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Background Currently, there is no agreed standard for exploring the antimicrobial activity of wound antiseptics in a phase 2/ step 2 test protocol. In the present study, a standardised in-vitro test is proposed, which allows to test potential antiseptics in a more realistically simulation of conditions found in wounds as in a suspension test. Furthermore, factors potentially influencing test results such as type of materials used as test carrier or various compositions of organic soil challenge were investigated in detail. Methods This proposed phase 2/ step 2 test method was modified on basis of the EN 14561 by drying the microbial test suspension on a metal carrier for 1 h, overlaying the test wound antiseptic, washing-off, neutralization, and dispersion at serial dilutions at the end of the required exposure time yielded reproducible, consistent test results. Results The difference between the rapid onset of the antiseptic effect of PVP-I and the delayed onset especially of polihexanide was apparent. Among surface-active antimicrobial compounds, octenidine was more effective than chlorhexidine digluconate and polihexanide, with some differences depending on the test organisms. However, octenidine and PVP-I were approximately equivalent in efficiency and microbial spectrum, while polihexanide required longer exposure times or higher concentrations for a comparable antimicrobial efficacy. Conclusion Overall, this method allowed testing and comparing differ liquid and gel based antimicrobial compounds in a standardised setting.

The aim of the present study was to compare the effect of chitosan nanoparticle, QMix, and 17% EDTA on the penetrability of a calcium silicate-based sealer into dentinal tubules using a confocal laser scanning microscope (CLSM). Sixty mandibular premolar teeth were selected and randomly divided into three groups (n = 20) before root canal preparation according to the solution used in the final rinse protocol: chitosan, QMix, and EDTA groups. Twenty teeth of each group were filled with a TotalFill BC sealers’ single gutta-percha cone and with 0.1% rhodamine B. The specimens were horizontally sectioned at 3 and 5 mm from the apex, and the slices were analyzed in CLSM (4×). Total percentage and maximum depth of sealer penetration were measured using confocal laser scanning microscopy with using Image J analysis software. Dentinal tubule’s penetration depth, percentage, and area were measured using imaging software. Kruskal–Wallis test was used for statistical analysis. The level of significance was set at 5%. Results of Kruskal–Wallis analysis showed that there was a significant difference in the percentage and depth of sealer penetration among all groups at 3 and 5 mm level sections (P < 0.05). Within the groups, the minimum sealer penetration depth was recorded for chitosan nanoparticle group. Greater depth of sealer penetration was recorded at 5 mm as compared to 3 mm in all the groups. Within the limitation of the present study, it can be concluded that QMix and EDTA promoted sealer penetration superior to that achieved by chitosan nanoparticle.

Background To determine whether 12 months of intensive medical therapy (IMT) improves HDL functionality parameters in subjects with type II diabetes (T2D). Methods Retrospective, randomized, and controlled 12-month IMT intervention trial that enrolled 13-subjects with T2D (age 51- years, fasting glucose 147 mg/dL, body mass index [BMI] 36.5 kg/m 2 ) and nine healthy control (46-years, fasting glucose 90 mg/dL, BMI 26.5 kg/m2). Subjects with T2D underwent IMT and HDL functionality measures (pro-inflammatory index of high-density lipoprotein (pHDL)), paraoxonase one (PON1), ceruloplasmin (Cp), and myeloperoxidase (MPO) activity were performed on samples at baseline and at 12-months following IMT. Results At baseline, pHDL index was significantly higher in subjects with T2D ( p  < 0.001) and apolipoprotein A-1 levels were significantly lower ( p  = 0.013) vs. controls. After 12-months, there was a trend for improved pHDL activity ( p  = 0.083), as indicated by intent-to-treat analysis, but when the non-adherent subject was omitted (per-protocol), significant attenuations in pHDL activity ( p  = 0.040) were noted; Δ pHDL activity at 12-months was associated with Δ weight ( r  = 0.62, p  = 0.032) and Δ fasting glucose ( r  = 0.65, p  = 0.022). Moreover, PON1 activity significantly improved ( p  < 0.001). The aforementioned occurred in association with improvements in inflammatory markers (i.e., C-reactive protein & tumor necrosis factor), hemoglobin A1C, fasting glucose, triglycerides, high-density lipoprotein levels and adipokines. Conclusion IMT ameliorates pHDL index and significantly improves anti-oxidative function, as measured by PON1. Improvements in weight and fasting glucose mediated the decrease in pHDL index. Pharmacological aids and lifestyle modification are required to improve cardiovascular risk factors, subsequent mortality risk, and promote T2D remission. Application of either form of therapy alone may only have relatively miniscule effects on the aforementioned factors, in relation to the aggregate.

Key Points Greater understanding of the complex and multifactorial pathogenesis of type 2 diabetes mellitus (T2DM) has informed the development of several new classes of glucose-lowering therapies Metformin remains the first-line pharmacotherapy for patients with T2DM, whereas the use of other well-established agents, such as sulfonylureas, meglitinides, pioglitazone and α-glucosidase inhibitors, varies in different regions Agents that enhance incretin activity (DPP-4 inhibitors), supplement endogenous GLP-1 (GLP-1 receptor agonists) or increase urinary glucose elimination (SGLT2 inhibitors) have low risk of hypoglycaemia and can assist weight control Treatment with two or three agents with different modes of action can be required as T2DM advances, and insulin therapy is required if other agents are unable to maintain adequate glycaemic control Glycaemic targets and the choice of glucose-lowering agents should be customized to meet the needs and circumstances of individual patients, which could be facilitated by future developments in pharmacogenomics Although the balance of benefits and risks for different agents varies between individual patients, early, effective and sustained glycaemic control delays the onset and reduces the severity of hyperglycaemia-related complications Several classes of glucose-lowering therapies are now available for treatment of type 2 diabetes mellitus. In this Review, the current knowledge relating to mechanisms of action, pharmacokinetics, pharmacodynamics and safety profiles is presented for members of each of these drug classes. Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.

Cortical sensory maps are remodeled during early life to adapt to the surrounding environment. Both sensory and contextual signals are important for induction of this plasticity, but how these signals converge to sculpt developing thalamocortical circuits remains largely unknown. Here we show that layer 1 (L1) of primary auditory cortex (A1) is a key hub where neuromodulatory and topographically organized thalamic inputs meet to tune the cortical layers below. Inhibitory interneurons in L1 send narrowly descending projections to differentially modulate thalamic drive to pyramidal and parvalbumin-expressing (PV) cells in L4, creating brief windows of intracolumnar activation. Silencing of L1 (but not VIP-expressing) cells abolishes map plasticity during the tonotopic critical period. Developmental transitions in nicotinic acetylcholine receptor (nAChR) sensitivity in these cells caused by Lynx1 protein can be overridden to extend critical-period closure. Notably, thalamocortical maps in L1 are themselves stable, and serve as a scaffold for cortical plasticity throughout life.

Dependence on exogenous serine means that tumour growth is restricted in mice on a low-serine diet; this effect on tumour growth can be amplified by antagonizing the antioxidant response. Exploring dietary restrictions in cancer therapy Tumours acquire different metabolic adaptations to foster accelerated growth. This can lead to their dependence on crucial nutrients for anabolism. It had been shown that some non-essential amino acids, including serine, are required for tumour growth in mice. This report explores the effect of serine deprivation in endogenous tumour mouse models, uncovering how different oncogenic adaptations lead tumours to rely on exogenous serine or upregulate its cellular synthesis. Dependence on exogenous serine renders tumours sensitive to serine-deprivation diets, and this effect on tumour growth can be amplified by antagonizing the anti-oxidant response. The authors take a step towards dissecting how the metabolic vulnerabilities of cancer may be explored therapeutically in the future. The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1 ). While some cancer cells upregulate de novo serine synthesis 2 , 3 , 4 , many others rely on exogenous serine for optimal growth 5 , 6 , 7 . Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models 7 , 8 . Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

New apparatus is used to maintain proliferating cancer cells in low-glucose conditions, demonstrating that mitochondrial oxidative phosphorylation (OXPHOS) is essential for optimal proliferation in these conditions; the most sensitive cell lines are defective in OXPHOS upregulation and may therefore be sensitive to current antidiabetic drugs that inhibit OXPHOS. Biguanides active against starved tumour cells Using a new continuous-flow culture apparatus called Nutrostat, designed to ensure constant and controlled extracellular nutrient levels, David Sabatini and colleagues screened cancer cell lines for genes important when cells experience low glucose levels. They found that the ability of cells to increase mitochondrial oxidative phosphorylation under conditions of low glucose was crucial. Cancer cells unable to do so due to impaired glucose utilization or mitochondrial DNA mutations were particularly sensitive to a class of compounds, biguanides, which are in use to treat diabetes. These findings may lead to new therapeutic applications of these drugs to treat tumours displaying such defects. As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues 1 , 2 , cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS 3 , 4 , when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function 5 . Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.

The tumour microenvironment contributes to cancer metastasis and drug resistance. However, most high throughput screening (HTS) assays for drug discovery use cancer cells grown in monolayers. Here we show that a multilayered culture containing primary human fibroblasts, mesothelial cells and extracellular matrix can be adapted into a reliable 384- and 1,536-multi-well HTS assay that reproduces the human ovarian cancer (OvCa) metastatic microenvironment. We validate the identified inhibitors in secondary in vitro and in vivo biological assays using three OvCa cell lines: HeyA8, SKOV3ip1 and Tyk-nu. The active compounds directly inhibit at least two of the three OvCa functions: adhesion, invasion and growth. In vivo , these compounds prevent OvCa adhesion, invasion and metastasis, and improve survival in mouse models. Collectively, these data indicate that a complex three-dimensional culture of the tumour microenvironment can be adapted for quantitative HTS and may improve the disease relevance of assays used for drug screening. Tumour microenvironment affects the outcome of pharmacological anticancer treatments. Here, Kenny et al . show that organotypic cultures of ovarian cancer cells can recapitulate metastasis. They identify several new compounds that block cancer invasion and metastasis and improve survival in mouse models.

Biguanides such as metformin, which is the most widely prescribed drug for type-2 diabetes, are shown to antagonize the actions of glucagon by decreasing the levels of cyclic AMP. Antidiabetics as glucagon antagonists Hyperglycaemia is a common consequence of insulin resistance, the inability of insulin to suppress glucose output by the liver. Biguanides such as phenformin and metformin are often used to lower excessive glucose levels, for example in patients with type-2 diabetes mellitus. Until recently metformin was thought to reduce glucose production by activating AMP-activated protein kinase. Here it is shown, however, that it antagonizes the actions of glucagon. Biguanides increase the levels of intracellular AMP and related nucleotides, thereby inhibiting the ability of glucagon to activate adenylyl cyclase. This results in reduced levels of cyclic AMP and protein kinase A activity, which blocks phosphorylation of substrates that are important for maintaining glucose output from hepatocytes. This work suggests that glucagon antagonists may have antidiabetic potential. Glucose production by the liver is essential for providing a substrate for the brain during fasting. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type-2 diabetes mellitus and other diseases of insulin resistance 1 , 2 . For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes 3 . Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments 4 . Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs.