Tris(2-chloroethyl) phosphate (TCEP) and tris(1chloro-2-propyl) phosphate (TCPP) are widely used as chlorinated organophosphate flame retardants (OPFRs) due to their fire-resistance capabilities. However, their extensive use has led to their permeation and pollution in aquatic environments. Using amphibians, which are non-model organisms, to test the toxic effects of OPFRs is relatively uncommon. This study examined the acute and chronic toxicity differences between TCEP and TCPP on Polypedates megacephalus tadpoles and evaluated the potential ecological risks to tadpoles in different aquatic environments using the risk quotient (RQ). In acute toxicity assay, the tadpole survival rates decreased with increased exposure time and concentrations, with TCEP exhibiting higher LC50 values than TCPP, at 305.5 mg/L and 70 mg/L, respectively. In the chronic assay, prolonged exposure to 300 µg/L of both substances resulted in similar adverse effects on tadpole growth, metamorphosis, and hepatic antioxidant function. Based on RQ values, most aquatic environments did not pose an ecological risk to tadpoles. However, the analysis showed that wastewater presented higher risks than rivers and drinking water, and TCPP posed a higher potential risk than TCEP in all examined aquatic environments. These findings provide empirical evidence to comprehend the toxicological effects of OPFRs on aquatic organisms and to assess the safety of aquatic environments.
BACKGROUND & AIMS: Epidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China. METHODS: We identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model. RESULTS: A total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence. CONCLUSION: Our study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.
Chronic constipation is a prevalent problem that significantly impacts older adults' well-being. This study aimed to explore how older adults describe constipation symptoms and impacts and understand the perceived taboo surrounding discussions on related issues. Twenty older adults with constipation were interviewed using a semi-structured format in Taiwan. The Interpretive Phenomenology Analysis approach was utilized for data analysis. Five techniques recommended by Lincoln and Guba (1985) were implemented to ensure the study's trustworthiness. The primary themes encompassed comprehensive portrayals of fecal characteristics, the discomfort symphony of constipation, emotional turbulence in the struggle against constipation, daily activities shadowed by constipation, and underlying factors contributing to communication taboos. Most participants considered the discussion of constipation taboo due to its association with an embarrassing secret, an unacceptable social norm and stigma, and apprehensions of potential gossip. Geriatric caregivers need to consider individual perspectives, communication taboos, and sociocultural contexts when addressing older adults' constipation.
Background: Methods for washed microbiota transplantation (WMT) through the mid-gut include transendoscopic enteral tubing (TET) and manual spiral nasojejunal tube (SNT) placement have not been studied. Methods: This prospective interventional study was performed at a single centre. Patients were divided into the SNT and mid-gut TET groups based on their conditions and wishes. In the SNT group, an SNT was passively inserted into the stomach, and abdominal X-rays were taken within 24 h to confirm tube placement in the small intestine. In the mid-gut TET group, mid-gut TET was placed in the small intestine for gastroscopy. Data on the clinical efficacy of WMT, intubation time, cost, overall comfort score, adverse reactions, etc., were collected from the two groups. Results: Sixty-three patients were included in the study (SNT group (n = 40) and mid-gut TET group (n = 23)). The clinical efficacy of WMT in the SNT and mid-gut TET groups was 90 % and 95.7 %, respectively (P = 0.644). Compared with the mid-gut TET group, the SNT group showed a shorter operation time (120 s vs. 258 s, P = 0.001) and a lower average cost (641.7 yuan vs. 1702.1 yuan, P = 0.001). There was no significant difference in the overall comfort score or the incidence of common discomfort symptoms between the two groups. Conclusion: The different implantation methods have different advantages; compared with mid-gut TET placement, manual SNT placement provides some benefits.
Oxidative Stress , Pulmonary Disease, Chronic Obstructive , Respiration, Artificial , Pulmonary Disease, Chronic Obstructive/drug therapy , Animals , Oxidative Stress/drug effects , Rats , Theophylline/pharmacology , Theophylline/analogs & derivatives , Theophylline/therapeutic use , Disease Models, Animal , Bronchodilator Agents/pharmacology , Bronchodilator Agents/therapeutic use
Triterpenoid saponins, a major bioactive component of liquorice, possess high hydrophilicity and often co-occur with other impurities of similar polarity. Additionally, subtle structural differences of some triterpenoid saponins bring challenges to comprehensive characterisation. In this study, triterpenoid saponins of three Glycyrrhiza species were systematically analysed using rapid resolution liquid chromatography quadrupole time-of-flight mass spectrometry (RRLC-Q-TOF-MS) coupled with mass defect filtering (MDF). Firstly, comprehensive date acquisition was achieved using RRLC-Q-TOF-MS. Secondly, a polygonal MDF method was established by summarizing known and speculated substituents and modifications based on the core structure to rapidly screen potential triterpenoid saponins. Thirdly, based on the fragmentation patterns of reference compounds, an identification strategy for characterisation of triterpenoid saponins was proposed. The strategy divided triterpenoid saponins into three distinct classes. By this strategy, 98 triterpenoid saponins including 10 potential new ones were tentatively characterised. Finally, triterpenoid saponins of three Glycyrrhiza species were further analysed using principle component analysis (PCA) and orthogonality partial least squares discriminant analysis (OPLS-DA). Among these, 18 compounds with variable importance in projections (VIP) > 1.0 and P values < 0.05 were selected to distinguish three Glycyrrhiza species. Overall, our study provided a reference for quality control and rational use of the three species.
BACKGROUND: Cardiac sodium channel NaV1.5 encoded by SCN5A is associated with arrhythmia disorders. However, the molecular mechanism underlying NaV1.5 expression remains to be fully elucidated. Previous studies have reported that 14-3-3 family acts as an adaptor involved in regulating kinetic characteristics of cardiac ion channels. OBJECTIVE: The purpose of this study was to establish 14-3-3ε/YWHAE, a member of 14-3-3 family, as a crucial regulator of NaV1.5 and explore the potential role of 14-3-3ε in the heart. METHODS: Western blotting, patch-clamping, real-time RT-PCR, RNA immunoprecipitation, electrocardiogram recording, echocardiography and histological analysis were performed. RESULTS: YWHAE overexpression significantly reduced the expression level of SCN5A mRNA and sodium current density, whereas YWHAE knockdown significantly increased SCN5A mRNA expression and sodium current density in HEK293/NaV1.5 and H9c2 cells. Similar results were observed in mice injected with adeno-associated virus serotype 9 (AAV9)-mediated YWHAE knockdown. The effect of 14-3-3ε on NaV1.5 expression was abrogated by knockdown of TBX5, a transcription factor of NaV1.5. An interaction between 14-3-3ε protein and TBX5 mRNA was identified, and YWHAE overexpression significantly decreased TBX5 mRNA stability without affecting SCN5A mRNA stability. Additionally, mice subjected to AAV9-mediated YWHAE knockdown exhibited shorter R-R intervals and higher prevalence of premature ventricular contractions. CONCLUSION: Our data unveil a novel regulatory mechanism of NaV1.5 by 14-3-3ε, and highlight the significance of 14-3-3ε in transcriptional regulation of NaV1.5 expression and cardiac arrhythmias.
Biosynthesis of paclitaxel (Taxol™) is a hot topic with extensive and durable interests for decades. However, it is severely hindered due to the very low titers of intermediates. In this study, Escherichia coli was employed to de novo synthesize a key intermediate of paclitaxel, taxadien-5α-yl-acetate (T5OAc). Plasmid-based pathway reconstruction and optimization were conducted for T5OAc production. The endogenous methylerythritol phosphate pathway was enhanced to increase the precursor supply. Three taxadien-5α-ol O-acetyltransferases were tested to obtain the best enzyme for the acetylation step. Metabolic burden was relieved to restore cell growth and promote production through optimizing the plasmid production system. In order to achieve metabolic balance, the biosynthesis pathway was regulated precisely by multivariate-modular metabolic engineering. Finally, in a 5-L bioreactor, the T5OAc titer was enhanced to reach 10.9 mg/L. This represents an approximately 272-fold increase in production compared to the original strain, marking the highest yield of T5OAc ever documented in E. coli, which is believed to be helpful for promoting the progress of paclitaxel biosynthesis.
Milk fat is an important indicator for evaluating the quality of cow's milk. In this study, we used bovine mammary epithelial cells (BMECs) to investigate the role and molecular mechanism of KLF4 in the regulation of milk fat synthesis. The results showed that KLF4 was more highly expressed in mammary tissues of high-fat cows compared with low-fat cows. KLF4 positively regulated the expression of genes related to milk fat synthesis in BMECs, increasing intracellular triglycerides content, and KLF4 promoted milk fat synthesis by activating the PI3K-AKT-mTOR signaling pathway. Furthermore, the results of animal experiments also confirmed that knockdown of KLF4 inhibited milk fat synthesis. In addition, yeast one-hybrid assays and dual-luciferase reporter gene assays confirmed that KLF4 directly targets and binds to the fatty acid synthase (FASN) promoter region to promote FASN transcription. These results demonstrate that KLF4 is a key transcription factor for milk fat synthesis in BMECs.
Ulcerative colitis (UC) is a chronic intestinal ailment which cannot be completely cured. The occurrence of UC has been on the rise in recent years, which is highly detrimental to patients. The effectiveness of conventional drug treatment is limited. The long-term usage of these agents can lead to substantial adverse effects. Therefore, the development of a safe and efficient dietary supplement is important for the prevention of UC. Echinacea purpurea polysaccharide (EPP) is one of the main bioactive substances in Echinacea purpurea. EPP has many favorable effects, such as antioxidative, anti-inflammatory, and antitumor effects. However, whether EPP can prevent or alleviate UC is still unclear. This study aims to analyze the effect and mechanism of EPP on UC in mice using a 3% dextran sulfate sodium (DSS)-induced UC model. The results showed that dietary supplementation with 200 mg/kg EPP significantly alleviated the shortening of colon length, weight loss, and histopathological damage in DSS-induced colitis mice. Mechanistically, EPP significantly inhibits the activation of the TLR4/NF-κB pathway and preserves the intestinal mechanical barrier integrity by enhancing the expression of claudin-1, ZO-1, and occludin and reducing the loss of goblet cells. Additionally, 16S rRNA sequencing revealed that EPP intervention reduced the abundance of Bacteroides, Escherichia-Shigella, and Klebsiella; the abundance of Lactobacillus increased. The results of nontargeted metabonomics showed that EPP reshaped metabolism. In this study, we clarified the effect of EPP on UC, revealed the potential function of EPP, and supported the use of polysaccharide dietary supplements for UC prevention.
Colitis, Ulcerative , Dextran Sulfate , Echinacea , Gastrointestinal Microbiome , NF-kappa B , Polysaccharides , Toll-Like Receptor 4 , Animals , Male , Mice , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/microbiology , Colon/drug effects , Colon/pathology , Colon/metabolism , Dietary Supplements , Disease Models, Animal , Echinacea/chemistry , Gastrointestinal Microbiome/drug effects , Mice, Inbred C57BL , NF-kappa B/metabolism , Polysaccharides/pharmacology , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism
The incidence of ulcerative colitis (UC) is increasing annually, and UC has a serious impact on patients' lives. Polysaccharides have gained attention as potential drug candidates for treating ulcerative colitis (UC) in recent years. Huaier (Trametes robiniophila Murr) is a fungus that has been used clinically for more than 1000 years, and its bioactive polysaccharide components have been reported to possess immunomodulatory effects, antitumour potential, and renoprotective effects. In this study, we aimed to examine the protective effects and mechanisms of Huaier polysaccharide (HP) against UC. Based on the H2O2-induced oxidative stress model in HT-29 cells and the dextran sulphate sodium salt (DSS)-induced UC model, we demonstrated that Huaier polysaccharides significantly alleviated DSS-induced colitis (weight loss, elevated disease activity index (DAI) scores, and colonic shortening). In addition, HP inhibited oxidative stress and inflammation and alleviated DSS-induced intestinal barrier damage. It also significantly promoted the expression of the mucin Muc2. Furthermore, HP reduced the abundance of harmful bacteria Escherichia-Shigella and promoted the abundance of beneficial bacteria Muribaculaceae_unclassified, Anaerotruncus, and Ruminococcaceae_unclassified to regulate the intestinal flora disturbance caused by DSS. Nontargeted metabolomics revealed that HP intervention would modulate metabolism by promoting levels of 3-hydroxybutyric acid, phosphatidylcholine (PC), and phosphatidylethanolamine (PE). These results demonstrated that HP had the ability to mitigate DSS-induced UC by suppressing oxidative stress and inflammation, maintaining the intestinal barrier, and modulating the intestinal flora. These findings will expand our knowledge of how HP functions and offer a theoretical foundation for using HP as a potential prebiotic to prevent UC.
Dextran Sulfate , Gastrointestinal Microbiome , Oxidative Stress , Polysaccharides , Gastrointestinal Microbiome/drug effects , Oxidative Stress/drug effects , Animals , Humans , Polysaccharides/pharmacology , Mice , Male , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/microbiology , Disease Models, Animal , Inflammation/drug therapy , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , HT29 Cells , Mice, Inbred C57BL , Colitis/chemically induced , Colitis/drug therapy
Significant impairment of pulmonary function has been demonstrated through long-term exposure to neonicotinoid insecticides, such as imidacloprid (IMI). However, the underlying mechanisms of lung injury induced by IMI remain unclear. In this study, a mouse model of IMI-induced pulmonary injury was established, and the toxicity and lung damage were assessed through mouse body weight, organ index, hematological parameters, and histopathological analysis of lung tissues. Furthermore, metabolomics and transcriptomics techniques were employed to explore the mechanistic aspects. Results from the toxicity assessments indicated that mouse body weight was significantly reduced by IMI, organ index was disturbed, and hematological parameters were disrupted, resulting in pulmonary injury. The mechanistic experimental results indicate that the differences in metabolites and gene expression in mouse lungs could be altered by IMI. Validation of the results through combined analysis of metabolomics and transcriptomics revealed that the mechanism by which IMI induces lung injury in mice might be associated with the activation of the TLR4 receptor, thereby activating the PI3K/AKT/NF-κB signaling pathway to induce inflammation in mouse lungs. This study provided valuable insights into the mechanisms underlying IMI-induced pulmonary damage, potentially contributing to the development of safer pest control strategies. The knowledge gained served as a robust scientific foundation for the prevention and treatment of IMI-related pulmonary injuries.
Insecticides , Lung Injury , NF-kappa B , Neonicotinoids , Nitro Compounds , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , Toll-Like Receptor 4 , Animals , Neonicotinoids/toxicity , Nitro Compounds/toxicity , Mice , Lung Injury/chemically induced , Signal Transduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , NF-kappa B/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Insecticides/toxicity , Toll-Like Receptor 4/metabolism , Lung/drug effects , Lung/pathology
Bioluminescence is a fascinating natural phenomenon, wherein organisms produce light through specific biochemical reactions. Among these organisms, Renilla luciferase (RLuc) derived from the sea pansy Renilla reniformis is notable for its blue light emission and has potential applications in bioluminescent tagging. Our study focuses on RLuc8, a variant of RLuc with eight amino acid substitutions. Recent studies have shown that the luminescent emitter coelenteramide can adopt multiple protonation states, which may be influenced by nearby residues at the enzyme's active site, demonstrating a complex interplay between protein structure and bioluminescence. Herein, using the quantum mechanical consistent force field method and the semimacroscopic protein dipole-Langevin dipole method with linear response approximation, we show that the phenolate state of coelenteramide in RLuc8 is the primary light-emitting species in agreement with experimental results. Our calculations also suggest that the proton transfer (PT) from neutral coelenteramide to Asp162 plays a crucial role in the bioluminescence process. Additionally, we reproduced the observed emission maximum for the amide anion in RLuc8-D120A and the pyrazine anion in the presence of a Na+ counterion in RLuc8-D162A, suggesting that these are the primary emitters. Furthermore, our calculations on the neutral emitter in the engineered AncFT-D160A enzyme, structurally akin to RLuc8-D162A but with a considerably blue-shifted emission peak, aligned with the observed data, possibly explaining the variance in emission peaks. Overall, this study demonstrates an effective approach to investigate chromophores' bimolecular states while incorporating the PT process in emission spectra calculations, contributing valuable insights for future studies of PT in photoproteins.
Pyrazines , Quantum Theory , Pyrazines/chemistry , Pyrazines/metabolism , Renilla/enzymology , Luciferases/chemistry , Luciferases/metabolism , Luminescence , Animals , Imidazoles/chemistry , Benzeneacetamides
Hexavalent chromium is a common pollutant in the environment. Long-term exposure to hexavalent chromium can cause damage to multiple organs. The kidney is one of the main organs that metabolizes heavy metal toxicity, and the accumulation of Cr (VI) in the body can lead to serious damage to kidney function. Studies have shown that ginseng polysaccharides have the function of preventing cisplatin-induced endoplasmic reticulum stress, inflammatory response, and apoptosis in renal cells, but their efficacy and mechanisms against hexavalent chromium-induced nephrotoxicity need to be explored. The aim of this study was to explore the efficacy and mechanism of ginseng polysaccharide against hexavalent chromium-induced nephrotoxicity. The results of pharmacodynamic experiments showed that ginseng polysaccharide could significantly reduce the kidney index, urea nitrogen (BUN), and serum creatinine (Cre) values of K2Cr2O7-treated mice. The results of mechanistic experiments showed that ginseng polysaccharides could alleviate oxidative stress, apoptosis, and biofilm damage in renal tissues caused by Cr (VI). Lipidomic correlation analysis showed that ginseng polysaccharides could protect the organism by regulating the expression of differential lipids. This study opens new avenues for the development of alternative strategies for the prevention of kidney injury caused by hexavalent chromium.
Apoptosis , Chromium , Kidney , Oxidative Stress , Panax , Polysaccharides , Panax/chemistry , Chromium/toxicity , Animals , Polysaccharides/pharmacology , Mice , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Apoptosis/drug effects , Male , Oxidative Stress/drug effects , Kidney Diseases/chemically induced , Kidney Diseases/prevention & control , Plant Extracts/pharmacology , Creatinine/blood
BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common disease in elderly men. There is increasing evidence that periodontitis increases the risk of BPH, but the specific mechanism remains unclear. This study aimed to explore the role and mechanism of the key periodontal pathogen Porphyromonas gingivalis (P. gingivalis) in the development of BPH. METHODS: The subgingival plaque (Sp) and prostatic fluid (Pf) of patients with BPH concurrent periodontitis were extracted and cultured for 16S rDNA sequencing. Ligature-induced periodontitis, testosterone-induced BPH and the composite models in rats were established. The P. gingivalis and its toxic factor P. gingivalis lipopolysaccharide (P.g-LPS) were injected into the ventral lobe of prostate in rats to simulate its colonization of prostate. P.g-LPS was used to construct the prostate cell infection model for mechanism exploration. RESULTS: P. gingivalis, Streptococcus oralis, Capnocytophaga ochracea and other oral pathogens were simultaneously detected in the Pf and Sp of patients with BPH concurrent periodontitis, and the average relative abundance of P. gingivalis was found to be the highest. P. gingivalis was detected in both Pf and Sp in 62.5% of patients. Simultaneous periodontitis and BPH synergistically aggravated prostate histological changes. P. gingivalis and P.g-LPS infection could induce obvious hyperplasia of the prostate epithelium and stroma (epithelial thickness was 2.97- and 3.08-fold that of control group, respectively), and increase of collagen fibrosis (3.81- and 5.02-fold that of control group, respectively). P. gingivalis infection promoted prostate cell proliferation, inhibited apoptosis, and upregulated the expression of inflammatory cytokines interleukin-6 (IL-6; 4.47-fold), interleukin-6 receptor-α (IL-6Rα; 5.74-fold) and glycoprotein 130 (gp130; 4.47-fold) in prostatic tissue. P.g-LPS could significantly inhibit cell apoptosis, promote mitosis and proliferation of cells. P.g-LPS activates the Akt pathway through IL-6/IL-6Rα/gp130 complex, which destroys the imbalance between proliferation and apoptosis of prostate cells, induces BPH. CONCLUSION: P. gingivalis was abundant in the Pf of patients with BPH concurrent periodontitis. P. gingivalis infection can promote BPH, which may affect the progression of BPH via inflammation and the Akt signaling pathway.
Interleukin-6 , Porphyromonas gingivalis , Prostatic Hyperplasia , Receptors, Interleukin-6 , Male , Prostatic Hyperplasia/complications , Porphyromonas gingivalis/pathogenicity , Rats , Humans , Animals , Interleukin-6/analysis , Interleukin-6/metabolism , Prostate , Periodontitis/complications , Periodontitis/microbiology , Aged , Middle Aged , Rats, Sprague-Dawley , Disease Models, Animal , Signal Transduction/physiology
Inflammatory bowel disease (IBD) is difficult to cure, and formulating a dietary plan is an effective means to prevent and treat this disease. Wheat peptide contains a variety of bioactive peptides with anti-inflammatory and antioxidant functions. The results of this study showed that preventive supplementation with wheat peptide (WP) can significantly alleviate the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. WP can increase body weight, alleviate colon shortening, and reduce disease activity index (DAI) scores. In addition, WP improved intestinal microbial disorders in mice with colitis. Based on LC-MS, a total of 313 peptides were identified in WP, 4 of which were predicted to be bioactive peptides. The regulatory effects of WP and four bioactive peptides on the Keap1-Nrf2 signaling pathway were verified in Caco-2 cells. In conclusion, this study demonstrated that WP alleviates DSS-induced colitis by helping maintain gut barrier integrity and targeting the Keap1-Nrf2 axis; these results provided a rationale for adding WP to dietary strategies to prevent IBD.
Colitis , Dextran Sulfate , Kelch-Like ECH-Associated Protein 1 , Mice, Inbred C57BL , NF-E2-Related Factor 2 , Peptides , Signal Transduction , Triticum , Animals , NF-E2-Related Factor 2/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Mice , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Dextran Sulfate/adverse effects , Signal Transduction/drug effects , Humans , Triticum/chemistry , Caco-2 Cells , Peptides/pharmacology , Male , Disease Models, Animal , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects
BACKGROUND: Ears are an important aesthetic feature that is vital to the overall attractiveness of the face. Although there have been many studies on the aesthetics of the auricle, there is currently a lack of consensus on the ideal proportion of auricle exposure for Asian women in frontal view. OBJECTIVES: This study aimed to investigate ideal proportion of auricle exposure in Asian women. METHODS: An observational study was carried out on the photographs of 84 women on the list of the 100 most beautiful faces in Asia (published by TCC Asia in 2020). The proportion of the distance between the outer canthus and the outermost point of auricle to the distance between the inner canthus and the outermost point of auricle was calculated as the auricle exposure proportion. Evaluators were asked to rank a set of photographs of the volunteer with varying auricle exposure proportions from most attractive to least attractive. RESULTS: Measurements of the photographs of the 84 women showed a mean ear exposure proportion of 0.600. With 487 questionnaire responses received, the proportion of auricle exposure that the evaluators considered most attractive was 0.600. People with aesthetic experience considered 0.625 the most attractive proportion, while the general group considered 0.600 the most attractive. CONCLUSIONS: The ideal proportion of the auricle exposure for Asian women is in the range of 0.60-0.625, which may help surgeons reconstruct aesthetically pleasing ears. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Herein, we report an electrochemical protocol for the dicarboxylation of aryl alkynes using CO2. With a graphite rod as the cathode and Al as the sacrificial anode, a series of valuable butenedioic acids are obtained in moderate to excellent yields with an E/Z ratio up to 50:1. This method features high E-selectivity, high step and atom economy, easy scalability, and a nice substrate scope, which renders it appealing for promising applications in organic synthesis and materials chemistry.
BACKGROUND: Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines. Dose optimization guided by nudix hydrolase 15 (NUDT15) has significantly reduced the early leucopenia rate, but there are no definitive biomarkers for late risk leucopenia prediction. AIM: To determine the predictive value of early monitoring of DNA-thioguanine (DNATG) or 6-thioguanine nucleotides (6TGN) for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn's disease (CD). METHODS: Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations. Late leucopenia was defined as a leukocyte count < 3.5 × 109/L over two months. RESULTS: Of 148 patients studied, late leucopenia was observed in 15.6% (17/109) of NUDT15/thiopurine methyltransferase (TPMT) normal and 64.1% (25/39) of intermediate metabolizers. In patients suffering late leucopenia, early DNATG levels were significantly higher than in those who did not develop late leucopenia (P = 4.9 × 10-13). The DNATG threshold of 319.43 fmol/µg DNA could predict late leucopenia in the entire sample with an area under the curve (AUC) of 0.855 (sensitivity 83%, specificity 81%), and in NUDT15/TPMT normal metabolizers, the predictive performance of a threshold of 315.72 fmol/µg DNA was much more remarkable with an AUC of 0.902 (sensitivity 88%, specificity 85%). 6TGN had a relatively poor correlation with late leucopenia whether in the entire sample (P = 0.021) or NUDT15/TPMT normal or intermediate metabolizers (P = 0.018, P = 0.55, respectively). CONCLUSION: Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD, especially the former.
Crohn Disease , Leukopenia , Methyltransferases , Purines , Sulfhydryl Compounds , Humans , Crohn Disease/drug therapy , DNA , Leukopenia/chemically induced , Leukopenia/diagnosis , Purines/adverse effects , Sulfhydryl Compounds/adverse effects , Thioguanine/analysis
Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.
