Ginger Ingredients Alleviate Diabetic Prostatic Complications: Effect on Oxidative Stress and Fibrosis

Prostatic complications are common in patients with diabetes. This study investigated the effect of different ginger ingredients: zingerone, geraniol, and 6-gingerol on the prostate in diabetic rats. Diabetes was induced in Wistar rats by streptozotocin intraperitoneal injection (50 mg/kg), and the rats were left for 10 weeks to develop prostatic complications. In diabetic treated groups, rats received daily oral zingerone, geraniol, and 6-gingerol in doses of 20, 200, and 75 mg/kg, respectively, in the last 8 weeks. Treatment with the compounds caused changes in the ventral prostate of diabetic animals as indicated by the columnar ductal epithelium and dense secretions. There was an amelioration of oxidative stress as evidenced by the lowering of prostate malondialdehyde and elevating prostate oxidized to reduced glutathione (GSH/GSSG) ratios by geraniol and 6-gingerol. None of the three ginger ingredients affected the hyperglycemia, reduction in body weight gain, and testosterone deficiency seen in diabetic animals. Interleukin-1β and interleukin-6 levels remained unchanged. However, zingerone and geraniol ameliorated the fibrosis in diabetic prostate through suppressing the elevated prostate transforming growth factor beta 1 (TGFβ1) and collagen IV. Therefore, ginger ingredients could be beneficial in alleviating diabetic prostatic complications through suppressing oxidative stress and tissue fibrosis

NORMAL VASCULAR REACTIVITY IS RESTORED BY APIGENIN IN DIABETIC RATS

Objective: Diabetes is a disease whose complications have serious implications for the health of sufferers; one of the most serious such complications is the deterioration of vascular reactivity. Apigenin is a natural flavonoid with PKC inhibiting and antioxidant properties. In this study, the impact of apigenin on vascular reactivity deterioration was investigated.Methods: Insulin resistance (IR) and insulin deficiency (ID) were induced by fructose and streptozotocin respectively. The isolated aortae vasoconstriction response to phenylephrine (PE) and potassium chloride (KCl) in addition to the vasodilation response to acetylcholine (ACh) and sodium nitroprusside (SNP) were tested.Results: IR and ID were associated with significantly exaggerated vasoconstriction to KCl and PE while significantly impaired vasodilation to ACh. Response to SNP was not significantly affected by both IR and ID. In vitro incubation with apigenin (7 7µM) for 20 min restored normal responses to PE, KCl and ACh in aortae isolated from insulin-resistant or insulin-deficient rats. Incubation for one hour with the PKC stimulant, phorbol 12-myristate 13-acetate (PMA, 800 nM) resulted in aortic impairment similar to that seen in aortae isolated from IR and ID animals. Incubation with both apigenin prevented PMA-induced exaggerated vasoconstriction response to both PE and KCl.Conclusion: Apigenin alleviates vascular exaggerated vasoconstriction and impaired dilation associated with diabetes or PKC activated

Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance:effect on low grade inflammation and the angiotensin system

BACKGROUND: We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Here we investigated the effect of xanthine oxidase (XO) inhibition on the cardiac complications of IR. METHODS: IR was induced in rats by a high fructose high fat diet for 12 weeks. Allopurinol, a standard XO inhibitor, was administered in the last 4 weeks before cardiac hemodynamics and electrocardiography, serum glucose, insulin, tumor necrosis factor alpha (TNFα), 8-isoprostane, uric acid, lactate dehydrogenase (LDH) and XO activity were measured. Expression of cardiac angiotensin II (AngII) and angiotensin receptor 1 (AT(1)) were assessed by immunofluorescence. RESULTS: IR animals had significant hyperuricemia which was inhibited by allopurinol administration. IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation. IR was accompanied by cardiac ischemia (reflected by increased QTc and T peak trend intervals) while XO inhibition alleviated the ECG abnormalities. When subjected to isoproterenol-induced ischemia, IR hearts were less resistant (reflected by larger ST height depression and higher LDH level) while XO inhibition alleviated the accompanying ischemia. In addition, XO inhibition prevented the elevation of serum 8-isoprostane and TNFα, and blocked elevated AngII and AT(1) receptor expression in the heart tissue of IR animals. However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia. CONCLUSIONS: XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system

Arginase inhibition alleviates hypertension in the metabolic syndrome

BACKGROUND AND PURPOSE: We have previously shown that arginase inhibition alleviates hypertension associated with in a diabetic animal model. Here, we investigated the protective effect of arginase inhibition on hypertension in metabolic syndrome. EXPERIMENTAL APPROACH: Metabolic syndrome was induced in rats by administration of fructose (10% in drinking water) for 12 weeks to induce vascular dysfunction. Three arginase inhibitors (citrulline, norvaline and ornithine) were administered daily in the last 6 weeks of study before and tail BP was recorded in conscious animals. Concentration response curves for phenylephrine (PE), KCl and ACh in addition to ACh-induced NO generation were obtained in thoracic aorta rings. Serum glucose, insulin, uric acid and lipid profile were determined as well as reactive oxygen species (ROS) and arginase activity. KEY RESULTS: Arginase activity was elevated in metabolic syndrome while significantly inhibited by citrulline, norvaline or ornithine treatment. Metabolic syndrome was associated with elevations in systolic and diastolic BP, while arginase inhibition significantly reduced elevations in diastolic and systolic BP. Metabolic syndrome increased vasoconstriction responses of aorta to PE and KCl and decreased vasorelaxation to ACh, while arginase inhibition completely prevented impaired responses to ACh. In addition, arginase inhibition prevented impaired NO generation and exaggerated ROS formation in metabolic syndrome. Furthermore, arginase inhibition significantly reduced hyperinsulinaemia and hypertriglyceridaemia without affecting hyperuricaemia or hypercholesterolaemia associated with metabolic syndrome. CONCLUSIONS AND IMPLICATIONS: Arginase inhibition alleviates hypertension in metabolic syndrome directly through endothelial-dependent relaxation/NO signalling protection and indirectly through inhibition of insulin resistance and hypertriglyceridaemia

Targeting AGEs Signaling Ameliorates Central Nervous System Diabetic Complications in Rats

Diabetes is a chronic endocrine disorder associated with several complications as hypertension, advanced brain aging, and cognitive decline. Accumulation of advanced glycation end products (AGEs) is an important mechanism that mediates diabetic complications. Upon binding to their receptor (RAGE), AGEs mediate oxidative stress and/or cause cross-linking with proteins in blood vessels and brain tissues. The current investigation was designed to investigate the effect of agents that decrease AGEs signaling, perindopril which increases soluble RAGE (sRAGE) and alagebrium which cleaves AGEs cross-links, compared to the standard antidiabetic drug, gliclazide, on the vascular and central nervous system (CNS) complications in STZ-induced (50 mg/kg, IP) diabetes in rats. Perindopril ameliorated the elevation in blood pressure seen in diabetic animals. In addition, both perindopril and alagebrium significantly inhibited memory decline (performance in the Y-maze), neuronal degeneration (Fluoro-Jade staining), AGEs accumulation in serum and brain, and brain oxidative stress (level of reduced glutathione and activities of catalase and malondialdehyde). These results suggest that blockade of AGEs signaling after diabetes induction in rats is effective in reducing diabetic CNS complications

A review on phytochemical, pharmacological and ethnopharmacological aspects of genus Trichodesma

333-347The genus Trichodesma belongs to the family Boraginaceae. The plants of this genus are widely distributed in tropical and subtropical regions of Africa, Asia, and Australia. Phytochemically, scientific reports on Trichodesma species so far revealed more than one hundred compounds from this genus, including hydrocarbons, phenols, flavonoids, sterols, terpenes and alkaloids have been isolated or identified. Medicinally, various reported biological activities of Trichodesma such as antimicrobial, antiparasitic, cytotoxic, anti-infection, antioxidant, anti-inflammatory, anti-irritant, antidiarrheal, antispasmodic, antimalarial, analgesic, antipyretic, anti-diabetic, diuretic, and hepatoprotective effects were discussed in this review otherwise. Also, the ethnopharmacological effects of this genus were reviewed. Among all the Trichodesma species, T. indicum is regarded as the most important one regarding its pharmacological values. The volatile oil of T. africanum L. showed high antioxidant activity

A review on phytochemical, pharmacological and ethnopharmacological aspects of genus Trichodesma

The genus Trichodesma belongs to the family Boraginaceae. The plants of this genus are widely distributed in tropical and subtropical regions of Africa, Asia, and Australia. Phytochemically, scientific reports on Trichodesma species so far revealed more than one hundred compounds from this genus, including hydrocarbons, phenols, flavonoids, sterols, terpenes and alkaloids have been isolated or identified. Medicinally, various reported biological activities of Trichodesma such as antimicrobial, antiparasitic, cytotoxic, anti-infection, antioxidant, anti-inflammatory, anti-irritant, antidiarrheal, antispasmodic, antimalarial, analgesic, antipyretic, anti-diabetic, diuretic, and hepatoprotective effects were discussed in this review otherwise. Also, the ethnopharmacological effects of this genus were reviewed. Among all the Trichodesma species, T. indicum is regarded as the most important one regarding its pharmacological values. The volatile oil of T. africanum L. showed high antioxidant activity

Enhanced calcium entry via activation of NOX/PKC underlies increased vasoconstriction induced by methylglyoxal

Advanced glycation end-products (AGEs) play a pivotal role in macro- and micro-vascular diabetic complications. We investigated the mechanism by which methylglyoxal (an endogenous generator of AGEs) affects vascular contractility using the isolated artery technique. Contractile responses to vasoconstrictors phenylephrine (PE), angiotensin II (Ang II), vasopressin (VP) and KCl were measured in the isolated rat aorta following one-our exposure to methylglyoxal (50-200μM). The perfused rat kidney was employed to confirm the effect of methylglyoxal on microvessels. Methylglyoxal-induced changes in cytosolic calcium were measured in the smooth muscle layer of the aorta with the calcium-sensing fluorophore Fluo-4 AM. Methylglyoxal significantly increased maximal contraction of the rat aorta to PE, Ang II and VP. Similar results were seen in response to the depolarizing vasoconstrictor KCl in macro and micro vessels. The methylglyoxal-induced increases in aortic contraction mediated by the agonist and KCl were endothelium independent. Methylglyoxal-induced increases in KCl-dependent aortic contraction were abolished after the removal of extracellular calcium or in the presence of the calcium channel blocker nifedipine. Incubation with the antioxidant N-acetyl-l-cysteine (NAC), apocynin (a nonselective NADPH oxidase (NOX) inhibitor) or chelerythrine (a protein kinase C (PKC) inhibitor) prior to methylglyoxal pre-treatment reversed the methylglyoxal-induced increases in the rat aortic contractility. In conclusion, the formation of AGEs increases vasoconstriction of both macro- and micro-vessels by increasing the voltage-activated calcium entry in vascular smooth muscles in a NOX and PKC dependent manne

Arginase overexpression and NADPH oxidase stimulation underlie impaired vasodilation induced by advanced glycation end products

Background: Advanced glycation endproducts (AGEs) play a major role in the development of many vascular complications that are mediated by endothelial dysfunction. The present work aimed to investigate the mechanism by which AGEs impair vasodilation.Methods: The effect of AGEs on vasodilation induced by acetylcholine or D NONOate was examined by incubating isolated rat aortae with different AGEs concentrations. ACh-induced nitric oxide generation was assessed using the fluorescent probe diaminofluorecein (DAF-FM). The effect of AGEs on expressionof mRNA for arginase 2, NADPH oxidase and endothelial nitric oxide synthase (eNOS) were determined by real-time PCR.Results: One-hour in vitro incubation of rat aortae with AGEs impaired endothelial-dependent vasodilation produced by ACh, while increasing D NONOate-induced vasodilation. Preincubation of aortae with L-ornithine, an arginase 2-inhibitor, prevented the impairment effect induced by AGEs on endothelial dependent vasodilation. Superoxide scavenging by tempol or NADPH oxidase inhibition by apocynin also blocked the effect of AGEs. AGEs decreased ACh-induced NO production and this was inhibited by both L-ornithine and apocynin. Furthermore, AGEs exposure increased arginase mRNA expression butdecreased mRNA expression for eNOS in isolated rat aortae.Conclusion: The present results indicate that AGEs impairs endothelial-dependent vasodilation, and this effect is mediated via arginase overexpression and NADPH oxidase stimulation

6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation

The aim of the present study is to investigate the effect and potential mechanism of action of 6-gingerol on alterations of vascular reactivity in the isolated aorta from diabetic rats. Male Wistar rats were divided into two experimental groups, control and diabetics. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg kg(−1)), and the rats were left for 10 weeks to develop vascular complications. The effect of in vitro incubation with 6-gingerol (0.3–3 μM) on the vasoconstrictor response of the isolated diabetic aortae to phenylephrine and the vasodilator response to acetylcholine was examined. Effect of 6-gingerol was also examined on aortae incubated with methylglyoxal as an advanced glycation end product (AGE). To investigate the mechanism of action of 6-gingerol, the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride (100 μM), guanylate cyclase inhibitor methylene blue (5 μM), calcium-activated potassium channel blocker tetraethylammonium chloride (10 mM), and cyclooxygenase inhibitor indomethacin (5 μM) were added 30 minutes before assessing the direct vasorelaxant effect of 6-gingerol. Moreover, in vitro effects of 6-gingerol on NO release and the effect of 6-gingerol on AGE production were examined. Results showed that incubation of aortae with 6-gingerol (0.3–10 μM) alleviated the exaggerated vasoconstriction of diabetic aortae to phenylephrine in a concentration-dependent manner with no significant effect on the impaired relaxatory response to acetylcholine. Similar results were seen in the aortae exposed to methylglyoxal. In addition, 6-gingerol induced a direct vasodilation effect that was significantly inhibited by Nω-nitro-l-arginine methyl ester hydrochloride and methylene blue. Furthermore, 6-gingerol stimulated aortic NO generation but had no effect on AGE formation. In conclusion, 6-gingerol ameliorates enhanced vascular contraction in diabetic aortae, which may be partially attributed to its ability to increase the production of NO and stimulation of cyclic guanosine monophosphate