Nutritional and medicinal plants as potential sources of enzyme inhibitors toward the bioactive functional foods: an updated review.

Enzymes are biologically active complex protein molecules that catalyze most chemical reactions in living organisms, and their inhibitors accelerate biological processes. This review emphasizes medicinal food plants and their isolated chemicals inhibiting clinically important enzymes in common diseases. A mechanistic overview was investigated to explain the mechanism of these food bases enzyme inhibitors. The enzyme inhibition potential of medicinal food plants and their isolated substances was searched in Ovid, PubMed, Science Direct, Scopus, and Google Scholar. Cholinesterase, amylase, glucosidase, xanthine oxidase, tyrosinase, urease, lipoxygenase, and others were inhibited by crude extracts, solvent fractions, or isolated pure chemicals from medicinal food plants. Several natural compounds have shown tyrosinase inhibition potential, including quercetin, glabridin, phloretin-4-O-ß-D-glucopyranoside, lupinalbin, and others. Some of these compounds' inhibitory kinetics and molecular mechanisms are also discussed. Phenolics and flavonoids inhibit enzyme activity best among the secondary metabolites investigated. Several studies showed flavonoids' significant antioxidant and anti-inflammatory activities, highlighting their medicinal potential. Overall, many medicinal food plants, their crude extracts/fractions, and isolated compounds have been studied, and some promising compounds depending on the enzyme have been found. Still, more studies are recommended to derive potential pharmacologically active functional foods.

Multifunctional role of Nobiletin in cancer chemoprevention.

The diversity of highly bioactive and pharmacologically active natural products which recognize essential biological targets having exquisite specificity, constitutes a massive pharmacological database for discovery of valuable drugs. The rapid accumulation of information has revealed chemopreventive role of nobiletin against wide variety of cancers. Recent efforts are now being expanded and new integrative omics technologies have illuminated continuously upgrading list of molecular mechanisms which underlie carcinogenesis and metastasis. In this mini-review, we explore the progress that has been made in the identification of promising molecular targets of nobiletin.

Frontiers of Ferroptosis in Cancer Treatment.

Recent phenomenal advancements in genomic and proteomic technologies and rapid breakthroughs in the interpretation of large gene expression datasets have enabled scientists to comprehensively characterize the gene signatures involved in ferroptosis. Ferroptosis is an iron-dependent form of non-apoptotic cell death that has gained the worthwhile attention of both basic and clinical researchers. Ferroptosis has dichotomous, context-dependent functions both as a tumor suppressor and promoter of carcinogenesis. Essentially, pharmacological modulation of ferroptosis by its induction as well as its inhibition holds enormous potential to overcome drug resistance and to improve the therapeutic potential of chemotherapeutic drugs in a wide variety of cancers.

Regulation of cell signaling pathways by Wogonin in different cancers: Mechanistic review.

Natural products have historically been invaluable as a premium source of therapeutic agents. Recent advancements in genomics and structural biology have portrayed a high-resolution landscape of the diversity of proteins targeted by pharmacologically active products from natural sources. Natural product research has generated valuable wealth of information and cutting-edge research-works have leveraged our conceptual knowledge altogether to a new level. Wogonin (5,7-dihydroxy-8-methoxyflavone) is an O-methylated flavone and has attracted noteworthy appreciation because of its ability to pharmacologically target plethora of cell signaling pathways in different cancers. In this mini-review, we have gathered scattered pieces of available scientific evidence to summarize how wogonin pharmaceutically targeted Wnt/?-catenin, JAK/STAT, VEGF/VEGFR and TRAIL-driven apoptotic pathways in wide variety of cancers. We have also critically analyzed how wogonin prevented carcinogenesis and metastasis in tumor-bearing mice. Although researchers have uncovered pleiotropic role of wogonin in the regulation of different oncogenic signaling cascades but there are visible knowledge gaps in our understanding related to regulation of non-coding RNAs by wogonin. Future studies must converge on the unraveling of additional drug targets for wogonin to achieve a fuller and realistic understanding of the chemopreventive properties of wogonin.

Comparison of anchorage loss between conventional and self-ligating brackets during canine retraction - A systematic review and meta-analysis.

INTRODUCTION: Anchorage is defined as the resistance to unwanted tooth movement. In orthodontics, loss of anchorage can be detrimental to treatment. The proponents of orthodontic self-ligating brackets (SLB) advocate the use of extremely light forces thereby reducing anchorage burden. Therefore, the aim of this study was to compare anchorage loss during canine retraction between conventional brackets (CB) and self-ligating brackets. METHODS: An electronic search was conducted on the Cochrane database, Scopus, Web of Science, PubMed, Dental & Oral Science and CINAHL, along with handsearching Google Scholar and clinicaltrials.gov. Randomized or non-randomized clinical trials published in the English language on human subjects were included. Orthodontic patients undergoing canine retraction after premolar extraction bonded with self-ligating brackets as the intervention and conventional brackets as the control group in a split mouth design were included. Primary outcome studied was anchorage loss; secondary outcomes were retraction velocity and total amount of canine retraction. Two researchers carried out data extraction and study selection independently. The risk of bias was calculated using the Cochrane's Risk of Bias Assessment tool. The RevMan software was used for quantitative synthesis of data. Effect estimate of the primary and secondary outcomes was expressed using weighted mean difference and 95% confidence intervals (CIs). Heterogeneity of the studies was evaluated using the Cochrane's test for heterogeneity (I2 Test); subgroup and sensitivity analyses were performed to investigate sources of heterogeneity among the studies. RESULTS: Results of the literature search across all databases yielded 10,439 hits, out of which five studies were included in the qualitative synthesis that met the inclusion criteria. Four studies were randomized control trials (RCTs) where as one was a non-randomized control trial, with 100 subjects included in this systematic review. All studies used a split mouth design. Of the five studies included, only one reported significant differences between CB and SLB for anchorage loss, retraction velocity and total amount of canine retraction (P-value≤0.001). Four studies were included in the meta-analysis, which showed no difference in the amount of anchorage between self-ligating and conventional brackets (weighted mean difference - 0.22; 95% CI [-0.82, 0.38]; P=0.48). Multiple subgroup analyses further revealed there were no significant differences between the intervention and control groups for all outcomes studied. CONCLUSION: This systematic review and meta-analysis found insufficient evidence to suggest a significant difference in anchorage loss between the CB and SLB groups. The scarcity of current evidence dictates that further studies are needed to canonically establish the clinical superiority of one over the other. REVIEW REGISTRATION: PROSPERO 2019 CRD42019133217.

Interleukin-6 selectively induces drug metabolism to potentiate the genotoxicity of dietary carcinogens in mammary cells.

Breast cancer is the most commonly diagnosed malignancy in females, the etiology being multifactorial and includes the role of lifestyle exposure to DNA-damaging chemicals such as dietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP). Both compounds require cytochrome P450 (CYP)-mediated metabolic activation to DNA-damaging species, and both induce transcriptional responses through the nuclear receptors Aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα). BaP and PhIP are mammary carcinogens in rodents. Clinically, circulating IL-6 expression is linked with poor prognosis of cancer and 35% of the deaths in breast cancer are linked with inflammation. The objective of this work was to investigate the molecular toxicology and local activation of BaP and PhIP in the presence of IL-6. Our laboratory has previously reported that miR27b can regulate CYP1B1 expression in colorectal cells, here we have investigated if this mechanism is working in mammary cell models, MCF-7 and MDA-MB-231 cells. Treatment (24 h) of cells with BaP (10 nM-10 µM) and PhIP (100 nM-100 µM) significantly induced genetic damage (micronuclei formation) in a dose-dependent manner in both cell lines. This effect was potentiated in the presence of human IL-6 at concentrations reported to be expressed in clinical breast cancer. On its own, IL-6 treatment failed to induce micronuclei frequency above the control levels in these cells. Compared to BaP or PhIP treatment alone, IL-6 plus BaP or PhIP selectively induced CYP1B1 significantly in both cell lines. Additionally, miR27b expression was downregulated by IL-6 treatments and transfection with miR27b inhibitor confirmed that miR27b is a regulator of CYP1B1 in both cell lines. These data show that BaP- and PhIP-induced DNA damage in mammary cells is potentiated by the inflammatory cytokine IL-6 and that inflammation-induced CYP expression, specifically CYP1B1 via miR27b, is responsible for this effect.

Correlation between radiographic parameters for the prediction of palatally impacted maxillary canines.

OBJECTIVE: This study aimed to identify radiographic parameters on routine orthopantomograms to aid in early diagnosis of palatally impacted canines. DESIGN: Split-mouth case-control study. SETTING: Single-centre university dental hospital. METHODS: Thirty-three individuals with palatally impacted canines and non-impacted contra-lateral teeth were recruited. Radiographic variables angle A, angle B, angle C, distance D, sector class and depth of vertical impaction were measured for both groups. Mann-Whitney U test and Spearman's correlation coefficient were used to analyse significant differences and association between variables with sector class and depth of vertical impaction, respectively. Logistic regression analysis determined radiographic parameters as predictors of palatal impaction. RESULTS: Significant differences were seen between sector class, depth of vertical impaction and the radiographic parameters between cases and controls ( P ⩽ 0.001). For cases, strong correlation was found for angle C between the impacted canine and occlusal plane (r = -0.28, P = 0.022) and perpendicular distance D of impacted canine to the occlusal plane (r = 0.81, P ⩽ 0.001) with the depth of vertical impaction. Logistic regression analysis showed the odds of canine impaction increase with an increase in angle B and angle C. CONCLUSIONS: Our study showed that greater depth of vertical impaction, sector class, increased perpendicular distance and reduced angulation from occlusal plane resulted in palatal impaction of permanent maxillary canines. The odds of palatal canine impaction increase nearly twofold with every 10 increase in angle B and angle C.

Does periodontally accelerated osteogenic orthodontics improve orthodontic treatment outcome? A systematic review and meta-analysis.

BACKGROUND: Periodontally accelerated osteogenic orthodontics (PAOO) can be used to improve periodontal conditions and accelerate tooth movement. OBJECTIVE: The aim of this systematic review and meta-analysis was to compare periodontal outcome and treatment duration of patients undergoing PAOO to accelerate orthodontic treatment. SEARCH METHOD: An electronic search was performed in four electronic databases including Pubmed, EBSCO Cochrane library, CINAHL Complete for randomized clinical trials till November 2017. A hand search was performed on clinicaltrials.gov and Google scholar. SELECTION CRITERIA: Randomized controlled trials reporting periodontal outcomes and treatment duration of PAOO in adult patients by evaluating treatment duration, root resorption, bone density and pocket depths were included. DATA COLLECTION AND ANALYSIS: Two authors conducted searches, data extraction and bias assessment with conflict resolution with a third author. Cochrane's tool for risk of bias assessment was used for evaluation. A manual search was conducted for additional studies. A quantitative synthesis of the pooled results was conducted. RESULTS: Five studies were included in the qualitative synthesis and two in the quantitative synthesis. A total of 56 patients underwent the PAOO technique; the effects of this therapy were compared with 21 patients who underwent corticotomy, 9 underwent non-extraction comprehensive orthodontic treatment and 15 underwent fixed mechanotherapy with extractions of first premolars. A random effect model was used for pocket depths and showed a non-significant difference between bioactive glass augmented corticotomy and corticotomy alone (weighted mean difference, -0.03; 95% CI, -0.16, 0.09). Bone density elucidated a non-significant difference between bioactive glass augmented corticotomy and corticotomy alone (weighted mean difference, 27.69; 95% CI, -2.29, 57.67). Fixed effect model was used for root length which revealed a non-significant difference between bioactive glass augmented corticotomy and corticotomy alone (weighted mean difference, 0.01; 95% CI, -0.00, 0.02). CONCLUSIONS: Studies showed significant improvements in periodontal health. Treatment duration was reduced in patients who underwent PAOO. Root resorption was not sufficiently evaluated by current literature.

Association Between Maxillary Posterior Segment Discrepancy And The Angulation Of Maxillary Molars In Patients With Different Vertical Growth Patterns.

BACKGROUND: The impaction of maxillary third molars causes the crowns of maxillary first and second molars to tip distally in patients with maxillary posterior segment discrepancy. The aim of this study was to compare the maxillary first and second molar angulations in patients with maxillary posterior segment discrepancy (MPSD) with non-maxillary posterior segment discrepancy (N-MPSD) and evaluate the effect of their angulations on various divergence patterns. METHODS: A cross-sectional study was conducted using the pre-treatment lateral cephalograms of 180 subjects which were divided into two groups, i.e., MPSD and N-MPSD. The Mann-Whitney U test was applied to compare various skeletal and dental parameters between the two groups and a pairwise comparison was made among the vertical growth patterns. The Kruskal Wallis test was used to compare the mean molar angulations and overbite among the three divergence patterns. RESULTS: The ratio of anterior to total palatal plane (p≤0.001) and the molar angulation (p≤0.001) showed significant differences between the MPSD and N-MPSD groups. In the MPSD group, significant differences were found between the overbite in the normo-divergent versus hyperdivergent (p≤0.001) and hypodivergent versus hyperdivergent groups (p≤0.001), and in the angulation of the first maxillary molars in the normo-divergent versus hyperdivergent groups (p≤0.001). CONCLUSIONS: MPSD causes reduced maxillary first and second molar angulations. A ratio of the anterior palatal plane to total palatal plane length of ≥0.51 was seen in patients with impacted maxillary third molars.

Mechanistic evidence that benzo[a]pyrene promotes an inflammatory microenvironment that drives the metastatic potential of human mammary cells.

Benzo[a]pyrene (B(a)P) is a major cancer-causing contaminant present in food such as cooked meats and cereals, and is ubiquitous in the environment in smoke derived from the combustion of organic material. Exposure to B(a)P is epidemiologically linked with the incidence of breast cancer. Although B(a)P is recognized as a complete genotoxic carcinogen, thought to act primarily via CYP-mediated metabolic activation to DNA-damaging species, there is also evidence that B(a)P exposure elicits other biological responses that promote development of the cancer phenotype. Here in mechanistic studies using human mammary cells MCF-7 and MDA-MB-231, we have explored mechanisms whereby B(a)P (10- 8 to 10- 5M) promotes inflammation pathways via TNF-α and NFκB leading to IL-6 upregulation, microRNA (Let7a, miR21 and miR29b) dysregulation and activation of VEGF. The miRNA dysregulation is associated with altered expression of inflammation mediators and increased migration and invasive potential of human mammary cancer cells. Our data suggest that mammary cell exposure to B(a)P results in perturbation of inflammation mediators and dysregulation of tumorigenic miRNAs, leading to an inflammation microenvironment that facilitates migration and invasion of mammary epithelial cells. These properties of B(a)P, together with its well-established metabolic activation to DNA-damaging species, offer mechanistic insights into its carcinogenic mode of action.

Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer.

Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. PhIP toxicity involves cytochrome P450 (CYP1 family)-mediated metabolic activation to DNA-damaging species, and transcriptional responses through Aryl hydrocarbon receptor (AhR) and estrogen-receptor-α (ER-α). Ethanol consumption is a modifiable lifestyle factor strongly associated with breast cancer risk. Ethanol toxicity involves alcohol dehydrogenase metabolism to reactive acetaldehyde, and is also a substrate for CYP2E1, which when uncoupled generates reactive oxygen species (ROS) and DNA damage. Here, using human mammary cells that differ in estrogen-receptor status, we explore genotoxicity of PhIP and ethanol and mechanisms behind this toxicity. Treatment with PhIP (10-7-10-4 M) significantly induced genotoxicity (micronuclei formation) preferentially in ER-α positive human mammary cell lines (MCF-7, ER-α+) compared to MDA-MB-231 (ER-α-) cells. PhIP-induced CYP1A2 in both cell lines but CYP1B1 was selectively induced in ER-α(+) cells. ER-α inhibition in MCF-7 cells attenuated PhIP-mediated micronuclei formation and CYP1B1 induction. PhIP-induced CYP2E1 and ROS via ER-α-STAT-3 pathway, but only in ER-α (+) MCF-7 cells. Importantly, simultaneous treatments of physiological concentrations ethanol (10-3-10-1 M) with PhIP (10-7-10-4 M) increased oxidative stress and genotoxicity in MCF-7 cells, compared to the individual chemicals. Collectively, these data offer a mechanistic basis for the increased risk of breast cancer associated with dietary cooked meat and ethanol lifestyle choices.