Naringenin mitigates behavioral alterations and provides neuroprotection against 3-nitropropinoic acid-induced Huntington's disease like symptoms in rats.

BACKGROUND: Naringenin is a powerful antioxidant and anti-inflammatory flavonoid which has been widely used as a therapeutic agent in various toxic models. However, few studies have clearly discussed the neuromodulatory effects of naringenin against different neurodegenerative disorders. AIM: We investigated the neuroprotective efficacy of naringenin against 3-nitropropionic acid (3-NP)-induced neurobehavioral, biochemical and histopathological alterations in rats. METHODS: Albino Wistar rats were randomly divided into three experimental groups. Group 1, the vehicle administered group, received saline. Group 2 received 3-NP (20 mg/kg body weight, i.p.) for 4 consecutive days. Group 3 received naringenin (50 mg/kg body weight, p.o.) twice daily for a period of 4 days, 30 min before and 6 h after the 3-NP administration. On the 5th day, neurobehavioral experiments were performed to access the behavioral outcomes and the striatum tissue was used for analysis of the monoamine oxidase (MAO) activity and serotonin (5-HT) levels. In addition, astrocytes activation was observed by glial fibrillary acidic protein (GFAP) immunostaining. RESULTS: Our results showed that naringenin co-treatment provides neuroprotection against 3-NP-induced neurological disorders. Naringenin also increased the MAO activity and 5-HT levels in the striatum. Moreover, co-treatment with naringenin reduced the expression of GFAP protein in the striatal part and significantly attenuated the neuronal cell death. The findings of the present study suggest that naringenin provides neuroprotection and mitigates neurobehavioral alterations in experimental rats. CONCLUSION: The results show that co-treatment with naringenin ameliorates 3-NP-induced HD-like symptoms in rats.

Key role of Extracellular RNA in hypoxic stress induced myocardial injury.

Myocardial infarction (MI), atherosclerosis and other inflammatory and ischemic cardiovascular diseases (CVDs) have a very high mortality rate and limited therapeutic options. Although the diagnosis is based on markers such as cardiac Troponin-T (cTrop-T), the mechanism of cTrop-T upregulation and release is relatively obscure. In the present study, we have investigated the mechanism of cTrop-T release during acute hypoxia (AH) in a mice model by ELISA & immunohistochemistry. Our study showed that AH exposure significantly induces the expression and release of sterile inflammatory as well as MI markers in a time-dependent manner. We further demonstrated that activation of TLR3 (mediated by eRNA) by AH exposure in mice induced cTrop-T release and Poly I:C (TLR3 agonist) also induced cTrop-T release, but the pre-treatment of TLR3 immuno-neutralizing antibody or silencing of Tlr3 gene or RNaseA treatment two hrs before AH exposure, significantly abrogated AH-induced Caspase 3 activity as well as cTrop-T release. Our immunohistochemistry and Masson Trichrome (MT) staining studies further established the progression of myocardial injury by collagen accumulation, endothelial cell and leukocyte activation and adhesion in myocardial tissue which was abrogated significantly by pre-treatment of RNaseA 2 hrs before AH exposure. These data indicate that AH induced cTrop-T release is mediated via the eRNA-TLR3-Caspase 3 pathway.

Inhibition of snake venom induced sterile inflammation and PLA2 activity by Titanium dioxide Nanoparticles in experimental animals.

Sterile inflammation (SI) is an essential process in response to snakebite and injury. The venom induced pathophysiological response to sterile inflammation results into many harmful and deleterious effects that ultimately leads to death. The available treatment for snakebite is antiserum which does not provide enough protection against venom-induced pathophysiological changes like haemorrhage, necrosis, nephrotoxicity and often develop hypersensitive reactions. In order to overcome these hindrances, scientists around the globe are searching for an alternative therapy to provide better treatment to the snake envenomation patients. In the present study TiO2 (Titanium dioxide)-NPs (Nanoparticles) has been assessed for antisnake venom activity and its potential to be used as an antidote. In this study, the synthesis of TiO2-NPs arrays has been demonstrated on p-type Silicon Si < 100 > substrate (∼30 ohm-cm) and the surface topography has been detected by Field-emission scanning electron microscopy (FESEM). The TiO2-NPs successfully neutralized the Daboia russelii venom (DRV) and Naja kaouthia venom (NKV)-induced lethal activity. Viper venom induced haemorrhagic, coagulant and anticoagulant activities were effectively neutralized both in in-vitro and in vivo studies. The cobra and viper venoms-induced sterile inflammatory molecules (IL-6, HMGB1, HSP70, HSP90, S100B and vWF) were effectively neutralised by the TiO2-NPs in experimental animals.

PGE2 -induced migration of human brain endothelial cell is mediated though protein kinase A in cooperation of EP receptors.

PGE2 plays a critical role in angiogenesis, ischemic, and neuro-inflammatory disorders of the brain, which breakdown the blood-brain barrier (BBB). However, the effects of PGE2 on human brain endothelial cell (HBECs) migration, a key process in the angiogenic response and BBB stability, are not well defined. In this study, we investigated the mechanism of PGE2 in HBECs migration in vitro. Here we showed that PGE2 stimulated migration of HBECs in a dose-time and matrix-dependent manner, evaluated by the Boyden chamber assay, but other prostanoids failed to do so. PGE2 receptor (EP2; butaprost), EP3 (sulprostone), and EP4 (PGE1 -OH) receptor agonists stimulated HBECs migration, but the silencing of EP significantly attenuated this effect. EP1 agonist (11-trinor PGE1 ) had no effect on HBECs migration on silencing of the EP1 receptor. We further showed that PGE2 stimulated cAMP production and activated protein kinase A (PKA), whereas pretreatment with the adenyl cyclase inhibitor (dideoxyadenosine; 1 µM) or PKA inhibitors, H89 (0.5 µM)/PKAI (1 µM), completely abrogated PGE2 -induced migration. Furthermore, silencing of the EP2/EP4 receptors significantly inhibited PGE2 -induced cAMP and PKA activation, whereas EP3 receptor silencing failed to do so. These results suggest that PGE2 regulates HBEC migration via cooperation of EP2, EP3, and EP4 receptors. Coupling of PGE2 to these receptors resulted in increased production of cAMP, which regulates HBEC migration via PKA pathway. The elucidation of molecular events involved is critical for the development of targeted strategies to treat cerebrovascular diseases associated with dysregulated angiogenesis.

Sterile Inflammatory Role of High Mobility Group Box 1 Protein: Biological Functions and Involvement in Disease.

High mobility group box 1 protein (HMGB1), a sterile inflammatory molecule and damage-associated molecular pattern (DAMP) released from various cells during stress has been implicated in inflammation. Several reports show that there is a direct relationship between inflammation and cardiovascular diseases (CVDs) such as thrombosis, hypertension, insulin resistance, preeclampsia, etc. Here, we intend to summarize the concept of the emerging link between HMGB1 and CVDs. Furthermore, we will discuss the possible therapeutic strategies that target HMGB1 for the treatment of different CVDs.

Recent advancement of piperidine moiety in treatment of cancer- A review.

Piperidine is an important pharmacophore, a privileged scaffold and an excellent heterocyclic system in the field of drug discovery which provides numerous opportunities in studying/exploring this moiety as an anticancer agent by acting on various receptors of utmost importance. Cancer is an uncontrolled division of cells that results in the formation of tumour which have the potential to migrate to other parts of the body (metastasis) finally becoming a major threat to human population. Since piperidine displayed great potential in this area it is being further probed to get novel entities for the treatment of cancer. This review throws light on recent biological expansions of piperidine along with structure activity relationships to deliver association between various synthesized newer/novel derivatives and receptor sites.

Design, synthesis and molecular docking of thiazolidinedione based benzene sulphonamide derivatives containing pyrazole core as potential anti-diabetic agents.

We herein report the design, synthesis and molecular docking studies of 2,4-thiazolidinedione derivatives containing benzene sulphonyl group which are docked against the Peroxisome Proliferator Activated Receptor (PPARγ) target. Compound 7p was most effective in lowering the blood glucose level as compared to standard drugs pioglitazone and rosiglitazone. Compound 7p exhibited potent PPAR-γ transactivation of 61.2% with 1.9 folds increase in gene expression. In molecular docking studies 7p showed excellent interactions with amino acids TYR 473, SER 289, HIE 449, TYR 327, ARG 288, MET 329 and LEU 228. Compound 7p did not cause any damage to the liver without any noteworthy weight gain and may be considered as promising candidates for the development of new antidiabetic agents.

Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads.