Immunomodulation of streptozotocin induced Type 1 diabetes mellitus in mouse model by Macrophage migration inhibitory factor-2 (MIF-2) homologue of human lymphatic filarial parasite, Wuchereria bancrofti.

Helminth parasites modulate the host immune system to ensure a long-lasting asymptomatic form of infection generally, mediated by the secretion of immunomodulatory molecules and one such molecule is a homologue of human host cytokine, Macrophage migratory Inhibitory Factor (hMIF). In this study, we sought to understand the role of homologue of hMIF from the lymphatic filarial parasite, Wuchereria bancrofti (Wba-MIF2), in the immunomodulation of the Streptozotocin (STZ)-induced Type1 Diabetes Mellitus (T1DM) animal model. Full-length recombinant Wba-MIF2 was expressed and found to have both oxidoreductase and tautomerase activities. Wba-MIF2 recombinant protein was treated to STZ induced T1DM animals, and after 5 weeks pro-inflammatory (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines and gene expressions were determined in sera samples and spleen respectively. Pro-inflammatory and anti-inflammatory cytokine levels were significantly (p<0.05) up-regulated and down-regulated respectively, in the STZ-T1DM animals, as compared to treated groups. Histopathology showed macrophage infiltration and greater damage of islets of beta cells in the pancreatic tissue of STZ-T1DM animals, than Wba-MIF2 treated STZ-T1DM animals. The present study clearly showed the potential of Wba-MIF2 as an immunomodulatory molecule, which could modulate the host immune system in the STZ-T1DM mice model from a pro-inflammatory to anti-inflammatory milieu.

Suspected cutaneous adverse drug reactions reported with traditional medicines: analysis of data for United Nations Asia region from WHO VigiBase.

Background: Data on traditional medicine-induced cutaneous adverse drug reactions (ADRs) is very scarce. The current secondary analysis based on the WHO database (VigiBase) of individual case safety reports (ICSRs) focuses on the suspected cutaneous ADRs linked to traditional medicines (TMs). Methods: All the ICSRs reported between 1st January 2016 and 30th June 2021 from the UN Asia region in VigiBase where at least one TM was suspected to cause cutaneous ADRs were included in the study. Data regarding demographic details, suspected drug, adverse reaction as per MedDRA term, the seriousness of the reaction, de-challenge, re-challenge, and clinical outcome for suspected cutaneous ADRs associated with TM were obtained from VigiBase and analyzed for frequency of reported events and suspected medicines. Findings: Total 3,523 ICSRs with 5,761 ADRs related to "skin and subcutaneous tissue disorders" were included in the analysis. Amongst these, 6.8% of ICSRs were reported as serious. Pruritus (29.6%), rash (20.3%), urticaria (18.9%), and hyperhidrosis (3.3%) were commonly reported ADRs. Artemisia argyi H.Lév. and Vaniot. (14.9%), Ginkgo biloba L. (5.1%), Vitis vinifera L. (4%), Vitex agnus-castus L. (3.8%), Silybum marianum (L.), Gaertn (3.5%), and Viscus album L. (2.7%) were some commonly suspected TMs for cutaneous ADRs. There were 46 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported with TMs during the study period. Death was reported in 5 ICSRs. Interpretation: TMs are linked with various cutaneous ADRS ranging from pruritus to toxic epidermal necrolysis which may have serious consequences. TMs listed as suspected offending agents in this analysis, should be kept in mind while dealing with suspected cutaneous ADRs. Clinicians should be more vigilant in detecting and reporting events associated with TMs.

Cyperus rotundus L. reverses the olanzapine-induced weight gain and metabolic changes-outcomes from network and experimental pharmacology.

Cyperus rotundus L. is used to treat multiple clinical conditions like inflammation, diarrhea, pyrosis, and metabolic disorders including diabetes and obesity. The present study aimed to predict the interaction of reported bioactives from Cyperus rotundus against obesity via network pharmacology and to evaluate the efficacy of hydroalcoholic extract of Cyperus rotundus against the olanzapine-induced weight gain and metabolic disturbances in experimental animals. Reported phytochemicals of Cyperus rotundus were retrieved from the open-source database(s) and published literature and their targets were predicted using SwissTargetPrediction, enriched in STRING, and bioactives-proteins-pathways network was constructed using Cytoscape. Further, the hydroalcoholic extract of Cyperus rotundus (100, 200, and 400 mg/kg/day, p.o.) was co-administered with olanzapine (2 mg/kg, i.p.) for 21 days in Sprague Dawley rats. During treatment, body weight and food intake were recorded; after the successful completion of 21 days of treatment, animals were fasted to perform oral glucose and insulin tolerance tests. Further, the animals were euthanized; blood and abdominal fat were collected for lipid profiling and histopathological examination respectively. Herein, network pharmacology predicted neuroactive ligand-receptor interaction as a primarily modulated pathway and protein tyrosine phosphatase 1b as a majorly triggered protein via the combined action of bioactives. Further, Cyperus rotundus significantly reversed weight gain, cumulative food intake, ameliorated the lipid and glucose metabolism, and promoted energy expenditure.

Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals.

Inflammation is one of the common events in the majority of acute as well as chronic debilitating diseases and represent a chief cause of morbidity in today's era of modern lifestyle. If unchecked, inflammation leads to development of rheumatoid arthritis, diabetes, cancer, Alzheimer's disease, and atherosclerosis along with pulmonary, autoimmune and cardiovascular diseases. Inflammation involves a complex network of many mediators, a variety of cells, and execution of multiple pathways. Current therapy for inflammatory diseases is limited to the steroidal and non-steroidal anti-inflammatory agents. The chronic use of these drugs is reported to cause severe adverse effects like gastrointestinal, cardiovascular, and renal abnormalities. There is a massive need to explore new anti-inflammatory agents with selective action and lesser toxicity. Plants and isolated phytoconstituents are promising and interesting sources of new anti-inflammatories. However, drug development from natural sources has been linked with hurdles like the complex nature of extracts, difficulties in isolation of pure phytoconstituents, and the yield of isolated compounds in minute quantities that is insufficient for subsequent lead development. Although various in-vivo and in-vitro models for anti-inflammatory drug development are available, judicious selection of appropriate animal models is a vital step in the early phase of drug development. Systematic evaluation of phytoconstituents can facilitate the identification and development of potential anti-inflammatory leads from natural sources. The present review describes various techniques of anti-inflammatory drug screening with its advantages and limitations, elaboration on biological targets of phytoconstituents in inflammation and biomarkers for the prediction of adverse effects of anti-inflammatory drugs. The systematic approach proposed through present article for anti-inflammatory drug screening can rationalize the identification of novel phytoconstituents at the initial stage of drug screening programs.

Nephroprotective activity of Bilvadi agada in gentamicin induced nephrotoxicity in male Wistar rats.

BACKGROUND: Gentamicin (GM) nephrotoxicity accounts for 10-30% of the acute renal failure (ARF) among drug-induced ARF. In Ayurveda such side effects are considered as the poisonous effects of low potent poisons called gara visa. Bilvadi agada (BA), a classical formulation is indicated in gara visa and most of its ingredients have proven for their nephroprotective activity. AIM: The aim was to evaluate the effect of BA in GM-induced nephrotoxicity in male Wistar rats. MATERIALS AND METHODS: BA, GM, normal saline were procured from standard companies. SETTINGS AND DESIGNS: Eighteen male Wistar rats were randomly divided into three groups, viz. Control group which received normal saline intraperitoneal (i.p.) daily for 8 days; toxic group received GM 80 mg/kg/day i.p. for 8 days, and trial group received both GM 80 mg/kg/day i.p. and BA 216 mg/each rat weighing ~200 g orally 1 h after administration of GM. STATISTICS: All the values were expressed as mean ± standard error and data were analyzed by applying one-way analysis of variance followed by Dunnett's test for multiple comparison. RESULTS: BA treated group showed a significant change (P < 0.05) in levels of serum creatinine, urine creatinine, and urine potassium. There was no significant change (P > 0.05) seen in serum potassium, sodium, chloride, calcium and phosphorus and urine sodium, chloride in all three groups. Glomerular congestion, interstitial edema, tubular necrosis, interstitial hemorrhage was reduced in BA treated group. The results of this study indicate that BA reduces GM-induced nephrotoxicity and it may be due to anti-inflammatory, immunomodulatory, diuretic and anti-oxidant properties of drugs. Further studies are necessary to explore the exact mechanism of BA in nephroprotection.

Apocynin improves endothelial function and prevents the development of hypertension in fructose fed rat.

BACKGROUND AND OBJECTIVES: Exaggerated production of superoxide and inactivation of nitric oxide have been implicated in pathogenesis of hypertension. NAD(P)H oxidase is one of the major source of reactive oxygen species in vasculature. In the present study, we aimed to determine the effect of chronic administration of Apocynin an NAD(P)H oxidase inhibitor on endothelial function and hypertension in fructose-fed rat. MATERIALS AND METHODS: Endothelial function, vascular superoxide, and nitric oxide production/bioavailability in aortas from fructose-fed rats and age-matched controls treated with or without apocynin were assessed using isometric tension studies in organ chambers. Systolic blood pressure was measured by the tail cuff method. RESULTS: In fructose-fed rats, acetylcholine-induced relaxation was impaired, vascular superoxide production was increased, and nitric oxide bioavailability was decreased along with an increase in systolic blood pressure compared to controls. Apocynin treatment prevented the increased generation of superoxide, decreased nitric oxide bioavailability, impaired acetylcholine-induced relaxation, and elevation of systolic blood pressure. CONCLUSION: Chronic administration of apocynin improves the endothelial function by reducing oxidative stress, improving NO bioavailability, and prevents the development hypertension in fructose-fed rat.

Involvement of nitric oxide in 5-HT(3) receptor agonist-induced fluid accumulation in jejunum and colon of anesthetized rats.

OBJECTIVES: The aim of the present study was to investigate the involvement of nitric oxide in 5-HT(3) receptor agonist-induced fluid accumulation in jejunum and colon of anesthetized rats. MATERIALS AND METHODS: Fluid movement in jejunum and colon were determined simultaneously in the same rat, by modifying the Beubler method. Nomega-nitro-L-arginine (L-NNA, 20 mg/kg, s.c) alone and in combination with L-arginine (L-Arg, 150 mg/kg s.c) or D-arginine (D-Arg, 150 mg/kg, s.c) were administered 30 min before administration of 1-PBG (18.5 mug/kg, i.v). RESULTS: Intravenous administration of 1-phenylbiguanide (1-PBG) induced a net secretion of fluid in both jejunum and colon. 1-PBG had a more prominent secretory effect in the colon, causing a three-fold increase in volume of fluid secreted/g of colon than in the jejunum. Pretreatment with (L-NNA) prevented the 1-PBG-induced fluid accumulation in both jejunum and colon. The inhibitory effect of L-NNA on 1-PBG-induced fluid accumulation was reversed by L-Arg but not by D-Arg. CONCLUSION: These results provide evidence that nitric oxide plays an important role in 5-HT(3) receptor agonist-induced fluid accumulation in jejunum and colon of anesthetized rats.

Elevation of systolic blood pressure in an animal model of olanzapine induced weight gain.

In the present study, we examined the effect of olanzapine on weight gain, systolic blood pressure and metabolic changes in rats. Female Sprague Dawley rats were treated with either vehicle or olanzapine (1 and 2 mg/kg i.p, twice daily) for 20 days. Body weight, food and water intake, systolic blood pressure, plasma glucose, insulin and lipid were measured. Olanzapine (1 and 2 mg/kg) significantly increased the body weight and systolic blood pressure. Whereas, food intake and plasma insulin and insulin resistance index, were elevated only at 1 mg/kg. In conclusion, olanzapine induced weight gain in rats is associated with elevation of systolic blood pressure.