Furin inhibition prevents hypoxic and TGFβ-mediated blood-brain barrier disruption

Hypoxic blood-brain barrier (BBB) dysfunction is a common feature of CNS diseases however mechanisms underlying barrier disturbance are still largely unknown. This study investigated the role of transforming growth factor β (TGFβ), a cytokine known to induce expression of the proprotein convertase Furin, in hypoxia-mediated barrier compromise.We show that exposure of brain endothelial cells (ECs) to hypoxia (1% O2) rapidly stimulates their migration. Additional exogenous TGFβ (0.4nM) exposure potentiated this effect and increased Furin expression in a TGFβ type I receptor activin-like kinase 5 (ALK5) - dependent manner (prevented by 10μM SB431542). Furin inhibition prevented hypoxia-induced EC migration and blocked TGFβ-induced potentiation suggesting existence of a feedback loop. TGFβ and Furin were also critical for hypoxia-induced BBB dysfunction. TGFβ treatment aggravated hypoxia-induced BBB permeability but ALK5 or Furin blockade reversed injury-induced permeability changes. Thus during insult Furin compromises endothelial integrity by mediating the effects of TGFβ. Targeting the Furin or ALK5 pathway may offer novel therapeutic strategies for improving BBB stability and CNS function during disease

Double primary bronchogenic carcinoma of the lung and papillary thyroid carcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Double primary bronchogenic carcinoma and papillary carcinoma of the thyroid are extremely rare. We describe the case of a patient who underwent surgical resection for these two cancers.</p> <p>Case presentation</p> <p>A 56-year-old man presented to our hospital complaining of a cough with blood-tinged sputum. A slowly growing mass in the left lobe of the lung had been noted for about 1 year. He underwent video-assisted thoracic surgery of the left lower lobe and mediastinal lymph node dissection through an 8 cm utility incision. Pathology revealed a well-differentiated adenocarcinoma and the dissected lymph nodes were negative for malignancy. He also complained of a mass in his neck, which had grown slowly for over 5 years. A computed tomography scan of the neck revealed a left thyroid mass compressing the trachea towards the right side. There was no cervical lymphadenopathy. A left thyroid lobectomy was performed and pathology revealed a papillary carcinoma. Thus, he underwent a second operation to remove the right lobe of the thyroid. He underwent subsequent adjuvant chemotherapy.</p> <p>Conclusion</p> <p>In a review of the literature, it appears that there has only been one previously reported case of these two cancers, which was in Japan. The relationship between these two cancers is still unclear, and more case reports are required to determine this relationship.</p

Activation of Multiple Apoptotic Pathways in Human Nasopharyngeal Carcinoma Cells by the Prenylated Isoflavone, Osajin

Osajin is a prenylated isoflavone showing antitumor activity in different tumor cell lines. The underlying mechanism of osajin-induced cancer cell death is not clearly understood. In the present study, the mechanisms of osajin-induced cell death of human nasopharyngeal carcinoma (NPC) cells were explored. Osajin was found to significantly induce apoptosis of NPC cells in a dose- and time-dependent manner. Multiple molecular effects were observed during osajin treatment including a significant loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, enhanced expression of Fas ligand (FasL), suppression of glucose-regulated protein 78 kDa (GRP78), and activation of caspases-9, -8, -4 and -3. In addition, up-regulation of proapoptotic Bax protein and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, osajin induces apoptosis in human NPC cells through multiple apoptotic pathways, including the extrinsic death receptor pathway, and intrinsic pathways relying on mitochondria and endoplasmic reticulum stress. Thus, osajin could be developed as a new effective and chemopreventive compound for human NPC

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Astrocyte-specific hypoxia-inducible factor 1 (HIF-1) does not disrupt the endothelial barrier during hypoxia in vitro

Background: Astrocytes (AC) are essential for brain homeostasis. Much data suggests that AC support and protect the vascular endothelium, but increasing evidence indicates that during injury conditions they may lose their supportive role resulting in endothelial cell activation and BBB disturbance. Understanding the triggers that flip this switch would provide invaluable information for designing new targets to modulate the brain vascular compartment. Hypoxia-inducible factor-1 (HIF-1) has long been assumed to be a culprit for barrier dysfunction as a number of its target genes are potent angiogenic factors. Indeed AC themselves, reservoirs of an array of different growth factors and molecules, are frequently assumed to be the source of such molecules although direct supporting evidence is yet to be published. Being well known reservoirs of HIF-1 dependent angiogenic molecules, we asked if AC HIF-1 dependent paracrine signaling drives brain EC disturbance during hypoxia. Methods: First we collected conditioned media from control and siRNA-mediated HIF-1 knockdown primary rat AC that had been exposed to normoxic or hypoxic conditions. The conditioned media was then used to culture normoxic and hypoxic (1% O$_{2}$) rat brain microvascular EC (RBE4) for 6 and 24 h. Various activation parameters including migration, proliferation and cell cycling were assessed and compared to untreated controls. In addition, tight junction localization and barrier stability per se (via permeability assay) was evaluated. Results: AC conditioned media maintained both normoxic and hypoxic EC in a quiescent state by suppressing EC metabolic activity and proliferation. By FACs we observed reduced cell cycling with an increased number of cells in G0 phase and reduced cell numbers in M phase compared to controls. EC migration was also blocked by AC conditioned media and in correlation hypoxic tight junction organization and barrier functionality was improved. Surprisingly however, AC HIF-1 deletion did not impact EC responses or barrier stability during hypoxia. Conclusions: This study demonstrates that AC HIF-1 dependent paracrine signaling does not contribute to AC modulation of EC barrier function under normoxic or hypoxic conditions. Thus other cell types likely mediate EC permeability in stress scenarios. Our data does however highlight the continuous protective effect of AC on the barrier endothelium. Exploring these protective mechanisms in more detail will provide essential insight into ways to prevent barrier disturbance during injury and disease

Do dehydroepiandrosterone, progesterone, and testosterone influence women’s depression and anxiety levels? Evidence from hair-based hormonal measures of 2105 rural Indian women

Depressive and anxiety disorders substantially contribute to the global burden of disease, particularly in poor countries. Higher prevalence rates for both disorders among women indicate sex hormones may be integrated in the pathophysiology of these disorders. The Kshetriya Gramin Financial Services study surveyed a random sample of 4160 households across 876 villages in rural Tamil Nadu, India. An interviewer-administered questionnaire was conducted to quantify depressive (K6-D) and anxiety (K6-A) symptoms. Alongside, hair samples for sex hormone profiling were collected from a subsample of 2105 women aged 18–85 years. Importantly, 5.9%, 14.8%, and 46.3% of samples contained non-detectable hormone levels for dehydroepiandrosterone, progesterone, and testosterone, respectively. Our primary analysis imputes values for the non-detectable sample and we check robustness of results when non-detectable values are dropped. In this cohort of women from rural India, higher depressive symptomatology is associated with lower levels of dehydroepiandrosterone and higher depressive and anxiety symptoms are associated with higher levels of testosterone. Progesterone shows no clear association with either depressive or anxiety symptoms. These results support a potential protective effect of higher endogenous dehydroepiandrosterone levels. An important caveat on the potential negative effect of hair testosterone levels on women’s mental health is that the testosterone analysis is sensitive to how non-detectable values are treated