PPARγ partial agonist LPSF/GQ-16 prevents dermal and pulmonary fibrosis in HOCl-induced systemic sclerosis (SSc) and modulates cytokine production in PBMC of SSc patients.

Thiazolidinediones (TZD) are synthetic molecules that have a range of biological effects, including antifibrotic and anti-inflammatory, and they may represent a promising therapeutic strategy for systemic sclerosis (SSc). The aim of this study was to investigate the immunomodulatory and antifibrotic properties of LPSF/GQ-16, a TZD derivative, in peripheral blood mononuclear cells (PBMC) from SSc patients and in a murine model of SSc HOCl-induced. The PBMC of 20 SSc patients were stimulated with phytohemagglutinin (PHA) and treated with LPSF/GQ-16 for 48 h, later cytokines in the culture supernatants were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA). Experimental SSc was induced by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. HOCl-induced SSc mice received daily treatment with LPSF/GQ-16 (30 mg/kg) through intraperitoneal injections during the same period. Immunological parameters were evaluated by flow cytometry and ELISA, and dermal and pulmonary fibrosis were evaluated by RT-qPCR, hydroxyproline dosage and histopathological analysis. In PBMC cultures, it was possible to observe that LPSF/GQ-16 modulated the secretion of cytokines IL-2 (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.001), IL-17A (p = 0.006), TNF (p < 0.001) and IFN-γ (p < 0.001). In addition, treatment with LPSF/GQ-16 in HOCl-induced SSc mice promoted a significant reduction in dermal thickening (p < 0.001), in the accumulation of collagen in the skin (p < 0.001), down-regulated the expression of fibrosis markers in the skin (Col1a1, α-Sma and Tgfß1, p < 0.001 for all) and lungs (Il4 and Il13, p < 0.001 for both), as well as reduced activation of CD4 + T cells (p < 0.001), B cells (p < 0.001) and M2 macrophages (p < 0.001). In conclusion, LPSF/GQ-16 showed immunomodulatory and antifibrotic properties, demonstrating the therapeutic potential of this molecule for SSc.

Multicenter study of the natural history and therapeutic responses of patients with chikungunya, focusing on acute and chronic musculoskeletal manifestations - a study protocol from the clinical and applied research in Chikungunya (REPLICK network).

BACKGROUND: Chikungunya is associated with high morbidity and the natural history of symptomatic infection has been divided into three phases (acute, post-acute, and chronic) according to the duration of musculoskeletal symptoms. Although this classification has been designed to help guide therapeutic decisions, it does not encompass the complexity of the clinical expression of the disease and does not assist in the evaluation of the prognosis of severity nor chronic disease. Thus, the current challenge is to identify and diagnose musculoskeletal disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course. METHODS: The study is the first product of the Clinical and Applied Research Network in Chikungunya (REPLICK). This is a prospective, outpatient department-based, multicenter cohort study in Brazil. Four work packages were defined: i. Clinical research; ii) Translational Science - comprising immunology and virology streams; iii) Epidemiology and Economics; iv) Therapeutic Response and clinical trials design. Scheduled appointments on days 21 (D21) ± 7 after enrollment, D90 ± 15, D120 ± 30, D180 ± 30; D360 ± 30; D720 ± 60, and D1080 ± 60 days. On these visits a panel of blood tests are collected in addition to the clinical report forms to obtain data on socio-demographic, medical history, physical examination and questionnaires devoted to the evaluation of musculoskeletal manifestations and overall health are performed. Participants are asked to consent for their specimens to be maintained in a biobank. Aliquots of blood, serum, saliva, PAXgene, and when clinically indicated to be examined, synovial fluid, are stored at -80° C. The study protocol was submitted and approved to the National IRB and local IRB at each study site. DISCUSSION: Standardized and harmonized patient cohorts are needed to provide better estimates of chronic arthralgia development, the clinical spectra of acute and chronic disease and investigation of associated risk factors. This study is the largest evaluation of the long-term sequelae of individuals infected with CHIKV in the Brazilian population focusing on musculoskeletal manifestations, mental health, quality of life, and chronic pain. This information will both define disease burden and costs associated with CHIKV infection, and better inform therapeutic guidelines.

Influence of the self-adhering strategy on microhardness, sorption, solubility, color stability, and cytotoxicity compared to bulk-fill and conventional resin composites.

OBJECTIVES: To analyze and compare, in vitro, the microhardness, sorption, solubility, color stability, and cytotoxicity of three types of resin composites: self-adhesive (SARC) (Dyad Flow (DF)/Kerr), bulk-fill (Filtek Bulk Fill Flow (FBF)/3 M ESPE), and conventional (Filtek Z350XT Flow (Z350)/3 M ESPE). MATERIALS AND METHODS: Thirty cylindrical specimens were prepared using a split metal mold (15 mm × 1 mm), divided into 3 groups (n = 10) according to the material used. Vickers hardness (VH) was calculated from three indentations (300gf/15 s) per specimen. The sorption and solubility were measured according to the ISO 4049:2009 specification after storing in distilled water for 7 days. The color of each resin composite was measured using a portable digital spectrophotometer according to the CIELAB system. After a 7-day immersion in coffee, the color variation (∆E) was calculated. Following the ISO 10993:2012, the cytotoxicity in Vero cells was evaluated through the MTT assay. The results were analyzed using the Kruskal-Wallis test to compare the studied groups. The Wilcoxon test was used to compare the assessments in each studied group. For cytotoxicity analysis, the data were compared by the ANOVA test (α = 0.05). RESULTS: DF showed the lowest VH (28.67), highest sorption (0.543 µg/mm3) and solubility (1.700 µg/mm3), and higher ∆E after 7 days of coffee immersion (p = 0.008). The resin composites studied were considered non-cytotoxic. CONCLUSIONS: The SARC presented inferior mechanical and physical-chemical properties than bulk-fill and conventional resin composites, with comparable cytotoxicity against Vero cells. CLINICAL RELEVANCE: The simplification of the clinical protocol of SARC can minimize the number of possible failures during the restorative technique. However, considering their inferior physical and mechanical properties, their coverage with materials of higher mechanical properties and physical-chemical stability should be considered.

Galectin-3 Expression in Pancreatic Cell Lines Under Distinct Autophagy-Inducing Stimulus.

Hypoxia and nutrient deprivation are responsible for inducing malignant behavior in neoplastic cells. In these conditions, metabolic stress leads the cells to enhance their autophagic flux and to activate key molecules for homeostasis maintenance. Galectin-3 (Gal-3) is upregulated in pancreatic cancer and it is activated under the hypoxic atmosphere. We aimed to analyze the most effective autophagic-inducing conditions in pancreatic ductal adenocarcinoma cells and the effect exerted under these conditions in association with hypoxia on the Gal-3 expression. Gal-3 and the microtubule-associated protein light chain 3 beta (LC3) were accessed through western blot and immunofluorescence. Degradative vacuole quantification was analyzed by transmission electronic microscopy, and inhibition of Gal-3 was performed using siRNA. According to the analyses, the most effective conditions in the inducement of autophagy for PANC-1 and MIA PaCa-2 cells were nutritional deprivation and complete amino acid/glucose deprivation, respectively. PANC-1 cells presented higher Gal-3 when they were submitted to 24 h of nutritional deprivation alone and simultaneously nutritional and oxygen deprivation. Inhibition of Gal-3 causes a decrease of LC3 levels in all experimental conditions. These results confirm that Gal-3 is modulated by microenvironment factors and the possibility of Gal-3 participating in an adaptive response from PDAC cells to extreme conditions.

Dexamethasone inhibits cytokine production in PBMC from systemic sclerosis patients.

Glucocorticoids (GC) are widely used in the treatment of SSc, although there is not much evidence to prove the benefits offered by these drugs in this disease. In this study, we evaluated the effects of a GC on cytokine production in peripheral blood mononuclear cells (PBMC) of SSc patients. The effect of dexamethasone (DEX) was evaluated in PBMC of 21 SSc patients and 10 healthy volunteers after stimulation of cells with anti-CD3 and anti-CD28. Cytokines IL-2, IL-4, IL-6, IL-10, IL-17A, IL-17F, IFN-γ, TNF, and IL-1ß were quantified in the culture supernatant by CBA or ELISA. Of the patients evaluated in this study, 8 (38%) were taking corticosteroids, and esophageal dysfunction was more frequent in these patients when compared to those who did not take corticosteroids. DEX (1.000 nM) treatment in PBMC of SSc patients stimulated with anti-CD3 and anti-CD28 promoted a significant reduction in IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF, IL-1ß (p < 0.001 for all), and IL-17F (p = 0.023) cytokines levels. We did not observe differences in response to in vitro treatment with DEX between groups of patients taking or not taking corticosteroids. In PBMC from healthy volunteers, we observed that DEX treatment significantly reduced IL-4, IFN-γ (p = 0.003 for both), IL-6, IL-10, IL-17A, and TNF (p = 0.002 for all) cytokines. These results show that DEX treatment in PBMC of SSc patients reduced the production of important cytokines involved in the pathogenesis of the disease, suggesting a possible mechanism of action of the CG in the treatment of SSc.

Anticancer properties of thiophene derivatives in breast cancer MCF-7 cells.

Substitutions in thiophene structure give rise to new derivatives with different biological and pharmacological activities. The present study investigated the cytotoxicity activity of some thiophene derivatives in breast cancer cells maintained in two-dimensional (2D) or in three-dimensional (3D) culture and evaluated the anticancer mechanism of these compounds. Cytotoxicity assays were performed against untransformed cells and against breast cancer cell MCF-7. Apoptosis analysis and in-vitro migration assay were also performed to evaluate the mechanism of induction of cell death. All thiophene derivatives reduced the cell viability in breast cancer cells, showing cytotoxic activity (IC50<30 µmol/l), and SB-200 compound showed the best selectivity index in MCF-7 cells compared with doxorubicin in 2D culture. All thiophene derivatives significantly induced G0/G1 phase cell cycle arrest. However, only SB-83 treatment was effective against motility of MCF-7 cells in 2D culture (P=0.0059). The SB-200 derivative treatment induced an increased proportion of acridine orange/Hoechst double-stained cells (35.35 vs. 3.14%, P=0.0002) compared with nontreated cells, with apoptosis morphological alterations independent of caspase 7 activation (P>0.05). MCF-7 cells became less responsive to SB-200 and to doxorubicin in 3D culture compared with cells in 2D culture (higher IC50 values); however, SB-200 showed a better cytotoxic effect compared with doxorubicin in 3D culture. Therefore, the current study provides an insight into anticancer potential of thiophene derivatives, and further studies should be conducted to understand the mechanism by which thiophene derivatives act on cancer cells.

Evaluation of Thiazolidine Derivatives with Potential Anti-ZIKV Activity.

OBJECTIVE: In this study, we have synthesized 19 Thiazolidine (TZD) derivatives to investigate their potential anti-ZIKV effects. METHODS: Nineteen thiazolidine derivatives were synthesized and evaluated for their cytotoxicity and antiviral activity against the ZIKA virus. RESULTS: Among them, six demonstrated remarkable selectivity against the ZIKV virus, exhibiting IC50 values of <5µM, and the other compounds did not demonstrate selectivity for the virus. Interestingly, several derivatives effectively suppressed the replication of ZIKV RNA copies, with derivatives significantly reducing ZIKV mRNA levels at 24 hours post-infection (hpi). Notably, two derivatives (ZKC-4 and -9) stood out by demonstrating a protective effect against ZIKV cell entry. Informed by computational analysis of binding affinity and intermolecular interactions within the NS5 domain's N-7 and O'2 positions, ZKC-4 and FT-39 displayed the highest predicted affinities. Intriguingly, ZKC-4 and ZKC-9 derivatives exhibited the most favorable predicted binding affinities for the ZIKV-E binding site. CONCLUSION: The significance of TZDs as potent antiviral agents is underscored by these findings, suggesting that exploring TZD derivatives holds promise for advancing antiviral therapeutic strategies.

Vitamin D Presented In Vitro Immunomodulatory Property on T Lymphocyte-Related Cytokines in Systemic Lupus Erythematosus.

Inflammatory T lymphocyte cytokines contribute to tissue damage in SLE patients. Vitamin D (Vit D) has a well-established immunomodulatory action, but few studies have addressed the effect of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) on peripheral blood mononuclear cells (PBMCs) in SLE patients. The aim of this study was to evaluate the immnunomodulatory effect of 1,25 (OH)2D3 on T lymphocyte-related cytokines. Blood from 27 female SLE patients was collected for PBMC isolation and anti-DNA, complement, and serum 25 (OH)D3 level measurements. PBMCs were stimulated with anti-CD3/anti-CD28 in the presence or absence of dexamethasone or various concentrations of 1,25 (OH)2D3 for 48 h. We assessed IL-17A, IL-22, IL-21, IL-9, IFN-γ, IL-4, IL-10, IL-2, IL-6, and TNF by cytometric bead assay (CBA) and enzyme immune assay (ELISA) on culture supernatant. The mean age of patients was 36.2 (± 10.5 years) and the median Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was 4 (0-6). The addition of 1,25 (OH)2D3 in PBMC culture reduced IL-17 A, IL-22, IL-9, and IFN-γ levels at 100 nM (p ≤ 0.0001). Furthermore, the addition of 1,25 (OH)2D3 at all concentrations increased IL-4 (p ≤ 0.0006), and 0.1 and 1 nM increased IL-10 (p ≤ 0.0004) and 0.1 nM increased IL-2 levels (p ≤ 0.0001). There was no difference regarding IL-21 and TNF levels. The addition of 1,25 (OH)2D3 in PBMC culture presented an inhibitory effect on proinflammatory cytokines and increased immunoregulatory cytokines in SLE patients, suggesting the beneficial effect of this vitamin.

Siglec 15 as a biomarker or a druggable molecule for non-small cell lung cancer.

Lung cancer has been the main cause of cancer mortality worldwide. Furthermore, lung cancer rates of new cases per year evidenced a large incidence of this neoplasm in both men and women. Because there is no biomarker for early detection, it is frequently detected late, at an advanced state. The introduction of multiple lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations has modified the therapy of lung cancer. Immunotherapy advances have resulted in substantial improvements in overall survival and disease-free survival, making immune checkpoint inhibitors (ICIs) a potential option for lung cancer treatment. Current PD-1/PD-L1/CTLA-4 immunotherapies have resulted in important response and survival rates. However, existing medicines only function in around 20% of unselected, advanced NSCLC patients, and primary and acquired resistance remain unsolved obstacles. Therefore, precise predictive indicators must be identified to choose the best patients for ICI treatment. Thus, Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) stands out as a potential tumor biomarker, with distinctive expression in normal tissues, in tumor immune involvement, and a high structural similarity to PD-L1. Understanding the tumor immune response and the search for new therapeutic targets leads to the improvement of therapeutic pathways directed at the tumor microenvironment. The present review aims to analyze Siglec-15 potential as a diagnostic, prognostic, and response biomarker in lung cancer, considering its results evidenced in the current literature.

High serum levels of galectins 1 and 4 in osteoarthritis patients.

BACKGROUND: Although immunostaining of galectins is associated with cartilage damage, the serum levels of these lectins in osteoarthritis (OA) are not fully understood. OBJECTIVE: Therefore, we evaluate the concentrations of galectins-1, 3, 4, and 7 in patients with osteoarthritis and correlate them with clinical parameters. METHODS: This cross-sectional study involved 60 osteoarthritis patients and 43 healthy volunteers, who had serum samples collected for galectins titration by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Our finds showed that the median values of gal-1 and 4 serum levels in patients were statistically higher (13,990 and 969.1 pg/mL, respectively) than in healthy controls (1,798 and 519.5 pg/mL) with p < 0.001. Further, gal-1 expressed higher levels in patients who had joint edema at the time of collection with a median value of 14,970 pg/mL. CONCLUSION: Surprisingly, galectin-4 appears to be involved in the osteoarthritis inflammation process as the well-known galectin-1.

Water-soluble Moringa oleifera Seed Lectin Exhibits Monoaminergic Pathway-linked Anti-depressive-like Effects in Mice.

OBJECTIVES: The present study investigated the anti-depressive-like (anti-immobility) effect of a lectin from Moringa oleifera seeds (WSMoL) in mice. METHODS: To evaluate an acute effect, the animals were treated with WSMoL (1, 2, and 4 mg/kg, i.p.) 30 min before the tail suspension test (TST). To investigate the involvement of monoaminergic and nitrergic signaling, the mice were pre-treated with selective antagonists. The role of the WSMoL carbohydrate-recognizing domain (CRD) was verified using previous blockage with casein (0.5 mg/mL). The subacute anti-immobility effect was also evaluated by administering WSMoL (1, 2, and 4 mg/kg, i.p.) once a day for 7 d. Finally, an open field test (OFT) was performed to identify possible interferences of WSMoL on animal locomotory behavior. RESULTS: WSMoL reduced the immobility time of mice in the TST at all doses, and combined treatment with fluoxetine (5 mg/kg, i.p.) and WSMoL (1 mg/kg) was also effective. The CRD appeared to be involved in the anti-immobility effect since the solution of WSMoL (4 mg/kg) pre-incubated with casein showed no activity. The lectin effect was prevented by the pre-treatment of mice with ketanserin, yohimbine, and SCH 23390, thereby demonstrating the involvement of monoaminergic pathways. In contrast, pre-treatment with L-NAME, aminoguanidine, and L-arginine did not interfere with lectin action. WSMoL exhibited a subacute effect in the TST, thereby reducing immobility time and increasing agitation time even on the seventh day. OFT data revealed that the anti-immobility effect was not caused by interference with locomotor behavior. CONCLUSION: WSMoL elicits an anti-depressant-like effect that is dependent on monoaminergic signaling.

Synthesis, ADMET Prediction, and Antitumor Profile of Phenoxyhydrazine- 1,3-thiazoles Derivatives.

BACKGROUND: Cancer is one of the most important barriers to increasing life expectancy in all countries in the 21st century. Investigations of new anti-cancer drugs with low side effects are an urgent demand for medicinal chemists. Considering the known antitumor and immunomodulatory activity of thiazoles, this work presents the synthesis and antineoplastic activity of new thiazoles. METHODS: The 22 new compounds (2a-v) were synthesized from different thiosemicarbazones and 2-bromoacetophenone. The compounds were evaluated on: MOLT-4, HL-60, HL-60/MX1, MM1S, SKMEL-28, DU145, MCF-7, and T47d. RESULTS: Compound 2b induced cellular viability on MOLT-4 (37.1%), DU145 (41.5%), and HL- 60/MX1 (58.8%) cells. On MOLT-4 cells, compound 2b exhibited an IC50 of 8.03 µM, and against DU145 cells, an IC50 of 6.04µM. Besides, at IC50 and fold of IC50, 20% to 30% of dead cells were found, most due to necrosis/late apoptosis. Most compounds no showed cytotoxicity against fibroblast cells L929 at the concentrations tested. The compound did not alter the cell cycle of DU145 cells when compared to the negative control. Therefore, compound 2b stands out against DU145 and MOLT-4 cells. CONCLUSION: Our study reinforced the importance of 1,3-thiazoles nuclei in antitumor activity. In addition, derivative 2b stands out against DU145 and MOLT-4 cells and could be a starting point for developing new antineoplastic agents.

Interaction study with DNA/HSA, anti-topoisomerase IIα, cytotoxicity and in vitro antiproliferative evaluations and molecular docking of indole-thiosemicarbazone compounds.

In this work we will discuss the antiproliferative evaluation and the possible mechanisms of action of indole-thiosemicarbazone compounds LTs with anti-inflammatory activity, previously described in the literature. In this perspective, some analyzes were carried out, such as the study of binding to human serum albumin (HSA) and to biological targets: DNA and human topoisomerase IIα (topo). Antiproliferative study was performed with DU-145, Jukart, MCF-7 and T-47D tumor lines and J774A.1, besides HepG2 macrophages and hemolytic activity. In the HSA interaction tests, the highest binding constant was 3.70 × 106 M-1, referring to LT89 and in the fluorescence, most compounds, except for LT76 and LT87, promoted fluorescent suppression with the largest Stern-Volmer constant for the LT88 3.55 × 104. In the antiproliferative assay with DU-145 and Jurkat strains, compounds LT76 (0.98 ± 0.10/1.23 ± 0.32 µM), LT77 (0.94 ± 0.05/1.18 ± 0.08 µM) and LT87 (0.94 ± 0.12/0.84 ± 0.09 µM) stood out, due to their IC50 values mentioned above. With the MCF-7 and T-47D cell lines, the lowest IC50 was presented by LT81 with values of 0.74 ± 0.12 µM and 0.68 ± 0.10 µM, respectively, followed by the compounds LT76 and LT87. As well as the positive control amsacrine, the compounds LT76, LT81 and LT87 were able to inhibit the enzymatic action of human Topoisomerase IIα.

Imidazolidine Derivatives in Cancer Research: What is known?

It is well known that cancer is the second leading cause of death worldwide. Due to this fact, new results for the treatment of cancer are constantly being introduced and verified. Imidazolidine derivatives regulate cell cycle progression and DNA stability. Structurally, a heterocyclic nucleus favors a direct DNA interaction and therefore, control of the DNA replication process. This review aims not only to discuss the role of imidazolidines in cancer therapy but also explore the functionality of such agents in the future aspects of cancer prognosis and treatment. Convincing data from 1996 to 2021 has presented imidazolidine derivatives as a relevant therapeutic tool to modulate cancer progression and malignancy. Here we highlight these aspects in a variety of cell lines, cancer types, involving in vitro and in vivo techniques.

Evaluation of long-term stability of SARS-CoV-2 nucleic acid extracted from human nasopharyngeal samples.

The maintenance of SARS-Cov-2 RNA samples poses a new challenge for laboratories and researchers. In addition, it is a requirement in order to identify what strain of the new coronavirus is predominant in a region, for instance. Therefore, it is a must to keep the quality and viability of stored RNA to respond to this and other valid questions. In other to test the quality of our samples and storing protocols, we randomly checked RNA samples four different times over one year using a second RT-PCR assay after the first test. The virus genes, N1 and N2, showed no significant increase in the media of the CT value between the first assay and subsequent times with p > 0.05. However, the human RP gene showed differences in the first three times analyzed, but within the acceptable sample cut-off, according to the test manufacturer. After one year, the RNA extracted from human nasopharyngeal specimens are viable to detect the virus SARS-CoV-2 genes with minor changes.

Treatment with biological therapy is associated with faster recovery and lower frequency of treatment switch among rheumatic patients with Chikungunya fever.

BACKGROUND/OBJECTIVE: The effects of Chikungunya virus (CHIKV) infection on patients with rheumatic diseases have not been extensively studied. Our aim was to compare the clinical course of patients with rheumatoid arthritis and spondyloarthritis, categorized according to the use or not of biologic disease modifying anti-rheumatic drugs (bDMARDs), during and after infection by CHIKV. METHODS: Patients from a northeastern Brazilian city that suffered an epidemic outbreak of Chikungunya fever (CHIK) between Oct 2015 and Jul 2016, on regular follow-up in a longitudinal registry of rheumatic patients (BiobadaBrasil), were invited to participate. Participants underwent a standardized clinical interview and collection of blood sample for serological tests (IgM/IgG) for CHIKV. A positive IgG was considered evidence of previous CHIKV infection. RESULTS: 105 patients (84 with rheumatoid arthritis, 17 with ankylosing spondylitis, and 4 with psoriatic arthritis) were evaluated. Most patients (58, 55.2%) were on therapy with bDMARDs. The overall prevalence of seropositivity for CHIKV was 47.6% (39.7% in patients on bDMARDs and 57.4% in those exclusively on conventional synthetic (cs-) DMARDs (p = 0.070). Among seropositive patients, asymptomatic disease had similar frequency in those treated and not treated with bDMARDs (39.1% versus 33.3%, respectively; p = 0.670). However, patients exclusively on csDMARDs presented significantly higher prevalence of articular symptoms beyond 3 months and switched treatment more often than patients on bDMARDs (p < 0.05 for both comparisons). CONCLUSIONS: Among rheumatic patients with CHIK, those on bDMARDs had shorter persistence of articular symptoms and switched treatment scheme less often than patients exclusively treated with csDMARDs.

Serum biomarkers associated with SARS-CoV-2 severity.

Immunity with SARS-CoV-2 infection during the acute phase is not sufficiently well understood to differentiate mild from severe cases and identify prognostic markers. We evaluated the immune response profile using a total of 71 biomarkers in sera from patients with SARS-CoV-2 infection, confirmed by RT-PCR and controls. We correlated biological marker levels with negative control (C) asymptomatic (A), nonhospitalized (mild cases-M), and hospitalized (severe cases-S) groups. Among angiogenesis markers, we identified biomarkers that were more frequently elevated in severe cases when compared to the other groups (C, A, and M). Among cardiovascular diseases, there were biomarkers with differences between the groups, with D-dimer, GDF-15, and sICAM-1 higher in the S group. The levels of the biomarkers Myoglobin and P-Selectin were lower among patients in group M compared to those in groups S and A. Important differences in cytokines and chemokines according to the clinical course were identified. Severe cases presented altered levels when compared to group C. This study helps to characterize biological markers related to angiogenesis, growth factors, heart disease, and cytokine/chemokine production in individuals infected with SARS-CoV-2, offering prognostic signatures and a basis for understanding the biological factors in disease severity.

Investigation of a new oxazolidine derivative in human resistance acute leukemia cells: deciphering its mechanism of action by label-free proteomic.

The present study aimed to evaluate the mechanism of action of the antineoplastic activity of an oxazolidine derivative, LPSF/NB-3 (5-(4-cloro-benzilideno)-3-etil-2-tioxo-oxazolidin-4-ona). Cytotoxicity assays were performed in peripheral blood mononuclear cells (PBMCs) and resistant acute leukemia cell line (HL-60/MX1) by the MTT method. LPSF/NB-3 exhibited cytotoxicity in HL-60/MX1, but it was not toxic to healthy cells in the highest dose tested (100 µM). The protein extract of HL-60/MX1 cells treated with LPSF/NB-3 was subjected to proteomic analysis using two-dimensional chromatography coupled to mass spectrometry. We could identify a total of 2652 proteins, in which 633 were statistically modulated. Within the group of protein considered for the quantitative analysis with the established criteria, 262 were differentially expressed, 146 with increased expression and 116 with decreased expression in the sample treated with LPSF/NB-3 compared to the control. The following differentially expressed pathways were found: involving regulation of the cytoskeleton, DNA damage, and transduce cellular signals. Networks that were highlighted are related to the immune system. The ELISA technique was used to assess the immunomodulatory potential of LPSF/NB-3 in PBMCs. We observed significant decrease of IFNγ (p < 0.01) and dose-response pattern of the cytokines IL-6, IL-17A, IL-22, and IL-10. Therefore, results suggest that LPSF/NB-3 appears to modulate important pathways, including cell cycle and immune system regulatory pathways.

Synthesis, anticancer activity and mechanism of action of new phthalimido-1,3-thiazole derivatives.

In this work, 22 new compounds were obtained and evaluated for their cytotoxic activity on peripheral blood mononuclear cells (PBMC) and eight different tumor cell lines. All compounds displayed IC50 values above 100 µM when assayed against PBMCs. The cytotoxic assays in tumor cell lines revealed that sub-series of phthalimido-bis-1,3-thiazoles (5a-f) exhibited the best anti-tumor activity profile, presenting viability values below 59 %. As a result, the IC50 value was calculated for compounds 5a-f and 4c, and compounds 5b and 5e were selected for further assays due to their best IC50s. Considering the results presented by the sub-series 5a-f, the importance of the 1,3-thiazole ring in improving the anti-tumor activity was pointed out. Together, the results highlighted the anti-tumor activity of phthalimido-bis-1,3-thiazole derivatives.

Alzheimer's disease: Is there a role for galectins?

Alzheimer's disease (AD) is the world's leading cause of neurological dysfunction, cognitive decline, and neuronal loss in the elderly. The sedimentation of beta amyloid (Aß)-containing plaque, and formation of tau-containing neurofibrillary tangles (NFTs) along with extensive neuroinflammation, are the events that characterize the pathogenesis of AD. Galectins (gal) are carbohydrate-containing-ligand molecules recognized as potential modulators of the brain microglia polarization, immunosurveillance, neuroinflammation, and neuroprotection. Galectins 1, 3, 4, 8, and 9 are amongst the 15 members of the galectin family which are expressed in the brain. These galectins possess a significant correlation with neuromodulation through the glial cell-induced cytokine production that plays either a complementary or antagonistic role in the disturbance of the CNS physiology. Therefore, elaborating the hypothesis of galectins in the development of AD is of potential interest. This review aims at discussing the interaction between galectins and the neuropathophysiology of AD. An understanding about how galectins communicate with AD progression could lead to the development of improved diagnostic and therapeutic strategies for this leading cause of dementia worldwide.