Endothelial CLEC-1b plays a protective role against cancer hematogenous metastasis.

Metastasis, which is the spread of cancer cells into distant organs, is a critical determinant of prognosis in patients with cancer, and blood vessels are the major route for cancer cells to spread systemically. Extravasation is a critical process for the hematogenous metastasis; however, its underlying molecular mechanisms remain poorly understood. Here, we identified that senescent ECs highly express C-type lectin domain family 1 member B (CLEC-1b), and that endothelial CLEC-1b inhibits the hematogenous metastasis of a certain type of cancer. CLEC-1b expression was enhanced in ECs isolated from aged mice, senescent cultured human ECs, and ECs of aged human. CLEC-1b overexpression in ECs prevented the disruption of endothelial integrity, and inhibited the transendothelial migration of cancer cells expressing podoplanin (PDPN), a ligand for CLEC-1b. Notably, target activation of CLEC-1b in ECs decreased the hematogenous metastasis in the lungs by cancer cells expressing PDPN in mice. Our data reveal the protective role of endothelial CLEC-1b against cancer hematogenous metastasis. Considering the high CLEC-1b expression in senescent ECs, EC senescence may play a beneficial role with respect to the cancer hematogenous metastasis.

Spermidine improves angiogenic capacity of senescent endothelial cells, and enhances ischemia-induced neovascularization in aged mice.

Aging is closely associated with the increased morbidity and mortality of ischemic cardiovascular disease, at least partially through impaired angiogenic capacity. Endothelial cells (ECs) play a crucial role in angiogenesis, and their angiogenic capacity declines during aging. Spermidine is a naturally occurring polyamine, and its dietary supplementation has exhibited distinct anti-aging and healthy lifespan-extending effects in various species such as yeast, worms, flies, and mice. Here, we explore the effects of spermidine supplementation on the age-related decline in angiogenesis both in vitro and in vivo. Intracellular polyamine contents were reduced in replicative senescent ECs, which were subsequently recovered by spermidine supplementation. Our findings reveal that spermidine supplementation improved the declined angiogenic capacity of senescent ECs, including migration and tube-formation, without affecting the senescence phenotypes. Mechanistically, spermidine enhanced both autophagy and mitophagy, and improved mitochondrial quality in senescent ECs. Ischemia-induced neovascularization was assessed using the hind-limb ischemia model in mice. Limb blood flow recovery and neovascularization in the ischemic muscle were considerably impaired in aged mice compared to young ones. Of note, dietary spermidine significantly enhanced ischemia-induced angiogenesis, and improved the blood flow recovery in the ischemic limb, especially in aged mice. Our results reveal novel proangiogenic functions of spermidine, suggesting its therapeutic potential against ischemic disease.

Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction.

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

Achievement of Target Serum Uric Acid Levels and Factors Associated with Therapeutic Failure among Japanese Men Treated for Hyperuricemia/Gout.

Objective To assess the rate of successfully achieving treatment goals among Japanese men with hyperuricemia/gout and identify factors influencing the success rate. Methods This cross-sectional study, conducted from January to December 2012, examined the serum uric acid (SUA) levels and clinical characteristics of 2,103 men with hyperuricemia/gout selected from an initial population of 136,770 individuals who participated in a workplace health checkup. The success rates (defined as SUA ≤6.0 mg/dL) were calculated, and a multivariate analysis was used to identify factors associated with "therapeutic failure" to achieve target SUA levels. Results The rate of successfully achieving the target SUA level was 37.5%. The body mass index (BMI) was significantly associated with therapeutic failure [25.0≤ Category (C) 2<27.5, adjusted odds ratio (AOR) =1.35; 27.5≤C3<30.0, AOR=1.69; C4 ≥ 30.0, AOR=1.94; relative to C1<25.0]. A significant positive association was also observed between waist circumference (WC) and therapeutic failure (85≤C2<90, OR=1.29; 90≤C3<95, OR=1.41; 95≤C4, OR=2.28; relative to C1<85.0 cm). Those with higher BMI/WC measurements were significantly more likely to have higher SUA levels than those with lower such measurements. The ongoing intake of dyslipidemia medication was identified as a protective factor against therapeutic failure. Discussion Our findings suggest a possible association between obesity and therapeutic failure, underscoring the importance of maintaining lipid profiles as part of managing SUA levels. Better management of both obesity and dyslipidemia may prevent future cardiovascular disorders by ensuring healthier SUA levels.

Unexpected T cell regulatory activity of anti-histone H1 autoantibody: its mode of action in regulatory T cell-dependent and -independent manners.

Induction of anti-nuclear antibodies against DNA or histones is a hallmark of autoimmune disorders, but their actual contribution to disease predisposition remains to be clarified. We have previously reported that autoantibodies against histone H1 work as a critical graft survival factor in a rat model of tolerogeneic liver transplantation. Here we show that an immunosuppressive anti-histone H1 monoclonal antibody (anti-H1 mAb) acts directly on T cells to inhibit their activation in response to T cell receptor (TCR) ligation. Intriguingly, the T cell activation inhibitory activity of anti-H1 mAb under suboptimal dosages required regulatory T (Treg) cells, while high dose stimulation with anti-H1 mAb triggered a Treg cell-independent, direct negative regulation of T cell activation upon TCR cross-linking. In the Treg cell-dependent mode of immunosuppressive action, anti-H1 mAb did not induce the expansion of CD4(+-)Foxp3(+) Treg cells, but rather potentiated their regulatory capacity. These results reveal a previously unappreciated T cell regulatory role of anti-H1 autoantibody, whose overproduction is generally thought to be pathogenic in the autoimmune settings.

Development of a two-step chromatography procedure that allows the purification of a high-purity anti-histone H1 monoclonal immunoglobulin M antibody with immunosuppressant activity.

In organ transplantation, the development of a novel immunosuppressant free of the need for permanent administration and any serious side effects has eagerly been awaited. We have previously reported that an anti-histone H1 polyclonal antibody has immunosuppressant activity. Here we prepared an anti-histone H1 monoclonal antibody as an analytical tool to elucidate its mechanism of immunosuppression. The isotype of this monoclonal antibody was immunoglobulin M. A monoclonal antibody prepared for administration to organ transplantation model animals should not contain any allogenic proteins and should have high purity. Therefore, we conducted a two-step chromatography procedure, consisting of strong anion-exchange chromatography and gel filtration chromatography, to purify an anti-histone H1 monoclonal immunoglobulin M antibody from the serum-free culture supernatant of hybridomas. Consequently, we successfully purified the monoclonal antibody at 96%, a purification rate at which its administration to organ transplantation model animals is possible.

Dietary pulverized konjac glucomannan prevents the development of allergic rhinitis-like symptoms and IgE response in mice.

Konjac is a traditional Japanese food with a peculiar texture, and it has been suggested that its main ingredient, konjac glucomannan (KGM), ameliorates metabolic disorders such as diabetes and hypercholesteremia. We have found that feeding with pulverized KGM (PKGM) prevents skin inflammation in a murine model of atopic dermatitis. Here, we show that dietary PKGM suppresses allergic rhinitis-like symptoms in mice upon immunization and nasal sensitization with ovalbumin (OVA). The PKGM-fed mice showed a much lower frequency of sneezing than in control animals. We also found that PKGM supplementation exclusively suppressed OVA-specific IgE response without affecting IgG1/IgG2a responses as well as systemic Th1/Th2 cytokine production. These results suggest that PKGM can be a beneficial foodstuff in preventing nasal allergy such as seasonal pollinosis.

[Clinical study on lung disease caused by non-tuberculous mycobacteriosis in the elderly].

AIM: This study was done to clarify the characteristics of elderly patients with nontuberculous mycobacteriosis. METHODS: We investigated the clinical features of 10 patients at an advanced age who had been given diagnosis of nontuberculous mycobacteriosis. RESULTS: Mycobacterium avium intracellulare complex (MAC) were detected in all cases. The age of the patients ranged from 65 to 92. Four cases had underlying respiratory diseases (old pulmonary tuberculosis in 3 cases, pulmonary emphysema in 1 case, bronchiectasia in 1 case). Six cases suffered from dementia. The symptoms were relatively nonspecific, such as low grade fever, fatigue, appetite loss in almost all cases in this study. On computed tomography (CT) scans of the chest, mainly small nodular infiltrates were seen. MAC was detected in clinical samples such as sputum, gastric juice and bronchial lavage. The examination of gastric juice was performed in 6 out of the 10 cases. Gastric juice samples were smear-positive for acid-fast bacilli in 5 of 6, and culture-positive for MAC in 5 of 6. The detection of MAC in gastric juice samples was higher than that in sputum samples on admission. CONCLUSION: Gastric juice might be useful to differentiate infection from casual isolation of MAC in elderly patients.