Benzofuran Iboga-Analogs Modulate Nociception and Inflammation in an Acute Mouse Pain Model.

Pain management following acute injury or post-operative procedures is highly necessary for proper recovery and quality of life. Opioids and non-steroidal anti-inflammatory drugs (NSAIDS) have been used for this purpose, but opioids cause addiction and withdrawal symptoms whereas NSAIDS have several systemic toxicities. Derivatives of the naturally occurring iboga alkaloids have previously shown promising behavior in anti-addiction of morphine by virtue of their interaction with opioid receptors. On this frontier, four benzofuran analogs of the iboga family have been synthesized and their analgesic effects have been studied in formalin induced acute pain model in male Swiss albino mice at 30 mg/kg of body weight dose administered intraperitoneally. The antioxidant, anti-inflammatory and neuro-modulatory effects of the analogs were analyzed. Reversal of tail flick latency, restricted locomotion and anxiogenic behavior were observed in iboga alcohol, primary amide and secondary amide. Local neuroinflammatory mediators' substance P, calcitonin gene related peptide, cyclooxygenase-2 and p65 were significantly decreased whereas the depletion of brain derived neurotrophic factor and glia derived neurotrophic factor was overturned on iboga analog treatment. Behavioral patterns after oral administration of the best analog were also analyzed. Taken together, these results show that the iboga family of alkaloid has huge potential in pain management.

Ameliorative effects of clindamycin - nanoceria conjugate: A ROS responsive smart drug delivery system for diabetic wound healing study.

BACKGROUND: Increased incidence of antibiotic-resistant species calls for development of new types of nano-medicine that can be used for healing of bacteria-caused wounds, such as diabetic foot ulcer. As diabetic patients have inefficient defense mechanism against reactive oxygen species (ROS) produced in our body as a by-product of oxygen reduction, the process of wound healing takes longer epithelialisation period. Ceria nanoparticles (CNPs) are well-known for their antibacterial and ROS-scavenging nature. Yet till now no significant effort has been made to conjugate ceria nanoparticles with drugs to treat diabetic wounds. METHODS: In this experiment, CNPs were synthesized in-house and clindamycin hydrochloride was loaded onto it by physical adsorption method for reactive oxygen species responsive drug delivery. Various physico-chemical characterisations such as Transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, Energy dispersive X-ray, Thermogravimetric study etc. were performed to affirm the formation of both nanoceria along with drug encapsulated nanoceria. RESULTS: Both of these as-prepared formulations inhibited the growth of Gram-positive as well as Gram-negative bacteria confirmed by Disk diffusion study; exhibiting their antibacterial effect. In-vitro drug release study was carried out in physiological environment both in absence and presence of hydrogen peroxide solution to test the reactive ROS-responsiveness of the drug loaded nanocomposites. It also exhibited faster wound healing in diabetes-induced rats. Therefore, it could successfully lower the amount of serum glucose level, inflammation cytokines, hepatotoxic and oxidative stress markers in diabetic rats as confirmed by various ex vivo tests conducted. CONCLUSION: Thus, drug loaded ceria nanoparticles have the potential to heal diabetic wounds successfully and can be considered to be useful for the fabrication of appropriate medicated suppositories beneficial for diabetic foot ulcer treatment in future.

Oleic acid prevents erythrocyte death by preserving haemoglobin and erythrocyte membrane proteins.

Haemolysis of erythrocytes upon exposure to haemato-toxic phenylhydrazine (PHZ), makes it an experimental model of anaemia and a partial model of ß-thalassaemia, where oxidative stress (OS) was identified as principal causative factor. Oleic acid (OA) was evidenced to ameliorate such stress with antioxidative potential. Erythrocytes were incubated in vitro using 1 mM PHZ, 0.06 nM OA. Erythrocyte membrane protein densities and haemoglobin (Hb) status were examined. Any interaction of Hb with PHZ/OA was checked by calorimetric and spectroscopic analysis using pure molecules. Occurrence of erythrocyte apoptosis and involvement of free iron in all groups were evaluated. PHZ exposure to erythrocytes results in OS with subsequent apoptosis as evidenced from increased lipid peroxidation and translocation of phosphatidylserine in outer membrane. Preservations of erythrocyte cytoskeletal architecture and membrane bound enzyme activity were found in presence of OA. Moreover, both heme and globin of Hb was examined to be conserved by OA. Presence of OA, impeded apoptosis also, possibly by thwarting Hb breakdown followed by free iron release and consequent free radical generation. Additionally, direct sequential binding of OA with PHZ endorsed another protective mechanism of OA toward erythrocytes. OA affords protection to erythrocytes by conserving its major components and prevents haemolysis which project OA as a haemato-protective agent. Apart from combating PHZ toxicity, anti-apoptotic action of OA strongly suggests its usage in anaemia and ß-thalassaemia patients to curb irreversible erythrocyte breakdown. This research strongly recommends OA in pure form or from dietary sources as a therapeutic against haemolytic disorders.

Enhanced inflammasome-mediated inflammation and impaired autophagy in peripheral blood mononuclear cells is associated with non-alcoholic fatty liver disease severity.

AIMS: Identification of the progress of non-alcoholic fatty liver disease (NAFLD) is crucial for their effective treatment. Circulating peripheral blood mononuclear cells (PBMC) could be a surrogate monitor instead of complicated and expensive biopsies. Changes in immuno-metabolic status in NAFLD patients may be reflected by an expression of different PBMC-specific molecular markers. It was hypothesized that impaired autophagy with enhanced inflammasome activation is a critical molecular event in PBMC that could contribute to systemic inflammation associated with NAFLD progression. MAIN METHODS: A cross-sectional study with a sample size of 50 subjects were undertaken from a governmental facility in Kolkata, India. Major anthropometric, biochemical, and dietary parameters were recorded. Cellular and serum samples of NAFLD patients were analyzed for oxidative stress, inflammation, inflammasome activation, and autophagic flux by western blot, flow cytometry, immunocytochemistry. KEY FINDINGS: Baseline anthropometric and clinical parameters were found associated with NAFLD severity. Elevated systemic inflammation was reflected by higher proinflammatory markers like iNOS, Cox-2, IL-6, TNF-α, IL-1ß, hsCRP in the serum of NAFLD subjects (p < 0.05). ROS-induced NLRP3 inflammasomes marker proteins were upregulated (p < 0.05) in PBMC along with NAFLD severity. Expression of autophagic markers such as LC3B, Beclin-1 and its regulator pAMPKα were found diminished (p < 0.05) with a concomitant rise of p62. Colocalization of NLRP3 with LC3B proteins in PBMC was found diminished along NAFLD severity. SIGNIFICANCE: Present data provide mechanistic evidence of impaired autophagy and intracellular ROS triggered inflammasome activation in PBMC, which could potentially exacerbate NAFLD severity.

Oleic acid as a restorative agent in alleviating adrenaline induced altered morphofunctional milieu of gastric tissue and mitochondria.

The role of oleic acid as a protective antioxidant has recently been recognized. The present study is aimed to explore whether oleic acid can afford protection to rat gastric tissue when challenged with adrenaline. Sixty adult healthy male albino rats were divided into 10 groups comprising of 6 animals each. First group constituted the control. Rats of the second group were injected sub-cutaneously with adrenaline bitartrate at the dose of 0.3mg/kg body weight, every day for a period of 17 days. Rats of the third, to the sixth groups were orally fed with different doses of oleic acid (2.5, 5, 10, 20 mg/kg body weight/day) respectively. The rats of seventh to tenth groups were orally fed with doses of oleic acid as mentioned above and subsequently injected with adrenaline bitartrate at 0.3mg/kg body weight sub-cutaneously. After the treatment period, the animals were euthanized through cervical dislocation following light ether anaesthesia and gastric tissues were collected for morphological and biochemical studies. Subcutaneously administered pharmacological dose of adrenaline bitartrate caused oxidative stress inducing gastric lesion in male albino rats as evident from the altered levels of biomarkers of oxidative stress, activities of antioxidant and mitochondrial enzymes related to energy metabolism with changes in tissue morphology. Pre-treatment of rats with oleic acid dose-dependently protected against these gastric injuries induced by adrenaline indicating the potentiality of oleic acid in protecting against adrenaline induced gastric injury in male albino rats where antioxidant mechanisms appear to play a pivotal role in mediating such protection.

An association study of severity of intellectual disability with peripheral biomarkers of disabled children in a rehabilitation home, Kolkata, India.

The current investigation has identified the biomarkers associated with severity of disability and correlation among plethora of systemic, cellular and molecular parameters of intellectual disability (ID) in a rehabilitation home. The background of study lies with the recent clinical evidences which identified complications in ID. Various indicators from blood and peripheral system serve as potential surrogates for disability related changes in brain functions. ID subjects (Male, age 10 ± 5 yrs, N = 45) were classified as mild, moderate and severe according to the severity of disability using standard psychometric analysis. Clinical parameters including stress biomarkers, neurotransmitters, RBC morphology, expressions of inflammatory proteins and neurotrophic factor were estimated from PBMC, RBC and serum. The lipid peroxidation of PBMC and RBC membranes, levels of serum glutamate, serotonin, homocysteine, ROS, lactate and LDH-A expression increased significantly with severity of ID whereas changes in RBC membrane ß-actin, serum BDNF, TNF-α and IL-6 was found non-significant. Structural abnormalities of RBC were more in severely disabled children compared to mildly affected ones. The oxidative stress remained a crucial factor with severity of disability. This is confirmed not only by RBC alterations but also with other cellular dysregulations. The present article extends unique insights of how severity of disability is correlated with various clinical, cellular and molecular markers of blood. This unique study primarily focuses on the strong predictors of severity of disability and their associations via brain-blood axis.

Papillary cystic acinic cell carcinoma of the parotid gland diagnosed on fine needle aspiration cytology.

The Cytomorphological features of Papillary Cystic Acinic Cell Carcinoma a rare malignant tumor of the Parotid gland in a 77 years male is described. The differential diagnosis and prognostic features are discussed.