Sarcoplasmic reticulum calcium ATPase (SERCA) proteolysis by matrix metalloproteinase-2 contributes to vascular dysfunction in early hypertension.

AIMS: Hypertension is associated with an increased activity of matrix metalloproteinase (MMP)-2 in the vasculature, which, in turn, proteolyzes extra- and intracellular proteins that lead to vascular dysfunction. The activity of sarcoplasmic reticulum calcium ATPase (SERCA) is decreased in the aortas of hypertensive rats. Increased activity of MMP-2 proteolyzed SERCA in rat heart during ischemia and reperfusion injury, thus impairing cardiac function. Therefore, we examined whether increased activity of MMP-2 in early hypertension contributes to proteolyze SERCA in the aortas, thus leading to maladaptive vascular remodeling and dysfunction. MAIN METHODS: Male Sprague-Dawley rats were submitted to two kidney-one clip (2K-1C) or Sham surgery and treated with doxycycline. Systolic blood pressure (SBP) was assessed by tail-cuff plethysmography. After 7 days, aortas were collected for zymography assays, Western blot to SERCA, ATPase activity assay, vascular reactivity, Ki-67 immunofluorescence and hematoxylin/eosin stain. KEY FINDINGS: SBP was increased in 2K-1C rats and doxycycline did not reduce it, but decreased MMP-2 activity and prevented SERCA proteolysis in aortas. Cross sectional area, media to lumen ratio and Ki-67 were all increased in the aortas of hypertensive rats and doxycycline decreased Ki-67. In 2K-1C rats, arterial relaxation to acetylcholine was impaired and doxycycline ameliorated it. SIGNIFICANCE: doxycycline reduced MMP-2 activity in aortas of 2K-1C rats and prevented proteolysis of SERCA and its dysfunction, thus ameliorating hypertension-induced vascular dysfunction.

Capsinoids Increase Antioxidative Enzyme Activity and Prevent Obesity-Induced Cardiac Injury without Positively Modulating Body Fat Accumulation and Cardiac Oxidative Biomarkers.

BACKGROUND/OBJECTIVES: Capsinoids are potential antioxidant agents capable of reducing oxidative damage and the resulting complications triggered by obesity. Thus, this study aimed to investigate the effects of capsinoids on adiposity and biomarkers of cardiac oxidative stress in obese rats induced by a high-fat diet. METHODS: Male Wistar rats were exposed to a high-fat diet for 27 consecutive weeks. After the characterization of obesity (week 19), some of the obese animals began to receive capsinoids (10 mg/kg/day) by orogastric gavage. Adiposity and comorbidities were assessed. In the heart, remodeling, injury, and biomarkers of oxidative stress were determined. RESULTS: The treatment did not reduce obesity-induced adiposity but was efficient in reducing cholesterol levels. Capsinoid treatment did not cause a difference in heart and LV mass, despite having reduced troponin I concentrations. Furthermore, capsinoids did not reduce the increase in the advanced oxidation of protein products and carbonylated proteins caused by obesity in cardiac tissue. In addition, obese rats treated with capsinoids presented high levels of malondialdehyde and greater antioxidant enzyme activity compared to untreated obese rats. CONCLUSIONS: In conclusion, treatment with capsinoids increases antioxidative enzyme activity and prevents obesity-induced cardiac injury without positively modulating body fat accumulation and cardiac oxidative biomarkers.

A proposal for analyzing the inflammatory and remodeling processes of mucosa in chronic rhinosinusitis with nasal polyposis through MRI.

OBJECTIVES: Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) is a disease characterized by chronic inflammation and tissue remodeling process. The remodeling process in nasal polyps has mainly been studied by histology analysis. However, it is limited to a polyp fragment and requires tissue removal. The present study aims to evaluate the ability of Magnetic Resonance Imaging (MRI) to depict and characterize the remodeling process in patients with CRSwNP. METHODS: 30 patients that met clinical diagnostic criteria for CRSwNP, without previous history of rhinosinusitis surgery were submitted to MRI scan (conventional, diffusion-weighted and DCE MRI) and compared with polyp tissue histological findings, IL-6 concentrations in the tissue and eosinophil count in the blood. The examinations were evaluated, independently, by two radiologists blinded to other radiological and histological data. The pathologist, blinded to MRI results, also compared the tissue sample from the most central and the most peripheral portion of the polypoid tissue adjacent to the floor of the nasal fossa. RESULTS: This study demonstrated a characteristic pattern of nasal polyps, whose peripheral portions of nasal polypoid tissue are edematous, whereas the central portions in the middle meatus and in the middle and upper ethmoid are predominantly fibrotic. ADC values found in the most anterior portion of the polyps may be a marker for radiological phenotyping the remodeling process. This non-invasive analysis presented a high degree of agreement in the fibrosis and edema rating by two radiologists and the histological analysis was concordant with the MRI findings. The polyps were characterized as eosinophilic, and no relationship was found between the severity of the eosinophilic inflammatory process or concentration of IL-6 and the remodeling process. CONCLUSION: MRI by using T2-weighted imaging sequence and ADCs values allows tissue characterization and is an effective tool for the differentiation of edematous and fibrotic components in CRSwNP.

Effects of Cannabidiol on Bone Quality in Ovariectomized Rats.

The incidence of osteoporosis and related fractures increases significantly with age, impacting public health and associated costs. Postmenopausal osteoporosis results from increased bone resorption due to decreased estrogen levels. The endocannabinoid system, especially cannabidiol (CBD), has shown therapeutic potential in modulating bone formation. This study investigated the effects of administration of CBD in rats after the onset of with ovariectomy-induced osteopenia (OVX). Forty-eight female Sprague‒Dawley rats were divided into four groups (n = 12): OVX + CBD, SHAM + CBD, OVX + vehicle, and SHAM + vehicle. CBD was administered intraperitoneally for 3 weeks. After euthanasia, the bone quality, mechanical properties, and bone microarchitecture of the femurs and lumbar vertebrae were assessed by microcomputed tomography (micro-CT), bone densitometry, mechanical tests, and histological and immunohistochemical analyses. CBD treatment improved the bone mineral density (BMD) of the lumbar vertebrae and increased the BV/TV% and Tb.N in the femoral neck. There were also improvements in the mechanical properties, such as the maximum force and stiffness of the femurs and vertebrae. CBD significantly increased the bone matrix in osteopenic femurs and vertebrae, Although did not significantly influence the expression of RANKL and OPG, in ovariectomized animals, there was an increase in osteoblasts and a decrease in osteoclasts. Determining the optimal timing for CBD use in relation to postovariectomy bone loss remains a crucial issue. Understanding when and how CBD can be most effective in preventing or treating bone loss is essential to emphasize the importance of early diagnosis and treatment of osteoporosis. However, further studies are needed to explore in more detail the efficacy and safety of CBD in the treatment of postmenopausal osteoporosis.

Examining the impact of varying low-level laser dose on cardiac failure.

Low-level laser therapy (LLLT) has been targeted as a promising tool that can mitigate post-infarction cardiac remodeling. However, there is no gold standard energy delivered to the heart and few studies have evaluated the impact of LLLT on cardiac performance. This study evaluated effects of repeated LLLT applications with different energies delivered to the infarcted myocardium. Echocardiography and hemodynamic measurements were applied to evaluate left ventricular (LV) performance in rats with large infarcts. ELISA, Western blot and biochemical assays were used to assess LV inflammation and oxidative stress. An 830-nm Laser Photon III semiconductor aluminum gallium arsenide diode (DMC, São Carlos, SP, Brazil) was applied transthoracically three times a week for 4 weeks based on the energy (i.e., 10J, 20J, and 40J; respectively). LLLT on 10J and 20J had a similar action in attenuating pulmonary congestion and myocardial fibrosis. Moreover, 10J and 20J attenuated LV end-diastolic pressure and improved +dP/dt and -dP/dt. All LLLT groups had lower levels of inflammatory mediators, but only the 10J group had normalized oxidative stress. All LLLT doses improved superoxide dismutase levels; however, only the 20J group showed a high content of the catalase. There was a lower level of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a in the infarcted myocardium, which it was normalized in the 20J and 40J groups. A higher phospholamban content was found in the 10J group. This study supports the beneficial LLLT role post-infarction. Apparently, the 10J and 20J doses show to be chosen for clinical translation.

Novel techniques and future developments in minimally invasive pectus repair.

After the paradigm shift in the treatment of excavated deformities caused by the introduction of the Nuss technique in 1998, several innovative technical modifications and new treatment modalities have radically changed the surgical approach of pectus excavatum in the last couple of years. These new trends attain different topics. On one hand, the use of three-dimensional (3D) printing and implant customization surge as a possibility for a wider audience as 3D printers become available with lower costs. They provide the surgeon with new elements that enable precise planning, simulation, and customized prostheses amidst a tendency to abandon standardization and incorporate personalized medicine. Another topic comprises mandatory sternal elevation, in the continuous search for safety first always. Complete thoracic remodeling as a goal of repair instead of addressing only focal depressions, leaving the upper chest or focal protrusions unresolved. Finally, although the current surgical approach has evolved significantly, many groups still use lateral stabilizers or direct implant fixation with sutures or wires to the ribs. These systems continue to prove unreliable in preventing implant displacement. Fortunately, the bridge technique, described in this review, has come to address this sometimes fatal issue with encouraging results. We provide an updated overview of the latest developments regarding these concepts, related to the current state-of-the-art of the treatment of pectus excavatum.

C-Phycocyanin Prevents Oxidative Stress, Inflammation, and Lung Remodeling in an Ovalbumin-Induced Rat Asthma Model.

Asthma is a chronic immunological disease related to oxidative stress and chronic inflammation; both processes promote airway remodeling with collagen deposition and matrix thickening, causing pulmonary damage and lost function. This study investigates the immunomodulation of C-phycocyanin (CPC), a natural blue pigment purified from cyanobacteria, as a potential alternative treatment to prevent the remodeling process against asthma. We conducted experiments using ovalbumin (OVA) to induce asthma in Sprague Dawley rats. Animals were divided into five groups: (1) sham + vehicle, (2) sham + CPC, (3) asthma + vehicle, (4) asthma + CPC, and (5) asthma + methylprednisolone (MP). Our findings reveal that asthma promotes hypoxemia, leukocytosis, and pulmonary myeloperoxidase (MPO) activity by increasing lipid peroxidation, reactive oxygen and nitrogen species, inflammation associated with Th2 response, and airway remodeling in the lungs. CPC and MP treatment partially prevented these physiological processes with similar action on the biomarkers evaluated. In conclusion, CPC treatment enhanced the antioxidant defense system, thereby preventing oxidative stress and reducing airway inflammation by regulating pro-inflammatory and anti-inflammatory cytokines, consequently avoiding asthma-induced airway remodeling.

The Involvement of microRNAs in Bone Remodeling Signaling Pathways and Their Role in the Development of Osteoporosis.

Bone remodeling, crucial for maintaining the balance between bone resorption and formation, relies on the coordinated activity of osteoclasts and osteoblasts. During osteoclastogenesis, hematopoietic stem cells (HSCs) differentiate into the osteoclast lineage through the signaling pathways OPG/RANK/RANKL. On the other hand, during osteoblastogenesis, mesenchymal stem cells (MSCs) differentiate into the osteoblast lineage through activation of the signaling pathways TGF-ß/BMP/Wnt. Recent studies have shown that bone remodeling is regulated by post-transcriptional mechanisms including microRNAs (miRNAs). miRNAs are small, single-stranded, noncoding RNAs approximately 22 nucleotides in length. miRNAs can regulate virtually all cellular processes through binding to miRNA-response elements (MRE) at the 3' untranslated region (3'UTR) of the target mRNA. miRNAs are involved in controlling gene expression during osteogenic differentiation through the regulation of key signaling cascades during bone formation and resorption. Alterations of miRNA expression could favor the development of bone disorders, including osteoporosis. This review provides a general description of the miRNAs involved in bone remodeling and their significance in osteoporosis development.

Prognosis recovery score of apical surgery Guided Bone Regeneration using cone beam computed tomography and digital bioinformatics.

Objective: Guided Bone Regeneration (GBR) is a dental surgical procedure that uses barrier membranes to prevent soft tissue invasion and conduct new bone growth. This study aimed to define a Prognosis Recovery score (PR score) to objectively classify post-surgery responders from non-responder patients who underwent GBR using Cone Beam Computed Tomography (CBCT). Methods: This prospective-observational-longitudinal-cohort study recruited 250 individuals who were assigned to: Conventional-Apical-Surgery (CAS, n = 39), Apical-Surgery using human fascia lata Membrane placement (ASM, n = 42), and Apical-Surgery using human fascia lata Membrane placement and lyophilized allograft Bone powder (ASMB, n = 39); and Apical-Surgery using collagen membrane Porcine origin and Bovine Bone-matrix (ASPBB, n = 130), an independent external validation cohort. Surgery was performed, and evolution was monitored by CBCTs at 0, 6-, 12-, 18-, and 24 months post-surgery. Results: Normalized lesion volumes were calculated, and non-linear time evolution morphology curves were characterized. The three-time evolution bone growth patterns were: a linear tendency (PR0), "S'' shaped log-logistic (PR1), and "C" cellular growth (PR2). The treatment success rates were PR2-46 %, PR2-88 %, and PR2-95 %/PR1-5% for CAS, ASM, and ASMB groups. The xenograft ASPBB counterpart achieved PR2-92 % and PR1-8%. The score PR had a sensitivity, specificity, and accuracy of 100 %. Conclusions: Patients' treatment success can be quantitatively, objectively, and precisely predicted with the Prognosis Recovery score (using only two CBCTs), according to their biological response to allograft or xenograft materials (time-evolution bone growth curves), reducing cost and radiation exposure. Clinical significance: Through digital imaging and bioinformatic analysis of bone regeneration observed in CBCTs, we defined a Prognosis Recovery (PR) score using only two CBCT volume assessments (0 and 6 months). The PR score allowed us to define three time-evolution curves depending on the biomaterials used and to classify patients in a quantitative, objective, and accurate way.

Cardiac biogenic amine profile and its relationship with parameters of cardiovascular disease in obesity.

AIMS: To identify the cardiac biogenic amine profile of obese rats and associate these compounds with parameters of cardiovascular disease. MAIN METHODS: Wistar rats (n = 20) were randomly distributed into two groups: control and obese. Obesity was induced by a high-sugar fat diet. Biochemical parameters were evaluated. Doppler Echocardiography and systolic blood pressure; interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), protein carbonylation, ferric reducing antioxidant power (FRAP), and catalase activity were measured in cardiac tissue. HPLC evaluated the cardiac biogenic profile. Data were compared using the Student's T or Mann-Whitney tests and Spearman's correlation at 5% significance. The principal component analysis (PCA) was performed. KEY FINDINGS: Obesity generated hypertension, cardiac remodeling and dysfunction, and imbalanced all biochemical, inflammatory, and oxidative markers (p < 0.001). Eight biogenic amines were found in cardiac tissue. Obesity increased serotonin and decreased agmatine, putrescine, cadaverine, and spermidine. Serotonin (r = 0.534 to 0.808) was strong and positively correlated with obesity, biochemical parameters, cardiac inflammation, oxidative stress, hypertension, cardiac remodeling, and dysfunction (p < 0.001). Spermidine (r = -0.560 to -0.680), putrescine (r = -0.532 to -0.805), cadaverine (r = -0.534 to -0.860), and agmatine (r = -0.579 to -0.884) were inversely correlated with the same parameters (p < 0.001). PCA allowed for distinguishing the control and obese groups. SIGNIFICANCE: There are strong correlations between cardiac biogenic amine levels, cardiac remodeling, and dysfunction resulting from obesity. CONCLUSION: There is an association between cardiac biogenic amines and cardiovascular disease in obesity. In addition, agmatine, putrescine, cadaverine, and, mainly, serotonin may be new biomarkers for cardiovascular health in obesity and help to improve the diagnosis and treatment of CVD resulting or not from obesity. However, more research is needed to support this conclusion.

The hydrogen sulfide donor 4-carboxyphenyl-isothiocyanate decreases blood pressure and promotes cardioprotective effect through reduction of oxidative stress and nuclear factor kappa B/matrix metalloproteinase (MMP)-2 axis in hypertension.

AIMS: Our aim was to evaluate whether the hydrogen sulfide (H2S) donor, 4-carboxyphenyl-isothiocyanate (4-CPI), exerts cardioprotective effect in the two kidney- one clip (2K-1C) rats through oxidative stress and MMP-2 activity attenuation and compare it with the classical H2S donor, Sodium Hydrosulfide (NaHS). MATERIALS AND METHODS: Renovascular hypertension (two kidneys-one clip; 2K-1C) was surgically induced in male Wistar rats. After two weeks, normotensive (2K) and hypertensive rats were intraperitoneally treated with vehicle (0.6 % dimethyl sulfoxide), NaHS (0.24 mg/Kg/day) or with 4-CPI (0.24 mg/Kg/day), for more 4 weeks. Systolic blood pressure (SBP) was evaluated weekly by tail-cuff plethysmography. Heart function was assessed by using the Millar catheter. Cardiac hypertrophy and fibrosis were evaluated by hematoxylin and eosin, and Picrosirius Red staining, respectively. The H2S was analyzed using WSP-1 fluorimetry and the cardiac oxidative stress was measured by lucigenin chemiluminescence and Amplex Red. MMP-2 activity was measured by in-gel gelatin or in situ zymography assays. Nox1, gp91phox, MMP-2 and the phospho-p65 subunit (Serine 279) nuclear factor kappa B (NF-κB) levels were evaluated by Western blotting. KEY FINDINGS: 4-CPI reduced blood pressure in hypertensive rats, decreased cardiac remodeling and promoted cardioprotection through the enhancement of cardiac H2S levels. An attenuation of oxidative stress, with inactivation of the p65-NF-κB/MMP-2 axis was similarly observed after NaHS or 4-CPI treatment in 2K-1C hypertension. SIGNIFICANCE: H2S is a mediator that promotes cardioprotective effects and decreases blood pressure, and 4-CPI seems to be a good candidate to reverse the maladaptive remodeling and cardiac dysfunction in renovascular hypertension.

Therapeutic dosage of isotretinoin in rats may influence orthodontic tooth movement.

Objective Isotretinoin, also known as 13-cis-retinoic acid, is an isomer of tretinoin, the oxidized form of Vitamin A. Orthodontic tooth movement (OTM) is the result of a cascade of inflammatory responses stimulated by a physical element that is the force generated by orthodontic appliances. Isotretinoin is mainly used among adolescents and young adults, and coincidentally it is this age group that also undergoes orthodontic treatment. Materials and Methods Fifty-five animals were used, and they were randomly divided into 11 groups, containing 5 animals in each group. Group 1: Control; Group 2: OTM for 7 days; Group 3: OTM for 14 days; Group 4: Treated with isotretinoin for 14 days with a dosage of 7.5 mg/kg/day; Group 5: Treated with isotretinoin for 14 days with a dosage of 1.0 mg/kg/day; Group 6: Treated with isotretinoin for 21 days with a dosage of 7.5 mg/kg/day; Group 7: Treated with isotretinoin for 21 days with a dosage of 1.0 mg/kg/day; Group 8: Treated with isotretinoin for 14 days with a dosage of 7.5 mg/kg/day and undergoing OTM for 7 days; Group 9: Treated with isotretinoin for 14 days with a dosage of 1.0 mg/kg/day and undergoing OTM for 7 days; Group 10: Treated with isotretinoin for 21 days with a dosage of 7.5 mg/kg/day and undergoing OTM for 14 days; Group 11: Treated with isotretinoin for 21 days with a dosage of 1.0 mg/kg/day and undergoing OTM for 14 days. In Groups 8, 9, 10 and 11, the animals were treated with isotretinoin for 7 days before OTM and maintained during the movement period in the respective groups. Results There was a significant difference in microtomographic parameters, including Trabecular Volume (BV/TV), Trabecular Thickness (Tb.Th), Number of Trabeculae (Tb.N), and Trabecular Separation (Tb.Sp), between the groups. The group that received orthodontic force in conjunction with isotretinoin treatment at a dosage of 7.5 mg/kg/day exhibited lower tooth displacement over a period of 21 days and 14 days. Conclusion Isotretinoin caused a reduction in tooth displacement during OTM when administered at a dose of 7.5 mg/kg/day and isotretinoin did change the microtomographic parameters of treated animals.

Quantitative Analysis of Innate Lymphoid Cells in Patients with ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) is one of the principal causes of death in Mexico and worldwide. AMI triggers an acute inflammatory process that induces the activation of different populations of the innate immune system. Innate lymphoid cells (ILCs) are an innate immunity, highly pleiotropic population, which have been observed to participate in tissue repair and polarization of the adaptive immune response. OBJECTIVE: We aimed to analyze the levels of subsets of ILCs in patients with ST-segment elevation myocardial infarction (STEMI), immediately 3 and 6 months post-AMI, and analyze their correlation with clinical parameters. RESULTS: We evaluated 29 STEMI patients and 15 healthy controls and analyzed the different subsets of circulating ILCs, immediately 3 and 6 months post-AMI. We observed higher levels of circulating ILCs in STEMI patients compared to control subjects and a significant correlation between ILC levels and cardiac function. We also found increased production of the cytokines interleukin 5 (IL-5) and interleukin 17A (IL-17A), produced by ILC2 cells and by ILC3 cells, respectively, in the STEMI patients. CONCLUSION: This study shows new evidence of the role of ILCs in the pathophysiology of AMI and their possible involvement in the maintenance of cardiac function.

Regulation of seed dormancy by histone post-translational modifications in the model plant Arabidopsis thaliana.

Plants synchronize their growth and development with environmental changes, which is critical for their survival. Among their life cycle transitions, seed germination is key for ensuring the survival and optimal growth of the next generation. However, even under favorable conditions, often germination can be blocked by seed dormancy, a regulatory multilayered checkpoint integrating internal and external signals. Intricate genetic and epigenetic mechanisms underlie seed dormancy establishment, maintenance, and release. In this review, we focus on recent advances that shed light on the complex mechanisms associated with physiological dormancy, prevalent in seed plants, with Arabidopsis thaliana serving as a model. Here, we summarize the role of multiple epigenetic regulators, but with a focus on histone modifications such as acetylation and methylation, that finely tune dormancy responses and influence dormancy-associated gene expression. Understanding these mechanisms can lead to a better understanding of seed biology in general, as well as resulting in the identification of possible targets for breeding climate-resilient plants.

Effects of plant protease inhibitors (Pep-3-EcTI, Pep-BbKI, and Pep-BrTI) versus corticosteroids on inflammation, remodeling, and oxidative stress in an asthma-COPD (ACO) model.

The peptide derived from E. contortisiliquum trypsin inhibitor (Pep-3-EcTI), peptide derived from kallikrein inhibitor isolated from B. bauhinioides (Pep-BbKI), and B. rufa peptide modified from B. bauhinioides (Pep-BrTI) peptides exhibit anti-inflammatory and antioxidant activities, suggesting their potential for treating asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO). We compared the effects of these peptides with dexamethasone (DX) treatment in an ACO model. In this study, 11 groups of male BALB/c mice were pre-treated under different conditions, including sensitization with intraperitoneal injection and inhalation of ovalbumin (OVA), intratracheal instillation of porcine pancreatic elastase (ELA), sensitization with intraperitoneal injection, and various combinations of peptide treatments with Pep-3-EcTI, Pep-BbKI, Pep-BrTI, dexamethasone, and non-treated controls (SAL-saline). Respiratory system resistance, airway resistance, lung tissue resistance, exhaled nitric oxide, linear mean intercept, immune cell counts in the bronchoalveolar lavage fluid, cytokine expression, extracellular matrix remodeling, and oxidative stress in the airways and alveolar septa were evaluated on day 28. Results showed increased respiratory parameters, inflammatory markers, and tissue remodeling in the ACO group compared to controls. Treatment with the peptides or DX attenuated or reversed these responses, with the peptides showing effectiveness in controlling hyperresponsiveness, inflammation, remodeling, and oxidative stress markers. These peptides demonstrated an efficacy comparable to that of corticosteroids in the ACO model. However, this study highlights the need for further research to assess their safety, mechanisms of action, and potential translation to clinical studies before considering these peptides for human use.

General regulatory factors exert differential effects on nucleosome sliding activity of the ISW1a complex.

BACKGROUND: Chromatin dynamics is deeply involved in processes that require access to DNA, such as transcriptional regulation. Among the factors involved in chromatin dynamics at gene regulatory regions are general regulatory factors (GRFs). These factors contribute to establishment and maintenance of nucleosome-depleted regions (NDRs). These regions are populated by nucleosomes through histone deposition and nucleosome sliding, the latter catalyzed by a number of ATP-dependent chromatin remodeling complexes, including ISW1a. It has been observed that GRFs can act as barriers against nucleosome sliding towards NDRs. However, the relative ability of the different GRFs to hinder sliding activity is currently unknown. RESULTS: Considering this, we performed a comparative analysis for the main GRFs, with focus in their ability to modulate nucleosome sliding mediated by ISW1a. Among the GRFs tested in nucleosome remodeling assays, Rap1 was the only factor displaying the ability to hinder the activity of ISW1a. This effect requires location of the Rap1 cognate sequence on linker that becomes entry DNA in the nucleosome remodeling process. In addition, Rap1 was able to hinder nucleosome assembly in octamer transfer assays. Concurrently, Rap1 displayed the highest affinity for and longest dwell time from its target sequence, compared to the other GRFs tested. Consistently, through bioinformatics analyses of publicly available genome-wide data, we found that nucleosome occupancy and histone deposition in vivo are inversely correlated with the affinity of Rap1 for its target sequences in the genome. CONCLUSIONS: Our findings point to DNA binding affinity, residence time and location at particular translational positions relative to the nucleosome core as the key features of GRFs underlying their roles played in nucleosome sliding and assembly.

New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review.

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of ß-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.

Bone Remodeling and Bone Structural Genes in Legg-Calvé-Perthes Disease: The OPG rs2073618 and IL-6 rs1800795 Are Associated with High Risk in Mexican Patients.

Legg-Calve-Perthes disease (LCPD) is an idiopathic avascular necrosis of the pediatric femoral head. Bone remodeling and bone structural genes have the potential to contribute to the progression of LCPD when there is disequilibrium between bone resorption and bone formation. A case-control study was performed to search for associations of several common polymorphisms in the genes Receptor Activator for Nuclear Factor κappa B (RANK), Receptor Activator for Nuclear Factor κappa B Ligand (RANKL), osteoprotegerin (OPG), interleukin (IL)-6, and type 1 collagen (COL1A1) with LCPD susceptibility in Mexican children. A total of 23 children with LCPD and 46 healthy controls were genotyped for seven polymorphisms (rs3018362, rs12585014, rs2073618, rs1800795, rs1800796, rs1800012, and rs2586498) in the RANK, RANKL, OPG, IL-6, and COL1A1 genes by real-time polymerase chain reaction with TaqMan probes. The variant allele (C) of IL-6 rs1800795 was associated with increased risk of LCPD (odds ratio [OR]: 3.8, 95% confidence interval [CI]: [1.08-13.54], p = 0.033), adjusting data by body mass index (BMI) and coagulation factor V (FV), the association with increased risk remained (OR: 4.9, 95% CI: [1.14-21.04], p = 0.025). The OPG polymorphism rs2073618, specifically GC-GG carriers, was associated with a more than fourfold increased risk of developing LCPD (OR: 4.34, 95% CI: [1.04-18.12], p = 0.033) when data were adjusted by BMI-FV. There was no significant association between RANK rs3018362, RANKL rs12585014, IL-6 rs1800796, COL1A1 rs1800012, and rs2586498 polymorphisms and LCPD in a sample of Mexican children. The rs1800975 and rs2037618 polymorphisms in the IL-6 and OPG genes, respectively, are informative markers of increased risk of LCPD in Mexican children.

Left ventricular concentric remodeling in COPD patients: A cross-sectional observational study.

OBJECTIVE: To investigate the association between left ventricular structure and disease severity in COPD patients. METHODS: Twenty-eight COPD patients were stratified according to the disease severity, using the BODE index, into Lower (n=17) and Higher (n=11) groups, composed of patients with lower severity (BODE <5) and higher severity (BODE ≥5), respectively. Left ventricle (LV) was assessed by 2D-echocardiography. BODE index was calculated using body mass index (BMI); forced expiratory volume in the first second (FEV1, %); modified Medical Research Council (mMRC) and distance walked during 6-minute walk test (6MWD). RESULTS: Patients in the Higher group showed lower oxygen arterial saturation (p=0.02), FEV1 (p<0.01) and 6MWD (p=0.02) and higher value of relative posterior wall thickness (RWT) compared to Lower group (p=0.02). There were significant associations between LV end-systolic diameter (LVESD) and BODE index (r=-0.38, p=0.04), LV end-diastolic diameter (LVEDD) and FEV1 (r=0.44, p=0.02), LVEDD and BMI (r=0.45, p=0.02), LVESD and BMI (r=0.54, p=0.003) and interventricular septal thickness and 6MWD (r=-0.39, p=0.04). CONCLUSIONS: More severe COPD patients, BODE score ≥5, may have higher RWT, featuring a possible higher concentric remodeling of LV in this group. Besides that, a greater disease severity may be related to LV chamber size reduction.

Functional analysis of airway remodeling is related with fibrotic mediators in asthmatic children.

BACKGROUND: Asthmatic children present variable degrees of airway inflammation, remodeling, and resistance, which correlate with disease control and severity. The chronic inflammatory process of the airway triggers airway remodeling, which reflects the degree of airway resistance. Pro-inflammatory and pro-fibrotic mediators are centrally involved in this process. OBJECTIVE: To investigate whether the levels of pulmonary and systemic pro-inflammatory and pro-fibrotic mediators present a correlation with the resistance of the respiratory system and of the proximal and distal airways. METHODS: 39 Asthmatic children (persistent mild and moderate) and 39 non-asthmatic children (both between 6 and 13 years old) were evaluated for anthropometric characteristics, lung function and mechanics, and pulmonary and systemic immune responses. RESULTS: Asthmatic children showed an increased number of blood eosinophils (p < 0.04), basophils (p < 0.04), monocytes (p < 0.002) and lymphocytes (p < 0.03). In addition, asthmatic children showed impaired lung function, as demonstrated by FEV1 (p < 0.0005) and FEV1/FVC (p < 0.004), decreased total resistance of the respiratory system (R5Hz; p < 0.009), increased resistance of the proximal airways (R20Hz; p < 0.02), increased elastance (Z5Hz; p < 0.02) and increased reactance (X5Hz; p < 0.002) compared to non-asthmatic children. Moreover, the following inflammatory factors were significantly higher in asthmatic than non-asthmatic children: GM-CSF in the breath condensate (BC) (p < 0.0001) and in the serum (p < 0.0001); TGF-beta in the BC (p < 0.0001) and in the serum (p < 0.004); IL-5 in the BC (p < 0.02) and in the serum (p < 0.01); IL-4 in the serum (p < 0.0002). CONCLUSIONS: Impulse oscillometry is a sensitive method to detect airway resistance in persistent mild and moderate asthmatic children, an event followed by increased levels of pro-inflammatory and pro-fibrotic mediators.