Vegi Ganga Modi Naidu

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.

Anti-inflammatory potential of thienopyridines as possible alternative to NSAIDs.

The present study was designed to evaluate the anti-inflammatory and antiarthritic activity of the new synthetic thienopyridine analogs. The anti-inflammatory activity of thienopyridines was assayed by using carrageenan; dextran and arachidonic acid induced paw edema models (acute), cotton pellet granuloma model (Sub acute) and Freunds complete adjuvant induced arthritis (chronic) in experimental rats. The compounds BN-4, BN-14 and BN-16 have shown significant inhibition of edema in carrageenan and arachidonic acid induced paw edema model at a dose of 100mg/kg compared to the dextran induced paw edema model and also showed significant inhibition in granuloma tissue formation and Freunds complete adjuvant induced arthritis in experimental rats. These thienopyridine analogs also inhibited the proinflammatory mediators such as Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β and Nitric Oxide (NO) in Lipopolysaccharide (LPS) challenged murine macrophages. Ulcerogenecity study results revealed less ulcerogenic potential of BN-4, BN-14 and BN-16 compared to nonsteroidal anti-inflammatory drug (NSAID) indomethacin in rats. In conclusion, the new thienopyridine analogs were promising for the potential use as anti-inflammatory agents for both acute and chronic inflammatory disorders with low toxic effects.

Review on emu products for use as complementary and alternative medicine

Emu (Dromaius novaehallandiae), the flightless bird native to Australia and found in many countries, is receiving much attention for its nutritional benefits as well as its medicinal value. Emu oil contains high amounts of polyunsaturated fatty acids and antioxidants. It has potent anti-inflammatory actions and thus can be used topically and orally to treat conditions such as mucositis, inflammatory bowel syndrome, and auricular inflammation, and to prevent chemotherapy-induced bone loss. Emu oil also has a hypocholesterolemic effect, transdermal penetration-enhancing activity, cosmetic and insect repellent activity, and so on. However, its mechanism(s) of actions are unclear and have not, to our knowledge, been studied to date. Previous studies suggest that the fatty acids of the ω-9, ω-6, and ω-3 series, which are present in emu oil, may act on cyclooxygenase, lipoxygenase, and lipoxin pathways to bring about its anti-inflammatory and other beneficial actions. The aim of this review was to provide a brief summary of the current knowledge of research on emu products, mainly emu oil, for the possible use as a complementary and alternative natural medicine for various chronic diseases. In this review we also highlighted the future research scope of emu oil for its possible antidiabetic activity. Thus, emu oil is an attractive pharmacologic agent to further explore for its therapeutic activity to treat various ailments.

Curcumin potentiates the anti-arthritic effect of prednisolone in Freund's complete adjuvant-induced arthritic rats

The present study was aimed at investigating the effect of curcumin in combination with prednisolone for the effective treatment of arthritis with reduced side effects when glucocorticoids therapy is indicated.

Adenosine conjugated lipidic nanoparticles for enhanced tumor targeting.

Delivering chemotherapeutics by nanoparticles into tumor is impeded majorly by two factors: nonspecific targeting and inefficient penetration. Targeted delivery of anti-cancer agents solely to tumor cells introduces a smart strategy because it enhances the therapeutic index compared with untargeted drugs. The present study was performed to investigate the efficiency of adenosine (ADN) to target solid lipid nanoparticles (SLN) to over expressing adenosine receptor cell lines such as human breast cancer and prostate cancer (MCF-7 and DU-145 cells), respectively. SLN were prepared by emulsification and solvent evaporation process using docetaxel (DTX) as drug and were characterized by various techniques like dynamic light scattering, differential scanning calorimeter and transmission electron microscopy. DTX loaded SLNs were surface modified with ADN, an adenosine receptors ligand using carbodiimide coupling. Conjugation was confirmed using infrared spectroscopy and quantified using phenol-sulfuric acid method. Conjugated SLN were shown to have sustained drug release as compared to unconjugated nanoparticles and drug suspension. Compared with free DTX and unconjugated SLN, ADN conjugated SLN showed significantly higher cytotoxicity of loaded DTX, as evidenced by in vitro cell experiments. The IC50 was 0.41 μg/ml for native DTX, 0.30 μg/ml for unconjugated SLN formulation, and 0.09 μg/ml for ADN conjugated SLN formulation in MCF-7 cell lines. Whereas, in DU-145, there was 2 fold change in IC50 of ADN-SLN as compared to DTX. IC50 was found to be 0.44 μg/ml for free DTX, 0.39 μg/ml for unconjugated SLN and 0.22 μg/ml for ADN-SLN. Annexin assay and cell cycle analysis assay further substantiated the cell cytotoxicity. Fluorescent cell uptake and competitive ligand-receptor binding assay corroborated the receptor mediated endocytosis pathway indicated role of adenosine receptors in internalization of conjugated particles. Pharmacokinetic studies of lipidic formulations depicted significant improvement in pharmacokinetic parameters than marketed formulation. ADN conjugated SLN proved to be an efficient drug delivery vehicle. Hence, ADN can be used as a potential ligand to target breast and prostate cancer.

Amelioration of streptozotocin-induced type 2 diabetes mellitus in Wistar rats by arachidonic acid

Traditionally arachidonic acid (AA, 20:4 n-6) is considered as a pro-inflammatory molecule since it forms precursor to prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs) that have pro-inflammatory actions. Type 2 diabetes mellitus (type 2 DM) is considered as a low-grade systemic inflammatory condition in which circulating PGs and LTs are increased. Streptozotocin (STZ)-induced type 2 DM is used as a model of human type 2 DM in which peripheral insulin resistance, increased plasma interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and hyperglycemia occurs. In the present study, we observed that oral supplementation of AA prevented STZ-induced type 2 DM in Wistar rats by restoring hyperglycemia, plasma levels of TNF-α and IL-6; adipose tissue NF-kB and lipocalin 2 (LPCLN2) and pancreatic tissue NF-kB and 5- and 12- lipoxygenase enzymes to normal. AA treatment enhanced insulin sensitivity and plasma lipoxin A4 (LXA4) levels, a potent anti-inflammatory molecule derived from AA. These results are supported by our previous studies wherein it was noted that plasma phospholipid content of AA and circulating LXA4 levels are low in those with type 2 DM. In a preliminary study, we also noted that high-fat-diet (HFD)-induced type 2 DM in Wistar rats can be prevented by oral supplementation of AA. These results suggest AA has anti-inflammatory and anti-diabetic actions by enhancing the production of its anti-inflammatory metabolite LXA4.

Abietic acid attenuates RANKL induced osteoclastogenesis and inflammation associated osteolysis by inhibiting the NF-KB and MAPK signaling

Osteoporosis is a major debilitating cause of fractures and decreases the quality of life in elderly patients. Bone homeostasis is maintained by bone forming osteoblasts and bone resorpting osteoclasts. Substantial evidences have shown that targeting osteoclasts using natural products is a promising strategy for the treatment of osteoporosis. In the current study, we investigated the osteoprotective effect of Abietic acid (AA) in in vitro and in vivo models of osteolysis. In vitro experiments demonstrated that, AA suppressed receptor activator of nuclear factor‐kappa B ligand (RANKL)‐induced osteoclastogenesis and F‐actin ring formation in a concentration dependent manner. Mechanistically, AA abrogated RANKL‐induced phosphorylation of IKKα/β (ser 176/180), IkBα (ser 32), and inhibited the nuclear translocation of NF‐κB. We also found that, AA attenuated the RANKL‐induced phosphorylation of MAPKs and decreased the expression of osteoclast specific genes such as TRAP, DC‐STAMP, c‐Fos, and NFATc1. Consistent with in vitro results, in vivo Lipoploysaccharide (LPS)‐induced osteolysis model showed that AA inhibited the LPS‐induced serum surge in cytokines TNF‐α and IL‐6. μ‐CT analysis showed that AA prevented the LPS‐induced osteolysis. Furthermore, histopathology and TRAP staining results suggested that AA decreased the number of osteoclasts in LPS‐injected mice. Taken together, we demonstrated that the osteoprotective action of AA is coupled with the inhibition of NF‐κB and MAPK signaling and subsequent inhibition of NFATc1 and c‐Fos activities. Hence, AA may be considered as a promising drug candidate for the treatment of osteoporosis.

n‐6 and n‐3 Fatty acids and their metabolites augment inhibitory action of doxorubicin on the proliferation of human neuroblastoma (IMR‐32) cells by enhancing lipid peroxidation and suppressing Ras, Myc, and Fos

Polyunsaturated fatty acids (PUFAs) have growth inhibitory action on tumor cells possibly, by augmenting free-radical generation and accumulation of lipid peroxides. This study focused on PUFAs and their metabolites role on IMR-32 cell proliferation with and without doxorubicin to elucidate their mechanism of action by employing cell viability assay (MTT), gene expression, and biochemical studies. All the PUFAs tested inhibited proliferation of IMR-32 cells in vitro on theirown and boosted the growth suppressive action of doxorubicin. Surprisingly indomethacin enhanced while NDGA inhibited growth of IMR32 cells. Proinflammatory and anti-inflammatory PUFA metabolites inhibited growth of IMR-32 cells and enhanced growth inhibitory action of doxorubicin. AA, EPA alone, and in combination with doxorubicin inhibited expression of genes: NF-kB, IkB, BCL-2, BAX, cytochrome C, caspase9,3, p53, 5-LOX, and enhanced levels of GPX. AA and EPA enhanced buildup of lipid peroxides and suppressed expression of Ras, Myc, and Fos. Based on these studies, it is proposed that accumulation of lipid peroxides seems to be the principle mechanism by which AA, EPA, and other PUFAs bring about their growth inhibitory action on tumor cells.