The role of matrix metalloproteinase-9 in cardiac remodeling and dysfunction and as a possible blood biomarker in heart failure.

Heart failure (HF) is the leading cause of morbidity and mortality in cardiovascular diseases, being responsible for many hospitalizations annually. HF is considered a public health problem with significant economic and social impact, which makes searches essential for strategies that improve the ability to predict and diagnose HF. In this way, biomarkers can help in risk stratification for a more personalized approach to patients with HF. Preclinical and clinical evidence shows the participation of matrix metalloproteinase 9 (MMP-9) in the HF process. In this review, we will demonstrate the critical role that MMP-9 plays in cardiac remodeling and dysfunction. We will also show its importance as a blood biomarker in acute and chronic HF patients.

Doxycycline Decreases Atherosclerotic Lesions in the Aorta of ApoE-/- and Ovariectomized Mice with Correlation to Reduced MMP-2 Activity.

Atherogenic events promote changes in vessel walls, with alteration of the redox state, and increased activity of matrix metalloproteinases (MMPs). Thus, this study aims to evaluate aortic remodeling, MMP activity, and reactive oxygen species (ROS) levels after treatment with doxycycline in ApoE-/- and ovariectomized mice (OVX). Female ApoE-/--knockout mice (5 weeks) were submitted to ovariectomy surgery to induce experimental menopause. They then received chow enriched with 1% cholesterol to induce hypercholesterolemia. The animals were divided into two experimental groups: ApoE-/-/OVX vehicle and ApoE-/-/OVX doxycycline (30 mg/kg) administered by gavage once a day for 28 days (15th to the 18th week of life). Blood samples were collected to measure total cholesterol and fractions. The aorta was used for morphometry and to measure the activity and expression of MMP-2 and ROS levels. The ApoE-/-/OVX doxycycline group showed no change in total and fraction cholesterol levels. However, there was a reduction in ROS levels, MMP-2 expression, and activity that correlated with a decrease in atherosclerotic lesions relative to the ApoE-/-/OVX vehicle (p > 0.05). Therefore, we conclude that doxycycline in ApoE-/-/OVX animals promotes a reduction in atherosclerotic lesions by reducing ROS and MMP-2 activity and expression.

Studies on the Phytochemical Profile of Ocimum basilicum var. minimum (L.) Alef. Essential Oil, Its Larvicidal Activity and In Silico Interaction with Acetylcholinesterase against Aedes aegypti (Diptera: Culicidae).

Aedes aegypti L. (Diptera: Culicidae) is an important transmitter of diseases in tropical countries and controlling the larvae of this mosquito helps to reduce cases of diseases such as dengue, zika and chikungunya. Thus, the present study aimed to evaluate the larvicidal potential of the essential oil (EO) of Ocimum basilicum var. minimum (L.) Alef. The EO was extracted by stem distillation and the chemical composition was characterized by gas chromatography coupled with mass spectrometry (GC/MS and GC-FID). The larvicidal activity of EO was evaluated against third instar Ae. aegypti following World Health Organization (WHO) standard protocol and the interaction of the major compounds with the acetylcholinesterase (AChE) was evaluated by molecular docking. The predominant class was oxygenated monoterpenes with a concentration of 81.69% and the major compounds were limonene (9.5%), 1,8-cineole (14.23%), linalool (24.51%) and methyl chavicol (37.41%). The O. basilicum var. minimum EO showed unprecedented activity against third instar Ae. aegypti larvae at a dose-dependent relationship with LC50 of 69.91 (µg/mL) and LC90 of 200.62 (µg/mL), and the major compounds were able to interact with AChE in the Molecular Docking assay, indicating an ecological alternative for mosquito larvae control.

Radiation therapy with curative intention in men with de novo metastatic prostate carcinoma: shoot'em all!

BACKGROUND: About 5% of prostate cancer cases are metastatic at diagnoses. Radiotherapy of both primary tumor and secondary lesions can be, in addition to systemic treatments, a radical alternative for selected patients. MATERIALS AND METHODS: Patients with de novo prostate carcinoma with bone or lymph node metastases were retrospectively reviewed. All patients received moderate hypofractionated IMRT/VMAT up to 63 Gy in 21 daily fractions of 3 Gy to prostate and metastases with neoadjuvant and concurrent androgen deprivation therapy (ADT). According to known advances some patients also received abiraterone, enzalutamide, or docetaxel. RESULTS: Between 2015-2020, we attended 26 prostate cancer patients (median age 69.5 years, range 52-84) with simultaneous oligometastases [mean 2.1 metastases, median 1.5 metastases (range 1-6)]. Eighteen patients (69%) presented lymph node metastases, 4 (15.5%) bone metastases and 4 (15.5%) both lymph node and bone metastases. With a median follow-up of 15.5 months (range 3-65 months), 16 patients (62%) are alive and tumor free while 10 (38%) are alive with tumor. Four patients (17%) developed tumor progression, out of irradiated area in all cases, with a median time to progression of 43.5 months (range 27-56 months). Actuarial progression-free survival (PFS) rates at 12 and 24 months were 94.1% and 84.7%, respectively. No grade > 2 acute or late complications were recorded. CONCLUSIONS: Simultaneous directed radical hypofractionated radiation therapy for prostate and metastases is feasible, well tolerated and achieves an acceptable PFS rate. However, further studies with longer follow-up are necessary to definitively address these observations.

Performance of the eclipse monitor unit objective tool utilizing volumetric modulated arc therapy for rectal cancer.

AIM: To assess the performance of the monitor unit (MU) Objective tool in Eclipse treatment planning system (TPS) utilizing volumetric modulated arc therapy (VMAT) for rectal cancer. BACKGROUND: Eclipse VMAT planning module includes a tool to control the number of MUs delivered: the MU Objective tool. This tool could be utilized to reduce the total number of MUs in rectal cancer treatments. MATERIALS AND METHODS: 20 rectal cancer patients were retrospectively studied using VMAT and the MU Objective tool. The baseline plan for each patient was selected as the one with no usage of the MU Objective tool. The number of MUs of this plan was set to be the reference number of MUs (MUref). Five plans were re-optimized for each patient only varying the Max MU parameter. The selected values were 30%, 60%, 90%, 120% and 150% of MUref for each patient. Differences with respect to the baseline plan were evaluated regarding MU number and parameters for PTVs coverage evaluation, PTVs homogeneity and OARs doses assessment. A two-tailed, paired-samples t-test was used to quantify these differences. RESULTS: Average relative differences in MU number obtained was 10% for Max MU values of 30% and 60% of MUref, respectively (p < 0.03). PTVs coverage and homogeneity were not compromised and discrepancies obtained with respect to baseline plans were not significant. Furthermore, maximum OARs doses deviations were also not significant. CONCLUSIONS: A 10% reduction in the MU number could be obtained without an alteration of PTV coverage and OARs doses for rectal cancer.

Management of interruptions in radiotherapy treatments: Adaptive implementation in high workload sites.

Owing to predictable or unpredictable causes, interruptions may arise during therapy. On average, the extension of fractionated radiotherapy treatments is prone to be delayed by several weeks and interruptions can come up extending overall treatment time (OTT). Clonogenic cells of aggressive tumors might benefit from this situation, modifying local control (LC). Preserving treatment quality in radiotherapy is an essential issue for the treatment outcome, and our institution is increasingly concerned about this line of work. Establishing some objective criteria to schedule patients that have suffered interruptions along their treatments is of capital importance and not a trivial issue. Publications strongly encourage departments to minimize the effect of lag periods during treatments. Therefore, in July 2017, our facility implemented the so called 'Protocol to Manage Interruptions in Radiotherapy', based on a scoring system for patient categorization that considers not only histology but also associated comorbidity and sequence of the therapy.

Moderate hypofractionated radiation therapy and pathologic response for soft tissue sarcomas (STS) of limbs and trunk: experience from a tertiary cancer center.

BACKGROUND: Preoperative radiation therapy following by limb-sparing or conservative surgery is a standard approach for limb and trunk STS. Data supporting hypofractionated radiotherapy schedules are scarce albeit biological sensitivity of STS to radiation would justify it. We sought to evaluate the impact of moderate hypofractionation on pathologic response and its influence on oncologic outcomes. MATERIAL AND METHODS: From October 2018 to January 2023, 18 patients with limb or trunk STS underwent preoperative radiotherapy at a median dose of 52.5 Gy (range 49.5-60 Gy) in 15 fractions of 3.5 Gy (3.3-4 Gy) with or without neoadjuvant chemotherapy. A favorable pathologic response (fPR) was considered as ≥ 90% tumor necrosis on specimen examination. RESULTS: All patients completed planned preoperative radiotherapy. Eleven patients (61.1%) achieved a fPR, and 7 patients (36.8%) a complete pathologic response with total disappearance of tumor cells. Nine patients (47%) developed grade 1-2 acute skin toxicity, and 7 patients (38.8%) had wound complications on follow-up. With a median follow-up of 14 months (range 1-40), no cases of local relapse were observed, and actuarial 3-year overall survival (OS) and distant metastases-free survival (DMFS) are 87% and 76.4%, respectively. In the univariate analysis, the presence of a favorable pathologic response (fPR) was associated with improved 3-year OS (100% vs. 56.03%, p = 0.058) and 3-year DMFS (86.91% vs. 31.46%, p = 0.002). Moreover, both complete or partial RECIST response and radiological stabilization of the tumor lesion showed a significant association with higher rates of 3-year distant metastasis-free survival (DMFS) (83% vs. 83% vs. 56%, p < 0.001) and 3-year overall survival (OS) (100% vs. 80% vs. 0, p = 0.002). CONCLUSIONS: Preoperative moderate hypofractionated radiation treatment for STS is feasible and well tolerated and associates encouraging rates of pathologic response that could have a favorable impact on final outcomes.

Dosimetrical and geometrical parameters in single-fraction lattice radiotherapy for the treatment of bulky tumors: Insights from initial clinical experience.

PURPOSE: This study aims to investigate lattice radiotherapy (LRT) for bulky tumor in 10 patients, analyzing geometrical and dosimetrical parameters and correlations among variables. METHODS: Patients were prescribed a single-fraction of 18 Gy to 50 % of each spherical vertex (1.5 cm diameter). Vertices were arranged in equidistant planes forming a triangular pattern. Center-to-center distance (Dc-c) between vertices was varied from 4 to 5 cm. A new method for calculating the valley-to-peak dose ratio (VPDR) was proposed and compared to other two from existing literature. GTV volumes (VGTV), vertex number (Nvert), low-dose related parameters and vertex D99%, D50%, and D1% were recorded. Beam-on time and Monitor Units (MU) were also evaluated. Correlations were assessed using Spearman's coefficient, with significant differences analyzed using Mann-Whitney U test. RESULTS: Tumor volumes ranged from 417 to 3615 cm3. Median vertex number was 14.5 (IQR:11.3-17.8). VPDR ranged from 0.16 to 0.28. Median D99% spanned from 10.0 to 13.7 Gy, median D50% exceeded 18.0 Gy, and median D1% surpassed 23.3 Gy. Periphery dose remained under 4.0 Gy. Plans exhibited high modulation, with median beam-on time and MU of 8.8 min (IQR:8.2-10.1) and 13,069 MU (IQR:11574-13639). Significant correlations were found between Nvert and VGTV (p < 0.01), MU (p < 0.02) and beam-on time (p < 0.01) and between Dc-c and two VPDR definitions (p < 0.02) and periphery dose (p < 0.01). Significant differences were observed among the three valley dose definitions (p < 0.01) and the three peak dose definitions (p < 0.01). CONCLUSIONS: Reporting geometrical and dosimetrical parameters in LRT is crucial, alongside the need for unified definitions of valley and peak doses.

Potential Biotechnological Applications of Venoms from the Viperidae Family in Central America for Thrombosis.

Central America is home to one of the most abundant herpetofauna in the Americas, occupying only 7% of the continent's total area. Vipers and lizards are among the most relevant venomous animals in medical practice due to the consequences of envenomation from the bite of these animals. A great diversity of biomolecules with immense therapeutic and biotechnological value is contained in their venom. This paper describes the prominent leading representatives of the family Viperidae, emphasizing their morphology, distribution, habitat, feeding, and venom composition, as well as the biotechnological application of some isolated components from the venom of the animals from these families, focusing on molecules with potential anti-thrombotic action. We present the leading protein families that interfere with blood clotting, platelet activity, or the endothelium pro-thrombotic profile. In conclusion, Central America is an endemic region of venomous animals that can provide many molecules for biotechnological applications.

Type I acquired cutis laxa: Report of a unique progressive case and short review.

Cutis laxa is a rare connective tissue disorder, characterized by a reduced number and abnormal properties of elastic fibers throughout the dermis, creating a clinical appearance of premature aging. It can be subdivided into inherited and acquired, the latter rarer than the former, and skin involvement may be localized or generalized. The etiology of acquired cutis laxa (ACL) remains unknown and there is no definitive treatment. We present the case of a 30-year-old man diagnosed with type I ACL with progressive systemic involvement at the renal, pulmonary, and digestive levels. Histological analysis of the skin revealed reduction and fragmentation of elastic fibers. Immunosuppressive treatment was started with prednisone, cyclophosphamide, and rituximab, with which a complete response to proteinuria was achieved and the progression of lung damage was limited. Autoimmune, infectious, and neoplastic diseases were ruled out.

MMP-2 and its implications on cardiac function and structure: Interplay with inflammation in hypertension.

Hypertension is one of the leading risk factors for the development of heart failure. Despite being a multifactorial disease, in recent years, preclinical and clinical studies suggest strong evidence of the pivotal role of inflammatory cells and cytokines in the remodeling process and cardiac dysfunction. During the heart remodeling, activation of extracellular matrix metalloproteinases (MMPs) occurs, with MMP-2 being one of the main proteases secreted by cardiomyocytes, fibroblasts, endothelial and inflammatory cells in cardiac tissue. In this review, we will address the process of cardiac remodeling and injury induced by the increase in MMP-2 and the main signaling pathways involving cytokines and inflammatory cells in the process of transcriptional, secretion and activation of MMP-2. In addition, an interaction and coordinated action between MMP-2 and inflammation are explored and significant in maintaining the cardiac cycle. These observations suggest that new therapeutic opportunities targeting MMP-2 could be used to reduce inflammatory biomarkers and reduce cardiac damage in hypertension.

Stereotactic body radiation therapy (SBRT) for spinal metastases: 12 years of a single center experience.

OBJECTIVE: To assess the clinical outcomes of patients with spine metastases treated with SBRT at our institution. MATERIALS AND METHODS: Patients with spine metastases treated with SBRT (1 fraction/18 Gy or 5 fractions/7 Gy) during the last 12 years have been analyzed. All patients were simulated supine in a vacuum cushion or with a shoulder mask. CT scans and MRI image registration were performed. Contouring was based on International Spine-Radiosurgery-Consortium-Consensus-Guidelines. Highly conformal-techniques (IMRT/VMAT) were used for treatment planning. Intra and interfraction (CBCT or X-Ray-ExacTrac) verification were mandatory. RESULTS: From February 2010 to January 2022, 129 patients with spinal metastases were treated with SBRT [1 fraction/18 Gy (75%) or 5 fractions/7 Gy] (25%). For patients with painful metastases (74/129:57%), 100% experienced an improvement in pain after SBRT. With a median follow-up of 14.2 months (average 22.9; range 0.5-140) 6 patients (4.6%) experienced local relapse. Local progression-free survival was different, considering metastases's location (p < 0.04). The 1, 2 and 3 years overall survival (OS) were 91.2%, 85.1% and 83.2%, respectively. Overall survival was significantly better for patients with spine metastases of breast and prostate cancers compared to other tumors (p < 0.05) and significantly worse when visceral metastases were present (p < 0.05), when patients were metastatic de novo (p < 0.05), and in those patients receiving single fraction SBRT (p: 0.01). CONCLUSIONS: According to our experience, SBRT for patients with spinal metastases was effective in terms of local control and useful to reach pain relief. Regarding the intent of the treatment, an adequate selection of patients is essential to propose this ablative approach.

One binge-type cycle of alcohol plus ketamine exposure induces emotional-like disorders associated with oxidative damage in adolescent female rats.

Drug abuse is a global public health problem among adolescents, with alcohol often used in association with other psychotropic drugs, such as ketamine. Considering the scarcity of evidence, this study aimed to investigate emotional behavioral effects induced by ethanol plus ketamine co-abuse, as well as oxidative biochemistry, and neurotrophic mediator in the prefrontal cortex and hippocampus in the early withdrawal of adolescent female rats. Animals were divided into control, ethanol, ketamine, and ethanol plus ketamine groups. The protocol administration was performed for 3 consecutive days (binge-like pattern). Behavioral assays of open field, elevated plus maze, and forced swim test were performed. After that, the prefrontal cortex and hippocampus were collected to evaluate oxidative biochemistry (reactive oxygen species-ROS; Antioxidant capacity against peroxyl radicals-ACAP; and lipid peroxidation). We found that isolated or combined ethanol and ketamine exposure displayed anxiety- and depressive-like profile, in a non-synergistically manner during early withdrawal. However, oxidative damage was aggravated in the co-administered animals than in isolated exposed subjects. We concluded that ethanol plus ketamine co-abuse may intensify oxidative damage in the hippocampus and prefrontal cortex in the early withdrawal of adolescent female rats, which was not reflected in the emotional behavioral phenotype. DATA AVAILABILITY STATEMENT: The datasets used and/or analyzed during the current investigation are available upon reasonable request from the corresponding author.

Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure.

Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF.

Intrafraction target shift comparison using two breath-hold systems in lung stereotactic body radiotherapy.

Background and purpose: In lung Stereotactic Body Radiotherapy (SBRT) respiratory management is used to reduce target motion due to respiration. This study aimed (1) to estimate intrafraction shifts through a Cone Beam Computed Tomography (CBCT) acquired during the first treatment arc when deep inspiration breath-hold (DIBH) was performed using spirometry-based (SB) or surface-guidance (SG) systems and (2) to analyze the obtained results depending on lesion localization. Material and methods: A sample of 157 patients with 243 lesions was analyzed. A total of 860 and 410 fractions were treated using SB and SG. Averaged intrafraction shifts were estimated by the offsets obtained when registering a CBCT acquired during the first treatment arc with the planning CT. Offsets were recorded in superior-inferior (SI), left-right (LR) and anterior-posterior (AP). Significance tests were applied to account for differences in average offsets and variances between DIBH systems. Systematic and random errors were computed. Results: Average offset moduli were 2.4 ± 2.2 mm and 3.5 ± 2.6 mm for SB and SG treatments (p < 0.001). When comparing SB and SG offset distributions in each direction no differences were found in average values (p > 0.3). However, variances were statistically smaller for SB than for SG (p < 0.001). The number of vector moduli offsets greater than 5 mm was 2.1 times higher for SG. Compared to other locations, lower lobe lesions moduli were at least 2.3 times higher. Conclusions: Both systems were accuracy-equivalent but not precision-equivalent systems. Furthermore, the SB system was more precise than the SG one. Despite DIBH, patients with lower lobe lesions had larger offsets than superior lobe ones, mainly in SI.

BmooMPα-I, a Metalloproteinase Isolated from Bothrops moojeni Venom, Reduces Blood Pressure, Reverses Left Ventricular Remodeling and Improves Cardiac Electrical Conduction in Rats with Renovascular Hypertension.

BmooMPα-I has kininogenase activity, cleaving kininogen releasing bradykinin and can hydrolyze angiotensin I at post-proline and aspartic acid positions, generating an inactive peptide. We evaluated the antihypertensive activity of BmooMPα-I in a model of two-kidney, one-clip (2K1C). Wistar rats were divided into groups: Sham, who underwent sham surgery, and 2K1C, who suffered stenosis of the right renal artery. In the second week of hypertension, we started treatment (Vehicle, BmooMPα-I and Losartan) for two weeks. We performed an electrocardiogram and blood and heart collection in the fourth week of hypertension. The 2K1C BmooMPα-I showed a reduction in blood pressure (systolic pressure: 131 ± 2 mmHg; diastolic pressure: 84 ± 2 mmHg versus 174 ± 3 mmHg; 97 ± 4 mmHg, 2K1C Vehicle, p < 0.05), improvement in electrocardiographic parameters (Heart Rate: 297 ± 4 bpm; QRS: 42 ± 0.1 ms; QT: 92 ± 1 ms versus 332 ± 6 bpm; 48 ± 0.2 ms; 122 ± 1 ms, 2K1C Vehicle, p < 0.05), without changing the hematological profile (platelets: 758 ± 67; leukocytes: 3980 ± 326 versus 758 ± 75; 4400 ± 800, 2K1C Vehicle, p > 0.05), with reversal of hypertrophy (left ventricular area: 12.1 ± 0.3; left ventricle wall thickness: 2.5 ± 0.2; septum wall thickness: 2.3 ± 0.06 versus 10.5 ± 0.3; 2.7 ± 0.2; 2.5 ± 0.04, 2K1C Vehicle, p < 0.05) and fibrosis (3.9 ± 0.2 versus 7.4 ± 0.7, 2K1C Vehicle, p < 0.05). We concluded that BmooMPα-I improved blood pressure levels and cardiac remodeling, having a cardioprotective effect.

In utero and lactational exposure to methylmercury elicits physical-chemical and morphological damages in the alveolar bone of offspring rats: The first toxicological findings.

Methylmercury (MeHg) is the most common organic form of mercury (Hg) that humans are exposed and is considered an environmental pollutant. Several populations that live in endemic regions of MeHg exposure are subject to the toxicant for long periods, including pregnant women and children, causing damage to several organs during early periods of development. Alveolar bone is an essential structure for the oral cavity, responsible for supporting teeth and masticatory forces. However, evidence on the effects of MeHg on alveolar bone and the intrauterine and lactation period is lacking. Thus, this study aimed to investigate the effects of MeHg exposure during gestation and lactation on the developing alveolar bone of offspring rats after maternal exposure. Dams were exposed during 41 days of pregnancy and lactation, and the mandibles of the offspring were collected. The alveolar bone was analyzed by Fourier Transform Infrared Spectroscopy to evaluate the physicochemical composition; by Scanning Electron Microscopy for ultrastructural evaluation; by histopathological, histochemical, and morphometric for tissue analyses. In addition, bone quality was assessed by X-ray microtomography. MeHg exposure altered the mineral composition and caused histological damage associated with a lower quantity and thickness of bone trabeculae, as well as reduced osteocyte density and collagen fiber content. A reduction in trabecular thickness and bone volume and an increase in trabecular spaces were observed and were associated with anatomical compromise of the vertical bone dimensions. Thus, the results suggest that the developing alveolar bone is susceptible to the toxic effects of MeHg when organisms are exposed during intrauterine and lactation periods. From a translational perspective, these changes in the alveolar bone can help us understand possible abnormalities induced by toxic metals and highlight the need for care for structures other than those already seen as targets for damage triggered by environmental MeHg exposure.

Fluoride exposure duringintrauterine and lactation periods promotes changes in the offspring rats' alveolar bone.

The importance of fluoride (F) for oral health is well established in the literature. However, evidence suggests that excessive exposure to this mineral is associated with adverse effects at different life stages and may affect many biological systems, especially mineralized tissues. The purpose of this study was to investigate the effects of F exposure during pregnancy and breastfeeding on the alveolar bone of the offspring since the alveolar bone is one of the supporting components of the dental elements. For this, the progeny rats were divided into three groups: control, 10 mg F/L, and 50 mg F/L for 42 (gestational and lactation periods). Analysis of the quantification of F levels in the alveolar bone by particle-induced gamma emission; Raman spectroscopy to investigate the physicochemical aspects and mineral components; computed microtomography to evaluate the alveolar bone microstructure and analyses were performed to evaluate osteocyte density and collagen quantification using polarized light microscopy. The results showed an increase in F levels in the alveolar bone, promoted changes in the chemical components in the bone of the 50 mg F/L animals (p < 0.001), and had repercussions on the microstructure of the alveolar bone, evidenced in the 10 mg F/L and 50 mg F/L groups (p < 0.001). Furthermore, F was able to modulate the content of organic bone matrix, mainly collagen; thus, this damage possibly reduced the amount of bone tissue and consequently increased the root exposure area of the exposed groups in comparison to a control group (p < 0.001). Our findings reveal that Fcan modulate the physicochemical and microstructural dimensions and reduction of alveolar bone height, increasing the exposed root region of the offspring during the prenatal and postnatal period. These findings suggest that F can modulate alveolar bone mechanical strength and force dissipation functionality.

"K-Powder" Exposure during Adolescence Elicits Psychiatric Disturbances Associated with Oxidative Stress in Female Rats.

Ketamine, also called 'K-powder' by abusers, an analog of phencyclidine, primarily acts as an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, therapeutically used as an anesthetic agent. Ketamine also stimulates the limbic system, inducing hallucinations and dissociative effects. At sub-anesthetic doses, ketamine also displays hallucinatory and dissociative properties, but not loss of consciousness. These behavioral consequences have elicited its recreational use worldwide, mainly at rave parties. Ketamine is generally a drug of choice among teenagers and young adults; however, the harmful consequences of its recreational use on adolescent central nervous systems are poorly explored. Thus, the aim of the present study was to characterize the behavioral and biochemical consequences induced by one binge-like cycle of ketamine during the early withdrawal period in adolescent female rats. Adolescent female Wistar rats (n = 20) received intraperitoneally administered ketamine (10 mg/kg/day) for 3 consecutive days. Twenty-four hours after the last administration of ketamine, animals were submitted to behavioral tests in an open field, elevated plus-maze, and forced swimming test. Then, animals were intranasally anesthetized with 2% isoflurane and euthanized to collect prefrontal cortex and hippocampus to assess lipid peroxidation, antioxidant capacity against peroxyl radicals, reactive oxygen species, reduced glutathione, and brain-derived neurotrophic factor (BDNF) levels. Our results found that 24 h after recreational ketamine use, emotional behavior disabilities, such as anxiety- and depression-like profiles, were detected. In addition, spontaneous ambulation was reduced. These negative behavioral phenotypes were associated with evidence of oxidative stress on the prefrontal cortex and hippocampus.

Matrix Metalloproteinases and Arterial Hypertension: Role of Oxidative Stress and Nitric Oxide in Vascular Functional and Structural Alterations.

Various pathophysiological mechanisms have been implicated in hypertension, but those resulting in vascular dysfunction and remodeling are critical and may help to identify critical pharmacological targets. This mini-review article focuses on central mechanisms contributing to the vascular dysfunction and remodeling of hypertension, increased oxidative stress and impaired nitric oxide (NO) bioavailability, which enhance vascular matrix metalloproteinase (MMP) activity. The relationship between NO, MMP and oxidative stress culminating in the vascular alterations of hypertension is examined. While the alterations of hypertension are not fully attributable to these pathophysiological mechanisms, there is strong evidence that such mechanisms play critical roles in increasing vascular MMP expression and activity, thus resulting in abnormal degradation of extracellular matrix components, receptors, peptides, and intracellular proteins involved in the regulation of vascular function and structure. Imbalanced vascular MMP activity promotes vasoconstriction and impairs vasodilation, stimulating vascular smooth muscle cells (VSMC) to switch from contractile to synthetic phenotypes, thus facilitating cell growth or migration, which is associated with the deposition of extracellular matrix components. Finally, the protective effects of MMP inhibitors, antioxidants and drugs that enhance vascular NO activity are briefly discussed. Newly emerging therapies that address these essential mechanisms may offer significant advantages to prevent vascular remodeling in hypertensive patients.