Self-harm and interpersonal violence due to high temperature from the global burden of disease study 2019: A 30-year assessment.

BACKGROUND: The impact of global warming on health due to climate change is increasingly studied, but the global burden of self-harm and interpersonal violence attributable to high temperature is still limited. This study aimed to systematically assess the burden of self-harm and interpersonal violence attributable to high temperature globally or by region and climate zone from 1990 to 2019. METHODS: We obtained the global, regional, and national deaths, disability-adjusted life years (DALYs), age-standardized mortality rates (ASMR), and age-standardized disability-adjusted life year rates (ASDR) of self-harm and interpersonal violence due to high temperature from 1990 to 2019 through the Global Burden of Disease Study (GBD) 2019. The burden of self-harm and interpersonal violence due to high temperature was estimated by age, sex, climate zone, the socio-demographic index (SDI), and the healthcare access and quality index (HAQ). Average annual percentage changes (AAPCs) in ASMR and ASDR were calculated for 1990-2019 using the Joinpoint model. RESULTS: From 1990 to 2019, the global deaths and DALYs related to self-harm and interpersonal violence due to high temperature increased from 20,002 (95% UI, 9243 to 41,928) and 1,107,216 (95% UI, 512,062 to 2,319,477) to 26,459 (95% UI, 13,574 to 47,265) and 1,382,487 (95% UI, 722,060 to 2,474,441), respectively. However, the ASMR and ASDR showed varying degrees of decreasing trends, with decreases of 13.36% and 12.66%, respectively. The ASMR was high and declining in low and low-middle SDI regions, particularly in tropical and subtropical regions. In addition, SDI and HAQ index were negatively correlated with ASMR in 204 countries and regions. CONCLUSIONS: The global burden of self-harm and interpersonal violence attributed to high temperature has decreased over the past 30 years, but the number of deaths and DALYs continues to rise. Climate change continues to make heat stress a significant risk factor for self-harm and interpersonal violence worldwide.

Design of prism coupling structure for liquid crystal cladding waveguide beam steerer.

This paper proposes an extended prism coupling analysis method to accurately analyze the coupling structure of liquid crystal (LC) cladding waveguide beam steerer. We analyze the effects of LC anisotropy on the coupling of transverse electric (TE) and transverse magnetic (TM) modes and derive the expression of the optical field distribution that perfectly matches the given coupling structure. Based on this method, we present the optimal coupling structure for Gaussian beam. Taking into account the practical manufacturing process, we propose a simplified coupling structure and perform a detailed analysis of its performance based on numerical simulations. Experimental results show a coupling efficiency of 91% and a coupling angle full width at half maximum (FWHM) of about ±0.02°, demonstrating the effectiveness of the proposed method in predicting the coupling performance of anisotropic cladding waveguides.

A global burden assessment of lung cancer attributed to residential radon exposure during 1990-2019.

This study aimed to explore the spatial and temporal trends of lung cancer burden attributable to residential radon exposure at the global, regional, and national levels. Based on the Global Burden of Disease Study (GBD) 2019, we collected the age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life rate (ASDR) of lung cancer attributable to residential radon exposure from 1990 to 2019. The Joinpoint model was used to calculate the annual average percentage change (AAPC) to evaluate the trend of ASMR and ASDR from 1990 to 2019. The locally weighted regression (LOESS) was used to estimate the relationship of the socio-demographic index (SDI) with ASMR and ASDR. In 2019, the global ASMR and ASDR for lung cancer attributable to residential radon exposure were 1.03 (95% CI: 0.20, 2.00) and 22.66 (95% CI: 4.49, 43.94) per 100 000 population, which were 15.6% and 23.0% lower than in 1990, respectively. According to the estimation, we found the lung cancer burden attributable to residential radon exposure declined significantly in high and high-middle SDI regions, but substantially increased in middle and low-middle SDI regions from 1990 to 2019. Across age and sex, the highest burden of lung cancer attributable to residential radon exposure was found in males and elderly groups. In conclusion, the global burden of lung cancer attributable to residential radon exposure showed a declining trend from 1990 to 2019, but a relatively large increase was found in the middle SDI regions. In 2019, the burden of lung cancer attributable to residential radon exposure remained high, particularly in males, the elderly, and high-middle SDI regions compared with other groups.

Application of Transfer Learning in EEG Decoding Based on Brain-Computer Interfaces: A Review.

The algorithms of electroencephalography (EEG) decoding are mainly based on machine learning in current research. One of the main assumptions of machine learning is that training and test data belong to the same feature space and are subject to the same probability distribution. However, this may be violated in EEG processing. Variations across sessions/subjects result in a deviation of the feature distribution of EEG signals in the same task, which reduces the accuracy of the decoding model for mental tasks. Recently, transfer learning (TL) has shown great potential in processing EEG signals across sessions/subjects. In this work, we reviewed 80 related published studies from 2010 to 2020 about TL application for EEG decoding. Herein, we report what kind of TL methods have been used (e.g., instance knowledge, feature representation knowledge, and model parameter knowledge), describe which types of EEG paradigms have been analyzed, and summarize the datasets that have been used to evaluate performance. Moreover, we discuss the state-of-the-art and future development of TL for EEG decoding. The results show that TL can significantly improve the performance of decoding models across subjects/sessions and can reduce the calibration time of brain-computer interface (BCI) systems. This review summarizes the current practical suggestions and performance outcomes in the hope that it will provide guidance and help for EEG research in the future.

Aberrant fucosylation of glycosphingolipids in human hepatocellular carcinoma tissues.

BACKGROUNDS & AIMS: Glycosylation promoting or inhibiting tumour cell invasion and metastasis is of crucial importance in current cancer research. Tumour-associated carbohydrate antigens are predominantly expressed on the tumour cell surface. Glycosphingolipids (GSLs) are members of the family. To perform glycosphingolipidomic assays on neutral GSLs obtained from solid hepatocellular carcinoma (HCC) tissues and paired peritumoural tissues by linear ion trap quadrupole-electrospray ionization mass spectrometry. METHODS: Qualitative and quantitative analysis of fucosylated neutral GSLs was performed in the positive ion mode on the LTQ-XL mass spectrometer and MALDI-TOF-MS. RESULTS: A group of fucosylated neutral GSLs in HCC was found to be expressed higher in the tumour tissues, as their proportion in total cellular GSLs was 3.3-fold higher in the tumour tissues than in the peritumoural tissues (P < 0.01). Moreover, qualitative analysis of the aberrant fucosylated GSLs were completed, and seven types of fucosylated GSLs that contained terminal Fuca2Gal- structure were identified by mass spectrometry. CONCLUSIONS: Our results may lead to improved immunotherapy of HCC and contribute to understanding the role of aberrant fucosylated GSLs in the development and progress of HCC in following studies.

Butyrate attenuates cold-induced hypertension via gut microbiota and activation of brown adipose tissue.

OBJECTIVE: Chronic exposure to cold temperature is known to elevate blood pressure, leading to a condition known as cold-induced hypertension (CIH). Our previous research suggested correlations between alterations in gut microbiota, decrease in butyrate level, and the onset and progression of CIH. However, the role of butyrate in CIH and the underlying mechanisms need further investigation. METHODS: We exposed Specific Pathogen Free (SPF) rats to continuous cold temperature (4 ± 1 °C) for 6 weeks to establish a CIH rat model. Rats were divided into different groups by dose and duration, and the rats under cold were administered with butyrate (0.5 or 1 g/kg/day) daily. We assessed hypertension-associated phenotypes, pathological morphological changes, and endocrine-related phenotypes of brown adipose tissue (BAT). The effects of butyrate on gut microbiota and intestinal content metabolism were evaluated by 16s RNA sequencing and non-targeted metabolomics, respectively. RESULTS: The systolic blood pressure (SBP) of rats exposed to cold after supplemented with butyrate were significantly lower than that of the Cold group. Butyrate may increase the species, abundance, and diversity of gut microbiota in rats. Specifically, butyrate intervention enriched beneficial bacterial genera, such as Lactobacillaceae, and decreased the levels of harmful bacteria genera, such as Actinobacteriota and Erysipeiotrichaceae. Cold exposure significantly increased BAT cells and the number of mitochondria. After butyrate supplementation, the levels of peroxisome proliferator-activated receptor gamma coactivator 1a and fibroblast growth factor 21 in BAT were significantly elevated (P < 0.05), and the volume and number of lipid droplets increased. The levels of ANG II and high-density lipoprotein were elevated in the Cold group but decreased after butyrate supplementation. CONCLUSION: Butyrate may attenuate blood pressure in CIH by promoting the growth of beneficial bacteria and the secretion of beneficial derived factors produced by BAT, thus alleviating the elevation of blood pressure induced by cold. This study demonstrates the anti-hypertensive effects of butyrate and its potential therapeutic mechanisms, offering novel insights to the prevention and treatment of CIH in populations living or working in cold environments.

Plastic phase transitions in tris(hydroxymethyl)aminomethane perchlorate.

Organic crystal materials with metal-free feature and intrinsically low molecular mass are highly desirable for applications in flexible smart devices. Here, we reported a plastic crystal, tris(hydroxymethyl)aminomethane perchlorate (Tris-HClO4), which crystallizes in the R3̄ space group at room temperature and undergoes plastic phase transition at 369 K, showing a large entropy gain of 70.5 J mol-1 K-1, much higher than its fusion entropy gain (12.9 J mol-1 K-1). PXRD measurement indicates that it has cubic lattice symmetry in the high-temperature phase. Moreover, it exhibits excellent dielectric permittivity switching properties and robust cyclic stability. This work could be the pathway for chemical designing multifunctional switchable materials with the motive of combining the idea of symmetry breaking and plastic phase transition.

Global burden study of lower respiratory infections linked to low temperatures: an analysis from 1990 to 2019.

Low temperature conditions have been linked to a heightened susceptibility to lower respiratory infections (LRIs). Yet, our comprehension of the LRIs' disease burden due to such conditions remains limited, especially when considering the diverse socio-demographic indexes (SDIs) and climate types across various nations and regions. We examined the variations over time and space in the impact of LRIs due to low temperatures across a diverse set of 204 nations and regions, each with unique SDIs and climate types, spanning the years 1990 to 2019. Data from the Global Burden of Disease Study 2019 was used for this retrospective analysis. The burden of LRIs attributable to low temperatures was estimated by stratifying by sex, age, country, climate type, and SDI, including age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life year rate (ASDR). We employed Joinpoint models to compute the annual average percent changes (AAPCs) in order to evaluate the trends in LRIs burden due to low temperatures from 1990 to 2019. Furthermore, we utilized Poisson age-period-cohort models to forecast the global and income-specific trends in LRIs burden due to low temperatures for the period 2020-2044. Generalized additive mixed models were used to fit changes in the disease burden of different climate regions. The relationship between SDI and both ASMR and ASDR was determined using models grounded in Gaussian process regression. In general, since the year 1990, there has been a significant reduction in the worldwide impact of LRIs due to low temperatures. This decrease is particularly noticeable among infants and the elderly, as well as in regions with a boreal climate and those with an average SDI. In 2019, LRIs induced by low temperatures showed an ASMR of 2.2 (95% CI: 1.34, 3.07) and an ASDR of 53.73 (95% CI: 17.5, 93.22) for every 100,000 individuals. A global reduction was observed in the ASMR and ASDR for LRIs over the period from 1990 to 2019, showing a decrease of 60.27% and 77.5%, in that order. For ASMR and ASDR, the AAPC values were found to be - 3.3 (95% CI: - 3.4, - 3.1) and - 5 (95% CI: - 5.2, - 4.9), in that order. However, a contrasting pattern was observed in southern Latin America, where an increase was noted in the ASMR for LRIs induced by low temperatures [AAPC: 0.5; 95% CI: (0.3, 0.8)]. Low temperature has decreased as an environmental risk factor for LRIs globally over 30 years, especially in middle SDI regions and boreal climates, but remains important for infants and the elderly population.

Psychological Responses of Chinese Medical Students to the COVID-19 Pandemic: Empirical Research Qualitative.

Aim: This study aims to explore the psychological reactions of medical students during the pandemic. Design: A qualitative study. Methods: A purposive sampling technique was employed, and a qualitative approach was adopted. Semi-structured questionnaires were utilized, and online interviews were conducted. Forty medical students were selected as participants for the interviews. The interview data were analyzed using Colaizzi's seven-step analysis method. Results: The study identified five themes related to the psychological reactions of medical students during the pandemic. Firstly, COVID-19's influence on medical careers was characterized by increased interest and determination in pursuing medical professions, heightened admiration for frontline workers, reinforced commitment to a medical career due to the pandemic, and recognition of the significance of medical education. Secondly, challenges and concerns in medical career pursuit were identified, including negative sentiments towards medical careers during COVID-19 and hesitations and concerns about entering the medical field amidst the pandemic. Thirdly, the impact on mental well-being encompassed diverse anxieties expressed by participants regarding control, transmission, treatment, and intentional spreading of the virus. Participants experienced an emotional progression from calmness to fear and anxiety, with heightened anxiety when relatives or acquaintances contracted COVID-19. Academic delays also contributed to anxiety among medical students. Fourthly, changes in behaviors and mindset were observed, including altered behaviors and mindset in response to the pandemic, as well as increased attention to personal hygiene and disease prevention measures. Lastly, expectations of medical students from government, public, and parents were explored. Conclusion: Understanding the psychological reactions of medical students during public health emergencies is crucial for their well-being and professional development. The findings have implications for medical education and the development of strategies to enhance the psychological well-being of medical students during similar crises.

SDH, a novel diarylheptane compound, alleviates dextran sulfate sodium (DSS)-induced colitis by reducing Th1/Th2/Th17 induction and regulating the gut microbiota in mice.

Ulcerative colitis, a chronic inflammatory condition affecting the rectum and colon to varying degrees, is linked to a dysregulated immune response and the microbiota. Sodium (aS,9R)-3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.12,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) emerges as a novel diarylheptane compound aimed at treating inflammatory bowel diseases. However, the mechanisms by which SDH modulates these conditions remain largely unknown. In this study, we assessed SDH's impact on the clinical progression of dextran sodium sulfate (DSS)-induced ulcerative colitis. Our results demonstrated that SDH significantly mitigated the symptoms of DSS-induced colitis, reflected in reduced disease activity index scores, alleviation of weight loss, shortening of the colorectum, and reduction in spleen swelling. Notably, SDH decreased the proportion of Th1/Th2/Th17 cells and normalized inflammatory cytokine levels in the colon. Furthermore, SDH treatment modified the gut microbial composition in mice with colitis, notably decreasing Bacteroidetes and Proteobacteria populations while substantially increasing Firmicutes, Actinobacteria, and Patescibacteria. In conclusion, our findings suggest that SDH may protect the colon from DSS-induced colitis through the regulation of Th1/Th2/Th17 cells and gut microbiota, offering novel insights into SDH's therapeutic potential.

Mass spectrometry based phospholipidomics of mammalian thymus and leukemia patients: implication for function of iNKT cells.

In previous studies phospholipids have been proved to be involved in biochemical, physiological, and pathological processes. As a special class of phospholipids, peroxisome-derived lipids (PDLs) have been proved to be potential ligands of invariant natural killer T (iNKT) cells in recent studies. Here, on the basis of phospholipidomics, we focused on the relative quantity of PDLs extracted from mammalian thymus or bone marrow using electrospray ionization mass spectrometry (MS). In phospholipid analysis, we identified 12 classes of phospholipids and accounted for their relative quantities by comparing their relative abundances in the MS(1) map. Our results show that PDLs are present in mammalian thymus as well as mouse spleen and liver. Interestingly, the relative quantity of PDLs extracted from human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) bone marrows is higher than that extracted from bone marrow of healthy donors. Our results may help to explain the close correlation between PDLs and iNKT cell function in thymus, spleen, liver, and especially in leukemia patients. We think that our phospholipidomics work may reveal a function of iNKT cells.

The association between multi-heavy metals exposure and lung function in a typical rural population of Northwest China.

BACKGROUND: Heavy metal exposure is acknowledged to be associated with decrease of lung function, but the relationship between metals co-exposure and lung function in rural areas of Northwest China remains unclear, particularly in an area famous for heavy metal pollution and solid fuel use. Therefore, the purpose of this study is to explore the effects of heavy metal exposure on lung function and the potential impacts of living habit in a rural cohort of Northwest China. METHODS: The study area included five villages of two regions in Northwestern China-Gansu province. All participants were recruited from the Dongdagou-Xinglong (DDG-XL) rural cohort in the study area. Urine levels of 10 common and representative heavy metals were detected by ICP-MS, including Cobalt (Co), Nickel (Ni), Molybdenum (Mo), Cadmium (Cd), Stibium (Sb), Copper (Cu), Zinc (Zn), Mercury (Hg), Lead (Pb), and Manganese (Mn). The lung function was detected by measuring percentages of predicted forced vital capacity (FVC%) and predicted forced expiratory volume in one second (FEV1%) as well as the ratio of FEV1/FVC. We also analyzed the association between heavy metals and pulmonary ventilation dysfunction (PVD). Restricted cubic spline, logistic regression, linear regression, and bayesian kernel machine regression (BKMR) model were used to analyze the relationship between heavy metal exposure and lung function. RESULTS: Finally, a total of 382 participants were included in this study with an average age of 56.69 ± 7.32 years, and 82.46% of them used solid fuels for heating and cooking. Single metal exposure analysis showed that the higher concentration of Hg, Mn, Sb, and lower Mo may be risk factors for PVD. We also found that FEV1% and FVC% were negatively correlated with Sb, Hg, and Mn, but positively correlated with Mo. The effect of mixed heavy metals exposure could be observed through BKMR model, through which we found the lung function decreased with the increase of heavy metal concentration. Furthermore, the males, BMI ≥ 24 kg/m2 and who used solid fuels showed a higher risk of PVD when exposed to Co, Zn, and Hg. CONCLUSIONS: Our results suggested that heavy metal exposure was associated with decrease of lung function regardless of single exposure or mixed exposure, particularly for Sb, Hg, Mn and those who use solid fuels.

Enhancement of motor imagery training efficiency by an online adaptive training paradigm integrated with error related potential.

Objective. Motor imagery (MI) is a process of autonomously modulating the motor area to rehearse action mentally without actual execution. Based on the neuroplasticity of the cerebral cortex, MI can promote the functional rehabilitation of the injured cerebral cortex motor area. However, it usually takes several days to a few months to train individuals to acquire the necessary MI ability to control rehabilitation equipment in current studies, which greatly limits the clinical application of rehabilitation training systems based on the MI brain-computer interface (BCI).Approach. A novel MI training paradigm combined with the error related potential (ErrP) is proposed, and online adaptive training of the MI classifier was performed using ErrP. ErrP is used to correct the output of the MI classification to obtain a higher accuracy of kinesthetic feedback based on the imagination intention of subjects while generating simulated labels for MI online adaptive training. In this way, we improved the MI training efficiency. Thirteen subjects were randomly divided into an experimental group using the proposed paradigm and a control group using the traditional MI training paradigm to participate in six MI training experiments.Main results. The proposed paradigm enabled the experimental group to obtain a higher event-related desynchronization modulation level in the contralateral brain region compared with the control group and 69.76% online classification accuracy of MI after three MI training experiments. The online classification accuracy reached 72.76% and the whole system recognized the MI intention of the subjects with an online accuracy of 82.61% after six experiments.Significance. Compared with the conventional unimodal MI training strategy, the proposed approach enables subjects to use the MI-BCI based system directly and achieve a better performance after only three training experiments with training left and right hands simultaneously. This greatly improves the usability of the MI-BCI-based rehabilitation system and makes it more convenient for clinical use.

Impact of high temperature on road injury mortality in a changing climate, 1990-2019: A global analysis.

BACKGROUND: Previous studies have shown that extreme heat likely increases the risk of road injuries. However, the global burden of road injuries due to high temperature and contributing factors remain unclear. This study aims to characterize the global, regional and national burden of road injuries due to high temperature from 1990 to 2019. METHODS: Based on the Global Burden of Disease (GBD) study 2019, we obtained the numbers and age-standardized mortality rates (ASMR) and age-standardized disability-adjusted life years (DALY) rates (ASDR) of the road injury due to high temperature at global, regional, and national levels from 1990 to 2019. The world is divided into five climate zones according to the average annual temperature of each country: tropical, subtropical, warm temperate, cold temperate, and boreal. We used the generalized additive models (GAM) to model the trends of road injuries globally and by region. RESULTS: Globally, between 1990 and 2019, the deaths of road injury attributable to high temperature increased significantly from 20,270 (95% uncertainty interval [UI], 7836 to 42,716) to 28,396 (95% UI, 13,311 to 51,178), and the DALYs increased from 1,169,309 (95% UI, 450,834 to 2,491,075) to 1,414,527 (95% UI, 658,347 to 2,543,613). But the ASMR and the ASDR slightly decreased by 8.49% and 13.16%, respectively. The burden of road injury death attributable to high temperature remained high in low SDI and tropical regions. In addition, road transport infrastructure investment per inhabitant is associated with the burden of road injuries attributable to high temperature. CONCLUSIONS: Globally, the ASMR and ASDR for road injuries attributable to high temperature decreased from 1990 to 2019, but the absolute death and DALYs continued to increase. Thus, concerning global warming, implementation of prevention and interventions to reduce road injuries from heat exposure should be stressed globally.

High expression of lactotriaosylceramide, a differentiation-associated glycosphingolipid, in the bone marrow of acute myeloid leukemia patients.

Glycosphingolipids (GSLs) are information-bearing biomolecules that play critical roles in embryonic development, signal transduction and carcinogenesis. Previous studies indicate that certain GSLs are associated with differentiation in acute myeloid leukemia (AML) cells. In this study, we collected bone marrow samples from healthy donors and AML patients and analyzed the GSL expression profiles comprehensively using electrospray ionization linear ion-trap mass spectrometry. The results showed that AML patients had higher expression of the GSL lactotriaosylceramide (Lc3), GM3 and neolactotetraosylceramide (nLc4) in their bone marrow than did the healthy donors (P < 0.05), especially the M1 subtype of AML. To further explore the molecular mechanisms of Lc3, we examined the expression of the Lc3 synthase ß1,3-N-acetylglucosaminyltransferase5 (ß3Gn-T5) and found that the bone marrow samples of AML patients had 16-fold higher expression of ß3Gn-T5 than those of healthy donors (P < 0.05). Our results suggest that AML-associated GSLs Lc3, GM3 and nLc4 are possibly involved in initiation and differentiation of AML.

Clinical Accuracy of 6 Intraocular Lens Power Calculation Formulas in Elongated Eyes, According to Anterior Chamber Depth.

PURPOSE: To investigate the influence of anterior chamber depth (ACD) on the accuracy of the Kane, EVO 2.0, Barrett Universal II (BU II), Olsen, SRK/T, and Haigis formulas in patients with elongated eyes. DESIGN: Retrospective case series study. METHODS: A total of 106 patients (106 eyes) diagnosed with high myopia (axial length ≥26 mm) were enrolled and divided into 3 subgroups according to preoperative ACD. Mean refractive error (ME), mean absolute refractive error (MAE), median absolute refractive error (MedAE), and proportions of eyes within ±0.25 D, ±0.50 D, ±0.75 D, and ±1.00 D were calculated. RESULTS: In all patients, the MedAE was lowest for the Kane formula (0.28 D), followed by the BU II (0.34 D). In the shallow ACD subgroup, EVO 2.0 formula produced the lowest MedAE (0.22 D), and the highest proportion of eyes within ±0.25 D (58%); the BU II (0.23 D, 50%) and Kane (0.25 D, 50%) formulas produced similar proportions. In the deep ACD group, the MedAEs of the Haigis and SRK/T formulas (0.68 D and 0.50 D, respectively) were significantly higher than those of the EVO 2.0 (0.37 D), Kane (0.30 D), BU II (0.43 D), and Olsen (0.34 D) formulas (P < 0.05). CONCLUSIONS: Overall, the Kane and EVO 2.0 formulas had the highest accuracy. EVO 2.0 and BU II formulas are recommended for patients with shallow ACD; the Kane formula is recommended for patients with deep ACD (especially patients with extremely elongated eyes). The SRK/T and Haigis formulas should be avoided as much as possible.

SDH, a novel diarylheptane compound, is a potential treatment for inflammatory bowel disease by restoring epithelial barrier function.

BACKGROUND: The global prevalence of inflammatory bowel disease (IBD) is increasing, and mucosal healing is the preferred treatment target of IBD. Sodium (aS,9 R)- 3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.12,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) is a novel diarylheptane compound, which is designed to treat IBD. Hence, we investigated the potent therapeutic activity of SDH against IBD and explored the underlying mechanisms, and determined if SDH is a safe and well-tolerated oral therapeutic for IBD treatment. METHODS: We characterized its therapeutic properties in vitro and in vivo using Caco-2 cell monolayer and dextran sodium sulfate (DSS)- or 2,4,6-trinitro-benzene sulfonic acid (TNBS)-induced colitis models. We conducted nonclinical toxicology and safety pharmacology research, including general toxicity, toxicokinetics, pharmacokinetics, metabolism and plasma protein binding, cardiovascular safety pharmacology, central nervous system safety pharmacology, respiratory safety pharmacology, fertility and early embryonic development toxicity, reverse mutation assay, chromosomal aberration assay and micronucleus test. RESULTS: The results showed that SDH promoted expression of tight junction proteins, and protected the integrity and permeability of the epithelial barrier in both cell and animal models. Moreover, lower doses of SDH showed the similar or better efficacy than cyclosporine A (CsA) and mesalazine in DSS- or TNBS-induced colitis animals. Furthermore, our results identified that SDH has satisfactory safety in these studies we tested. In summary, SDH restored the epithelial barrier through tight junction proteins and was expected to be a novel therapeutic agent for the treatment of IBD.

DGT, a novel heterocyclic diterpenoid, effectively suppresses psoriasis via inhibition of STAT3 phosphorylation.

BACKGROUND AND PURPOSE: Psoriasis is a chronic immune-mediated inflammatory skin disease that easily recurs and is difficult to cure. DGT is a novel synthetic heterocyclic diterpenoid, whose structure has not been previously reported. We have investigated the action of DGT against psoriasis, specifically the hyperproliferation of epidermal keratinocytes, angiogenesis and pathogenic inflammatory responses. EXPERIMENTAL APPROACH: We investigated its pharmacokinetics in skin after topical administration. We characterized its pharmacological actions in vitro and in vivo using cell proliferation assay, cell apoptosis assay, diethylstilbestrol-induced mouse vaginal epithelial cell mitosis model, tube formation assay, cell migration assay, chick embryonic chorioallantoic membrane (CAM) assay, histological, flow cytometric analysis and imiquimod (IMQ)-induced psoriasis-like model. KEY RESULTS: DGT was found to be mainly distributed in the epidermis and dermis, which indicated that DGT was suitable as a topical treatment. DGT inhibited cell proliferation and induced apoptotic cell death of keratinocytes in vitro and in vivo. Moreover, DGT inhibited endothelial cell proliferation, tube formation and migration of in vitro angiogenesis, as well as in vivo CAM angiogenesis. In an IMQ-induced psoriasis-like skin inflammation murine model, topical application of DGT ameliorated keratinocyte proliferation and inflammatory response, especially in IL-17-related psoriasiform dermatitis. Furthermore, our results demonstrated that DGT prevented these pathological processes of psoriasis through suppression of STAT3 phosphorylation. CONCLUSION AND IMPLICATIONS: DGT has great potential as a novel therapeutic agent for the treatment of psoriatic skin disease.