Prevention, inhibition, and degradation effects of melittin alone and in combination with vancomycin and rifampin against strong biofilm producer strains of methicillin-resistant Staphylococcus epidermidis

Methicillin-resistant Staphylococcus epidermidis (MRSE) bacteria are being recognized as true pathogens as they are able to resist methicillin and commonly form biofilms. Recent studies have shown that antimicrobial peptides (AMPs) are promising agents against biofilm-associated bacterial infections. In this study, we aimed to explore the antibiofilm activity of melittin, either alone or in combination with vancomycin and rifampin, against biofilm-producing MRSE strains. Minimum biofilm preventive concentration (MBPC), minimum biofilm inhibition concentration (MBIC), and minimum biofilm eradication concentration (MBEC), as well as fractional biofilm preventive-, inhibitory-, and eradication concentrations (FBPCi, FBICi, and FBECi), were determined for the antimicrobial agents tested. Cytotoxicity and hemolytic activity of melittin at its synergistic concentration were examined on human embryonic kidney cells (HEK-293) and Red Blood Cells (RBCs), respectively. The effect of melittin on the downregulation of biofilm-associated genes was explored using Real-Time PCR. MBPC, MBIC, and MBEC values for melittin were in the range of 0.625–20, 0.625–20, and 10–40 μg/μL, respectively. Melittin showed high synergy (FBPCi, FBICi and FBECi < 0.5). The synergism resulted in a 64–512-fold, 2–16 and 2–8-fold reduction in melittin, rifampicin and vancomycin concentrations, respectively. The synergistic melittin concentration found to be effective did not manifest either cytotoxicity on HEK-293 or hemolytic activity on RBCs. Results showed that melittin downregulated the expression of biofilm-associated icaA, aap, and psm genes in all isolates tested, ranging from 0.04-folds to 2.11-folds for icaA and from 0.05 to 3.76-folds for aap and psm. The preventive and therapeutic indexes of melittin were improved 8-fold when combined with vancomycin and rifampin. Based on these findings, the combination of melittin with conventional antibiotics could be proposed for treating or preventing biofilm-associated MRSE infections

Bacterial biofilm in colorectal cancer: What is the real mechanism of action?

Human colorectal cancer is the third most common cancer around the world. Colorectal cancer has various risk factors, but current works have bolded a significant activity for the microbiota of the human colon in the development of this disease. Bacterial biofilm has been mediated to non-malignant pathologies like inflammatory bowel disease but has not been fully documented in the setting of colorectal cancer. The investigation has currently found that bacterial biofilm is mediated to colon cancer in the human and linked to the location of human cancer, with almost all right-sided adenomas of colon cancers possessing bacterial biofilm, whilst left-sided cancer is rarely biofilm positive. The profound comprehension of the changes in colorectal cancer can provide interesting novel concepts for anticancer treatments. In this review, we will summarize and examine the new knowledge about the links between colorectal cancer and bacterial biofilm. © 202

Discovery of AZD3199, an inhaled ultralong acting β2 receptor agonist with rapid onset of action

A series of dibasic des-hydroxy β2 receptor agonists has been prepared and evaluated for potential as inhaled ultra-long acting bronchodilators. Determination of activities at the human β-adrenoreceptors demonstrated a series of highly potent and selective β2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by; onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i. t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultra-long acting inhaled β2 receptor agonist with rapid onset of action

Assessing and Selecting Sustainable and Resilient Suppliers in Agri-Food Supply Chains Using Artificial Intelligence: A Short Review

[EN] The supplier evaluation and selection process is critical to increase the sustainability and resilience of the agri-food supply chain. Therefore, in this sector, it is necessary to consider sustainability and resilience criteria in the supplier evaluation and selection process. The use of arti¿cial intelligence techniques allows managing of a lot of information and the reduction of uncertainty for decision making. The objective of this article is to analyze articles that address the selection of suppliers in agrifood supply chains that pursue to increase their sustainability and resilience by using arti¿cial intelligence techniques to analyze the techniques and criteria used and draw conclusions.Authors of this publication acknowledge the contribution of the Project 691249, RUC-APS "Enhancing and implementing Knowledge based ICT solutions within high Risk and Uncertain Conditions for Agriculture Production Systems" (www.ruc-aps.eu), funded by the European Union under their funding scheme H2020-MSCA-RISE-2015.Zavala-Alcívar, A.; Verdecho Sáez, MJ.; Alfaro Saiz, JJ. (2020). Assessing and Selecting Sustainable and Resilient Suppliers in Agri-Food Supply Chains Using Artificial Intelligence: A Short Review. 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Effects of Charge and Substituent on the S∙∙∙N Chalcogen Bond

Neutral complexes containing a S···N chalcogen bond are compared with similar systems in which a positive charge has been added to the S-containing electron acceptor, using high-level ab initio calculations. The effects on both XS···N and XS+···N bonds are evaluated for a range of different substituents X = CH3, CF3, NH2, NO2, OH, Cl, and F, using NH3 as the common electron donor. The binding energy of XMeS···NH3 varies between 2.3 and 4.3 kcal/mol, with the strongest interaction occurring for X = F. The binding is strengthened by a factor of 2–10 in charged XH2S+···NH3 complexes, reaching a maximum of 37 kcal/mol for X = F. The binding is weakened to some degree when the H atoms are replaced by methyl groups in XMe2S+···NH3. The source of the interaction in the charged systems, like their neutral counterparts, is derived from a charge transfer from the N lone pair into the σ*(SX) antibonding orbital, supplemented by a strong electrostatic and smaller dispersion component. The binding is also derived from small contributions from a CH···N H-bond involving the methyl groups, which is most notable in the weaker complexes

Mechanical adaptation of trabecular bone morphology in the mammalian mandible

Alveolar bone, together with the underlying trabecular bone, fulfils an important role in providing structural support against masticatory forces. Diseases such as osteoporosis or periodontitis cause alveolar bone resorption which weakens this structural support and is a major cause of tooth loss. However, the functional relationship between alveolar bone remodelling within the molar region and masticatory forces is not well understood. This study investigated this relationship by comparing mammalian species with different diets and functional loading (Felis catus, Cercocebus atys, Homo sapiens, Sus scrofa, Oryctolagus cuniculus, Ovis aries). We performed histomorphometric analyses of trabecular bone morphology (bone volume fraction, trabecular thickness and trabecular spacing) and quantified the variation of bone and tooth root volumes along the tooth row. A principal component analysis and non-parametric MANOVA showed statistically significant differences in trabecular bone morphology between species with contrasting functional loading, but these differences were not seen in sub-adult specimens. Our results support a strong, but complex link between masticatory function and trabecular bone morphology. Further understanding of a potential functional relationship could aid the diagnosis and treatment of mandibular diseases causing alveolar bone resorption, and guide the design and evaluation of dental implants

Diabetes Stimulates Osteoclastogenesis by Acidosis-Induced Activation of Transient Receptor Potential Cation Channels

Patients with type 1 diabetes have lower bone mineral density and higher risk of fractures. The role of osteoblasts in diabetes-related osteoporosis is well acknowledged whereas the role of osteoclasts (OCLs) is still unclear. We hypothesize that OCLs participate in pathological bone remodeling. We conducted studies in animals (streptozotocin-induced type 1 diabetic mice) and cellular models to investigate canonical and non-canonical mechanisms underlying excessive OCL activation. Diabetic mice show an increased number of active OCLs. In vitro studies demonstrate the involvement of acidosis in OCL activation and the implication of transient receptor potential cation channel subfamily V member 1 (TRPV1). In vivo studies confirm the establishment of local acidosis in the diabetic bone marrow (BM) as well as the ineffectiveness of insulin in correcting the pH variation and osteoclast activation. Conversely, treatment with TRPV1 receptor antagonists re-establishes a physiological OCL availability. These data suggest that diabetes causes local acidosis in the BM that in turn increases osteoclast activation through the modulation of TRPV1. The use of clinically available TRPV1 antagonists may provide a new means to combat bone problems associated with diabetes

VILIP-1 Downregulation in Non-Small Cell Lung Carcinomas: Mechanisms and Prediction of Survival

VILIP-1, a member of the neuronal Ca++ sensor protein family, acts as a tumor suppressor gene in an experimental animal model by inhibiting cell proliferation, adhesion and invasiveness of squamous cell carcinoma cells. Western Blot analysis of human tumor cells showed that VILIP-1 expression was undetectable in several types of human tumor cells, including 11 out of 12 non-small cell lung carcinoma (NSCLC) cell lines. The down-regulation of VILIP-1 was due to loss of VILIP-1 mRNA transcripts. Rearrangements, large gene deletions or mutations were not found. Hypermethylation of the VILIP-1 promoter played an important role in gene silencing. In most VILIP-1-silent cells the VILIP-1 promoter was methylated. In vitro methylation of the VILIP-1 promoter reduced its activity in a promoter-reporter assay. Transcriptional activity of endogenous VILIP-1 promoter was recovered by treatment with 5′-aza-2′-deoxycytidine (5′-Aza-dC). Trichostatin A (TSA), a histone deacetylase inhibitor, potently induced VILIP-1 expression, indicating that histone deacetylation is an additional mechanism of VILIP-1 silencing. TSA increased histone H3 and H4 acetylation in the region of the VILIP-1 promoter. Furthermore, statistical analysis of expression and promoter methylation (n = 150 primary NSCLC samples) showed a significant relationship between promoter methylation and protein expression downregulation as well as between survival and decreased or absent VILIP-1 expression in lung cancer tissues (p<0.0001). VILIP-1 expression is silenced by promoter hypermethylation and histone deacetylation in aggressive NSCLC cell lines and primary tumors and its clinical evaluation could have a role as a predictor of short-term survival in lung cancer patients