Senescence-associated secretory phenotypes in mesenchymal cells contribute to cytotoxic immune response in oral lichen planus.

Oral lichen planus is a chronic inflammatory condition that adversely affects the oral mucosa; however, its etiology remains elusive. Consequently, therapeutic interventions for oral lichen planus are limited to symptomatic management. This study provides evidence of the accumulation of senescent mesenchymal cells, CD8 + T cells, and natural killer cells in patients with oral lichen planus. We profiled the patients' tissues using the National Center for Biotechnology Information Gene Expression Omnibus database and found that senescence-related genes were upregulated in these tissues by gene set enrichment analysis. Immunohistochemical analysis showed increased senescent mesenchymal cells in the subepithelial layer of patients with oral lichen planus. Single-cell RNA-seq data retrieved from the Gene Expression Omnibus database of patients with oral lichen planus revealed that mesenchymal cells were marked by the upregulation of senescence-related genes. Cell-cell communication analysis using CellChat showed that senescent mesenchymal cells significantly influenced CD8 + T cells and natural killer cells via CXCL12-CXCR4 signaling, which is known to activate and recruit CD8 + T cells and NK cells. Finally, in vitro assays demonstrated that the secretion of senescence-associated factors from mesenchymal cells stimulated the activation of T cells and natural killer cells and promoted epithelial cell senescence and cytotoxicity. These findings suggest that the accumulation of mesenchymal cells with senescence-associated secretory phenotype may be a key driver of oral lichen planus pathogenesis.

Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by the involvement of multiple organs. Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in SLE patients. Hence, designing effective drugs is pivotal for treating individuals with LN. Fisetin plays a senolytic role by specifically eliminating senescent cells, inhibiting cell proliferation, and exerting anti-inflammatory, anti-oxidant, and anti-tumorigenic effects. However, limited research has been conducted on the utility and therapeutic mechanisms of fisetin in chronic inflammation. Similarly, whether the effects of fisetin depend on cell type remains unclear. In this study, we found that LN-prone MRL/lpr mice demonstrated accumulation of Ki-67-positive myofibroblasts and p15INK4B-positive senescent tubular epithelial cells (TECs) that highly expressed transforming growth factor ß (TGF-ß). TGF-ß stimulation induced senescence of NRK-52E renal TECs and proliferation of NRK-49F renal fibroblasts, suggesting that TGF-ß promotes senescence and proliferation in a cell type-dependent manner, which is inhibited by fisetin treatment in vitro. Furthermore, fisetin treatment in vivo reduced the number of senescent TECs and myofibroblasts, which attenuated kidney fibrosis, reduced senescence-associated secretory phenotype (SASP) expression, and increased TEC proliferation. These data suggest that the effects of fisetin vary depending on the cell type and may have therapeutic effects in complex and diverse LN pathologies.

Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonomic nerves and Schwann cells occurred in the bone marrow and central nervous system of SLE model mice. A neurotoxic drug increased mortality and induced severe neuropathy and multiple organ damage, while a neuroprotective drug prevented multiple organ damage. The administration of bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on a 3-dimensional fiber scaffold improved bone marrow neuropathy, skin lesions, kidney function, and mortality. Our results reveal that bone marrow neuropathy influence multiple organ damage associated with SLE, and improvement of bone marrow neuropathy by intrathecal injection of BMSC may be a target for SLE multiple-organ damage.

Altered regulation of mesenchymal cell senescence in adipose tissue promotes pathological changes associated with diabetic wound healing.

Pathologic diabetic wound healing is caused by sequential and progressive deterioration of hemostasis, inflammation, proliferation, and resolution/remodeling. Cellular senescence promotes wound healing; however, diabetic wounds exhibit low levels of senescent factors and accumulate senescent cells, which impair the healing process. Here we show that the number of p15INK4B + PDGFRα + senescent mesenchymal cells in adipose tissue increases transiently during early phases of wound healing in both non-diabetic mice and humans. Transplantation of adipose tissue from diabetic mice into non-diabetic mice results in impaired wound healing and an altered cellular senescence-associated secretory phenotype (SASP), suggesting that insufficient induction of adipose tissue senescence after injury is a pathological mechanism of diabetic wound healing. These results provide insight into how regulation of senescence in adipose tissue contributes to wound healing and could constitute a basis for developing therapeutic treatment for wound healing impairment in diabetes.

Accumulation of Senescent Neural Cells in Murine Lupus With Depression-Like Behavior.

Neuropsychiatric manifestations targeting the central, peripheral, and autonomic nervous system are common in systemic lupus erythematosus (SLE); collectively, these symptoms are termed neuropsychiatric SLE (NPSLE). Among a wide variety of neuropsychiatric symptoms, depression is observed in about 24-39% of SLE patients. Several cytokines and chemokines have been identified as biomarkers or therapeutic targets of NPSLE; in particular, the levels of type 1 interferons, TNFs, and IL-6 are elevated in SLE patient's cerebrospinal fluid (CSF), and these factors contribute to the pathology of depression. Here, we show that senescent neural cells accumulate in the hippocampal cornu ammonis 3 (CA3) region in MRL/lpr SLE model mice with depressive behavior. Furthermore, oral administration of fisetin, a senolytic drug, reduced the number of senescent neural cells and reduced depressive behavior in the MRL/lpr mice. In addition, transcription of several senescence and senescence-associated secretory phenotype (SASP) factors in the hippocampal region also decreased after fisetin treatment in the MRL/lpr mice. These results indicate that the accumulation of senescent neural cells in the hippocampus plays a role in NPSLE pathogenesis, and therapies targeting senescent cells may represent a candidate approach to treat NPSLE.

Therapeutic responses to a frontal/executive programme in autism spectrum disorder: Comparison with schizophrenia.

INTRODUCTION: Studies on autism spectrum disorder in recent years have controversially indicated similarities with schizophrenia. Cognitive dysfunction is present in both disorders, and while there is a rich array of interventions for cognitive dysfunction in schizophrenia, there are few such treatments for autism spectrum disorder. In this study, we have investigated a potentially useful approach in autism spectrum disorder by comparing autism spectrum disorder with schizophrenia in regard to the characteristics of cognitive dysfunction and therapeutic response to cognitive remediation therapy. METHOD: We studied seven patients with autism spectrum disorder and eight patients with schizophrenia, using a frontal/executive programme as the intervention. The characteristics of cognitive dysfunction in autism spectrum disorder before frontal/executive programme and the therapeutic response to frontal/executive programme in autism spectrum disorder patients were compared with those in schizophrenia patients, based on evaluation of cognitive function and social function. The changes in cognitive and social function after treatment in each patient group were compared using the Mann-Whitney's U test. RESULTS: The severity of cognitive dysfunction did not differ significantly between autism spectrum disorder and schizophrenia. Frontal/executive programme was effective in autism spectrum disorder, with subjects showing about the same therapeutic response as in schizophrenia. CONCLUSION: Frontal/executive programme appears to be useful for patients with autism spectrum disorder. Furthermore, the similarities in cognitive dysfunction and therapeutic response between autism spectrum disorder and schizophrenia are highly relevant to the recent debate concerning the similarity between these two disease concepts.

The effects of cognitive remediation therapy using the frontal/executive program for autism spectrum disorder.

OBJECTIVE: The cognitive features and treatment of autism spectrum disorder have been the subject of much debate in recent years. Therapeutic approaches to date have focused on skills acquisition, support tailored to the characteristics of autism spectrum disorder, and interventions in social cognitive functioning; there have been few reports describing interventions aimed at neurocognitive dysfunction. In this study, we focus on impairment of executive functioning in autism spectrum disorder patients and investigate improvements in executive functioning and their generalization to social functioning. METHOD: The intervention adopted for this study was cognitive remediation therapy using the frontal/executive program. To investigate the effectiveness of frontal/executive program, 15 subjects who consented to participate in the study were randomly assigned to an intervention group or control group. Frontal/executive program was administered to the intervention group for about six months. Both groups were evaluated using the same scales: BACS-J, WCST, and CPT for cognitive assessment; SCoRS-J, GAF, and LASMI for social functioning; and GSE for self-efficacy. RESULTS: Both groups had lower scores for cognitive functioning than normal individuals at baseline. After completion of frontal/executive program, the intervention group showed improved performance on BACS-J for overall score, digit sequencing, verbal fluency, and Tower of London tasks. Improvements were also seen on SCoRS-J and LASMI scales of social functioning. CONCLUSIONS: This was the first study to use frontal/executive program to focus on neurocognitive dysfunction in autism spectrum disorder patients. Frontal/executive program is effective in improving impaired executive functioning in autism spectrum disorder patients and may also lead to improvements in some aspects of social functioning.

[Factors associated with the psychological impact of the Great East Japan earthquake on high school students 1 year and 4 months after the disaster].

The purpose of this study was to investigate factors associated with the psychological impact of the Great East Japan Earthquake on high school students 1 year and 4 months after the disaster, and clarify support needs of the students. In the outreach program for students of three high schools in coastal areas of southern Miyagi Prefecture, Japan, 1,973 students were surveyed after obtaining informed consent for participation. Questionnaires included: the Quick Inventory of Depressive Symptomatology (QIDS-J), Self-rating Anxiety Scale (SAS), Impact of Event Scale-revised (IES-R), and Connor-Davidson Resilience Scale (CD-RISC10). All scores were compared using SPSS 20.0 J between school grades, locations of the schools, and extent of damage due to the Great East Japan Earthquake. Our analysis showed a significant positive correlation between school grades and the level of anxiety. PTSR scores, but not anxiety nor depressive scores, of students whose lives have suffered extensive damage were significantly higher than those of students who have not. Students of high schools which have suffered extensive damage and use temporary buildings showed significantly higher levels of depression and anxiety, and significantly lower resilience, compared to students of high schools which were not damaged. Although previous findings demonstrated that younger children have a higher risk of being influenced by disasters, symptoms related to PTSR and depression were found frequently in the high school students as well. Among the high school students, our analysis showed a positive correlation between the level of anxiety and school grades, probably because the disaster has affected an influential and pivotal point in their lives.

Discrepancy of neural response between exogenous and endogenous task switching: an event-related potentials study.

Task switching is a well-known cognitive paradigm to explore task-set reconfiguration processes such as rule shifting. In particular, endogenous task switching is thought to differ qualitatively from stimulus-triggered exogenous task switching. However, no previous study has examined the neural substrate of endogenous task switching. The purpose of the present study is to explore the differences between event-related potential responses to exogenous and endogenous rule switching at cue stimulus. We modified two patterns of cued switching tasks: exogenous (bottom-up) rule switching and endogenous (top-down) rule switching. In each task cue stimulus was configured to induce switching or maintaining rule. In exogenous switching tasks, late positive deflection was larger in the switch rule condition than in the maintain rule condition. However, in endogenous switching tasks late positive deflection was unexpectedly larger in the maintain-rule condition than in the switch-rule condition. These results indicate that exogenous rule switching is explicit stimulus-driven processes, whereas endogenous rule switching is implicitly parallel processes independent of external stimulus.