AIM: The present study was conducted to investigate the possible mechanism of actions underlying the systemic antinociception activity of the essential oil of Zingiber zerumbet (EOZZ) in chemical-induced nociception tests in mice.
MATERIALS AND METHODS: Acetic acid-induced abdominal constriction, capsaicin-, glutamate- and phorbol 12-myristate 13-acetate-induced paw licking tests in mice were employed in the study. In all experiments, EOZZ was administered systemically at the doses of 50, 100, 200 and 300 mg/kg.
RESULTS: It was shown that EOZZ given to mice via intraperitoneal and oral routes at 50, 100, 200 and 300 mg/kg produced significant dose dependent antinociception when assessed using acetic acid-induced abdominal writing test with calculated mean ID(50) values of 88.84 mg/kg (80.88-97.57 mg/kg) and 118.8 mg/kg (102.5-137.8 mg/kg), respectively. Likewise, intraperitoneal administration of EOZZ at similar doses produced significant dose dependent inhibition of neurogenic pain induced by intraplantar injection of capsaicin (1.6 μg/paw), glutamate (10 μmol/paw) and phorbol 12-myristate 13-acetate (1.6μg/paw) with calculated mean ID(50) of 128.8 mg/kg (118.6-139.9 mg/kg), 124.8 mg/kg (111.4-139.7 mg/kg) and 40.29 (35.39-45.86) mg/kg, respectively. It was also demonstrated that pretreatment with l-arginine (100mg/kg, i.p.), a nitric oxide precursor significantly reversed antinociception produced by EOZZ suggesting the involvement of l-arginine/nitric oxide pathway. In addition, methylene blue (20mg/kg, i.p.) significantly enhanced antinociception produced by EOZZ. Administration of glibenclamide (10mg/kg, i.p.), an ATP-sensitive K(+) channel antagonist significantly reversed antinociceptive activity induced by EOZZ.
CONCLUSION: Together, the present results suggested that EOZZ-induced antinociceptive activity was possibly related to its ability to inhibit glutamatergic system, TRPV1 receptors as well as through activation of l-arginine/nitric oxide/cGMP/protein kinase C/ATP-sensitive K(+) channel pathway.
RESULTS: Both doses of the alcohol extract of S. polycystum and the 300 mg kg(-1) water extract, significantly reduced blood glucose and glycosylated haemoglobin (HbA1C ) levels. Serum total cholesterol, triglyceride levels and plasma atherogenic index were significantly decreased after 22 days treatment in all seaweed groups. Unlike metformin, S. polycystum did not significantly change plasma insulin in the rats, but increased the response to insulin.
CONCLUSION: The consumption of either ethanolic or water extracts of S. polycystum dose dependently reduced dyslipidaemia in type 2 diabetic rats. S. polycystum is a potential insulin sensitiser, for a comestible complementary therapy in the management of type 2 diabetes which can help reduce atherogenic risk.
AIM OF THE STUDY: Phytochemical investigation and assessment of pharmacological mechanism(s) involved in anti-ulcer effect of methanolic extract of the seeds of E. conferta.
MATERIALS AND METHODS: Bioactive phytoconstituents were isolated by column chromatography. These were identified by spectroscopic techniques including infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) and mass spectrometry. Methanolic extract (MEC) of the seeds was prepared by cold maceration and its anti-ulcerogenic potential was evaluated using indomethacin (50 mg/kg) and water immersion stress models in male rats. The animals were pre-treated with different doses of MEC (400 and 800 mg/kg) and the therapeutic effect was compared with standard drug i.e. ranitidine (RANT; 50 mg/kg). The ameliorative effects of MEC were investigated on gastric juice pH, total acidity, free acidity and ulcer index. The assays of malionaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) and pro-inflammatory cytokines i.e. interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were carried out to find out the possible mechanism(s) of protection. Further, histopathological changes were also studied.
RESULTS: Chromatography studies and further confirmation by spectroscopic techniques revealed the presence of four different compounds in MEC i.e oleic acid (1), stearic acid (2), ascorbic acid (3) and quercetin (4). MEC exhibited anti-ulcerogenic effect in dose dependent manner which may be attributed to suppression of pro-inflammatory cytokines (IL-6, TNF-α) and MDA (112.7%), and up-regulation of protective factors such as CAT (90.48%), SOD (92.77%) and GSH (90.01%). Ulcer inhibition, reduction in total and free acidity and increase in gastric juice pH were observed in MEC treated rats as compared to disease control animals. Histopathological findings confirmed decreased cell infiltration, less epithelial cell damage and regeneration of gastric mucosa in dose dependent manner.
CONCLUSIONS: The anti-ulcer effect of MEC may be attributed to its ability to scavenge free radicals and anti-inflammatory property via suppression of TNF-α and IL-6, thus offers a complete and holistic approach for management of peptic ulcer.
EXPERIMENTAL DESIGN: Tumor tissue EGFRm status was determined at screening using the central cobas tissue test or a local tissue test. Baseline circulating tumor (ct)DNA EGFRm status was retrospectively determined with the central cobas plasma test.
RESULTS: Of 994 patients screened, 556 were randomized (289 and 267 with central and local EGFR test results, respectively) and 438 failed screening. Of those randomized from local EGFR test results, 217 patients had available central test results; 211/217 (97%) were retrospectively confirmed EGFRm positive by central cobas tissue test. Using reference central cobas tissue test results, positive percent agreements with cobas plasma test results for Ex19del and L858R detection were 79% [95% confidence interval (CI), 74-84] and 68% (95% CI, 61-75), respectively. Progression-free survival (PFS) superiority with osimertinib over comparator EGFR-TKI remained consistent irrespective of randomization route (central/local EGFRm-positive tissue test). In both treatment arms, PFS was prolonged in plasma ctDNA EGFRm-negative (23.5 and 15.0 months) versus -positive patients (15.2 and 9.7 months).
CONCLUSIONS: Our results support utility of cobas tissue and plasma testing to aid selection of patients with EGFRm advanced NSCLC for first-line osimertinib treatment. Lack of EGFRm detection in plasma was associated with prolonged PFS versus patients plasma EGFRm positive, potentially due to patients having lower tumor burden.
METHODS: MCF-7 and MDA-MB231 cells were treated with several concentrations of FKA. The apoptotic analysis was done through the MTT assay, BrdU assay, Annexin V analysis, cell cycle analysis, JC-1 mitochondrial dye, AO/PI dual staining, caspase 8/9 fluorometric assay, quantitative real time PCR and western blot. For the metastatic assays, the in vitro scratch assay, trans-well migration/invasion assay, HUVEC tube formation assay, ex vivo rat aortic ring assay, quantitative real time PCR and western blot were employed.
RESULTS: We have investigated the effects of FKA on the apoptotic and metastatic process in two breast cancer cell lines. FKA induces apoptosis in both MCF-7 and MDA-MB231 in a dose dependent manner through the intrinsic mitochondrial pathway. Additionally, FKA selectively induces a G2/M arrest in the cell cycle machinery of MDA-MB231 and G1 arrest in MCF-7. This suggests that FKA's anti-cancer activity is dependent on the p53 status. Moreover, FKA also halted the migration and invasion process in MDA-MB231. The similar effects can be seen in the inhibition of the angiogenesis process as well.
CONCLUSIONS: FKA managed to induce apoptosis and inhibit the metastatic process in two breast cancer cell lines, in vitro. Overall, FKA may serve as a promising candidate in the search of a new anti-cancer drug especially in halting the metastatic process but further in vivo evidence is needed.
METHODOLOGY/PRINCIPAL FINDINGS: Four ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis.
CONCLUSIONS/SIGNIFICANCE: Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.
METHODS: A total of 300 day old male broiler chicks were assigned to four dietary n-3 PUFA ascending levels as the treatment groups (T1: 0.5; T2: 8.0; T3: 11.5; T4: 16.5) using combinations of tuna oil and sunflower oil. All diets were isocaloric and isonitrogenous. On day 28, all birds were challenged with IBD virus. Antibody titer, cytokine production, bursa lesion pre and post-challenge and lymphoid organ weight were recorded.
RESULTS: On d 42 the highest body weight was observed in the T2 and T3 and the lowest in T4 chickens. Feed conversion ratio of the T2 broilers was significantly better than the other groups. Although productive parameters were not responded to the dietary n-3 PUFA in a dose-dependent manner, spleen weight, IBD and Newcastle disease antibody titers and IL-2 and IFN-γ concentrations were constantly elevated by n-3 PUFA enrichment.
CONCLUSIONS: Dietary n-3 PUFA enrichment may improve the immune response and IBD resistance, but the optimum performance does not coincide with the optimum immune response. It seems that dietary n-3 PUFA modulates the broiler chicken performance and immune response in a dose-dependent manner. Thus, a moderate level of dietary n-3 PUFA enrichment may help to put together the efficiency of performance and relative immune response enhancement in broiler chickens.
BACKGROUND: Drug eluting stent (DES) implantation is the treatment of choice for coronary artery disease (CAD) leaving only marginal indications for the use of bare metal stents (BMS). However, selected treatment populations with DES contraindications such as patients who cannot sustain 6-12 months of dual antiplatelet therapy (DAPT) remain candidates for BMS implantations.
METHODS: Thin strut bare metal stenting in a priori defined subgroups were investigated in a non-randomized, international, multicenter «all comers» observational study. Primary endpoint was the 9-month TLR rate whereas secondary endpoints included the 9-month MACE and procedural success rates.
RESULTS: A total of 783 patients of whom 98 patients had AF underwent BMS implantation. Patient age was 70.4 ± 12.8 years. Cardiovascular risk factors in the overall population were male gender (78.2%, 612/783), diabetes (25.2%, 197/783), hypertension (64.1%, 502/783), cardiogenic shock (4.9%, 38/783) and end stage renal disease (4.9%, 38/783). In-hospital MACE was 4.1% (30/783) in the overall population. The 9-month TLR rate was 4.5% (29/645) in the non-AF group and 3.3% (3/90) in the AF group (P = 0.613). At 9 months, the MACE rate in the AF-group and non-AF group was not significantly different either (10.7%, 69/645 vs. 6.7%, 6/90; P = 0.237). Accumulated stroke rates were 0.3% (2/645) in the non-AF subgroup at baseline and 1.1% (1/90) in the AF subgroup (P = 0.264).
CONCLUSION: Bare metal stenting in AF patients delivered acceptably low TLR and MACE rates while having the benefit of a significantly shorter DAPT duration in a DES dominated clinical practice. © 2015 Wiley Periodicals, Inc.
METHODS: A discovery cohort of Malaysian Chinese descent (NPC patients, n = 140; Healthy controls, n = 256) were genotyped using Illumina® HumanOmniExpress BeadChip. PennCNV and cnvPartition calling algorithms were applied for CNV calling. Taqman CNV assays and digital PCR were used to validate CNV calls and replicate candidate copy number variant region (CNVR) associations in a follow-up Malaysian Chinese (NPC cases, n = 465; and Healthy controls, n = 677) and Malay cohort (NPC cases, n = 114; Healthy controls, n = 124).
RESULTS: Six putative CNVRs overlapping GRM5, MICA/HCP5/HCG26, LILRB3/LILRA6, DPY19L2, RNase3/RNase2 and GOLPH3 genes were jointly identified by PennCNV and cnvPartition. CNVs overlapping GRM5 and MICA/HCP5/HCG26 were subjected to further validation by Taqman CNV assays and digital PCR. Combined analysis in Malaysian Chinese cohort revealed a strong association at CNVR on chromosome 11q14.3 (Pcombined = 1.54x10-5; odds ratio (OR) = 7.27; 95% CI = 2.96-17.88) overlapping GRM5 and a suggestive association at CNVR on chromosome 6p21.3 (Pcombined = 1.29x10-3; OR = 4.21; 95% CI = 1.75-10.11) overlapping MICA/HCP5/HCG26 genes.
CONCLUSION: Our results demonstrated the association of CNVs towards NPC susceptibility, implicating a possible role of CNVs in NPC development.