Organophosphates are a class of organic compounds that are important for living organisms, forming the building blocks for DNA, RNA, and some essential cofactors. Furthermore, non‐natural ...organophosphates are widely used in industrial applications, including as pesticides; in laundry detergents; and, unfortunately, as chemical weapons agents. In some cases, the natural degradation of organophosphates can take thousands of years; this longevity creates problems associated with handling and the storage of waste generated by such phosphate esters, in particular. Efforts to develop new catalysts for the cleavage of phosphate esters have progressed in recent decades, mainly in the area of homogeneous catalysis. In contrast, the development of heterogeneous catalysts for the hydrolysis of organophosphates has not been as prominent. Herein, examples of heterogeneous systems are described and the importance of the development of heterogeneous catalysts applicable to organophosphate hydrolysis is highlighted, shedding light on recent advances related to different solid matrices that have been employed.
Finding support: Organophosphates have been used as pesticides; laundry detergents; and, unfortunately, as chemical weapons. In some cases, natural degradation can take thousands of years. Herein, examples of heterogeneous systems applicable to organophosphate hydrolysis are discussed to shed light on recent advances related to the different solid matrices that are employed.
Innate immune response against Brucella abortus involves activation of Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Among the NLRs involved in the recognition of B. abortus are NLRP3 and ...AIM2. Here, we demonstrate that B. abortus triggers non-canonical inflammasome activation dependent on caspase-11 and gasdermin-D (GSDMD). Additionally, we identify that Brucella-LPS is the ligand for caspase-11 activation. Interestingly, we determine that B. abortus is able to trigger pyroptosis leading to pore formation and cell death, and this process is dependent on caspase-11 and GSDMD but independently of caspase-1 protease activity and NLRP3. Mice lacking either caspase-11 or GSDMD were significantly more susceptible to infection with B. abortus than caspase-1 knockout or wild-type animals. Additionally, guanylate-binding proteins (GBPs) present in mouse chromosome 3 participate in the recognition of LPS by caspase-11 contributing to non-canonical inflammasome activation as observed by the response of Gbpchr3-/- BMDMs to bacterial stimulation. We further determined by siRNA knockdown that among the GBPs contained in mouse chromosome 3, GBP5 is the most important for Brucella LPS to be recognized by caspase-11 triggering IL-1β secretion and LDH release. Additionally, we observed a reduction in neutrophil, dendritic cell and macrophage influx in spleens of Casp11-/- and Gsdmd-/- compared to wild-type mice, indicating that caspase-11 and GSDMD are implicated in the recruitment and activation of immune cells during Brucella infection. Finally, depletion of neutrophils renders wild-type mice more susceptible to Brucella infection. Taken together, these data suggest that caspase-11/GSDMD-dependent pyroptosis triggered by B. abortus is important to infection restriction in vivo and contributes to immune cell recruitment and activation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gliomas are the most common type of primary brain tumors, presenting high mortality and recurrence rates that highlight the need for the development of more efficient therapies. In that context, we ...investigated iron(
iii
) (FeL) and copper(
ii
) (CuL) complexes containing the tetradentate ligand 2-{(3-chloro-2-hydroxy-propyl)-pyridin-2-ylmethyl-amino-methyl}-phenol (L) as potential antimetastatic compounds in glioma cells. These complexes were designed to act as mimetics of antioxidant metalloenzymes (catalases and superoxide dismutase) and thus interfere with the production of reactive oxygen species (ROS), important signaling molecules that have been linked to the induction of Epithelial-Mesenchymal Transition (EMT) in cancer cells, a process associated with cancer invasion and aggressiveness. The results obtained have revealed that,
in vitro
, both compounds act as superoxide dismutase or catalase mimetics, and this translated in glioma cells into a decrease in ROS levels in FeL-treated cells. In addition, both complexes were found to inhibit the migration of monolayer-grown H4 cells and lead to decreased expression of EMT markers. More importantly, this behavior was recapitulated in 3D spheroids models, where CuL in particular was found to completely inhibit the invasion ability of glioma cells, with or without cellular irradiation with X-rays, which is suggestive of these compounds' potential to be used in combination with radiotherapy. Overall, the results herein obtained describe the novel use of these complexes as agents that are able to interfere with regulation of EMT and the invasive behavior of glioma cells, an application that deserves to be further explored.
Iron and copper complexes with antioxidant activity able to inhibit tumor metastasis by inhibiting epithelial-mesenchymal transition in glioma cells.
Brucella abortus is the causative agent of brucellosis, which causes abortion in domestic animals and undulant fever in humans. This bacterium infects and proliferates mainly in macrophages and ...dendritic cells, where it is recognized by pattern recognition receptors (PRRs) including Nod‐like receptors (NLRs). Our group recently demonstrated the role of AIM2 and NLRP3 in Brucella recognition. Here, we investigated the participation of NLRP12 in innate immune response to B. abortus. We show that NLRP12 inhibits the early production of IL‐12 by bone marrow‐derived macrophages upon B. abortus infection. We also observed that NLRP12 suppresses in vitro NF‐κB and MAPK signaling in response to Brucella. Moreover, we show that NLRP12 modulates caspase‐1 activation and IL‐1β secretion in B. abortus infected‐macrophages. Furthermore, we show that mice lacking NLRP12 are more resistant in the early stages of B. abortus infection: NLRP12−/− infected‐mice have reduced bacterial burdens in the spleens and increased production of IFN‐γ and IL‐1β compared with wild‐type controls. In addition, NLRP12 deficiency leads to reduction in granuloma number and size in mouse livers. Altogether, our findings suggest that NLRP12 plays an important role in negatively regulating the early inflammatory responses against B. abortus.
Brucella activates NLRP12 leading to reduction on NF‐κB and MAPK phosphorylation and modulating the production of IL‐1β and IL‐12.
Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon ...genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions. HIF-1α stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1α renders mice more susceptible to B. abortus infection. Mechanistically, activation of STING by B. abortus infection drives the production of mitochondrial reactive oxygen species (mROS) that ultimately influences HIF-1α stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1α stabilization and IL-1β release independently of its cognate receptor GPR91. Collectively, these data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during B. abortus infection that is orchestrated by STING via HIF-1α pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Sex-difference in adolescent mice revealed an avoidance behavior pattern in females.•Females showed higher risk assessment in the predator odor risk-taking.•Female mice expressed higher levels of ...BDNF exon-IV mRNA in the mPFC.•BDNF exon-IV expression was positively correlated with risk assessment behavior.
Adolescence is as a period of development characterized by impulsive and risk-seeking behaviors. Risk behaviors (RB) involves exposure to dangerous or negative consequences to achieve goal-directed behaviors, such as reward-seeking. On the other hand, risk aversion/assessment behaviors allow the individual to gather information or avoid potentially threatening situations. Evidence has suggested that both behavioral processes, RB and risk assessment (RA), may have sex-differences. However, sex-specific behavioral patterns implicated in RB and RA are not fully understood. To address that, we investigated sex differences in risk-behavioral parameters in a decision-making task developed for rodents. In addition, we investigated the potential role of sex-dependent differences in gene expression of brain-derived neurotrophic factor (BDNF) exon IV in the medial prefrontal cortex (mPFC), which has been implicated to mediate PFC-related behavioral dysfunctions. Male and female C57BL/6J adolescent mice were evaluated in the elevated plus-maze (EPM) to assess anxiety-like behaviors and in the predator-odor risk taking (PORT) task. The PORT task is a decision-making paradigm in which a conflict between the motivation towards reward pursuit and the threat elicited by predatory olfactory cues (coyote urine) is explored. After behavioral testing, animals were euthanized and BDNF exon IV gene expression was measured by RT-qPCR. Comparative and correlational analyses for behavioral and molecular parameters were performed for both sexes. We observed that female mice spent more time exploring the middle chamber of the PORT apparatus in the aversive condition, which is an indicative of avoidance behavior. Female mice also had a higher latency to collect the reward than male mice and presented less time exploring the open arms of the EPM. BDNF exon IV gene expression was higher among females, and there was a positive correlation between the BDNF and PORT behavioral parameters. Our findings suggest sex-dependent effects in the PORT task. Females presented higher RA and avoidance behavior profile and expressed higher levels of BDNF exon IV in the mPFC. Moreover, higher BDNF expression was correlated with RA behaviors, which suggests that adolescent females tend to evaluate the risks more than adolescent males and that BDNF gene expression may be mediating decision-making processes.
The immune system is armed with a broad range of receptors to detect and initiate the elimination of bacterial pathogens. Inflammasomes are molecular platforms that sense a diverse range of microbial ...insults to develop appropriate host response. In that context, noncanonical inflammasome arose as a sensor for Gram‐negative bacteria‐derived LPS leading to the control of infections. This review describes the role of caspase‐11/gasdermin‐D‐dependent immune response against Gram‐negative bacteria and presents an overview of guanylate‐binding proteins (GBPs) at the interface of noncanonical inflammasome activation. Indeed, caspase‐11 acts as a receptor for LPS and this interaction elicits caspase‐11 autoproteolysis that is required for its optimal catalytic activity. Gasdermin‐D is cleaved by activated caspase‐11 generating an N‐terminal domain that is inserted into the plasmatic membrane to form pores that induce pyroptosis, a cell death program involved in intracellular bacteria elimination. This mechanism also promotes IL‐1β release and potassium efflux that connects caspase‐11 to NLRP3 activation. Furthermore, GBPs display many features to allow LPS recognition by caspase‐11, initiating the noncanonical inflammasome response prompting the immune system to control bacterial infections. In this review, we discuss the recent findings and nuances related to this mechanism and its biological functions.
Review on the role of GBPs as major players on noncanonical inflammasome activation.
is a facultative intracellular bacterium that causes brucellosis, a prevalent zoonosis that leads to abortion and infertility in cattle, and undulant fever, debilitating arthritis, endocarditis, and ...meningitis in humans. Signaling pathways triggered by
involves stimulator of IFN genes (STING), which leads to production of type I IFNs. In this study, we evaluated the pathway linking the unfolded protein response (UPR) and the endoplasmic reticulum-resident transmembrane molecule STING, during
infection. We demonstrated that
infection induces the expression of the UPR target gene
and
in murine macrophages through a STING-dependent pathway. Additionally, we also observed that STING activation was dependent on the bacterial second messenger cyclic dimeric GMP. Furthermore, the
-induced UPR is crucial for induction of multiple molecules linked to type I IFN signaling pathway, such as IFN-β, IFN regulatory factor 1, and guanylate-binding proteins. Furthermore, IFN-β is also important for the UPR induction during
infection. Indeed, IFN-β shows a synergistic effect in inducing the IRE1 axis of the UPR. In addition, priming cells with IFN-β favors
survival in macrophages. Moreover,
-induced UPR facilitates bacterial replication in vitro and in vivo. Finally, these results suggest that
-induced UPR is triggered by bacterial cyclic dimeric GMP, in a STING-dependent manner, and that this response supports bacterial replication. In summary, association of STING and IFN-β signaling pathways with
-induced UPR unravels a novel link between innate immunity and endoplasmic reticulum stress that is crucial for bacterial infection outcome.
Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain ...regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A. Prenatal exposure to green tea polyphenols containing EGCG protects from brain defects induced by overexpression of DYRK1A.
In order to produce more robust and possibly more active analogues of the natural compound EGCG, here we synthetized new EGCG-like molecules with several structural modifications to the EGCG skeleton. We replaced the ester boun of EGCG with a more resistant amide bond. We also replaced the oxygen ring by a methylene group. And finally, we positioned a nitrogen atom within this ring. The selected compound was shown to maintain the non-competitive property of EGCG and to correct biochemical and behavioral defects present in a DS mouse model. In addition it showed high stability and specificity.
Display omitted
•Novel epigallocatechin gallate (EGCG) analogues as a new class of DYRK1A inhibitors.•EGCG derivatives were synthesized.•7cc showed IC50 value of 0.5 μM against DYRK1A and was shown to act as a non competitive inhibitor.•7cc showed inhibited ERK2 phosphorylation in mouse brain.•7cc was more stable in plasma compared to EGCG.•7cc showed no toxicity during embryogenesis and corrected working memory deficit in a Down syndrome model.
Ether lipids are compounds present in many living organisms including humans that feature an ether bond linkage at the
sn
-1 position of the glycerol. This class of lipids features singular ...structural roles and biological functions. Alkyl ether lipids and alkenyl ether lipids (also identified as plasmalogens) correspond to the two sub-classes of naturally occurring ether lipids. In 1979 the discovery of the structure of the platelet-activating factor (PAF) that belongs to the alkyl ether class of lipids increased the interest in these bioactive lipids and further promoted the synthesis of non-natural ether lipids that was initiated in the late 60’s with the development of edelfosine (an anticancer drug). More recently, ohmline, a glyco glycero ether lipid that modulates selectively SK3 ion channels and reduces in vivo the occurrence of bone metastases, and other glyco glycero ether also identified as GAEL (glycosylated antitumor ether lipids) that exhibit promising anticancer properties renew the interest in this class of compounds. Indeed, ether lipid represent a new and promising class of compounds featuring the capacity to modulate selectively the activity of some membrane proteins or, for other compounds, feature antiproliferative properties via an original mechanism of action. The increasing interest in studying ether lipids for fundamental and applied researches invited to review the methodologies developed to prepare ether lipids. In this review we focus on the synthetic method used for the preparation of alkyl ether lipids either naturally occurring ether lipids (e.g., PAF) or synthetic derivatives that were developed to study their biological properties. The synthesis of neutral or charged ether lipids are reported with the aim to assemble in this review the most frequently used methodologies to prepare this specific class of compounds.
PDF
