Experimental models of chemically induced Parkinson's disease in zebrafish at the embryonic larval stage: a systematic review.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra that results in a decrease in dopamine levels, resulting in motor-type disturbances. Different vertebrate models, such as rodents and fish, have been used to study PD. In recent decades, Danio rerio (zebrafish) has emerged as a potential model for the investigation of neurodegenerative diseases due to its homology to the nervous system of humans. In this context, this systematic review aimed to identify publications that reported the utilization of neurotoxins as an experimental model of parkinsonism in zebrafish embryos and larvae. Ultimately, 56 articles were identified by searching three databases (PubMed, Web of Science, and Google Scholar). Seventeen studies using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 4 1-methyl-4-phenylpyridinium (MPP+), 24 6-hydroxydopamine (6-OHDA), 6 paraquat/diquat, 2 rotenone, and 6 articles using other types of unusual neurotoxins to induce PD were selected. Neurobehavioral function, such as motor activity, dopaminergic neuron markers, oxidative stress biomarkers, and other relevant parameters in the zebrafish embryo-larval model were examined. In summary, this review provides information to help researchers determine which chemical model is suitable to study experimental parkinsonism, according to the effects induced by neurotoxins in zebrafish embryos and larvae.

Predictive Factors of Extubation Failure in COVID-19 Mechanically Ventilated Patients.

Purpose: We investigated whether COVID-19 patients on mechanical ventilation (MV) had a different extubation outcome compared to non-COVID-19 patients while identifying predictive factors of extubation failure in the former. Methods: A retrospective, single-center, and observational study was done on 216 COVID-19 patients admitted to an intensive care unit (ICU) between March 2020 and March 2021, aged ≥ 18 years, in use of invasive MV for more than 24 h, which progressed to weaning. The primary outcome that was evaluated was extubation failure during ICU stay. A statistical analysis was performed to evaluate the association of patient characteristics with extubation outcome, and a Poisson regression model determined the predictive value. Results: Seventy-seven patients were extubated; the mean age was 57.2 years, 52.5% were male, and their mean APACHE II score at admission was 17.8. On average, MV duration until extubation was 8.7 ± 3.7 days, with 14.9 ± 10.1 days of ICU stay and 24.6 ± 14.0 days with COVID-19 symptoms. The rate of extubation failure (ie, the patient had to be reintubated during their ICU stay) was 22.1% (n = 17), while extubation was successful in 77.9% (n = 60) of cases. Failure was observed in only 7.8% of cases when evaluated 48 hours after extubation. The mean reintubation time was 4.28 days. After adjusting the analysis for age, sex, during of symptoms, days under MV, dialysis, and PaO2/FiO2 ratio, some parameters independently predicted extubation failure: age ≥ 66 years (APR = 5.12 [1.35-19.46]; p = 0.016), ≥ 31 days of symptoms (APR = 5.45 [0.48-62.19]; p = 0.016), and need for dialysis (APR = 5.10 [2.00-13.00]; p = 0.001), while a PaO2/FiO2 ratio >300 decreased the probability of extubation failure (APR = 0.14 [0.04-0.55]; p = 0.005). The presence of three predictors (ie, age ≥ 66 years, time of symptoms ≥ 31 days, need of dialysis, and PaO2/FiO2 ratio < 200) increased the risk of extubation failure by a factor of 23.0 (95% CI, 3.34-158.5). Conclusion: COVID-19 patients had an extubation failure risk that was almost three times higher than non-COVID-19 patients, with the extubation of the former being delayed compared to the latter. Furthermore, an age ≥ 66 years, time of symptoms ≥ 31 days, need of dialysis, and PaO2/FiO2 ratio > 200 were independent predictors for extubation failure, and the presence of three of these characteristics increased the risk of failure by a factor of 23.0.

Effects of glyphosate on zebrafish: a systematic review and meta-analysis.

Glyphosate herbicide is widely used in worldwide crop production. Consequently, its active ingredient, surfactants, and adjuvants commonly reach the aquatic ecosystem, thereby harming the biota. An investigation into how this herbicide affects aquatic species is important, especially in fish, as they have the ability to absorb and concentrate toxins. We aimed to evaluate the effects of glyphosate on the embryonic, larval and adult stages of zebrafish (Danio rerio), an appreciable organismal model. In this sense, we performed a meta-analysis using published articles from online databases (PubMed and ScienceDirect), which covered studies published until 2022. From a massive compilation of studies evaluating the effects of active substance glyphosate and Glyphosate-Based Herbicides (GBH) on zebrafish, we selected 36 studies used in downstream analyses. Overall, we report that glyphosate affects developmental stages and demonstrates toxicity and damage in zebrafish. We observed that embryos exposed to glyphosate exhibit increased mortality. There was also an increase in the number of morphological abnormalities related to yolk sac oedema, pericardial oedema, spinal curvature and body malformations, and a decrease in body size was observed. Furthermore, there was a decrease in the number of beats. The biochemical results demonstrated an increase in reactive oxygen species and antioxidant capacity against peroxyl radicals in the gills. The literature shows that glyphosate decreased the distance covered and the mean speed of the animals and increased the number of rotations. We concluded that glyphosate causes damage in the embryonic, larval and adult stages of this species. These results are valid for zebrafish and can be applied to other freshwater fish species. Graphical abstract.

Salivary cytokines as biomarkers of oral cancer: a systematic review and meta-analysis.

BACKGROUND: Oral cancer (OC) is usually diagnosed at advanced clinical stages due to its asymptomatic nature and absence of pathognomonic signs in its early development phase. Delayed diagnosis is one of the major causes of OC treatment failure and poor prognosis. Development of alternative diagnostic approaches are imperative for improving early detection and therapeutic success rates. Salivary cytokines (SC) have been studied as potential diagnostic biomarkers for OC and may represent a potential tool for improvement of its early detection. METHODS: In this systematic review and meta-analysis we identified SC studied as OC biomarkers by systematically reviewing the PubMed and Cochrane Library databases using the terms: "oral cancer", "cytokine", and "saliva", and also combined with "interleukin" or "interferon". Only case-control studies that measured SC by ELISA from treatment naïve patients were included in the qualitative review. For the meta-analysis were included all comparable studies that provided enough data (sample size, mean and standard deviation or standard error of the mean) for SC levels in OC patients, non-cancer controls and patients with oral potentially malignant disorders (OPMD), including leukoplakia. Comparisons with patients with oral lichen planus (OLP) and gingivitis were included in the qualitative analysis. RESULTS: A total of 28 articles (from 2004 to 2018) were included in the systematic review, describing 10 different SC, being IL-8 and IL-6 the most studied ones. SC levels were consistently higher among OC patients when compared to healthy controls and to patients with OPMD, OLP and gingivitis. Meta-analysis including 23 eligible studies showed that IL-8, IL-6, TNF-α, IL-1ß and IL-10 salivary levels were significantly higher in OC patients compared to controls; and that IL-8, IL-6, TNF-α and IL-1ß salivary levels were also higher in OC patients compared to individuals with OPMD. When compared to healthy controls, OPMD patients showed significantly higher IL-6 and TNF-α salivary levels. CONCLUSIONS: Our analyses showed that the salivary levels of some cytokines are consistently different among OC, OPMD and healthy patients, indicating that these SC may represent potential diagnostic biomarkers for OC and OPMD. Despite of that, SC levels were highly variable among studies, suggesting that further technical improvement and standardization for SC measurement by ELISA is needed in order to successfully translate these biomarkers to the clinical practice.

Fullerene (C60) particle size implications in neurotoxicity following infusion into the hippocampi of Wistar rats.

The buckminsterfullerene (C60) is considered as a relevant candidate for drug and gene delivery to the brain, once it has the ability to cross the blood-brain barrier. However, the biological implications of this nanomaterial are not fully understood, and its safety for intracerebral delivery is still debatable. In this study, we investigated if C60 particle size could alter its biological effects. For this, two aqueous C60 suspensions were used with maximum particle size up to 200nm and 450nm. The suspensions were injected in the hippocampus, the main brain structure involved in memory processing and spatial localization. In order to assess spatial learning, male Wistar rats were tested in Morris water maze, and the hippocampal BDNF protein levels and gene expression were analyzed. Animals treated with C60 up to 450nm demonstrated impaired spatial memory with a significant decrease in BDNF protein levels and gene expression. However, an enhanced antioxidant capacity was observed in both C60 treatments. A decrease in reactive oxygen species levels was observed in the treatments with suspensions containing particles measuring with up to 450nm. Thiobarbituric acid reactive substances, glutamate cysteine ligase, and glutathione levels showed no alterations among the different treatments. In conclusion, different particle sizes of the same nanomaterial can lead to different behavioral outcomes and biochemical parameters in brain tissue.

Effects of quercetin in preclinical models of Parkinson's disease: A systematic review.

Parkinson's disease (PD) is a neurodegenerative disease that affects dopaminergic neurons, thus impairing dopaminergic signalling. Quercetin (QUE) has antioxidant and neuroprotective properties that are promising for the treatment of PD. This systematic review aimed to investigate the therapeutic effects of QUE against PD in preclinical models. The systematic search was performed in PubMed, Scopus and Web of Science. At the final screening stage, 26 articles were selected according to pre-established criteria. Selected studies used different methods for PD induction, as well as animal models. Most studies used rats (73.08%) and mice (23.08%), with 6-OHDA as the main strategy for PD induction (38.6%), followed by rotenone (30.8%). QUE was tested immersed in oil, nanosystems or in free formulations, in varied routes of administration and doses, ranging from 10 to 400 mg/kg and from 5 to 200 mg/kg in oral and intraperitoneal administrations, respectively. Overall, evidence from published data suggests a potential use of QUE as a treatment for PD, mainly through the inhibition of oxidative stress, neuroinflammatory response and apoptotic pathways.

Snake venom, a potential treatment for melanoma. A systematic review.

Despite advances in treating patients with melanoma, there are still many treatment challenges to overcome. Studies with snake venom-derived proteins/peptides describe their binding potential, and inhibition of some proliferative mechanisms in melanoma. The combined use of these compounds with current therapies could be the strategic gap that will help us discover more effective treatments for melanoma. The present study aimed to carry out a systematic review identifying snake venom proteins and peptides described in the literature with antitumor, antimetastatic, or antiangiogenic effects on melanoma and determine the mechanisms of action that lead to these anti-tumor effects. Snake venoms contain proteins and peptides which are antiaggregant, antimetastatic, and antiangiogenic. The in vivo results are encouraging, considering the reduction of metastases and tumor size after treatment. In addition to these results, it was reported that these venom compounds could act in combination with chemotherapeutics (Acurhagin-C; Macrovipecetin), sensitizing and preparing tumor cells for treatment. There is a consensus that snake venom is a promising strategy for the improvement of antimelanoma therapies, but it has been little explored in the current context, combined with inhibitors, immunotherapy or tumor microenvironment, for example. We suggest Lebein as a candidate for combination therapy with BRAF inhibitors.

Neuroprotective Effect of Vitamin D on Behavioral and Oxidative Parameters of Male and Female Adult Wistar Rats Exposed to Mancozeb (manganese/zinc ethylene bis-dithiocarbamate).

The constant exposure of rural workers to pesticides is a serious public health problem. Mancozeb (MZ) is a pesticide  linked to hormonal, behavioral, genetic, and neurodegenerative effects, mainly related to oxidative stress. Vitamin D is a promising molecule that acts as a protector against brain aging. This study aimed to evaluate the neuroprotective role of vitamin D in adult male and female Wistar rats exposed to MZ. Animals received 40 mg/kg of MZ i.p. and 12.5 µg/kg or 25 µg/kg vitamin D by gavage, twice a week, for 6 weeks. The concentration of manganese had a significant increase in the hippocampus of both sexes and in the striatum of females, unlike zinc, which did not show a significant increase. MZ poisoning led to mitochondrial changes in brain tissues and promoted anxiogenic effects, especially in females. Alterations in antioxidant enzymes, mainly in the catalase activity were observed in intoxicated rats. Taken together, our results showed that exposure to MZ leads to the accumulation of manganese in brain tissues, and the behavior and metabolic/oxidative impairment were different between the sexes. Furthermore, the administration of Vitamin D was effective in preventing the damage caused by the pesticide.

Combination of Curcumin and Photodynamic Therapy Based on the Use of Red Light or Near-Infrared Radiation in Cancer: A Systematic Review.

BACKGROUND: Photodynamic therapy (PDT) is a therapeutic intervention that can be applied to cancer treatment. The interaction between a photosensitizer (PS), ideal wavelength radiation, and tissue molecular oxygen triggers a series of photochemical reactions responsible for producing reactive oxygen species. These highly reactive species can decrease proliferation and induce tumor cell death. The search for PS of natural origin extracted from plants becomes relevant, as they have photoactivation capacity, preferentially targeting tumor cells and because they do not present any or little toxicity to healthy cells. OBJECTIVE: Our work aimed to carry out a qualitative systematic review to investigate the effects of curcumin (CUR), a molecule considered as PS of natural origin, on PDT, using red light or near-infrared radiation in tumor models. METHODS: A systematic search was performed in three databases (PubMed, Scopus, and Web of Science) using the PICOT method, retrieving a total of 1,373 occurrences. At the end of the peer screening, 25 eligible articles were included in this systematic review using inclusion, exclusion, and eligibility criteria. RESULTS: CUR, whether in its free state, associated with metal complexes or other PS and in a nanocarrier system, was considered a relevant PS for PDT using red light or near-infrared against tumoral models in vitro and in vivo, acting by increasing cytotoxicity, inhibiting proliferation, inducing cell death mainly by apoptosis, and changing oxidative parameters. CONCLUSION: The results found in this systematic review suggest the potential use of CUR as a PS of natural origin to be applied in PDT against many neoplasms, encouraging further search in PDT against cancer and serving as an investigative basis for upcoming pre-clinical and clinical applications.

Subcutaneous injection of multipotent mesenchymal stromal cells admixed with melanoma cells in mice favors tumor incidence and growth: a systematic review and meta-analysis.

Multipotent mesenchymal stem/stromal cells (MSCs) have strong tropism towards cancer cells, thus being tested as tools for the targeted delivery of therapeutic substances for the treatment of melanoma. However, different experimental approaches for melanoma induction and MSC treatment can have a direct impact on the outcomes. Systematic search was carried out in three databases (PubMed, Scopus, and Web of Science) to include all studies, where stem cells were used as intervention for animal models for melanoma. Selected articles were classified according to SYRCLE's risk of bias tool for animals' studies. Experimental variables and published data for tumor incidence and growth were extracted from the eligible articles and standardized using Hedge's G for random effects meta-analysis and meta-regression. From 627 entries, 11 articles were eligible for meta-analysis. All studies tested the effects of a single injection of mesenchymal stem/stromal cells (MSCs) (from bone marrow or adipose tissue) admixed with B16 mouse melanoma cells (B16-F0 or B16-F10) or with human melanoma cells (A375 or M4Beu) in mice. Mean SYRCLE score was 3.09 out of 10. Results from random effects meta-analysis indicate that MSCs favored both tumor incidence and tumor growth (p = 0.001) in melanoma. Our results show that MSCs are protumorigenic in co-injection mice models for melanoma, increasing both tumor incidence and growth.

Effects of learning on mTOR pathway gene expression in the brain of zebrafish (Danio rerio) of different ages.

Target of rapamycin (TOR) is a protein kinase involved in the modulation of mRNA translation and, therefore, in the regulation of protein synthesis. In neurons, the role of TOR is particularly important in the consolidation of long-term memory (LTM). One of the modulators of TOR is brain-derived neurotrophic factor (BDNF), which activates the TOR signaling pathway to promote protein synthesis, synapse strengthening, and the creation of new neural networks. We investigated the gene expression pattern of this pathway during memory consolidation in zebrafish of different ages. Our findings demonstrate that TOR activation in old animals occurs in the early phase of consolidation, and follows a pattern identical to that of BDNF expression. In younger animals, this increase in activation did not occur, and changes in BDNF expression were also not so remarkable. Furthermore, the expression of the main proteins regulated by the synthesis of TOR (i.e., 4EBP and p70S6K) remained identical to that of TOR in all age groups.