To describe the laboratory parameters and biomarkers of the cytokine storm syndrome associated with severe and fatal COVID-19 cases. A search with standardized descriptors and synonyms was performed ...on November 28.sup.th, 2020 of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, LILACS, and IBECS to identify studies of interest. Grey literature searches and snowballing techniques were additionally utilized to identify yet-unpublished works and related citations. Two review authors independently screened the retrieved titles and abstracts, selected eligible studies for inclusion, extracted data from the included studies, and then assessed the risk of bias using the Newcastle-Ottawa Scale. Eligible studies were those including laboratory parameters-including serum interleukin-6 levels-from mild, moderate, or severe COVID-19 cases. Laboratory parameters, such as interleukin-6, ferritin, hematology, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer, were extracted from the studies. Meta-analyses were conducted using the laboratory data to estimate mean differences with associated 95% confidence intervals. This review points to interleukin-6, ferritin, leukocytes, neutrophils, lymphocytes, platelets, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer as important biomarkers of cytokine storm syndrome. Elevated levels of interleukin-6 and hyperferritinemia should be considered as red flags of systemic inflammation and poor prognosis in COVID-19.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Fenebrutinib (GDC‐0853) is a noncovalent, oral, and highly selective inhibitor of Bruton’s tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic ...lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo‐controlled study.
Methods
Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI‐4) response at week 48.
Results
Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI‐4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group–based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK‐dependent plasmablast RNA signature, anti–double‐stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo.
Conclusion
While fenebrutinib had an acceptable safety profile, the primary end point, SRI‐4 response, was not met despite evidence of strong pathway inhibition.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The initiation and progression of periodontitis might involve a local renin‐angiotensin system in periodontal tissue. This study hypothesized that Losartan treatment could promote ...protection to rats submitted to experimental periodontitis (EP) by attenuating alveolar bone loss due to reduction in inflammatory cytokines, better reactive oxidant species regulation and maintenance of the balance between bone formation and resorption factors.
Methods
One hundred and thirty rats were submitted to EP with a silk suture thread (4.0) placed around the lower right first molar for 1, 3, 7, and 14 consecutive days. The study comprised four groups: G1—control without EP; G2—animals with EP treated with water; G3—Losartan‐treated animals (treatment started at the same day of EP induction), and G4—animals previously treated with Losartan for 30 days followed by induction of EP and continuity of treatment.
Results
G2 rats had greater bone loss volume, increased number, and thickness and decreased separation of trabeculae. On the other hand, G4 animals showed significant improvements in these parameters. Histological analysis revealed that EP favors inflammatory cell infiltration and junctional epithelium, cementum with alveolar bone crest destruction, but animals pretreated with Losartan (G4) did not show these features. Although the G3 animals did not demonstrate the improvements detected in G4, mRNA expression results were similar. In mandibular tissue, EP promoted mRNA increases for ACE, AT1 receptor, and inflammatory mediators as well as decreases for antioxidant enzymes. However, Losartan treatments attenuated these responses in addition to promoting an increase in bone formation markers and transcription factors.
Conclusion
AT1 receptor modulates EP progression.
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BFBNIB, CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
There are limited data about the influence of stent composition on immune responses after percutaneous coronary intervention (PCI).
The aim was to compare the effects of PCI with conventional ...cobalt-chromium bare metal stent (BMS) and drug-eluting stent (DES) implantation on the modulation of humoral and cellular immune responses.
A randomised, single-centre, open pilot study involving patients with stable coronary artery disease eligible for PCI was performed. Blood samples were collected from the peripheral artery (PA) and the coronary sinus (CS) at baseline and 40 weeks following PCI. IgM and IgG autoantibodies (Abs), anti-oxLDL and anti-ApoB-D, as well as cytokine levels were evaluated by enzyme-linked immunosorbent assay.
A total of 30 patients of 60 years mean age were included, 68% of whom were men. At the nine-month follow-up, a modulation in the levels of cytokines and autoantibodies was observed in both stent type groups. However, no difference was observed in the modulation of these markers between stents.
The stent type promotes modulations in cellular and humoral immune responses in the long-term, with differences in the magnitude of effects in specific immune responses.
(1) Background: Malignant gliomas are aggressive tumors characterized by fast cellular growth and highly invasive properties. Despite all biological and clinical advances in therapy, the standard ...treatment remains essentially palliative. Therefore, searching for alternative therapies that minimize adverse symptoms and improve glioblastoma patients' outcomes is imperative. Natural products represent an essential source in the discovery of such new drugs. Plants from the cerrado biome have been receiving increased attention due to the presence of secondary metabolites with significant therapeutic potential. (2) Aim: This study provides data on the cytotoxic potential of 13 leaf extracts obtained from plants of 5 families (Anacardiaceae, Annonaceae, Fabaceae, Melastomataceae e Siparunaceae) found in the Brazilian cerrado biome on a panel of 5 glioma cell lines and one normal astrocyte. (3) Methods: The effect of crude extracts on cell viability was evaluated by MTS assay. Mass spectrometry (ESI FT-ICR MS) was performed to identify the secondary metabolites classes presented in the crude extracts and partitions. (4) Results: Our results revealed the cytotoxic potential of Melastomataceae species
and
. Additionally, comparing the four partitions obtained from
crude extract indicates that the chloroform partition had the greatest cytotoxic activity against the glioma cell lines. The partitions also showed a mean IC
close to chemotherapy, temozolomide; nevertheless, lower toxicity against normal astrocytes. Analysis of secondary metabolites classes presented in these crude extracts and partitions indicates the presence of phenolic compounds. (5) Conclusions: These findings highlight
chloroform partition as a promising component and may guide the search for the development of additional new anticancer therapies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Environmental pollution with chromium (Cr) is harmful to humans, animals and plants, while in plants it causes diminished growth, anatomical alterations and death. In the present study, the potential ...value of marigold (Tagetes erecta) in the phytoremediation of Cr has been investigated. The randomized experimental design involved the exposure of plants to nutrient solutions containing 0.00, 0.04, 0.08, 0.12, 0.16 or 0.24 mmol L−1 Cr(III). Chromium toxicity was observed at Cr(III) concentrations ≥ 0.12 mmol L−1 as demonstrated by diminished growth of the aerial parts and reduced density of the root system. Increasing Cr(III) concentrations in the nutrient solution resulted in a higher bioaccumulation of total Cr in the tissues, although translocation from roots to aerial parts was not efficient (maximum value of 25% at 0.12 mmol L−1 Cr(III)). The Cr bioaccumulation was up to 11-fold greater in roots than in the aerial parts. Tagetes erecta exhibited leaf plasticity when exposed to Cr, indicating the existence of a tolerance mechanism to Cr in this species. Chromium caused a reduction in xilem vases, resulting in a plastic effect in T. erecta leaves that increased the metal tolerance in culture solution. Tagetes spp. are potential Cr hyperaccumulators; at Cr(III) concentrations up to 0.12 mmol L−1, the plants accumulated levels above that proposed for hyperaccumulators and still maintained a considerable growth and even flourished. However, this study was conducted in nutrient solution, and studies on species confirmation as Cr hyperaccumulator should be conducted in soils for further clarification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Acute exercise increases reactive oxygen species (ROS) levels, including hydrogen peroxide (H2 O2 ). H2 O2 promotes endothelial nitric oxide synthase (eNOS) activation and ...phosphorylation in endothelial cells. With this in mind, the present study was designed to evaluate ex vivo eNOS phosphorylation in rat aortas incubated with H2 O2 and to test this hypothesis in vivo in the aortas of rats submitted to acute exercise. Methods For ex vivo studies, six groups of aortic tissue were formed: control, H2 O2 , N-acetylcysteine (NAC), LY294002, compound C, and LY294002 plus compound C. While incubation with H2 O2 increased Akt, AMPK and eNOS phosphorylation, pre-incubation with NAC strongly reduced the phosphorylation of these enzymes. For in vivo studies, male Wistar rats were divided into four groups: control, cont + NAC, exercise, and exer + NAC. After a 3 h swimming session, animals were decapitated and aortas were excised for biochemical and immunoblotting analysis. Results Acute exercise increased superoxide levels and dichlorofluorescein (DCF) concentrations, and this increase was related to phosphorylation of Akt, AMPK and eNOS. On the other hand, use of NAC reduced superoxide levels and DCF concentration. Reduced superoxide levels and DCF in the exer + NAC group were associated with decreased Akt, AMPK and eNOS phosphorylation. These results appear to be connected with vascular function because VASP phosphorylation increased in acute exercise and decreased in exer + NAC. Conclusion Our results indicate that ROS induced by acute exercise play the important role of activating eNOS, a process apparently mediated by Akt and AMPK.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cervical cancer is the third most common in Brazilian women. The chemotherapy used for the treatment of this disease can cause many side effects; then, to overcome this problem, new treatment options ...are necessary. Natural compounds represent one of the most promising sources for the development of new drugs. In this study, 13 different species of 6 families from the Brazilian Cerrado vegetation biome were screened against human cervical cancer cell lines (CCC). Some of these species were also evaluated in one normal keratinocyte cell line (HaCaT). The effect of crude extracts on cell viability was evaluated by a colorimetric method (MTS assay). Extracts from
,
,
,
,
,
, and
showed half-maximal inhibitory concentration (IC
) values < 30 μg/mL for at least one CCC.
and
extracts were selective for CCC. Mass spectrometry (Electrospray Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (ESI FT-ICR MS)) of
identified fatty acids and flavonols as secondary compounds. One of the
fractions, 7C24 (from chloroform partition), increased H2AX phosphorylation (suggesting DNA damage), PARP cleavage, and cell cycle arrest in CCC. Kaempferol-3-O-rhamnoside and oleic acid were bioactive molecules identified in 7C24 fraction. These findings emphasize the importance of investigating bioactive molecules from natural sources for developing new anti-cancer drugs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Acceptance of a COVID-19 vaccine in patients with immune-mediated diseases was high.•COVID-19 vaccine acceptance may be hampered by some comorbidities and treatments.•The short duration of trials ...was the main concern behind COVID-19 vaccine hesitancy.
To identify potential predictors of COVID-19 vaccine hesitancy (C19-VH) in adults with immune-mediated inflammatory diseases (IMID).
A total of 1000 IMID patients were enrolled in this web-based cross-sectional study. A standardised and self-administered survey was designed by members of the Brazilian Society of Rheumatology Steering Committee for Infectious and Endemic diseases and distributed to IMID patients spread across Brazil.
Of the 908 (90.8%) respondents eligible for analysis, 744 (81.9%) were willing to get vaccinated against COVID-19. In our multivariable logistic regression model, concurrent malignancy, fibromyalgia, hydroxychloroquine use, and recent corticosteroid pulse therapy were independently associated with higher odds of C19-VH. The short duration of COVID-19 vaccine clinical trials was the main reason for C19-VH.
We identified novel characteristics potentially associated with C19-VH among adults with IMID. Greater awareness on the safety and efficacy of COVID-19 vaccines is needed for both IMID patients and attending physicians.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
DM64 is a toxin-neutralizing serum glycoprotein isolated from
, an ophiophagous marsupial naturally resistant to snake envenomation. This 64 kDa antitoxin targets myotoxic phospholipases A
, which ...account for most local tissue damage of viperid snakebites. We investigated the noncovalent complex formed between native DM64 and myotoxin II, a myotoxic phospholipase-like protein from
venom. Analytical ultracentrifugation (AUC) and size exclusion chromatography indicated that DM64 is monomeric in solution and binds equimolar amounts of the toxin. Attempts to crystallize native DM64 for X-ray diffraction were unsuccessful. Obtaining recombinant protein to pursue structural studies was also challenging. Classical molecular modeling techniques were impaired by the lack of templates with more than 25% sequence identity with DM64. An integrative structural biology approach was then applied to generate a three-dimensional model of the inhibitor bound to myotoxin II. I-TASSER individually modeled the five immunoglobulin-like domains of DM64. Distance constraints generated by cross-linking mass spectrometry of the complex guided the docking of DM64 domains to the crystal structure of myotoxin II, using Rosetta. AUC, small-angle X-ray scattering (SAXS), molecular modeling, and molecular dynamics simulations indicated that the DM64-myotoxin II complex is structured, shows flexibility, and has an anisotropic shape. Inter-protein cross-links and limited hydrolysis analyses shed light on the inhibitor's regions involved with toxin interaction, revealing the critical participation of the first, third, and fifth domains of DM64. Our data showed that the fifth domain of DM64 binds to myotoxin II amino-terminal and beta-wing regions. The third domain of the inhibitor acts in a complementary way to the fifth domain. Their binding to these toxin regions presumably precludes dimerization, thus interfering with toxicity, which is related to the quaternary structure of the toxin. The first domain of DM64 interacts with the functional site of the toxin putatively associated with membrane anchorage. We propose that both mechanisms concur to inhibit myotoxin II toxicity by DM64 binding. The present topological characterization of this toxin-antitoxin complex constitutes an essential step toward the rational design of novel peptide-based antivenom therapies targeting snake venom myotoxins.
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