Innate immune response against Brucella abortus involves activation of Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Among the NLRs involved in the recognition of B. abortus are NLRP3 and ...AIM2. Here, we demonstrate that B. abortus triggers non-canonical inflammasome activation dependent on caspase-11 and gasdermin-D (GSDMD). Additionally, we identify that Brucella-LPS is the ligand for caspase-11 activation. Interestingly, we determine that B. abortus is able to trigger pyroptosis leading to pore formation and cell death, and this process is dependent on caspase-11 and GSDMD but independently of caspase-1 protease activity and NLRP3. Mice lacking either caspase-11 or GSDMD were significantly more susceptible to infection with B. abortus than caspase-1 knockout or wild-type animals. Additionally, guanylate-binding proteins (GBPs) present in mouse chromosome 3 participate in the recognition of LPS by caspase-11 contributing to non-canonical inflammasome activation as observed by the response of Gbpchr3-/- BMDMs to bacterial stimulation. We further determined by siRNA knockdown that among the GBPs contained in mouse chromosome 3, GBP5 is the most important for Brucella LPS to be recognized by caspase-11 triggering IL-1β secretion and LDH release. Additionally, we observed a reduction in neutrophil, dendritic cell and macrophage influx in spleens of Casp11-/- and Gsdmd-/- compared to wild-type mice, indicating that caspase-11 and GSDMD are implicated in the recruitment and activation of immune cells during Brucella infection. Finally, depletion of neutrophils renders wild-type mice more susceptible to Brucella infection. Taken together, these data suggest that caspase-11/GSDMD-dependent pyroptosis triggered by B. abortus is important to infection restriction in vivo and contributes to immune cell recruitment and activation.
Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity, abnormal kidney function and ...associated increases in tubular sodium reabsorption initiate hypertension, which is often mild before the development of target organ injury. Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal and renal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin. The renal and neurohormonal pathways of obesity and hypertension are intertwined. For example, leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway, and kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation. Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity. Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension. Patient management therefore often requires multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes and inflammation. If more effective strategies for the prevention and control of obesity are not developed, cardiorenal, metabolic and other obesity-associated diseases could overwhelm health-care systems in the future.
Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in ...macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome-deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1β (IL-1β) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production.
This paper presents the results of an opinion poll conducted in Brazil on the perception of social isolation during the COVID-19 pandemic. The questionnaire was prepared on Google Forms, disseminated ...through social networks, with questions about the socioeconomic profile and factors associated with isolation. A non-probabilistic sample was obtained with 16,440 respondents. Data were analyzed using the Stata 13 software. Social interaction was the most affected aspect among people with higher education and income (45.8%), and financial problems caused a more significant impact (35%) among people with low income and education. Those who practice some physical activity showed lower levels of stress 13%, as well as greater normality in sleep 50.3%. People who reported living in worse habitability conditions reported willingness to remain isolated for less time, 73.9%. Among non-isolated people (10.7% of the total sample), 75.8% believe that social isolation will reduce the number of victims of COVID-19. We conclude, based on this sample, that the perception about social isolation as a pandemic mitigation action varies by income, education, age, and gender. However, most believe that it is the most appropriate control measure and are willing to wait as long as necessary to contribute to the fight against COVID-19.
Leishmania RNA virus (LRV) is an important virulence factor associated with the development of mucocutaneous Leishmaniasis, a severe form of the disease. LRV-mediated disease exacerbation relies on ...TLR3 activation, but downstream mechanisms remain largely unexplored. Here, we combine human and mouse data to demonstrate that LRV triggers TLR3 and TRIF to induce type I IFN production, which induces autophagy. This process results in ATG5-mediated degradation of NLRP3 and ASC, thereby limiting NLRP3 inflammasome activation in macrophages. Consistent with the known restricting role of NLRP3 for Leishmania replication, the signaling pathway triggered by LRV results in increased parasite survival and disease progression. In support of this data, we find that lesions in patients infected with LRV+ Leishmania are associated with reduced inflammasome activation and the development of mucocutaneous disease. Our findings reveal the mechanisms triggered by LRV that contribute to the development of the debilitating mucocutaneous form of Leishmaniasis.
Few reports have described the clinical and prognostic characteristics of endometrial cancer, which is increasing worldwide, in large patient series in Brazil. Our objective was to analyze the ...clinicopathological characteristics, prognostic factors, and outcomes of patients with endometrial cancer treated and followed at a tertiary Brazilian institution over a 10-year period.This retrospective study included 703 patients diagnosed with endometrial cancer who were treated at a public academic tertiary hospital between 2008 and 2018. The following parameters were analyzed: age at diagnosis, race, body mass index, serum CA125 level before treatment; histological type and grade, and surgical stage. Outcomes were reported relative to histological type, surgical staging, serum CA125, lymph-vascular space involvement (LVSI), and lymph-node metastasis. The median patient age at diagnosis was 63 (range, 27-93) years (6.4% were <50 years). Minimally invasive surgeries were performed in 523 patients (74.4%). Regarding histological grade, 468 patients (66.5%) had low-grade endometrioid histology and 449 patients (63.9%) had stage I tumors. Tumors exceeded 2.0 cm in 601 patients (85.5%). Lymphadenectomy was performed in 551 cases (78.4%). LVSI was present in 208 of the patients' tumors (29.5%). Ninety-three patients (13.2%) had recurrent tumors and 97 (13.7%) died from their malignant disease. The robust prognostic value of FIGO stage and lymph node status were confirmed. Other important survival predictors were histological grade and LVSI overall survival: hazard ratio (HR) = 3.75, p < 0.001 and HR = 2.01, p = 0.001; recurrence: HR = 2.49, p = 0.004 and HR = 3.22, p = 0.001, respectively). Disease-free (p = 0.087) and overall survival (p = 0.368) did not differ significantly between patients with stage II and III disease. These results indicate that prognostic role of cervical involvement should be explored further. This study reports the characteristics and outcomes of endometrial cancer in a large population from a single institution, with systematic surgical staging, a predominance of minimally invasive procedures, and well-documented outcomes. Prognostic factors in the present study population were generally similar to those in other countries, though our patients' tumors were larger than in studies elsewhere due to later diagnosis. Our unexpected finding of similar prognoses of stage II and III patients raises questions about the prognostic value of cervical involvement and possible differences between carcinomas originating in the lower uterine segment versus those originating in the body and fundus. The present findings can be used to guide public policies aimed at improving the diagnosis and treatment of endometrial cancer in Brazil and other similar countries.
In the search for new strategies to control Aedes aegypti Linnaeus (Diptera: Culicidae), several studies have successfully related pyriproxyfen (PPF) tarsal transference to breeding sites ...(autodissemination), as well as the sterilization potential of females exposed to PPF. Potential PPF autodissemination by mosquito feces after the ingestion of sugar baits has also been proposed. Therefore, the present work evaluated several parameters, e.g., fecal production, residuality under dry and aqueous conditions, PPF excretion affecting emergence inhibition (EI) by fecal deposits of Ae. aegypti fed with attractive toxic sugar baits (ATSBs) containing PPF as well as their reproductive potential. Females were fed with ATSBs offered as droplets and the feces were collected using filter paper and transferred to plastic cups with L3 larvae to evaluate EI. The residual effect of feces in aqueous and dry conditions and PPF excretion on EI was obtained by keeping the feces in water or dried for different time intervals and using feces collected at 24-h intervals, respectively. Females received a bloodmeal after feeding on ATSBs, eggs and larval counting expressed the reproductive potential. The fecal mass was not affected by PPF concentration, but EI increased from 33 to 54% as the PPF concentration increased. The PPF excretion in the feces exceeded 96 h. The residual effect in the EI for feces kept in water was reduced by more than 60% after 30 d but was not affected under dry conditions. The fecundity and fertility of the females were reduced up to 51% and 97%, respectively.
Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. ...Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin–angiotensin–aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin–angiotensin–aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.
Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also ...called syndrome X. Support for this concept initially came from clinical and population studies showing correlations among hyperinsulinemia, insulin resistance, and elevated BP in individuals with metabolic syndrome. Short-term studies in experimental animals and in humans provided additional evidence that hyperinsulinemia may evoke increases in sympathetic nervous system (SNS) activity and renal sodium retention that, if sustained, could increase BP. Although insulin infusions may increase SNS activity and modestly raise BP in rodents, chronic insulin administration does not significantly increase BP in lean or obese insulin-resistant rabbits, dogs, horses, or humans. Multiple studies in humans and experimental animals have also shown that severe insulin resistance and hyperinsulinemia may occur in the absence of elevated BP. These observations question whether insulin resistance and hyperinsulinemia are major factors linking obesity/metabolic syndrome with hypertension. Other mechanisms, such as physical compression of the kidneys, activation of the renin-angiotensin-aldosterone system, hyperleptinemia, stimulation of the brain melanocortin system, and SNS activation, appear to play a more critical role in initiating hypertension in obese subjects with metabolic syndrome. However, the metabolic effects of insulin resistance, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased BP to cause vascular and kidney injury that can exacerbate the hypertension and associated injury to the kidneys and cardiovascular system.
L'hyperinsulinémie et l'insulinorésistance ont été décrits il y a plus de 30 ans comme étant des facteurs importants contribuant à une pression artérielle (PA) élevée associée à l'obésité et au syndrome métabolique, également appelé syndrome X. Ce concept a été initialement soutenu par des études cliniques et démographiques montrant des corrélations entre l'hyperinsulinémie, l'insulinorésistance et une PA élevée chez les personnes atteintes du syndrome métabolique. Des études de court terme sur des animaux de laboratoire et chez l'Homme ont fourni des preuves supplémentaires que l'hyperinsulinémie peut provoquer une augmentation de l'activité du système nerveux sympathique (SNS) et de la rétention de sodium au niveau rénal qui, si elle est maintenue, pourrait augmenter la PA. Bien que les perfusions d'insuline puissent accroître l'activité du SNS et augmenter légèrement la PA chez les rongeurs, l'administration chronique d'insuline n'augmente pas significativement la PA chez les individus insulinorésistants maigres ou obèses, que ce soit chez les lapins, les chiens, les chevaux ou chez l’Homme. De multiples études chez l'Homme et les animaux de laboratoire ont également montré qu'une hyperinsulinémie et une insulinorésistance sévère peuvent survenir en absence de PA élevée. Ces observations amènent à se demander si l’insulinorésistance et l'hyperinsulinémie sont des facteurs majeurs liant l'obésité et le syndrome métabolique à l'hypertension. D'autres mécanismes, tels que la compression physique des reins, l'activation du système rénine-angiotensine-aldostérone, l'hyperleptinémie, la stimulation du système à mélanocortine du cerveau et l'activation du SNS, semblent jouer un rôle plus critique dans l'initiation de l'hypertension chez les sujets obèses atteints d'un syndrome métabolique. Cependant, les effets métaboliques de l'insulinorésistance, notamment l'hyperglycémie et la dyslipidémie, semblent interagir en synergie avec l'augmentation de la PA pour provoquer des lésions vasculaires et rénales qui peuvent exacerber l'hypertension et les dommages associés aux reins et au système cardiovasculaire.
Zou and colleagues are publishing in this issue of The Journal of Clinical Hypertension, result of one of their studies in which they found that human corin genetic polymorphisms is involved in blood ...pressure control, more specifically in salt sensitivity. It is being published in this journal shortly after a literature review indicated another 18 genes were also involved in salt sensitivity, however corin gene. This dynamism of newly discovered genes shows the complexity of studying the genetic control of arterial hypertension and explains its known preliotropic characteristic. In this commentary, the study by Zou and colleagues is placed in the context of recent evidence on the genetics of high blood pressure and the future perspectives resulting from this and other studies are presented in the context of the clinical application of genetics in the prevention and treatment of high blood pressure.
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