Effect of butylphthalide combined with idebenone on vascular dementia: A retrospective observational analysis.

To explore the efficacy and safety of butylphthalide combined with idebenone in the treatment of vascular dementia. The clinical data of 126 patients with vascular dementia who were admitted to our hospital between March 2021 and February 2023 were retrospectively reviewed. Among them, 62 patients received butylphthalide alone (single group) and 64 patients received butylphthalide combined with idebenone (combined group). Cognitive function scores, serum inflammatory factor levels, oxidative stress index levels, and incidence of adverse reactions were compared between the 2 groups before and after treatment. After treatment, the Hasegawa Dementia Scale, Mini Mental State Examination Scale, and activities of daily living scores in both groups were higher than before treatment, and the scores in the combined group were higher than before treatment (P < .05). After treatment, the levels of serum C-reactive protein, tumor necrosis factor-α, and interleukin 6 in both groups were lower than those before treatment, and those in the combined group were lower than those in the simple group (P < .05). After treatment, the levels of serum glutathione peroxidase and superoxide dismutase in the 2 groups were higher than those before treatment, and the level of malondialdehyde was lower than that before treatment. The levels of serum glutathione peroxidase and superoxide dismutase in the combined group were higher than those in the simple group, and the level of malondialdehyde was lower than that in the simple group (P < .05). There was no significant difference in the incidence of adverse reactions between the combined group (6.25%) and the simple group (3.23%) (P > .05). Compared with butylphthalide alone, intervention of butylphthalide combined with idebenone on vascular dementia can effectively reduce the degree of inflammatory and oxidative stress reactions, improve cognitive function, and promote the ability to perform activities of daily living in a safe manner.

Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.

BACKGROUND: Heterologous boosting is suggested to be of use in populations who have received inactivated COVID-19 vaccines. We aimed to assess the safety and immunogenicity of a heterologous vaccination with the mRNA vaccine CS-2034 versus the inactivated BBIBP-CorV as a fourth dose, as well as the efficacy against the SARS-CoV-2 omicron (BA.5) variant. METHODS: This trial contains a randomised, double-blind, parallel-controlled study in healthy participants aged 18 years or older (group A) and an open-label cohort in participants 60 years and older (group B), who had received three doses of inactivated whole-virion vaccines at least 6 months before enrolment. Pregnant women and people with major chronic illnesses or a history of allergies were excluded. Eligible participants in group A were stratified by age (18-59 years and ≥60 years) and then randomised by SAS 9.4 in a ratio of 3:1 to receive a dose of the mRNA vaccine (CS-2034, CanSino, Shanghai, China) or inactivated vaccine (BBIBP-CorV, Sinopharm, Beijing, China). Safety and immunogenicity against omicron variants of the fourth dose were evaluated in group A. Participants 60 years and older were involved in group B for safety observations. The primary outcome was geometric mean titres (GMTs) of the neutralising antibodies against omicron and seroconversion rates against BA.5 variant 28 days after the boosting, and incidence of adverse reactions within 28 days. The intention-to-treat group was involved in the safety analysis, while all patients in group A who had blood samples taken before and after the booster were involved in the immunogenicity analysis. This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575). FINDINGS: Between Oct 13, and Nov 22, 2022, 320 participants were enrolled in group A (240 in the CS-2034 group and 80 in the BBIBP-CorV group) and 113 in group B. Adverse reactions after vaccination were more frequent in CS-2034 recipients (158 [44·8%]) than BBIBP-CorV recipients (17 [21·3%], p<0·0001). However, most adverse reactions were mild or moderate, with grade 3 adverse reactions only reported by eight (2%) of 353 participants receiving CS-2034. Heterologous boosting with CS-2034 elicited 14·4-fold (GMT 229·3, 95% CI 202·7-259·4 vs 15·9, 13·1-19·4) higher concentration of neutralising antibodies to SARS-CoV-2 omicron variant BA.5 than did homologous boosting with BBIBP-CorV. The seroconversion rates of SARS-CoV-2-specific neutralising antibody responses were much higher in the mRNA heterologous booster regimen compared with BBIBP-CorV homologous booster regimen (original strain 47 [100%] of 47 vs three [18·8%] of 16; BA.1 45 [95·8%] of 48 vs two [12·5%] 16; and BA.5 233 [98·3%] of 240 vs 15 [18·8%] of 80 by day 28). INTERPRETATION: Both the administration of mRNA vaccine CS-2034 and inactivated vaccine BBIBP-CorV as a fourth dose were well tolerated. Heterologous boosting with mRNA vaccine CS-2034 induced higher immune responses and protection against symptomatic SARS-CoV-2 omicron infections compared with homologous boosting, which could support the emergency use authorisation of CS-2034 in adults. FUNDING: Science and Technology Commission of Shanghai, National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Danshensu Enhances Cerebral Angiogenesis in Mice by Regulating the PI3K/Akt/Mtor/VEGF Signaling Axis.

BACKGROUND: Cerebral infraction seriously affects the life quality of patients. Danshensu has been reported to exhibit anti-inflammatory and vascular protective effects. However, the therapeutic function of Danshensu in cerebral vascular injury is still unclear. METHODS: Middle cerebral artery occlusion (MCAO) was used to construct the cerebral infraction model. Wound healing and tube formation assays were used to evaluate angiogenesis in vitro. Western blot assay was used to evaluate the activation of the PI3K/Akt/mTOR signaling pathway. The laser Doppler scanner was used to measure the regional cerebral blood flow (rCBF) in the area around the infarction, and the adhesion removal test was used to measure the sensorimotor function. The Modified Neurological Severity Score was performed to evaluate the cognitive functions of mice. RESULTS: Danshensu promoted the proliferation of bEnd.3 cells and angiogenesis in vitro. Danshensu upregulated the expression of VEGF through PI3K/Akt/mTOR signaling pathway in bEnd.3 cells. Danshensu improved rCBF restoration and attenuated the behavioral deficits in mice post-MCAO/R. CONCLUSION: Danshensu enhances angiogenesis through the PI3K/Akt/mTOR/VEGF signaling pathway in a mouse model of cerebral ischemic injury.

NLRP3 inflammasome inhibitor ameliorates ischemic stroke by reprogramming the phenotype of microglia/macrophage in a murine model of distal middle cerebral artery occlusion.

Stroke is one of the leading causes of death and disability worldwide. NLRP3 inflammasome has an essential role in the neuropathology of stroke. Recent studies report that shifting the microglial M1 phenotype to the M2 phenotype protects against ischemic stroke. In the present study, the precise effects of Tranilast, a NLPR3 inflammasome inhibitor, on stroke were evaluated. We established a murine model of distal middle cerebral artery occlusion (dMCAO) and administered Tranilast to dMCAO-induced stroke mice. The NLRP3 level, caspase 1 activity, and infarct volume stroke mice were measured. The sensorimotor function, pro-inflammatory cytokine production, and M1/M2 marker expression were measured. The M1 phenotype was induced by treatment of BV2 microglia with lipopolysacharide and interferon γ, and these BV-2 cells were further treated with Tranilast. The expression of CD16 and CD206 was monitored. dMCAO increased the NLRP3 expression and enhanced caspase 1 activity. Tranilast treatment significantly decreased the infarct volume, improved sensorimotor function, and suppressed the production of inflammatory cytokines in stroke mice. Moreover, Tranilast decreased the M1 marker level while promoting the expression of M2 markers. In summary, our findings suggest that Tranilast ameliorates ischemic stroke through stimulating M2 polarization of microglia.

cVEMP and VAT for the diagnosis of vestibular migraine.

BACKGROUND: Although the diagnostic criteria of vestibular migraine (VM) have already been defined, various clinical manifestations of VM and the lack of pathognomonic biomarker result in high rate of misdiagnosis and mismanagement. A timely and accurate diagnosis tool for the evaluation of VM is highly needed. OBJECTIVE: The current study aims to investigate the potential feasibility of cervical vestibular evoked myogenic potential (cVEMP) and vestibular autorotation test (VAT) as a diagnosis tool for VM. METHODS: A total of 211 subjects were recruited into the current study with all subjects meeting the inclusion and exclusion criteria. The subjects were divided into 3 groups: healthy control group, general migraine group and VM group. Test of cVEMP and VAT was conducted in all the groups, and the generated data were statistically compared. RESULTS: Compared with the other two groups, cVEMP P13-N23 amplitudes of VM patients showed a significant decline. Mean latency values of the VM group had no significant difference in comparison with other groups. Asymmetry ratios showed increased level in VM patients compared to the control groups, without significant difference. VAT results showed that all the horizontal gain, horizontal phase, vertical gain and vertical phase differ from the other two groups to varying degrees at higher frequency. CONCLUSION: cVEMP and VAT have potential usage in the assessment of VM and can serve as powerful tool in diagnosis of VM.

Effects of exogenous melatonin on photosynthesis and physiological characteristics of chry-santhemum seedlings under high temperature stress.

We examined the effects of exogenous melatonin (MT) on the resistance of Chrysanthemum morifolium 'Jinba' to high temperature stress. Chrysanthemum leaves were sprayed with 200 µmol·L-1MT, and then subjected to high temperature stress at 40 ℃ (day)/ 35 ℃ (night). The ultrastructure of chloroplast and thylakoid of chrysanthemum leaves were observed, and the photosynthetic and physiological indices were measured. The results showed that the chloroplast and thyla-koid structures of chrysanthemum were damaged under high temperature stress. The chlorophyll contents and maximum fluorescence (Fm) were significantly reduced, while the OJIP curve changed with the fluorescence of K and J points increased. The net photosynthetic rate (Pn), transpiration rate (Tr) and stomatal conductance (gs) were significantly decreased, while the internal CO2 concentration (Ci) was significantly increased. The relative conductivity (REC), malondialdehyde (MDA), reactive oxygen species (ROS), osmotic adjustment substances content and antioxidant enzyme activity all increased significantly. Spraying exogenous MT onto leaves could maintain the integrity of chloroplast and thylakoid structure under high temperature in chrysanthemum and significantly decrease the increment in the K and J points of OJIP curve. Exogenous application of MT alleviated the inhibition of high temperature stress on photosynthesis and fluorescence of chrysanthemum, as indicated by significantly higher Fm, Pn, gs, Tr and photosynthetic pigment contents and lower Ci. Exogenous MT also significantly reduced the REC, MDA and ROS contents of chrysanthemum under high temperature stress, and enhanced the osmotic adjustment substances content and antioxidant enzyme activity in chrysanthemum leaves. It suggested that exogenous MT could protect the integrity of chloroplast structure of chrysanthemum leaves, enhance photosynthesis, inhibit the excessive production of ROS in the plants under high temperature stress, improve the activity of antioxidant enzyme system, reduce the level of membrane peroxidation and keep the integrity of lipid membrane, and thus improve the ability of chrysanthemum plants to resist high temperature stress.

Energy quota trading can achieve energy savings and emission reduction: evidence from China's pilots.

Climate change mitigation and adaptation are common global challenges, and how to accelerate carbon neutrality and green recovery is a major global issue. Market-oriented emission reduction policy has been widely concerned for its unique advantages, but most of the current market-oriented emission reduction policies are based on the consideration of end-of-pipe governance and lack of effective control of source reduction. Energy quota trading (EQT) is an innovation of an energy-saving and emission reduction system, which is based on the idea of source reduction. However, it is unknown about the evaluation of the effect of the EQT policy from the macro perspective. Based on the related statistical data of energy consumption, combined with the ARIMA model, STIRPAT model, and the synthetic control method (SCM), this paper analyzes the energy consumption distribution in China from 2001 to 2020 and comprehensively evaluates the effect of EQT in the pilots. The results show that: (1) The overall energy consumption in China shows a steady upward trend, and its distribution is unbalanced. (2) In absolute perspective, EQT can realize the "double control" of the total amount and intensity in energy saving and emission reduction, and the intensity control effect is better than the total amount control effect. (3) In relative perspective, EQT can enhance the potential of energy saving and emission reduction in the pilots, in which it needs to take the regional characteristics into account. The policy effect is still significant when eliminating some unobservable factors, which indicate that the policy is effective and can be replicated nationwide. The study comprehensively evaluates the effect of ETS from multiple perspectives, which can effectively avoid the misjudgment of the policy effectiveness caused by the single dimension evaluation, while it can also be used as a reference for the government to perfect the policies of energy management system and emission control system. Furthermore, the development of EQT is an important catalyst for policymakers to coordinate policies to accelerate the achievement of carbon-neutral targets and a more resilient low-carbon development model.

Influential Factors and Spatiotemporal Characteristics of Carbon Intensity on Industrial Sectors in China.

Based on the extended STIRPAT model and panel data from 2005 to 2015 in 20 industrial sectors, this study investigates the influential factors of carbon intensity, including employee, industry added value, fixed-assets investment, coal consumption, and resource tax. Meanwhile, by expanding the spatial weight matrix and using the Spatial Durbin Model, we reveal the spatiotemporal characteristics of carbon intensity. The results indicate that Manufacturing of Oil Processing and Coking Processing (S7), Manufacturing of Non-metal Products (S10), Smelting and Rolling Process of Metal (S11), and Electricity, Gas, Water, Sewage Treatment, Waste and Remediation (S17) contribute most to carbon intensity in China. The carbon intensity of 20 industrial sectors presents a spatial agglomeration characteristic. Meanwhile, industry added value inhibits the carbon intensity; however, employee, coal consumption, and resource tax promote carbon intensity. Finally, coal consumption appears to have spillover effects, and the employee has an insignificant impact on the carbon intensity of industrial sectors.

Analysis of the spillover effect of energy intensity among provinces in China based on space-time lag model.

Based on inter-provincial energy intensity data in China from 1996 to 2016, using the model combining STIRPAT and dynamic SDM analyzes energy intensity and its influencing factors under the conditions of spatial lag, time lag, and space-time lag. Considering endogenous issues, it then explores the basic characteristics of energy intensity in space and its path dependence. The results show that spatial distribution of energy intensity in China is uneven and generally shows a pattern of decreasing from northwest to southeast. Energy intensity itself has a significant spillover effect, which can affect neighboring regions through pollution heaven effect and pollution halo effect. It can also be reduced as a result of the joint effect of driving factors. Economic development level, foreign direct investment, and technological progress have significant effects on reducing energy intensity, while industrial structure and urbanization rate increase it. The difference among driving factors lies in spatial spillover effect, and the short-term indirect effect is greater than the long-term one. Therefore, the key to realize China mode of green development is to promote factors of reducing energy intensity brought into full play and the inhibitory factors effectively controlled.

Bioinformatics Analysis of the Expression of ATP Binding Cassette Subfamily C Member 3 (ABCC3) in Human Glioma.

OBJECTIVE: To investigate the expression of the ABCC3 gene in human glioma and its correlation with the patient's prognosis. METHODS: The cancer genome atlas (TCGA) database was used to analyze the differential expression of the ABCC3 gene in human glioma. The STRING database was used to construct the protein-protein interaction (PPI) network of the ABCC3 gene coding protein. The co-expression genes relevant to the ABCC3 gene were analyzed by the Pearson correlation test. A log-rank test was used to analyze the difference of overall survival (OS) and disease-free survival (DFS) between the high and low ABCC3 gene expression groups. RESULTS: The expression level of the ABCC3 gene in glioma tissues was lower than that of corresponding normal brain tissues. The PPI network contains 51 nodes with the average node degree of 13.3 and the local clustering coefficient of 0.72 which indicated that the PPI enrichment was significant (p<0.001). Ten hub genes (ABCC3,NR1I2,NR1H4,-CYP7A1,SLC10A1,CYP3A4,UGT1A1,UGT1A8,UGT1A6 and ALB) were identified by the cytoscape software. The KEGG analysis was enriched in drug metabolism - cytochrome P450 and PPAR signaling pathway. CFI gene expression level was positive correlated with the ABCC3 expression level (r=0.71, p<0.05). And the CNRIP1 gene expressed was negative correlated with ABCC3 expression (r=-0.43, p<0.05). The overall survival (HR=2.8, P<0.05) and disease-free survival rates (HR=2.0, P<0.05) of patients with ABCC3 low expression glioma were significantly higher than those of patients with high expression of ABCC3. Conclusion The expression level of the ABCC3 gene in glioma was decreased compared to normal brain tissue. The overall survival and disease-free survival of in the ABCC3 low-expression group was significant decreased.

Essential role of Wnt5a-Ror1/Ror2 signaling in metanephric mesenchyme and ureteric bud formation.

Spatiotemporally regulated interaction between the metanephric mesenchyme (MM) and Wolffian duct (WD) is essential for the induction of a single ureteric bud (UB). The MM then interacts with the tip of the UB to induce outgrowth and branching of the UB, which in turn promotes growth of the adjacent MM. The Ror family receptor tyrosine kinases, Ror1 and Ror2, have been shown to act as receptors for Wnt5a to mediate noncanonical Wnt signaling. Previous studies have shown that Ror2-mutant mice exhibit ectopic formation of the UB, due to abnormal juxtaposition of the MM to the WD. We show here that both Ror1 and Ror2 are expressed in the mesenchyme between the MM and WD during UB formation. Although Ror1-mutant mice show no apparent defects in UB formation, Ror1;Ror2-double-mutant mice exhibit either defects in UB outgrowth and branching morphogenesis, associated with the loss of the MM from the UB domain, or ectopic formation of the UB. We also show genetic interactions between Ror1 and Wnt5a during UB formation. These findings suggest that Wnt5a-Ror1/Ror2 signaling regulates cooperatively the formation of the MM at the proper position to ensure normal development of the UB.

[Associativity between differentiation potential and VEGF secretory capability of immortalized human mesenchymal stem cells].

OBJECTIVE: To investigate the multi-differentiation potential and VEGF secretory volume of monoclonal immortalized human mesenchymal stem cells (hMSC-TERT) and to determine the relationship between them. METHODS: Monoclonal hMSC-TERT were isolated using limiting dilution. The growth curves of them were detected by method of MTT. ELISA was used to detect the concentration of VEGF in the supernatant of those monoclonal hMSC-TERT. Their adipocytic, osteogenic, neuronal differentiation potential in vitro were determined by Oil Red O staining, Von Kossa staining and immunocytochemistry for Tubulin-ßIII antibody. Those Monoclonal hMSC-TERT were transplanted into the subcutaneously of severe combined immunodeficiency (SCID) mice. The grafts of those cells were removed and analyzed by immunohistochemistry for pathologic tissue markers to discover the multi-differentiation potential of those monoclonal hMSC-TERT in vivo. RESULTS: There was statistically significant difference between different monoclonal hMSC-TERT in mult differentiation potential and the decreased concentration of VEGF in the supernatant of those monoclonal hMSC-TERT from the 3(rd) day to the 5(th) day. The positive rates of CK in grafts formed by those monoclonal hMSC-TERT in SCID mice were direct correlation with the decreased concentration of VEGF in the supernatant of those cells. CONCLUSION: The secretory capability of VEGF of those monoclonal hMSC-TERT may direct correlation with the epithelial differentiation potential of those cells.

[Effect of monoclonal or different cell seeding densities on the differentiation potential of immortalized human mesenchymal stem cells in vitro and in vivo].

OBJECTIVE: To determine whether monoclonality or different cell seeding densities could influence the differentiation potential of immortalized human mesenchymal stem cells (hMSC-TERT) and to find an effective cultural method of hMSC-TERT in vitro. METHODS: From the parental hMSC-TERT cell line, we derived 30 monoclonal cell lines and two independent cell lines based on different plating densities during expansion in culture. Their adipocytic, osteogenic, neuronal differentiation potential in vitro and multidirectional differentiation potential in vivo were analyzed by immunohistochemistry for pathologic tissue markers. RESULTS: Monoclonal cell lines and the cell line derived at low seeding density had a lower differentiation potential in vitro than the cell line derived at higher cell seeding density. The differentiation potential of monoclonal hMSC-TERT cells were dissimilar. Some of monoclonal hMSC-TERT lines expressed epithelial differentiation potential in vivo while the parental hMSC-TERT cells line did not. CONCLUSION: Multiclonal hMSC-TERT cells cultured in high seeding density can keep the differentiation potential, cloning the hMSC-TERT cells before transplantation to find the special clones for special purpose of transplantation.