[Occurrence and Risk Assessment of N-nitrosamines and Their Precursors in Qingjiang River Basin].

N-nitrosamines are a type of nitrogen-containing organic pollutant with high carcinogenicity and mutagenicity. In the main drinking water sources of small and medium-sized towns in China, the contamination levels of N-nitrosamines remain unclear. In addition, there is still lack of research on the concentration of N-nitrosamines and their precursors in tributary rivers. In this study, eight N-nitrosamines and their formation potentials （FPs） were investigated in the Qingjiang River, which is a primary tributary of the Yangtze River. The sewage discharge sites were also monitored, and the environmental influencing factors, carcinogenic and ecological risks caused by N-nitrosamines, and their precursors were evaluated. The results showed that six N-nitrosamines were detected in water samples of the Qingjiang River, among which NDMA [（10 ±15） ng·L-1], NDEA [（9.3 ±9.3） ng·L-1], and NDBA [（14 ±7.8） ng·L-1] were the dominant N-nitrosamines, whereas seven N-nitrosamines were detected in chloraminated water samples, among which NDMA-FP [（46 ±21） ng·L-1], NDEA-FP [（26 ±8.3） ng·L-1], and NDBA-FP [（22 ±13） ng·L-1] were the dominant N-nitrosamine FPs. The concentrations of N-nitrosamines in the middle reaches of the Qingjiang River were higher than those in the upper and lower reaches. Furthermore, the concentrations of N-nitrosamines in the sample sites of sewage discharge and tributaries were significantly higher than those in other sampling sites. The monitoring results at the direct sewage discharge points indicated that the main source of N-nitrosamines in river water was the sewage carrying N-nitrosamines and their precursors. In addition, the concentrations of the three dominant N-nitrosamines including NDMA, NDBA, and NDEA were positively correlated with each other, mainly because of their similar sewage sources. The average carcinogenic risk to residents due to N-nitrosamine in drinking water sources was 2.4×10-5, indicating a potential carcinogenic risk. Moreover, due to the high concentrations of N-nitrosamine formation potentials in the Qingjiang River, the carcinogenic risk of drinking water may be even higher. The ecological risk assessment showed that the ecological risk quotient values of N-nitrosamines in the Qingjiang River watershed were lower than 0.002, which was negligible.

Optimizing the Utilization of Steel Slag in Cement-Stabilized Base Layers: Insights from Freeze-Thaw and Fatigue Testing.

This paper presents a study on the mechanical properties of cement-stabilized steel-slag-based materials under freeze-thaw cycles for a highway project in Xinjiang. Using 3D scanning technology the specimen model conforming to the real steel slag shape was established. The objectives of the study are as follows: to explore the sensitivity between the macro- and micro-parameters of the specimen and to establish a non-linear regression equation; and to study the changes in mechanical properties of materials under freeze-thaw cycles, fatigue loading, and coupled freeze-thaw cycle-fatigue loading. The results show that there are three stages of compression damage of the specimen, namely, linear elasticity, peak plasticity, and post-peak decline. Maximum contact forces between cracks and particles occur mainly in the shear zone region within the specimen. The compression damage of the specimen is a mixed tensile-shear damage dominated by shear damage. When freeze-thaw cycles or fatigue loads are applied alone, the flexural strength and fatigue life of the specimens show a linear relationship of decline. The decrease in flexural modulus at low stress is divided into the following: a period of rapid decline, a relatively smooth period, and a period of fracture, with a tendency to change towards linear decay with increasing stress. In the case of freeze-thaw-fatigue coupling, the flexural modulus of the specimen decreases drastically by about 50% in the first 2 years, and then enters a period of steady decrease in flexural modulus in the 3rd-5th years.

Health effect of multiple air pollutant mixture on sarcopenia among middle-aged and older adults in China.

BACKGROUND: As the global aging process accelerates, the health challenges posed by sarcopenia among middle-aged and older adults are becoming increasingly prominent. However, the available evidence on the adverse effects of air pollution on sarcopenia is limited, particularly in the Western Pacific region. This study aimed to explore relationships of multiple air pollutants with sarcopenia and related biomarkers using the nationally representative database. METHODS: Totally, 6585 participants aged over 45 years were enrolled from the China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 3443 of them were followed up until 2015. Air pollutants were estimated from high-resolution satellite-based spatial-temporal models. In the cross-sectional analysis, we used generalized linear regression, unconditional logistic regression analytical and restricted cubic spline (RCS) methods to assess the single-exposure and non-linear effects of multiple air pollutants on sarcopenia and related surrogate biomarkers (serum creatinine and cystatin C). Several popular mixture analysis techniques such as Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression, and quantile-based g-computation (Qgcomp) were further used to examinate the combined effects of multiple air pollutants. Logistic regression was used to further analyze the longitudinal association between air pollution and sarcopenia. RESULTS: Each interquartile range increase in PM2.5, PM10 and NO2 was significantly associated with an increased risk of sarcopenia, with adjusted odds ratios (aORs) of 1.09 [95 % confidence interval (CI): 1.01, 1.20], 1.24 (95 % CI: 1.14, 1.35) and 1.18 (95 % CI: 1.08, 1.28), respectively. Our findings also showed that five air pollutants were significantly associated with the sarcopenia index. In addition, employing a mixture analysis approach, we confirmed significant combined effects of air pollution mixtures on sarcopenia risk and associated biomarkers, with PM10 and PM2.5 identified as major contributors to the combined effect. The results of the exposure-response (E-R) relationships, subgroup analysis, longitudinal analysis and sensitivity analysis all showed the unfavorable impact of air pollution on sarcopenia risk and related vulnerable populations. CONCLUSIONS: Single-exposure and co-exposure to multiple air pollutants were positively associated with sarcopenia among middle-aged and older adults in China. Our study provided new evidence that air pollution mixture was significantly associated with sarcopenia related biomarkers.

Industrial effluents and N-nitrosamines in karst aquatic systems: a study on distribution and ecological implications.

The discharge of electroplating wastewater, containing high concentrations of N-nitrosamines, poses significant risks to human health and aquatic ecosystems. Karst aquatic environment is easily impacted by N-nitrosamines due to the fragile surface ecosystem. However, it's still unclear in understanding N-nitrosamine transformation in karst water systems. To explore the response and transport of nine N-nitrosamines in electroplating effluent within both karst surface water and groundwater, different river and groundwater samples were collected from both the upper and lower reaches of the effluent discharge areas in a typical karst industrial catchment in Southwest China. Results showed that the total average concentrations of N-nitrosamines (∑NAs) in electroplating effluent (1800 ng/L) was significantly higher than that in the receiving river water (130 ng/L) and groundwater (70 ng/L). The dynamic nature of karst aquifers resulted in comparable average concentrations of ∑NAs in groundwater (70 ng/L) and river water (79 ng/L) at this catchment. Based on the principal component analysis and multiple linear regression analysis, the electroplating effluent contributed 89% and 53% of N-nitrosamines to the river water and groundwater, respectively. The results based on the species sensitivity distribution model revealed N-nitrosodibutylamine as a particularly toxic compound to aquatic organisms. Furthermore, the average N-nitrosamine carcinogenic risk was significantly higher in lower groundwater reaches compared to upper reaches. This study represents a pioneering effort in considering specific N-nitrosamine properties in evaluating their toxicity and constructing species sensitivity curves. It underscores the significance of electroplating effluent as a primary N-nitrosamine source in aquatic environments, emphasizing their swift dissemination and significant accumulation in karst groundwater.

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice.

AIMS: Ferroptosis is a form of iron-regulated cell death implicated in ischemic heart disease. Our previous study revealed that Sirtuin 3 (SIRT3) is associated with ferroptosis and cardiac fibrosis. In this study, we tested whether the knockout of SIRT3 in cardiomyocytes (SIRT3cKO) promotes mitochondrial ferroptosis and whether the blockade of ferroptosis would ameliorate mitochondrial dysfunction. METHODS AND RESULTS: Mitochondrial and cytosolic fractions were isolated from the ventricles of mice. Cytosolic and mitochondrial ferroptosis were analyzed by comparison to SIRT3loxp mice. An echocardiography study showed that SIRT3cKO mice developed heart failure as evidenced by a reduction of EF% and FS% compared to SIRT3loxp mice. Comparison of mitochondrial and cytosolic fractions of SIRT3cKO and SIRT3loxp mice revealed that, upon loss of SIRT3, mitochondrial, but not cytosolic, total lysine acetylation was significantly increased. Similarly, acetylated p53 was significantly upregulated only in the mitochondria. These data demonstrate that SIRT3 is the primary mitochondrial deacetylase. Most importantly, loss of SIRT3 resulted in significant reductions of frataxin, aconitase, and glutathione peroxidase 4 (GPX4) in the mitochondria. This was accompanied by a significant increase in levels of mitochondrial 4-hydroxynonenal. Treatment of SIRT3cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) for 14 days significantly improved preexisting heart failure. Mechanistically, Fer-1 treatment significantly increased GPX4 and aconitase expression/activity, increased mitochondrial iron­sulfur clusters, and improved mitochondrial membrane potential and Complex IV activity. CONCLUSIONS: Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron­sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

Balanced Solution versus Normal Saline in Predicted Severe Acute Pancreatitis: A Stepped Wedge Cluster Randomized Trial.

OBJECTIVE: To compare the effect of balanced multielectrolyte solutions(BMES) versus normal saline(NS) for intravenous fluid on chloride levels and clinical outcomes.in patients with predicted severe acute pancreatitis (pSAP). SUMMARY BACKGROUND DATA: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown. METHODS: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (APACHE II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase(Sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day3. Secondary endpoints included a composite of clinical and laboratory measures. RESULTS: Overall, 259 patients were enrolled from eleven sites to receive NS(n=147) or BMES(n=112). On trial day3, the mean chloride level was significantly lower in patients who received BMES(101.8 mmol/L(SD4.8) versus 105.8 mmol/L(SD5.9), difference -4.3 mmol/L [95%CI -5.6 to -3.0 mmol/L];P<0.001). For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome(19/112,17.0% versus 43/147,29.3%, P=0.024) and increased organ failure-free days (3.9 d(SD2.7) versus 3.5days(SD2.7), P<0.001) by trial day7. They also spent more time alive and out of ICU(26.4 d(SD5.2) versus 25.0days(SD6.4), P=0.009) and hospital(19.8 d(SD6.1) versus16.3days(SD7.2), P<0.001) by trial day30. CONCLUSIONS: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits(Trial registration number: ChiCTR2100044432).

Gas chromatography-ion mobility spectrometry (GC-IMS) technique and its recent applications in grain research.

Grains are the primary source of food for most people worldwide and constitute a major source of carbohydrates. Many novel technologies are being employed to ensure the safety and reliability of grain supply and production. Gas chromatography-ion mobility spectrometry (GC-IMS) can effectively separate and sensitively detect volatile organic compounds. It possesses advantages such as speed, convenience, high sensitivity, no pretreatment, and wide applicability. In recent years, many studies have shown that the application of GC-IMS technology for grain flavor analysis can play a crucial role in grains. This article elucidates the working principle of GC-IMS technology, reviews the application of GC-IMS in grains in the past 5 years. GC-IMS technology is mainly applied in four aspects in grains. In grain classification, it distinguishes varieties, quality, origin, production year, and processing methods based on the trace differences in volatile organic compounds, thereby fulfilling various grain classification requirements such as origin tracing, geographical indication product recognition, variety identification, production year identification, and detection of counterfeit and inferior grain samples. In optimizing the processing technology of grains and their products, it can improve food flavor, reduce undesirable flavors, and identify better processing parameters. In grain storage, it can determine the storage time, detect spoilage phenomena such as mold and discoloration during storage, eliminate pests affecting storage, and predict the vitality of seeds after storage. In aroma evaluation of grains and their processed products, it can assess the impact of new raw materials, new technologies, fermentation processes, and even oral processing on the quality of grain products. This article also summarizes the characteristics of GC-IMS technology, compiles typical grain flavor compounds, and provides prospects for the future application of GC-IMS. © 2024 Society of Chemical Industry.

Identification of sedative-hypnotic compounds shared by five medicinal Polyporales mushrooms using UPLC-Q-TOF-MS/MS-based untargeted metabolomics.

BACKGROUND: Five Polyporales mushrooms, namely Amauroderma rugosum, Ganoderma lucidum, G. resinaceum, G. sinense and Trametes versicolor, are commonly used in China for managing insomnia. However, their active components for this application are not fully understood, restricting their universal recognition. PURPOSE: In this study, we aimed to identify sedative-hypnotic compounds shared by these five Polyporales mushrooms. STUDY DESIGN AND METHODS: A UPLC-Q-TOF-MS/MS-based untargeted metabolomics, including OPLS-DA (orthogonal projection of potential structure discriminant analysis) and OPLS (orthogonal projections to latent structures) analysis together with mouse assays, were used to identify the main sedative-hypnotic compounds shared by the five Polyporales mushrooms. A pentobarbital sodium-induced sleeping model was used to investigate the sedative-hypnotic effects of the five mushrooms and their sedative-hypnotic compounds. RESULTS: Ninety-two shared compounds in the five mushrooms were identified. Mouse assays showed that these mushrooms exerted sedative-hypnotic effects, with different potencies. Six triterpenes [four ganoderic acids (B, C1, F and H) and two ganoderenic acids (A and D)] were found to be the main sedative-hypnotic compounds shared by the five mushrooms. CONCLUSION: We for the first time found that these six triterpenes contribute to the sedative-hypnotic ability of the five mushrooms. Our novel findings provide pharmacological and chemical justifications for the use of the five medicinal mushrooms in managing insomnia.

Analysing N-nitrosamine occurrence and sources in karst reservoirs, Southwest China.

N-nitrosamines in reservoir water have drawn significant attention because of their carcinogenic properties. Karst reservoirs containing dissolved organic matter (DOM) are important drinking water sources and are susceptible to contamination because of the fast flow of various contaminants. However, it remains unclear whether N-nitrosamines and their precursor, DOM, spread in karst reservoirs. Therefore, this study quantitatively investigated the occurrence and sources of N-nitrosamines based on DOM properties in three typical karst reservoirs and their corresponding tap water. The results showed that N-nitrosamines were widely spread, with detection frequencies > 85%. Similar dominant compounds, including N-nitrosodimethylamine, N-nitrosomethylethylamine, N-nitrosopyrrolidine, and N-nitrosodibutylamine, were observed in reservoirs and tap water, with average concentrations of 4.7-8.9 and 2.8-6.7 ng/L, respectively. The average carcinogenic risks caused by these N-nitrosamines were higher than the risk level of 10-6. Three-dimensional fluorescence excitation-emission matrix modeling revealed that DOM was composed of humus-like component 1 (C1) and protein-like component 2 (C2). Fluorescence indicators showed that DOM in reservoir water was mainly affected by exogenous pollution and algal growth, whereas in tap water, DOM was mainly affected by microbial growth with strong autopoietic properties. In the reservoir water, N-nitrosodiethylamine and N-nitrosopiperidine were significantly correlated with C2 and biological indicators, indicating their endogenously generated sources. Based on the principal component analysis and multiple linear regression methods, five sources of N-nitrosamines were identified: agricultural pollution, microbial sources, humus sources, degradation processes, and other factors, accounting for 46.8%, 36.1%, 7.82%, 8.26%, and 0.96%, respectively. For tap water, two sources, biological reaction processes, and water distribution systems, were identified, accounting for 75.7% and 24.3%, respectively. Overall, this study presents quantitative information on N-nitrosamines' sources based on DOM properties in typical karst reservoirs and tap water, providing a basis for the safety of drinking water for consumers.

Risk factors of post-operative diarrhoea in patients with pancreatic cancer after neoadjuvant chemotherapy: A retrospective cohort study.

BACKGROUND: Post-operative diarrhoea is a common adverse event after pancreatic surgery. While the risk factors for this condition have been identified, the increasing trend of administering chemotherapy before surgery might change these factors. This study aimed to identify the risk factors of post-operative diarrhoea in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. DESIGN: A retrospective cohort study. METHODS: Patients who underwent neoadjuvant chemotherapy and pancreatectomy because of PDAC between 2021 and 2023 were included. The preoperative characteristics of, operative details of and post-operative outcomes in patients with and without post-operative diarrhoea were collected and compared. The independent risk factors of post-operative diarrhoea were identified using logistic regression analysis. STROBE checklist was used. RESULTS: Post-operative diarrhoea occurred in 65 out of 145 (44.8%) patients during hospitalization. Elevated white blood cell count, advanced tumour stage, and late abdominal drain removal were independent risk factors for post-operative diarrhoea (p < .001, p = .006 and p = .009, respectively). CONCLUSIONS: Some perioperative factors influence post-operative diarrhoea in patients who undergo neoadjuvant chemotherapy. More attention should be paid to patients at a higher risk of post-operative diarrhoea, with an emphasis on high-quality management for these patients.

p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD. METHODS: We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p534KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF. RESULTS: Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice, as well as in p534KR mice after transverse aortic constriction. In vitro, p534KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice. CONCLUSIONS: Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.

DNA Methylation and Chromatin Accessibility Impact Subgenome Expression Dominance in the Common Carp (Cyprinus carpio).

DNA methylation and chromatin accessibility play important roles in gene expression, but their function in subgenome expression dominance remains largely unknown. We conducted comprehensive analyses of the transcriptome, DNA methylation, and chromatin accessibility in liver and muscle tissues of allotetraploid common carp, aiming to reveal the function of epigenetic modifications in subgenome expression dominance. A noteworthy overlap in differential expressed genes (DEGs) as well as their functions was observed across the two subgenomes. In the promoter and gene body, the DNA methylation level of the B subgenome was significantly different than that of the A subgenome. Nevertheless, differences in DNA methylation did not align with changes in homoeologous biased expression across liver and muscle tissues. Moreover, the B subgenome exhibited a higher prevalence of open chromatin regions and greater chromatin accessibility, in comparison to the A subgenome. The expression levels of genes located proximally to open chromatin regions were significantly higher than others. Genes with higher chromatin accessibility in the B subgenome exhibited significantly elevated expression levels compared to the A subgenome. Contrastingly, genes without accessibility exhibited similar expression levels in both subgenomes. This study contributes to understanding the regulation of subgenome expression dominance in allotetraploid common carp.

EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in non-small cell lung cancer.

Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.

Impact of agricultural activities on the occurrence of N-nitrosamines in an aquatic environment.

N-Nitrosamines, nitroso compounds with strong carcinogenic effects on humans, have been frequently detected in natural waters. In agricultural areas, there is typically a lack of drinking water treatment processes and distribution systems. As a result, residents often consume groundwater as drinking water which may contain N-nitrosamines, necessitating the investigation of the occurrence, sources, and carcinogenic risk of N-nitrosamines within the groundwater of agricultural areas. This study identified eight N-nitrosamines in groundwater and river water in the Jianghan Plain, a famous agricultural region in central China. N-Nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosomorpholine (NMOR), N-nitrosopyrrolidine (NPYR), and N-nitrosodi-n-butylamine (NDBA) were detected in groundwater, with NDMA being the main compound detected (up to 52 ng L-1). Comparable concentrations of these N-nitrosamines were also found in river water. From laboratory experiments, we found a tremendous potential for the formation of N-nitrosamines in groundwater. Principal component analysis and multiple linear regression analysis results showed that the primary sources of N-nitrosamines in groundwater were the uses of nitrogen fertilizers and pesticides carrying specific N-nitrosamines such as NPYR. The average total carcinogenic risk values of detected N-nitrosamines were higher than the acceptable risk level (10-5), suggesting a potential carcinogenic risk of groundwater. Further research is urgently needed to minimize N-nitrosamine levels in the groundwater of agricultural areas, particularly in those where pesticides and fertilizers are heavily used.

Intrathecal injections of angiotensin IV and oxytocin conjugates induce antihyperalgesia and antiallodynia in both sexes of rats.

Our previous studies have established that intrathecal oxytocin (OT) and angiotensin IV (Ang IV) injections induce antihyperalgesia and antiallodynia in rodents. Ang IV, a renin-angiotensin system hexapeptide, acts as an endogenous inhibitor that inhibits the oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP). The pain inhibitory effects by Ang IV were found to be through its inhibition on IRAP to potentiate the effect of OT. However, these effects were found to be with a significant sex difference, which could be partially due to the higher expression of IRAP at the spinal cords of female. Therefore, we synthesized Ang IV and OT conjugates connected with a peptide bond and tested for their effects on hyperalgesia and allodynia. Carrageenan-induced hyperalgesia and partial sciatic nerve ligation (PSNL) were performed using rat models. Conjugates Ang IV-OT (Ang IV at the N-terminal) and OT-Ang IV (OT at the N-terminal) were synthesized and intrathecally injected into male and female rats. Our results showed that Ang IV-OT exhibited prominent antihyperalgesia in male rats, particularly during hyperalgesia recovery, whereas OT-Ang IV was more effective during development stage. Ang IV-OT showed clear antihyperalgesia in female rats, but OT-Ang IV had no significant effect. Notably, both conjugates alleviated neuropathic allodynia in male rats; however, OT-Ang IV had no effect in female rats, whereas Ang IV-OT induced significant antiallodynia. In conclusion, Ang IV-OT has greater therapeutic potential for treating hyperalgesia and allodynia than OT-Ang IV. Its effects were not affected by sex, unlike those of OT and OT-Ang IV, extending its possible clinical applications.

Post-Graphene 2D Materials: Structures, Properties, and Cancer Therapy Applications.

Cancer is one of the most serious diseases challenging human health and life span. Cancer has claimed millions of lives worldwide. Early diagnosis and effective treatment of cancer are very important for the survival of patients. In recent years, 2D nanomaterials have shown great potential in the development of anticancer treatment by combining their inherent physicochemical properties after surface modification. 2D nanomaterials have attracted great interest due to their unique nanosheet structure, large surface area, and extraordinary physicochemical properties. This article reviews the advantages and application status of emerging 2D nanomaterials for targeted tumor synergistic therapy compared with traditional therapeutic strategies. In order to investigate novel potential anticancer strategies, this paper focuses on the surface modification, cargo delivery capability, and unique optical properties of emerging 2D nanomaterials. Finally, the current problems and challenges in cancer treatment are summarized and prospected.

Irisin protected hemopoietic stem cells and improved outcome of severe bone marrow failure.

Acquired aplastic anemia (AA) is a bone marrow failure (BMF) disease, characterized by fatty bone marrow (BM) and BM hypocellularity resulted from auto-immune dysregulated T cells-mediated destruction of BM haemopoietic stem cells (HPSC). The objective of this study was to investigate potential therapeutic effect of irisin, a molecule involved in adipose tissue transition, on AA mouse model. Our results showed that the concentration of irisin in serum was lower in AA patients than in healthy controls, suggesting a role of irisin in the pathogenesis of AA. In the AA mice, irisin administration prolonged the survival rate, prevented or attenuated peripheral pancytopenia, and preserved HPSC in the BM. Moreover, irisin also markedly reduced BM adipogenesis. In vitro results showed that irisin increased both cell proliferation and colony numbers of HPSC. Furthermore, our results demonstrated that irisin upregulated the expression of mitochondrial ATPase Inhibitory Factor 1 (IF1) in HPSC, inhibited the activation of mitochondrial fission protein (DRP1) and enhanced aerobic glycolysis. Taken together, our findings indicate novel roles of irisin in the pathogenesis of AA, and in the protection of HPSC through stimulation of proliferation and regulation of mitochondria function, which provides a proof-of-concept for the application of irisin in AA therapy.

A Nanozymatic-Mediated Smartphone Colorimetric Sensing Platform for the Detection of Dimethyl Phthalate (DMP) and Dibutyl Phthalate (DBP).

Plasticizers are a type of toxic substance that may remain in food, posing significant health risks including carcinogenic, teratogenic, mutagenic, and other adverse effects. In this study, a novel strategy was employed by combining Pt@Au nanozymes with high catalytic properties to created two catalytic signal probes, designated as Pt@Au@Ab1 and Pt@Au@Ab2, specifically designed for the detection of dimethyl phthalate (DMP) and dibutyl phthalate (DBP). These catalytic signal probes served as the foundation for the development of a colorimetric immunoassay, enabling the simultaneous detection of both DMP and DBP. The colorimetric immunoassay is capable of detecting DMP in the range of 0.5-100 µg/L with a limit of detection as low as 0.1 µg/L and DBP in the range of 1-32 µg/L with a low limit of detection of 0.5 µg/L. The developed immunoassay can be used for the determination of the DMP and DBP in baijiu and plastic bottled drinks. The recovery rate is in the range of 96.4% and 100.5% and the coefficient of variation is between 1.0% and 7.2%. This innovative colorimetric immunoassay offers a robust tool for the simultaneous quantification of DMP and DBP in real samples.

Accumulation of endogenous adenosine improves cardiomyocyte metabolism via epigenetic reprogramming in an ischemia-reperfusion model.

Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.