Shared genetic architecture between type 2 diabetes and COVID-19 severity.

PURPOSE: Patients with type 2 diabetes (T2D) have demonstrated a higher risk for developing more severe cases of COVID-19, but the complex genetic mechanism between them is still unknown. The aim of the present study was to untangle this relationship using genetically based approaches. METHODS: By leveraging large-scale genome-wide association study (GWAS) summary statistics of T2D and COVID-19 severity, linkage disequilibrium score regression and Mendelian randomization (MR) analyses were utilized to quantify the genetic correlations and causal relationships between the two traits. Gene-based association and enrichment analysis were further applied to identify putative functional pathways shared between T2D and COVID-19 severity. RESULTS: Significant, moderate genetic correlations were detected between T2D and COVID-19 hospitalization (rg = 0.156, SE = 0.057, p = 0.005) or severe disease (rg = 0.155, SE = 0.057, p = 0.006). MR analysis did not support evidence for a causal effect of T2D on COVID-19 hospitalization (OR 1.030, 95% CI 0.979, 1.084, p = 0.259) or severe disease (OR 0.999, 95% CI 0.934, 1.069, p = 0.982). Genes having pgene < 0.05 for both T2D and COVID-19 severe were significantly enriched for biological pathways, such as response to type I interferon, glutathione derivative metabolic process and glutathione derivative biosynthetic process. CONCLUSIONS: Our findings further confirm the comorbidity of T2D and COVID-19 severity, but a non-causal impact of T2D on severe COVID-19. Shared genetically modulated molecular mechanisms underlying the co-occurrence of the two disorders are crucial for identifying therapeutic targets.

Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia.

The brain endothelium is an important therapeutic target for the inhibition of cerebrovascular dysfunction in ischemic stroke. Previously, we documented the important regulatory roles of microRNAs in the cerebral vasculature, in particular the cerebral vascular endothelium. However, the functional significance and molecular mechanisms of other classes of non-coding RNAs in the regulation of cerebrovascular endothelial pathophysiology after stroke are completely unknown. Using RNA sequencing (RNA-seq) technology, we profiled long non-coding RNA (lncRNA) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD), an in vitro mimic of ischemic stroke conditions. After 16h of OGD exposure, the expression levels for 362 of the 10,677 lncRNAs analyzed changed significantly, including a total of 147 lncRNAs increased and 70 lncRNAs decreased by more than 2-fold. Among them, the most highly upregulated lncRNAs include Snhg12, Malat1, and lnc-OGD 1006, whereas the most highly downregulated lncRNAs include 281008D09Rik, Peg13, and lnc-OGD 3916. Alteration of the most highly upregulated/downregulated ODG-responsive lncRNAs was further confirmed in cultured BMECs after OGD as well as isolated cerebral microvessels in mice following transient middle cerebral artery occlusion (MCAO) and 24h reperfusion by the quantitative real-time PCR approach. Moreover, promoter analysis of altered ODG-responsive endothelial lncRNA genes by bioinformatics showed substantial transcription factor binding sites on lncRNAs, implying potential transcriptional regulation of those lncRNAs. These findings are the first to identify OGD-responsive brain endothelial lncRNAs, which suggest potential pathological roles for these lncRNAs in mediating endothelial responses to ischemic stimuli. Endothelial-selective lncRNAs may function as a class of novel master regulators in cerebrovascular endothelial pathologies after ischemic stroke.

Clinical and radiographic characteristics in pulmonary endometriosis: based on five cases.

OBJECTIVE: This study aims to improve the diagnostic and therapeutic efficacy through analysis of clinical and radiographic characteristics in pulmonary endometriosis. MATERIALS AND METHODS: This retrospective study was conducted from January 1998 to December 2008. The clinical and radiographic characteristics of five patients diagnosed as pulmonary endometriosis were evaluated. RESULTS: Among the five female patients of reproductive age, one case presented with recurrent pneumothorax, four cases presented with recurrent hemoptysis. Episode of pneumothorax and hemoptysis had the close association with the menstrual cycle. Except for pneumothorax case, the computed tomography (CT) scans during menstruation showed patchy opacification or infiltration (n = 4). Histopathologic examination of the resected specimen conformed typical endometrial tissue in the lungs. Misdiagnosis occurred involving spontaneous pneumothorax (n = 1), pulmonary tuberculosis (TB) (n = 3), and bronchiectasis (n = 1). CONCLUSION: Pulmonary endometriosis is prone to misdiagnosis. The combination of medical history and CT scans in association with menstrual cycle was useful to make the differential diagnosis after effective diagnostic treatment of hormone therapy.

Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells.

Insoluble fibrils of amyloid-beta peptide (Abeta) are the major component of senile and vascular plaques found in the brains of Alzheimer's disease (AD) patients. Abeta has been implicated in neuronal and vascular degeneration because of its toxicity to neurons and endothelial cells in vitro; some of these cells die with characteristic features of apoptosis. We used primary cultures of murine cerebral endothelial cells (CECs) to explore the mechanisms involved in Abeta-induced cell death. We report here that Abeta(25-35), a cytotoxic fragment of Abeta, induced translocation of the apoptosis regulator termed second-mitochondria-derived activator of caspase (Smac) from the intramembranous compartment of the mitochondria to the cytosol 24 hr after exposure. In addition, we demonstrated that X chromosome-linked inhibitor-of-apoptosis protein (XIAP) coimmunoprecipitated with Smac, suggesting that the two proteins bound to one another subsequent to the release of Smac from the mitochondria. Abeta(25-35) treatment also led to rapid AP-1 activation and subsequent expression of Bim, a member of the BH3-only family of proapoptotic proteins. Bim knockdown using an antisense oligonucleotide strategy suppressed Abeta(25-35)-induced Smac release and resulted in attenuation of CEC death. Furthermore, AP-1 inhibition, with curcumin or c-fos antisense oligonucleotide, reduced bim expression. These results suggest that Abeta activates an apoptotic cascade involving AP-1 DNA binding, subsequent bim induction, followed by Smac release and binding to XIAP, resulting in CEC death.

Effect of dextromethorphan, a NMDA antagonist, on DNA repair in rat photochemical thrombotic cerebral ischemia.

Photochemical thrombotic ischemia model was used to study the possible roles of excision repair cross-complementing group 6 (ERCC6), a DNA repair gene, in the neuroprotection of dextromethorphan (DM), a NMDA antagonist, in ischemic brain injury. The results showed that no obvious ERCC6 mRNA expression was found in the perifocal area of irradiated cerebral cortex before 24 h postischemia. Then, the number of ERCC6 mRNA positive cells gradually enhanced, and attained a peak value at 72 h after light irradiation, which followed a declined tendency at 7-day postlesion. These results suggest that DNA repair gene ERCC6 mRNA expression in the perifocal area may be involved in the pathophysiological processes following the photochemical thrombotic cerebral ischemia. By the administration of DM, we observed that it can significantly upregulate the expression of ERCC6 mRNA in the perifocal area at 48 h after ischemic event. The neuroprotective mechanisms of DM may be related to the upregulation of DNA repair gene ERCC6 mRNA.

Altered expression of glutamate transporter GLAST mRNA in rat brain after photochemically induced focal ischemia.

BACKGROUND: The neurotransmitter glutamate is involved in fast excitatory synaptic transmission in the mammalian brain. Glutamate released from presynaptic terminals must be removed rapidly from the synaptic cleft by high affinity, sodium-dependent glutamate transporters to keep the extracellular glutamate concentration low to protect neuron from glutamate excitotoxicity, which is the major pathological mechanism of brain ischemia. GLAST is one of the identified four subtypes of the glutamate transporter system and has been suggested to play an important role in some pathological conditions. But until recently, very little information existed the concerning relationship between GLAST expression and cerebral ischemia. METHODS: Nonradioactive in situ hybridization was employed to evaluate the changes of glutamate transporter GLAST mRNA expression in rat cerebral cortex and hippocampus following photochemically induced focal cortical ischemia. RESULTS: GLAST mRNA expression in cerebral pyramid cells below the infarcted area did not change at 3 h, significantly decreased at 12 h, recovered to the control level at 24 h, and significantly increased at 72 h following the ischemic lesion. No changes in GLAST mRNA expression were observed in all subfields of the hippocampal complex. CONCLUSIONS: The present findings suggest that the time-course changes of GLAST mRNA expression after ischemia may be correlated with the pathogenesis of photosensitive ischemic brain damage.

Effect of glutamate transporter on neuronal damage induced by photochemical thrombotic brain ischemia.

To study the effects of glutamate transporters on the pathogenesis of brain infarct, pharmacological and histological analyses were carried out on the thrombotic focal ischemic model. Expression of mRNA coding for the glutamate transporter GLAST increased significantly in the penumbra at 72 h following the ischemia. Combined with confocal laser scanning microscopic analysis, double staining showed expression of GLAST mRNA in both neurons and glial cells in the penumbra. L-trans-Pyrrolidine-2,4-dicarboxylate (L-trans-PDC), a glutamate uptake inhibitor, dose-dependently enhanced the volume of the infarct induced by the ischemia. The results suggest that a compensatory increase in the activity of glutamate transporter may accompany pathological changes after ischemic injury.

Neuroprotective action of dextromethorphan in rat photochemically-induced focal cerebral ischemia.

AIM: To study the effects of dextromethorphan (Dex) on photochemically-induced focal cerebral ischemia in rats. METHODS: Anesthetized rats undergone 10-min light irradiation on exposed skull after rose bengal injection were pretreated with saline and Dex at 3 doses (12.5, 25, and 50 mg.kg-1, i.p., 15 min before ischemia). The alteration of volume of lesioned cortical region, regional cerebral blood flow (CBF), bcl-2 and bax expression at penumbra area were studied. RESULTS: Dex dose-dependently decreased the infarcted volume (17%, 26%, and 50% reduction, respectively). Pretreatment with Dex at a dose of 50 mg.kg-1 improved the postischemic hypoperfusion compared with the control at 20 and 30 min after lesion (both 31% increase), and also upregulated the expression of anti-apoptosis gene bcl-2. CONCLUSION: Dex protects against ischemic neuronal damage in this model and its effects on CBF and bcl-2 expression may contribute to its neuroprotective action.

Distribution of somatostatin mRNA containing neurons in the primary pain relaying nuclei of the rat.

BACKGROUND: The spinal trigeminal nucleus and the dorsal horn of the spinal cord are the critical areas in relaying noxious impulses. They also contain large amounts of somatostatin-like immunoreactivities. Early publications focussed on immunohistochemical studies and were devoid of a detailed description of the distribution of somatostatin in the two nuclei at the molecular level. METHOD: Frontal tissue sections from the mudulla and the spinal cord of eight rats were examined and a non-radioactive in situ hybridization histochemical procedure was adopted to study the distribution of somatostatin mRNA positive neurons in the two nuclei. RESULTS: A widespread distribution of somatostatin mRNA containing neurons was shown in the two nuclei at all levels. The positive neuron profiles were normally round or oval in shape and small to medium in size. Three types of cells were identified, which were associated with the intensity of the hybridization signals. The highest density of somatostatin mRNA positive neuron profiles was found in the gelatinous subnucleus at the caudal part of the spinal trigeminal nucleus and in the substantia gelatinosa of the dorsal horn at the levels of the cervical and lumbar cords. Most of them belonged to type I neurons. CONCLUSIONS: The present findings are compared to reports of previous studies. It is suggested that somatostatin in the two nuclei may play an important role in the modulation and transmission of pain signals.