Ramakrishna Sistla

Anti-Inflammatory Treatments for Chronic Diseases: A Review

Inflammation is viewed as one of the major causes for the development of different diseases like cancer, cardiovascular disease, diabetes, obesity, osteoporosis, rheumatoid arthritis, inflammatory bowel disease, asthma, and CNS related diseases such as depression and parkinsons disease; and this fervent phenomenon provides space for understanding different inflammatory markers. Increasing evidences have elucidated the outcome of inflammatory pathways dysregulation resulting in many symptoms of chronic diseases. The detection of transcription factors such as nuclear factor kappa-B (NF-κB), STAT and their gene products such as COX-2, cytokines, chemokines and chemokine receptors has laid molecular foundation for the important role of inflammation in chronic diseases in which the NF-κB is reported as a major mediator which makes a possible way for the development of new therapeutic approaches using synthetic and natural compounds that might eventually decrease the prevalence of these diseases. Even if many inflammatory markers like TNF-α, IL-1, IL-6, IL-8 and C-reactive protein (CRP) are reported to be the major key factors with proved role in several inflammatory diseases, IL-1 and TNF-α are the important cytokines that can induce the expression of NF-κB which is the potential target in these inflammatory diseases. This review aims to explore and summarize that how some drugs and natural compounds show their modulatory activity in inflammatory pathways and chronic inflammatory markers in these inflammatory diseases.

Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage

Nephrotoxicity is an important complication in cancer patients undergoing cisplatin therapy. Oxidative stress, inflammation and apoptosis/necrosis are the major patho-mechanisms of cisplatin induced nephrotoxicity. In the present study, hesperidin, a naturally-occurring bioflavonoid has been demonstrated to have protective effect on cisplatin-induced renal injury in rats. Cisplatin intoxication resulted in structural and functional renal impairment which was revealed by massive histopathological changes and elevated blood urea nitrogen and serum creatinine levels, respectively. Renal injury was associated with oxidative stress/lipid peroxidation as evident by increased reactive oxygen species (ROS) and malondialdehyde (MDA) formation with decreased levels of antioxidants such as reduced glutathione, vitamin C, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione-S-transferase. Cisplatin administration also triggered inflammatory response in rat kidneys by inducing pro-inflammatory cytokine, TNF-α, with the increased expression of myeloperoxidase (MPO). Furthermore, cisplatin increased the activity of caspase-3 and DNA damage with decreased tissue nitric oxide levels. Hesperidin treatment significantly attenuated the cisplatin-induced oxidative stress/lipid peroxidation, inflammation (infiltration of leukocytes and pro-inflammatory cytokine), apoptosis/necrosis (caspase-3 activity with DNA damage) as well as increased expression of nitric oxide in the kidney and improved renal function. Thus, our results suggest that hesperidin co-administration may serve as a novel and promising preventive strategy against cisplatin-induced nephrotoxicity.

Design and evaluation of polymer coated carvedilol loaded solid lipid nanoparticles to improve the oral bioavailability: a novel strategy to avoid intraduodenal administration.

Solid lipid nanoparticles are most promising delivery systems for the enhancement of bioavailability of highly lipophilic drugs those prone to the first pass metabolism. But burst release of drug from solid lipid nanoparticles in acidic environment such as gastric milieu precludes its usage as oral delivery system. Studies on SLN revealed intraduodenal administration as an alternative route for SLN administration. But clinically it is an inappropriate route for repeated administration of drugs to patients. Hence, we prepared N-carboxymethyl chitosan (MCC) coated carvedilol loaded SLN to protect the rapid release of carvedilol in acidic environment. Positively charged carvedilol loaded SLN were developed using monoglyceride as lipid and soya lecithin and poloxamer 188 as surfactants and stearylamine as charge modifier. These SLN were characterized for particle size, zeta potential, entrapment efficiency, crystallinity and stability studies. Further these SLN were coated with N-carboxymethyl chitosan and confirmed by change in zetapotential and X-ray Photon Spectroscopic analysis. Effect of polymer coating on drug release profiles were studied simulated gastric and intestinal fluids. Effect of polymer coating on oral bioavailability of carvedilol loaded SLN were studied in rats after oral administration. MCC coated SLN improved the bioavailability of carvedilol compared uncoated SLN after oral administration. Insignificant difference in bioavailability was observed compared to intraduodenal administration of SLN. Hence, MCC coated SLN is a novel strategy to avoid intrduodenal administration.

Ameliorative Effect of Fisetin on Cisplatin-Induced Nephrotoxicity in Rats via Modulation of NF-κB Activation and Antioxidant Defence

Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5mg/kg) caused marked renal damage, characterized by a significant (P<0.05) increase in serum creatinine, blood urea nitrogen (BUN) and relative weight of kidney with higher kidney MDA (malondialdehyde), tROS (total reactive oxygen species), caspase 3, GSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (P<0.05) attenuated the increase in lipid peroxidation, caspase-3 and ROS generation and enhanced the levels of reduced glutathione, tissue nitrite level and activities of SOD, CAT, GSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.

Xanthan gum stabilized gold nanoparticles: Characterization, biocompatibility, stability and cytotoxicity

Xanthan gum (XG) has been widely used in food, pharmaceutical and cosmetic industries. In the present study, we explored the potential of XG in the synthesis of gold nanoparticle. XG was used as both reducing and stabilizing agent. The effect of various formulation and process variables such as temperature, reaction time, gum concentration, gum volume and gold concentration, in GNP preparation was determined. The XG stabilized, rubey-red XGNP were obtained with 5 ml of XG aqueous solution (1.5 mg/ml). The optimum temperature was 80°C whereas the reaction time was 3 h. The optimized nanoparticles were also investigated as drug delivery carrier for doxorubicin hydrochloride. DOX loaded gold nanoparticles (DXGP) were characterized by dynamic light scattering, TEM, FTIR, and DSC analysis. The synthesized nanoparticle showed mean particle size of 15-20 nm and zeta potential -29.1 mV. The colloidal stability of DXGP was studied under different conditions of pH, electrolytes and serum. Nanoparticles were found to be stable at pH range between pH 5-9 and NaCl concentration up to 0.5 M. In serum, nanoparticles showed significant stability up to 24h. During toxicity studies, nanoparticles were found biocompatible and non-toxic. Compared with free DOX, DXGP displayed 3 times more cytotoxicity in A549 cells. In conclusion, this study provided an insight to synthesize GNP without using harsh chemicals.

Cationic glycolipids with cyclic and open galactose head groups for the selective targeting of genes to mouse liver.

Toward probing an hitherto unexplored structure-activity issue namely, the relative in vitro and in vivo efficacies of cationic glycolipids with cyclic and acyclic sugar heads for targeting of genes to liver, we have designed and synthesized two novel series of cationic glycolipids with cyclic (lipids 1-5) and open d-galactose heads (lipids 6-10) containing varying spacer arm lengths in between the sugar and positively charged nitrogen atoms. Among the cyclic glycolipids, lipid 3 with six methylene units spacer in between the quaternary nitrogen atom and among the glycolipids with the open-sugar heads, lipid 6 with only two methylene units spacer were found to be the most efficacious in targeting genes to cultured HepG2 (human hepatocarcinoma cells) and primary hepatocytes. Findings in the fluorescence resonance energy transfer (FRET) studies revealed biomembrane fusibilities as important physico-chemical parameters behind the varying spacer arm dependencies in the two series. Importantly, both the serum compatible glycolipids 3 &6 were found to be equally efficacious in selectively targeting genes to mouse livers under systemic settings. The significantly reduced efficiencies of the glycolipids 3 &6 in transfecting primary hepatocytes as well as mice pretreated with asialofetuin (the ligands of asialoglycoprotein receptors) support the notion that the cellular uptake of the lipoplexes prepared from both the open and the cyclic sugar-head series is mediated via asialoglycoprotein receptor. In summary, our present findings demonstrate for the first time that cationic glycolipids with cyclic sugar-head require longer spacer arms than their acyclic sugar-head counterparts for efficient gene transfection and both the series hold equal promise for selective gene targeting to liver under systemic settings.

Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: Possible mechanism of nephroprotection

Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney.

Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles

UNLABELLED Docetaxel is used in the treatment of many types of cancer, but its entry into the brain is restricted by p-glycoprotein (p-gp) efflux. A potential drug-drug interaction exists between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system, and ketoconazole can inhibit p-gp efflux of docetaxel at blood brain barrier. Hence, these two drugs were loaded in solid lipid nanoparticles (SLNPs) and surface of these NPs were modified with folic acid for brain targeting. These NPs were characterized for particle size, zeta potential, entrapment efficiency, in vitro drug release, cytotoxicity, and cell uptake in brain endothelial cell lines. Plasma and brain pharmacokinetics have shown increased brain uptake of docetaxel with surface-modified dual drug-loaded SLNPs. Brain permeation coefficient (K(in)) of folate-grafted docetaxel and ketoconazole loaded SLNPs was 44 times higher than that of Taxotere. Hence, these NPs were suitable for the delivery of lipophilic anticancer drugs to the brain. FROM THE CLINICAL EDITOR In this paper, successful delivery of docetaxel and ketoconazole is reported using solid lipid nanoparticles surface modified with folic acid for brain targeting, which may pave the way to optimized clinical applications of lipophilic anticancer drugs to the brain.

Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways

Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.