ПЕРВИЧНАЯ ПРОФИЛАКТИКА КАК ЭФФЕКТИВНЫЙ ОТВЕТ НА ЭПИДЕМИЮ АЛЛЕРГИЧЕСКИХ БОЛЕЗНЕЙ

Rapid growth of incidence of allergic diseases in the last 40 years allows us naming allergy the pandemic of the XXI century. Allergic diseases harm not only individual patients, but the society in whole in the form of progressive increase in direct and indirect costs. According to the latest estimates, more than 150 mn people suffer from allergies, whereas more than 250 mn patients in Europe are expected to suffer from allergies in the next decade. National and international documents stating rules of preventing and treating allergic diseases must become current guidelines for clinicians everywhere. The article summarizes the latest recommendations of the European Academy of Allergology and Clinical Immunology (2014) and of the National Food Allergy Guidelines. The article presents evidence-based methods of primary allergy prevention in infants. Modern primary food allergy prevention may consist of exclusively breast feeding for at least 4 6 months; if breast feeding is not feasible, prevention may be attained by means of using preventive hypoallergenic formulas with confirmed low allergenicity and not introducing supplemental feeding before the age of 4 months. Evidence-based studies do not confirm effectiveness of any dietary restrictions of pregnant and nursing women regardless of whether they belong to the risk group or not.Стремительный рост частоты аллергических болезней в последние 40 лет позволяет назвать аллергию пандемией ХХI в. Аллергические болезни причиняют ущерб не только отдельным больным, но и обществу в целом в виде прогрессирующего роста прямых и косвенных затрат. По последним подсчетам, аллергией страдают более 150 млн человек, а уже в следующем десятилетии в Европе прогнозируется более 250 млн пациентов. Современным руководством для врача клинической практики повсеместно должны стать национальные и международные документы, формирующие правила предупреждения и лечения аллергических болезней. В статье обобщены последние рекомендации Европейской академии аллергологии и клинической иммунологии 2014 г. и Национального руководства по пищевой аллергии; приведены методы первичной профилактики аллергии у детей раннего возраста с позиции доказательной медицины. Современная первичная профилактика пищевой аллергии может осуществляться за счет исключительно грудного вскармливания не менее 4–6 мес; в случае невозможности естественного вскармливания — за счет использования профилактических гипоаллергенных смесей с доказанной сниженной аллергенностью, введения прикорма не ранее 4 мес жизни. Эффективность каких-либо диетических ограничений в питании беременной и кормящей женщины вне зависимости от принадлежности к группе риска в настоящее время не находит подтверждения в исследованиях, проведенных по принципам доказательно медицины.

Detailed Regulatory Mechanism of the Interaction between ZO-1 PDZ2 and Connexin43 Revealed by MD Simulations

The gap junction protein connexin43 (Cx43) binds to the second PDZ domain of Zonula occludens-1 (ZO-1) through its C-terminal tail, mediating the regulation of gap junction plaque size and dynamics. Biochemical study demonstrated that the very C-terminal 12 residues of Cx43 are necessary and sufficient for ZO-1 PDZ2 binding and phosphorylation at residues Ser (-9) and Ser (-10) of the peptide can disrupt the association. However, only a crystal structure of ZO-1 PDZ2 in complex with a shorter 9 aa peptide of connexin43 was solved experimentally. Here, the interactions between ZO-1 PDZ2 and the short, long and phosphorylated Cx43 peptides were studied using molecular dynamics (MD) simulations and free energy calculation. The short peptide bound to PDZ2 exhibits large structural variations, while the extension of three upstream residues stabilizes the peptide conformation and enhanced the interaction. Phosphorylation at Ser(-9) significantly weakens the binding and results in conformational flexibility of the peptide. Glu210 of ZO-1 PDZ2 was found to be a key regulatory point in Cx43 binding and phosphorylation induced dissociation

PRIMARY PREVENTION AS AN EFFECTIVE RESPONSE TO THE EPIDEMIC OF ALLERGIC DISEASES

Rapid growth of incidence of allergic diseases in the last 40 years allows us naming allergy the pandemic of the XXI century. Allergic diseases harm not only individual patients, but the society in whole in the form of progressive increase in direct and indirect costs. According to the latest estimates, more than 150 mn people suffer from allergies, whereas more than 250 mn patients in Europe are expected to suffer from allergies in the next decade. National and international documents stating rules of preventing and treating allergic diseases must become current guidelines for clinicians everywhere. The article summarizes the latest recommendations of the European Academy of Allergology and Clinical Immunology (2014) and of the National Food Allergy Guidelines. The article presents evidence-based methods of primary allergy prevention in infants. Modern primary food allergy prevention may consist of exclusively breast feeding for at least 4 6 months; if breast feeding is not feasible, prevention may be attained by means of using preventive hypoallergenic formulas with confirmed low allergenicity and not introducing supplemental feeding before the age of 4 months. Evidence-based studies do not confirm effectiveness of any dietary restrictions of pregnant and nursing women regardless of whether they belong to the risk group or not

A functional interaction between the MAGUK protein hDlg and the gap junction protein Connexin 43 in cervical tumour cells

Gap junctions, composed of connexins, allow direct intercellular communication. Gap junctions are often lost during the development of malignancy, although the processes behind this are not fully understood. Connexin 43 (Cx43) is a widely expressed connexin with a long cytoplasmic C-terminal tail that contains several potential protein interaction domains. Previously, in a model of cervical carcinogenesis we showed loss of gap junctional communication correlated with relocalisation of Cx43 to the cytoplasm late in tumourigenesis. Now we demonstrate a similar pattern of altered expression for the Discs Large (hDlg) MAGUK family tumour suppressor protein in the cervical tumour cells, with partial co-localisation of Cx43 and hDlg in an endosomal/lysosomal compartment. Relocalisation of these proteins is not due to a general disruption of cell membrane integrity or connexin targeting. Cx43 (via its C-terminus) and hDlg interact directly in vitro and can form a complex in cells. This novel interaction requires the N and C-termini of hDlg. hDlg is not required for Cx43 internalisation in W12GPXY cells. Instead, hDlg appears to have a role in maintaining a cytoplasmic pool of Cx43. These results demonstrate that hDlg is a physiologically relevant regulator of Cx43 in transformed epithelial cells

Domain-swapped dimerization of ZO-1 PDZ2 generates specific and regulatory connexin43-binding sites

PDZ domain scaffold proteins are capable of assembling macromolecular protein complexes in diverse cellular processes through PDZ-mediated binding to a short peptide fragment at the carboxyl tail of target proteins. How each PDZ domain specifically recognizes its target protein(s) remains a major conceptual question, as at least a few out of the several hundred PDZ domains in each eukaryotic genome share overlapping binding properties with any given target protein. Here, we show that the domain-swapped dimerization of zonula occludens-1 PDZ2 generates a distinct interface that functions together with the well-separated canonical carboxyl tail-binding pocket in each PDZ unit in binding to connexin43 (Cx43). We further demonstrate that the charge–charge interaction network formed by residues in the PDZ dimer interface and upstream residues of the Cx43 peptide not only provides the unprecedented interaction specificity for the complex but may also function as a phosphorylation-mediated regulatory switch for the dynamics of the Cx43 gap junctions. Finally, we provide evidence that such domain-swapped dimer assembly also occurs in other PDZ domain scaffold proteins. Therefore, our findings present a new paradigm for understanding how some PDZ domain proteins specifically bind to and regulate the functions of their target proteins