Mechanistic insights into the beneficial effects of curcumin on insulin resistance: Opportunities and challenges.

The past couple of decades in particular have seen a rapid increase in the prevalence of type 2 diabetes mellitus (T2DM), a debilitating metabolic disorder characterised by insulin resistance. The insufficient efficacy of current management strategies for insulin resistance calls for additional therapeutic options. The preponderance of evidence suggests potential beneficial effects of curcumin on insulin resistance, while modern science provides a scientific basis for its potential applications against the disease. Curcumin combats insulin resistance by increasing the levels of circulating irisin and adiponectin, activating PPARγ, suppressing Notch1 signalling, and regulating SREBP target genes, among others. In this review, we bring together the diverse areas pertaining to our current understanding of the potential benefits of curcumin on insulin resistance, associated mechanistic insights, and new therapeutic possibilities.

Phenotypic Prioritization of Diphyllin Derivatives That Block Filoviral Cell Entry by Vacuolar (H+ )-ATPase Inhibition.

Many viruses use endosomal pathways to gain entry into cells and propagate infection. Sensing of endosomal acidification is a trigger for the release of many virus cores into the cell cytosol. Previous efforts with inhibitors of vacuolar ATPase have been shown to block endosomal acidification and affect viral entry, albeit with limited potential for therapeutic selectivity. In this study, four novel series of derivatives of the vacuolar ATPase inhibitor diphyllin were synthesized to assess their potential for enhancing potency and anti-filoviral activity over cytotoxicity. Derivatives that suitably blocked cellular entry of Ebola pseudotyped virus were further evaluated as inhibitors of endosomal acidification and isolated human vacuolar ATPase activity. Several compounds with significant increases in potency over diphyllin in these assays also separated from cytotoxic doses in human cell models by >100-fold. Finally, three derivatives were shown to be inhibitors of replication-competent Ebola viral entry into primary macrophages with similar potencies and enhanced selectivity toward antiviral activity.

2,4-dihydroxy benzaldehyde derived Schiff bases as small molecule Hsp90 inhibitors: rational identification of a new anticancer lead.

Hsp90 is a molecular chaperone that heals diverse array of biomolecules ranging from multiple oncogenic proteins to the ones responsible for development of resistance to chemotherapeutic agents. Moreover they are over-expressed in cancer cells as a complex with co-chaperones and under-expressed in normal cells as a single free entity. Hence inhibitors of Hsp90 will be more effective and selective in destroying cancer cells with minimum chances of acquiring resistance to them. In continuation of our goal to rationally develop effective small molecule azomethines against Hsp90, we designed few more compounds belonging to the class of 2,4-dihydroxy benzaldehyde derived imines (1-13) with our validated docking protocol. The molecules exhibiting good docking score were synthesized and their structures were confirmed by IR, (1)H NMR and mass spectral analysis. Subsequently, they were evaluated for their potential to suppress Hsp90 ATPase activity by Malachite green assay. The antiproliferative effect of the molecules were examined on PC3 prostate cancer cell lines by adopting 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay methodology. Finally, schiff base 13 emerged as the lead molecule for future design and development of Hsp90 inhibitors as anticancer agents.

Molecular docking study, synthesis and biological evaluation of Schiff bases as Hsp90 inhibitors.

Heat shock protein 90 (Hsp90) is an emerging attractive target for the discovery of novel cancer therapeutic agents. Docking methods are powerful in silico tools for lead generation and optimization. In our mission to rationally develop novel effective small molecules against Hsp90, we predicted the potency of our designed compounds by Sybyl surflex Geom X docking method. The results of the above studies revealed that Schiff bases derived from 2,4-dihydroxy benzaldehyde/5-chloro-2,4-dihydroxy benzaldehyde demonstrated effective binding with the protein. Subsequently, a few of them were synthesized (1-10) and characterized by IR, (1)HNMR and mass spectral analysis. The synthesized molecules were evaluated for their potential to suppress Hsp90 ATPase activity by Malachite green assay. The anticancer studies were performed by 3-(4,5-dimethythiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. The software generated results was in satisfactory agreement with the evaluated biological activity.

Evaluation of subgingivally delivered 0.5% clarithromycin as an adjunct to nonsurgical mechanotherapy in the management of chronic periodontitis: a short-term double blinded randomized control trial.

OBJECTIVE: As the risk involved with systemic antimicrobials (high doses, microbial resistance, adverse reactions, etc.) restricts their use and local delivery of antimicrobials into periodontal pockets improves periodontal health, this study was designed to investigate the effects of subgingivally delivered clarithromycin (CLM; 0.5%) as an adjunct to nonsurgical mechanotherapy in chronic periodontitis subjects. METHODS: Ninety-eight patients were categorized into two treatment groups: scaling and root planing (SRP) plus 0.5% CLM (test; group 1) and SRP plus placebo (control; group 2). Clinical parameters included gingival index (GI), sulcus bleeding index (SBI), plaque index (PI), probing depth (PD), and periodontal attachment level (PAL), recorded at 4, 8 and 12 weeks. The concentration of 0.5% CLM in gingival fluid was estimated by reverse-phase high pressure liquid chromatography. anova, the chi-square test and the Scatterthwaite test were used for statistical analysis. RESULTS: Patients treated with SRP + CLM showed enhanced reductions in GI, SBI, and PD, and gains in PAL (P < 0.001) over time, as compared with the placebo group. However, no statistically significant differences were noted for PI. The mean concentration of CLM was detected in gingival crevicular fluid for up to 7 weeks, fulfilling the conditions for a controlled-release device. CONCLUSION: Adjunctive use of 0.5% CLM as a controlled drug delivery system enhanced the clinical outcome up to 3 months.

Effect of non surgical periodontal therapy on gingival crevicular fluid and serum visfatin concentration in periodontal health and disease.

Visfatin is a pleiotropic mediator which acts as growth factor, cytokine, enzyme involved in energy including nicotinamide adenine dinucleotide metabolism and has been recently demonstrated to exert several pro-inflammatory functions. The purpose of this study is to evaluate the Visfatin concentration in gingival crevicular fluid (GCF) and serum in patients with chronic periodontitis, and to evaluate the effect of non-surgical periodontal therapy on the GCF and serum visfatin concentration. 30 subjects (age range: 25 to 52 years) were selected and divided into two groups based on the gingival index, probing depth, periodontal attachment level, and radiologic parameters (bone loss): group 1 (15 subjects with healthy periodontium), group 2 (15 subjects with chronic periodontitis), while, Group 2 patients after 8 weeks of the treatment (scaling and root planning, SRP) constituted group 3. GCF samples (by microcapillary pipettes) and serum samples (by venipuncture) were collected to estimate the levels of Visfatin using enzyme linked immunosorbent assay kit. The mean Visfatin concentration in GCF and serum was observed to be the highest in group 2 and lowest in group 1. While concentration in group 3 was similar to group 1. The concentration of Visfatin in GCF and serum decreased after SRP. The Visfatin concentration in GCF and serum found to be highest in chronic periodontitis group and decreases after treatment. Hence Visfatin values can be considered as an "inflammatory marker" can be explored in future as a potential therapeutic target in the treatment of periodontal disease.

Gingival crevicular fluid and serum cystatin c levels in periodontal health and disease.

Cystatin C (CSTC) is an inhibitor of cysteine proteinases and could play a protective and regulatory role under inflammatory conditions. The present study was designed to assess the concentration of CSTC in gingival crevicular fluid (GCF) and serum, to find out their association if any, in periodontal health and disease. 30 subjects were selected divided into 3 groups consisting of 10 subjects in each group based on clinical parameters: periodontally healthy group, gingivitis group and chronic periodontitis group, while, chronic periodontitis group after 8 weeks of the treatment (scaling and root planing) constituted after periodontal therapy group. GCF and serum samples were collected from all subjects to estimate the levels of CSTC by ELISA. The mean CSTC concentration in GCF and serum was observed to be the highest in periodontitis group and lowest in periodontally healthy group with intermediate concentration in gingivitis group and after periodontal therapy group. CSTC concentration in GCF and serum increased proportionally with the severity of periodontal disease (from health to periodontitis group) and decreased after treatment. This suggests that CSTC increases with disease progression to prevent further periodontal degeneration and decreases after treatment due to bone metabolic homeostasis. Further, longitudinal prospective studies involving larger population are needed to confirm the findings of present study and to better understand the role of CSTC in the pathogenesis of periodontal diseases.

Association of serum and crevicular visfatin levels in periodontal health and disease with type 2 diabetes mellitus.

BACKGROUND: Levels of visfatin in serum and gingival crevicular fluid (GCF) were explored in patients with periodontal health, periodontal disease with and without type 2 diabetes mellitus (t2 DM) and were found to be elevated with periodontal disease, and were correlated with periodontal clinical parameters. DM and chronic periodontitis (CP) are associated with each other. Adipokines, specifically visfatin, are secreted from adipocytes and are thought to cause insulin resistance. The purpose of this study is to determine the presence of visfatin in serum and GCF in t2 DM among individuals with CP and to find an association, if any. METHODS: Thirty individuals (15 males and 15 females) were selected based on their clinical parameters into three groups: group 1 (10 healthy), group 2 (10 well-controlled t2 DM among individuals with CP), and group 3 (10 individuals with CP and without diabetes). Serum and GCF samples were collected to estimate the levels of visfatin using enzyme linked immunosorbent assay. RESULTS: The mean visfatin concentration increased in both serum and GCF in individuals with t2 DM with CP. Also, it was observed that visfatin in both serum and GCF correlated positively with all the periodontal parameters. CONCLUSIONS: All the samples in each group tested positive for visfatin assay. Serum and GCF visfatin concentration in both t2 DM with CP and individuals with CP and without diabetes correlated positively with all the clinical parameters. Additional large-scale longitudinal studies should be performed to confirm positive correlations.

Risk factors for chronic kidney diseases may include periodontal diseases, as estimated by the correlations of plasma pentraxin-3 levels: a case-control study.

BACKGROUND: Pentraxins are classical mediators of inflammation and markers of acute-phase reactions. Pentraxin-3 (PTX3) is believed to be a true independent indicator of disease activity. It has been associated with clinical outcomes in incident chronic kidney disease (CKD) and periodontal diseases. Periodontitis is lately being considered as a risk factor for CKD. However, no data are available on elevated PTX3 in patients with CKD associated with periodontitis. METHOD: Sixty subjects were divided into three groups (n = 20) based on glomerular filtration rate (GFR) and periodontal parameters: healthy (group-1), CKD (group-2), and CKD with periodontitis (group-3). Plasma samples obtained from each patient were quantified for PTX3 using Enzyme-linked Immunosorbent Assay (ELISA). RESULTS: Both patient groups with CKD had higher plasma PTX3 concentrations than control subjects. However, there was no significant difference between the two groups (groups 2 and 3). In all groups, plasma PTX3 correlated positively with periodontal parameters. Group 3 patients had higher concentrations of PTX3 (6.338 ng/ml) than group 2 (5.41 ng/ml) and group 1 (1.835 ng/ml). CONCLUSIONS: Within the limits of the present study, the difference in plasma PTX3 levels between groups 2 and 3 was not found to be statistically significant (P > 0.05). However, as PTX3 values correlated positively with periodontal parameters, this model could contribute to identifying individuals with periodontitis at high risk of CKD. Thus, periodontal disease could serve as a risk factor for developing CKD. Further large-scale studies nullifying the confounders for CKD are warranted to confirm positive results.

Gingival crevicular fluid and serum visfatin concentration: their relationship in periodontal health and disease.

BACKGROUND: Visfatin is a pleiotropic mediator that acts as growth factor, cytokine, and enzyme involved in energy including nicotinamide adenine dinucleotide metabolism and was recently demonstrated to exert several proinflammatory functions. The purpose of this study is to determine the presence of visfatin in gingival crevicular fluid (GCF) and serum samples and to find out their association, if any. METHODS: At the beginning of the study, 40 individuals (20 males and 20 females; age range: 23 to 53 years) were selected and divided into three groups based on the gingival index, probing depths, clinical attachment levels, and radiologic parameters (bone loss). Group 1 (10 patients with healthy periodontium; age range: 25-36 years), group 2 (15 patients with gingivitis; age range: 25-36 years), and group 3 (15 patients with chronic periodontitis; age range: 23-53 years) GCF (by microcapillary pipettes) and serum (by venipuncture) samples were collected to estimate levels of visfatin using an enzyme-linked immunosorbent assay kit. RESULTS: Mean visfatin concentrations increased in GCF and serum with the severity of disease from healthy to gingivitis to periodontitis groups and differed significantly (P <0.05). However, it was found that GCF values were higher than serum values. The highest to lowest visfatin concentrations were found in groups 3 through 1, respectively. Visfatin in GCF and serum correlated positively with periodontal parameters in the chronic periodontitis group. CONCLUSIONS: The results suggest that GCF and serum visfatin concentrations increase with the severity of periodontal disease. Hence, visfatin values were considered an inflammatory marker in periodontal disease in GCF and serum. Visfatin also deserves further consideration as a therapeutic target.

Levels of pentraxin-3 in gingival crevicular fluid and plasma in periodontal health and disease.

BACKGROUND: Pentraxins are classic mediators of inflammation and markers of acute-phase reactions. Pentraxin-3 (PTX3) is the first-identified long pentraxin and is believed to be a true independent indicator of disease activity. Although a classic pentraxin, C-reactive protein, and its association with various systemic diseases is well documented in the periodontal literature, there is no data on PTX3 to our knowledge. METHODS: Forty participants (20 males and 20 females; age range: 23 to 50 years) were involved in the study. Participants were divided into three groups based on gingival index, probing depth, and clinical attachment level: the healthy group (group 1; n = 10), gingivitis group (group 2; n = 15), and periodontitis group (group 3; n = 15). Gingival crevicular fluid (GCF) and plasma samples collected from each subject were quantified for PTX3 levels using an enzyme-linked immunosorbent assay. RESULTS: In tandem with the disease progression from healthy to gingivitis to periodontitis, the mean PTX3 concentrations increased in GCF and plasma. However, GCF values were higher than plasma values. It was found that PTX3 concentration was highest in group 3 and lowest in group 1. PTX3 concentrations also correlated positively with periodontal parameters. CONCLUSIONS: GCF and plasma PTX3 concentrations correlated positively in all groups. However, within the limits of the present study, the differences in plasma PTX3 levels were not found to be statistically significant. Hence, GCF PTX3 values were considered a marker of inflammatory activity in periodontal disease. However, PTX3 deserves further consideration as a therapeutic target. Additional large-scale studies should be carried out to confirm positive correlations.