Diuretic effects of Hecogenin and Hecogenin acetate via aldosterone synthase inhibition.

Hecogenin (HEC) is a steroidal saponin found in many plant species and serves as a precursor for steroidal drugs. The diuretic effects of HEC and its derivative, hecogenin acetate (HA), remain largely unexplored. The present study aimed to explore the potential diuretic effects of HEC and HA compared to furosemide (FUR) and spironolactone (SPIR). Additionally, the study aimed to explore the underlying mechanism particularly focusing on aldosterone synthase gene expression. Fifty-four Sprague-Dawley rats were allocated into nine groups (Group 1-9). Group 1 (control) received the vehicle, Groups 2 received FUR 10 mg/kg, Group 3, 4, and 5 were given HEC, while Groups 6, 7 and 8 received HA i.p at doses of 5, 10, and 25 mg/kg, respectively. Group 9 received SPIR i.p at the dose of 25 mg/kg. Urine volume, diuretic index and diuretic activity were monitored at 1, 2, 3, 4, 5, 6, and 24 h post-administration. Treatment was given daily for seven days. After that, rats were sacrificed and blood was collected for serum electrolytes determination. Adrenal glands were dissected out for gene expression studies. The results revealed that HEC and HA at the administered doses significantly and dose-dependently increased urine and electrolyte excretion. These results were primarily observed at 25 mg/kg of each compound. Gene expression studies demonstrated a dose-dependent reduction in aldosterone synthase gene expression, suggesting aldosterone synthesis inhibition as a potential mechanism for their diuretic activity. Notably, HA exhibited more pronounced diuretic effects surpassing those of HEC. This enhanced diuretic activity of HA can be attributed to its stronger impact on aldosterone synthase inhibition. These findings offer valuable insights into the diuretic effects of both HEC and HA along with their underlying molecular mechanisms.

Protective Effects of 2-Methoxyestradiol on Acute Isoproterenol-Induced Cardiac Injury in Rats.

Myocardial injury (MI) is an important pathological driver of mortality worldwide., and arises as a result of imbalances between myocardial oxygen demand and supply. In MI, oxidative stress often leads to inflammatory changes and apoptosis. Current therapies for MI are known to cause various adverse effects. Consequently, the development of new therapeutic agents with a reduced adverse event profile is necessary. In this regard, 2-methoxyestradiol (2ME), the metabolic end-product of oestradiol, possesses anti-inflammatory and antioxidant properties. The aim of this research is to assess the impact of 2ME on cardiac injury caused by isoproterenol (ISO) in rats. Animals were separated into six groups; controls, and those receiving 2ME (1 mg/kg), ISO (85 mg/kg), ISO + 2ME (0.25 mg/kg), ISO + 2ME (0.5 mg/kg), and ISO + 2ME (1 mg/kg). 2ME significantly attenuated ISO-induced changes in electrocardiographic changes and the cardiac histological pattern. This compound also decreased lactate dehydrogenase activity, creatine kinase myocardial band and troponin levels. The ability of 2ME to act as an antioxidant was shown by a decrease in malondialdehyde concentration, and the restoration of glutathione levels and superoxide dismutase activity. Additionally, 2ME antagonized inflammation and cardiac cell apoptosis, a process determined to be mediated, at least partially, by suppression of Gal-3/TLR4/MyD88/NF-κB signaling pathway. 2ME offers protection against acute ISO-induced MI in rats and offers a novel therapeutic management option.

2-Methoxyestradiol inhibits carotid artery intimal hyperplasia induced by balloon injury via inhibiting JAK/STAT axis in rats.

Intimal hyperplasia (IH) is a common complication of vascular interventional procedures that leads to narrowing of the vessel lumen. 2-Methoxyestradiol (2ME), an estrogen metabolite, has numerous pharmacological actions, including vasoprotective and antiproliferative activities. The present study aimed to evaluate the potential of 2ME, prepared as a self-nanoemulsifying drug delivery system (SNEDDS), to inhibit IH induced by balloon injury (BI) in the rat carotid artery. The prepared 2ME SNEDDS had a particle size of 119 ± 2.3 nm and a zeta potential of -7.1 ± 1.4 mV. Animals were divided into 5 groups, namely control, sham, BI, BI + 2ME (100 µg/kg), and BI + 2ME (250 µg/kg). The obtained data indicated that 2ME significantly inhibited IH as indicated by the histological and morphometric assessment of the intima, media and lumen areas. This was associated with enhanced expression of Bax and inhibited expression of Bcl2 mRNA. Furthermore, 2ME exhibited significant antioxidant properties as evidenced by prevention of malondialdehyde accumulation as well as superoxide dismutase and catalase enzymatic exhaustion. In addition, 2ME showed significant anti-inflammatory actions as it significantly inhibited vascular content of interleukin-6, tumor necrosis factor-alpha, and nuclear factor-κB. The observed vasoprotective activities of 2ME were accompanied by inhibition of Janus kinase/signal transducers and activators of transcription (JAK/STAT) protein expression. In conclusion, this study revealed that 2ME ameliorates balloon injury-induced IH in rats via suppressing JAK/STAT axis. This may help to develop new strategies to combat IH.

2-Methoxyestradiol ameliorates metabolic syndrome-induced hypertension and catechol-O-methyltransferase inhibited expression and activity in rats.

Metabolic syndrome (MetS) is a common disorder that is associated with hypertension and poses a significant cardiovascular risk. Deactivation of extra-neuronal norepinephrine is mediated by catechol-O-methyltransferase (COMT). Endogenous 2-methoxyestradiol (2ME) is a product of COMT activity. The current study investigated the impact of 2ME on MetS-induced hypertension and the possible alterations in COMT expression and activity in rats. Animals were randomly divided into 4 groups. Group 1 received drinking water and standard food pellets. Groups 2, 3 and 4 were subjected to experimental induction of MetS. Animals in groups 3 and 4 were given daily IP injection of 2ME (25 and 50 mg/kg, respectively). MetS animals showed significant increases in body weight gain and visceral fat, fasting blood glucose and serum insulin and insulin resistance. Meanwhile, MetS was associated with a significant hypertriglyceridemia. Further, MetS significantly increased systolic, diastolic and mean arterial blood pressure. These effects were associated with significant reduction in COMT expression in the liver, kidneys and aorta as well as reduced hepatic activity. 2ME inhibited the alterations in body weight gain, visceral fat accumulation, fasting blood glucose and serum insulin, insulin resistance and serum triglycerides. Elevations in blood pressure were significantly inhibited by 2ME. Also, it attenuated the decrease in liver, kidney and aorta COMT expression and hepatic COMT activity. MetS was associated with elevated epinephrine and norepinephrine levels. Only the higher dose of 2ME significantly mitigated the rise in epinephrine level. In conclusion, 2ME protects against MetS-induced hypertension and averts COMT inhibited expression and activity.

2-Methoxyestradiol Attenuates Testosterone-Induced Benign Prostate Hyperplasia in Rats through Inhibition of HIF-1α/TGF-ß/Smad2 Axis.

Benign prostatic hyperplasia (BPH) is a common disorder in the male population. 2-Methoxyestradiol (2ME) is an end metabolite of estrogens with pleiotropic pharmacological properties. This study aimed to explore the potential ameliorative effects of 2ME against testosterone-induced BPH in rats. 2-Methoxyestradiol (50 and 100 mg/kg, dissolved in DMSO) prevented the rise in prostatic index and weight in comparison to testosterone-alone-treated animals for 2 weeks. Histological examination indicated that 2ME ameliorated pathological changes in prostate architecture. This was confirmed by the ability of 2ME to decrease the glandular epithelial height when compared to the testosterone group. Also, 2ME improved testosterone-induced oxidative stress as it inhibited the rise in lipid peroxide content and the exhaustion of superoxide dismutase (SOD) activity. The beneficial effects of 2ME against the development of BPH were substantiated by assessing proliferation markers, preventing the rise in cyclin D1 protein expression and enhancing Bax/Bcl2 mRNA ratio. It significantly reduced prostate content of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), nuclear factor κB (NF-κB), and transforming growth factor ß (TGF-ß). In addition, 2ME reduced hypoxia-inducible factor 1-α (HIF-1α) and phospho-Smad2 (p-Smad2) protein expression compared to the testosterone group. In conclusion, 2ME attenuates experimentally induced BPH by testosterone in rats through, at least partly, inhibition of HIF-1α/TGF-ß/Smad2 axis.

Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies - A review.

Recent strategies for the treatment of cancer, other than just tumor cell killing have been under intensive development, such as anti-angiogenic therapeutic approach. Angiogenesis inhibition is an important strategy for the treatment of solid tumors, which basically depends on cutting off the blood supply to tumor micro-regions, resulting in pan-hypoxia and pan-necrosis within solid tumor tissues. The differential activation of angiogenesis between normal and tumor tissues makes this process an attractive strategic target for anti-tumor drug discovery. The principles of anti-angiogenic treatment for solid tumors were originally proposed in 1972, and ever since, it has become a putative target for therapies directed against solid tumors. In the early twenty first century, the FDA approved anti-angiogenic drugs, such as bevacizumab and sorafenib for the treatment of several solid tumors. Over the past two decades, researches have continued to improve the performance of anti-angiogenic drugs, describe their drug interaction potential, and uncover possible reasons for potential treatment resistance. Herein, we present an update to the pre-clinical and clinical situations of anti-angiogenic agents and discuss the most recent trends in this field.

Icariin protects against thioacetamide-induced liver fibrosis in rats: Implication of anti-angiogenic and anti-autophagic properties.

BACKGROUND: Liver fibrosis is a major health problem. The current study evaluated the potential of icariin (ICA) to guard against thioacetamide (TAA)-induced liver fibrosis in rats. METHODS: Four groups of male rats were treated as follows: group 1 was the control group, group 2 was given TAA (200mg/kg), group 3 was administered ICA (50mg/kg) and TAA (200mg/kg), and group 4 was given ICA (50mg/kg) alone. Animal treatment was continued for four weeks. RESULTS: Co-administration of ICA guarded against TAA hepatotoxicity as indicated by significant inhibition in the rise of serum ALT and AST activities and albumin concentrations. This was accompanied by inhibition of reduced glutathione depletion, superoxide dismutase exhaustion, and lipid peroxide accumulation. In addition, ICA inhibited the pathological alterations in liver architecture induced by TAA. The antifibrotic activity of ICA was verified by reduced hepatic collagen deposition in liver sections stained with Masson's trichrome and hepatic Col-1α mRNA and hydroxyproline contents compared to the TAA-treated group. The antiangiogenic activity of ICA was evidenced by lowered levels of mRNA of Ang-1 and protein expression of VEGF, PDGF-ß, and CTGF immunohistochemically. Further, the anti-autophagic property of ICA was evidenced by amelioration of the decrease in mTOR and p70S6 kinase expression and an increase in TLR4, NFκB, IL1-ß, and COX-2 immunohistochemically. Moreover, ICA antagonized the increase in HMGB1, TGF-ß, and Beclin-1 and the decrease in BAMBI hepatic mRNA levels. CONCLUSIONS: ICA inhibits TAA-induced liver fibrosis in rats, possibly via inhibition of angiogenesis and autophagy.

Gingerol protects against experimental liver fibrosis in rats via suppression of pro-inflammatory and profibrogenic mediators.

6-Gingerol (Gin) is known to possess hepatoprotective effects. Liver fibrosis is a major health concern that results in significant morbidity and mortality. There is no FDA-approved medication for liver fibrosis. The present work aimed at exploring the beneficial effects of Gin against liver fibrosis in rats. Experimental fibrosis was induced by challenging animals with CCl4 for 6 weeks. Gin significantly ameliorated the increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, albumin, total cholesterol (TC) and triglyceride (TG) concentrations, and liver index. These effects were confirmed by light and electron microscopic examinations. The antifibrotic effects were confirmed by examining Masson trichrome-stained liver sections which indicated reduced collagen deposition in Gin-treated animals. Further, Gin administration hampered alpha-smooth muscle actin (α-SMA) expression and significantly reduced hepatic content of transforming growth factor-beta (TGF-ß). Also, Gin elicited profound antioxidant actions as indicated by preventing reduced glutathione (GSH) depletion and lipid peroxide accumulation. The observed antifibrotic activities involved decreased production of nuclear factor κB (NF-κB), tumor necrosis factor alpha (TNF-α), expression of toll-like receptor 4 (TLR4), intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM). Involvement of Gin anti-inflammatory activity was verified by the decreased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in livers of animals treated with Gin. Thus, it can be concluded that Gin protects against CCl4-induced liver fibrosis in rats. This can be ascribed, at least partly, to its antioxidant, anti-inflammatory effects as well as the inhibition of NF-κB/TLR-4 expression.

Curcumin-Zein Nanospheres Improve Liver Targeting and Antifibrotic Activity of Curcumin in Carbon Tetrachloride-Induced Mice Liver Fibrosis.

Liver fibrosis is a major health problem that has no satisfactory medication. Curcumin, (CUR) although known for its antifibrotic activity, has limited medicinal use owing to its poor oral pharmacokinetic properties and targeting efficiency. The current study aimed at exploring the ability of zein (ZN) nanospheres to improve the liver targeting and antifibrotic activity of CUR in a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis. Four different formulae of ZN-loaded CUR were prepared and examined in terms of particle size, zeta potential, encapsulation efficiency, and in vitro permeation. The formula containing a CUR to ZN ratio of 1:3 showed optimum nanosphere properties and was subjected to further investigations. Under a scanning electron microscope, the selected formula showed spherical particles with uniform size distribution. In normal mice, the selected formula exhibited improved bioavailability and liver targeting efficiency compared to raw CUR. The nanosphere preparation also offered significant protection against CCl4-induced liver function deterioration, histopathological changes, and oxidative stress in mice. Compared to raw CUR, CUR-ZN was significantly more effective in attenuating the rise in hepatic gene expression of collagen-1, tissue inhibitor of metalloproteinase-2, and transforming growth factor beta, as well as the downregulation of matrix metalloproteinase-2 expression. Masson's trichrome staining confirmed the higher antifibrotic activity of the nanospheres that ameliorated the rise in hepatic hydroxyproline content and collagen-1-immunopositive areas in mice liver sections. In conclusion, CUR-ZN nanospheres demonstrated improved liver targeting efficiency and antifibrotic activity in comparison to raw CUR in CCl4-induced liver fibrosis in mice.

Ameliorative effect of lycopene against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced rat liver microsomal toxicity: an in vitro study.

The objective of the current study was to investigate the potential oxidative damage of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hepatic microsomal fractions in vitro and to further elucidate the potential modulatory effect of lycopene. Rat liver microsomes were divided into four groups. Group I served as a control and is incubated with vehicle (toluene). Groups II and IV were incubated with 20 µM lycopene for 1 h before further incubating; groups III and IV with 15 nM of TCDD for further 1 h. Hydrogen peroxide (H2O2) production, lipid peroxidation (LPO), protein carbonyl content and activities of uridine 5'-diphospho-glucuronyltransferase (UDPGT) and P450 were significantly increased. Moreover, the activity of antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalse, glutathione-S-transferase and glutathione reductase as well as the microsomal thiol content were significantly decreased. Incubation with lycopene (group IV) maintained near normal activities of the enzymes, normalized thiol and carbonyl content and significantly reduced LPO and H2O2 production. In conclusion, the findings of the study indicate that TCDD induces a significant oxidative stress in liver microsomes as manifested by increased LPO, H2O2 production, protein carbonyl content and activities of UDPGT and P450 and decreased antioxidant enzymes activities and thiol content. By the reversal of biochemical and oxidative markers toward normalcy, the protective role of lycopene is illuminated in rat liver microsomal toxicity.

Anti-inflammatory activity of selected plants from Saudi Arabia.

Thirteen selected Saudi Arabian plants, belonging to seven different families, were tested for possible anti-inflammatory activity using the carrageenin-induced paw edema model in rats. The methanolic extracts of Vernonia schimperi, Trichodesma trichodesmoides var. tomentosum, and Anabasis articulata exhibited the highest anti-inflammatory activity. The active extracts were further subjected to fractionation with chloroform, ethyl acetate, and n-butanol and tested together with their mother liquor for their anti-inflammatory activity in the same rat model. The most potent fractions were the n-butanol fractions of Anabasis articulata and Vernonia shimperi and the aqueous mother liquor of Trichodesma trichodesmoides. Nevertheless, the three potent methanolic extracts showed higher anti-inflammatory activities than their individual fractions. The antioxidant properties were assessed by their in vitro 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging activities. It was concluded that the anti-inflammatory activity is dependent, at least in part, on the reduction of prostaglandin (PGE2) and tumour necrosis factor-alpha (TNF-alpha) levels and cyclooxygenase-2 (COX-2) activity.

Evaluation of the potential cardioprotective activity of some Saudi plants against doxorubicin toxicity.

Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumours. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. The local Saudi flora is very rich in a variety of plants of quite known folkloric or traditional medicinal uses. Tribulus macropterus Boiss., Olea europaea L. subsp. africana (Mill.) P. S. Green, Tamarix aphylla (L.) H. Karst., Cynomorium coccineum L., Cordia myxa L., Calligonum comosum L' Hér, and Withania somnifera (L.) Dunal are Saudi plants known to have antioxidant activities. The aim of the current study was to explore the potential protective effects of methanolic extracts of these seven Saudi plants against DOX-induced cardiotoxicity in rats. Two plants showed promising cardioprotective potential in the order Calligonum comosum > Cordia myxa. The two plant extracts showed potent in vitro radical scavenging and antioxidant properties. They significantly protected against DOX-induced alterations in cardiac oxidative stress markers (GSH and MDA) and cardiac serum markers (CK-MB and LDH activities). Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. In conclusion, C. comosum and C. myxa exerted protective activity against DOX-induced cardiotoxicity, which is, at least partly, due to their antioxidant effect.

Anti-inflammatory and antiproliferative activities of date palm pollen (Phoenix dactylifera) on experimentally-induced atypical prostatic hyperplasia in rats.

BACKGROUND: Atypical prostatic hyperplasia (APH) is a pseudoneoplastic lesion that can mimic prostate adenocarcinoma because of its cytologic and architectural features. Suspension of date palm pollen (DPP) is an herbal mixture that is widely used in folk medicine for male infertility. The aim of the present study was to evaluate the effect of DPP suspension and extract on APH-induced rats. METHODS: APH was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100mg/kg), DPP suspension (250, 500 and 1000 mg/kg), and lyophilized DPP extract (150,300 and 600 mg/kg) were given orally daily for 30 days. All medications were started 7 days after castration and along with testosterone and citral. RESULTS: The histopathological feature in APH-induced prostate rats showed evidence of hyperplasia and inflammation. Immunohistochemical examination revealed that the expressions of IL-6, IL-8, TNF-α, IGF-1 and clusterin were increased, while the expression of TGF-ß1 was decreased that correlates with presence of inflammation. Moreover, histopathological examination revealed increased cellular proliferation and reduced apoptosis in ventral prostate. Both saw palmetto and DPP treatment has ameliorated these histopathological and immunohistochemical changes in APH-induced rats. These improvements were not associated with reduction in the prostatic weight that may be attributed to the persistence of edema. CONCLUSION: DPP may have a potential protective effect in APH-induced Wistar rats through modulation of cytokine expression and/or upregulation of their autocrine/paracrine receptors.

Changes in nitric oxide and free radical levels in rat gastrocnemius muscle during contraction and fatigue.

1. The ratio of nitric oxide (NO) to free radicals is critical during skeletal muscle contraction. Changes in this ratio have been suggested to play a role in muscle fatigue. 2. The aim of the present study was to investigate the changes in NO and free radicals during tetanic and subtetanic contraction and fatigue in the gastrocnemius muscle of adult male Wistar rats. 3. Rats were subjected to either low- or high-frequency stimulation (10 and 100 Hz, respectively) of the right gastrocnemius muscle. Both groups were further subdivided into untreated (0.9% NaCl solution), N(G) -nitro-L-arginine methyl ester (L-NAME)-treated and reduced glutathione (GSH)-treated groups. Rats were administered their treatments intraperitoneally 30 min prior to electrical stimulation. 4. Levels of both NO and lipid peroxides increased significantly during peak force contraction for either type of contractions, with a more significant response during subtetanic contraction. Treatment with L-NAME significantly reduced the maximal force and this effect was more marked in the low frequency-stimulated group. Although peroxides levels were reduced by GSH, it had no significant effect on force production. In L-NAME-treated rats, the onset of 50% fatigue was accelerated with a significant increase in peroxides levels, whereas the opposite effects were observed after GSH treatment. 5. Current results reflect the importance of endogenous NO, as an anti-oxidant, in aiding muscle performance by overcoming oxidative stress during fatigue. They provide a possible explanation as to why patients with myopathies like Duchenne muscular dystrophy, in which dystrophin is lacking suffer from muscle weakness and fatigue easily.

Protective effect of bilberry (Vaccinium myrtillus) against doxorubicin-induced oxidative cardiotoxicity in rats.

BACKGROUND: Doxorubicin (DOX) is a commonly used chemotherapeutic agent. It is associated with serious dose-limiting cardiotoxicity, which is at least partly caused by generation of reactive oxygen species (ROS). Supplementations with bilberries were effective in reducing oxidative stress in many tissue injuries due their high content of antioxidants. The present study investigated the potential protective effect of bilberry extract against DOX-induced cardiotoxicity in rats. MATERIAL/METHODS: Rats were treated orally with a methanolic extract of bilberry for 10 days. DOX was injected intraperitoneally on day 7. Twenty-four hours after the last bilberry administration, rats were subjected to ECG study. Blood was then withdrawn and cardiac tissues were dissected for assessment of oxidative stress and cardiac tissue injury. Cardiac tissues were also subjected to histopathological examination. RESULTS: Bilberry extract significantly inhibited DOX-provoked reduced glutathione depletion and accumulation of oxidized glutathione, malondialdehyde and protein carbonyls in cardiac tissues. This was accompanied by significant amelioration of reduced cardiac catalase, superoxide dismutase, and glutathione peroxidase activities; and increased cardiac myeloperoxidase activity in response to DOX challenge. Pretreatment with bilberry significantly guarded against DOX-induced increase in serum activities of lactate dehydrogenase, creatine phosphokinase and creatine kinase-MB, as well as the level of troponin I. Bilberry alleviated ECG changes in rats treated with DOX and attenuated its pathological changes. CONCLUSIONS: Bilberry protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to its antioxidant activity.

Mechanisms of the antihyperglycemic activity of Retama raetam in streptozotocin-induced diabetic rats.

Retama raetam (RR) fruits are used in Saudi traditional medicine for the treatment of diabetes. Current study aimed at evaluating the potential and mechanisms of the antidiabetic activity of the RR methanolic extract in streptozotocin-induced diabetic rats. Oral LD(50) of the extract was found to be 1995 mg/kg. The extract was administered once orally to STZ-diabetic rats at three dose levels; 100, 250 or 500 mg/kg/day for 4 consecutive weeks. RR extract at 250 or 500 mg/kg significantly lowered blood glucose levels at the 3rd and 1st week of treatment, respectively. Meanwhile, oral glucose tolerance test indicated that the same two doses significantly lowered glucose levels at 30 and 60 min after glucose challenge. Administration of RR extract at 500 mg/kg/day for 4 consecutive weeks significantly increased serum insulin level. In vitro studies indicated that the extract significantly inhibits glucose absorption by rat isolated intestine. The extract neither altered glucose uptake by rat isolated psoas muscle nor the activity of hepatic microsomal glucose-6-phosphatase. In conclusion, the methanolic extract of RR improves STZ-induced diabetes in rats. This can be attributed, at least partly, to stimulating pancreatic insulin release and reducing intestinal glucose absorption.

Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats.

Doxorubicin (DOX) is a widely used cancer chemotherapeutic agent. However, it generates free oxygen radicals that result in serious dose-limiting cardiotoxicity. Supplementations with berries were proven effective in reducing oxidative stress associated with several ailments. The aim of the current study was to investigate the potential protective effect of cranberry extract (CRAN) against DOX-induced cardiotoxicity in rats. CRAN was given orally to rats (100mg/kg/day for 10 consecutive days) and DOX (15mg/kg; i.p.) was administered on the seventh day. CRAN protected against DOX-induced increased mortality and ECG changes. It significantly inhibited DOX-provoked glutathione (GSH) depletion and accumulation of oxidized glutathione (GSSG), malondialdehyde (MDA), and protein carbonyls in cardiac tissues. The reductions of cardiac activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were significantly mitigated. Elevation of cardiac myeloperoxidase (MPO) activity in response to DOX treatment was significantly hampered. Pretreatment of CRAN significantly guarded against DOX-induced rise of serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), creatine kinase-MB (CK-MB) as well as troponin I level. CRAN alleviated histopathological changes in rats' hearts treated with DOX. In conclusion, CRAN protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to CRAN's antioxidant activity.

Gastroprotective effects of the insulin sensitizers rosiglitazone and metformin against indomethacin-induced gastric ulcers in Type 2 diabetic rats.

1. Gastric ulcers are common in Type 2 diabetic patients. Of all drugs used in the treatment of Type 2 diabetes, the insulin sensitizers thiazolidinediones (e.g. rosiglitazone) and metformin exhibit additional effects in ameliorating oxidative stress and inflammation, rendering them attractive candidates for the prevention of gastric ulcer in Type 2 diabetes. Thus, the aim of the present study was to evaluate the gastroprotective effects of rosiglitazone and metformin against indomethacin-induced gastric ulcer in Type 2 diabetic and non-diabetic rats. 2. Diabetes was induced by a single injection of streptozotocin (60 mg/kg, i.p., dissolved in 0.1 mol/L cold citrate buffer, pH 4.5), 15 min after administration of 120 mg/kg, i.p., nicotinamide. Three weeks after the successful induction of diabetes, rats were subjected to pyloric ligation and then injected immediately with 30 mg/kg, i.p., indomethacin. Three hours after indomethacin administration, rats were killed and gastric injury was evaluated. Ranitidine (50 mg/kg) was used as a reference drug and was administered in a single oral dose 1 h before indomethacin injection, as were rosiglitazone (3 mg/kg) and metformin (500 mg/kg). 3. Both rosiglitazone and metformin exhibited gastroprotective effects, as evidenced by significant decreases in the ulcer index, free and total acid output in gastric juice and gastric mucosal malondialdehyde concentrations, with concomitant increases in gastric juice pH (only with rosiglitazone), mucin concentrations, gastric mucosal concentrations of nitric oxide and catalase activity compared with untreated diabetic rats. Conversely, rosiglitazone and metformin had no effect on peptic activity and gastric mucosal prostaglandin E(2) content, particularly in the diabetic group, compared with the untreated groups. 4. In conclusion, rosiglitazone and metformin protect Type 2 diabetic rats against indomethacin-induced gastric ulceration, most possibly via antisecretory actions, enhanced mucosal protection and anti-oxidant activity. Rosiglitazone seems to be provide superior gastroprotection to metformin.

Angiotensin-converting enzyme inhibition and angiotensin AT(1)-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity.

Doxorubicin (Dox) is a potent anticancer agent; its clinical use is limited for its marked cardiotoxicity and nephrotoxicity. The present study investigated the possible protective effect of telmisartan, an angiotensin AT(1)-receptor blocker versus captopril, an angiotensin-converting enzyme inhibitor, on Dox-induced cardiotoxicity and nephrotoxicity in rats. Rats were allocated into four groups. Control group, Dox group, Dox+telmisartan group, and Dox+captopril group. Cardiotoxicity and nephrotoxicity were assessed biochemically and histopathologically. Frozen heart and kidney specimens were used for estimation of lipid peroxides product (MDA), reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and nitric oxide (NO). Expression of induced nitric oxide synthase (iNOS) was detected by immunohistochemistry. Coadministration of either telmisartan or captopril with Dox equally decreased the biochemical markers of both cardiotoxicity (LDH and CK-MP) and nephrotoxicity (urea and creatinine). Both telmisartan and captopril attenuated the effects of Dox on oxidative stress parameters and NO. Histopathologically, coadministration of either drug with Dox was able to attenuate Dox-induced myocardial fibrosis and renal tubular damage. Immunohistochemistry, expression of iNOS was increased in both cardiac and renal tissues. Both telmisartan and captopril significantly and equally attenuated the effect of Dox on all measured parameters. These results suggested that telmisartan has protective effects equal to that of captopril against Dox-induced cardiotoxicity and nephrotoxicity; implying that angiotensin II pathway plays a role in Dox-induced cardiac and renal damage. The protective effect of either drug relies, at least in part, on their antioxidant effects and decreased the expression of iNOS.

Melatonin protects against hydrogen peroxide-induced gastric injury in rats.

1. Melatonin (MT) is a pineal hormone that is also abundant in the gut and has a well known role in scavenging oxygen free radicals. The aim of the present study was to evaluate the potential protective effects of MT against H(2)O(2)-induced gastric lesions in rats. 2. An experimental model of gastric ulceration was established in rats using 15% H(2)O(2). Melatonin (12.5, 25 or 50 mg/kg, intagastrically) was administered to rats 30 min before H(2)O(2) challenge. 3. Intragastric administration of H(2)O(2) resulted in haemorrhagic lesions in the fundic area of the stomach. Furthermore, H(2)O(2) induced gastric oxidative stress, as indicated by depletion of reduced glutathione (GSH), inhibition of glutathione peroxidase (GPx) activity and elevation of malonedialdehyde (MDA) levels. These effects were accompanied by decreased gastric tissue levels of prostaglandin (PG) E(2) and nitric oxide (NO), as well as increased levels of tumour necrosis factor (TNF)-alpha. Administration of MT (12.5, 25 or 50 mg/kg) 30 min before H(2)O(2) significantly attenuated the development of gastric lesions in a dose-dependent manner. The protective effects of MT were accompanied by significant inhibition of the H(2)O(2)-induced reduction in gastric content of GSH and GPx activity and elevation in MDA levels. Furthermore, MT antagonized H(2)O(2)-induced reduction of gastric PGE(2) and NO levels and elevation of TNF-alpha. 4. In conclusion, MT protects rat gastric mucosa against H(2)O(2)-induced damage. The observed protective effects of MT can be attributed, at least in part, to its anti-oxidant properties, preservation of PGE(2) and NO levels, as well as inhibition of TNF-alpha induction in gastric tissues.