Deficit of PKHD1L1 in the dentate gyrus increases seizure susceptibility in mice.

Epilepsy is a chronic neurological disorder featuring recurrent, unprovoked seizures, which affect more than 65 million people worldwide. Here, we discover that the PKHD1L1, which is encoded by polycystic kidney and hepatic disease1-like 1 (Pkhd1l1), wildly distributes in neurons in the central nervous system (CNS) of mice. Disruption of PKHD1L1 in the dentate gyrus region of the hippocampus leads to increased susceptibility to pentylenetetrazol-induced seizures in mice. The disturbance of PKHD1L1 leads to the overactivation of the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK)-Calpain pathway, which is accompanied by remarkable degradation of cytoplasmic potassium chloride co-transporter 2 (KCC2) level together with the impaired expression and function of membrane KCC2. However, the reduction of membrane KCC2 is associated with the damaged inhibitory ability of the vital GABA receptors, which ultimately leads to the significantly increased susceptibility to epileptic seizures. Our data, thus, indicate for the first time that Pkhd1l1, a newly discovered polycystic kidney disease (PKD) association gene, is required in neurons to maintain neuronal excitability by regulation of KCC2 expression in CNS. A new mechanism of the clinical association between genetic PKD and seizures has been built, which could be a potential therapeutic target for treating PKD-related seizures.

Infection evaluation in the early period after liver transplantation: A single-center exploration.

BACKGROUND: Infection is a significant risk factor that impacts for perioperative morbidity and mortality in liver transplantation (LTx) patients and is difficult to evaluate quantitatively in the early posttransplantation period. Thus, a biomarker to assess the risk of infection and the prognosis of the recipient is highly desirable. METHODS: A total of 128 consecutive patients with end-stage liver diseases undergoing LTx between January 1, 2020 and December 31, 2021, at the First Affiliated Hospital of Zhejiang University School of Medicine, were screened retrospectively. Graft preservation fluid and blood samples were collected for culture, and other perioperative laboratory examination results were recorded, for assessment of infection status. RESULTS: After a follow-up period of 30 days, the survival rate among the 128 LTx recipients was 94.5%. Multivariable regression analysis showed that the logarithmically transformed neutrophil-to-lymphocyte ratio (NLR) (HR = 3.548, 95% CI: ; p = .041) on post-LTx day 1 and graft preservation fluid culture positivity (HR = 12.032, 95% CI: ; p = .006) were independent predictive factors for early prognosis after LTx. CONCLUSIONS: Positive graft preservation fluid culture and the logarithmically transformed NLR on post-LTx day 1 were independent predictive factors for early prognosis after LTx. The logarithmically transformed NLR could provide an earlier indication than culture results in clinical practice.

The Streptococcus mutans irvA gene encodes a trans-acting riboregulatory mRNA.

In both prokaryotes and eukaryotes, insight into gene function is typically obtained by in silico homology searches and/or phenotypic analyses of strains bearing mutations within open reading frames. However, the studies herein illustrate how mRNA function is not limited to the expression of a cognate protein. We demonstrate that a stress-induced protein-encoding mRNA (irvA) from the dental caries pathogen Streptococcus mutans directly modulates target mRNA (gbpC) stability through seed pairing interactions. The 5' untranslated region of irvA mRNA is a trans riboregulator of gbpC and a critical activator of the DDAG stress response, whereas IrvA functions independently in the regulation of natural competence. The irvA riboregulatory domain controls GbpC production by forming irvA-gbpC hybrid mRNA duplexes that prevent gbpC degradation by an RNase J2-mediated pathway. These studies implicate a potentially ubiquitous role for typical protein-encoding mRNAs as riboregulators, which could alter current concepts in gene regulation.

Construction of the machine learning-based live birth prediction models for the first in vitro fertilization pregnant women.

BACKGROUND: This study was to conduct prediction models based on parameters before and after the first cycle, respectively, to predict live births in women who received fresh or frozen in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) for the first time. METHODS: This retrospective cohort study population consisted of 1,857 women undergoing the IVF cycle from 2019 to 2021 at Huizhou Municipal Central Hospital. The data between 2019 and 2020 were completely randomly divided into a training set and a validation set (8:2). The data from 2021 was used as the testing set, and the bootstrap validation was carried out by extracting 30% of the data for 200 times on the total data set. In the training set, variables are divided into those before the first cycle and after the first cycle. Then, predictive factors before the first cycle and after the first cycle were screened. Based on the predictive factors, four supervised machine learning algorithms were respectively considered to build the predictive models: logistic regression (LR), random forest (RF), extreme gradient boosting (XGBoost), and light gradient boosting machine (LGBM). The performances of the prediction models were evaluated by the area under the receiver operator characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. RESULTS: Totally, 851 women (45.83%) had a live birth. The LGBM model showed a robust performance in predicting live birth before the first cycle, with AUC being 0.678 [95% confidence interval (CI): 0.651 to 0.706] in the training set, 0.612 (95% CI: 0.553 to 0.670) in the validation set, 0.634 (95% CI: 0.511 to 0.758) in the testing set, and 0.670 (95% CI: 0.626 to 0.715) in the bootstrap validation. The AUC value in the training set, validation set, testing set, and bootstrap of LGBM to predict live birth after the first cycle was 0.841 (95% CI: 0.821 to 0.861), 0.816 (95% CI: 0.773 to 0.859), 0.835 (95% CI: 0.743 to 0.926), and 0.839 (95% CI: 0.806 to 0.871), respectively. CONCLUSION: The LGBM model based on the predictive factors before and after the first cycle for live birth in women showed a good predictive performance. Therefore, it may assist fertility specialists and patients to adjust the appropriate treatment strategy.

Analysis of the prevalence and related factors of primary hypertension among adolescents and children in the Taicang area.

OBJECTIVE: To investigate the prevalence of hypertension in adolescents and children in the Taicang area and analyse related factors to provide a theoretical basis for the prevention and control of hypertension in this region. METHODS: A total of 1,000 students who were visited and surveyed in primary schools in the Taicang area in 2021 were selected for statistical testing using a cluster random sampling method, and a survey was conducted on their dietary habits. dietary habits, such as the consumption of meals that included protein-rich animal products, beans and dairy products, vegetables and fruits, salty foods and fried food, was taken into consideration, along with physical fitness indices, waist-to-height ratio and waist circumference. RESULTS: Of the 1,000 adolescents and children surveyed, 222 were classified into the hypertensive group and 778 into the normotensive group. There were 138 boys (a prevalence rate of 6.3%) and 84 girls (a prevalence rate of 4.1%) in the hypertensive group. The physical fitness indices of the hypertensive group were significantly higher than those of the normotensive group. Concerning dietary structure, the frequency of cereal intake between the two groups was comparable, while the hypertensive group's intake of vegetables, fruits, beans and dairy products was significantly lower than that of the normotensive group. Finally, a logistic multivariate regression analysis of related factors was carried out, and it was concluded that waist-to-height ratio, waist circumference and salty and fried food intake were positively correlated with the prevalence of hypertension. CONCLUSION: The prevalence of hypertension among adolescents and children in the Taicang area is high. Body weight and dietary structure can be used as reference indicators for the prevalence of hypertension in this age group.

Diagnostic value of peripheral TiM-3, NT proBNP, and Sestrin2 testing in left-to-right shunt congenital heart disease with heart failure.

BACKGROUND: Left-to-right shunt congenital heart disease is more likely to induce recurrent respiratory infections in the patients which exacerbate pulmonary hypertension and thereby impairs cardiac function. It is urgent to explore a non-invasive and accurate diagnostic method that can show the cardiac anatomy and associated malformations in clinical research. OBJECTIVE: To determine the diagnostic value of peripheral mucin domain protein-3 (Tim-3), N-terminal pro-brain natriuretic peptide (NT proBNP), sestrin2 testing in patients with the left-to-right shunt congenital heart disease and heart failure. METHODS: Fifty-two neonates with with left to right shunt congenital heart disease and 30 healthy neonates were enrolled. Blood samples were collected within 24 h of admission from newborns for determining the content of TiM-3, NT proBNP, and Sestrin2. Analyzing the ROC curve provided insight into the diagnostic accuracy. Both a Spearman's rank correlation test and a logistic regression analysis were carried out. RESULTS: TiM-3, NT proBNP, and Sestrin2 levels in peripheral blood were statistically different in the three groups (P < 0.05). There were significant differences in LVEF and LVFS among the three groups (P < 0.05). When used to diagnose heart failure in conjunction with left-to-right shunt congenital heart disease, TiM-3, NT proBNP, and Sestrin2 exhibited sensitivity of 58.3, 58.3, and 83.3%, respectively, and specificity of 85.0, 72.5, and 70.0%. ROC curve analysis showed that the AUCs of Tim-3, NT proBNP, and sestrin2 in predicting the outcome of left-to-right shunted congenital heart disease combined with heart failure were 0.744 (95% CI, 0.580 to 0.908), 0.608 (95% CI, 0.359 to 0.857), respectively 0.744 (95% CI 0.592 to 0.896). CONCLUSION: Tim-3, NT proBNP, and sestrin2 can accurately differentiate heart failure from non-combined heart failure from left-to-right shunt congenital heart disease.

Insufficient HtrA2 causes meiotic defects in aging germinal vesicle oocytes.

BACKGROUND: High-temperature requirement protease A2 (HtrA2/Omi) is a mitochondrial chaperone that is highly conserved from bacteria to humans. It plays an important role in mitochondrial homeostasis and apoptosis. In this study, we investigated the role of HtrA2 in mouse oocyte maturation. METHODS: The role of HtrA2 in mouse oocyte maturation was investigated by employing knockdown (KD) or overexpression (OE) of HtrA2 in young or old germinal vesicle (GV) oocytes. We employed immunoblotting, immunostaining, fluorescent intensity quantification to test the HtrA2 knockdown on the GV oocyte maturation progression, spindle assembly checkpoint, mitochondrial distribution, spindle organization, chromosome alignment, actin polymerization, DNA damage and chromosome numbers and acetylated tubulin levels. RESULTS: We observed a significant reduction in HtrA2 protein levels in aging germinal vesicle (GV) oocytes. Young oocytes with low levels of HtrA2 due to siRNA knockdown were unable to complete meiosis and were partially blocked at metaphase I (MI). They also displayed significantly more BubR1 on kinetochores, indicating that the spindle assembly checkpoint was triggered at MI. Extrusion of the first polar body (Pb1) was significantly less frequent and oocytes with large polar bodies were observed when HtrA2 was depleted. In addition, HtrA2 knockdown induced meiotic spindle/chromosome disorganization, leading to aneuploidy at metaphase II (MII), possibly due to the elevated level of acetylated tubulin. Importantly, overexpression of HtrA2 partially rescued spindle/chromosome disorganization and reduced the rate of aneuploidy in aging GV oocytes. CONCLUSIONS: Collectively, our data suggest that HtrA2 is a key regulator of oocyte maturation, and its deficiency with age appears to contribute to reproduction failure in females.

Mining prognostic markers of Asian hepatocellular carcinoma patients based on the apoptosis-related genes.

BACKGROUND: Apoptosis-related genes(Args)play an essential role in the occurrence and progression of hepatocellular carcinoma(HCC). However, few studies have focused on the prognostic significance of Args in HCC. In the study, we aim to explore an efficient prognostic model of Asian HCC patients based on the Args. METHODS: We downloaded mRNA expression profiles and corresponding clinical data of Asian HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The Args were collected from Deathbase, a database related to cell death, combined with the research results of GeneCards、National Center for Biotechnology Information (NCBI) databases and a lot of literature. We used Wilcoxon-test and univariate Cox analysis to screen the differential expressed genes (DEGs) and the prognostic related genes (PRGs) of HCC. The intersection genes of DEGs and PGGs were seen as crucial Args of HCC. The prognostic model of Asian HCC patients was constructed by least absolute shrinkage and selection operator (lasso)- proportional hazards model (Cox) regression analysis. Kaplan-Meier curve, Principal Component Analysis (PCA) analysis, t-distributed Stochastic Neighbor Embedding (t-SNE) analysis, risk score curve, receiver operating characteristic (ROC) curve, and the HCC data of ICGC database and the data of Asian HCC patients of Kaplan-Meier plotter database were used to verify the model. RESULTS: A total of 20 of 56 Args were differentially expressed between HCC and adjacent normal tissues (p < 0.05). Univariate Cox regression analysis showed that 10 of 56 Args were associated with survival time and survival status of HCC patients (p < 0.05). There are seven overlapping genes of these 20 and 10 genes, including BAK1, BAX, BNIP3, CRADD, CSE1L, FAS, and SH3GLB1. Through Lasso-Cox analysis, an HCC prognostic model composed of BAK1, BNIP3, CSE1L, and FAS was constructed. Kaplan-Meier curve, PCA, t-SNE analysis, risk score curve, ROC curve, and secondary verification of ICGC database and Kaplan-Meier plotter database all support the reliability of the model. CONCLUSIONS: Lasso-Cox regression analysis identified a 4-gene prognostic model, which integrates clinical and gene expression and has a good effect. The expression of Args is related to the prognosis of HCC patients, but the specific mechanism remains to be further verified.

Anti-inflammatory activity of berberine in non-alcoholic fatty liver disease via the Angptl2 pathway.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide. Recent studies have shown that the Angptl2 pathway mediated hepatic inflammatory response plays an important role in the progression of nonalcoholic fatty liver disease. Our study investigated the possible molecular mechanisms of berberine (BBR) in the treatment of the liver inflammatory response in the livers of rats with high-fat diet-induced NAFLD via the Angptl2 pathway. RESULTS: At the end of 12 weeks, compared with the control group rats, the high-fat- diet group rats showed obvious pathological and biochemical changes. The levels of pro-infalmmatory cytokines (CCL2, TNF-α) were increased, the infiltration of inflammatory cells (CCR2) was elevated, and the hepatic mRNA and protein levels of Angptl2, NF-κB and Foxo1 were increased to different degrees. Nevertheless, following treatment with BBR, liver tissue pathology, biochemical data, and Angptl2 pathway-related genes expression were significantly ameliorated. CONCLUSIONS: Our findings demonstrate that BBR might attenuate the liver inflammatory response in the livers of rats with high-fat diet-induced NAFLD through the regulation of the Angptl2 pathway.

Julichrome Monomers from Marine Gastropod Mollusk-Associated Streptomyces and Stereochemical Revision of Julichromes Q3 ⋠5 and Q3 ⋠3.

Two julichrome monomers, julichromes Q11 (1) and Q12 (2), along with five known julichromes (Q10 , Q3 ⋅ 5 , Q3 ⋅ 3 , Q6 ⋅ 6 , Q6 , 3-7) and four known anthraquinones (chrysophanol, 4-acetylchrysophanol, islandicin, huanglongmycin A, 8-11), were isolated from the marine gastropod mollusk Batillaria zonalis-associated Streptomyces sampsonii SCSIO 054. This is the first report of julichromes isolated from a marine source. Extensive dissection of 1D and 2D NMR datasets combined with X-ray crystallography enabled rigorous elucidation of the previously reported configurations of julichrome Q3 ⋅ 5 (4) and related julichrome Q3 ⋅ 3 (5); both of the configuration at C(9) needs to be revised. In addition, julichrome Q12 (2) was found to display antibacterial activity against Micrococcus luteus and Bacillus subtilis with MICs of 2.0 and 8.0 µg mL-1 ; four compounds (1, 3, 6, 7) also showed inhibitory activities against an array of methicillin-resistant Staphylococcus aureus, S. aureus and S. simulans AKA1 with MIC values ranging from 8 to 64 µg mL-1 .

Dynamic changes of Sonic Hedgehog signaling pathway in gastric mucosa of rats with MNNG-induced gastric precancerous lesions.

OBJECTIVE: To explore the changes of Sonic Hedgehog (Shh) signaling pathway in the stomach mucosa during the formation of gastric precancerous lesions. METHODS: A total of 72 suckling rats in half genders were randomly and equally divided into the normal group and model group. The rats in the model group were administered with 0.1 ml 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) at the dosage of 800 mg/L for 10 days, whereas the rats in the normal group were similarly administered with normal saline. A total of 12 rats in each group were killed at the end of 10th, 22nd, and 34th weeks in half gender, respectively. Histopathological changes of the gastric mucosa were observed by hematoxylin and eosin (HE) staining; the levels of Shh, Ptch1, Smo, Gli1, Gli2, Gli3, SuFu, Cyclin D1, Cyclin E1, c-Myc, and ß-actin mRNAs in the gastric mucosa were determined by real-time polymerase chain reaction; while the protein expression of Shh, Ptch1, Smo, Gli1, SuFu, Cyclin D1, Cyclin E1, c-Myc, and p-c-Myc was detected by western blot analysis. RESULTS: With the development of atrophy and dysplasia of gastric mucosa, the levels of Shh, Smo, Gli1, Cyclin D1, Cyclin E1, and c-Myc mRNAs increased, while those of Ptch1 and SuFu decreased. The expression of Shh, Smo, Gli1, Cyclin D1, Cyclin E1, and p-c-Myc proteins were elevated, while the expression of Ptch1 and SuFu proteins were decreased, however, without statistical difference. CONCLUSIONS: Shh signaling is activated during the formation of gastric precancerous lesions, which indicates that the Shh signaling pathway participates in the development and progression of gastric precancerous lesions.

Liquid-liquid phase equilibrium and the effect of a water-soluble polymer on the interaction between droplets in water-in-oil microemulsions.

The liquid-liquid phase equilibria of {water/PEG200/sodium bis(2-ethylhexyl)sulfosuccinate (AOT)/n-decane} with the molar ratio of water to AOT being 37.9 and various concentrations cPEG of PEG in water were measured in this study. The critical exponent ß corresponding to the width of the coexistence curve was determined, which showed good agreement with the 3D-Ising value and supported the proposal of the pseudo binary droplet solution for these multiple microemulsions. A previously developed thermodynamic approach based on the Carnahan-Starling-van der Waals type equation was improved and used to analyze the coexistence curve data of {water/PEG200/AOT/n-decane} microemulsions to deduce the interaction properties between droplets and further to investigate the effect of the additive PEG200 on these interactions. It was found that the addition of PEG200 into the {water/AOT/n-decane} microemulsion resulted in the decrease in the critical temperature and the interaction enthalpy and entropy. Both the interaction enthalpy and entropy decreased first, then increased with an increase of cPEG and had minimum values at cPEG = 25 g L-1, which showed the same tendency as the isothermal titration microcalorimetric results for the {water/PEG200/AOT/isooctane} microemulsion we reported very recently. The effects of the interaction enthalpy and the entropy on the phase separation and their dependences on cPEG were discussed and related to the effects of the additive on the rigidity of the interface layer of the microemulion droplet.

The heat capacities and critical behaviors of binary ionic solutions.

The heat capacities of nine binary room temperature ionic solutions {[C4mim][BF4] + 1,2-butandiol}, {[C8mim][BF4] + 1-pentanol}, {[C8mim][BF4] + 2-pentanol}, {[C8mim][BF4] + 1-hexanol}, {[C8mim][BF4] + 1-heptanol}, {[C8mim][PF6] + 1-propanol}, {[C8mim][PF6] + 1-butanol}, {[C8mim][PF6] + 2-butanol} and {[C8mim][PF6] + tert-butanol} are reported herein. The combination of the data obtained with the corresponding measured coexistence curves infers that the critical asymmetry parameter of the coexistence curves linearly varies with the molar volume ratio of the two components for each of the studied binary ionic solutions after the heat capacity contribution is considered. This indicates the importance of the heat capacity contribution to the critical asymmetry. For further analysis of the critical characteristics of the ionic solutions, a large amount of experimental data was collected and systematically discussed in detail regarding which critical character is important in the binary ionic solutions. A general increasing tendency for the RPM (restricted primitive model)-rescaled critical parameters with the relative permittivity εr,c of the solvent at the critical temperature of the corresponding system was found. This is attributed not only to the screening effect of the solvent medium, but also to solvophobic interactions, which both increase with εr,c. This study also demonstrates that the critical amplitudes increased, while the relative contribution of the heat capacity to the asymmetry of the coexistence curve decreased with an increase in εr,c.

Tetrahydropalmatine Prevents High-Fat Diet-Induced Hyperlipidemia in Golden Hamsters (Mesocricetus Auratus).

BACKGROUND Hyperlipidemia is a major cause of atherosclerotic cardiovascular disease. Tetrahydropalmatine (THP) can exhibit hepatoprotective, anti-arrhythmic, and anti-inflammatory activities. The mechanism of THP on the hyperlipidemia remains unknown; therefore, the present study explored the role of THP in hyperlipidemia. MATERIAL AND METHODS We established an animal model of hyperlipidemia by high-fat diet (HFD) feeding. Blood samples were obtained for determination of serum cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), pro-inflammatory cytokines, and CYP7A1 expression. Histology was performed and inflammation was detected in the liver using hematoxylin-eosin (HE) staining and enzyme-linked immunosorbent assay (ELISA), respectively. The mRNA and protein levels of TLR4 and TRAF-6 were determined by quantitative real-time PCR (qPCR) and Western blot, respectively. RESULTS THP suppressed hepatic lipid accumulation and reduced serum levels of TC, TG, LDL-c, and HDL-c in HFD-fed golden hamsters. THP increased cholesterol 7 a-hydroxylase (CYP7A1) expression and prevented inflammation by the limited reduction in interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expressions in serum and liver. THP slightly increased the ratio of the body/liver weight. THP inhibited the mRNA and protein levels of Toll-like receptor 4 (TLR4) and TNF-receptor associated factor-6 (TRAF-6). CONCLUSIONS These results suggest that THP attenuates hyperlipidemia by multiple effects, including hepatoprotective and anti-inflammatory effects. Moreover, THP also suppressed the expressions of TLR4 and TRAF-6 in golden hamsters.

The imbalance of Th17/Treg cells is involved in the progression of nonalcoholic fatty liver disease in mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common, chronic liver disease worldwide. Recent studies have shown that T helper (Th) 17 and regulatory T (Treg) cells play critical roles in various disorders of liver inflammation. Here, we explored the value of polyene phosphatidylcholine capsules (PPC) for regulating the imbalance of Th17/Treg cells in the pathogenesis of mice with NAFLD. METHODS: C57BL/6 mice were randomly divided into three groups as follows:normal diet (ND), high-fat diet (HF),and HF plus PPC(HF + PPC). The frequencies of splenic Th17 and Treg cells were measured by flow cytometry, and their related cytokines were analyzed by CBA and real-time PCR. RESULTS: At the end of 24 weeks, mice in the HF group had a higher frequency of intrahepatic Th17 cells,and a lower proportion of Treg cells compared with the ND group. The levels of Th17 cell-related cytokines (IL-6, IL-17 and IL-23) in serum and in liver tisse were increased,and the hepatic mRNA levels of RORγt, STAT3 and IL-6 were also increased. By contrast,the FoxP3 mRNA level was decreased in the HF group. Moreover, significant pathological and biochemical changes in the liver, as well as serum biochemical changes, were found in mice with NAFLD. Interestingly, following treatment with PPC, the levels of liver inflammation,frequencies of Th17/Treg cells and associated cytokines,and biochemical data were significantly altered. CONCLUSION: These findings demonstrate a critical role for PPC in partially attenuating liver inflammatory responses in mice with NAFLD that involves the imbalance of Treg/Th17 cells and associated cytokines.

[Effects of pure total flavonoids from Citrus changshan-huyou on blood lipid metabolism in hyperlipidemic rats].

To observe and investigate the effects and mechanisms of the pure total flavonoids from Citrus changshan-huyou(PTFC) on blood lipid metabolism in hyperlipidemic rats. SD rats were fed with high fat diet for 4 weeks to induce hyperlipidemic rats model, meanwhile three dosages (50, 100, 200 mg•kg ⁻¹â€¢d ⁻¹) of PTFC were administrated intragastrically for 4 weeks respectively.After 2 weeks of modeling, their tail blood was taken and serum TC, TG, and HDL-C levels were detected by biochemical method and their body weight was measured. After 4 weeks of modeling, their body weight was measured and liver weight was measured, then the levels of TC, TG, HDL-C, LDL-C, ALT, AST, MDA and SOD in serum were detected to calculate lipid comprehensive index(LDL-C/HDL-C and LDL-C/TC ratios) and atherogenic index(AI); in addition, MDA and SOD levels were detected by biochemical method. The hitopathological changes of the liver tissues were observed by HE staining; the protein expression levels of PPAR-α, Lpl, and Lipc were detected by ELISA; and the mRNA expression levels of PPAR-α in the liver tissue were detected by Real-time PCR. The results showed that gavage administration of the PTFC significantly decreased the body weight, liver weight, liver index, serum ALT and AST activities, the levels of serum TC, TG, LDL-C, LDL-C/HDL-C, AI and increased serum HDL and LDL/TC level. Moreover, the PTFC significantly enhanced SOD activity and decreased the concentration of MDA in serum and liver tissue. Further mechanism investigation indicated that PTFC inhibited serum lipid accumulation by increasing the expressions PPAR-α, Lpl, Lipc protein and PPAR-α mRNA of the liver tissues. PTFC could actively regulate blood lipid metabolism by ameliorating hepatic function, improving the body's antioxidant capacity, lowering levels of oxidative stress, as well as positively regulating the expression levels of PPAR-α, Lpl, Lipc protein and PPAR-α mRNA of the liver tissues in rats.

Polyhydroxylated fullerenols regulate macrophage for cancer adoptive immunotherapy and greatly inhibit the tumor metastasis.

Adoptive immunotherapy is a highly effective approach for cancer treatment. Several potential adoptive immunotherapies have high (though reversible) toxicities with disappointing results. Polyhydroxylated fullerenols have been demonstrated as promising antitumor drugs with low toxicities. In this study, we investigate whether polyhydroxylated fullerenols (C60(OH)22 and Gd@C82(OH)22) contribute to cancer immunotherapy by regulating macrophages. Our results show that fullerenols treatment enhances mitochondrial metabolism, phagocytosis and cytokine secretion. Moreover, activated macrophages inhibit the growth of several cancer cell types. It is likely that this inhibition is dependent on an NF-κB-mediated release of multiple cytokines. Using a lung metastasis model, we also show that autologous macrophages greatly suppress cancer cell metastasis to lung when they are activated by C60(OH)22 and Gd@C82(OH)22. More importantly, Gd@C82(OH)22 are shown to have stronger ability than C60(OH)22 to improve the macrophage function, which shed light on the rational design for nanomedicine and clinical application. FROM THE CLINICAL EDITOR: The interest in the use of immunotherapy in cancer has rekindled recently. However, many approaches have shown disappointing results. In this study, the authors investigated the effects of polyhydroxylated fullerenol nanoparticles on regulating macrophages for immunotherapy. These positive findings may point a novel way to cancer treatment.

[Correlation of oxidative stress with sperm DNA integrity and semen parameters in infertile men with varicocele].

OBJECTIVE: To investigate the relationship of oxidative stress with DNA integrity and semen parameters in infertile men with varicocele (VC). METHODS: This prospective study included 98 infertile males with VC. According to the levels of reactive oxygen species (ROS) in the semen, we divided the patients into a high ROS group (n=44) and a low ROS group (n=54), determined the sperm DNA fragmentation index (DFI), motility and morphology, and analyzed their correlation with ROS in the two groups of patients. RESULTS: Compared with the patients of the low ROS group, those of the high ROS group showed a significantly higher DFI (27.38±8.10 vs 34.49±6.05, P=0.039) and a higher concentration of seminal leukocytes (ï¼»0.65±0.15ï¼½×106/ml vs ï¼»0.86±0.41ï¼½×106/ml, P=0.022), but lower sperm motility (ï¼»36.16±22.83ï¼½% vs ï¼»18.22±25.21ï¼½%, P=0.017), percentage of progressively motile sperm (ï¼»23.34±11.53ï¼½% vs ï¼»16.34±9.22ï¼½%, P=0.041), sperm curvilinear velocity (ï¼»27.03±6.21ï¼½ vs ï¼»20.62±4.38ï¼½ µm/s, P=0.013), and sperm linearity (ï¼»29.75±8.24ï¼½% vs ï¼»18.30±7.93ï¼½%, P=0.024). Spearman correlation analysis indicated that the ROS level was correlated positively with the concentration of seminal leukocytes (r=0.41, P<0.01) and DFI (r=0.21, P=0.006), but negatively with sperm curvilinear velocity (r=－0.24, P=0.017), linearity (r=－0.24, P=0.021), motility (r=－0.31, P=0.002), and the percentage of progressively motile sperm (r=－0.41, P=0.012). Additionally, the sperm DFI manifested a significant negative correlation with sperm motility (r=－0.29, P<0.01) and the percentage of progressively motile sperm (r=－0.34, P<0.01). CONCLUSIONS: The level of seminal ROS is positively correlated with the sperm DFI in infertile men with varicocele, and both the ROS level and DNA integrity are associated with semen parameters.

[Effect of total flavones of hawthorn leafonon expression of COX-2/Nrf2 in liver of rats with nonalcoholic steatohepatitis].

To explore the effect of total flavones from hawthorn leaf on (THFL) on the expression of COX-2/Nrf2 in the liver tissues of rats with nonalcoholic steatohepatitis (NASH), and discuss its anti-NASH mechanism, thirty-two SD rats were randomly divided into the normal group, model group, THFL high dose group and low dose group, 8 in each group. High fat diet was given to the rats for 12 weeks to establish the NASH models, and the high and low dose groups were administered with TFHL at the dosage of 250, 125 mg•kg⁻¹â€¢d⁻¹ respectively. Steatosis and the inflammatory changes of the liver tissues in rats were observed by HE staining; T-AOC level was detected by colorimetry; the level of 8-OHdG and the protein expressions of COX-2, Nrf2 and HO-1 in the liver tissues were determined by immunohistochemistry; and the mRNA expressions of COX-2, Nrf2 and HO-1 in liver tissues were detected by Real time-PCR. Compared with the normal group, the liver steatosis, ballooning degeneration for inflammatory degree and NAFLD activity scores (NAS) were significantly increased in model group, while total antioxidant capacity (T-AOC) was decreased, DNA damage marker 8-OHdG level was increased, and the mRNA and protein expressions of COX-2, Nrf2 and HO-1 were significantly increased. After the administration of high and low dose of TFHL, the inflammation degree of the liver tissues and NAS were significantly decreased, 8-OHdG level and COX-2mRNA and protein expressions were decreased, and the mRNA and protein expressions of Nrf2 and HO-1 were significantly increased when compared with the model group. COX-2/Nrf2 pathway was involved in the development and progression of NASH induced by high fat diet. TFHL could prevent the development of NASH by promoting the expression Nrf2/HO-1, regulating and inhibiting the over expression of COX-2, and further attenuating the cell injury and hepatic inflammation caused by oxidation reaction.

Regulation of pure total flavonoids from Citrus on TH17/Treg balance in mice with NASH.

This study aimed to investigate the involved immunologic mechanism of pure total flavonoids from Citrus (PTFC) on the development of non-alcoholic steatohepatitis (NASH). C57BL/6 mice were fed with high .fat diet for 16 weeks to induce the NASH model, and from the 7th week three dosages (25, 50 and 100 mg x kg(-1) x d(-1)) of PTFC were administrated intragastric for 10 weeks respectively. Serum TG, CHOL, ALT, AST were determined by biochemical assay, histopathological changes of the liver tissue were observed by HE staining, expression of RORyt and Foxp3 mRNA of the liver tissue was detected by Real-time PCR, and serum IL-17, IL-6, IL-10 and IL-4 were determined by.Cytometric Beads Array. As a result, we find that after the administration of PTFC, the in- flammation of the liver tissue of NASH mice was attenuated, liver function was improved, and the expression of RORgammat mRNA was higher in the liver tissue while which was lower of Foxp3 mRNA, the level of proinflammatory cytokines IL-17 and IL-6 decreased and the level of suppressive cytokines IL-10 and IL-4 increased. These data show that PTFC protects the development of NASH through regulating the Th17/Treg balance and attenuating inflammation.