Development of a tetrahydroindazolone-based HDAC6 inhibitor with in-vivo anti-arthritic activity.

Histone deacetylase 6 (HDAC6) induces the expression of pro-inflammatory cytokines in macrophages; therefore, HDAC inhibitors may be beneficial for the treatment of macrophage-associated immune disorders and chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis. Structure-activity relationship studies were conducted on various phenyl hydroxamate HDAC6 inhibitors with indolone/indazolone-based bi- or tricyclic ring moieties as the cap group aiming to develop novel anti-arthritic drug candidates. Several compounds exhibited nanomolar activity and HDAC6 selectivity greater than 500-fold over HDAC1. Compound 21, a derivative with the tetrahydroindazolone cap group, is a potent HDAC6 inhibitor with an IC50 of 18 nM and 217-fold selectivity over HDAC1 and showed favorable oral bioavailability in animals. Compound 21 increases the acetylation level of tubulin without affecting histone acetylation in cutaneous T-cell lymphoma cells and inhibits TNF-α secretion in LPS-stimulated macrophage cells. The anti-arthritic effects of compound 21 were evaluated using a rat adjuvant-induced arthritis (AIA) model. Treatment with compound 21 significantly reduced the arthritis score, and combination treatment with methotrexate showed a synergistic effect in AIA models. We identified a novel HDAC6 inhibitor, compound 21, with excellent in vivo anti-arthritic efficacy, which can lead to the development of oral anti-arthritic drugs.

A mathematical model to evaluate the role of memory B and T cells in heterologous secondary dengue infection.

We propose a mathematical model to investigate the antibody-dependent enhancement (ADE) phenomenon during secondary dengue infection. The model consists of an ODE system that describes the interaction of the dengue virus with macrophages and memory B and T cell role during the infection. The qualitative model analysis is done in terms of memory B and T cell cloning parameters and the basic reproduction number R0. In the absence of memory B and T cell cloning, if R0<1 the dengue virus population extinguishes, while for R0>1, it tends asymptotically to a positive equilibrium. However, when we consider the memory B cell cloning, it is possible to occur dengue infection even when R0<1. Memory T cells have an essential role in eliminating the possibility of ADE occurrence when R0<1.

Assessing the effects of diagnostic sensitivity on schistosomiasis dynamics.

Schistosomiasis is a parasite infection that affects millions of people around the world. It is endemic in 13 different states in Brazil and responsible for increasing morbidity in the population. One of its main characteristics is a heterogeneous distribution of worm burden in the human population, which makes the diagnosis difficult. We aimed to investigate how the sensitivity of the diagnostic method may contribute to successful control interventions against infections in a population. In order to do that, we present an ordinary differential equations model that considers three levels of worm burden in the human population, a snail population, and a miracidium reservoir. Through a steady-state analysis and its local stability, we show how this worm-burden heterogeneity can be responsible for the persistence of infection, especially due to reinfection in the highest level of worm burden. The analysis highlights sensitive diagnosis, besides treatment and sanitary improvements, as a key factor for schistosomiasis transmission control.

Competition for nutritional resources masks the true frequency of bacterial mutants.

BACKGROUND: It is widely assumed that all mutant microorganisms present in a culture are able to grow and form colonies, provided that they express the features required for selection. Unlike wild-type Escherichia coli, PHO-constitutive mutants overexpress alkaline phosphatase and hence can hydrolyze glycerol-2-phosphate (G2P) to glycerol and form colonies on plates having G2P as the sole carbon source. These mutations mostly occur in the pst operon. However, the frequency of PHO-constitutive colonies on the G2P selective plate is exceptionally low. RESULTS: We show that the rate in which spontaneous PHO-constitutive mutations emerge is about 8.0 × 10-6/generation, a relatively high rate, but the growth of most existing mutants is inhibited by their neighboring wild-type cells. This inhibition is elicited only by non-mutant viable bacteria that can take up and metabolize glycerol formed by the mutants. Evidence indicates that the few mutants that do form colonies derive from microclusters of mutants on the selective plate. A mathematical model that describes the fate of the wild-type and mutant populations under these circumstances supports these results. CONCLUSION: This scenario in which neither the wild-type nor the majority of the mutants are able to grow resembles an unavoidable "tragedy of the commons" case which results in the collapse of the majority of the population. Cooperation between rare adjacent mutants enables them to overcome the competition and eventually form mutant colonies. The inhibition of PHO-constitutive mutants provides an example of mutant frequency masked by orders of magnitude due to a competition between mutants and their ancestral wild-type cells. Similar "tragedy of the commons-like" cases may occur in other settings and should be taken into consideration while estimating true mutant frequencies and mutation rates.

Polyphyllin D Shows Anticancer Effect through a Selective Inhibition of Src Homology Region 2-Containing Protein Tyrosine Phosphatase-2 (SHP2).

Natural products have continued to offer tremendous opportunities for drug development, as they have long been used in traditional medicinal systems. SHP2 has served as an anticancer target. To identify novel SHP2 inhibitors with potential anticancer activity, we screened a library containing 658 natural products. Polyphyllin D was found to selectively inhibit SHP2 over SHP1, whereas two other identified compounds (echinocystic acid and oleanolic acid) demonstrated dual SHP1 and SHP2 inhibition. In a cell-based assay, polyphyllin D exhibited cytotoxicity in Jurkat cells, an acute lymphoma leukemia cell line, whereas the other two compounds were ineffective. Polyphyllin D also decreased the level of phosphorylated extracellular signal-regulated kinase (p-ERK), a proliferation marker in Jurkat cells. Furthermore, knockdown of protein tyrosine phosphatase (PTP)N6 (SHP1) or PTPN11 (SHP2) decreased p-ERK levels. However, concurrent knockdown of PTPN6 and PTPN11 in Jurkat cells recovered p-ERK levels. These results demonstrated that polyphyllin D has potential anticancer activity, which can be attributed to its selective inhibition of SHP2 over SHP1.

Mathematical Model of Interaction Between Bacteriocin-Producing Lactic Acid Bacteria and Listeria. Part 1: Steady States and Thresholds.

Mathematical modeling is an important tool to assessing quantitative conjectures and to answer specific questions. In the modeling, we assume that a competitor represented by a lactic acid bacterium produces antimicrobial compounds (substances that kill microorganisms or inhibit their growth), such as lactic acid and bacteriocins, with some cost to its own growth. Bacteriocins are protein compounds with antimicrobial effect against related species and bacteria such as Listeria monocytogenes, which is foodborne pathogen that cause listeriosis. From the analysis of the model, we found the thresholds which determine the existence of multiple equilibria and we studied their stability, in order to evaluate the interaction between lactic acid bacteria and L. monocytogenes.

Mathematical Model of Interaction Between Bacteriocin-Producing Lactic Acid Bacteria and Listeria. Part 2: Bifurcations and Applications.

The big challenge for the food industry is the attending to demands for minimally processed foods, avoiding intense heat treatments and reducing the addition of chemical preservatives, but at the same time ensuring microbiological safety of these products. Lactic acid bacteria are traditionally used in the production of fermented foods. They are responsible for the production of antimicrobial compounds, such as organic acids and bacteriocins, which are protein compounds with bactericidal effect against related species and bacteria such as Listeria monocytogenes and Staphylococcus aureus. Aiming to study quantitatively the biological control as a technique of conservation, we developed a mathematical model to describe the interaction between lactic acid bacteria and Listeria in the food. The steady state and dynamical trajectories analyses of the model permit us to study the suitability of including lactic acid bacteria in order to reduce the growth of Listeria in food.

Mathematical modeling of the transmission of SARS-CoV-2-Evaluating the impact of isolation in São Paulo State (Brazil) and lockdown in Spain associated with protective measures on the epidemic of CoViD-19.

Coronavirus disease 2019 (CoViD-19), with the fatality rate in elder (60 years old or more) being much higher than young (60 years old or less) patients, was declared a pandemic by the World Health Organization on March 11, 2020. A mathematical model considering young and elder subpopulations under different fatality rates was formulated based on the natural history of CoViD-19 to study the transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The model considered susceptible, exposed, asymptomatic, pre-symptomatic, mild CoViD-19, severe CoViD-19, and recovered compartments, besides compartments of isolated individuals and those who were caught by test. This model was applied to study the epidemiological scenario resulting from the adoption of quarantine (isolation or lockdown) in many countries to control the rapid propagation of CoViD-19. We chose as examples the isolation adopted in São Paulo State (Brazil) in the early phase but not at the beginning of the epidemic, and the lockdown implemented in Spain when the number of severe CoViD-19 cases was increasing rapidly. Based on the data collected from São Paulo State and Spain, the model parameters were evaluated, and we obtained a higher estimation for the basic reproduction number R0 (9.24 for São Paulo State, and 8 for Spain) compared to the currently accepted estimation of R0 around 2 using the SEIR (susceptible, exposed, infectious, and recovered compartments) model. In comparison with the lockdown in Spain, the relatively early adoption of the isolation in São Paulo State resulted in enlarging the period of the first wave of the epidemic and delaying its peak. The model allowed to explain the flattening of the epidemic curves by quarantine when associated with the protective measures (face mask, washing hands with alcohol and gel, and social distancing) adopted by the population. The description of the epidemic under quarantine and protections can be a background to foreseen the epidemiological scenarios from the release strategies, which can help guide public health policies by decision-makers.

The scope of thallium nitrate oxidative cyclization of chalcones; synthesis and evaluation of isoflavone and aurone analogs for their inhibitory activity against interleukin-5.

The oxidative cyclization of 2'-hydroxy-6'-cyclohexylmethoxychalcones 5 using thallium (III) nitrate (TTN) in alcoholic solvents produced isoflavones 2 and (or) aurones 3 depending on the electronic nature of p-substituents on ring B. Chalcones with strong electron donating substituents (OH, OCH(3)) were exclusively converted to isoflavones 2. Chalcone with weak electron donating substituents (CH(2)CH(3)) was transformed into isoflavone 2 and the aurone 3 in approximate ratio 1:1. Chalcones with hydrogen or electron withdrawing substituents (Cl, CHO, COOCH(3), and NO(2)) formed aurones 3. Synthesized isoflavones 2 and aurones 3 were evaluated for their inhibitory activity against interleukin-5. Among them, 5-(cyclohexylmethoxy)-3-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (2h, >100% inhibition at 50 microM, IC(50)=6.1 microM) gave most potent activity. All the aurones 3 were inactive.

Spatial spreading of West Nile Virus described by traveling waves.

In this work, we propose a spatial model to analyze the West Nile Virus propagation across the USA, from east to west. West Nile Virus is an arthropod-borne flavivirus that appeared for the first time in New York City in the summer of 1999 and then spread prolifically among birds. Mammals, such as humans and horses, do not develop sufficiently high bloodstream titers to play a significant role in the transmission, which is the reason to consider the mosquito-bird cycle. The model aims to study this propagation based on a system of partial differential reaction-diffusion equations taking the mosquito and the avian populations into account. Diffusion and advection movements are allowed for both populations, being greater in the avian than in the mosquito population. The traveling wave solutions of the model are studied to determine the speed of disease dissemination. This wave speed is obtained as a function of the model's parameters, in order to assess the control strategies. The propagation of West Nile Virus from New York City to California state is established as a consequence of the diffusion and advection movements of birds. Mosquito movements do not play an important role in the disease dissemination, while bird advection becomes an important factor for lower mosquito biting rates.

A simple mathematical model to describe antibody-dependent enhancement in heterologous secondary infection in dengue.

We develop a mathematical model to describe the role of antibody-dependent enhancement (ADE) in heterologous secondary infections, assuming that antibodies specific to primary dengue virus (DENV) infection are being produced by immunological memory. The model has a virus-free equilibrium (VFE) and a unique virus-presence equilibrium (VPE). VFE is asymptotically stable when VPE is unstable; and unstable, otherwise. Additionally, there is an asymptotic attractor (not a fixed point) due to the fact that the model assumes unbounded increase in memory cells. In the analysis of the model, ADE must be accounted in the initial stage of infection (a window of time of few days), period of time elapsed from the heterologous infection until the immune system mounting an effective response against the secondary infection. We apply the results yielded by model to evaluate ADE phenomonon in heterologous DENV infection. We also associate the possible occurrence of severe dengue with huge viremia mediated by ADE phenomenon.

Describing the geographic spread of dengue disease by traveling waves.

Dengue is a human disease transmitted by the mosquito Aedes aegypti. For this reason geographical regions infested by this mosquito species are under the risk of dengue outbreaks. In this work, we propose a mathematical model to study the spatial dissemination of dengue using a system of partial differential reaction-diffusion equations. With respect to the human and mosquito populations, we take into account their respective subclasses of infected and uninfected individuals. The dynamics of the mosquito population considers only two subpopulations: the winged form (mature female mosquitoes), and an aquatic population (comprising eggs, larvae and pupae). We disregard the long-distance movement by transportation facilities, for which reason the diffusion is considered restricted only to the winged form. The human population is considered homogeneously distributed in space, in order to describe localized dengue dissemination during a short period of epidemics. The cross-infection is modeled by the law of mass action. A threshold value as a function of the model's parameters is obtained, which determines the rate of dengue dissemination and the risk of dengue outbreaks. Assuming that an area was previously colonized by the mosquitoes, the rate of disease dissemination is determined as a function of the model's parameters. This rate of dissemination of dengue disease is determined by applying the traveling wave solutions to the corresponding system of partial differential equations.

The role of alkoxy group on the A ring of isoflavones in the inhibition of interleukin-5.

Novel isoflavones were found to be potent inhibitors of interleukin-5 (Il-5). 5-Benzyloxy-3-(4-hydroxyphenyl)-4H-chromen-4-one (2a, 87.8% inhibition at 50 microM, IC50 = 15.3 microM) was initially identified as a potent inhibitor of IL-5. Its activity was comparable to that of budesonide or sophoricoside (1a). The benzyloxy group appeared to be critical for the enhancement of the IL-5 inhibitory activity. To identify the role of this hydrophobic moiety, 5-cyclohexylmethoxy (2d), 7-cyclohexylmethoxy (2e), 5-cyclohexylethoxy (2f), 5-cyclohexylpropoxy (2g), 5-(2-methylpropoxy) (2h), 5-(3-methylbutoxy) (2i), 5-(4-methylpentoxy) (2j) and 5-(2-ethylbutoxy) (2k) analogs were prepared and tested for their effects on the bioactivity of IL-5. Compounds 2d (IC50 = 5.8 microM), 2e (IC50 = 4.0 microM) and 2j (IC50 = 7.2 microM) exhibited the most potent activities. Considering the cLog P values of compounds 2 and the different three dimensional structures of 2d and 2e, the alkoxy group on ring A contributed to their cell permeability for the enhancement of activity, rather than playing a role in the ligand motif binding to the receptor. The optimum alkoxy group should be one that provides cLog P values of compounds 2 in the range of 4.13 to 4.39.

[Estimation of the basic reproducibility number for American tegumentary leishmaniasis in two sites in northeastern Salta Province, Argentina]. / Estimación del número de reproducibilidad basal para la leishmaniasis tegumentar americana en dos localidades del nordeste de la Provincia de Salta, Argentina.

A SIR-type deterministic mathematical model for three hosts is applied to analyze the transmission process for American tegumentary leishmaniasis in Río Blanco and Las Carmelitas, located in northeastern Salta Province, Argentina, and to derive the expression for the baseline reproducibility number Ro. The model is implemented in the MATLAB environment, and based on data from endemic areas, simulations are performed and numerical estimations of Ro are obtained. Río Blanco shows Ro = 4.689 and Las Carmelitas Ro = 1.948. By studying the model numerically, we also estimate the force of infection, namely 0.239 and 0.171 (unit 1/year), respectively. The simulations show that in Río Blanco, the endemic phase was more sustained than the inter-epidemic phase in Las Carmelitas. The estimations of these epidemiological parameters indicate where the Ministry of Health and Provincial Health Department will experience greater difficulty in controlling and eradicating the disease.

The transovarial transmission in the dynamics of dengue infection: Epidemiological implications and thresholds.

The anthropophilic and peridomestic female mosquito Aedes aegypti bites humans to suck blood to maturate fertilized eggs, during which dengue virus can be spread between mosquito and human populations. Besides this route of transmission, there is a possibility of dengue virus being passed directly to offspring through transovarial (or vertical) transmission. The effects of both horizontal and transovarial transmission routes on the dengue virus transmission are assessed by mathematical modeling. From the model, the reproduction number is obtained and the contribution of transovarial transmission is evaluated for different levels of horizontal transmission. Notably, the transovarial transmission plays an important role in dengue spread when the reproduction number is near one. Another threshold parameter arises, which is the product of the fractions of the susceptible populations of humans and mosquitoes. Interestingly, these two threshold parameters can be obtained from three different approaches: the spectral radius of the next generation matrix, the Routh-Hurwitz criteria and M-matrix theory.

The role of the hydrophobic group on ring A of chalcones in the inhibition of interleukin-5.

Novel chalcones were found as potent inhibitors of interleukin-5 (11-5). 1-(6-Benzyloxy-2-hydroxyphenyl)-3-(4-hydroxyphenyl)propenone (2a, 78.8% inhibition at 50 microM, IC50 = 25.3 microM) was initially identified as a potent inhibitor of IL-5. This activity is comparable to that of budesonide or sophoricoside (1a). The benzyloxy group appears to be critical for the enhancement of the IL-5 inhibitory activity. To identify the role of this hydrophobic moiety, cyclohexyloxy (2d), cyclohexylmethoxy (2c), cyclohexylethoxy (2e), cyclohexylpropoxy (2f), 2-methylpropoxy (2g), 3-methylbutoxy (2h), 4-methylpentoxy (2i), and 2-ethylbutoxy (2j) analogs were prepared and tested for their effects on IL-5 bioactivity. Compounds 2c (IC50 = 12.6 microM), 2d (IC50 = 12.2 microM), and 2i (IC50 = 12.3 microM) exhibited the most potent activity. Considering the cLog P values of 2, the alkoxy group contributes to the cell permeability of 2 for the enhancement of activity, rather than playing a role in ligand motif binding to the receptor. The optimum alkoxy group in ring A of 2 should be one that provides the cLog P of 2 in the range of 4.22 to 4.67.

Fitting the Incidence Data from the City of Campinas, Brazil, Based on Dengue Transmission Modellings Considering Time-Dependent Entomological Parameters.

Four time-dependent dengue transmission models are considered in order to fit the incidence data from the City of Campinas, Brazil, recorded from October 1st 1995 to September 30th 2012. The entomological parameters are allowed to depend on temperature and precipitation, while the carrying capacity and the hatching of eggs depend only on precipitation. The whole period of incidence of dengue is split into four periods, due to the fact that the model is formulated considering the circulation of only one serotype. Dengue transmission parameters from human to mosquito and mosquito to human are fitted for each one of the periods. The time varying partial and overall effective reproduction numbers are obtained to explain the incidence of dengue provided by the models.

Comparison between schistosomiasis transmission modelings considering acquired immunity and age-structured contact pattern with infested water.

In order to analyze the effects of acquired immunity and the contact pattern with infested water on the overall transmission of schistosomiasis, a semi-stochastic model is proposed. The model's assumptions are the simplest possible to enhance the differences between two hypotheses. With respect to the human host, it is assumed the mounting of an immune response after elapsing a fixed period of time L from the first infection, which is partially effective and never lost. With respect to the contact pattern with infested water, it is assumed a decreasing age-related function. Both models are compared to a purely random model, which is taken as the basic model.

The basic reproduction number obtained from Jacobian and next generation matrices - A case study of dengue transmission modelling.

The basic reproduction number is a key parameter in mathematical modelling of transmissible diseases. From the stability analysis of the disease free equilibrium, by applying Routh-Hurwitz criteria, a threshold is obtained, which is called the basic reproduction number. However, the application of spectral radius theory on the next generation matrix provides a different expression for the basic reproduction number, that is, the square root of the previously found formula. If the spectral radius of the next generation matrix is defined as the geometric mean of partial reproduction numbers, however the product of these partial numbers is the basic reproduction number, then both methods provide the same expression. In order to show this statement, dengue transmission modelling incorporating or not the transovarian transmission is considered as a case study. Also tuberculosis transmission and sexually transmitted infection modellings are taken as further examples.