The repositioned drugs disulfiram/diethyldithiocarbamate combined to benznidazole: Searching for Chagas disease selective therapy, preventing toxicity and drug resistance

Chagas disease (CD) affects at least 6 million people in 21 South American countries besides several thousand in other nations all over the world. It is estimated that at least 14,000 people die every year of CD. Since vaccines are not available, chemotherapy remains of pivotal relevance. About 30% of the treated patients cannot complete the therapy because of severe adverse reactions. Thus, the search for novel drugs is required. Here we tested the benznidazole (BZ) combination with the repositioned drug disulfiram (DSF) and its derivative diethyldithiocarbamate (DETC) upon Trypanosoma cruzi in vitro and in vivo. DETC-BZ combination was synergistic diminishing epimastigote proliferation and enhancing selective indexes up to over 10-fold. DETC was effective upon amastigotes of the BZ- partially resistant Y and the BZ-resistant Colombiana strains. The combination reduced proliferation even using low concentrations (e.g., 2.5 µM). Scanning electron microscopy revealed membrane discontinuities and cell body volume reduction. Transmission electron microscopy revealed remarkable enlargement of endoplasmic reticulum cisternae besides, dilated mitochondria with decreased electron density and disorganized kinetoplast DNA. At advanced stages, the cytoplasm vacuolation apparently impaired compartmentation. The fluorescent probe H2-DCFDA indicates the increased production of reactive oxygen species associated with enhanced lipid peroxidation in parasites incubated with DETC. The biochemical measurement indicates the downmodulation of thiol expression. DETC inhibited superoxide dismutase activity on parasites was more pronounced than in infected mice. In order to approach the DETC effects on intracellular infection, peritoneal macrophages were infected with Colombiana trypomastigotes. DETC addition diminished parasite numbers and the DETC-BZ combination was effective, despite the low concentrations used. In the murine infection, the combination significantly enhanced animal survival, decreasing parasitemia over BZ. Histopathology revealed that low doses of BZ-treated animals presented myocardial amastigote, not observed in combination-treated animals. The picrosirius collagen staining showed reduced myocardial fibrosis. Aminotransferase de aspartate, Aminotransferase de alanine, Creatine kinase, and urea plasma levels demonstrated that the combination was non-toxic. As DSF and DETC can reduce the toxicity of other drugs and resistance phenotypes, such a combination may be safe and effective

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Hepatic myofibroblasts derived from Schistosoma mansoni-infected mice are a source of IL-5 and eotaxin: controls of eosinophil populations in vitro

Abstract Background Hepatic myofibroblasts are relevant for pathogenesis of S. mansoni infection. In normal liver, these perisinusoidal cells are quiescent, express the lipocyte phenotype, and are located in the Disse’s space, being the major site of vitamin A storage. When activated, they convert to myofibroblasts and contribute to granulomatous and diffuse liver fibrosis. In the present work, we observed that myofibroblasts obtained from granulomatous periovular inflammatory reactions in schistosome-infected mice (GR-MF) produce in vitro immunomodulatory cytokines for eosinophil activation: IL-5 and eotaxin. Methods and results The secretory activity of GR-MF was detected after TGF-β and IL-13 stimulation using 2D and 3D cell culture systems. In a mixed co-culture system using GR-MF with hematopoietic bone marrow cells from infected mice, we observed eosinophil survival that was dependent upon IL-5 and eotaxin, since antibodies against this cytokines decreased eosinophil population, as measured by eosinophil peroxidase activity. Conclusion These results indicate that GR-MF may contribute to maintenance of local eosinophilia in schistosomal hepatic granulomas, and can function as immunoregulatory cells, besides their role in production of fibrosis

Technology Readiness Level Roadmap for Developing Innovative Herbal Medicinal Products

Despite the vast global botanical diversity, the pharmaceutical development of herbal medicinal products (HMPs) remains underexploited. Of over 370,000 described plant species, only a few hundred are utilized in HMPs. Most of these have originated from traditional use, and only a minority come from megadiverse countries. Exploiting the pharmacological synergies of the hundreds of compounds found in poorly studied plant species may unlock new therapeutic possibilities, enhance megadiverse countries’ scientific and socio-economic development, and help conserve biodiversity. However, extensive constraints in the development process of HMPs pose significant barriers to transforming this unsatisfactory socio-economic landscape. This paper proposes a roadmap to overcome these challenges, based on the technology readiness levels (TRLs) introduced by NASA to assess the maturity of technologies. It aims to assist research entities, manufacturers, and funding agencies from megadiverse countries in the discovery, development, and global market authorization of innovative HMPs that comply with regulatory standards from ANVISA, EMA, and FDA, as well as WHO and ICH guidelines

Translational Research on Chagas Disease: Focusing on Drug Combination and Repositioning

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a major neglected disease endemic to Latin America, associated to significant morbimortality comprising a remarkable socioeconomic problem mainly for low-income tropical populations. The present chapter focuses translational research on Chagas disease, approaching drug combinations and repositioning, particularly exploiting the parasite oxidative stress by prospecting prooxidant compounds combined with antagonists of antioxidant systems, for developing low-cost and safe therapies for this infection. The pertinent literature on protozoal parasitic diseases is reviewed as well as on repurposing disulfiram aiming the combination with the Chagas disease drug of choice benznidazole. Both disulfiram and its first derivative sodium diethyldithiocarbamate (DETC) are able not only to inhibit p-glycoprotein, possibly reverting resistance phenotypes, but also to reduce toxicity of numerous other drugs, heavy metals, etc. Therefore, this innovation, presently in clinical research, may furnish a novel therapeutic for T. cruzi infections overcoming the adverse effects and refractory cases that impair the effectiveness of Chagas disease treatment

Measurement of inclusive and differential cross sections of single top quark production in association with a W boson in proton-proton collisions at s\sqrt{s} = 13.6 TeV

International audienceThe first measurement of the inclusive and normalised differential cross sections of single top quark production in association with a W boson in proton-proton collisions at a centre-of-mass energy of 13.6 TeV is presented. The data were recorded with the CMS detector at the LHC in 2022, and correspond to an integrated luminosity of 34.7 fb$^{-1}$. The analysed events contain one muon and one electron in the final state. For the inclusive measurement, multivariate discriminants exploiting the kinematic properties of the events are used to separate the signal from the dominant top quark-antiquark production background. A cross section of 82.3 $\pm$ 2.1 (stat) ${}^{+9.9}_{-9.7}$ (syst) $\pm$ 3.3 (lumi) pb is obtained, consistent with the predictions of the standard model. A fiducial region is defined according to the detector acceptance to perform the differential measurements. The resulting differential distributions are unfolded to particle level and show good agreement with the predictions at next-to-leading order in perturbative quantum chromodynamics

Measurement of inclusive and differential cross sections of single top quark production in association with a W boson in proton-proton collisions at s\sqrt{s} = 13.6 TeV

International audienceThe first measurement of the inclusive and normalised differential cross sections of single top quark production in association with a W boson in proton-proton collisions at a centre-of-mass energy of 13.6 TeV is presented. The data were recorded with the CMS detector at the LHC in 2022, and correspond to an integrated luminosity of 34.7 fb$^{-1}$. The analysed events contain one muon and one electron in the final state. For the inclusive measurement, multivariate discriminants exploiting the kinematic properties of the events are used to separate the signal from the dominant top quark-antiquark production background. A cross section of 82.3 $\pm$ 2.1 (stat) ${}^{+9.9}_{-9.7}$ (syst) $\pm$ 3.3 (lumi) pb is obtained, consistent with the predictions of the standard model. A fiducial region is defined according to the detector acceptance to perform the differential measurements. The resulting differential distributions are unfolded to particle level and show good agreement with the predictions at next-to-leading order in perturbative quantum chromodynamics

Search for the Higgs boson decays to a ρ0\rho^0, ϕ\phi, or K∗0^{*0} meson and a photon in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThree rare decay processes of the Higgs boson to a $\rho$(770)$^0$, $\phi$(1020), or K$^{*}$(892)$^0$ meson and a photon are searched for using $\sqrt{s}$ = 13 TeV proton-proton collision data collected by the CMS experiment at the LHC. Events are selected assuming the mesons decay into a pair of charged pions, a pair of charged kaons, or a charged kaon and pion, respectively. Depending on the Higgs boson production mode, different triggering and reconstruction techniques are adopted. The analyzed data sets correspond to integrated luminosities up to 138 fb$^{-1}$, depending on the reconstructed final state. After combining various data sets and categories, no significant excess above the background expectations is observed. Upper limits at 95% confidence level on the Higgs boson branching fractions into $\rho$(770)$^0$$\gamma$, $\phi$(1020)$\gamma$, and K$^{*}$(892)$^0\gamma$ are determined to be 3.7 $\times$ 10$^{-4}$, 3.0 $\times$ 10$^{-4}$, and 3.0 $\times$ 10$^{-4}$, respectively. In case of the $\rho$(770)$^0$$\gamma$ and $\phi$(1020)$\gamma$ channels, these are the most stringent experimental limits to date

Measurement of inclusive and differential cross sections of single top quark production in association with a W boson in proton-proton collisions at s\sqrt{s} = 13.6 TeV

International audienceThe first measurement of the inclusive and normalised differential cross sections of single top quark production in association with a W boson in proton-proton collisions at a centre-of-mass energy of 13.6 TeV is presented. The data were recorded with the CMS detector at the LHC in 2022, and correspond to an integrated luminosity of 34.7 fb$^{-1}$. The analysed events contain one muon and one electron in the final state. For the inclusive measurement, multivariate discriminants exploiting the kinematic properties of the events are used to separate the signal from the dominant top quark-antiquark production background. A cross section of 82.3 $\pm$ 2.1 (stat) ${}^{+9.9}_{-9.7}$ (syst) $\pm$ 3.3 (lumi) pb is obtained, consistent with the predictions of the standard model. A fiducial region is defined according to the detector acceptance to perform the differential measurements. The resulting differential distributions are unfolded to particle level and show good agreement with the predictions at next-to-leading order in perturbative quantum chromodynamics