A Wolff-Parkinson-White syndrome diagnosed by multimodal imaging.

The absence of left atrial appendage (LAA) is relatively rare, especially with type A Wolff-Parkinson-White syndrome. Secondly, we diagnosed it by multimodal imaging including two-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE), CT, electrophysiological examination, and 3D electro anatomical mapping system, which is more comprehensive.

Glass transition and dynamics of semiflexible polymer brushes.

The glass transition and dynamics of densely grafted semiflexible polymer brushes are studied by molecular dynamics simulation. The glass transition temperature (Tg) increases with the polymer rigidity. The local glass transition temperature (Tg,local) is estimated from the temperature-dependent dynamics of individual segments including the lateral position fluctuation and lateral mean square displacement. Different from the flexible polymer brush, Tg,local of semiflexible polymer brushes is roughly independent of the segment height. Our simulation reveals that the glass transition is in synchronism with an abrupt change of the chain conformation in semiflexible polymer brushes. When the temperature drops to near Tg, the semiflexible polymer chains elongate, tilt, and become more ordered. Moreover, enhanced segmental dynamics is observed at temperatures just above Tg for the semiflexible polymer brushes.

Simulation on diffusivity and statistical size of polymer chains in polymer nanocomposites.

The dynamical and conformational properties of polymer chains are affected significantly by strongly attractive nanoparticles. The adsorption of polymer chains on nanoparticles not only reduces the dynamics but also changes the conformation of polymer chains. For orderly distributed nanoparticles of size roughly the same as the radius of gyration of polymer chains, the variation of the diffusivity is highly related to that of the statistical size and can be explained mainly from the adsorption of polymers. In particular, both the polymer's size and diffusivity reach the minimum when the number of polymer chains matches the number of nanoparticles where polymer chains are mostly adsorbed on separate nanoparticles. The behavior of diffusivity can be explained from the cooperation of polymer adsorption and nanoparticle-exchange motion. Adsorption of the polymer chain slows down the diffusion, whereas the nanoparticle-exchange motion accelerates the diffusion of polymer chains.

Diffusivity and glass transition of polymer chains in polymer nanocomposites.

The diffusivity and glass transition of polymer chains in polymer nanocomposites are studied by using dynamic Monte Carlo simulation. Nanoparticles are modeled as immobile and distributed in a cubic lattice in the system. The diffusion coefficient D of polymer chains is reduced, while the glass transition temperature Tg is increased by nanoparticles. Our results show that the effect of nanoparticles can be summarized as D = D0[1 - exp(-α·ID/2Rg)] and Tg = Tg,0[1 - exp(-α·ID/2Rg)]-1, with D0 and Tg,0 being the diffusion coefficient and the glass transition temperature in the absence of nanoparticles, Rg the radius of gyration of polymer chains, and ID the surface spacing between nearest-neighbor nanoparticles. The parameter α that governs the dynamics of polymer chains decreases with increasing nanoparticles' size or decreasing the temperature. Our results also show that smaller nanoparticles exert a stronger influence on the polymer dynamics at the same concentration of nanoparticles, whereas larger nanoparticles show a stronger effect at the same ID.

Time course of changes in maternal left ventricular function during subsequent pregnancy in women with a history of gestational hypertensive disorders.

Women with a history of gestational hypertensive disorders (GHD) are at increased risk for developing perinatal cardiovascular complications (e.g., gestational hypertension, preeclampsia, etc.) in subsequent pregnancies. The underlying mechanisms remain uncertain, but impaired maternal left ventricular function may be one contributing factor for these complications. We evaluated the time course of changes in left ventricular function before, during, and after pregnancy in women with prior GHD. Sixteen women with a history of GHD (the high-risk group) and 25 women without such a history (controls) were enrolled. Resting hemodynamic and echocardiographic measurements were longitudinally performed before pregnancy, during early pregnancy (4-8 wk of gestation), during late pregnancy (32-36 wk of gestation), and postpartum (6-10 wk after delivery). Pregnancy outcomes were obtained after delivery. At prepregnancy, there was no difference in blood pressure and heart rate between the groups. Corrected isovolumic relaxation time was longer, E/ e' was larger, and Tei index was greater in the high-risk group than controls. Moreover, the rate of GHD during the study was significantly greater in the high-risk group than controls [odds ratio = 8.94 (95% confidence interval: 1.55-51.5), P = 0.007]. Multiple logistic regression analysis adjusted for age demonstrated that prepregnancy E/ e' was an independent predictor for GHD ( P = 0.017). Thus, women with a history of GHD have modestly impaired cardiac function prepregnancy compared with controls, which identifies an increased susceptibility to developing cardiovascular complications during a subsequent pregnancy.

Augmented venoarteriolar response with ageing is associated with morning blood pressure surge.

NEW FINDINGS: What is the central question of this study? The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied. What is the main finding and its importance? Older adults exhibit an augmented VAR in response to leg dependency. The age-related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning. ABSTRACT: The venoarteriolar response (VAR) is a non-adrenergic, non-baroreflex-mediated mechanism of vasoconstriction, which has been proposed to contribute ∼45% of the increase in total peripheral resistance during orthostasis. Despite its importance in human cardiovascular control during orthostatic stress, there is no information available regarding the impact of age and sex on the VAR or its role in diurnal blood pressure (BP) variation. We studied 33 (15 women) young (mean ± SD; 28 ± 4 years old) and 26 (12 women) older (71 ± 3 years old) healthy individuals. Brachial and femoral blood flow were measured using Doppler ultrasound. The percentage reduction in vascular conductance (blood flow/mean BP) during 4 min of limb dependency (35-40 cm below the heart level) was used to assess the VAR. The morning surge in BP was assessed using 24 h ambulatory BP monitoring. Peak VAR in the lower limb, but not in the upper limb, was significantly higher in the older than the younger adults (33 ± 4 versus 26 ± 6%, older versus young; P < 0.05). There was no sex difference in the VAR in either the young or the older group. A greater leg VAR was related to a greater morning surge in BP in older adults (r = -0.4, P = 0.02) but not in the young adults (r = -0.26, P = 0.1). Thus, advancing age enhances the VAR in the lower limb and is associated with the morning blood pressure surge in older adults. Sex does not affect this local axonal reflex in healthy humans.

[Analgesic effect and central mechanisms of CQ prescription on cancer invasion induced mirror image pain in model mice].

This study aimed to analyze the analgesic effect and related central mechanisms of CQ prescription on cancer invasion induced mirror image pain (CIIMIP)in model mice.In the study, male BALB/c mice were randomly divided into normal group, operation control group (injected with 0.2 mL inactivated S180 sarcoma cell sap), model group (injected with 0.2 mL S180 sarcoma cell sap on the right leg near the greater trochanter of femur) and CQ prescription low dose group (intraperitoneally injected with CQ prescription 100 mg•kg⁻¹ on the basis of model mice), CQ prescription middle dose group (intraperitoneally injected with CQ prescription 150 mg•kg⁻¹ on the basis of model mice), and CQ prescription high dose group (intraperitoneally injected with CQ prescription 200 mg•kg⁻¹ on the basis of model mice). Mechanical withdraw threshold (MWT) of the mirror image lateral hind paws were evaluated by Von Frey hairs before modeling and after surgery. The levels of glutamate (Glu), gamma aminobutyric acid (GABA), glycine (Gly), and taurine (Tau) in the L3-L5 spinal cord were measured by the high performance liquid chromatography-fluorescence detector (HPLC-FLD); AimPlex detection technology with multiple factors was used to detect the levels of regulated on activation in normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP-3) in the L3-L5 spinal cord. Then we observed the influence of GABAa receptor antagonist (Bicuculline) on analgesic effect of CQ prescription.The results indicated that CQ prescription could remarkably increase MWT of model mice(P<0.01, P<0.05), decrease the level of Glu(P<0.01, P<0.05), improve the levels of GABA, Gly, Tau(P<0.01, P<0.05), lower the ratio of Glu/GABA(P<0.01, P<0.05), and reduce the levels of RANTES, MCP-3(P<0.05) in the L3-L5 spinal cord, and GABAa receptor antagonist significantly blocked the analgesic effect of CQ prescription at two time points(P<0.05).This study showed that CQ prescription had significant analgesic effect on CIIMIP model mice, and its mechanism was associated with regulating the balance between excitability amino acid(EAA) and inhibitory amino acid (IAA) transmitters in central nervous system, partially activating GABAa receptor, and reducing the release of RANTES and MCP-3 in the spinal cord.

Balancing selection and recombination as evolutionary forces caused population genetic variations in golden pheasant MHC class I genes.

BACKGROUND: The major histocompatibility complex (MHC) genes are vital partners in the acquired immune processes of vertebrates. MHC diversity may be directly associated with population resistance to infectious pathogens. Here, we screened for polymorphisms in exons 2 and 3 of the IA1 and IA2 genes in 12 golden pheasant populations across the Chinese mainland to characterize their genetic variation levels, to understand the effects of historical positive selection and recombination in shaping class I diversity, and to investigate the genetic structure of wild golden pheasant populations. RESULTS: Among 339 individual pheasants, we identified 14 IA1 alleles in exon 2 (IA1-E2), 11 IA1-E3 alleles, 27 IA2-E2 alleles, and 28 IA2-E3 alleles. The non-synonymous substitution rate was significantly greater than the synonymous substitution rate at sequences in the IA2 gene encoding putative peptide-binding sites but not in the IA1 gene; we also found more positively selected sites in IA2 than in IA1. Frequent recombination events resulted in at least 9 recombinant IA2 alleles, in accordance with the intermingling pattern of the phylogenetic tree. Although some IA alleles are widely shared among studied populations, large variation occurs in the number of IA alleles across these populations. Allele frequency analysis across 2 IA loci showed low levels of genetic differentiation among populations on small geographic scales; however, significant genetic differentiation was observed between pheasants from the northern and southern regions of the Yangtze River. Both STRUCTURE analysis and F-statistic (F ST ) value comparison classified those populations into 2 major groups: the northern region of the Yangtze River (NYR) and the southern region of the Yangtze River (SYR). CONCLUSIONS: More extensive polymorphisms in IA2 than IA1 indicate that IA2 has undergone much stronger positive-selection pressure during evolution. Moreover, the recombination events detected between the genes and the intermingled phylogenetic pattern indicate that interlocus recombination accounts for much of the allelic variation in IA2. Analysis of the population differentiation implied that homogenous balancing selection plays an important part in maintaining an even distribution of MHC variations. The natural barrier of the Yangtze River and heterogeneous balancing selection might help shape the NYR-SYR genetic structure in golden pheasants.

Quality evaluation of five commercial enzyme linked immunosorbent assay kits for detecting aflatoxin b1 in feedstuffs.

The objective of this study was to evaluate the quality of five commercial enzyme linked immunosorbent assay (ELISA) kits (A, B, C, D, and E) from different suppliers for detecting aflatoxin B1 (AFB1). AFB1-free corn samples supplemented with different levels of AFB1 (5, 10, and 20 µg/kg) were used as positive controls and 6 replicates of each control sample were tested to evaluate the accuracy and precision of these kits. In addition, we also evaluated the performance of these ELISA kits for AFB1 in 30 feed samples, including corn, distillers dried grains with soluble, wheat samples, soybean meal, and poultry feed, which were verified by high performance liquid chromatography. Results showed that the coefficients of variation ranged from 1.18% to 16.22% in intra-plate and 2.85% to 18.04% in inter-plate for the determination of AFB1. The half maximal inhibitory concentration for five kits ranged from 3.72 to 7.22 µg/kg. The quantitation limits of AFB1 were all under the legal limit in China but somewhat inconsistent with kit instructions. Although the recovery rate of four of the five kits were either less than 90% or more than 110%, all these values were acceptable in practice. Two kits had high false positive rates (C and E). In conclusion, our results revealed that the qualities of five tested ELISA kits were significantly different.

Combined effects of temperature and avermectins on life history and stress response of the western flower thrips, Frankliniella occidentalis.

Temperature and pesticide are two important factors that affect survival, reproduction and other physiological processes of insects. To determine interactions of elevated temperature and avermectins treatment on the western flower thrips, Frankliniella occidentalis, newly emerged adults were exposed to combinations of three temperatures (21, 26 and 33 °C) and two avermectins concentrations (0, 45 ppm), and survival rate, reproduction, longevity, antioxidant enzymes activities and heat shock proteins (hsps) induction were analyzed. The results showed that the survival, longevity and reproduction of F. occidentalis decreased with increased temperature and avermectins treatment. While elevated temperature and avermectins treatment significantly decreased activity of SOD, activities of POD and GST significantly increased after exposure to elevated temperature, avermectins or their combination. Elevated temperature had no effect on activity of CAT, but it was obviously improved by the combination of temperature and avermectins treatment. Expression analysis of hsps showed that four heat shock proteins (hsp90, hsc702, hsp60 and hop) were up-regulated by the induction of elevated temperature with small fold changes. After treatment with avermectins, expression levels of hsp90, hsc701, hsc702 and hop were significantly up-regulated with increased temperature and higher than those of their respective control at higher temperature. Surprisingly, expression level of hps60 was down-regulated with increased temperature, but the expression level at 21 or 26 °C remained higher than that of control. Overall, our studies suggest that elevated temperature enhance toxicity of avermectins and their combination induced acute oxidative damage to F. occidentalis. Therefore, consideration of temperature in evaluating avermectins toxicity is necessary to make accurate prediction of its effect on F. occidentalis and other insects.

[Plasma concentration and pharmacokinetics of ursolic acid carried in self-microemulsifying drug delivery system in rats studied by UPLC-MS/MS].

This study is to report the establishment of an UPLC-MS/MS method for the determination of plasma concentration of UA carried in self-microemulsifying drug delivery system (SMEDDS) and its pharmacokinetics in rats. It was used for determination and analysis when serum with internal standard was extracted from C18 solid-phase column. Acquity UPLC BEH C18 column (100 mm x 2.1 mm, 1.7 microm) was used for separation. The mobile phase was acetonitrile -0.1% ammonia with gradient elution at the flow rate of 0.2 mL x min(-1). The column temperature was 40 degrees C and the detection wave length was 210 nm. It was detected by negative ion using electrospray ionization source (ESI) and scanned by multiple reaction ion monitoring (MRM) mode. The liner relationship of UA was very good in the range of 1.19-3 815.00 ng x mL(-1) (r = 0.999 0). Recovery rate of different concentrations were 87.42%-89.95%. The precision of inter-day and intra-day were less than 11%. The method developed in our study was proved to be sensitive, rapid and simple. It is suitable for the pharmacokinetic study of UA-SMEDDS in rats.

[Effect of synchronous perfusion of NaN3 in changes in content of cholinergic neurotransmitter in medial prefrontal cortex and hippocampal extra-cellular fluid].

OBJECTIVE: To observe the effect of synchronous perfusion of specific respiratory chain complex IV inhibitor sodium azide (NaN3) in brain on rat ventromedial prefrontal cortex (mPFC) and acetylcholine (ACh) and choline (Ch) contents in hippocampal extra-cellular fluid, and establish the AD rat model induced by mitochondrial acute injury. METHOD: The synchronous dual-probe dual-channel brain microdialysis sampling technology was applied to synchronously perfuse modified Ringer's solution containing NaN3 (50 micro mol L-1) and neostigmine (2 micro mol L-1) into mPFC and hippocampus of conscious, freely moving normal rats, and continuously collect dialysates from different encephalic areas. Dynamic contents of ACh and Ch were determined by high performance liquid chromatography-post-column immobilized enzyme reactor-electrochemical process. RESULT: ACh and Ch contents in mPFC extracellular fluid of normal rats were higher than that in hippocampus. During the process of perfusion, NaN3 could significantly reduce ACh in mPFC/hippocampal extra-cellular fluid, but remarkably increase Ch, and constantly inhibit the recovery of ACh and Ch contents in mPFC/hippocampus. CONCLUSION: The synchronous perfusion of NaN3in rat mPFC and hippocampus can injure functions of the cholinergic nerve projection area, and cause the acute AD model with ACh and Ch metabolic disorders. This model can be used in pathogenetic and pharmacological studies.

[Preparation and Determination of Insulin-like Growth Factor I in Deer Antler, Heart and Blood].

OBJECTIVE: To optimize the method for preparation of the insulin-like growth factor I (IGF-I ) in deer antler, and to determine the IGF-I in deer antler, heart and blood. METHODS: Ultrasonic extraction was used to extract IGF-I from different tissues of deer with ammonia-ammonium acetate buffer, followed by ultrafiltration and solid phase extraction to concentrate and purify the samples. At the same time, ethanol precipitation method was carried out in the purification of IGF-I ultrafiltratein deer antler, a parallel test proceeded and radio immune assay (RIA) was set to determine the IGF-I in deer antler, heart and blood. RESULTS: The IGF-I (60.8 ng/g) in deer antler by solid phase extraction was only existed in 30% methanol aqueous solution which was much higher than that (46.1 ng/g) by ethanol precipitation method. The quantities of IGF-I in deer antler, heart and blood were significantly different, it was 61.9 ng/g in antler and 21.9 ng/mL in blood, while there was no IGF-I tested in deer heart. CONCLUSION: Solid phase extraction is superior to ethanol precipitation method in preparing IGF-I in deer antler and it is clear that the IGF-I contained in deer antler is significantly higher than that in deer heart and blood, so it is the best choice to take IGF-I from deer antler.

Effects of returning paddy field to wetland on composition and stability of soil aggregates in the Yellow River Delta.

The composition and stability of soil aggregates are important indicators for measuring soil quality, which would be affected by land use changes. Taking wetlands with different returning years (2 and 15 years) in the Yellow River Delta as the research object, paddy fields and natural wetlands as control, we analyzed the changes in soil physicochemical properties and soil aggregate composition. The results showed that soil water content, total organic carbon, dissolved organic carbon and total phosphorus of the returning soil (0-40 cm) showed an overall increasing trend with returning period, while soil pH and bulk density was in adverse. There was no significant change in clay content, electrical conductivity, and total nitrogen content. The contents of macro-aggregates and micro-aggregates showed overall increasing and decreasing trend with returning period, respectively. The stability of aggregates in the topsoil (0-10 cm) increased with returning years. Geometric mean diameter and mean weight diameter increased by 8.9% and 40.4% in the 15th year of returning, respectively, while the mass proportion of >2.5 mm fraction decreased by 10.5%. There was no effect of returning on aggregates in subsoil (10-40 cm). Our results indicated that returning paddy field to wetland in the Yellow River Delta would play a positive role in improving soil structure and aggregate stability.

Biotransformation of Bioactive Metabolites in Cassiae Semen by Endogenous Enzymes and Probiotics.

The present study evaluated the potential of endogenous enzymes and probiotics in transforming bioactive metabolites to reduce the purgative effect and improve the functional activity of Cassiae Semen and verified and revealed the biotransformation effect of endogenous enzymes. Although probiotics, especially Lactobacillus rhamnosus, exerted the transformation effect, the endogenous enzymes proved to be more effective in transforming the components of Cassiae Semen. After biotransformation by endogenous enzymes for 12 h, the levels of six anthraquinones in Cassiae Semen increased by at least 2.98-fold, and free anthraquinones, total phenolics, and antioxidant activity also showed significant improvement, accompanied by an 82.2% reduction in combined anthraquinones responsible for the purgative effect of Cassiae Semen. Further metabolomic analysis revealed that the biotransformation effect of endogenous enzymes on the bioactive metabolites of Cassiae Semen was complex and diverse, and the biotransformation of quinones and flavonoids was particularly prominent and occurred by three primary mechanisms, hydrolyzation, methylation, and dimerization, might under the action of glycosyl hydrolases, SAM-dependent methyltransferases, and CYP450s. Accordingly, biotransformation by endogenous enzymes emerges as a mild, economical, food safety risk-free, and effective strategy to modify Cassiae Semen into an excellent functional food.

[Study on correlation between neuropsychological features and Chinese medical syndrome types in patients with Wilson's disease].

OBJECTIVE: To explore the correlation between neuropsychological features and Chinese medical syndrome types in Wilson's disease (WD) patients, thus providing evidence for early intervention by syndrome typing. METHODS: Totally 96 WD patients were assigned to Gan-Dan damp-heat syndrome (GDDHS, 31 cases), Gan-Shen yin deficiency syndrome (GSYDS, 47 cases), and qi-blood deficiency syndrome (QBDS, 18 cases) by syndrome typing. Three items of neuropsychological testing were performed in them, i.e., Raven's standard progressive matrices (R'SPM), Stroop color-word test (CWT), trail making test (TMT). The correlations between the integrals of Chinese medical syndrome types and results of the 3 tests were analyzed. RESULTS: (1) There was statistical difference in the total scores of R'SPM, the word interference time of CWT, and interference effects of TMT among the 3 syndrome types (P <0.01, P <0.05). There was statistical difference in the total scores of R'SPM and the word interference time of CWT in patients of QBDS, when compared with those of GDDHS and GSYDS (P <0.05). There was statistical difference in interference effects of TMT in patients of GDDHS, when compared with those of QBDS and GSYDS (P <0.05). (2) The integrals of the 3 syndrome types were negatively correlated with the total scores of R'SPM (P <0.01). The integral of GDDHS was significantly positively correlated with the interference effects of TMT (P <0.01). The integral of GSYDS was significantly positively correlated with TMT-B time consumption and interference effects of TMT (P <0. 05). The integral of QBDS was significantly positively correlated with the word interference time of CWT (P <0.05). CONCLUSIONS: There was correlation between neuropsychological changes of WD patients and Chinese medical syndrome types. The severity of asthenia syndrome was sequenced from high to low as QBDS > GSYDS > GDDHS. The severity of asthenia was higher than that of asthenia.

[Analgesic effect of CQM on prosopalgia model rats and its impact on exciting amino acid neurotransmitters].

OBJECTIVE: To observe the analgesic effect of CQM on photochemically-induced prosopalgia model rats, and discuss its impact on the exciting amino acid neurotransmitter-glutamate (Glu). METHOD: Male SD rats were randomly divided into the sham operation group and the prosopalgia group. And the latter was subdivided into the model group, the gabapentin group (100 mg kg(-1)), and the CQM low-dose (35 mg x kg(-1)) and CQM high-dose (70 mg x kg(-1)) groups. The mechanical allodynia test was adopted to evaluate the pain behavior of rats, and reflect the efficacy with the mechanical withdrawal thresholds. The rat striatum extra-cellular fluid was collected by brain micro-dialysis. The Glu level of samples was measured by high performance liquid chromatography-fluorescene detector (HPLC-FLD). RESULT: Compared to the control group, the threshold of the mechanical allodynia of the IoN injury group was decreased significantly (P < 0.05), and the concentration of Glu was increased dramatically (P < 0.05). Compared to the model group, the mechanical allodynia of photochemically-induced prosopalgia model rats increased significantly (P < 0.01), with a notable increase in brain Glu concentration (P < 0.05). Compared with the model group, all of mechanical withdrawal thresholds increased. Among them, the CQM high-dose group showed a remarkably growth at three time points (P < 0.05), with the maximum up to (23 +/- 7.3) g. And the gabapentin group showed a remarkably growth at two time points (P < 0.05), with the maximum up to (20.5 +/- 9.2) g. All of the drug groups showed significantly lower Glu concentrations in rat brains than the model group (P < 0.05). CONCLUSION: CQM can ease the mechanical allodynia of photochemically-induced prosopalgia model rats. Its analgesic effect may be related to the decrease of Glu concentrations in striatum extra-cellular fluid.

Anti-apoptosis and anti-inflammation activity of circ_0097010 downregulation in lipopolysaccharide-stimulated periodontal ligament cells by miR-769-5p/Krüppel like factor 6 axis.

Background/purpose: Periodontitis is a prevalent infectious inflammatory disease. Growing evidence has revealed important roles for circular RNAs (circRNAs) and circRNA sponge activity in periodontitis. Here, we elucidated the precise part of circ_0097010 in periodontitis pathogenesis. Materials and methods: Human periodontal ligament cells (hPDLCs) were exposed to lipopolysaccharide (LPS). Cell viability, proliferation and apoptosis were evaluated by CCK-8 assay, EdU incorporation assay and flow cytometry, respectively. Circ_0097010, microRNA (miR)-769-5p and Krüppel like factor 6 (KLF6) were quantified by qRT-PCR and Western blot. Interleukin 6 (IL-6) level, tumor necrosis factor-α (TNF-α) secretion, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were detected by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were used to confirm the direct relationship between miR-769-5p and circ_0097010 or KLF6. Results: Our data showed that LPS repressed cell proliferation and induced cell apoptosis and inflammation in hPDLCs. Circ_0097010 was upregulated in periodontitis samples and LPS-exposed hPDLCs. Downregulation of circ_0097010 exerted anti-apoptosis and anti-inflammation functions in LPS-exposed hPDLCs. Mechanistically, circ_0097010 acted as a miR-769-5p sponge, and reduced abundance of miR-769-5p reversed the anti-apoptosis and anti-inflammation effects of circ_0097010 suppression. KLF6 was a direct miR-769-5p target, and miR-769-5p-mediated inhibition of KLF6 possessed anti-apoptosis and anti-inflammation functions in LPS-induced hPDLCs. Moreover, circ_0097010 controlled KLF6 expression by miR-769-5p. Conclusion: These data identify circ_0097010 as a key regulator of LPS-induced inflammation and apoptosis in hPDLCs and highlight a novel mechanism of circ_0097010 regulation through miR-769-5p/KLF6 axis.