ACE I/D polymorphism is a risk factor for the clinical severity of COVID-19 in Brazilian male patients.

BACKGROUND: The renin-angiotensin system is potentially involved in the pathogen-host interaction in the disease caused by SARS-CoV-2, since the angiotensin-converting enzyme (ACE) 2 serves as a receptor for the virus. The impact of the pandemic in specific regions and ethnic groups highlights the importance of investigating genetic factors that disrupt the balance of the system in response to SARS-CoV-2 infection, especially in genes with ethnic frequency variations. Therefore, this study aimed to evaluate the influence of the ACE I/D polymorphism on the incidence and severity of COVID-19 in a sample of the Brazilian population. METHODS AND RESULTS: 70 severe cases and 355 mild cases patients were evaluated. DNA extraction was performed using a QIAamp DNA Blood Mini kit. Genotyping of ACE I/D polymorphism was performed. Clinical outcomes were obtained from the patients' records. We found an association between the ACE I/D polymorphism and the incidence or severity of COVID-19 in male participants. Moreover, we observed a relationship between severity and increasing age and body weight and a higher frequency of II genotype individuals among those who had a cough as their symptoms in mild patients. No differences were observed in leukocyte count or other parameters related to the inflammatory response in severe patients. CONCLUSIONS: Our data showed the influence of the ACE I/D polymorphism on severity of COVID-19 in males, as well as on the occurrence of cough in patients with mild symptoms, with a higher incidence in those carrying the I allele.

Kinin receptors regulate skeletal muscle regeneration: differential effects for B1 and B2 receptors.

OBJECTIVE AND DESIGN: After traumatic skeletal muscle injury, muscle healing is often incomplete and produces extensive fibrosis. Bradykinin (BK) reduces fibrosis in renal and cardiac damage models through the B2 receptor. The B1 receptor expression is induced by damage, and blocking of the kallikrein-kinin system seems to affect the progression of muscular dystrophy. We hypothesized that both kinin B1 and B2 receptors could play a differential role after traumatic muscle injury, and the lack of the B1 receptor could produce more cellular and molecular substrates for myogenesis and fewer substrates for fibrosis, leading to better muscle healing. MATERIAL AND METHODS: To test this hypothesis, tibialis anterior muscles of kinin receptor knockout animals were subjected to traumatic injury. Myogenesis, angiogenesis, fibrosis, and muscle functioning were evaluated. RESULTS: Injured B1KO mice showed a faster healing progression of the injured area with a larger amount of central nucleated fiber post-injury when compared to control mice. In addition, they exhibited higher neovasculogenic capacity, maintaining optimal tissue perfusion for the post-injury phase; had higher amounts of myogenic markers with less inflammatory infiltrate and tissue destruction. This was followed by higher amounts of SMAD7 and lower amounts of p-SMAD2/3, which resulted in less fibrosis. In contrast, B2KO and B1B2KO mice showed more severe tissue destruction and excessive fibrosis. B1KO animals had better results in post-injury functional tests compared to control animals. CONCLUSIONS: We demonstrate that injured skeletal muscle tissues have a better repair capacity with less fibrosis in the presence of B2 receptor and absence of B1 receptor, including better performances in functional tests.

PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice.

Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy.

The Effect of Association between Fat Mass and Obesity-associated Gene Polymorphism (rs9939609) on the Body Composition of Older People: A Systematic Review.

BACKGROUND: The aging population is growing faster than any other age group worldwide. Associated with aging, the prevalence of overweight and obesity is a potential risk factor for the development and aggravation of numerous pathologies. A genetic factor often associated with obesity is the fat mass and obesity-associated (FTO) (rs9939609) gene polymorphism, which has been extensively investigated in children, young, and adults. However, few studies have been carried out on the older population. This review aimed to verify the influence of the FTO (rs9939609) gene polymorphism on the body composition of the older population. METHODS: We conducted a systematic review and meta-analysis on PubMed, Scielo, and LILACS databases. Statistical analysis for meta-analysis was performed using mean values of Body Mass Index (BMI) and standard deviations. RESULTS: The results did not show significant differences between FTO genotypes and BMI values (-0.32, 95% CI -0.45 to -0.19, I2 = 0%, p = 0.52). However, 59% of the studies identified some influence on body composition, obesity, or comorbidities. CONCLUSION: Few publications verify FTO polymorphism effects on specific groups of the older population, suggesting a reduction in the influence of this gene on the BMI with advancing age. However, we believe that more controlled studies in older populations should be performed.

Bradykinin B2 Receptor Signaling Increases Glucose Uptake and Oxidation: Evidence and Open Questions.

The Kinin B2 receptor (B2R) is classically involved in vasodilation and inflammatory responses. However, through the observation of hypoglycemic effects of Angiotensin-I-Converting Enzyme (ACE) inhibitors, this protein has been related to metabolic glucose modulation in physiological and pathophysiological contexts. Although several studies have evaluated this matter, the different methodologies and models employed, combined with the distinct target organs, results in a challenge to summarize and apply the knowledge in this field. Therefore, this review aims to compile human and animal data in order to provide a big picture about what is already known regarding B2R and glucose metabolism, as well to suggest pending investigation issues aiming at evaluating the role of B2R in relation to glucose metabolism in homeostatic situations and metabolic disturbances. The data indicate that B2R signaling is involved mainly in glucose uptake in skeletal muscle and adipose tissue, acting as a synergic player beside insulin. However, most data indicate that B2R induces increased glucose oxidation, instead of storage, via activation of a broad signaling cascade involving Nitric Oxide (NO) and cyclic-GMP dependent protein kinase (PKG). Additionally, we highlight that this modulation is impaired in metabolic disturbances such as diabetes and obesity, and we provide a hypothetic mechanism to explain this blockade in light of literature data provided for this review, as well as other authors.

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4.

Introduction: Lipopolysaccharide (LPS) is a systemic response-triggering endotoxin, which has the kidney as one of its first targets, thus causing acute injuries to this organ. Physical exercise is capable of promoting physiological alterations and modulating inflammatory responses in the infectious process through multiple parameters, including the toll-like receptor (TLR)-4 pathway, which is the main LPS signaling in sepsis. Additionally, previous studies have shown that physical exercise can be both a protector factor and an aggravating factor for some kidney diseases. This study aims at analyzing whether physical exercise before the induction of LPS endotoxemia can protect kidneys from acute kidney injury. Methods: C57BL/6J male mice, 12 weeks old, were distributed into four groups: (1) sedentary (control, N = 7); (2) sedentary + LPS (N = 7); (3) trained (N = 7); and (4) trained + LPS (N = 7). In the training groups, the animals exercised 5×/week in a treadmill, 60 min/day, for 4 weeks (60% of max. velocity). Sepsis was induced in the training group by the application of a single dose of LPS (5 mg/kg i.p.). Sedentary animals received LPS on the same day, and the non-LPS groups received a saline solution instead. All animals were euthanized 24 h after the administration of LPS or saline. Results: The groups receiving LPS presented a significant increase in serum urea (p < 0.0001) and creatinine (p < 0.001) concentration and renal gene expression of inflammatory markers, such as tumor necrosis factor alpha and interleukin-6, as well as TLRs. In addition, LPS promoted a decrease in reduced glutathione. Compared to the sedentary + LPS group, trained + LPS showed overexpression of a gene related to kidney injury (NGAL, p < 0.01) and the protein levels of LPS receptor TLR-4 (p < 0.01). Trained + LPS animals showed an expansion of the tubulointerstitial space in the kidney (p < 0.05) and a decrease in the gene expression of hepatic AOAH (p < 0.01), an enzyme involved in LPS clearance. Conclusion: In contrast to our hypothesis, training was unable to mitigate the renal inflammatory response caused by LPS. On the contrary, it seems to enhance injury by accentuating endotoxin-induced TLR-4 signaling. This effect could be partly due to the modulation of a hepatic enzyme that detoxifies LPS.

Paternal exercise protects against liver steatosis in the male offspring of mice submitted to high fat diet.

Parental lifestyle has been related to alterations in the phenotype of their offspring. Obese sires can induce offspring insulin resistance as well as increase susceptibility to obesity. On the other hand, obese sires submitted to voluntary exercise ameliorate the deleterious metabolic effects on their offspring. However, there are no studies reporting the effect of programmed exercise training of lean sires on offspring metabolism. AIMS: This study aimed to investigate the role of swimming training of sires for 6 weeks on the offspring metabolic phenotype. MAIN METHODS: Male C57BL/6 mice fed a control diet were divided into sedentary and swimming groups. After the exercise, they were mated with sedentary females, and body weight and molecular parameters of the offspring were subsequently monitored. KEY FINDINGS: Swimming decreased the gene expression of Fasn and Acaca in the testes and increased the AMPK protein content in the testes and epididymis of the sires. The progeny presented a low weight at P1, which reached a normal level at P60 and at P90 the animals were challenged with HFD for 16 weeks. The male offspring of trained sires presented less body weight gain than the control group. The level of steatosis decreased in the male offspring from trained sires. The gene expression of Prkaa2, Ppar-1α and Cpt-1 was also increased in the liver of male offspring from trained sires. SIGNIFICANCE: Taken together, these findings suggest that paternal exercise training can improve the metabolic profile in the liver of the progeny, thereby ameliorating the effects of obesity.

Aerobic but not Resistance Exercise Can Induce Inflammatory Pathways via Toll-Like 2 and 4: a Systematic Review.

BACKGROUND: Only a few studies have addressed the relationship between toll-like receptors 2 and 4 (TLR2 and TLR4) and the production of local and systemic cytokines in response to physical exercise, and they have produced conflicting results. We aimed to determine whether acute and chronic exercise outcomes are associated with changes in TLR2 and TLR4 expression and signaling and if so, the mechanisms that connect them. METHODS: PubMed database were consulted. This systematic review selected 39 articles, 26 involving humans and 13 based on rodents. RESULTS: In acute resistance exercise studies, 75% reported a decrease in TLR4 or TLR2 expression and 25% did not find differences. For chronic resistance exercise studies, 67% reported a reduction of expression and 33% did not find differences. Studies of both types reported reductions in pro-inflammatory cytokines. In acute aerobic exercise studies, 40% revealed a decline in the expression of the receptors, 7% reported no significant difference, 40% showed an increase, and 13% did not evaluate their expression. Fifty-eight percent of studies of chronic aerobic exercise revealed a reduction in expression, 17% did not find a difference, and 25% reported increases; they also suggested that the expression of the receptors might be correlated with that of inflammatory cytokines. In studies on combined exercise, 50% reported a decline in receptors expression and 50% did not find a difference. CONCLUSIONS: The majority of the articles (54%) link different types of exercise to a decline in TLR4 and TLR2 expression. However, aerobic exercise may induce inflammations through its influence on these receptor pathways. Higher levels of inflammation were seen in acute sessions (40%) than regular sessions (25%).