Comprehensive analysis of gastrointestinal side effects in COVID-19 patients undergoing combined pharmacological treatment with azithromycin and hydroxychloroquine: a systematic review and network meta-analysis.

During the COVID-19 pandemic, several drugs were repositioned and combined to quickly find a way to mitigate the effects of the infection. However, the adverse effects of these combinations on the gastrointestinal tract are unknown. We aimed investigate whether Hydroxychloroquine (HD), Azithromycin (AZ), and Ivermectin (IV) used in combination for the treatment of COVID-19, can lead to the development of gastrointestinal disorders. This is a systematic review and network meta-analysis conducted using Stata and Revman software, respectively. The protocol was registered with PROSPERO (CRD42023372802). A search of clinical trials in Cochrane Library databases, Embase, Web of Science, Lilacs, PubMed, Scopus and Clinicaltrials.gov conducted on November 26, 2023. The eligibility of the studies was assessed based on PICO criteria, including trials that compared different treatments and control group. The analysis of the quality of the evidence was carried out according to the GRADE. Six trials involving 1,686 COVID-19 patients were included. No trials on the association of HD or AZ with IV met the inclusion criteria, only studies on the association between HD and AZ were included. Nausea, vomiting, diarrhea, abdominal pain and increased transaminases were related. The symptoms of vomiting and nausea were evaluated through a network meta-analysis, while the symptom of abdominal pain was evaluated through a meta-analysis. No significant associations with these symptoms were observed for HD, AZ, or their combination, compared to control. Low heterogeneity and absence of inconsistency in indirect and direct comparisons were noted. Limitations included small sample sizes, varied drug dosages, and potential publication bias during the pandemic peak. This review unveils that there are no associations between gastrointestinal adverse effects and the combined treatment of HD with AZ in the management of COVID-19, as compared to either the use of a control group or the administration of the drugs individually, on the other hand, highlighting the very low or low certainty of evidence for the evaluated outcomes. To accurately conclude the absence of side effects, further high-quality randomized studies are needed.

Protective effect of alpha-ketoglutarate against water-immersion restraint stress-induced gastric mucosal damage in mice.

Gastric lesions have several aetiologies, among which stress is the most prominent. Therefore, identification of new therapies to prevent stress is of considerable importance. Alpha-ketoglutarate (α-kg) several beneficial effects and has shown promise in combating oxidative stress, inflammation, and premature aging. Thus, this study aimed to evaluate the protective effect of α-kg in a gastric damage model by water-immersion restraint stress (WIRS). Pretreatment with α-kg decreased stress-related histopathological scores of tissue oedema, cell loss, and inflammatory infiltration. The α-kg restored the percentage of type III collagen fibres. Mucin levels were preserved as well as the structure and area of the myenteric plexus ganglia were preserved after pretreatment with α-kg. Myeloperoxidase (MPO) levels and the expression of pro-inflammatory cytokines (TNF-α and IL-1ß) were also reduced following α-kg pretreatment. Decreased levels of glutathione (GSH) in the stress group were restored by α-kg. The omeprazole group was used as standard drug e also demonstrated improve on some parameters after the exposition to WIRS as inflammatory indexes, GSH and mucin. Through this, was possible to observe that α-kg can protect the gastric mucosa exposed to WIRS, preserve tissue architecture, reduce direct damage to the mucosa and inflammatory factors, stimulate the production of type III collagen and mucin, preserve the myenteric plexus ganglia, and maintain antioxidant potential. Due to, we indicate that α-kg has protective activity of the gastric mucosa, demonstrating its ability to prevent damage associated with gastric lesions caused by stress.

BR-bombesin: a novel bombesin-related peptide from the skin secretion of the Chaco tree frog (Boana raniceps) with physiological gastric effects.

Bombesin mediates several biological activities in the gastrointestinal (GI) tract and central nervous system in mammals, including smooth muscle contraction, secretion of GI hormones and regulation of homeostatic mechanisms. Here, we report a novel bombesin-like peptide isolated from Boana raniceps. Its amino acid sequence, GGNQWAIGHFM-NH2, was identified and structurally confirmed by HPLC, MS/MS and 454-pyrosequencing; the peptide was named BR-bombesin. The effect of BR-bombesin on smooth muscle contraction was assessed in ileum and esophagus, and its anti-secretory activity was investigated in the stomach. BR-bombesin exerted significant contractile activity with a concentration-response curve similar to that of commercially available bombesin in ileum strips of Wistar rats. In esophageal strips, BR-bombesin acted as an agonist, as many other bombesin-related peptides act, although with different behavior compared to the muscarinic agonist carbachol. Moreover, BR-bombesin inhibited stomach secretion by approximately 50% compared to the untreated control group. This novel peptide has 80% and 70% similarity with the 10-residue C-terminal domain of human neuromedin B (NMB) and human gastrin releasing peptide (GRP10), respectively. Molecular docking analysis revealed that the GRP receptor had a binding energy equal to - 7.3 kcal.mol-1 and - 8.5 kcal.mol-1 when interacting with bombesin and BR-bombesin, respectively. Taken together, our data open an avenue to investigate BR-bombesin in disorders that involve gastrointestinal tract motility and acid gastric secretion.

Anti-inflammatory effect of L-cysteine (a semi-essential amino acid) on 5-FU-induced oral mucositis in hamsters.

Oral mucositis is an inflammation of the oral mucosa mainly resulting from the cytotoxic effect of 5-fluorouracil (5-FU). The literature shows anti-inflammatory action of L-cysteine (L-cys) involving hydrogen sulfide (H2S). In view of these properties, we investigate the effect of L-cys in oral mucositis induced by 5-FU in hamsters. The animals were divided into the following groups: saline 0.9%, mechanical trauma, 5-FU 60-40 mg/kg, L-cys 10/40 mg and NaHS 27 µg/kg. 5-FU was administered on days 1st to 2nd; 4th day excoriations were made on the mucosa; 5th-6th received L-cys and NaHS. For data analysis, histological analyses, mast cell count, inflammatory and antioxidants markers, and immunohistochemistry (cyclooxygenase-2(COX-2)/inducible nitric oxide synthase (iNOs)/H2S) were performed. Results showed that L-cys decreased levels of inflammatory markers, mast cells, levels of COX-2, iNOS and increased levels of antioxidants markers and H2S when compared to the group 5-FU (p < 0.005). It is suggested that L-cys increases the H2S production with anti-inflammatory action in the 5-FU lesion.

Premises among SARS-CoV-2, dysbiosis and diarrhea: Walking through the ACE2/mTOR/autophagy route.

Recently, a new coronavirus (SARS-CoV-2) was discovered in China. Due to its high level of contagion, it has already reached most countries, quickly becoming a pandemic. Although the most common symptoms are related to breathing problems, SARS-CoV-2 infections also affect the gastrointestinal tract culminating in inflammation and diarrhea. However, the mechanisms related to these enteric manifestations are still not well understood. Evidence shows that the SARS-CoV-2 binds to the angiotensin-converting enzyme receptor 2 (ACE2) in host cells as a viral invasion mechanism and can infect the lungs and the gut. Other viruses have already been linked to intestinal symptoms through binding to ACE2. In turn, this medical hypothesis article conjectures that the ACE2 downregulation caused by the SARS-CoV-2 internalization could lead to decreased activation of the mechanistic target of mTOR with increased autophagy and lead to intestinal dysbiosis, resulting in diarrhea. Besides that, dysbiosis can directly affect the respiratory system through the lungs. Although there are clues to other viruses that modulate the ACE2/gut/lungs axis, including the participation of autophagy and dysbiosis in the development of gastrointestinal symptoms, there is still no evidence of the ACE2/mTOR/autophagy pathway in SARS-CoV-2 infections. Thus, we propose that the new coronavirus causes a change in the intestinal microbiota, which culminates in a diarrheal process through the ACE2/mTOR/autophagy pathway into enterocytes. Our assumption is supported by premises that unregulated intestinal microbiota increases the susceptibility to other diseases and extra-intestinal manifestations, which can even cause remote damage in lungs. These putative connections lead us to suggest and encourage future studies aiming at assessing the aforementioned hypothesis and regulating dysbiosis caused by SARS-CoV-2 infection, in order to confirm the decrease in lung injuries and the improvement in the prognosis of the disease.

Novel Ocellatin Peptides Mitigate LPS-induced ROS Formation and NF-kB Activation in Microglia and Hippocampal Neurons.

Cutaneous secretions of amphibians have bioactive compounds, such as peptides, with potential for biotechnological applications. Therefore, this study aimed to determine the primary structure and investigate peptides obtained from the cutaneous secretions of the amphibian, Leptodactylus vastus, as a source of bioactive molecules. The peptides obtained possessed the amino acid sequences, GVVDILKGAAKDLAGH and GVVDILKGAAKDLAGHLASKV, with monoisotopic masses of [M + H]± = 1563.8 Da and [M + H]± = 2062.4 Da, respectively. The molecules were characterized as peptides of the class of ocellatins and were named as Ocellatin-K1(1-16) and Ocellatin-K1(1-21). Functional analysis revealed that Ocellatin-K1(1-16) and Ocellatin-K1(1-21) showed weak antibacterial activity. However, treatment of mice with these ocellatins reduced the nitrite and malondialdehyde content. Moreover, superoxide dismutase enzymatic activity and glutathione concentration were increased in the hippocampus of mice. In addition, Ocellatin-K1(1-16) and Ocellatin-K1(1-21) were effective in impairing lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) formation and NF-kB activation in living microglia. We incubated hippocampal neurons with microglial conditioned media treated with LPS and LPS in the presence of Ocellatin-K1(1-16) and Ocellatin-K1(1-21) and observed that both peptides reduced the oxidative stress in hippocampal neurons. Furthermore, these ocellatins demonstrated low cytotoxicity towards erythrocytes. These functional properties suggest possible to neuromodulatory therapeutic applications.

Comparison between resting metabolic rate and indirect calorimetry in postmenopausal women / Comparação de equações preditivas de taxa metabólica de repouso com calorimetria indireta em mulheres pós-menopáusicas

ABSTRACT Objective To compare resting metabolic rate values determined by indirect calorimetry with values estimated using different predictive equations in lean and overweight postmenopausal women. Methods Twenty-four women, who had stopped menstruating for at least two years, were subjected to anthropometric measurements and indirect calorimetry after 12-hour overnight fasting to determine, mathematically and experimentally, resting metabolic rate values. Results There was no difference in the indirect calorimetry values between the groups evaluated. Difference values of resting metabolic rate were obtained with all equations used. For the lean women, there was no difference between the values obtained by indirect calorimetry and those estimated using the equations proposed by Food and Agricultural Organization, Fredix, Lazzer, and Schofield. However, in the overweight group, the resting metabolic rate values estimated using the Institute of Medicine, Berstein and Owen equations were different from those obtained by indirect calorimetry. Conclusion This study suggests that differences in body composition in postmenopausal women influence the accuracy of predictive equations, demonstrating the need for more accurate estimation methods for resting metabolic rate in postmenopausal women with different body compositions.

RESUMO Objetivo Comparar os valores de taxa metabólica de repouso determinados por calorimetria indireta com os valores obtidos utilizando diferentes equações preditivas em mulheres pós-menopausicas eutróficas e com sobrepeso. Métodos Vinte e quatro mulheres com pelo menos dois anos de menopausa foram submetidas à avaliações antropométricas e à calorimetria indireta após 12 horas de jejum para determinar, matematicamente e experimentalmente, a taxa metabólica de repouso. Resultados Os valores para calorimetria indireta não diferiram entre os grupos e a taxa metabólica de repouso predita por equações foi diferente para todas as equações usadas. Para o grupo de eutróficas, as equações que não foram estatisticamente diferentes da calorimetria indireta foram Food and Agricultural Organization, Fredix, Lazzer e Schofield. No entanto, apenas as equações Berstein e Owen foram significativamente diferentes comparadas com calorimetria indireta para o grupo sobrepeso. Conclusão O presente estudo sugere que diferenças na composição corporal em mulheres na pós-menopausa modificam a precisão de equações que predizem a taxa metabólica de repouso, demonstrando a necessidade de aprimorar métodos de estimação de taxa metabólica de repouso em mulheres pós-menopáusicas com diferentes composições corporais.

Aerobic fitness profile of youth soccer players: effects of chronological age and playing position / Perfil aeróbio de jovens jogadores de futebol: efeitos da idade cronológica e da posição tática

Abstract To establish a profile of the aerobic fitness in young soccer players, it is critical to consider different intervenient factors such as maturity status, chronological age and playing position. The aim of this study was to identify the biological maturation, chronological age, and playing position effects on physical and physiological characteristics of young soccer players. Two hundred and one soccer players of 11-19 years old were divided into groups relative to their maturity status, chronological age and playing position. A maximal exercise test was performed to determine peak oxygen uptake (VO2peak) and ventilatory thresholds (VT1 and VT2) parameters in a treadmill. Biological maturation showed no significant effect on relative values (mL•kg-1•min-1) of VO2peak, VT2 and VT1 (0.004 < h2 < 0.039), but showed large positive effect on maximal aerobic speed (MAS) and speed at VT2 (VT2speed). Chronological age showed a medium positive effect on relative values of VO2peak, VT2 and VT1 (0.095 < h2 < 0.137) and a large positive effect on MAS and VT2speed. Relative values of VO2peak and VT1 showed no significant differences among groups for playing position (P>0.05; 0.044 < h2 < 0.051). However, goalkeepers showed significant lower relative values for VT2 and VT2speed than other playing positions and a medium positive effect was observed (P<0.05; 0.077 < h2 < 0.119). Chronological age showed a medium to large positive effect on aerobic fitness parameters, while biological maturation showed a positive effect only on MAS and VT2speed. Playing position showed a medium positive effect on VT2 and VT2speed.

Resumo Para identificar o perfil aeróbico de jovens jogadores de futebol é necessário considerar fatores intervenientes como maturação biológica, idade cronológica e posição tática. O objetivo do presente estudo foi identificar o efeito da maturação biológica, idade cronológica e posição tática sobre as características físicas e fisiológicas de jovens jogadores de futebol. Duzentos e um jogadores de futebol com idades entre 11-19 anos foram divididos em grupos de acordo com estágio maturacional, idade cronológica e posição tática. Um teste máximo foi realizado para determinar o consumo de oxigênio de pico (VO2pico) e limiares ventilatórios (LV1 e LV2). A maturação biológica não apresentou efeitos significativos sobre os valores relativos (mL•kg-1•min-1) de VO2pico, LV2 e LV1 (0,004 < η2 < 0,039), mas apresentou elevado efeito sobre velocidade aeróbia máxima (VAM) e velocidade em LV2 (LV2velocidade). A idade cronológica apresentou efeito positivo médio sobre os valores relativos de VO2pico, LV2 e LV1 (0,095 < η2 < 0,137), e elevado efeito positivo sobre VAM e LV2velocidade. A posição tática não apresentou diferenças significativas sobre os valores relativos de VO2pico e LV1 entre os grupos (P>0,05; 0,044 < η2 < 0,051). Entretanto, goleiros apresentaram significativamente menores valores relativos de LV2 e LV2velocidade em comparação com outras posições táticas, com efeito positivo médio sendo identificado (P<0,05; 0,077 < η2 < 0,119). A idade cronológica apresentou efeito positivo de médio a elevado sobre o perfil aeróbio, entretanto, a maturação biológica não apresentou efeito, exceto para VAM e LV2velocidade. A posição tática apresentou efeitos positivos sobre LV2 e LV2velocidade.

Acylated Ghrelin and Circulatory Oxidative Stress Markers Responses to Acute Resistance and Aerobic Exercise in Postmenopausal Women.

BACKGROUND: Since exercise increases the production of reactive oxygen species in different tissues, the objective of this study is to evaluate, compare and correlate the acute effects of aerobic and resistance exercise in circulatory markers of oxidative stress and acylated ghrelin (AG) in postmenopausal women. METHODS: Ten postmenopausal women completed different protocols: a control session (CON), an aerobic exercise session (AERO); and a single-set (SSR) or 3-set (MSR) resistance exercise protocol. RESULTS: After exercise, both MSR (P = .06) and AERO (P = .02) sessions showed significant increased lipid peroxidation compared with baseline levels. CON and SSR sessions showed no differences after exercise. No differences were found between sessions at any time for total glutathione, glutathione dissulfide or AG concentrations. CONCLUSIONS: Exercise significantly increased lipid peroxidation compared with baseline values. As pro oxidant stimuli is necessary to promote chronic adaptations to the antioxidant defenses induced by exercise, our findings are important to consider when evaluating exercise programs prescription variables aiming quality of life in this population.