Analysis of cantharidin-induced kidney injury and the protective mechanism of resveratrol in mice determined by liquid chromatography/mass spectrometry-based metabonomics.

Cantharidin (CTD) is the main active component in the traditional Chinese medicine Mylabris and an effective anti-tumor agent. However, it is relatively toxic and exhibits nephrotoxicity, which limits its clinical use. However, its toxic mechanism is not clear. The toxic effects of CTD exposure on the kidney and the protective effect of resveratrol (RES) were studied in a mouse model, by determination of serum biochemical and renal antioxidant indicators, histopathological and ultrastructural observation, and metabonomics. After CTD exposure, serum uric acid, creatinine, and tissue oxidative stress indicators increased, and the renal glomerular and tubular epithelial cells showed clear pathological damage. Ultrastructure observation revealed marked mitochondrial swelling, endoplasmic reticulum dilation, and the presence of autophagy lysosomes in glomerular epithelial cells. RES ameliorated the renal injury induced by CTD. Metabonomics analysis indicated that CTD can induce apoptosis and oxidative damage in kidney cells, mainly by disrupting sphingolipid and glutathione metabolism, increasing sphingosine and sphingomyelin levels, and decreasing glutathione levels. RES counteracts these effects by regulating renal cell proliferation, the inflammatory response, oxidative stress, and apoptosis, by improving the levels of phosphatidylcholine (PC), LysoPC, and lysophosphatidyl glycerol in the glycerophospholipid metabolism pathway, thereby reducing CTD-induced nephrotoxicity. The mechanisms of CTD-induced renal injury and the protective effect of RES were revealed by metabonomics, providing a basis for evaluating clinical treatment regimens to reduce CTD-induced nephrotoxicity.

Therapeutic Efficacy of Intravitreal Conbercept Injections with or without Focal Macular Photocoagulation for Diabetic Macular Edema.

Objective: This study aimed to investigate the effectiveness and safety of intravitreal conbercept injections with or without focal macular photocoagulation in the treatment of diabetic macular edema (DME). Methods: This retrospective study included 60 DME patients (60 eyes) divided into two treatment groups. The conbercept group received monthly intravitreal injections for 5 consecutive sessions, while the combination therapy group received intravitreal injections and focal macular photocoagulation. Changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were observed before and at months 1, 3, 6, 9, and 12 after treatment in both groups, along with the number of intravitreal conbercept injections administered. Results: At 1, 3, 6, 9, and 12 months after treatment, both the conbercept and combined treatment groups showed improvement in best-corrected visual acuity (BCVA) and decrease in central macular thickness (CMT) compared to before treatment, with statistical significant differences (P < .05). However, the differences in BCVA and CMT between the two groups at each time point after treatment were not significant (P > .05). During the 1-year follow-up period, the mean number of injections in the combined treatment group was 6.3±0.8, which was less than that in the conbercept treatment group (7.6 ± 0.9), with a significant difference (t = 5.556, P < .001). The incidence of subconjunctival hemorrhage was 10.9% and 10.5% in the two groups, respectively, with no significant inter-group difference (χ² = 0.013, P = .908). None of the patients exhibited serious treatment-related ocular and systemic complications during the treatment period. Conclusions: Treatment of DME with intravitreal conbercept injections, whether with or without focal macular photocoagulation, is safe and effective in improving the patients' visual acuity and retinal anatomy. However, patients who receive combined treatment require fewer intravitreal injections than those who receive conbercept treatment alone.

Transcriptomic profiling and differential analysis reveal the renal toxicity mechanisms of mice under cantharidin exposure.

Cantharidin (CTD), extracted from the traditional Chinese medicine mylabris, has shown significant curative effects against a variety of tumors, but its clinical application is limited by its high toxicity. Studies have revealed that CTD can cause toxicity in the kidneys; however, the underlying molecular mechanisms remain unclear. In this study, we investigated the toxic effects in mouse kidneys following CTD treatment by pathological and ultrastructure observations, biochemical index detection, and transcriptomics, and explored the underlying molecular mechanisms by RNA sequencing (RNA-seq). The results showed that after CTD exposure, the kidneys had different degrees of pathological damage, altered uric acid and creatinine levels in serum, and the antioxidant indexes in tissues were significantly increased. These changes were more pronounced at medium and high doses of CTD. RNA-seq analysis revealed 674 differentially expressed genes compared with the control group, of which 131 were upregulated and 543 were downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that many differentially expressed genes were closely related to the stress response, the CIDE protein family, and the transporter superfamily, as well as the MAPK, AMPK, and HIF-1 pathways. The reliability of the RNA-seq results was verified by qRT-PCR of the six target genes. These findings offer insight into the molecular mechanisms of renal toxicity caused by CTD and provide an important theoretical basis for the clinical treatment of CTD-induced nephrotoxicity.

Childhood maltreatment and suicidal ideation in Chinese children and adolescents: the mediating role of mindfulness.

BACKGROUND: Childhood maltreatment (CM) has been associated with suicidal ideation (SI) in children and adolescents, yet the mediating role of mindfulness in this association remains unclear. This study aims to test the mediation of mindfulness in CM-SI association among a large sample of Chinese children and adolescents. METHODS: A population-based cross-sectional study of 3455 children and adolescents aged 10-17 years from southwest China Yunnan province was conducted. Information from the participants was collected by using a comprehensive self-administered questionnaire. The Chinese version of the Childhood Trauma Questionnaire (CTQ), Five Facet Mindfulness Questionnaire (FFMQ), and the Beck Scale for Suicidal Ideation (BSSI) were used to measure CM, mindfulness and SI. Univariate and multivariate binary logistic regression models were used to estimate the crude and adjusted associations between CM, mindfulness and SI (one-week, one-year, lifetime). Pathway analysis was subsequently performed to test the mediation of mindfulness in CM-SI association. RESULTS: The findings showed that mindfulness, CM and SI were significantly correlated with each other (p < 0.05). Mindfulness is a significant mediator in CM-SI association, accounted for 7.5, 11.4, and 17.6% of the total associations for one-week SI, one-year SI, and lifetime SI, respectively. For the five types of CM, the highest level of mediation via mindfulness had been found for physical neglect (PN) and one-year SI (34.3%), followed by emotional neglect (EN) and one-year SI (30.2%), sexual abuse (SA) and one-year SI (25.4%). CONCLUSIONS: Our study findings highlight the intervention potential of mindfulness in preventing CM associated suicidal risk. Future longitudinal studies are warranted to corroborate the effectiveness of mindfulness-based intervention for Chinese children and adolescents.

Potential Mechanism and Effects of Different Selenium Sources and Different Effective Microorganism Supplementation Levels on Growth Performance, Meat Quality, and Muscle Fiber Characteristics of Three-Yellow Chickens.

A trial was conducted to investigate the effects of different Se sources, including sodium selenite (S-Se) and selenium yeast (Y-Se) and different effective microorganism (EM) addition levels on growth performance, meat quality, and muscle fiber characteristics of three-yellow chickens and its potential mechanism. A total of 400 birds were randomly distributed into 4 groups (S-Se, S-Se + EM, Y-Se, and Y-Se + EM groups) consisting of a 2 × 2 factorial arrangement. The main factors were the source of Se (ISe = inorganic Se: 0.2 mg/kg S-Se; OSe = organic Se: 0.2 mg/kg Y-Se) and the level of EM (HEMB = high EM: 0.5% EM; ZEMB = low EM: 0% EM). Each treatment had 5 replicates and each replicate consisted of 20 broiler chickens. The trial lasted for 70 days. The results showed that, in breast muscle, the broiler chickens fed OSe source decreased the pH24h, drip loss, shear force, perimeter, cross-sectional area, and diameter, but increased the a 24 h * and density compared with the broiler chickens fed ISe source (p < 0.05); broiler chickens supplied with HEMB level decreased the cross-sectional area and diameter, but increased the pH24h, a 24 h , * and density compared with the broiler chickens supplied with ZEMB level (p < 0.05). In thigh muscle, OSe source and HEMB level also could improve the meat quality and change muscle fiber characteristics of broiler chickens (p < 0.05). Meat quality was correlated with the muscle fiber characteristics (p < 0.05). OSe source and HEMB level could regulate the expression levels of muscle fiber-relative genes in the breast and thigh muscles (p < 0.05). In conclusion, OSe source and HEMB level could improve the meat quality of the breast and thigh muscles of three-yellow chickens by changing the muscle fiber characteristics, and they changed the muscle fiber characteristics by regulating the expression levels of muscle fiber-relative genes.

Productive Performance, Serum Antioxidant Status, Tissue Selenium Deposition, and Gut Health Analysis of Broiler Chickens Supplemented with Selenium and Probiotics-A Pilot Study.

The effect and interaction of dietary selenium (Se) and probiotics on three yellow chicken growth performance, tissue Se content, antioxidant capacity, and gut health were studied from 0 to 70 days of age. A total of 400 one-day-old broilers were distributed into four groups (I-Se, O-Se, I-Se + pros, and O-Se + pros groups) consisting of a 2 × 2 factorial design. The main factors were the source of Se (I-Se = inorganic Se: 0.2 mg/kg sodium selenite; O-Se = organic Se: 0.2 mg/kg Selenium yeast) and the level of probiotics (0.5% EM or 0% EM, the component of EM mainly includes Lactobacillus and Yeast at the dose of 2 × 108 cfu/kg and 3 × 107 cfu/kg, respectively). Each treatment had 5 duplicates consisting of 20 broilers. The results showed that the I-Se group had a greater (p < 0.05) ratio of feed: weight gain (F/G) of broilers at Starter (0−35 d) than the other treatments. Compared to the I-Se group, the O-Se group increased (p < 0.05) Se concentrations in the liver, pancreas, breast muscles, thigh muscle, and the activity of total antioxidative capacity (T-AOC) in serum, as well as the relative abundance of Barnesiella and Lactobacillus in cecum. Meanwhile, probiotics enhanced (p < 0.05) Se concentrations in the pancreas, thigh muscle, serum, and the activity of T-AOC and glutathione peroxidase (GSH-Px), the duodenum's ratio of villi height to crypt depth (V/C), the jejunum villus height and V/C, and the ileum's villus height. Furthermore, the significant interactions (p < 0.05) between Se sources and the level of probiotics were observed in Se concentrations in the pancreas, thigh muscle, serum, crypt depth of duodenum, and villus height of jejunum of birds, and Barnesiella abundance in the cecal. In conclusion, our results demonstrate that the combination of O-Se + pros can improve broiler early growth performance, tissue Se content in the pancreas, thigh muscle, and serum, promote intestinal development, and regulate the composition of intestinal flora, suggesting a better combination. These findings provide an effective method of nutrient combination addition to improving the performance of three yellow chickens.

EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction.

Epigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, µM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 µM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 µM). Large scale atomistic simulations (>100 µs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG's anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.

Tea Consumption and Cognitive Impairment: A Cross-Sectional Study among Chinese Elderly.

BACKGROUND: Laboratorial and epidemiological researches suggested that tea exhibited potential neuroprotective effect which may prevent cognitive impairment, but there were few data among the elderly aged 60 years and above in China. OBJECTIVE: The objective was to explore the relationship between characteristics of tea consumption and cognitive impairment. DESIGN: We analyzed the baseline data from Zhejiang Major Public Health Surveillance Program (ZPHS) which was conducted in 2014. Totally 9,375 residents aged 60 years and above were recruited in this study. Face-to-face interview based on a self-developed questionnaire was performed for each participant. Detailed tea consumption habits were included in the questionnaire. Cognitive impairment screening was performed by using Mini-Mental State Examination (MMSE). Education-specific cut-off points for Chinese were applied to determine the status of cognitive impairment. Logistic regression analysis was used to calculate odds ratios (ORs) of cognitive impairment associated with tea consumption. RESULTS: The means (SD) of MMSE scores for the subjects who did not consume tea and consumed <2 cups/d, 2-4 cups/d, ≥4 cups/d were 23.3 (SD = 5.61), 23.8 (SD = 5.60), 24.5 (SD = 5.63) and 25.0 (SD = 5.08), respectively. An inverse correlation was found between tea consumption (of all types) and prevalence of cognitive impairment. Volume of tea consumption was significantly associated with cognitive impairment: compared with non-consumption participants, those who consumed < 2 cups/d, 2-4 cups/d, and ≥4 cups/d were observed ORs of 0.77 (95% CI: 0.56, 1.07), 0.62 (95% CI: 0.47, 0.81), and 0.49 (95% CI: 0.36, 0.66), respectively. Compared with non-consumption, black tea presented a positive correlation with cognitive function after controlling for potential confounders (OR = 0.52, 95% CI: 0.28, 0.95), while green tea showed no significant difference (OR = 1.04, 95% CI: 0.72, 1.51). Participants who consumed weak tea, moderate tea or strong tea more often were observed a better cognitive status when compared with those who did not have tea, with an OR of 0.51 (95% CI: 0.28, 0.92), 0.32 (95% CI: 0.19, 0.56) and 0.42 (95% CI: 0.22, 0.78) after adjusting for the potential confounders. But there was no statistically significant difference between any two of these ORs. CONCLUSION: Black tea consumption was association with better cognitive performance among the elderly aged 60 years and above in China, while green tea presented no correlation. The positive association of cognitive status with tea consumption was not limited to particular type of concentration.

Practical method for the rapid screening of xanthine oxidase inhibitors in herbal extracts by high-performance liquid chromatography based on on-line precolumn enzymatic reaction.

A high-performance liquid chromatography method with on-line precolumn enzymatic reaction for the screening of xanthine oxidase inhibitors in natural extracts was developed. In this method, the enzymatic reaction occurred at the capillary inlet during a predetermined waiting period, after which the reaction product, uric acid, was separated and detected by liquid chromatography using ultraviolet absorption at 295 nm. Enzyme inhibition can be read out directly from the reduced peak area of uric acid in comparison to a reference chromatogram obtained in the absence of any inhibitor. In the present study, the availability of on-line precolumn enzymatic reaction with ultraviolet detection was firstly evaluated by determining the inhibitory mechanism and IC50 values of allopurinol, a commercially available positive drug. Then, the newly developed method was applied to screening of ten natural extracts from traditional Chinese medicine and as a result, the extract of Epimedium sagittatum (Sieb. et Zucc.) Maxim was found to be most positive for xanthine oxidase inhibition. The results obtained were compared with those obtained by offline enzyme assay and the effectiveness of the present method was confirmed. A rapid, low-cost, and fully automated method for xanthine oxidase inhibitor screening was proposed.

Plasticity of gene expression in injured human dorsal root ganglia revealed by GeneChip oligonucleotide microarrays.

Root avulsion from the spinal cord occurs in brachial plexus lesions. It is the practice to repair such injuries by transferring an intact neighbouring nerve to the distal stump of the damaged nerve; avulsed dorsal root ganglia (DRG) are removed to enable nerve transfer. Such avulsed adult human cervical DRG ( [Formula: see text] ) obtained at surgery were compared to controls, for the first time, using GeneChip oligonucleotide arrays. We report 91 genes whose expression levels are clearly altered by the injury. This first study provides a global assessment of the molecular events or "gene switches" as a consequence of DRG injuries, as the tissues represent a wide range of surgical delay, from 1 to 100 days. A number of these genes are novel with respect to sensory ganglia, while others are known to be involved in neurotransmission, trophism, cytokine functions, signal transduction, myelination, transcription regulation, and apoptosis. Cluster analysis showed that genes involved in the same functional groups are largely positioned close to each other. This study represents an important step in identifying new genes and molecular mechanisms in human DRG, with potential therapeutic relevance for nerve repair and relief of chronic neuropathic pain.