Muramyl Dipeptide Induces NOD2-Dependent Ly6Chigh Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection

Bacterial peptidoglycan-derived muramyl dipeptide (MDP) and derivatives have long-recognized antiviral properties but their mechanism of action remains unclear. In recent years, the pattern-recognition receptor NOD2 has been shown to mediate innate responses to MDP. Here, we show that MDP treatment of mice infected with Influenza A virus (IAV) significantly reduces mortality, viral load and pulmonary inflammation in a NOD2-dependent manner. Importantly, the induction of type I interferon (IFN) and CCL2 chemokine was markedly increased in the lungs following MDP treatment and correlated with a NOD2-dependent enhancement in circulating monocytes. Mechanistically, the protective effect of MDP could be explained by the NOD2-dependent transient increase in recruitment of Ly6Chigh “inflammatory” monocytes and, to a lesser extent, neutrophils to the lungs. Indeed, impairment in both Ly6Chigh monocyte recruitment and survival observed in infected Nod2-/- mice treated with MDP was recapitulated in mice deficient for the chemokine receptor CCR2 required for CCL2-mediated Ly6Chigh monocyte migration from the bone marrow into the lungs. MDP-induced pulmonary monocyte recruitment occurred normally in IAV-infected and MDP-treated Ips-1-/- mice. However, IPS-1 was required for improved survival upon MDP treatment. Finally, mycobacterial N-glycolyl MDP was more potent than N-acetyl MDP expressed by most bacteria at reducing viral burden while both forms of MDP restored pulmonary function following IAV challenge. Overall, our work sheds light on the antiviral mechanism of a clinically relevant bacterial-derived compound and identifies the NOD2 pathway as a potential therapeutic target against IAV

Synthesis of adenosine analogues

Adenosine (Rys. 1) is a purine nucleoside playing an important role in human body. It is involved in key pathways such as purinergic nucleic acid base synthesis, amino acid metabolism and modulation of cellular metabolic status [1,2]. Adenosine acts through the four types of adenosine receptors: A1, A2A, A2B and A3 belonging to the G protein-coupled receptor family [3]. In physiological conditions this nucleoside is present in a micromolar range [5]. However, when metabolic stress occurs extracellular level of adenosine raises revealing its protective properties. Depending on an activated receptor subtype, adenosine demonstrates cardioprotective and neuroprotective activity during hypoxia or ischemia, it stimulates the immunological system [6, 7]. Besides many potential applications, adenosine is used mainly for the treatment of paroxysmal supraventricular tachycardia. Limitations are linked to a very short blood half-time and no receptor specificity [8]. This review is focused on novel literature data about synthesis of adenosine analogues with interesting biological activities. In order to influence adenosine receptor selectivity and pharmacokinetic properties a nucleoside structure can be modified in purine [14, 15, 17, 22, 26, 27, 35] or sugar ring [29, 32]. New interesting compounds are also synthesized by cyclisation of adenosine [36]. Modification of adenosine structure allowed obtaining compounds with targeted action: antiarrhythmic [11, 12], antinociceptive [9], antilipolytic [13], antiviral [29] or anticancer [35]

Parametryzacja modelu detrutusu pelagicznego, Głębia Gdańska, Morze Bałtyckie

This paper presents a zero-dimensional particulate detritus model (Figure 1) and a comprehensive description of parameterisation processes that influence the non-living organic matter (detritus) concentration in the whole water column. Mathematically, the particulate pelagic detritus concentration can be described as a variable dependent on the number of its sources and sinks. Temporal supplies in the pelagic detritus concentration are affected by the natural mortality of phytoplankton and zooplankton as well as by the faecal pellets that enter the detritus pool. On the other hand, sedimentation, grazing of detritus by zooplankton and mineralization of pelagic detritus act as sinks that reduce the detritus concentration in the water column. The aim of this model study was to calibrate the detritus model under the environmental conditions typical of the Gdańsk Deep in the southern Baltic Sea.Przedmiotem badań jest parametryzacja zero wymiarowego Modelu Detrytusu Pelagicznego (PDM). Stężenie detrytusu pelagicznego w wodzie morskiej jest determinowane równowagą ustaloną pomiędzy źródłami i ubytkami martwej, zawieszonej materii organicznej. Do źródeł zalicza się: śmiertelność fito- i zooplanktonu oraz odchody zooplanktonu. Wśród ubytków detrytusu wyróżnić można natomiast sedymentację, wyżeranie przez zooplankton oraz rozkład biochemiczny. Przedstawione badania opisują oddziaływanie temperatury, stężenia związków biogenicznych, nasłonecznienia oraz biomasy fito- i zooplanktonu na stężenie detrytusu pelagicznego w wodzie morskiej. Parametryzacja przeprowadzona została w typowych dla południowego rejonu Morza Bałtyckiego zakresach zmiennych. Detrytus pelagiczny razem z fito- i zooplanktonem są komponentami niezbędnymi do opisania zmienności stężeń zawieszonego węgla organicznego (POC) będącego istotnym składnikiem obiegu węgla w środowisku morskim. Prawidłowa parametryzacja PDM stanowi zatem podstawę dla numerycznego opisu aktualnej i przyszłej zmienności stężeń POC w wodzie Morza Bałtyckiego

Quest for new immunosuppressive drugs

Transplantology is getting more and more important in medicine. Development of surgical techniques and immunosuppressive treatment enabled to establish successful transplantations with various organs and tissues. However, allografts are recognized as foreign tissues and stimulate rejection, i.e. a strong immunological response which, if not stopped, results in complete destruction of the transplanted tissue. In order to prevent the rejection patients have to be treated with immunosuppressive drugs after transplantation. Unfortunately, such a damping of immune system poses a risk of cancer or severe infections. The treatment itself is also toxic, notably when applied in a long-term maintenance therapy. Currently, adverse effects of immunosuppressive drugs are recognized as the ones to be involved significantly in chronic rejection and limitation of long survival of grafted tissues. Whereas prevention of acute rejection is mostly successful, there is still no efficient treatment for chronic graft rejection. Reduction of a dose of immunosuppressive drugs or an invention of new active substances is considered the most promising solution. Nowadays, immunosuppressive drugs can be divided into the three main groups: agents which inhibit production of cytokines taking part in cells’ activation (glicocorticosteroids, calcineurine inhibitors, mTOR inhibitors), antiproliferative compounds (azathiopirin, mycophenolate mofetil, mycophenolic acid sodium salt), and antibodies. In this article we present new investigations towards immunosuppressive drugs, their structures and synthetic methods

Palate dimensions in six-year-old children with unilateral cleft lip and palate: A six-center study on dental casts

Objective To compare palatal dimensions in 6-year-old children with unilateral cleft lip and palate (UCLP) treated by different protocols with those of noncleft children. Design Retrospective intercenter outcome study. Patients Upper dental casts from 129 children with repaired UCLP and 30 controls were analyzed by the trigonometric method. Setting Six European cleft centers. Main outcome measures Sagittal, transverse, and vertical dimensions of the palate were observed. Statistics Palate variables were analyzed with descriptive methods and nonparametric tests. Regarding several various characteristics measured on a relatively small number of subjects, hierarchical, k-means clustering, and principal component analyses were used. Results Mean values of the observed dimensions for five cleft groups differed significantly from the control (p &lt; .05). The group with one-stage closure of the cleft differed significantly from all other cleft groups in most variables (p &lt; .05). Principal component analysis of all 159 cases identified three clusters with specific morphologic characteristics of the palate. A similar number of treated children were classified into each cluster, while all children without clefts were classified in the same cluster. The percentage of treated children from a particular group that fit this cluster ranged from 0% to 70% and increased with age at palatal closure and number of primary surgical procedures. Conclusion At 6 years of age, children with stepwise repair and hard palate closure after the age of two more frequently result in palatal dimensions of noncleft control than children with earlier palatal closure and one-stage cleft repair. </jats:sec