Foretinib, a c-MET receptor tyrosine kinase inhibitor, tackles multidrug resistance in cancer cells by inhibiting ABCB1 and ABCG2 transporters.

BACKGROUND: ABC transporter-mediated multidrug resistance (MDR) remains a major obstacle for cancer pharmacological treatment. Some tyrosine kinase inhibitors (TKIs) have been shown to reverse MDR. The present study was designed to evaluate for the first time whether foretinib, a multitargeted TKI, can circumvent ABCB1 and ABCG2-mediated MDR in treatment-resistant cancer models. METHODS: Accumulation of fluorescent substrates of ABCB1 and ABCG2 in ABCB1-overexpressing MES-SA/DX5 and ABCG2-overexpressing MCF-7/MX and their parenteral cells was evaluated by flow cytometry. The growth inhibitory activity of single and combination therapy of foretinib and chemotherapeutic drugs on MDR cells was examined by MTT assay. Analysis of combined interaction effects was performed using CalcuSyn software. RESULTS: It was firstly proved that foretinib increased the intracellular accumulation of rhodamine 123 and mitoxantrone in MES-SA/DX5 and MCF-7/MX cancer cells, with accumulation ratios of 12 and 2.2 at 25 µM concentration, respectively. However, it did not affect the accumulation of fluorescent substrates in the parental cells. Moreover, foretinib synergistically improved the cytotoxic effects of doxorubicin and mitoxantrone. The means of combination index (CI) values at fraction affected (Fa) values of 0.5, 0.75, and 0.9 were 0.64 ± 0.08 and 0.47 ± 0.09, in MES-SA/DX5 and MCF-7/MX cancer cells, respectively. In silico analysis also suggested that the drug-binding domain of ABCB1 and ABCG2 transporters could be considered as potential target for foretinib. CONCLUSION: Overall, our results suggest that foretinib can target MDR-linked ABCB1 and ABCG2 transporters in clinical cancer therapy.

Transmission of high arterial pressure into renal microvessels during venous-clamping augments ischaemia/reperfusion-induced acute kidney injury in anaesthetized rats.

AIM: In two recent studies, we observed that a 30-min renal vein clamping caused formation of interstitial haemorrhagic congestion in ischaemic and ischaemic/reperfused kidney along with the development of severer acute kidney injury (AKI) than renal artery or pedicle clamping. It was suggested that the transmission of high arterial pressure into renal microvessels during vein occlusion probably causes the occurrence of interstitial haemorrhagic congestion that augments AKI. The present investigation aimed to evaluate this suggestion by reducing renal perfusion pressure (RPP) during renal venous occlusion. METHODS: Anaesthetized male Sprague-Dawley rats were divided into three groups (n = 8), which underwent a 2-h reperfusion period following 30-min bilateral renal venous clamping along with reduced RPP (VIR-rRPP group) or without reduced RPP (VIR group) and an equivalent period after sham-operation (Sham group). RESULTS: The VIR-rRPP group compared with VIR group had lower levels of kidney malondialdehyde and tissue damages as epithelial injuries of proximal tubule and thick ascending limb, vascular congestion, intratubular cast and oedema, along with the less reductions in renal blood flow, creatinine clearance, Na+ -reabsorption, K+ and urea excretion, urine osmolality and free-water reabsorption. Importantly, the formation of intensive interstitial haemorrhagic congestion in the VIR group was not observed in the VIR-rRPP group. CONCLUSION: These results indicate that the transmission of high arterial pressure into renal microvessels during venous occlusion leads to rupturing of their walls and the formation of interstitial haemorrhagic congestion, which has an augmenting impact on ischaemia/reperfusion-induced renal structural damages and haemodynamic, excretory and urine-concentrating dysfunctions.

Bilateral renal denervation prevents the development of hypertension during diet-induced obesity in male rats.

NEW FINDINGS: What is the central question of this study? What is the role of the renal nerves in the development of obesity, hyperlipidaemia and hypertension during the long-term feeding of a moderately high-fat diet in male obesity-prone rats? What is the main finding and its importance? The renal nerves play a prominent mediatory role, without influencing the establishment of visceral adiposity and atherogenic hyperlipidaemia, in the induction and progression of pressure natriuresis impairment and hypertension during the developmental period of diet-induced obesity. ABSTRACT: Feeding a moderately high-fat (MHF) diet in male Sprague-Dawley rats induces obesity, pressure natriuresis impairment and hypertension. This study investigated the role of the renal nerves in the impaired pressure natriuresis and hypertension caused by feeding a MHF diet. After collecting baseline data on day 0, 12 rats remained on a low-fat diet (LF group) while the others were switched onto a MHF diet and diverged into obesity-resistant (OR) or obesity-prone (OP). After 4 weeks, half of the OR and OP rats underwent bilateral renal denervation (BRD) to generate four groups: OR, OR/BRD, OP and OP/BRD (n = 12). During 10 weeks, body weight, obesity index, systolic pressure and renal excretory function were measured regularly. After 10 weeks, renal excretory responses to acute salt loading and renal autoregulation were evaluated. The OP and OP/BRD groups had greater increases of body weight and obesity index during the dietary period compared to the other groups, and by week 10 their body weight (425.1 ± 7.2 and 411.9 ± 5.1 g) became considerably larger than that of the LF group (358.5 ± 6.2 g). Renal sodium excretion was reduced by ∼20% at week 4 in the OP and OP/BRD groups, while only the OP group had lower sodium excretion at weeks 6-8 and higher systolic pressure over weeks 5-10 than the other groups and its week 10 systolic pressure reached 138.1 ± 6.7 versus 123.6 ± 2.7 mmHg of the LF group. The OP group showed delayed renal excretory responses to salt loading with rightward and downward shifts in renal autoregulatory curves. Therefore, the renal nerves exert a main mediatory role in the development of pressure natriuresis impairment and hypertension as obesity is established due to the long-term consumption of the MHF diet in male OP rats.

Toxicological Effects of Glycyrrhiza glabra (Licorice): A Review.

Licorice (Glycyrrhiza glabra) has been considered as an herbal drug since ancient time. Nowadays, it is a well-known spice that possesses worth pharmacological effects. However, some relevant articles have revealed negative impacts of licorice in health. By considering the great wishes in using herbal medicine, it is important to show adverse effects of herbal medicine in health. At present, there are misunderstandings toward the safety of herbal medicines. Herein, we gathered scientific research projects on the toxicity effects of licorice and glycyrrhizin to highlight their safety. In this regards, we categorized our findings about the toxicity effects of licorice and glycyrrhizin in acute, sub-acute, sub-chronic, and chronic states. Besides, we discussed on the cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of licorice and glycyrrhizin as well as their developmental toxicity. This review disclosed that G. glabra and glycyrrhizin salts are moderately toxic. They need to be used with caution during pregnancy. G. glabra and glycyrrhizin possess selective cytotoxic effects on cancerous cells. The most important side effects of licorice and glycyrrhizin are hypertension and hypokalemic-induced secondary disorders. Licorice side effects are increased by hypokalemia, prolonged gastrointestinal transient time, decreased type 2 11-beta-hydroxysteroid dehydrogenase activities, hypertension, anorexia nervosa, old age, and female sex. Copyright © 2017 John Wiley & Sons, Ltd.

Targeting DNA damage response in pancreatic ductal adenocarcinoma: A review of preclinical and clinical evidence.

Pancreatic ductal adenocarcinoma (PDAC) is associated with one of the most unfavorable prognoses across all malignancies. In this review, we investigate the role of inhibitors targeting crucial regulators of DNA damage response (DDR) pathways, either as single treatments or in combination with chemotherapeutic agents and targeted therapies in PDAC. The most prominent clinical benefit of PARP inhibitors' monotherapy is related to the principle of synthetic lethality in individuals harboring BRCA1/2 and other DDR gene mutations as predictive biomarkers. Moreover, induction of BRCAness with inhibitors of RTKs, including VEGFR and c-MET and their downstream signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT/mTOR in order to expand the application of PARP inhibitors in patients without DDR mutations, has also been addressed. Other DDR-targeting agents beyond PARP inhibitors, including inhibitors of ATM, ATR, CHEK1/2, and WEE1 have also demonstrated their potential in preclinical models of PDAC and may hold promise in future studies.

Synthesis and cytotoxic activity evaluation of novel imidazopyridine carbohydrazide derivatives.

Two series of novel imidazo[1,2-a]pyridine-2-carbohydrazide derivatives have been designed, synthesized, and evaluated for cytotoxic activity. Target compounds were designed in two series: aryl hydrazone derivatives that were devoid of triazole moiety (7a-e) and aryl triazole bearing group (11a-e). In vitro cytotoxicity screening was carried out using MTT assay against three human cancer cells including breast cancer (MCF-7), colon cancer (HT-29), and leukemia (K562) cell lines as well as a non-cancer cell line (Vero). Compound 7d bearing 4-bromophenyl pendant from aryl hydrazone series exhibited the highest cytotoxic potential with IC50 values of 22.6 µM and 13.4 µM against MCF-7 and HT-29 cells, respectively, while it was not toxic towards non-cancer cells up to the concentration of 100 µM. Cell cycle analysis revealed that 7d increased the number of MCF-7 cells in the G0/G1 phase and also induced apoptosis in these cells as revealed by Hoechst 33,258 staining. The molecular mechanism contributing to the anti-proliferative effect of the most potent compound was investigated in silico using Super Pred software and introduced PDGFRA as a plausible target for 7d. Molecular docking and molecular dynamic studies demonstrated Lys627 and Asp836 as key residues interacting with the active compound. Overall, 7d could serve as a suitable candidate for further modifications as a lead anticancer structure.

Cardiorenal Protections of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes.

Cardiovascular disease and renal complications raise the risk of death and morbidity in patients with type 2 diabetes (T2D). Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a novel class of glucose-lowering drug that increases urine glucose excretion while decreasing blood glucose levels in type 2 diabetes patients by inhibiting glucose reabsorption. In the present article, we review the discovery and development of SGLT2i as a new T2D treatment approach for T2D; thereafter, we consider different cell-based methods for the evaluation of SGLT2i. Finally, we provide evidences from both clinical and experimental studies which bring up the cardio-renal protective effects of SGLT2i. We performed a literature search using PubMed, Google Scholar, and Web of Science to identify publications on preclinical and clinical studies of cardiorenal protective action of SGLT2i and their suggested mechanisms. SGLT2i have shown good effects in the improvement of cardiovascular and renal complications independent of glucose lowering effects. Besides controlling blood glucose levels, SGLT2i were found to exhibit therapeutic benefits on the kidney and cardiovascular system by lowering diabetic glomerular hyperfiltration, blood pressure (BP), body weight, uric acid concentrations, lipid peroxidation, inflammation, etc. As a result of their distinct mode of action, SGLT2i have emerged as a promising treatment option for T2D and maybe T1D due to their increased urine excretion of glucose. It has been demonstrated that SGLT2i have considerable protective effects on diabetic nephropathy (DN) and cardiomyopathy in well-designed experimental and clinical investigations.

Comparison of the effects of high-intensity interval and moderate-intensity continuous training on inflammatory markers, cardiorespiratory fitness, and quality of life in breast cancer patients.

BACKGROUND: As the effectiveness of breast cancer treatment has improved, a growing number of long-term breast cancer survivors are seeking help for unique health problems. These patients may be at increased risk of cardiovascular disease due to the side effects of treatment. The positive impact of most types of exercise has been repeatedly reported in people with cancer, but the most effective exercise approaches for maximum beneficial adaptations remain controversial. Thus, this study aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on inflammatory indices, adipokines, metabolic markers, body composition, cardiorespiratory fitness, and quality of life in breast cancer patients during adjuvant endocrine therapy. METHODS: Thirty non-metastatic breast cancer patients during adjuvant endocrine therapy who had been treated with chemotherapy and/or radiotherapy were recruited from Iran and randomized to HIIT, MICT, or control groups for a supervised exercise intervention that took place 3 times a week for 12 weeks. The training intensity was determined based on the peak oxygen uptake (VO2peak), and the volume of training was matched in HIIT and MICT based on the VO2peak. Body composition, functional capacity, cardiorespiratory fitness, metabolic indices, sex hormones, adipokines, and inflammatory markers were assessed before and after the intervention. RESULTS: The VO2peak increased by 16.8% in the HIIT group in comparison to baseline values (mean difference = 3.61 mL/kg/min). HIIT significantly improved the VO2peak compared to control (mean difference = 3.609 mL/kg/min) and MICT (mean differences = 2.974 mL/kg/min) groups. Both HIIT (mean difference = 9.172 mg/dL) and MICT (mean difference = 7.879 mg/dL) interventions significantly increased high-density lipoprotein cholesterol levels compared to the control group. The analysis of covariance showed that physical well-being significantly improved in MICT compared to control group (mean difference = 3.268). HIIT significantly improved the social well-being compared to the control group (mean difference = 4.412). Emotional well-being subscale was significantly improved in both MICT (mean difference = 4.248) and HIIT (mean difference = 4.412) compared to the control group. Functional well-being scores significantly increased in HIIT group compared with control group (mean difference = 3.35) . Significant increase were also observed in total functional assessment of cancer therapy-General scores in both HIIT (mean difference = 14.204) and MICT groups (mean difference = 10.036) compared with control group. The serum level of suppressor of cytokine signaling 3 increased significantly (mean difference = 0.09 pg/mL) in the HIIT group compared to the baseline. There were no significant differences between groups for body weight, body mass index, fasting blood glucose, insulin resistance, sex hormone binding globulin, total cholesterol, low-density lipoprotein cholesterol, adipokines, interleukin-6, tumor necrosis factor-α, or interleukin-10. CONCLUSION: HIIT can be used as a safe, feasible, and time-efficient intervention to improve cardiovascular fitness in breast cancer patients. Both HIIT and MICT modalities enhance quality of life. Further large-scale studies will help determine whether these promising results translate into improved clinical and oncological outcomes.

Effectiveness of a process-based executive function intervention on arithmetic knowledge of children with Developmental Dyscalculia.

BACKGROUND: Arithmetic knowledge has long been known as an essential factor for educational and vocational success. AIMS: This study aims to explore the effectiveness of a process-based Executive Function (EF) intervention program on the improvement of components of arithmetic. METHODS AND PROCEDURE: A goal-directed sampling method was applied in this study. Participants were assigned into active control and experimental groups. Semi-experimental design with pre-test, post-test and follow-up was utilized in this research. Participants were included in this study based on their WISC-IV and Key-Math test performance. 30 male students aged 8-10 years with a formal diagnosis of Developmental Dyscalculia (DD), selected from a learning disability center in Ahvaz, Iran, participated in the study. The pre-test took 1 month, the intervention including 17 sessions, took two months and the post-test took 1 month. All the students' arithmetic knowledge were tested in pre-test, post-test, and 3 months after post-test to test the longevity of the intervention effects. Repeated measure Univariate Analysis of Variance was conducted in this study. OUTCOMES AND RESULTS: The results indicate that the students who attended the intervention, outperformed control group in the components of factual and procedural arithmetic in post-test and follow-up, however; the performance of two groups in conceptual knowledge was not different. This study contributes to the emerging evidence that EF intervention may improve factual and procedural arithmetic knowledge in children with DD. CONCLUSIONS AND IMPLICATIONS: Process-based EF interventions can improve arithmetic knowledge of students with DD, which can contribute to the literature of this area WHAT THIS PAPER ADDS?: The current research helps cognitive science to present a more meticulous theoretical and conceptual pattern for EF components and math, using process-based EF intervention programs with arithmetic content. Furthermore, this research allows for specification of cognitive fundamentals of arithmetic development and understanding the mechanisms underlying the transfer effect of EF intervention to math. The findings of this research can contribute to evidence-based EF intervention studies and help educational psychologists in preparation of appropriate curricula based on the fundamental components of arithmetic development in preschool and primary school.

Temporal patterns of alterations in obesity index, lipid profile, renal function and blood pressure during the development of hypertension in male, but not female, rats fed a moderately high-fat diet.

CONTEXT: Male Sprague-Dawley rats consuming a moderately high-fat (MHF)-diet diverge into obesity-prone (OP) with hypertension and obesity-resistant. OBJECTIVES: To study the temporal inter-relationships between body-weight, obesity-index, plasma lipid-profile, renal functional parameters and systolic-pressure alterations during 10-weeks feeding MHF or normal diet to male and female rats. METHODS: Body-weight, obesity-index and systolic-pressure were measured weekly, while metabolic-cage and blood-sampling protocols were performed every other week. After 10-weeks, renal excretory responses to acute salt-loading and renal autoregulation were examined. RESULTS: The male-OP group had progressively increased body-weight, plasma-triglyceride and systolic-pressure from Weeks 2, 4 and 5, respectively, lower renal sodium-excretion at weeks 4-8 and finally, delayed excretory response to salt-loading and rightward and downward shifts in renal autoregulatory curves compared to all other groups. CONCLUSION: Feeding the MHF-diet in male-OP rats led to a greater weight-gain and adiposity followed by the development of atherogenic-hyperlipidaemia and persistently impaired pressure-natriuresis to induce hypertension.

Nigella sativa and its main constituent, thymoquinone protect against glycerol-induced acute kidney injury in rats.

Objective: Rhabdomyolysis is a life-threatening disease caused by releasing myoglobin from injured myocytes, which results in acute kidney injury. In this study, the effect of aqueous-alcoholic extract of Nigella sativa (NS) and thymoquinone (TQ) on rhabdomyolysis-induced kidney damage in rats was investigated. Materials and Methods: There were five groups of rats (n=8): Control, rhabdomyolysis, rhabdomyolysis treated with NS aqueous-alcoholic extract (200 and 400 mg/kg) and TQ (15 mg/kg). Treatments were given for 7 days (two days before and four days after glycerol injection). Glycerol was injected intramuscularly on the third day of the experiment for induction of rhabdomyolysis. Renal function parameters on the first, fourth, and seventh days of the experiment and renal oxidative stress and histological changes at the end of this study were assessed. Results: Glycerol injection caused a significant increase in serum level of urea, creatinine, creatine phosphokinase, urine output and tissue MDA compared to the control animals (p<0.05-0.001). Administration of NS extract and TQ significantly decreased serum urea and creatinine on days 4 and 7, creatine phosphokinase on day 4, and urine output on day 7 compared to the rhabdomyolysis group (p<0.05-0.001). Compared to the rhabdomyolysis group, treatment with NS extract and TQ improved kidney histological abnormalities (p<0.01-0.001). The catalase enzyme activity in the group treated with NS 400 mg/kg and thiol content in the NS 400 mg/kg and TQ groups were significantly higher than those of the rhabdomyolysis group (p<0.05-0.01). Conclusion: NS extract and to some extent TQ protect the kidney from rhabdomyolysis-induced injury.

Escitalopram and progressive muscle relaxation training are both effective for the treatment of hot flashes in patients with breast cancer: a randomized controlled trial.

INTRODUCTION: Available treatments for hot flashes in patients with breast cancer are not always tolerable or effective for all patients. METHODS: Patients diagnosed to have primary breast cancer were randomly allocated to receive 10 mg of escitalopram, placebo, or progressive muscle relaxation therapy. Patients were asked to report the frequency and duration of hot flashes during day and night, at baseline and after ten weeks of treatment, and completed the menopause rating scale. RESULTS: Eighty-two patients were randomly assigned to receive escitalopram (n = 26), PMRT (n = 28), and placebo (n = 28). PMRT and escitalopram could effectively decrease number and duration of diurnal and nocturnal HFs in patients with breast cancer, with a better effect observed from escitalopram. They could both decrease the total score of MRS. CONCLUSION: Both escitalopram ad PMRT can reveal nocturnal and diurnal HFs in terms of frequency and duration in patients with breast cancer.

Antifungal activity of some essential oils against toxigenic Aspergillus species.

Increasing attentions have been paid on the application of essential oils and plant extracts for control of postharvest pathogens due to their natural origin and less appearance of resistance in fungi pathogens. Some Aspergillus species are toxigenic and responsible for many cases of food and feed contamination. Some Toxins that produce with some Aspergillus species are known to be potent hepatocarcinogens in animals and humans. The present work evaluated the parameters of antifungal activity of the essential oils of Zataria multiflora, Thymus migricus, Satureja hortensis, Foeniculum vulgare, Carum capticum and thiabendazol fungicide on survival and growth of different species of Aspergillus. Aerial part and seeds of plant species were collected then dried and its essential oils isolated by means of hydrodistillation. Antifungal activity was evaluated in vitro by poisonous medium technique with PDA medium at six concentrations. Results showed that all essential oils could inhibit the growth of Aspergillus species. The essential oil with the best effect and lowest EC50 and MIC (Minimum Inhibitory Concentration) was Z. multiflora (223 microl/l and 650 microl/l, respectively). The chemical composition of the Z. multiflora essential oil was analyzed by GC-MS.

Epidermal neural crest stem cell transplantation as a promising therapeutic strategy for ischemic stroke.

INTRODUCTION: Cell-based therapy is considered as promising strategy to cure stroke. However, employing appropriate type of stem cell to fulfill many therapeutic needs of cerebral ischemia is still challenging. In this regard, the current study was designed to elucidate therapeutic potential of epidermal neural crest stem cells (EPI-NCSCs) compared to bone marrow mesenchymal stem cells (BM-MSCs) in rat model of ischemic stroke. METHODS: Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) for 45 minutes. Immediately after reperfusion, EPI-NCSCs or BM-MSCs were transplanted via intra-arterial or intravenous route. A test for neurological function was performed before ischemia and 1, 3, and 7 days after MCAO. Also, infarct volume ratio and relative expression of 15 selected target genes were evaluated 7 days after transplantation. RESULTS: EPI-NCSCs transplantation (both intra-arterial and intravenous) and BM-MSCs transplantation (only intra-arterial) tended to result in a better functional outcome, compared to the MCAO group; however, this difference was not statistically significant. The infarct volume ratio significantly decreased in NCSC-intra-arterial, NCSC-intravenous and MSC-intra-arterial groups compared to the control. EPI-NCSCs interventions led to higher expression levels of Bdnf, nestin, Sox10, doublecortin, ß-III tubulin, Gfap, and interleukin-6, whereas neurotrophin-3 and interleukin-10 were decreased. On the other hand, BM-MSCs therapy resulted in upregulation of Gdnf, ß-III tubulin, and Gfap and down-regulation of neurotrophin-3, interleukin-1, and interleukin-10. CONCLUSION: These findings highlight the therapeutic effects of EPI-NCSCs transplantation, probably through simultaneous induction of neuronal and glial formation, as well as Bdnf over-expression in a rat model of ischemic stroke.