Search

ObjectiveTo study the combined use of preservatives in food in China and to evaluate the intake level of common preservatives and their cumulative exposure risk.MethodsThe exposures of common preservatives were calculated by simple distribution assessment method based on the maximum allowable usage of preservatives of National Food Safety Standards the Use of Food Additives GB 2760—2014 and consumption data from the fifth Chinese Total Diet Study. The cumulative exposure risk was evaluated by the hazard index method （HI） based on the combined use of preservatives in Chinese food in the global new product database， the exposures and acceptable daily intake （ADI） of preservatives.Results43.36% of foods that use preservatives in China use two or more preservatives， the highest utilization rate is binary combination （31.78%）， with a maximum of 6 combinations. Consider only the population exposure risk of one preservative alone， the daily average exposure in the diet of the general population and the high food consumption group （P95） in sodium benzoate， potassium sorbate and sodium diacetate were lower than their corresponding ADI. The daily average exposure in the diet of the general population in nisin， sodium nitrate and sodium dehydroacetate were lower than their corresponding ADI， but the high food consumption group （P95） were higher than their corresponding ADI. Cumulative assessment shows that the average exposure of the most common binary and ternary preservative combinations in the general population has an HI of less than 1， but the mean value of HI of the most common quaternary and quintuple and the P95 of HI of binary， ternary， quaternary and quintuple preservative combinations in the general population has an HI of greater than 1. Cumulative assessment shows that the preservatives of common preservative combinations are used alone， and some individuals have the problem of excessive intake， but if used in combination， there may be 1.47~1.75 times the health risks of individuals.ConclusionFood preservatives are often used in combination in China. The cumulative exposure risk of the most common binary， ternary， quaternary， and quintuple preservative combinations has gradually increased. Cumulative assessment shows that the use of the most quaternary and quintuple preservative combinations has created health risks for some people， and practical usage of these preservatives should be monitored and more accurately evaluated. When the food additives with the same anticorrosive function are mixed， each of which accounted for the maximum use of their dosage should not exceed 1.

Fungal peritonitis, an uncommon complication in continuous ambulatory peritoneal dialysis (CAPD), has recently garnered increased attention due to its incidence and potential mortality. To the best of our knowledge, this is the first confirmed case of Neosartorya hiratsukae (N. hiratsukae) causing CAPD-related peritonitis in a patient with chronic nephrotic syndrome in Guangzhou, China. After prompt removal of the peritoneal catheter and active antifungal therapy, no clinical manifestations of peritonitis were observed. Our report underscores the importance of enhancing clinical awareness regarding N. hiratsukae and ensuring timely diagnosis in cases of CAPD-related fungal peritonitis.

Oligonucleotide drugs are shining in clinical therapeutics, but efficient and safe delivery systems severely limit their widespread use. A disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the disulfide unit CSSC dihedral angle induced by different substituents directly affects the effectiveness of this technology and its stability. Previously, we constructed a trivalent low dihedral angle disulfide unit that can effectively promote the cellular uptake of small molecules. Here, we constructed a novel disulfide unit-masked oligonucleotide hybrid based on a low dihedral angle disulfide unit, motivated by prodrug design. Cellular imaging results showed that such a system exhibited superior cellular delivery efficiency than the commercial Lipo2000 without cytotoxicity. The thiol reagents significantly reduced its cellular uptake (57–74%), which proved to be endocytosis-independent. In addition, in vivo distribution experiments in mice showed that such systems can be rapidly distributed in liver tissues with a duration of action of more than 24 h, representing a potential means of silencing genes involved in the pathogenesis of liver-like diseases. In conclusion, this trivalent disulfide unit-masked system we constructed can effectively deliver large oligonucleotide drugs.

Abstract Background The impact of triglyceride-glucose (TyG) index, a surrogate marker for insulin resistance, on the risk of cardiovascular disease (CVD) in general populations remains controversial. We aimed to comprehensively study the relationship between TyG index with the risk of incident CVD events in the general population in Shanghai. Methods A total of 42,651 participants without previous history of CVD events from Shanghai Suburban Adult Cohort and Biobank (SSACB) were included. SSACB was a community-based natural population cohort study using multistage cluster sampling method. TyG index was calculated as Ln [fasting serum triglyceride (mg/dL) * fasting blood glucose (mg/dL)/2]. Kaplan-Meier curves, log-rank test and cox proportional hazards model were used to calculate the association between TyG index and incident CVD, including stroke and coronary heart disease (CHD). Restricted cubic spline analyses were used to determine whether there was a non-linear relationship between TyG index and CVD events. Results During a median follow-up of 4.7 years, 1,422 (3.3%) individuals developed CVD, including 674 (1.6%) cases of stroke and 732 (1.7%) cases of CHD. A one unit increment higher TyG index was associated with [HR(95%CI)] 1.16(1.04–1.29) in CVD and with 1.39(1.19–1.61) in stroke. Only linear relationships between TyG and CVD/stroke were observed, while no relationship was observed with CHD after adjustments for confounders. In subgroup analyses, younger (

A small molecule disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the CSSC dihedral angle of the disulfide unit caused by diverse substituents directly affects the effectiveness of this technology platform as well as its own chemical stability. The highly stable open-loop relaxed type disulfide unit plays a limited role in drug delivery due to its low dihedral angle. Here, we have built a novel disulfide unit starship based on the 3,4,5-trihydroxyphenyl skeleton through trigonometric bundling. The intracellular delivery results showed that the trigonometric bundling of the disulfide unit starship effectively promoted cellular uptake without any toxicity, which is far more than 100 times more active than that of equipment with a single disulfide unit in particular. Then, the significant reduction in cell uptake capacity (73–93%) using thiol erasers proves that the trigonometric bundling of the disulfide starship is an endocytosis-independent internalization mechanism via a dynamic covalent disulfide exchange mediated by thiols on the cell surface. Furthermore, analysis of the molecular dynamics simulations demonstrated that trigonometric bundling of the disulfide starship can significantly change the membrane curvature while pushing lipid molecules in multiple directions, resulting in a significant distortion in the membrane structure and excellent membrane permeation performance. In conclusion, the starship system we built fully compensates for the inefficiency deficiencies induced by poor dihedral angles.

ObjectiveTo assess the risk of exposure in the population in 7 provinces and cities in China， the intake of glutamates （calculated for glutamic acid） in Chinese restaurant diners was calculated and compared with the recommended intake.MethodsA multi-stage stratified and population-proportional whole-group random sampling method was used to randomly select condiments in seven provinces/municipalities： Beijing， Chongqing， Liaoning， Shandong， Guangxi， Jiangsu， and Shaanxi. Ultra-performance liquid chromatography-tandem mass spectrometry method was used to determine the glutamate content of collected condiments. The glutamate intake was calculated based on individual consumption and body weight data obtained during the investigation based on a simple distribution model of restaurant diners.ResultsThe highest levels of glutamates were found in flavoring agents and enhancers， followed by chicken essence/chicken powder， solid compound condiments other than chicken essence， liquid compound condiments， soy sauce， semi-solid compound condiments based on animal ingredients， spices， and brewing preparation sauces， etc. The lowest levels of glutamates were found in salt and salt substitutes. The mean glutamate intake of a meal for restaurant diners was 47.87 mg/kg·BW， accounting for 39.89% of the ADI set by JECFA. The mean glutamate intake for a day was 61.33 mg/kg·BW when considering food consumed outside the restaurant during the day， accounting for 51.11% of the ADI. Among diners of different restaurant sizes， medium-sized restaurants had the highest intake of glutamates during a meal， with a median intake of 44.46 mg/kg·BW， followed by large restaurants and small restaurants， with significant differences （P0.05）， and the mean values as a proportion of ADI were

ObjectiveTo investigate the contamination levels of anthraquinone （9，10-anthraquinone as representative） in tea for sale in border areas in China， and to assess the exposure level and health risk of anthraquinone for residents.MethodsThe content of anthraquinone （9，10-anthraquinone as representative） in samples of tea for sale in border areas was determined by gas chromatography-tandem mass spectrometry （GC-MS/MS）. Based on food safety risk monitoring data of 9，10-anthraquinone in tea for sale in border areas from 2016 to 2017， combined with the consumption data of tea for sale in border areas for residents in the Inner Mongolia Autonomous Region， the Tibet Autonomous Region， and Qinghai Province， the exposure level of residents to anthraquinone through the consumption of tea for sale in border areas was estimated by deterministic estimate methods. Exposure results were compared with the acceptable daily intake （ADI： 6.8 µg/kg·BW）.ResultsAmong 141 samples， the anthraquinone detection rate was 75.18%， and the average content was 0.029 2 mg/kg. Up to now， the limit standard for anthraquinone has not yet been set in China. The maximum residue levels （MRLs）of anthraquinone in tea are set at 0.02 mg/kg by European Union （EU） No 1146/2014. The total over-standard rate was 57.45%. In addition， the over-standard rate of stereotyped packaging and bulk packaging was 64.63% and 47.46%， respectively. The results of the deterministic evaluation show that the average daily exposure of anthraquinone from tea for sale in border areas of the whole population in the Inner Mongolia Autonomous Region， the Tibet Autonomous Region， and Qinghai Province in China was 9.37×10-4 µg/kg·BW， 0.013 8% of the ADI. High consumer exposure （95th percentile， P95） was 3.12×10-3 µg/kg·BW， 0.045 9% of the ADI. Among the different sex-age groups， the average daily exposure and P95 daily exposure of women in the age group of 45-59 years were the highest， which were 1.41×10-3 and 6.16×10-3 µg/kg·BW， respectively. However， neither exceeded the ADI.ConclusionThe results of the exposure assessment showed that the health risk for the residents of the Inner Mongolia Autonomous Region， the Tibet Autonomous Region， and Qinghai Province due to dietary exposure to anthraquinone through tea for sale in border areas was low and at an acceptable level. As anthraquinone contamination is prevalent in tea for sale in border areas， it is necessary to identify the source of anthraquinone residue， and some effective measures should be taken to control it. In addition， to respond positively to the limits of anthraquinone content in tea from China exported to the EU and other countries， it is recommended that the relevant authorities should study reasonable limits for anthraquinone in tea as soon as possible.

ObjectiveTo establish the risk assessment method of food disinfectant with the peroxyacetic acid disinfectant for poultry slaughtering and processing as the model disinfectant.MethodsReferring to the risk assessment methods of food disinfectants from international organizations， the risk assessment method of food disinfectants suitable for China was established by considering the health effects， efficacy， and antimicrobial resistance. The safety of peroxyacetic acid disinfectant used for carcass disinfection during poultry slaughtering was assessed using the established method.ResultsUnder the setting condition， the health risk of the ingredients of the peroxyacetic acid disinfectant （peroxyacetic acid， acetic acid， hydrogen peroxide， and 1-hydroxyethylidine-1，1-diphosphonic acid） and the disinfection byproducts and reaction products after the treatment did not need priority attention. Based on the literature search results， the use of peroxyacetic acid disinfectants may not lead to decreased efficacy of fungicides and/or be associated with antimicrobial resistance.ConclusionThe risk assessment method for food disinfectants in China was established， which can be used as a methodological reference for the safety assessment of the new food disinfectant products in the future.

Background Carotid intima‐media thickness (cIMT) has been widely used as a predictor of future cardiovascular disease (CVD); however, various definitions of cIMT exist. This study provides a systematic review and meta‐analysis of the associations between different cIMT definitions and CVD. Methods and results A systematic review of the different cIMT definitions used in prospective cohort studies was performed. The relationships between cIMT of different definitions (common carotid artery IMT [CCA‐IMT], internal carotid artery IMT [ICA‐IMT], combined segments [combined‐IMT], mean CCA‐IMT, and maximum CCA‐IMT) with future stroke, myocardial infarction (MI), and CVD events were analyzed using random effects models. Among 2287 articles, 18 articles (14 studies) with >10 different cIMT definitions were identified and included in our meta‐analysis. After adjusting for age and sex, a 1‐SD increase in CCA‐IMT was associated with future stroke (hazard ratio [HR], 1.32 [95% CI, 1.27–1.38]), MI (HR, 1.27 [95% CI, 1.22–1.33]), and CVD events (HR, 1.28 [95% CI, 1.19–1.37]). A 1‐SD increase in ICA‐IMT was related to future stroke (HR, 1.25 [95% CI, 1.11–1.42]) and CVD events (HR, 1.25 [95% CI, 1.04–1.50]) but not MI (HR, 1.26 [95% CI, 0.98–1.61]). A 1‐SD increase in combined‐IMT was associated with future stroke (HR, 1.30 [95% CI, 1.08–1.57]) and CVD events (HR, 1.36 [95% CI, 1.23–1.49]). Maximum CCA‐IMT was more strongly related than mean CCA‐IMT with risk of MI, and both measures were similarly associated with stroke and CVD events. Conclusions Combined‐IMT is more strongly associated with CVD events compared with single‐segment cIMT definitions. Maximum CCA‐IMT shows a stronger association with MI than mean CCA‐IMT. Further research is warranted to validate our findings and to standardize the cIMT measurement protocol, as well as to explore underlying mechanisms.

WAAM has emerged as a promising technique for manufacturing medium- and large-scale metal parts due to its high material deposition efficiency and automation level. However, its high heat accumulation and complex thermal evolution strongly affect the resulting microstructures and mechanical properties. The heterogeneous and unpredictable nature of these properties hinder the widespread application of WAAM in the steel construction industry. In this study, an artificial neural network (ANN) hardness model is developed, based on a thermal–metallurgical model for mild steel. The objective is to establish non-linear relationships between the input process parameters and the desired output, i.e., hardness. The thermal–metallurgical model utilizes a well-distributed heat source model, a death-and-birth algorithm, and a metallurgical model to simulate the temperature field and to calculate the microstructure phase fraction. The temperature prediction errors at four thermocouple positions are mostly below 20%. Because of the limited experimental data, twenty-five simulation experiments are performed using the L25 orthogonal array based on the Taguchi method. The analysis of variance (ANOVA) reveals that the travel speed has the greatest impact on hardness. With the dataset from the thermal–metallurgical model, an ANN model to predict hardness is developed. A comparison to experimental data shows excellent performance and accuracy, with the Mean Absolute Percentage Error (MAPE) of ANN predictions within 10% of the targeted hardness.

The accurate diagnosis and effective therapy of malignant tumors is still a challenge owing to its poor prognosis, recurrence, and drug resistance. In this study, a tumor microenvironment responsive and high O2-economic effect nano-theranostic agent GOx@NPs was constructed through the self-assembly of GOx and CDDO-Fe, which was synthesized by coupling natural chemotherapeutic drug CDDO-Me blocked by ferrocene (Fc) with near-infrared (NIR) fluorescence probe hemicyanine (I-CyOH) via redox-responsive linker dimercaptoisopropionyl, and then introducing tamoxifen (estrogen receptor target fragment) to hemicyanine to enhance the active targeting ability. The NIR fluorescence probe I-CyOH not only achieved an accurate diagnosis, but also possessed photodynamic therapy (PDT) effect. The active targeting fragment tamoxifen enhanced the accumulation of pathological site and alleviated the hypoxia microenvironment through the inhibition of mitochondrial respiratory to reinforce the PDT efficiency of I-CyOH. Moreover, the combination of Fc and GOx could achieve starvation therapy and enhance chemodynamic therapy (CDT). In vitro and vivo experiments exhibited that the effective dual sensitive synergistic therapy possessed significant therapy efficiency and lower side effects. This study provides a valuable strategy for constructing dual sensitization and high economic of intelligent nano-theranostic agents for tumor diagnosis and synergistic cancer therapy.

Abstract Background Studies on the effect of sleep duration on cardiovascular health have contradictory findings. Underlying health issues may have led to inconsistent results and warrant consideration. We aim to assess the relationship of night sleep duration with incident cardiovascular disease (CVD) in a general population, taking into consideration underlying chronic diseases. Methods Data from Shanghai Suburban Adult Cohort and Biobank with a median follow-up of 5.1 years was used, including 33,883 adults aged 20–74 years old. Incident CVD cases were reported and recorded by the Center for Disease Prevention and Control in Songjiang, Shanghai. We used Cox proportional hazard regression models and restricted cubic spline (RCS) analysis to explore the relationship between different sleep groups and sleep duration with incident CVD outcomes, through stratification by gender and age, as well as different health conditions, with adjustments for potential confounders. Results Long sleep duration (> 9 h) compared to > 7 to ≤ 8 h was associated with overall incident CVD in participants aged ≥ 50 years old: HR(95%CI) = 2.07 (1.15, 3.74) for 50-59y and 1.43 (1.04, 1.93) for 60-74y. RCS analysis showed a J-shaped relationship between sleep and CVD risk in those ≥ 50y, which was confirmed only in those with a chronic health condition. Non-linear relationships between sleep and CVD risk factors, such as BMI, blood glucose and glycated haemoglobin, were observed. Conclusions Long sleep duration is associated with increased risk of CVD in people ≥ 50y. However, CVD risk factors and underlying health conditions such as hypertension, and diabetes, may play a driving role in the relationship.

ObjectiveTo study the contamination level of mineral oil hydrocarbons in complementary foods for infants and young children and assess its potential health impact for consumers aged 0­3 years old in China.MethodsThe contents of mineral oil saturated hydrocarbons （MOSH） and mineral oil aromatic hydrocarbons （MOAH） were determined by on­line high­performance liquid chromatography coupled with gas chromatography and flame ionization detector. Based on the food consumption data of Chinese residents in 2015， the exposure to mineral oil hydrocarbons in complementary foods of Chinese infants and young children aged 0­3 years old was assessed by simple distribution method.ResultsThe overall detection rate of MOSH （C16-C35） in 4 types of complementary foods （canned foods， rice flour， noodles， and biscuits or molar sticks） in total of 138 commercially available complementary food samples was 45.65%， and the mean contamination level in different types of complementary foods was in the range of 0.55-4.40 mg/kg. The MOAH was only detected in 1 sample of noodles and 4 samples of biscuits or molar sticks. The overall detection rate of MOAH was 3.62%. The average daily exposure and high food consumption （P95） daily exposure of MOSH （C16­C35） for complementary foods consumer only population were 6.21 and 19.27 μg/kg·BW， respectively. The margins of exposure of all age groups were higher than 100.ConclusionThe health risk from dietary exposure to MOSH by consuming complementary foods is very low for infants and young children aged 0­3 years old in China. Attention should be paid to the contamination of MOAH in complementary foods for infants and young children.

Rheumatoid arthritis (RA) is an inflammatory condition that causes severe cartilage degradation and synovial damage in the joints with multiple systemic implications. Previous studies have revealed that fibroblast-like synoviocytes (FLSs) play a pivotal role in the pathogenesis of RA. The appropriate regulation of FLS function is an efficient approach for the treatment of this disease. In the present study, we explored the effects of methyl canthin-6-one-2-carboxylate (Cant), a novel canthin-6-one alkaloid, on the function of FLSs. Our data showed that exposure to Cant significantly suppressed RA-FLS migration and invasion properties in a dose-dependent manner. Meanwhile, pre-treatment with Cant also had an inhibitory effect on the release of several pro-inflammatory cytokines, including IL-6 and IL-1β, as well as the production of MMP1 and MMP3, which are important mediators of FLS invasion. In further mechanistic studies, we found that Cant had an inhibitory effect on the Hippo/YAP signaling pathway. Treatment with Cant suppressed YAP expression and phosphorylation on serine 127 and serine 397 while enhancing LATS1 and MST1 levels, both being important upstream regulators of YAP. Moreover, YAP-specific siRNA or YAP inhibition significantly inhibited wound healing as well as the migration and invasion rate of FLS cells, an impact similar to Cant treatment. Meanwhile, the over-expression of YAP significantly reversed the Cant-induced decline in RA-FLS cell migration and invasion, indicating that YAP was required in the inhibitory effect of Cant on the migration and invasion of RA-FLS cells. Additionally, supplementation of MMP1, but not MMP3, in culture supernatants significantly reversed the inhibitory effect of Cant on RA-FLS cell invasion. Our data collectively demonstrated that Cant may suppress RA-FLS migration and invasion by inhibiting the production of MMP1 via inhibiting the YAP signaling pathway, suggesting a potential of Cant for the further development of anti-RA drugs.

ObjectiveTo carry out the theoretical risk assessment for food colorants in the National food safety standard-standards for uses of food additives (GB 2760—2014) by Budget method and deterministic assessment.MethodsBudget method was applied for calculating the theoretical maximum daily intake of food colorants which had ADI values and maximum use levels. For the additives whose intakes were higher than their ADIs, simple distribution assessment was performed with food consumption data from a Chinese total diet study in 2012.ResultsThere are totally 21 food colorants have both ADI values and maximum use levels in GB 2760—2014. These 21 food colorants were included in the assessment by Budget method . The maximum theoretical daily intake of 15 food colorants exceeded their ADIs. Then, these 15 food colorants were assessed by simple distribution assessment. The result showed that the average intakes were below ADIs but the P95 intakes of 2 food colorants exceeded the ADIs in the whole population. Among consumers, the average intakes were also below ADIs, but the P95 intakes of 8 food colorants exceeded the ADIs.ConclusionThe health risks of most food colorant intakes in the national standard were at low levels. However, a few food colorants showed a requirement for further assessment with the actual concentrations in foods to confirm their health risk level.

ObjectiveTo explore the concentrations of rare earth elements (Rare earth elements, REEs) in drinking water in rare earth mining and non-mining areas in Shandong, Guangdong, and Jiangxi provinces of China.MethodsTypical rare earth mining areas and 3 non-mining areas in the 3 provinces were selected for investigation. Drinking water of people in mining areas and non-mining areas were collected for 3 consecutive days by duplicate portion method. The contents of La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Sc and Y in water samples were determined by inductively coupled plasma mass spectrometry (ICP-MS).ResultsThe detection rate of each REEs in drinking water of mining and non-mining area was 12.98% to 86.64% and 1.07% to 69.04%, respectively. The average content of total REEs in drinking water in the mining area was 6.974 μg/L, with the maximum of 178.290 μg/L. The main elements were Ce, La, Nd, Y, Sc and Pr (≈90.0%). The average content of total REEs in drinking water in non-mining area was 0.772 μg/L, significantly lower than that in mining area (P0.05).ConclusionThe contents of REEs in drinking water of mining area are higher than that of non-mining areas. Risk assessment of REEs exposure by drinking water should be further carried out for residents in mining areas.

BackgroundThis study aimed to summarize and analyse the risk factors, clinical features, as well as prevention and treatment of limb ischemia complications in patients on veno-arterial extracorporeal membrane oxygenation (V-A ECMO).MethodsWe retrospectively analyzed 179 adult patients who had undergone V-A ECMO support in the Cardiac Care Unit of the First Hospital of Lanzhou University between March 2019 and December 2021. Patients were divided into the limb ischemia group (LI group) and the non-limb ischemia group (nLI group) according to whether limb ischemia occurred on the ipsilateral side of femoral artery cannulation. In the LI group, patients were salvaged with a distal perfusion cannula (DPC) according to each patient's clinical conditions. The baseline data and ECMO data were compared between the two groups, and risk factors for limb ischemia complications were screened using multiple logistic regression analysis.ResultsOverall, 19 patients (10.6%) had limb ischemia complications, of which 5 (2.8%) were improved after medication adjustment, 12 (8.4%) were salvaged with a DPC, and 2 had undergone surgical intervention. There were significant differences in terms of Extracorporeal Cardiopulmonary Resuscitation (ECPR), Intra-aortic balloon pump (IABP), peak vasoactive-inotropic score (VIS) within 24 h after ECMO (VIS-max), Left ventricular ejection fraction (LVEF), weaning from ECMO, and discharge rate between the two groups. ECPR, IABP, and VIS-max in the LI group were significantly higher than those in the nLI group, whereas weaning from ECMO, discharge rate, and LVEF were significantly lower in the LI group compared to those in the nLI group. Furthermore, multiple logistic regression analysis revealed that diabetes [odds ratio (OR) = 4.338, 95% confidence interval (CI): 1.193–15.772, P = 0.026], IABP (OR = 1.526, 95% CI: 1.038–22.026, P = 0.049) and VIS-max (OR = 1.054, 95% CI: 1.024–1.085, P < 0.001) were independent risk factors for limb ischemia complications in patients who underwent V-A ECMO.ConclusionDiabetes, prevalence of IABP and VIS-max value in analyzed groups were independent risk factors for predicting limb ischemia complications in patients who underwent V-A ECMO. The cannulation strategy should be optimized during the establishment of V-A ECMO, and limb ischemia should be systematically evaluated after ECMO establishment. A DPC can be used as a salvage intervention for the complications of critical limb ischemia.

As the incidence of global food allergies increases year-by-year, food allergic diseases have become a growing concern in food safety and public health issue circles. In this paper, the characteristics of food allergens, allergenicity mechanism, clinical manifestations, common allergenic foods, and main exposure sources were introduced. The formulation method and the latest adjustment of food allergen threshold and reference dose were summarized, and several internationally recognized risk assessment method of food allergens were also summarized, which provides the theoretical basis for the next step of food allergy risk assessment in our country.

Abstract Chronic pain is a significant public health problem that afflicts nearly 30% of the global population, but current pharmacotherapies are insufficient. Previous report indicated that N-demethylsinomenine, an active metabolite of sinomenine, is efficacious against postoperative pain. The present study investigated whether N-demethylsinomenine is effective for chronic painful conditions or whether repeated treatment alters its effect. Both chronic constriction injury (CCI) surgery and complete Freund’s adjuvant (CFA) intraplantar injection induced significant and reliable mechanical allodynia at least for 7 days. Acute treatment with N-demethylsinomenine (10–40 mg/kg, i.p.) dose-dependently attenuated the mechanical allodynia both in CCI-induced neuropathic pain and CFA-induced inflammatory pain in mice. The potency of N-demethylsinomenine for reducing CFA-induced mechanical allodynia was slightly higher than sinomenine. During the period of repeated treatment, N-demethylsinomenine maintained its anti-allodynic effect against both neuropathic and inflammatory pain without producing carry-over effect. Pretreatment with bicuculline, a selective γ-aminobutyric acid type A (GABAA) receptor antagonist, almost completely blocked the anti-allodynia of N-demethylsinomenine (40 mg/kg) both in CCI and CFA-treated mice. Our findings indicated that N-demethylsinomenine exhibits GABAA receptor-mediated anti-allodynic effects in mouse models of neuropathic and inflammatory pain, suggesting it may be a useful novel pharmacotherapy for the control of chronic pain.

Aims: Osteoarthritis (OA) is a disabling joint disorder and mechanical loading is an important pathogenesis. This study aims to investigate the benefits of less mechanical loading created by intermittent tail suspension for knee OA. Methods: A post-traumatic OA model was established in 20 rats (12 weeks old, male). Ten rats were treated with less mechanical loading through intermittent tail suspension, while another ten rats were treated with normal mechanical loading. Cartilage damage was determined by gross appearance, Safranin O/Fast Green staining, and immunohistochemistry examinations. Subchondral bone changes were analyzed by micro-CT and tartrate-resistant acid phosphatase (TRAP) staining, and serum inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA). Results: Our radiographs showed that joint space was significantly enlarged in rats with less mechanical loading. Moreover, cartilage destruction was attenuated in the less mechanical loading group with lower histological damage scores, and lower expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, matrix metalloproteinase (MMP)-3, and MMP-13. In addition, subchondral bone abnormal changes were ameliorated in OA rats with less mechanical loading, as reduced bone mineral density (BMD), bone volume/tissue volume (BV/TV), and number of osteophytes and osteoclasts in the subchondral bone were observed. Finally, the level of serum inflammatory cytokines was significantly downregulated in the less mechanical loading group compared with the normal mechanical loading group, as well as the expression of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), caspase-1, and interleukin 1β (IL-1β) in the cartilage. Conclusion: Less mechanical loading alleviates cartilage destruction, subchondral bone changes, and secondary inflammation in OA joints. This study provides fundamental insights into the benefit of non-weight loading rest for patients with OA.

A method combining crystal plasticity (CP), the eXtended Finite Element Method (XFEM), and cohesive zone model (CZM) with traction separation law is developed for an Al-Cu-Mg alloy to predict the effect of grain orientation on fatigue crack propagation (FCP) during stage ΙΙ within a single crystal. The simulation results show that of all the orientations, Goss grain possesses the largest fatigue crack deflection, then followed by Cube orientation. Comparatively, Brass, Copper, S and Random grains have relatively small crack deflection angles. Besides, it is found that Goss grain with the largest fatigue crack deflection possesses the lowest FCP rate as compared with other orientations. The results of simulations are consistent with previous experimental observations. This indicates that this coupled CP XFEM CZM simulation method is capable of well predicting the effect of grain orientation on FCP during fatigue stage ΙΙ of Al-Cu-Mg single crystal.

Stress formation of monocrystals and bicrystals is investigated in specific oriented grains and grain boundaries of AA2024 alloy by using Crystal Plasticity Finite Element Method (CPFEM). The simulations show that the maximum Schmid factor (SF) value and the number of equivalent initial slip system (EISS) play a principal role in controlling the magnitude of internal stress within monocrystals. For bicrystal model, Goss and Cube grains are not the best ones for relieving stress concentration caused by their orientations, but they are the best ones for relieving grain boundary (GB) stress concentration. To this end, the dependence relations are discussed between GB stress and an advanced comprehensive factor combining SF, and geometry compatibility factor for 5 independent slip systems. It is found that this proposed comprehensive factor considering the contribution from 5 to independent slip systems effectively improves its dependence on GB stress.

Summary: It has been shown that histone deacetylase (HDAC) inhibitors hold considerable therapeutic potentials for treating neurodegeneration-related diseases including Parkinson disease (PD). Here, we synthesized an HDAC inhibitor named as HGC and examined its neuroprotective roles in PD models. Our results showed that HGC protects dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced insults. Furthermore, in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model mice, HGC application rectifies behavioral defects, improves tyrosine hydroxylase-positive neurons in the midbrain, and maintains mitochondrial integrity and functions. Mechanistically, mass spectrometry data revealed that HGC stimulates acetylation modification at lysine 28 of NDUFV1. Inhibition of HDAC6 by HGC is responsible for this acetylation modification. Functional tests showed that, as well as HGC, NDUFV1 exhibits beneficial roles against MPP+ injuries. Moreover, knockdown of NDUFV1 abolishes the neuroprotective roles of HGC. Taken together, our data indicate that HGC has a great therapeutic potential for treating PD and NDUFV1 might be a target for developing drugs against PD.

Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the “double-locked” strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-β-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of β-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first “key”) and pH (second “key”), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.

Chemodynamic therapy (CDT) based on intracellular Fenton reactions is attracting increasing interest in cancer treatment. A simple and novel method to regulate the tumor microenvironment for improved CDT with satisfactory effectiveness is urgently needed. Therefore, glutathione (GSH)/ROS (reactive oxygen species) dual-responsive supramolecular nanoparticles (GOx@BNPs) for chemo–chemodynamic combination therapy were constructed via host–guest complexation between water-soluble pillar[6]arene and the ferrocene-modified natural anticancer product betulinic acid (BA) prodrug, followed by encapsulation of glucose oxidase (GOx) in the nanoparticles. The novel supramolecular nanoparticles could be activated by the overexpressed GSH and ROS in the tumor microenvironment (TME), not only accelerating the dissociation of nanoparticles—and, thus, improving the BA recovery and release capability in tumors—but also showing the high-efficiency conversion of glucose into hydroxyl radicals (·OH) in succession through intracellular Fenton reactions. Investigation of antitumor activity and mechanisms revealed that the dramatic suppression of cancer cell growth induced by GOx@BNPs was derived from the elevation of ROS, decrease in ATP and mitochondrial transmembrane potential (MTP) and, finally, cell apoptosis. This work presents a novel method for the regulation of the tumor microenvironment for improved CDT, and the preparation of novel GSH/ROS dual-responsive supramolecular nanoparticles, which could exert significant cytotoxicity against cancer cells through the synergistic interaction of chemodynamic therapy, starvation therapy, and chemotherapy (CDT/ST/CT).

Abstract The Catsper channel is a sperm-specific, Ca2+-permeable, pH-dependent, and low voltage-dependent channel that is essential for the hyperactivity of sperm flagellum, chemotaxis towards the egg, capacitation and acrosome reaction. All of these physiological events require calcium entry into sperm cells. Remarkably, Catsper genes are exclusively expressed in the testis during spermatogenesis, and are sensitive to ion channel-induced pH change, such as NHEs, Ca2+ATPase, K+ channel, Hv1 channel and HCO3 − transporters. Furthermore, the Catsper channel is regulated by some physiological stimulants, such as progesterone, cyclic nucleotides (e.g., cAMP, cGMP), zona pellucida (ZP) glycoproteins and bovine serum albumin (BSA). All of these factors normally stimulate Ca2+ entry into sperm through the Catsper channel. In addition, the Catsper channel may be a potential target for male infertility treatment or contraception. This review will focus on the structure, functions, regulation mechanisms and medicinal targets of the Catsper channel.

Metal oxide-polymer nanocomposite has been proven to have selective bactericidal effects against the main and common pathogens (Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli)) that can cause harmful infectious diseases. As such, this study looked into the prospect of using TiO2/ZnO with linear low-density polyethylene (LLDPE) to inactivate S. aureus and E. coli. The physical, structural, chemical, mechanical, and antibacterial properties of the nanocomposite were investigated in detail in this paper. The production of reactive species, such as hydroxyl radicals (•OH), holes (h+), superoxide anion radicals (O2•¯), and zinc ion (Zn2+), released from the nanocomposite were quantified to elucidate the underlying antibacterial mechanisms. LLDPE/25T75Z with TiO2/ZnO (1:3) nanocomposite displayed the best performance that inactivated S. aureus and E. coli by 95% and 100%, respectively. The dominant reactive active species and the zinc ion release toward the superior antibacterial effect of nanocomposite are discussed. This work does not only offer depiction of the effective element required for antimicrobial biomedical appliances, but also the essential structural characteristics to enhance water uptake to expedite photocatalytic activity of LLDPE/metal oxide nanocomposite for long term application.