The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration.

BACKGROUND: T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive. METHODS: GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice. RESULTS: We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression. CONCLUSIONS: This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis.

T-LAK cell-oriented protein kinase (TOPK) potently promotes malignant proliferation of tumour cells and is considered as a maker of tumour progression. Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of keratinocytes. However, the role of TOPK in psoriasis has not been well elucidated. This study aims to investigate the expression and role of TOPK in psoriasis, and the role of TOPK inhibitor in psoriasis attenuation. Gene Expression Omnibus datasets derived from psoriasis patients and psoriatic model mice were screened for analysis. Skin specimens from psoriasis patients were collected for TOPK immunohistochemical staining to investigate the expression and localization of TOPK. Next, psoriatic mice model was established to further confirm TOPK expression pattern. Then, TOPK inhibitor was applied to investigate the role of TOPK in psoriasis progression. Finally, cell proliferation assay, apoptosis assay and cell cycle analysis were performed to investigate the potential mechanism involved. Our study showed that TOPK was upregulated in the lesions of both psoriasis patients and psoriatic model mice, and TOPK levels were positively associated with psoriasis progression. TOPK was upregulated in psoriatic lesions and expressed predominantly by epidermal keratinocytes. In addition, TOPK levels in epidermal keratinocytes were positively correlated with epidermal hyperplasia. Furthermore, topical application of TOPK inhibitor OTS514 obviously alleviated disease severity and epidermal hyperplasia. Mechanismly, inhibiting TOPK induces G2/M phase arrest and apoptosis of keratinocytes, thereby attenuating epidermal hyperplasia and disease progression. Collectively, this study identifies that upregulation of TOPK in keratinocytes promotes psoriatic progression, and inhibiting TOPK attenuates epidermal hyperplasia and psoriatic progression.

Over 1-year duration and age difference of SARS-CoV-2 antibodies in convalescent COVID-19 patients.

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglouilin G (IgG) and immunoglouilin M (IgM) antibodies have been widely used to assist clinical diagnosis. Our previous study reported a discrepancy in SARS-CoV-2 antibody response between male and female coronavirus disease 2019 (COVID-19) patients. However, the duration and discrepancy between ages as well as sexes of SARS-CoV-2 antibody in convalescent COVID-19 patients have not been clarified. In this study, a total of 538 health-examination individuals who were confirmed with SARS-CoV-2 infection a year ago were enrolled. Blood samples were collected and detected for IgM and IgG antibodies. Among these convalescent patients, 12.80% were detected positive for IgM antibodies. The positive rates for IgM antibody were close between sexes: for males, this is 9.17% and for females 13.75%. However, the IgG antibody was detected positive in as much as 82.90% convalescent patients and the positive rates were nearly the same between males (82.57%) and females (82.98%). Besides this, the level of IgM and IgG antibodies showed no difference between male and female convalescent patients. The level of IgG antibodies showed a significant difference between ages. The elder patients (over 35 years old) maintained a higher level of IgG antibody than the younger patients (under or equal 35 years old) after recovering for 1 year. In addition, IgG antibody was more vulnerable to disappear in younger patients than in elder patients. Overall, our study identified over 1-year duration of SARS-CoV-2 antibody and age difference of IgG antibody response in convalescent COVID-19 patients. These findings may provide new insights into long-term humoral immune response, vaccines efficacy and age-based personalized vaccination strategies.

A comparison study of SARS-CoV-2 IgG antibody between male and female COVID-19 patients: A possible reason underlying different outcome between sex.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China at the end of 2019 has spread throughout the world and caused many thousands of deaths. The previous study reported a higher severe status rate and mortality rate in male patients in China. However, the reason underlying this difference has not been reported. The convalescent plasma containing a high level of SARS-CoV-2 immunoglobulin G (IgG) antibody has been used in clinical therapy and achieved good effects in China. In this study, to compare the differences of the SARS-CoV-2 IgG antibody between male and female patients, a total number of 331 patients confirmed SARS-CoV-2 infection were enrolled. The serum of these patients was collected during hospitalization and detected for the SARS-CoV-2 IgG antibody. Our data showed that the concentration of IgG antibody in mild, general, and recovering patients showed no difference between male and female patients. In severe status, compared with male patients, there were more female patients having a relatively high concentration of serum SARS-CoV-2 IgG antibody. In addition, the generation of IgG antibody in female patients was stronger than male patients in disease early phase. Our study identified a discrepancy in the SARS-CoV-2 IgG antibody level in male and female patients, which may be a potential cause leading to a different outcome of Coronavirus Disease 2019 between sex.

Examining Childhood Maltreatment and School Bullying Among Adolescents: A Cross-Sectional Study From Anhui Province in China.

Although a body of research has established the relationship between childhood maltreatment and bullying in Western culture backgrounds, few studies have examined the association between childhood maltreatment experiences and bullying in China. Moreover, to date, the relationship between multiple types of childhood maltreatment and cyber bullying is poorly understood. This study examined the association between multiple types of childhood maltreatment (physical abuse, emotional abuse, sexual abuse, physical neglect, and emotional neglect) and multiple forms of school bullying (physical, verbal, relational, and cyber). A cross-sectional study using three-stage random cluster-sampling approach was conducted in Tongling, Chuzhou, and Fuyang, in Anhui Province. Self-reported questionnaires were completed by 5,726 middle school students to assess their school bullying involvement and childhood maltreatment experiences. A multivariable logistic regression analysis was used to explore the relationship between each single type of childhood maltreatment and each single form of school bullying. Each type of childhood maltreatment was associated with increased risk for involvement in each form of bullying as bullies, victims, and bully-victims. Specifically, both childhood physical neglect and emotional neglect were associated with increased risk for involvement in each form of school bullying. Each type of childhood maltreatment was associated with involvement in cyber bullying. Students who experienced multiple types of childhood maltreatment seem to report more forms of school bullying. Furthermore, multiple forms of school bullying caused the co-occurrence of several forms of school bullying. Our results indicated a significant association between school bullying and childhood maltreatment among adolescents. Interventions to reduce school bullying encompassing prevention toward childhood maltreatment might get better results in China.