Effect of erythropoietin on SOFA score, Glasgow Coma Scale and mortality in traumatic brain injury patients: a randomized-double-blind controlled trial.

Background: Recent studies suggest that erythropoietin has an anti-inflammatory effect on the central nervous system. The authors aimed to investigate the effect of erythropoietin on Glasgow Coma Scale (GCS), Sequential Organ Failure Assessment (SOFA) scores, and the mortality rate of traumatic brain injury (TBI) patients. Methods: Sixty-eight patients with available inclusion criteria were randomly allocated to the control or intervention groups. In the intervention group, erythropoietin (4000 units) was administrated on days 1, 3, and 5. In the control group, normal saline on the same days was used. The primary outcomes were the GCS and SOFA score changes during the intervention. The secondary outcomes were the ventilation period during the first 2 weeks and the 3-month mortality rate. Results: Erythropoietin administration significantly affected SOFA score over time (P=0.008), but no significant effect on the GCS, and duration of ventilation between the two groups was observed. Finally, erythropoietin had no significant effect on the three-month mortality (23.5% vs. 38.2% in the erythropoietin and control group, respectively). However, the mortality rate in the intervention group was lower than in the control group. Conclusion: Our finding showed that erythropoietin administration in TBI may improve SOFA score. Therefore, erythropoietin may have beneficial effects on early morbidity and clinical improvement in TBI patients.

Clinical uses and safety concerns of tyrosine kinase inhibitors with a focus on novel drugs: A narrative review.

Objective:To review the safety issues surrounding tyrosine kinase inhibitors (TKIs), specifically, hematological adverse effects, cardiovascular issues, renal adverse effects and nephrotoxicity, endocrine system adverse effects, concerns related to the reproductive system, dermatological and gastrointestinal adverse effects. Data Sources: A literature search was performed through Web of Science, PubMed, Google Scholar, Scopus, and the Food and Drug Administration. Data Summary: Several safety issues have been raised following the use of TKIs. Most TKIs show hematological side effects. Considering cardiovascular toxicities, as opposed to imatinib which is relatively safe, new-generation TKIs may be associated with severe cardiovascular side effects. Both acute and chronic renal failure were reported with TKIs such as gefitinib, imatinib, pazopanib, sorafenib, and sunitinib. Many endocrine adverse effects have been reported including hypercholesterolemia and hypertriglyceridemia (with lorlatinib) and thyroid dysfunction (with dasatinib). TKIs may interfere with fetus implantation, growth, and gonadal development. Females receiving TKIs and encountering unwanted pregnancy may have a normal pregnancy, miscarriage, or an abnormality in the fetus. Skin toxicity has been identified as the most debilitating adverse effect in patients receiving EGFR-TKI. Gastrointestinal side effects are common with TKIs. Diarrhea was the most frequently reported adverse effect of many TKIs. Conclusions: TKIs are increasingly taking up a critical role in the treatment of cancers due to their specific action toward malignant cells compared to conventional cytotoxic chemotherapy. Despite a dramatic improvement in the survival of patients with cancer following approval of TKIs, various early and late adverse effects were reported.

Subcutaneous Tissue Response to Adseal and Sure-Seal Root Sealers in Rats: a Histopathological Study.

Introduction and objectives: One of the essential phases of root canal treatment is root canal obturation. Solid or semi-solid materials are the most common obturating materials (paste or softened form). Sealer is a biomaterial that enables the sealing process to be carried. This study aimed to evaluate the inflammatory response to Adseal sealer and Sure-Seal Root sealer in rats. Materials and methods:This experimental study was conducted on 28 Wistar rats that were divided into four groups of seven animals per group based on four time periods (7, 14, 30 and 60 days). Each rat received subcutaneous implants containing Adseal sealer (Meta Biomed, Cheongju, Korea) and Sure-Seal Root sealer (Sure Dent Corporation, Gyeonggi-do, South Korea) tubes as well as an empty tube as a control. After the insertion of the tubes, the first to fourth groups were sacrificed on days 7, 14, 30 and 60, respectively, by injecting a high dose of anesthetics. Subsequently, the histopathologic features of the samples were investigated. Data were analyzed in SPSS software (version 26) using Freidman, Wilcoxon, Kruskal-Wallis and Mann-Whitney U tests. A p-value less than 0.05 was considered statistically significant. Results:On day 7, the severity of inflammation was higher in the Adseal sealer and Sure-Seal Root sealer groups compared to the control group. Moreover, on day 14, the level of inflammation was higher in the Sure-Seal Root sealer group than the Adseal sealer and control groups. In addition, on days 30 and 60, the severity of inflammation was similar in both the case and control groups and decreased in all samples. Formation of granulation tissue was observed in all samples on day 14. There was fibrosis tissue in the Sure-Seal Root sealer samples (71.4%) on day 60; however, no fibrosis tissue was observed in the Adseal sealer and control groups. Conclusion:It is concluded that the Sure-Seal Root sealer might lead to a more inflammatory response compared to the Ad Seal sealer. However, due to decreasing inflammation in sealers over time, both sealers are biocompatible.

Quercetin ameliorates Di (2-ethylhexyl) phthalate-induced nephrotoxicity by inhibiting NF-κB signaling pathway.

This study aimed to evaluate the possible protective effects of quercetin, a natural flavonoid, against nephrotoxicity induced by Di (2-ethylhexyl) phthalate (DEHP) in kidney tissue of rats and human embryonic kidney (HEK) 293 cell line. The HEK-293 cells were treated with different concentrations of quercetin 24 h before treatment with monoethylhexyl phthalate (MEHP). Male rats were treated with 200-mg/kg DEHP, 200-mg/kg DEHP plus quercetin (50 and 100 mg/kg), and 200-mg/kg DEHP plus vitamin E (20 mg/kg) for 45 days by gavage. Quercetin treatment reduced cytotoxicity and oxidative damage inducing by MEHP in HEK-293 cells. The in vivo findings showed that 100-mg/kg quercetin significantly suppressed DEHP-induced kidney damage. For exploring the involved mechanisms, the expressions of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) genes were determined via real-time Polymerase chain reaction (PCR) assay. High dose of quercetin significantly decreased the gene expressions of NF-κB and TNFα, whereas the alternations of Nrf2 and HO-1 gene expressions were not significant in quercetin groups in compared with DEHP group. These findings suggested that the suppression of DEHP-induced nephrotoxicity via quercetin is correlated, at least in part, with its potential to regulate NF-κB signaling pathway.

Phytochemical identification, acute and subchronic oral toxicity assessments of hydroalcoholic extract of Acroptilon repens in BALB/c mice: A toxicological and mechanistic study.

Acroptilon repens (L.) DC, commonly known as Rhaponticum repens, is a popular traditional phytomedicine. The current study was conducted to evaluate the acute and subchronic toxicity of the hydroalcoholic extract of this herb with regard to its terpenoid contents in a BALB/c mice model and to investigate the toxicity of this medicinal herb. Identification of extract components of the plant was done using gas chromatography (GC)-mass spectrometry. In order to establish the acute toxicity model, a single dose of 2000 mg/kg of the extract was given orally to male mice and in the subchronic toxicity study, the extract was consecutively administered at doses 250, 500, and 1000 mg/kg for 28 days. After 28 and 42 days, signs of toxicity and mortality were observed. Organ weight changes and the toxicity-associated parameters such as biochemical indicators, oxidative stress indices, mitochondrial parameters, apoptosis-associated gene expression levels, and pro-inflammatory cytokines were evaluated along with the histopathological examination. GC analysis showed that the terpenoids are the major components of the extract. The LD50 value (2 g/kg) was obtained in the acute toxicity assay; the subchronic administration caused a significant elevation in the serum biomarkers as well as in the levels of lipid peroxidation, protein carbonyl, and ROS. Besides, significant reductions in the superoxide dismutase and catalase activities were observed. This toxic effect was further confirmed by histological studies, cytokine assay, and gene expression assays. Following the treatment discontinuation, the abnormalities in the values of biochemical parameters and histopathological changes returned to normal. These findings demonstrate that the subchronic administration of the hydroalcoholic extract of A. repens can reversibly cause toxicity by inducing oxidative stress and mitochondrial dysfunction.

The Protective Effects of L-Carnitine and Zinc Oxide Nanoparticles Against Diabetic Injury on Sex Steroid Hormones Levels, Oxidative Stress, and Ovarian Histopathological Changes in Rat.

Diabetes mellitus is a common chronic metabolic disorder. This study aimed to investigate the effects of co-treatment with L-carnitine (LC) and zinc oxide nanoparticles (ZnONPs) on serum levels of sex hormones, oxidative stress, and ovarian histopathology in streptozotocin (STZ)-induced diabetic rats. Female Wistar rats (n = 56, 180-220 g) received a single intraperitoneal (IP) injection of STZ (65 mg/kg). They were randomly assigned into the following groups: diabetic group (Dia), Dia+Met group (100 mg metformin/kg/day), Dia+LC group (200 mg/kg/day), Dia+ZnONPs group (10 mg/kg/day), and Dia+LC+ZnONPs group (200 mg LC/kg/day and 10 mg ZnONPs/kg/day). Control group (Ctl) received the same volume of STZ solvent. After 21 days of treatment, blood serum was centrifuged for sex hormone assays. The right ovary was used for biochemical analysis, and the left ovary was fixed in 10% neutral buffered formalin for histological assessment. The levels of estradiol, progesterone, FSH, and LH significantly increased in the Dia+ZnONPs+LC group (P < 0.001) compared with the Dia group. Co-treatment with LC and ZnONPs reduced malondialdehyde and carbonyl protein and increased glutathione, catalase, and superoxide dismutase activities in ovarian tissue compared with the Dia group (P < 0.05). Moreover, the number of all ovarian follicles significantly increased in this group compared with the Dia group (P < 0.05). The results of this study indicated that co-treatment with LC and ZnONPs could preserve ovarian function by increasing sex hormones levels and antioxidant activity and decreasing lipid peroxidation in diabetic rats. Therefore, this compound supplementation may improve ovulation and fertility in people with diabetes mellitus.

The implication of mitochondrial dysfunction and mitochondrial oxidative damage in di (2-ethylhexyl) phthalate induced nephrotoxicity in both in vivo and in vitro models.

Di-(2-ethylhexyl) phthalate (DEHP) and its main metabolite, monoethylhexyl phthalic acid (MEHP), are a serious threat to human and animals' health in the current century. However, their exact mechanism to induce nephrotoxicity is not clear. In the current study, we addressed toxic effects of MEHP and DEHP on embryonic human kidney cells (HEK-293 cell line) and kidney tissue of rats, respectively. In the HEK-293, MTT assay and oxidative stress parameters were measured after treatment with different concentrations of MEHP. For in vivo study, rats were treated with different doses of DEHP (50, 100, 200, 400 mg/kg) via gavage administration for 45 days. The renal function biomarkers (BUN and creatinine) were determined in serum of rats. Mitochondrial toxic parameters including MTT, mitochondrial membrane potential (MMP), mitochondrial swelling, and also oxidative stress parameters were measured in isolated kidney mitochondria. Histopathological effects of DEHP were also evaluated in rats' kidneys. We demonstrated that MEHP induced oxidative stress and cytotoxicity in HEK-293 cells in a concentration dependent manner. The administration of DEHP led to histopathological changes in kidney tissue, which concurred with BUN and creatinine alternations in serum of rats. The results of present study showed a significant mitochondrial dysfunction and oxidative stress confirmed by enhancement of mitochondrial swelling, mitochondrial reactive oxygen species (ROS) and malondialdehyde (MDA), and reduction of MMP and mitochondrial glutathione (GSH). Taken together, this study showed that DEHP/MEHP resulted in mitochondrial dysfunction and oxidative damage, which suggest a vital role of mitochondria in DEHP/MEHP-induced nephrotoxicity.

Effect of Prunus Mahaleb L. Seed Extract on Ethylene glycol- and Ammonium Chloride-Induced Urolithiasis in BALB/c Mice.

BACKGROUND: Kidney stone disease can be quite painful, recurrent, and affects many people. Despite advances in drug therapy, there is still a need to find effective drugs with fewer complications for long-term treatment of kidney stones and to prevent its recurrence. The present study aimed to evaluate the effect of Prunus Mahaleb L. seed extract on ethylene glycol- and ammonium chloride-induced urolithiasis in BALB/c mice. METHODS: The Prunus Mahaleb L. seeds were collected in Mashhad (Iran) in June 2017. Urolithiasis was induced in male BALB/c mice by adding ethylene glycol (EG) 0.75% (v/v) and ammonium chloride (AC) 2% (w/v) to their drinking water for 21 consecutive days. A total of 72 animals were randomly divided into six groups of twelve animals each. Group 1 received purified water as control; group 2 received EG+AC in drinking water; groups 3-5 received the extracts by gavage in dosages of 100, 300, 500 mg/kg body weight, respectively; and group 6 received 888 mg/kg Sankol by gavage. Note that urolithiasis was induced in groups 3-6 in the same manner as in group 2. The data were analyzed using GraphPad Prism Software (version 5.01). RESULTS: The group receiving Prunus Mahaleb L. extract in a 500 mg/kg dose responded better to the treatment and less damage to the kidney tissue was observed. The serum parameters remarkably decreased in the calculi-induced animals. Besides, the acute toxicity test showed that the use of the extract was safe in animals. CONCLUSION: The results showed that the use of Prunus Mahaleb L. extract effectively prevented the formation of kidney stones.

Doxorubicin and liposomal doxorubicin induce senescence by enhancing nuclear factor kappa B and mitochondrial membrane potential.

AIMS: Senescence is a state ensuing aging to eliminate age-associated damage with an irreversible cell-cycle arrest mechanism, which is historically believed to be one of the tumor responses to therapy. Doxorubicin as an anti-cancer drug has been used in cancer treatment for a long time. Liposomal doxorubicin (Ldox) is a liposomal formulation of doxorubicin, which increases the doxorubicin permanency. The aim of this study was to examine the toxicity of these two formulations by comparing them in terms of their ability to induce cellular senescence. MAIN METHODS: The study groups included a control group, three DOX (0.75, 0.5, 0.1 mg/kg/BW) and three Ldox groups (0.1, 0.05, 0.025 mg/kg/BW). Heart tissues were studied regarding oxidative stress assessment, mitochondrial function, inflammatory markers and biochemical and histopathological evaluation. Real-Time PCR was used for P53 and SA ß-gal expression. KEY FINDINGS: Based on the results, the highest doses of Dox and Ldox (0.75 and 0.1 mg/kg/BW respectively) significantly increased the level of inflammatory markers and according to other factors especially p53 and SA ß-gal expression, both were able to induce senescence but the changes in Ldox were less tangible than the Dox.

Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model.

Cyclophosphamide (CP), as a chemotherapy drug, induces hepatotoxicity through causing oxidative stress. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties. The present study was designed to investigate the protective effects of ATV against CP-induced hepatotoxicity in rat. In this experimental study, 32 rats were treated with ATV orally at a dose of 10 mg/kg for 10 consecutive days, 5 days before and 5 days after the administration of a single intraperitoneal injection of CP (150 mg/kg). The hepatoprotective effect of ATV was evaluated by measuring liver function markers, oxidative markers, histological and immunohistochemical assays. The biochemical results showed that administration of CP increased hepatic biomarkers enzymes as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels. CP increased malondialdehyde (MDA), protein carbonyl (PC) and decreased glutathione (GSH) content in rats. Moreover, administration of CP was associated with periportal leucocyte infiltration, dilation sinusoids, hepatocyte vacuolation, congestion and hemorrhage in livers of rats. CP significantly increased immunoreactivity of caspase-3 as a marker of apoptosis in liver tissue. ATV markedly mitigated liver injury through reduction in oxidative stress biomarkers, histopathological findings and apoptosis. The antioxidant and anti-apoptotic activities of ATV are main proposed mechanisms involved in its hepatoprotective effects against CP-induced hepatic injury.

Atorvastatin attenuates the ovarian damage induced by cyclophosphamide in rat: An experimental study.

BACKGROUND: Cyclophosphamide (CP), as an anticancer agent, causes ovarian toxicity and subsequent infertility in women. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties. OBJECTIVE: The aim of this study was to investigate the protective effect of ATV against CP-induced ovarian injury in rat. MATERIALS AND METHODS: In this experimental study, thirty-two female Wistar rats were randomly divided into four groups as I) control, II) ATV (10 mg/kg), III) CP (150 mg/kg), and IV) CP +ATV. The ATV treated groups were received ATV for 10 days via oral gavage. In the CP+ATV group, ATV was administrated on 5 days before and 5 days after CP injection. Histological structure, apoptosis (caspase-3), oxidative stress parameters as malondialdehyde, reactive oxygen species, protein carbonyl levels and cell viability were evaluated in ovary tissue by histological scores, immunohistochemistry, histochemical and biochemical assays. The levels of estrogen and progesterone hormones were measured on the 12th day of study. RESULTS: ATV pretreatment significantly decreased the levels of oxidative stress biomarkers as malondialdehyde, reactive oxygen species and protein carbonyl levels and increased cell death in CP-treated rats as compared with the CP alone group. ATV significantly increased estrogen and progesterone levels in CP-treated rats. In addition, the histological examination showed ATV mitigated acute inflammation, degenerative cells in stroma and follicles, stromal edema, vacuolization, atresia of the follicles and congestion of blood vessels in the CP-treated animals. Furthermore, ATV significantly reduced immunoreactivity level of caspase-3 in CP-treated rats. CONCLUSION: Our results showed that the ATV with antioxidant and anti-apoptosis (caspase-3) activities protected ovarian against CP-induced toxicity.

Coenzyme Q10 remarkably improves the bio-energetic function of rat liver mitochondria treated with statins.

CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase. Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans. However, their long-term administration is associated with a variety of myopatic complaints. The aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet (HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not? Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The first group considered as regular control and fed with a RD. Groups 2-7 including HFD control, CoQ10 (10mg/kg), simvastatin (30mg/kg), atorvastatin (30mg/kg), simvastatin+CoQ10 or atorvastatin+CoQ10 treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood samples were collected for biochemical examinations. The rat liver mitochondria were isolated and several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined. We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels. Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment and improved by co-administration with CoQ10.