Lisofylline mitigates cardiac inflammation in a mouse model of obesity through improving insulin secretion and activating cardiac AMPK signaling pathway.

Obesity has emerged as a leading cause of death in the last few decades, mainly due to associated cardiovascular diseases. Obesity, inflammation, and insulin resistance are strongly interlinked. Lisofylline (LSF), an anti-inflammatory agent, demonstrated protection against type 1 diabetes, as well as reduced obesity-induced insulin resistance and adipose tissue inflammation. However, its role in mitigating cardiac inflammation associated with obesity is not well studied. Mice were divided into 4 groups; the first group was fed regular chow diet, the second was fed regular chow diet and treated with LSF, the third was fed high fat diet (HFD), and the fourth was fed HFD and treated with LSF. Cardiac inflammation was interrogated via expression levels of TNF α, interleukins 6 and 10, phosphorylated STAT4 and lipoxygenases 12 and 12/15. Apoptosis and expression of the survival gene, AMPK, were also evaluated. We observed that LSF alleviated obesity-induced cardiac injury indirectly by improving both pancreatic ß-cell function and insulin sensitivity, as well as, directly via upregulation of cardiac AMPK expression and downregulation of cardiac inflammation and apoptosis. LSF may represent an effective therapy targeting obesity-induced metabolic and cardiovascular complications.

Treg cells depletion is a mechanism that drives microvascular dysfunction in mice with established hypertension.

BACKGROUND: Microvascular dysfunction is a major complication in hypertensive patients. We previously reported that CD4+CD25+ T regulatory cells (Treg) play an important preventive role in hypertension-induced vascular dysfunction. However, whether Treg cells therapy and autophagy inhibition could rescue Treg cells survival and microvascular function in established hypertension is an important question that remained unanswered. METHODS & RESULTS: Here we showed that Treg cells from mice model of established hypertension displayed an enhanced apoptotic rate, which was rescued with Treg cells transfer and autophagy inhibition. We also showed increased autophagy in mesenteric resistance artery (MRA) in mice with established hypertension. Importantly, the inhibition of autophagy or one single transfer of Treg cells into mice with established hypertension improved the microvascular function independently of high blood pressure. The protection involves the modulation of interleukin-10 (IL-10), inflammation, endoplasmic reticulum (ER) stress, oxidative stress, Akt, and eNOS. CONCLUSIONS: The present study suggests that Treg cells survival is regulated by autophagy. Also, Treg cells as a cellular therapy aimed at rescuing the microvascular function through an autophagy-dependent mechanism and independently of arterial blood pressure lowering effects. Because our mouse model of established hypertension mimics the clinical situation, our results have the potential for new therapeutic approaches that involve the manipulation of Treg cells and autophagy to overcome established hypertension-induced cardiovascular complications.

Essential role for smooth muscle cell stromal interaction molecule-1 in myocardial infarction.

OBJECTIVES: Stromal interacting molecule-1 (STIM1) plays a role in coordinating calcium signaling in different cell types. The increase or deletion of STIM1 expression in cardiomyocyte causes cardiac complication. Moreover, the deletion of STIM1 in endothelial cell causes vascular endothelial dysfunction. However, the disruption of STIM1 in smooth muscle cells (SMC) has no effect on endothelial function but protects vascular function when mice are infused with angiotensin-II. Nevertheless, the role of SMC-STIM1 in acute and chronic myocardial infarction (MI) induced by acute ischemia-reperfusion injury and permanent coronary artery occlusion is unknown. METHODS AND RESULTS: Stim1 were generated and crossed into the SM22α-Cre backgrounds. SM22α-Cre causes deletion of STIM1 floxed genes in adult SMC (Stim1). Control and Stim1 mice were subjected to acute ischemia-reperfusion injury. Hearts were then harvested and incubated with triphenyltetrazolium chloride to determine the infarct size. In control mice which are subjected to ischemia-reperfusion, the heart developed a significant infarct associated with an increase in STIM1 expression. Interestingly, the infarct size was substantially reduced in Stim1 mice. The protection in Stim1 mice against ischemia-reperfusion injury involves the modulation of endoplasmic reticulum stress, apoptosis, oxidative stress, protein kinase B, and mitogen-activated protein (MAP) kinase (ERK1/2 and p38) signaling, and inflammation. Furthermore, in another model of chronic MI induced by permanent coronary artery occlusion, SMC-STIM1 disruption significantly reduced myocardial infarct size and improved cardiac function. CONCLUSION: Our results provide new evidence that SMC-STIM1 disruption is a novel mechanism that protects the heart from MI through reduction of endoplasmic reticulum stress, oxidative stress, MAP-Kinase, apoptosis, and inflammation.

Essential role for EGFR tyrosine kinase and ER stress in myocardial infarction in type 2 diabetes.

We previously reported that EGFR tyrosine kinase (EGFRtk) activity and endoplasmic reticulum (ER) stress are enhanced in type 2 diabetic (T2D) mice and cause vascular dysfunction. In the present study, we determined the in vivo contribution of EGFRtk and ER stress in acute myocardial infarction induced by acute ischemia (40 min)-reperfusion (24 h) (I/R) injury in T2D (db-/db-) mice. We treated db-/db- mice with EGFRtk inhibitor (AG1478, 10 mg/kg/day) for 2 weeks. Mice were then subjected to myocardial I/R injury. The db-/db- mice developed a significant infarct after I/R injury. The inhibition of EGFRtk significantly reduced the infarct size and ER stress induction. We also determined that the inhibition of ER stress (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) in db-/db- significantly decrease the infarct size indicating that ER stress is a downstream mechanism to EGFRtk. Moreover, AG1478 and TUDCA reduced myocardium p38 and ERK1/2 MAP-kinases activity, and increased the activity of the pro-survival signaling cascade Akt. Additionally, the inhibition of EGFRtk and ER stress reduced cell apoptosis and the inflammation as indicated by the reduction in macrophages and neutrophil infiltration. We determined for the first time that the inhibition of EGFRtk protects T2D heart against I/R injury through ER stress-dependent mechanism. The cardioprotective effect of EGFRtk and ER stress inhibition involves the activation of survival pathway, and inhibition of apoptosis, and inflammation. Thus, targeting EGFRtk and ER stress has the potential for therapy to overcome myocardial infarction in T2D.

Essential Role of IL-12 in Angiogenesis in Type 2 Diabetes.

Recently, IL-12 emerged as a critical player in type 2 diabetes complications. We previously reported that ischemia-induced angiogenesis is compromised in type 2 diabetic mice. In this study, we determined that IL-12 disruption rescued angiogenesis and arteriogenesis in type 2 diabetic mice. To induce type 2 diabetes, wild-type (WT), p40IL-12-/- (p40-/-), and p35IL-12-/- (p35-/-) mice were fed a high-fat diet (HFD) for 12 weeks. Body weight, glucose test tolerance, and insulin test tolerance were assessed. After 12 weeks of an HFD, the femoral artery was ligated and blood flow recovery was measured every week for 4 weeks. WT, p40-/-, and p35-/- mice fed an HFD become obese after 12 weeks and exhibit glucose intolerance and insulin resistance. Blood flow recovery was fully restored in 2 to 3 weeks after femoral artery ligation in all groups of mice fed a normal diet. However, after 12 weeks of an HFD, blood flow recovery was compromised in WT mice, whereas it was fully recovered in p40-/- and p35-/- mice. The mechanism of blood flow recovery involves an increase in capillary/arteriole density, endothelial nitric oxide synthase/Akt/vascular endothelial growth factor receptor 2 signaling, and a reduction in oxidative stress and inflammation. The disruption of IL-12 promotes angiogenesis and increases blood flow recovery in obese type 2 diabetic mice by an endothelial nitric oxide synthase/Akt/vascular endothelial growth factor receptor 2/oxidative stress-inflammation-dependent mechanism.

Cardiac Mitochondrial Respiratory Dysfunction and Tissue Damage in Chronic Hyperglycemia Correlate with Reduced Aldehyde Dehydrogenase-2 Activity.

Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial isozyme of the heart involved in the metabolism of toxic aldehydes produced from oxidative stress. We hypothesized that hyperglycemia-mediated decrease in ALDH2 activity may impair mitochondrial respiration and ultimately result in cardiac damage. A single dose (65 mg/kg; i.p.) streptozotocin injection to rats resulted in hyperglycemia with blood glucose levels of 443 ± 9 mg/dl versus 121 ± 7 mg/dl in control animals, p<0.0001, N = 7-11. After 6 months of diabetes mellitus (DM) induction, the rats were sacrificed after recording the functionality of their hearts. Increase in the cardiomyocyte cross sectional area (446 ± 32 µm2 Vs 221 ± 10 µm2; p<0.0001) indicated cardiac hypertrophy in DM rats. Both diastolic and systolic dysfunctions were observed with DM rats compared to controls. Most importantly, myocardial ALDH2 activity and levels were reduced, and immunostaining for 4HNE protein adducts was increased in DM hearts compared to controls. The mitochondrial oxygen consumption rate (OCR), an index of mitochondrial respiration, was decreased in mitochondria isolated from DM hearts compared to controls (p<0.0001). Furthermore, the rate of mitochondrial respiration and the increase in carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-induced maximal respiration were also decreased with chronic hyperglycemia. Chronic hyperglycemia reduced mitochondrial OXPHOS proteins. Reduced ALDH2 activity was correlated with mitochondrial dysfunction, pathological remodeling and cardiac dysfunction, respectively. Our results suggest that chronic hyperglycemia reduces ALDH2 activity, leading to mitochondrial respiratory dysfunction and consequently cardiac damage and dysfunction.

Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction.

OBJECTIVES: Chronic hypertension is the most critical risk factor for cardiovascular disease, heart failure, and stroke. APPROACH AND RESULTS: Here we show that wild-type mice infused with angiotensin II develop hypertension, cardiac hypertrophy, perivascular fibrosis, and endothelial dysfunction with enhanced stromal interaction molecule 1 (STIM1) expression in heart and vessels. All these pathologies were significantly blunted in mice lacking STIM1 specifically in smooth muscle (Stim1(SMC-/-)). Mechanistically, STIM1 upregulation during angiotensin II-induced hypertension was associated with enhanced endoplasmic reticulum stress, and smooth muscle STIM1 was required for endoplasmic reticulum stress-induced vascular dysfunction through transforming growth factor-ß and nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways. Accordingly, knockout mice for the endoplasmic reticulum stress proapoptotic transcriptional factor, CCAAT-enhancer-binding protein homologous protein (CHOP(-/-)), were resistant to hypertension-induced cardiovascular pathologies. Wild-type mice infused with angiotensin II, but not Stim1(SMC-/-) or CHOP(-/-) mice showed elevated vascular nicotinamide adenine dinucleotide phosphate oxidase activity and reduced phosphorylated endothelial nitric oxide synthase, cGMP, and nitrite levels. CONCLUSIONS: Thus, smooth muscle STIM1 plays a crucial role in the development of hypertension and associated cardiovascular pathologies and represents a promising target for cardiovascular therapy.

Increased 4-hydroxy-2-nonenal-induced proteasome dysfunction is correlated with cardiac damage in streptozotocin-injected rats with isoproterenol infusion.

Increase in 4-hydroxy-2-nonenal (4HNE) due to oxidative stress has been observed in a variety of cardiac diseases such as diabetic cardiomyopathy. 4HNE exerts a damaging effect in the myocardium by interfering with subcellular organelles like mitochondria by forming adducts. Therefore, we hypothesized that increased 4HNE adduct formation in the heart results in proteasome inactivation in isoproterenol (ISO)-infused type 1 diabetes mellitus (DM) rats. Eight-week-old male Sprague Dawley rats were injected with streptozotocin (STZ, 65 mg kg(-1) ). The rats were infused with ISO (5 mg kg(-1) ) for 2 weeks by mini pumps, after 8 weeks of STZ injection. We studied normal control (n = 8) and DM + ISO (n = 10) groups. Cardiac performance was assessed by echocardiography and Millar catheter at the end of the protocol at 20 weeks. Initially, we found an increase in 4HNE adducts in the hearts of the DM + ISO group. There was also a decrease in myocardial proteasomal peptidase (chymotrypsin and trypsin-like) activity. Increases in cardiomyocyte area (446 ± 32·7 vs 221 ± 10·83) (µm(2) ), per cent area of cardiac fibrosis (7·4 ± 0·7 vs 2·7 ± 0·5) and cardiac dysfunction were also found in DM + ISO (P < 0·05) relative to controls. We also found increased 4HNE adduct formation on proteasomal subunits. Furthermore, reduced aldehyde dehydrogenase 2 activity was observed in the myocardium of the DM + ISO group. Treatment with 4HNE (100 µM) for 4 h on cultured H9c2 cardiomyocytes attenuated proteasome activity. Therefore, we conclude that the 4HNE-induced decrease in proteasome activity may be involved in the cardiac pathology in STZ-injected rats infused with ISO. Copyright © 2016 John Wiley & Sons, Ltd.

Impaired ALDH2 activity decreases the mitochondrial respiration in H9C2 cardiomyocytes.

Reactive oxygen species (ROS)-mediated reactive aldehydes induce cellular stress. In cardiovascular diseases such as ischemia-reperfusion injury, lipid-peroxidation derived reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are known to contribute to the pathogenesis. 4HNE is involved in ROS formation, abnormal calcium handling and more importantly defective mitochondrial respiration. Aldehyde dehydrogenase (ALDH) superfamily contains NAD(P)(+)-dependent isozymes which can detoxify endogenous and exogenous aldehydes into non-toxic carboxylic acids. Therefore we hypothesize that 4HNE afflicts mitochondrial respiration and leads to cell death by impairing ALDH2 activity in cultured H9C2 cardiomyocyte cell lines. H9C2 cardiomyocytes were treated with 25, 50 and 75 µM 4HNE and its vehicle, ethanol as well as 25, 50 and 75 µM disulfiram (DSF), an inhibitor of ALDH2 and its vehicle (DMSO) for 4 h. 4HNE significantly decreased ALDH2 activity, ALDH2 protein levels, mitochondrial respiration and mitochondrial respiratory reserve capacity, and increased 4HNE adduct formation and cell death in cultured H9C2 cardiomyocytes. ALDH2 inhibition by DSF and ALDH2 siRNA attenuated ALDH2 activity besides reducing ALDH2 levels, mitochondrial respiration and mitochondrial respiratory reserve capacity and increased cell death. Our results indicate that ALDH2 impairment can lead to poor mitochondrial respiration and increased cell death in cultured H9C2 cardiomyocytes.

Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin.

Reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are generated in the myocardium in cardiac disease. 4HNE and other toxic aldehydes form adducts with proteins, leading to cell damage and organ dysfunction. Aldehyde dehydrogenases (ALDHs) metabolize toxic aldehydes such as 4HNE into nontoxic metabolites. Both ALDH levels and activity are reduced in cardiac disease. We examined whether reduced ALDH2 activity contributes to cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin (STZ). These mice exhibited most of the characteristics of metabolic syndrome/type-2 diabetes mellitus (DM): increased blood glucose levels depicting hyperglycemia (415.2 ± 18.7 mg/dL vs. 265.2 ± 7.6 mg/dL; P < 0.05), glucose intolerance with normal plasma insulin levels, suggesting insulin resistance and obesity as evident from increased weight (44 ± 3.1 vs. 34.50 ± 1.32 g; P < 0.05) and body fat. Myocardial ALDH2 activity was 60% lower in these mice (0.1 ± 0.012 vs. 0.04 ± 0.015 µmol/min/mg protein; P < 0.05). Myocardial 4HNE levels were also elevated in the hyperglycemic hearts. Co-immunoprecipitation study showed that 4HNE formed adducts on myocardial ALDH2 protein in the mice exhibiting metabolic syndrome/type-2 DM, and they had obvious cardiac hypertrophy compared with controls as evident from increased heart weight (HW), HW to tibial length ratio, left ventricular (LV) mass and cardiomyocyte hypertrophy. Cardiomyocyte hypertrophy was correlated inversely with ALDH2 activity (R (2 )= 0.7; P < 0.05). Finally, cardiac dysfunction was observed in mice with metabolic syndrome/type-2 DM. Therefore, we conclude that reduced ALDH2 activity may contribute to cardiac hypertrophy and dysfunction in mice presenting with some of the characteristics of metabolic syndrome/type-2 DM when on a high-fat diet and low-dose STZ injection.

Antihypertensive and cardioprotective effects of the Lagenaria siceraria fruit in NG-nitro-L-arginine methyl ester (L-NAME) induced hypertensive rats.

CONTEXT: Lagenaria siceraria (Molina) Standl. (Cucurbitacae) (LS) has been reported to possess cardioprotective, antihyperlipidemic, and diuretic activities. OBJECTIVE: To evaluate antihypertensive and cardioprotective effects of the Lagenaria siceraria fruit powder in N(G)-nitro-L-arginine methyl ester (L-NAME) induced hypertension in rats. MATERIALS AND METHODS: Male Wistar rats were divided in four groups. Control 2% gum acacia p.o., L-NAME (40 mg/kg p.o.), LS (500 mg/kg p.o.) + L-NAME (40 mg/kg p.o.), L-arginine (100 mg/kg p.o.) + L-NAME (40 mg/kg p.o.). Treatment period was 4 weeks. On day 29 serum marker enzymes, cholesterol and heamodynamic parameters were measured. Histology of heart was performed. LS powder was characterized by HPLC. RESULT: Systolic blood pressures were increased by L-NAME (p < 0.001). In both drug treated groups systolic and diastolic blood pressures were reduced significantly (p < 0.001) compared to L-NAME. In L-NAME group significantly (p < 0.01) elevated cholesterol which was reduced (p < 0.05) by LS treatment. In L-NAME group inflammation and necrosis (0-35%) was present in heart whereas there was no change in myocardium of LS and L-arginine treated rats. Vitexin, orientin and isoorientin were detected in methanol extract of LS powder. DISCUSSION AND CONCLUSION: L-NAME induced hypertension in rats was reduced by treatment with LS. The absence of necrosis, inflammation in the heart and significant reduction in serum cholesterol in LS and L-arginine treated rats indicated cardioprotective activity. Antioxidant activity of orientin and isoorientin appears to reduce the L-NAME induced damage. It is concluded that LS fruit possess antihypertensive and cardioprotective activity.

Cardioprotective Activity of Methanol Extract of fruit of Trichosanthes cucumerina on Doxorubicin-induced Cardiotoxicity in Wistar Rats.

AIM AND OBJECTIVE: The objective was to determine the activity of methanol extract of fruit of Trichosanthes cucumerina in doxorubicin-induced cardiotoxicity in rats. MATERIALS AND METHODS: The methanol extract of fruit of T. cucumerina was prepared. Male Wistar rats were divided in four groups. Group I was vehicle control. Group II animals received doxorubicin 4 mg/kg i.p. on days 21, 28, 35, and 42. Group III and IV animals were treated with methanol extract of T. cucumerina (500 and 1000 mg/kg, respectively) for 49 days. Doxorubicin was administered on days 21, 28, 35, and 42 days. The parameters of study were body weight, serum biomarkers, ECG, blood pressure, and left ventricular function. At the end of the study, the histology of heart, liver, and kidney was carried out. RESULTS: Cardiac toxicity by doxorubicin was manifested as body weight loss, elevated serum LDH and CK-MB, increased ST, QT and QRS complex, reduced blood pressure, and left ventricular function. The methanol extract of T. cucumerina significantly decreased LDH and CK-MB, reduced ST, QT interval and QRS complex, increased heart rate, restored blood pressure, and left ventricular function. Doxorubicin caused liver and kidney necrosis, cellular infiltration, and vascular changes that indicated injury. CONCLUSION: T. cucumerina (1000 mg/kg) reduced the severity of doxorubicin-induced cardiac damage especially in heart. It is concluded that doxorubicin-induced cardiotoxicity is reduced by pretreatment with methanol extract of fruit of T. cucumerina.

Effect of Lagenaria siceraria fruit powder on sodium oxalate induced urolithiasis in Wistar rats.

BACKGROUND: In spite of advances in the present practice of medicine, the formation and growth of calculi continues to trouble mankind, as there is no satisfactory drug to treat kidney stones. In India, many indigenous drugs are in use for the treatment of urinary calculus disease. OBJECTIVE: The present study was intended to determine anti-urolithiatic effect of Lagenaria siceraria fruit powder (LSFP) against sodium oxalate (NaOx) induced urolithiasis in rats. MATERIALS AND METHODS: Animals were grouped as Vehicle Group (received vehicle gum acacia 2% w/v 1 mL/kg/p.o.), NaOx Group(Sodium oxalate 70 mg/kg,i.p.), LSFP Group (500 mg/kg, p.o. LSFP suspended in gum acacia 2% + Sodium oxalate 70 mg/kg), Cystone Group (500 mg/kg, p.o. Cystone suspended in gum acacia 2% + Sodium oxalate 70 mg/kg). RESULT: The increased severity of microscopic calcium oxalate (CaOx) crystals deposition along with increased concentration in the kidney was seen after 7 days of NaOx (70 mg/kg, i.p.) pre-treatment. LSFP (500 mg/kg, p.o.) and standard marketed formulation Cystone (500 mg/kg, p.o.) caused a significant reversal of NaOx-induced changes in ion excretion and urinary CaOx concentration in 7 days treatment. CONCLUSION: From the results, it was concluded that LSFP showed beneficial effect against urolithiasis by decreasing CaOx excretion and preventing crystal deposition in the kidney tubules.

Antihypertensive and Diuretic Effects of the Aqueous Extract of Colocasia esculenta Linn. Leaves in Experimental Paradigms.

Colocasia esculenta Linn (CE) is traditionally used for the treatment of various ailments such as high blood pressure, rheumatic pain, pulmonary congestion, etc. Hence in present study, the effect of aqueous extract of CE leaves (AECE) was evaluated for antihypertensive and acute diuretic activity in rats. Preliminary phytochemical evaluation revealed the presence of carbohydrate, saponins, tannins, and flavonoids in AECE. The animals did not show any sign of toxicity and mortality after the administration of AECE 2000 mg/Kg in acute oral toxicity study. The administration of AECE (100, 200, and 400 mg/Kg/day, p.o.) for six weeks and AECE (10, 20, and 40 mg/Kg, IV) on the day of experiment in renal artery-occluded hypertensive rats and AECE (20 and 40 mg/Kg, IV) in noradrenalin-induced hypertension in rats produced significant (p < 0.05) anti-hypertensive effects. AECE (400 mg/Kg, p.o.) showed positive diuretic activity at 5 h. AECE (200 and 400 mg/Kg, p.o.) significantly increased sodium and chloride content of urine in 5 h and 24 h and additionally potassium in 24 h urine. Hence, the results of the present study revealed the antihypertensive and weak diuretic activity of AECE. These effects may be attributed due to the ACE inhibitory, vasodilatory, ß-blocking, and/ or Ca(2+) channel blocking activities, which were reported for the phytoconstitunts, specifically flavonoids such as vitexin, isovitexin, orientin, and isoorientin present in the leaves of CE.

Biocompatible gellan gum-reduced gold nanoparticles: cellular uptake and subacute oral toxicity studies.

Currently gold nanoparticles are being explored for drug delivery and other biomedical applications; therefore it is necessary to study the fate of such nanoparticles inside the body. The objective of the present study was to investigate the cellular uptake and toxicity of the gold nanoparticles synthesized using a microbial polysaccharide, gellan gum, as a capping and reducing agent. The cellular uptake of gold nanoparticles was studied on mouse embryonic fibroblast cells, NIH3T3 and human glioma cell line, LN-229. The cellular uptake study indicated that the gellan gum-reduced gold nanoparticles were located in cancer cells (LN-229) while no uptake was observed in normal mouse embryonic fibroblast cells (NIH3T3). The toxicity of the gold nanoparticles was evaluated by carrying out subacute 28 day oral toxicity studies in rats. Subacute administration of gum-reduced gold nanoparticles to the rats did not show any hematological or biochemical abnormalities. The weight and normal architecture of various organs did not change compared with control. The current findings, while establishing the specific uptake of nanoparticles into cancerous cells, also demonstrates that the gellan gum-reduced gold nanoparticles are devoid of toxicity in animals following oral administration.

Acute and subacute toxicity studies of chitosan reduced gold nanoparticles: a novel carrier for therapeutic agents.

The objective of the present study was to evaluate the oral toxicity of chitosan reduced gold nanoparticles so as to demonstrate its applicability for drug delivery application. Acute oral toxicity studies in female rats documented no deaths or treatment related complications. The LD50 value of gold nanoparticles was found to be greater than 2000 mg/kg. In case of sub-acute oral toxicity studies, gold nanoparticles were administered orally to male and female rats for a period of 28-days. At the end of study blood samples were collected for haematology and biochemical analysis. For histopathological analysis, organs of animals were weighed and processed for examination. All animals survived the duration of the study, with no significant changes in clinical signs, body weight, food consumption, hematological parameters, organ weights and histopathological findings. These studies establish that chitosan reduced gold nanoparticles produced no treatment related toxicity in rats following oral administration, thus can be exploited for potential therapeutic applications.