Microglia, the missing link in the brain-gut-hypertension axis

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Redox signaling, Nox5 and vascular remodeling in hypertension

Purpose of review: Extensive data indicate a role for reactive oxygen species (ROS) and redox signaling in vascular damage in hypertension. However, molecular mechanisms underlying these processes remain unclear, but oxidative post-translational modification of vascular proteins is critical. This review discusses how proteins are oxidatively modified and how redox signaling influences vascular smooth muscle cell growth and vascular remodeling in hypertension. We also highlight Nox5 as a novel vascular ROS-generating oxidase. Recent findings: Oxidative stress in hypertension leads to oxidative imbalance that affects vascular cell function through redox signaling. Many Nox isoforms produce ROS in the vascular wall, and recent findings show that Nox5 may be important in humans. ROS regulate signaling by numerous processes including cysteine oxidative post-translational modification such as S-nitrosylation, S-glutathionylation and sulfydration. In vascular smooth muscle cells, this influences cellular responses to oxidative stimuli promoting changes from a contractile to a proliferative phenotype. Summary: In hypertension, Nox-induced ROS production is increased, leading to perturbed redox signaling through oxidative modifications of vascular proteins. This influences mitogenic signaling and cell cycle regulation, leading to altered cell growth and vascular remodeling in hypertension

Vascular smooth muscle contraction in hypertension

Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex interacting systems such as the renin angiotensin aldosterone system (RAAS), sympathetic nervous system, immune activation and oxidative stress, which influence vascular smooth muscle function. Vascular smooth muscle cells are highly plastic and in pathological conditions undergo phenotypic changes from a contractile to a proliferative state. Vascular smooth muscle contraction is triggered by an increase in intracellular free calcium concentration ([Ca2+]i), promoting actin-myosin cross-bridge formation. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase (ROCK), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling, reactive oxygen species and reorganization of the actin cytoskeleton. Activation of immune/inflammatory pathways and noncoding RNAs are also emerging as important regulators of vascular function. Vascular smooth muscle cell [Ca2+]i, not only determines the contractile state but also influences activity of many calcium-dependent transcription factors and proteins thereby impacting the cellular phenotype and function. Perturbations in vascular smooth muscle cell signaling and altered function influence vascular reactivity and tone, important determinants of vascular resistance and blood pressure. Here we discuss mechanisms regulating vascular reactivity and contraction in physiological and pathophysiological conditions and highlight some new advances in the field, focusing specifically on hypertension

Assessment of hygienic conditions of ground pepper (Piper nigrum L.) on the market in São Paulo city, by means of two methodologies for detecting the light filth

Pepper should to be collected, processed, and packed under optimum conditions to avoid the presence of foreign matter. The hygienic conditions of ground pepper marketted in São Paulo city were assessed in determining the presence of foreign matter by means of two extraction methodologies. This study was carried out during a six-month time period from May to September 2006. The occurrence of light impurities was determined either by the flotation technique following the methodology recommended by AOAC or by enzyme – linked immunosorbent assay (ELISA). It was observed that 100% of the examined samples contained insect fragments, and many samples were housing more than one type of foreign matter. Twentytwo percent of samples were unqualified for consumption owing to the occurrence of rodent hairs. For the calibration of ELISA test for quantification of insect contamination level in pepper samples, a range of standard-infested samples was prepared in adding 1, 2, 4, 8 and 10 insects in a control sample to estimate the number of insects in the analyzed samples by measuring optical densities (OD) values with a spectrophotometer. Among the 22 samples, 36.4% of samples presented OD values close to that corresponding to the standard infested with eight insects, 40.9% of samples were comparable to OD of the standard infested with four insects, 18.2% comparable to standard with 10 insects, and 4.5% to the standard with two insects. According to the results observed in the present study, the technique described in AOAC official methods manual was found more suitable for detecting not only the insects but also the additional impurities in analyzed samples, while ELISA is specific to detect myosin from the insect muscle, which undergoes serious degradation with time. Keywords: Pepper, ELISA test , Light filth, AOAC official method

Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma.

BACKGROUND: Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC). METHODS: Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months. RESULTS: Median pretherapeutic serum GGT level was 25 U l(-1). Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l(-1) was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l(-1)), normal high (17.5 to <34.5 U l(-1)), elevated (34.5 to <181.5 U l(-1)), and highly elevated (⩾181.5 U l(-1)). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit. CONCLUSIONS: Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design

Vascular biology of superoxide-generating NADPH oxidase 5 (Nox5)- implications in hypertension and cardiovascular disease

SIGNIFICANCE: NADPH oxidases (Nox) of which there are 7 isoforms (Nox1-5, Duox1/Duox2) are professional oxidases functioning as ROS-generating enzymes. ROS are signaling molecules important in physiological processes. Increased ROS production and altered redox signaling in the vascular system have been implicated in the pathophysiology of cardiovascular diseases, including hypertension, and have been attributed, in part, to increased Nox activity. RECENT ADVANCES: Nox1,2,4,5 are expressed and functionally active in human vascular cells. While Nox1,2,4 have been well characterized in models of cardiovascular disease, little is known about Nox5. This may relate to the lack of experimental models because rodents lack NOX5. However, recent studies have advanced the field by i) elucidating mechanisms of Nox5 regulation, ii) identifying Nox5 variants, iii) characterizing Nox5 expression and iv) discovery of Nox5 crystal structure. Moreover, studies in human Nox5-expressing mice have highlighted a putative role for Nox5 in cardiovascular disease. CRITICAL ISSUES: Although growing evidence indicates a role for Nox-derived ROS in cardiovascular (patho)physiology, the exact function of each isoform remains unclear. This is especially true for Nox5. FUTURE DIRECTIONS: Future directions should focus on clinically-relevant studies to discover the functional significance of Noxs, and Nox5 in particular, in human health and disease. Two important recent studies will impact future directions. Firstly, Nox5 is the first Nox to be crystalized. Secondly GWAS identified Nox5 as a novel blood pressure-associated gene. These discoveries, together with advancements in Nox5 biology and biochemistry, will facilitate discovery of drugs th at selectively target Noxs to interfere with uncontrolled ROS generation

Associations Between Presenting Symptoms, Clinicopathological Parameters, and Prognosis in a Contemporary Series of Patients With Renal Cell Carcinoma

PURPOSE: To evaluate the impact of presenting symptoms on survival in a contemporary series of patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: We prospectively recorded data on the presenting symptoms, pathology, and RCC-specific survival of 633 consecutive RCC patients who underwent surgery between 2003 and 2012. RESULTS: Four hundred thirty-three RCCs (68%) were incidental, 111 (18%) were associated with local symptoms, and 89 (14%) were associated with systemic symptoms. Among those with incidental RCC, 317 patients (73%) were completely asymptomatic and 116 patients (27%) presented with symptoms not related to the tumor. During a median follow-up interval of 40 months (interquartile range: 39 to 69 months), 77 patients died from RCC. In univariate analyses, symptom classification was significantly associated with RCC-specific survival (p<0.001). Patients with incidental RCC and unrelated symptoms tended to have worse prognosis than did patients who were completely asymptomatic, although this difference was not statistically significant (p=0.057). The symptom classification was associated with advanced TNM stages (p<0.001) and grade (p<0.001). CONCLUSIONS: This study confirms that presenting symptoms are associated with tumor characteristics and survival. The majority of RCCs are diagnosed incidentally in patients without any symptoms or with symptoms not related to RCC. Patients in the latter group tend to have a worse prognosis than do patients who are completely asymptomatic. With the increasing number of incidentally diagnosed RCCs, substratification of patients with incidental tumors may be prognostically relevant

Caracterização molecular de Cryptosporidium spp. de pacientes de área urbana do Brasil infectados por HIV

Cryptosporidium spp. são importantes causas de doenças entéricas em humanos, mas podem também ser encontrados em animais. O presente estudo descreve a frequência relativa de diversas espécies de Cryptosporidium em amostras de humanos da cidade de São Paulo, Brasil, obtidas de janeiro a julho de 2007. Análises de sequências de produtos de nested PCR direcionadas ao genes codificadores da menor unidade ribosomal e da proteina de parede de oocistos revelaram 17 (63,0%) isolados de C. hominis, quatro (14,8%) C. parvum, cinco (18,5%) C. felis, e um (3,7%) C. canis. Estes resultados sugerem que, em ambientes urbanos no Brasil, o genótipo adaptado ao gato pode desempenhar potencial papel na transmissão zoonótica de criptosporidiose, enquanto a transmissão antroponótica da criptosporidiose causada pelo C. hominis parece predominar.Cryptosporidium spp. are important cause of enteric disease in humans, but may also infect animals. This study describes the relative frequency of several Cryptosporidium species found in human specimens from HIV infected patients in the São Paulo municipality obtained from January to July 2007. Sequence analysis of the products of nested-PCR based on small subunit rRNA and Cryptosporidium oocyst wall protein coding genes revealed 17 (63.0%) isolates of C. hominis, four (14.8%) C. parvum, five (18.5%) C. felis and one (3.7%) C. canis. These findings suggest that, in urban environments of Brazil, the cat adapted C. felis may play a potential role in the zoonotic transmission of cryptosporidiosis whereas the anthroponotic transmission of cryptosporidiosis caused by C. hominis seems to predominate