Expression of Snail1 in epithelial cells triggers an epithelial-mesenchymal transition (EMT). Here, we demonstrate that the synthesis of Zeb2, a transcriptional repressor of E-cadherin, is ...up-regulated after Snail1-induced EMT. Snail1 does not affect the synthesis of Zeb2 mRNA, but prevents the processing of a large intron located in its 5'-untranslated region (UTR). This intron contains an internal ribosome entry site (IRES) necessary for the expression of Zeb2. Maintenance of 5'-UTR Zeb2 intron is dependent on the expression of a natural antisense transcript (NAT) that overlaps the 5' splice site in the intron. Ectopic overexpression of this NAT in epithelial cells prevents splicing of the Zeb2 5'-UTR, increases the levels of Zeb2 protein, and consequently down-regulates E-cadherin mRNA and protein. The relevance of these results is demonstrated by the strong association between NAT presence and conservation of the 5'-UTR intron in cells that have undergone EMT or in human tumors with low E-cadherin expression. Therefore, the results presented in this article reveal the existence of a NAT capable of activating Zeb2 expression, explain the mechanism involved in this activation, and demonstrate that this NAT regulates E-cadherin expression.
A large number of nutrients and bioactive ingredients found in milk play an important role in the nourishment of breast-fed infants and dairy consumers. Some of these ingredients include ...physiologically relevant compounds such as vitamins, peptides, neuroactive compounds and hormones. Conversely, milk may contain substances-drugs, pesticides, carcinogens, environmental pollutants-which have undesirable effects on health. The transfer of these compounds into milk is unavoidably linked to the function of transport proteins. Expression of transporters belonging to the ATP-binding cassette (ABC-) and Solute Carrier (SLC-) superfamilies varies with the lactation stages of the mammary gland. In particular, Organic Anion Transporting Polypeptides 1A2 (OATP1A2) and 2B1 (OATP2B1), Organic Cation Transporter 1 (OCT1), Novel Organic Cation Transporter 1 (OCTN1), Concentrative Nucleoside Transporters 1, 2 and 3 (CNT1, CNT2 and CNT3), Peptide Transporter 2 (PEPT2), Sodium-dependent Vitamin C Transporter 2 (SVCT2), Multidrug Resistance-associated Protein 5 (ABCC5) and Breast Cancer Resistance Protein (ABCG2) are highly induced during lactation. This review will focus on these transporters overexpressed during lactation and their role in the transfer of products into the milk, including both beneficial and harmful compounds. Furthermore, additional factors, such as regulation, polymorphisms or drug-drug interactions will be described.
Background
The therapeutic approach to myofascial TMD should focus on pain relief and rehabilitation of function.
Objective
This study investigated whether pressure release technique (PRT) is ...effective for reducing pain in people with chronic myofascial temporomandibular disorders (TMD).
Methods
A single‐blinded randomised parallel‐group trial, with 3 months follow‐up was conducted. A total of 72 patients were randomly allocated to receive PRT or sham PRT. Primary outcome was pain assessed with a visual analogue scale (VAS). Secondary outcomes included pressure pain thresholds (PPTs), range of opening of the mouth (ROM), Neck Disability Index (NDI), Pain Catastrophizing Scale (PCS), Tampa Scale for Kinesiophobia (TSK‐11), State–Trait Anxiety Index (STAI) and State–Trait Depression Index (ST‐DEP). All parameters were assessed at baseline, at the end of the treatment and at 3 months follow‐up. Statistical analysis was performed by ANOVA.
Results
There were significant main effects of time, group and interaction between time and group (F ≥ 21.92; p < .001) on VAS pain. Post hoc tests showed a significant reduction in VAS pain scores in the PRT group (≥31.9%; p < .001). Effect sizes were moderate in the PRT group at all follow‐up periods (≥1.25 Cohen's d). Also, there were significant effects of time in secondary outcomes (F ≥ 9.65; p < .001), and there were also interactions between time and group (F ≥ 3.82; p < .002) with better effects in the PRT group.
Conclusions
The inclusion of PRT to conventional management with occlusal splints and self‐care management appears to be effective to improve self‐reported levels of pain in patients with chronic myofascial TMD pain. Retrospectively registered (ClinicalTrials.gov: NCT03619889).
The inclusion of PRT to conventional management with occlusal splints and self‐care management appears to be effective to improve self‐reported levels of pain in with chronic myofascial patients TMD pain. The combined treatment of the cervical and masticatory muscles significantly improved the opening of the mouth and cervical functionality as well as a clear improvement in the parameters of kinesiophobia, which could in turn improve motor behavior. In addition, PRT significantly improved the psychosocial factors of catastrophization, anxiety and depression.
Breast cancer ranks first in women, and is the second cause of death in this gender. In addition to genetics, the environment contributes to the development of the disease, although the factors ...involved are not well known. Among the latter is the influence of microorganisms and, therefore, attention is recently being paid to the mammary microbiota. We hypothesize that the risk of breast cancer could be associated with the composition and functionality of the mammary/gut microbiota, and that exposure to environmental contaminants (endocrine disruptors, EDCs) might contribute to alter these microbiota.
We describe a case-control clinical study that will be performed in women between 25 and 70 years of age. Cases will be women diagnosed and surgically intervened of breast cancer (stages I and II). Women with antecedents of cancer or advanced tumor stage (metastasis), or who have received antibiotic treatment within a period of 3 months prior to recruitment, or any neoadjuvant therapy, will be excluded. Controls will be women surgically intervened of breast augmentation or reduction. Women with oncological, gynecological or endocrine history, and those who have received antibiotic treatment within a period of 3 months prior to recruitment will also be excluded. Blood, urine, breast tissue and stool samples will be collected. Data regarding anthropometric, sociodemographic, reproductive history, tumor features and dietary habits will be gathered. Metabolomic studies will be carried out in stool and breast tissue samples. Metagenomic studies will also be performed in stool and breast tissue samples to ascertain the viral, fungal, bacterial and archaea populations of the microbiota. Quantitation of estrogens, estrogen metabolites and EDCs in samples of serum, urine and breast tissue will also be performed.
This is the first time that the contribution of bacteria, archaea, viruses and fungi together with their alteration by environmental contaminants to the risk of breast cancer will be evaluated in the same study. Results obtained could contribute to elucidate risk factors, improve the prognosis, as well as to propose novel intervention studies in this disease.
ClinicalTrials.gov NCT03885648 , 03/25/2019. Retrospectively registered.
The ATP‐binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and ...secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6‐hydroxymelatonin, and 6‐sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK‐II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild‐type and Abcg2−/− mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2−/− mice was between 1.5 and 6‐fold higher compared to the wild‐type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (>sixfold increase for 6‐sulfatoxymelatonin in Abcg2−/− mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild‐type compared with Abcg2−/− lactating female mice. In addition, melatonin metabolites showed a higher milk‐to‐plasma ratio in wild‐type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity.
Thiabendazole (TBZ) is a broad–spectrum anthelmintic and fungicide used in humans, animals, and agricultural commodities. TBZ residues are present in crops and animal products, including milk, posing ...a risk to food safety and public health. ABCG2 is a membrane transporter which affects bioavailability and milk secretion of xenobiotics. Therefore, the aim of this work was to characterize the role of ABCG2 in the in vitro transport and secretion into milk of 5–hydroxythiabendazole (5OH–TBZ), the main TBZ metabolite. Using MDCK–II polarized cells transduced with several species variants of ABCG2, we first demonstrated that 5OH–TBZ is efficiently in vitro transported by ABCG2. Subsequently, using Abcg2 knockout mice, we demonstrated that 5OH–TBZ secretion into milk was affected by Abcg2, with a more than 2–fold higher milk concentration and milk to plasma ratio in wild–type mice compared to their Abcg2–/– counterpart.
•5OH-thiabendazole is in vitro transported by murine, human, ovine, and bovine ABCG2.•In vitro transport of 5OH-thiabendazole is affected by the bovine Y581S SNP.•ABCG2 transporter increases milk secretion of 5OH-thiabendazole.
Objectives
Information on the recently COVID‐19‐associated pulmonary aspergillosis (CAPA) entity is scarce. We describe eight CAPA patients, compare them to colonised ICU patients with coronavirus ...disease 2019 (COVID‐19), and review the published literature from Western countries.
Methods
Prospective study (March to May, 2020) that included all COVID‐19 patients admitted to a tertiary hospital. Modified AspICU and European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria were used.
Results
COVID‐19‐associated pulmonary aspergillosis was diagnosed in eight patients (3.3% of 239 ICU patients), mostly affected non‐immunocompromised patients (75%) with severe acute respiratory distress syndrome (ARDS) receiving corticosteroids. Diagnosis was established after a median of 15 days under mechanical ventilation. Bronchoalveolar lavage was performed in two patients with positive Aspergillus fumigatus cultures and galactomannan (GM) index. Serum GM was positive in 4/8 (50%). Thoracic CT scan findings fulfilled EORTC/MSG criteria in one case. Isavuconazole was used in 4/8 cases. CAPA‐related mortality was 100% (8/8). Compared with colonised patients, CAPA subjects were administered tocilizumab more often (100% vs. 40%, p = .04), underwent longer courses of antibacterial therapy (13 vs. 5 days, p = .008), and had a higher all‐cause mortality (100% vs. 40%, p = .04). We reviewed 96 similar cases from recent publications: 59 probable CAPA (also putative according modified AspICU), 56 putative cases and 13 colonisations according AspICU algorithm; according EORTC/MSG six proven and two probable. Overall, mortality in the reviewed series was 56.3%.
Conclusions
COVID‐19‐associated pulmonary aspergillosis must be considered a serious and potentially life‐threatening complication in patients with severe COVID‐19 receiving immunosuppressive treatment.
Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), ...albendazole sulfone (ABZSO
) and albendazole 2-aminosulphone (ABZSO
-NH
). ABZSO and ABZSO
are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was
transported by ABCG2. The aim of this work is to correlate the
interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using
transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO
and ABZSO
-NH
are
substrates of both.
assays carried out with wild-type and Abcg2
lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2
mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly
substrates of ABCG2 and actively secreted into milk by ABCG2.
Aims
Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre‐ and ...post‐capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre‐ and post‐capillary PH (CpcPH).
Methods and results
The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE‐HF) trial is a multicentre, randomized, parallel, placebo‐controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n = 39) or placebo (n = 41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo‐corrected mean difference of 0.62 Wood units, 95% confidence interval CI −0.38, 1.61, p = 0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo‐corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p = 0.026), without significant differences in other pre‐specified secondary outcomes.
Conclusions
SPHERE‐HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre‐specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.
Summary of the study outline, flowchart, and results of the primary and secondary outcomes. The β3 selective agonist mirabegron did not improve pulmonary haemodynamics in adult patients with combined pre‐ and post‐capillary pulmonary hypertension associated with symptomatic heart failure. On secondary outcomes, a significant improvement in right ventricular ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life. PP, per protocol population.
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