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Chemical constituents from the ethanol extract of Picrorhiza scrophulariiflora were isolated and purified by column chromatography. Their structures were identified by HR-MS, 1D and 2D-NMR, and their cytotoxicity was assessed by CCK-8 assay. Four compounds were isolated and identified as follows: 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosterol-5,25-diene-22-one(1), 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,24-diene-22-one(2), 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5-ene-22-one(3) and 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,23-(E)-diene-22-one(4). Compound 1 represents a new cucurbitane glycoside. The half inhibitory concentrations of the 4 compounds exceeded 100 µmol·L~(-1) against four tumor cell lines, indicating no significant cytotoxicity.

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L-ascorbic acid (ASA) is a micronutrient that is essential for reproduction, growth, and immunity in animals. Due to the loss of enzyme L-gulono-1,4-lactone oxidase (GLO), most aquatic animals lack the capacity for ASA biosynthesis and therefore require supplementation with exogenous ASA. Recent studies have shown that 2-keto-L-gulonic acid (2KGA), a novel potential precursor of ASA, can enhance plant growth and improve stress resistance by promoting the synthesis and accumulation of ASA. Our hypothesis is that 2-keto-L-gulonic acid (2KGA) plays a similar role in aquatic animals. To investigate this, we conducted an in vivo trial to examine the effects of exogenous 2KGA supplementation on ASA metabolism and growth of zebrafish (Danio rerio). Zebrafish were categorized into groups based on their dietary intake, including a basal diet (CK group), a basal diet supplemented with 800 mg/kg ASA (ASA group), and 800 mg/kg 2KGA-Na (2KGA group) for a duration of three weeks. The results demonstrated a significant increase in ASA content in zebrafish treated with 2KGA (34.82% increase, p < 0.05) compared to the CK group, reaching a consistent level with the ASA group (39.61% increase, p < 0.05). Furthermore, the supplementation of 2KGA significantly improved growth parameters relevant to zebrafish (specific growth rate increased by 129.04%, p < 0.05) and enhanced feed utilization (feed intake increased by 15.65%, p < 0.05). Positive correlations were observed between growth parameters, feed utilization, whole-body chemical composition, and ASA content. Our findings suggest that supplementation with exogenous 2KGA can serve as a novel approach for elevating ASA synthesis in aquatic animals, and further investigation of its underlying mechanism is required.

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Introduction: High altitude-related hypoxia-induced organ damage significantly impacts people who are exposed to acute high-altitude environment. At present, kidney injury still lacks effective treatment strategies. Iridium nanozymes (Ir-NPs) are a nanomaterial with various enzymatic activities and are expected to be used in kidney injury treatment. Methods: In this study, we simulated a high-altitude environment (6000 m) to induce a kidney injury model, and explored the therapeutic effect of Ir-NPs in mice with kidney injury in this environment. Changes in the microbial community and metabolites were analyzed to explore the possible mechanism underlying the improvement of kidney injury during acute altitude hypoxia in mice treated with Ir-NPs. Results: It was discovered that plasma lactate dehydrogenase and urea nitrogen levels were considerably increased in mice exposed to acute altitude hypoxia compared to mice in a normal oxygen environment. Furthermore, there was a substantial increase in IL-6 expression levels in hypoxic mice; contrastingly, Ir-NPs decreased IL-6 expression levels, reduced the levels of succinic acid and indoxyl sulfate in the plasma and kidney pathological changes caused by acute altitude hypoxia. Microbiome analysis showed that bacteria, such as Lachnospiraceae_UCG_006 predominated in mice treated with Ir-NPs. Conclusion: Correlation analysis of the physiological, biochemical, metabolic, and microbiome-related parameters showed that Ir-NPs could reduce the inflammatory response and protect kidney function under acute altitude hypoxia, which may be related to intestinal flora distribution regulation and plasma metabolism in mice. Therefore, this study provides a novel therapeutic strategy for hypoxia-related kidney injury, which could be applied to other hypoxia-related diseases.

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Background: Preventing suicide among adolescents is an urgent global public-health challenge, especially in Africa. Accordingly, the aim of this study was to examine the relationship between the early initiation (< 12 years old) of substance use (cigarette smoking, alcohol use, and drug use) and attempted suicide among in-school adolescents in seven African countries. Methods: Data on the early initiation of substance use and on attempted suicide among in-school adolescents over the previous 12 months in Benin, Liberia, Mauritius, Mozambique, Namibia, Seychelles, and the United Republic of Tanzania were collected from Global School-based Student Health Surveys and were pooled to determine the overall prevalence of these behaviors in adolescents. Univariate and multivariate logistic regressions were then performed to evaluate country-specific associations between the early initiation of substance use and attempted suicide in these adolescents, followed by meta-analyses to evaluate overall pooled associations. Results: In the abovementioned seven African low- or middle-income countries (LMICs), overall weighted prevalences of attempted suicide and early initiation of cigarette smoking, alcohol use, and drug use among in-school adolescents were 16.05, 7.76, 17.68, and 3.48%, respectively. Multivariate logistic regression analyses revealed that relative to non-smoking, the early initiation of smoking was significantly associated with attempted suicide in these adolescents [OR (95% CI) = 1.783 (1.219-2.348)]. Additionally, the relationship between early initiation of cigarette smoking and attempted suicide is mostly driven by a higher association in girls [OR (95% CI) = 1.867 (1.031-2.703)] than boys [OR (95% CI) = 1.392 (0.995-1.789)]. Moreover, relative to not using other drugs, the early and later initiation of other drug use were also significantly associated with attempted suicide in these adolescents [ORs (95% CIs) = 2.455 (1.701-3.208) and 1.548 (1.198-1.898)]. Conclusion: Programs that can eliminate or decrease the early initiation of substance use among adolescents should be implemented in African LMICs to prevent subsequent suicide attempts, especially among adolescent girls.

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Salt stress has long been a prominent obstacle that restricts crop growth, and increasing the L-ascorbic acid (ASA) content of crops is an effective means of alleviating this stress. 2-Keto-L-gulonic acid (2KGA) is a precursor used in industrial ASA production as well as an ASA degradation product in plants. However, to date, no study has investigated the effects of 2KGA on ASA metabolism and salt stress. Here, we evaluated the potential of using 2KGA to improve crop resistance to salt stress (100mM NaCl) through a cultivation experiment of non-heading Chinese cabbage (Brassica campestris ssp. chinensis). The results showed that the leaf and root biomass were significantly improved by 2KGA application. The levels of metabolites and enzymes related to stress resistance were increased, whereas the hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents were decreased. Lipid peroxidation and cell membrane damage were alleviated following 2KGA treatment. Positive correlations were found between photosynthetic pigments and organic solutes, ASA and photosynthetic pigments, and ASA and antioxidant enzymes. In contrast, negative correlations were observed between antioxidant enzymes and H2O2/MDA. Moreover, the expression levels of L-gulono-1,4-lactone oxidase, GDP-mannose pyrophosphorylase, dehydroascorbate reductase-3, and ascorbate peroxidase were increased by 2KGA treatment. These results suggested that exogenous 2KGA application can relieve the inhibitory effect of salt stress on plant growth, and the promotion of ASA synthesis may represent a critical underlying mechanism. Our findings have significant implications for the future application of 2KGA or its fermentation residue in agriculture.

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Escherichia coli K1 is the most common Gram-negative bacteria causing neonatal meningitis. Polymorphonuclear leukocyte (PMN) transmigration across the blood-brain barrier (BBB) is the hallmark of bacterial meningitis. Reportedly, the deletion of virulence factor cglD (E44:ΔcglD) from E44 is responsible for a less efficient PMN transendothelial migration ability. In the present study, we found that complementation of the cglD gene into E44:ΔcglD mutant strain might restore the PMN count and myeloperoxidase level in a neonatal mouse meningitis. Using human brain microvascular endothelial cells (HBMECs), the main model of the BBB in vitro, we found that E44:ΔcglD mutant strain induced a less efficient PMN adhesion to HBMECs and down-regulated chemokines CXCL1, CXCL6 and CXCL8 and adhesion molecule E-selectin, compared with the E44 strain. Complementation of cglD restored the PMN adhesion to HBMECs and the level of these proteins. E44:ΔcglD mutant strain also induced a less efficient NF-κB pathway activation in HBMECs and reduced the soluble p65 (sp65) level in the cerebral spinal fluid of newborn mice, compared with the E44 strain. Complementation of cglD restored the NF-κB pathway activation and increased the sp65 levels. This suggests that cglD in E44 contributes to NF-κB pathway activation in the brain endothelium to promote PMN adhesion to HBMECs and transendothelial migration. Our identified novel requirement of cglD for immune activation and subsequent PMN entry into the central nervous system suggests that therapies directed at neutralising this molecule will be beneficial in preventing bacterial meningitis progression.

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Glycyl-l-histidyl-l-lysine (GHK)-Cu is considered to be an activator of tissue remodeling, and has been used in cosmetic products. In this study, we prepared liposomes encapsulating GHK-Cu and analyzed their effect on human umbilical vein endothelial cells (HUVECs) proliferation and scald wound healing in mice. The nanoscaled GHK-Cu-liposomes promoted HUVECs proliferation, with a 33.1% increased rate. Flow cytometry analysis showed increased cell number at G1 stage and decreased cell number at G2 stage after GHK-Cu-liposomes treatment. Western blotting indicated that the expression of vascular endothelial growth factor and fibroblast grow factors-2 were both enhanced, as well as cell cycle-related proteins CDK4 and CyclinD1. In a mice scald model, angiogenesis in burned skin treated with GHK-Cu-liposomes was better compared with free GHK-Cu, and immunofluorescence analysis showed enhanced signal of CD31 and Ki67 in GHK-Cu-liposomes treated mice. Moreover, the wound healing time was shortened to 14 days post injury. Our results provide the evidence that GHK-Cu-liposomes could be utilized as a treatment for skin wounds.

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The present study developed a CYP3A4-expressed Caco-2 monolayer model at which effects of the efflux-metabolism alliance on the transport and uptake of clausenamide (CLA) enantiomers as CYP3A4 substrates were investigated. The apparent permeability coefficients (Papp) of (-) and (+)CLA were higher in the absorptive direction than those in the secretory direction with efflux ratios (ER) of 0.709±0.411 and 0.867±0.250 (×10(-6)cm/s), respectively. Their bidirectional transports were significantly reduced by 75.6-87.5% after treatment with verapamil (a P-glycoprotein inhibitor) that increased the rate of metabolism by CYP3A4, whereas the CYP3A4 inhibitor ketoconazole treatment markedly enhanced the basolateral to apical flux of (-) and (+)CLA with ERs being 2.934±1.432 and 1.877±0.148(×10(-6)cm/s) respectively. These changes could be blocked by the duel CYP3A4/P-glycoprotein inhibitor cyclosporine A, consequently, Papp values for CLA enantiomers in both directions were significantly greater than those obtained by using verapamil or ketoconazole, and their ERs were similar to those following (-) or (+)-isomer treatment alone. Furthermore, the uptake of (-)CLA was more than that of (+)CLA in the transfected cells. Incubation with ketoconazole decreased the intracellular concentrations of the two enantiomers. This effect disappeared in the presence of a CYP3A4 inducer dexamethasone. These results indicated that CYP3A4 could influence P-gp efflux, transport and uptake of CLA enantiomers as CYP3A4 substrates and that a duel inhibition to CYP3A4/ P-glycoprotein could enhance their absorption and bioavailability, which provides new insight into the efflux-metabolism alliance and will benefit the clinical pharmacology of (-)CLA as a candidate drug for treatment of Alzheimer's disease.

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OBJECTIVE: Green tea polyphenols (GTPs) are now being considered possible protective agents in neurodegenerative diseases such as Alzheimer's disease (AD). Previous studies suggested that GTPs could inhibit amyloid fibril formation and protect neurons from toxicity induced by ß-amyloid. However, whether GTPs can ameliorate learning and memory impairments and also reduce tau hyperphosphorylation induced by okadaic acid (OA) in rats remains unclear. The aim of this study was to determine if GTPs have neuroprotection against OA-induced neurotoxicity. METHODS: In this work, rats were pretreated with GTPs by intragastric administration for 4 wk. Then OA was microinjected into the right dorsal hippocampus. Morris water maze tests were used to test the ethologic changes in all groups, and tau protein hyperphosphorylation was detected both in vivo and in vitro. RESULTS: The ethologic test indicated that the staying time and swimming distance in the target quadrant were significantly decreased after OA treatment, whereas rats pretreated with GTPs stayed longer in the target quadrant. Methyl thiazolyl tetrazolium assay and lactate dehydrogenase leakage showed that GTPs greatly ameliorated primary hippocampal neurons damage induced by OA. Furthermore, reduced hyperphosphorylated tau protein was detected with GTPs pretreatment. CONCLUSION: Taken together, our results suggest that GTPs have neuroprotection against OA-induced neurotoxicity.

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