Assessment of the Mutagenic Activity of Extracts of Brazilian Propolis in Topical Pharmaceutical Formulations on Mammalian Cells In Vitro and In Vivo

Propolis possesses various biological activities such as antibacterial, antifungal, anti-inflammatory, anesthetic and antioxidant properties. A topically applied product based on Brazilian green propolis was developed for the treatment of burns. For such substance to be used more safely in future clinical applications, the present study evaluated the mutagenic potential of topical formulations supplemented with green propolis extract (1.2, 2.4 and 3.6%) based on the analysis of chromosomal aberrations and of micronuclei. In the in vitro studies, 3-h pulse (G1 phase of the cell cycle) and continuous (20 h) treatments were performed. In the in vivo assessment, the animals were injured on the back and then submitted to acute (24 h), subacute (7 days) and subchronic (30 days) treatments consisting of daily dermal applications of gels containing different concentrations of propolis. Similar frequencies of chromosomal aberrations were observed for cultures submitted to 3-h pulse and continuous treatment with gels containing different propolis concentrations and cultures not submitted to any treatment. However, in the continuous treatment cultures treated with the 3.6% propolis gel presented significantly lower mitotic indices than the negative control. No statistically significant differences in the frequencies of micronuclei were observed between animals treated with gels containing different concentrations of propolis and the negative control for the three treatment times. Under the present conditions, topical formulations containing different concentrations of green propolis used for the treatment of burns showed no mutagenic effect in either test system, but 3.6% propolis gel was found to be cytotoxic in the in vitro test

Leishmania braziliensis Subverts Necroptosis by Modulating RIPK3 Expression

Leishmania braziliensis infection causes skin ulcers, typically found in localized cutaneous leishmaniasis (LCL). This tissue pathology associates with different modalities of cell necrosis, which are subverted by the parasite as a survival strategy. Herein we examined the participation of necroptosis, a specific form of programmed necrosis, in LCL lesions and found reduced RIPK3 and PGAM5 gene expression compared to normal skin. Assays using infected macrophages demonstrated that the parasite deactivates both RIPK3 and MLKL expression and that these molecules are important to control the intracellular L. braziliensis replication. Thus, LCL-related necroptosis may be targeted to control infection and disease immunopathology

Early Suppression of Macrophage Gene Expression by Leishmania braziliensis

Leishmania braziliensis is an intracellular parasite that resides mostly in macrophages. Both the parasite genome and the clinical disease manifestations show considerable polymorphism. Clinical syndromes caused by L. braziliensis include localized cutaneous (CL), mucosal (ML), and disseminated leishmaniasis (DL). Our prior studies showed that genetically distinct L. braziliensis clades associate with different clinical types. Herein, we hypothesized that: (1) L. braziliensis induces changes in macrophage gene expression that facilitates infection; (2) infection of macrophages with strains associated with CL (clade B), ML (clade C), or DL (clade A) will differentially affect host cell gene expression, reflecting their different pathogenic mechanisms; and (3) differences between the strains will be reflected by differences in macrophage gene expression after initial exposure to the parasite. Human monocyte derived macrophages were infected with L. braziliensis isolates from clades A, B, or C. Patterns of gene expression were compared using Affymetrix DNA microarrays. Many transcripts were significantly decreased by infection with all isolates. The most dramatically decreased transcripts encoded proteins involved in signaling pathways, apoptosis, or mitochondrial oxidative phosphorylation. Some transcripts encoding stress response proteins were up-regulated. Differences between L. braziliensis clades were observed in the magnitude of change, rather than the identity of transcripts. Isolates from subjects with metastatic disease (ML and DL) induced a greater magnitude of change than isolates from CL. We conclude that L. braziliensis enhances its intracellular survival by inhibiting macrophage pathways leading to microbicidal activity. Parasite strains destined for dissemination may exert a more profound suppression than less invasive L. braziliensis strains that remain near the cutaneous site of inoculation

Micronuclei induced by reverse transcriptase inhibitors in mononucleated and binucleated cells as assessed by the cytokinesis-block micronucleus assay

This study evaluated the clastogenic and/or aneugenic potential of three nucleoside reverse transcriptase inhibitors (zidovudine - AZT, lamivudine - 3TC and stavudine - d4T) using the cytokinesis-block micronucleus (CBMN) assay in human lymphocyte cultures. All three inhibitors produced a positive response when tested in binucleated cells. The genotoxicity of AZT and 3TC was restricted to binucleated cells since there was no significant increase in the frequency of micronuclei in mononucleated cells. This finding indicated that AZT and 3TC caused chromosomal breakage and that their genotoxicity was related to a clastogenic action. In addition to the positive response observed with d4T in binucleated cells, this drug also increased the frequency of micronuclei in mononucleated cells, indicating clastogenic and aneugenic actions. Since the structural differences between AZT and 3TC and AZT and d4T involve the 3' position in the 2'-deoxyribonucleoside and in an unsaturated 2',3',dideoxyribose, respectively, we suggest that an unsaturated 2', 3', dideoxyribose is responsible for the clastogenic and aneugenic actions of d4T

Lutzomyia longipalpis Saliva Induces Heme Oxygenase-1 Expression at Bite Sites

Sand flies bite mammalian hosts to obtain a blood meal, driving changes in the host inflammatory response that support the establishment of Leishmania infection. This effect is partially attributed to components of sand fly saliva, which are able to recruit and activate leukocytes. Our group has shown that heme oxygenase-1 (HO-1) favors Leishmania survival in infected cells by reducing inflammatory responses. Here, we show that exposure to sand fly bites is associated with induction of HO-1 in vivo. Histopathological analyses of skin specimens from human volunteers experimentally exposed to sand fly bites revealed that HO-1 and Nrf2 are produced at bite sites in the skin. These results were recapitulated in mice ears injected with a salivary gland sonicate (SGS) or exposed to sand fly bites, indicating that vector saliva may be a key factor in triggering HO-1 expression. Resident skin macrophages were the main source HO-1 at 24–48 h after bites. Additionally, assays in vivo after bites and in vitro after stimulation with saliva both demonstrated that HO-1 production by macrophages was Nrf2-dependent. Collectively, our data demonstrates that vector saliva induces early HO-1 production at the bite sites, representing a major event associated with establishment of naturally-transmitted Leishmania infections

Comorbidity of Common Mental Disorders with Cancer and Their Treatment Gap: Findings from the World Mental Health Surveys

Objective This study aimed to study the comorbidity of common mental disorders (CMDs) and cancer, and the mental health treatment gap among community residents with active cancer, cancer survivors and cancer-free respondents in 13 high-income and 11 low-middle-income countries. Methods Data were derived from the World Mental Health Surveys (N = 66,387; n = 357 active cancer, n = 1373 cancer survivors, n = 64,657 cancer-free respondents). The World Health Organization/Composite International Diagnostic Interview was used in all surveys to estimate CMDs prevalence rates. Respondents were also asked about mental health service utilization in the preceding 12 months. Cancer status was ascertained by self-report of physician\u27s diagnosis. Results Twelve-month prevalence rates of CMDs were higher among active cancer (18.4%, SE = 2.1) than cancer-free respondents (13.3%, SE = 0.2) adjusted for sociodemographic confounders and other lifetime chronic conditions (adjusted odds ratio (AOR) = 1.44, 95% CI 1.05-1.97). CMD rates among cancer survivors (14.6%, SE = 0.9) compared with cancer-free respondents did not differ significantly (AOR = 0.95, 95% CI 0.82-1.11). Similar patterns characterized high-income and low-middle-income countries. Of respondents with active cancer who had CMD in the preceding 12 months, 59% sought services for mental health problems (SE = 5.3). The pattern of service utilization among people with CMDs by cancer status (highest among persons with active cancer, lower among survivors and lowest among cancer-free respondents) was similar in high-income (64.0%, SE = 6.0; 41.2%, SE = 3.0; 35.6%, SE = 0.6) and low-middle-income countries (46.4%, SE = 11.0; 22.5%, SE = 9.1; 17.4%, SE = 0.7). Conclusions Community respondents with active cancer have higher CMD rates and high treatment gap. Comprehensive cancer care should consider both factors

findings from the World Health Organization World Mental Health surveys

Funding Information: The World Health Organization World Mental Health (WMH) Survey Initiative is supported by the United States National Institute of Mental Health (NIMH; R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the United States Public Health Service (R13-MH066849, R01-MH069864 and R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical Inc., GlaxoSmithKline and Bristol-Myers Squibb. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork and consultation on data analysis. The Argentina survey—Estudio Argentino de Epidemiología en Salud Mental (EASM)— was supported by a grant from the Argentinian Ministry of Health (Ministerio de Salud de la Nación). The São Paulo Megacity Mental Health Survey is supported by the State of São Paulo Research Foundation (FAPESP) Thematic Project Grant 03/00204–3. The Colombian National Study of Mental Health (NSMH) is supported by the Ministry of Social Protection. The ESEMeD surveys were funded by the European Commission (contracts QLG5–1999-01042; SANCO 2004123 and EAHC 20081308), the Piedmont Region, Italy, Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain (FIS 00/0028), Ministerio de Ciencia y Tecnología, Spain (SAF 2000– 158-CE), Departament de Salut, Generalitat de Catalunya, Spain, Instituto de Salud Carlos III (CIBER CB06/02/0046, RETICS RD06/0011 REM-TAP) and other local agencies and by an unrestricted educational grant from GlaxoSmithKline. Implementation of the Iraq Mental Health Survey (IMHS) and data entry were carried out by the staff of the Iraqi MOH and MOP with direct support from the Iraqi IMHS team with funding from both the Japanese and European Funds through the United Nations Development Group Iraq Trust Fund (UNDG ITF). The Lebanese Evaluation of the Burden of Ailments and Needs of the Nation (L.E.B.A.N.O.N.) is supported by the Lebanese Ministry of Public Health, the WHO (Lebanon), National Institute of Health/Fogarty International Center (R03 TW006481–01), anonymous private donations to IDRAAC, Lebanon and unrestricted grants from, Algorithm, AstraZeneca, Benta, Bella Pharma, Eli Lilly, Glaxo Smith Kline, Lundbeck, Novartis, OmniPharma, Pfizer, Phenicia, Servier, UPO. The Mexican National Comorbidity Survey (MNCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT-G30544-H), with supplemental support from the PanAmerican Health Organization (PAHO). Te Rau Hinengaro: the New Zealand Mental Health Survey (NZMHS) is supported by the New Zealand Ministry of Health, Alcohol Advisory Council and the Health Research Council. The Nigerian Survey of Mental Health and Wellbeing (NSMHW) is supported by the WHO (Geneva), the WHO (Nigeria) and the Federal Ministry of Health, Abuja, Nigeria. The Peruvian World Mental Health Study was funded by the National Institute of Health of the Ministry of Health of Peru. The Portuguese Mental Health Study was carried out by the Department of Mental Health, Faculty of Medical Sciences, NOVA University of Lisbon, with collaboration of the Portuguese Catholic University, and was funded by Champalimaud Foundation, Gulbenkian Foundation, Foundation for Science and Technology (FCT) and Ministry of Health. The Romania WMH study projects ‘Policies in Mental Health Area’ and ‘National Study regarding Mental Health and Services Use’ were carried out by the National School of Public Health and Health Services Management (former National Institute for Research and Development in Health, present National School of Public Health Management and Professional Development, Bucharest), with technical support of Metro Media Transilvania, the National Institute of Statistics—National Centre for Training in Statistics, SC. Cheyenne Services SRL, Statistics Netherlands and were funded by the Ministry of Public Health (former Ministry of Health) with supplemental support of Eli Lilly Romania SRL. The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; grant 044708) and the John W. Alden Trust. None of the funders had any role in the design, analysis, interpretation of results or preparation of this paper. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of the World Health Organization, other sponsoring organizations, agencies or governments. J.J.M. received the John Cade Fellowship APP1056929 from the National Health and Medical Research Council and the Niels Bohr Professorship from the Danish National Research Foundation. A complete list of all within-country and cross-national WMH publications can be found at http://www.hcp.med. harvard.edu/wmh/. Publisher Copyright: © 2017 Society for the Study of AddictionBackground and aims: Prior research has found bidirectional associations between psychotic experiences (PEs) and selected substance use disorders. We aimed to extend this research by examining the bidirectional association between PEs and various types of substance use (SU) and substance use disorders (SUDs), and the influence of antecedent mental disorders on these associations. Design, setting, participants and measurements: We used data from the World Health Organization World Mental Health surveys. A total of 30 902 adult respondents across 18 countries were assessed for (a) six types of life-time PEs, (b) a range of types of SU and DSM-IV SUDs and (c) mental disorders using the Composite International Diagnostic Interview. Discrete-time survival analyses based on retrospective age-at-onset reports examined the bidirectional associations between PEs and SU/SUDs controlling for antecedent mental disorders. Findings: After adjusting for demographics, comorbid SU/SUDs and antecedent mental disorders, those with prior alcohol use disorders [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.2–2.0], extra-medical prescription drug use (OR = 1.5, 95% CI = 1.1–1.9), alcohol use (OR = 1.4, 95% CI = 1.1–1.7) and tobacco use (OR = 1.3, 95% CI = 1.0–1.8) had increased odds of subsequent first onset of PEs. In contrast, those with temporally prior PEs had increased odds of subsequent onset of tobacco use (OR = 1.5, 95% CI = 1.2–1.9), alcohol use (OR = 1.3, 95% CI = 1.1–1.6) or cannabis use (OR = 1.3, 95% CI = 1.0–1.5) as well as of all substance use disorders (ORs ranged between 1.4 and 1.5). There was a dose response relationship between both count and frequency of PEs and increased subsequent odds of selected SU/SUDs. Conclusions: Associations between psychotic experiences (PEs) and substance use/substance use disorders (SU/SUDs) are often bidirectional, but not all types of SU/SUDs are associated with PEs. These findings suggest that it is important to be aware of the presence of PEs within those with SUDs or at risk of SUDs, given the plausibility that they may each impact upon the other.publishersversionpublishe