«More Does Not Mean Better» - An Approach to the Toxicological Risk Assessment of Heavy Metals Lead and Cadmium and Herbicides Linuron, Fluazifop-P-Butyl, and Cycloxydim in Dry True Chamomile (Chamomilla recutita L. Rauschert)

Kadmij i rezidua navedenih triju herbicida u osušenom cvijetu industrijski uzgojene kamilice bili su povišeni iznad preporučenih podnošljivih vrijednosti. Rezultati su razmotreni s obzirom na postojeću zakonsku regulativu o herbicidima u Republici Hrvatskoj i postojećim preporukama FAO/WHO te na procjenu pojedinačnog i zbirnog toksikološkog rizika u ljudi. Kritički je razmotrena i odbačena uobičajena poljodjelska praksa pretjerane uporabe herbicida. Preporuča se prospektivna primjena biljaka kao prirodnih indikatora onečišćenja čovjekova okoliša te za procjenu toksikološkog opterećenja u čovjekovu prehrambenom lancu.Cadmium and all three enumerated herbicide residues in dried samples of industrially grown true chamomile were found to be above the suggested and accepted tolerance values. The results are discussed with regard to the current Croatian regulation and FAO/WHO recommendations on herbicides and to human toxicology risk assessment. The paper gives a critical evaluation of the herbicide overuse in agricultural practice and strongly discouraged such practice. The authors advocate prospective use of plants as natural indicators of environmental contamination and toxicological burden of the human food chain

Th2-TRMs Maintain Life-Long Allergic Memory in Experimental Asthma in Mice

Allergic asthma is a chronic inflammatory remitting-relapsing disease affecting the airways. Long-lived allergen-specific memory CD4+ T helper 2 (Th2) cells in mice persist in lungs for more than 2 years after the induction of experimental allergic asthma (EAA). To further understand lung Th2 memory cells, we tracked CD4+ T cells in spleen and lungs from healthy mice, through the initiation of acute EAA, recovery (remission), and allergen-induced disease relapse. We identified a lung CD3+CD4+ cell subset that expresses CD44hiCD62L−CD69+ST2+, produces Th2 cytokines, and mediates allergen-induced disease relapse despite treatment with FTY720 and anti-CD4 antibody. These cells reside in the lung tissue for the lifetime of mice (>665 days) and represent long-lived pathogenic Th2 tissue resident memory cells (TRMs) that maintain “allergic memory” in lung. We speculate that these data implicate that human Th2-TRMs sentinels in lungs of patients are poised to rapidly respond to inhaled allergen and induce asthma attacks and that therapeutic approaches targeting these cells may provide relief to patients with allergic asthma

Synthesis and Anti-inflammatory Activity of Novel Furochromenes

A series of variously substituted furochromenes, hemiacetals 2, acetals 3, and rearranged compounds 4, were synthesized from variously substituted 4-hydroxycoumarins and evaluated in several in vitro assays, inhibition of mast cell degranulation induced by the activation of Fcε receptor type I or calci-um ionophore and leukotriene B4 (LTB4) inhibition. The most active derivatives, 3p and 4p (8-iso-propyl substitution in coumarin ring) and 3r (5-methyl-8-chloro substitution), showed significant inhibition of mast cell degranulation (Fctriggered) and LTB4, and exhibited significant local anti-inflammatory activity in PMA induced ear edema in CD1 mice, with potency equal (compounds 3p and 4p) or better (compound 3r) in comparison with zileuton, a reference drug used. It might be a promising direction for developing novel drugs as potential agents for the treatment of allergies and other inflammatory diseases.(doi: 10.5562/cca2240

CRISPR/Cas9 Immunoengineering of Hoxb8-Immortalized Progenitor Cells for Revealing CCR7-Mediated Dendritic Cell Signaling and Migration Mechanisms in vivo

To present antigens to cognate T cells, dendritic cells (DCs) exploit the chemokine receptor CCR7 to travel from peripheral tissue via afferent lymphatic vessels to directly enter draining lymph nodes through the floor of the subcapsular sinus. Here, we combined unlimited proliferative capacity of conditionally Hoxb8-immortalized hematopoietic progenitor cells with CRISPR/Cas9 technology to create a powerful experimental system to investigate DC migration and function. Hematopoietic progenitor cells from the bone marrow of Cas9-transgenic mice were conditionally immortalized by lentiviral transduction introducing a doxycycline-regulated form of the transcription factor Hoxb8 (Cas9-Hoxb8 cells). These cells could be stably cultured for weeks in the presence of doxycycline and puromycin, allowing us to introduce additional genetic modifications applying CRISPR/Cas9 technology. Importantly, modified Cas9-Hoxb8 cells retained their potential to differentiate in vitro into myeloid cells, and GM-CSF-differentiated Cas9-Hoxb8 cells showed the classical phenotype of GM-CSF-differentiated bone marrow-derived dendritic cells. Following intralymphatic delivery Cas9-Hoxb8 DCs entered the lymph node in a CCR7-dependent manner. Finally, we used two-photon microscopy and imaged Cas9-Hoxb8 DCs that expressed the genetic Ca2+ sensor GCaMP6S to visualize in real-time chemokine-induced Ca2+ signaling of lymph-derived DCs entering the LN parenchyma. Altogether, our study not only allows mechanistic insights in DC migration in vivo, but also provides a platform for the immunoengineering of DCs that, in combination with two-photon imaging, can be exploited to further dissect DC dynamics in vivo

Utjecaj tvrdokorne infekcije bakterijom helicobacter pylori na izraženost bcl-2 u upalnim stanicama želučane sluznice

Chronic Helicobacter (H.) pylori infection is an etiological factor related to gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The expression of bcl-2 protein significantly decreases as the grade of MALT lymphoma advances. The aim of this study was to evaluate bcl-2 expression in inflammatory cells in lamina propria in gastric biopsy samples collected from two groups of patients with chronic gastritis divided on the basis of the success or failure of H. pylori eradication. Sixty-five patients with chronic gastritis were divided into two groups of 45 and 20 patients according to their therapeutic response. The gastric mucosa samples were analyzed histologically in both groups of patients before and after standard therapy (for eradicated, after one therapeutic cycle; and for non-eradicated, after three therapeutic cycles) for H. pylori density, urease activity and bcl-2 expression. In the eradicated group of patients, H. pylori eradication was accompanied by significantly lower grades of bacterial colonization and lower urease activity in the corpus and antrum. Bcl-2 expression in inflammatory cells showed no statistically significant changes in either patient group at either location. There was no between-group difference in bcl-2 expression either. In conclusion, persistent long-lasting H. pylori infection is associated with higher grades of bacterial colonization and higher urease activity but not with bcl-2 expression in inflammatory cells.Kronična infekcija bakterijom Helicobacter (H.) pylori je etiološki čimbenik želučanog adenokarcinoma i limfoma limfoidnog tkiva povezanog sa sluznicom (MALT limfoma). Izraženost proteina bcl-2 značajno se smanjuje s napredovanjem stupnja MALT limfoma. Cilj ove studije bio je procijeniti izraženost bcl-2 u upalnim stanicama lamine proprije u uzorcima dobivenim želučanom biopsijom u dvjema skupinama bolesnika s kroničnim gastritisom podijeljenim prema uspješnoj ili neuspješnoj eradikaciji H. pylori. Ukupno je 65 bolesnika s kroničnim gastritisom podijeljeno u dvije skupine od po 45 i 20 bolesnika prema terapijskom odgovoru. U objema skupinama su uzorci želučane sluznice analizirani histološki prije i nakon standardne terapije (kod onih s uspješnom eradikacijom nakon jednog terapijskog ciklusa, a u onih s neuspješnom eradikacijom nakon tri terapijska ciklusa) na gustoću H. pylori, aktivnost ureaze i izraženost bcl-2. Eradikacija H. pylori u skupini bolesnika s uspješnom eradikacijom bila je praćena značajno nižim stupnjem bakterijske kolonizacije i nižom aktivnošću ureaze u korpusu i antrumu. Izraženost bcl-2 nije se statistički značajno promijenila ni na jednoj lokaciji ni u jednoj skupini bolesnika. Isto tako, nije bilo nikakve razlike među dvjema skupinama bolesnika u izraženosti bcl-2. Zaključuje se kako je dugotrajna ustrajna infekcija bakterijom H. pylori povezana s višim stupnjem bakterijske kolonizacije i višom aktivnošću ureaze, ali nije povezana s izraženošću bcl-2 u upalnim stanicama

Neutralization of the SARS-CoV-2 Delta variant after heterologous and homologous BNT162b2 or ChAdOx1 nCoV-19 vaccination

Within the last decades, plant-based diets have received increasing interest for their potential benefits to human and environmental health. The concept of plant-based diet, however, varies widely in its definition. Current definitions range from the exclusion of all animal products to diets that include meat, fish, and dairy in varying quantities. Therefore, the main objectives of this review were twofold: (a) to investigate how researchers use the term plant-based diet in nutrition intervention studies and (b) what types of food a plant-based diet may include. Searching two databases, we found that the term 'plant-based diet' evokes varying ideas to researchers and clinicians. Fifty percent of the retrieved studies that included a plant-based dietary intervention completely proscribed animal products and used the term plant-based diet interchangeably with a vegan diet. In contrast, an ~33% of trials included dairy products and 20% of dietary interventions emphasized a semi-vegetarian dietary pattern. Based on specific examples, we point out how the usage of the umbrella term 'plant-based diet' may cause significant ambiguity. We often encountered incomplete descriptions of plant-based dietary interventions, which makes comparison and reproducibility of studies difficult. As a consequence, we urge others to use the term 'plant-based diet' only in conjunction with a detailed dietary description. To facilitate this process, we provide a template of a standardized plant-based intervention reporting checklist. Finally, the present review also highlights the urgent need for a consensus definition of the term plant-based diet and its content

Unprecedented Epimerization of an Azithromycin Analogue: Synthesis, Structure and Biological Activity of 2′-Dehydroxy-5″-Epi-Azithromycin

Certain macrolide antibiotics, azithromycin included, possess anti-inflammatory properties that are considered fundamental for their efficacy in the treatment of chronic inflammatory diseases, such as diffuse pan-bronchiolitis and cystic fibrosis. In this study, we disclose a novel azithromycin analog obtained via Barton–McCombie oxidation during which an unprecedented epimerization on the cladinose sugar occurs. Its structure was thoroughly investigated using NMR spectroscopy and compared to the natural epimer, revealing how the change in configuration of one single stereocenter (out of 16) profoundly diminished the antimicrobial activity through spatial manipulation of ribosome binding epitopes. At the same time, the anti-inflammatory properties of parent macrolide were retained, as demonstrated by inhibition of LPS- and cigarette-smoke-induced pulmonary inflammation. Not surprisingly, the compound has promising developable properties including good oral bioavailability and a half-life that supports once-daily dosing. This novel anti-inflammatory candidate has significant potential to fill the gap in existing anti-inflammatory agents and broaden treatment possibilities

Case Report: Convalescent Plasma Therapy Induced Anti-SARS-CoV-2 T Cell Expansion, NK Cell Maturation and Virus Clearance in a B Cell Deficient Patient After CD19 CAR T Cell Therapy.

Here, we described the case of a B cell-deficient patient after CD19 CAR-T cell therapy for refractory B cell Non-Hodgkin Lymphoma with protracted coronavirus disease 2019 (COVID-19). For weeks, this patient only inefficiently contained the virus while convalescent plasma transfusion correlated with virus clearance. Interestingly, following convalescent plasma therapy natural killer cells matured and virus-specific T cells expanded, presumably allowing virus clearance and recovery from the disease. Our findings, thus, suggest that convalescent plasma therapy can activate cellular immune responses to clear SARS-CoV-2 infections. If confirmed in larger clinical studies, these data could be of general importance for the treatment of COVID-19 patients