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Krishnendu Manna,1,* Zareen S Khan,2,* Moumita Saha,3,* Snehasis Mishra,3 Nilesh Gaikwad,4 Jatindra Nath Bhakta,1 Kaushik Banerjee,2 Krishna Das Saha3 1Department of Food & Nutrition, University of Kalyani, Nadia, West Bengal, India; 2National Referral Laboratory, ICAR-National Research Centre for Grapes, Pune, Maharashtra, 412307, India; 3Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, 700032, India; 4ICAR-National Research Centre on Pomegranate, Solapur, Maharashtra, 413255, India*These authors contributed equally to this workCorrespondence: Krishna Das Saha, Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, West Bengal, 700032, India, Tel +91 33 2499 5810, Fax +91 33 2473 5197, Email krishna@iicb.res.in Kaushik Banerjee, National Referral Laboratory, ICAR-National Research Centre for Grapes, Pune, Maharashtra, 412307, India, Email kbgrape@yahoo.comObjective: Grape Seed Extract is a natural source of various polyphenols, which have been shown to possess potent antioxidant and free radical-scavenging activities. The earlier studies have reported that grape seed extract exhibits broad-spectrum pharmacological activities. Therefore, studying the hepatoprotective effects and elucidation of mechanisms of action of the Indian Variety, Manjari Medika grape seed extract (GSE), may give an insight into therapeutic benefits. Methotrexate (MTX) is the first-line pharmacological therapy for different rheumatic diseases. The major adverse events such as hepatotoxicity are evident even in the low doses used for the treatment. The present study investigated the role of MTX on hepatic damage in murine liver and the plausible protective effects of the Indian grape variety, Manjari Medika grape seed extract, in ameliorating it.Methods and Results: To assess the hepatological modulation, mice were divided into eight groups to investigate the ameliorative potential of this GSE (75 and 125 mg/kg) and correlate the experimental findings. The active components of the extract were assessed through UPLC-(ESI)-QToF-MS analysis. On the other hand, various biochemical and immunological indices were carried out to correlate the experimental data. The result demonstrated that the prophylactic administration of GSE reduced MTX-induced hepatic toxicity indices, which subsequently restored the hepatic morphological architecture. Moreover, the application of GSE in a dual dosage (75 and 125 mg/kg) suppressed MTX-induced reactive oxygen species generation, followed by lipid peroxidation and cellular nitrite formation. MTX-induced inflammasome activation through the redox-assisted cascade of TLR4/NF-κB signaling was further reduced by applying the GSE. The results showed that the activation of cytoprotective transcription factor Nrf2 enhanced the level of endogenous antioxidants. Furthermore, through the regulation of TLR4/NF-κB and Nrf2/HO-1 axis, this extract could reduce the MTX-mediated hepatic damage.Conclusion: Our findings suggest that Manjari Medika seed extract could be used as a therapeutic agent to relieve the side effects of MTX and other hepatic disorders.Graphical Abstract: Keywords: hepatic fibrosis, Kupffer cells, Manjari Medika grape seed extract, proanthocyanidins, inflammasome, antioxidant response

Moumita Saha,1 Krishnendu Manna,2 Krishna Das Saha1 1Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India; 2Department of Food and Nutrition, University of Kalyani, Kalyani, West Bengal, IndiaCorrespondence: Krishna Das Saha, Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, West Bengal, 700032, India, Tel +91 33 2499 5810, Fax +91 33 2473 5197, Email krishna@iicb.res.inBackground: NLRP3 inflammasome activation plays a critical role in mediating inflammation and NASH (non-alcoholic steatohepatitis) progression that ultimately leads to cirrhosis and hepatocellular carcinoma. Melatonin (MLT) controls high-fat diet-induced NASH in the murine model by modulating NLRP3 mediated inflammation. P2X7R-mediated inflammasome activation is reported in several inflammatory models including NASH.Objective: The role of MLT in P2X7R-mediated inflammation in the NASH model has not yet been explored. The present study investigated the role of MLT in amending high-fat diet-induced nonalcoholic steatohepatitis in the murine liver.Methods: To evaluate the hepatological changes, mice were divided into four groups to investigate the improvement potential of this MLT (10 and 20 mg/kg) and to assess the experimental findings. Histology, biochemical assays, ELISA, FACS analysis, Western blotting, and IF were performed to assess the physical and molecular changes upon melatonin treatment.Results: The result demonstrated that MLT administration reduced HFD (high-fat diet)-induced non-alcoholic steatohepatitic indices, which successively restored the hepatic morphological architecture and other pathophysiological features too. Moreover, the application of MLT suppressed HFD-induced activation of the inflammasome and through TLR4/NF-κB signaling. Herein, we report that MLT significantly suppresses P2X7R expression and calcium influx along with inflammasome in both in vitro and in vivo. The docking study revealed a strong binding affinity of MLT with P2X7R. Moreover, the results also showed that the Nrf2 level was boosted which may normalize the expression of antioxidant proteins that safeguard against oxidative damage triggered by inflammation. Furthermore, some matrix metalloproteinases like MMP 2 and MMP 9 were repressed and TIMP-1 level was increased, which also signifies that MLT could improve liver fibrosis in this model.Conclusion: Based on our findings, this study may conclude that MLT could be used as a therapeutic agent in the high-fat diet-induced NASH model as it has persuasive anti-inflammatory potential.Graphical Abstract: Keywords: melatonin, NASH, NAFLD, inflammasome, P2X7, inflammation, Kupffer cells

Krishnendu Manna,1,* Snehasis Mishra,1,* Moumita Saha,1 Supratim Mahapatra,1 Chirag Saha,1 Govind Yenge,2 Nilesh Gaikwad,2 Ramkrishna Pal,2 Dasharath Oulkar,3 Kaushik Banerjee,3 Krishna Das Saha1 1Cancer Biology and Inflammatory Disorder Division, Council of Scientific & Industrial Research–Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India; 2Postharvest Technology Laboratory, Indian Council of Agricultural Research-National Research Centre on Pomegranate, Solapur 413255, Maharashtra, India; 3National Referral Laboratory, Indian Council of Agricultural Research-National Research Centre for Grapes, Pune 412307, Maharashtra, India *These authors contributed equally to this work Background: Diabetic nephropathy (DN), an end-stage renal disorder, has posed a menace to humankind globally, because of its complex nature and poorly understandable intricate mechanism. In recent times, functional foods as potential health benefits have been gaining attention of consumers and researchers alike. Rich in antioxidants, the peel and seed of pomegranate have previously demonstrated protection against oxidative-stress-related diseases, including cardiovascular disorders, diabetes, and cancer.Purpose: This study was designed to investigate the ameliorative role of pomegranate peel extract–stabilized gold nanoparticle (PPE-AuNP) on streptozotocin (STZ)-induced DN in an experimental murine model.Methods: Following the reduction methods, AuNP was prepared using the pomegranate peel ellagitannins and characterized by particle size, physical appearance, and morphological architecture. Modulatory potential of PPE-AuNP was examined through the plethora of biochemical and high throughput techniques, flow cytometry, immunoblotting, and immunofluorescence.Results: The animals treated with PPE-AuNP markedly reduced the fasting blood glucose, renal toxicity indices, and serum TC and TG in a hyperglycemic condition. As evident from an increased level of plasma insulin level, PPE-AuNP normalized the STZ-induced pancreatic β-cell dysfunction. The STZ-mediated suppression of endogenous antioxidant response was restored by the PPE-AuNP treatment, which reduced the generation of LPO as well as iROS. Furthermore, the hyperglycemia-mediated augmentation of protein glycation, followed by the NOX4/p-47phox activation, diminished with the application of PPE-AuNP. The histological and immunohistochemical findings showed the protective efficacy of PPE-AuNP in reducing STZ-induced glomerular sclerosis and renal fibrosis. In addition, it reduced proinflammatory burden through the modulation of the MAPK/NF-κB/STAT3/cytokine axis. Simultaneously, PI3K/AKT-guided Nrf2 activation was evident upon the PPE-AuNP application, which enhanced the antioxidant response and maintained hyperglycemic homeostasis.Conclusion: The findings indicate that the use of PPE-AuNPs might act as an economic therapeutic remedy for alleviating DN. Keywords: pomegranate polyphenol, gold nanoparticle, diabetic kidney disease, advanced glycation end-product, NF-κB, STAT3, Nrf2

Sladjana Skopelja-Gardner,1,* Madhurima Saha,1,* Perla Abigail Alvarado-Vazquez,2 Brenna S Liponis,1 Elena Martinez,1 E Alfonso Romero-Sandoval2 1Department of Anesthesiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 2Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC, USA *These authors contributed equally to this work. Abstract: Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) and its substrates (extracellular signal-regulated kinase [ERK] and p38) play an important role in pathophysiological mechanisms of acute postoperative and chronic neuropathic pain in the spinal cord. This study aimed to understand the role of MKP-3 and its target MAPKs at the site of surgical incision in nociceptive behavior. Wild-type (WT) and MKP-3 knockout (KO) mice underwent unilateral plantar hind paw incision. Mechanical allodynia was assessed by using von Frey filaments. Peripheral ERK-1/2 and p38 phosphorylation were measured by Western blot. Cell infiltration was determined using hematoxylin and eosin histological staining. Peripheral phosphorylated ERK-1/2 (p-ERK-1/2) inhibition was performed in MKP-3 KO mice. In WT mice, mechanical hypersensitivity was observed on postoperative day 1 (0.69±0.17 g baseline vs 0.13±0.08 g day 1), which resolved normally by postoperative day 12 (0.46±0.08 g, N=6). In MKP-3 KO mice, this hypersensitivity persisted at least 12 days after surgery (0.19±0.06 g; N=6). KO mice displayed higher numbers of infiltrating cells (51.4±6 cells/0.1 mm2) than WT mice (8.7±1.2 cells/0.1 mm2) on postoperative day 1 (vs 5–6 cells/0.1 mm2 at baseline) that returned to baseline 12 days after surgery (10–12 cells/0.1 mm2). In WT mice, peripheral p-p38 and p-ERK-1/2 expression increased (5- and 3-fold, respectively) on postoperative days 1 and 5, and returned to basal levels 7–12 days after surgery (N=3 per group). Peripheral p-p38 levels in MKP-3 KO mice followed a similar expression pattern as WT mice. Peripheral p-ERK-1/2 levels in MKP-3 KO mice remained elevated 12 days after surgery (2.5-fold, N=3 per group). Administration of PD98059 (MEK inhibitor, N=8, vehicle N=9) reduced p-ERK-1/2 expression in the incised tissue and blocked hypersensitivity in MKP-3 KO mice (N=6). The findings of this study suggest that MKP-3 is pivotal for normal resolution of acute postoperative allodynia, through the regulation of peripheral p-ERK-1/2. Keywords: DUSP-6, p38, ERK

The purpose of this study was to evaluate the impact of pedagogical intervention on early childhood education professionals' emotional availability to children with different temperament characteristics. Participants were 136 children (intervention group = 87; control group = 49) aged 1-6 years from 16 early childhood and care centres in Finland. The PedaSens intervention was a 9-month programme that included theory and video-based training for the professionals. Adult-child interaction was assessed with the Emotional Availability Scales before and after the intervention, and children's temperament was assessed with the Early Childhood Behavior Questionnaire. According to results, early childhood professionals' emotional availability increased in the intervention group, especially to children with high levels of activity and pleasure seeking and with low levels of attentional focusing. We argue that the quality of interaction in early childhood education and care can be increased by targeting professional trainings to support children with different temperament characteristics.

The controlled synthesis of two‐dimensional nanocrystals of graphene particles instead of amorphous carbon quantum dots is highly challenging and requires tremendous efforts to optimize the reaction conditions. It has been observed that as a significant bio‐compatible zero‐dimensional material, graphene quantum dots are considered as a novel material for opto‐electronics, energy, biological and environmental applications. However, very few are known about their utilization in photocatalytic degradation of pesticides, especially organochlorine pesticides which are resistant to removal by conventional wastewater treatment methods. In this work, graphene quantum dots were produced from rice husk at relatively low temperatures, resulting in an average particle size of 3.3 nm. The high resolution transmission electron microscopy clearly showed the formation of spherical quantum dots having lattice fringes and the selected area electron diffraction pattern showed the crystallinity of the graphene quantum dots. A study of photodegradation of three highly toxic organochlorine pesticides namely, dichlorodiphenyl trichloro ethane, cypermethrin and fenvalerate were carried out using as‐synthesized graphene quantum dots from rice husk. Interestingly, all these pesticides were found to be degraded around 60 % to 70 % under visible light conditions. It confirmed that synthesized graphene quantum dots from rice husk can act as prominent photocatalyst for the degradation of pesticides and other pollutants. [ABSTRACT FROM AUTHOR]

Background: For a long older age and the presence of alarm features are regarded as indications for prompt endoscopy in patients with dyspepsia. We aimed to find out the value of alarm features in diagnosing serious organic upper gastrointestinal lesions in patients with dyspepsia. Material & methods: In this observational study clinical variables and endoscopic findings of consecutive patients with dyspepsia were recorded in a semi-structured questionnaire. Univariate and multivariate logistic regression was done stepwise to identify predictors for endoscopic findings. A simplified predictor model was built with the age and the presence of any predictor alarm feature to find out the diagnostic accuracy of this model for the significant endoscopic lesion. Results: Among 304 patients (M=134, F=170) one or more alarm features were present in 193 cases (63.5%). Significant organic lesions were found in 84(27.6%) cases. Age >45 years (OR 2.608), abdominal lump (OR 4.489) and family history of upper gastrointestinal cancer (OR 3.880) were found as independent predictors of major endoscopic findings. Using a simplified predictor model of age e" 45 years or the presence of any predictive alarm feature, sensitivity, specificity, positive predictive value, and negative predictive value were 32.4 %, 82.5 %, 79.8% and 36.4% respectively for a significant endoscopic lesion. For upper gastrointestinal cancers, these values were 6%, 100.0%, 100.0% and 47.3% respectively. Conclusion: The predictive value of the age and the presence of alarm features alone are not optimal for significant endoscopic findings in patients with dyspepsia. A newer and more accurate predictive model is a time demand for organic UGI lesions, especially for malignancies. [ABSTRACT FROM AUTHOR]

In this manuscript, we establish a fixed point theorem for F -Suzuki contraction mapping over a non-triangular metric space and also give a discussion as remarks on the non-triangular metric structure. Moreover we introduce non-triangular metric-like space and prove a fixed point theorem for Ćirić quasi-contraction mapping therein using the property S. Examples have been cited in order to examine the validity of the underlying space and in support of our fixed point theorems. [ABSTRACT FROM AUTHOR]