Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review).

The etiopathogenesis of type 1 diabetes mellitus (T1DM) is a complex multifactorial process that involves an intricate network of genetic, epigenetic, immunological, and environmental factors. Despite the advances in recent years, some aspects of the mechanisms involved in triggering the disease are still unclear. Infections with certain viruses have been suggested as possible environmental triggers for the autoimmune process that leads to selective and progressive destruction of pancreatic ß-cells and insufficiency of insulin production, which is its hallmark. In this review, advances in knowledge and evidence that suggest the participation of certain viruses in the mechanisms of disease initiation and progression are described. It has been accepted that environmental factors, including viruses, can initiate and possibly sustain, accelerate, or slow down the autoimmune process and consequently damage insulin-producing pancreatic ß-cells. Although the role of these agents, especially human enteroviruses, has been exhaustively studied as the most likely triggers of the activation of autoimmunity that destroys pancreatic islets and leads to T1DM, certain doubts remain. Clinical epidemiological and experimental studies in humans and animals provide consistent and increasing evidence that persistent viral infections, especially with human enteroviruses and rotavirus infections, are associated with an increased risk of the disease in individuals genetically predisposed to autoimmunity.

Identification and evaluation of thermotolerance of yeasts from milk in natura exposed to high temperature and slow and fast pasteurization.

Milk is considered one of the basic raw materials of animal origin; it must present hygienic quality and physical-chemical properties suitable for processing and human consumption. Thus, the ingestion of milk in natura when not properly treated can be characterized as an opportunistic route of transmission of possible microbial pathogens, which can offer risks to public health. The present study aimed the yeast identification, to analyze the thermo-resistance of yeasts isolated from fresh milk, and to trace the susceptibility profile of the isolates to antifungal agents. For this, 23 samples of fresh milk type B, collected by manual or mechanical milking, were stored in collective refrigeration tanks of farms located in the Metropolitan Region of Natal and nearby, State of Rio Grande do Norte (RN), Brazil. Twenty samples of fresh milk commercially traded in the city of Ceará-Mirim RN were also analyzed. The yeasts were quantified by count of colony-forming units (CFU). All isolated species were treated by slow pasteurization (62-64 °C for 30 min) and fast (72-75 °C for 20 s), as well as by boiling (100 °C). Fifty yeast strains were obtained, and the species were identified as Candida tropicalis (28%), Candida parapsilosis (14%), Candida albicans (12%), Candida glabrata (10%), Candida krusei (10%), Kluyveromyces marxianus (10%), Candida guilliermondii (8%), Candida rugosa (2%), Candida orthopsilosis (2%), Pichia manshurica (2%), and Kodamaea ohmeri (2%). Five isolates showed resistance to the antifungal agents tested. Among all the isolates submitted to heat treatment, 80% were resistant to fast pasteurization and 60% to boiling, but none of them resisted the slow pasteurization. The milk collected through mechanical milking and stored in collective cooling tanks, presented higher rates of yeast contamination, compared to milk samples collected by manual milking and kept under the same storage conditions.

Antibiofilm and Anti-Candidal Activities of the Extract of the Marine Sponge Agelas dispar.

This study aimed to determine the antifungal and antibiofilm activities of Agelas dispar on biofilm-producing Candida species. The methanolic extract of A. dispar was obtained and the fraction Ag2 showed inhibitory activity for all 13 Candida strains tested, in concentrations ranging from 2.5 to 0.15625 mg/mL. Antifungal activity of fungicidal nature was seen between 5.0 and 0.3125 mg/mL of extract against the strains. All the strains were classified as biofilm producers. The methanolic extract Ag2 was tested at concentrations of 2.5 and 1.25 mg/mL for antibiofilm activity against the biofilm formation and maturation in all the strains of the genus Candida. Treated and untreated biofilm samples were selected for visualization using scanning electron microscopy (SEM). SEM allowed the visualization of the quantitative decrease in the microbial community, alterations of structural morphology, and destruction of both the formation and maturation of biofilms, at the cellular level. The mechanism of action of this fraction is suggested to be at the plasma membrane and/or cell wall alteration level. Therefore, the use of the methanolic extract of A. dispar may be a promising antifungal and antibiofilm therapeutic strategy against different species of the genus Candida.

The role of HPV-induced epigenetic changes in cervical carcinogenesis (Review).

Cervical cancer is associated with infection by certain types of human papillomaviruses (HPVs), and this affects women worldwide. Despite the improvements in prevention and cure of HPV-induced cervical cancer, it remains the second most common type of cancer in women in the least developed regions of the world. Epigenetic modifications are stable long-term changes that occur in the DNA, and are part of a natural evolutionary process of necessary adaptations to the environment. They do not result in changes in the DNA sequence, but do affect gene expression and genomic stability. Epigenetic changes are important in several biological processes. The effects of the environment on gene expression can contribute to the development of numerous diseases. Epigenetic modifications may serve a critical role in cancer cells, by silencing tumor suppressor genes, activating oncogenes, and exacerbating defects in DNA repair mechanisms. Although cervical cancer is directly related to a persistent high-risk HPV infection, several epigenetic changes have been identified in both the viral DNA and the genome of the infected cells: DNA methylation, histone modification and gene silencing by non-coding RNAs, which initiate and sustain epigenetic changes. In the present review, recent advances in the role of epigenetic changes in cervical cancer are summarized.

Biology and pathogenesis of human osteosarcoma.

Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or apoptosis control during osteogenesis, allowing the survival of cells which have undergone alterations during differentiation. Epigenetic events, including DNA methylation, histone modifications, nucleosome remodeling and expression of non-coding RNAs have been identified as possible risk factors for the tumor. It has been reported that p53 target genes or those genes that have their activity modulated by p53, in addition to other tumor suppressor genes, are silenced in OS-derived cell lines by hypermethylation of their promoters. In osteogenesis, osteoblasts are formed from pluripotent mesenchymal cells, with potential for self-renewal, proliferation and differentiation into various cell types. This involves complex signaling pathways and multiple factors. Any disturbance in this process can cause deregulation of the differentiation and proliferation of these cells, leading to the malignant phenotype. Therefore, the origin of OS seems to be multifactorial, involving the deregulation of differentiation of mesenchymal cells and tumor suppressor genes, activation of oncogenes, epigenetic events and the production of cytokines.

In Vitro Antioxidant, Anti-Biofilm, and Solar Protection Activities of Melocactus zehntneri (Britton & Rose) Pulp Extract.

Cactaceae plants are important due to their nutritional and therapeutic values. This study aimed to identify the phytochemical profile and biological activities of six Melocactus zehntneri pulp extracts: hexane extract (HE), chloroform extract (CE), ethanol extract (EE), methanol extract (ME), final water extract (FWE), and water extract (WE). Sugar, phenolic compounds, and protein content of the extracts were determined. Then thin layer chromatography (TLC) was performed to detect the presence of terpenes (ursolic and oleanolic acids), saponins, sugars, and glycoproteins. These extracts were analyzed for antioxidant activity via in vitro assay. HE showed 75% ferric chelating activity. All extracts showed 80-100% superoxide and hydroxyl radical-scavenging activities, respectively. Further, all extracts at 25 µg/mL showed 60% activity against DPPH. Moreover, in the 3T3 cells lines, no cytotoxicity was observed; however, therapeutic activity against the effects of the H2O2 treatment was exhibited. Finally, the polar extracts (EE, ME, FWE, and WE), particularly WE, elicited activity against the biofilms of Staphylococcus epidermidis, and HE and CE expressed a capacity for solar protection.

Th17 response in patients with cervical cancer.

Persistent infection by high-risk human papillomavirus (HR-HPV) is the main risk factor for uterine cervical cancer (UCC). However, viral infection alone is not sufficient for the development and progression of premalignant cervical lesions for cancer. In previous years it has been suggested that the adaptive immune response triggered by the differentiation of naïve helper T cells in Th17 cells may serve an important role in disease development. It has been hypothesized that Th17 cells may be involved in the promotion of UCC, as high levels of interleukin 17 (IL17) expression have been detected in the mucosa of the uterine cervix of patients affected by the disease. However, the role of Th17 cells in the tumor development and progression remains unclear. It is believed that the immune response of the Th17 type during persistent infection of the genital tract with HR-HPV triggers chronic inflammation with a long duration with the production of IL17 and other pro-inflammatory cytokines, creating a favorable environment for tumor development. These cytokines are produced by immune system cells in addition to tumor cells and appear to function by modulating the host immune system, resulting in an immunosuppressive response as opposed to inducing an effective protective immune response, thus contributing to the growth and progression of the tumor. In the present review, the latest advances are presented about the function of Th17 cells and the cytokines produced by them in the development and progression of UCC.

Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer.

Macrophage migration inhibitory factor (MIF) emerged in recent years as an important inflammation mediator, playing a prominent role in the pathogenesis of various types of malignant neoplasm. MIF is a glycoprotein that presents a wide spectrum of biological activities and exerts a complex interaction with various cellular signaling pathways, causing imbalance of homeostasis. Experimental and clinical studies show that high levels of MIF are found in almost all types of human cancers and are implicated in seemingly all stages of development of the tumors. The production of MIF is triggered through an autocrine signal emitted by tumor cells, and stimulates the production of cytokines, chemokines, and growth as well as angiogenic factors that lead to growth of the tumor, increasing its aggressiveness and metastatic potential. MIF is produced by virtually all types of human body cells, in response to stress caused by different factors, leading to pathological conditions such as chronic inflammation and immunomodulation with suppression of immune surveillance and of immune response against tumors, angiogenesis, and carcinogenesis. In this review, we present recent advances on the biological activity of MIF, the signaling pathways with which it is involved and their role in tumorigenesis.

Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review).

Inflammation is a defense strategy against invading agents and harmful molecules that is activated immediately following a stimulus, and involves the release of cytokines and chemokines, which activate the innate immune response. These mediators act together to increase blood flow and vascular permeability, facilitating recruitment of effector cells to the site of injury. Following resolution of the injury and removal of the stimulus, inflammation is disabled, but if the stimulus persists, inflammation becomes chronic and is strongly associated with cancer. This is likely to be due to the fact that the inflammation leads to a wound that does not heal, requiring a constant renewal of cells, which increases the risk of neoplastic transformation. Debris from phagocytosis, including the reactive species of oxygen and nitrogen that cause damage to DNA already damaged by the leukotrienes and prostaglandins, has an impact on inflammation and various carcinogenic routes. There is an association between chronic inflammation, persistent infection and cancer, where oncogenic action is mediated by autocrine and paracrine signals, causing changes in somatic cells under the influence of the microbial genome or of epigenetic factors. Among the infectious agents associated with cancer, certain genotypes of human papillomavirus (HPV) stand out. HPV is responsible for virtually all cases of cervical cancer and a lower proportion of cancers of the vagina, vulva, anus, penis and a number of extragenital cancers. In the present review, recent advances in the mechanisms involved in the inflammatory response are presented with their participation in the process of carcinogenesis, emphasizing the role of chronic inflammation in the development of HPV-induced cervical cancer.

Kodamaea (Pichia) ohmeri fungemia in a pediatric patient admitted in a public hospital.

Kodamaea (Pichia) ohmeri is a yeast species that has not been reported to be a frequent cause of human infections. The current report describes a case of fungemia caused by K. ohmeri in a 3-year-old female patient hospitalized in the public hospital Maria Alice Fernandes, Natal, RN, Brazil. The patient had previously received antimicrobial therapy due to a peritoneal infection and nosocomial pneumonia, and had a central venous catheter implanted. Kodamaea ohmeri was isolated from blood and the tip of the catheter, 48 h after its implantation. The yeast was identified by standard microbiological methods and sequence analysis of the D1/D2 domains and the ITS 1 + 2 spacer regions of the ribosomal DNA. On CHROMagar Candida medium, the isolate showed a color change from pink to blue. The yeast was susceptible to amphotericin B, and liposomal AmB was used successfully to clear the infection.

Production of extracellular proteases by Mucor circinelloides using d-glucose as carbon source / substrate

Recently, some Mucorales species have been reported as protease producers. The production of extracellular proteases by Mucor circinelloides using glucose as substrate was studied. Experiments were carried out with different D-glucose concentrations (40, 60 and 80 g/L). Biomass, pH and protease activity were determined. Although biomass production had reached best yields for the medium containing D-glucose in a concentration of 80 g/L, the enzymatic production was higher when the substrate concentration was reduced to 40 g/L. The yield factor for product on cell growth and the yield factor for product on carbon substrate were higher when the microorganism grew in medium containing 40 g/L glucose. The kinetics parameters suggest that this strain seems to be promising as an alternative microorganism for protease production.