Summary
As part of the innate immune response, neutrophils are at the forefront of defence against infection, resolution of inflammation and wound healing. They are the most abundant leucocytes in ...the peripheral blood, have a short lifespan and an estimated turnover of 1010 to 1011 cells per day. Neutrophils efficiently clear microbial infections by phagocytosis and by oxygen‐dependent and oxygen‐independent mechanisms. In 2004, a new neutrophil anti‐microbial mechanism was described, the release of neutrophil extracellular traps (NETs) composed of DNA, histones and anti‐microbial peptides. Several microorganisms, bacterial products, as well as pharmacological stimuli such as PMA, were shown to induce NETs. Neutrophils contain relatively few mitochondria, and derive most of their energy from glycolysis. In this scenario we aimed to analyse some of the metabolic requirements for NET formation. Here it is shown that NETs formation is strictly dependent on glucose and to a lesser extent on glutamine, that Glut‐1, glucose uptake, and glycolysis rate increase upon PMA stimulation, and that NET formation is inhibited by the glycolysis inhibitor, 2‐deoxy‐glucose, and to a lesser extent by the ATP synthase inhibitor oligomycin. Moreover, when neutrophils were exposed to PMA in glucose‐free medium for 3 hr, they lost their characteristic polymorphic nuclei but did not release NETs. However, if glucose (but not pyruvate) was added at this time, NET release took place within minutes, suggesting that NET formation could be metabolically divided into two phases; the first, independent from exogenous glucose (chromatin decondensation) and, the second (NET release), strictly dependent on exogenous glucose and glycolysis.
Summary
Rheumatoid arthritis is a disabling autoimmune disease with a high global prevalence. Treatment with disease‐modifying anti‐arthritic drugs (DIMARDs) has been routinely used with beneficial ...effects but with adverse long‐term consequences; novel targeted biologics and small‐molecule inhibitors are promising options. In this study, we investigated whether purified omega unsaturated fatty acids (ω‐UFAs) and dialysable leukocyte extracts (DLEs) prevented the development of arthritis in a model of collagen‐induced arthritis (CIA) in mice. We also investigated whether the transcription factor NF‐κB and the NLRP3 inflammasome were involved in the process and whether their activity was modulated by treatment. The development of arthritis was evaluated for 84 days following treatment with nothing, dexamethasone, DLEs, docosahexaenoic acid, arachidonic acid, and oleic acid. Progression of CIA was monitored by evaluating clinical manifestations, inflammatory changes, and histological alterations in the pads’ articular tissues. Both DLEs and ω‐UFAs led to an almost complete inhibition of the inflammatory histopathology of CIA and this was concomitant with the inhibition of NF‐kB and the inhibition of the activation of NLRP3. These data suggest that ω‐UFAs and DLEs might have NF‐κB as a common target and that they might be used as ancillary medicines in the treatment of arthritis.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons that results in progressive paralysis and muscular atrophy. There are ...many molecules and genes involved in neuromuscular degeneration in ALS; among these, matrix metalloproteinases (MMPs). MMPs play an important role in the pathology of ALS, and MMP-1, 2, 3, and 9 might serve as disease progression markers. Tissue inhibitors of metalloproteinases (TIMPS) might also function as progression markers in ALS because they participate in regulating the proteolytic activity of MMPs. Moreover, a diversity of genes also plays a role in the pathogenesis of ALS; most MMPs-coding genes present variants related to the pathological proteolytic activity. This short review, however, will focus on the role of matrix metalloproteinases in ALS.
•The role of matrix metalloproteinases in ALS•The matrix metalloproteinases are involved in the neuromuscular degeneration in ALS.•TIMPs might to function as progression markers in ALS•The metalloproteinase activity is responsible of the remodeling in both physiological and pathological tissues•The variants of MMPs-coding genes are related with the pathological proteolytic activity.
Specific mortality rates have been widely used to monitor the main impacts of the COVID-19 pandemic; however, a more meaningful measure is the Years of Life Lost (YLL) due to the disease, considering ...it takes into account the premature nature of each death. We estimated the YLL due to COVID-19 between January 2020 and December 2021 in 49 countries for which information was available, developing an analytical method that mathematically refines that proposed by the World Health Organization. We then calculated YLL rates overall, as well as by sex and life cycle. Additionally, we estimated the national cost-effective budgets required to manage COVID-19 from a health system perspective. During the two years of analysis, we estimated that 85.6 million years of life were lost due to COVID-19 in the 49 countries studied. However, due to a lack of data, we were unable to analyze the burden of COVID-19 in about 75% of the countries in the world. We found no difference in the magnitude of YLL rates by gender but did find differences according to life cycle, with older adults contributing the greatest burden of YLL. The COVID-19 pandemic has posed a significant burden of disease, which has varied between countries. However, due to the lack of quality and disaggregated data, it has been difficult to monitor and compare the pandemic internationally. Therefore, it is imperative to strengthen health information systems in order to prepare for future pandemics as well as to evaluate their impacts.
Neutrophils play an important role in the control of pathogens through several mechanisms, including phagocytosis and the formation of neutrophil extracellular traps (NETs). The latter consists of ...DNA as a backbone with embedded antimicrobial peptides, histones, and proteases, providing a matrix to entrap and in some cases to kill microbes. Some metabolic requirements for NET formation have recently been described. The virus-induced formation of NETs and the role of these traps in viral infections remain scarcely reported. Here, we analyzed whether dengue virus serotype-2 (DENV-2) induces NET formation and the DENV-2 effect on phorbol myristate acetate (PMA)-induced NETs.
Peripheral blood-derived neutrophils were exposed in vitro to DENV-2 or exposed to DENV-2 and then stimulated with PMA. NET formation was assessed by fluorescence microscopy. Cell membrane Glut-1, glucose uptake, and reactive oxygen species (ROS) production were assessed.
DENV-2 does not induce the formation of NETs. Moreover, DENV-2 inhibits PMA-induced formation of NETs by about 80%. This effect is not related to the production of ROS. The mechanism seemingly accountable for this inhibitory effect is the DENV-2-mediated inhibition of PMA-induced glucose uptake by neutrophils.
Our results suggest that DENV-2 inhibits glucose uptake as a metabolism-based way to avoid the formation of NETs.
Abstract Although murine leprosy is no longer a common illness, our understanding of the biology of this disease is incomplete. One particular example of this concerns the etiologic agent ...Mycobacterium lepraemurium (MLM). MLM is a fastidious microorganism that is difficult to grow in axenic media; in a way, this has hampered attempts to thoroughly study its physiological and metabolic characteristics. MLM is an obligate intracellular bacillus that invades macrophages and replicates profusely with a generation time that oscillates between 0.5 and 11 days. In the present study, we have successfully maintained MLM alive for more than 12 days in vitro, providing us with an opportunity to study its susceptibility to several anti-leprosy agents and other drugs. To achieve this, we used a fluorescence reduction assay of alamar blue (a resazurin) in a microplate format (microplate-alamar-blue-assay; MABA), which is a highly sensitive, practical, and inexpensive method for assaying cell viability. We found that MLM was highly susceptible to clofazimine and rifampicin and was less susceptible to streptomycin, thiacetazone, kanamycin, dapsone, and ethionamide, in that order. MLM was not susceptible to four plant triterpenoids (oleanolic acid, neolignan-c, sitosterol, and ursolic acid) for which bactericidal activity has been reported in M. tuberculosis . Because the MABA has high sensitivity, it can be used to monitor the activity of microorganisms that are difficult to cultivate (such as M. lepraemurium ), in response to various drugs, thus offering a method to complement the study of murine leprosy, about which many questions remain unanswered.
Host immunity to Mycobacterium leprae encompasses a spectrum of mechanisms that range from cellular immunity-driven protection to damage associated with humoral immunity as in type-2 leprosy ...reactions. Although type I interferons (IFNs) participate in eliminating intracellular pathogens, their contribution to the production of antibodies and CD3+ FOXP3+ regulatory T cells (Tregs) in BCG vaccine-mediated protection in leprosy is unknown. BCGphipps (BCGph) priming followed by intramuscular hIFN-α 2b boost significantly reduced lesion size and Mycobacterium lepraemurium growth in the skin. T follicular regulatory cells (TFR), a subset of Tregs induced by immunization or infection, reside in the germinal centers (GCs) and modulate antibody production. We found impaired Treg induction and improved GCs in draining lymph nodes of BCGph primed and hIFN-α 2b boosted mice. Moreover, these mice elicited significant amounts of IL-4 and IL-10 in serum. Thus, our results support the adjuvant properties of hIFN-α 2b in the context of BCGph priming to enhance protective immunity against skin leprosy.
The goal of this work is to compile and discuss molecules of marine origin reported in the scientific literature with anti-parasitic activity against Trichomonas, Giardia, and Entamoeba, parasites ...responsible for diseases that are major global health problems, and Microsporidial parasites as an emerging problem. The presented data correspond to metabolites with anti-parasitic activity in human beings that have been isolated by chromatographic techniques from marine sources and structurally elucidated by spectroscopic and spectrometric procedures. We also highlight some semi-synthetic derivatives that have been successful in enhancing the activity of original compounds. The biological oceanic reservoir offers the possibility to discover new biologically active molecules as lead compounds to develop new drug candidates. The molecular variety is extensive and must be correctly explored and managed. Also, it will be necessary to take some actions to preserve the source species from extinction or overharvest (e.g., by cryopreservation of coral spermatozoa, oocytes, embryos, and larvae) and coordinate appropriate exploitation to increase the chemical knowledge of the natural products generated in the oceans. Additional initiatives such as the total synthesis of complex natural products and their derivatives can help to prevent overharvest of the marine ecosystems and at the same time contribute to the discovery of new molecules.
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•Natural active components of marine organisms have specific biological properties.•The marine compounds have multiple anti-parasitic activity.•The semi-synthetic derivatives of natural active components of marine organism are candidates for new drugs.
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