Ibrutinib topical delivery for melanoma treatment: The effect of nanostructured lipid carriers' composition on the controlled drug skin deposition.

Melanoma is responsible for more than 80% of deaths related to skin diseases. Ibrutinib (IBR), a Bruton's tyrosine kinase inhibitor, has been proposed to treat this type of tumor. However, its low solubility, extensive first-pass effect, and severe adverse reactions with systemic administration affect therapeutic success. This study proposes developing and comparing the performance of two compositions of nanostructured lipid carriers (NLCs) to load IBR for the topical management of melanomas in their early stages. Initially, the effectiveness of IBR on melanoma proliferation was evaluated in vitro, and the results confirmed that the drug reduces the viability of human melanoma cells by inducing apoptosis at a dose that does not compromise dermal cells. Preformulation tests were then conducted to characterize the physical compatibility between the drug and the selected components used in NLCs preparation. Sequentially, two lipid compositions were used to develop the NLCs. Formulations were then characterized and subjected to in vitro release and permeation tests on porcine skin. The NLCs containing oleic acid effectively controlled IBR release over 24 h compared to the NLCs composed of pomegranate seed oil. Furthermore, the nanoparticles acted as permeation enhancers, increasing the fluidity of the lipids in the stratum corneum, as determined by EPR spectroscopy, which stimulated the IBR penetration more profoundly into the skin. However, the NLCs composition also influenced the permeation promotion factor. Thus, these findings emphasize the importance of the composition of NLCs in controlling and increasing the skin penetration of IBR and pave the way for future advances in melanoma therapy.

Molecular and functional anticancer effects of GLP/G9a inhibition by UNC0646 in MeWo melanoma cells.

In recent years, histone methyltransferases (HMTs) have emerged as important therapeutic targets in cancer due to their oncogenic role. Herein, we used the GLP/G9a inhibitor UNC0646 to assess whether the inhibition of such HMTs could induce cell death in MeWo melanoma cells. Furthermore, we investigated the cellular and molecular mechanisms involved in the observed cell death events. Finally, we performed a functional genomics analysis of 480 melanoma samples to characterize G9a/GLP involvement in melanoma. Interestingly, after UNC0646 treatment, MeWo cells underwent apoptosis, followed by loss of mitochondrial membrane potential and the generation of reactive oxygen species (ROS). Furthermore, MeWo cells treated with UNC0646 showed cell cycle arrest and inhibition of proliferation. At the molecular level, UNC0646 treatment increased the transcriptional levels of CDK1 and BAX, and decreased BCL-2 mRNA levels. Finally, we performed a functional enrichment analysis, which demonstrated that dozens of biological pathways were enriched in melanoma samples according to GLP and G9a expression, including apoptosis and necrosis. Taken together, our data show that inhibition of GLP/G9a using UNC0646 exerts anticancer effects on melanoma cells by controlling their proliferation and inducing apoptosis.

Estimating Public Economic Gains from Early Breast Cancer and Curative Treatment: A Case Study in Human Epidermal Growth Factor Receptor (HER-2) Positive Targeted Therapies.

INTRODUCTION: Cancer diagnosis influences the choices that patients make regarding current and future labor market activity. These choices have implications for governments based on resulting changes in taxes paid and benefits received. In this analysis we explore how human growth receptor 2 (HER2)-positive residual invasive breast cancer and different treatments influence government accounts excluding health costs. METHODS: HER2-positive early breast cancer (eBC) health states from a published disease model were used to establish likelihood of working and wage impact at different stages of disease. The indirect productivity losses for an average woman aged 49 years were translated into fiscal consequences to government by applying an established government perspective-modeling framework. The fiscal projections (discounted) include gross tax revenue by disease stage, government transfer costs related to time off work and early retirement ,and net fiscal balance (e.g., gross taxes-transfers) in three countries Canada, Portugal, and Brazil. RESULTS: The net fiscal balance in Canada for a healthy woman was C$109,551 compared with a HER2-positive eBC woman treated with trastuzumab emtansine (C$69,767) or trastuzumab (C$62,971). A similar pattern was observed in the three countries but reflecting the overall tax burden in each country, labor force activity, and available public benefits. Age at diagnosis was an important determinant of the likely net fiscal balance, as this influences the remaining working years. DISCUSSION: Women diagnosed with HER2-positive eBC were estimated to pay less lifetime gross taxes and receive more in sickness benefits compared with healthy women. Treatments that improve outcomes are likely to offer fiscal gains for government from improved work force participation.

Senescence on Dental Pulp Cells: Effects on Morphology, Migration, Proliferation, and Immune Response.

INTRODUCTION: Evidence indicates that senescence can affect essential dental pulp functions, such as defense capacity and repair, consequently affecting the successes of conservative endodontic treatments. This study aims to evaluate the effects of senescence on the morphology, migration, proliferation, and immune response of human dental pulp cells. METHODS: Cells were treated with doxorubicin to induce senescence, confirmed by ß-galactosidase staining. Morphological changes, cellular proliferation, and migration were evaluated by scanning electron microscopy, trypan blue cells, and the scratch method, respectively. Modifications in the immune response were evaluated by measuring the genes for pro-inflammatory cytokines tumor necrosis factor alpha and interleukin (IL)-6 and anti-inflammatory cytokines transforming growth factor beta 1 and IL-10 using the real time polymerase chain reaction assay. RESULTS: An increase in cell size and a decrease in the number of extensions were observed in senescent cells. A reduction in the proliferative and migratory capacity was also found in senescent cells. In addition, there was an increase in the gene expression of inflammatory cytokines tumor necrosis factor alpha and IL-6 and a decrease in the gene expression of IL-10 and transforming growth factor beta-1, suggesting an exacerbated inflammatory situation associated with immunosuppression. CONCLUSIONS: Cellular senescence is possibly a condition that affects prognoses of conservative endodontic treatments, as it affects primordial cellular functions related to this treatment.

Photobiomodulation Therapy to Treat Snakebites Caused by Bothrops atrox: A Randomized Clinical Trial.

Importance: Bothrops venom acts almost immediately at the bite site and causes tissue damage. Objective: To investigate the feasibility and explore the safety and efficacy of low-level laser therapy (LLLT) in reducing the local manifestations of B atrox envenomations. Design, Setting, and Participants: This was a double-blind randomized clinical trial conducted at Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, in Manaus, Brazil. A total of 60 adult participants were included from November 2020 to March 2022, with 30 in each group. Baseline characteristics on admission were similarly distributed between groups. Data analysis was performed from August to December 2022. Intervention: The intervention group received LLLT combined with regular antivenom treatment. The laser used was a gallium arsenide laser with 4 infrared laser emitters and 4 red laser emitters, 4 J/cm2 for 40 seconds at each application point. Main Outcomes and Measures: Feasibility was assessed by eligibility, recruitment, and retention rates; protocol fidelity; and patients' acceptability. The primary efficacy outcome of this study was myolysis estimated by the value of creatine kinase (U/L) on the third day of follow-up. Secondary efficacy outcomes were (1) pain intensity, (2) circumference measurement ratio, (3) extent of edema, (4) difference between the bite site temperature and that of the contralateral limb, (5) need for the use of analgesics, (6) frequency of secondary infections, and (7) necrosis. These outcomes were measured 48 hours after admission. Disability assessment was carried out from 4 to 6 months after patients' discharge. P values for outcomes were adjusted with Bonferroni correction. Results: A total of 60 patients (mean [SD] age, 43.2 [15.3] years; 8 female individuals [13%] and 52 male individuals [87%]) were included. The study was feasible, and patient retention and acceptability were high. Creatine kinase was significantly lower in the LLLT group (mean [SD], 163.7 [160.0] U/L) 48 hours after admission in relation to the comparator (412.4 [441.3] U/L) (P = .03). Mean (SD) pain intensity (2.9 [2.7] vs 5.0 [2.4]; P = .004), circumference measurement ratio (6.6% [6.6%] vs 17.1% [11.6%]; P < .001), and edema extent (25.8 [15.0] vs 40.1 [22.7] cm; P = .002) were significantly lower in the LLLT group in relation to the comparator. No difference was observed between the groups regarding the mean difference between the bite site temperature and the contralateral limb. Secondary infections, necrosis, disability outcomes, and the frequency of need for analgesics were similar in both groups. No adverse event was observed. Conclusions and Relevance: The data from this randomized clinical trial suggest that the use of LLLT was feasible and safe in a hospital setting and effective in reducing muscle damage and the local inflammatory process caused by B atrox envenomations. Trial Registration: Brazilian Registry of Clinical Trials Identifier: RBR-4qw4vf.

l-Asparaginase Type II from Fusarium proliferatum: Heterologous Expression and In Silico Analysis.

The search for new drug-producing microorganisms is one of the most promising situations in current world scientific scenarios. The use of molecular biology as well as the cloning of protein and compound genes is already well established as the gold standard method of increasing productivity. Aiming at this increase in productivity, this work aims at the cloning, purification and in silico analysis of l-asparaginase from Fusarium proliferatum in Komagataella phaffii (Pichia pastoris) protein expression systems. The l-asparaginase gene (NCBI OQ439985) has been cloned into Pichia pastoris strains. Enzyme production was analyzed via the quantification of aspartic B-hydroxamate, followed by purification on a DEAE FF ion exchange column. The in silico analysis was proposed based on the combined use of various technological tools. The enzymatic activity found intracellularly was 2.84 IU/g. A purification factor of 1.18 was observed. The in silico analysis revealed the position of five important amino acid residues for enzymatic activity, and likewise, it was possible to predict a monomeric structure with a C-score of 1.59. The production of the enzyme l-asparaginase from F. proliferatum in P. pastoris was demonstrated in this work, being of great importance for the analysis of new methodologies in search of the production of important drugs in therapy.

Molecular characterization of juvenile fish from the Amazon estuary using DNA barcoding approach.

The efficiency of the DNA barcoding relies on sequencing fragment of the Cytochrome C Subunit I (COI) gene, which has been claimed as a tool to biodiversity identification from distinct groups. Accordingly, the goal of this study was to identify juvenile fish species along an estuary of Caeté River in the Brazilian Blue Amazon based on. For this purpose, we applied the DNA barcoding and discuss this approach as a tool for discrimination of species in early ontogenetic stages. A 500-bp fragment was obtained from 74 individuals, belonging to 23 species, 20 genera, 13 families and seven orders. About 70% of the 46 haplotypes revealed congruence between morphological and molecular species identification, while 8% of them failed in identification of taxa and 22% demonstrated morphological misidentification. These results proved that COI fragments were effective to diagnose fish species at early life stages, allowing identifying all samples to a species-specific status, except for some taxa whose COI sequences remain unavailable in public databases. Therefore, we recommend the incorporation of DNA barcoding to provide additional support to traditional identification, especially in morphologically controversial groups. In addition, periodic updates and comparative analyses in public COI datasets are encouraged.

Particle swarm optimizer for the surface plasmon resonance effect on metal gratings.

In this work, the spectral dependence of optimum parameters of the surface plasmon resonance (SPR) effect on metallized sinusoidal diffraction gratings, under normal incidence, was determined using the particle swarm optimization method. The method was chosen due to its simplicity and effectiveness in providing reliable results, relative to direct search or gradient methods. The Rayleigh's hypothesis, which restricts the analysis to the case of shallow gratings, is used to model the diffracted fields across the interface between the sensing medium and metal. A penalty function was applied to avoid the occurrence of singularities and violation of the validity of the Rayleigh hypothesis. Using this procedure, the optimum values of grating periodicity and amplitude that maximized the sensitivity function for gold, silver, copper, and aluminum-metals that yield high quality factor SPR effects-were determined in a wavelength range between 500 and 1600 nm, for both gaseous and aqueous sensing media.

Transfer of functions based on equivalence class formation using musical stimuli.

Empirical evidence has supported that musical excerpts written in major and minor modes are responsible for evoking happiness and sadness, respectively. In this study, we evaluated whether the emotional content evoked by musical stimuli would transfer to abstract figures when they became members of the same equivalence class. Participants assigned to the experimental group were submitted to a training procedure to form equivalence classes comprising musical excerpts (A) and meaningless abstract figures (B, C, and D). Afterward, transfer of function was evaluated using a semantic differential. Participants in the control group showed positive semantic differential scores for major mode musical excerpts, negative scores for minor mode musical excerpts, and neutral scores for the B, C, and D stimuli. Participants in the experimental groups showed positive semantic differential scores for visual stimuli equivalent to the major modes and negative semantic differential scores for visual stimuli equivalent to the minor modes. These results indicate transfer of function of emotional content present in musical stimuli through equivalence class formation. These findings could provide a more comprehensive understanding of the effects of using emotional stimuli in equivalence class formation experiments and in transfer of function itself.

Prognostic implications of the ID1 expression in acute myeloid leukemia patients treated in a resource-constrained setting.

INTRODUCTION: The aberrant expression of the inhibitor of DNA binding (ID1) gene has been frequently associated with the leukemogenesis and prognostication acute myeloid leukemia (AML), although its clinical importance has never been investigated in patients treated outside well-controlled clinical trials. METHODS: Using quantitative real-time polymerase chain reaction, we investigated the role of the ID1 expression in the clinical outcomes of non-selected patients with acute myeloid leukemia treated in a real-life setting. RESULTS: Overall, 128 patients were enrolled. Patients with high ID1 expression had a lower 3-year overall survival (OS) rate of 9%, with the 95% confidence interval (95%CI) at 3 to 20%, compared to patients with a low ID1 expression (22%, 95%CI: 11 - 34%) (p = 0.037), although these findings did not retain significance after adjustment (hazard ratio (HR): 1.5, 95%CI: 0.98 - 2.28; p = 0.057). The ID1 expression had no impact on post-induction outcomes (disease-free survival, p = 0.648; cumulative incidence of relapse, p = 0.584). CONCLUSIONS: Although we are aware thar our data are confronted with many variables that cannot be fully controlled, including drug unavailability, risk-adapted treatment, comorbidities and the time from diagnosis to treatment initiation, we are firm believers that such an initiative can provide more realistic data on understudied populations, in particular those from low- and middle-income countries.

The Peptide Salamandrin-I Modulates Components Involved in Pyroptosis and Induces Cell Death in Human Leukemia Cell Line HL-60.

Amphibian secretions have been extensively investigated for the production of bioactive molecules. Salamandrin-I is an antioxidant peptide, isolated from the skin secretion of the fire salamander, that has induced no toxicity in microglia or erythrocytes. Importantly, the administration of antioxidants may constitute an adequate therapeutic approach to cancer treatment. Here, with the purpose of better characterizing the therapeutic potential of salamandrin-I, we investigated whether this antioxidant peptide also exerts anticancer activity, using the human leukemia cell line HL-60 as a cancer model. Salamandrin-I treatment induced a significant reduction in HL-60 proliferation, which was accompanied by cell cycle arrest. Furthermore, the peptide-induced cell death showed a significant increase in the LDH release in HL-60 cells. The cellular toxicity exerted by salamandrin-I is possibly related to pyroptosis, since the HL-60 cells showed loss of mitochondrial membrane potential and hyperexpression of inflammasome components following the peptide treatment. This is the first demonstration of the anticancer potential of the salamandrin-I peptide. Such results are important, as they offer relevant insights into the field of cancer therapy and allow the design of future bioactive molecules using salamandrin-I as a template.

Lycopene from Red Guava (Psidium guajava L.): From Hepatoprotective Effect to Its Use as Promising Self-Emulsifying Drug Delivery System for Anti-Inflammatory and Antioxidant Applications.

Lycopene is a carotenoid with potential use in the treatment of chronic illnesses. Here, different formulations of lycopene were studied: lycopene-rich extract from red guava (LEG), purified lycopene from red guava (LPG) and a self-emulsifying drug delivery system loaded with LPG (nanoLPG). The effects of administering orally various doses of LEG to hypercholesterolemic hamsters were evaluated regarding the liver function of the animals. The cytotoxicity of LPG in Vero cells was analyzed by a crystal violet assay and by fluorescence microscopy. In addition, nanoLPG was employed in stability tests. LPG and nanoLPG were tested for their cytotoxic effect on human keratinocytes and antioxidant capacity on cells in an endothelial dysfunction model in an isolated rat aorta. Finally, the effect of different nanoLPG concentrations on the expression of immune-related genes (IL-10, TNF-α, COX-2 and IFN-γ) from peripheral blood mononuclear cells (PBMC) using real-time PCR was also analyzed. Results suggest that LEG, despite not being able to improve blood markers indicative of liver function in hypercholesterolemic hamsters, reduced hepatic degenerative changes. Additionally, LPG did not show cytotoxicity in Vero cells. In relation to nanoLPG, the effects produced by heat stress evaluated by Dynamics Light Scattering (DLS) and visually were loss of color, texture change and phase separation after 15 days without interfering with the droplet size, so the formulation proved to be efficient in stabilizing the encapsulated lycopene. Although LPG and nanoLPG showed moderate toxicity to keratinocytes, which may be related to cell lineage characteristics, both revealed potent antioxidant activity. LPG and nanoLPG showed vasoprotective effects in aortic preparations. The gene expression assay indicates that, although no significant differences were observed in the expression of IL-10 and TNF-α, the PBMCs treated with nanoLPG showed a reduction in transcriptional levels of IFN-γ and an increased expression of COX-2. Thus, the work adds evidence to the safety of the use of lycopene by humans and shows that tested formulations, mainly nanoLPG due to its stability, stand out as promising and biosafe products for the treatment of diseases that have oxidative stress and inflammation in their etiopathology.

The Combination of Synoeca-MP Antimicrobial Peptide with IDR-1018 Stimulates Proliferation, Migration, and the Expression of Pro-Regenerative Genes in Both Human Skin Cell Cultures and 3D Skin Equivalents.

In skin lesions, the development of microbial infection affects the healing process, increasing morbidity and mortality rates in patients with severe burns, diabetic foot, and other types of skin injuries. Synoeca-MP is an antimicrobial peptide (AMP) that exhibits activity against several bacteria of clinical importance, but its cytotoxicity can represent a problem for its positioning as an effective antimicrobial compound. In contrast, the immunomodulatory peptide IDR-1018 presents low toxicity and a wide regenerative potential due to its ability to reduce apoptotic mRNA expression and promote skin cell proliferation. In the present study, we used human skin cells and a 3D skin equivalent models to analyze the potential of the IDR-1018 peptide to attenuate the cytotoxicity of synoeca-MP, as well as the influence of synoeca-MP/IDR-1018 combination on cell proliferation, regenerative processes, and wound repair. We found that the addition of IDR-1018 significantly improved the biological properties of synoeca-MP on skin cells without modifying its antibacterial activity against S. aureus. Likewise, in both melanocytes and keratinocytes, the treatment with synoeca-MP/IDR-1018 combination induces cell proliferation and migration, while in a 3D human skin equivalent model, it can accelerate wound reepithelization. Furthermore, treatment with this peptide combination generates an up-regulation in the expression of pro-regenerative genes in both monolayer cell cultures and in 3D skin equivalents. This data suggests that the synoeca-MP/IDR-1018 combination possesses a good profile of antimicrobial and pro-regenerative activity, opening the door to the development of new strategies for the treatment of skin lesions.

Prospecting Local Treatments Used in Conjunction with Antivenom Administration Following Envenomation Caused by Animals: A Systematic Review.

Envenomation caused by venomous animals may trigger significant local complications such as pain, edema, localized hemorrhage, and tissue necrosis, in addition to complications such as dermonecrosis, myonecrosis, and even amputations. This systematic review aims to evaluate scientific evidence on therapies used to target local effects caused by envenomation. The PubMed, MEDLINE, and LILACS databases were used to perform a literature search on the topic. The review was based on studies that cited procedures performed on local injuries following envenomation with the aim of being an adjuvant therapeutic strategy. The literature regarding local treatments used following envenomation reports the use of several alternative methods and/or therapies. The venomous animals found in the search were snakes (82.05%), insects (2.56%), spiders (2.56%), scorpions (2.56%), and others (jellyfish, centipede, sea urchin-10.26%). In regard to the treatments, the use of tourniquets, corticosteroids, antihistamines, and cryotherapy is questionable, as well as the use of plants and oils. Low-intensity lasers stand out as a possible therapeutic tool for these injuries. Local complications can progress to serious conditions and may result in physical disabilities and sequelae. This study compiled information on adjuvant therapeutic measures and underscores the importance of more robust scientific evidence for recommendations that act on local effects together with the antivenom.

Effects of Ethanolic and Aqueous Extracts of Garcinia gardneriana Leaves in an In Vivo Experimental Model Induced by a Hyperlipidic Diet.

The study of medicinal plants, such as the genus Garcinia (Clusiaceae), in the treatment of non-communicable chronic diseases has aroused the interest of researchers. However, there are no studies in the literature that have investigated the effects of Garcinia gardneriana in experimental models of obesity for possible metabolic alterations. Swiss mice receiving a high-fat diet were supplemented with aqueous or ethanolic extract of G. gardneriana at doses of 200 or 400 mg/kg/day. It was found that there was a reduction in food consumption in experimental groups compared with the control groups, and the group supplemented with aqueous extract at a dose of 200 mg/kg/daydisplayed a reduction in weight. The results showed an increase in the values of high density lipoprotein (HDL-c), total cholesterol, triglycerides and fasting blood glucose. G. gardneriana did not protect against insulin resistance, and caused in an increase in monocyte chemoattractant protein-1 (MCP-1) concentrations and a reduction in interleukin 10 (IL-10). In addition, hepatic steatosis and microvesicular steatosis were indicated. It was revealed that, under the experimental conditions in the study, G. gardneriana did not prevent weight gain or comorbidities; that is, a different behavior was obtained from that described in the literature with regard to the medicinal potential of the Garcinia species, which is probably related to the phytochemical properties.

Antioxidant and Neuroprotective Effects of the First Tryptophyllin Found in Snake Venom (Bothrops moojeni).

In this study, we report the isolation, characterization, and synthesis of the peptide BmT-2 belonging to the tryptophyllins family, isolated from the venom of the snake Bothrops moojeni. This is the first time a tryptophyllin is identified in snake venom. We tested whether BmT-2 had cytotoxic effects and antioxidant activity in a set of experiments that included both in vitro and cell-based assays. BmT-2 presented a radical scavenging activity toward ABTS• and AAPH-derived radicals. BmT-2 protected fluorescein, DNA molecules, and human red blood cells (RBCs) from free radicals generated by the thermal decomposition of AAPH. The novel tryptophyllin was not toxic in cell viability tests, where it (up to 0.4 mg/mL) did not cause hemolysis of human RBCs and did not cause significant loss of cell viability, showing a CC50 > 1.5 mM for cytotoxic effects against SK-N-BE(2) neuroblastoma cells. BmT-2 prevented the arsenite-induced upregulation of Nrf2 in Neuro-2a neuroblasts and the phorbol myristate acetate-induced overgeneration of reactive oxygen species and reactive nitrogen species in SK-N-BE(2) neuroblastoma cells. Electronic structure calculations and full atomistic reactive molecular dynamics simulations revealed the relevant contribution of aromatic residues in BmT-2 to its antioxidant properties. Our study presents a novel peptide classified into the family of the tryptophyllins, which has been reported exclusively in amphibians. Despite the promising results on its antioxidant activity and low cytotoxicity, the mechanisms of action of BmT-2 still need to be further elucidated.

Regulatory T-Cell Enhancement, Expression of Adhesion Molecules, and Production of Anti-Inflammatory Factors Are Differentially Modulated by Spheroid-Cultured Mesenchymal Stem Cells.

The culture of mesenchymal stem cells (MSCs) as spheroids promotes a more physiological cellular behavior, as it more accurately reflects the biological microenvironment. Nevertheless, mixed results have been found regarding the immunosuppressive properties of spheroid-cultured MSCs (3D-MSCs), the mechanisms of immunoregulation of 3D-MSCs being scarcely described at this point. In the present study, we constructed spheroids from MSCs and compared their immunosuppressive potential with that of MSCs cultured in monolayer (2D-MSCs). First, we evaluated the ability of 2D-MSCs and 3D-MSCs to control the activation and proliferation of T-cells. Next, we evaluated the percentage of regulatory T-cells (Tregs) after the co-culturing of peripheral blood mononuclear cells (PBMCs) with 2D-MSCs and 3D-MSCs. Finally, we investigated the expression of adhesion molecules, as well as the expressions of several anti-inflammatory transcripts in 2D-MSCs and 3D-MSCs maintained in both inflammatory and non-inflammatory conditions. Interestingly, our data show that several anti-inflammatory genes are up-regulated in 3D-MSCs, and that these cells can control T-cell proliferation. Nevertheless, 2D-MSCs are more efficient in suppressing the immune cell proliferation. Importantly, contrary to what was observed in 3D-MSCs, the expressions of ICAM-1 and VCAM-1 are significantly upregulated in 2D-MSCs exposed to an inflammatory environment. Furthermore, only 2D-MSCs are able to promote the enhancement of Tregs. Taken together, our data clearly show that the immunosuppressive potential of MSCs is significantly impacted by their shape, and highlights the important role of cell-cell adhesion molecules for optimal MSC immunomodulatory function.

Ezrin is highly expressed and a druggable target in chronic lymphocytic leukemia.

AIMS: Despite the development of therapeutic strategies for chronic lymphocytic leukemia (CLL), most patients remain incurable, relapse, or refractory to current treatments, indicating the need to expand the antineoplastic repertoire for this disease. Ezrin (EZR) is a known oncogene in solid tumors and plays a key role in cell survival and BCR-mediated signaling activation in B-cell lymphomas. However, its role in hematological neoplasms remains poorly explored. MAIN METHODS: The present study assessed EZR expression in samples from CLL patients and healthy donors and evaluated the cellular and molecular effects of a pharmacological EZR inhibitor, NSC305787, in CLL cellular models. KEY FINDINGS: EZR was highly expressed and positively associated with relevant signaling pathways related to CLL development and progression, including TP53, PI3K/AKT/mTOR, NF-κB, and MAPK. NSC305787 reduced viability, clonogenicity, and cell cycle progression and induced apoptosis in CLL cells. Pharmacological EZR inhibition also attenuated ERK, S6RP, and NF-κB activation, indicating that EZR not only associates with but also activates these signaling pathways in CLL. Ex vivo assays revealed that the EZR inhibition-induced cell viability reduction was independent of molecular risk and the Binet stage. SIGNIFICANCE: Our study provides insights into EZR as a pharmacological target in CLL, shedding light on a novel strategy for treating this disease.

Distinct plasma chemokines and cytokines signatures in Leishmania guyanensis-infected patients with cutaneous leishmaniasis.

The immunopathology associated with Leishmaniasis is a consequence of inflammation. Upon infection with Leishmania, the type of host-immune response is determinant for the clinical manifestations that can lead to either self-healing or chronic disease. Multiple pathways may determine disease severity. A comparison of systemic immune profiles in patients with cutaneous leishmaniasis caused by L. guyanensis and healthy individuals with the same socio-epidemiological characteristics coming from the same endemic areas as the patients is performed to identify particular immune profile and pathways associated with the progression of disease development. Twenty-seven plasma soluble circulating factors were evaluated between the groups by univariate and multivariate analysis. The following biomarkers pairs IL-17/IL-9 (ρ=0,829), IL-17/IL-12 (ρ=0,786), IL-6/IL-1ra (ρ=0,785), IL-6/IL-12 (ρ=0,780), IL-1ß/G-CSF (ρ=0,758) and IL-17/MIP-1ß (ρ=0,754) showed the highest correlation mean among the patient while only INF-γ/IL-4 (ρ=0.740), 17/MIP-1ß (ρ=0,712) and IL-17/IL-9 (ρ=0,707) exhibited positive correlation among the control group. The cytokine IL-17 and IL1ß presented the greater number of positive pair correlation among the patients. The linear combinations of biomarkers displayed IP-10, IL-2 and RANTES as the variables with the higher discriminatory activity in the patient group compared to PDGF, IL-1ra and eotaxin among the control subjects. IP-10, IL-2, IL-1ß, RANTES and IL-17 seem to be predictive value of progression to the development of disease among the Lg-infected individuals.

Anti-inflammatory effect evaluation of naringenin and its incorporation into a chitosan-based film for transdermal delivery.

Naringenin is a bioflavonoid mainly found in citrus fruits. It presents many pharmacological benefits, including a remarkable anti-inflammatory activity, but its oral bioavailability is poor. To overcome this drawback, this work proposes a transdermal administration of such bioflavonoid, considering its use in the chronic treatment of inflammatory conditions. For this, it aims to develop a chitosan-based film that guarantees a consistent transdermal delivery of the drug. First, naringenin's in vitro anti-inflammatory effect on T-cell proliferation was evaluated, followed by research on the modulation of gene expression for inflammatory factors in peripheral blood mononuclear cells. Chitosan films were then prepared and characterized. Afterward, naringenin release profile from a selected film was determined as well as the drug permeation across porcine skin provided by the film. Naringenin induced the expression of the anti-inflammatory factors IL-10 and TGF-ß1 while inhibiting the expression of the pro-inflammatory cytokine IL-1ß and limiting T-cell proliferation. The chitosan film was successfully developed, and the drug was progressively released to the physiological media following both first order and Korsmeyer-Peppas kinetics. When topically applied, the chitosan film guaranteed a constant and continuous diffusion of naringenin across the skin over 72 h. Indeed, the permeation flux of naringenin was 0.30 ± 0.01 µg/cm2/h, which means a concentration in the receptor solution 14-fold (p < 0.05) higher than that provided by the drug solution. Thus, the chitosan film represents a promising transdermal alternative for the long-term treatment of inflammatory conditions using naringenin.