Real-life appraisal on blood pressure targets achievement in adult outpatients at high cardiovascular risk

Background and aim: Although hypertension guidelines highlight the benefits of achieving the recommended blood pressure (BP) targets, hypertension control rate is still insufficient, mostly in high or very high cardiovascular (CV) risk patients. Thus, we aimed to estimate BP control in a cohort of patients at high CV risk in both primary and secondary prevention. Methods and results: A single-center, cross-sectional study was conducted by extracting data from a medical database of adult outpatients aged 40–75 years, who were referred to our Hypertension Unit, Rome (IT), for hypertension assessment. Office BP treatment targets were defined according to 2018 ESC/ESH guidelines as: a)<130/80 mmHg in individuals aged 40–65 years; b)<140/80 mmHg in subjects aged >65 years. Primary prevention patients with SCORE <5% were considered to be at low-intermediate risk, whilst individuals with SCORE ≥5% or patients with comorbidities were defined to be at very high risk. Among 6354 patients (47.2% female, age 58.4 ± 9.6 years), 4164 (65.5%) were in primary prevention with low-intermediate CV risk, 1831 (28.8%) in primary prevention with high-very high CV risk and 359 (5.6%) in secondary prevention. In treated hypertensive outpatients, uncontrolled hypertension rate was significantly higher in high risk primary prevention than in low risk primary prevention and secondary prevention patients (18.4% vs 24.4% vs. 12.5%, respectively; P < 0.001). In high risk primary prevention diabetic patients only 10% achieved the recommended BP targets. Conclusions: Our data confirmed unsatisfactory BP control among high-risk patients, both in primary and secondary prevention, and suggest the need for a more stringent BP control policies in these patients

Brain overexpression of uncoupling protein-2 (Ucp2) delays renal damage and stroke occurrence in stroke-prone spontaneously hypertensive rats

The downregulation of uncoupling protein-2 (UCP2) is associated with increased brain and kidney injury in stroke-prone spontaneously hypertensive rats (SHRSP) fed with a Japanese style hypersodic diet (JD). Systemic overexpression of UCP2 reduces organ damage in JD-fed SHRSP. We examined the effect of brain-specific UCP2 overexpression on blood pressure (BP), stroke occurrence and kidney damage in JD-fed SHRSP. Rats received a single i.c.v. injection of a lentiviral vector encoding UCP2 (LV-UCP2), or an empty vector. The brain delivery of LV-UCP2 significantly delayed the occurrence of stroke and kidney damage. The large reduction of proteinuria observed after LV-UCP2 injection was unexpected, because BP levels were unchanged. At the time of stroke, rats treated with LV-UCP2 still showed a large UCP2 upregulation in the striatum, associated with increases in OPA1 and FIS1 protein levels, and reductions in PGC1-α, SOD2, TNFα mRNA levels and NRF2 protein levels. This suggested UCP2 overexpression enhanced mitochondrial fusion and fission and reduced oxidative damage and inflammation in the striatum of JD-fed SHRSP rats. Our data suggest the existence of central mechanisms that may protect against hypertension-induced organ damage independently of BP, and strengthen the suitability of strategies aimed at enhancing UCP2 expression for the treatment of hypertensive damage

Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat

UCP2 maps nearby the lod score peak of STR1-stroke QTL in the SHRSP rat strain. We explored the potential contribution of UCP2 to the high-salt diet (JD)-dependent increased stroke susceptibility of SHRSP. Male SHRSP, SHRSR, two reciprocal SHRSR/SHRSP-STR1/QTL stroke congenic lines received JD for 4 weeks to detect brain UCP2 gene/protein modulation as compared with regular diet (RD). Brains were also analyzed for NF-\u3baB protein expression, oxidative stress level and UCP2-targeted microRNAs expression level. Next, based on knowledge that fenofibrate and Brassica Oleracea (BO) stimulate UCP2 expression through PPAR\u3b1 activation, we monitored stroke occurrence in SHRSP receiving JD plus fenofibrate versus vehicle, JD plus BO juice versus BO juice plus PPAR\u3b1 inhibitor. Brain UCP2 expression was markedly reduced by JD in SHRSP and in the (SHRsr.SHRsp-(D1Rat134-Mt1pa)) congenic line, whereas NF-\u3baB expression and oxidative stress level increased. The opposite phenomenon was observed in the SHRSR and in the (SHRsp.SHRsr-(D1Rat134-Mt1pa)) reciprocal congenic line. Interestingly, the UCP2-targeted rno-microRNA-503 was significantly upregulated in SHRSP and decreased in SHRSR upon JD, with consistent changes in the two reciprocal congenic lines. Both fenofibrate and BO significantly decreased brain microRNA-503 level, upregulated UCP2 expression and protected SHRSP from stroke occurrence. In vitro overexpression of microRNA-503 in endothelial cells suppressed UCP2 expression and led to a significant increase of cell mortality with decreased cell viability. Brain UCP2 downregulation is a determinant of increased stroke predisposition in high-salt-fed SHRSP. In this context, UCP2 can be modulated by both pharmacological and nutraceutical agents. The microRNA-503 significantly contributes to mediate brain UCP2 downregulation in JD-fed SHRSP

Disulfiram modulated ROS–MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties

BACKGROUND: Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs). METHODS: The effect of DS on BC cell lines and BCSCs was determined by MTT, western blot, CSCs culture and CSCs marker analysis. RESULTS: Disulfiram was highly toxic to BC cell lines in vitro in a copper (Cu)-dependent manner. In Cu-containing medium (1 mu M), the IC50 concentrations of DS in BC cell lines were 200-500 nM. Disulfiram/copper significantly enhanced (3.7-15.5-fold) cytotoxicity of paclitaxel (PAC). Combination index isobologram analysis demonstrated a synergistic effect between DS/Cu and PAC. The increased Bax and Bcl2 protein expression ratio indicated that intrinsic apoptotic pathway may be involved in DS/Cu-induced apoptosis. Clonogenic assay showed DS/Cu-inhibited clonogenicity of BC cells. Mammosphere formation and the ALDH1(+VE) and CD24(Low)/CD44(High) CSCs population in mammospheres were significantly inhibited by exposure to DS/Cu for 24 h. Disulfiram/copper induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways. Meanwhile, the constitutive NF kappa B activity in BC cell lines was inhibited by DS/Cu. CONCLUSION: Disulfiram/copper inhibited BCSCs and enhanced cytotoxicity of PAC in BC cell lines. This may be caused by simultaneous induction of ROS and inhibition of NF kappa B. British Journal of Cancer (2011) 104, 1564-1574. doi: 10.1038/bjc.2011.126 www.bjcancer.com Published online 12 April 2011 (C) 2011 Cancer Research U

Distinct genes related to drug response identified in ER positive and ER negative breast cancer cell lines

Breast cancer patients have different responses to chemotherapeutic treatments. Genes associated with drug response can provide insight to understand the mechanisms of drug resistance, identify promising therapeutic opportunities, and facilitate personalized treatment. Estrogen receptor (ER) positive and ER negative breast cancer have distinct clinical behavior and molecular properties. However, to date, few studies have rigorously assessed drug response genes in them. In this study, our goal was to systematically identify genes associated with multidrug response in ER positive and ER negative breast cancer cell lines. We tested 27 human breast cell lines for response to seven chemotherapeutic agents (cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, and paclitaxel). We integrated publicly available gene expression profiles of these cell lines with their in vitro drug response patterns, then applied meta-analysis to identify genes related to multidrug response in ER positive and ER negative cells separately. One hundred eighty-eight genes were identified as related to multidrug response in ER positive and 32 genes in ER negative breast cell lines. Of these, only three genes (DBI, TOP2A, and PMVK) were common to both cell types. TOP2A was positively associated with drug response, and DBI was negatively associated with drug response. Interestingly, PMVK was positively associated with drug response in ER positive cells and negatively in ER negative cells. Functional analysis showed that while cell cycle affects drug response in both ER positive and negative cells, most biological processes that are involved in drug response are distinct. A number of signaling pathways that are uniquely enriched in ER positive cells have complex cross talk with ER signaling, while in ER negative cells, enriched pathways are related to metabolic functions. Taken together, our analysis indicates that distinct mechanisms are involved in multidrug response in ER positive and ER negative breast cells. © 2012 Shen et al

Genome-Wide Identification and Analysis of Grape Aldehyde Dehydrogenase (ALDH) Gene Superfamily

The completion of the grape genome sequencing project has paved the way for novel gene discovery and functional analysis. Aldehyde dehydrogenases (ALDHs) comprise a gene superfamily encoding NAD(P)(+)-dependent enzymes that catalyze the irreversible oxidation of a wide range of endogenous and exogenous aromatic and aliphatic aldehydes. Although ALDHs have been systematically investigated in several plant species including Arabidopsis and rice, our knowledge concerning the ALDH genes, their evolutionary relationship and expression patterns in grape has been limited.A total of 23 ALDH genes were identified in the grape genome and grouped into ten families according to the unified nomenclature system developed by the ALDH Gene Nomenclature Committee (AGNC). Members within the same grape ALDH families possess nearly identical exon-intron structures. Evolutionary analysis indicates that both segmental and tandem duplication events have contributed significantly to the expansion of grape ALDH genes. Phylogenetic analysis of ALDH protein sequences from seven plant species indicates that grape ALDHs are more closely related to those of Arabidopsis. In addition, synteny analysis between grape and Arabidopsis shows that homologs of a number of grape ALDHs are found in the corresponding syntenic blocks of Arabidopsis, suggesting that these genes arose before the speciation of the grape and Arabidopsis. Microarray gene expression analysis revealed large number of grape ALDH genes responsive to drought or salt stress. Furthermore, we found a number of ALDH genes showed significantly changed expressions in responses to infection with different pathogens and during grape berry development, suggesting novel roles of ALDH genes in plant-pathogen interactions and berry development.The genome-wide identification, evolutionary and expression analysis of grape ALDH genes should facilitate research in this gene family and provide new insights regarding their evolution history and functional roles in plant stress tolerance

Breed and adaptive response modulate bovine peripheral blood cells’ transcriptome

Background: Adaptive response includes a variety of physiological modifications to face changes in external or internal conditions and adapt to a new situation. The acute phase proteins (APPs) are reactants synthesized against environmental stimuli like stress, infection, inflammation. Methods: To delineate the differences in molecular constituents of adaptive response to the environment we performed the whole-blood transcriptome analysis in Italian Holstein (IH) and Italian Simmental (IS) breeds. For this, 663 IH and IS cows from six commercial farms were clustered according to the blood level of APPs. Ten extreme individuals (five APP+ and APP- variants) from each farm were selected for the RNA-seq using the Illumina sequencing technology. Differentially expressed (DE) genes were analyzed using dynamic impact approach (DIA) and DAVID annotation clustering. Milk production data were statistically elaborated to assess the association of APP+ and APP- gene expression patterns with variations in milk parameters. Results: The overall de novo assembly of cDNA sequence data generated 13,665 genes expressed in bovine blood cells. Comparative genomic analysis revealed 1,152 DE genes in the comparison of all APP+ vs. all APP- variants; 531 and 217 DE genes specific for IH and IS comparison respectively. In all comparisons overexpressed genes were more represented than underexpressed ones. DAVID analysis revealed 369 DE genes across breeds, 173 and 73 DE genes in IH and IS comparison respectively. Among the most impacted pathways for both breeds were vitamin B6 metabolism, folate biosynthesis, nitrogen metabolism and linoleic acid metabolism. Conclusions: Both DIA and DAVID approaches produced a high number of significantly impacted genes and pathways with a narrow connection to adaptive response in cows with high level of blood APPs. A similar variation in gene expression and impacted pathways between APP+ and APP- variants was found between two studied breeds. Such similarity was also confirmed by annotation clustering of the DE genes. However, IH breed showed higher and more differentiated impacts compared to IS breed and such particular features in the IH adaptive response could be explained by its higher metabolic activity. Variations of milk production data were significantly associated with APP+ and APP- gene expression patterns

The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis

High aldehyde dehydrogenase (ALDH) activity can be used to identify tumor-initiating and metastasis-initiating cells in various human carcinomas, including prostate cancer. To date, the functional importance of ALDH enzymes in prostate carcinogenesis, progression and metastasis has remained elusive. Previously we identified strong expression of ALDH7A1 in human prostate cancer cell lines, primary tumors and matched bone metastases. In this study, we evaluated whether ALDH7A1 is required for the acquisition of a metastatic stem/progenitor cell phenotype in human prostate cancer. Knockdown of ALDH7A1 expression resulted in a decrease of the α2hi/αvhi/CD44+ stem/progenitor cell subpopulation in the human prostate cancer cell line PC-3M-Pro4. In addition, ALDH7A1 knockdown significantly inhibited the clonogenic and migratory ability of human prostate cancer cells in vitro. Furthermore, a number of genes/factors involved in migration, invasion and metastasis were affected including transcription factors (snail, snail2, and twist) and osteopontin, an ECM molecule involved in metastasis. Knockdown of ALDH7A1 resulted in decreased intra-bone growth and inhibited experimentally induced (bone) metastasis, while intra-prostatic growth was not affected. In line with these observations, evidence is presented that TGF-β, a key player in cancer invasiveness and bone metastasis, strongly induced ALDH activity while BMP7 (an antagonist of TGF-β signaling) down-regulated ALDH activity. Our findings show, for the first time, that the ALDH7A1 enzyme is functionally involved in the formation of bone metastases and that the effect appeared dependent on the microenvironment, i.e., bone versus prostate