Schisanhenol ameliorates non-alcoholic fatty liver disease via inhibiting miR-802 activation of AMPK-mediated modulation of hepatic lipid metabolism.

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is a common metabolic liver disease worldwide. Currently, satisfactory drugs for NAFLD treatment remain lacking. Obesity and diabetes are the leading causes of NAFLD, and compounds with anti-obesity and anti-diabetic activities are considered suitable candidates for treating NAFLD. In this study, biochemical and histological assays revealed that a natural lignan schisanhenol (SAL) effectively decreased lipid accumulation and improved hepatic steatosis in free fatty acid (FFA)-treated HepG2 cells and high-fat diet (HFD)-induced NAFLD mice. Further, molecular analyses, microRNA (miRNA)-seq, and bioinformatics analyses revealed that SAL may improve NAFLD by targeting the miR-802/adenosine monophosphate-activated protein kinase (AMPK) pathway. Liver-specific overexpression of miR-802 in NAFLD mice significantly impaired SAL-mediated liver protection and decreased the protein levels of phosphorylated (p)-AMPK and PRKAB1. Dual-luciferase assay analysis further confirmed that miR-802 inhibits hepatic AMPK expression by binding to the 3' untranslated region of mouse Prkab1 or human PRKAA1. Additionally, genetic silencing of PRKAA1 blocked SAL-induced AMPK pathway activation in FFA-treated HepG2 cells. The results demonstrate that SAL is an effective drug candidate for treating NAFLD through regulating miR-802/AMPK-mediated lipid metabolism.

Omadacycline in the treatment of scrub typhus: Three case reports.

BACKGROUND: Scrub typhus is a naturally occurring acute infectious disease that is primarily transmitted through the bites of chiggers or larval mites infected by Orientia tsutsugamushi (O. tsutsugamushi). Omadacycline, a novel tetracycline, exhibits potent antibacterial efficacy against both typical bacteria and atypical pathogens. However, omadacycline application in the treatment of scrub typhus remains limited. CASE SUMMARY: In the present work, we report several cases of scrub typhus, with the main clinical symptoms being fever, the formation of eschars or ulcers, local or systemic lymphadenopathy, headache, myalgia and rash. Blood samples were collected before omadacycline was administered, and O. tsutsugamushi infection was confirmed through targeted next-generation sequencing (tNGS). After two days of treatment, the patients' symptoms, including fever, were alleviated, with no adverse drug reactions. CONCLUSION: tNGS is an effective method for diagnosing scrub typhus. Omadacycline can be considered an alternative option for antiinfective therapy in patients with O. tsutsugamushi infections.

Preoperative inter-arm differences and normative-based thresholds for lymphedema in Chinese breast cancer patients: Insights from a large cohort study.

Objective: Early detection and diagnosis of lymphedema are crucial for effective treatment and prevention of its progression. Normative-based diagnostic thresholds can enhance diagnostic accuracy in the absence of preoperative measurements. This study aimed to investigate preoperative inter-arm differences and the associated factors, as well as to determine normative-based thresholds for lymphedema in Chinese breast cancer patients. Methods: This study utilized baseline data from a large cohort of Chinese breast cancer patients. Bilateral arm circumferences were measured at the wrist and at 10 cm intervals proximally up to 40 cm. Arm volumes were calculated using the truncated cone formula. Paired t test, repeated measures analysis of variance, and regression analysis were performed. Results: A total of 1707 breast cancer patients were included. Paired t tests showed that the dominant arm circumferences and volumes were significantly larger than those of the nondominant arm (P < 0.001). Regression analysis and repeated measures analysis of variance revealed that hand dominance was the influencing factor of inter-arm differences (P < 0.05). Normative-based thresholds determined by two standard deviations above the mean inter-arm volume ratio were 1.057 for the dominant arm and 1.079 for the nondominant arm. Conclusions: The absolute and relative normative-based thresholds for Chinese breast cancer patients differed slightly from the commonly used diagnostic criteria and those reported in Western populations and among Chinese healthy women. The normal variability and asymmetry associated with arm dominance underscore the importance of preoperative baseline assessments. Implementing normative-based diagnostic thresholds can facilitate more accurate lymphedema diagnosis when preoperative measurements are unavailable. Trial registration: Registration No. ChiCTR2200057083.

Spatially lipidomic characterization of patient-derived organoids by whole-mount autofocusing SMALDI mass spectrometry imaging.

BACKGROUND: Patient-derived organoids (PDOs) are multi-cellular cultures with specific three-dimensional (3D) structures. Tumor organoids (TOs) offer a personalized perspective for assessing treatment response. However, the presence of normal organoid (NO) residuals poses a potential threat to their utility for personalized medicine. There is a crucial need for an effective platform capable of distinguishing between TO and NO in cancer organoid cultures. RESULTS: We introduced a whole-mount (WM) preparation protocol for in-situ visualization of the lipidomic distribution of organoids. To assess the efficacy of this method, nine breast cancer organoids (BCOs) and six normal breast organoids (NBOs) were analyzed. Poly-l-lysine (PLL) coated slides, equipped with 12 well chambers, were utilized as a carrier for the high-throughput analysis of PDOs. Optimizing the fixation time to 30 min, preserved the integrity of organoids and the fidelity of lipid compounds. The PDOs derived from the same organoid lines exhibited similar lipidomic profiles. BCOs and NBOs were obviously distinguished based on their lipidomic signatures detected by WM autofocusing (AF) scanning microprobe matrix-assisted laser desorption/ionization (SMALDI) mass spectrometry imaging (MSI). SIGNIFICANCE: A whole-mount (WM) preparation protocol was developed to visualize lipidomic distributions of the organoids' surface. Using poly-l-lysine coated slides for high-throughput analysis, the method preserved organoid integrity and distinguished breast cancer organoids (BCOs) from normal breast organoids (NBOs) based on their unique lipidomic profiles using autofocusing scanning microprobe matrix-assisted laser desorption/ionization (SMALDI) mass spectrometry imaging.

Evaluation and modeling of diaphragm displacement using ultrasound imaging for wearable respiratory assistive robot.

Introduction: Assessing the influence of respiratory assistive devices on the diaphragm mobility is essential for advancing patient care and improving treatment outcomes. Existing respiratory assistive robots have not yet effectively assessed their impact on diaphragm mobility. In this study, we introduce for the first time a non-invasive, real-time clinically feasible ultrasound method to evaluate the impact of soft wearable robots on diaphragm displacement. Methods: We measured and compared diaphragm displacement and lung volume in eight participants during both spontaneous and robotic-assisted respiration. Building on these measurements, we proposed a human-robot coupled two-compartment respiratory mechanics model that elucidates the underlying mechanism by which our extracorporeal wearable robots augments respiration. Specifically, the soft robot applies external compression to the abdominal wall muscles, inducing their inward movement, which consequently pushes the diaphragm upward and enhances respiratory function. Finally, we investigated the level and shape of various robotic assistive forces on diaphragm motion. Results: This robotic intervention leads to a significant increase in average diaphragm displacement by 1.95 times and in lung volume by 2.14 times compared to spontaneous respiration. Furthermore, the accuracy of the proposed respiratory mechanics model is confirmed by the experimental results, with less than 7% error in measurements of both diaphragm displacement and lung volume. Finally, the magnitude of robotic assistive forces positively correlates with diaphragm movement, while the shape of the forces shows no significant relationship with diaphragm activity. Conclusion: Our experimental findings validate the effective assistance mechanism of the proposed robot, which enhances diaphragm mobility and assists in ventilation through extracorporeal robotic intervention. This robotic system can assist with ventilation while increasing diaphragm mobility, potentially resolving the issue of diaphragm atrophy. Additionally, this work paves the way for improved robotic designs and personalized assistance, tailored to the dynamics of the diaphragm in respiratory rehabilitation.

Both nutrients and macrophytes regulate organic carbon burial: Insights from high-resolution spatiotemporal records of a large shallow lake (Baiyangdian) in eastern China.

Both ecological regime shifts and carbon cycling in lakes have been the subject of global debates in recent years. However, the direct linkage between them is poorly understood. Lake Baiyangdian, a representative large shallow lake with the coexistence of a macrophyte-dominated area (MDA) and an algae-dominated area (ADA) in eastern China, allowing better understanding of the relationship between regime shifts and organic carbon (OC) burial in lakes. On the basis of Bayesian isotopic mixing modelling of C/N ratios and δ13C values, the sediment OC is primarily of autochthonous origin. The mean OC burial rate (OCBR) was 39 g C m-2 yr-1 before eutrophication occurred in 1990 and increased approximately 2.7-fold to 106 g C m-2 yr-1 after eutrophication. Partial least squares path modelling revealed that this change can be largely attributed to enhanced primary productivity and rapid burial as a result of intensified human perturbation. In terms of spatial patterns, the OCBR was greater in the MDA than in the ADA, which may be related to the different burial and mineralization processes of debris from macrophytes and algae. It then deduced that a decrease in the OCBR and an increase in the mineralization rate might have occurred after a shift from a macrophyte-dominated state to an algae-dominated state. Our findings highlight that eutrophication generally increases OC burial by enhancing lake primary productivity. However, once nutrient levels reach a critical range, lake ecosystems may shift from a macrophyte-dominated state to an algae-dominated state, which can lead to a significant reduction in the carbon burial capacity of lakes. Therefore, more attention should be given to avoiding shifts in eutrophic lakes, as such shifts can alter carbon cycling.

Vinpocetine alleviates the abdominal aortic aneurysm progression via VSMCs SIRT1-p21 signaling pathway.

Abdominal aortic aneurysm (AAA) is a degenerative disease that caused mortality in people aged >65. Senescence plays a critical role in AAA pathogenesis. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. Our Previous study found cyclic nucleotide phosphodiesterase 1C (PDE1C) exacerbate AAA through aggravate vascular smooth muscle cells (VSMCs) senescence by downregulating Sirtuin1 (SIRT1) expression and activity. Vinpocetine as a selective inhibitor of PDE1 and a clinical medication for cerebral vasodilation, it is unclear whether vinpocetine can rely on SIRT1 to alleviate AAA. This study showed that pre-treatment with vinpocetine remarkably prevented aneurysmal dilation and reduced aortic rupture in elastase-induced AAA mice. In addition, the elastin degradation, MMP (matrix metalloproteinase) activity, macrophage infiltration, ROS production, collagen fibers remodeling, and VSMCs senescence were decreased in AAA treated with vinpocetine. While these effects were unable to exert in VSMCs-specific SIRT1 knockout AAA mice. Accordingly, we revealed that vinpocetine suppressed migration, proliferation, and senescence in VSMCs. Moreover, vinpocetine reduced SIRT1 degradation by inhibiting lysosome-mediated autophagy. In conclusion, this study indicated that vinpocetine may be as a potential drug for therapy AAA through alleviate VSMCs senescence via the SIRT1-dependent pathway.

Comparative Analysis of Risk Factors and Dietary Status of High-risk Groups of Stroke in Urban and Rural Areas of Xiangtan City.

Objective: This study aimed to explore the risk factors and dietary status of middle-aged and elderly people at high risk of stroke in urban and rural areas of Xiangtan City, with a view to providing a basis for formulating stroke prevention and control strategies in urban and rural areas of Xiangtan City. Methods: Using the cluster sampling method, a total of 8,453 permanent residents aged ≥40 years old were selected from Yuetang Street, Yuetang District, and Jiangshe Town, Yuhu District, Xiangtan City in 2020 and 2021 for face-to-face questionnaire surveys to collect their demographic information, daily life Method, family history, height, weight, waist circumference, blood pressure, blood sugar, blood lipids, glycosylated hemoglobin, homocysteine and other indicators, and analyze them. Results: A total of 8453 permanent residents were screened in this study, and a total of 1804 stroke high-risk patients (including stroke and TIA, 21.34%) were screened out, including 973 urban residents (23.53%), and 831 rural residents (19.25%), and the distinction had statistical significance (P < .05); 263 stroke sufferers were screened out, and the prevalence ratio was 3.11%. The exposure rates of risk factors for high-risk groups in urban and rural areas of Xiangtan City from high to low are hypertension, dyslipidemia, smoking, family history of stroke, diabetes, obesity, lack of exercise and atrial fibrillation or heart valve disease. The high-risk groups for urban strokes The proportions of lack of exercise (23.54%) and obesity (38.44%) were significantly higher than the proportions of lack of exercise (17.09%) and obesity (22.64%) in rural areas. The high-risk groups in rural areas had hypertension (87.73%) and a history of TIA (2.89%). The proportion of patients with hypertension (82.43%) and TIA history (1.34%) was significantly higher than those in urban areas, and the differences were statistically significant (P < .05). The proportion of rural residents who eat a salty diet (17.93%) and eat fruits ≤2 days/week (93.98%) is significantly higher than that of urban residents who eat a salty diet (14.49%) and eat fruits ≤2 days/week (59.61%). There are differences. Statistically significant (P < .05), the proportion of urban residents who consume vegetables ≤2 days/week (11.91%) is significantly lower than the proportion of urban residents who consume vegetables ≤2 days/week (28.98%) (P < .01). Conclusion: The high-risk factors for stroke in Xiangtan City are mainly hypertension, dyslipidemia, smoking history, family history of stroke, and diabetes. Tailored public health measures should be taken by residents to address the different risk status and dietary habits of urban and rural populations. Especially dietary intervention for rural residents.

Causal relationships of lifestyle behaviours and body fat distribution on diabetic microvascular complications: a Mendelian randomization study.

Objectives: To determine the causal correlations of lifestyle behaviours and body fat distribution on diabetic microvascular complications through a Mendelian Randomization (MR). Methods: Genetic variants significantly associated with lifestyle behaviours, abdominal obesity, generalized obesity and diabetic microvascular complications were extracted from the UK Biobank (UKB) and FinnGen. The inverse variance weighted (IVW) method was regarded as the primary method. The main results were presented in odds ratio (OR) per standard deviation (SD) increase, and a series of sensitivity analyses were also conducted to validate the stability of the results. Results: There was a positive causal correlation between smoking and the development of diabetic retinopathy (OR = 1.16; 95%CI: 1.04-1.30; p = 0.01). All of the indicators representing abdominal obesity had a statistically significant causal association with diabetic microvascular complications. Concerning generalized obesity, there were significant causal associations of body mass index (BMI) on diabetic nephropathy (OR = 1.92; 95%CI: 1.58-2.33; p < 0.001), diabetic retinopathy (OR = 1.27; 95%CI: 1.15-1.40; p < 0.001), and diabetic neuropathy (OR = 2.60; 95%CI: 1.95-3.45; p < 0.001). Other indicators including leg fat mass (left), and arm fat mass (left) also had a significant positive causality with diabetic microvascular complications. Conclusion: Our findings suggested that smoking has a genetically causal association with the development of diabetic retinopathy rather than diabetic nephropathy and diabetic neuropathy. In addition, both abdominal obesity and generalized obesity are risk factors for diabetic microvascular complications. To note, abdominal obesity represented by waist circumference (WC) is the most significant risk factor.

Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus. / 人脐带间å 质干细胞通过IGF1R-CHK2-p53信号轴减轻2åž‹ç³–å°¿ç— é›„æ€§å¤§é¼ ç³–å°¿ç— è‚¾ç— .

Diabetes mellitus (DM) is a disease syndrome characterized by chronic hyperglycaemia. A long-term high-glucose environment leads to reactive oxygen species (ROS) production and nuclear DNA damage. Human umbilical cord mesenchymal stem cell (HUcMSC) infusion induces significant antidiabetic effects in type 2 diabetes mellitus (T2DM) rats. Insulin-like growth factor 1 (IGF1) receptor (IGF1R) is important in promoting glucose metabolism in diabetes; however, the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains unclear. In this study, a DM rat model was induced with high-fat diet feeding and streptozotocin (STZ) administration and rats were infused four times with HUcMSC. Blood glucose, interleukin-6 (IL-6), IL-10, glomerular basement membrane, and renal function were examined. Proteins that interacted with IGF1R were determined through coimmunoprecipitation assays. The expression of IGF1R, phosphorylated checkpoint kinase 2 (p-CHK2), and phosphorylated protein 53 (p-p53) was examined using immunohistochemistry (IHC) and western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of 8-hydroxydeoxyguanosine (8-OHdG). Flow cytometry experiments were used to detect the surface markers of HUcMSC. The identification of the morphology and phenotype of HUcMSC was performed by way of oil red "O" staining and Alizarin red staining. DM rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane, increased the expression of IGF1 and IGF1R. IGF1R interacted with CHK2, and the expression of p-CHK2 was significantly decreased in IGF1R-knockdown cells. When cisplatin was used to induce DNA damage, the expression of p-CHK2 was higher than that in the IGF1R-knockdown group without cisplatin treatment. HUcMSC infusion ameliorated abnormalities and preserved kidney structure and function in DM rats. The expression of IGF1, IGF1R, p-CHK2, and p-p53, and the level of 8-OHdG in the DM group increased significantly compared with those in the control group, and decreased after HUcMSC treatment. Our results suggested that IGF1R could interact with CHK2 and mediate DNA damage. HUcMSC infusion protected against kidney injury in DM rats. The underlying mechanisms may include HUcMSC-mediated enhancement of diabetes treatment via the IGF1R-CHK2-p53 signalling pathway.

Synergistic cytotoxicity and in vitro antioxidant activity of hederagenin and its glycoside from quinoa.

Although a series of studies confirm the bioactivities of hederagenin and its glycosides, their synergistic effects and potential mechanisms are still worthy of further exploration. This work investigated the synergistic cytotoxicity and in vitro antioxidant activity of hederagenin and hederagenin 28-O-ß-d-glucopyranoside (28-Glc-hederagenin). Hederagenin and 28-Glc-hederagenin inhibited HeLa cell growth and their combination further strengthened this effect. The combination of hederagenin and 28-Glc-hederagenin significantly increased the rate of apoptotic cells, suggesting the presence of a synergistic effect between the two substances. This combination also enhanced in vitro antioxidant activity compared with individual treatments. A network pharmacology and molecular docking-based approach was performed to explore the underlying mechanisms of hederagenin and 28-Glc-hederagenin against cervical cancer and oxidant damage. This work identified 18 related Kyoto Encyclopedia of Genes and Genome pathways, 202 related biological process terms, 17 related CC terms, and 35 related molecular function terms and then revealed 30 nodes and 196 edges. Subsequently, two highly connected clusters and the top four targets were identified. Molecular docking showed potent binding affinity of hederagenin and 28-Glc-hederagenin toward core targets associated with both cervical cancer and oxidant damage. This work may provide scientific basis for the combined use of hederagenin and its glycosides as dietary supplements.

Targeting lymph nodes for enhanced cancer vaccination: From nanotechnology to tissue engineering.

Lymph nodes (LNs) occupy a critical position in initiating and augmenting immune responses, both spatially and functionally. In cancer immunotherapy, tumor-specific vaccines are blooming as a powerful tool to suppress the growth of existing tumors, as well as provide preventative efficacy against tumorigenesis. Delivering these vaccines more efficiently to LNs, where antigen-presenting cells (APCs) and T cells abundantly reside, is under extensive exploration. Formulating vaccines into nanomedicines, optimizing their physiochemical properties, and surface modification to specifically bind molecules expressed on LNs or APCs, are common routes and have brought encouraging outcomes. Alternatively, porous scaffolds can be engineered to attract APCs and provide an environment for them to mature, proliferate and migrate to LNs. A relatively new research direction is inducing the formation of LN-like organoids, which have shown positive relevance to tumor prognosis. Cutting-edge advances in these directions and discussions from a future perspective are given here, from which the up-to-date pattern of cancer vaccination will be drawn to hopefully provide basic guidance to future studies.

Diagnostic, monitoring, and prognostic value of combined detection of cerebrospinal fluid heparin-binding protein, interleukin-6, interleukin-10, and procalcitonin for post-neurosurgical intracranial infection.

OBJECTIVE: Intracranial infection is a common complication after neurosurgery and can increase the length of hospital stay, affect patient prognosis, and increase mortality. We aimed to investigate the value of the combined detection of cerebrospinal fluid (CSF) heparin-binding protein (HBP), interleukin-6 (IL-6), interleukin-10 (IL-10), and procalcitonin (PCT) for post-neurosurgical intracranial infection. METHODS: This study assessed the diagnostic values of CSF HBP, IL-6, IL-10, PCT levels, and combined assays for post-neurosurgical intracranial infection with the area under the receiver operating characteristic (ROC) curve by retrospectively analysing biomarkers of post-neurosurgical patients. RESULTS: The CSF HBP, IL-6, IL-10, and PCT levels were significantly higher in the infected group than the uninfected group and the control group (P < 0.001). The indicators in the groups with severe intracranial infections were significantly higher than those in the groups with mild intracranial infections (P < 0.001), and the groups with poor prognoses had significantly higher indexes than the groups with good prognoses. According to the ROC curve display, the AUC values of CSF HBP, IL-6, IL-10, and PCT were 0.977 (95 % CI 0.952-1.000), 0.973 (95 % CI 0.949-0.998), 0.884 (95 % CI 0.823-0.946), and 0.819 (95 % CI 0.733-0.904), respectively. The AUC of the combined test was 0.996 (95 % CI 0.989-1.000), which was higher than those of the four indicators alone. CONCLUSION: The combined detection can be an important indicator for the diagnosis and disease monitoring of post-neurosurgical intracranial infection.

Medical knowledge graph completion via fusion of entity description and type information.

Medical Knowledge Graphs (MKGs) are vital in propelling big data technologies in healthcare and facilitating the realization of medical intelligence. However, large-scale MKGs often exhibit characteristics of data sparsity and missing facts. Following the latest advances, knowledge embedding addresses these problems by performing knowledge graph completion. Most knowledge embedding algorithms rely solely on triplet structural information, overlooking the rich information hidden within entity property sets, leading to bottlenecks in performance enhancement when dealing with the intricate relations of MKGs. Inspired by the semantic sensitivity and explicit type constraints unique to the medical domain, we propose BioBERT-based graph embedding model. This model represents an evolvable framework that integrates graph embedding, language embedding, and type information, thereby optimizing the utility of MKGs. Our study utilizes not only WordNet as a benchmark dataset but also incorporates MedicalKG to compare and corroborate the specificity of medical knowledge. Experimental results on these datasets indicate that the proposed fusion framework achieves state-of-art (SOTA) performance compared to other baselines. We believe that this incremental improvement provides promising insights for future medical knowledge graph completion endeavors.

Accelerating Intersystem Crossing in Multiresonance Thermally Activated Delayed Fluorescence Emitters via Long-Range Charge Transfer.

Multiresonance thermally activated delayed fluorescence (MR-TADF) emitters are excellent candidates for high-performance organic light-emitting diodes (OLEDs) due to their narrowband emission properties. However, the inherent mechanism of regulating the rate of intersystem crossing (ISC) is ambiguous in certain MR-TADF skeletons. Herein, we propose a mechanism of accelerating ISC in B/S-based MR-TADF emitters by peripheral modifications of electron-donating groups (EDGs) without affecting the narrowband emission property. The long-range charge transfer (LRCT) stems from the introduced EDG leading to high-lying singlet and triplet excited states. The ISC process is accelerated by the enhanced spin-orbital coupling (SOC) between the singlet short-range charge transfer (SRCT) and triplet LRCT manifolds. Meanwhile, the narrowband emission derived from the MR-type SRCT state is well retained as expected in the peripherally modified MR-TADF emitters. This work reveals the regulation mechanism of photophysical properties by high-lying LRCT excited states and provides a significant theoretical basis for modulating the rate of ISC in the further design of MR-TADF materials.

Theoretical Study on the Reaction between Carcinogenic 2,5-Dichloro-1,4-benzoquinone and tert-Butyl Hydroperoxide: Self-Catalysis and Water Catalysis.

The potentially carcinogenic halobenzoquinones (HBQs) have been recently identified in drinking water as disinfection byproducts. Several radical intermediates in the reaction of 2,5-dichloro-1,4-benzoquinone (DCBQ) and t-butyl hydroperoxide (t-BuOOH), which may induce DNA damage, were detected experimentally, and metal-independent decomposition reactions of t-BuOOH by DCBQ were proposed. It has not yet been confirmed by theoretical calculations. The theoretical study in this work provides insights into the details of the reaction. An unprecedented self-catalysis mechanism of organic hydroperoxides, that is, the reactant t-BuOOH also has a catalytic effect, was uncovered at the molecular level. Moreover, as the solvent, water molecules also clearly have an efficient catalytic effect. Due to the catalysis of t-BuOOH and water, the metal-independent reaction of t-BuOOH and DCBQ can occur under moderate conditions. Our findings about the novel catalytic effect of organic hydroperoxides t-BuOOH could offer a unique perspective into the design of new catalysts and an understanding of the catalytic biological, environmental, and air pollution reactions. Furthermore, organic hydroperoxide t-BuOOH could serve as a proton shuttle, where the proton transfer process is accompanied by simultaneous charge transfer. Therefore, organic hydroperoxides may disrupt the vital proton transfer process in biological systems and may give rise to unexpected toxicity.

Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension.

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

Chiral Recognition of Chiral (Hetero)Cyclic Derivatives Probed by Tetraaza Macrocyclic Chiral Solvating Agents via 1H NMR Spectroscopy.

In the field of chiral recognition, chiral cyclic organic compounds, especially heterocyclic organic compounds, have attracted little attention and have been rarely studied as chiral substrates by means of 1H NMR spectroscopy. In this paper, enantiomers of thiohydantoin derivatives, representing typical five-membered N,N-heterocycles, have been synthesized and utilized for assignment of absolute configuration and analysis of enantiomeric excess. All enantiomers have been successfully differentiated with the assistance of novel tetraaza macrocyclic chiral solvating agents (TAMCSAs) by 1H NMR spectroscopy. Surprisingly, unprecedented nonequivalent chemical shift values (up to 2.052 ppm) of the NH proton of substrates have been observed, a new milestone in the evaluation of enantiomers. To better understand the intermolecular interactions between host and guest, Job plots and theoretical calculations of (S)-G1 and (R)-G1 with TAMCSA 1a were investigated and revealed significant geometric differentiation between the diastereomers. In order to evaluate practical applications of the present systems in analyzing optical purity of chiral substrates, enantiomeric excesses of a typical substrate (G1) with different optical compositions in the presence of a representative TAMCSA (1a) can be accurately calculated based on the integration of the NH proton's signal peaks. Importantly, this work provides a significant breakthrough in exploring and developing the chiral recognition of chiral heterocyclic organic compounds by 1H NMR spectroscopy.

Reference intervals for cardiometabolic risk factors in China: a national multicenter cross-sectional study on an adult population sample.

Background: The reference intervals (RIs) of adult blood lipid parameters currently used in China are not derived from the results of research in local populations and have not been adjusted for age and sex. In this study, we aimed to determine accurate RIs for blood lipid parameters and blood glucose (GluG) for Chinese adults using a national multicenter study. Methods: A total of 11,333 adults between 18 and 90 years of age were recruited in seven representative regions in China between June 2020 and December 2020. Hospitals participating in the study were regrouped into two geographical regions, southern China (Changsha, Chengdu, Hangzhou, and Nanning) and northern China (Beijing, Shenyang, and Ningxia), according to their geographical and administrative location. All samples were freshly collected and measured collectively in one laboratory on the Mindray full Automatic biochemical analyzer chemistry BS2000 analytical systems. Outliers were removed using the Tukey test. Three-level nested analysis of variance and scatter plot were used to explore the variations in sex, age, and region. Percentile curves of each indicator were plotted using the least mean square (LMS) method. The lower limit (2.5th percentile) and the upper limit (97.5th percentile) of the RI were determined by using nonparametric statistical methods. We also calculated the 90% confidence interval (CI) for the lower and upper limits. Results: A total of 8,283 participants were enrolled in the final analysis, with 3,593 (43.4%) men and 4,690 (56.6%) women. Regionality was observed in three analytes [small dense low density lipoprotein cholesterol (sd-LDLC), GluG, and apolipoprotein A1 (ApoA1)]. In northern China, the sd-LDLC and GluG levels in Shenyang were significantly higher than those in Ningxia and Beijing (P<0.05). In southern China, the sd-LDLC and GluG levels in Nanning were significantly higher than those in the three other cities (P<0.05), whereas the sd-LDLC and GluG levels in Chengdu were significantly lower than those in the three other cities (P<0.05). The level of ApoA1 in Chengdu was significantly higher than that in the three other cities. The homocysteine (HCY) level in male participants was clearly higher than that in female participants [ratio of standard deviation (SDR)sex =0.56], whereas the levels of high density lipoprotein cholesterol (HDLC) (SDRsex =0.40) and ApoA1 (SDRsex =0.27) in males were lower. The GluG and HCY level increased gradually with age. In females aged 45-55 years, there was an interesting change in scatter charts, where triglyceride (TG) and total cholesterol (TC) increased rapidly. We also found that for the age group of >55 years, the levels of TG and TC in females gradually surpassed those in males. Conclusions: The findings of this study may help establish age- and sex-specific reference values for the blood lipids of Chinese adults and serve as a valuable guide for the screening, diagnosis, treatment, prevention, and monitoring of cardiovascular disease (CVD).