Tryptamine-gallic acid hybrid prevents non-steroidal anti-inflammatory drug-induced gastropathy: correction of mitochondrial dysfunction and inhibition of apoptosis in gastric mucosal cells

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.     

Congenital syphilis in Argentina: Experience in a pediatric hospital

In spite of being preventable, Congenital syphilis (CS) is still an important, and growing health problem worldwide. Fetal infection can be particularly aggressive, but newborns can be asymptomatic at birth and, if left untreated, develop systemic compromise afterwards with poor prognosis. We analyzed 61 CS diagnosis cases between 1987–2019 presenting at the Buenos Aires Children’ Hospital. The distribution of cases showed a bimodal curve, with a peak in 1992–1993 and in 2014–2017. Median age at diagnosis was 2 months (IQ 1–6 months). The main clinical findings were: bone alterations (59%); hepatosplenomegaly (54.1%); anemia (62.8%); skin lesions (42.6%) and renal compromise (33.3%). Cerebrospinal fluid (CSF) was abnormal in 5 patients, normal in 45 and was not available for 11 patients. Remarkably, spinal lumbar puncture did not modify therapeutic decisions in any case. Between mothers, only 46% have been tested for syphilis during pregnancy and 60.5% patients had non-treponemal titers equal to or less than fourfold the maternal titer. Intravenous penicillin G was prescribed for all except one patient, who received ceftriaxone with good therapeutic response. During follow-up, 1.6% infants died, 6.5% had persistent kidney disorders and 1.6% showed bone sequelae damage. RPR titers decreased after treatment, reaching negative seroconversion in 43% subjects at a median of 26.4 months. Low adherence to follow up was observed due to inherent vulnerable and low-income population characteristics in our cohort. Our results highlight a rising tendency in cases referred for CS in our population with high morbidity related to delayed diagnosis. A good therapeutic response was observed. CS requires a greater effort from the health system to adequately screen for this disease during pregnancy, and to detect cases earlier, to provide an adequate diagnosis and treatment.     

The Increased Risk of Road Crashes in Attention Deficit Hyperactivity Disorder (ADHD) Adult Drivers: Driven by Distraction? Results from a Responsibility Case-Control Study

Background and Objective

Both distractions (external and internal) and attention-deficit/hyperactivity disorder (ADHD) are serious risk factors for traffic crashes and injuries. However, it is still unknown if ADHD (a chronic condition) modifies the effect of distractions (irregular hazards) on traffic crashes. The objective of this study was to assess the effects of distractions and ADHD on traffic crash responsibility.

Methods

A responsibility case-control study was conducted in the adult emergency department of Bordeaux University Hospital, France. Subjects were recruited among drivers injured in a motor vehicle crash between April 2010 and August 2011. Responsibility levels were estimated using a standardized method. Frequencies of exposures were compared between drivers responsible and drivers not responsible for the crash. Independent risk factors were identified using a multivariate logistic regression including test interactions between distractions and ADHD.

Results

A total of 777 subjects were included in the analysis. Factors associated with responsibility were distraction induced by an external event (adjusted OR (aOR)  = 1.47; 95% confidence interval (CI) [1.06–2.05]), distraction induced by an internal thought (aOR = 2.38; CI: [1.50–3.77]) and ADHD (aOR = 2.18 CI: [1.22–3.88]). The combined effect of ADHD and external distractions was strongly associated with responsibility for the crash (aOR = 5.79 CI: [2.06–16.32]). Interaction assessment showed that the attributable proportion due to the interaction among participants with both exposures was 68%.

Discussion

Adults with ADHD are a population at higher risk of being responsible for a road traffic crash when exposed to external distractions. This result reinforces the need to diagnose adult ADHD and to include road safety awareness messages delivered by the physician. Developing advanced driver assistance systems devoted to the management of attention lapses is also increasingly relevant for these drivers.     

Expanding the Knowledge of the Geographic Distribution of Trypanosoma cruzi TcII and TcV/TcVI Genotypes in the Brazilian Amazon

Trypanosoma cruzi infection is a complex sylvatic enzooty involving a wide range of animal species. Six discrete typing units (DTUs) of T. cruzi, named TcI to TcVI, are currently recognized. One unanswered question concerning the epidemiology of T. cruzi is the distribution pattern of TcII and hybrid DTUs in nature, including their virtual absence in the Brazilian Amazon, the current endemic area of Chagas disease in Brazil. Herein, we characterized biological samples that were collected in previous epizootiological studies carried out in the Amazon Basin in Brazil. We performed T. cruzi genotyping using four polymorphic genes to identify T. cruzi DTUs: mini-exon, 1f8, histone 3 and gp72. This analysis was conducted in the following biological samples: (i) two T. cruzi isolates obtained by culturing of stools from the triatomine species Rhodnius picttipes and (ii) five serum samples from dogs in which trypomastigotes were observed during fresh blood examination. We report for the first time the presence of TcII and hybrid DTUs (TcV/TcVI) in the Amazon region in mixed infections with TcI. Furthermore, sequencing of the constitutive gene, gp72, demonstrated diversity in TcII even within the same forest fragment. These data show that TcII is distributed in the five main Brazilian biomes and is likely more prevalent than currently described. It is very probable that there is no biological or ecological barrier to the transmission and establishment of any DTU in any biome in Brazil.     

The innate immunity of a marine red alga involves oxylipins from both the eicosanoid and octadecanoid pathways

The oxygenated derivatives of fatty acids, known as oxylipins, are pivotal signaling molecules in animals and terrestrial plants. In animal systems, eicosanoids regulate cell differentiation, immune responses, and homeostasis. In contrast, terrestrial plants use derivatives of C18 and C16 fatty acids as developmental or defense hormones. Marine algae have emerged early in the evolution of eukaryotes as several distinct phyla, independent from the animal and green-plant lineages. The occurrence of oxylipins of the eicosanoid family is well documented in marine red algae, but their biological roles remain an enigma. Here we address the hypothesis that they are involved with the defense mechanisms of the red alga Chondrus crispus. By investigating its association with a green algal endophyte Acrochaete operculata, which becomes invasive in the diploid generation of this red alga, we showed that (1) when challenged by pathogen extracts, the resistant haploid phase of C. crispus produced both C20 and C18 oxylipins, (2) elicitation with pathogen extracts or methyl jasmonate activated the metabolism of C20 and C18 polyunsaturated fatty acids to generate hydroperoxides and cyclopentenones such as prostaglandins and jasmonates, and (3) C20 and C18 hydroperoxides as well as methyl jasmonate did induce shikimate dehydrogenase and Phe ammonialyase activities in C. crispus and conferred an induced resistance to the diploid phase, while inhibitors of fatty acid oxidation reduced the natural resistance of the haploid generation. The dual nature of oxylipin metabolism in this alga suggests that early eukaryotes featured both animal- (eicosanoids) and plant-like (octadecanoids) oxylipins as essential components of innate immunity mechanisms.     

Differential effect of cholesterol and its biosynthetic precursors on membrane dipole potential

Dipole potential is the potential difference within the membrane bilayer, which originates due to the nonrandom arrangement of lipid dipoles and water molecules at the membrane interface. Cholesterol, a representative sterol in higher eukaryotic membranes, is known to increase membrane dipole potential. In this work, we explored the effects of immediate (7-DHC and desmosterol) and evolutionary (ergosterol) precursors of cholesterol on membrane dipole potential, monitored by the dual wavelength ratiometric approach utilizing the probe di-8-ANEPPS. Our results show that the effect of these precursors on membrane dipole potential is very different from that observed with cholesterol, although the structural differences among them are subtle. These results assume relevance, since accumulation of cholesterol precursors due to defective cholesterol biosynthesis has been reported to result in several inherited metabolic disorders such as the Smith-Lemli-Opitz syndrome. Interestingly, cholesterol (and its precursors) has a negligible effect on dipole potential in polyunsaturated membranes. We interpret these results in terms of noncanonical orientation of cholesterol in these membranes. Our results constitute the first report on the effect of biosynthetic and evolutionary precursors of cholesterol on dipole potential, and imply that a subtle change in sterol structure can significantly alter the dipolar field at the membrane interface.