Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion. The GLP-1 receptor agonist, exendin-4, has similar properties to GLP-1 and is currently in clinical use for type 2 diabetes mellitus. As GLP-1 and exendin-4 confer cardioprotection after myocardial infarction, this study was designed to assess the neuroprotective effects of exendin-4 against cerebral ischemia–reperfusion injury. Mice received a transvenous injection of exendin-4, after a 60-minute focal cerebral ischemia. Exendin-4-treated vehicle and sham groups were evaluated for infarct volume, neurologic deficit score, various physiologic parameters, and immunohistochemical analyses at several time points after ischemia. Exendin-4 treatment significantly reduced infarct volume and improved functional deficit. It also significantly suppressed oxidative stress, inflammatory response, and cell death after reperfusion. Furthermore, intracellular cyclic AMP (cAMP) levels were slightly higher in the exendin-4 group than in the vehicle group. No serial changes were noted in insulin and glucose levels in both groups. This study suggested that exendin-4 provides neuroprotection against ischemic injury and that this action is probably mediated through increased intracellular cAMP levels. Exendin-4 is potentially useful in the treatment of acute ischemic stroke

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Combined Use of N-Palmitoyl-Glycine-Histidine Gel and Several Penetration Enhancers on the Skin Permeation and Concentration of Metronidazole

N-Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than with the administration of a conventional oral formulation. The objective of this study was to increase the skin permeation of metronidazole (MTZ), a hydrophilic drug, after the topical application of Pal-GH gel. An evaluation of the combined effect of chemical penetration enhancers (CPEs), such as isopropyl myristate (IPM), propylene glycol (PG), ethanol, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO), on skin permeation was also conducted. We found that a 5% Pal-GH gel containing 1% MTZ (F5MTZ) exhibited a 2.7-fold higher MTZ permeation through excised hairless rat skin than its solution. Furthermore, F5PG-MTZ and F5IPM-MTZ further increased the skin permeation of MTZ when compared to F5MTZ. Interestingly, F5PG-MTZ enhanced the skin penetration of MTZ, although no enhancement effect was observed for an MTZ solution containing PG. Thus, a Pal-GH formulation containing PG and IPM may enhance the skin permeation of MTZ

Analysis for Stroke Etiology in Duplicated/Accessory MCA-Related Cerebral Infarction: Two Case Report and Brief Literature Review

Duplication and accessory of the middle cerebral artery (MCA) constitute a rare congenital variation. MCA anomalies are found at a lesser frequency than the vascular anomalies of the other major intracranial arteries. Duplicated/accessory MCA was usually noted incidentally with subarachnoid hemorrhage, due to resulted aneurysmal formation. However, duplicated/accessory MCA-related cerebral infarction is rarer. We report two cases of cerebral infarction due to dissection at the entry of the duplicate/accessory MCA. Both cases were similar in dissected site and clinical course, without headache or injury. In 20 previously reported cases and our two cases of duplicated/accessory MCA-related infarction, mean age (55.8 ± 21.2 years) was slightly younger for cerebral infarction, and stroke etiology was mainly embolism. The main etiologies of stroke were embolism and dissection. Considering embolism etiology, proximal site of arterial diameter changing lesion was a common site for embolism, as duplicated/accessory MCA was usually smaller than normal M1 segment. In cerebral dissection cases, the dissected site was similar to our cases. Numerous mechanisms of dissection were considered, but they mainly included dysfunction of the media and endothelium or shearing stress at the entry of duplication. As the detailed mechanisms of cerebral dissection remain unknown, clinicians should include a differential diagnosis for MCA dissection

Analysis for Stroke Etiology in Duplicated/Accessory MCA-Related Cerebral Infarction: Two Case Report and Brief Literature Review

Duplication and accessory of the middle cerebral artery (MCA) constitute a rare congenital variation. MCA anomalies are found at a lesser frequency than the vascular anomalies of the other major intracranial arteries. Duplicated/accessory MCA was usually noted incidentally with subarachnoid hemorrhage, due to resulted aneurysmal formation. However, duplicated/accessory MCA-related cerebral infarction is rarer. We report two cases of cerebral infarction due to dissection at the entry of the duplicate/accessory MCA. Both cases were similar in dissected site and clinical course, without headache or injury. In 20 previously reported cases and our two cases of duplicated/accessory MCA-related infarction, mean age (55.8 ± 21.2 years) was slightly younger for cerebral infarction, and stroke etiology was mainly embolism. The main etiologies of stroke were embolism and dissection. Considering embolism etiology, proximal site of arterial diameter changing lesion was a common site for embolism, as duplicated/accessory MCA was usually smaller than normal M1 segment. In cerebral dissection cases, the dissected site was similar to our cases. Numerous mechanisms of dissection were considered, but they mainly included dysfunction of the media and endothelium or shearing stress at the entry of duplication. As the detailed mechanisms of cerebral dissection remain unknown, clinicians should include a differential diagnosis for MCA dissection

Endothelial cell proliferation in swine experimental aneurysm after coil embolization.

After coil embolization, recanalization in cerebral aneurysms adversely influences long-term prognosis. Proliferation of endothelial cells on the coil surface may reduce the incidence of recanalization and further improve outcomes after coil embolization. We aimed to map the expression of proliferating tissue over the aneurysmal orifice and define the temporal profile of tissue growth in a swine experimental aneurysm model. We compared the outcomes after spontaneous thrombosis with those of coil embolization using histological and morphological techniques. In aneurysms that we not coiled, spontaneous thrombosis was observed, and weak, easily detachable proliferating tissue was evident in the aneurysmal neck. In contrast, in the coil embolization group, histological analysis showed endothelial-like cells lining the aneurysmal opening. Moreover, immunohistochemical and morphological analysis suggested that these cells were immature endothelial cells. Our results indicated the existence of endothelial cell proliferation 1 week after coil embolization and showed immature endothelial cells in septal tissue between the systemic circulation and the aneurysm. These findings suggest that endothelial cells are lead to and proliferate in the former aneurysmal orifice. This is the first examination to evaluate the temporal change of proliferating tissue in a swine experimental aneurysm model

Pirfenidone Improves Familial Idiopathic Pulmonary Fibrosis without Affecting Serum Periostin Levels

Background: Antifibrotic agents have been approved for the treatment of idiopathic pulmonary fibrosis (IPF). However, the efficacy of these drugs in the treatment of familial IPF (FIPF) has not been previously reported. Case presentation: We report the case of a 77-year-old man with FIPF, successfully treated with pirfenidone. His uncle died due to IPF, and his niece was diagnosed with the disease. He had worsening dyspnea two months prior to admission to our hospital. Upon admission, he had desaturation when exercising and broad interstitial pneumonia. Administration of pirfenidone improved his dyspnea, desaturation, and the reticular shadow on his chest radiograph. Increased fibrotic marker levels KL-6 and SP-D were also normalized in six months; treatment had no effect on his serum periostin level. Pirfenidone has been effective for over two years. Conclusion: Antifibrotic agents such as pirfenidone may be useful for the management of FIPF, as well as cases of sporadic IPF