Publications

2021
Mark Feldman, Ronit Vogt Sionov, Raphael Mechoulam, and Doron Steinberg. 2021. “Anti-biofilm activity of cannabidiol against candida albicans.” Microorganisms, 9, 2, Pp. 1–17. Abstract
Candida albicans is a common fungal pathogen in humans. Biofilm formation is an important virulence factor of C. albicans infections. We investigated the ability of the plant-derived cannabidiol (CBD) to inhibit the formation and removal of fungal biofilms. Further, we evaluated its mode of action. Our findings demonstrate that CBD exerts pronounced time-dependent inhibitory effects on biofilm formation as well as disruption of mature biofilm at a concentration range below minimal inhibitory and fungicidal concentrations. CBD acts at several levels. It modifies the architecture of fungal biofilm by reducing its thickness and exopolysaccharide (EPS) production accompanied by downregulation of genes involved in EPS synthesis. It alters the fungal morphology that cor-related with upregulation of yeast-associated genes and downregulation of hyphae-specific genes. Importantly, it represses the expression of C. albicans virulence-associated genes. In addition, CBD increases ROS production, reduces the intracellular ATP levels, induces mitochondrial membrane hyperpolarization, modifies the cell wall, and increases the plasma membrane permeability. In conclusion, we propose that CBD exerts its activity towards C. albicans biofilm through a multi-target mode of action, which differs from common antimycotic agents, and thus can be explored for further development as an alternative treatment against fungal infections.
Muna Aqawi, Ronit Vogt Sionov, Ruth Gallily, Michael Friedman, and Doron Steinberg. 2021. “Anti-Biofilm Activity of Cannabigerol against Streptococcus mutans.” Microorganisms, 9, 10. Abstract
Streptococcus mutans is a common cariogenic bacterium in the oral cavity involved in plaque formation. Previous studies showed that Cannabigerol (CBG) has bacteriostatic and bacteriocidic activity against S. mutans. The aim of the present study was to study its effect on S. mutans biofilm formation and dispersion. S. mutans was cultivated in the presence of CBG, and the resulting biofilms were examined by CV staining, MTT assay, qPCR, biofilm tracer, optical profilometry, and SEM. Gene expression was determined by real-time qPCR, extracellular polysaccharide (EPS) production was determined by Congo Red, and reactive oxygen species (ROS) were determined using DCFH-DA. CBG prevented the biofilm formation of S. mutans shown by reduced biofilm biomass, decreased biofilm thickness, less EPS production, reduced DNA content, diminished metabolic activity, and increased ROS levels. CBG altered the biofilm roughness profile, resulting in a smoother biofilm surface. When treating preformed biofilms, CBG reduced the metabolic activity of S. mutans with a transient effect on the biomass. CBG reduced the expression of various genes involved in essential metabolic pathways related to the cariogenic properties of S. mutans biofilms. Our data show that CBG has anti-biofilm activities against S. mutans and might be a potential drug for preventive treatment of dental caries.
Bruria Hirsh Raccah, Bar Biton, Offer Amir, Israel Gotsman, Dean Nahman, and Ilan Matok. 2021. “Anti-Remodeling Cardiac Therapy in Patients With Duchenne Muscular Dystrophy, Meta-Analysis Study.” Frontiers in pharmacology, 12, Pp. 769896. Abstract
{Background: Almost all Duchenne muscular dystrophy (DMD) patients that reach their 30s present cardiomyopathy. As a result, this population remains under-treated. There is no sufficient proof of the efficacy of anti-remodeling cardiac therapy for DMD cardiomyopathy (DMDCM). We aim to assess the efficacy of anti-remodeling cardiac therapy for DMDCM by using meta-analysis. Methods: PubMed (MEDLINE), Embase, and Cochrane library were searched through January 2021. Randomized control trials, case-control studies, and observational studies that reported assessments of cardiovascular outcomes and death of participants using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid-receptor antagonists and Ivabradine, were included. The primary outcome was total mortality. Secondary outcomes included changes in left ventricular ejection fraction (LVEF), serum natriuretic peptide levels (BNP), and heart rate (HR). Data were extracted for eligibility by two independent reviewers. Random-effects meta-analysis was used to pool results. Results: Twelve studies with 439 patients were included in our meta-analysis. Treated patients have lower HR, mean difference of -17 beats per minute (CI [-25]-[-9], p < 0.01). The LVEF was improved in treated patients, with a mean difference of LVEF of 3.77% (CI 0.44-7.12, p < 0.03). Although mortality rates did not reach statistical significance there was a trend for total mortality reduction (hazard ratio 0.36, CI (0.1-1.25)
Nino Tetro, Sonia Moushaev, Miri Shmuel, and Sara Eyal. 2021. “Antiseizure medications and fetal nutrients: Effects on choline transporters in a human placental cell line.” Epilepsia, 62, 6, Pp. 1451–1459. Abstract
Objective: Many nutrients essential to the fetus and for proper function of the placenta itself cannot freely diffuse across membrane barriers, and their transplacental transfer depends on transporters. Our previous studies provided evidence for altered expression of transporters for folic acid in trophoblasts exposed to antiseizure medications (ASMs). The goal of the current study was to explore the effects of older and newer ASMs on the expression and function of uptake transporters for choline, which interacts with folate at pathways for methyl group donation. Methods: BeWo cells were incubated for 2 or 5 days with valproate (42, 83, or 166 µg/ml), carbamazepine (6 or 12 µg/ml), levetiracetam (10 or 30 µg/ml), lamotrigine (3 or 12 µg/ml), lacosamide (5, 10, or 20 µg/ml), or their vehicles (n = 6/treatment group). Quantitative polymerase chain reaction (PCR) analysis was utilized to study the effects of ASMs on the transcript levels of the choline transporters SLC44A1 (CTL1) and SLC44A2 (CTL2). Transporter protein expression in valproate-treated cells was assessed by western blot analysis. Choline and acetylcholine were quantified in cell lysates by a choline/acetylcholine assay kit. Results: Compared with controls, valproate and levetiracetam at high therapeutic concentrations (83 and 30 µg/ml, respectively) lowered choline transporter transcript levels by up to 42% and 26%, and total choline levels by 20% and 21%, respectively (p <.05). At 83 $μ$g/ml, valproate additionally reduced CTL1 and CTL2 protein expression, by 39 ± 21% and 61 ± 13% (mean ± SD), respectively (p <.01). Carbamazepine reduced SLC44A1 transcript levels, whereas lacosamide modestly decreased the expression of SLC44A2. Lamotrigine did not alter choline transporter expression. Significance: Antiseizure medications, particularly at high therapeutic concentrations, can interfere with the placental uptake of choline. In line with current knowledge from pregnancy registries and clinical studies, the present in vitro findings further support careful adjustment of maternal ASM doses during pregnancy.
Noam Y. Steinman, Tan Hu, Aviv Dombrovsky, Meital Reches, and Abraham J. Domb. 2021. “Antiviral Polymers Based on N -Halamine Polyurea.” Biomacromolecules, Pp. acs.biomac.1c00920. Publisher's Version
Alexander Botvinnik, Pushkar Shivam, Yoav Smith, Gunjan Sharma, Udy Olshevsky, Ofra Moshel, Zakhariya Manevitch, Nuria Climent, Harold Oliva, Elena Britan-Rosich, and Moshe Kotler. 2021. “APOBEC3G rescues cells from the deleterious effects of DNA damage.” FEBS Journal. Abstract
Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (hA3G), a member of the APOBEC family, was described as an anti-HIV-1 restriction factor, deaminating reverse transcripts of the HIV-1 genome. Several types of cancer cells that express high levels of A3G, such as diffuse large B-cell lymphoma cells and glioblastomas, show enhanced cell survival after ionizing radiation and chemotherapy treatments. Previously, we showed that hA3G promotes (DNA) double-strand breaks repair in cultured cells and rescues transgenic mice from a lethal dose of ionizing radiation. Here, we show that A3G rescues cells from the detrimental effects of DNA damage induced by ultraviolet irradiation and by combined bromodeoxyuridine and ultraviolet treatments. The combined treatments stimulate the synthesis of cellular proteins, which are exclusively associated with A3G expression. These proteins participate mainly in nucleotide excision repair and homologous recombination DNA repair pathways. Our results implicate A3G inhibition as a potential strategy for increasing tumor cell sensitivity to genotoxic treatments.
Claudia Schmidt, Tomer Babu, Hana Kostrhunova, Annika Timm, Uttara Basu, Ingo Ott, Valentina Gandin, Viktor Brabec, and Dan Gibson. 2021. “Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?” Journal of Medicinal Chemistry, 64, 15, Pp. 11364–11378. Abstract
"Multi-action"Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH3)2(PhB)(CA4)Cl2] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.
Young-Mo Kim, Faridah Abas, Yong-Seo Park, Yang-Kyun Park, Kyung-Sik Ham, Seong-Gook Kang, Martyna Lubinska-Szczygeł, Aviva Ezra, and Shela Gorinstein. 2021. “Bioactivities of Phenolic Compounds from Kiwifruit and Persimmon.” Molecules (Basel, Switzerland), 26, 15. Abstract
Fruit used in the common human diet in general, and kiwifruit and persimmon particularly, displays health properties in the prevention of heart disease. This study describes a combination of bioactivity, multivariate data analyses and fluorescence measurements for the differentiating of kiwifruit and persimmon, their quenching and antioxidant properties. The metabolic differences are shown, as well in the results of bioactivities and antioxidant capacities determined by ABTS, FRAP, CUPRAC and DPPH assays. To complement the bioactivity of these fruits, the quenching properties between extracted polyphenols and human serum proteins were determined by 3D-fluorescence spectroscopy studies. These properties of the extracted polyphenols in interaction with the main serum proteins in the human metabolism (human serum albumin (HSA), $\alpha$-$\beta$-globulin ($\alpha$-$\beta$ G) and fibrinogen (Fgn)), showed that kiwifruit was more reactive than persimmon. There was a direct correlation between the quenching properties of the polyphenols of the investigated fruits with serum human proteins, their relative quantification and bioactivity. The results of metabolites and fluorescence quenching show that these fruits possess multiple properties that have a great potential to be used in industry with emphasis on the formulation of functional foods and in the pharmaceutical industry. Based on the quenching properties of human serum proteins with polyphenols and recent reports in vivo on human studies, we hypothesize that HSA, $\alpha$-$\beta$ G and Fgn will be predictors of coronary artery disease (CAD).
Nikhil Biswas, Aiman Abu Ammar, Marina Frušić-Zlotkin, Naama Adi-Hen, Yonat Lehman-Katabi, Yael Levi-Kalisman, Taher Nassar, and Simon Benita. 2021. “Biodistribution and efficacy of the anticancer drug, oxaliplatin palmitate acetate, in mice.” International Journal of Pharmaceutics, 604. Abstract
Oxaliplatin palmitate acetate (OPA), a platinum (IV) oxaliplatin derivative, was previously designed with the aim to improve the platinum-based anti-cancer therapy. In this work, we further explore the potential of OPA in extensive in vitro and in vivo studies. OPA in pancreatic (BxPC3-luc), lung (NCI-H1993) and liver (Hep3B) cancer cell lines showed a higher toxicity in comparison to oxaliplatin. The in vitro release kinetic experiments of OPA from the nanoparticles (NPs) under sink conditions exhibited a very rapid profile. Furthermore, OPA cannot be considered a prodrug of oxaliplatin, based on the OPA intact molecule pharmacokinetic profile study in rats. The formation of oxaliplatin from the biodegradation of OPA ranges only from 5% to 7% and both drugs were rapidly eliminated from the plasma. Pharmacokinetics of OPA PLGA nanoparticles in mice showed that nanoparticles failed to prolong the release of OPA in the plasma and did not add any therapeutic benefit over OPA solution, as suggested by the rapid in vitro release of OPA from nanoparticles. In pancreatic xenograft BxPC3-luc cancer model, both OPA in solution and OPA nanoparticles inhibited the tumor growth, equally and significantly, as compared to oxaliplatin. In liver xenograft Hep3B cancer model, OPA solution and cisplatin demonstrated good and similar antitumor efficacy. In lung xenograft NCI-H1993 cancer model, OPA solution, with a significant antitumor efficacy, was superior to cisplatin, which did not differ from the vehicle. In conclusion, OPA may offer a promising advance in platinum-based chemotherapy against various forms of cancers in an adequate dose and schedule.
Nikhil Biswas, Aiman Abu Ammar, Marina Frušić-Zlotkin, Naama Adi-Hen, Yonat Lehman-Katabi, Yael Levi-Kalisman, Taher Nassar, and Simon Benita. 2021. “Biodistribution and efficacy of the anticancer drug, oxaliplatin palmitate acetate, in mice.” International journal of pharmaceutics, 604, Pp. 120740. Abstract
Oxaliplatin palmitate acetate (OPA), a platinum (IV) oxaliplatin derivative, was previously designed with the aim to improve the platinum-based anti-cancer therapy. In this work, we further explore the potential of OPA in extensive in vitro and in vivo studies. OPA in pancreatic (BxPC3-luc), lung (NCI-H1993) and liver (Hep3B) cancer cell lines showed a higher toxicity in comparison to oxaliplatin. The in vitro release kinetic experiments of OPA from the nanoparticles (NPs) under sink conditions exhibited a very rapid profile. Furthermore, OPA cannot be considered a prodrug of oxaliplatin, based on the OPA intact molecule pharmacokinetic profile study in rats. The formation of oxaliplatin from the biodegradation of OPA ranges only from 5% to 7% and both drugs were rapidly eliminated from the plasma. Pharmacokinetics of OPA PLGA nanoparticles in mice showed that nanoparticles failed to prolong the release of OPA in the plasma and did not add any therapeutic benefit over OPA solution, as suggested by the rapid in vitro release of OPA from nanoparticles. In pancreatic xenograft BxPC3-luc cancer model, both OPA in solution and OPA nanoparticles inhibited the tumor growth, equally and significantly, as compared to oxaliplatin. In liver xenograft Hep3B cancer model, OPA solution and cisplatin demonstrated good and similar antitumor efficacy. In lung xenograft NCI-H1993 cancer model, OPA solution, with a significant antitumor efficacy, was superior to cisplatin, which did not differ from the vehicle. In conclusion, OPA may offer a promising advance in platinum-based chemotherapy against various forms of cancers in an adequate dose and schedule.
Reem Odi, Valentina Franco, Emilio Perucca, and Meir Bialer. 2021. “Bioequivalence and switchability of generic antiseizure medications (ASMs): A re-appraisal based on analysis of generic ASM products approved in Europe.” Epilepsia, 62, 2, Pp. 285–302. Abstract
The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%–111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.
Yoel Goldstein, Sarah Spitz, Keren Turjeman, Florian Selinger, Yechezkel Barenholz, Peter Ertl, Ofra Benny, and Danny Bavli. 2021. “Breaking the Third Wall: Implementing 3D-Printing Technics to Expand the Complexity and Abilities of Multi-Organ-on-a-Chip Devices.” Micromachines, 12, 6. Abstract
The understanding that systemic context and tissue crosstalk are essential keys for bridging the gap between in vitro models and in vivo conditions led to a growing effort in the last decade to develop advanced multi-organ-on-a-chip devices. However, many of the proposed devices have failed to implement the means to allow for conditions tailored to each organ individually, a crucial aspect in cell functionality. Here, we present two 3D-print-based fabrication methods for a generic multi-organ-on-a-chip device: One with a PDMS microfluidic core unit and one based on 3D-printed units. The device was designed for culturing different tissues in separate compartments by integrating individual pairs of inlets and outlets, thus enabling tissue-specific perfusion rates that facilitate the generation of individual tissue-adapted perfusion profiles. The device allowed tissue crosstalk using microchannel configuration and permeable membranes used as barriers between individual cell culture compartments. Computational fluid dynamics (CFD) simulation confirmed the capability to generate significant differences in shear stress between the two individual culture compartments, each with a selective shear force. In addition, we provide preliminary findings that indicate the feasibility for biological compatibility for cell culture and long-term incubation in 3D-printed wells. Finally, we offer a cost-effective, accessible protocol enabling the design and fabrication of advanced multi-organ-on-a-chip devices.
Yoel Goldstein, Sarah Spitz, Keren Turjeman, Florian Selinger, Yechezkel Barenholz, Peter Ertl, Ofra Benny, and Danny Bavli. 2021. “Breaking the third wall: Implementing 3d-printing technics to expand the complexity and abilities of multi-organ-on-a-chip devices.” Micromachines, 12, 6. Abstract
The understanding that systemic context and tissue crosstalk are essential keys for bridg-ing the gap between in vitro models and in vivo conditions led to a growing effort in the last decade to develop advanced multi-organ-on-a-chip devices. However, many of the proposed devices have failed to implement the means to allow for conditions tailored to each organ individually, a crucial aspect in cell functionality. Here, we present two 3D-print-based fabrication methods for a generic multi-organ-on-a-chip device: One with a PDMS microfluidic core unit and one based on 3D-printed units. The device was designed for culturing different tissues in separate compartments by integrating individual pairs of inlets and outlets, thus enabling tissue-specific perfusion rates that facilitate the generation of individual tissue-adapted perfusion profiles. The device allowed tissue crosstalk using microchannel configuration and permeable membranes used as barriers between individual cell culture compartments. Computational fluid dynamics (CFD) simulation confirmed the capability to generate significant differences in shear stress between the two individual culture compartments, each with a selective shear force. In addition, we provide preliminary findings that indicate the feasibility for biological compatibility for cell culture and long-term incubation in 3D-printed wells. Finally, we offer a cost-effective, accessible protocol enabling the design and fabrication of advanced multi-organ-on-a-chip devices.
Valentina Franco, Meir Bialer, and Emilio Perucca. 2021. “Cannabidiol in the treatment of epilepsy: Current evidence and perspectives for further research.” Neuropharmacology, 185, Pp. 108442. Abstract
The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on 'Cannabinoids'.
Bruno V.S. Valiate, Celso M. Queiroz-Junior, Francesca Levi-Schaffer, Izabela Galvão, and Mauro M. Teixeira. 2021. “CD300a contributes to the resolution of articular inflammation triggered by MSU crystals by controlling neutrophil apoptosis.” Immunology. Abstract
Gout is an inflammatory disease triggered by deposition of monosodium urate (MSU) crystals in the joints, resulting in high neutrophil influx and pain. Here, we studied the role of the inhibitory receptor CD300a in the resolution process in a murine model of gout. We found increased CD300a expression on neutrophils emigrated to the joint. When compared to WT mice, CD300a−/− mice had persistent neutrophil influx till 24 hr after MSU injection. This was associated with increased concentration of IL-1$\beta$ and greater tissue damage in the joints of CD300a−/− mice. There was an increase in the percentage of apoptotic neutrophils in the synovial lavage of WT mice, as compared to CD300a−/− mice. This difference was reflected in the decline of efferocytic events in the synovial cavity of CD300a−/− mice 24 hr after MSU injection. A CD300a agonistic antibody was shown, for the first time, to increase apoptosis of human neutrophils, and this was associated with cleavage of caspase-8. In conclusion, our results reveal an important role of CD300a in the control of leucocyte infiltration, IL-1$\beta$ production and caspase-8 cleavage in neutrophils, contributing to the resolution of inflammation triggered by MSU injection.
Yara Zoabi, Fidan Rahimli Alekberli, Yael Minai-Fleminger, Ron Eliashar, and Francesca Levi-Schaffer. 2021. “CD48 Expression on Eosinophils in Nasal Polyps of Chronic Rhinosinusitis Patients.” International archives of allergy and immunology, Pp. 1–9. Abstract
INTRODUCTION: The pathogenesis of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNPs) is not yet completely understood. Based on current knowledge, the infiltration of mast cells and eosinophils in nasal polyps (NPs) plays an important role. This study aimed to investigate the interplay of asthma and allergy etiopathology in CRSwNPs patients by specifically studying tissue mast cells and eosinophils and the pro-inflammatory marker CD48. METHODS: Immunohistochemistry was used to assess eosinophils, mast cells, and CD48 expressing eosinophils infiltrating NPs, and flow cytometry was used to assess surface receptors expression on eosinophils from digested NPs. RESULTS: Immunohistochemical analyses showed that mast cell infiltration in NPs is higher in allergic patients in comparison to nonallergic patients; eosinophils infiltration in asthmatic NPs was significantly elevated in comparison to the nonasthmatic NPs, and membrane CD48 (mCD48) expression on eosinophils infiltrating nonallergic asthmatic NPs was highly elevated in comparison to the other subgroups. Similarly, mCD48 and its high-affinity ligand m2B4's expression on eosinophils from enzymatically digested NPs were significantly higher in nonallergic asthmatics in comparison to allergic asthmatics. CONCLUSIONS: Eosinophil infiltration in NPs for asthmatic patients, and mast cell infiltration for allergic patients, may be used as reliable biomarkers for endotyping CRSwNPs. In addition, CD48 in asthmatic patients who developed CRSwNPs could be regarded as a potential target for treatment.
Victoria Rotshild, Bruria Hirsh-Raccah, Ian Miskin, Mordechai Muszkat, and Ilan Matok. 2021. “Comparing the clinical efficacy of COVID-19 vaccines: a systematic review and network meta-analysis.” Scientific reports, 11, 1, Pp. 22777. Abstract
New Coronavirus Disease 2019 (COVID-19) vaccines are available to prevent the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We compared the efficacy of new COVID-19 vaccines to prevent symptomatic and severe disease in the adult population and to prevent symptomatic COVID-19 among the elderly. Leading medical databases were searched until August 30, 2021. Published phase 3 randomized controlled trials (RCTs) evaluated efficacy of the vaccine to prevent symptomatic and sever COVID-19 in adults were included. Two reviewers independently evaluated the literature search results and independently extracted summary data. The risk of bias was evaluated using the Cochrane Risk of Bias Assessment Tool. We performed a network meta-analysis (NMA) according to PRISMA-NMA 2015 to pool indirect comparisons between different vaccines regarding their relative efficacy. The primary outcomes were the efficacy of the vaccine against symptomatic COVID-19 in adults (PROSPERO registration number: CRD42021235364). Above 200,000 adult participants from eight phase 3 RCTs were included in NMA, of whom 52% received the intervention (active COVID-19 vaccine). While each of nine vaccines was tested in the unique clinical trial as compared to control, based on indirect comparison, BNT162b2 and mRNA-1273 vaccines were ranked with the highest probability of efficacy against symptomatic COVID-19 (P-scores 0.952 and 0.843, respectively), followed by Gam-COVID-Vac (P-score 0.782), NVX-CoV23730 (P-score 0.700), CoronaVac (P-score 0.570), BN02 (P-score 0.428), WIV04 (P-score 0.327), and Ad26.COV2.S (P-score 0.198). No statistically significant difference was seen in the ability of the vaccines to prevent symptomatic disease in the elderly population. No vaccine was statistically significantly associated with a decreased risk for severe COVID-19 than other vaccines, although mRNA-1273 and Gam-COVID-Vac have the highest P-scores (0.899 and 0.816, respectively), indicating greater protection against severe disease than other vaccines. In our indirect comparison, the BNT162b2 and mRNA-1273 vaccines, which use mRNA technology, were associated with the highest efficacy to prevent symptomatic COVID-19 compared to other vaccines. This finding may have importance when deciding which vaccine to use, together with other important factors as availability of the vaccines, costs, logistics, side effects, and patient acceptability.
Michal Weitman, Corina Bejar, Michal Melamed, Tehilla Weill, Inessa Yanovsky, Shani Zeeli, Abraham Nudelman, and Marta Weinstock. 2021. “Comparison of the tissue distribution and metabolism of AN1284, a potent anti-inflammatory agent, after subcutaneous and oral administration in mice.” Naunyn-Schmiedeberg's Archives of Pharmacology. Abstract
This study is to compare the tissue distribution and metabolism of AN1284 after subcutaneous and oral administration at doses causing maximal reductions in IL-6 in plasma and tissues of mice. Anti-inflammatory activity of AN1284 and its metabolites was detected in lipopolysaccharide (LPS) activated RAW 264.7 macrophages. Mice were given AN1284 by injection or gavage, 15 min before LPS. IL-6 protein levels were measured after 4 h. Using a liquid chromatography/mass spectrometry method we developed, we showed that AN1284 is rapidly metabolized to the indole (AN1422), a 7-OH derivative (AN1280) and its glucuronide. AN1422 has weaker anti-inflammatory activity than AN1284 in LPS-activated macrophages and in mice. AN1284 (0.5 mg/kg) caused maximal reductions in IL-6 in the plasma, brain, and liver when injected subcutaneously and after gavage only in the liver. Similar reductions in the plasma and brain required a dose of 2.5 mg/kg, which resulted in 5.5-fold higher hepatic levels than after injection of 0.5 mg/kg, but 7, 11, and 19-fold lower ones in the plasma, brain, and kidneys, respectively. Hepatic concentrations produced by AN1284 were 2.5 mg/kg/day given by subcutaneously implanted mini-pumps that were only 12% of the peak levels seen after acute injection of 0.5 mg/kg. Similar hepatic concentrations were obtained by (1 mg/kg/day), administered in the drinking fluid. These were sufficient to decrease hepatocellular damage and liver triglycerides in previous experiments in diabetic mice. AN1284 can be given orally by a method of continuous release to treat chronic liver disease, and its preferential concentration in the liver should limit any adverse effects.
Lior Minkowicz, Arie Dagan, Vladimir Uvarov, and Ofra Benny. 2021. “Controlling Calcium Carbonate Particle Morphology, Size, and Molecular Order Using Silicate.” Materials (Basel, Switzerland), 14, 13. Abstract
Calcium carbonate (CaCO(3)) is one of the most abundant substances on earth and has a large array of industrial applications. Considerable research has been conducted in an effort to synthesize calcium carbonate microparticles with controllable and specific morphologies and sizes. CaCO(3) produced by a precipitation reaction of calcium nitrate and sodium carbonate solution was found to have high polymorphism and batch to batch variability. In this study, we investigated the polymorphism of the precipitated material and analyzed the chemical composition, particle morphology, and crystalline state revealing that the presence of silicon atoms in the precipitant is a key factor effecting particle shape and crystal state. An elemental analysis of single particles within a polymorphic sample, using energy-dispersive X-ray spectroscopy (EDS) conjugated microscopy, showed that only spherical particles, but not irregular shaped one, contained traces of silicon atoms. In agreement, silicon-containing additives lead to homogenous, amorphous nanosphere particles, verified by X-ray powder diffraction (XRD). Our findings provide important insights into the mechanism of calcium carbonate synthesis, as well as introducing a method to control the precipitants at the micro-scale for many diverse applications.
Lior Minkowicz, Arie Dagan, Vladimir Uvarov, and Ofra Benny. 2021. “Controlling calcium carbonate particle morphology, size, and molecular order using silicate.” Materials, 14, 13. Abstract
Calcium carbonate (CaCO3) is one of the most abundant substances on earth and has a large array of industrial applications. Considerable research has been conducted in an effort to synthesize calcium carbonate microparticles with controllable and specific morphologies and sizes. CaCO3 produced by a precipitation reaction of calcium nitrate and sodium carbonate solution was found to have high polymorphism and batch to batch variability. In this study, we investigated the polymorphism of the precipitated material and analyzed the chemical composition, particle morphology, and crystalline state revealing that the presence of silicon atoms in the precipitant is a key factor effecting particle shape and crystal state. An elemental analysis of single particles within a polymorphic sample, using energy‐dispersive X‐ray spectroscopy (EDS) conjugated microscopy, showed that only spherical particles, but not irregular shaped one, contained traces of silicon atoms. In agreement, silicon‐containing additives lead to homogenous, amorphous nanosphere particles, verified by X‐ray powder diffraction (XRD). Our findings provide important insights into the mechanism of calcium carbonate synthesis, as well as introducing a method to control the precipitants at the micro‐scale for many diverse applications.