Alpha lipoic acid selectively inhibits proliferation and adhesion to fibronectin of v-H-ras-transformed 3Y1 cells

Here, we focused on the effects of racemic α-lipoic acid on proliferation and adhesion properties of 3Y1 rat fibroblasts and the v-H-ras-transformed derivative, HR-3Y1-2 cells. Racemic α-lipoic acid inhibited proliferation of HR-3Y1-2 but not 3Y1 cells at 0.3 and 1.0 mM. R-(+)-α-lipoic acid also inhibited proliferation of HR-3Y1-2 cells equivalent to that of racemic α-lipoic acid. In addition, racemic α-lipoic acid decreased intracellular reactive oxygen species levels in HR-3Y1 cells but not 3Y1 cells. Next, we evaluated the effects of racemic α-lipoic acid on cell adhesion to fibronectin. The results indicated that racemic α-lipoic acid decreased adhesive ability of HR-3Y1-2 cells to fibronectin-coated plates. As blocking antibody experiment revealed that β1-integrin plays a key role in cell adhesion in this experimental system, the effects of racemic α-lipoic acid on the expression of β1-integrin were examined. The results indicated that racemic α-lipoic acid selectively downregulated the expression of cell surface β1-integrin expression in HR-3Y1-2 cells. Intriguingly, exogenous hydrogen peroxide upregulated cell surface β1-integrin expression in 3Y1 cells. Taken together, these data suggest that reduction of intracellular reactive oxygen species levels by α-lipoic acid could be an effective means of ameliorating abnormal growth and adhesive properties in v-H-ras transformed cells

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

Does Swallowing Function Recover in the Long Term in Patients With Surgically Treated Tongue Carcinomas?

Purpose: The present study aims to measure the post-surgical swallowing function in patients five years after operative treatment of tongue carcinoma. Patients and Methods: Using a retrospective cohort study design, the investigators enrolled post-surgical patients treated for tongue carcinomas in Hokkaido University Hospital. The primary outcome variable was the Oropharyngeal Swallow Efficiency (OPSE) determined by videofluoroscopic evaluation and the OPSE at present was compared with that at discharge. Other variables included present nutritional status (Body Mass Index: BMI, Serum Albumin), dietary intake, self-rating of the present swallowing function, and occurrence of pneumonia. Statistical analysis used the paired t-test and Spearman's rank correlation. Results: The swallowing function was assessed in 20 patients (11 males and 9 females) subjected to surgical treatment of tongue carcinomas; the median age was 70 years (range 56-90 years) at the present evaluation. The mean values of the liquid OPSE and paste OPSE at present were 26.6±21.2 and 21.9±22.5, respectively. The mean values for BMI and serum albumin at present were 22.2±3.4 and 4.5±0.3g/dl respectively. All patients had a full oral intake of foods, with a mean self-rated value of 6.4±2.5, an acceptable value as evaluated by the patients. Pneumonia requiring hospitalization had not occurred in these patients. Conclusions: Long-term follow-up of patients following operative treatment of tongue carcinomas demonstrate acceptable levels of oral function and nutritional status despite objective measures of poor swallowing efficiency assessed using a videofluoroscopy