Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They ...affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies.
SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD.
Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term.
Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.
La esquizencefalia es una malformación poco común del sistema nervioso central, caracterizada por la presencia de hendiduras encefálicas que se extienden desde la superficie pial hasta los ...ventrículos laterales. Habitualmente se asocia a otras comorbilidades, como parálisis cerebral infantil y crisis convulsivas, que afectan de manera significativa la calidad de vida, el desenvolvimiento social y la adaptación ambiental de los pacientes. Es una entidad cuyo tratamiento es sintomático, por lo cual el abordaje se enfoca en el control de las convulsiones y en la rehabilitación, la cual minimiza el retraso neuro-psicológico que pueden presentar estos pacientes. Se reporta el caso de un paciente pediátrico con esquizencefalia de labio abierto (el subtipo clínico que cursa con peor pronóstico) con una evolución clínica favorable, libre de crisis convulsivas y sin necesidad de farmacoterapia. Actualmente, después de haber realizado un proceso de rehabilitación adaptada y temprana, presenta un déficit neurológico mínimo, con un desarrollo motor y psicológico completo, y un desenvolvimiento social satisfactorio.
BACKGROUND:Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and ...atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined.
METHODS:Adcy9-inactivated (Adcy9) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtgAdcy9 and CETPtgAdcy9), were submitted to an atherogenic protocol (injection of an AAV8 adeno-associated virus serotype 8 expressing a PCSK9 proprotein convertase subtilisin/kexin type 9 gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated.
RESULTS:Adcy9 mice had a 65% reduction in aortic atherosclerosis compared to WT (P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9 mice compared to WT animals (P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9 mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9 (P<0.01 for all). Aortic endothelium from Adcy9 mice allowed significantly less adhesion of splenocytes compared to WT (P<0.05). Adcy9 mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume (P<0.01 for both). Feed efficiency was increased in Adcy9 compared to WT mice (P<0.01), which was accompanied by prolonged cardiac RR interval (P<0.05) and improved nocturnal heart rate variability (P=0.0572). Adcy9 inactivation–induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtgAdcy9 mice (P>0.05 versus CETPtgAdcy9).
CONCLUSIONS:Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.
Abstract
Background
SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors for entry into cells, and the serine protease TMPRSS2 for S protein priming. ...Inhibition of protease activity or the engagement with ACE2 and NRP1 receptors has been shown to be an effective strategy for blocking infectivity and viral spreading. Valproic acid (VPA; 2-propylpentanoic acid) is an epigenetic drug approved for clinical use. It produces potent antiviral and anti-inflammatory effects through its function as a histone deacetylase (HDAC) inhibitor. Here, we propose VPA as a potential candidate to tackle COVID-19, in which rapid viral spread and replication, and hyperinflammation are crucial elements.
Results
We used diverse cell lines (HK-2, Huh-7, HUVEC, Caco-2, and BEAS-2B) to analyze the effect of VPA and other HDAC inhibitors on the expression of the ACE-2 and NRP-1 receptors and their ability to inhibit infectivity, viral production, and the inflammatory response. Treatment with VPA significantly reduced expression of the ACE2 and NRP1 host proteins in all cell lines through a mechanism mediated by its HDAC inhibitory activity. The effect is maintained after SARS-CoV-2 infection. Consequently, the treatment of cells with VPA before infection impairs production of SARS-CoV-2 infectious viruses, but not that of other ACE2- and NRP1-independent viruses (VSV and HCoV-229E). Moreover, the addition of VPA 1 h post-infection with SARS-CoV-2 reduces the production of infectious viruses in a dose-dependent manner without significantly modifying the genomic and subgenomic messenger RNAs (gRNA and sg mRNAs) or protein levels of N protein. The production of inflammatory cytokines (TNF-α and IL-6) induced by TNF-α and SARS-CoV-2 infection is diminished in the presence of VPA.
Conclusions
Our data showed that VPA blocks three essential processes determining the severity of COVID-19. It downregulates the expression of ACE2 and NRP1, reducing the infectivity of SARS-CoV-2; it decreases viral yields, probably because it affects virus budding or virions stability; and it dampens the triggered inflammatory response. Thus, administering VPA could be considered a safe treatment for COVID-19 patients until vaccines have been rolled out across the world.
Abstract only
Introduction:
Studies of Illness perception in patients with acute coronary syndrome (ACS) conducted in Canada and Finland showed that genetic factors, stress and lifestyle behaviors ...are the most common perceived cause of ACS (unstable angina, myocardial infarction). As illness perception is influenced by the personal experience of the illness and its management, as well as by cultural and social factors, we conducted a study to assess illness perception in patients with acute coronary syndrome in Argentina.
Methods:
Descriptive, cross-sectional, multicenter study. Adults over 18 years old hospitalized for ACS participated in the study. The day of discharge from the Coronary Care Unit, each subject completed a questionnaire generated and validated in Argentina aimed at assessing illness perception. Clinical data were collected by the treating physician at each participating institution.
Results:
109 patients between 33 and 84 years old (mean SD age = 61 12 years, 70% male) were enrolled; 57% was diagnosed with ACS without ST-segment elevation and 37% was diagnosed with acute myocardial infarction (MI) with ST-segment elevation; in 6% the acute MI was indeterminate. Many patients attributed the heart disease to their traditional cardiovascular risk factors: 93% to hypertension, 81% to cholesterol, 71% to diabetes mellitus, 69% to physical inactivity, 67% to obesity, 63% to smoking. Only 30% of patients with a positive family history identified it as a risk factor. Stress, anxiety, and personality were identified as the cause for their heart disease in 71%, 64%, and 42% of patients, respectively. The majority of patients (74%) considered that they should improve the adherence to medications after discharge and 80% that should attend the medical follow-ups.
Conclusion:
Most patients identified their modifiable risk factors as causal for coronary heart disease. Only 30% of participants with a positive family history recognized it as a risk factor. A high percentage of patients recognized suboptimal behaviors in relation to medication adherence and medical follow-ups.
Droughts driven by global change are triggering worldwide forest dieback, a phenomenon that is predicted to worsen. We combined genome-wide single nucleotide polymorphisms (SNPs) and ...dendrochronological approaches to assess genetically-based individual tree vulnerability to past extreme droughts that caused massive mortality of coihue (Nothofagus dombeyi (Mirb.) Blume) forests in northern Patagonia, Argentina. We collected fresh leaves and wood cores from pairs of trees, one with a healthy crown (HC) and another with a partially affected crown (PA), at four sites impacted by droughts in 1998, 2008, and 2014. We used dendrochronological techniques to estimate parameters in terms of growth trends due to drought and genomic analysis to assess the relationship of genomic variation with water stress. While 5155 neutral loci did not differentiate PA from HC trees, a set of 33 adaptive SNPs did, 8 of which were related to water stress. Association analysis between genomic variants and dendrophenotypic traits yielded 6 SNPs that were associated with a growth measure as resilience to cope with drought. Our preliminary results indicate that susceptibility to drought in N. dombeyi could be determined at the genomic level. The combination of these approaches provides a framework for the identification and analysis of candidate genes for stress response in non-model species.
Celotno besedilo
Dostopno za:
BF, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
