Amelioration of nephrotoxicity by targeting ferroptosis: role of NCOA4, IREB2, and SLC7a11 signaling.

Nephrotoxicity is a common complication that limits the clinical utility of cisplatin. Ferroptosis is an iron-dependent necrotic cell death program that is mediated by phospholipid peroxidation. The molecular mechanisms that disrupt iron homeostasis and lead to ferroptosis are yet to be elucidated. In this study, we aimed to investigate the involvement of nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor that mediates ferroptosis and autophagic degradation of ferritin in nephrotoxicity. Adult male Sprague-Dawley rats were randomly-assigned to four groups: control group, cisplatin (Cis)-treated group, deferiprone (DEF)-treated group, and Cis+DEF co-treated group. Serum, urine, and kidneys were isolated to perform biochemical, morphometric, and immunohistochemical analysis. Iron accumulation was found to predispose to ferroptotic damage of the renal tubular cells. Treatment with deferiprone highlights the role of ferroptosis in nephrotoxicity. Upregulation of NCOA4 in parallel with low ferritin level in renal tissue seems to participate in iron-induced ferroptosis. This study indicated that ferroptosis may participate in cisplatin-induced tubular cell death and nephrotoxicity through iron-mediated lipid peroxidation. Iron dyshomeostasis could be attributed to NCOA4-mediated ferritin degradation.

Curcumin Prevents Renal Damage of l-NAME Induced Hypertension in by Reducing MMP-2 and MMP-9.

In the present study, we investigated whether curcumin administration would interfere with the main renal features of l-NAME-induced hypertension model. For this purpose, we conducted both in vitro and in vivo experiments to evaluate renal indicators of inflammation, oxidative stress, and metalloproteinases (MMPs) expression/activity. Hypertension was induced by l-NAME (70 mg/kg/day), and Wistar rats from both control and hypertensive groups were treated with curcumin (50 or 100 mg/kg/day; gavage) or vehicle for 14 days. Blood and kidneys were collected to determine serum creatinine levels, histological alterations, oxidative stress, MMPs expression and activity, and ED1 expression. l-NAME increased blood pressure, but both doses of curcumin treatment reduced these values. l-NAME treatment increased creatinine levels, glomeruli area, Bowman's space, kidney MMP-2 activity, as well as MMP-9 and ED1 expression, and reduced the number of glomeruli. Curcumin treatment prevented the increase in creatinine levels, MMP-2 activity, and reduced MMP-2, MMP-9, ED1, and superoxide levels, as well as increased superoxide dismutase activity and partially prevented glomeruli alterations. Moreover, curcumin directly inhibited MMP-2 activity in vitro. Thus, our main findings demonstrate that curcumin reduced l-NAME-induced hypertension and renal glomerular alterations, inhibited MMP-2 and MMP-9 expression/activity, and reduced oxidative stress and inflammatory processes, which may indirectly impact hypertension-induced renal outcomes.

A new parameter in predicting contrast-induced nephropathy: Osaka prognostic score.

OBJECTIVE: Nowadays, the frequency of complications is also increasing following the increasing frequency of coronary angiography and percutaneous coronary intervention. Contrast-induced nephropathy is one of the most common of these complications. This study aimed to investigate the relationship between the Osaka prognostic score, which has previously been shown to have prognostic importance in gastrointestinal malignancies, and the development of contrast-induced nephropathy. METHODS: The study retrospectively examined the data of 1,498 patients who underwent coronary angiography and percutaneous coronary intervention due to acute coronary syndrome between 2018 and 2023. Demographic characteristics and laboratory findings were retrospectively collected from patients' charts and electronic medical records. RESULTS: Osaka prognostic score (0.84±0.25 vs. 2.2±0.32, p<0.001) was higher in patients who developed contrast-induced nephropathy. Also, Osaka prognostic score [OR 2.161 95%CI (1.101-4.241), p<0.001] was found to be an independent risk factor along with age, diabetes mellitus, systolic pulmonary artery pressure, hemoglobin, hemoglobin, C-reactive protein, albumin, N-terminal brain natriuretic peptide, and systemic immune-inflammation index. The receiver operating characteristic curve showed that the optimal cutoff value of Osaka prognostic score to predict the development of contrast-induced nephropathy was 1.5, with a sensitivity of 83.4 and a specificity of 65.9% [area under the curve: 0.874 (95%CI: 0.850-0.897, p≤0.001)]. CONCLUSION: Osaka prognostic score may be an easily calculable, user-friendly, and useful parameter to predict the development of contrast-induced nephropathy in patients undergoing percutaneous coronary intervention after acute coronary syndromes.

Angiotensin II-independent abnormal renal vascular reactivity during puromycin nephropathy.

Experimental glomerulonephritis results in hypertension that is sensitive to salt. Nevertheless, salt retention alone cannot explain the increase in blood pressure. Angiotensin antagonistic therapy reduces hypertension caused by puromycin amino nucleosides (PAN). We investigated the hypothesis that PAN modifies renal vascular reactivity through processes dependent on angiotensin. Long-Evans rats were given an intraperitoneal injection of either puromycin (150 mg/kg) or saline (controls). Group 1 was fed a normal sodium diet (NSD, n = 9). Group 2 was given 30 mg/L of quinapril (Q) in addition to NSD (NSD + Q; n = 6). Group 3 received a high sodium diet (HSD, n = 7), and Group 4 received HSD + Q (n = 7). Systolic blood pressure (SBP), plasma creatinine, proteinuria, and sodium balance were monitored for 12 days. On day 15, renal vascular reactivity was assessed by administering increasing doses of angiotensin II, acetylcholine (ACh), and sodium nitroprusside (SNP) directly into the renal artery. SBP progressively increased in all PAN groups. This increase in SBP was greater in the HSD groups and was not significantly altered by Q treatment. SBP increased by 22 ± 4% (NSD), 51 ± 5% (NSD + Q), 81 ± 10% (HSD), and 65 ± 8% (HSD + Q). The renal blood flow of PAN rats did not return to baseline despite their normal renal vasoconstrictor responses to angiotensin II. Additionally, they showed reduced renal vasodilator responses to SNP and Ach. The vasodilator responses to both vasodilators were surprisingly unaffected by the inhibition of the angiotensin-converting enzyme (ACE). Renal vasodilator responses to both endothelium-dependent and independent variables were reduced in early PAN-induced hypertension. We found that the angiotensin-mediated mechanism is not responsible for this altered renal vasoreactivity.

Protective effect of coenzyme Q10 in cyclophosphamide-induced kidney damage in rats.

OBJECTIVE: We aimed to investigate the effect of coenzyme q10 on cyclophosphamide-induced kidney damage in rats. METHODS: A total of 30 female Wistar-Albino rats were utilized to form three groups. In group 1 (control group) (n=10), no drugs were given. In group 2 (cyclophosphamide group) (n=10), 30 mg/kg intraperitoneal cyclophosphamide was administered for 7 days. In group 3 (cyclophosphamide+coenzyme q10 group) (n=10), 30 mg/kg cyclophosphamide and 10 mg/kg coenzyme q10 were given for 7 days via intraperitoneal route. Right kidneys were removed in all groups. Blood malondialdehyde levels and activities of catalase and superoxide dismutase were measured. Histopathological damage was evaluated by examining the slides prepared from kidney tissue using a light microscope. RESULTS: Tissue damage was significantly higher in the cyclophosphamide group than in the cyclophosphamide+coenzyme q10 group (p<0.05). The malondialdehyde levels were significantly higher and the activities of superoxide dismutase and catalase were lower in the cyclophosphamide group than in the cyclophosphamide+coenzyme q10 group (p<0.05). CONCLUSION: Coenzyme q10 may be a good option to prevent cyclophosphamide-induced kidney damage.

Synergistic Renoprotective Effects of Green Tea Extract and Gemigliptin against Tacrolimus-Induced Nephrotoxicity in Mice / Efectos Renoprotectores Sinérgicos del Extracto de Té Verde y Gemigliptina contra la Nefrotoxicidad Inducida por Tacrolimus en Ratones

SUMMARY: Although tacrolimus (TAC) significantly reduces allograft rejection incidence in solid-organ transplantation, its long-term use is associated with an increased risk of TAC-induced nephrotoxicity. In this study, we investigated the renoprotective effects of green tea extract (GTE) with or without the dipeptidyl peptidase 4 inhibitor, gemigliptin, by assessing serum creatinine levels, the amount of proteinuria, and histopathology in TAC-induced nephrotoxicity. TAC-induced nephrotoxicity was induced by intraperitoneal TAC injection, GTE was administered via subcutaneous injection, and gemigliptin was administered orally. Mice with TAC-induced nephrotoxicity exhibited a significant increase in both serum creatinine levels and 24-hour urine protein. However, when treated with GTE via subcutaneous injection, mice showed a decrease in serum creatinine levels and the amount of proteinuria. When GTE was combined with gemigliptin, further renoprotective effects were observed in biochemical assessments, consistent with the attenuation of TAC-induced nephrotoxicity in histopathology. The expression of p53 protein was lower in the mice treated with the combination of GTE and gemigliptin compared to mice with TAC-induced nephrotoxicity. Our results demonstrate that the combination of GTE and gemigliptin treatment reveals synergistic renoprotective effects by decreasing the expression of p53 protein. These findings suggest that the combination of GTE and gemigliptin could potentially be used as a prophylactic or therapeutic strategy for TAC-induced nephrotoxicity.

Aunque tacrolimus (TAC) reduce significativamente la incidencia de rechazo de aloinjertos en trasplantes de órganos sólidos, su uso a largo plazo se asocia con un mayor riesgo de nefrotoxicidad inducida por TAC. En este estudio, investigamos los efectos renoprotectores del extracto de té verde (GTE) con o sin el inhibidor de la dipeptidil peptidasa 4, gemigliptina, mediante la evaluación de los niveles de creatinina sérica, la cantidad de proteinuria y la histopatología en la nefrotoxicidad inducida por TAC. La nefrotoxicidad inducida por TAC se indujo mediante inyección intraperitoneal de TAC, el GTE se administró mediante inyección subcutánea y la gemigliptina se administró por vía oral. Los ratones con nefrotoxicidad inducida por TAC mostraron un aumento significativo tanto en los niveles de creatinina sérica como en la proteína en orina de 24 horas. Sin embargo, cuando se trataron con GTE mediante inyección subcutánea, los ratones mostraron una disminución en los niveles de creatinina sérica y en la cantidad de proteinuria. Cuando se combinó GTE con gemigliptina, se observaron efectos renoprotectores adicionales en las evaluaciones bioquímicas, lo que concuerda con la atenuación de la nefrotoxicidad inducida por TAC en histopatología. La expresión de la proteína p53 fue menor en los ratones tratados con la combinación de GTE y gemigliptina en comparación con los ratones con nefrotoxicidad inducida por TAC. Nuestros resultados demuestran que la combinación de tratamiento con GTE y gemigliptina revela efectos renoprotectores sinérgicos al disminuir la expresión de la proteína p53. Estos hallazgos sugieren que la combinación de GTE y gemigliptina podría usarse potencialmente como estrategia profiláctica o terapéutica para la nefrotoxicidad inducida por TAC.

Associations among environmental exposure to trace elements and biomarkers of early kidney damage in the pediatric population.

BACKGROUND: In kidney damage, molecular changes can be used as early damage kidney biomarkers, such as Kidney Injury Molecule-1 and Neutrophil gelatinase-associated lipocalin. These biomarkers are associated with toxic metal exposure or disturbed homeostasis of trace elements, which might lead to serious health hazards. This study aimed to evaluate the relationship between exposure to trace elements and early damage kidney biomarkers in a pediatric population. METHODS: In Tlaxcala, a cross-sectional study was conducted on 914 healthy individuals. The participants underwent a medical review and a socio-environmental questionnaire. Five early damage kidney biomarkers were determined in the urine with Luminex, and molybdenum, copper, selenium, nickel, and iodine were measured with ICP-Mass. RESULTS: The eGFR showed a median of 103.75 mL/min/1.73 m2. The median levels for molybdenum, copper, selenium, nickel, and iodine were 24.73 ng/mL, 73.35 ng/mL, 4.78 ng/mL, 83.68 ng/mL, and 361.83 ng/mL, respectively. Except for molybdenum and nickel, the other trace elements had significant associations with the eGFR and the early kidney damage biomarkers. Additionally, we report the association of different exposure scenarios with renal parameters. DISCUSSION: and Conclusions. Among the explored metals, exposure to Cu and iodine impairs renal function. In contrast, Se may manifest as a beneficial metal. Interactions of Mo-Se and Mo-Iodine seem to alter the expression of NGAL; Mo-Cu for CLU; Mo-Cu, Mo-Se, and Mo-iodine for Cys-C and a-1MG; and Mo-Cu and Mo-iodine for KIM-1; were noticed. Our study could suggest that trace element interactions were associated with early kidney damage biomarkers.

An integrated view of cisplatin-induced nephrotoxicity, hepatotoxicity, and cardiotoxicity: characteristics, common molecular mechanisms, and current clinical management.

Cisplatin (CP) is a chemotherapy drug widely prescribed to treat various neoplasms. Although fundamental for the therapeutic action of the drug, its cytotoxic mechanisms trigger adverse effects in several tissues, such as the kidney, liver, and heart, which limit its clinical use. In this sense, studies point to an essential role of damage to nuclear and mitochondrial DNA associated with oxidative stress, inflammation, and apoptosis in the pathophysiology of tissue injuries. Due to the limitation of effective preventive and therapeutic measures against CP-induced toxicity, new strategies with potential cytoprotective effects have been studied. Therefore, this article is timely in reviewing the characteristics and main molecular mechanisms common to renal, hepatic, and cardiac toxicity previously described, in addition to addressing the main validated strategies for the current management of these adverse events in clinical practice. We also handle the main promising antioxidant substances recently presented in the literature to encourage the development of new research that consolidates their potential preventive and therapeutic effects against CP-induced cytotoxicity.

Therapeutic treatment with phosphodiesterase-4 inhibitors alleviates kidney injury and renal fibrosis by increasing MMP-9 in a doxorubicin-induced nephrotoxicity mouse model.

Nephrotic syndrome (NS) is associated with kidney dysfunction and is an important cause of morbidity and mortality in industrialized countries. Here, we evaluated the effects of the phosphodiesterase-4 (PDE-4) inhibitors rolipram and roflumilast on a doxorubicin-induced NS model. Early-stage rolipram treatment preserved glomerular filtration barrier function, as indicated by reduced serum protein and albumin loss and the prevention of hypercholesterolemia. These effects were associated with reduced glomerular and tubular lesions and abrogated renal cell apoptosis. In addition, rolipram treatment reduced inflammation, which was characterized by a decrease in macrophage accumulation and reduced levels of CCL2 and TNF in the kidneys. Rolipram also reduced renal fibrosis, which was associated with decreased α-smooth muscle actin (α-SMA) area and increased metalloproteinase 9 (MMP9) activity in renal tissue. Late-stage rolipram or roflumilast treatment preserved glomerular filtration barrier function, as characterized by reduced serum albumin loss, decreased proteinuria, and the prevention of hypercholesterolemia. Importantly, only roflumilast treatment was associated with a reduction in glomerular and tubular lesions at this time point. In addition, both rolipram and roflumilast reduced renal tissue fibrosis and MMP9 activity in renal tissue.

Benefits of high-intensity interval training compared to continuous training to reduce apoptotic markers in female rats with cisplatin nephrotoxicity - possible modulatory role of IL-11.

Apoptotic signaling pathways are involved in acute kidney injury (AKI) induced by the antineoplastic drug cisplatin (Cis). Mechanical stress is known to increase interleukin (IL) -11, a pleiotropic cytokine with antiapoptotic and antinecrotic effects. We compared the impact of high-intensity interval training (HIIT) with low-intensity continuous training (LICT) and moderate-intensity continuous training (MICT) on renal levels of IL-11 and the expression of apoptotic markers in female rats with nephrotoxicity induced by Cis. For that, the animals were divided into five groups (n = 7): control and sedentary (C + S); Cis and sedentary (Cis + S); Cis and LICT (Cis + LICT); Cis and MICT (Cis + MICT) and Cis and HIIT (Cis + HIIT). At the end of 8 weeks of treadmill running, the rats received a single injection of Cis (5 mg/kg), and 7 days later they were euthanized. Serum and kidney samples were collected to assess the blood urea nitrogen (BUN), gene expression of TNF receptor 1 (TNFR1) and 2 (TNFR2), caspase-3, (p38) MAPK (MAPK14), p53, Bax, Bak, Bcl-2, and Bcl-xL, renal levels of IL-11, IL-8, and p53, and immunolocalization of cleaved caspase-3, Bax, Bcl-2, and (p38) MAPK in renal tissue. Our data indicate that all trained groups showed a significant intensity-dependent increase in renal levels of IL-11 associated with reduced local expression of proapoptotic and increased antiapoptotic markers, but these effects were more pronounced with HIIT. So, HIIT appears to provide superior renoprotection than traditional continuous training by modulating apoptotic signaling pathways, and this effect can be related to the increase in renal levels of IL-11.

Toxicological effects of thimerosal on rat kidney: a histological and biochemical study / Efeitos toxicológicos do timerosal no rim de rato: um estudo histológico e bioquímico

Thimerosal is an organomercurial compound, which is used in the preparation of intramuscular immunoglobulin, antivenoms, tattoo inks, skin test antigens, nasal products, ophthalmic drops, and vaccines as a preservative. In most of animal species and humans, the kidney is one of the main sites for mercurial compounds deposition and target organs for toxicity. So, the current research was intended to assess the thimerosal induced nephrotoxicity in male rats. Twenty-four adult male albino rats were categorized into four groups. The first group was a control group. Rats of Group-II, Group-III, and Group-IV were administered with 0.5µg/kg, 10µg/kg, and 50µg/kg of thimerosal once a day, respectively. Thimerosal administration significantly decreased the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione reductase (GR), glutathione (GSH), and protein content while increased the thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) levels dose-dependently. Blood urea nitrogen (BUN), creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, urinary albumin and creatinine clearance was reduced dose-dependently in thimerosal treated groups. The results demonstrated that thimerosal significantly increased the inflammation indicators including nuclear factor kappaB (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activities, DNA and histopathological damages dose-dependently. So, the present findings ascertained that thimerosal exerted nephrotoxicity in male albino rats.(AU)

O timerosal é um composto organomercurial, utilizado na preparação de imunoglobulina intramuscular, antivenenos, tintas de tatuagem, antígenos de teste cutâneo, produtos nasais, gotas oftálmicas e vacinas como conservante. Na maioria das espécies animais e nos humanos, o rim é um dos principais locais de deposição de compostos de mercúrio e órgãos-alvo de toxicidade. Assim, a presente pesquisa teve como objetivo avaliar a nefrotoxicidade induzida pelo timerosal em ratos machos. Vinte e quatro ratos albinos machos adultos foram categorizados em quatro grupos. O primeiro grupo era um grupo de controle. Ratos do Grupo II, Grupo III e Grupo IV receberam 0,5µg / kg, 10µg / kg e 50µg / kg de timerosal uma vez ao dia, respectivamente. A administração de timerosal diminuiu significativamente as atividades de catalase (CAT), superóxido dismutase (SOD), peroxidase (POD), glutationa redutase (GR), glutationa (GSH) e conteúdo de proteína, enquanto aumentou as substâncias reativas ao ácido tiobarbitúrico (TBARS) e peróxido de hidrogênio (H2O2) níveis dependentes da dose. Os níveis de nitrogênio ureico no sangue (BUN), creatinina, urobilinogênio, proteínas urinárias, molécula de lesão renal-1 (KIM-1) e lipocalina associada à gelatinase de neutrófilos (NGAL) aumentaram substancialmente. Em contraste, a albumina urinária e a depuração da creatinina foram reduzidas de forma dependente da dose nos grupos tratados com timerosal. Os resultados demonstraram que o timerosal aumentou significativamente os indicadores de inflamação, incluindo fator nuclear kappaB (NF-κB), fator de necrose tumoral-α (TNF-α), interleucina-1β (IL-1β), níveis de interleucina-6 (IL-6) e atividades da ciclooxigenase-2 (COX-2), DNA e danos histopatológicos dependentes da dose. Portanto, os presentes achados verificaram que o timerosal exerceu nefrotoxicidade em ratos albinos machos.(AU)

Toxicological effects of thimerosal on rat kidney: a histological and biochemical study / Efeitos toxicológicos do timerosal no rim de rato: um estudo histológico e bioquímico

Thimerosal is an organomercurial compound, which is used in the preparation of intramuscular immunoglobulin, antivenoms, tattoo inks, skin test antigens, nasal products, ophthalmic drops, and vaccines as a preservative. In most of animal species and humans, the kidney is one of the main sites for mercurial compounds deposition and target organs for toxicity. So, the current research was intended to assess the thimerosal induced nephrotoxicity in male rats. Twenty-four adult male albino rats were categorized into four groups. The first group was a control group. Rats of Group-II, Group-III, and Group-IV were administered with 0.5µg/kg, 10µg/kg, and 50µg/kg of thimerosal once a day, respectively. Thimerosal administration significantly decreased the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione reductase (GR), glutathione (GSH), and protein content while increased the thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) levels dose-dependently. Blood urea nitrogen (BUN), creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, urinary albumin and creatinine clearance was reduced dose-dependently in thimerosal treated groups. The results demonstrated that thimerosal significantly increased the inflammation indicators including nuclear factor kappaB (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activities, DNA and histopathological damages dose-dependently. So, the present findings ascertained that thimerosal exerted nephrotoxicity in male albino rats.

O timerosal é um composto organomercurial, utilizado na preparação de imunoglobulina intramuscular, antivenenos, tintas de tatuagem, antígenos de teste cutâneo, produtos nasais, gotas oftálmicas e vacinas como conservante. Na maioria das espécies animais e nos humanos, o rim é um dos principais locais de deposição de compostos de mercúrio e órgãos-alvo de toxicidade. Assim, a presente pesquisa teve como objetivo avaliar a nefrotoxicidade induzida pelo timerosal em ratos machos. Vinte e quatro ratos albinos machos adultos foram categorizados em quatro grupos. O primeiro grupo era um grupo de controle. Ratos do Grupo II, Grupo III e Grupo IV receberam 0,5µg / kg, 10µg / kg e 50µg / kg de timerosal uma vez ao dia, respectivamente. A administração de timerosal diminuiu significativamente as atividades de catalase (CAT), superóxido dismutase (SOD), peroxidase (POD), glutationa redutase (GR), glutationa (GSH) e conteúdo de proteína, enquanto aumentou as substâncias reativas ao ácido tiobarbitúrico (TBARS) e peróxido de hidrogênio (H2O2) níveis dependentes da dose. Os níveis de nitrogênio ureico no sangue (BUN), creatinina, urobilinogênio, proteínas urinárias, molécula de lesão renal-1 (KIM-1) e lipocalina associada à gelatinase de neutrófilos (NGAL) aumentaram substancialmente. Em contraste, a albumina urinária e a depuração da creatinina foram reduzidas de forma dependente da dose nos grupos tratados com timerosal. Os resultados demonstraram que o timerosal aumentou significativamente os indicadores de inflamação, incluindo fator nuclear kappaB (NF-κB), fator de necrose tumoral-α (TNF-α), interleucina-1β (IL-1β), níveis de interleucina-6 (IL-6) e atividades da ciclooxigenase-2 (COX-2), DNA e danos histopatológicos dependentes da dose. Portanto, os presentes achados verificaram que o timerosal exerceu nefrotoxicidade em ratos albinos machos.

Antioxidant extract of black rice prevents renal dysfunction and renal fibrosis caused by ethanol-induced toxicity.

This study was conducted to evaluate the protective role of extracted natural antioxidants from black rice and their effect on kidney failure and renal cirrhosis caused by ethanol-induced toxicity. Antioxidant activity in terms of total phenol content, flavonoid compounds and anthocyanin, as well as antioxidant capacity, was determined in an extract of black rice. The findings noted that the black rice extract contained high amounts of antioxidant activity and capacity. Total phenolic compounds from black rice extract were fractionated using HPLC and the results showed that ferulic, sinapic, ascorbic, salicylic and coumaric acids were the highest in the extract. Biological experiments were performed on male albino adult rats (40 animals, 10 rats for each group), divided into four groups. After five weeks, kidney functions and protein fractions were assessed. In addition, superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) enzyme activities were determined in all groups. The results found that kidney function, total protein, albumin and globulin were affected by renal dysfunction and renal fibrosis in the positive control (PC), whereas groups 3 and 4 noted an improvement in renal function nearly or equal to the healthy rats which were fed on a basal diet. Furthermore, the PC group showed significantly decreased levels of enzymatic antioxidants, namely SOD and GSH with a concomitant elevated MDA level compared with those in the negative rats fed on a basal diet. Groups 3 and 4 also reported improvements in enzyme activity. These results were further supported by histopathological findings which revealed a curative effect in groups 3 and 4, which avoided renal dysfunction and renal fibrosis from ethanol-induced toxicity. From the results, it can be said that the black rice extract with the highest amounts of antioxidants led to improvements in all parameters, especially kidney function, total protein, albumin, and globulin, in addition to enzyme activity. Therefore, black rice can be recommended as a benefit to general health.

SAFETY OF LONG-TERM PROTON PUMP INHIBITORS: FACTS AND MYTHS.

BACKGROUND: Proton pump inhibitors (PPIs) are one of the most prescribed drugs in the world. Frequent use and long-term maintenance of these drugs drew the attention of researchers for sporadic adverse effects reports. OBJECTIVE: The purpose of this narrative review is to discuss appropriate data and causality related to these adverse events and PPIs. METHODS: A narrative review was conducted by systematizing information about safety and adverse events on PPIs from 2015 to 2020. A structured search on Pubmed was performed to identify systematic reviews and meta-analysis investigating the following situations: a) gastric cancer; b) micronutrients deficiency; c) acid rebound; d) infections; e) fractures; f) dementia; g) kidney disease; and h) sudden death and cardiovascular changes. RESULTS: Recent studies have potentially associated PPIs with some adverse events as osteoporosis-related fractures. There are also reports of intestinal infections, including Clostridium difficile, besides poor vitamins absorption and minerals such as vitamin B12, magnesium, and iron. Furthermore, there are some dementia, pneumonia, kidney disease, myocardial infarction, and stroke reports. For kidney diseases, studies consistently suggest that the use of PPI may be associated with an increased risk of adverse kidney events, especially in the elderly, with long-term PPI use and pre-existing kidney disease. Another additional question is whether chronic PPI use would also lead to the onset of gastric cancer. The abrupt discontinuation of PPIs is also related to increased gastric acid production above pre-PPI treatment levels; this phenomenon is called acid rebound. CONCLUSION: The key to mitigate adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration. Although these adverse effects have a potential clinical impact, their causal association is still subject to validation.

Renal damage induced by cadmium and its possible therapy by mitochondrial transplantation.

Cadmium (Cd) is one of the most toxic metals without biological function, and its accumulation in living organisms has been reported. The kidney is a target organ in Cd toxicity; it has been observed that Cd causes kidney damage even at low concentrations, and Cd damage can quickly progress to chronic kidney disease. The mitochondria play a fundamental role in the nephrotoxicity of Cd; Cd enters the mitochondria and affects the electron transport system (ETS), increases the production of reactive oxygen species (ROS), decreases the mitochondrial membrane potential (Δψm), alters mitochondrial dynamics, induces mutations in mitochondrial deoxyribonucleic acid (mtDNA) and decreased biogenesis leading to increased mitophagy, autophagy, and inevitably apoptosis. Existing therapies to treat Cd nephrotoxicity are currently based on antioxidant and chelating compounds, but despite their promising effects, they have some limitations; therefore, Cd nephrotoxicity continues to represent a global health problem. Mitochondrial transplantation is a new experimental approach with positive results by reversing mitochondrial alterations in cardiac and kidney dysfunction mainly caused by oxidative stress. Hence, the current review discusses the role of mitochondria in Cd-induced toxicity in the kidney and proposes mitochondrial transference as a novel therapy based on transplanting healthy mitochondria to cells with Cd-compromised mitochondria. This review is the first to propose mitochondrial transplantation as a treatment for heavy metal-induced kidney damage.

Swim training reverses some effects of nandrolone decanoate in wistar rats / El entrenamiento en natación revierte algunos efectos del decanoato de nandrolona en los ratones wistar / Treinamento de natação reverte alguns efeitos do decanoato de nandrolona em ratos wistar

ABSTRACT Introduction: The indiscriminate use of androgenic steroids may have deleterious effects on human tissue. Objectives: Evaluate the effects of chronic administration of the steroid nandrolone decanoate (DECA) on autonomic cardiovascular modulation, kidney morphometry and the association between these variables in Wistar rats subjected to physical training with swimming. Methods: Thirty-two male Wistar rats aged 20 weeks were distributed among four experimental groups according to the training received: sedentary control (SC), sedentary treated with DECA (SD), trained control (TC) and trained treated with DECA (TD). The hemodynamic parameters, including blood pressure and variations in systolic blood pressure (SBPV) and diastolic blood pressure (DBPV), and kidney morphometry were evaluated. The level of significance adopted was 5%. Results: The SD group had higher baseline SBP and DBP values when compared to the SC, TC and TD groups, which were similar to each other. The rats in the SD group had higher systolic blood pressure (SBPV) and diastolic blood pressure (DBPV) variation values and higher absolute and normalized values in the LF band of the DBPV when compared to the animals in the SC, TC and TD groups. The animals in the SD group had a significantly higher rate of kidney fibrosis compared to the SC, TC and TD groups. There were no significant differences between the sympathetic modulation of SBPV through the LF component and kidney fibrosis. Conclusions: Physical training with swimming was effective in preventing the increase in blood pressure levels and lowering the occurrence of kidney fibrosis in animals treated with anabolic steroids. Level of Evidence IV; Series of cases .

RESUMEN Introducción: El uso indiscriminado de esteroides androgénicos puede tener consecuencias nocivas para el organismo. Objetivo: Evaluar los efectos de la administración crónica del esteroide decanoato de nandrolona (DECA) en ratones Wistar sometidos a entrenamiento físico con natación, sobre la modulación autonómica cardiovascular, morfometría renal y asociación entre esas variables. Métodos: Fueron utilizados 32 ratones Wistar machos con edad de 20 semanas, distribuidos en 4 grupos experimentales de acuerdo con el tratamiento recibido: sedentarios controles (SC), sedentarios que recibieron el DECA (SD), entrenados controles (EC) y entrenados que recibieron el DECA (ED). Se evaluaron parámetros hemodinámicos, como presión arterial y variación de la presión arterial sistólica (VPAS) y diastólica (VPAD) y morfometría renal. El nivel de significancia adoptado fue de 5%. Resultados: El grupo SD presentó valores basales mayores de PAS y PAD cuando comparados a los grupos SC, EC y ED, los cuales fueron semejantes entre sí. Los animales del grupo SD tuvieron valores mayores de la variancia de VPAS y VPAD y valores absolutos mayores y normalizados de la banda LF de la VPAD, en comparación con los animales de los grupos SC, EC y ED. El grupo SD tuvo tasa significativamente mayor de fibrosis renal en comparación con los animales de los grupos SC, EC y ED. No se evidenciaron diferencias considerables entre la modulación simpática de la VPAS a través del componente LF y fibrosis renal. Conclusiones: El entrenamiento físico con natación fue efectivo en prevenir el aumento de niveles presóricos y disminuir la ocurrencia de fibrosis renal en animales tratados con esteroide anabolizante. Nivel de Evidencia IV; Serie de casos .

RESUMO Introdução: O uso indiscriminado de esteroides androgênicos pode ter consequências deletérias no organismo. Objetivo: Avaliar os efeitos da administração crônica do esteroide decanoato de nandrolona (DECA) em ratos Wistar submetidos a treinamento físico com natação sobre a modulação autônoma cardiovascular, morfometria renal e associação entre essas variáveis. Métodos: Foram utilizados 32 ratos Wistar machos com idade de 20 semanas, distribuídos em 4 grupos experimentais de acordo com o tratamento recebido: sedentários controles (SC), sedentários que receberam o DECA (SD), treinados controles (TC) e treinados que receberam o DECA (TD). Avaliaram-se parâmetros hemodinâmicos, como pressão arterial e variação da pressão arterial sistólica (VPAS) e diastólica (VPAD) e morfometria renal. O nível de significância adotado foi de 5%. Resultados: O grupo SD apresentou valores basais maiores de PAS e PAD quando comparado aos grupos SC, TC e TD, os quais foram semelhantes entre si. Os animais do grupo SD tiveram valores maiores da variância da VPAS e VPAD e valores absolutos maiores e normalizados da banda LF da VPAD, em comparação com os animais dos grupos SC, TC e TD. O grupo SD teve taxa significativamente maior de fibrose renal em comparação com os animais dos grupos SC, TC e TD. Não se evidenciaram diferenças consideráveis entre a modulação simpática da VPAS através do componente LF e fibrose renal. Conclusões: O treinamento físico com natação foi efetivo em prevenir o aumento de níveis pressóricos e diminuir a ocorrência de fibrose renal em animais tratados com esteroide anabolizante. Nível de Evidência IV; Série de casos .

7-Chloro-4-(phenylselanyl) quinoline reduces renal oxidative stress induced by oxaliplatin in mice.

The object of this study was to evaluate the relationship between oxidative damage induced by oxaliplatin (OXA) and the therapeutic potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in kidney of mice. Mice received OXA (10 mg/kg) or vehicle intraperitoneally (days 0 and 2). Oral administration of 4-PSQ (1 mg/kg) or vehicle was performed on days 2 to 14. On day 15 the animals were euthanized and the kidneys and blood were collected. The effect of OXA and (or) 4-PSQ on urea, thiobarbituric acid reactive species, nonprotein thiol (NPSH), and protein carbonyl (PC) levels were investigated. Moreover, renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), δ-aminolevulinic acid dehydratase (δ-ALA-D), and Na+,K+ ATPase activities were evaluated. Our findings revealed an increase on urea levels and significant renal oxidative damage in OXA-induced mice. OXA exposure increased SOD, GPx, and GST activities and caused a reduction on NPSH levels and CAT and GR activities. Na+,K+ ATPase and δ-ALA-D activities were reduced by OXA. 4-PSQ decreased plasmatic urea levels and renal oxidative damage. SOD, GPx, CAT, GR, and Na+,K+ ATPase activities were restored by 4-PSQ. 4-PSQ may be a good prototype for the treatment of OXA-induced renal injury.

Current jakinibs for the treatment of rheumatoid arthritis: a systematic review.

OBJECTIVE: One-third of patients with severe rheumatoid arthritis (RA) do not achieve remission or low disease activity, or they have side effects from cDMARD and bDMARD. They will need a new treatment option such as the small molecule JAK inhibitors. In this systematic review, we evaluate the efficacy and safety data of the current jakinibs: tofacitinib, peficitinib, decernotinib, upadacitinib, baricitinib and filgotinib in patients in whom treatment with conventional or biological disease-modifying antirheumatic drugs (cDMARD and/or bDMARD) failed. METHODS: We searched for randomized controlled trials comparing efficacy and safety of jakinibs for RA treatment using the Web of Science, Scopus, PubMed, and clinicaltrials.gov databases with the terms: "rheumatoid arthritis" OR "arthritis rheumatoid" OR "RA" AND "inhibitor" OR "jak inhibitor" AND "clinical trial" OR "treatment" OR "therapy". RESULTS: All jakinibs achieved good results in ACR 20, 50, 70 and with CRP-DAS28 for LDA and remission, upadacitinib showed better results compared to the others. In ESR-DAS28 for remission, tofacitinib achieved the best result. Regarding the safety of all jakinibs, peficitinib, baricitinib and filgotinib did not register deaths in their studies unlike tofacitinib that presented 11 deaths. Despite all benefits of jakinibs, the use in patients with severe liver and kidney disease should be avoided. CONCLUSIONS: Jakinibs in monotherapy or in combination with methotrexate can be considered a viable alternative in the treatment of moderate-to-severe RA. Even after failures with combination of cDMARDS and bDMARDS, jakinibs demonstrated efficacy.