Purpose
Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively ...impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis.
Methods
A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion.
Results
Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis.
Conclusions
IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
BACKGROUND Mitochondria are multitasking organelles involved in ATP synthesis, reactive oxygen species (ROS) production, calcium signalling and apoptosis; and mitochondrial defects are known to cause ...physiological dysfunction, including infertility. The goal of this review was to identify and discuss common themes in mitochondrial function related to mammalian reproduction. METHODS The scientific literature was searched for studies reporting on the several aspects of mitochondrial activity in mammalian testis, sperm, oocytes, early embryos and embryonic stem cells. RESULTS ATP synthesis and ROS production are the most discussed aspects of mitochondrial function. Metabolic shifts from mitochondria-produced ATP to glycolysis occur at several stages, notably during gametogenesis and early embryo development, either reflecting developmental switches or substrate availability. The exact role of sperm mitochondria is especially controversial. Mitochondria-generated ROS function in signalling but are mostly described when produced under pathological conditions. Mitochondria-based calcium signalling is primarily important in embryo activation and embryonic stem cell differentiation. Besides pathologically triggered apoptosis, mitochondria participate in apoptotic events related to the regulation of spermatogonial cell number, as well as gamete, embryo and embryonic stem cell quality. Interestingly, data from knock-out (KO) mice is not always straightforward in terms of expected phenotypes. Finally, recent data suggests that mitochondrial activity can modulate embryonic stem cell pluripotency as well as differentiation into distinct cellular fates. CONCLUSIONS Mitochondria-based events regulate different aspects of reproductive function, but these are not uniform throughout the several systems reviewed. Low mitochondrial activity seems a feature of ‘stemness’, being described in spermatogonia, early embryo, inner cell mass cells and embryonic stem cells.
Microplastics (MPs) are widely distributed in marine ecosystems, and their ubiquitous presence is raising concern, particularly about possible impacts on fisheries resources. In tropical regions, ...shellfish fisheries represent an essential source of income and subsistence for traditional communities, and adverse effects on these resources may have severe consequences on human health. In the present study, bivalve molluscs of the species Anomalocardia flexuosa, captured in the region of the Itapessoca estuary in Pernambuco, Brazil, were analysed. A total of 90% of the individuals presented MP particles in their tissue. We observed an average of 5.15 ± 3.80 MP particles per individual, and for each gram of soft tissue, 3.66 ± 2.59 MP particles were found. Our results showed that MPs are present in clams captured on the Pernambuco coast and that the species studied proved to be suitable for monitoring the levels of microplastic pollution.
•This is the first record of microplastic in Anomalocardia flexuosa in South America.•Microplastics were present in 90% of the specimens analysed.•For each gram of A. flexuosa soft tissue, 3.66 ± 2.59 microplastic particles were found.•Anomalocardia flexuosa can be used to monitor the levels of MP contamination.
Objectives
Characterize the cell profile and immunostaining of proinflammatory markers in an experimental model of bisphosphonate‐related osteonecrosis of the jaw (BRONJ).
Materials and Methods
Male ...Wistar rats (n = 6–7) were treated chronically with saline solution or zoledronic acid (ZA) at 0.04, 0.20, and 1.00 mg kg−1 (1.4 × 10−7, 6.9 × 10−6, and 3.4 × 10−5 mol kg−1), and subsequently, the first left inferior molar was extracted. Were performed counting of viable and empty osteocyte lacunae, viable and apoptotic osteoclasts, polymorphonuclear neutrophil, mast cells (toluidine blue), and the positive presence cells for CD68, tumor necrosis factor‐alpha (TNF‐α), IL (interleukin)‐1β, inducible nitric oxide synthase (iNOS), nuclear factor‐kappa B (NF‐kB) and IL‐18 binding protein (IL‐18 bp).
Results
BRONJ was showed in ZA treated with 0.20 and 1.00 mg kg−1. There is a dose dependent increase in percentage of empty osteocyte lacunae (P < 0.001) and apoptotic osteoclasts (P < 0.001), counting of total osteoclasts (P = 0.003), polymorphonuclear neutrophil cells (P = 0.009), cytoplasmic‐positive cells of CD68 (P < 0.001), TNF‐α (P = 0.001), IL‐1β (P = 0.001), iNOS (P < 0.001), NF‐kB (P = 0.006), and nuclear‐positive cells of NF‐kB (P = 0.011). Consequently, there is no difference in mast cells (P = 0.957), and IL‐18 bp immunostaining decreases dose dependently (P = 0.005).
Conclusions
BRONJ is characterized by increases in immunostaining for proinflammatory markers and NF‐kB and inversely associated with cells exhibiting IL‐18 bp.
Hypersensitivity pneumonitis (HP) is an immune-mediated syndrome triggered by inhalation of a wide variety of allergens, to which an individual has previously been sensitized. More than 200 agents ...responsible for the disease have already been identified; however, HP occurs only in a small number of individuals exposed to causal antigens. The present report provides an overview of the role of antigen role in HP, highlighting its diversity, research methods, and prevention strategies, as well as the impact on disease prognosis following elimination of antigen. HP is an underdiagnosed disease and, therefore, it is difficult to accurately estimate its incidence. Triggering antigens can be divided into six broad categories: bacteria, fungi, mycobacteria, animal and plant proteins, chemicals, and metals, represented by disease prototypes. The identification of causal antigen is a major challenge; it is impossible to obtain in about 30–60% of cases. The acute form of HP, with early detection and immediate eviction of causal antigen, tends to have an excellent prognosis. In the chronic form, partial recovery of disease is still possible; however, some cases tend to progress to fibrosis, even after removal from exposure. In conclusion, HP diagnosis should be based on a proactive search for potential antigen sources, although their identification is hampered by the lack of standardized methods of demonstrating the specific antigen sensitization. Antigen avoidance is a critical determinant in disease prognosis.
Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight ...into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that "dreams are the royal road to the unconscious" is clinically useful, after all.
Breast cancer represents the second most prevalent tumor-related cause of death among women. Although studies have already been published regarding the association between breast tumors and miRNAs, ...this field remains unclear. MicroRNAs (miRNAs) are defined as non-coding RNA molecules, and are known to be involved in cell pathways through the regulation of gene expression. Melatonin can regulate miRNAs and genes related with angiogenesis. This hormone is produced naturally by the pineal gland and presents several antitumor effects. The aim of this study was to understand the action of melatonin in the regulation of miRNA-152-3p in vivo and in vitro.
In order to standardize the melatonin treatment in the MDA-MB-468 cells, we carried out the cell viability assay at different concentrations. PCR Array plates were used to identify the differentiated expression of miRNAs after the treatment with melatonin. The relative quantification of the target gene expression (IGF-IR, HIF-1α and VEGF) was performed by real-time PCR. For the tumor development, MDA-MB-468 cells were implanted in female BALB/c mice, and treated or not treated with melatonin. Moreover, the quantification of the target genes protein expression was performed by immunocytochemistry and immunohistochemistry.
Relative quantification shows that the melatonin treatment increases the gene expression of miR-152-3p and the target genes, and decreased protein levels of the genes both in vitro and in vivo.
Our results confirm the action of melatonin on the miR-152-3p regulation known to be involved in the progression of breast cancer.
Purpose
Gastrointestinal mucositis is a common side effect of cancer chemotherapy. Platelet-activating factor (PAF) is produced during gut inflammation. There is no evidence that PAF participates in ...antineoplastic-induced intestinal mucositis. This study evaluated the role of PAF in 5-fluorouracil (5-FU)-induced intestinal mucositis using a pharmacological approach and PAF receptor knockout mice (PAFR
−/−
).
Methods
Wild-type mice or PAFR
−/−
mice were treated with 5-FU (450 mg/kg, i.p.). Other mice were treated with saline or BN52021 (20 mg/kg, s.c.), an antagonist of the PAF receptor, once daily followed by 5-FU administration. After the third day of treatment, animals were sacrificed and tissue samples from the duodenum were removed for morphologic evaluation. In addition, myeloperoxidase activity and the cytokine concentration were measured.
Results
5-FU treatment decreased the duodenal villus height/crypt depth ratio, increased MPO activity, and increased the concentration of TNF-α, IL-1β and KC in comparison with saline-treated animals. In PAFR
−/−
mice and PAFR antagonist-treated mice, 5-FU-dependent intestinal damage was reduced and a decrease in duodenal villus height/crypt depth ratio was attenuated. However, the 5-FU-dependent increase in duodenum MPO activity was not affected. Without PAFR activation, 5-FU treatment did not increase the TNF-α, IL-1β and KC concentration.
Conclusions
In conclusion, our study establishes the role of PAFR activation in 5-FU-induced intestinal mucositis. This study implicates treatment with PAFR antagonists as novel therapeutic strategy for this condition.
In this paper, mobile robotics and present tools used in localization, mapping, and navigation of a mobile robot are discussed. The main purpose of this paper is, given a map represented by the ...incidence matrix of a petri net (PN), to evaluate the use of radio-frequency identification (RFID) technology to recognize the position of a robot in this map as well as the use of the PN dynamics as the cognition system of this robot. Thus, cards with RFID technology were placed at each intersection of structured environment (labyrinth) ways. A robot equipped with an RFID reader at its bottom moves until it passes over these cards. When this happens, the vehicle performs actions, such as turning right or left according to the map defined in its algorithm. Once the above-mentioned actions are performed, it goes straight to the next card. To ensure that this happens, there is a black line connecting each card to its neighbor cards. The robot is equipped with three infrared sensors, so it can detect and follow these lines. The results show that the robot can get out of one RFID card and reach the next one since they are connected by a black line. Without these lines, due to the limitations in the structure of the robot, it loses its way and cannot return. Still, the robot is able to execute the necessary navigation movements, in the case of stopping, moving forward, and turning right and left. These movements are correctly coordinated by the PN dynamics. The robot knows which card it is on and goes to the next card according to the previously established map. Each path of the robot is mathematically modeled by the incidence matrix of a petri net. Therefore, it managed to reach the destination in each of the four proposed paths. The PN that represents path 1 has the same number of places and transitions and has curves only to the left. On path 2, a right turn was added. In path 3, besides the two-way curves, RP has more places than transitions. Lastly, in path 4, there is a crossing in the path, that is, the robot goes through the same card twice, making the right and different decisions in each case according to the respective maps. Experimental results show that this approach has feasibility and effectiveness.
The carotid bodies (CBs) are peripheral chemoreceptor organs classically described as being O2 sensors, which are increasingly emerging as core players in metabolic control. Herein we evaluated CB ...activity in prediabetes patients and determined its correlation with dysmetabolism clinical features.
Prediabetes patients were recruited at the Cardiology Service, Hospital Santa Marta, Centro Hospitalar Lisboa Central, EPE (CHLC-EPE). The study was approved by CHLC-EPE and NOVA Medical School Ethics Committee. Thirty-three prediabetic and 14 age-matched, non-prediabetic, volunteers had their peripheral chemosensitivity evaluated by the Dejours test. Serum biomarkers of metabolic disease, insulin sensitivity (HOMA-IR), blood pressure, carotid intima-media thickness (cIMT) and glucose tolerance were assessed.
CB chemosensitivity was significantly increased in prediabetic group (P < 0.01). Fasting blood, glucose intolerance, fasting insulin and HOMA-IR were significantly higher in prediabetes patients. Insulin resistance correlated both with peripheral chemosensitivity, assessed by the Dejours test (P < 0.05) and with abdominal circumference (P < 0.01). HbA1c correlated with HOMA-IR (P < 0.05) and left cIMT (P < 0.05) in prediabetes patients.
We conclude that CB is overactive in prediabetes subjects and that peripheral chemosensitivity correlates with fasting insulin and insulin resistance representing a novel non-invasive functional biomarker to forecast early metabolic disease.
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