Lactobacillus rhamnosus induced epithelial cell apoptosis,ameliorates inflammation and prevents colon cancer development in an animal model

Background/AimProbiotics have been suggested as prophylactic measure in colon carcinogenesis. This study aimed at determining the potential prophylactic activity of Lactobacillus rhamnosus GG CGMCC 1.2134 (LGG) strain on colorectal carcinogenesis via measuring its effect on Nuclear factor kappa B (NFκB) inflammatory pathway and apoptosis.Materials and methods64 Sprague Dawley rats were grouped into four as follows; Group 1 (Healthy control), Group 2 (LGG), Group 3 (cancer control Dimethyl hydrazine (DMH)) and Group 4 (LGG + DMH). LGG was administered orally to LGG and LGG + DMH groups. Colon carcinogenesis was chemically induced in LGG + DMH and DMH groups by weekly injection of 40 mg/kg DMH. Animals were sacrificed after 25 weeks of experiment and tumor characteristics assessed. The change in expression of NFκB-p65, COX-2, TNFα, Bcl-2, Bax, iNOS, VEGFα, β-catenin, Casp3 and p53 were evaluated by western blotting and qRT-PCR.ResultsLGG treatment significantly reduced tumor incidence, multiplicity and volume in LGG + DMH treatment group compared to DMH cancer control group. Also, LGG treatment reduced the expression of β-catenin and the inflammatory proteins NFκB-p65, COX-2 and TNFα; the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic proteins Bax, casp3 and p53 compared with DMH group.ConclusionLGG have a potential protection effect against colon carcinogenesis; inducing apoptosis and ameliorating inflammation, and may hold a promise as bio-therapeutic dietary agent.     

Evaluation of antidiabetic effect of total calystegines extracted from Hyoscyamus albus

BackgroundHyoscyamus albus L. (Solanaceae) an old medicinal plant is a rich source of tropane and nortropane alkaloids which confers to this plant a number of very interesting and beneficial therapeutic effects.PurposeCalystegines that are polyhydroxylated alkaloids and imino-sugars poccess significant glycosidases inhibitory activities and are therefore good candidats for the treatment of diabetes mellitus.Study designCalystegines extracted from Hyoscyamys albus seeds were tested for teir acute oral toxicity and investigated for their in-vivo antidiabetic effect on Streptozotocine induced diabetes in mice.MethodesCalystegines were extracted from the seeds plant using an Ion exchange column; the remaining extract was then administrated orally to mice at several single doses for acute toxicity assay. A dose of 130 mg/kg streptozotocine was injected to mice to induce diabetes mellitus, and diabetic mice were treated orally during 20 days with 10 mg/kg and 20 mg/kg calystegines and 20 mg/kg glibenclamide as the reference drug.ResultsAcute oral toxicity showed that calystegines are not toxic up to a dose of 2000 mg/kg with absence of any signs of intoxication and damages in Liver and kidney tissues.The nortropane alkaloids markedly reduced blood glucose levels and lipid parameters of diabetic mice to normal concentrations after 20 days of treatment at 10 mg/kg and 20 mg/ kg (p < 0.05). Histopathological study of diabetic mice pancreas indicated that calystegines of Hyoscyamus albus have minimized streptozotocine damages on β-cells of islets of langerhans, stimulated β-cells regeneration and improved with this insulin secretion.ConclusionThe findings of this study suggest that calystegines are potent antidiabetic agents with antihyperglicemic and hypolipidemic effects, and a protective fonction on pancreas in streptozotocin induced diabetes in mice.     

Enhancement of orofacial antinociceptive effect of carvacrol,a monoterpene present in oregano and thyme oils,by β-cyclodextrin inclusion complex in mice

Orofacial pain is associated with diagnosis of chronic pain of head, face, mouth, neck and all the intraoral structures. Carvacrol, a naturally occurring isoprenoid with diverse class of biological activities including anti-inflammatory, analgesic, antitumor and antioxidant properties. Now, the antinociceptive effect was studied in mice pretreatment with carvacrol (CARV) and β-cyclodextrin complex containing carvacrol (CARV-βCD) in formalin-, capsaicin-, and glutamate- induced orofacial nociception. Mice were pretreated with vehicle (0.9% Nacl, p.o.), CARV (10 and 20 mg/kg, p.o.), CARV-βCD (10 and 20 mg/kg, p.o.) or MOR (10 mg/kg, i.p.) before the nociceptive behavior induced by subcutaneous injections (s.c.) of formalin (20 μl, 2%), capsaicin (20 μl, 2.5 μg) or glutamate (20 μl, 25 μM) into the upper lip respectively. The interference on motor coordination was determined using rotarod and grip strength meter apparatus. CARV-βCD reduced the nociceptive during the two phases of the formalin test, whereas CARV did not produced the reduction in face-rubbing behavior in the initial phase. CARV-βCD (20 mg/kg, p.o.) produced 49.3% behavior pain while CARV alone at 20 mg/kg, p.o, produced 28.7% of analgesic inhibition in the second phase of formalin test. CARV, CARV-βCD and Morphine (MOR) showed a significant reduction against nociception caused by capsaicin or glutamate injection. Thus the encapsulation of carvacrol in β-cyclodextrin can acts as a considerable therapeutic agent with pharmacological interest for the orofacial pain management.     

The influence of lipoic acid on caveolin-1-regulated antioxidative enzymes in the mouse model of acute ulcerative colitis

AimThis study was undertaken to verify if two-weeks treatment of lipoic acid (LA) influence colon damage and pro-inflammatory cytokine synthesis during DSS-induced acute colitis. Moreover, as LA has anti-oxidative properties, we analyzed its influence on the level of antioxidative enzymes, HO-1 and eNOS, and their regulator- caveolin-1.MethodsLA was administrated to male C57/BALBc mice at a dose of 25 or 50 mg/kg/day (i.p.) for 21 days. Acute colitis was induced by administration of 4% DSS (w/v) in drinking water for 5 days, followed by 2 days of normal drinking water. Mice in LA + DSS groups were treated with LA (25 or 50 mg/kg/day; i.p.) starting 14 days prior to 4% DSS. Control group received saline for 21 days. In the colon tissue we measured myeloperoxidase activity (MPO), IL-1β, IL-6, IL-17A, IL-23 (ELISA method), and tissue level of cav-1, phospho-eNOS, total eNOS and HO-1 (Western blot).ResultsAdministration of DSS significantly increased total colon damage (p < 0.001), myeloperoxidase (MPO) activity (p < 0.05) and pro-inflammatory IL-6 (p < 0.05). There was also a tendency towards higher IL-1β, IL-17A, and IL-23 in the colon. LA alone did not influence total colon damage, MPO activity, and pro-inflammatory cytokines concentration compared to control (p < 0.05). Notably, mice treated with LA and DSS had significantly decreased total colon damage score (p < 0.001), despite augmented colon MPO activity (p < 0.01), but similar (IL-17A) or even significantly higher level (IL-1β, IL-23) as compared to the DSS group (p < 0.05). IL-6 was insignificantly decreased after LA treatment at a dose of 50 mg/kg.In acute colitis there was a tendency towards an increase in cav-1 and HO-1 and a decrease p-eNOS/total eNOS ratio. Moreover, the LA + DSS groups had higher expression of HO-1 and p-eNOS/total eNOS (p < 0.05) compared to the DSS group, and a tendency towards higher cav-1 level. The changes did not depend on LA dose.ConclusionOur study indicated that LA, at lower doses, may influence cav-1-regulated antioxidative enzyme levels (HO-1 and p-eNOS/total eNOS) despite an increase in colon pro-inflammatory cytokine levels during acute colitis. Hence, LA treatment may be – to some extent – beneficial in attenuation of acute colitis.     

Evaluation of anti-diabetic and anti-tumoral activities of bioactive compounds from Phoenix dactylifera L’s leaf: In vitro and in vivo approach

Among various chronic disorders, cancer and diabetes mellitus are the most common disorders. This study was designed to evaluate the effectiveness of hydroalcoholic extract of Phoenix dactylifera L. leaves (HEPdL) in animal models of type II diabetes in vitro/in vivo and in a human melanoma-derived cell line (IGR-39). A liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis was also performed to determine the amount of phenolic and flavonoid compounds in this plant. The physicochemical results by LC–MS/MS analysis of HEPdL showed the presence of 10 phenolic compounds. The in vitro study showed that the extract exhibited a more specific and potent inhibitor of α-glucosidase than α-amylase with an IC₅₀ value of 20 ± 1 μg/mL and 30 ± 0.8 μg/mL, respectively. More importantly, the in vivo study of the postprandial hyperglycemia activity with (20 mg/kg) of HEPdL showed a decrease in plasma glucose levels after 60 min in resemblance to the glucor (acarbose) (50 mg/kg) effect. The oral administration of HEPdL (20 mg/kg) in alloxan-induced diabetic mices for 28 days showed a more significant anti-diabetic activity than that of the drug (50 mg/kg). Moreover, cytotoxicity effects of HEPdL in IGR-39 cancer cell lines were tested by MTT assay. This extract was effective in inhibiting cancer cells growth (IGR-39) at dose 35 and 75 μg/mL. These results confirm ethnopharmacological significance of the plant and could be taken further for the development of an effective pharmaceutical drug against diabetes and cancer.     

Roles of monoaminergic,antioxidant defense and neuroendocrine systems in antidepressant-like effect of Cnestis ferruginea Vahl ex DC (Connaraceae) in rats

We have earlier reported antidepressant-like effect of Cnestis ferruginea and its bioflavonoid constituent, amentoflavone in behavioural paradigms but its effects on neurochemical and neuroendocrine systems are yet to be elucidated. This study sought to investigate the effect of subchronic treatment of C. ferruginea (CF) on monoamines system, hypothalamo-pituitary adrenal axis and nitrosative/oxidative stresses. Male albino rats (150–200 g) randomly divided into seven groups; Group I: vehicle treated (0.2%^v/_v Tween 80 in normal saline (10 ml/kg; p.o.; unstressed), Group II: vehicle treated + restraint stress, Group III: imipramine (20 mg/kg; p.o.), Group IV–VI: CF (12.5, 50, or 100 mg/kg; p.o., respectively), Group VII: CF 6.25 + imipramine 5 mg/kg. One hour post-treatment, animals were subjected to 20 min restraint stress and 6 min, forced swim test (FST) for a period of 14 days. CF (12.5, 50 and 100 mg/kg) produced significant reduction in immobility time and an increase in climbing behaviour. CF attenuated repeated restraint stress × FST-induced serum corticosterone [F(6,28) = 5.45,P < 0.01]. Exposure of rats to FST + restraint stress paradigms produced significant (P < 0.05) increase in malondialdehyde and nitrite level, also reduced the glutathione level and superoxide dismutase activity which was reversed by subchronic treatment of rats with CF. Restraint stress × FST significantly decreased NA, DA and 5-HT concentrations, with increased DA and 5-HT turnover ratios in discrete brain regions which was ameliorated by CF or imipramine subchronic treatment. These results suggest that the antidepressant-like effect of C. ferruginea involved enhancement of monoamines and antioxidant as well as normalization of neuroendocrine systems.     

Involvement of l-arginine-nitric oxide pathway in anxiolytic-like effects of zinc chloride in rats

PurposeZinc is crucial for normal development of the brain, and Zinc deficiency has been shown to associate with neurological disorders (e.g. anxiety) through interactions with several neurotransmitter systems such as nitric oxide (NO). In this regard, our study aimed to evaluate the possible involvement of l-arginine NO pathway on anxiolytic effects of zinc in adult male rats.MethodsZinc chloride at doses of 2.5 and 10 mg/kg (intraperitoneal or ip) or saline (1 ml/kg, ip) were injected 30 min before the anxiety test. Zinc administrated rats (10 mg/kg) were pre-treated with intra-CA1 microinjection of l-arginine in sub-effective dose of 1 μg/rat (dorsal hippocampus, vehicle: saline1 μl/rat). In addition, zinc chloride and NG-nitro-l-arginine methyl ester (l-NAME) were intraperitoneally co-administrated in sub-effective doses of 2.5 mg/kg and 80 mg/kg, respectively. The percentage of open arm time (OAT%), percentage of open arm entry (OAE%), as measures of anxiety, and total number of arm entries, as measures of locomotor activity, were recorded.ResultsTreatment with zinc (10 mg/kg) markedly produced an increase in OAT% and OAE% in the Elevated plus maze test (EPM). A decrease of OAT% and OAE% was shown in groups which received zinc (10 mg/kg) and l-arginine (1 μg/rat) concomitantly as compared to the control group. Moreover, an increase of OAE% was revealed in the group exposed to Zinc (2.5 mg/kg) and l-NAME (80 mg/kg) co-administration. Although, Two-way ANOVA showed no significant differences of anxiety indices in rats received drug + zinc chloride in compare to the zinc pretreated with saline group.ConclusionAnxiolytic- like effect of zinc reversed by nitric oxide precursor l-arginine. Additionally, the synergistic effects of l-NAME and ZnCl₂ were shown in the EPM. Thus our findings suggest that at least in part the anxiolytic effects of zinc can be mediated through the nitric oxide system.     

Cerebral effects of three resuscitation protocols in uncontrolled haemorrhagic shock: A randomised controlled experimental study

BackgroundTo compare haemodynamic and cerebral variables during aggressive fluid resuscitation vs. administration of a hypertonic starch solution (HS) combined with either noradrenaline [norepinephrine] or arginine vasopressin in an animal model of uncontrolled haemorrhagic shock.MethodsAfter Animal Investigational Committee approval, 24 anaesthetised pigs underwent a liver trauma. At haemodynamic decompensation, animals were randomly assigned to receive fluid resuscitation (6% HES 130/0.4, 20 mL/kg, and Ringer, 40 mL/kg; FR group, n = 8), or noradrenaline (bolus 20 μg/kg, continuously 1 μg/kg/min) combined with HS (7.2% NaCl/6% HES 200/0.5; 4 mL/kg) (n = 8; NA/HS group), or vasopressin (bolus 0.2 U/kg, continuously 0.04 U/kg/min) combined with HS (4 mL/kg) (n = 8; AVP/HS group), respectively. Thirty minutes after drug administration, bleeding was controlled manually.ResultsMean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), and brain tissue oxygen pressure (P_btO₂) decreased significantly with haemorrhage in all groups (p < 0.05). AVP/HS resulted in a faster and higher increase of MAP and CPP compared to both NA/HS and FR (p < 0.001 vs. FR; p < 0.01 vs. NA/HS). Compared to FR, P_btO₂ increased faster with AVP/HS and NA/HS (p < 0.05) after therapy, and ICP was lower at the end of the study period (p < 0.05). All animals (8/8) of the AVP/HS group survived, compared to 4/8 and 4/8 in the NA/HS and FR group, respectively (p = 0.07).ConclusionsFollowing uncontrolled haemorrhagic shock in this animal model, combination of HS with arginine vasopressin increased CPP and cerebral oxygenation faster than aggressive fluid resuscitation, without re-increasing ICP.     

Fish oil prevents colon cancer by modulation of structure and function of mitochondria

Cancer cells are more susceptible to metabolic perturbations due to impaired electron transport chain (ETC) that promote uncontrolled proliferation. Mitochondria play a pivotal role in bioenergetics and apoptosis, hence are considered as a promising target in tumor cell eradication. Therefore, the present study is designed to elucidate chemopreventive action of fish oil (FO) in combination with corn oil (CO) on mitochondria in colorectal cancer (CRC). Male Wistar rats were divided into groups depending on dietary regimen—Control group, FO + CO(1:1) and FO + CO(2.5:1). These groups were further subdivided depending on whether these received a weekly intraperitoneal injection of ethylenediamine tetra-acetic acid (EDTA) or N,N-dimethylhydrazine dihydrochloride (DMH) for a period of 4 weeks. The animals sacrificed 48 h and 16 weeks after EDTA/DMH treatment constituted initiation and post-initiation phase respectively. The structural and functional alterations in mitochondria were evaluated using transmission electron microscopy (TEM) and by assaying electron transport chain (ETC) enzymes. Mitochondrial lipid composition and cholesterol levels were also assessed. DMH treatment led to mitochondrial degeneration, disrupted cristae and a significant decrease in ETC complexes suggestive of metabolic reprogramming. Moreover, an increase in cholesterol and cardiolipin (CL) levels in post-initiation phase led to evasion of apoptosis. FO in both the ratios resulted in stabilization and increase in number of mitochondria, however, FO + CO(2.5:1) + DMH group also exhibited mitophagy and crystolysis alongwith altered dynamics in ETC which facilitated apoptosis. It also decreased cholesterol and CL levels to increase apoptosis. Fish oil targets mitochondria in a dose dependent manner that augments apoptosis and hence attenuates carcinogenesis.     

Superiority of postmortem liver fentanyl concentrations over peripheral blood influenced by postmortem interval for determination of fentanyl toxicity

ObjectiveThe current study was undertaken to determine the relationship between postmortem (PM) peripheral blood (PB) and liver fentanyl concentrations and the role of measuring liver fentanyl concentrations in cause of death investigations in medical examiner cases in which fentanyl was identified.Design and methodsFB and liver tissue were routinely collected at autopsy from 4 Minnesota medical examiners' offices in 2010–2011. Samples were analyzed by gas chromatography–mass spectrometry (GC–MS).ResultsPB fentanyl ranged from < 2–15 μg/L in non-drug related deaths (n = 5), < 2–22 μg/L from mixed drug toxicity (n = 26) and 3.7–56 μg/L from fentanyl toxicity (n = 33). Liver fentanyl ranged from 11 to 104 μg/kg, 6 to 235 μg/kg, and 18 to 365 μg/kg, respectively. PB and liver fentanyl showed a modest correlation (r = 0.67). PM interval to the liver/blood ratio showed a decreasing ratio over increasing PM interval in cases from fentanyl and mixed drug toxicity. Liver fentanyl concentrations best define therapeutic use at < 23 μg/kg and fatal toxicity at > 56 μg/kg, without substantial overlap as found in blood fentanyl concentrations.ConclusionDiscriminatory liver fentanyl concentrations suggestive of therapeutic or toxic drug levels may better assist cause of death determination in cases of suspected fentanyl toxicity than postmortem PB concentrations. Peripheral blood fentanyl concentrations appear to undergo postmortem redistribution, associated with an increasing PM interval.     

New pathways driving the experimental hepatoprotective action of tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) against acute hepatotoxicity

PurposeIn absence of liver protective drugs, a large number of hepatopathies may arise during drug administration. This study was executed to investigate the possible new pathways underlying the hepatoprotective effect of Tempol (4-hydroxy-2,2,6,6- tetramethylpiperidine-1-oxyl), following oral administration of carbon tetrachloride in mice.Methods and resultsThirty albino mice were randomized into 3 equal groups. The duration of study was 28 days. The groups were classified as follows: Group I (healthy control): received saline, in the same volume of CCl₄ dose, daily, orally, for 14 days, then sacrificed. Group II: received CCl₄, as a single oral dose only, of 1 ml/kg body weight, dissolved in olive oil (1:1 v/v), the animals of this group were sacrificed 14 days after CCl₄ single dose intoxication. Group III (protective Tempol treated): received a single dose of Tempol, 20 mg/kg, orally, daily for 14 days. Two hours after the last Tempol dose, animals of group III received a single oral dose of CCl₄. Fourteen days later, animals were scarified to collect blood and liver tissues for analysis. Tempol pretreatment significantly captured elevated levels of ALT and AST activities, lipid peroxidation, total bilirubin and increased total thiol and catalase contents. Notably, it significantly reduced the expression of tumor necrosis factor-alpha (TNF-α), Caspase-3 and endoplasmic reticulum (ER) inositol-requiring enzyme 1(IRE1) mRNAs, which is an ER trans membrane sensor that activates the unfolded protein response (UPR) to maintain the ER and cellular function.ConclusionPretreatment with Tempol has potential hepatoprotective effects against acute liver injury, induced by CCl₄, through antioxidant and anti-inflammatory activities.     

Alterations of Na+/K+-ATPase,cholinergic and antioxidant enzymes activity by protocatechuic acid in cadmium-induced neurotoxicity and oxidative stress in Wistar rats

BackgroundThis study assessed the possible protective mechanisms of protocatechuic acid (PCA) against cadmium (Cd)-induced oxidative stress and neurotoxicity in rats.MethodsMale wistar strain rats weighing between 150–160 g were purchased and acclimatized for two weeks. The rats were divided into seven groups of seven each; NC group received normal saline, CAD group received 6 mg/kg of Cd-solution, CAD + PSG group received Cd-solution and prostigmine (5 mg/kg), CAD + PCA-10 and CAD + PCA-20 groups received Cd-solution and PCA (10 mg/kg and 20 mg/kg) respectively, PCA-10 and PCA-20 groups received 10 mg/kg and 20 mg/kg PCA each. Animals were administered normal saline, Cd and PCA daily by oral gavage for 21 days. After which the animals were sacrificed, the brain excised, homogenized and centrifuged. The activities of enzymes (Na⁺/K⁺-ATPase, cholinesterases, catalase, glutathione peroxidase, superoxide dismutase) and levels of oxidative stress markers (lipid peroxidation and reduced glutathione) linked to neurodegeneration were subsequently assessed.ResultsSignificant (p < 0.05) alterations in the enzyme activities and levels of oxidative stress markers were observed in CAD group when compared to the NC group. However, the activities of the enzymes were reversed in CAD + PSG and CAD + PCA groups.ConclusionsPCA may protect against cadmium-induced neurotoxicity by altering the activities of Na⁺/K⁺-ATPase, acetylcholinesterase, butyrylcholinesterase and endogenous antioxidant enzymes.     

Improved cisplatin delivery in cervical cancer cells by utilizing folate-grafted non-aggregated gelatin nanoparticles

PurposeCisplatin is highly effective in the treatment of cervical cancer. However, in therapeutic doses, cisplatin induces several adverse effects due to undesirable tissue distribution. Therefore, it is worth targeting cisplatin in cervical cancer cells by implicating non-aggregated ligand-modified nanotherapeutics.Methods and resultsHere, we report the preparation of non-aggregated folic acid-conjugated gelatin nanoparticles of cisplatin (Cis-GNs-FA) by two-step desolvation method with mean particle size of 210.6 ± 9.6 nm and 140.5 ± 10.9 nm for Cis-GNs to improve the drug delivery in cervical cancer, HeLa cells. FTIR and DSC spectra confirmed the presence and stability of cisplatin in gelatin matrix. Furthermore, amorphization of cisplatin in nanoparticles was ascertained by PXRD. Drug release followed a first-order release kinetic at both pH ∼ 5.6 (cervical cancer pH) and pH ∼ 7.4. In addition, a significant (P < 0.05) decrease in IC₅₀ value (8.3 μM) and enhanced apoptosis were observed in HeLa cells treated with Cis-GNs-FA as compared to Cis-GNs (15.1 μM) and cisplatin solution (40.2 μM). In contrast, A549 lung cancer cells did not discriminate between Cis-GNs-FA and Cis-GNs due to the absence of folate receptors-α (FR-α). Consistently, higher cellular uptake, 80.54 ± 7.60% was promoted by Cis-GNs-FA significantly (two-way ANOVA, P < 0.05) greater than 51.68 ± 9.78%, by Cis-GNs. This was also illustrated by CLSM images, which indicated that Cis-GNs-FA preferably accumulated in the cytoplasm of HeLa cells nearby nucleus by following receptor-mediated endocytosis pathway as compared to Cis-GNs.ConclusionTherefore, Cis-GNs-FA warrants further in-depth in vitro and in vivo investigations to scale up the technology for clinical translation.     

The feasibility and acceptability of a diet and exercise trial in overweight and obese black breast cancer survivors: The Stepping STONE study

PurposeBlack breast cancer survivors have high rates of obesity and low physical activity levels. Little is known about the acceptability and feasibility of interventions in this population.ObjectiveA two-arm RCT was launched to assess the efficacy of a culturally targeted 12-week multimodal lifestyle intervention in overweight and obese black survivors.MethodsIntervention components included nutrition education, exercise groups, and survivor-led motivational interviewing phone sessions. The analytic sample included women who completed the trial (intervention n = 10; control n = 12). Anthropometric measures, physical activity, and VO_2max were assessed at baseline and follow-up. Change scores (intervention vs. control) were assessed with Wilcoxon rank-sum tests. A process evaluation assessed intervention acceptability.ResultsOverall adherence was 70% and overall satisfaction was high (86%). Despite the 5% weight loss target, the intervention group lost 0.8% but BMI improved. Total physical activity levels increased in the intervention vs. control arm (+ 3501 MET min/week vs. + 965 MET min/week, respectively). VO_2max improved in the intervention group (+ 0.10 ± 1.03 kg/L/min). Intervention participants reduced energy intake (− 207.3 ± 31.5 kcals) and showed improvements in fat intake (− 15.5 ± 3.8 g), fiber (+ 3.2 ± 1.2 g) and % energy from fat (− 4.8 ± 3.1%). Survivors suggested providing diet/exercise information within a cancer context.ConclusionsGroup and individualized intervention strategies are acceptable to black survivors. Observed differences between self-report and objective outcomes may suggest reporting bias or changes in body composition. Increasing supervised intervention components and assessment of body composition will be important for future trials.     

Urtica dioica leaves modulates hippocampal smoothened-glioma associated oncogene-1 pathway and cognitive dysfunction in chronically stressed mice

The present study was aimed to evaluate the effect of Urtica dioica (UD) extract against chronic unpredictable stress (CUS)-induced associative memory dysfunction and attempted to explore the possible mechanism. Male Swiss albino mice (25–30 g) were divided into six groups, viz. group-I received 0.3% carboxymethyl cellulose and served as control (CTRL), group II was exposed to CUS (21 days) and received vehicle (CUS), group III was subjected to CUS and received Hypericum perforatum extract (350 mg/kg, p.o.) (CUS + HYP), group IV received Hypericum perforatum extract (350 mg/kg, p.o.) (CTRL + HYP); group V was subjected to CUS and received UD extract (50 mg/kg, p.o.) (CUS + UD), group VI received UD extract (50 mg/kg, p.o.) (CTRL + UD). CUS significantly induced body weight loss (p < 0.05) and associative memory impairment in step down task (p < 0.05) as compared to control mice. CUS significantly downregulated Smo (p < 0.05), Gli1 (p < 0.01), cyclin D1 (p < 0.05), BDNF (p < 0.01), TrKB (p < 0.01) and MAPK1 (p < 0.01) mRNA expression in hippocampus as compared to control mice. CUS significantly increased the levels of TBARS (p < 0.01) and nitric oxide (p < 0.001), and decreased catalase (p < 0.001) and total thiol (p < 0.01) in plasma resulting in oxidative stress and inflammation. Chronic UD administration significantly reverted CUS mediated body weight loss (p < 0.05) and cognitive impairment (p < 0.05). UD administration significantly decreased the levels of TBARS (p < 0.01) and nitric oxide (p < 0.05), and increased the levels of catalase (p < 0.01) and total thiol (p < 0.05) in plasma. Chronic UD administration significantly upregulated hippocampal Smo (p < 0.05), Gli1 (p < 0.001), cyclin D1 (p < 0.05), BDNF (p < 0.05), TrKB (p < 0.05) and MAPK1 (p < 0.05) in stressed mice. Further, UD extract did not reverse cyclopamine induced downregulation of Gli1 and Ptch1 mRNA in hippocampal slices. UD modulated Smo-Gli1 pathway in the hippocampus as well as exerted anti-inflammatory and antioxidant effects. UD extract might prove to be effective for stress mediated neurological disorders.     

Antileishmanial,antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract

Currently, there is no effective vaccine available, and chemotherapy is the main approach for treatment of cutaneous leishmaniasis (CL). During recent decades, studies have demonstrated that a number of plant-derived compounds may act as new therapeutic tools against leishmaniasis. This study was evaluated the antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier (oak) extract. The total amount of phenolic and flavonoid compounds was measured in oak extract. High performance liquid chromatography (HPLC) analysis was also performed to determine the amount of quercetin and gallic acid in this plant. This extract (0–80 g/mL) was evaluated in vitro against promastigote and intracellular amastigote forms of Leishmania major (MRHO/IR/75/ER) using MTT assay and in a macro-phage model, respectively. Then oak extract was tested on CL in infected male BALB/c mice with L. major in order to evaluate the antileishmanial activity topically. Moreover, cytotoxicity effects of oak in murine macrophage cells were tested by MTT assay. Antioxidative activity of oak was also determined by the 2,2-diphenyl-1,1-picrylhydrazyl (DPPH) scavenging test. The amount of phenolic and flavonoid compounds in the oak extract was 57.50 and 1.86%, respectively. The amount of quercetin and gallic acid in the oak extract was 0.0064 and 0.22%, respectively. The findings revealed that oak significantly (P < 0.05) inhibited the growth rate of promastigote of (IC₅₀ 12.65 μg/mL) and amastigotes (IC₅₀ 10.31 μg/mL) as a dose-dependent response. In the in vivo assay, after 4 weeks of treatment, 91.6, 66.66, and 50% recovery was observed in the infected mice treated with 20, 10, and 5 mg/kg of oak extract, respectively. After treatment of the infected mice with the concentration of 10 and 20 mg/kg of oak, the mean diameter of lesions, parasite load and mean number of parasites was significantly (P < 0.05) reduced. Selectivity index of greater than 10 for oak revealed that oak extract had no cytotoxic effects on macrophage cells. Moreover, DPPH test demonstrated that radical inhibition occurred at greater power with increasing the concentration of oak. To conclude, the present study showed potent antileishmanial and antioxidant activity of oak extract; whereas this plant had no toxic effect on mammalian cells.     

Antidepressant effect of pramipexole in mice forced swimming test: A cross talk between dopamine receptor and NMDA/nitric oxide/cGMP pathway

Pramipexole is a dopamine D2 receptor agonist indicated for treating Parkinson disorder. This study was aimed to investigate the effect of pramipexole in forced swimming test (FST) in mice and the possible involvement of activation of D2 receptors and inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) on this effect. Intraperitoneal administration of pramipexole (1⿿3 mg/kg) reduced the immobility time in the FST similar to fluoxetine (20 mg/kg, i.p.). This effect of pramipexole (1 mg/kg, i.p.) was ceased when mice were pretreated with haloperidol (0.15 mg/kg, i.p,) and sulpiride (5 mg/kg, i.p) as D2 receptor antagonists, NMDA (75 mg/kg,i.p.), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.05 mg/kg, i.p., a NMDA receptor antagonist) l-NG-Nitro arginine methyl ester (l-NAME, 10 mg/kg, i.p., a non-specific nitric oxide synthase (NOS) inhibitor), 7-nitroindazole (30 mg/kg, i.p., a neuronal NOS inhibitor) and methylene blue (10 mg/kg, i.p.), an inhibitor of both NOS and soluble guanylyl cyclase (sGC) in combination with the sub-effective dose of pramipexole (0.3 mg/kg, i.p.) reduced the immobility. Altogether, our data suggest that the antidepressant-like effect of pramipexole is dependent on the activation of D2 receptor and inhibition of either NMDA receptors and/or NO-cGMP synthesis. These results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of pramipexole and reinforce the role of D2 receptors, NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant mechanism of this agent.     

Antidiabetic activity of Syzygium calophyllifolium in Streptozotocin-Nicotinamide induced Type-2 diabetic rats

The study was initiated to determine the antidaibetic activity of Syzygium calophyllifolium in Streptozotocin-Nicotinamide (STZ-NA) induced diabetic rats. The rats were treated with 100 and 200 mg/kg of the Syzygium calophyllifolium bark methanol extract (SCBM) and compared with the diabetic, normal and standard glibenclamide groups. The blood glucose level and body weight of the rats in different groups were monitored at regular intervals. The serum, blood biochemical and histopathological parameters of liver, kidney and pancreas were also analyzed. In vivo antioxidants like SOD, CAT, GST, GSH and GR levels were estimated in liver and kidney. SCBM (100 mg/kg) extract could reduce the blood glucose level from the 15th day itself (213.67 mg/dL) and the best reduction was observed till the end of the study with 259.25 mg/dL (200 mg/kg). Initial decrease in body weight was recovered after drug treatment and an increase in body weight was observed on the 4th week. The haematological parameters like total haemoglobin, packed cell volume percentage, total WBC and RBC content were found normal compared to that of normal untreated rats. Glibenclamide was also equally effective. The higher dose of SCBM extract could normalize the triglycerides, HDL, cholesterol and VLDL constituents in blood serum to the levels almost similar to that of normal rats. The results of the in vivo antioxidant levels showed that there are no significant difference in SOD, GSH and GR levels in all the groups compared to the normal control. SCBM and SMBM at 200 mg/kg dose were much effective over the lower dose. The histology revealed that SCBM 200 mg/kg could protect the cellular architecture of liver kidney and pancreas. The results from the study confirm ethnopharmacological significance of the plant and could be taken further for the development of an effective pharmaceutical drug against diabetes.     

A sex comparison of reactive knee stiffness regulation strategies under cognitive loads

BackgroundSex differences may exist in cognitive faculties and neuromuscular strategies for maintaining joint stability. The purpose of this study was to assess whether preparatory and reactive knee stiffening strategies are affected differently in males and females exposed to sex-biased cognitive loads.Methods20 male and 20 female volunteers were tested for knee joint stiffness and quadriceps and hamstring muscle activation patterns throughout a rapid eccentric knee extension perturbation. Participants were tested under 3 cognitive loads (Benton's Judgment of Line Orientation; Symbol Digit modalities Test; and Serial 7's) and a control condition. Apparent knee joint stiffness and muscle activation amplitude and timing were quantified throughout the perturbation across the 4 conditions.FindingsReactive knee stiffness values were significantly less during the cognitive tasks compared to the control condition (Judgment of Line Orientation = 0.034 Nm/deg/kg, Symbol Digit Modalities Test = 0.037 Nm/deg/kg, Serial 7's = 0.037 Nm/deg/kg, control = 0.048 Nm/deg/kg). Females had greater normalized total apparent stiffness than males. The quadriceps muscles had faster and greater activation than the hamstring muscles; however, no group differences were observed. No overall differences in muscle activation (magnitude and timing) were found between the cognitive loading tasks.InterpretationCognitive loading may decrease the ability of healthy individuals to reactively stiffen their knee joint and appears to interfere with the normal stiffness regulation strategies. This may elucidate an extrinsic risk factor for non-contact knee ligament injury.