Development of Ac2-26 Mesoporous Microparticle System as a Potential Therapeutic Agent for Inflammatory Bowel Diseases.

Introduction: Inflammatory bowel diseases (IBDs) disrupt the intestinal epithelium, leading to severe chronic inflammation. Current therapies cause adverse effects and are expensive, invasive, and ineffective for most patients. Annexin A1 (AnxA1) is a pivotal endogenous anti-inflammatory and tissue repair protein in IBD. Nanostructured compounds loading AnxA1 or its active N-terminal mimetic peptides improve IBD symptomatology. Methods: To further explore their potential as a therapeutic candidate, the AnxA1 N-terminal mimetic peptide Ac2-26 was incorporated into SBA-15 ordered mesoporous silica and covered with EL30D-55 to deliver it by oral treatment into the inflamed gut. Results: The systems SBA-Ac2-26 developed measurements revealed self-assembled rod-shaped particles, likely on the external surface of SBA-15, and 88% of peptide incorporation. SBA-15 carried the peptide Ac2-26 into cultured Raw 264.7 macrophages and Caco-2 epithelial cells. Moreover, oral administration of Eudragit-SBA-15-Ac2-26 (200 µg; once a day; for 4 days) reduced colitis clinical symptoms, inflammation, and improved epithelium recovery in mice under dextran-sodium sulfate-induced colitis. Discussion: The absorption of SBA-15 in gut epithelial cells is typically low; however, the permeable inflamed barrier can enable microparticles to cross, being phagocyted by macrophages. These findings suggest that Ac2-26 is successfully delivered and binds to its receptors in both epithelial and immune cells, aligning with the clinical results. Conclusion: Our findings demonstrate a simple and cost-effective approach to delivering Ac2-26 orally into the inflamed gut, highlighting its potential as non-invasive IBD therapy.

Risk predictors of advanced hepatic fibrosis in patients with nonalcoholic fatty liver disease - a survey in a university hospital in Brazil

ABSTRACT Objective: Describe the clinical profile of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) and analyze the risk predictors of hepatic fibrosis in outpatient follow-up at a university hospital. Subjects and methods: Demographic, clinical and laboratory data of a cohort of 143 patients with biopsy-proven NAFLD were retrospectively analysed under univariate analyses. Diagnostic accuracy, determined by AUROC, was evaluated for variables that showed a significant difference in univariate comparison analysis and diagnostic performances were determined by sensitivity and specificity. Results: The mean age of studied patients were 48 years, 66.4% of them were women. Age, presence of diabetes mellitus, hypertension, metabolic syndrome and laboratory variables such as AST/ALT ratio, GGT, platelet count and fasting glucose were significantly associated with advanced fibrosis. FIB-4 and NAFLD fibrosis score (AUROC 0.82 and 0.89, respectively) outperformed APRI (AUROC 0.73) for advanced liver fibrosis and cirrhosis (P of 0.04). Conclusion: In our study, metabolic syndrome, diabetes, hypertension, AST/ALT ratio, GGT, platelet count and fasting glucose were associated with hepatic fibrosis in patients with NAFLD. The non-invasive tests FIB-4 and NAFLD fibrosis score showed the best accuracy to stratify disease severity.

Development of Annexin A1-surface-functionalized metal-complex multi-wall lipid core nanocapsules and effectiveness on experimental colitis.

Annexin A1 (AnxA1), a 37KDa protein, is secreted by inflammatory and epithelial cells and displays anti-inflammatory and wound healing activities in intestinal bowel diseases. Herein, we aimed to functionalize recombinant AnxA1 (AnxA1) on multi-wall lipid core nanocapsules (MLNC) and investigate its effectiveness on experimental colitis. MLNC were prepared by covering lipid core nanocapsules (LNC) with chitosan, which coordinates metals to specific protein chemisorption sites. Therefore, MLNC were linked to Zn2+ and AnxA1 was added to form MLNC-AnxA1. LNC, MLNC and MLNC-AnxA1 presented average size of 129, 152 and 163 nm, respectively, and similar polydispersity indexes (0.xx); incorporation of chitosan inverted the negative potential zeta; the coordination efficiency of AnxA1 was 92.22 %, and transmission electron microscope photomicrograph showed MLNC-AnxA1 had a spherical shape. The effectiveness of MLNC-AnxA1 was measured in Dextran Sulfate Sodium (DSS)-induced colitis in male C57BL/6 mice. DSS (2 % solution) was administered from days 1-6; saline, LNC, MLNC, MLNC-AnxA1 or AnxA1 were administered, once a day, by oral or intraperitoneal (i.p.) routes, from days 6-9. Clinical parameters of the disease were measured from day 0-10 and gut tissues were collected for histopathology, immunohistochemistry and flow cytometry analyses. Only i.p. treatment with MLNC-AnxA1 reduced weight loss, diarrhea and disease activity index, and prevented loss of colonic structure integrity; induced the switch of macrophages into M2 phenotype in the lamina propria; recovered the colonic histoarchitecture by decreasing dysplasia of crypts, inflammation and ulcerations; restored the expression of claudin-1 Zonna-occludens-1 tight junctions in the inflamed gut; and induced stem cell proliferation in intestinal crypts. Associated, data highlight the functionalization of MLNC with AnxA1 as a tool to improve the local actions of such protein in the inflamed gut by inducing resolution of inflammation and tissue repair.

Risk predictors of advanced hepatic fibrosis in patients with nonalcoholic fatty liver disease - a survey in a university hospital in Brazil.

Objective: Describe the clinical profile of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) and analyze the risk predictors of hepatic fibrosis in outpatient follow-up at a university hospital. Methods: Demographic, clinical and laboratory data of a cohort of 143 patients with biopsy-proven NAFLD were retrospectively analysed under univariate analyses. Diagnostic accuracy, determined by AUROC, was evaluated for variables that showed a significant difference in univariate comparison analysis and diagnostic performances were determined by sensitivity and specificity. Results: The mean age of studied patients were 48 years, 66.4% of them were women. Age, presence of diabetes mellitus, hypertension, metabolic syndrome and laboratory variables such as AST/ALT ratio, GGT, platelet count and fasting glucose were significantly associated with advanced fibrosis. FIB-4 and NAFLD fibrosis score (AUROC 0.82 and 0.89, respectively) outperformed APRI (AUROC 0.73) for advanced liver fibrosis and cirrhosis (P of 0.04). Conclusion: In our study, metabolic syndrome, diabetes, hypertension, AST/ALT ratio, GGT, platelet count and fasting glucose were associated with hepatic fibrosis in patients with NAFLD. The non-invasive tests FIB-4 and NAFLD fibrosis score showed the best accuracy to stratify disease severity.

Xenobiotics Delivered by Electronic Nicotine Delivery Systems: Potential Cellular and Molecular Mechanisms on the Pathogenesis of Chronic Kidney Disease.

Chronic kidney disease (CKD) is characterized as sustained damage to the renal parenchyma, leading to impaired renal functions and gradually progressing to end-stage renal disease (ESRD). Diabetes mellitus (DM) and arterial hypertension (AH) are underlying diseases of CKD. Genetic background, lifestyle, and xenobiotic exposures can favor CKD onset and trigger its underlying diseases. Cigarette smoking (CS) is a known modified risk factor for CKD. Compounds from tobacco combustion act through multi-mediated mechanisms that impair renal function. Electronic nicotine delivery systems (ENDS) consumption, such as e-cigarettes and heated tobacco devices, is growing worldwide. ENDS release mainly nicotine, humectants, and flavorings, which generate several byproducts when heated, including volatile organic compounds and ultrafine particles. The toxicity assessment of these products is emerging in human and experimental studies, but data are yet incipient to achieve truthful conclusions about their safety. To build up the knowledge about the effect of currently employed ENDS on the pathogenesis of CKD, cellular and molecular mechanisms of ENDS xenobiotic on DM, AH, and kidney functions were reviewed. Unraveling the toxic mechanisms of action and endpoints of ENDS exposures will contribute to the risk assessment and implementation of proper health and regulatory interventions.

Polymorphisms in vitamin D receptor gene, but not vitamin D levels, are associated with polycystic ovary syndrome in Brazilian women.

This study aimed to investigate the association between vitamin D (VitD) levels, polymorphisms in VDR gene (ApaI, BsmI, FokI, and TaqI) and the polycystic ovary syndrome (PCOS) in a group of Brazilian women. A total of 100 patients with PCOS and 100 control women were included. The quantification of 25-hydroxyvitamin D (25(OH)D) was performed in high-performance liquid chromatography (HPLC). Polymorphisms on VDR gene were performed by PCR-RFLP. The BsmI AG genotype was more frequent in PCOS group, while the GG genotype was more frequent in the control group (p = .007). The frequency of the Taql CC genotype was higher in PCOS group, while the CT genotype was the most frequent in the control group (p = .021). Mean serum VitD levels were similar between the groups. However, there was a negative correlation between VitD levels and Ferriman-Gallwey score (p = .031, r = -.260) in the PCOS group. The TaqI and BsmI polymorphisms were associated with PCOS. Moreover, VitD levels are associated with the clinical hyperandrogenism. The data suggest the role of VitD in PCOS development and its complications.

Evaluation of PCSK9 levels and its genetic polymorphisms in women with polycystic ovary syndrome.

Dyslipidemia is one of the common metabolic disorders in Polycystic Ovary Syndrome (PCOS). Proprotein convertase subtilisin kexin type 9 (PCSK9) is a new component of lipid metabolism and correlated to the development of dyslipidemia and atherosclerosis. This protein acts by preventing the recycling of LDL receptors (LDL-r) back to the cell surface and thus generates higher levels of LDLc. The objective of this study was to evaluate the PCSK9 polymorphisms rs505151 (c.2009A>G), rs562556 (c.1420A>G) and rs11206510 (T>C) and plasma PCSK9 levels in PCOS. A group of women with PCOS (n=97), and a group of healthy women (control, n=99) were selected. Biochemical parameters were determined by using Vitros system and polymorphisms were assessed by TaqMan SNP Genotyping Assays. Plasma PCSK9 levels or PCSK9 polymorphisms were not associated with PCOS. The genotype rs11206510TT was associated with higher levels of PCSK9 in both groups. The population investigated (PCOS+control groups) with the rs505151AA genotype presented higher HDLc levels. The GG genotype regarding rs562556 polymorphism was associated with higher HDLc in PCOS group, while the AA genotype carriers had higher plasma testosterone levels when evaluated all women in a same group. The results were the same by comparing recessive and dominant model despite PCOS or both groups altogether. Our results suggest that PCSK9 is not altered specifically in PCOS, but it could be associated with in lipid and androgen metabolism in Brazilian women.

Haptoglobin levels, but not Hp1-Hp2 polymorphism, are associated with polycystic ovary syndrome.

PURPOSE: Proteomic studies suggest an association between haptoglobin (Hp) and polycystic ovary syndrome (PCOS). Hp is a classic inflammatory marker and binds to the intravascular hemoglobin, avoiding the oxidative damages that can be caused by free hemoglobin. Inflammation and oxidative stress are important in the pathogenesis of the PCOS, one of the most frequent metabolic diseases in women. METHODS: To validate these proteomic studies, we developed a controlled cross-sectional study that aimed to evaluate the Hp levels and allelic and genotypic frequencies of Hp1-Hp2 polymorphism in Brazilian women with PCOS. We also investigated the correlation between Hp levels and several important parameters in PCOS as follows: body mass index (BMI), waist circumference (WC), fasting glucose, post-prandial glucose, homeostatic model assessment (HOMA), lipid accumulation product (LAP), C-reactive protein (CRP), and metabolization test of tetrazolium salts (MTTs-serum antioxidant capacity). RESULTS: Plasma Hp levels were higher in the PCOS group than in controls [8.20 (4.04) g/L; 7.98 (3.31) g/L; p = 0.018]. No significant difference was observed in the frequency of Hp1-Hp2 genotypes under additive, recessive, or dominant model of inheritance between the PCOS and the control groups. Plasma Hp levels did not differ according to the genotype. However, plasma Hp showed a negative correlation with MTT (r = - 0.383; p = 0.028), as well as a positive correlation with CRP (r = 0.361; p = 0.014) in the PCOS group. CONCLUSION: Hp1-Hp2 polymorphism is not associated with PCOS but plasma Hp could be a potential biomarker for PCOS and its complications.

Desenvolvimento da morfologia derivacional nos primeiros anos do ensino fundamental / Morphological awareness development in the first years of primary education

Consciência morfológica é a habilidade de refletir sobre os morfemas. Essa habilidade está relacionada à aquisição da leitura e da escrita. A maioria dos estudos nessa área foca no desenvolvimento da morfologia flexional. Menos se sabe sobre a morfologia derivacional. Este estudo verificou o desenvolvimento da morfologia derivacional. Trinta e sete crianças de primeiro e terceiro ano responderam a uma tarefa de decisão lexical que exigia que a criança julgasse um par de palavras com base na morfologia da língua portuguesa. Os resultados mostraram que as crianças de primeiro ano fizeram julgamentos ao nível de chance. As crianças de terceiro ano tiveram desempenho acima do nível de chance. No entanto, não houve diferença estatisticamente significativa entre as séries escolares. Esses resultados contradizem os usualmente encontrados na literatura. O tipo de tarefa e a natureza do sistema escolar são apontados como possíveis explicações para as diferenças nos resultados.

Morphological awareness is the ability to reflect upon a word´s morphemes. This ability is related to reading and spelling acquisition. Most studies carried out in the Portuguese language have focused on the development of flexional morphology. Less is known about derivational morphology. This study looked at the development of derivational morphology. Thirty-seven children from grades one and three were given a lexical decision task that required judging a pair of words on the basis of Portuguese language morphology. The results showed that first grade children made the judgments at random levels. Third grade children had above random performance. However, no grade effects were found for comparisons between grades. These results are different from the ones usually found in the literature. The type of task used and the nature of the school system are possible explanation for differences in performance.

Desenvolvimento da morfologia derivacional nos primeiros anos do ensino fundamental

Consciência morfológica é a habilidade de refletir sobre os morfemas. Essa habilidade está relacionada à aquisição da leitura e da escrita. A maioria dos estudos nessa área foca no desenvolvimento da morfologia flexional. Menos se sabe sobre a morfologia derivacional. Este estudo verificou o desenvolvimento da morfologia derivacional. Trinta e sete crianças de primeiro e terceiro ano responderam a uma tarefa de decisão lexical que exigia que a criança julgasse um par de palavras com base na morfologia da língua portuguesa. Os resultados mostraram que as crianças de primeiro ano fizeram julgamentos ao nível de chance. As crianças de terceiro ano tiveram desempenho acima do nível de chance. No entanto, não houve diferença estatisticamente significativa entre as séries escolares. Esses resultados contradizem os usualmente encontrados na literatura. O tipo de tarefa e a natureza do sistema escolar são apontados como possíveis explicações para as diferenças nos resultados.(AU)

Morphological awareness is the ability to reflect upon a word´s morphemes. This ability is related to reading and spelling acquisition. Most studies carried out in the Portuguese language have focused on the development of flexional morphology. Less is known about derivational morphology. This study looked at the development of derivational morphology. Thirty-seven children from grades one and three were given a lexical decision task that required judging a pair of words on the basis of Portuguese language morphology. The results showed that first grade children made the judgments at random levels. Third grade children had above random performance. However, no grade effects were found for comparisons between grades. These results are different from the ones usually found in the literature. The type of task used and the nature of the school system are possible explanation for differences in performance.(AU)