Insights of potential trypanocidal effect of the synthetic derivative (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one: in vitro assay, MEV analysis, quantum study, molecular docking, molecular dynamics, MPO analysis, and predictive ADMET.

This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD50 rate > 500 mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy.

Influence of hydroxyurea on tubular phosphate handling in sickle cell nephropathy.

OBJECTIVE: This study aims to evaluate the markers of tubular phosphate handling in adults with sickle cell anemia (SCA) and the influence of hydroxyurea (HU), the degree of anemia and Hb F concentration on these markers. METHODS: Eighty-eight steady state SCA patients in outpatient follow-up in Fortaleza, Ceara, Brazil and 31 healthy individuals were included in this study. Vitamin D (25OHD) was measured by enzyme-bound fluorescence assay, intact parathyroid hormone (iPTH) by electrochemiluminescence, and serum and urinary phosphate and creatinine by colorimetric methods. Details of Hb F and HU use were obtained from clinical records. Tubular reabsorption of phosphate (TRP) and maximum tubular reabsorption of phosphate (MTRP) were calculated. SCA patients were stratified according to the use of HU, degree of anemia and percentage of Hb F. The significance level was set for p-values <0.05. RESULTS: Compared to controls the 25OHD level (25 ± 11 vs. 30 ± 9 pg/mL) was lower in SCA, while serum phosphate and MTRP were higher (3.86 ± 0.94 vs. 3.46 ± 0.72 and 3.6 ± 1.21 vs. 3.21 ± 0.53, respectively). There was no significant difference in iPTH, TRP and phosphaturia. Serum phosphate showed correlation with TRP (r = 0.32; p-value = 0.008) and MTRP (r = 0.9; p-value <0.001) in SCA. Patients taking HU, especially those with Hb F >10 % presented reduced serum phosphate levels, and TRP and MTRP rates. Those with mild anemia presented reduced serum phosphate levels and MTRP rates. CONCLUSION: Serum phosphate levels and renal phosphate reabsorption rate were increased in SCA. HU use, high Hb F concentration and total Hb were associated with better control of tubular phosphate handling markers.

Endothelium-related biomarkers enhanced prediction of kidney support therapy in critically ill patients with non-oliguric acute kidney injury.

Acute kidney injury (AKI) is a common condition in hospitalized patients who often requires kidney support therapy (KST). However, predicting the need for KST in critically ill patients remains challenging. This study aimed to analyze endothelium-related biomarkers as predictors of KST need in critically ill patients with stage 2 AKI. A prospective observational study was conducted on 127 adult ICU patients with stage 2 AKI by serum creatinine only. Endothelium-related biomarkers, including vascular cell adhesion protein-1 (VCAM-1), angiopoietin (AGPT) 1 and 2, and syndecan-1, were measured. Clinical parameters and outcomes were recorded. Logistic regression models, receiver operating characteristic (ROC) curves, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used for analysis. Among the patients, 22 (17.2%) required KST within 72 h. AGPT2 and syndecan-1 levels were significantly greater in patients who progressed to the KST. Multivariate analysis revealed that AGPT2 and syndecan-1 were independently associated with the need for KST. The area under the ROC curve (AUC-ROC) for AGPT2 and syndecan-1 performed better than did the constructed clinical model in predicting KST. The combination of AGPT2 and syndecan-1 improved the discrimination capacity of predicting KST beyond that of the clinical model alone. Additionally, this combination improved the classification accuracy of the NRI and IDI. AGPT2 and syndecan-1 demonstrated predictive value for the need for KST in critically ill patients with stage 2 AKI. The combination of AGPT2 and syndecan-1 alone enhanced the predictive capacity of predicting KST beyond clinical variables alone. These findings may contribute to the early identification of patients who will benefit from KST and aid in the management of AKI in critically ill patients.

Neonatal polycythemia: prevalence, risk factors and predictors of severity.

BACKGROUND: Polycythemia is a disorder with several causes and risk factors. The clinical presentation is variable, ranging from asymptomatic newborns to cases with severe physiological changes. The aim of this study was to assess the prevalence, risk factors and predictors of severity of polycythemia in a Portuguese level III Neonatal Intensive Care Unit (NICU). METHODS: Case-control study of all term newborns with the diagnosis of polycythemia admitted to the NICU of the São João Universitary Hospital Center, Porto, Portugal, from January 1, 1999 to December 31, 2019; and who met one of the following inclusion criteria were eligible for the study: 1) Hct>65% or Hb>22 g/dL; and 2) Hb≥21 g/dL with clinical manifestations of polycythemia. RESULTS: A total of 53 newborns fulfilled the inclusion criteria and were included in the study, corresponding to a prevalence of 0.57%. Birth outside the hospital was the only risk factor with statistical significance. Of 53 cases, 51 (96.23%) had symptomatic polycythemia. The most frequent symptoms were: hyperbilirubinemia (69.81%), hypoglycemia (52.83%), thrombocytopenia (50.94%), cardiorespiratory (33.96%), and neurological symptoms (33.96%). Of the 53 newborns evaluated, 41 (77.36%) needed treatment. The only risk factors that influenced the hematocrit value were maternal diabetes and fetal growth restriction. CONCLUSIONS: The best way to improve the prognosis of polycythemia is to identify the risk factors present throughout pregnancy and make an early diagnosis and treatment. Out-of-hospital births should be avoided. The diagnosis should not be excluded, even if hemoglobin and hematocrit are within normal limits.

Elongation on aliphatic chain improves selectivity of 2-hydroxy-3,4,6-trimethoxyphenyl chalcone on Trypanosoma cruzi.

Aim: Our objective was to investigate the trypanocidal effect of the chalcone (2E,4E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-5-phenylpenta-2,4-dien-1-one (CPNC). Material & methods: Cytotoxicity toward LLC-MK2 host cells was assessed by MTT assay, and the effect on Trypanosoma cruzi life forms (epimastigotes, trypomastigotes and amastigotes) was evaluated by counting. Flow cytometry analysis was performed to evaluate the possible mechanisms of action. Finally, molecular docking simulations were performed to evaluate interactions between CPNC and T. cruzi enzymes. Results: CPNC showed activity against epimastigote, trypomastigote and amastigote life forms, induced membrane damage, increased cytoplasmic reactive oxygen species and mitochondrial dysfunction on T. cruzi. Regarding molecular docking, CPNC interacted with both trypanothione reductase and TcCr enzymes. Conclusion: CPNC presented a trypanocidal effect, and its effect is related to oxidative stress, mitochondrial impairment and necrosis.

Syndecan-1 levels predict septic shock in critically ill patients with COVID-19.

BACKGROUND: The clinical picture of coronavirus disease 2019 (COVID-19)-associated sepsis is similar to that of sepsis of other aetiologies. The present study aims to analyse the role of syndecan-1 (SDC-1) as a potential predictor of septic shock in critically ill patients with COVID-19. METHODS: This is a prospective study of 86 critically ill patients due to COVID-19 infection. Patients were followed until day 28 of hospitalization. Vascular biomarkers, such as vascular cell adhesion protein-1, SDC-1, angiopoietin-1 and angiopoietin-2, were quantified upon admission and associated with the need for vasopressors in the first 7 d of hospitalization. RESULTS: A total of 86 patients with COVID-19 (mean age 60±16 y; 51 men [59%]) were evaluated. Thirty-six (42%) patients died during hospitalization and 50 (58%) survived. The group receiving vasopressors had higher levels of D-dimer (2.46 ng/ml [interquartile range {IQR} 0.6-6.1] vs 1.01 ng/ml [IQR 0.62-2.6], p=0.019) and lactate dehydrogenase (929±382 U/l vs 766±312 U/l, p=0.048). The frequency of deaths during hospitalization was higher in the group that received vasoactive amines in the first 24 h in the intensive care unit (70% vs 30%, p=0.002). SDC-1 levels were independently associated with the need for vasoactive amines, and admission values >269 ng/ml (95% CI 0.524 to 0.758, p=0.024) were able to predict the need for vasopressors during the 7 d following admission. CONCLUSIONS: Syndecan-1 levels predict septic shock in critically ill patients with COVID-19.

Endothelial Biomarkers in Critically Ill COVID-19 Patients: Potential Predictors of the Need for Dialysis.

INTRODUCTION: The aim of this was to evaluate the function of vascular biomarkers to predict the need for hemodialysis in critically ill patients with COVID-19. METHODS: This is a prospective study with 58 critically ill patients due to COVID-19 infection. Laboratory tests in general and vascular biomarkers, such as VCAM-1, syndecan-1, angiopoietin-1, and angiopoietin-2, were quantified on intensive care unit (ICU) admission. RESULTS: There was a 40% death rate. VCAM and Ang-2/Ang-1 ratio on ICU admission were associated with the need for hemodialysis. Vascular biomarkers (VCAM-1, syndecan-1, angiopoietin-2/angiopoietin-1 ratio) were predictors of death and their cutoff values were useful to stratify patients with a worse prognosis. In the multivariate cox regression analysis with adjusted models, VCAM-1 (OR 1.13 [CI 95%: 1.01-1.27]; p = 0.034) and Ang-2/Ang-1 ratio (OR 4.87 [CI 95%: 1.732-13.719]; p = 0.003) were associated with the need for dialysis. CONCLUSION: Vascular biomarkers, mostly VCAM-1 and Ang-2/Ang-1 ratio, showed better efficiency to predict the need for hemodialysis in critically ill COVID-19 patients.

Exploring the neuroprotective potential of antimicrobial peptides from Dinoponera quadriceps venom against pentylenetetrazole-induced seizures in vivo.

Epilepsy affects around 50 million people worldwide and 30% of patients have difficulty controlling the disease. The search for substances that can fill the existing gaps in the treatment of epilepsy is of great importance. Arthropod venoms are promising sources for this purpose due to the presence of small peptides that modulate the activity of ion channels and neuron receptors. The aim of this study was to investigate dinoponeratoxins from the Dinoponera quadriceps ant venom (M-PONTX-Dq3a, M-PONTX-Dq3b and M-PONTX-Dq3c) as potential anticonvulsants. We evaluated them in a seizure model induced by pentylenetetrazole (PTZ) in male swiss mice. Interestingly, intraperitoneal treatment with each peptide increased the time until the first seizure and the percentage of survival, with M-PONTX-Dq3b showing the best results. M-PONTX-Dq3a was discarded due to the appearance of some signs of toxicity with the increase in malondialdehyde (MDA) levels in the striatum. Both, M-PONTX-Dq3b and M-PONTX-Dq3c decreased iNOS and TNF-α in the hippocampus. Notably, M-PONTX-Dq3c treatment decreased the levels of MDA and nitrite in the cortex and hippocampus. Our results indicate that, M-PONTX-Dq3b and M-PONTX-Dq3c have anticonvulsant activity and exhibit anti-inflammatory effects in epilepsy, offering new perspectives for biopharmaceutical development.

Valorization of the Red Seaweed Gracilaria gracilis Through a Biorefinery Approach.

The interest in seaweeds as an abundant feedstock to obtain valuable and multitarget bioactive ingredients is continuously growing. In this work, we explore the potential of Gracilaria gracilis, an edible red seaweed cultivated worldwide for its commercial interest as a source of agar and other ingredients for cosmetic, pharmacological, food, and feed applications. G. gracilis growth conditions were optimized through vegetative propagation and sporulation while manipulating the physicochemical conditions to achieve a large biomass stock. Green extraction methodologies with ethanol and water were performed over the seaweed biomass. The bioactive potential of extracts was assessed through a set of in vitro assays concerning their cytotoxicity, antioxidant, and antimicrobial properties. Additionally, dried seaweed biomass was incorporated into pasta formulations to increase food's nutritional value. Pigments extracted from G. gracilis have also been incorporated into yogurt as a natural colorant, and their stability was evaluated. Both products were submitted to the appreciation of a semi-trained sensorial panel aiming to achieve the best final formulation before reaching the market. Results support the versatility of G. gracilis whether it is applied as a whole biomass, extracts and/or pigments. Through implementing several optimized protocols, this work allows the development of products with the potential to profit the food, cosmetic, and aquaculture markets, promoting environmental sustainability and a blue circular economy. Moreover, and in line with a biorefinery approach, the residual seaweed biomass will be used as biostimulant for plant growth or converted to carbon materials to be used in water purification of the in-house aquaculture systems of MARE-Polytechnic of Leiria, Portugal.

Trypanocidal potential of synthetic p-aminochalcones: In silico and in vitro evaluation.

Chagas disease (CD) is a neglected tropical disease of worldwide health concern, caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi), endemic in Latin America and present in North America and Europe. The WHO recommended drug for CD, benznidazole has low safety profile and several limitations. Therefore, an entity with better therapeutic potential to treat CD is required. Chalcones are an important class of compounds, which have shown antichagasic potential. Thus, the objective of this study was to evaluate the activity of synthetic p-aminochalcones against T. cruzi. Chalcones 1 and 2 were synthesized by Claisen-Schmidt condensation and characterized by both spectroscopic and theoretical methods. Initially, they were submitted to molecular docking simulations using cruzain and trypanothione reductase (TR) enzymes. It was expected to observe the possible interactions of chalcones with the catalytic site and other important regions of these main pharmacological targets of T. cruzi. Their cytotoxicity within host cells were assessed by MTT reduction assay using LLC-MK2 cells, with CC50 = 85.6 ± 9.2 µM and 1115 ± 381.7 µM for chalcones 1 and 2, respectively. These molecules were also tested against epimastigote and trypomastigote life forms of T. cruzi, causing reduction in the number of viable parasites. For the evaluation of the effect on intracellular amastigotes, infected LLC-MK2 cells were incubated with the chalcones for 24 h, causing reduction in the percentage of infected cells and the number of amastigotes/100 cells. Finally, flow cytometry assays were performed for analyzing cell death mechanisms (7-AAD/AxPE labelling), cytoplasmic ROS accumulation (DCFH-DA assay) and mitochondrial transmembrane potential disruption (Rho123 assay). Both chalcones (1 and 2) caused membrane damage, ROS accumulation and mitochondrial depolarization. In conclusion, the synthetic p-aminochalcones presented trypanocidal effect, causing membrane damage and oxidative stress. Their mechanism of action may be related to cruzain and TR inhibition.

New Insights into the Dermocosmetic Potential of the Red Seaweed Gelidium corneum.

This work addresses the potential of the red seaweed Gelidium corneum as a source of bioactive ingredients for skin health and wellness in response to the growing awareness regarding the significance of sustainable strategies in developing new nature-based dermocosmetic products. Hydroalcoholic extracts from the dried biomass were subjected to sequential liquid-liquid partitions, affording five different fractions (F1-F5). Their cosmetic potential was assessed through a set of in vitro assays concerning their antioxidant, photoprotective, and healing properties. Additionally, their cytotoxicity in HaCaT cells and their capacity to induce inflammation in RAW 264.7 cells were also evaluated. As a proof-of-concept, O/W emulsions were prepared, and emulsion stability was assessed by optical microscopy, droplet size analysis, centrifugation tests, and rheology analysis. Furthermore, in vivo tests were conducted with the final formulation to assess its antioxidant capacity. At subtoxic concentrations, the most lipophilic fraction has provided photoprotection against UV light-induced photooxidation in HaCaT cells. This was conducted together with the aqueous fraction, which also displayed healing capacities. Regarding the physical and stability assays, the best performance was achieved with the formulation containing 1% aqueous extract, which exhibited water retention and antioxidant properties in the in vivo assay. In summary, Gelidium corneum displayed itself as a potential source of bioactive ingredients with multitarget properties for dermatological use.

Marine-Derived Components: Can They Be a Potential Therapeutic Approach to Parkinson's Disease?

The increase in the life expectancy average has led to a growing elderly population, thus leading to a prevalence of neurodegenerative disorders, such as Parkinson's disease (PD). PD is the second most common neurodegenerative disorder and is characterized by a progressive degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The marine environment has proven to be a source of unique and diverse chemical structures with great therapeutic potential to be used in the treatment of several pathologies, including neurodegenerative impairments. This review is focused on compounds isolated from marine organisms with neuroprotective activities on in vitro and in vivo models based on their chemical structures, taxonomy, neuroprotective effects, and their possible mechanism of action in PD. About 60 compounds isolated from marine bacteria, fungi, mollusk, sea cucumber, seaweed, soft coral, sponge, and starfish with neuroprotective potential on PD therapy are reported. Peptides, alkaloids, quinones, terpenes, polysaccharides, polyphenols, lipids, pigments, and mycotoxins were isolated from those marine organisms. They can act in several PD hallmarks, reducing oxidative stress, preventing mitochondrial dysfunction, α-synuclein aggregation, and blocking inflammatory pathways through the inhibition translocation of NF-kB factor, reduction of human tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6). This review gathers the marine natural products that have shown pharmacological activities acting on targets belonging to different intracellular signaling pathways related to PD development, which should be considered for future pre-clinical studies.

Syndecan-1 predicts hemodynamic instability in critically ill patients under intermittent hemodialysis.

Introduction: Up to 70% of intermittent hemodialysis (IHD) sessions in critically ill patients are complicated by hemodynamic instability. Although several clinical characteristics have been associated with hemodynamic instability during IHD, the discriminatory capacity of predicting such events during IHD sessions is less defined. In the present study, we aimed to analyse endothelium-related biomarkers collected before IHD sessions and their capacity to predict hemodynamic instability related to IHD in critically ill patients. Methods: In this prospective observational study, we enrolled adult critically ill patients with acute kidney injury who required fluid removal with IHD. We screened each included patient daily for IHD sessions. Thirty minutes before each IHD session, each patient had a 5-mL blood collection for measurement of endothelial biomarkers-vascular cell adhesion molecule-1 (VCAM-1), angiopoietin-1 and -2 (AGPT1 and AGPT2) and syndecan-1. Hemodynamic instability during IHD was the main outcome. Analyses were adjusted for variables already known to be associated with hemodynamic instability during IHD. Results: Plasma syndecan-1 was the only endothelium-related biomarker independently associated with hemodynamic instability. The accuracy of syndecan-1 for predicting hemodynamic instability during IHD was moderate [area under the receiver operating characteristic curve 0.78 (95% confidence interval 0.68-0.89)]. The addition of syndecan-1 improved the discrimination capacity of a clinical model from 0.67 to 0.82 (P < .001) and improved risk prediction, as measured by net reclassification improvement. Conclusion: Syndecan-1 is associated with hemodynamic instability during IHD in critically ill patients. It may be useful to identify patients who are at increased risk for such events and suggests that endothelial glycocalyx derangement is involved in the pathophysiology of IHD-related hemodynamic instability.

Serum il-18 and rs187238 single nucleotide polymorphism are associated with high-density lipoprotein changes in covid-19 outpatients.

AIM: COVID-19 is an inflammatory disease and its prognosis is associated with cardiovascular risk, which can be associated with changes in lipoprotein metabolism. The single nucleotide polymorphism (SNP) rs187238 of Interleukin (IL)-18 is extensively reported in association with worsening inflammatory and cardiovascular disease (CVD). This study evaluated the association of IL-18 levels and its SNP rs187238 with lipoprotein profile changes in COVID-19 outpatients. METHODS: Observational, analytical, cross-sectional study that evaluated 250 patients with respiratory syndrome, 36% (n = 90) with COVID-19. Serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), apolipoproteins A-I and B (Apo A-I and Apo B) and IL-18 levels were determined. Polymorphism genotyping was done by real-time polymerase chain reaction (qPCR). The significance level was p < 0.05. RESULTS: Patients with COVID-19 showed a reduction in TC and HDL-c, without difference in IL-18. HDL-c and LDL-c had a high frequency outside the reference values. There was a negative correlation of IL-18 with HDL-c and a positive correlation with Apo B/Apo A-I ratio. The frequencies of the C (wild) and G (polymorphic) alleles between patients with and without COVID-19 followed the Hardy-Weinberg equilibrium. However, COVID-19 was associated with reduced HDL-c and Apo A-I values in patients with the CC genotype. CONCLUSION: IL-18 levels and its SNP rs187238 were associated with decreased HDL-c and Apo A-I in COVID-19 outpatients.

Piplartine-Inspired 3,4,5-Trimethoxycinnamates: Trypanocidal, Mechanism of Action, and In Silico Evaluation.

Chagas disease (CD) is one of the main neglected tropical diseases that promote relevant socioeconomic impacts in several countries. The therapeutic options for the treatment of CD are limited, and parasite resistance has been reported. Piplartine is a phenylpropanoid imide that has diverse biological activities, including trypanocidal action. Thus, the objective of the present work was to prepare a collection of thirteen esters analogous to piplartine (1-13) and evaluate their trypanocidal activity against Trypanosoma cruzi. Of the tested analogues, compound 11 ((E)-furan-2-ylmethyl 3-(3,4,5-trimethoxyphenyl)acrylate) showed good activity with IC50 values = 28.21 ± 5.34 µM and 47.02 ± 8.70 µM, against the epimastigote and trypomastigote forms, respectively. In addition, it showed a high rate of selectivity to the parasite. The trypanocidal mechanism of action occurs through the induction of oxidative stress and mitochondrial damage. In addition, scanning electron microscopy showed the formation of pores and leakage of cytoplasmic content. Molecular docking indicated that 11 probably produces a trypanocidal effect through a multi-target mechanism, including affinity with proteins CRK1, MPK13, GSK3B, AKR, UCE-1, and UCE-2, which are important for the survival of the parasite. Therefore, the results suggest chemical characteristics that can serve for the development of new trypanocidal prototypes for researching drugs against Chagas disease.

Effect from dinoponeratoxin M-PONTXDq3a arginine and lysine substituted analogues against Staphylococcus aureus strains.

The growing incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections is associated with increased mortality rates, which has generated interest in the development of antimicrobial peptides (AMP), such as those found in the giant ant Dinoponera quadríceps. In order to improve the net positive charge and the antibacterial activity of the AMP, amino acids with positive side chain single substituted analogues have been proposed, mainly arginine or lysine. The present work aims to study the antimicrobial activity of the analogues of M-PONTX-Dq3a, a 23 amino acid AMP identified in the D. quadriceps venom. M-PONTX-Dq3a[1-15], a fragment containing the 15 central amino acids, and eight derivatives of single arginine or lysine substituted analogues were proposed. The antimicrobial activity of peptides was evaluated against Staphylococcus aureus ATCC 6538 P (MSSA) and ATCC 33591 (MRSA) strains, followed by minimum inhibitory concentration (MIC), minimum lethal concentration (MLC), and minimum biofilm inhibitory concentration (MBIC) measurement. The membrane permeability was then assessed via crystal violet assay and flow cytometry analysis. The effect of exposure time on microbial viability (Time-Kill) was evaluated. Finally, ultrastructural alterations were evaluated through scanning electron microscopy (SEM). Both arginine-substituted peptides [Arg]3M-PONTX-Dq3a[1-15] and [Arg]4M-PONTX-Dq3a[1-15], showed lowest MIC and MLC values (each 0.78 µM). In the biofilm formation assays, the peptide [Arg]3M-PONTX-Dq3a [1-15] showed MBIC of 3.12 µM against the two tested strains. Both peptides were able to alter the membrane permeability approximately by 80%. The treatment with MIC was able to eliminate bacteria after 2 h of contact on the other hand, treatment with half of the MIC, the population of both bacterial strains remained constant for up to 12 h, indicating a possible bacteriostatic effect. The SEM results showed that the treatment with the lowest concentration (0.78 µM) of both peptides caused disruption of the cell membrane, destabilization of the intercellular interaction and the CLM of [Arg]4M-PONTX-Dq3a [1-15] resulted in the complete eradication of the bacteria. Thus, this study describes two AMPs active against MSSA and MRSA and also inhibits the biofilm formation of these stains. This study finds [Arg]3M-PONTX-Dq3a[1-15] and [Arg]4M-PONTX-Dq3a[1-15] as alternative substances to treat resistant and/or biofilm-forming strains.

Use of probiotics in patients with chronic kidney disease on hemodialysis: a randomized clinical trial / Uso de probióticos em pacientes com doença renal crônica em hemodiálise: um ensaio clínico randomizado

ABSTRACT Introduction: Supplementation with probiotics for patients with chronic kidney disease (CKD) may be associated with decreased systemic inflammation. Objective: To assess the impact of oral supplementation with probiotics for patients with CKD on hemodialysis. Method: This double-blind randomized clinical trial included 70 patients on hemodialysis; 32 were given oral supplementation with probiotics and 38 were in the placebo group. Blood samples were collected at the start of the study and patients were given oral supplementation with probiotics or placebo for three months. The probiotic supplement comprised four strains of encapsulated Gram-positive bacteria: Lactobacillus Plantarum A87, Lactobacillus rhamnosus, Bifidobacterium bifidum A218 and Bifidobacterium longum A101. Patients were given one capsule per day for 3 months. Blood samples were taken throughout the study to check for inflammatory biomarkers. Non-traditional biomarkers Syndecan-1, IFN-y, NGAL, and cystatin C were measured using an ELISA kit, along with biochemical parameters CRP, calcium, phosphorus, potassium, PTH, GPT, hematocrit, hemoglobin, glucose, and urea. Results: Patients given supplementation with probiotics had significant decreases in serum levels of syndecan-1 (239 ± 113 to 184 ± 106 ng/mL, p = 0.005); blood glucose levels also decreased significantly (162 ± 112 to 146 ± 74 mg/dL, p = 0.02). Conclusion: Administration of probiotics to patients with advanced CKD was associated with decreases in syndecan-1 and blood glucose levels, indicating potential improvements in metabolism and decreased systemic inflammation.

Resumo Introdução: A suplementação com probióticos na doença renal crônica (DRC) pode estar associada à redução do processo inflamatório sistêmico. Objetivo: Avaliar a suplementação oral com probióticos em pacientes com DRC em hemodiálise. Método: Ensaio clínico, duplo cego, randomizado com 70 pacientes em hemodiálise, sendo 32 do grupo que recebeu o suplemento de probióticos e 38 do grupo placebo. Inicialmente ocorreu a coleta de sangue e suplementação oral com probióticos ou placebo durante três meses. O suplemento probiótico foi composto pela combinação de 4 cepas de bactérias Gram-positivas encapsuladas: Lactobacillus Plantarum A87, Lactobacillus rhamnosus, Bifidobacterium bifidum A218 e Bifidobacterium longum A101, sendo 1 cápsula do suplemento ao dia, durante 3 meses. Após esse período foram feitas novas coletas de sangue para dosagem dos biomarcadores inflamatórios. Foram analisados os biomarcadores não tradicionais: Syndecan-1, IFN-y, NGAL e cistatina C pelo método ELISA, e os seguintes parâmetros bioquímicos: PCR, cálcio, fósforo, potássio, PTH, TGP, hematócrito, hemoglobina, glicose e ureia. Resultados: Os pacientes que receberam suplemento tiveram diminuição significativa dos níveis séricos de syndecan-1 (de 239 ± 113 para 184 ± 106 ng/mL, p = 0,005). Outro parâmetro que diminuiu significativamente nos pacientes que receberam suplemento foi a glicemia (de 162 ± 112 para 146 ± 74 mg/dL, p = 0,02). Conclusão: O uso de probióticos na DRC avançada esteve associado à redução dos níveis de syndecan-1 e glicemia, sinalizando possível melhora no metabolismo e redução do processo inflamatório sistêmico.

Monitoring Renal Function in HIV Patients Without Kidney Disease Using Endothelial Biomarkers: A Prospective Pilot Study.

This study aimed to investigate the association between novel biomarkers and renal injury in people with HIV (PWH). A cohort study was carried out with PWH under chronic use of antiretroviral therapy (ART), followed at a public outpatient service. Clinical and laboratory parameters of the patients were evaluated year by year, from 2015 [at baseline (year 1, Y1)] to 2019 [year 5 (Y5)]. At baseline, biomarkers of renal damage (e.g., neutrophil gelatinase-associated lipocalin-NGAL, monocyte chemoattractant protein-1-MCP-1, and kidney injury molecule-1-KIM-1) and endothelial activation or glycocalyx damage [e.g., intercellular adhesion molecule 1 (ICAM-1), E-selectin, and syndecan-1] were quantified using enzyme-linked immunosorbent assays and their levels were used to classify patients into different groups. However, only syndecan-1 showed a significant correlation with serum creatinine (p < .001) and glomerular filtration rate (GFR) (p = .003) over the years. Moreover, both serum creatinine and GFR in almost 5 years were significantly associated with serum levels of syndecan-1 at baseline. The multivariate linear regression with confounders showed a significant and independent association between GFR and levels of syndecan-1 and CD4 cell count in the beginning of the study, as well as age in Y5. The data reinforce the screening for kidney diseases with novel biomarkers, especially syndecan-1, as an important strategy for a timely diagnostic and therapeutic approach.

Subclinical signs of podocyte injury associated with Circulating Anodic Antigen (CAA) in Schistosoma mansoni-infected patients in Brazil.

BACKGROUND: The long-term effects of schistosomiasis on the glomerulus may contribute to the development of chronic kidney disease. This study aimed to investigate baseline Schistosoma mansoni-Circulating Anodic Antigen (CAA) levels and their association with kidney biomarkers related to podocyte injury and inflammation in long-term follow-up after praziquantel (PZQ) treatment. METHODS: Schistosoma infection was diagnosed by detecting CAA in urine using a quantitative assay based on lateral flow using luminescent up-converting phosphor reporter particles. A cutoff threshold of 0.1 pg/mL CAA was used to diagnose Schistosoma infection (baseline) in a low-prevalence area in Ceará, Northeast, Brazil. Two groups were included: CAA-positive and CAA-negative individuals, both of which received a single dose of PZQ at baseline. Urinary samples from 55 individuals were evaluated before (baseline) and at 1, 2, and 3 years after PZQ treatment. At all time points, kidney biomarkers were quantified in urine and adjusted for urinary creatinine levels. RESULTS: CAA-positive patients had increased baseline albuminuria and proteinuria and showed greater associations between kidney biomarkers. CAA levels correlated only with Vascular Endothelial Growth Factor (VEGF) (podocyte injury) levels. Increasing trends were observed for malondialdehyde (oxidative stress), monocyte chemoattractant protein-1 (inflammation marker), and VEGF. In the follow-up analysis, no relevant differences were observed in kidney biomarkers between the groups and different periods. CONCLUSIONS: S. mansoni-infected individuals presented subclinical signs of glomerular damage that may reflect podocyte injury. However, no causal effect on long-term renal function was observed after PZQ treatment.