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Graphical abstract, Diabetes mellitus is a well-known danger element for the progression of male reproductive dysfunctions. Available evidence supports oxidative stress to be the underlying mechanism for the manifestation of testicular dysfunctions during diabetes, and this relation represents an attractive target to antagonize these complications. Artemisia judaica L. is known to have antidiabetic and antioxidant characteristics. The possible protective effect of Artemisia judaica against diabetes-induced testicular disorders was not explored. In this investigation, we planned to estimate the possible protective effect of Artemisia judaica extract against diabetes-induced testicular disorders in male rats. The blood levels of insulin, glucose, glycosylated hemoglobin, testosterone, luteinizing hormone and follicle stimulating hormone were evaluated in rats after 12 weeks of Artemisia judaica treatment. Further, oxidative stress markers were determined in their testicular tissue. Epididymal fluid and testicular histological changes were also assessed. Expression of proliferating cell nuclear antigen has been evaluated in testis. Testicular mRNA expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 as the significant transcription factors in controlling antioxidant system were evaluated by real-time polymerase chain reaction. Artemisia judaica extracts have the ability to ameliorate the elevation in the serum glucose and blood glycosylated hemoglobin and the reduction in insulin, testosterone, follicle stimulating hormone and luteinizing hormone caused by streptozotocin-induced diabetes. It induced a significant recovery of the testicular oxidative stress markers, sperm characteristics and improved histopathological findings of the testes. Treatment with Artemisia judaica extracts led to an increase in proliferating cell nuclear antigen protein expression. Reduction of testicular oxidative stress potential in streptozotocin-treated groups was confirmed by upregulation of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1.

The concomitant use of olive leaves (OL) and glyburide (GLB) is a possible therapy for diabetic patients. However, there is no report about the effect of OL on the antidiabetic effect of GLB till now. In the current study, the possible interaction of olive leaves extract (OLE) with GLB was assessed to determine if there was any pharmacological benefit over GLB alone. Seven groups of male Sprague Dawley rats were used. Normal rats of the 1st group treated with 2 mL/kg of 3% Tween 80 (vehicle). The 2nd–5th groups were diabetic rats received vehicle, GLB (5 mg/kg), OLE low dose and OLE high dose respectively, while the 6th–7th groups administered combinations of GLB plus OLE low dose and GLB plus OLE high dose, respectively. All treatments were administered orally once daily for 8 weeks.The use of GLB+OLE-500 obviously improved fasting blood glucose (FBG), insulin and glycated hemoglobin (HbA1c) in diabetic rats (95.5 ± 5.55 mg/dL, 6.8 ± 0.16 mg/dL and 6.1 ± 0.29%, respectively) compared to those treated with GLB monotherapy (140.0 ± 6.36 mg/dL, 5.4 ± 0.19 mg/dL and 7.0 ± 0.20%, respectively). The lipid profile [triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)] was significantly improved in diabetic rats exposed to GLB+OLE-500 (35.6 ± 1.51 mg/dL, 48.5 ± 2.74 mg/dL, 25.1 ± 1.21 mg/dL and 17.0 ± 0.82 mg/dL, respectively) in comparison with diabetic group exposed to GLB alone (43.2 ± 2.15 mg/dL, 56.8 ± 2.14 mg/dL, 18.6 ± 0.96 mg/dL, 23.0 ± 1.26 mg/dL, respectively). Additionally, the benefit impacts of GLB+OLE-500GLB+OLE-500 therapy on the antioxidant and lipid peroxidation parameters in the pancreatic tissues of diabetic rats were higher than those of GLB monotherapy. Moreover, GLB plus OLE-500 combination had the greatest effect on restoration of the insulin content of Beta (β) cells and reduction of the glucagon and somatostatin of Alpha (α) and Delta (δ) endocrine cells in the pancreatic islets among the different treatment. The current study suggests that OL and GLB combination could cause herb-drug interactions through modulation of insulin receptor (INR), glucose transporter 2 (Slc2a2) and peroxisome proliferator-activated receptor α (PPAR-α) genes expression in the liver of diabetic rats. Keywords: Olea europaea, Streptozotocin, Glyburide, INR, Slc2a2, PPAR-α, Rat

Background This study evaluates the anti-cancer effects of Tadalafil (potent PDE-5 inhibitor) in female albino wistar rats against n-methyl n-nitrosourea induced mammary gland carcinogenesis. Methods The animals were selected and randomly divided among four groups and each group contains six animals per group. The animal tissue and serum samples were evaluated for the presence of antioxidant parameters and the cellular morphology was studied using carminic staining, haematoxylin staining and scanning electron microscopy followed by immunoblotting analysis. Results On the grounds of hemodynamic recordings and morphology, n-methyl n-nitrosourea treated group showed distorted changes along with distorted morphological parameters. For morphological analysis, the mammary gland tissues were evaluated using scanning electron microscopy, whole mount carmine staining, haematoxylin and eosin staining. The serum samples were evaluated for the evaluation of oxidative stress markers and inflammatory markers. The level of caspase 3 and 8 were also evaluated for the estimation of apoptosis. The fatty acid profiling of mammary gland tissue was evaluated using fatty acid methyl esters formation. The mitochondrial mediated apoptosis and inflammatory markers were evaluated using immunoblotting assay. Conclusion The results confirm that Tadalafil treatment restored all the biological markers to the normal and its involvement in mitochondrial mediated death apoptosis pathway along with inhibition of inflammatory markers.

Momordica charantia is used in folk medicine to manage diabetes mellitus. In this study, we investigated the possible herb-drug interaction between M. charantia fruit extract (MCFE) and glibenclamide (GLB) in streptozotocin-diabetic rats. Rats were divided into 7 groups. The 1st group received 3% Tween 80. The 2nd–5th groups were diabetic rats received vehicle, GLB (5 mg/kg), MCFE (250 and 500 mg/kg), respectively. The 6th–7th groups administered GLB plus MCFE (250 and 500 mg/kg), respectively. After 8 weeks, fasting blood glucose (FBG), insulin and glycosylated hemoglobin (HbA1c) levels were assessed. Histopathological and immunohistochemical examinations of the pancreases were done. Quantitative RT-PCR was used to analyze hepatic mRNA expression of insulin receptor (INR), glucose transporter 2 (Slc2a2) and peroxisome proliferator-activated receptor α (PPAR-α) genes. All medicaments greatly reduced FBG in diabetic rats when compared with diabetic control group. GLB plus MCFE combination was better than GLB alone in improving levels of insulin and HbA1c. All medicaments restored insulin content of pancreatic β-cells and reduced glucagon and somatostatin of alpha and delta endocrine cells. Moreover, GLB plus MCFE-500 was the most efficient in restoring INR, Slc2a2 and PPAR-α mRNA expression to their normal levels. In conclusion, MCFE in combination with GLB gives greater glycemic improvement than GLB monotherapy. Keywords: Momordica charantia, Streptozotocin, Glibenclamide, INR, Slc2a2, PPAR-α

Estrogen receptor-positive mammary gland carcinoma and its involvement in regulation of overexpressed hypoxia-inducible factor-1α and fatty acid synthase level in hypoxia influenced cancer cells are the present molecular crosstalk of this entire study. To test the hypothesis, we have proceed our study through chemical activation of prolyl hydroxylase 2 which leads to inhibition of hypoxia-inducible factor-1α and fatty acid synthase in ER+MCF-7 cancer cell line and n-methyl-n-nitrosourea induced mammary gland carcinoma rat model. ER+MCF-7 cells were evident with array of nuclear changes when stained through acridine orange/ethidium bromide. Afterward, JC-1 staining of the cells was evident in mitochondrial depolarization. The cells were arrested in G2/M phase when analyzed with flow cytometry. The morphological analysis of rat mammary gland tissue revealed decrease in alveolar buds, restoration of histopathological features along with intra-arterial cushion. The western blotting and fold change expressions of the genes validating the anticancer efficacy of BBAPH-1 is mediated through mitochondria-mediated apoptosis pathway. BBAPH-1 also modulates the expression of prolyl hydroxylase-2 with significant curtailment of hypoxia-inducible factor-1α, fatty acid synthase expression, and their respective downstream markers. These finding suggest that the BBAP-1-mediated activation of prolyl hydroxylase-2 significantly decreased the level of hypoxia-inducible factor-1α and fatty acid synthase. BBAPH-1 also activates the mitochondria-mediated death apoptosis pathway.

Diabetes mellitus (DM) has emerged as a public healthcare problem. Sustained hyperglycemia has been linked with many complications including impaired male fertility Olive tree (Olea europaea L.) leaves have been extensively used in traditional remedies worldwide to control blood glucose level in DM. In this study, the beneficial role of olive leaves extract (OLE) was investigated to combat diabetes-induced adverse effect on testicular tissues. Thirty male Wistar rats were divided into 5 equal groups: normal control group, streptozotocin (STZ)-diabetic group and diabetic groups which were given glibenclamide (GLB) or OLE at 250 and 500 mg/kg for 9 weeks to investigate the efficiency of olive leaves extract (OLE) in reducing the deleterious effect of diabetes on the reproductive system of male rats. Rats were checked for serum glucose, insulin, testosterone and gonadotropins. Also, testicular antioxidants, epididymal sperm characteristics and testicular histopathology were assessed. Expression of the testicular steroidogenic enzymes, cholesterol side-chain cleavage enzyme (P450 scc) and 17β-hydroxysteroid dehydrogenase (17β-HSD) was examined. Moreover, androgen receptor and proliferating cell nuclear antigen (PCNA) protein immunohistochemistry were assessed in testes. STZ-induced diabetes significantly increased serum glucose. However, STZ significantly decreased serum levels of insulin, testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Marked reductions in testicular antioxidants with elevated malondialdehyde (MDA) parallel with deterioration of the testicular histoarchitecture and epididymal sperm characteristics were recorded. Administration of GLB or OLE (250 and 500 mg/kg) resulted in a significant recovery of the above mentioned parameters in STZ-diabetic rats. Interestingly, OLE shows greater glycemic improvement and testicular protection than GLB with the highest percentage protection exhibited by the OLE high dose. Furthermore, OLE significantly induced testicular steroidogenesis in diabetic rat as evidenced by elevated P450 scc and 17β-HSD mRNA expression. The study proves that OLE possesses a potential protective role against diabetes-induced reproductive disorders, which may be due to its antioxidant activity and its ability to normalize testicular steroidogenesis. Keywords: Diabetes, FBG, STZ, Fertility, Sperm characteristics, Testosterone, P450scc and 17β-HSD

Simple Summary A considerable number of diabetic patients are in favour of using oral antidiabetic drugs in combination with certain herbs instead of using oral antidiabetic drugs alone. Artemisia judaica (AJ) is one of the herbs documented to have antidiabetic effects. This study examined the effect of using combination of A. judaica extract (AJE) and the oral hypoglycemic drug glyburide (GLB, 5 mg/kg) on diabetic rats. Fasting blood glucose (FBG), insulin levels, glycated hemoglobin (HbA1c) percentage, serum lipid profile, and oxidative stress biomarkers were estimated. The histopathological examination of the pancreas and the immunohistochemical analysis of anti-insulin, anti-glucagon, and anti-somatostatin protein expressions were also performed. The analysis of the hepatic mRNA expression of peroxisome proliferator-activated receptor α (PPAR-α) and nuclear factor erythroid 2-related factor-2 (Nrf2) genes was performed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Combination of GLB and 500 mg/kg of AJE highly improved FBG, insulin levels, HbA1c, and lipid profile in blood when compared with GLB monotherapy. Furthermore, GLB plus 500 mg/kg of AJE combination was the most successful in restoring insulin content in the β-cells and diminished the levels of glucagon and somatostatin of the α- and δ-endocrine cells in the pancreatic islets, restoring PPAR-α and Nrf2 mRNA expression in the liver. In conclusion, these data indicate that GLB plus 500 mg/kg of AJE combination gives greater glycemic improvement than GLB monotherapy. Abstract Several members of the genus Artemisia are used in both Western and African traditional medicine for the control of diabetes. A considerable number of diabetic patients switch to using oral antidiabetic drugs in combination with certain herbs instead of using oral antidiabetic drugs alone. This study examined the effect of Artemisia judaica extract (AJE) on the antidiabetic activity of glyburide (GLB) in streptozotocin (STZ)-induced diabetes. Forty-two male Wistar rats were divided into seven equal groups. Normal rats of the first group were treated with the vehicle. The diabetic rats in the second–fifth groups received vehicle, GLB (5 mg/kg), AJE low dose (250 mg/kg), and AJE high dose (500 mg/kg), respectively. Groups sixth–seventh were treated with combinations of GLB plus the lower dose of AJE and GLB plus the higher dose of AJE, respectively. All administrations were done orally for eight weeks. Fasting blood glucose (FBG) and insulin levels, glycated hemoglobin (HbA1c) percentage, serum lipid profile, and biomarkers of oxidative stress were estimated. The histopathological examination of the pancreas and the immunohistochemical analysis of anti-insulin, anti-glucagon, and anti-somatostatin protein expressions were also performed. The analysis of the hepatic mRNA expression of PPAR-α and Nrf2 genes were performed using quantitative RT-PCR. All treatments significantly lowered FBG levels when compared with the STZ-control group with the highest percentage reduction exhibited by the GLB plus AJE high dose combination. This combination highly improved insulin levels, HbA1c, and lipid profile in blood of diabetic rats compared to GLB monotherapy. In addition, all medicaments restored insulin content in the β-cells and diminished the levels of glucagon and somatostatin of the α- and δ-endocrine cells in the pancreatic islets. Furthermore, the GLB plus AJE high dose combination was the most successful in restoring PPAR-α and Nrf2 mRNA expression in the liver. In conclusion, these data indicate that the GLB plus AJE high dose combination gives greater glycemic improvement in male Wistar rats than GLB monotherapy.

Background In the present study, fatty acid synthesis is targeted to combat mammary gland carcinoma by activating prolyl hydroxylase-2 with Voacamine alone and in combination with Tamoxifen. It was hypothesized that the activation of prolyl hydroxylase-2 would inhibit the hypoxia-induced fatty acid synthesis and mammary gland carcinoma. Mammary gland carcinoma was induced with a single dose administration of N-methyl-N-nitrosourea (50 mg/kg,i.p.) and treatment with Voacamine and Tamoxifen 15 days after carcinogen administration. Results At the end of the study, hemodynamic profiling of animals was recorded to assess the cardiotoxic potential of the drug. Blood serum was separated and subjected to nuclear magnetic resonance spectroscopy. Carmine staining and histopathology of mammary gland tissue were performed to evaluate the anti-angiogenic potential of the drug. The antioxidant potential of the drug was measured with antioxidant markers. Western blotting was performed to study the effect of the drug at the molecular level. Conclusion Results of the study have shown that Voacamine treatment stopped further decrease in body weight of experimental animals. The hemodynamic study evidenced that Voacamine at a low dose is safe in cardiac patients. Microscopic evaluation of mammary gland tissue documented the anti-angiogenic potential of Voacamine and Tamoxifen therapy. Perturbed serum metabolites were also restored to normal along with antioxidant markers. Immunoblotting of mammary gland tissue also depicted restoration of proteins of the hypoxic and fatty acid pathway. Conclusively, Voacamine and its combination with Tamoxifen activated prolyl hydroxylase-2 to combat mammary gland carcinoma.

The present study was undertaken to evaluate the antidiabetic and hypolipidemic action of leaf extract of Barleria cristata Linn in rats. Diabetes was induced in the rats by a single intraperitoneal (IP) injection of alloxan (150 mg/kg) and randomly divided into 7 groups. Animals were treated with low (250 mg/kg) and high (500 mg/kg) doses of ethyl acetate leaf extract (EALE) and hydro-alcoholic leaf extract (HALE) up to 21 days. The body weight and blood glucose level (BGL) were measured on weekly basis. The rats were killed under mild ether anesthesia on 21st day, blood and the vital organ were collected to estimate biochemical parameters and to study histopathological changes. A single-dose administration of alloxan induced hyperglycemia in all the groups. A regular increase in BGL was observed in toxic control groups when compared with the normal control. Daily oral administration of rats with extracts (HALE and EALE) and standard drug (Glimepiride, 5 mg/kg), reduced elevated BGL significantly (p

Objective: The study explored the chemoprophylactic potential of roflumilast against 1,2-dimethylhydrazine (DMH) actuated preneoplastic colon damage in albino Wistar rats. Methods: Animals were arbitrarily divided into five groups of six animals each. DMH was used to induce preneoplastic colon damage (20 mg/kg/7 days, subcutaneously, for 42 days). Roflumilast was administered subcutaneously at two doses (1 and 5 mg/kg/day, from day 28 to 42). At the end of the study, the animals were recorded for the electrocardiographic changes and heart rate variability (HRV) paradigms on 42nd day, using PowerLab system. Blood samples were collected from all the animals to measure hydrogen sulfide (H2S) and nitric acid. The colon tissue was dissected out and analyzed for inflammatory markers, biochemical parameters including, superoxide dismutase, thiobarbituric acid reactive substances, catalase, and glutathione reductase and histopathology. Results: DMH caused derangement of HRV factors, abnormal antioxidant markers, and elevated levels of inflammatory markers. H2S and nitric oxide levels upsurge in DMH-treated rats and promoted preneoplastic damage. Histopathologically, loss of crypts, goblet cells, and distorted lamina propria were observed in toxic group. Treatment with roflumilast was able to curtail down oxidative stress and inflammatory markers and stabilitate the hemodynamic derangements as well as was able to restore the normal architecture of colonic mucosa. Conclusion: The findings from the present study conclude that treatment with roflumilast positively modulates the preneoplastic colon damage.

Background: The current study was attempted to inquest the role of combination therapy of Voacamine and Vincristine for the prevention of mammary gland carcinoma through prolyl hydroxylase‐2 activation. The prolyl hydroxylase‐2 activation leads the downregulation of hypoxia‐inducible factor‐1α and fatty acid synthase. Over expression of hypoxia inducible factor-1α and fatty acid synthase is previously reported in solid tumor of mammary gland. Methods: After screening a battery of natural compounds which were similar to vincristine, vocamine was selected as a possible prolyl hydroxylase‐2 activator and justify its activity using 7, 12-Dimethylbenz[a]anthracene induced rat model. The combination therapy was evaluated for cardiac toxicity using hemodynamic profile. The angiogenic markers were evaluated using carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity through haematoxylin and eosin staining. The combination therapy also delineated the markers of oxidative stress favorably. Afterwards, the disruption of fatty acids was evaluated using gas chromatography. Results: The immunoblotting analysis validated that combination therapy has a potential to switch on the prolyl hydroxylase‐2 activity and thus initiate proteolytic degradation of hypoxia‐inducible factor‐1α and its consequence effects. The combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells.Conclusion: The present study explores the role of voacamine in activation of prolyl hydroxylase‐2 which can decrease over expression of hypoxia‐inducible factor‐1α and fatty acid synthase in cells of mammary gland carcinoma.

// Subhadeep Roy 1 , Atul Kumar Rawat 2 , Shreesh Raj Sammi 3 , Uma Devi 4 , Manjari Singh 1 , Swetlana Gautam 1 , Rajnish Kumar Yadav 1 , Jitendra Kumar Rawat 1 , Lakhveer Singh 1 , Mohd. Nazam Ansari 5 , Abdulaziz S. Saeedan 5 , Rakesh Pandey 3 , Dinesh Kumar 2 and Gaurav Kaithwas 1 1 Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow (UP), India 2 Central for Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Lucknow (UP), India 3 Department of Microbial Technology and Nematology, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow (UP), India 4 Department of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, Sam Higginbottom Institute of Agricultural Sciences and Technology, Allahabad (UP), India 5 Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, KSA Correspondence to: Gaurav Kaithwas, email: gauravpharm@hotmail.com Keywords: alpha linolenic acid, apoptosis, polyunsaturated fatty acid, hypoxia, fatty acid synthase Received: February 06, 2017 Accepted: June 12, 2017 Published: July 25, 2017 ABSTRACT Alpha linolenic acid is an essential polyunsaturated fatty acid and is reported to have the anti-cancer potential with no defined hypothesis or mechanism/s. Henceforth present study was in-quested to validate the effect of alpha linolenic acid on mitochondrial apoptosis, hypoxic microenvironment and de novo fatty acid synthesis using in-vitro and in-vivo studies. The IC 50 value of alpha linolenic acid was recorded to be 17.55μM against ER+MCF-7 cells. Treatment with alpha linolenic acid was evident for the presence of early and late apoptotic signals along with mitochondrial depolarization, when studied through acridine orange/ethidium bromide and JC-1 staining. Alpha linolenic acid arrested the cell cycle in G2/M phase. Subsequently, the in-vivo efficacy was examined against 7, 12-dimethylbenz anthracene induced carcinogenesis. Treatment with alpha linolenic acid demarcated significant effect upon the cellular proliferation as evidenced through decreased in alveolar bud count, restoration of the histopathological architecture and loss of tumor micro vessels. Alpha linolenic acid restored the metabolic changes to normal when scrutinized through 1 H NMR studies. The immunoblotting and qRT-PCR studies revealed participation of mitochondrial mediated death apoptosis pathway and curtailment of hypoxic microenvironment after treatment with alpha linolenic acid. With all above, it was concluded that alpha linolenic acid mediates mitochondrial apoptosis, curtails hypoxic microenvironment along with inhibition of de novo fatty acid synthesis to impart anticancer effects.

The present work was undertaken to study the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on 1, 2-dimethyhydrazine (DMH) induced colon cancer and role of the cholinergic anti-inflammatory pathways (CAP) in the same. Groups of rats were randomly divided into ten groups (n = 8). DMH administration was very well apparent for autonomic dysfunction as observed through distorted hemodynamic (electrocardiogram and heart rate variability), increased aberrant crypt foci and flat neoplastic lesions (methylene blue staining, scanning electron microscopy and Hematoxylin and eosin staining). DMH administration was also recorded for per-oxidative damage. taVNS application restored the autonomic function, cellular morphology and curtailed the oxidative damage. DMH application conspicuously inhibited the mitochondrial apoptosis which was restored back after taVNS application, when scrutinized through immunoblotting and quantitative real time polymerase chain reaction studies. taVNS application up-regulated the CAP as perceived through increased expression for α7 nicotinic acetylcholine receptor(α7nAchR) and decreased expression for nuclear factor kappa-ligand-chain-enhancer of activated B cells (NFκBp65), tissue necrosis factor-α and high mobility group box-1 at protein and mRNA levels. All in all, taVNS up-surged the CAP to counteract DMH induced colon carcinogenesis. Among all the stimulation parameters used, taVNS 3 (pulse width-1 ms, frequency-6 Hz, voltage-6 v, duration-240 min) was observed to be the most effective. Since only chemotherapy and surgery are available options for management of CRC, which are troublesome and painful, there is currently no non-invasive method available for management of CRC. Results of the current study affirmed the effectiveness of taVNS against DMH induced colon cancer. The present study established taVNS as a novel and non-invasive approach toward the management of CRC.

Autism spectrum disorders (ASDs) are often considered to be genetic. They are characterized by unificational behavioral abnormalities which are classified in two basic domains: social relations and social communication, and restricted and repetitive pattern of behaviors and activity. Clinical research has evidenced that genetic and environmental factors play a major role in the development of ASD, and it is contemplated to be a multifactorial as well. Augmentation in the field of molecular genetics and neuroscience allows the pharmacologist to explore more features of ASDs using genetic, humanoid, and nonhumanoid models. Hence, the present review was undertaken to elucidate the major concepts associated with the models of ASD, such as gene or chromosome incrimination; face, predict, and construct validities; behavioral assays; and advantages and disadvantages of preclinical models along with constrains in developing genetic models for ASD.

The present study was aimed to enumerate the role of metformin-associated H2S release against lipopolysaccharide (LPS) induced neuroinflammation. Five groups of animals were subjected to treatment as control (normal saline), toxic control (LPS, 125 µg/kg, i.p.), and three separate groups treated with 6.25, 12.5, and 25 mg/kg of metformin along with LPS for a period of 28 days. LPS was administered on 1st, 2nd, 3rd, 4th, 23rd, 24th, 25th and 26th day. The animals were evaluated for behavioral (elevated plus maze, rotarod and actophotometer); biochemical (plasma and tissue H2S, COX, LOX and NO), antioxidant (TBARS, SOD, catalase, protein carbonyl and GSH) and liver toxicity (SGOT and SGPT) markers. The brain tissues were further evaluated histopathologically, free fatty acid profile and NF-κB expression. The LPS could not hasten any significant behavioral, biochemical, antioxidant and histopathological changes in the brain tissue. LPS also failed to modify the free fatty acid profile and NF-κB expression in the brain tissue. The LPS demarcated a well-defined peripheral inflammation as perceived through the plasma H2S, NO, SGOT and SGPT. Metformin administration demonstrated a marked effect on the peripheral inflammation induced by LPS. The LPS (i.p.) administration is devoid of any neuroinflammatory effects; however, precipitates peripheral inflammatory reactions and the same can could be attributed to the fact that LPS is devoid of/confined by very minimal permeability across the blood brain barrier. Metformin demonstrated a significant effect on peripheral inflammatory reactions precipitated through LPS.

The present study was undertaken to evaluate the effect of palonosetron (PAL) against 1,2-dimethylhydrazine (DMH)-induced colon cancer. Wistar albino rats were randomly divided into four groups (n = 8). Group 1 served as normal control (1 mM EDTA + saline, 2 ml per kg per day, s.c.); group 2 toxic control; group 2, 3 and 4 received DMH (20 mg per kg per week, s.c.), for 6 weeks; groups 3 and 4 also received PAL (0.25 and 0.50 mg per kg per day, p.o) for 6 weeks. DMH treated rats showed altered heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), distorted antioxidant markers (TBAR's, SOD, catalase, GSH) and increased levels inflammatory markers (COX). The colonic surface architecture, studied using scanning electron microscopy (SEM), revealed aberrant crypts (500×) and preneoplastic nodules (2000×). PAL treatment helped to minimize the ACF count, and restored oxidative and inflammatory markers favorably. To further validate our results, we directed our study to define the effect of PAL on acetylcholine (Ach) neurotransmission using a simple model organism, C. elegans. Increased cholinergic transmission by PAL (8 μM) was evident in the worms when studied through an aldicarb assay. However, PAL (2 μM, 4 μM and 8 μM) treatment negatively modulated nAchR, when evaluated using the levamisole assay. The increased synaptic Ach levels can be attributed to the decreased levels of acetylcholinesterase (AchE), which could be attributed to the decreased genomic levels of ace-1 and ace-2. The above findings were also supported by the fact, that we observed decreased AchE activity in PAL treated rats. In addition the downregulation in the expression of unc-38 (one of the necessary components of nAchR) sufficiently links with the decreased nAchR activity. Our findings emphasize the potential role of PAL in the suppression of colon carcinogenesis.

The present study was designed to evaluate the effects of phenidone (Dual inhibitor of COX-2 and 5-LOX, DuCLOX-2/5 inhibitor) on various aspects of cancer chemoprevention. Treatment with the phenidone was inquested to validate the implications of dual inhibition of arachidonic acid (AA) metabolism against MNU induced mammary gland carcinogenesis. MNU treated rat showed altered hemodynamic profile, distorted cellular architecture, upregulated inflammatory enzyme markers (COX, LOX, Nitric oxide and hydrogen sulfide) and distorted oxidative stress markers (thiobarbituric acid reactive substances, protein carbonyl, superoxide dismutase, catalase and glutathione). Phenidone treatment regulated histological architecture in the experimental animals similar to control. The treatment with phenidone favorably regulated the levels of inflammatory markers, and oxidative stress markers against toxic treatment. Our findings emphasize the potential role of phenidone in suppression of mammary gland carcinoma against the deleterious effects of MNU.

The aim of the present study is to evaluate the effect of gamma linolenic acid (GLA) on mitochondrial mediated death apoptosis, hypoxic microenvironment and cholinergic anti-inflammatory pathway against 7, 12-dimethylbenz (a) anthracene (DMBA) induced mammary gland carcinoma. The effects of GLA were evaluated morphologically and biochemically against DMBA induced mammary gland carcinoma. The metabolic study was done for evaluation of biomarkers using 1H NMR. The present study was also verified through immunoblotting and qRT-PCR studies for the evaluation of various pathways. GLA treatment has a delineate implementation upon morphology of the tissues when evaluated through carmine staining, hematoxyline and eosin staining and scanning electron microscopy. GLA also demarked a commendatory proclamation of the fifteen key serum metabolites analogous with amino acid metabolism and fatty acid metabolism when recognized through1H NMR studies. The immunoblotting and qRT-PCR studies accomplished that GLA mediated mitochondrial death apoptosis, curtail hypoxic microenvironment along with hindrance of de novo fatty acid synthesis and also mediate the cholinergic anti-inflammatory pathway to proclaim its anticancer effects.

Mefloquine was retrieved as a glucagon -like peptide-1 receptor agonist and, therefore, evaluated for its antidiabetic potential against non-insulin-dependent diabetes mellitus (NIDDM) in experimental animals. NIDDM was induced by single intraperitoneal injection of streptozotocin and nicotinamide (60 + 110 mg/kg) in albino wistar rats. The experimental animals were scrutinised for electrocardiographic (ECG) and heart rate variability (HRV) factors to study the autonomic dysfunction along with blood glucose, serum insulin, and liver glycogen levels for glycemic control. Simultaneously, antioxidant markers (TBARs, protein carbonyl, GSH, SOD, catalase) and inflammatory markers (COX, LOX, NO) were scrutinized as well. Oral administration of mefloquine normalised the heart rate with favourable regulation of time and frequency domain HRV parameters. Mefloquine restored the blood glucose, serum insulin, and liver glycogen levels favourably in diabetic rats. Treatment with mefloquine curtailed the antioxidant markers with favourable regulation of inflammatory signals. Mefloquine was also found to be less hepatotoxic in contrast to the standard metformin, providing an integrated advantage as an antidiabetic agent.

The purpose of this study was to investigate the therapeutic effects and underlying mechanism of alpha-linolenic acid based intra-mammary nano-suspension (ALA-NS) on both in vitro antimicrobial and in vivo activity. The ALA-NS formulated and optimized for parameters like particle size, zeta potential, polydispersity index, sedimentation volume, and stability studies. In vitro, our results showed that ALA-NS (F1 and F2) have the higher zone of inhibition and lower minimum inhibitory concentration (MIC) value than ALA and cefotaxime alone against mastitis-causing pathogens. In vivo, our results showed that ALA-NS (F1 and F2) restored the altered oxidative biomarkers (superoxide dismutase, catalase, glutathione, TBARs, and protein carbonyl) along with histopathological changes in lipopolysaccharides (LPS) treated rats. Western blot results indicated that ALA-NS (F1 and F2) inhibited LPS induced inflammatory proteins (NFκBp65, COX, LOX, and IFN-γ) in rat mammary epithelial cells. ALA-NS (F1 and F2) also suppressed the hypoxia inducible factor-1α (HIF-1α) and upregulated prolyl-hydroxylase (PHD-2), sterol regulatory element binding protein (SREBP-1c), and fatty acid synthase (FASN) protein expression. In addition, ALA-NS upregulated the pro-apoptotic (BAX and BAD) and downregulated anti-apoptotic (BCL-2 and BCL-XL) proteins expression in rat mammary epithelial tissue. In conclusion, we found that ALA-NS (F1 and F2) have in vitro antimicrobial activity and protective effects on LPS-induced mastitis in rats.

This study was undertaken to investigate the effect of α-chymotrypsin on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized into four groups (six animals in each). Group I (sham control 0.9 % normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v.); Group III (α-chymotrypsin, 5 mg/kg, p.o.); Group IV (α-chymotrypsin, 10 mg/kg p.o.). Toxicity was induced by single i.v. injection of MNU followed by α-chymotrypsin supplementation therapy for 100 days. MNU treatment was evident with increased alveolar bud count, differentiation score, upregulated inflammatory enzymes markers (COX, LOX and NO) antioxidative stress markers (TBARs, SOD, catalase and GSH).MNU associated toxicity was also ascertained by PGP 9.5 and NF-κB expression in the mammary gland tissue followed by FAME analysis for fatty acid profiling. α-chymotrypsin afforded significant protection against the deleterious effects of MNU.

Cancer is a leading cause of death and major health concern worldwide. The animal and human studies support the presumption that inflammation directs the cancer initiation and progression. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are the key players in the inflammatory cascade contributing towards the angiogenesis, tumor cell invasiveness, and disruption in the pathways of cellular proliferation/apoptosis. Contemporary studies have particularized a promising role of COX-2 and 5-LOX inhibitors in cancer chemoprevention. The present review is a pursuit to define implications of dual COX-2 and 5-LOX (DuCLOX-2/5) inhibition on various aspects of cancer augmentation and chemoprevention.

The defatted aqueous methanolic extract of the air‐dried aerial parts of Plantago major, collected from Nile delta, Egypt, was evaluated for its antioxidant and hepatoprotective effects. The major phenolic constituent; acteoside was isolated. Meanwhile, P. major exhibited potent hepatoprotective effect as it inhibited the serum activity elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma‐glutamyl transferase (GGT) enzymes and total and direct bilirubin. It increased the serum total protein and albumin and attenuated CCl₄‐induced lipid peroxidation (LPO) and increased GSH in the liver homogenates. Liver histopathology supported the biochemical findings. Acteoside inhibited lipopolysaccharide induced production of nitric oxide in RAW264.7 macrophages (IC₅₀, 75.0 μM) and scavenged both superoxide radical (IC₅₀, 1.51 μM) and DPPH radical (IC₅₀ of 11.27 µM). P. major showed significant DPPH scavenging activity in vitro (IC₅₀, 7.32 μg/mL). It could be concluded that, P. major has potent antioxidant, anti‐inflammatory, and hepatoprotective activities. PRACTICAL APPLICATIONS: Plantago major L. is an edible plant that is used as food, particularly at the end of spring, just before the harvest of common vegetables. The plant grows wildly at canal banks of the Nile delta in Egypt and represents a very cheap food for farmers when frequent vegetables are not available. The research showed that the defatted aqueous methanolic extract has potential antioxidant and hepatoprotective effects in rats. The effect was very similar to the commercially used drug silymarin; indicating that it could be used as very cheap healthy food, food supplement or neutraceutical preparation to provide liver support for patients suffering from hepatic dysfunction. The main constituent acteoside was isolated and exhibited potent antioxidant and anti‐inflammatory activities in vitro, besides being safe on primary rat hepatocytes. Therefore this project provides a very cheap hepatoprotective drug for liver support, and a source of safe antioxidant and anti‐inflammatory compound.

The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, ω-3) and gamma-linolenic acid (GLA, 18:3, ω-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect.

Background The present study was in quested to study the effects of β-sitosterol on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Methods Animals were randomized and divided into four groups of eight animals each. Group I (sham control 1 % CMC in normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v); Group III (MNU 47 mg/kg, i.v + β-sitosterol, 10 mg/kg, p.o); Group IV (MNU 47 mg/kg, i.v + β-sitosterol, 20 mg/kg, p.o). Toxicity was induced by single i.v. injection of MNU followed by β-sitosterol supplementation therapy for 115 days at the dose mentioned above. Results Treatment with β-sitosterol evidenced decrease in the alveolar bud and lobule score in the whole mount of the mammary gland. β-sitosterol exhibited diminishing effect on oxidative stress through synchronizing lipid and enzymatic antioxidant defense. A significant decrease in the saturated and unsaturated fatty acid was evident with the MNU treatment and β-sitosterol demonstrated a marked effect on it. Pgp 9.5 expression was dose dependently upregulated by β-sitosterol treatment in comparison to MNU treatment. On the contrary, downregulated NF-kB expression was perceived, when β-sitosterol was concomitantly administered with MNU. Conclusion β-sitosterol afforded significant protection against the deleterious effects of MNU.