RESUMO
Lisdexamfetamine dimesylate (LDX) is a prodrug of dextroamphetamine, which has been widely recommended for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). There are still no data in the literature relating the possible toxic effects of LDX in the kidney. Therefore, the present study aims to evaluate the effects of LDX exposure on morphological, oxidative stress, cell death and inflammation parameters in the kidneys of male pubertal Wistar rats, since the kidneys are organs related to the excretion of most drugs. For this, twenty male Wistar rats were distributed randomly into two experimental groups: LDX group-received 11,3 mg/kg/day of LDX; and Control group-received tap water. Animals were treated by gavage from postnatal day (PND) 25 to 65. At PND 66, plasma was collected to the biochemical dosage, and the kidneys were collected for determinations of the inflammatory profile, oxidative status, cell death, and for histochemical, and morphometric analyses. Our results show that there was an increase in the number of cells marked for cell death, and a reduction of proximal and distal convoluted tubules mean diameter in the group that received LDX. In addition, our results also showed an increase in MPO and NAG activity, indicating an inflammatory response. The oxidative status showed that the antioxidant system is working undisrupted and avoiding oxidative stress. Therefore, LDX-exposition in male rats during the peripubertal period causes renal changes in pubertal age involving inflammatory mechanisms, antioxidant activity and apoptosis process.
Assuntos
Antioxidantes , Apoptose , Rim , Dimesilato de Lisdexanfetamina , Estresse Oxidativo , Ratos Wistar , Animais , Masculino , Apoptose/efeitos dos fármacos , Ratos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/patologia , Maturidade Sexual/efeitos dos fármacosRESUMO
Chronic kidney disease (CKD) has been recognized as a significant global health problem due to being an important contributor to morbidity and mortality. Inflammation is the critical event that leads to CKD development orchestrated by a complex interaction between renal parenchyma and immune cells. Particularly, the crosstalk between tubular epithelial cells (TECs) and macrophages is an example of the critical cell communication in the kidney that drives kidney fibrosis, a pathological feature in CKD. Metabolism dysregulation of TECs and macrophages can be a bridge that connects inflammation and fibrogenesis. Currently, some evidence has reported how cellular lipid disturbances can affect kidney disease and cause tubulointerstitial fibrosis highlighting the importance of investigating potential molecules that can restore metabolic parameters. Vitamin D (VitD) is a hormone naturally produced by mammalian cells in a coordinated manner by the skin, liver, and kidneys. VitD deficiency or insufficiency is prevalent in patients with CKD, and serum levels of VitD are inversely correlated with the degree of kidney inflammation and renal function. Proximal TECs and macrophages produce the active form of VitD, and both express the VitD receptor (VDR) that evidence the importance of this nutrient in regulating their functions. However, whether VitD signaling drives physiological and metabolism improvement of TECs and macrophages during kidney injury is an open issue to be debated. In this review, we brought to light VitD as an important metabolic modulator of lipid metabolism in TECs and macrophages. New scientific approaches targeting VitD e VDR signaling at the cellular metabolic level can provide a better comprehension of its role in renal physiology and CKD progression.
RESUMO
Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.
Assuntos
Rejeição de Enxerto , Inflamassomos , Biomarcadores , Rim , Fatores de TranscriçãoRESUMO
The zebrafish is an animal model of increasing use in many biomedical fields of study, including toxicology, inflammation, and tissue regeneration. In this paper, we have investigated the inflammatory effects of Loxosceles intermedia's venom (LIV) on zebrafish, as well as the effects of Maresin 2 (Mar2) and Resolvin D5 (RvD5), two specialized pro-resolving mediators (SPMs), in the context of tissue regeneration after fin fold amputation. Furthermore, increasing concentrations of LIV (250-2000 ng) were assayed for their haemolytic effects in vitro, and, afterwards, the same concentrations were evaluated in vivo, when injected intraperitoneally. LIV caused haemolysis in human red blood cells (RBCs), but not in zebrafish RBCs. The survival curve was also not altered by LIV injection, regardless of venom dosage. Histological analysis of renal and hepatic tissues, as well as the whole animal, revealed no pathological differences between LIV-injected and PBS-injected groups. Fin fold regeneration was not altered between LIV-injected and control groups, nor in the presence of MaR2 and RvD5. Results of swimming behavioral analysis also did not differ between groups. Moreover, in silico data indicated differences between human and zebrafish cell membrane lipid constitutions, such as in phospholipases D preferred substrates, that could lead to the protection of zebrafish against LIV. Although our data implies that zebrafish cannot be used as a toxicological model for LIV studies, the absence of observed toxicological effects paves the way for the comprehension of the venom's mechanism of action in mammals and the fundamental evolutionary processes involved.