Hinokione: an abietene diterpene with pancreatic ß cells regeneration and hypoglycemic activity, and other derivatives with novel structures from the woods of Agathis dammara.

In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1-4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI-MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure-activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into ß cells, thereby promoting the regeneration of pancreatic ß cells.

3D-Printed proangiogenic patches of photo-crosslinked gelatin and polyurethane hydrogels laden with vascular cells for treating vascular ischemic diseases.

Engineering vascularized tissues remains a promising approach for treating ischemic cardiovascular diseases. The availability of 3D-bioprinted vascular grafts that induce therapeutic angiogenesis can help avoid necrosis and excision of ischemic tissues. Here, using a combination of living cells and biodegradable hydrogels, we fabricated 3D-printed biocompatible proangiogenic patches from endothelial cell-laden photo-crosslinked gelatin (EC-PCG) bioink and smooth muscle cell-encapsulated polyurethane (SMC-PU) bioink. Implantation of 3D-bioprinted proangiogenic patches in a mouse model showed that EC-PCG served as an angiogenic capillary bed, whereas patterned SMC-PU increased the density of microvessels. Moreover, the assembled patterns between EC-PCG and SMC-PU induced the geometrically guided generation of microvessels with blood perfusion. In a rodent model of hindlimb ischemia, the vascular patches rescued blood flow to distal tissues, prevented toe/foot necrosis, promoted muscle remodeling, and increased the capillary density, thereby improving the heat-escape behavior of ischemic animals. Thus, our 3D-printed vascular cell-laden bioinks constitute efficient and scalable biomaterials that facilitate the engineering of vascular patches capable of directing therapeutic angiogenesis for treating ischemic vascular diseases.

Analysis of clinical characteristics of infections caused by shewanella species.

PURPOSE: The Shewanella genus is a rare pathogen of marine origin. In recent years, there has been a continuous increase in infection cases caused by this bacterium, and we have observed the uniqueness of infections caused by this microorganism. MATERIALS AND METHODS: This study conducted a retrospective analysis of the medical history and laboratory examination data of patients infected with the Shewanella genus over the past decade. Additionally, it employed bioinformatics methods to analyze the relevant virulence factors and antibiotic resistance genes associated with the Shewanella genus. RESULTS: Over the past 10 years, we have isolated 51 cases of Shewanella, with 68.82% being Shewanella putrefaciens (35/51 cases) and 31.37% being Shewanella algae (16/51 cases). Infected individuals often had underlying diseases, with 39.22% (20/51) having malignant tumors and 25.49% (13/51) having liver and biliary system diseases primarily characterized by stones. The majority of patients, 62.74% (32/51), exhibited mixed infections, including one case with a combination of infections from three other types of bacteria and five cases with a combination of infections from two other types of bacteria. The identified microorganisms were commonly resistant to ticarcillin-clavulanic acid (23.5%), followed by cefoperazone-sulbactam (19.6%), ciprofloxacin (17.6%), and cefotaxime (17.6%). Bioinformatics analysis indicates that Shewanella can express bile hydrolysis regulators and fatty acid metabolism regulators that aid in adapting to the unique environment of the biliary tract. Additionally, it expresses abundant catalase, superoxide dismutase, and two-component signal transduction system proteins, which may be related to environmental adaptation. Shewanella also expresses various antibiotic resistance genes, including beta-lactamases and aminoglycoside modification enzymes. Iron carriers may be one of its important virulence factors. CONCLUSIONS: We speculate that the Shewanella genus may exist as a specific colonizer in the human body, and under certain conditions, it may act as a pathogen, leading to biliary infections in the host.

Regulation of Erythroid Differentiation via the HIF1α-NFIL3-PIM1 Signaling Axis Under Hypoxia.

Aims: Erythropoiesis is controlled by several factors, including oxygen level under different circumstances. However, the role of hypoxia in erythroid differentiation and the underlying mechanisms are poorly understood. We studied the effect and mechanism of hypoxia on erythroid differentiation of K562 cells and observed the effect of hypoxia on early erythropoiesis of zebrafish. Results: Compared with normal oxygen culture, both hemin-induced erythroid differentiation of K562 cells and the early erythropoiesis of zebrafish were inhibited under hypoxic treatment conditions. Hypoxia-inducible factor 1 alpha (HIF1α) plays a major role in the response to hypoxia. Here, we obtained a stable HIF1α knockout K562 cell line using the CRISPR-Cas9 technology and further demonstrated that HIF1α knockout promoted hemin-induced erythroid differentiation of K562 cells under hypoxia. We demonstrated an HIF1-mediated induction of the nuclear factor interleukin-3 (NFIL3) regulated in K562 cells under hypoxia. Interestingly, a gradual decrease in NFIL3 expression was detected during erythroid differentiation of erythropoietin-induced CD34+ hematopoietic stem/progenitor cells (HSPCs) and hemin-induced K562 cells. Notably, erythroid differentiation was inhibited by enforced expression of NFIL3 under normoxia and was promoted by the knockdown of NFIL3 under hypoxia in hemin-treated K562 cells. In addition, a target of NFIL3, pim-1 proto-oncogene, serine/threonine kinase (PIM1), was obtained by RNA microarray after NFIL3 knockdown. PIM1 can rescue the inhibitory effect of NFIL3 on hemin-induced erythroid differentiation of K562 cells. Innovation and Conclusion: Our findings demonstrate that the HIF1α-NFIL3-PIM1 signaling axis plays an important role in erythroid differentiation under hypoxia. These results will provide useful clues for preventing the damage of acute hypoxia to erythropoiesis.

Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Multicomponent Intervention on Improving the Cognitive Ability of Older Adults with Mild Cognitive Impairment: A Pilot Randomized Controlled Trial.

This pilot randomized controlled trial aimed to evaluate the feasibility and potential outcomes of an innovative 16-session multicomponent intervention model to improve cognitive abilities in older adults with mild cognitive impairment (MCI) by promoting healthy lifestyle, cognitive skills, tai chi and mindfulness practices. This study was a multicentre, randomized controlled, two-arm, parallel-group, unblinded trial in Hong Kong. 57 Chinese older adults with MCI recruited from three local elderly centers were randomly assigned to either the control or intervention group. The study results support the feasibility and efficacy of the multicomponent intervention, and recommend future larger-scale randomized control trials.

Correlations among serum alpha-(1,6)-fucosyltransferase and early symptoms associated with Parkinson's disease: A cross-sectional retrospective study.

Alpha-(1,6)-fucosyltransferase (FUT8) has been found to play a role in modulating the central immune system and inflammatory responses. Limited studies have assessed the correlations between serum FUT8 levels and various non-motor symptoms associated with early Parkinson's disease (PD). Therefore, our research aims to investigate the associations between serum FUT8 levels and symptoms such as smell dysfunction, sleep duration, sleep problems, and MMSE scores in PD patients. FUT8 and neurofilament light chain (NfL) levels were measured using enzyme-linked immunosorbent assays (ELISA). We analyzed the correlations between serum FUT8 levels, NfL, and early symptoms of PD using Spearman's correlation, multiple linear regression, and logistic regression models. The expression of FUT8 in CSF samples from PD patients was significantly upregulated, with its protein levels in CSF being positively associated with serum levels. Furthermore, there were significant positive associations between serum FUT8 levels with NfL levels, smell dysfunction, short sleep duration, and long sleep duration. However, a significant inverse relationship was observed between FUT8 levels and MMSE scores. Additionally, we explored gender and age differences in the correlations of FUT8 levels and early symptoms in patients. This study reveals that increased FUT8 levels are positively correlated with a higher risk of early PD-associated symptoms. These findings suggest that serum FUT8 could serve as a promising biomarker for the early detection of PD.

An adaptive predefined time sliding mode control for uncertain nonlinear cyber-physical servo system under cyber attacks.

Malicious attacks are often inevitable in cyber-physical systems (CPS). Accuracy in Cyber physical system for position tracking of servos is the major concern now a days. In high precision industrial automation, it is very hard to achieve accuracy in tracking especially under malicious cyber-attacks, control saturations, parametric perturbations and external disturbances. In this paper, we have designed a novel predefined time (PDT) convergence sliding mode adaptive controller (PTCSMAC) for such kind of cyber physical control system. Main key feature of our control is to cope these challenges that are posed by CPS systems such as parameter perturbation, control saturation, and cyber-attacks and the whole system then upgrade to a third-order system to facilitate adaptive control law. Then, we present an adaptive controller based on the novel PDT convergent sliding mode surface (SMS) combined with a modified weight updated Extreme Learning Machine (ELM) which is used to approximate the uncertain part of the system. Another significant advantage of our proposed control approach is that it does not require detailed model information, guaranteeing robust performance even when the system model is uncertain. Additionally, our proposed PTCSMAC controller is nonsingular regardless of initial conditions, and is capable of eradicating the possibility of singularity problems, which are frequently a concern in numerous CPS control systems. Finally, we have verified our designed PTCSMAC control law through rigorous simulations on CPS seeker servo positioning system and compared the robustness and performance of different existing techniques.

Design and analysis of ELM-based predefined time sliding mode adaptive controller for PMLM position control under physical constraints.

Achieving accurate position tracking for robotics and industrial servo systems is an extremely challenging task, particularly when dealing with control saturation, parameter perturbation, and external disturbance. To address these challenges, a predefined time convergent sliding mode adaptive controller (PTCSMAC) has been proposed for a permanent magnet linear motor (PMLM). A novel sliding mode surface (SMS) with predefined time convergence PDTC has been constructed, which ensures that the error converges to zero within the prescribed time. The system not only meets the expected performance standards but also has a uniformly bounded motor speed. The trajectory tracking error in SMS is proven to converge to zero within the predefined time. This predefined time stability of the closed-loop system has been demonstrated by using the Lyapunov stability criterion with PDTC. The convergence time (CT) can be arbitrarily set, and the upper bound of it is not affected by the initial value and control parameters of the system. A new updated version of extreme learning machine (ELM) is introduced to approximate the uncertain part of the system based on PDTC. The ELM is also provided with the hyperbolic tangent function to estimate the saturation constraint. This is done by converting the function into a linear function concerning the unconstrained control input variable. Then, based on established stability, a novel sliding mode adaptive controller (PTCSMAC) with predefined time convergence is designed. The convergence time (CT) of the controller is unaffected by the initial conditions as well as the control parameters. The rigorous numerical simulations on the PMLM model with complex disturbances verify the strong robustness and high-precision tracking characteristic of the proposed control law.

Compounds from Agathis dammara exert hypoglycaemic activity by enhancing glucose uptake: lignans, terpenes and others.

In this study, two new kaurane diterpenes (16, 17), together with 12 lignans (1-12), a triterpene (15), and two other compounds (13, 14) were isolated from the woods of Agathis dammara. The structure of the new compound was determined by HR ESIMS and 1D/2D NMR spectroscopy, and its absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. Compounds 5, 11, 14 exhibit significant hypoglycaemic activity in zebrafish, and their mechanism of action is to enhance glucose uptake in zebrafish.

Gigahertz electromagnetic pulse emission from femtosecond relativistic laser-irradiated solid targets.

The interactions between high-intensity laser and matter produce particle flux and electromagnetic radiation over a wide energy range. The generation of extremely intense transient fields in the radio frequency-microwave regime has been observed in femtosecond-to-nanosecond laser pulses with 1011-1020-W/cm2 intensity on both conductive and dielectric targets. These fields typically cause saturation and damage to electronic equipment inside and near an experimental chamber; nevertheless, they can also be effectively used as diagnostic tools. Accordingly, the characterization of electromagnetic pulses (EMPs) is extremely important and currently a popular topic for present and future laser facilities intended for laser-matter interaction. The picosecond and sub-picosecond laser pulses are considerably shorter than the characteristic electron discharge time (∼0.1 ns) and can be efficient in generating GHz EMPs. The EMP characterization study of femtosecond laser-driven solid targets is currently mainly in the order of 100 mJ laser energy, in this study, the EMP generated by intense (Joule class) femtosecond laser irradiation of solid targets has been measured as a function of laser energy, laser pulse duration, focal spot size, and target materials. And a maximum electric field of the EMP reaching up to 105 V/m was measured. Analyses of experimental results confirm a direct correlation between measured EMP energy and laser parameters in the ultrashort pulse duration regime. The EMP signals generated by femtosecond laser irradiation of solid targets mainly originate from the return current inside the target after hot electron excitation. Numerical simulations of EMP are performed according to the target charging model, which agree well with the experimental results.

Guided Online Mindfulness-Based Intervention for Community Residents with Emotional Distress during the COVID-19 Pandemic.

This study aimed to assess the efficacy of a guided online mindfulness-based intervention (iMBI) for community residents experiencing emotional distress during the COVID-19 pandemic in Hong Kong. In a randomized controlled trial, 64 participants were recruited from collaborating community-based mental health service units in Hong Kong and assigned to either the treatment (n = 32) or control (n = 32) groups. The treatment group received a guided iMBI consisting of 16 online modules, weekly telephone counseling, and two half-day online workshops on mindfulness practice. In contrast, the waitlist control group did not receive any intervention during the initial stage. Using a 2 (two groups) × time (pre versus post) repeated measures linear mixed model and one-way analysis of variance, authors demonstrated that the treatment group experienced a significantly larger reduction in anxiety and depressive symptoms with a large effect size compared with the control group. Additionally, the treatment group showed a significantly greater improvement in mindfulness with a moderate effect size. The findings support the effectiveness of guided iMBI for community residents experiencing emotional distress during the COVID-19 pandemic in Hong Kong.

MRI economics: Balancing sample size and scan duration in brain wide association studies.

A pervasive dilemma in neuroimaging is whether to prioritize sample size or scan duration given fixed resources. Here, we systematically investigate this trade-off in the context of brain-wide association studies (BWAS) using resting-state functional magnetic resonance imaging (fMRI). We find that total scan duration (sample size × scan duration per participant) robustly explains individual-level phenotypic prediction accuracy via a logarithmic model, suggesting that sample size and scan duration are broadly interchangeable. The returns of scan duration eventually diminish relative to sample size, which we explain with principled theoretical derivations. When accounting for fixed costs associated with each participant (e.g., recruitment, non-imaging measures), we find that prediction accuracy in small-scale BWAS might benefit from much longer scan durations (>50 min) than typically assumed. Most existing large-scale studies might also have benefited from smaller sample sizes with longer scan durations. Both logarithmic and theoretical models of the relationships among sample size, scan duration and prediction accuracy explain well-predicted phenotypes better than poorly-predicted phenotypes. The logarithmic and theoretical models are also undermined by individual differences in brain states. These results replicate across phenotypic domains (e.g., cognition and mental health) from two large-scale datasets with different algorithms and metrics. Overall, our study emphasizes the importance of scan time, which is ignored in standard power calculations. Standard power calculations inevitably maximize sample size at the expense of scan duration. The resulting prediction accuracies are likely lower than would be produced with alternate designs, thus impeding scientific discovery. Our empirically informed reference is available for future study design: WEB_APPLICATION_LINK.

[Distribution Characteristics of Arsenic in Drinking Water in China and Its Health Risk Based on Disability-adjusted Life Years].

Long-term exposure to arsenic can lead to functional damage to many organs and can be life-threatening. It is of great significance to analyze the distribution characteristics of arsenic in water and evaluate its potential risk for preventing and controlling human health hazards caused by water-derived arsenic. Based on the published data from 2000 to 2022, the geographical distribution characteristics of arsenic in drinking water across China were systematically analyzed in detail, and the health risk of arsenic in drinking water was quantitatively assessed using disability-adjusted life years (DALYs), which represent the burden of disease. The results showed that the average concentration of arsenic in drinking water in China was (2.88 ±0.33) µg·L-1, which was lower than the limit of 10 µg·L-1 set by the standard for drinking water quality (GB 5749-2022). Nevertheless, the arsenic in drinking water in some provinces, including Shanxi, Inner Mongolia, and Ningxia, was still higher than the limit. The arsenic concentration in drinking water in northern China was higher than that in southern China, and that in rural areas was higher than that in cities. The estimated health risk of arsenic in drinking water (1.63×10-6 DALYs per person-year) was higher than the acceptable risk level of waterborne exposure of 1.0×10-6 DALYs per person-year set by the World Health Organization. The personal health risks related to arsenic in drinking water in the six geographical regions were ranked as follows:North China > Northeast China > Central South China > Northwest China > Southwest China > East China. Almost all (99.4%) of the health burden associated with water arsenic was attributable to skin and lung cancer, which caused 2 905.25 and 1 513.96 DALYs per year, respectively. Most (78.0%) of the health burden was borne by people aged 45 years or older. In addition, given the proportion of each age group in the total population, older persons over the age of 60 bear a higher drinking-water-associated arsenic burden at the individual level than others, and attention should be consequently paid to them when controlling the risk of arsenic in water.

Impacts of polypropylene microplastics on the distribution of cadmium, enzyme activities, and bacterial community in black soil at the aggregate level.

Microplastics (MPs) can co-occur widely with heavy metals in soil. This study intended to investigate the influences of the co-exposure of polyethylene MPs (0.5 %, w/w) and cadmium (Cd) in black soil on the Cd distribution, enzyme activities, and bacterial communities in both bulk soil and different sized soil aggregates (> 1, 0.50-1, 0.25-0.50, and < 0.25 mm aggregates) after a 90-day incubation. Our results showed that the existence of MPs increased the distributions of Cd in >1 mm and < 0.25 mm soil aggregates and decreased its distributions in 0.50-1 mm and 0.25-0.50 mm soil aggregates. About 12.15 %-17.65 % and 9.03 %-11.13 % of Cd were distributed in the exchangeable and oxidizable forms in bulk soil and various sized soil aggregates after the addition of MPs which were higher than those in the only Cd-treated soil (11.17 %-14.72 % and 8.66 %-10.43 %, respectively), while opposite tendency was found for Cd in the reducible form. Urease and ß-glucosidase activities in the Cd-treated soils were 1.14-1.18 and 1.07-1.31 times higher than those in the Cd-MPs treated soils. MPs disturbed soil bacterial community at phylum level and increased the bacteria richness in bulk soil. The levels of predicted functional genes which are linked to the biodegradation and metabolism of exogenous substances and soil C and N cycles were altered by the co-exposure of Cd and MPs. The findings of this study could help deepen our knowledge about the responses of soil properties, especially microbial community, to the co-occurrence of MPs and heavy metals in soil.

Prediction of positive pulmonary nodules based on machine learning algorithm combined with central carbon metabolism data.

BACKGROUND: Lung cancer causes a huge disease burden, and early detection of positive pulmonary nodules (PPNs) as an early sign of lung cancer is extremely important for effective intervention. It is necessary to develop PPNs risk recognizer based on machine learning algorithm combined with central carbon metabolomics. METHODS: The study included 2248 participants at high risk for lung cancer from the Ma'anshan Community Lung Cancer Screening cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) was used to screen 18 central carbon-related metabolites in plasma, recursive feature elimination (RFE) was used to select all 42 features, followed by five machine learning algorithms for model development. The performance of the model was evaluated using area under the receiver operator characteristic curve (AUC), accuracy, precision, recall, and F1 scores. In addition, SHapley Additive exPlanations (SHAP) was performed to assess the interpretability of the final selected model and to gain insight into the impact of features on the predicted results. RESULTS: Finally, the two prediction models based on the random forest (RF) algorithm performed best, with AUC values of 0.87 and 0.83, respectively, better than other models. We found that homogentisic acid, fumaric acid, maleic acid, hippuric acid, gluconic acid, and succinic acid played a significant role in both PPNs prediction model and NPNs vs PPNs model, while 2-oxadipic acid only played a role in the former model and phosphopyruvate only played a role in the NPNs vs PPNs model. This model demonstrates the potential of central carbon metabolism for PPNs risk prediction and identification. CONCLUSION: We developed a series of predictive models for PPNs, which can help in the early detection of PPNs and thus reduce the risk of lung cancer.

Lipid characteristics of lung tissue in silicosis rat model were studied based on lipid metabolomics.

Silicosis is a common occupational disease caused by the long-term inhalation of large amounts of silica dust. Lipid metabolism plays an important role in the progression of silicosis, but its contributing mechanism remains unclear. The aim of this study was to investigate the differential lipid metabolites and active metabolic pathways in silicosis rat lung tissue. We first constructed a silicosis rat model, and randomly divided 24 male SD rats into control group (C), silicosis group for 1 week (S1W), silicosis group for 2 weeks (S2W) and silicosis group for 4 weeks (S4W) with 6 rats in each group. 1 mL SiO2 suspension (50 mg/mL) or normal saline were injected into the trachea, and the rats were killed at 1 week, 2 weeks and 4 weeks, respectively. The lung tissue pathology of the rats was observed by HE staining and VG staining, and the plasma TC and FC levels were detected by the kit. Western blot was used to detect the expression of lipid-related factors CD36, PGC1α and LXR. In addition, lipidomics analysis of lung tissue samples was performed using UPLC-IMS-QTOF mass spectrometer to screen out potential differential metabolites in silicosis models and analyze lipid enrichment, and verified the expression of differential gene CHPT1 in the metabolic pathway. HE and VG staining showed that the number of nodules and fibrosis increased in a time-dependent manner in the silicosis model group, and the levels of TC, FC and CE in silicosis plasma increased. Western blot results showed that PGC1α and LXR decreased in the silicosis model group, while CD36 expression increased. In addition, metabolomics screened out 28 differential metabolites in the S1W group, 32 in the S2W group, and 22 in the S4W group, and found that the differential metabolites were mainly enriched in metabolic pathways such as glycerophospholipid metabolism and ether lipid metabolism, and the expression of differential gene CHPT1 in the metabolic pathway was decreased in the silicosis model group. These results suggest that there are significant changes in lipid metabolites in lung tissue in silicosis rat models, and glycerophospholipid metabolism was significantly enriched, suggesting that glycerophospholipids play an important role in the progression of silicosis. The differential metabolites and pathways reported in this study may provide new ideas for the pathogenesis of silicosis.

Targeted metabolomics reveals the association between central carbon metabolism and pulmonary nodules.

With the widespread application of low-dose computed tomography (LDCT) technology, pulmonary nodules have aroused more attention. Significant alteration in plasma metabolite levels, mainly amino acid and lipid, have been observed in patients of PNs. However, evidence on the association between central carbon metabolism and PNs are largely unknown. The aim of this study was to investigate the underlying association of PNs and plasma central carbon metabolites. We measured the levels of 16 plasma central carbon metabolites in 1954 participants who gained LDCT screening in MALSC cohort. The inverse probability weighting (IPW) technique was used to control for bias due to self-selection for LDCT in the assessed high-risk population. The least absolute shrinkage and selection operator (LASSO) penalized regression was used to deal with the problem of multicollinearity among metabolites and the combined association of central carbon metabolites with PNs was estimated by using quantile g-computation (QgC) models. A quartile increase in 3-hydroxybutyric acid, gluconic acid, succinic acid and hippuric acid was positively associated with the PNs risk, whereas a quartile increase in 2-oxadipic acid and fumaric acid was negatively associated with the risk of PNs in multiple-metabolite models. A positive but insignificant joint associations of the mixture of 16 metabolites with PNs was observed by using QgC models analyses. Further studies are warranted to clarify the association between circulating metabolites and PNs and the biological mechanisms.

Oleanolic acid derivative alleviates cardiac fibrosis through inhibiting PTP1B activity and regulating AMPK/TGF-ß/Smads pathway.

Cardiac fibrosis (CF) in response to persistent exogenous stimuli or myocardial injury results in cardiovascular diseases (CVDs). Protein tyrosine phosphatase 1B (PTP1B) can promote collagen deposition through regulating AMPK/TGF-ß/Smads signaling pathway, and PTP1B knockout improves cardiac dysfunction against overload-induced heart failure. Oleanolic acid (OA) has been proven to be an inhibitor of PTP1B, and its anti-cardiac remodeling effects have been validated in different mouse models. To improve the bioactivity of OA and to clarify whether OA derivatives with stronger inhibition of PTP1B activity have greater prevention of cardiac remodeling than OA, four new OA derivatives were synthesized and among them, we found that compound B had better effects than OA in inhibiting cardiac fibrosis both in vivo in the isoproterenol (ISO)-induced mouse cardiac fibrosis and in vitro in the TGF-ß/ISO-induced 3T3 cells. Combining with the results of molecular docking, surface plasmon resonance and PTP1B activity assay, we reported that OA and compound B directly bound to PTP1B and inhibited its activity, and that compound B showed comparable binding capability but stronger inhibitory effect on PTP1B activity than OA. Moreover, compound B presented much greater effects on AMPK activation and TGF-ß/Smads inhibition than OA. Taken together, OA derivative compound B more significantly alleviated cardiac fibrosis than OA through much greater inhibition of PTP1B activity and thus much stronger regulation of AMPK/TGF-ß/Smads signaling pathway.