Oncogenic and immunological roles of RACGAP1 in pan-cancer and its potential value in nasopharyngeal carcinoma.

A particular GTPase-activating protein called RACGAP1 is involved in apoptosis, proliferation, invasion, metastasis, and drug resistance in a variety of malignancies. Nevertheless, the role of RACGAP1 in pan-cancer was less studied, and its value of the expression and prognostic of nasopharyngeal carcinoma (NPC) has not been explored. Hence, the goal of this study was to investigate the oncogenic and immunological roles of RACGAP1 in various cancers and its potential value in NPC. We comprehensively analyzed RACGAP1 expression, prognostic value, function, methylation levels, relationship with immune cells, immune infiltration, and immunotherapy response in pan-cancer utilizing multiple databases. The results discovered that RACGAP1 expression was elevated in most cancers and suggested poor prognosis, which could be related to the involvement of RACGAP1 in various cancer-related pathways such as the cell cycle and correlated with RACGAP1 methylation levels, immune cell infiltration and reaction to immunotherapy, and chemoresistance. RACGAP1 could inhibit anti-tumor immunity and immunotherapy responses by fostering immune cell infiltration and cytotoxic T lymphocyte dysfunction. Significantly, we validated that RACGAP1 mRNA and protein were highly expressed in NPC. The Gene Expression Omnibus database revealed that elevated RACGAP1 expression was associated with shorter PFS in patients with NPC, and RACGAP1 potentially influenced cell cycle progression, DNA replication, metabolism, and immune-related pathways, resulting in the recurrence and metastasis of NPC. This study indicated that RACGAP1 could be a potential biomarker in pan-cancer and NPC.

Comparative efficacy of concurrent training types on lower limb strength and muscular hypertrophy: A systematic review and network meta-analysis.

Objective: This study aims to compare, through quantitative analysis, the effectiveness of different endurance training types on increasing lower limb strength and muscle cross-sectional area (MCSA) in concurrent training. Methods: This systematic literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [PROSPERO ID: CRD42023396886]. Web of Science, SportDiscuss, Pubmed, Cochrane, and Scopus were systematically searched from their inception date to October 20, 2023. Results: A total of 40 studies (841 participants) were included in this meta-analysis. MCSA analysis showed that, compared to resistance training alone, concurrent high-intensity interval running training and resistance training and concurrent moderate-intensity continuous cycling training and resistance training were more effective (SMD = 0.15, 95% CI = -0.46 to 0.76, and SMD = 0.07, 95% CI = -0.24 to 0.38 respectively), while other modalities of concurrent training not. Lower body maximal strength analysis showed that all modalities of concurrent training were inferior to resistance training alone, but concurrent high-intensity interval training and resistance training showed an advantage in four different concurrent training modalities (SMD = -0.08, 95% CI = -0.25 to 0.08). For explosive strength, only concurrent high-intensity interval training and resistance training was superior to resistance training (SMD = 0.06, 95% CI = -0.21 to 0.33). Conclusion: Different endurance training types have an impact on the effectiveness of concurrent training, particularly on lower limb strength. Adopting high-intensity interval running as the endurance training type in concurrent training can effectively minimize the adverse effects on lower limb strength and MCSA.

[Non-targeted metabolomics of spleen and liver metabolism in mice treated with Pruni Semen processed with different methods].

Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to investigate the impacts of Pruni Semen processed with different methods(raw and fried) on the liver and spleen metabolism in mice. A total of 24 male mice were randomly assigned to three groups: raw Pruni Semen group, fried Pruni Semen group, and control(deionized water) group. Mice in the three groups were orally administrated with 0.01 g·mL~(-1) Pruni Semen decoction or deionized water for one week. After that, the liver and spleen tissues were collected, and liquid chromatography-mass spectrometry(LC-MS)-based metabolomic analysis was carried out to investigate the impact of Pruni Semen on the liver and spleen metabolism in mice. Compared with thte control group, the raw Pruni Semen group showed up-regulation of 11 metabolites and down-regulation of 57 metabolites in the spleen(P<0.05), as well as up-regulation of 15 metabolites and down-regulation of 58 metabolites in the liver(P<0.05). The fried Pruni Semen group showed up-regulation of 31 metabolites and down-regulation of 10 metabolites in the spleen(P<0.05), along with up-regulation of 26 metabolites and down-regulation of 61 metabolites in the liver(P<0.05). The differential metabolites identified in the raw Pruni Semen group were primarily associated with alanine, aspartate, and glutamate metabolism, purine metabolism, amino sugar and nucleotide sugar metabolism, and D-glutamine and D-glutamate metabolism. The differential metabolites identified in the fried Pruni Semen group predominantly involved riboflavin metabolism, amino sugar and nucleotide sugar metabolism, purine metabolism, alanine, aspartate, and glutamate metabolism, D-glutamine and D-glutamate metabolism, and glutathione metabolism. The findings suggest that both raw and fried Pruni Semen have the potential to modulate the metabolism of the liver and spleen in mice by influencing the glutamine and glutamate metabolism.

Residential surrounding greenness is associated with improved lung function in adults: a cross-sectional study in eastern China.

BACKGROUND: While benefits of greenness exposure to health have been reported, findings specific to lung function are inconsistent. The purpose of this study is to assess the correlations of greenness exposure with multiple lung function indicators based on chronic obstructive pulmonary disease (COPD) monitoring database from multiple cities of Anhui province in China. METHODS: We assessed the greenness using the annual average of normalized difference vegetation index (NDVI) with a distance of 1000-meter buffer around each local community or village. Three types of lung function indicators were considered, namely indicators of obstructive ventilatory dysfunction (FVC, FEV1, FEV1/FVC, and FEV1/FEV3); an indicator of large-airway dysfunction (PEF); indicators of small-airway dysfunction (FEF25%, FEF50%, FEF75%, MMEF, FEV3, FEV6, and FEV3/FVC). Linear mixed effects model was used to analyze associations of greenness exposure with lung function through adjusting age, sex, educational level, occupation, residence, smoking status, history of tuberculosis, family history of lung disease, indoor air pollution, occupational exposure, PM2.5, and body mass index. RESULTS: A total of 2768 participants were recruited for the investigations. An interquartile range (IQR) increase in NDVI was associated with better FVC (153.33mL, 95%CI: 44.07mL, 262.59mL), FEV1 (109.09mL, 95%CI: 30.31mL, 187.88mL), FEV3 (138.04mL, 95%CI: 39.43mL, 236.65mL), FEV6 (145.42mL, 95%CI: 42.36mL, 248.47mL). However, there were no significant associations with PEF, FEF25%, FEF50%, FEF75%, MMEF, FEV1/FVC, FEV1/FEV6, FEV3/FVC. The stratified analysis displayed that an IQR increase in NDVI was related with improved lung function in less than 60 years, females, urban populations, nonsmokers, areas with medium concentrations of PM2.5 and individuals with BMI of less than 28 kg/m2. Sensitivity analyses based on another greenness indice (enhanced vegetation index, EVI) and annual maximum of NDVI remained consistent with the main analysis. CONCLUSIONS: Our findings supported that exposure to greenness was strongly related with improved lung function.

Design, synthesis and evaluation of quinoline-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease.

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual eeAChE/eqBuChE inhibitor with IC50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1ß and NO. In addition, compound 3f presented significant neuroprotective effect on Aß25-35-induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl3-induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.

Development of novel salicylic acid-donepezil-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid-donepezil-rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC50 = 0.53 µM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD.

Development of naringenin-O-carbamate derivatives as multi-target-directed liagnds for the treatment of Alzheimer's disease.

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC50 = 9.7 µM) inhibitor. In addition, compound 3c significantly inhibited self-induced Aß1-42 aggregation, and it could activate UPS degradation pathway in HT22 cells and clear the aggregated proteins associated with AD. Moreover, compound 3c was a selective metal chelator, and it significantly inhibited and disaggregated Cu2+-mediated Aß1-42 aggregation. Furthermore, compound 3c displayed remarkable neuroprotective effect and anti-inflammatory property. Interestingly, compound 3c displayed good hepatoprotective effect by its antioxidant activity. More importantly, compound 3c demonstrated favourable blood-brain barrier penetration in vitro and drug-like property. Therefore, compound 3c was a promising multifunctional agent for the treatment of AD.

Bacillus subtilis WB800N alleviates diabetic wounds in mice by regulating gut microbiota homeostasis and TLR2.

OBJECTIVE: This study aims to investigate the effect of Bacillus subtilis WB800N on diabetic wounds. METHODS: Haematoxylin & eosin (H&E) staining was used to observe the healing of skin wounds. Collagen deposition was assessed by Masson staining. Western blotting and qRT-PCR were used to detect vascular endothelial-related factors (VWF), CD31, TLR2, NLRP3, ASC and Caspase-1 expression. 16S rDNA sequencing detected microbiota distribution. The concentrations of IL-1ß and IL-37 were measured by ELISA. Apoptosis was measured by the TUNEL assay. RESULTS: Compared with the control group, wound healing was delayed in diabetic mice. The wound area in the Bacillus subtilis group decreased more significantly than the diabetic wound group. H&E staining showed that Bacillus subtilis WB800N promoted wound healing and increased re-epithelialization. Masson staining showed that Bacillus subtilis WB800N increased collagen deposition in mice with diabetic wounds. Bacillus subtilis WB800N upregulated VWF and CD31 protein expression in diabetic wounds mice. The 16S rDNA results showed that Bacillus subtilis WB800N reduced the diversity of the gut microbiota of diabetic wounds mice and regulated the microbial composition. At the genus level, Bacillus subtilis WB800N reduced the relative abundance of Muribaculaceae and CG - 005 in diabetic wounds mice, whilst increasing the relative abundance of Lactobacillus. Bacillus subtilis WB800N increased the expression of TLR2, NLRP3, ASC and Caspase-1. Bacillus subtilis WB800N increased the concentrations of IL-1ß and IL-37 in serum. Bacillus subtilis WB800N upregulated cell apoptosis. The TLR2 antagonist Sparstolonin B (SsnB) reduced the expression of TLR2, NLRP3, ASC, Caspase-1, IL-1ß and IL-37 and the apoptosis in diabetic wounds mice, whilst the combined intervention of Bacillus subtilis and SsnB reversed the effect of SsnB treatment alone. CONCLUSION: Bacillus subtilis WB800N alleviated diabetic wound healing by regulating gut microbiota homeostasis and TLR2. SIGNIFICANCE AND IMPACT OF RESEARCH: Our findings might provide potential therapeutic targets for diabetic wounds.

Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies.

Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC50 = 0.87 µM) and huBuChE (IC50 = 3.3 µM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-α production, and significantly inhibited self-mediated Aß1-42 aggregation (60.6%) and huAChE-mediated induced Aß1-40 aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Aß1-42-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [11C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations.

Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease.

Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC50 = 0.32, 0.56, 0.54, 0.73, and 0.86 µM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Aß1-42 aggregation, and potent neuroprotective effect on Aß1-42-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood-brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [11C]5f demonstrated that [11C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.

Development of naringenin-O-alkylamine derivatives as multifunctional agents for the treatment of Alzheimer's disease.

In this study, a series of naringenin-O-alkylamine derivatives were designed and obtained by introducing an alkylamine fragment into the naringenin skeleton. The in vitro biological activity results revealed that compounds 5f and 7k showed good antioxidant activity with ORAC values of 2.3eq and 1.2eq, respectively. Compounds 5f and 7k were reversible and excellent huAChE inhibitors with IC50 values of 0.91 µM and 0.57 µM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced Aß1-42 aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited huAChE-Aß1-40 aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu2+-induced Aß1-42 aggregation with 73.5% and 68.7% inhibition rates, respectively. Furthermore, compounds 5f and 7k could cross the blood-brain barrier in vitro and displayed good neuroprotective effects and anti-inflammatory properties. Further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed a good hepatoprotective effect by its antioxidant activity. The in vivo study displayed that compound 5f significantly improved scopolamine-induced mice memory impairment. Therefore, compound 5f was a potential multifunctional candidate for the treatment of AD.

Prevalence of Fatty Liver among Children under Multiple Machine Learning Models.

OBJECTIVES: To analyze the possible factors causing fatty liver in children based on ultrasound data of children in south Texas, and to establish machine learning models of fatty liver in children to provide ideas for the prevention and treatment of fatty liver in children. METHODS: The binary classification model of fatty liver problem in obese children in Texas was established under the multiple model. First, we selected important features using the CatBoost algorithm. Second, the best parameters of the algorithm were selected on the training set and the validation set by using the grid search method, and all six models were tested on the test set. The six models then were compared by area under the curve value, precision, accuracy, recall rate, and F1 score in a model evaluation. Then, two algorithms, logic regression and CatBoost, were selected to establish prediction models of fatty liver disease in children. RESULTS: We selected body mass index, height, liver size, kidney volume, glomerular filtration rate, and liver diameter as the features used in the machine learning model. The prediction models we chose showed that children with higher body mass index at the same age tended to have a greater probability of fatty liver. CONCLUSIONS: Based on the analysis of the results of the two prediction models established by logistic regression and CatBoost, we determined that the mean probability of fatty liver in severely obese children was between 74.47% and 92.22%, 73.45% and 85.41% in obese children, and slightly higher in boys than in girls, with a mean difference of 3.00% to 3.95%.

Exploring the relationship between basketball rotation and competitive performance using substitution network analysis.

The aim of this exploratory study is (1) to determine the relationship between substitution network (Sub-N) parameters and teams' standings and (2) to find out the key individual performance indicators that differentiated substitution groups of players, and explore the association between players' percentages and team's standing within the obtained substitution groups. A total of 574,214 substitution events during the last 10 NBA seasons were analysed to construct Sub-N for each team observation. Three different player groups were obtained after clustering their playing time, clustering coefficient and vulnerability. Team's clustering coefficient, standard deviation of vulnerability and out-degree centrality of starters exhibited moderate to strong correlations with team's standing during playoffs (r = 0.54-0.76). The regression models showed that defensive win share (beta = 0.54-0.67), turnovers (-0.15 to -0.25) and assists (0.12-0.26) were predictive for all players' net ratings, and the role players who scored more points presented higher net ratings (0.34). Finally, players from top-playoff teams exhibited lower absolute value of vulnerabilities (r = 0.80). The findings demonstrate the feasibility of Sub-N for exploring the association between rotation and competitive performance, and provide quantitative reference for coaching staff to optimize substitution structures and rosters.

Design, synthesis and evaluation of cinnamic acid hybrids as multi-target-directed agents for the treatment of Alzheimer's disease.

Herein, combining 1,2,3,4-tetrahydroisoquinoline and benzylpiperidine groups into cinnamic acid derivatives, a series of novel cinnamic acid hybrids was rationally designed, synthesized and evaluated by the multi-target-directed ligands (MTDLs) strategy. Hybrid 4e was the most promising one among these hybrids with a reversible huBuChE inhibitor (IC50 = 2.5 µM) and good MAO-B inhibition activity (IC50 = 1.3 µM) and antioxidant potency (ORAC = 0.4 eq). Moreover, compound 4e significantly inhibited self-mediated Aß1-42 aggregation (65.2% inhibition rate). Compound 4e exhibited remarkable anti-inflammatory propery and neuroprotective effect. Furthermore, compound 4e displayed favourable blood-brain barrier penetration via parallel artificial membrane permeation assay (PAMPA). The obtained results also revealed that compound 4e significantly improved dyskinesia recovery rate and response efficiency on AD model zebrafish. Further, 4e did not show obvious acute toxicity at dose up to 1500 mg/kg in vivo and improved scopolamine-induced memory impairment. Importantly, compound 4e showed good stability in both artificial gastric fluid and artificial intestinal fluid. Therefore, compound 4e presented a promising multi-targeted active molecule for treating AD.

Clinical efficacy and safety of a focused-radiofrequency device on middle and lower face rejuvenation: a retrospective clinical study.

The aim of the present study was to evaluate the efficacy and safety of a unipolar focused-RF device used to rejuvenate the middle and lower face and to create an assessment system. This retrospective study comprised 52 patients with mild-to-moderate skin laxity and wrinkles who received 1-3 treatments 1 month apart and were followed up for 1-7 months. At baseline and post-treatment, three blinded observers measured facial contour and lines, analyzed VISIA scores, and assessed the results using Alexiades Comprehensive Grading Scale (ACGS) and Global Aesthetic Improvement Scale (GAIS). Significant improvements were observed (P < .05) in facial width (left 5.95%, right 5.66%), nasolabial folds (left 18.98%, right 20.56%), marionette lines (left 18.88%, right 25.80%), and cheek lines (left 3.35%, right 3.05%) and in the scores of wrinkles (15.37%), texture (13.67%), pores (6.48%), and red areas (6.57%) using VISIA. There was an obvious reduction in wrinkles, laxity, erythema/telangiectasia based on ACGS, and 75% improved and 5.8% much improved using GAIS. There was no severe side effect. We suggest that the unipolar focused-RF device is an effective and safe technique for middle and lower face rejuvenation and provides a series of comprehensive assessment methods based on standardized photos using VISIA.

A Low-Cost MEMS Missile-Borne Compound Rotation Modulation Scheme.

Rotation modulation (RM) has been widely used in navigation systems to significantly improve the navigation accuracy of inertial navigation systems (INSs). However, the traditional single-axis rotation modulation cannot achieve the modulation of all the constant errors in the three directions; thus, it is not suitable for application in highly dynamic environments due to requirements for high precision in missiles. Aiming at the problems of error accumulation and divergence in the direction of rotation axis existing in the traditional single-axis rotation modulation, a novel rotation scheme is proposed. Firstly, the error propagation principle of the new rotation modulation scheme is analyzed. Secondly, the condition of realizing the error modulation with constant error is discussed. Finally, the original rotation modulation navigation algorithm is optimized for the new rotation modulation scheme. The experiment and simulation results show that the new rotation scheme can effectively modulate the error divergence of roll angle and improve the accuracy of roll angle by two orders of magnitude.

Comparison of intensity-modulated radiation therapy alone vs. intensity-modulated radiation therapy combined with chemotherapy in elderly nasopharyngeal carcinoma patients (aged >65 years).

PURPOSE: The efficacy and tolerability of adding chemotherapy to radiotherapy in the era of intensity-modulated radiation therapy (IMRT) remain controversial among older patients with nasopharyngeal carcinoma (NPC). The present study compared IMRT alone with IMRT in combination with chemotherapy in elderly NPC patients. METHODS: Between January 2011 and December 2014, 102 patients aged >65 years with NPC who received IMRT alone (IMRT group) or IMRT in combination with chemotherapy (IMRT/CT group) were enrolled. Patients from both treatment arms were pair-matched (1:1 ratio) based on six clinical factors. Differences in overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method and Cox proportional hazards models, whereas the toxicity profile was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4. RESULTS: No significant differences were noted in OS (72.1% vs. 72.5%, p = 0.799), DFS (65.9% vs. 70.1%, p = 0.733), LRRFS (76.4% vs. 71.6%, p = 0.184), and DMFS (90.8% vs. 98.0%, p = 0.610) between the IMRT and IMRT/CT groups. Multivariate analyses showed that chemotherapy was not an independent factor for OS, DFS, LRRFS, and DMFS. However, the incidences of grade 3 vomiting/nausea (p = 0.000), leukopenia/neutropenia (p = 0.000), thrombocytopenia (p = 0.041), and anemia (p = 0.040) were significantly higher in the IMRT/CT group compared with the IMRT group. No grade 4 toxicities were observed. CONCLUSION: IMRT alone was similar to IMRT/CT in treating elderly NPC patients (age >65 years), with comparable survival outcomes and less grade 3 toxicities.

Histone demethylase Jmjd3 modulates osteoblast apoptosis induced by tumor necrosis factor-alpha through directly targeting RASSF5.

Purpose: Regulation of gene expression is fine-tuned by a dynamic equilibrium between repressive modifications and transcriptional activation of histone tails. Jumonji domain-containing 3 (Jmjd3), also known as KDM6B, is a specific histone demethylase for trimethylation on histone H3 lysine 27 (H3K27me3) that specifically removes the methylation of H3K27me3 and promotes gene expression. Our previous study showed that Jmjd3 inhibits serum deprivation-induced osteoblast apoptosis. In this study, we clarified the role of Jmjd3 in tumor necrosis factor-alpha (TNF-α)-induced osteoblast apoptosis. Materials and Methods: Jmjd3 activity was inhibited by GSK-J4. Transfection of osteoblastic murine MC3T3-E1 cells with short hairpin RNA (shRNA) was used to establish stable Jmjd3 knockdown cells. Osteoblast apoptosis was detected using Annexin V-APC/PI staining, cysteinyl aspartate specific protease-3 (caspase-3) activity assays, and Western blot. Real-time polymerase chain reaction (PCR) and chromatin immunoprecipitation (ChIP) assays were performed to clarify the mechanism responsible for Jmjd3-regulated osteoblast apoptosis induced by TNF-α. Results: Based on Annexin V-APC/PI staining, caspase-3 activation, and poly ADP-ribose polymerase (PARP) cleavage, pretreatment with GSK-J4 and knockdown of Jmjd3 by shRNA transfection each inhibited osteoblast apoptosis. Furthermore, knockdown of Jmjd3 decreased the expression of Ras association domain family 5 (RASSF5), which is a pro-apoptotic gene of the Ras associated domain family. H3K27me3 levels in the promoter region of RASSF5 were up-regulated in the Jmjd3 knockdown cells. Conclusions: Jmjd3 regulated TNF-α-induced osteoblast apoptosis by targeting RASSF5.

Association of hemoglobin glycation index and its interaction with obesity/family history of hypertension on hypertension risk: a community-based cross-sectional survey.

BACKGROUND: Hemoglobin glycation index (HGI) is considered to be a convenient measurable indicator to assess the inter-individual variation of HbA1c. In the present study, we tested the relationship between HGI and risk of hypertension, and further explored the possible interacting influences of HGI with other such factors on hypertension risk among Chinese individuals. METHODS: The eligible subjects were chosen from a community-based cross-sectional survey in China. We collected relevant data and clinical indicators for each participant. HGI was calculated as "measured HbA1c-predicted HbA1c" and divided into four categories according to quartile. The following indicators were used to assess interactive effects: (1) relative excess risk due to interaction (RERI); (2) attributable proportion due to interaction (AP); and (3) synergy index (SI). Statistical analysis was performed using R software. RESULTS: Specifically, 1777 eligible participants were selected in this cross-sectional survey. There were 433 subjects who were identified to have hypertension (24.4%). A significant increase in the prevalence of hypertension from Q1 to Q4 of HGI was observed (p < 0.001). Multivariable logistic model demonstrated that subjects at the highest HGI group had a substantially increased risk of being hypertensive than subjects in the first quartile of HGI, as indicated by the OR value of 1.87 (95% CI 1.26-2.78). Moreover, a significant interaction between family history of hypertension and HGI on hypertension risk was detected (RERI: 1.36, 95% CI 0.11-2.63; AP: 0.43, 95% CI 0.17-0.69; and SI:2.68, 95% CI 1.10-6.48). The interactive effect between HGI and abdominal obesity was also found to be significant, as estimated by the value of RERI (1.04, 95% CI 0.24-1.85), AP (0.33, 95% CI 0.11-0.56) and SI (1.96, 95% CI 1.01-3.79). However, in the analysis of the interaction between HGI and general obesity, only the AP value (0.28, 95% CI 0.01-0.54) was observed to be significant. CONCLUSION: High HGI was independently associated with the risk of hypertension. Moreover, HGI significantly shared interactions with obesity and family history of hypertension that influenced the risk of hypertension.

Daphnetin inhibits proliferation and inflammatory response in human HaCaT keratinocytes and ameliorates imiquimod-induced psoriasis-like skin lesion in mice.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease. Keratinocytes hyperproliferation and excessive inflammatory response contribute to psoriasis pathogenesis. The agents able to attenuate keratinocytes hyperproliferation and excessive inflammatory response are considered to be potentially useful for psoriasis treatment. Daphnetin exhibits broad bioactivities including anti-proliferation and anti-inflammatory. This study aims to evaluate the anti-psoriatic potential of daphnetin in vitro and in vivo, and explore underlying mechanisms. METHODS: HaCaT keratinocytes was stimulated with the mixture of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) to establish psoriatic keratinocyte model in vitro. Cell viability was measured using Cell Counting Kit-8 (CCK-8). Quantitative Real-Time PCR (qRT-PCR) was performed to measure the mRNA levels of hyperproliferative marker gene keratin 6 (KRT6), differentiation marker gene keratin 1 (KRT1) and inflammatory factors IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. Western blotting was used to detect the protein levels of p65 and p-p65. Indirect immunofluorescence assay (IFA) was carried out to detect p65 nuclear translocation. Imiquimod (IMQ) was used to construct psoriasis-like mouse model. Psoriasis severity (erythema, scaling) was scored based on Psoriasis Area Severity Index (PASI). Hematoxylin and eosin (H&E) staining was performed to examine histological change in skin lesion. The expression of inflammatory factors including IL-6, TNF-α, IL-23A and IL-17A in skin lesion was measured by qRT-PCR. RESULTS: Daphnetin attenuated M5-induced hyperproliferation in HaCaT keratinocytes. M5 stimulation significantly upregulated mRNA levels of IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. However, daphnetin treatment partially attenuated the upregulation of those inflammatory cytokines. Daphnetin was found to be able to inhibit p65 phosphorylation and nuclear translocation in HaCaT keratinocytes. In addition, daphnetin significantly ameliorate the severity of skin lesion (erythema, scaling and epidermal thickness, inflammatory cell infiltration) in IMQ-induced psoriasis-like mouse model. Daphnetin treatment attenuated IMQ-induced upregulation of inflammatory cytokines including IL-6, IL-23A and IL-17A in skin lesion of mice. CONCLUSIONS: Daphnetin was able to attenuate proliferation and inflammatory response induced by M5 in HaCaT keratinocytes through suppression of NF-κB signaling pathway. Daphnetin could ameliorate the severity of skin lesion and improve inflammation status in IMQ-induced psoriasis-like mouse model. Daphnetin could be an attractive candidate for future development as an anti-psoriatic agent.