Cross-sectional study of sublingual varicosities: systemic exposures.

PURPOSE: Sublingual varicose veins are a common vascular lesion with different names, such as caviar tongue or vascular malformations. This study aimed to investigate whether there is an association between sublingual varicose veins and cardiovascular diseases by observing arterial hypertension, diabetes, thrombosis, and infarction. In addition, to evaluate a series of thrombi that affected the oral cavity and to analyze their clinical aspects and relate them to possible systemic alterations. METHODS: This is a cross-sectional study consisting of a sample of 134 varicosities, 23 vascular malformations, and 4 thrombosis. RESULTS: Lingual varicosities are more frequently observed in women aged 57.4 ± 16.4 years. Hypertension was present in lingual varicosities (n = 73), as well as diabetes (n = 107), reports of thrombosis (n = 41), and infarction (n = 45). Arterial hypertension was decompensated (n = 12). The most frequent underlying diseases were diabetes (p < 0.001), infarction (p = 0.012), and thrombosis (p = 0.004), and the most commonly used drug was losartan. CONCLUSION: It can be inferred from the present study that lingual varicosities are related to cardiovascular diseases and can serve as a parameter to measure their decompensation.

Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients.

Hepatoblastoma is a very rare embryonal liver cancer supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. In this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. Our data disclosed a low mutational background and pointed out to a novel set of candidate genes for hepatoblastoma biology, which were shown to impact gene expression levels. Only three recurrently mutated genes were detected: CTNNB1 and two novel candidates, CX3CL1 and CEP164. A relevant finding was the identification of a recurrent mutation (A235G) in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed upregulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 pathway occurs in hepatoblastomas. In inflammatory regions of hepatoblastomas, CX3CL1/CX3CR1 were not detected in the infiltrated lymphocytes, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative labeling in tumor cells, but strongly positive infiltrated lymphocytes. Altogether, these data suggested that CX3CL1/CX3CR1 upregulation may be a common feature of hepatoblastomas, potentially related to chemotherapy response and progression. In addition, three mutational signatures were identified in hepatoblastomas, two of them with predominance of either the COSMIC signatures 1 and 6, found in all cancer types, or the COSMIC signature 29, mostly related to tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C>A mutations. Overall, we present here novel candidate genes for hepatoblastoma, with evidence that CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with progression, besides reporting specific mutational signatures.

Hepatic Estrogen Sulfotransferase Distantly Sensitizes Mice to Hemorrhagic Shock-Induced Acute Lung Injury.

Hemorrhagic shock (HS) is a potential life-threatening condition that may lead to injury to multiple organs, including the lung. The estrogen sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates estrogens. In this report, we showed that the expression of Est was markedly induced in the liver but not in the lung of female mice subject to HS and resuscitation. Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury (ALI), including interstitial edema, neutrophil mobilization and infiltration, and inflammation. The pulmonoprotective effect of Est ablation or inhibition was sex-specific, because the HS-induced ALI was not affected in male Est-/- mice. Mechanistically, the pulmonoprotective phenotype in female Est-/- mice was accompanied by increased lung and circulating levels of estrogens, attenuated pulmonary inflammation, and inhibition of neutrophil mobilization from the bone marrow and neutrophil infiltration to the lung, whereas the pulmonoprotective effect was abolished upon ovariectomy, suggesting that the protection was estrogen dependent. The pulmonoprotective effect of Est ablation was also tissue specific, as loss of Est had little effect on HS-induced liver injury. Moreover, transgenic reconstitution of human EST in the liver of global Est-/- mice abolished the pulmonoprotective effect, suggesting that it is the EST in the liver that sensitizes mice to HS-induced ALI. Taken together, our results revealed a sex- and tissue-specific role of EST in HS-induced ALI. Pharmacological inhibition of EST may represent an effective approach to manage HS-induced ALI.

Estrogen sulfotransferase in the metabolism of estrogenic drugs and in the pathogenesis of diseases.

INTRODUCTION: Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen sulfotransferase (SULT1E1 or EST) is a phase II conjugating enzyme that belongs to the family of cytosolic sulfotransferases. The expression of SULT1E1 can be detected in many tissues, including the liver. SULT1E1 catalyzes the transfer of a sulfate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to any available hydroxyl group in estrogenic molecules. The substrates of SULT1E1 include the endogenous and synthetic estrogens. Upon SULT1E1-mediated sulfation, the hydrosolubility of estrogens increases, preventing the binding between the sulfated estrogens and the estrogen receptor (ER). This sulfated state of the estrogens is not irreversible, as the steroid sulfatase (STS) can convert sulfoconjugated estrogens to free estrogens. The expression of SULT1E1 is inducible by several diseases that involve tissue inflammation, such as type 2 diabetes, sepsis, and ischemia-reperfusion injury. Areas covered: This systematic literature review aims to summarize the role of SULT1E1 in the metabolism of estrogenic drugs and xenobiotics, and the role of SULT1E1 in the pathogenesis of several diseases, including cancer, metabolic disease, sepsis, liver injury, and cystic fibrosis. Meanwhile, ablation or pharmacological inhibition of SULT1E1 can affect the outcomes of the aforementioned diseases. Expert opinion: In addition to its role in metabolizing estrogenic drugs, SULT1E1 is unexpectedly being unveiled as a mediator for the disease effect on estrogen metabolism and homeostasis. Meanwhile, because the expression and activity of SULT1E1 can affect the outcome of diseases, the same sulfotransferase and the reversing enzymes STS can be potential therapeutic targets to prevent or manage diseases. Accumulating evidence suggest that the physiological and pathophysiological effects of SULT1E1 can be estrogen-independent and it is necessary to elucidate what other possible substrates may be recognized by the enzyme. Moreover, human studies are paramount to confirm the human relevance of the animal studies.

Activation of Constitutive Androstane Receptor Ameliorates Renal Ischemia-Reperfusion-Induced Kidney and Liver Injury.

Acute kidney injury (AKI) is associate with high mortality. Despite evidence of AKI-induced distant organ injury, a relationship between AKI and liver injury has not been clearly established. The goal of this study is to investigate whether renal ischemia-reperfusion (IR) can affect liver pathophysiology. We showed that renal IR in mice induced fatty liver and compromised liver function through the downregulation of constitutive androstane receptor (CAR; -90.4%) and inhibition of hepatic very-low-density lipoprotein triglyceride (VLDL-TG) secretion (-28.4%). Treatment of mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) prevented the development of AKI-induced fatty liver and liver injury, which was associated with the attenuation of AKI-induced inhibition of VLDL-TG secretion. The hepatoprotective effect of TCPOBOP was abolished in CAR-/- mice. Interestingly, alleviation of fatty liver by TCPOBOP also improved the kidney function, whereas CAR ablation sensitized mice to AKI-induced kidney injury and lethality. The serum concentrations of interleukin-6 (IL-6) were elevated by 27-fold after renal IR, but were normalized in TCPOBOP-treated AKI mice, suggesting that the increased release of IL-6 from the kidney may have mediated the AKI responsive liver injury. Taken together, our results revealed an interesting kidney-liver organ cross-talk in response to AKI. Given the importance of CAR in the pathogenesis of renal IR-induced fatty liver and impaired kidney function, fatty liver can be considered as an important risk factor for kidney injury, and a timely management of hepatic steatosis by CAR activation may help to restore kidney function in patients with AKI or kidney transplant.