Structural and Property Characterizations of Dual-Responsive Core-Shell Tecto Dendrimers for Tumor Penetration and Gene Delivery Applications.

Core-shell tecto dendrimers (CSTDs) with excellent physicochemical properties and good tumor penetration and gene transfection efficiency have been demonstrated to have the potential to replace high-generation dendrimers in biomedical applications. However, their characterization and related biological properties of CSTDs for enhanced tumor penetration and gene delivery still lack in-depth investigation. Herein, three types of dual-responsive CSTDs are designed for thorough physicochemical characterization and investigation of their tumor penetration and gene delivery efficiency. Three types of CSTDs are prepared through phenylborate ester bonds of phenylboronic acid (PBA)-decorated generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers as cores and monose (galactose, glucose, or mannose)-conjugated G3 PAMAM dendrimers as shells and thoroughly characterized via NMR and other techniques. It is shown that the produced CSTDs display strong correlation signals between the PBA and monose protons, similar hydrodynamic diameters, and dual reactive oxygen species- and pH-responsivenesses. The dual-responsive CSTDs are proven to have structure-dependent tumor penetration property and gene delivery efficiency in terms of small interference RNA for gene silencing and plasmid DNA for gene editing, thus revealing a great potential for different biomedical applications.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Machine learning models for early prediction of potassium lowering effectiveness and adverse events in patients with hyperkalemia.

The aim of this study was to develop a model for early prediction of adverse events and treatment effectiveness in patients with hyperkalemia. We collected clinical data from patients with hyperkalemia in the First Hospital of Zhejiang University School of Medicine between 2015 and 2021. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to analyze the predictors on the full dataset. We randomly divided the data into a training group and a validation group, and used LASSO to filter variables in the training set. Six machine learning methods were used to develop the models. The best model was selected based on the area under the curve (AUC). Shapley additive exPlanations (SHAP) values were used to explain the best model. A total of 1074 patients with hyperkalemia were finally enrolled. Diastolic blood pressure (DBP), breathing, oxygen saturation (SPO2), Glasgow coma score (GCS), liver disease, oliguria, blood sodium, international standardized ratio (ISR), and initial blood potassium were the predictors of the occurrence of adverse events; peripheral edema, estimated glomerular filtration rate (eGFR), blood sodium, actual base residual, and initial blood potassium were the predictors of therapeutic effect. Extreme gradient boosting (XGBoost) model achieved the best performance (adverse events: AUC = 0.87; therapeutic effect: AUC = 0.75). A model based on clinical characteristics was developed and validated with good performance.

The clinical trajectory of peripheral blood immune cell subsets, T-cell activation, and cytokines in septic patients.

OBJECTIVE AND DESIGN: Changes in the immune status of patients with sepsis may have a major impact on their prognosis. Our research focused on changes in various immune cell subsets and T-cell activation during the progression of sepsis. METHODS AND SUBJECTS: We collected data from 188 sepsis patients at the First Affiliated Hospital of Zhejiang University School of Medicine. The main focus was on the patient's immunocyte subset typing, T-cell activation/Treg cell analysis, and cytokine assay, which can indicate the immune status of the patient. RESULTS: The study found that the number of CD4+ T cells, CD8+ T cells, NK cells, and B cells decreased early in the disease, and the decrease in CD4+ and CD8+ T cells was more pronounced in the death group. T lymphocyte activation was inhibited, and the number of Treg cells increased as the disease progressed. T lymphocyte inhibition was more significant in the death group, and the increase in IL-10 was more significant in the death group. Finally, we used patients' baseline conditions and immunological detection indicators for modeling and found that IL-10, CD4+ Treg cells, CD3+HLA-DR+ T cells, and CD3+CD69+ T cells could predict patients' prognosis well. CONCLUSION: Our study found that immunosuppression occurs in patients early in sepsis. Early monitoring of the patient's immune status may provide a timely warning of the disease.

Evaluation of New Folate Receptor-mediated Mitoxantrone Targeting Liposomes In Vitro.

Background: Ligand-mediated liposomes targeting folate receptors (FRs) that are overexpressed on the surface of tumor cells may improve drug delivery. However, the properties of liposomes also affect cellular uptake and drug release.

Objective: Mitoxantrone folate targeted liposomes were prepared to increase the enrichment of drugs in tumor cells and improve the therapeutic index of drugs by changing the route of drug administration.

Methods: Liposomes were prepared with optimized formulation, including mitoxantrone folatetargeted small unilamellar liposome (MIT-FSL), mitoxantrone folate-free small unilamellar liposome (MIT-SL), mitoxantrone folate-targeted large unilamellar liposome (MIT-FLL), mitoxantrone folate-free large unilamellar liposomes (MIT-LL). Cells with different levels of folate alpha receptor (FRα) expression were used to study the differences in the enrichment of liposomes, the killing effect on tumor cells, and their ability to overcome multidrug resistance.

The results of the drug release experiment showed that the particle size of liposomes affected their release behavior. Large single-compartment liposomes could hardly be effectively released, while small single-compartment liposomes could be effectively released, MIT-FSL vs MIT-FLL and MIT-SL vs MIT-LL had significant differences in the drug release rate (P<0.0005). Cell uptake experiments results indicated that the ability of liposomes to enter folic acid receptor-expressing tumor cells could be improved after modification of folic acid ligands on the surface of liposomes and it was related to the expression of folate receptors on the cell surface. There were significant differences in cell uptake rates (p<0.0005) for cells with high FRα expression (SPC-A-1 cells), when MIT-FSL vs MIT-SL and MIT-FLL vs MIT-LL. For cells with low FRα expression (MCF-7 cells), their cell uptake rates were still different (p<0.05), but less pronounced than in SPC-A-1 cells. The results of the cell inhibition experiment suggest that MIT-FLL and MIT-LL had no inhibitory effect on cells, MIT-FSL had a significant inhibitory effect on cells and its IC50 value was calculated to be 4502.4 ng/mL, MIT-SL also had an inhibitory effect, and its IC50 value was 25092.1 ng/mL, there was a statistical difference (p<0.05), MIT-FSL had a higher inhibitory rate than MIT-SL at the same drug concentration. Afterward, we did an inhibitory experiment of different MIT-loaded nanoparticles on MCF-7 cells compared to the drug-resistant cells (ADR), Observing the cell growth inhibition curve, both MIT-FSL and MIT-SL can inhibit the growth of MCF-7 and MCF-7/ADR cells. For MCF- 7 cells, at the same concentration, there is little difference between the inhibition rate of MITFSL and MIT-SL, but for MCF-7/ADR, the inhibition rate of MIT-FSL was significantly higher than that of MIT-SL at the same concentration (P<0.05).

Conclusion: By modifying folic acid on the surface of liposomes, tumor cells with high expression of folic acid receptors can be effectively targeted, thereby increasing the enrichment of intracellular drugs and improving efficacy. It can also change the delivery pathway, increase the amount of drug entering resistant tumor cells, and overcome resistance.

Study on the dynamic effects of plateau hypoxic and cold environment on the thermal adaptation of short-term sojourners in Xizang.

The plateau hypoxic environment can affect the thermoregulation process of the human body, and due to the different acclimatization ability to the hypoxic environment, the thermal requirements among the people who enter Xizang at different times may be different. Accordingly, this study aims to clarify how plateau hypoxic environments influence the physiological and subjective responses of people entering Xizang at different times. And field experiments were conducted in Xi'an and Lhasa, respectively, to compare the thermal responses and oxygen responses of the subjects under different temperature conditions on the plain, the first day of entering Xizang and the 15th day of entering Xizang. The results showed that under the hypoxic environment, the thermal sensation of the subjects decreased. With the extension of the time entering Xizang, the influence of the hypoxic environment on thermal comfort was gradually weakened, but under the low temperature environment, the effect of hypoxia on thermal response was not significantly reduced. The results of this study can help to reveal how plateau hypoxic environments affect human thermal comfort and provide a theoretical basis for the design of indoor thermal environment parameters suitable for sojourners entering Xizang at different times.

Hydroxycitric Acid Alleviated Lung Ischemia-Reperfusion Injury by Inhibiting Oxidative Stress and Ferroptosis through the Hif-1α Pathway.

Lung ischemia-reperfusion injury (LIRI) is a prevalent occurrence in various pulmonary diseases and surgical procedures, including lung resections and transplantation. LIRI can result in systemic hypoxemia and multi-organ failure. Hydroxycitric acid (HCA), the primary acid present in the peel of Garcinia cambogia, exhibits anti-inflammatory, antioxidant, and anticancer properties. However, the effects of HCA on LIRI remain unknown. To investigate the impact of HCA on LIRI in mice, the mice were randomly divided into four groups: the control group, the I/R model group, and the I/R + low- or high-dose HCA groups. Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia for 12 h followed by reoxygenation for 6 h to simulate in vitro LIRI. The results demonstrated that administration of HCA effectively attenuated lung injury, inflammation, and edema induced by ischemia reperfusion. Moreover, HCA treatment significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels while decreasing iron content and increasing superoxide dismutase (SOD) levels after ischemia-reperfusion insult. Mechanistically, HCA administration significantly inhibited Hif-1α and HO-1 upregulation both in vivo and in vitro. We found that HCA could also alleviate endothelial barrier damage in H/R-induced HUVECs in a concentration-dependent manner. In addition, overexpression of Hif-1α counteracted HCA-mediated inhibition of H/R-induced endothelial cell ferroptosis. In summary, these results indicate that HCA alleviated LIRI by inhibiting oxidative stress and ferroptosis through the Hif-1α pathway.

[Characterization of a D-mannitol oxidase from Paenibacillus sp. and its application in the preparation of D-mannose].

D-mannose has many functional activities and is widely used in food, medicine, agriculture and other industries. D-mannitol oxidase that can efficiently convert D-mannitol into D-mannose has potential application in the enzymatic preparation of D-mannose. A D-mannitol oxidase (PsOX) was found from Paenibacillus sp. HGF5. The similarity between PsOX and the D-mannitol oxidase (AldO) from Streptomyces coelicolor was 50.94%. The molecular weight of PsOX was about 47.4 kDa. A recombinant expression plasmid pET-28a-PsOX was constructed and expressed in Escherichia coli BL21(DE3). The Km and kcat/Km values of PsOX for D-mannitol were 5.6 mmol/L and 0.68 L/(s·mmol). Further characterization of PsOX showed its optimal pH and temperature were 7.0 and 35 ℃, respectively, while its enzyme activity could be stably remained below 60 ℃. The molar conversion rate of 400 mmol/L D-mannitol by PsOX was 95.2%. The whole cells of PsOX and AldO were used to catalyze 73 g/L D-mannitol respectively. The reaction catalyzed by PsOX completed in 9 h and 70 g/L D-mannose was produced. PsOX showed a higher catalytic efficiency compared to that of AldO. PsOX may facilitate the enzymatic preparation of D-mannose as a novel D-mannose oxidase.

Multifunctional Proximity Labeling Strategy for Lipid Raft-Specific Sialic Acid Tracking and Engineering.

Lipid raft-specific glycosylation has been implicated in many biological processes, including intracellular trafficking, cell adhesion, signal transduction, and host-pathogen interactions. The major predicament in lipid raft-specific glycosylation research is the unavailability of tools for tracking and manipulating glycans on lipid rafts at the microstructural level. To overcome this challenge, we developed a multifunctional proximity labeling (MPL) platform that relies on cholera toxin B subunit to localize horseradish peroxidase on lipid rafts. In addition to the prevailing electron-rich amino acids, modified sialic acid was included in the horseradish peroxidase-mediated proximity labeling substrate via purposefully designed chemical transformation reactions. In combination with sialic acid editing, the self-renewal of lipid raft-specific sialic acid was visualized. The MPL method enabled tracking of lipid raft dynamics under methyl-ß-cyclodextrin and mevinolin treatments; in particular, the alteration of lipid rafts markedly affected cell migration. Furthermore, we embedded functional molecules into the method and implemented raft-specific sialic acid gradient engineering. Our novel strategy presents opportunities for tailoring lipid raft-specific sialic acids, thereby regulating interactions associated with lipid raft regions (such as cell-virus and cell-microenvironment interactions), and can aid in the development of lipid raft-based therapeutic regimens for tumors.

Oxygen comfort evaluation method based on symptom index for short-term internal migrants to Tibet.

In Tibet, the hypobaric-hypoxic environment found at high altitudes leads to dysfunction in short-term internal migrants and has noticeable effects on physiology, psychological health, and comfort level. Therefore, it is essential to accurately determine the degree of hypoxia and improve the hypoxic environment of plateaus. Despite advances in the medical diagnosis and treatment of pathological hypoxic injuries, there are some limitations in the oxygenic evaluation of internal migrants with mild hypoxia. An oxygen comfort evaluation method (OCEM) based on typical anoxic symptomatology and physiological indices is proposed in this study. Experiments with different oxygen concentrations were conducted to measure anoxic symptomatology and physiological indices. Using item and exploratory factor analyses, 19 symptom indices were screened to predict oxygen sensation in humans. Finally, the OCEM was established using an artificial neural network and fuzzy mathematics method and its accuracy was verified through a field survey. The results showed that the artificial neural network model using symptomatologic indices could predict human oxygen sensation, with an area under the receiver operating characteristic curve of 0.630-0.913 and prediction accuracy of 93 %. Oxygen comfort can be predicted from the oxygen sensation and typical physiological indices using the fuzzy mathematics method; the weighted kappa coefficient was 0.825, indicating a strong correlation between the predicted and actual values. The proposed OCEM can help determine the oxygen comfort conditions of high-altitude internal migrants and provide a basis for indoor oxygen environment regulation in high-altitude buildings.

Diffusible signal factor primes plant immunity against Xanthomonas campestris pv. campestris (Xcc) via JA signaling in Arabidopsis and Brassica oleracea.

Background: Many Gram-negative bacteria use quorum sensing (QS) signal molecules to monitor their local population density and to coordinate their collective behaviors. The diffusible signal factor (DSF) family represents an intriguing type of QS signal to mediate intraspecies and interspecies communication. Recently, accumulating evidence demonstrates the role of DSF in mediating inter-kingdom communication between DSF-producing bacteria and plants. However, the regulatory mechanism of DSF during the Xanthomonas-plant interactions remain unclear. Methods: Plants were pretreated with different concentration of DSF and subsequent inoculated with pathogen Xanthomonas campestris pv. campestris (Xcc). Pathogenicity, phynotypic analysis, transcriptome combined with metabolome analysis, genetic analysis and gene expression analysis were used to evaluate the priming effects of DSF on plant disease resistance. Results: We found that the low concentration of DSF could prime plant immunity against Xcc in both Brassica oleracea and Arabidopsis thaliana. Pretreatment with DSF and subsequent pathogen invasion triggered an augmented burst of ROS by DCFH-DA and DAB staining. CAT application could attenuate the level of ROS induced by DSF. The expression of RBOHD and RBOHF were up-regulated and the activities of antioxidases POD increased after DSF treatment followed by Xcc inoculation. Transcriptome combined with metabolome analysis showed that plant hormone jasmonic acid (JA) signaling involved in DSF-primed resistance to Xcc in Arabidopsis. The expression of JA synthesis genes (AOC2, AOS, LOX2, OPR3 and JAR1), transportor gene (JAT1), regulator genes (JAZ1 and MYC2) and responsive genes (VSP2, PDF1.2 and Thi2.1) were up-regulated significantly by DSF upon Xcc challenge. The primed effects were not observed in JA relevant mutant coi1-1 and jar1-1. Conclusion: These results indicated that DSF-primed resistance against Xcc was dependent on the JA pathway. Our findings advanced the understanding of QS signal-mediated communication and provide a new strategy for the control of black rot in Brassica oleracea.

Assessment of pulmonary fibrosis induced by paraquat using Al18F-NODA-FAPI-04 PET/CT.

The lack of a highly sensitive method to evaluate paraquat (PQ)-induced pulmonary fibrosis and predict disease progression remains an unresolved clinic issue. Fibroblast activation protein (FAP) may play an important role in the pathogenesis of PQ-induced pulmonary fibrosis. We aimed to evaluate the role of FAP in the PQ-induced pulmonary fibrosis and the utility of fibroblast activation protein inhibitor (FAPI) for positron emission tomography (PET) imaging in PQ-induced pulmonary fibrosis. In our study, two cases of PQ poisoning were presented and FAPI PET/CT was performed as a novel imaging technique. The uptake of FAPI increased in both cases of PQ poisoning. Animal experiments were then performed to validate the findings in the patients. Physiological FAPI lung uptake was higher in mice of the PQ group than in the control group. The results of histological analysis and Western blot were consistent with the findings of PET/CT imaging. The pulmonary fibrosis animal model was developed by intragastric gavage of PQ. PET/CT imaging was performed after injection of FAPI. Lung tissues of mice were collected for fibrosis assessment after imaging. Immunohistochemistry for FAP, histology and Western blot for collagen were performed to further validate the imaging findings. In conclusion, FAPI was involved in the pathogenesis of fibrosis induced by PQ, and PET/CT with FAPI could detect lung fibrogenesis, making it a promising tool to assess early disease activity and predict disease progression.

Development and validation of a predictive model for the assessment of potassium-lowering treatment among hyperkalemia patients.

BACKGROUND: Hyperkalemia is common among patients in emergency department and is associated with mortality. While, there is a lack of good evaluation and prediction methods for the efficacy of potassium-lowering treatment, making the drug dosage adjustment quite difficult. We aimed to develop a predictive model to provide early forecasting of treating effects for hyperkalemia patients. METHODS: Around 80% of hyperkalemia patients (n=818) were randomly selected as the training dataset and the remaining 20% (n=196) as the validating dataset. According to the serum potassium (K+) levels after the first round of potassium-lowering treatment, patients were classified into the effective and ineffective groups. Multivariate logistic regression analyses were performed to develop a prediction model. The receiver operating characteristic (ROC) curve and calibration curve analysis were used for model validation. RESULTS: In the training dataset, 429 patients had favorable effects after treatment (effective group), and 389 had poor therapeutic outcomes (ineffective group). Patients in the ineffective group had a higher percentage of renal disease (P=0.007), peripheral edema (P<0.001), oliguria (P=0.001), or higher initial serum K+ level (P<0.001). The percentage of insulin usage was higher in the effective group than in the ineffective group (P=0.005). After multivariate logistic regression analysis, we found age, peripheral edema, oliguria, history of kidney transplantation, end-stage renal disease, insulin, and initial serum K+ were all independently associated with favorable treatment effects. CONCLUSION: The predictive model could provide early forecasting of therapeutic outcomes for hyperkalemia patients after drug treatment, which could help clinicians to identify hyperkalemia patients with high risk and adjust the dosage of medication for potassium-lowering.

Core-shell tecto dendrimer-mediated cooperative chemoimmunotherapy of breast cancer.

Development of effective nanomedicines to deal with tumor immunogenicity and immunosuppression is vital to improve the immunotherapy efficacy. Herein, we developed a programmed strategy not only to activate the tumoral immune microenvironment through immunogenic cell death (ICD) effect but also to promote the maturation of dendritic cells (DCs) in lymph nodes through two modules of core-shell tecto dendrimer (CSTD)-based nanomedicines. The CSTDs with amplified tumor enhanced permeability and retention effect and improved gene delivery efficiency were formed by supramolecular self-assembly of generation 5 (G5) poly(amidoamine) dendrimers as cores and G3 dendrimers as shells. One module was employed to load doxorubicin for cancer cell chemotherapy to generate ICD, while the other module with partial surface modification of zwitterions and mannose was used for serum-enhanced YTHDF1 siRNA delivery to DCs to stimulate their maturation. These two modular CSTD-based nanomedicine formulations enable enhanced chemoimmunotherapy of an orthotopic breast tumor model through programmed treatment of cancer cells and DCs, and synergistic modulation of the maturation of DCs to activate the CD8+/CD4+ T cells for tumor killing. The developed CSTD-enabled nanomodules with improved drug/gene delivery performance may be applicable to tackle other cancer types via collaborative chemoimmunotherapy.

Ultrasound-enhanced theranostics of orthotopic breast cancer through a multifunctional core-shell tecto dendrimer-based nanomedicine platform.

Design of multifunctional nanoplatforms combined with ultrasound-targeted microbubble destruction (UTMD) technology for enhanced tumor accumulation is feasible to solve the bottleneck of theranostics. Herein, we present the development of zwitterion-modified gadolinium (Gd)-chelated core-shell tecto dendrimers (CSTDs) as a nanomedicine platform (PCSTD-Gd) for enhanced magnetic resonance (MR) imaging-guided chemo-gene therapy of orthotopic breast cancer with the assistance of UTMD. In our design, CSTDs synthesized via supramolecular recognition of ß-cyclodextrin and adamantane were covalently linked with tetraazacyclododecane tetraacetic acid-Gd(III) chelators, modified with 1,3-propane sultone to achieve good protein-resistance property, and used for co-delivery of an microRNA 21 inhibitor (miR 21i) and an anticancer drug doxorubicin (DOX). The overall design is quite advantageous and cooperative. The CSTDs with a greater size than single-generation core dendrimers have amplified the enhanced permeability and retention effect for better passive tumor targeting, with a larger r1 relaxivity for sensitive MR imaging and serum-enhanced gene delivery efficiency due to the better compaction ability as well as the protein resistance ability, and with larger interior space for improved drug loading. Through the unique design and the assistance of UTMD, the obtained PCSTD-Gd/DOX/miR 21i polyplexes enable enhanced MR imaging-guided combined chemo-gene therapy of an orthotopic breast cancer model in vivo.

Dry response and acclimated characteristics of people ascending the Tibetan Plateau.

Due to a long period of low humidity, exposure to the dry environment of the Tibetan Plateau can cause skin and respiratory diseases and threaten human health. To examine the characteristics of acclimatization response to humidity comfort in visitors to the Tibetan Plateau based on an examination of the targeted effect and mechanism of the dry environment. A scale corresponding to local dryness symptoms was proposed. Eight participants were selected to conduct a two-week plateau experiment and a one-week plain experiment under six humidity ratios, respectively, to explore the characteristics of dry response and acclimatization of people entering the plateau. The results indicate that duration has a significant effect on human dry response. On the sixth day after entering Tibet, the degree of dryness reached the maximum, and acclimatization to the plateau environment began on the 12th day. The sensitivity of different body parts to the change in a dry environment was different. When the indoor humidity ratio increased from 9.04 g/kg to 21.77 g/kg, the symptoms of dry skin were most significantly relieved by 0.5 units of scale. After de-acclimatization, the degree of dryness in the eyes was most significantly alleviated, reducing by nearly one scale. The analysis of human symptom indicators in a dry environment shows that subjective and physiological indices are influential and essential in measuring human comfort in a dry environment. This study extends our understanding of dry environment responses and cognition of human comfort and lays a solid foundation for humid built environments in the plateau.

Tripterygium wilfordii Hook.f. ameliorates paraquat-induced lung injury by reducing oxidative stress and ferroptosis via Nrf2/HO-1 pathway.

Paraquat (PQ) poisoning can induce acute lung injury and fibrosis and has an extremely high mortality rate. However, no effective treatments for PQ poisoning have been established. In this study, the potential efficacy of Tripterygium wilfordii Hook.f. (TwHF) in alleviating PQ-induced lung injury and fibrosis was investigated in a mouse model. Mice were randomly assigned to the control, PQ, PQ + TwHF1 (pretreatment before inducing poisoning), and PQ + TwHF2 (treatment after poisoning) groups. The mice in the PQ + TwHF1 group were pretreated with TwHF for 5 days before receiving one dose of PQ (120 mg/kg) and then received a daily oral gavage of the indicated dosages of TwHF until sacrifice. The mice in the PQ + TwHF2 group were treated with TwHF 2 h after PQ exposure until sacrifice. The pathological analysis and Fapi PET/CT showed that treatment with TwHF attenuated lung injury. And TwHF reduced pulmonary oxidative stress, as indicated by the reduction in, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels, as well as by the increase in superoxide dismutase (SOD) levels. Accordingly, the Perls DAB staining showed increased iron concentrations and western blotting revealed a decreased GPX4 expression after PQ exposure, as well as the mitigation of the overexpression of Nrf2 and HO-1 induced by PQ. In conclusion, our study demonstrated the potential of TwHF as a treatment for PQ-induced lung injury and fibrosis. The protective mechanism of this medicinal herb may involve the regulation of ferroptosis.

Defining reference values for body composition indices by magnetic resonance imaging in UK Biobank.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for evaluating body composition. However, the reference ranges have not been established. METHODS: Three lean tissue and seven adipose tissue parameters based on MRI data from the UK Biobank were used in this study. Participants with European ancestry and data on at least one parameter were screened. Age- and sex-specific percentile curves were generated using the lambda-mu-sigma method. Three levels of reference ranges were provided, which were equivalent to the mean ± 1 standard deviation (SD), 2 SDs and 2.5 SDs. RESULTS: The final analysis set for each parameter ranged from 4842 to 14 148 participants (53.4%-56.6% women) with a median age of 61. For lean tissue parameters, compared with those at age 45, the median total lean tissue volume and total thigh fat-free muscle volume at age 70 were 2.83 and 1.73 L, and 3.02 and 1.51 L lower in men and women, respectively. The median weight-to-muscle ratios at age 45 were 0.51 and 0.83 kg/L lower compared with those at age 70 in men and women, respectively. Adipose tissue parameters showed inconsistent differences. In men, the median muscle fat infiltration, visceral adipose tissue (VAT) volume, total abdominal adipose tissue index and abdominal fat ratio were 1.48%, 0.32 L, 0.08 L/m2 and 0.4 higher, and the median abdominal subcutaneous adipose tissue (ASAT) volume and total adipose tissue volume were 0.47 and 0.41 L lower, respectively, at age 70 than at age 45. The median total trunk fat volume was approximately 9.53 L at all ages. In women, the median muscle fat infiltration and VAT volume were 1.68% and 0.76 L higher, respectively, at age 70 than at age 45. The median ASAT volume, total adipose tissue volume, total trunk fat volume, total abdominal adipose tissue index and abdominal fat ratio were 0.35 L, 0.78 L, 1.12 L, 0.49 L/m2 and 0.06 higher, respectively, at age 60 than at age 45. The medians of the former three parameters were 0.33 L, 0.14 L and 0.20 L lower, at age 70 than at age 60. The medians of the latter two parameters were approximately 3.64 L/m2 and 0.55 at ages between 60 and 70. CONCLUSIONS: We have established reference ranges for MRI-measured body composition parameters in a large community-dwelling population. These findings provide a more accurate assessment of abnormal adipose and muscle conditions.

Adult patients with allied disorders of Hirschsprung's disease in emergency department: An 11-year retrospective study.

BACKGROUND: In the past years, only a few studies with a limited number of adult patients analyzed clinical features of allied disorders of Hirschsprung's disease (ADHD), most of which were individual case reports or lacked detailed clinical information. Although many studies have reported patients presenting to the emergency department (ED) with recurrent abdominal symptoms for a number of disorders, there are few data involving ADHD. However, owing to a lack of awareness of the disease, misdiagnoses and mistreatments are common. Severe complications such as perforation, bleeding, malabsorption, and even death in ADHD had been reported by many studies. AIM: To assist ED clinicians in having a more comprehensive understanding of this disease and making an early suspected diagnosis of ADHD more effectively. METHODS: We enrolled 53 patients who visited the ED and were eventually diagnosed with ADHD over the past 11 years in our hospital. Their basic information, clinical manifestations, and imaging findings were analyzed. Blood indices were compared between the ADHD and irritable bowel syndrome (IBS) groups. RESULTS: Adult patients with ADHD had a mean age of 48.8 ± 14.3 years, and 77.4% had been treated before admission. The transverse colon was the most common dilated part (73.6%), and constipation (67.9%) was the most common symptom. ADHD patients can present with uncommon symptoms and false-negative imaging findings. Logistic regression analysis indicated that body mass index (BMI) [odds ratio (OR) = 0.786, P = 0.013], cholinesterase (per 1000 units; OR = 0.693, P = 0.008), and blood chlorine (OR = 0.816, P = 0.022) were determined to be independent related factors between the ADHD and IBS groups. The area under the receiver operating characteristics curve of these three indices combined was 0.812 (P < 0.001). CONCLUSION: Emergency physicians should be vigilant regarding patients with chronic constipation, abdominal pain, or abdominal distension, and consider the possibility of ADHD despite its rarity. Abdominal computed tomography examination is recommended as a useful tool in the suspected diagnosis of ADHD. BMI, cholinesterase, and blood chlorine have good discriminative abilities between ADHD and IBS. The nutritional status of adult patients with ADHD is worthy of further attention. Surgical treatment for adult patients with ADHD is important and inevitable.

The role of protein acetylation in carcinogenesis and targeted drug discovery.

Protein acetylation is a reversible post-translational modification, and is involved in many biological processes in cells, such as transcriptional regulation, DNA damage repair, and energy metabolism, which is an important molecular event and is associated with a wide range of diseases such as cancers. Protein acetylation is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) in homeostasis. The abnormal acetylation level might lead to the occurrence and deterioration of a cancer, and is closely related to various pathophysiological characteristics of a cancer, such as malignant phenotypes, and promotes cancer cells to adapt to tumor microenvironment. Therapeutic modalities targeting protein acetylation are a potential therapeutic strategy. This article discussed the roles of protein acetylation in tumor pathology and therapeutic drugs targeting protein acetylation, which offers the contributions of protein acetylation in clarification of carcinogenesis, and discovery of therapeutic drugs for cancers, and lays the foundation for precision medicine in oncology.