Sapir Ron-Doitch, Marina Frušić-Zlotkin, Yoram Soroka, Danielle Duanis-Assaf, Dalit Amar, Ron Kohen, and Doron Steinberg. 2021. “eDNA-Mediated Cutaneous Protection Against UVB Damage Conferred by Staphylococcal Epidermal Colonization.” Microorganisms, 9, 4. Abstract
The human skin is a lush microbial habitat which is occupied by a wide array of microorganisms. Among the most common inhabitants are Staphylococcus spp., namely Staphylococcus epidermidis and, in ≈20% of healthy individuals, Staphylococcus aureus. Both bacteria have been associated with cutaneous maladies, where they mostly arrange in a biofilm, thus achieving improved surface adhesion and stability. Moreover, our skin is constantly exposed to numerous oxidative environmental stressors, such as UV-irradiation. Thus, skin cells are equipped with an important antioxidant defense mechanism, the Nrf2-Keap1 pathway. In this work, we aimed to explore the morphology of S. aureus and S. epidermidis as they adhered to healthy human skin and characterize their matrix composition. Furthermore, we hypothesized that the localization of both types of bacteria on a healthy skin surface may provide protective effects against oxidative stressors, such as UV-irradiation. Our results indicate for the first time that S. aureus and S. epidermidis assume a biofilm-like morphology as they adhere to ex vivo healthy human skin and that the cultures' extracellular matrix (ECM) is composed of extracellular polysaccharides (EPS) and extracellular DNA (eDNA). Both bacterial cultures, as well as isolated S. aureus biofilm eDNA, conferred cutaneous protection against UVB-induced apoptosis. This work emphasized the importance of skin microbiota representatives in the maintenance of a healthy cutaneous redox balance by activating the skin's natural defense mechanism.
Amichai Perlman, Rachel Goldstein, Lotan Choshen Cohen, Bruria Hirsh-Raccah, David Hakimian, Ilan Matok, Yosef Kalish, Daniel E. Singer, and Mordechai Muszkat. 2021. “Effect of Enzyme-Inducing Antiseizure Medications on the Risk of Sub-Therapeutic Concentrations of Direct Oral Anticoagulants: A Retrospective Cohort Study.” CNS Drugs, 35, 3, Pp. 305–316. Abstract
Background: Stroke and thromboembolic events occurring among patients taking direct oral anticoagulants (DOACs) have been associated with low concentrations of DOACs. Enzyme-inducing antiseizure medications (EI-ASMs) are associated with enhanced cytochrome-P450-mediated metabolism and enhanced P-glycoprotein-mediated transport. Objective: The aim of this study was to evaluate the effect of concomitant EI-ASM use on DOAC peak concentrations in patients treated in clinical care. Methods: We performed a retrospective cohort study of patients treated with DOACs for atrial fibrillation and venous thromboembolic disease in an academic general hospital. In total, 307 patients treated with DOACs between August 2015 and January 2020 were reviewed. Clinical characteristics and peak DOAC plasma concentrations of patients co-treated with an EI-ASM were compared with those of patients not treated with an EI-ASM. An apixaban dose score (ADS) was defined to account for apixaban dosage and the number of apixaban dose-reduction criteria. Results: In total, 177 peak DOAC plasma concentrations (including apixaban, rivaroxaban, and dabigatran) from 131 patients were measured, including 24 patients co-treated with an EI-ASM and 107 controls not treated with an EI-ASM. The proportion of patients with DOAC concentrations below the expected range was significantly higher among EI-ASM users than among patients not taking an EI-ASM (37.5 vs. 9.3%, respectively; p = 0.0004; odds ratio 5.82; 95% confidence interval [CI] 2.03–16.66). Most of these patients were treated with apixaban (85%); however, sensitivity analysis results were also significant (p = 0.031) for patients with non-apixaban DOACs. In patients co-treated with apixaban and an EI-ASM, median apixaban peak concentration was 106 ng/mL (interquartile range [IQR] 71–181) compared with 150 ng/mL (IQR 94–222) in controls (p = 0.019). In multivariable analysis, EI-ASM use was associated with 6.26-fold increased odds for apixaban concentration below the expected range (95% CI 2.19–17.90; p = 0.001). Apixaban concentrations were significantly associated with EI-ASM use, moderate enzyme inhibitor use, and ADS. Conclusions: Concurrent EI-ASM and DOAC use presents a possible risk for DOAC concentrations below the expected range. The clinical significance of the interaction is currently unclear.
Nino Tetro, Roua Hamed, Erez Berman, and Sara Eyal. 2021. “Effects of antiseizure medications on placental cells: Focus on heterodimeric placental carriers.” Epilepsy research, 174, Pp. 106664. Abstract
OBJECTIVE: Appropriate placental nutrient transfer is essential for optimal fetal development. We have previously shown that antiseizure medications (ASMs) can alter the expression of placental carriers for folate and thyroid hormones. Here we extended our analysis to heterodimeric carriers that mediate the placental uptake of amino acids and antioxidant precursors. We focused on the L-type amino acid transporter (LAT)2/SLC7A8, the cystine/glutamate antiporter xCT/SLC7A11, and their chaperone 4F2hc/SLC3A2. METHODS: BeWo cells were exposed for two or five days to therapeutic concentrations of valproate, levetiracetam, carbamazepine, lamotrigine, or lacosamide. Transcript levels were measured by quantitative PCR. Levetiracetam effects on placental carriers were further explored using a tailored gene array. RESULTS: At five days, 30 $μ$g/mL levetiracetam (high therapeutic concentrations) significantly reduced the expression of all studied genes (p < 0.05). Carbamazepine treatment was associated with lower SLC7A8 (LAT2) expression (p < 0.05), whereas valproate increased the transcript levels of this transporter by up to 2.0-fold (p < 0.01). Some of these effects were already observed after two incubation days. Lamotrigine did not alter gene expression, and lacosamide slightly elevated SLC3A2 levels (p < 0.05). The array analysis confirmed the trends observed for levetiracetam and identified additional affected genes. SIGNIFICANCE: Altered expression of placental heterodimeric transporters may represent a mechanism by which ASM affect fetal development. The placental effects are differential, with valproate, carbamazepine and levetiracetam as the more active compounds. The concentration-dependence of those ASM effects are in line with established dose-dependent teratogenicity implying that ASM doses should be adjusted during pregnancy with caution.
Bareket Daniel, Ariela Livne, Guy Cohen, Shirin Kahremany, and Shlomo Sasson. 2021. “Endothelial Cell-Derived Triosephosphate Isomerase Attenuates Insulin Secretion from Pancreatic Beta Cells of Male Rats.” Endocrinology (United States), 162, 3. Abstract
Insulin secretion from pancreatic beta cells is tightly regulated by glucose and paracrine signals within the microenvironment of islets of Langerhans. Extracellular matrix from islet microcapillary endothelial cells (IMEC) affect beta-cell spreading and amplify insulin secretion. This study was aimed at investigating the hypothesis that contact-independent paracrine signals generated from IMEC may also modulate beta-cell insulin secretory functions. For this purpose, conditioned medium (CMp) preparations were prepared from primary cultures of rat IMEC and were used to simulate contact-independent beta cell-endothelial cell communication. Glucose-stimulated insulin secretion (GSIS) assays were then performed on freshly isolated rat islets and the INS-1E insulinoma cell line, followed by fractionation of the CMp, mass spectroscopic identification of the factor, and characterization of the mechanism of action. The IMEC-derived CMp markedly attenuated first-and second-phase GSIS in a time-and dose-dependent manner without altering cellular insulin content and cell viability. Size exclusion fractionation, chromatographic and mass-spectroscopic analyses of the CMp identified the attenuating factor as the enzyme triosephosphate isomerase (TPI). An antibody against TPI abrogated the attenuating activity of the CMp while recombinant human TPI (hTPI) attenuated GSIS from beta cells. This effect was reversed in the presence of tolbutamide in the GSIS assay. In silico docking simulation identified regions on the TPI dimer that were important for potential interactions with the extracellular epitopes of the sulfonylurea receptor in the complex. This study supports the hypothesis that an effective paracrine interaction exists between IMEC and beta cells and modulates glucose-induced insulin secretion via TPI-sulfonylurea receptor-KATP channel (SUR1-Kir6.2) complex attenuating interactions.
Yoel Goldstein, Katerina Tischenko, Yifat Brill-Karniely, and Ofra Benny. 2021. “Enhanced Biomechanically Mediated "Phagocytosis" in Detached Tumor Cells.” Biomedicines, 9, 8. Abstract
Uptake of particles by cells involves various natural mechanisms that are essential for their biological functions. The same mechanisms are used in the engulfment of synthetic colloidal drug carriers, while the extent of the uptake affects the biological performance and selectivity. Thus far, little is known regarding the effect of external biomechanical stimuli on the capacity of the cells to uptake nano and micro carriers. This is relevant for anchorage-dependent cells that have detached from surfaces or for cells that travel in the body such as tumor cells, immune cells and various circulating stem cells. In this study, we hypothesize that cellular deformability is a crucial physical effector for the successful execution of the phagocytosis-like uptake in cancer cells. To test this assumption, we develop a well-controlled tunable method to compare the uptake of inert particles by cancer cells in adherent and non-adherent conditions. We introduce a self-designed 3D-printed apparatus, which enables constant stirring while facilitating a floating environment for cell incubation. We reveal a mechanically mediated phagocytosis-like behavior in various cancer cells, that was dramatically enhance in the detached cell state. Our findings emphasize the importance of including proper biomechanical cues to reliably mimic certain physiological scenarios. Beyond that, we offer a cost-effective accessible research tool to study mixed cultures for both adherent and non-adherent cells.
Reem Odi, Roberto William Invernizzi, Tamar Gallily, Meir Bialer, and Emilio Perucca. 2021. “Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know.” Pharmacology & therapeutics, 226, Pp. 107866. Abstract
In 2020, racemic-fenfluramine was approved in the U.S. and Europe for the treatment of seizures associated with Dravet syndrome, through a restricted/controlled access program aimed at minimizing safety risks. Fenfluramine had been used extensively in the past as an appetite suppressant, but it was withdrawn from the market in 1997 when it was found to cause cardiac valvulopathy. Available evidence indicates that appetite suppression and cardiac valvulopathy are mediated by different serotonergic mechanisms. In particular, appetite suppression can be ascribed mainly to the enantiomers d-fenfluramine and d-norfenfluramine, the primary metabolite of d-fenfluramine, whereas cardiac valvulopathy can be ascribed mainly to d-norfenfluramine. Because of early observations of markedly improved seizure control in some forms of epilepsy, fenfluramine remained available in Belgium through a Royal Decree after 1997 for use in a clinical trial in patients with Dravet syndrome at average dosages lower than those generally prescribed for appetite suppression. More recently, double-blind placebo-controlled trials established its efficacy in the treatment of convulsive seizures associated with Dravet syndrome and of drop seizures associated with Lennox-Gastaut syndrome, at doses up to 0.7 mg/kg/day (maximum 26 mg/day). Although no cardiovascular toxicity has been associated with the use of fenfluramine in epilepsy, the number of patients exposed to date has been limited and only few patients had duration of exposure longer than 3 years. This article analyzes available evidence on the mechanisms involved in fenfluramine-induced appetite suppression, antiseizure effects and cardiovascular toxicity. Despite evidence that stimulation of 5-HT(2B) receptors (the main mechanism leading to cardiac valvulopathy) is not required for antiseizure activity, there are many critical gaps in understanding fenfluramine's properties which are relevant to its use in epilepsy. Particular emphasis is placed on the remarkable lack of publicly accessible information about the comparative activity of the individual enantiomers of fenfluramine and norfenfluramine in experimental models of seizures and epilepsy, and on receptors systems considered to be involved in antiseizure effects. Preliminary data suggest that l-fenfluramine retains prominent antiseizure effects in a genetic zebrafish model of Dravet syndrome. If these findings are confirmed and extended to other seizure/epilepsy models, there would be an incentive for a chiral switch from racemic-fenfluramine to l-fenfluramine, which could minimize the risk of cardiovascular toxicity and reduce the incidence of adverse effects such as loss of appetite and weight loss.
S Rakedzon, A Neuberger, AJ Domb, N Petersiel, and E Schwartz. 2021. “From hydroxychloroquine to ivermectin: what are the anti-viral properties of anti-parasitic drugs to combat SARS-CoV-2?” Journal of travel medicine, 28, 2. Abstract
BACKGROUND: Nearly a year into the COVID-19 pandemic, we still lack effective anti-SARS-CoV-2 drugs with substantial impact on mortality rates except for dexamethasone. As the search for effective antiviral agents continues, we aimed to review data on the potential of repurposing antiparasitic drugs against viruses in general, with an emphasis on coronaviruses. METHODS: We performed a review by screening in vitro and in vivo studies that assessed the antiviral activity of several antiparasitic agents: chloroquine, hydroxychloroquine (HCQ), mefloquine, artemisinins, ivermectin, nitazoxanide (NTZ), niclosamide, atovaquone and albendazole. RESULTS: For HCQ and chloroquine we found ample in vitro evidence of antiviral activity. Cohort studies that assessed the use of HCQ for COVID-19 reported conflicting results, but randomized controlled trials (RCTs) demonstrated no effect on mortality rates and no substantial clinical benefits of HCQ used either for prevention or treatment of COVID-19. We found two clinical studies of artemisinins and two studies of NTZ for treatment of viruses other than COVID-19, all of which showed mixed results. Ivermectin was evaluated in one RCT and few observational studies, demonstrating conflicting results. As the level of evidence of these data is low, the efficacy of ivermectin against COVID-19 remains to be proven. For chloroquine, HCQ, mefloquine, artemisinins, ivermectin, NTZ and niclosamide, we found in vitro studies showing some effects against a wide array of viruses. We found no relevant studies for atovaquone and albendazole. CONCLUSIONS: As the search for an effective drug active against SARS-CoV-2 continues, we argue that pre-clinical research of possible antiviral effects of compounds that could have antiviral activity should be conducted. Clinical studies should be conducted when sufficient in vitro evidence exists, and drugs should be introduced into widespread clinical use only after being rigorously tested in RCTs. Such a search may prove beneficial in this pandemic or in outbreaks yet to come.
Moriya Weitz, Alaa Khayat, and Rami Yaka. 2021. “GABAergic projections to the ventral tegmental area govern cocaine-conditioned reward.” Addiction Biology, 26, 4. Abstract
Elevated dopamine (DA) levels in the reward system underlie various drug-related behaviors, including addiction. As a major DA source in the reward system, the ventral tegmental area (VTA) is highly regulated by GABAergic inputs projected from different brain regions. It was previously shown that cocaine exposure reduces GABAA-mediated inhibitory postsynaptic currents (IPSCs) in VTA DA neurons; however, the specific GABAergic input underlying this inhibitory effect remains unknown. Here, using optogenetics, we separately activate and characterize different GABAergic afferents innervating the VTA, focusing on the rostromedial tegmental nucleus (RMTg) and the nucleus accumbens (NAc). GABAA-mediated IPSCs were recorded from VTA DA neurons, and the effect of DA-induced inhibition was measured in an afferent-specific manner. In addition, to examine the effect of enhanced GABAergic tone on the rewarding properties of cocaine, we exogenously activated the different GABAergic inputs during the acquisition phase of cocaine conditioned place preference (CPP). We found that acute cocaine exposure strongly attenuates GABAA-mediated IPSCs in VTA DA neurons from both inhibitory sources. Furthermore, exogenous light activation of both RMTg and NAc afferents in the VTA during the acquisition of cocaine-CPP significantly reduced the rewarding properties of cocaine. This behavioral observation was correlated with the reduction in the neuronal activity of VTA DA neurons as measured by the expression of c-fos. Together, these results emphasize the critical role of these GABAergic inputs to the VTA in modulating and potentially interrupting cocaine reward.
Paweł Paśko, Agnieszka Galanty, Małgorzata Tyszka-Czochara, Paweł Żmudzki, Paweł Zagrodzki, Joanna Gdula-Argasińska, Ewelina Prochownik, and Shela Gorinstein. 2021. “Health Promoting vs Anti-nutritive Aspects of Kohlrabi Sprouts, a Promising Candidate for Novel Functional Food.” Plant Foods for Human Nutrition, 76, 1, Pp. 76–82. Abstract
Kohlrabi sprouts are just gaining popularity as the new example of functional food. The study was focused on the influence of germination time and light conditions on glucosinolates, phenolic acids, flavonoids, and fatty acids content in kohlrabi sprouts, in comparison to the bulbs. The effect of kohlrabi products on SW480, HepG2 and BJ cells was also determined. The length of sprouting time and light availability significantly influenced the concentrations of the phenolic compounds. Significant differences in progoitrin concentrations were observed between the sprouts harvested in light and in the darkness, with significantly lower content for darkness conditions. Erucic acid was the dominant fatty acid found in sprouts (14.5–34.5%). Sprouts and bulbs were less toxic to normal than to cancer cells. The sprouts stimulated necrosis (56.4%) more than apoptosis (34.1%) in SW480 cells, while the latter effect was predominant for the bulbs. Both sprouts and bulbs caused rather necrosis (45.5 and 63.9%) than apoptosis (32 and 32.5%) in HepG2 cells. Graphical Abstract: [Figure not available: see fulltext.]
Raviv Dharan, Asaf Shemesh, Abigail Millgram, Ran Zalk, Gabriel A. Frank, Yael Levi-Kalisman, Israel Ringel, and Uri Raviv. 2021. “Hierarchical Assembly Pathways of Spermine-Induced Tubulin Conical-Spiral Architectures.” ACS Nano, 15, 5, Pp. 8836–8847. Abstract
Tubulin, an essential cytoskeletal protein, assembles into various morphologies by interacting with an array of cellular factors. One of these factors is the endogenous polyamine spermine, which may promote and stabilize tubulin assemblies. Nevertheless, the assembled structures and their formation pathways are poorly known. Here we show that spermine induced the in vitro assembly of tubulin into several hierarchical architectures based on a tubulin conical-spiral subunit. Using solution X-ray scattering and cryo-TEM, we found that with progressive increase of spermine concentration tubulin dimers assembled into conical-frustum-spirals of increasing length, containing up to three helical turns. The subunits with three helical turns were then assembled into tubules through base-to-top packing and formed antiparallel bundles of tubulin conical-spiral tubules in a distorted hexagonal symmetry. Further increase of the spermine concentration led to inverted tubulin tubules assembled in hexagonal bundles. Time-resolved experiments revealed that tubulin assemblies formed at higher spermine concentrations assembled from intermediates, similar to those formed at low spermine concentrations. These results are distinct from the classical transition between twisted ribbons, helical, and tubular assemblies, and provide insight into the versatile morphologies that tubulin can form. Furthermore, they may contribute to our understanding of the interactions that control the composition and construction of protein-based biomaterials.
Carmil Azran, Nirvana Hanhan-Shamshoum, Tujan Irshied, Tomer Ben-Shushan, Dror Dicker, Arik Dahan, and Ilan Matok. 2021. “Hypothyroidism and levothyroxine therapy following bariatric surgery: a systematic review, meta-analysis, network meta-analysis, and meta-regression.” Surgery for Obesity and Related Diseases, 17, 6, Pp. 1206–1217. Abstract
Background: Many health benefits of bariatric surgery are known and well-studied, but there is scarce data on the benefits of bariatric surgery on the thyroid function. Objective: We aimed to make a meta-analysis regarding the impact of bariatric surgery on thyroid-stimulating hormone (TSH) levels, levothyroxine dose, and the status of subclinical hypothyroidism. Setting: Systematic review and meta-analysis. Methods: PubMed, EMBASE, and Cochrane Library were searched up to December 2020 for relevant clinical studies. Random-effects model was used to pool results. Network meta-analysis was performed, incorporating direct and indirect comparisons among different types of bariatric surgery. Meta-regression analysis was performed to evaluate the impact of moderator variables on TSH levels and required levothyroxine dose after surgery. We followed the PRISMA guidelines for data selection and extraction. PROSPERO registry number: CRD42018105739. Results: A total of 28 studies involving 1284 patients were included. There was a statistically significant decrease in TSH levels after bariatric surgery (mean difference = −1.66 mU/L, 95%CI [−2.29, −1.03], P <.0001). In meta-regression analysis, we found that the following moderator variables: length of follow-up, mean age, baseline TSH, and preoperative thyroid function, could explain 1%, 43%, 68%, and 88% of the between-study variance, respectively. Furthermore, subclinical hypothyroidism was completely resolved in 87% of patients following bariatric surgery. In addition, there was a statistically significant decrease of levothyroxine dose in frank hypothyroid patients following bariatric surgery (mean difference = −13.20 mcg/d, 95%CI [−19.69, −6.71]). In network meta-analysis, we found that discontinuing or decreasing levothyroxine dose was significant following Roux-en-Y gastric bypass, 1 anastomosis gastric bypass, and sleeve gastrectomy, (OR = 31.02, 95%CI [10.34, 93.08]), (OR = 41.73, 95%CI [2.04, 854.69]), (OR = 104.03, 95%CI [35.79, 302.38]), respectively. Conclusions: Based on our meta-analysis, bariatric surgery is associated with the resolution of subclinical hypothyroidism, a decrease in TSH levels, and a decrease in levothyroxine dose.
Batya Isaacson, Maya Baron, Rachel Yamin, Gilad Bachrach, Francesca Levi-Schaffer, Zvi Granot, and Ofer Mandelboim. 2021. “The inhibitory receptor CD300a is essential for neutrophil-mediated clearance of urinary tract infection in mice.” European Journal of Immunology, 51, 9, Pp. 2218–2224. Abstract
Neutrophils play a crucial role in immune defense against and clearance of uropathogenic Escherichia coli (UPEC)-mediated urinary tract infection, the most common bacterial infection in healthy humans. CD300a is an inhibitory receptor that binds phosphatidylserine and phosphatidylethanolamine, presented on the membranes of apoptotic cells. CD300a binding to phosphatidylserine and phosphatidylethanolamine, also known as the “eat me” signal, mediates immune tolerance to dying cells. Here, we demonstrate for the first time that CD300a plays an important role in the neutrophil-mediated immune response to UPEC-induced urinary tract infection. We show that CD300a-deficient neutrophils have impaired phagocytic abilities and despite their increased accumulation at the site of infection, they are unable to reduce bacterial burden in the bladder, which results in significant exacerbation of infection and worse host outcome. Finally, we demonstrate that UPEC's pore forming toxin $\alpha$-hemolysin induces upregulation of the CD300a ligand on infected bladder epithelial cells, signaling to neutrophils to be cleared.
Limor Rubin, Collin T Stabler, Adi Schumacher-Klinger, Cezary Marcinkiewicz, Peter I Lelkes, and Philip Lazarovici. 2021. “Neurotrophic factors and their receptors in lung development and implications in lung diseases.” Cytokine & growth factor reviews, 59, Pp. 84–94. Abstract
Although lung innervation has been described by many studies in humans and rodents, the regulation of the respiratory system induced by neurotrophins is not fully understood. Here, we review current knowledge on the role of neurotrophins and the expression and function of their receptors in neurogenesis, vasculogenesis and during the embryonic development of the respiratory tree and highlight key implications relevant to respiratory diseases.
Hadas Pahima, Pier Giorgio Puzzovio, and Francesca Levi-Schaffer. 2021. “A novel mast cell-dependent allergic peritonitis model.” Clinical and Experimental Immunology, 205, 3, Pp. 306–315. Abstract
Typical murine models of allergic inflammation are induced by the combination of ovalbumin and aluminum hydroxide. However, accumulating evidence indicates that, in models of asthma and atopic dermatitis, allergic inflammation can be generated in the absence of aluminum hydroxide. Moreover, co-administration of Staphylococcus aureus enterotoxin B with ovalbumin can enhance inflammation. The objective of this study was to establish a rapid and mast cell-dependent murine model of allergic inflammation by inducing allergic peritonitis using ovalbumin and S. aureus enterotoxin B. Allergic peritonitis was induced in C57BL/6 mice by subcutaneous sensitization and intraperitoneal challenge with ovalbumin and S. aureus enterotoxin B. Disease characteristics were assessed by flow cytometry, enzyme-linked immunosorbent assay (ELISA), trypan blue exclusion and colorimetric assays. The time–course of the allergic peritonitis revealed a peak of peritoneal inflammation 48 h after challenge, as assessed by total cells and eosinophil counts. The decrease of cell numbers started 96 h post-challenge, with complete clearance within 168 h. Moreover, significantly higher levels of tryptase and increased vascular permeability were found 30 min following challenge. Allergic inflammation induction by ovalbumin and S. aureus enterotoxin B was impaired in mast cell-deficient mice and partially restored by mice reconstitution with bone marrow-derived mast cells, indicating the mast cell role in this model. We present a novel model of allergic peritonitis that is mast cell-dependent, simple and robust. Moreover, the use of S. aureus enterotoxin B better resembles human allergic inflammation, which is known to be characterized by the colonization of S. aureus.
Ihab Abd-Elrahman, Taher Nassar, Noha Khairi, Riki Perlman, Simon Benita, and Dina Ben Yehuda. 2021. “Novel targeted mtLivin nanoparticles treatment for disseminated diffuse large B-cell lymphoma.” Oncogene, 40, 2, Pp. 334–344. Abstract
We previously showed that Livin, an inhibitor of apoptosis protein, is specifically cleaved to produce a truncated protein, tLivin, and demonstrated its paradoxical proapoptotic activity. We further demonstrated that mini-tLivin (MTV), a 70 amino acids derivative of tLivin, is a proapoptotic protein as potent as tLivin. Based on these findings, in this study we aimed to develop a venue to target MTV for the treatment of diffuse large B-cell lymphoma (DLBCL). MTV was conjugated to poly (lactide-co-glycolic acid) surface-activated nanoparticles (NPs). In order to target MTV-NPs we also conjugated CD40 ligand (CD40L) to the surface of the NPs and evaluated the efficacy of the bifunctional CD40L-MTV-NPs. In vitro, CD40L-MTV-NPs elicited significant apoptosis of DLBCL cells. In a disseminated mouse model of DLBCL, 37.5% of MTV-NPs treated mice survived at the end of the experiment. Targeting MTV-NPs using CD40L greatly improved survival and 71.4% of these mice survived. CD40L-MTV-NPs also greatly reduced CNS involvement of DLBCL. Only 20% of these mice presented infiltration of lymphoma to the brain in comparison to 77% of the MTV-NPs treated mice. In a subcutaneous mouse model, CD40L-MTV-NPs significantly reduced tumor volume in correlation with significant increased caspase-3 activity. Thus, targeted MTV-NPs suggest a novel approach to overcome apoptosis resistance in cancer.
Liad Hinden, Aviram Kogot-Levin, Joseph Tam, and Gil Leibowitz. 2021. “Pathogenesis of diabesity-induced kidney disease: role of kidney nutrient sensing.” The FEBS journal. Abstract
Diabetes kidney disease (DKD) is a major healthcare problem associated with increased risk for developing end-stage kidney disease and high mortality. It is widely accepted that DKD is primarily a glomerular disease. Recent findings however suggest that kidney proximal tubule cells (KPTCs) may play a central role in the pathophysiology of DKD. In diabetes and obesity, KPTCs are exposed to nutrient overload, including glucose, free-fatty acids and amino acids, which dysregulate nutrient and energy sensing by mechanistic target of rapamycin complex 1 and AMP-activated protein kinase, with subsequent induction of tubular injury, inflammation, and fibrosis. Pharmacological treatments that modulate nutrient sensing and signaling in KPTCs, including cannabinoid-1 receptor antagonists and sodium glucose transporter 2 inhibitors, exert robust kidney protective effects. Shedding light on how nutrients are sensed and metabolized in KPTCs and in other kidney domains, and on their effects on signal transduction pathways that mediate kidney injury, is important for understanding the pathophysiology of DKD and for the development of novel therapeutic approaches in DKD and probably also in other forms of kidney disease.
Nethanel Friedman, Arie Dagan, Jhonathan Elia, Sharon Merims, and Ofra Benny. 2021. “Physical properties of gold nanoparticles affect skin penetration via hair follicles.” Nanomedicine : nanotechnology, biology, and medicine, 36, Pp. 102414. Abstract
Drug penetration through the skin is significant for both transdermal and dermal delivery. One mechanism that has attracted attention over the last two decades is the transport pathway of nanoparticles via hair follicle, through the epidermis, directly to the pilosebaceous unit and blood vessels. Studies demonstrate that particle size is an important factor for drug penetration. However, in order to gain more information for the purpose of improving this mode of drug delivery, a thorough understanding of the optimal physical particle properties is needed. In this study, we fabricated fluorescently labeled gold nanoparticles (GNP) with a tight control over the size and shape. The effect of the particles' physical parameters on follicular penetration was evaluated histologically. We used horizontal human skin sections and found that the optimal size for polymeric particles is 0.25 $μ$m. In addition, shape penetration experiments revealed gold nanostars' superiority over spherical particles. Our findings suggest the importance of the particles' physical properties in the design of nanocarriers delivered to the pilosebaceous unit.
Dan Gibson. 2021. “Platinum(IV) anticancer agents; are we en route to the holy grail or to a dead end?” Journal of inorganic biochemistry, 217, Pp. 111353. Abstract
Pt(IV) complexes are designed as prodrugs that are intended to overcome resistance. Pt(IV) prodrugs are activated inside cancer cells releasing cytotoxic Pt(II) drugs as well as two axial ligands that can be used to confer favorable pharmacological properties to the prodrug. The ligands can be innocent spectators, cancer targeting agents or bioactive moieties. The choice of axial ligands determines the chemical and pharmacological properties of the prodrugs. Over the years, several approaches were employed in attempts to increase the selectivity of the prodrugs to cancer cells and to utilize multi-action prodrugs to overcome resistance. In this review, we critically examine several of these approaches in order to evaluate the validity of some of the working hypotheses that are driving the current research.
Awanish Kumar and Abraham J. Domb. 2021. “Polymerization Enhancers for Cyanoacrylate Skin Adhesive.” Macromolecular Bioscience. Abstract
Cyanoacrylate glues are a renowned synthetic tissue sealant that cures rapidly through polymerization at room temperature, felicitating medical glues to treat skin wounds and surgical openings. Despite a wide range of cyanoacrylates available, only 2-octyl cyanoacrylates (OCA) provides the best biocompatibility. In this study, the polymerization and adhesive properties of 2-octyl cyanoacrylates (OCA) are explored in the presence of a highly biocompatible and biochemically inert polymer, poly(ethylene glycol) polyhedral oligomeric silsesquioxane (PEG-POSS). The effect of PEG-POSS on the polymerization of OCA is examined on a plastic surface and over pig skin. A peel-test is performed to evaluate the strength of OCA adhesive properties between two pieces of pig skin samples. Additionally, thin films of OCA are prepared using different fillers and evaluated for tear test. The results reveal that when applied on the plastic or pig skin, PEG-POSS initiated polymerization in OCA yields a high molecular weight OCA polymer with much better adhesive properties compared to commercially available cyanoacrylate adhesives. The relative change in the molecular weights of OCA compared to commercially available cyanoacrylate bioadhesives such as Dermaflex is much higher. The pig skin peeling test shows that OCA needs higher peeling force than Dermaflex.
Alexey Bingor, Matityahu Azriel, Lavi Amiad, and Rami Yaka. 2021. “Potentiated Response of ERK/MAPK Signaling is Associated with Prolonged Withdrawal from Cocaine Behavioral Sensitization.” Journal of molecular neuroscience : MN. Abstract
Among the neuroadaptations underlying the expression of cocaine-induced behaviors are modifications in glutamate-mediated signaling and synaptic plasticity via activation of mitogen-activated protein kinases (MAPKs) within the nucleus accumbens (NAc). We hypothesized that exposure to cocaine leads to alterations in MAPK signaling in NAc neurons, which facilitates changes in the glutamatergic system and thus behavioral changes. We have previously shown that following withdrawal from cocaine-induced behavioral sensitization (BS), an increase in glutamate receptor expression and elevated MAPK signaling was evident. Here, we set out to determine the time course and behavioral consequences of inhibition of extracellular signal-regulated kinase (ERK) or NMDA receptors following withdrawal from BS. We found that inhibiting ERK by microinjection of U0126 into the NAc at 1 or 6 days following withdrawal from BS did not affect the expression of BS when challenged with cocaine at 14 days. However, inhibition of ERK 1 day before the cocaine challenge abolished the expression of BS. We also inhibited NR2B-containing NMDA receptors in the NAc by microinjection of ifenprodil into the NAc following withdrawal from BS, which had no effect on the expression of BS. However, microinjection of ifenprodil to the NAc 1 day before challenge attenuated the expression of BS similar to ERK inhibition. These results suggest that following a prolonged period of withdrawal, NR2B-containing NMDA receptors and ERK activity play a critical role in the expression of cocaine behavioral sensitization.