SAnDReS 2.0: Development of machine-learning models to explore the scoring function space.

Classical scoring functions may exhibit low accuracy in determining ligand binding affinity for proteins. The availability of both protein-ligand structures and affinity data make it possible to develop machine-learning models focused on specific protein systems with superior predictive performance. Here, we report a new methodology named SAnDReS that combines AutoDock Vina 1.2 with 54 regression methods available in Scikit-Learn to calculate binding affinity based on protein-ligand structures. This approach allows exploration of the scoring function space. SAnDReS generates machine-learning models based on crystal, docked, and AlphaFold-generated structures. As a proof of concept, we examine the performance of SAnDReS-generated models in three case studies. For all three cases, our models outperformed classical scoring functions. Also, SAnDReS-generated models showed predictive performance close to or better than other machine-learning models such as KDEEP, CSM-lig, and ΔVinaRF20. SAnDReS 2.0 is available to download at https://github.com/azevedolab/sandres.

Nutritional strategies cause memory damage and alter biochemical parameters without causing neuroinflammation.

Obesity results from an energy imbalance and has been considered an epidemic due to its increasing rates worldwide. It is classified as a low-grade chronic inflammatory disease and has associated comorbidities. Different nutritional strategies are used for the purpose of weight loss, highlighting low-carbohydrate (LC) diets, ketogenic diets, and intermittent fasting (IF). These strategies can lead to metabolic and behavioral changes as they stimulate different biochemical pathways. Therefore, this study evaluated memory, energy metabolism, neuroinflammation, oxidative stress, and antioxidant defense parameters in mice subjected to an LC diet, ketogenic diet (KD), or IF. Eighty male Swiss mice, 60 days old, were divided into 4 groups: control, LC, KD, or IF. Body weight was measured weekly, and food intake every 48 h. After 15 days of nutritional interventions, the animals were subjected to the behavioral object recognition test and subsequently euthanized. Then, visceral fat was removed and weighed, and the brain was isolated for inflammatory and biochemical analysis. We concluded from this study that the LC and KD strategies could damage memory, IF improves the production of adenosine triphosphate (ATP), and the LC, KD, and IF strategies do not lead to neuroinflammatory damage but present damage at the level of oxidative stress.

Effects of temperature on growth, development, and survival of amphibian larvae: macroecological and evolutionary patterns.

Temperature affects the rate of biochemical and physiological processes in amphibians, influencing metamorphic traits. Temperature patterns, as those observed in latitudinal and altitudinal clines, may impose different challenges on amphibians depending on how species are geographically distributed. Moreover, species' response to environmental temperatures may also be phylogenetically constrained. Here, we explore the effects of acclimation to higher temperatures on tadpole survival, development, and growth, using a meta-analytical approach. We also evaluate whether the latitude and climatic variables at each collection site can explain differences in species' response to increasing temperature and whether these responses are phylogenetically conserved. Our results show that species that develop at relatively higher temperatures reach metamorphosis faster. Furthermore, absolute latitude at each collection site may partially explain heterogeneity in larval growth rate. Phylogenetic signal of traits in response to temperature indicates a non-random process in which related species resemble each other less than expected under Brownian motion evolution (BM) in all traits, except survival. The integration of studies in a meta-analytic framework allowed us to explore macroecological and macroevolutionary patterns and provided a better understanding of the effects of climate change on amphibians.

Data Base similarity (DBsimilarity) of natural products to aid compound identification on MS and NMR pipelines, similarity networking, and more.

INTRODUCTION: We developed Data Base similarity (DBsimilarity), a user-friendly tool designed to organize structure databases into similarity networks, with the goal of facilitating the visualization of information primarily for natural product chemists who may not have coding experience. METHOD: DBsimilarity, written in Jupyter Notebooks, converts Structure Data File (SDF) files into Comma-Separated Values (CSV) files, adds chemoinformatics data, constructs an MZMine custom database file and an NMRfilter candidate list of compounds for rapid dereplication of MS and 2D NMR data, calculates similarities between compounds, and constructs CSV files formatted into similarity networks for Cytoscape. RESULTS: The Lotus database was used as a source for Ginkgo biloba compounds, and DBsimilarity was used to create similarity networks including NPClassifier classification to indicate biosynthesis pathways. Subsequently, a database of validated antibiotics from natural products was combined with the G. biloba compounds to identify promising compounds. The presence of 11 compounds in both datasets points to possible antibiotic properties of G. biloba, and 122 compounds similar to these known antibiotics were highlighted. Next, DBsimilarity was used to filter the NPAtlas database (selecting only those with MIBiG reference) to identify potential antibacterial compounds using the ChEMBL database as a reference. It was possible to promptly identify five compounds found in both databases and 167 others worthy of further investigation. CONCLUSION: Chemical and biological properties are determined by molecular structures. DBsimilarity enables the creation of interactive similarity networks using Cytoscape. It is also in line with a recent review that highlights poor biological plausibility and unrealistic chromatographic behaviors as significant sources of errors in compound identification.

Relaxation intervention to improve diabetic foot ulcer healing: protocol for a pilot study with a nested qualitative study.

OBJECTIVE: A mixed-methods approach nested in a pilot three-arm randomised controlled trial (RCT) was conducted to evaluate the feasibility and acceptability of an intervention of progressive muscle relaxation with guided imagery (experimental group) compared to a neutral guided imagery placebo (active control group) and a group that did not receive any psychological intervention (passive control group). The purpose was to inform a future definitive RCT that will test its effectiveness. Qualitatively, this study examined patients and health professionals' perspectives regarding the relaxation intervention, in order to assess the acceptability and applicability of relaxation as an adjuvant therapy. METHOD: Participants must have had a diagnosis of diabetes and diabetic foot disease; one or two active hard-to-heal ulcers at the time of the assessment; and clinical levels of stress or anxiety or depression. Participants were randomised and assessed at three timepoints after the first hospital consultation for hard-to-heal diabetic foot ulcer (DFU). RESULTS: Rates of eligibility, recruitment, refusal, adherence to study protocol, participation in follow-up and dropout, and patients' satisfaction with the relaxation intervention were assessed as primary outcomes. Secondary outcomes were DFU healing; patients' DFU-related quality of life; physical and mental quality of life; perceived stress; emotional distress; adherence to DFU care; perceptions of DFU; as well as arterial systolic/diastolic pressure and heart rate. CONCLUSION: The results of this pilot study contributed to clarification and better elucidation of the benefits of relaxation techniques regarding patients' HRQoL and DFU healing. DECLARATION OF INTEREST: Funding: This study was conducted at the Psychology Research Centre (CIPsi/UM) School of Psychology, University of Minho, Portugal and supported by the Foundation for Science and Technology (FCT) through the Portuguese State Budget (UIDB/01662/2020) and by a PhD fellowship from FCT assigned to GF (SFRH/BD/131780/2017) and an FCT grant (PTDC/PSI-GER/28163/2017) assigned to MGP. The authors have no conflicts of interest to declare.

High concentrations of fructose cause brain damage in mice.

Excessive fructose consumption is associated with the incidence of obesity and systemic inflammation, resulting in increased oxidative damage and failure to the function of brain structures. Thus, we hypothesized that fructose consumption will significantly increase inflammation, oxidative damage, and mitochondrial dysfunction in the mouse brain and, consequently, memory damage. The effects of different fructose concentrations on inflammatory and biochemical parameters in the mouse brain were evaluated. Male Swiss mice were randomized into four groups: control, with exclusive water intake, 5%, 10%, and 20% fructose group. The 10% and 20% fructose groups showed an increase in epididymal fat, in addition to higher food consumption. Inflammatory markers were increased in epididymal fat and in some brain structures. In the evaluation of oxidative damage, it was possible to observe significant increases in the hypothalamus, prefrontal cortex, and hippocampus. In the epididymal fat and in the prefrontal cortex, there was a decrease in the activity of the mitochondrial respiratory chain complexes and an increase in the striatum. Furthermore, short memory was impaired in the 10% and 20% groups but not long memory. In conclusion, excess fructose consumption can cause fat accumulation, inflammation, oxidative damage, and mitochondrial dysfunction, which can damage brain structures and consequently memory.

Relaxation intervention to improve diabetic foot ulcer healing: Results from a pilot randomized controlled study.

This pilot randomised controlled study (RCT) aimed to assess the feasibility and acceptability of a progressive muscle relaxation with guided imagery intervention (experimental group [EG]) compared to a neutral guided imagery placebo (active control group [ACG]) and standard care to diabetic foot ulcer [DFU] treatment (passive control group [PCG]), to decide on the need for a definitive RCT. Diabetic foot patients with one or two chronic DFU and significant levels of stress/anxiety/depression were recruited and assessed during a period of 6 months, at three moments. Primary outcomes: feasibility rates and satisfaction with relaxation sessions. Secondary outcomes: DFU healing score, DFU-related quality of life (DFUQoL), physical and mental HRQoL, stress and emotional distress, DFU representations, arterial blood pressure, and heart rate. A total of 146 patients completed the baseline (T0) assessment with 54 participants presenting significant distress being randomised into three groups. Patients were assessed 2 months post-intervention (T1) and 4 months after T1 (T2). Feasibility rates showed reduced values on eligibility, recruitment and inclusion in the study, although with an acceptable rate of refusal lower than 10%. On average, participants reported being satisfied with relaxation sessions and recommended them to other patients. Differences between groups showed that, at T1, PCG participants reported higher levels of stress than those from EG and ACG. Within-group differences showed improvements in stress, distress, DFUQoL and DFU extent over time only in EG and ACG. Only EG showed significant changes in DFU representations at T1. The results suggest that relaxation may be a promising coping strategy to deal with DFU distress and an important adjuvant therapy for DFU healing, supporting the implementation of a definitive RCT.

Educational Interventions on Diabetic Foot Self-Care: A Study Protocol for a Pragmatic Randomized Controlled Trial.

Diabetic foot is one of the most serious complications of diabetes and foot ulcer recurrence has been associated with poor foot care. Educational programs may work as a vehicle for promoting knowledge and adequate foot self-care behaviors, reducing potential ulcerative complications in the diabetic foot, and promoting a better quality of life. This study protocol will analyze the impact of two different educational strategies - an instructive video (Experimental Group 1) compared to a foot care leaflet with real-time guided reading (Experimental Group 2) and standard care (Control Group) - on adherence and knowledge about diabetic foot care and patients' perception of their foot health. This study is a Pragmatic Randomized Controlled Trial of a non-pharmacological treatment. Participants need to have a diabetic foot diagnosis and attend a Diabetic Foot Multidisciplinary Consultation at two hospitals from the North of Portugal. Participants will be assessed at the first appointment of the diabetic foot consultation (T0), two weeks after (T1), and three months later, at follow-up (T2). Primary outcomes will be adherence and knowledge about diabetic foot care and general foot health. Secondary outcomes will be illness representations regarding diabetic foot. The results of this study will inform educational interventions to decrease diabetic foot ulcers, amputation rates, and the costs associated with both, contributing to foot care adherence and improve patient's quality of life.

Roundup Original DI® and thermal stress affect survival, morphology and thermal tolerance in tadpoles of Boana faber (Hylidae, Anura).

In amphibians, stressful environments can lead to accelerated metamorphosis at the expense of total length, resulting in the occurrence of morphological abnormalities. Many studies have linked the occurrence of these phenomena to the pollution of habitats by pesticides and thermal stress. Here, we assessed how exposure to Roundup Original DI® and higher constant temperatures affect the survival of Boana faber tadpoles and estimate the CL5096hs for the population. In addition, we evaluated how exposure to Roundup affects larval growth, morphology and thermal tolerance. Our findings suggest that even at sublethal doses, Roundup Original DI® may affect the survival of Boana faber larvae. There also appears to be an additive effect between Roundup and temperature increase on larval survival, however, we need to further explore this point to determine a pattern, proving to be a promising issue to be investigated in the future. We observed effects of chronic exposure to the herbicide formulation on the morphology and growth of the tadpoles, resulting in a reduction in total length and differences in the shape of the larvae. Although we did not recover any direct effects of herbicide exposure on CTMax, we did observe an upward trend in CTMax for tadpoles exposed to Roundup. Understanding how anthropogenic changes affect anuran persistence is fundamental for the management and conservation of the species and can be considered an initial step toward the formulation of legislations that regulate the use of herbicides.

NMR as a tool for compound identification in mixtures.

INTRODUCTION: Natural products and metabolomics are intrinsically linked through efforts to analyze complex mixtures for compound annotation. Although most studies that aim for compound identification in mixtures use MS as the main analysis technique, NMR has complementary advances that are worth exploring for enhanced structural confidence. OBJECTIVE: This review aimed to showcase a portfolio of the main tools available for compound identification using NMR. MATERIALS AND METHODS: COLMAR, SMART-NMR, MADByTE, and NMRfilter are presented using examples collected from real samples from the perspective of a natural product chemist. Data are also made available through Zenodo so that readers can test each case presented here. CONCLUSION: The acquisition of 1 H NMR, HSQC, TOCSY, HSQC-TOCSY, and HMBC data for all samples and fractions from a natural products study is strongly suggested. The same is valid for MS analysis to create a bridged analysis between both techniques in a complementary manner. The use of NOAH supersequences has also been suggested and demonstrated to save NMR time.

Relax to Heal? Perspectives of Patients with Diabetic Foot Ulcers and Health Professionals on Relaxation Sessions for Wound Healing.

OBJECTIVE: To explore patients' and healthcare professionals' (HPs') perspectives on the suitability/acceptability of a relaxation intervention, its effects on patients' well-being and diabetic foot ulcer (DFU) healing, and its incorporation into the multidisciplinary management of patients with diabetic foot. METHODS: This qualitative study was nested within a three-arm pilot randomized controlled trial. Patients with a chronic DFU received four relaxation sessions. Investigators then interviewed patients, physicians, and nurses involved with diabetic foot consultations. Interviews were audio-recorded, transcribed, and analyzed using thematic content analysis. RESULTS: Five themes emerged from patient's interviews about the suitability/acceptability of the relaxation intervention: perceptions regarding the psychological intervention, distress, the relaxation technique, changes in the patient's life, and changes in DFU/contribution to healing. Three themes emerged from interviews with HPs: perceptions regarding relaxation, changes in the patient, and changes in DFU/healing. Regarding the feasibility of the relaxation intervention, three themes emerged for both patients and HPs: suggested modifications, stressors/difficulties, and impact of COVID-19 pandemic. The utility theme emerged only in HP interviews, with subthemes of patients' distress, psychological interventions, relaxation intervention, and integration of the psychologist in the team. CONCLUSIONS: These findings provide evidence for the suitability/acceptability, feasibility, and utility of a relaxation intervention in diabetic foot consultations.

Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study protocol.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.

Effects of Ethanolic Extract of Cynara cardunculus (Artichoke) Leaves on Neuroinflammatory and Neurochemical Parameters in a Diet-Induced Mice Obesity Model.

This study aimed to evaluate the effect of Cynara cardunculus leaf ethanol extract on inflammatory and oxidative stress parameters in the hypothalamus, prefrontal cortex, hippocampus, striatum, cerebral cortex and liver of high-fat diet-induced obese mice. Food intake, body weight, visceral fat weight, and liver weight were also evaluated. Male Swiss mice were divided into control (low-fat purified diet) and obese (high-fat purified diet) groups. After 6 weeks, mice were divided into control + saline, control + C. cardunculus leaf ethanol extract, obese + saline, obese + C. cardunculus leaf ethanol extract. Cynara cardunculus leaf ethanol extract (1600 mg/kg/day) or saline was administered orally for 4 weeks. Brain structures (hypothalamus, hippocampus, prefrontal cortex, striatum and cerebral cortex) and liver were removed. Treatment with C. cardunculus leaf ethanol extract did not affect body weight but did reduce visceral fat. Obesity can cause inflammation and oxidative stress and increase the activity of antioxidant enzymes in brain structures. Treatment with ethanolic extract of C. cardunculus leaves partially reversed the changes in inflammatory damage parameters and oxidative damage parameters and attenuated changes in the antioxidant defense. The C. cardunculus leaf ethanol extract benefited from the brains of obese animals by partially reversing the changes caused by the consumption of a high-fat diet and the consequent obesity. These results corroborate those of studies indicating that the C. cardunculus leaf ethanol extract can contribute to the treatment of obesity.

Quality of Life in Patients with Diabetic Foot Ulcers: A Cross-sectional Study.

OBJECTIVE: To analyze the associations among and contributions of sociodemographic, clinical, and psychological variables to quality of life (QoL) related to diabetic foot ulcers (DFUs; DFUQoL). METHODS: The sample comprised 70 patients with DFUs who answered the following questionnaires: the Hospital Anxiety and Depression Scale, Illness Perception Questionnaire-Brief, Diabetic Foot Ulcer-Short Form, Medical Term Recognition test, and a sociodemographic and clinical questionnaire. Pearson and biserial correlation coefficients, hierarchical regressions, and moderation analyses were conducted to study the relationships among variables. RESULTS: The results showed that a large DFU, threatening representations about DFU, and more psychological distress were associated with lower DFUQoL. Also, more psychological distress, more threatening DFU representations, and taking antibiotics contributed to worse DFUQoL. Clinically significant levels of psychological distress moderated the relationship between the DFU extent and negative emotions. CONCLUSIONS: This study showed that QoL and its domains were associated with psychological distress and that QoL was more influenced by DFU representations than by a larger-sized wound, emphasizing the importance of psychological interventions in the treatment of patients with DFUs.

Habitual versus affective motivations in obsessive-compulsive disorder and alcohol use disorder.

OBJECTIVE: To (1) confirm whether the Habit, Reward, and Fear Scale is able to generate a 3-factor solution in a population of obsessive-compulsive disorder and alcohol use disorder (AUD) patients; (2) compare these clinical groups in their habit, reward, and fear motivations; and (3) investigate whether homogenous subgroups can be identified to resolve heterogeneity within and across disorders based on the motivations driving ritualistic and drinking behaviors. METHODS: One hundred and thirty-four obsessive-compulsive disorder (n = 76) or AUD (n = 58) patients were assessed with a battery of scales including the Habit, Reward, and Fear Scale, the Yale-Brown Obsessive-Compulsive Scale, the Alcohol Dependence Scale, the Behavioral Inhibition/Activation System Scale, and the Urgency, (lack of ) Premeditation, (lack of ) Perseverance, Sensation Seeking, and Positive Urgency Impulsive Behavior Scale. RESULTS: A 3-factor solution reflecting habit, reward, and fear subscores explained 56.6% of the total variance of the Habit, Reward, and Fear Scale. Although the habit and fear subscores were significantly higher in obsessive-compulsive disorder (OCD) and the reward subscores were significantly greater in AUD patients, a cluster analysis identified that the 3 clusters were each characterized by differing proportions of OCD and AUD patients. CONCLUSIONS: While affective (reward- and fear-driven) and nonaffective (habitual) motivations for repetitive behaviors seem dissociable from each other, it is possible to identify subgroups in a transdiagnostic manner based on motivations that do not match perfectly motivations that usually described in OCD and AUD patients.

Contributors and Moderators of Quality of Life in Caregivers of Alzheimer´s Disease Patients.

Aim and objective: This study aimed to identify the variables that contributed to Quality of Life (QoL) of Alzheimer's Disease (AD) caregivers, taking into consideration the caregiving context, stressors, role strains, and resources.Methods: The sample included 102 caregivers of AD patients who answered the following instruments: Depression, Anxiety and Stress Scale-21; Satisfaction with Social Support Scale; Revised Memory and Behavioral Problems Checklist; Family Communication and Satisfaction Scales; Spiritual and Religious Attitudes in Dealing with Illness; and Quality of Life in Alzheimer's Disease - Caregiver Version.Results: Caregivers who were employed, chose the caregiving role, and received help in caring showed better QoL. Also, being younger, less caregiving daily hours, caring for patients with less memory and behavior problems, lower distress, and family satisfaction predicted better QoL. Finally, spirituality was a moderator between family communication and QoL but not between family satisfaction and QoL.Conclusion: Caregiving-context variables (age, professional status, choosing to care, receiving help in the caregiving role and duration of daily care); role strains (family dissatisfaction); stressors (caregivers' distress and patients' memory and behavioral problems); and resources (spirituality) had an impact on caregivers' QoL emphasizing the adequacy of the Stress Process Model. Intervention should also focus on spirituality given its moderating role.

Use of technology in endodontics by undergraduate dental students in a south-eastern state of Brazil.

INTRODUCTION: This study aimed to determine the level of incorporation of current technologies for endodontic treatment in undergraduate dentistry courses in a south-eastern state of Brazil. METHODS: For data collection, a self-assessment-based online questionnaire was created using the "Google Forms" platform, consisting of 12 multiple-choice and a few open-ended questions. The questions were related to the use of current technologies for diagnosis, imaging, use of ultrasonics in endodontics, instrumentation, use of apex locator, microscopy, photodynamic therapy and thermoplastic techniques during endodontic treatment. The questionnaire was sent to 54 dental schools in Minas Gerais. RESULTS: The results show low technological incorporation during the various stages of endodontic treatment by undergraduate students in dentistry courses in Minas Gerais. CONCLUSION: Despite the availability of several technologies to help perform different stages of endodontic treatment, it was observed that most universities do not teach the use of these technologies. Additional studies are needed to correlate how the lack of incorporation of these technologies could impact on the quality of the endodontic learning for undergraduate students.

Validation of the Short-Form Survivor Unmet Needs Survey in older patients with myeloma.

BACKGROUND: Multiple myeloma (MM) affects mainly the older population and is the second most prevalent haematologic cancer. MM patients' unmet needs are diverse, arise at different stages, and are associated with greater psychological distress. This study examined the psychometric properties of the Short-Form Survivor Unmet Needs Survey (SF-SUNS) in Portuguese MM patients. METHODS: This cross-sectional study included 213 MM patients. The internal consistency of the scale was analyzed with Cronbach's α. Principal component analysis and confirmatory factor analysis were used to assess construct validity. Convergent validity was examined by using correlations with quality of life, satisfaction with social support, and psychological morbidity. Multiple regression analyses were conducted to explore the contribution of sociodemographic and clinical variables to unmet needs. RESULTS: The Portuguese SF-SUNS's factor structure follows the original's structure, although it includes fewer items. For each domain, Cronbach's α was ≤0.70, the minimum acceptable criterion. For construct validity, only unmet relationship and emotional needs had significant correlations (r ≥ 0.40)-specifically negative associations with quality of life and social support and positive associations with psychological morbidity. Regarding patient variables and SF-SUNS results, only cancer stage contributed significantly to unmet information needs, with patients at stage I reporting more needs than patients at stage III. CONCLUSIONS: The SF-SUNS represents a valid and reliable tool to assess unmet needs among Portuguese MM patients. It may be useful in designing and monitoring interventions to improve well-being in cancer survivors.

Taba: A Tool to Analyze the Binding Affinity.

Evaluation of ligand-binding affinity using the atomic coordinates of a protein-ligand complex is a challenge from the computational point of view. The availability of crystallographic structures of complexes with binding affinity data opens the possibility to create machine-learning models targeted to a specific protein system. Here, we describe a new methodology that combines a mass-spring system approach with supervised machine-learning techniques to predict the binding affinity of protein-ligand complexes. The combination of these techniques allows exploring the scoring function space, generating a model targeted to a protein system of interest. The new model shows superior predictive performance when compared with classical scoring functions implemented in the programs Molegro Virtual Docker, AutoDock4, and AutoDock Vina. We implemented this methodology in a new program named Taba. Taba is implemented in Python and available to download under the GNU license at https://github.com/azevedolab/taba. © 2019 Wiley Periodicals, Inc.

N-acetylcysteine reduces amphotericin B deoxycholate nephrotoxicity and improves the outcome of murine cryptococcosis.

Cryptococcosis is a life-threatening fungal infection, and its current treatment is toxic and subject to resistance. Drug repurposing represents an interesting approach to find drugs to reduce the toxicity of antifungals. In this study, we evaluated the combination of N-acetylcysteine (NAC) with amphotericin B (AMB) for the treatment of cryptococcosis. We examined the effects of NAC on fungal morphophysiology and on the macrophage fungicidal activity 3 and 24 hours post inoculation. The therapeutic effects of NAC combination with AMB were investigated in a murine model with daily treatments regimens. NAC alone reduced the oxidative burst generated by AMB in yeast cells, but did not inhibit fungal growth. The combination NAC + AMB decreased capsule size, zeta potential, superoxide dismutase activity and lipid peroxidation. In macrophage assays, NAC + AMB did not influence the phagocytosis, but induced fungal killing with different levels of oxidative bursts when compared to AMB alone: there was an increased reactive oxygen species (ROS) after 3 hours and reduced levels after 24 hours. By contrast, ROS remained elevated when AMB was tested alone, demonstrating that NAC reduced AMB oxidative effects without influencing its antifungal activity. Uninfected mice treated with NAC + AMB had lower concentrations of serum creatinine and glutamate-pyruvate transaminase in comparison to AMB. The combination of NAC + AMB was far better than AMB alone in increasing survival and reducing morbidity in murine-induced cryptococcosis, leading to reduced fungal burden in lungs and brain and also lower concentrations of pro-inflammatory cytokines in the lungs. In conclusion, NAC + AMB may represent an alternative adjuvant for the treatment of cryptococcosis.