SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein.

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson's disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice.

Stimulation of Angiotensin Converting Enzyme 2: A Novel Treatment Strategy for Diabetic Nephropathy.

Despite current therapies for diabetic nephropathy, many patients continue to progress to end-stage renal disease requiring renal replacement therapy. While the precise mechanisms underlying diabetic nephropathy remain to be determined, it is well established that chronic activation of the renin angiotensin aldosterone system (RAAS) plays a substantial role in the pathogenesis of diabetic nephropathy. Angiotensin converting enzyme 2 (ACE2), the enzyme responsible for activating the reno-protective arm of the RAAS converts angiotensin (Ang) II into Ang 1-7 which exerts reno-protective effects.

Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia?

Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia.

Endothelial-specific overexpression of cationic amino acid transporter-1 prevents loss of kidney function in heart failure.

Heart failure (HF) is associated with impaired L-arginine transport. In the present study, we tested the hypothesis that augmented L-arginine transport prevents the loss of kidney function in HF. Renal function was assessed in wildtype mice (WT), transgenic mice with HF (dilated cardiomyopathy, DCM) and double transgenic mice (double transgenic mice with DCM and CAT-1 overexpression, HFCAT-1) with HF and endothelial-specific overexpression of the predominant L-arginine transporter, cationic amino acid transporter-1 (CAT-1) (n=4-8/group).

Impaired l-arginine-nitric oxide pathway contributes to the pathogenesis of resistant hypertension.

The precise mechanisms underlying resistant hypertension remain elusive. Reduced nitric oxide (NO) bioavailability is frequently documented in chronic kidney disease, obesity, diabetes and advanced age, all of which are risk factors for resistant hypertension. Sympathetic overactivity and chronic activation of the renin-angiotensin system are salient features of resistant hypertension.

Serelaxin attenuates renal inflammation and fibrosis in a mouse model of dilated cardiomyopathy.

New Findings: What is the central question of this study? The aim was to determine the renoprotective effects of serelaxin in the setting of chronic heart failure. What are the main findings and its importance? Our data indicate that serelaxin can reduce renal fibrosis and inflammation in experimental heart failure. Currently, there are no effective treatments to rescue renal function in heart failure patients, and our data suggest that serelaxin might have the potential to reduce renal fibrosis and inflammation in heart failure.

Pharmacological hypothesis: Nitric oxide-induced inhibition of ADAM-17 activity as well as vesicle release can in turn prevent the production of soluble endothelin-converting enzyme.

Endothelin-1 (ET-1) and nitric oxide (NO) are two highly potent vasoactive molecules with opposing effects on the vasculature. Endothelin-converting enzyme (ECE) and nitric oxide synthase (NOS) catalyse the production of ET-1 and NO, respectively. It is well established that these molecules play a crucial role in the initiation and progression of cardiovascular diseases and have therefore become targets of therapy.

The Cardiovascular and Neurotoxic Effects of the Venoms of Six Bony and Cartilaginous Fish Species.

Fish venoms are often poorly studied, in part due to the difficulty in obtaining, extracting, and storing them. In this study, we characterize the cardiovascular and neurotoxic effects of the venoms from the following six species of fish: the cartilaginous stingrays Neotrygon kuhlii and Himantura toshi, and the bony fish Platycephalus fucus, Girella tricuspidata, Mugil cephalus, and Dentex tumifrons. All venoms (10-100 μg/kg, i.

Stimulating the Activity of Amyloid-Beta Degrading Enzymes: A Novel Approach for the Therapeutic Manipulation of Amyloid-Beta Levels.

Alzheimer's disease is a debilitating neurological disease placing significant burden on health care budgets around the world. It is widely believed that accumulation of amyloid-beta (Aβ) in the brain is a key event that initiates neurodegeneration, thus the clearance of Aβ from brain could be a key therapeutic strategy. Aβ exists in an equilibrium in healthy individuals, and recent research would suggest that dysfunction in the clearance pathways is the driving force behind its accumulation.

Canopy Venom: Proteomic Comparison among New World Arboreal Pit-Viper Venoms.

Central and South American pitvipers, belonging to the genera Bothrops and Bothriechis, have independently evolved arboreal tendencies. Little is known regarding the composition and activity of their venoms. In order to close this knowledge gap, venom proteomics and toxin activity of species of Bothriechis, and Bothrops (including Bothriopsis) were investigated through established analytical methods.

Effects of Dietary l-Arginine on Nitric Oxide Bioavailability in Obese Normotensive and Obese Hypertensive Subjects.

Obesity related hypertension is a major risk factor for resistant hypertension. We do not completely understand the mechanism(s) underlying the development of obesity related hypertension which hinders the development of novel treatment strategies for this condition. Data from experimental studies and small clinical trials indicate that transport of l-arginine, the substrate for nitric oxide (NO), and subsequent NO production are reduced in obesity induced hypertension.

Role of Renal Oxidative Stress in the Pathogenesis of the Cardiorenal Syndrome.

Renal dysfunction and heart failure commonly co-exist; it is termed the cardiorenal syndrome (CRS). This combination of renal and cardiac impairment presents a substantial clinical challenge and is associated with adverse prognosis. The pathogenesis of the CRS is complex, including chronic activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, together with reduced renal perfusion.

N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure.

Oxidative stress plays a central role in the pathogenesis of heart failure. We aimed to determine whether the antioxidantN-acetylcysteine can attenuate cardiac fibrosis and remodeling in a mouse model of heart failure. Minipumps were implanted subcutaneously in wild-type mice (n = 20) and mice with cardiomyopathy secondary to cardiac specific overexpression of mammalian sterile 20-like kinase 1 (MST-1;n = 18) to administerN-acetylcysteine (40 mg/kg per day) or saline for a period of 8 weeks.

N-terminal domain of Bothrops asper Myotoxin II Enhances the Activity of Endothelin Converting Enzyme-1 and Neprilysin.

Neprilysin (NEP) and endothelin converting enzyme-1 (ECE-1) are two enzymes that degrade amyloid beta in the brain. Currently there are no molecules to stimulate the activity of these enzymes. Here we report, the discovery and characterisation of a peptide referred to as K49-P1-20, from the venom of Bothrops asper which directly enhances the activity of both ECE-1 and NEP.

Cardio-protective effects of combined l-arginine and insulin: Mechanism and therapeutic actions in myocardial ischemia-reperfusion injury.

Reduced nitric oxide (NO) bioavailability plays a central role in the pathogenesis of myocardial ischemia-reperfusion injury (I-R), and reduced l-arginine transport via cationic amino acid transporter-1 is a key contributor to the reduced NO levels. Insulin can increase NO levels by increasing the transport of its substrate l-arginine but insulin alone exerts minimal cardiac protection in I-R. We hypothesized that combined insulin and l-arginine may provide cardioprotective effects in the setting of myocardial I-R.

Augmented Endothelial-Specific L-Arginine Transport Blunts the Contribution of the Sympathetic Nervous System to Obesity Induced Hypertension in Mice.

Augmenting endothelial specific transport of the nitric oxide precursor L-arginine via cationic amino acid transporter-1 (CAT1) can prevent obesity related hypertension. We tested the hypotheses that CAT1 overexpression prevents obesity-induced hypertension by buffering the influence of the sympathetic nervous system (SNS) on the maintenance of arterial pressure and by buffering pressor responses to stress. Wild type (WT; n=13) and CAT1 overexpressing mice (CAT+; n=13) were fed a normal or a high fat diet for 20 weeks.

Pathogenesis and treatment of the cardiorenal syndrome: Implications of L-arginine-nitric oxide pathway impairment.

A highly complex interplay exists between the heart and kidney in the setting of both normal and abnormal physiology. In the context of heart failure, a pathophysiological condition termed the cardiorenal syndrome (CRS) exists whereby dysfunction in the heart or kidney can accelerate pathology in the other organ. The mechanisms that underpin CRS are complex, and include neuro-hormonal activation, oxidative stress and endothelial dysfunction.

Augmented endothelial l-arginine transport ameliorates pressure-overload-induced cardiac hypertrophy.

What is the central question of this study? What is the potential role of endothelial NO production via overexpression of the l-arginine transporter, CAT1, as a mitigator of cardiac hypertrophy? What is the main finding and its importance? Augmentation of endothelium-specific l-arginine transport via CAT1 can attenuate pressure-overload-dependent cardiac hypertrophy and fibrosis. Our findings support the conclusion that interventions that improve endothelial l-arginine transport may provide therapeutic utility in the setting of myocardial hypertrophy. Such modifications may be introduced by exercise training or locally delivered gene therapy, but further experimental and clinical studies are required.

Nitric oxide inhibits the production of soluble endothelin converting enzyme-1.

This study examined the effect of nitric oxide on the production of soluble ECE-1. Activity of ECE-1 in media was measured using a quenched fluorescent substrate assay, and expressed as a percentage of control. Endothelial cells were incubated with the nitric oxide donor Diethylenetriamine NONOate (DETA; 250-800 µM), NOS substrate L-Arg (200-1,000 µM), a L-Arg transport inhibitor (L-Lys; 10 µM) and NOS inhibitors (L-Gln and N5-[imino(nitroamino)methyl]-L-ornithine, methyl ester, monohydrochloride (L-NAME); 10-100 µM).