It is known that local tissue injuries incurred by snakebites are quickly instilled causing extensive, irreversible, tissue destruction that may include loss of limb function or even amputation. Such ...injuries are not completely neutralized by the available antivenins, which in general are focused on halting systemic effects. Therefore it is prudent to investigate the potential antiophidic effects of natural and synthetic compounds, perhaps combining them with serum therapy, to potentially attenuate or eliminate the adverse local and systemic effects of snake venom. This study assessed a group of quinones that are widely distributed in nature and constitute an important class of natural products that exhibit a range of biological activities. Of these quinones, lapachol is one of the most important compounds, having been first isolated in 1882 from the bark of Tabebuia avellanedae.
It was investigated the ability of lapachol and some new potential active analogues based on the 2-hydroxi-naphthoquinone scaffold to antagonize important activities of Bothrops venoms (Bothrops atrox and Bothrops jararaca) under different experimental protocols in vitro and in vivo. The bioassays used to test the compounds were: procoagulant, phospholipase A2, collagenase and proteolytic activities in vitro, venom-induced hemorrhage, edematogenic, and myotoxic effects in mice. Proteolytic and collagenase activities of Bothrops atrox venom were shown to be inhibited by lapachol and its analogues 3a, 3b, 3c, 3e. The inhibition of these enzymatic activities might help to explain the effects of the analogue 3a in vivo, which decreased skin hemorrhage induced by Bothrops venom. Lapachol and the synthetic analogues 3a and 3b did not inhibit the myotoxic activity induced by Bothrops atrox venom. The negative protective effect of these compounds against the myotoxicity can be partially explained by their lack of ability to effectively inhibit phospholipase A2 venom activity. Bothrops atrox venom also induced edema, which was significantly reduced by the analogue 3a.
This research using a natural quinone and some related synthetic quinone compounds has shown that they exhibit antivenom activity; especially the compound 3a. The data from 3a showed a decrease in inflammatory venom effects, presumably those that are metalloproteinase-derived. Its ability to counteract such snake venom activities contributes to the search for improving the management of venomous snakebites.
Meningococcal meningitis is a severe central nervous system infection that occurs when
(
) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a ...human-specific pathogen,
models are greatly limited and pose a significant challenge.
cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific
interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study
host-pathogen interactions, and provide an overview of host responses to
infection. Using iPSC-BECs, we first confirmed that multiple
strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs.
was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines
,
,
,
, and
, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that
disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon
challenge. In accordance with tight junction loss, a sharp loss in
endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of
-responsive host genes. Altogether, this model provides novel insights into
pathogenesis, including an impact of
on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to
traversal of BECs.
Anthracycline doxorubicin (DOX) is still widely used as a chemotherapeutic drug for some solid tumors. Although DOX is highly effective, its side effects are limiting factors, such as cardio, nephro ...and hepatotoxicity. As such, approaches used to mitigate these adverse effects are highly encouraged. Omega 3 (ω-3), which is a class of long-chain polyunsaturated fatty acids, has been shown to have anti-inflammatory and antioxidant effects in preclinical bioassays. Thus, we evaluated the protective effects of ω-3 supplementation on hepatotoxicity and nephrotoxicity induced by multiple DOX administrations in rodents. Male Wistar rats (10 rats/group) were treated daily with ω-3 (400 mg/kg/day) by gavage for six weeks. Two weeks after the first ω-3 administration, the rats received DOX (3.5 mg/kg, intraperitoneal, 1×/week) for four weeks. DOX treatment reduced body weight gain increased systemic genotoxicity and caused liver-related (increase in serum ALT levels, thickness of the Glisson's capsule, compensatory proliferation and p65 levels) and kidney-related (increase in serum urea and creatinine levels, and incidence of tubular dilatation) deleterious outcomes. In contrast, ω-3 supplementation was safe and abrogated the DOX-related enhancement of systemic genotoxicity, serum urea and creatinine levels. Furthermore, ω-3 intervention reduced by 50% the incidence of kidney histological lesions while reducing by 40-50% the p65 protein level, and the proliferative response in the liver induced by DOX. Our findings indicate that ω-3 intervention attenuated the DOX-induced deleterious effects in the liver and kidney. Therefore, our findings may inspire future mechanistical investigations and clinical interventions with ω-3 on the reported outcomes.
Preregistration is a method to increase research transparency by documenting research decisions on a public, third-party repository prior to any influence by data. It is becoming increasingly popular ...in all subfields of psychology and beyond. Adherence to the preregistration plan may not always be feasible and even is not necessarily desirable, but without disclosure of deviations, readers who do not carefully consult the preregistration plan might get the incorrect impression that the study was exactly conducted and reported as planned. In this paper, we have investigated adherence and disclosure of deviations for all articles published with the Preregistered badge in
Psychological Science
between February 2015 and November 2017 and shared our findings with the corresponding authors for feedback. Two out of 27 preregistered studies contained no deviations from the preregistration plan. In one study, all deviations were disclosed. Nine studies disclosed none of the deviations. We mainly observed (un)disclosed deviations from the plan regarding the reported sample size, exclusion criteria and statistical analysis. This closer look at preregistrations of the first generation reveals possible hurdles for reporting preregistered studies and provides input for future reporting guidelines. We discuss the results and possible explanations, and provide recommendations for preregistered research.
Finding new therapeutic approaches towards colorectal cancer (CRC) is of increased relevance, as CRC is one of the most common cancers worldwide. CRC standard therapy includes surgery, chemotherapy, ...and radiotherapy, which may be used alone or in combination. The reported side effects and acquired resistance associated with these strategies lead to an increasing need to search for new therapies with better efficacy and less toxicity. Several studies have demonstrated the antitumorigenic properties of microbiota-derived short-chain fatty acids (SCFAs). The tumor microenvironment is composed by non-cellular components, microbiota, and a great diversity of cells, such as immune cells. The influence of SCFAs on the different constituents of the tumor microenvironment is an important issue that should be taken into consideration, and to the best of our knowledge there is a lack of reviews on this subject. The tumor microenvironment is not only closely related to the growth and development of CRC but also affects the treatment and prognosis of the patients. Immunotherapy has emerged as a new hope, but, in CRC, it was found that only a small percentage of patients benefit from this treatment being closely dependent on the genetic background of the tumors. The aim of this review was to perform an up-to-date critical literature review on current knowledge regarding the effects of microbiota-derived SCFAs in the tumor microenvironment, particularly in the context of CRC and its impact in CRC therapeutic strategies. SCFAs, namely acetate, butyrate, and propionate, have the ability to modulate the tumor microenvironment in distinct ways. SCFAs promote immune cell differentiation, downregulate the expression of pro-inflammatory mediators, and restrict the tumor-induced angiogenesis. SCFAs also sustain the integrity of basement membranes and modulate the intestinal pH. CRC patients have lower concentrations of SCFAs than healthy individuals. Increasing the production of SCFAs through the manipulation of the gut microbiota could constitute an important therapeutic strategy towards CRC due to their antitumorigenic effect and ability of modulating tumor microenvironment.
Phenolic compounds detection in fruit extracts from: açai, bacuri, buriti, blackberry, black mulberry, blueberry, juçara, physalis, raspberry, and tamarillo, have been performed by reverse-phase high ...performance liquid chromatography with electrochemical detection (RP-HPLC-EC), using two detectors in series: a wall-jet detector flow cell with a glassy carbon electrode, and a thin-layer flow cell detector with a boron doped diamond electrode. This methodology, in gradient elution mode, was successfully used to detect seventeen phenolic compounds in the fruit extracts. The total antioxidant capacity of the fruit extracts by the electrochemical quantitative index (EI) and the method of capture of diphenilpicrilhydrazil (DPPH●) free radical “efficient concentration” (EC50), was evaluated. A very good correlation between EI and EC50 assays has been obtained, the fruit with the highest total antioxidant capacity being blackberry, while physalis exhibited the lowest antioxidant power.
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•Flavonoids identification in 10 red fruit extracts.•RP-HPLC-EC using two detectors in series.•Detectors: wall-jet glassy carbon and thin-layer boron doped diamond electrode.•The EI determination of fruit extracts total antioxidant capacity.•The EC50 assays determination of fruit extracts total antioxidant capacity.
The p53 tumor suppressor is widely found to be mutated in human cancer. This protein is regarded as a molecular hub regulating different cell responses, namely cell death. Compelling data have ...demonstrated that the impairment of p53 activity correlates with tumor development and maintenance. For these reasons, the reactivation of p53 function is regarded as a promising strategy to halt cancer. In the present work, the recombinant mutant p53R280K DNA binding domain (DBD) was produced for the first time, and its crystal structure was determined in the absence of DNA to a resolution of 2.0 Å. The solved structure contains four molecules in the asymmetric unit, four zinc(II) ions, and 336 water molecules. The structure was compared with the wild-type p53 DBD structure, isolated and in complex with DNA. These comparisons contributed to a deeper understanding of the mutant p53R280K structure, as well as the loss of DNA binding related to halted transcriptional activity. The structural information derived may also contribute to the rational design of mutant p53 reactivating molecules with potential application in cancer treatment.
The colon microbiota is an important player in colorectal cancer (CRC) development, which is responsible for most of the cancer-related deaths worldwide. During carcinogenesis, the colon microbiota ...composition changes from a normobiosis profile to dysbiosis, interfering with the production of short-chain fatty acids (SCFAs). Each SCFA is known to play a role in several biological processes but, despite their reported individual effects, colon cells are exposed to these compounds simultaneously and the combined effect of SCFAs in colon cells is still unknown. Our aim was to explore the effects of SCFAs, alone or in combination, unveiling their biological impact on CRC cell phenotypes. We used a mathematical model for the prediction of the expected SCFA mixture effects and found that, when in mixture, SCFAs exhibit a concentration addition behavior. All SCFAs, alone or combined at the physiological proportions founded in the human colon, revealed to have a selective and anticancer effect by inhibiting colony formation and cell proliferation, increasing apoptosis, disturbing the energetic metabolism, inducing lysosomal membrane permeabilization, and decreasing cytosolic pH. We showed for the first time that SCFAs are specific towards colon cancer cells, showing promising therapeutic effects. These findings open a new road for the development of alternatives for CRC therapy based on the increase in SCFA levels through the modulation of the colon microbiota composition.
Phenolic composition and in vitro total antioxidant capacity have been evaluated, in red and white Portuguese wines, by electrochemical methods, spectrophotometric methods, and reverse‐phase high ...performance liquid chromatography with electrochemical detection (HPLC‐EC). The different phenolic compounds present in seventeen red and white wines, with different grape varieties, and from different geographical locations, were successfully identified and detected. The wines in vitro total antioxidant capacity, using the method of capture of diphenilpicrilhydrazil (DPPH.) free radical “efficient concentration” (EC50), and the electrochemical quantitative index (EI), was determined. The wine with the highest total antioxidant capacity exhibited the lowest antioxidant power, and the EI and EC50 assays had a very good correlation.
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