Betaine alleviates doxorubicin-related cardiotoxicity via suppressing oxidative stress and inflammation via the NLRP3/SIRT1 pathway.

Cardiotoxicity is one of the side effects of the anti-cancer drug doxorubicin (DOX) that limits its clinical application. Betaine (BT) is a natural agent with promising useful effects against inflammation and oxidative stress (OS). We assessed the effects of BT on DOX-induced cardiotoxicity in mice. Forty-two male NMRI mice were assigned to six groups: I: control; II: BT (200 mg/kg; orally, alone); III: DOX (2.5 mg/kg; six injections (ip)) for two weeks; IV, V, VI: BT (50 mg/kg, 100 mg/kg, and 200 mg/kg; orally, once a day for two weeks, respectively) plus DOX administration. The cardiac enzymes like cardiac troponin-I (cTn-I), lactate dehydrogenase (LDH), and creatine kinase-MB (CK-MB) were assessed in serum. Oxidative/inflammatory markers like nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione level (GSH), and glutathione peroxidase (GPx) activities were determined in cardiac tissue. The expressions of NOD-like receptor protein 3 (NLRP3), caspase-1, interleukin (IL)-1ß, and silent information regulator 1 (SIRT1) proteins were also evaluated in cardiac tissue. The results indicated that DOX significantly increased LDH, CK-MB, cTn-I, MDA, and NO levels and also the caspase-1, NLRP3, and IL-1ß expression. Furthermore, DOX caused a significant reduction in the GSH levels and SOD, CAT, GPX activities, and the expression of SIRT1 protein in heart tissue. However, BT significantly improved all studied parameters. The findings were confirmed by histopathological assessments of the heart. BT can protect against DOX-induced cardiotoxicity by suppressing the activation of NLRP3 and OS by stimulating the SIRT1 pathway.

Betaine ameliorates arsenic-induced kidney injury in mice by mitigating oxidative stress-mediated inflammation.

Arsenic, an environmental pollutant and poisonous metalloid, has adverse effects on different body organs, including the kidneys. Betaine is a natural nutrient that has many beneficial health effects. This research was conducted to examine the impact of betaine on nephrotoxicity caused by inorganic arsenic (NaAsO2) in mice. Mice were separated into following groups: control, NaAsO2 (50 ppm), NaAsO2 (50 ppm) + betaine (500 mg/kg), and betaine (500 mg/kg). Mice were received NaAsO2 via drinking water for 8 consecutive weeks and betaine was given to the animals via gavage once daily in the 7th and 8th weeks of the study. Upon completion of the study, the mice were euthanized and samples of serum and kidney were obtained for further evaluations. Administration of NaAsO2 increased the levels of blood urea nitrogen and creatinine in the serum. It enhanced the amounts of renal malondialdehyde and decreased the total thiol levels, as well as the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). Furthermore, it enhanced the levels of renal inflammatory indicators (tumor necrosis factor-alpha and nitric oxide). Western blot results exhibited an increase in the protein expression of nuclear factor kappa B (NF-κB), and phosphorylated NF-κB in NaAsO2-treated mice. Histopathological results also confirmed kidney damage caused by NaAsO2. However, treatment with betaine improved NaAsO2-related kidney injuries in mice. The results of this work indicated that betaine can attenuate kidney damage caused by NaAsO2 by inhibiting oxidative stress and inflammation.

Protective effects of diosmin on doxorubicin-induced testicular toxicity in rat.

Doxorubicin (DOX) can be applied to treat several cancers. DOX-induced oxidative stress causes testicular damage. Diosmin (DIO), as a potent antioxidant, reduces many drugs' side effects. We determined DIO therapeutic effects on DOX-related testicular toxicity. Forty rats were assigned to five groups as control, DOX (2.5 mg/kg six i.p. injections at equal intervals over two weeks), DOX + DIO (25, 50, 100 mg/kg, orally, daily, for two weeks) groups. Oxidative and antioxidant markers, fertility parameters levels, sperm parameters, and a histopathological examination were analyzed. DOX group showed a significant decrease in the number of spermatogonia, primary spermatocytes, and sertoli cells, seminiferous tubular diameter, seminiferous luminal diameter, and seminiferous epithelial height. Moreover, testosterone levels, glutathione (GSH) levels, catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities showed a significant decrease. Furthermore, nitric oxide (NO) and malondialdehyde (MDA) contents and also follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels showed a significant increase in the DOX group compared to the control group. DIO improved DOX-related alterations in levels of hormones, spermatogonia, spermatocytes, and sertoli cell number, and seminiferous diameters (tubular, luminal, and epithelial height). Furthermore, GSH level, SOD, GPx, and CAT activities showed a significant increase, and MDA and NO contents showed a significant decrease in the DOX + DIO group than the DOX group. The results indicate that DIO mitigate DOX-induced testicular toxicity by its anti-oxidant activity.

Neuroprotective effects of dimethyl fumarate against manic-like behavior induced by ketamine in rats.

Medications for treating bipolar disorder (BD) are limited and can cause side effects if used chronically. Therefore, efforts are being made to use new agents in the control and treatment of BD. Considering the antioxidant and anti-inflammatory effects of dimethyl fumarate (DMF), this study was performed to examine the role of DMF on ketamine (KET)-induced manic-like behavior (MLB) in rats. Forty-eight rats were randomly divided into eight groups, including three groups of healthy rats: normal, lithium chloride (LiCl) (45 mg/kg, p.o.), and DMF (60 mg/kg, p.o.), and five groups of MLB rats: control, LiCl, and DMF (15, 30, and 60 mg/kg, p.o.), which received KET at a dose of 25 mg/kg, i.p. The levels of total sulfhydryl groups (total SH), thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α), as well as the activity of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the prefrontal cortex (PFC) and hippocampus (HPC), were measured. DMF prevented hyperlocomotion (HLM) induced by KET. It was found that DMF could inhibit the increase in the levels of TBARS, NO, and TNF-α in the HPC and PFC of the brain. Furthermore, by examining the amount of total SH and the activity of SOD, GPx, and CAT, it was found that DMF could prevent the reduction of the level of each of them in the brain HPC and PFC. DMF pretreatment improved the symptoms of the KET model of mania by reducing HLM, oxidative stress, and modulating inflammation.

Dimethyl fumarate attenuates paraquat-induced pulmonary oxidative stress, inflammation and fibrosis in mice.

Paraquat (PQ) is the most important cationic bipyridyl herbicide in the agricultural industry, which is very toxic to humans and animals and causes disruption in many organs, mainly in the lungs. Dimethyl fumarate (DMF) is an immune-modulating drug used in the treatment of multiple sclerosis and psoriasis shows antioxidant, anti-inflammatory, and antifibrotic effects. In this study, the ameliorative effects of DMF (10, 30 and 100 mg/kg, orally) on PQ (30 mg/kg) model of lung damage were evaluated in male mice. DMF was given daily for 7 days and PQ was administrated in the fourth day in a single dose. On the eighth day, the animals were sacrificed, and their lung tissue were removed. The results indicated that DMF can ameliorate PQ-induced the significant increase in lung index, hydroxyproline, as well as TBARS, TGF-ß, NF-κB and decrease in the amount of total thiol, catalase, glutathione peroxidase, superoxide dismutase, Nrf-2, and INF-γ. The histopathological results confirmed indicated findings. The results showed that the protective effect of DMF on PQ-induced toxicity is mediated through antioxidant, anti-inflammatory and antifibrotic activities.

Diosmin prophylaxis reduces gentamicin-induced kidney damage in rats.

Gentamicin is an essential aminoglycoside antibiotic, but it is only used to treat severe bacterial infections due to its high nephrotoxicity in patients. We evaluated the preventive effects of diosmin (as a natural ingredient) on gentamicin-related kidney damage in rats. In this research, 28 male Wistar rats were divided into four groups: control, gentamicin (100 mg/kg (i.p.), daily for 1 week), gentamicin plus diosmin (50 mg/kg, p.o., daily for 2 weeks), and diosmin (50 mg/kg/day, p.o. for 2 weeks). After the final gavage, blood samples were collected for the determination of blood urea nitrogen (BUN) and creatinine. Kidneys are used for biochemical, inflammatory, and histological tests. The concentrations of creatinine, BUN, nitric oxide, malondialdehyde, tumor necrosis factor α (TNF-α), and interleukin 1 beta (IL-1ß) were significantly increased. But, the level of glutathione and activities of catalase, glutathione peroxidase, and superoxide dismutase decreased during treatment with gentamicin. On the other hand, the concentrations of creatinine, BUN, nitric oxide, malondialdehyde, TNF-α, and IL-1ß were significantly reduced, and the glutathione level, activities of catalase, and glutathione peroxidase were significantly increased via co-administration with diosmin. Diosmin had ameliorative impacts against gentamicin-related kidney injury due to its antioxidant and anti-inflammatory activities.

Protective effects of berberine as a natural antioxidant and anti-inflammatory agent against nephrotoxicity induced by cyclophosphamide in mice.

PURPOSE: Cyclophosphamide is an alkylating agent with nephrotoxicity that constrains its clinical application. Berberine is an isoquinoline derivative alkaloid with biological functions like antioxidant and anti-inflammatory. The current research intended to examine the nephroprotective impacts of berberine against cyclophosphamide-stimulated nephrotoxicity. METHODS: Forty animal subjects were randomly separated into five categories of control (Group I), cyclophosphamide (200 mg/kg, i.p., on 7th day) (Group II), and groups III and IV that received berberine 50 and 100 mg/kg orally for seven days and a single injection of cyclophosphamide on 7th day. Group V as berberine (100 mg/kg, alone). On day 8, blood samples were drawn from the retro-orbital sinus to determine serum levels of blood urea nitrogen (BUN), creatinine (Cr), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) as biomarkers for kidney injury. Nitric oxide (NO), malondialdehyde (MDA) and glutathione (GSH) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities as oxidative stress factors, tumor necrosis factor-α (TNF-α) and interleukin 1 beta (IL-1ß) levels as inflammatory mediators were assessed in kidney tissue. RESULTS: The results of this study demonstrated that berberine was able to protect remarkably the kidney from CP-induced injury through decreasing the level of BUN, Cr, NGAL, KIM-1, NO, MDA TNF-α, IL-1ß and increasing the level of GSH, CAT, SOD, and GPx activities. CONCLUSION: Berberine may be employed as a natural agent to prevent cyclophosphamide-induced nephrotoxicity through anti-oxidant and anti-inflammatory effects.

Pretreatment with Gallic Acid Mitigates Cyclophosphamide Induced Inflammation and Oxidative Stress in Mice.

BACKGROUND: Cyclophosphamide (CP) as an alkylating compound has been widely applied to treat cancer and autoimmune diseases. CP is observed to be nephrotoxic in humans and animals because it produces reactive oxygen species. Gallic Acid (GA), a polyhydroxy phenolic compound, is reported to exhibit antioxidant and anti-inflammatory effects. OBJECTIVE: The current research aimed at evaluating the GA effect on CP-related renal toxicity. METHODS: In total, 35 male mice were assigned to 5 groups. Group1: receiving normal saline, group 2: CP group, receiving one CP injection (200 mg/kg; i.p.) on day 6. Groups 3 and 4: GA+CP, GA (10 and 30 mg/kg; p.o.; respectively) received through six consecutive days plus CP on the 6th day 2 hr after the last dose of GA, group 5: received GA (30 mg/kg; p.o.) for six consecutive days. Then on day 7, blood samples were collected for determining Creatinine (Cr), serum kidney injury molecule-1 (KIM-1), Blood Urea Nitrogen (BUN), and Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentrations. Malondialdehyde (MDA), Nitric Oxide (NO) concentration, Catalase (CAT), Superoxide Dismutase (SOD), Glutathione (GSH), Glutathione Peroxidase (GPx) activities, and IL-1ß, TNF-α levels were assessed in renal tissue. RESULTS: CP administration significantly increases KIM-1, NGAL, Cr, BUN, MDA, NO, IL-1ß, and TNF-α level. It also decreases GSH concentration, SOD, GPx, and CAT function. Pretreatment with GA prevented these changes. Histopathological assessments approved the GA protective effect. CONCLUSION: Our results showed that GA is possibly effective as a protective agent in cyclophosphamide- associated toxicities.

Berberine ameliorates testosterone-induced benign prostate hyperplasia in rats.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a major urologic problem that mostly develops in older males. Oxidative stress and inflammation influence the occurrence of BPH. Berberine (BBR) is a natural ingredient that has antioxidant and anti-inflammatory properties. The current research aims at examining the effects of BBR on testosterone-stimulated BPH in rats. METHODS: Animals were randomly categorized to six groups. In the control group, normal saline and olive oil were injected as the vehicle. BPH group: received testosterone (3 mg/kg, subcutaneous, 28 days), BPH + BBR groups; received BBR (25 and 50 mg/kg, p.o, 28 days), BPH + finasteride groups: received finasteride (1 mg/kg, p.o, 28 days), BBR (50 mg/kg, p.o, alone) was administered for subjects in the BBR group. On the 29th day, after anesthesia, cervical dislocation was used to kill the subjects. Serum concentration of testosterone and dihydrotestosterone was measured and prostate tissues were excised and used for biochemical, inflammation, and histological analysis. RESULTS: BBR prevented increased serum concentrations of testosterone and dihydrotestosterone. BBR considerably reduced BPH-stimulated oxidative stress and inflammation through preventing the rise in lipid peroxidation and nitrite concentration and declined the accumulations of pro-inflammatory cytokines (e.g. interleukin 1ß and tumor necrosis factor α) and declining the depletion rate of GSH and the function of catalase and superoxide dismutase. Histopathological investigations reported that administration of BBR could suppress testosterone-stimulated BPH. CONCLUSION: This study demonstrated that BBR could significantly prevent the development of BPH in rats.

Carnosol attenuates bleomycin-induced lung damage via suppressing fibrosis, oxidative stress and inflammation in rats.

AIMS: Bleomycin, an important toxic anti-cancer agent, induces pulmonary fibrosis. The significance of oxidative stress and inflammation in promoting of bleomycin-induced idiopathic pulmonary fibrosis (IPF) has been reported. Thus, we evaluated the protective effects of carnosol as a robust natural antioxidant and anti-inflammatory agent for bleomycin-related IPF in rats. MAIN METHODS: Male Wistar rats (n = 40) were randomly assigned to five groups. Group 1 was administrated with saline (intratracheally) on day 7 and oral gavage of dimethyl sulfoxide (DMSO, 0.05%) from day 1 to day 28. Group 2 received a single dose of bleomycin (intratracheally, 7.5 UI/kg) on day 7 and oral gavage of saline for 28 days. Groups 3, 4 and 5 were administrated with bleomycin (single dose) on day 7, along with oral administration of carnosol (at doses 10, 20 and 40 mg/kg, respectively) from day 1 to day 28. The lungs were isolated to measure the histopathological and biochemical and inflammatory markers. KEY FINDINGS: Carnosol treatment significantly reduced malondialdehyde, nitric oxide, protein carbonyl, tumor necrosis factor- α, interleukin-6 levels and myeloperoxidase activity in the lungs of rats exposed to bleomycin. Also, lung glutathione content, catalase, glutathione peroxidase and superoxide dismutase activities significantly increased in the carnosol/bleomycin-treated group than the bleomycin group. Lung index, hydroxyproline content, fibrosis and histopathological changes, also significantly decreased by carnosol therapy. SIGNIFICANCE: Treatment with carnosol can modulate biochemical and histological alterations caused by bleomycin. Thus, it can be regarded as an appropriate therapeutic approach for IPF.

Epicatechin ameliorative effects on methotrexate-induced hepatotoxicity in mice.

BACKGROUND: Due to the fact that methotrexate is widely used both as an immunosuppressive drug and as a chemotherapy agent, many studies are needed to reduce the side effects of this drug on non-target organs. PURPOSE: This study was designed to investigate the effects of epicatechin (Epi) on MTX (methotrexate)-induced hepatotoxicity in mice. RESEARCH DESIGN: After 1 week for adaptation, we randomly divided 42 male Naval Medical Research Institute mice into six groups: (I) control; (II) Epi (100 mg/kg, po); (III) MTX (20 mg/kg, i.p.) on the fifth day; and (IV, V, and VI) Epi (25, 50, and 100 mg/kg, po) + MTX (20 mg/kg, i.p.) on the fifth day. At day 10, the mice were sacrificed and serum factors, oxidative stress markers, and inflammatory cytokines were measured. RESULTS: MTX increased activity level of serum enzymes (alanine aminotransferase and aspartate aminotransferase), lipid peroxidation marker (malondialdehyde), and inflammatory factors including interleukin-1 beta, tumor necrosis factor-alpha, and nitric oxide. Furthermore, MTX decreased glutathione level and activity level of catalase, superoxide dismutase, and glutathione peroxidase. Epi was able to reduce the destructive effects of oxidative/antioxidant system imbalance and inflammatory reactions and also histopathological damage in MTX intoxicated mice. Epi pretreatment reduced liver dysfunction by improving the antioxidant defense system, anti-inflammatory effects, and alleviation of histopathological damage in MTX hepatotoxicity. CONCLUSIONS: Accordingly, Epi can be used as a therapeutic agent in hepatotoxicity associated with MTX chemotherapy.

Anticancer Effects of Valproic Acid via Regulation of Epigenetic Mechanisms in Non-small-cell Lung Cancer A549 Cell Line.

Epigenetic mechanisms are the most important factors contributing to both the development and metastasis of cancer cells. We aimed to scrutinize the role of epigenetic alternations of genes involved in cancer metastasis, including CD44v6 (metastasis indicator) and Nm23-H1 (a novel tumor suppressor), in the A549 lung cancer cell line. The A549 cells were cultured in the DMEM medium. Valproic acid (VPA) was used as a histone deacetylase inhibitor. Caspase-3 activity was assessed by adding DEVD-pNA substrate to the cell lysate. Gene expression was determined by real-time PCR. Finally, protein expression was assessed by western blot. The results showed that VA significantly decreased the expression of the CD44v6 gene and its protein level. This was further accompanied by lower expressions of MMP-2 and MMP-9 genes. On the other hand, the expression of Nm23-H1 and its protein were significantly increased in the cells accompanied by higher activity of caspase-3 (P ˂ 0.05). Our results showed that epigenetic regulation of CD44v6, Nm23-H1, MMP-2, and MMP-9 might be involved in the pathogenesis and metastasis of lung cancer. Therefore, the use of histone deacetylase inhibitors can be effective in the suppression of metastases and the treatment of these tumors.

Protective effects of apigenin on altered lipid peroxidation, inflammation, and antioxidant factors in methotrexate-induced hepatotoxicity.

Methotrexate (MTX) is used as an effective chemotherapeutic agent against autoimmune diseases and tumors. Oxidative stress and inflammation are involved in the pathogenesis of MTX-induced damage. This study aimed at examining the ameliorating effects of apigenin (API) as a natural antioxidant on MTX-induced hepatotoxicity. The rats were classified into four groups: group I: normal saline-treated, group II: MTX-treated (20 mg/kg, ip, single dose at day 7), group III: MTX + API-treated (20 mg/kg, po), and group IV: API-treated. API was administrated for 9 days. Alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) were used as biochemical factors of MTX-induced hepatic injury. In hepatic tissues, the levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), and activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as oxidative stress markers along with inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1ß) were assessed. Our results showed that MTX administration significantly increased ALP, ASP, ALT, MDA, NO, TNF-α, and IL-1ß levels and significantly decreased antioxidant factors such as GSH, CAT, GPx, and SOD. The API pretreatment group showed a significant rise in hepatic antioxidant markers, besides significant reductions in the serum levels of AST, ALT, and ALP and hepatic content of MDA, TNF-α, NO, and IL-1ß. In addition, the hepatoprotective effect of API was confirmed by histological evaluation of the liver. API can prevent MTX-induced hepatotoxicity through mitigation of oxidative stress and inflammation.

Alleviation of Liver Dysfunction, Oxidative Stress and Inflammation Underlies the Protective Effect of Ferulic Acid in Methotrexate-Induced Hepatotoxicity.

INTRODUCTION: In multiple studies, involvement of oxidative stress in the pathogenesis of methotrexate (MTX)-mediated liver damage has been confirmed. Use of many drugs has been examined experimentally in order to prevent or diminish oxidative stress. However, no study has yet examined the effects of ferulic acid (FA) on MTX-induced liver damage. This study aimed at evaluating the effects of FA on protection against liver damage induced by MTX in mice. MATERIALS AND METHODS: In this the mice were divided into five groups in a random manner: I) control; II) MTX (20 mg/kg); III and IV) FA (50 and 100 mg/kg) + MTX; and V) FA (100 mg/kg), and we measured serum factors, oxidative stress and inflammatory factors. RESULTS: In the MTX group, accumulation of inflammatory cells, accumulation of red blood cell (RBC), and nuclear pyknosis (NP) were detected in the liver. In line with the histological data, the levels of nitric oxide (NO), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α increased (TNF-α), whereas the reduced glutathione (GSH), catalase (CAT), total antioxidant capacity (TAC), superoxide dismutase (SOD), and glutathione peroxidase (GPx) content reduced in the MTX group. However, FA ameliorated these hazardous effects in the antioxidant and anti-inflammatory systems in MTX-treated groups. CONCLUSION: Based on our findings, oxidative stress impairment and MTX-induced liver damage were ameliorated following FA pretreatment at both histological and biochemical levels. Therefore, FA can be effectively used in abrogation of MTX-induced toxicity.

Protective effect of alpha-lipoic acid on di-(2-ethylhexyl) phthalate-induced testicular toxicity in mice.

Phthalates are synthetic chemicals, widely used as plasticizers due to their flexibility in plastics. Human populations may be exposed to phthalates through direct contact or environmental contamination. Most studies have focused on the effects of phthalates on the reproductive tract and have classified these compounds as endocrine disruptors. In this study, we aimed to investigate the possible oxidative damage induced by di-(2-ethylhexyl) phthalate (DEHP) in the mouse testis and to evaluate the regulatory effects of alpha-lipoic acid (LA). For this purpose, forty male mice were divided into four experimental groups. Group I received normal saline (2 mL/kg; p.o.) and corn oil (5 mL/kg; p.o.) as the control group, group II received DEHP (2 g/kg; p.o.), group III received DEHP and LA (20 mg/kg; p.o.), and group IV was treated with LA alone; treatments continued for 2 weeks. The glutathione level (GSH), as well as glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities, was determined in mice. In addition, serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, interleukin-1ß (IL-1ß), and tumor necrosis factor-alpha (TNF-α) were measured. Nitric oxide (NO) level, malondialdehyde (MDA) level, sperm characteristics, and histological changes of the testes were also evaluated. The results showed that 2 g/kg of DEHP could significantly decrease the sperm motility. Based on our findings, DEHP significantly reduced the production and count of sperms; these toxic effects were associated with alterations in the serum hormone levels. In the DEHP group, a significant reduction was reported in the serum testosterone, FSH, and LH levels. LA improved DEHP-induced changes in hormonal levels and sperm index. According to our findings, treatment with DEHP triggered histopathological changes and oxidative stress, which were normalized by LA pretreatment. In conclusion, DEHP disrupts the testicular function in rats, at least partly through induction of oxidative stress. On the other hand, LA exhibits potential protective effects on testicular toxicity induced by DEHP.

Tropisetron attenuates tumor growth and progression in an experimental model of mouse lung cancer.

The antineoplastic effects of 5-hydroxytryptamine (5-HT) receptor antagonists have been shown in previous studies. However, the exact underlying mechanisms mediating these antineoplastic effects are unclear. In the present study, we assessed the antineoplastic effects of tropisetron, a 5-HT receptor antagonist, in an experimental model of lung cancer in BALB/c mouse. Lewis lung carcinoma cell line was used to induce lung cancer. Mice were divided into four groups (n = 6) as follows: tumor-bearing mice + tropisetron (5 mg/kg intraperitoneally [IP]), tumor-bearing mice + tropisetron (10 mg/kg IP), tumor-bearing mice + saline, healthy mice + tropisetron (10 mg/kg). Tumor burden, interferon-γ (IFN-γ), interleukin (IL)-4, pathological response, Ki-67, and E-cadherin were assessed using enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Comet assay was used to assess DNA toxicity. Tropisetrone-treated animals (either 5 or 10 mg/kg) showed significantly lower tumor sizes at the day 24th after tumor induction. Tropisetron received animals also showed significantly higher levels of IFN-γ, E-cadherin, pathologic response, and necrotic cells compared to the saline-treated counterparts. In addition, the levels of IL-4, and Ki-67 were significantly lower in tropisetrone treated mice in comparison with control. Furthermore, tropisteron coadministration signifcantly reduced H2 O2 -induced DNA toxicity while treatment with tropisteron alone showed no adverse effect on DNA. Tropisetrone can be used as a potential antineoplastic drug in lung cancer. This agent can promote its antineoplastic effects in part through modulating inflammatory and proliferating markers.

The Utility of Leukocyte Esterase Strip Test in the Diagnosis of Pediatric Septic Arthritis.

BACKGROUND: Most tests used to diagnose pediatric septic arthritis are either not accurate or do not produce rapid results. A leukocyte esterase (LE) strip test has previously been validated for the diagnosis of adult native and periprosthetic joint infections. The purpose of this prospective study was to: (1) evaluate the performance characteristics of the LE strip test in the diagnosis of pediatric septic arthritis and (2) determine the false positive rate of LE strip test on the aseptic synovial fluid (SF). METHODS: Between May 2016 and November 2018, SF was obtained from children who were hospitalized at our tertiary referral center on the basis of suspicion of septic arthritis. All patients underwent arthrocentesis, and the aspirate was tested with LE strip test, leukocyte count, and culture. Twenty-five patients satisfied the inclusion criteria. For the second part of the study, SF from 25 children undergoing surgery for developmental dysplasia of the hip was collected and tested with LE strip test, leukocyte count, and culture. RESULTS: In the first part of this study, 19 joints were classified as septic and 6 as aseptic. Considering a positive LE strip test ("++" and "+++" readings) indicative of septic arthritis yielded a sensitivity of 100%, specificity of 83%, positive predictive value of 95%, and negative predictive value of 100%. In the second part, all 25 patients with an aseptic SF had a negative test result ("-" and "+" readings). CONCLUSIONS: The LE strip test seems to be a valuable additional tool in the diagnosis of pediatric septic arthritis. The LE strip test has the advantages of being inexpensive and simple, providing real-time results and having a perfect negative predictive value to rule out the diagnosis of septic arthritis. LEVEL OF EVIDENCE: Level II-diagnostic.

Crocin ameliorates methotrexate-induced liver injury via inhibition of oxidative stress and inflammation in rats.

BACKGROUND: Methotrexate (MTX) is used commonly in the treatment of various cancers and inflammatory diseases; nevertheless, the associated hepatotoxicity has limited its clinical application. Crocin (CRO) is described as a natural carotenoid with analgesic, antioxidant, and antiinflammatory properties. This study aimed to determine the effects of CRO on MTX-induced hepatotoxicity. METHODS: For pretreatment, CRO at doses of 25 and 50 mg/kg (po), as well as 20 mg/kg (ip) of MTX, was injected in rats. RESULTS: MTX led to hepatotoxicity, as confirmed by the significant increase in liver markers, histopathological changes, decreased GSH content, and reduced antioxidant enzyme activity (i.e., CAT, SOD, and GPx). It increased TNF-α, IL-1ß, lipid peroxidation, and nitric oxide levels. Nevertheless, by increasing antioxidant defense in hepatic tissues and reducing oxidative stress and proinflammatory mediators, pretreatment with CRO could alleviate hepatotoxicity. CONCLUSION: CRO can inhibit MTX-induced hepatotoxicity through improving antioxidant defense and reducing oxidative stress and inflammation.

Epicatechin protective effects on bleomycin-induced pulmonary oxidative stress and fibrosis in mice.

Lung fibrosis is a chronic and intermittent pulmonary disease, caused by damage to the lung parenchyma due to inflammation and fibrosis. Epicatechin (Epi) as a flavonoid has antioxidant and anti-inflammatory properties. This study was conducted to evaluate the effect of Epi on oxidative stress, inflammation and pulmonary fibrosis induced by bleomycin (BLM) in mice. Accordingly, animals were randomly assigned into two groups of 7 and 14 days to evaluate the role of Epi in the early oxidative and late fibrotic phases of BLM-induced pulmonary injury, respectively. Each group was divided into six subgroups include control, Epi 100 mg/kg, BLM, and BLM groups pretreated with 25, 50 and 100 mg/kg Epi, respectively, from three days before until 7 or 14 days after BLM. Lung tissue oxidative stress markers including the activity of superoxide dismutase, glutathione peroxidase, catalase and the levels of malondialdehyde and glutathione were determined. Furthermore, alveolitis and inflammation were evaluated by Szapiel grading scores. In addition, fibrotic markers including lung hydroxyproline content, level of transforming growth factor beta and Ashcroft fibrotic grading of lung fibrosis were examined. Epi exerted protective effects against BLM-induced pulmonary injury in a dose-dependent manner in two early and late phases of lung injury. Oxidative stress markers persisted until the late fibrotic phase, as pro-fibrotic events were present in the early oxidative phase of BLM-induced injury. Finally, it is concluded that Epi can protect the lung against BLM-induced pulmonary oxidative stress, inflammation and fibrosis.

The Outcome of Salter Innominate Osteotomy for Developmental Hip Dysplasia before and after 3 Years Old.

BACKGROUND: Developmental dysplasia of the hip (DDH) is one of the most important and challenging conditions in the field of pediatric orthopedics; if not diagnosed and treated in time, it would lead to remarkable morbidity. Methods of treatment based on the patient's age can vary. The aim of this study is to compare the outcomes of Salter osteotomy surgery in two groups of patients under and over three years old. METHODS: In this retrospective study, medical records of patients who had undergone innominate Salter osteotomy, within the past ten years, due to non-pathological DDH were collected. Mean follow up of all patients is 70.28 months (min=25, max=118). RESULTS: eventy patients were selected including 85 operated hips. Radiological satisfaction based on modified Severin score system rate was 86% and 85% for lower three years old group and second group, respectively. In clinical assessment, it was found that results in 82% of the patients under 3 years old and 82.9% of patients older than three years old were satisfactory. There was no statistically significant difference between the two groups based on Modified MacKay criterion. CONCLUSION: Results in both groups of patients under and over 3 years old were found satisfactory. Difference in patient satisfaction rates based on clinical and radiological outcomes was not statistically significant between the two groups. It should also be noted that complications such as redislocation and deep wound infection would cause poor clinical and radiological outcomes.