Houman Alimoradi

Effects of Juglans regia L. leaf extract on hyperglycemia and lipid profiles in type two diabetic patients: A randomized double-blind, placebo-controlled clinical trial

ETHNOPHARMACOLOGICAL RELEVANCE The Juglans regia L. leaf has been traditionally used for treatment of diabetes mellitus in Iran. But yet, no controlled human study has determined its efficacy in diabetic patients. The present study was designed to investigate the effects of the Juglans regia leaf extract on hyperglycemia and lipid profiles in type II diabetic patients. MATERIALS AND METHOD Total 61 patients, suffering from type II diabetes with fasting blood glucose (FBG) between 150 and 200mg/dL, glycated hemoglobin (HbA1c) between 7% and 9% and aged between 40 and 60 years were selected, and randomly divided in to two groups of Juglans regia and placebo. First group received 100mg Juglans regia leaf extract in capsules form two times a day for 3 months and other group received 100mg placebo capsule with the same dosage. The standard anti-diabetic therapy (metformin and glibenclamide, and nutritional regimen) was continued in both groups. At the baseline and after three months the FBG, insulin, HbA1c, cholesterol, triglyceride, HDL, LDL and liver and renal function tests were determined. In addition general satisfaction with the treatment was identified using health questionnaires. RESULTS The results indicated that FBG, HbA1c, total cholesterol and triglyceride levels in Juglans regia treated patients significantly decreased compared with the baseline and with placebo group. Patients in Juglans regia group were significantly satisfied with Juglans regia treatment compared with the placebo group. No liver, kidney and other side effects were observed in the groups, except more GI events (specially a mild diarrhea) associated with extract treatment at the beginning of the study. CONCLUSION In conclusion, treatment of type II diabetic patients with 100mg Juglans regia leaf extract two times a day for three months improves lipid profile and glycemic control without any tangible adverse effects.

Lithium Attenuates Peripheral Neuropathy Induced by Paclitaxel in Rats

As a cancer chemotherapeutic agent, paclitaxel (Taxol® ) causes dose-related peripheral neuropathy in human beings. The mechanisms underlying this toxicity are currently unknown, and there are no validated treatments for its prevention or control. To assess whether lithium as a pre-treatment and at subtherapeutic dose could prevent the peripheral neuropathy produced by it, rats were treated with paclitaxel (2 mg/kg i.p. every other day for a total of 16 times) and/or lithium chloride (300 mg/l) via water supply. General toxicity and body-weight were measured regularly during the experiment. To evaluate the sensory and motor neuropathy hot-plate, open-field test and nerve conduction velocity were used. In rats treated with only paclitaxel, there was behavioural, electrophysiological and histological evidence of a mixed sensorimotor neuropathy after 16 injections. Lithium robustly reduced the rate of mortality and general toxicity. Paclitaxel-induced sensorimotor neuropathy was significantly improved as indicated by changes in hotplate latency, total distance moved and a significant increase in sciatic, sural and tail sensory or motor nerve conduction velocity. The same results were observed in histopathological examinations; however, dorsal root ganglion neurons did not significantly change in the paclitaxel-treated groups. These results suggest that lithium, at subtherapeutic doses, can prevent both motor and sensory components of paclitaxel neuropathy in rats. Thus, lithium at these doses, as an inexpensive and relatively safe salt, may be useful clinically in preventing the neuropathy induced by paclitaxel treatment.

The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity

Vincristine (VCR) peripheral neuropathy is a dose-limiting side effect. Several studies have shown that tropisetron, a 5-HT3 receptor antagonist, exerts anti-inflammatory and immunomodulatory properties. Current study was designed to investigate a suppressive effect of tropisetron on VCR-induced neuropathy and whether this effect exerts through the 5-HT3 receptor or not. Neuropathy was induced in rats by administration of vincristine (0.5mg/kg, 3 intraperitoneal injections on alternate days) and in treatment group, tropisetron (3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3 receptor agonist (15mg/kg); tropisetron (3mg/kg) plus mCPBG (15mg/kg); granisetron, another selective 5-HT3 receptor antagonist (3mg/kg) were administered intraperitoneally 1h prior to vincristine injection. Hot plate, open field tests (total distance moved, mean velocity and percentage of total duration of the movement) and motor nerve conduction velocity (MNCV) were performed to evaluate the sensory and motor neuropathy. Further, plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) and the level of TNF-α in sciatic nerve were assessed as well as histological examination. In only VCR-treated rats hot plate latencies were significantly increased, total distance moved, mean velocity, total duration of the movement and sciatic MNCV significantly decreased compared with control. In tropisetron and tropisetron plus mCPBG groups, one injection of tropisetron prior to each VCR injection robustly diminished TNF-α and IL-2 levels, and also prevented mixed sensory-motor neuropathy, as indicated by less mortality rate, better general conditions, behavioral and electrophysiological studies. Moreover, pathological evidence confirmed the results obtained from other findings. But granisetron and mCPBG had no significant effect on the mentioned parameters. In conclusion, these studies demonstrate that tropisetron significantly suppressed VCR-induced neuropathy and could be a neuroprotective agent for prevention of VCR-induced neuropathy via a receptor-independent pathway.

Tropisetron ameliorates early diabetic nephropathy in streptozotocin-induced diabetic rats.

It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that tropisetron exerts anti‐inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of tropisetron on early diabetic nephropathy in streptozotocin‐induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with tropisetron (3 mg/kg); (iv) normal rats treated with tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor‐α were also determined. Streptozotocin‐treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor‐α, and urinary albumin excretion. Both granisetron and tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor‐α, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti‐oxidative and anti‐inflammatory mechanisms that appear to be independent of the 5‐HT3 receptor.

Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer

Abstract Sildenafil is an approved drug for the treatment of erectile dysfunction. The drug exerts its action through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. In this work, we tested whether the aforementioned effects of sildenafil on tumour vasculatures could result in an improvement of anticancer drug concentration in tumour tissues and hence improves its anticancer effect. Sildenafil when added to doxorubicin showed synergistic anticancer activity against 4T1 breast cancer cells in vitro. Adding 1, 30 and 100 μM of Viagra to 1 μM of doxorubicin resulted in 1.8-fold, 6.2-fold and 21-fold statistically significant increases in its cytotoxic effect, respectively. As a result, 4T1 tumour-bearing mice showed up to 2.7-fold increase in drug concentrations of the fluorescent Dye DiI and doxorubicin in tumour tissues, as well as their nanoformulations. Animals treated with the combinations of both Sildenafil citrate and doxorubicin showed a statistically significant 4.7-fold reduction in tumour size compared to doxorubicin alone. This work highlights the effect of Sildenafil on tumour vasculatures and provides a rational for further testing the combination on breast cancer patients.

Inhibition of calcineurin/NFAT pathway plays an essential role in renoprotective effect of tropisetron in early stage of diabetic nephropathy.

Recent studies have shown that calcineurin plays a central role in hypertrophy and extracellular matrix (ECM) accumulation in glomeruli at the early stages of diabetic nephropathy. Tropisetron is an effective antiemetic drug which also can potently inhibit calcineurin. The aim of this study was to investigate whether tropisetron can prevent glomerular hypertrophy and ECM expansion in early diabetic nephropathy. Streptozotocin (STZ)-induced diabetic rats were treated with tropisetron and cyclosporine A, a pharmacological calcineurin inhibitor, and the renal function and the expression of calcineurin and fibronectin were then assessed as well as nuclear localization of nuclear factor of activated T-cell c1 (NFATc1). 2 weeks after diabetes induction, all STZ-treated rats showed hyperglycemia, polyuria, body weight loss and renal dysfunction, as evidenced by increased glomerular filtration rate (GFR), along with a marked pathological changes in kidney. Calcineurin expression was increased in association with increased nuclear localization of the calcineurin substrate NFATc1 and fibronectin expression in glomeruli of diabetic rats. In parallel, the diabetic glomeruli became hypertrophic with an increase in kidney weight. Tropisetron, as potent as cyclosporine A, significantly ameliorated the early nephropathy symptoms, potentially through suppression of calcineurin expression, nuclear localization of NFATc1 and accumulation of fibronectin, and thereby reduced hypertrophy in glomeruli of diabetic rats. In conclusion, our results showed that tropisetron could ameliorate kidney injury in the early stage of diabetic nephropathy in rats. The renoprotective effects of tropisetron can be attributed, at least in part, to the suppression of diabetes-induced increases in calcineurin expression in kidney tissue.

Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems.

Kelussia odoratissima Mozaff attenuates thromboembolic brain injury, possibly due to its Z-ligustilide content

Abstract Primary objective: Essential oil (EO) of Kelussia odoratissima Mozaff, whose main composition is Z-ligustilide, has been shown to have strong antioxidant and anti-inflammatory effects and potent neuroprotective properties. Research design: This study examined whether or not the EO could ameliorate brain damage and behavioural dysfunction in a thromboembolic model of stroke in rats and compare its effects to that of the purified Z-ligustilide. Methods and procedures: Stroke was induced in rats by middle cerebral artery occlusion using an autologous pre-formed clot. EO (10 mg kg–1 and 45 mg kg–1) and Z-ligustilide (20 mg kg–1) were injected intraperitoneally 1 h prior to embolization. Behavioural scores, infarct size and brain oedema, as well as the level of tumour necrosis factor-alpha (TNF-α), malondialdehyde, glutathione, catalase and superoxide dismutase activity were determined in the ipsilateral cortex 24 hours following stroke induction. Main outcomes and results: EO (45 mg kg–1), statistically similar to Z-ligustilide (20 mg kg–1), curtailed brain infarction and oedema, improved behavioural scores and prevented enhanced oxidative stress and TNF-α level in the ischaemic brain tissues. Conclusions: The findings provide the first evidence of effectiveness of the extract in a thromboembolic model of stroke, whose action can be mediated, at least in part, by the antioxidative and anti-inflammatory mechanisms.

The effect of chronic hyperthyroidism and restored euthyroid state by methimazole therapy in rat small mesenteric arteries.

Not much has been reported about the effects of hyperthyroidism and its correction on resistance vessels, and just two inconsistent studies have investigated the impacts of restored euthyroidism on vascular reactivity. In this regard, we designed the current study to evaluate the vascular reactivity of the mesenteric arteries of hyperthyroid and restore euthyroid rats. Hyperthyroidism was induced by administration of triiodothyronine (T3; 300μg/kg, i.p., for 12 weeks in T3 group). Euthyroidism was restored by administration of T3 for 8 weeks and then T3+Methimazole (0.003% in drinking water) for 4 weeks (T3+MMI group). According to the McGregor method, vascular relaxation and contractility response were measured in response to acetylcholine or phenylephrine respectively. We found that maximal contractility response (Emax) to phenylephrine in the T3 group was significantly decreased (P<0.001), and Emax to acetylcholine was significantly increased compared with the saline group (P<0.05). When N(G)-nitro-L-arginine methyl ester (L-NAME, 3×10(-4)M) was used, Emax to acetylcholine in the T3 group was still higher than the saline group (P<0.05). However, decrease in maximal response of the T3 group was significantly greater than the saline group (P<0.01). We also showed that when euthyroidism is restored by methimazole therapy, enhanced acetylcholine-induced vasorelaxation and impaired contractility response to phenylephrine were normalized, as there was no significant difference in Emax of the T3+MMI group versus the saline group (P>0.05). In conclusion, synthesis of both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in mesenteric arteries significantly increased as a consequence of hyperthyroidism, and this abnormal vascular reactivity is corrected by methimazole therapy.

Encapsulation of tDodSNO Generates a Photoactivated Nitric Oxide Releasing Nanoparticle for Localized Control of Vasodilation and Vascular Hyperpermeability

ABSTRACT We report the synthesis and characterization of a photoactive nitric oxide (NO) releasing nanoparticle (NP) by encapsulation of the NO donor tert‐dodecane S‐nitrosothiol (tDodSNO) into a co‐polymer of styrene and maleic anhydride (SMA) to afford SMA‐tDodSNO. Encapsulation did not affect tDodSNOs stability or NO release profile, but imparted water solubility and protection from degradation reactions with glutathione. Under photoactivation the NP acted as a potent NO donor, with photoactivation acting as a switch to induce localized vasodilation in aortic rings (Symbol 660 nM at 2700 W/m2) and cause vascular hyperpermeability in mesenteric beds (8‐fold increase in dye uptake at 1 &mgr;M SMA‐tDodSNO with 460 W/m2 photoactivation). The NP was markedly superior as a photoactive NO donor in comparison to the S‐nitrosothiols GSNO and SNAP, which are commonly used in experimental studies, as well as sodium nitroprusside, a clinically used vasodilator. Future development of this NP may find wide ranging therapeutic applications for treating cardiovascular disease and other disorders related to NO signaling, as well as enhancing macromolecular drug delivery to target organs through selective hyperpermeability. Supporting information describing the biophysical characterization of SMA‐tDodSNO is supplied in an accompanying Data in Brief article (Alimoradi et al., doi: 10.1016/j.dib.2018.10.149). Symbol. No Caption available. Graphical abstract Figure. No Caption available. HighlightsNanoparticle encapsulation of the nitric oxide donor tDodSNO generated a water soluble formulation SMA‐tDodSNO.Nanoparticle encapsulation did not change tDodSNO’s nitric oxide release profile.Nanoparticle encapsulation protected tDodSNO from degradation by reduced glutathione.Photoactivation of SMA‐tDodSNO dynamically regulated vasodilation in aortic rings.Photoactivation of SMA‐tDodSNO caused vascular hyperpermeability in mesenteric beds.