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Podocyte injury is closely related to proteinuria and the progression of chronic kidney disease (CKD). Currently, there is no conclusive understanding about the mechanisms involved in albumin overload and podocyte apoptosis response. In this study, we sought to explore the ways by which intracellular albumin can mediate podocyte apoptosis. Here, immortalized mouse podocytes were treated with bovine serum albumin (BSA) at different times and concentrations, in the presence or absence of SB203580 (0.1 µM, inhibitor of mitogen-activated-protein kinase – p38MAPK). Using immunofluorescence images, flow cytometry and immunoblotting, we observed a time-dependent intracellular accumulation of fluorescent albumin-FITC-BSA, followed by concentration-and time-dependent effect of intracellular albumin overload on podocyte apoptosis, which was mediated by increased expression of the chaperone glucose-regulated-protein 78 (GRP 78) and phosphorylated inositol-requiring enzyme 1 alpha (pIRE1-α), as well as protein kinase C delta (PKC-δ), p38MAPK and cleaved caspase 12 expression. SB203580 prevented the cleavage of caspase 12 and the albumin-mediated podocyte apoptosis. These results suggest that intracellular albumin overload is associated with endoplasmic reticulum (ER) stress and upregulation of PKC-δ/p38MAPK/caspase 12 pathway, which may be a target for future therapeutic of albumin-induced podocyte apoptosis.

The present study aimed to investigate the interaction between early diabetes and renal IR-induced AKI and to clarify the mechanisms involved. C57BL/6J mice were assigned to the following groups: (1) sham-operated; (2) renal IR; (3) streptozotocin (STZ—55 mg/kg/day) and sham operation; and (4) STZ and renal IR. On the 12th day after treatments, the animals were subjected to bilateral IR for 30 min followed by reperfusion for 48 h, at which time the animals were euthanized. Renal function was assessed by plasma creatinine and urea levels, as well urinary protein contents. Kidney morphology and gene and protein expression were also evaluated. Compared to the sham group, renal IR increased plasma creatinine, urea and albuminuria levels and decreased Nphs1 mRNA expression and nephrin and WT1 protein staining. Tubular injury was observed with increased Havcr 1 and Mki 67 mRNA expression accompanied by reduced megalin staining. Renal IR also resulted in increased SQSTM1 protein expression and increased proinflammatory and profibrotic factors mRNA expression. Although STZ treatment resulted in hyperglycemia, it did not induce significant changes in renal function. On the other hand, STZ treatment aggravated renal IR-induced AKI by exacerbating renal dysfunction, glomerular and tubular injury, inflammation, and profibrotic responses. Thus, early diabetes constitutes a relevant risk factor for renal IR-induced AKI.

Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS.

Background Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis. In the present study, we investigated whether the chronic effects of Ang II via AT1 receptor (AT1R) would result in endoplasmic reticulum (ER) stress/PKC-delta/p38 MAPK stimulation, and consequently podocyte apoptosis. Methods Wistar rats were treated with Ang II (200 ng·kg −1 ·min −1 , 42 days) and or losartan (10 mg·kg −1 ·day −1 , 14 days). Immortalized mouse podocyte were treated with 1 μM Ang II and/or losartan (1 μM) or SB203580 (0.1 μM) (AT1 receptor antagonist and p38 MAPK inhibitor) for 24 h. Kidney sections and cultured podocytes were used to evaluate protein expression by immunofluorescence and immunoblotting. Apoptosis was evaluated by flow cytometry and intracellular pH (pHi) was analyzed using microscopy combined with the fluorescent probe BCECF/AM. Results Compared with controls, Ang II via AT1R increased chaperone GRP 78/Bip protein expression in rat glomeruli ( p  < 0.001) as well as in podocyte culture ( p  < 0.01); increased phosphorylated eIf2-α ( p  < 0.05), PKC-delta ( p  < 0.01) and p38 MAPK ( p  < 0.001) protein expression. Furthermore, Ang II induced p38 MAPK-mediated late apoptosis and increased the Bax/Bcl-2 ratio ( p  < 0.001). Simultaneously, Ang II via AT1R induced p38 MAPK-NHE1-mediated increase of pHi recovery rate after acid loading. Conclusion Together, our results indicate that Ang II-induced podocyte apoptosis is associated with AT1R/ER stress/PKC-delta/p38 MAPK axis and enhanced NHE1-mediated pHi recovery rate.

Bladder carcinoma (BC) is the tenth most frequent malignancy worldwide, with high morbidity and mortality rates. Despite recent treatment advances, high-grade BC and muscle-invasive BC present with significant progression and recurrence rates, urging the need for alternative treatments. The microRNA-21 (miR-21) has superexpression in many malignancies and is associated with cellular invasion and progression. One of its mechanisms of action is the regulation of RECK, a tumor suppressor gene responsible for inhibiting metalloproteinases, including MMP9. In a high-grade urothelial cancer cell line, we aimed to assess if miR-21 downregulation would promote RECK expression and decrease MMP9 expression. We also evaluated cellular migration and proliferation potential by inhibition of this pathway. In a T24 cell line, we inhibited miR-21 expression by transfection of a specific microRNA inhibitor (anti-miR-21). There were also control and scramble groups, the last with a negative microRNA transfected. After the procedure, we performed a genetic expression analysis of miR-21, RECK, and MMP9 through qPCR. Migration, proliferation, and protein expression were evaluated via wound healing assay, colony formation assay, flow cytometry, and immunofluorescence.After anti-miR-21 transfection, miR-21 expression decreased with RECK upregulation and MMP9 downregulation. The immunofluorescence assay showed a significant increase in RECK protein expression ( p  < 0.0001) and a decrease in MMP9 protein expression ( p  = 0.0101). The anti-miR-21 transfection significantly reduced cellular migration in the wound healing assay ( p  < 0.0001). Furthermore, in the colony formation assay, the anti-miR-21 group demonstrated reduced cellular proliferation ( p  = 0.0008), also revealed in the cell cycle analysis by flow cytometry ( p  = 0.0038). Our results corroborate the hypothesis that miR-21 is associated with BC cellular migration and proliferation, revealing its potential as a new effective treatment for this pathology.

By the fact that pregnant and postpartum women are currently using COVID-19 vaccines, ensure their safety is critical. So, more safety evidence is crucial to include this new technology to their vaccine's calendar and to develop public policies regarding the support and training of Health Care Personnel. This study aims to describe the adverse events (AE) of COVID-19 vaccines in pregnant and postpartum women in the early stage of vaccination campaign in Brazil. An observational cross-sectional study using data from the Brazilian surveillance information system to characterize the AE of COVID-19 vaccines (Sinovac/Butantan, Pfizer/BioNTech, AstraZeneca and Janssen) in Brazilian pregnant and postpartum women from April to August 2021. Frequency and incidence rate of AE for COVID-19 vaccines were assessed. 3,333 AE following immunization were reported for the study population. AE incidence was 309.4/100,000 doses (95% CI 297.23, 321.51). Within the vaccines available, Sinovac/Butantan had the lowest incidence (74.08/100,000 doses; 95% CI 63.47, 84.69). Systemic events were the most frequent notified (82.07%), followed by local (11.93%) and maternal (4.74%), being most of them classified as non-severe (90.65%). Our results corroborate the recommendation of vaccination for these groups. Even though, further studies appraising a longer observation time are still needed to provide a broader safety aspect for the vaccines currently under use for this population.

Indigenous schools in Brazil aim to provide equitable education to both Indigenous and non-Indigenous communities. As of 2022, there were 3,411 such schools operating nationwide, serving the entire Indigenous population. However, an analysis of educational data reveals significant non-compliance with legislation designed to integrate Indigenous culture into the curriculum. Our research demonstrates that the school system frequently falls short of its legal obligation to promote and safeguard Indigenous cultural values. The systematic suppression of culturally specific materials and native languages is particularly alarming and appears to be associated with the influence of far-right political administrations. This study analyzes school census data from 2009 to 2022, employing chi-square tests, Cramer's V tests, descriptive statistics and for robustness hierarchical mixed models to examine the relationship between political ideology and educational practices.

Leishmaniasis is caused by protozoan parasites of the genus Leishmania . In recent years, natural compounds have attracted significant interest due to their potential efficacy and lower toxicity compared to synthetic chemical compounds. This review analyzed studies retrieved from the PubMed and Google Scholar databases, focusing on the use of flavonoids against Leishmania amazonensis . Only studies testing flavonoids with known activity against the parasite were included and categorized according to their leishmanicidal efficacy. Based on the criteria established to identify the most comprehensive studies, 52 were included in the analysis. Of these, three studies met at least 13 of the evaluation parameters (70%) and were considered the most complete. Analysis of IC 50 values reported in these articles revealed the activity of 69 flavonoids. Among the assays on amastigote forms, 33 reported high activity, and six reported moderate activity. For assays on promastigote forms, 32 experiments reported high activity, 16 showed moderate activity, and two demonstrated weak activity. Of the flavonoids tested, morelloflavone-4‴O-β-D-glycosyl and pinostrobin showed the highest activity, while naringenin exhibited the weakest activity, specifically against promastigote forms. In the cytotoxicity assays, carajurin and luteolin exhibited the highest selectivity indices reported in the articles. This review emphasizes the importance of studying flavonoids, particularly those extracted from plants and propolis, to advance our understanding and treatment of L. amazonensis infections.

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase-expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.

The Americas were the last continent colonized by humans carrying malaria parasites. Plasmodium falciparum from the New World shows very little genetic diversity and greater linkage disequilibrium, compared with its African counterparts, and is clearly subdivided into local, highly divergent populations. However, limited available data have revealed extensive genetic diversity in American populations of another major human malaria parasite, P. vivax. We used an improved sample preparation strategy and next-generation sequencing to characterize 9 high-quality P. vivax genome sequences from northwestern Brazil. These new data were compared with publicly available sequences from recently sampled clinical P. vivax isolates from Brazil (BRA, total n = 11 sequences), Peru (PER, n = 23), Colombia (COL, n = 31), and Mexico (MEX, n = 19). We found that New World populations of P. vivax are as diverse (nucleotide diversity π between 5.2 × 10-4 and 6.2 × 10-4) as P. vivax populations from Southeast Asia, where malaria transmission is substantially more intense. They display several non-synonymous nucleotide substitutions (some of them previously undescribed) in genes known or suspected to be involved in antimalarial drug resistance, such as dhfr, dhps, mdr1, mrp1, and mrp-2, but not in the chloroquine resistance transporter ortholog (crt-o) gene. Moreover, P. vivax in the Americas is much less geographically substructured than local P. falciparum populations, with relatively little between-population genome-wide differentiation (pairwise FST values ranging between 0.025 and 0.092). Finally, P. vivax populations show a rapid decline in linkage disequilibrium with increasing distance between pairs of polymorphic sites, consistent with very frequent outcrossing. We hypothesize that the high diversity of present-day P. vivax lineages in the Americas originated from successive migratory waves and subsequent admixture between parasite lineages from geographically diverse sites. Further genome-wide analyses are required to test the demographic scenario suggested by our data.