Ionizable copolymer functionalized magnetic nanocomposite as an adsorbent for boosting the extraction selectivity of aristolochic acids.

Aristolochic acid nephropathy (AAN) has drawn increasing public attention. Organic anion transporters (OATs) are considered to be responsible for mediating nephrotoxicity of aristolochic acids (AAs), as AAs are typical OAT1 substrates that exhibit anionic properties and contain one hydrophobic domain. Inspired by the OAT1 three-dimensional structure or substrate/protein interactions involved in transport, we designed a magnetic polymeric hybrid, mimicking the effect of basic and aromatic residues of OAT1, for efficient enriching aristolochic acid I (AA I) and aristolochic acid II (AA II) in Traditional Chinese patent medicines (TCPM). N, N-dimethylaminopropyl acrylamide (DMAPAm) was used as a cationic monomer and copolymerized with divinylbenzene (DVB) onto the surface of monodisperse magnetic nanoparticles (denoted as MNs@SiO2T-DvbDam). The magnetic polymer hybrid demonstrated high selectivity and capacity for AAs, which was mainly attributed to (1) electrostatic interactions from the cationic or basic moiety of DMAPAm and (2) the hydrophobic and π-π stacking interactions from the aromatic ring of DVB. Additionally, the surface of the hybrid exhibited amphiphilic property according to the ionization of DMAPAm, thus improving the compatibility of the adsorbent with the aqueous sample matrix. This strategy was proven to be robust in the analysis of real drug samples, which was characterized by a good linearity, high recovery and satisfactory reusability. This work confirmed that the proposed tool could be a promising candidate for enhancing the extraction selectivity of AAs in Traditional Chinese medicines (TCM).

Nitric oxide synthase and its function in animal reproduction: an update.

Nitric oxide (NO), a free radical labile gas, is involved in the regulation of various biological functions and physiological processes during animal reproduction. Recently, increasing evidence suggests that the biological role and chemical fate of NO is dependent on dynamic regulation of its biosynthetic enzyme, three distinct nitric oxide synthase (NOS) according to their structure, location and function. The impact of NOS isoforms on reproductive functions need to be timely elucidated. Here, we focus on and the basic background and latest studies on the development, structure, importance inhibitor, location pattern, complex functions. Moreover, we summarize the exactly mechanisms which involved some cell signal pathways in the regulation of NOS with cellular and molecular level in the animal reproduction. Therefore, this growing research area provides the new insight into the important role of NOS male and female reproduction system. It also provides the treatment evidence on targeting NOS of reproductive regulation and diseases.

Multipartite entanglement criterion via generalized local uncertainty relations.

We study the detection of multipartite entanglement based on the generalized local uncertainty relations. A sufficient criterion for the entanglement of four-partite quantum systems is presented in terms of the local uncertainty relations. Detailed examples are given to illustrate the advantages of our criterion. The approach is generalized to general multipartite entanglement cases.

Cancer cell membrane-cloaked mesoporous silica nanoparticles with a pH-sensitive gatekeeper for cancer treatment.

Nanoparticular drug delivery system (NDDS) has great potential for enhancing the efficacy of traditional chemotherapeutic drugs. However, it is still a great challenge to fabricate a biocompatible NDDS with simple structure capable of optimizing therapeutic efficacy, such as high tumor accumulation, suitable drug release profile (e.g. no premature drug leakage in normal physiological conditions while having a rapid release in cancer cells), low immunogenicity, as well as good biocompatibility. In this work, a simple core/shell structured nanoparticle was fabricated for prostate cancer treatment, in which a mesoporous silica nanoparticle core was applied as a container to high-efficiently encapsulate drugs (doxorubicin, DOX), CaCO3 interlayer was designed to act as sheddable pH-sensitive gatekeepers for controlling drug release, and cancer cell membrane wrapped outlayer could improve the colloid stability and tumor accumulation capacity. In vitro cell experiments demonstrated that the as-prepared nanovehicles (denoted as DOX/MSN@CaCO3@CM) could be efficiently uptaken by LNCaP-AI prostate cancer cells and even exhibited a better anti-tumor efficiency than free DOX. In addition, Live/Dead cell detection and apoptosis experiment demonstrated that MSN/DOX@CaCO3@CM could effectively induce apoptosis-related death in prostate cancer cells. In vivo antitumor results demonstrated that DOX/MSN@CaCO3@CM administration could remarkably suppress the tumor growth. Compared with other tedious approaches to optimize the therapeutic efficacy, this study provides an effective drug targeting system only using naturally biomaterials for the treatment of prostate cancer, which might have great potential in clinic usage.

The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer.

We previously demonstrated that histamine H4 receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non-small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti-EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC.

[Protective Effect of Angiotensin Converting Enzyme 2 (ACE2) Against Chronic Intermittent Hypoxia-induced Pulmonary Oxidative Stress Injury in Rats].

OBJECTIVE: To determine changes of angiotensin converting enzyme 2 (ACE2) in the development of chronic intermittent hypoxia (CIH)-induced pulmonary injury in rats and its mechanism. METHODS: 96 adult male Wistar rats were randomly allocated into four groups: control (UC) group, chronic intermittent hypoxia (CIH) group, normal saline treated CIH (NS) group, and edaravone treated CIH (NE) group. Each group contained four subgroups of rats (n = 6) subjecting to 1 week, 2 weeks, 3 weeks, and 4 weeks experiment, respectively. No intervention was given to rats in the UC group. Rats in the experimental groups were exposed to alternating cycles of nitrogen and compressed air. Rats in the NS and NE groups received daily injection of 0.9% normal saline (3 mg/ kg) and edaravone (3 mg/kg), respectively. Pulmonary sections were taken and stained with hematoxylin-eosin (HE). The levels of malondialdehyde (MDA), ACE2, ACE2 mRNA, and angiotensin II (Ang II) mRNA in the rat homogenate pulmonary samples were measured. RESULTS: Rats in the CIH and NS groups showed high levels of interstitial edema, alveolar atelectasis, and inflammatory cell infiltration in alveolar epithelial cells. The pulmonary injury got worse over time. Rats in the NE group showed later occurrence-and milder pulmonary injury compared with those in the NS group. Rats in the CIH and NS groups had higher levels of MDA and Ang II mRNA (which increased over time) than those in the UC group (P < 0.05). The expression of ACE2 and the level of ACE2 mRNA increased in rats in the CIH group (P < 0.05), and peaked at 2 weeks (P < 0.05). Rats in the NE group had moderately increased levels of MDA and Ang II mRNA compared with those in the NS group (P < 0.05); moderately increased levels of expression of ACE2 and ACE2 mRNA compared with those in the UC and SC groups (P < 0.05). The pulmonary level of Ang II mRNA was positively correlated with MDA (r = 0.782, P < 0.01) in rats in the CIH group. CONCLUSION: CIH can activate oxidation stress and Ang II, which maybe an important mechanism of CIH-induced pulmonary injury.

Associations of Polymorphisms in HRH2, HRH3, DAO, and HNMT Genes with Risk of Chronic Heart Failure.

The pathophysiological functions of cardiac histamine level and related histamine receptors during the development of chronic heart failure (CHF) were intensively investigated previously. However, the relevance of polymorphisms in histamine-related genes, such as HRH2, HRH3, DAO, and HNMT, with CHF remains largely neglected. This study herein aims to analyze the clinical associations of polymorphisms in those genes with CHF risk. A total of 333 unrelated Chinese Han CHF patients and 354 ethnicity-matched healthy controls were recruited and 11 single nucleotide polymorphisms (SNPs) were genotyped. We found that the HRH3 rs3787429 polymorphism was associated with CHF risk (p < 0.001). The T allele of rs3787429 exhibited protective effect against CHF under the dominant (ORs = 0.455; 95% CIs = 0.322-0.642) and additive models (ORs = 0.662; 95% CIs = 0.523-0.838), while, for SNPs in HRH2, DAO, and HNMT, no significant associations were observed in the present study. These findings for the first time screen out one SNP (rs3787429) of HRH3 gene that was significantly associated with CHF in Chinese Han population, which may be a novel biomarker for personal prevention and treatment of CHF and provides novel highlights for investigating the contribution of this disease.

[Crypotanshione reduces the expression of metadherin in DU145 prostate cancer cells].

OBJECTIVE: To investigate the effects of crypotanshinone (CPT) on the proliferation and apoptosis of DU145 prostate cancer cells as well as on the metadherin expression and the downstream PI3K/AKT signaling pathway in the DU145 cells. METHODS: We treated DU145 prostate cancer cells with different concentrations of CPT for 24, 48, and 72 hours followed by evaluation of the proliferation and apoptosis of the cells by MTT assay and TUNEL, respectively. We determined the expressions of metadherin protein and mRNA in the DU145 cells by Western blot and RT-PCR respectively at different time points after CPT treatment. We also detected the expressions of the proteins metadherin, AKT, p-AKT, and Bcl-2 in the CPT-treated DU145 cells at 48 hours. RESULTS: CPT significantly inhibited the proliferation of the DU145 cells in a dose- and time-dependent manner (P < 0.05). After treatment with 10 µmol/L CPT for 24, 48, and 72 hours, the apoptosis rates of the DU145 cells were (29.42 ± 4.51), (55.07 ± 5.67) and (70.84 ± 4.66)%, respectively, significantly higher than (3.1 ± 2.48)% in the control group (P < 0.05). The expression of metadherin was remarkably downregulated at the transcription and translation levels (P < 0.05) and the expressions of the AKT signaling pathway and the Bcl-2 protein were markedly inhibited in the DU145 cells after treated with 10 µmol/L CPT for 48 hours (P < 0.05). CONCLUSION: CPT can inhibit the proliferation and induce the apoptosis of DU145 prostate cancer cells, which may be associated with its suppression of the downstream PI3K/AKT signaling pathway by reducing the expression of metadherin in the DU145 cells.

Lack of Association between rs2067474 Polymorphism in Histamine Receptor H2 Gene and Breast Cancer in Chinese Han Population.

Histamine H2 receptor (HRH2) was previously suggested to affect the proliferation of breast cancer cells and disease-free survival of breast cancer patients. Furthermore, a common polymorphism, rs2067474, was identified in an enhancer element of the HRH2 gene promoter and was reported to be associated with various diseases including cancer. However, the relationship between this polymorphism and breast cancer risk and malignant degree remains unclear. The aim of this study was to clarify the clinical association of rs2067474 polymorphism with breast cancer. A total of 201 unrelated Chinese Han breast cancer patients and 238 ethnicity-matched health controls were recruited and rs2067474 polymorphism was genotyped. Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotype with breast cancer according to 3 genetic models (dominant, recessive, and additive). Although the percentage of hormone receptor negative cases tended to be higher in AA genotypes, we did not find any significant associations of rs2067474 polymorphism with breast cancer risk or with related clinicopathological parameters in the present study, which indicates that rs2067474 polymorphism of HRH2 gene might not be a risk factor in the development of breast cancer in Chinese Han population.

[Effect of IL-18BP on Fractalkine chemokine expression in the kidney tissue of rats with renal fibrosis].

OBJECTIVE: To study the expression of Fractalkine (FKN) in the kidney tissue of rats with renal fibrosis and the effect of IL-18BP on FKN. METHODS: Male Wister rats were randomly assigned to sham-operation (n=24), unilatral ureteral obstruction (UUO, n=22), and IL-18 binding protein (IL-18BP) treatment groups (n=23). The UUO model was prepared by unilateral ureteral ligation in the later two groups. The IL-18BP treatment group received an intraperitoneal injection of IL-18BP (0.1 mg/kg) every other day after UUO inducement, for 7 times, while normal saline was administered in the other two groups. Seven or eight rats of every group were sacrificed at 3, 7 or 14 days after IL-18BP or normal saline injections. FKN levels at various times were detected by immunohistochemistry and Western blot. RESULTS: Compared with the sham-operation group, FKN levels in the kidney tissue of the untreated UUO group increased significantly at all time points (P<0.01). IL-18BP treatment decreased significantly FKN levels in the kidney tissue at all time points compared with the untreated UUO group (P<0.01). CONCLUSIONS: IL-18BP treatment may down-regulate the increased FKN levels of the rat kidney tissue caused by UUO, possibly thus delays the occurrence and development of renal fibrosis.

[Effects of hypothermia plus dexamethasone on eNOS expression and spermatogenic cell apoptosis after testicular torsion reduction].

OBJECTIVE: To investigate the protective effects of hypothermia combined with dexamethasone on the testis of rats after testicular torsion reduction and on the expression of eNOS and apoptosis of spermatogenic cells. METHODS: We made unilateral testicular torsion models in 80 adolescent male Sprague-Dawley rats by 720 degrees torsion of the left testis, and then randomly divided them into four groups of equal number to be treated with normal temperature + physiological saline (group A), hypothermia + physiological saline (group B), hypothermia + dexamethasone (group C), and normal temperature + dexamethasone (group D). After 48 hours, we collected the testes, observed pathological changes of the testicular tissue by HE staining under the light microscope, determined the expression of eNOS by immunohistochemistry, and detected the apoptosis of spermatogenic cells by TUNEL. RESULTS: HE staining showed different degrees of testicular tissue injury in all the four groups of rats, most obvious in group A, while protective effect was observed in the other three groups. Immunohistochemistry revealed significantly more positive cells and higher positive staining intensity in the torsion (left) testis in group A than in B (P < 0.05), C (P < 0.01) and D (P < 0.01). The nuclei were deep brown or brown. Lots of apoptotic spermatogenic cells were seen in the torsion testis of group A, with a significantly higher apoptosis index (31.12 +/- 4.68) than in B (16.58 +/- 6.22) (P < 0.05), C (8.60 +/- 1.15) (P < 0.01) and D (13.52 +/- 3.06) (P < 0.01). CONCLUSION: Ischemia-reperfusion injury after testicular torsion reduction can increase the apoptosis of spermatogenic cells and decrease testicular reproductivity. Hypothermia combined with dexamethasone can protect the testis from injury as well as the reproductive function of the testis after testicular torsion reduction.