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The Sigma-1 Receptor (Sigmar1) is a stress-activated chaperone and a promising target for pharmacological modulation due to its ability to induce multiple cellular responses. Yet, it is unknown how Sigmar1 is involved in cardiorenal syndrome type 4 (CRS4) in which renal damage results in cardiac dysfunction. This study explored the role of Sigmar1 and its ligands in a CRS4 model induced by unilateral ureteral obstruction (UUO) in male and female C57BL/6 mice. We evaluated renal and cardiac dysfunction markers, Sigmar1 expression, and cardiac remodeling through time (7, 12, and 21 days) and after chronically administering the Sigmar1 agonists PRE-084 (1 mg/kg/day) and SA4503 (1 mg/kg/day), and the antagonist haloperidol (2 mg/kg/day), for 21 days after UUO using colorimetric analysis, RT-qPCR, histology, immunohistochemistry, enzyme-linked immunosorbent assay, RNA-seq, and bioinformatics. We found that obstructive nephropathy induces Sigmar1 expression in the kidneys and heart, and that Sigmar1 stimulation with its agonists PRE-084 and SA4503 aggravates cardiac dysfunction and remodeling in both sexes. Still, their effects are significantly more potent in males. Our findings reveal essential differences associated with sex in the development of CRS4 and should be considered when contemplating Sigmar1 as a pharmacological target.
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Gastric cancer (GC) remains a significant global health challenge, with high mortality rates, especially in developing countries. Current treatments are invasive and have considerable risks, necessitating the exploration of safer alternatives. Quercetin (QRC), a flavonoid present in various plants and foods, has demonstrated multiple health benefits, including anticancer properties. This study investigated the therapeutic potential of QRC in the treatment of GC. We utilized advanced molecular techniques to assess the impact of QRC on GC cells, examining its effects on cellular pathways and gene expression. Our findings indicate that QRC significantly inhibits GC cell proliferation and induces apoptosis, suggesting its potential as a safer therapeutic option for GC treatment. Further research is required to validate these results and explore the clinical applications of QRC in cancer therapy.
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Apoptose , Proliferação de Células , Biologia Computacional , Quercetina , Neoplasias Gástricas , Quercetina/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Humanos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Background: Cardiorenal syndrome (CRS) type 4 is prevalent among the chronic kidney disease (CKD) population, with many patients dying from cardiovascular complications. However, limited data regarding cardiac transcriptional changes induced early by CKD is available. Methods: We used a murine unilateral ureteral obstruction (UUO) model to evaluate renal damage, cardiac remodeling, and transcriptional regulation at 21 days post-surgery through histological analysis, RT-qPCR, RNA-seq, and bioinformatics. Results: UUO leads to significant kidney injury, low uremia, and pathological cardiac remodeling, evidenced by increased collagen deposition and smooth muscle alpha-actin 2 expression. RNA-seq analysis identified 76 differentially expressed genes (DEGs) in UUO hearts. Upregulated DEGs were significantly enriched in cell cycle and cell division pathways, immune responses, cardiac repair, inflammation, proliferation, oxidative stress, and apoptosis. Gene Set Enrichment Analysis further revealed mitochondrial oxidative bioenergetic pathways, autophagy, and peroxisomal pathways are downregulated in UUO hearts. Vimentin was also identified as an UUO-upregulated transcript. Conclusions: Our results emphasize the relevance of extensive transcriptional changes, mitochondrial dysfunction, homeostasis deregulation, fatty-acid metabolism alterations, and vimentin upregulation in CRS type 4 development.
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The utilization of food as a therapeutic measure for various ailments has been a prevalent practice throughout history and across different cultures. This is exemplified in societies where substances like Hibiscus sabdariffa have been employed to manage health conditions like hypertension and elevated blood glucose levels. The inherent bioactive compounds found in this plant, namely, delphinidin-3-sambubioside (DS3), quercetin (QRC), and hibiscus acid (HA), have been linked to various health benefits. Despite receiving individual attention, the specific molecular targets for these compounds remain unclear. In this study, computational analysis was conducted using bioinformatics tools such as Swiss Target Prediction, ShinnyGo 0.77, KEGG, and Stringdb to identify the molecular targets, pathways, and hub genes. Supplementary results were obtained through a thorough literature search in PubMed. DS3 analysis revealed potential genetic alterations related to the metabolism of nitrogen and glucose, inflammation, angiogenesis, and cell proliferation, particularly impacting the PI3K-AKT signaling pathway. QRC analysis demonstrated interconnected targets spanning multiple pathways, with some overlap with DS3 analysis and a particular focus on pathways related to cancer. HA analysis revealed distinct targets, especially those associated with pathways related to the nervous system. These findings emphasize the necessity for focused research on the molecular effects of DS3, QRC, and HA, thereby providing valuable insights into potential therapeutic pathways.
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Antocianinas , Citratos , Hibiscus , Quercetina , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/análise , Fosfatidilinositol 3-QuinasesRESUMO
TiO2, ZnO, and their combination (TiO2−ZnO) at different molar ratios and pH values (Ti−Zn A and B 3:1, 1:1, and 1:3) via the sol−gel method were characterized by SEM, XRD, UV-Vis, and FT-IR. Moreover, antibacterial tests of the nanoparticles were conducted against Escherichia coli (E. coli), Salmonella paratyphi (S. paratyphi), Staphylococcus aureus (S. aureus), and Listeria monocytogenes (L. monocytogenes). The indirect bandgap of the Ti−Zn binary oxide synthesized in the basic process at molar ratios of 3:1, 1:1, and 1:3 exhibited a higher eV (3.31, 3.30, and 3.19 eV, respectively) compared to pure TiO2 (3.2 eV) and synthesized in the acid process (3.22, 3.29, and 3.19 eV at same molar ratio, respectively); in addition, the results of the indirect bandgap were interesting due to a difference found by other authors. Moreover, the sol−gel method promoted the formation of a spherical, semi-sphere, and semi-hexagonal shape (TiO2, Ti−Zn 1:1, and Ti−Zn 1:3) with a size ≤ 150 nm synthesized during the acid process, with a crystallite size of ~71, ~12, ~34, and ~21 nm, respectively, while ZnO NPs developed a hexagonal and large size (200−800 nm) under the same synthesis process (acid). Samples were classified as TiO2 anatase phase (basic synthesis); however, the presented changes developed in the rutile phase (24% rutile phase) at an acid pH during the synthesis process. Moreover, Ti−Zn maintained the anatase phase even with a molar ratio of 1:3. The most interesting assessment was the antibacterial test; the Ti−Zn A (1:3) demonstrated a bacteriostatic effect compared with all treatments except ZnO, which showed a similar effect in dark conditions, and only Gram-positive bacteria were susceptible (Listeria monocytogenes > Staphylococcus aureus). Therefore, the Ti−Zn characteristic suggests that the results have potential in treating wastewater as well as in pharmaceutical (as drug carriers) and medical applications.
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Myocardial damage in acute myocardial infarctions (AMI) is primarily the result of ischemia−reperfusion injury (IRI). Recognizing the timing of transcriptional events and their modulation by cardioprotective strategies is critical to address the pathophysiology of myocardial IRI. Despite the relevance of pigs for translational studies of AMI, only a few have identified how transcriptomic changes shape cellular signaling pathways in response to injury. We systematically reviewed transcriptomic studies of myocardial IRI and cardioprotection in Sus scrofa. Gene expression datasets were analyzed for significantly enriched terms using the Enrichr analysis tool, and statistically significant results (adjusted p-values of <0.05) for Signaling Pathways, Transcription Factors, Molecular Functions, and Biological Processes were compared between eligible studies to describe how these dynamic changes transform the myocardium from an injured and inflamed tissue into a scar. Then, we address how cardioprotective interventions distinctly modulate the myocardial transcriptome and discuss the implications of uncovering gene regulatory networks for cardiovascular pathologies and translational applications.
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Osteopontin (OPN) is a phosphoglycoprotein involved in bone remodelling, wound healing, cell adhesion, tissue remodelling, and immune response that is distributed widely in normal adult tissues. OPN biological activity is regulated by thrombin and matrix metalloproteinases (MMPs) cleavage, where the full-length (OPN-FL) protein and the cleaved OPN-N are associated with autoimmune diseases such as systemic lupus erythematosus (SLE). OPN overexpression has been associated with a predisposition to SLE and bad prognosis since OPN could mediate a sustained polyclonal B cell activation that besides to intracellular OPN (iOPN) form, promote the T follicular helper (TFH) cells and enhance anti-nuclear antibody production. Currently, the role of OPN in lupus nephritis (LN) has been reported and extensively studied; however, no data are available about the potential mechanism of OPN in neuropsychiatric SLE (NPSLE). In this review, we highlighted the contribution of OPN and iOPN in LN and NPSLE immunopathology.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Humanos , Osteopontina , PrognósticoRESUMO
Ischemia-reperfusion (I/R) injury, an inevitable result of kidney transplantation, triggers early inflammatory events that affect graft viability. Evidence from human transplantation and preclinical models of I/R suggests that a female hormonal environment positively influences the ability to recover from ischemic injury. However, the mechanisms behind these effects remain mostly unexplored. Here, we studied the influence of sex on pro-inflammatory mediators involved in the pathophysiology of acute I/R injury in male, female, and female ovariectomized (OVX) Wistar rats that underwent unilateral renal ischemia for 45 min, followed by 24 h of reperfusion. We found improved renal function, reduced cytokine expression, and decreased infiltration of myeloperoxidase-positive cells in females after I/R, when compared to their male and female OVX counterparts. Remarkably, citrullination of histone H3 was exacerbated in serum and renal tubules of females after I/R. In contrast, we observed lower levels of citrullinated histone H3 in male and female OVX rats in response to I/R, mostly in neutrophil extracellular traps. Our results demonstrate that female sex promotes renal I/R tolerance by attenuating pro-inflammatory mediators involved in I/R-induced damage.
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Hormônios Esteroides Gonadais/metabolismo , Histonas/metabolismo , Inflamação/imunologia , Transplante de Rim , Rim/metabolismo , Traumatismo por Reperfusão/imunologia , Animais , Citrulinação , Resistência à Doença , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Rim/patologia , Masculino , Ovariectomia , Ratos Wistar , Traumatismo por Reperfusão/epidemiologia , Caracteres Sexuais , Fatores SexuaisRESUMO
Neuropsychiatric systemic lupus erythematosus (NPSLE) is associated with learning and memory deficit. Murine model of lupus induced by pristane in BALB/c mice is an experimental model that resembles some clinical and immunological SLE pathogenesis. Nevertheless, there is no experimental evidence that relates this model to cognitive dysfunction associated with NR2A/2B relative expression. To evaluate cognitive impairment related to memory deficits in a murine model of lupus induced by pristane in BALB/c mice related to mRNA relative expression levels of NR2A/2B hippocampal subunits in short and long-term memory task at 7 and 12 weeks after LPS exposition in a behavioral test with the use of Barnes maze. A total of 54 female BALB/c mice 8-12 weeks old were included into 3 groups: 7 and 12 weeks using pristane alone (0.5 mL of pristane) by a single intraperitoneal (i.p.) injection. A control group (single i.p. injection of 0.5 mL NaCl 0.9%) and pristane plus LPS exposure using single i.p. pristane injection and LPS of E. coli O55:B5, in a dose of 3mg/kg diluted in NaCl 0.9% 16 weeks post-pristane administration. To determine cognitive dysfunction, mice were tested in a Barnes maze. Serum anti-Sm antibodies and relative expression of hippocampal NR2A/2B subunits (GAPDH as housekeeping gene) with SYBR green quantitative reverse transcription polymerase chain reaction and 2-ΔΔCT method were determined in the groups. Downregulation of hippocampal NR2A subunit was more evident than NR2B in pristane and pristane+LPS at 7 and 12 weeks of treatment and it is related to learning and memory disturbance assayed by Barnes maze. This is the first report using the murine model of lupus induced by pristane that analyzes the NMDA subunit receptors, finding a downregulation of NR2A subunit related to learning and memory disturbance being more evident when they were exposed to LPS.