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Background: Dipeptidyl peptidase IV has been reported to be an important target for the development and discovery of new therapies for diabetes mellitus type II. Objective: The main aim of this study was to discover chemical entities that target the inhibition of DPP IV and feature potent hypoglycemic action. Methods: A structure-based virtual screening was applied to discover new hypoglycemic agents. Molecular docking was performed to compute the binding free energies. Molecular dynamics simulations were done to evaluate the binding stability of resulted hits. Results: Seven small non-peptide potential inhibitors of Dipeptidyl peptidase IV with 3-imino-4-(4- substituted phenyl)-1, 2, 5-thiadiazolidine-1,1-dioxide scaffold were discovered. The binding free energies ranged from -24.50 to -36.06 kJ/mol. Molecular dynamics simulations revealed high stability of all protein-ligand complexes with low root mean square deviation over 10 ns simulation time. The tested compounds expressed a significant reduction in blood glucose level up to 90% with excellent oral glucose tolerance test after 120 minutes of injection in a diabetes mellitus type II animal model. A promising release of insulin was observed with a potential hypoglycemic activity for all compounds. Conclusion: The virtual screening was successful to discover potent hypoglycemic agents with drug-like properties that may need more consideration for future studies and development.

Nowadays, volatile oils are increasingly being used for their medicinal and curing properties. Myrtus communis, a native aromatic and medicinal plant in Saudi Arabia, has been used in folk medicine...

Detection of autoantibodies in sera of rheumatoid arthritis (RA) patients has an important role in diagnosis and management strategies. Recently, another type of autoantibodies has been detected with activity against carbamylated proteins (anti-CarP) which may play an important role in the diagnosis of RA. The aim of this study was to raise knowledge about the diagnostic and prognostic value of anti-CarP antibodies in RA.Seventy RA patients and thirty-four controls were included in this study. DAS28 was used to evaluate disease activity. Joint erosions were assessed by Larsen score using plain X-ray of involved joints of hands and feet. Serum samples were analyzed for anti-CarP antibody titer using the ELISA technique.Out of 70 patients, 35.7% were positive for anti-CarP and only 5.88% of controls had high titer above the cut-off value. A total of 24.29% of the patients were RF-negative and 30% were ACPA-negative. Five patients (29.41%) of the negative RF group were positive for anti-CarP. Four patients (19%) of the ACPA-negative group were positive for anti-CarP, and three patients (4.28%) of the total number of patients were triple negative and seventeen (24.28%) were triple positive. There was a significant correlation between anti-CarP titer and both DAS28 and Larsen scores only in the positive anti-CarP group. In addition, there was a strong association between anti-CarP antibody titer and joint erosions at both baseline and after 1-year follow-up.Presence of the anti-CarP antibodies in sera of RA patients may have a prognostic value as it correlates with the disease activity and joint erosions; moreover, it may have a diagnostic value in rheumatoid arthritis especially in RF- and ACPA-negative patients. Key Points • This study was carried out to raise our knowledge about the importance of anti-CarP antibodies in predicting the prognosis of RA. • This study was carried out to assess the correlation between anti-CarP antibodies, disease activity, and joint erosions. • This study was carried out to state the extent to which we can rely on the anti-CarP antibodies as a biomarker for prediction of RA.

Background Specific autoantibodies are considered as an important marker in autoimmune rheumatic diseases and are of great value for the diagnosis and prognosis of systemic lupus erythematosus (SLE) patients. A total of eighteen autoantibodies were analyzed for their positivity in SLE patients and we evaluated the clinical relevance of the five most frequent autoantibodies: anti-dsDNA, anti-nucleosome, anti-histone, anti-Ro60, and anti-Ro52 on disease activity and renal affection in SLE Egyptian patients. Results Immunological profile and correlation of the five autoantibodies with disease activity and histopathological pattern of renal involvement were analyzed for 190 SLE patients. Lupus nephritis (LN) patients showed much worse constitutional and mucocutaneous manifestations than patients without nephritis. Autoantibody profile showed a significant increased frequency of anti-dsDNA, anti-nucleosome, anti-histone, anti-Ro-60, and anti-Ro52 antibodies in LN patients. The impact of the co-positivity of the autoantibodies on the renal function was obvious. Moreover, the disease activity increased by the increased frequency of autoantibodies positivity in LN patients. ROC curve analysis showed that anti-nucleosome had the highest sensitivity; 93% followed by anti-dsDNA 83.3% then anti-histone 73.8%, but anti-Ro60 and anti-Ro52 showed a humble sensitivity. Furthermore, the highest frequency of positivity for the five autoantibodies was found in class-III and class-IV LN patients. Conclusion Detection of anti-dsDNA, anti-nucleosome, anti-histone, and anti-Ro60 in SLE patients may be important for predicting disease progression and kidney affection. Moreover, anti-nucleosome and anti-dsDNA show high sensitivity and specificity for lupus nephritis, thus patients with four to five positive autoantibody panels should be kept under close monitoring as they may warrant considering aggressive therapy to control their disease and prevent renal damage.

Background Chronic inflammation in ulcerative colitis (UC) patients is the major risk factor for colitis-associated colon cancer (CAC). Recent evidences have shown that microRNAs (miRNAs) are implicated in CAC pathogenesis. However, the interaction of miRNAs with the transcription factors that alleviate CAC has not been reported. Methods 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3′-diindolylmethane (DIM) were used to activate aryl hydrocarbon receptor (Ahr) in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC in mice. Real-time PCR was used to quantify the mRNAs of miRNA and coding genes while western blot and ELISA were used to quantify protein levels. Silencing miRNA was carried out by means of electroporation and locked nucleic acid (LNA)-miRNA. Results Inducing CAC in mice upregulated miR-132 expression in the colon, spleen and lymph nodes at all stages of disease development. Activation of Ahr by TCDD or DIM boosted miR-132 expression and alleviated CAC severity by suppression of macrophage infiltration and pro-inflammatory cytokines. Interestingly, TCDD, but not DIM, augmented a cholinergic anti-inflammation by inducing acetylcholinesterase (AChE)-targeting miR-132. This anti-inflammation was manifested by suppressed production of TNF-α, IL-1β and IL-6. Silencing miR-132 in vivo in TCDD-treated mice abrogated the cholinergic anti-inflammation and exacerbated CAC. In addition, inhibition of miR-132 in vitro in CD4 + cells and macrophages mitigated the inhibitory effect of TCDD on AChE catalytic activity. Conclusion Our findings identify miR-132 as a new molecule implicated in CAC pathogenesis, and reveal that miR-132 mediates the ameliorating effects of TCDD on CAC, suggesting miR-132 as a promising therapeutic candidate to control autoimmune inflammation and tumorigenesis in CAC patients.

Obesity represents a major challenge to the pharmaceutical community due to the minimal availability of anti-obesity drugs and drawbacks of current weight-loss agents. The study was designed to evaluate the use of sage oil as a potential anti-obesity agent via its effect on different physiological, biochemical, and hormonal parameters in rats. Rats were divided into two groups: one group was continued on a standard commercial rodent diet and served as the non-obese control. The other group was fed a high-fat diet for seven weeks to prepare an obese rat model. Then, the obese rats were divided into three groups; one group remained without treatment as positive control, the other two groups received 100 mg/kg orally of the sage oil for 10 or 20 days. The results of the present study showed that treatment with sage oil significantly decreased rats’ food intake, epididymal fat, and body weight, and improved their lipid profile levels; it also modulated the leptin resistance. This anti-obesity effect of sage oil was associated with the increased expression of adiponectin and decreased both of leptin and sterol regulatory element-binding protein (SREBP-1c) levels, and this effect may be mediated through AMPK activation. Additionally, the sage oil did not have any effects on the liver’s integrity, as was proven by the non-altered ALT levels.

EACS 2016 Paper No. 115Smart structural control is now emerging as an alternative to conventional earthquake resistant design and traditional structural control techniques. Fuzzy control is one of the promising control strategies that could be used for this function. Magnetorheological (MR) dampers are considered one of the promising semi-active control devices that can be used to control the structural response of buildings under earthquake excitation. The properties of MR dampers can be controlled using several control techniques such as Fuzzy Logic. In this paper, a fuzzy control scheme is proposed to control the response of a three degree of freedom system under earthquake excitation. The system is equipped with three MR dampers with one for each degree of freedom, i.e., floor. The system comprises an optimization component which identifies the most optimum firing sequence of the MR dampers in order to achieve the best controlled response. It is envisaged that not all three MR dampers are fired simultaneously; only selected ones are fired as per the decision of the optimization scheme. A comparative analysis is, finally, conducted in order to demonstrate the validity of the proposed scheme.

Long-standing diabetes is associated with increased oxidative stress and cardiac fibrosis. This, in turn, contributes to the progression of cardiomyopathy. The present study was sought to investigate whether the free radical scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol) can protect against diabetic cardiomyopathy and to explore the specific underlying mechanism(s) in this setting. Diabetes was induced in rats by a single intraperitoneal injection dose of streptozotocin (50 mg/kg). These animals were treated with tempol (18 mg kg(-1) day(-1), orally) for 8 weeks. Our results showed significant increases in collagen IV and fibronectin protein levels and a marked decrease in matrix metalloproteinase-2 (MMP-2) activity measured by gelatin-gel zymography alongside elevated cardiac transforming growth factor (TGF)-β level determined using ELISA or immunohistochemistry in cardiac tissues of diabetic rats compared with control. This was accompanied by an increased in the oxidative stress as evidenced by increased reactive oxygen species (ROS) production and decreased antioxidant enzyme capacity along with elevated lactate dehydrogenase (LDH) and creatine kinase (CK-MB) serum levels as compared with the control. Tempol treatment significantly corrected the changes in the cardiac extracellular matrix, TGF-β, ROS or serum LDH, CK-MB levels, and normalized MMP-2 activity along with preservation of cardiac tissues integrity of diabetic rats against damaging responses. Moreover, tempol normalized the elevated systolic blood pressure and improved some cardiac functions in diabetic rats. Collectively, our data suggest a potential protective role of tempol against diabetes-associated cardiac fibrosis in rats via reducing oxidative stress and extracellular matrix remodeling.

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer death world wide, with an estimated mortality rate of about one million deaths annually. Galectin-3 is widely spread among different types of cells and tissues. Galectin-3 found intracellularly in nucleus and cytoplasm. Galectin-3 affects numerous biological processes and seems to be involved in different physiological and pathophysiological conditions, such as development, immune reactions, and neoplastic transformation and metastasis. In this study, we found over expression of galectin-3 protein and mRNA, in HCC tissue compared with normal liver tissue. In addition, we found expression of galectin-3 in the nuclear protein fraction. The overexpression of galectin-3 was accompanied with elevated levels of serum nitrite and aminotransferases (AST and ALT).

From the methanolic extract of fresh fruits of Solanum reflexum Schrank, a major compound was isolated and identified as; aculeatiside-A 1. The structure of the isolated compound was elucidated on the basis of 1H and 13C and DEPT-13C-NMR; in addition to comparison with reported data. The cytotoxic effect of aculeatiside-A on hepatocellular carcinoma cells and its mechanism was investigated. It was accomplished that aculeatiside-A inhibit the growth of HepG-2 cells significantly by induction of apoptosis. Marked morphological changes of apoptosis were observed clearly. The results for the first time demonstrate that aculeatiside-A has significant anti-proliferation effect by induction of apoptosis on hepatocellular carcinoma cells in-vitro, down regulation of Survivin and Bcl-2 expressions as well as up regulation of Bax and P53 expression may be one of the important apoptotic inducing mechanisms.

The antioxidant activity of the ethanolic extract of brown propolis was determined by in- vitro antioxidant assays via 1,1-diphenyl-2-picryl-hydrazyl (DPPH·) free radical scavenging activity and phosphomolybdenum method.The brown propolis extract had an effective DPPH· scavenging activity at 20-200µg/ml concentrations. Moreover, the in-vivo experiments showed that brown propolis extract has a powerful antioxidant and lipid peroxidation inhibitory activity in the liver tissues challenged with CCl4. On the other hand, we foundthat pretreatment of rats with propolis extract protected gastric tissues against indomethacin -induced gastropathy as demonstrated from reduction in the ulcer index, attenuation of histopathological changes and amelioration of the altered oxidative stress biomarkers like glutathione, thiobarbituric acid reactive substance levels and superoxide dismutase activity in gastric tissues. In conclusion, total ethanolic extract of brown propolis exposed major anti -oxidant and anti-ulcer activities.

BackgroundDespite the remarkable progress to fight against breast cancer, metastasis remains the dominant cause of treatment failure and recurrence. Therefore, control of invasiveness potential of breast cancer cells is crucial. Accumulating evidences suggest Aryl hydrocarbon receptor (Ahr), a helix-loop-helix transcription factor, as a promising target to control migration and invasion in breast cancer cells. Thus, an Ahr-based exploration was performed to identify a new Ahr agonist with inhibitory potentials on cancer cell motility.MethodsFor prediction of potential interactions between Ahr and candidate molecules, bioinformatics analysis was carried out. The interaction of the selected ligand with Ahr and its effects on migration and invasion were examined in vitro using the MDA-MB-231 and T47D cell lines. The silencing RNAs were transfected into cells by electroporation. Expressions of microRNAs (miRNAs) and coding genes were quantified by real-time PCR, and the protein levels were detected by western blot.ResultsThe in silico and in vitro results identified Flavipin as a novel Ahr agonist. It induces formation of Ahr/Ahr nuclear translocator (Arnt) heterodimer to promote the expression of cytochrome P450 family 1 subfamily A member 1 (Cyp1a1). Migration and invasion of MDA-MB-231 and T47D cells were inhibited with Flavipin treatment in an Ahr-dependent fashion. Interestingly, Flavipin suppressed the pro-metastatic factor SRY-related HMG-box4 (Sox4) by inducing miR-212/132 cluster. Moreover, Flavipin inhibited growth and adhesion of both cell lines by suppressing gene expressions of B-cell lymphoma 2 (Bcl2) and integrinα4 (ITGA4).ConclusionTaken together, the results introduce Flavipin as a novel Ahr agonist, and provide first evidences on its inhibitory effects on cancer cell motility, suggesting Flavipin as a candidate to control cell invasiveness in breast cancer patients.

There are still no data available on the relationship between postural stability and occlusal status among the elderly.To examine relationships between postural stability and occlusal status through a cohort study among elderly Japanese.Oral examination, occlusal status, postural stability and a questionnaire were conducted and given to 87 community-dwelling Japanese at enrolment.The average occlusal pressure of the female group was statistically higher than the male group while average occlusal pressure and postural stability length were lesser in the group with more remaining teeth. Postural stability area and number of remaining teeth showed statistically significant correlations. Postural stability length was lesser in the group with strong occlusal force. Furthermore, the number of decayed teeth was fewer in the good hygiene group.This study identified a close relationship between occlusal status and postural stability of Japanese older individuals. Occlusal hypofunction was observed more in those with occlusal problems, and a decrease in their occlusal functions resulted in postural instability.

To assess caries risk and check the presence of four commonly found oral cariogenic bacteria in "8020" achievers.Initial report based on Japan's newly implemented "8020" campaign, which aims to promote health and awareness in older people. Simply stated, the goal is, at 80 years, to maintain 20 teeth.Healthy community-dwelling elderly individuals of Okayama Prefecture, Japan.One hundred sixty individuals aged 80 and older with 20 of their own natural teeth.General and oral health conditions, caries risk assessment using the Cariostat method, and polymerase chain reaction (PCR) detection of four oral cariogenic bacteria.The participants had an average of 24.7 teeth, of which 12.1 were sound, 12.2 were treated, and 0.4 were untreated. Based on Cariostat scores, 64.4% had low caries risk. Using PCR, Streptococcus mutans, S. sobrinus, Lactobacillus casei, and L. plantarum were detected in 51.3%, 23.1%, 40%, and 25% of the participants, respectively. S. mutans (P.001), S. sobrinus (P=.002), L. casei (P.001), and L. plantarum (P=.001) deoxyribonucleic acid band was detected more in participants with high caries risk scores.Participants with low caries risk scores had low prevalence of cariogenic bacteria, 20 or more sound teeth, and fewer missing teeth. Incorporating caries risk assessment, using the Cariostat and PCR analysis, in the "8020" campaign in health systems worldwide will contribute to a better life for the aging society, initiate research interest regarding the program, and improve current health policies.