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Background Allergic reactions to mosquito bites are an increasing clinical concern. Due to the lack of availability of mosquito salivary allergens, they are underdiagnosed. Here, we reported a newly cloned mosquito Aedes ( Ae.) aegypti salivary allergen. Methods A cDNA encoding a 30- kDa Ae. aegypti salivary protein, designated Aed a 3, was isolated from an expression library. The full-length cDNA was cloned into a baculovirus expression vector, and recombinant Aed a 3 ( rAed a 3) was expressed, purified, and characterized. Skin prick tests with purified rAed a 3 and Ae. aegypti bite tests were performed in 43 volunteers. Serum rAed a 3-specific IgE levels were measured in 28 volunteers. Results The primary nucleotide sequence, deduced amino acid sequence, and IgE-binding sites of Aed a 3 were identified. rAed a 3-selected antibodies recognized a 30- kDa Ae. aegypti saliva protein. rAed a 3 bound IgE in mosquito-allergic volunteers and the binding could be inhibited by the addition of natural mosquito extract dose dependently. Immediate skin test reactions to rAed a 3 correlated significantly with mosquito bite-induced reactions. Of the bite test-positive volunteers, 32% had a positive rAed a 3 skin test and 46% had specific IgE. No bite test-negative volunteers reacted to rAed a 3 in either the skin tests or the IgE assays, confirming the specificity of the assay. Conclusions Aed a 3 that corresponds to the Aegyptin protein is a major mosquito salivary allergen. Its recombinant form has biological activity and is suitable for use in skin tests and specific IgE assays in mosquito-allergic individuals. [ABSTRACT FROM AUTHOR]

Emerging evidence shows that elevated cholesterol levels are detrimental to health. However, it is unclear whether there is an association between cholesterol and the pituitary. We investigated the effects of a high-cholesterol diet on pituitary hormones using in vivo animal studies and an epidemiological study. In the animal experiments, rats were fed a high-cholesterol or control diet for 28 weeks. In rats fed the high-cholesterol diet, serum levels of thyroid-stimulating hormone (TSH; also known as thyrotrophin), luteinising hormone (LH) and follicle-stimulating hormone (FSH) produced by the basophilic cells of the anterior pituitary were elevated in a time-dependent manner. Among these hormones, TSH was the first to undergo a significant change, whereas adrenocorticotrophic hormone (ACTH), another hormone produced by basophilic cells, was not changed significantly. As the duration of cholesterol feeding increased, cholesterol deposition increased gradually in the pituitary. Histologically, basophilic cells, and especially thyrotrophs and gonadotrophs, showed an obvious increase in cell area, as well as a potential increase in their proportion of total pituitary cells. Expression of the β-subunit of TSH, FSH and LH, which controls hormone specificity and activity, exhibited a corresponding increase. In the epidemiological study, we found a similar elevation of serum TSH, LH and FSH and a decrease in ACTH in patients with hypercholesterolaemia. Significant positive correlations existed between serum total cholesterol and TSH, FSH or LH, even after adjusting for confounding factors. Taken together, the results of the present study suggest that the high-cholesterol diet affected the levels of hormones derived from anterior pituitary basophilic cells. This phenomenon might contribute to the pituitary functional disturbances described in hypercholesterolaemia. [ABSTRACT FROM AUTHOR]

Background Family-centred service ( FCS) has become essential to parents of children with cerebral palsy ( CP) and professionals in Chinese paediatric rehabilitation services. FCS practice meets the unique needs of the child and family, through facilitation of optimal service provision delivered by professionals, and ensures service systems to be flexible, appropriate and actively responsive to the family needs. Parents used the Measure of Processes of Care 20 ( MPOC-20) questionnaire to evaluate and verify the efficacy of use in China. The aims of the present study were twofold: to assess the validity and reliability of the Chinese MPOC-20, and investigate the range of parents' satisfaction with service provision in an FCS practice using the MPOC-20. Methods The Chinese MPOC-20 was selected to assess parent satisfaction with service provision of professionals in FCS practice. Participants were parents of children under 8 years of age with CP, who had received rehabilitation services between May 2012 and May 2013, and were receiving rehabilitation services in May 2013 at a hospital outpatient department and a rehabilitation centre. Results The reliability and validity of the Chinese MPOC-20 were confirmed. Parents evaluated FCS practice with the MPOC-20 survey. Respectful and supportive care was rated with the highest score and providing general information the lowest. Parents according to the data were dissatisfied with the lack of information. Conclusions Parents fairly evaluated service provision of professionals in FCS practice with the Chinese MPOC-20. Professionals received feedback reports of parents, summaries of the inadequacy of service delivery, and developed and implemented ameliorated measures in the FCS policy to strive to provide exemplary service. [ABSTRACT FROM AUTHOR]

Aim To determine whether the cisplatin plus etoposide ( EP) combination was more efficacious and less toxic than other platinum-based regimens for patients with extensive-stage small-cell lung cancer. Methods We performed an extensive literature search (from their inception to July 2010). Two reviewers independently assessed search results and methodological quality of included studies. Pooled hazard ratios ( HRs) and relative risks ( RRs) were calculated according to a random-effects model. Results Twelve randomised, controlled trials involving seven different platinum-based chemotherapy regimens were included into this meta-analysis. The meta-analysis showed that compared with EP regimen, irinotecan plus cisplatin ( IP) might decrease the risk of death ( HR = 0.87, 95% confidence interval ( CI) 0.78-0.97, P = 0.01) (five trials), unlike the sensitivity analysis ( HR = 0.91, 95% CI 0.81-1.02, P = 0.12), progression-free survival ( HR = 0.95, 95% CI 0.86-1.05, P = 0.28) and overall response rate ( RR 1.08, 95% CI 0.93-1.24) that were not superior for IP. IP regimen produced more non-haematological toxicities and less haematological toxicities. One trial found that etoposide + cisplatin + epirubicin + cyclophosphamide and cisplatin + etoposide + ifosfamide regimen might prolong the overall survival respectively. Etoposide + cisplatin + epirubicin + cyclophosphamide regimen also might improve progression-free survival but with high rate of haematological toxicities. None of the other trials included in the study demonstrated a significant improvement in survival. Conclusions There is no strong evidence that any clinical advantage for extensive small-cell lung carcinoma patients requiring chemotherapy when comparing EP with other platin-based regimens, with exception of IP that might prolong overall survival. The decision to prescribe which chemotherapy should take into consideration both cost and treatment preference. [ABSTRACT FROM AUTHOR]

Background Studies have found that the IL-23/Th17 pathway plays an important role in the pathogenesis of atopic dermatitis ( AD) and severe and steroid-resistant asthma. Targeting IL-23/Th17 pathway with monoclonal antibodies (mAb) has been successful in the reduction of skin and airway inflammation in animal models. However, the mAb has a short half-life, requiring repeated administrations. For the long-term suppression of IL-23/Th17 pathway, we have previously developed an IL-23p40 peptide-based virus-like particle vaccine, which induces long-lasting autoantibodies to IL-23. Objective We sought to evaluate the effects of this IL-23p40 peptide-based vaccine on the down-regulation of allergic skin and airway inflammation in mice. Methods Mice were subcutaneously injected three times with the IL-23p40 vaccine, or the vaccine carrier protein or saline as controls. Two weeks later, mice were epicutaneously sensitized with ovalbumin four times at a 2-week interval. One week after the final sensitization, mice were nasally administrated with ovalbumin daily for 3 days. One day later, bronchoalveolar lavage fluids ( BALF), sera, lung and skin tissues were obtained and analysed. Results Mice immunized with the vaccine produced high levels of IgG antibodies to IL-23, p40 and IL-12 that in vitro inhibited IL-23-dependent IL-17 production. The numbers of total cells, neutrophils, and eosinophils in BALF were significantly reduced in the vaccine group, compared with controls. The levels of IL-13, IL-5, IL-23 and, IL-17 in BALF and levels of serum ovalbumin-specific IgE, IgG1, and total IgE were also significantly decreased. Histological analysis showed less inflammation of the lung and skin tissues in the vaccine group, compared with controls. Conclusion and Clinical Relevance Administration of an IL-23p40 peptide-based vaccine down-regulates allergic skin and airway inflammation, suggesting that this strategy may be a potential therapeutic approach in the treatment of AD and asthma. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 1312-1317 (2010) Aims Lipotoxicity has recently been shown to be an important risk factor underlying the pathogenesis of pre-diabetes. However, clinical evidence supporting the treatment of pre-diabetes by improving lipotoxicity is lacking. Here, we conducted an open-label, randomized, controlled trial to investigate whether fenofibrate, the widely used hypolipidaemic agent, might benefit pre-diabetes, with metfomin and diet control, the recommended intervention methods, as positive controls. Methods Newly diagnosed pre-diabetes patients ( n = 120) with hypertriglyceridaemia (plasma triglyceride levels between 1.8 and 4.5 mmol/l) were randomly assigned by computer-generated randomization sequence to either control group (no intervention), fenofibrate group (200 mg once a day), metformin group (500 mg three times a day) or diet-controlled group (diet recommendation). Plasma biochemistry examination was performed every 2 months. The primary endpoint was the outcome of the natural course of pre-diabetes, evaluated by oral glucose tolerance test after 6-month follow-up. Results Twenty subjects in the fenofibrate group, 24 subjects in the metformin group and 25 subjects in both the diet-controlled group and the control group finished the trial. Fenofibrate, metformin and diet control had protective effects on hypertriglyceridaemic pre-diabetes, evidenced by 53.3, 70 and 30% participants regressed to normoglycaemia, respectively. The effects of fenofibrate and metformin were comparable ( P > 0.05), while diet control was less effective ( P < 0.05). Liver damage occurred in six subjects in the fenofibrate group and gastrointestinal symptoms occurred in four subjects in the metformin group. No serious adverse events occurred. Conclusion Controlling lipotoxicity by fenofibrate could effectively ameliorate the natural course of hypertriglyceridaemic pre-diabetes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The mechanism by which chronic alcohol consumption impairs insulin sensitivity is unclear. We investigated the role of the Gs alpha-mediated pathway in decreasing insulin sensitivity in skeletal muscle after ethanol consumption. METHODS: Sixty male Wistar rats, divided into four groups, received either distilled water (controls; group I) or ethanol, which was administered by a gastric tube as a single daily dose of 5 g/kg (group II), 2.5 g/kg (group III), or 0.5 g/kg (group IV). After 20 weeks, fasting plasma glucose and serum insulin levels were measured. The hyperinsulinemic-euglycemic clamp study was performed under anesthesia to estimate whole-body insulin sensitivity. Insulin-stimulated glucose uptake was measured in vitro in dissected gastrocnemius muscle. Expression of glut4, Gs alpha, and Gi alpha was quantified using real-time PCR analysis and western blotting. cAMP levels were measured by ELISA. RESULTS: Compared with controls, the following observations were made: (1) the hyperinsulinemic-euglycemic clamp study revealed impaired insulin action at the whole-body level after ethanol treatment; (2) chronic ethanol feeding at 5 g/kg and 2.5 g/kg significantly decreased both basal and insulin-stimulated glucose uptakes in isolated skeletal muscle (p<0.05), which was accompanied by decreased expression of glut4 (p<0.05); (3) Gs alpha (mRNA and protein) expression in skeletal muscle was significantly increased in all three ethanol groups (p<0.05), and cAMP levels were also increased by ethanol treatment (p<0.05); and (4) there was no significant change in Gi alpha expression in all three ethanol groups. CONCLUSIONS: Chronic ethanol exposure decreased insulin-induced glucose uptake in rat skeletal muscle, which was associated with increased expression of Gs alpha. Because Gs alpha is a negative regulator of insulin sensitivity, the alteration in Gs alpha expression may contribute to the ethanol-induced impairment of insulin signal transduction. [ABSTRACT FROM AUTHOR]

The relationships between extra- and intra-cellular carbonic anhydrase, calcification rate, utilization of dissolved inorganic carbon (DIC) and culture age were investigated in a high-calcifying strain of Emiliania huxleyi. The detection of carbonic anhydrase was dependent on culture age; neither the extra-cellular activity of intact cells nor activity in crude homogenates was detected until the stationary phase. By the stationary phase DIC in the medium was totally depleted and the calcification rate had decreased by 60%. Extra- and intra-cellular carbonic anhydrase was stimulated by Na+ but not Cl ions. The isolation of intact organelles by isopycnic gradient centrifugation from exponential and stationary phase cultures of high calcifying cells showed high carbonic anhydrase activity in the chloroplast fraction but carbonic anhydrase was not detected in low-calcifying cells even after gradient centrifugation. Although 50 μM ethoxyzolamide was an effective inhibitor of carbonic anhydrase activity in vitro, photosynthetic 14CO2 fixation was only inhibited 30%, calcification rate 10% and the internal inorganic carbon pool unaffected in intact cells. It is proposed that chloroplast carbonic anhydrase maintains the steady state flux of CO2 from the chloroplast envelope to Rubisco, much of the CO2 arising by release from HCO3-, in the cytosol, required to maintain cytoplasmic pH near neutrality in high-calcifying cells. [ABSTRACT FROM AUTHOR]

A response by Z. Peng to a letter to the editor about his article "Targeting IL-23 by employing a p40 peptide-based vaccine ameliorates murine allergic skin and airway inflammation" is presented.

ABSTRACT High temperature isothermal fatigue (IF) and in-phase thermo-mechanical fatigue (TMF) tests in load control were carried out in cast hot work die steel. At the same load amplitude, the fatigue lives obtained in the in-phase TMF tests are lower than those obtained in the isothermal tests. Observations of fracture surface and the response of stress–strain reveal that cyclic creep in the tensile direction occurs and the intergranular cracks dominate in TMF tests, whereas cyclic creep in the compressive direction occurs and the path of the crack growth is mainly transgranular in IF tests. A model of life prediction, based on the Chaboche law, was discussed. Damage coefficients that are functions of the maximum temperature and the variation of temperature are introduced in the model so as to evaluate TMF lives in load control. With this method, the lifetime prediction gives results corresponding well to experimental data. [ABSTRACT FROM AUTHOR]

Aim: This study examined the diabetes burden in Fujian Province, China, from 1990 to 2019, comparing it with China and global levels to inform policymakers., Materials and Methods: We used data from GBD 2019 to analyse diabetes prevalence, death, and disability-adjusted life-years (DALYs). We assessed the average annual percentage change (AAPC) and estimated the impact of 17 risk factors. An age-period-cohort model evaluated age, period, and cohort effects on diabetes metrics. Bayesian models forecasted prevalence and DALYs for 2020-2030, with frontier analysis linking DALYs to per capita GDP., Results: In 2019, Fujian Province had approximately 2,359,179 diabetes cases with a prevalence rate of 4423.82 (95% UI 4004.12-4864.55) per 100,000 and an age-standardised DALYs of 475.00 (375.63-589.49) per 100,000, both lower than China and global averages. From 1990 to 2019, Fujian Province's age-standardised mortality rate remained higher than the China average, but the gap narrowed compared with 1990. Elderly males showed a pronounced increase in mortality. The period effect indicated a turning point during 2005-2009. DALYs increased among men and decreased among women over cohorts. By 2030, the DALYs rate is projected to decrease by 6.59%. Frontier analysis showed that compared with the same economic level, the effective difference in diabetes disease burden in Fujian Province was small, but there was room for improvement., Conclusion: From 1990 to 2019, Fujian Province's age-standardised diabetes prevalence slightly increased, while mortality and DALYs declined. Significant gender and age disparities existed, highlighting the need for targeted strategies for elderly males. Fujian Province's success in diabetes management can provide a model for other regions., (© 2025 John Wiley & Sons Ltd.)

This study aimed to investigate the expression pattern and mechanisms of Pyruvate Dehydrogenase Phosphatase Catalytic Subunit 1 (PDP1) in the progression of breast cancer (BC). PDP1, known for its involvement in cell energy metabolism, was found to be overexpressed in BC tissues. Notably, low PDP1 expression aligns with improved overall survival (OS) in BC patients. In this study, we found that PDP1 was overexpressed among BC tissues and low PDP1 expression showed a better prognosis for the patients with BC. PDP1 knockdown suppressed cell amplification and migration and triggered cell apoptosis in BC cells. In vivo assessments through a xenograft model unveiled the pivotal role and underlying mechanisms of PDP1 knockdown. RNA sequencing and kyoto encyclopedia of genes and genomes analysis of RNAs from PDP1 knockdown and normal MCF7 cells revealed 1440 differentially expressed genes, spotlighting the involvement of the JAK/STAT3 signaling pathway in BC progression. Western blot results implied that PDP1 knockdown led to a loss of p-STAT3, whereas overexpression of PDP1 induced the p-STAT3 expression. Cell counting kit-8 assay showed that PDP1 overexpression significantly raised MDA-MB-231 and MCF7 cell viability while STAT3 inhibitor S3I-201 recovered the cell growth to normal level. To summarize, PDP1 promotes the progression of BC through STAT3 pathway by regulating p-STAT3. The findings contribute to understanding the molecular mechanisms underlying BC progression, and opening avenues for targeted therapeutic approaches., (© 2024 John Wiley & Sons Ltd.)

Aim: We investigated the mechanism, whereby tumor necrosis factor-like ligand 1A (TL1A) mediates the A1 differentiation of astrocytes in postoperative cognitive dysfunction (POCD)., Methods: The cognitive and behavioral abilities of mice were assessed by Morris water maze and open field tests, while the levels of key A1 and A2 astrocyte factors were detected by RT-qPCR. Immunohistochemical (IHC) staining was used to examine the expression of GFAP, western blot was used to assay the levels of related proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory cytokines., Results: The results showed that TL1A could promote the progression of cognitive dysfunction in mice. Astrocytes differentiated into A1 phenotype, while unobvious changes were noted in astrocyte A2 biomarkers. Knockout of NLRP3 or intervention with NLRP3 inhibitor could inhibit the effect of TL1A, improving the cognitive dysfunction and suppressing the A1 differentiation., Conclusion: Our results demonstrate that TL1A plays an important role in POCD in mice, which promotes the A1 differentiation of astrocytes through NLRP3, thereby exacerbating the progression of cognitive dysfunction., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aim: This study was aimed at exploring the mechanism by which aurantiamide (Aur) targeted NLRP3 to suppress microglial cell polarization., Methods: The 7-month-old APP/PS1 mice and C57BL/6 mice were applied to be the study objects, and Aur was administered intragastrically to APP/PS1 mice at 10 mg/kg and 20 mg/kg. The changes in the neurocognitive function of mice were measured by Morris Water Maze (MWM) test. In the in vitro experiments, the mouse BV2 cells were employed as the study objects, which were subject to treatment with 10 μM and 20 μM Aur and induced with LPS and IFN-γ in order to activate BV2 cells and induce their M1 polarization., Results: Aur was found to suppress the M1 polarization of mouse microglia, reduce central neuroinflammation, and improve the cognitive function in mice. Meanwhile, Aur suppressed the activation and the expression of NLRP3 inflammasome. The results of experiments in vitro demonstrated that Aur inhibited the activation and M1 polarization of BV2 cells., Conclusion: Aur targets NLRP3 and suppresses the activation of NLRP3 inflammasome., (© 2022 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background: Although alcohol-related liver disease (ALD) is a global health threat, there are no specific effective treatments for it. Thus, efforts at preventing ALD are important and could be enhanced by using strategies based on validated risk and protective factors for the disease., Methods: The literature on factors influencing the risk for ALD was systematically searched from PubMed, Embase, and the Cochrane library databases from inception to June 2022. Factors suitable for quantitative analysis were submitted to meta-analysis using fixed-effects and random-effects models to calculate each factor's risk ratio (RR) and 95% confidence interval (CI)., Results: Ten cohort studies (covering 1,005,339 subjects) that reported a clear causal relationship were included in the analysis, involving 11 potential risk factors (sex, race, education level, body mass index, alcohol consumption, types of alcoholic beverage, duration of drinking, drinking frequency, smoking, coffee consumption, and tea consumption). Three of these factors (sex, alcohol consumption, and smoking) were subjected to meta-analysis, and the results showed that male sex (RR = 2.84, 95% CI = 1.86-4.36), alcohol consumption ≥280 g/week (RR = 4.96, 95% CI = 2.71-9.07), and smoking (RR = 2.39, 95% CI = 1.97-2.89) were risk factors for ALD., Conclusions: Many factors are likely to influence the incidence of ALD, and male sex, heavy alcohol consumption, and smoking increase the risk of ALD. The relationship between other factors and ALD risk needs further evaluation., (© 2022 Research Society on Alcoholism.)

Human G protein-coupled receptor 56 (GPR56) is encoded by gene ADGRG1 from chromosome 16q21 and is homologously encoded in mice, at chromosome 8. Both 687 and 693 splice forms are present in humans and mice. GPR56 has a 381 amino acid-long N-terminal extracellular segment and a GPCR proteolysis site upstream from the first transmembrane domain. GPR56 is mainly expressed in the heart, brain, thyroid, platelets, and peripheral blood mononuclear cells. Accumulating evidence indicates that GPR56 promotes the formation of myelin sheaths and the development of oligodendrocytes in the cerebral cortex of the central nervous system. Moreover, GPR56 contributes to the development and differentiation of hematopoietic stem cells, induces adipogenesis, and regulates the function of immune cells. The lack of GPR56 leads to nervous system dysfunction, platelet disorders, and infertility. Abnormal expression of GPR56 is related to the malignant transformation and tumor metastasis of several cancers including melanoma, neuroglioma, and gastrointestinal cancer. Metabolic disorders and cardiovascular diseases are also associated with dysregulation of GPR56 expression, and GPR56 is involved in the pharmacological resistance to some antidepressant and cancer drug treatments. In this review, the molecular structure, expression profile, and signal transduction of GPR56 are introduced, and physiological and pathological functions of GRP56 are comprehensively summarized. Attributing to its significant biological functions and its long N-terminal extracellular region that interacts with multiple ligands, GPR56 is becoming an attractive therapeutic target in treating neurological and hematopoietic diseases., (© 2022 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Objective: We did a network meta-analysis and systematic review among patients seeking for maximum anchorage and provided a guidance of selecting certain systems in clinical practice., Methods: Seven databases were searched, and randomized controlled trials (RCTs) published with no language restrictions from January 1994 to February 2021 comparing any of the following seven anchorage systems for maximum anchorage orthodontic treatment were selected(PROSPERO: CRD42019117995). A network meta-analysis (NMA) was then conducted to integrate direct evidence with indirect evidence based on logical inference to compare and rank treatments for maximum anchorages in the capacity of maintaining anchorage and duration of total treatment time., Results: Nine publications with 522 participants were considered eligible and were taken into evaluation. According to the capacity of anchorage reinforcement, three skeleton anchorages including miniscrew implants, midpalate implants and Onplant midpalate implants were significantly more effective than conventional anchorages including headgears, TPAs and Nance buttons respectively. According to conventional anchorages, headgears and Nance buttons were significantly more effective than TPA. The strategy ranking reflected the same results as above. However, miniscrew implants required the longest total treatment time., Conclusions: In general, miniscrew impants are most effective in reserving anchorage. Nance buttons require the least total treatment time. Total evidence is graded as moderate. Midpalatal implants might be the best choice when doing treatment planning because it has the most favorable balance between effectiveness and treatment time. But data analysis of the acceptability and acquisition cost of those anchorage systems must be done to make final decisions., (© 2021 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

This study aimed to identify the prognostic factors in patients with Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL), comparing the efficacy of radiotherapy (RT) for the WR-DLBCL patients in the pre-rituximab and rituximab eras. We conducted a retrospective analysis of 134 patients diagnosed with WR-DLBCL. Univariate and multivariate analyses were performed to identify the prognostic factors for WR-DLBCL. Then, we divided these patients into the rituximab plus chemotherapy group (R-chemotherapy) (n = 88) and chemotherapy group (n = 46), and the Kaplan-Meier and Cox regression model analyses were applied to investigate the treatment value of RT in both the groups. Multivariate analysis revealed international prognostic index (IPI) ≥ 3 and chemotherapy without rituximab as significant risk factors for the progression-free survival (PFS, IPI ≥ 3: p = 0.001; chemotherapy without rituximab: p = 0.002) and overall survival (OS, IPI ≥ 3, p < 0.001; chemotherapy without rituximab, p = 0.024). Rituximab combined with chemotherapy significantly improved PFS (p = 0.002) and OS (p = 0.006) in these patients. RT did not significantly contribute to the survival in the overall cohort analysis, whereas in the subgroup analysis, RT significantly improved the PFS (p = 0.025) and OS (p = 0.029) for the patients in the chemotherapy group, but not in the R-chemotherapy group. In conclusion, the WR-DLBCL patients could benefit from RT in the pre-rituximab era, whereas the addition of rituximab to chemotherapy significantly improved the survival of WR-DLBCL patients, and the clinical benefit of RT was reduced., (© 2021 John Wiley & Sons Ltd.)

Our previous study has found that aureusidin can inhibit inflammation by targeting myeloid differentiation 2 (MD2) protein. Structural optimization of aureusidin gave rise to a derivative named CNQX. LPS was used to induce inflammation in intestinal macrophages; flow cytometry, PI staining and Hoechst 33342 staining were used to detect the apoptotic level of macrophages; enzyme-linked immunosorbent assay (ELISA) was utilized to detect the expression level of inflammatory factors (including IL-1β, IL-18 and TNF-α); immunofluorescence staining was used to investigate the expression of MD2; Western blot was employed to measure the protein level of TLR4, MD2, MyD88 and p-P65. As a result, CNQX with IC50 of 2.5 μM can significantly inhibit the inflammatory damage of macrophages, decrease apoptotic level, reduce the expression level of inflammatory factors and simultaneously decrease the expression level of TLR4, MD2, MyD88 as well as p-P65. Caco-2 cell line was used to simulate the intestinal mucosal barrier in vitro, LPS was employed to induce cell injury in Caco-2 (to up-regulate barrier permeability), and CNQX with IC50 of 2.5 μl was used for intervention. Flow cytometry was used to detect the apoptotic level of Caco-2 cells, trans-epithelial electric resistance (TEER) was measured, FITC-D was used to detect the permeability of the intestinal mucosa, and Western blot was used to detect the expression levels of tight junction proteins (including occludin, claudin-1, MyD88, TLR4 and MD2). As a result, CNQX decreased the apoptotic level of Caco-2 cells, increased TEER value, decreased the expression levels of MyD88, TLR4 and MD2, and increased the protein levels of tight junction proteins (including occludin and claudin-1). C57BL/6 wild-type mice were treated with drinking water containing Dextran sulphate sodium (DSS) to establish murine chronic colitis model. After CQNX intervention, we detected the bodyweight, DAI score and H&E tissue staining to evaluate the life status and pathological changes. Immunohistochemistry (IHC) staining was used to detect the expression of MD2 protein, tight junction protein (including occludin and claudin-1). Transmission electron microscopy and FITC-D were used to detect intestinal mucosal permeability. Western blot was used to detect the expression levels of tight junction proteins (including occludin, claudin-1, MyD88, TLR4 and MD2) in the intestinal mucosa tissue. Consequently, CNQX can inhibit the intestinal inflammatory response in mice with colitis, inhibit the mucosal barrier injury, increase the expression of tight junction proteins (including occludin and claudin-1) and decrease the expression levels of MyD88, TLR4 and MD2. Mechanistically, pull-down and immunoprecipitation assays showed that CNQX can inhibit the activation of TLR4/MD2-NF-κB by binding to MD2 protein. Collectively, in this study, we found that CNQX can suppress the activation of TLR4 signals by targeting MD2 protein, thereby inhibiting inflammation and mucosal barrier damage of chronic colitis., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The previous study by our group has found that miRNA-22 can inhibit pyroptosis by targeting GSDMD and improve the memory and motor ability of mice with Alzheimer's disease (AD) mice by inhibiting inflammatory response. In recent years, stem cells and their exosomes have been reported to have good therapeutic effects on AD; therefore, we hypothesize that miRNA-22 is likely to play a synergistic therapeutic effect. In this study, adipose-derived mesenchymal stem cells (ADMSCs) were transfected into miRNA-22 mimic to obtain miRNA-22 loaded exosomes (Exo-miRNA-22), which was further used for the treatment and nerve repair of AD. In brief, 4-month-old APP/PS1 mice were assigned into the control group, Exo and Exo-miRNA-22 groups. After exosome transplantation, we observed changes in the motor and memory ability of mice. In addition, ELISA was used to detect the expression of inflammatory factors in cerebrospinal fluid and peripheral blood, Nissl staining was used to assess the survival of mouse nerve cells, immunofluorescence staining was used to determine the activation of microglia, and Western blot was utilized to detect the expression of pyroptosis-related proteins. As a result, the nerve function and motor ability were significantly higher in mice in the Exo-miRNA-22 group than those in the control group and Exo group. Meanwhile, the survival level of nerve cells in mice was higher in the Exo-miRNA-22 group, and the expression of inflammatory factors was lower than that of the Exo group, indicating Exo-miRNA-22 could significantly suppress neuroinflammation. In vitro culture of PC12 cells, Aβ 25-35 -induced cell damage, detection of PC12 apoptotic level, the release of inflammatory factors and the expression of pyroptosis-related proteins showed that Exo-miRNA-22 could inhibit PC12 apoptosis and significantly decrease the release of inflammatory factors. In this study, we found that miRNA-22-loaded ADMSC-derived exosomes could decrease the release of inflammatory factors by inhibiting pyroptosis, thereby playing a synergetic therapeutic role with exosomes on AD, which is of great significance in AD research., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Proteoglycans (PGs) are largely glycosylated proteins, consisting of a linkage sugar, core proteins, and glycosaminoglycans (GAGs). To date, more than 40 kinds of PGs have been identified, and they can be classified as intracellular, cell surface, pericellular, and extracellular PGs according to cellular locations. To illustrate, extracellular PGs are known for regulating the homeostasis of the extracellular matrix; cell-surface PGs play a role in mediating cell adhesion and binding various growth factors. In the field of periodontology, PGs are implicated in cellular proliferation, migration, adhesion, contractility, and anoikis, thereby exerting a profound influence on periodontal tissue development, wound repair, the immune response, biomechanics, and pathological process. Additionally, the expression patterns of some PGs are dynamic and cell-specific. Therefore, determining the roles and spatial-temporal expression patterns of PGs in the periodontium could shed light on treatments for wound healing, tissue regeneration, periodontitis, and gingival overgrowth. In this review, close attention is paid to the distributions, functions, and potential applications of periodontal PGs. Related genetically modified animal experiments and involved signal transduction cascades are summarized for improved understanding of periodontal PGs. To date, however, there is a large amount of speculation on this topic that requires rigorous experiments for validation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Trisomy 12 is a rare autosomal aneuploidy. All postnatally diagnosed individuals with trisomy 12 have been mosaic for this chromosome abnormality. We herein report an infant girl presented at 2 weeks of age with severe congenital heart defect, tracheobronchomalacia, and dysmorphic features. All of the dysmorphic features of this patient fit into the known phenotype spectrum of mosaic trisomy 12, although this patient uniquely presented with macrocephaly. Tracheo-bronchomalacia has been described once previously but had a significant impact on this patient's clinical course. The patient passed away at 2-month-old due to cardiac and respiratory complications. Chromosomal single nucleotide polymorphism (SNP) microarray analysis on a peripheral blood sample from the patient revealed trisomy 12 in approximately 50% of cells. Concurrent fluorescence in situ hybridization analysis of uncultured blood cells detected a comparable level of trisomy 12 mosaicism. Compared to conventional cytogenetics, SNP microarray examines all nucleated cells without sampling bias, has an increased power to estimate mosaicism level, and can provide a quick assessment of the underlying mechanism. Here we demonstrate the utilization of SNP microarray in the clinical diagnosis of those once considered rare disorders but might have been missed by conventional cytogenetic techniques., (© 2021 Wiley Periodicals LLC.)

The present study was designed to investigate the role of β-amyloid (Aβ 1-42 ) in inducing neuronal pyroptosis and its mechanism. Mice cortical neurons (MCNs) were used in this study, LPS + Nigericin was used to induce pyroptosis in MCNs (positive control group), and Aβ 1-42 was used to interfere with MCNs. In addition, propidium iodide (PI) staining was used to examine cell permeability, lactate dehydrogenase (LDH) release assay was employed to detect cytotoxicity, immunofluorescence (IF) staining was used to investigate the expression level of the key protein GSDMD, Western blot was performed to detect the expression levels of key proteins, and enzyme-linked immunosorbent assay (ELISA) was utilized to determine the expression levels of inflammatory factors in culture medium, including IL-1β, IL-18 and TNF-α. Small interfering RNA (siRNA) was used to silence the mRNA expression of caspase-1 and GSDMD, and Aβ 1-42 was used to induce pyroptosis, followed by investigation of the role of caspase-1-mediated GSDMD cleavage in pyroptosis. In addition, necrosulfonamide (NSA), an inhibitor of GSDMD oligomerization, was used for pre-treatment, and Aβ 1-42 was subsequently used to observe the pyroptosis in MCNs. Finally, AAV9-siRNA-caspase-1 was injected into the tail vein of APP/PS1 double transgenic mice (Alzheimer's disease mice) for caspase-1 mRNA inhibition, followed by observation of behavioural changes in mice and measurement of the expression of inflammatory factors and pyroptosis-related protein. As results, Aβ 1-42 could induce pyroptosis in MCNs, increase cell permeability and enhance LDH release, which were similar to the LPS + Nigericin-induced pyroptosis. Meanwhile, the expression levels of cellular GSDMD and p30-GSDMD were up-regulated, the levels of NLRP3 inflammasome and GSDMD-cleaved protein caspase-1 were up-regulated, and the levels of inflammatory factors in the medium were also up-regulated. siRNA intervention in caspase-1 or GSDMD inhibited Aβ 1-42 -induced pyroptosis, and NSA pre-treatment also caused the similar inhibitory effects. The behavioural ability of Alzheimer's disease (AD) mice was relieved after the injection of AAV9-siRNA-caspase-1, and the expression of pyroptosis-related protein in the cortex and hippocampus was down-regulated. In conclusion, Aβ 1-42 could induce pyroptosis by GSDMD protein, and NLRP3-caspase-1 signalling was an important signal to mediate GSDMD cleavage, which plays an important role in Aβ 1-42 -induced pyroptosis in neurons. Therefore, GSDMD is expected to be a novel therapeutic target for AD., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

High mortality of patients with cervical cancer (CC) stresses the imperative of prognostic biomarkers for CC patients. Additionally, the vital status of post-translational modifications (PTMs) in the progression of cancers has been reported by numerous researches. Therefore, the purpose of this research was to dig a prognostic signature correlated with PTMs for CC. We built a five-mRNA (GALNTL6, ARSE, DPAGT1, GANAB and FURIN) prognostic signature associated with PTMs to predict both disease-free survival (DFS) (hazard ratio [HR] = 3.967, 95% CI = 1.985-7.927; P < .001) and overall survival (HR = 2.092, 95% CI = 1.138-3.847; P = .018) for CC using data from The Cancer Genome Atlas database. Then, the robustness of the signature was validated using GSE44001 and the Human Protein Atlas (HPA) database. CIBERSORT algorithm analysis displayed that activated CD4 memory T cell was also an independent indicator for DFS (HR = 0.426, 95% CI = 0.186-0.978; P = .044) which could add additional prognostic value to the signature. Collectively, the PTM-related signature and activated CD4 memory T cell can provide new avenues for the prognostic predication of CC. These findings give further insights into effective treatment strategies for CC, providing opportunities for further experimental and clinical validations., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: The high-fat diet (HFD)-induced obesity is responsible for the testosterone deficiency (TD). However, the mechanism remains unknown. Mitochondrial homeostasis is proved to be important for maintaining the function of steroidogenic acute regulatory protein (StAR), the first rate-limiting enzyme in testosterone synthesis. As the key regulator of mitochondrial membrane permeability, cyclophilin D (CypD) plays a crucial role in maintaining mitochondrial function. In this study, we sought to elucidate the role of CypD in the expression of StAR affected by HFD., Methods: To analyse the influence of CypD on StAR in vivo and in vitro, mouse models of HFD, CypD overexpression and CypD knockout (Ppif -/- ) as well as Leydig cells treated with palmitic acid (PA) and CypD overexpression plasmids were examined with an array of metabolic, mitochondrial function and molecular assays., Results: Compared with the normal diet mice, consistent with reduced testosterone in testes, the expressions of StAR in both mRNA and protein levels in HFD mice were down-regulated, while expressions of CypD were up-regulated. High-fat intake impaired mitochondrial function with the decrease in StAR in Leydig cells. Overexpression of CypD inhibited StAR expressions in vivo and in vitro. Compared with C57BL/6 mice with HFD, expressions of StAR were improved in Ppif -/- mice with HFD., Conclusions: Mitochondrial CypD involved in the inhibitory effect of HFD on StAR expression in testes., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Within lymphoid tissues, chronic lymphocytic leukaemia (CLL) cells interact with mesenchymal stromal cells (MSC). Inhibitors of phosphoinositide 3-kinase delta (PI3Kδ) cause release of CLL cells from lymphoid tissues into blood. PI3Kδ inhibitors are thought to target only CLL and other immune cells because PI3Kδ expression is restricted to haematopoietic cells. We found that PI3Kδ is unexpectedly expressed in primary MSC derived from CLL patients and healthy donors. PI3Kδ inhibition in MSC using idelalisib or duvelisib significantly reduced their ability to support CLL migration and adhesion. These observations provide the first evidence that PI3Kδ is expressed and functional in CLL MSC., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Emerging epidemiological studies indicate that hypercholesterolaemia is a risk factor for testosterone deficiency. However, the underlying mechanism is unclear. Testicular Leydig cells are the primary source of testosterone in males. To identify the effect and mechanism of cholesterol overload on Leydig cell function, rats were fed with a HC (HC) diet to induce hypercholesterolaemia. During the 16-week feeding period, serum testosterone levels were reduced in a time-dependent manner in rats fed the HC diet. Accordingly, these steroidogenic enzymes within the Leydig cells, including steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage cytochrome P450 (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD), were down-regulated. Notably, the HC-fed rats showed evident endoplasmic reticulum (ER) stress in the testis, including a dilated ER as an evident pathological change in the Leydig cell ultrastructure, up-regulated ER stress biomarker (binding immunoglobulin protein) levels and activation of the activating transcription factor 6 (ATF6)-related unfolded protein response pathway. Further analysis showed that when 4-phenyl butyric acid (4-PBA) was used to block ER stress in HC-fed rats for 8 weeks, the testosterone deficiency was significantly alleviated. Our findings suggested that high dietary cholesterol intake affected serum testosterone levels by down-regulating steroidogenic enzymes and that activated ER stress might serve as the underlying mechanism., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background and Aims: Methadone maintenance therapy (MMT) is associated with improved outcomes for children exposed to maternal opioid dependence in utero. We examined Ontario's population of pregnant women on MMT and determined the impact of timing of MMT initiation on perinatal outcomes., Design: Cohort study., Setting: Ontario, Canada., Participants: Women eligible for public drug benefits and on MMT during pregnancy between 2005 and 2015., Measurements: We stratified women based on their timing of MMT initiation: (1) stabilized prior to conception, (2) newly initiated prior to conception, (3) initiation in trimester 1, (4) initiation in trimester 2 or (5) initiation in trimester 3. The primary outcomes in the multivariable logistic regression analysis were key perinatal health indicators: small for gestational age, preterm birth, congenital anomalies, severe maternal morbidity, caesarean section and induced labor. Secondary outcomes were specific to maternal opioid dependence: neonatal abstinence syndrome (NAS), admission to a neonatal intensive care unit (NICU), NAS treatment, removal from mother's custody at hospital discharge and neonatal death., Findings: Among 1842 women on MMT during pregnancy, 87.6% (n = 1614) initiated MMT before conception. Almost a quarter of their infants (22.2%; n = 408) were born small for gestational age, 17.5% (n = 323) were preterm and 5.9% (n = 109) were born with a congenital anomaly. The odds of primary outcomes occurring did not differ based on timing of methadone initiation; however, infants of mothers who initiated methadone during pregnancy had up to a fourfold increase in the odds of social services removal at the hospital [adjusted odds ratio (aOR) range = 3.70-4.19] compared with those whose mothers were stabilized on MMT prior to conception., Conclusions: Later initiation of methadone maintenance therapy among pregnant women in Ontario, Canada has not been found to be clearly related to most key perinatal adverse health outcomes., (© 2018 Society for the Study of Addiction.)

Background & Aims: Currently, using biopsy specimens to confirm suspicious liver lesions of early hepatocellular carcinoma are not entirely reliable because of insufficient sampling amount and inaccurate sampling location. It is necessary to develop a signature to aid early hepatocellular carcinoma diagnosis using biopsy specimens even when the sampling location is inaccurate., Methods: Based on the within-sample relative expression orderings of gene pairs, we identified a simple qualitative signature to distinguish both hepatocellular carcinoma and adjacent non-tumour tissues from cirrhosis tissues of non-hepatocellular carcinoma patients., Results: A signature consisting of 19 gene pairs was identified in the training data sets and validated in 2 large collections of samples from biopsy and surgical resection specimens. For biopsy specimens, 95.7% of 141 hepatocellular carcinoma tissues and all (100%) of 108 cirrhosis tissues of non-hepatocellular carcinoma patients were correctly classified. Especially, all (100%) of 60 hepatocellular carcinoma adjacent normal tissues and 77.5% of 80 hepatocellular carcinoma adjacent cirrhosis tissues were classified to hepatocellular carcinoma. For surgical resection specimens, 99.7% of 733 hepatocellular carcinoma specimens were correctly classified to hepatocellular carcinoma, while 96.1% of 254 hepatocellular carcinoma adjacent cirrhosis tissues and 95.9% of 538 hepatocellular carcinoma adjacent normal tissues were classified to hepatocellular carcinoma. In contrast, 17.0% of 47 cirrhosis from non-hepatocellular carcinoma patients waiting for liver transplantation were classified to hepatocellular carcinoma, indicating that some patients with long-lasting cirrhosis could have already gained hepatocellular carcinoma characteristics., Conclusions: The signature can distinguish both hepatocellular carcinoma tissues and tumour-adjacent tissues from cirrhosis tissues of non-hepatocellular carcinoma patients even using inaccurately sampled biopsy specimens, which can aid early diagnosis of hepatocellular carcinoma., (© 2018 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Background: Lipotoxicity plays an important role in the pathogenesis of β-cell dysfunction. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that exerts beneficial effects on the number and function of islet β cells. However, the effect of lipotoxicity on GLP-1 secretion is still unknown., Methods: Twenty-five patients who were newly diagnosed with diabetes were recruited from 400 subjects based on 75-g Oral Glucose Tolerance Test. Patients were divided into diabetes (DM) and DM combined with hypertriglyceridaemia (DM + HTG) groups according to their serum triglyceride (TG) levels. Seventy-one normal controls and 17 patients with isolated hypertriglyceridaemia were matched by age and gender., Results: Total and active fasting GLP-1 and 2-hour GLP-1 levels were not significantly altered among the 4 groups. However, total and active ΔGLP-1 levels (the difference between 2-hour GLP-1 and fasting GLP-1 levels) were significantly reduced in the isolated HTG, DM, and DM + HTG groups, particularly the DM + HTG group. The ratio of serum active GLP-1 (AGLP-1) to total GLP-1 (TGLP-1) levels was also decreased in patients with isolated HTG, suggesting that active GLP-1 secretion may be more seriously impaired. Both ΔTGLP-1 and ΔAGLP-1 levels were negatively correlated with serum TG levels, body mass index and fasting plasma glucose (FPG) levels and positively correlated with HDL-C levels. According to the multivariate linear regression analysis, only TG and FPG levels were independently associated with ΔTGLP-1 and ΔAGLP-1 levels., Conclusion: Impaired GLP-1 secretion was associated with hypertriglyceridaemia and diabetes, and a more obvious association was noted in hypertriglyceridaemic patients with diabetes., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background & Aims: Concerns are raised about the representativeness of cell lines for tumours due to the culture environment and misidentification. Liver is a major metastatic destination of many cancers, which might further confuse the origin of hepatocellular carcinoma cell lines. Therefore, it is of crucial importance to understand how well they can represent hepatocellular carcinoma., Methods: The HCC-specific gene pairs with highly stable relative expression orderings in more than 99% of hepatocellular carcinoma but with reversed relative expression orderings in at least 99% of one of the six types of cancer, colorectal carcinoma, breast carcinoma, non-small-cell lung cancer, gastric carcinoma, pancreatic carcinoma and ovarian carcinoma, were identified., Results: With the simple majority rule, the HCC-specific relative expression orderings from comparisons with colorectal carcinoma and breast carcinoma could exactly discriminate primary hepatocellular carcinoma samples from both primary colorectal carcinoma and breast carcinoma samples. Especially, they correctly classified more than 90% of liver metastatic samples from colorectal carcinoma and breast carcinoma to their original tumours. Finally, using these HCC-specific relative expression orderings from comparisons with six cancer types, we identified eight of 24 hepatocellular carcinoma cell lines in the Cancer Cell Line Encyclopedia (Huh-7, Huh-1, HepG2, Hep3B, JHH-5, JHH-7, C3A and Alexander cells) that are highly representative of hepatocellular carcinoma. Evaluated with a REOs-based prognostic signature for hepatocellular carcinoma, all these eight cell lines showed the same metastatic properties of the high-risk metastatic hepatocellular carcinoma tissues., Conclusions: Caution should be taken for using hepatocellular carcinoma cell lines. Our results should be helpful to select proper hepatocellular carcinoma cell lines for biological experiments., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The effect of leucine on glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells is quite controversial, and mechanism involved in the effect has not been elucidated yet. Consequently, we aimed to investigate effect of leucine on GSIS and its mechanism focusing on contribution of AMP-activated protein kinase (AMPK) and pancreatic/duodenal homeobox-1 (PDX-1). Rat insulinoma beta-cells (INS-1, RIN m5F, DN-PDX-1#28 and PDX-1#6) were cultured with or without leucine, AICAR (AMPK agonist) or compound C (AMPK antagonist) for 48 hrs. In contrast to control, AICAR treatment decreased GSIS at high glucose and insulin content, also impaired protein and mRNA expression of PDX-1 and its downstream targets, glucokinase (GCK) and glucose transporter 2 (GLUT2). Compound C treatment had the opposite effects. We observed that neither AICAR nor compound C could affect expression of GCK and GLUT2 when PDX-1 expression was absent. Chronic leucine exposure inhibited GSIS at high glucose and insulin content in a dose-dependent manner, concomitant with an increase in AMPK and a decrease in PDX-1, GCK and GLUT2. The inhibitory effects of leucine was potentiated by AICAR treatment and rescued by compound C treatment. Finally, the inhibition of PDX-1 could potentiate the impaired effects induced by leucine whereas overexpression of PDX-1 could protect the cell from impairment induced by leucine. The study indicated that chronic leucine might result in an increase in AMPK and then a decrease in PDX-l, in turn to depress GCK and GLUT2 resulting in decreased GSIS at high glucose and insulin content.