The Role of Regulatory Cell Death in Vitiligo.

Vitiligo is one of the common chronic autoimmune skin diseases in clinic, which is characterized by localized or generalized depigmentation and seriously affects the physical and mental health of patients. At present, the pathogenesis of vitiligo is not clear; mainly, heredity, autoimmunity, oxidative stress, melanocyte (MC) self-destruction, and the destruction, death, or dysfunction of MCs caused by various reasons are always the core of vitiligo. Regulatory cell death (RCD) is an active and orderly death mode of cells regulated by genes, which widely exists in various life activities, plays a pivotal role in maintaining the homeostasis of the organism, and is closely related to the occurrence and development of many diseases. With the deepening of the research and understanding of RCD, people gradually found that there are many different forms of RCD in the lesions and perilesional skin of vitiligo patients, such as apoptosis, autophagy, pyroptosis, ferroptosis, and so on. Different cell death modes have different mechanisms in vitiligo, and different RCDs can interact and regulate each other. In this article, the mechanism related to RCD in the pathogenesis of vitiligo is reviewed, which provides new ideas for exploring the pathogenesis and targeted treatment of vitiligo.

Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations.

Background: Mucolipidosis type II (MLII), or I-cell disease, is a rare lysosomal storage disease (LSD) caused by variants in the GNPTAB gene. MLII patients exhibit clinical phenotypes in the prenatal or neonatal stage, such as marked dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, and mental and motor developmental abnormalities. The median age at diagnosis for MLII is 0.7 years, the median survival is 5.0 years, and the median age at death is 1.8 years. No cure for MLII exists. Methods: Sanger sequencing of the GNPTAB gene identified the compound heterozygous mutations c.673C > T in exon 7 and c.1090C > T in exon 9, which were novel double heterozygous mutations first reported in China. For the first time, we describe our experience in the use of HSCT for MLII. Our patient underwent HSCT with cells from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor at 12 months of age. Myeloid neutrophil and platelet engraftment occurred on Days 10 and 11, respectively. Results: The patient's limb muscle tension was significantly reduced, and his gross and fine motor skills were improved four months after transplantation. DST(Developmental Screen Test) results showed that the patient's fine motor skills and mental development were improved compared with before HSCT. Conclusion: MLII is a very severe lysosomal storage disease, to date, only 3 cases have been reported on the use of HSCT to treat MLII. Our data show that HSCT is a potential way to prolong the life of patients and improve their quality of life. Due to the lack of comparable data and time, the exact benefit remains unclear in MLII patients. Longer-term follow-up and in-depth prospective studies are indispensable.

Validation of an 8-item Recovery Assessment Scale (RAS-8) for people with schizophrenia in China.

BACKGROUND: The 24-item Recovery Assessment Scale (RAS) is the most widely-used and well-validated tool for measuring recovery for people with mental illness. The current study aims to assess the reliability and validity of an 8-item short form of RAS (RAS-8) among a Chinese sample of people living with schizophrenia. METHODS: A sample of 400 people living with schizophrenia were recruited for scale validation. Internal consistency was tested by calculating Cronbach's α. Test-retest reliability was calculated using the intraclass correlation coefficient (ICC) for the total score and weighted kappa for each item. Factor structure was tested with confirmatory factor analysis, and concurrent validity was examined by investigating the correlation of the RAS-8 with patient symptoms, disability, depression, anxiety, patient functioning, quality of life and general health. RESULTS: The RAS-8 full scale and subscales showed good internal consistency with Cronbach's alpha ranging from 0.87 to 0.92. ICC of 0.99 and weighted kappa ranged from 0.62 to 0.88, which generally indicates good test-retest reliability. The findings supported an a priori two-factor structure, χ2/df = 2.93, CFI = 0.98, TLI = 0.98, RMSEA = 0.07, SRMR = 0.035. Concurrent validity of the RAS-8 was further supported by its significant negative correlations with patient symptoms (r = -0.24, p < 0.01), disability (r = -0.30, p < 0.01), depression (r = -0.16, p < 0.05), and anxiety (r = -0.14, p < 0.05), and its significant positive relationships with patient functioning (r = 0.26, p < 0.01), quality of life (r = 0.39, p < 0.01) and general health (r = 0.34, p < 0.01). CONCLUSIONS: This study confirmed the reliability and validity of an 8-item short-form RAS for people living with schizophrenia in Chinese communities. The validation of the RAS-8 allows for its use as an alternative for the full RAS as a rapid assessment tool in clinical and research settings. The findings are discussed for their implications for application and validation with other populations and in other countries.

High expression of TGR5 predicts a poor prognosis in patients with pancreatic cancer.

Previous studies have showed that bile acids (BAs) play essential roles in the progression of various human cancers, and the G-protein coupled bile acid receptor-1 (Gpbar-1, or TGR5), a receptor of BAs, has been reported to connect BAs with cancers. However, little is known about the prognostic role of TGR5 in pancreatic cancer. In this study, we found that the expression of TGR5 was significantly higher in the cancerous tissues than the adjacent normal tissues by immunohistochemical staining (81.6% vs. 36.8%). Meanwhile, TGR5 was positively correlated with lymph node metastasis (P=0.021) and advanced stage (P=0.011). Finally, univariate analysis showed that patients with high TGR5 expression (P<0.001), lymph node metastasis (P=0.002) and advanced tumor stage (P=0.008) had decreased overall survival, and Cox proportional hazards regression analysis confirmed that TGR5 expression was an independent predictor of the overall survival of patients with pancreatic cancer (P=0.019). Our findings suggested that TGR5 might serve as an important predictor of poor survival in pancreatic cancer.

The dual role and therapeutic potential of high-mobility group box 1 in cancer.

High-mobility group box 1 (HMGB1) is an abundant protein in most eukaryocytes. It can bind to several receptors such as advanced glycation end products (RAGE) and Toll-like receptors (TLRs), in direct or indirect way. The biological effects of HMGB1 depend on its expression and subcellular location. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it possesses more complicated functions, including regulating cell proliferation, autophagy, inflammation and immunity. During tumor development, HMGB1 has been characterized as both a pro- and anti-tumoral protein by either promoting or suppressing tumor growth, proliferation, angiogenesis, invasion and metastasis. However, the current knowledge concerning the positive and negative effects of HMGB1 on tumor development is not explicit. Here, we evaluate the role of HMGB1 in tumor development and attempt to reconcile the dual effects of HMGB1 in carcinogenesis. Furthermore, we would like to present current strategies targeting against HMGB1, its receptor or release, which have shown potentially therapeutic value in cancer intervention.

Metformin: a review of its potential indications.

Metformin is the most commonly prescribed drug for type 2 diabetes mellitus. In recent years, in addition to glucose lowering, several studies have presented evidence suggesting some potential role for metformin, such as antitumor effect, antiaging effect, cardiovascular protective effect, neuroprotective effect or an optional treatment for polycystic ovary syndrome. This paper will critically review the role of metformin to provide reference for doctors and researchers.

Myeloid-Derived Suppressor Cells Associated With Disease Progression in Primary HIV Infection: PD-L1 Blockade Attenuates Inhibition.

OBJECTIVE: Events occurring during the initial phase of human immunodeficiency virus (HIV) infection are intriguing because of their dramatic impact on the subsequent course of the disease. In particular, the relationship between myeloid-derived suppressor cells (MDSCs) and HIV pathogenesis in primary infection remains unknown and the mechanism of MDSCs in HIV infection are incompletely defined. METHODS: The frequency of MDSC expression in patients with primary HIV infection (PHI) and chronic HIV infection was measured, and the association with disease progression was studied. Programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9) expression on MDSCs was measured and in vitro blocking experiments were performed to study the role of PD-L1 in MDSCs' inhibition. RESULTS: We found increased levels of HLA-DRCD14CD33CD11b granulocytic(G)-MDSCs in PHI individuals compared with normal controls, which correlated with viral loads and was negatively related to CD4 T-cell levels. When cocultured with purified G-MDSCs, both proliferation and interferon-γ secretion by T cell receptor (TCR)-stimulated CD8 T cells from HIV-infected patients were significantly inhibited. We also demonstrated that PD-L1, but not Gal-9, expression on HLA-DRCD14CD33CD11b cells increased during HIV infection. The suppressive activity of G-MDSCs from HIV-infected patients was attenuated by PD-L1 blockade. CONCLUSIONS: We found a significant increase in G-MDSCs in PHI patients that was related to disease progression and PD-L1 was used by MDSCs to inhibit CD8 T cells in HIV infection. Our data improve the understanding of HIV pathogenesis in PHI.

TM4SF1 Promotes Metastasis of Pancreatic Cancer via Regulating the Expression of DDR1.

Transmembrane-4-L-six-family-1(TM4SF1), a four-transmembrane L6 family member, is highly expressed in various pancreatic cancer cell lines and promotes cancer cells metastasis. However, the TM4SF1-associated signaling network in metastasis remains unknown. In the present study, we found that TM4SF1 affected the formation and function of invadopodia. Silencing of TM4SF1 reduced the expression of DDR1 significantly in PANC-1 and AsPC-1 cells. Through double fluorescence immuno-staining and Co-immunoprecipitation, we also found that TM4SF1 colocalized with DDR1 and had an interaction with DDR1. In addition, upregulating the expression of DDR1 rescued the inhibitory effects of cell migration and invasion, the expression of MMP2 and MMP9 and the formation and function of invadopodia when TM4SF1 silenced. In pancreatic cancer tissues, qRT-PCR and scatter plots analysis further determined that TM4SF1 had a correlation with DDR1. Collectively, our study provides a novel regulatory pathway involving TM4SF1, DDR1, MMP2 and MMP9, which promotes the formation and function of invadopodia to support cell migration and invasion in pancreatic cancer.

Inhibition of Aurora kinases induces apoptosis and autophagy via AURKB/p70S6K/RPL15 axis in human leukemia cells.

Leukemia is a common malignancy of blood cells with poor prognosis in many patients. Aurora kinases, a family of serine/threonine kinases, play a key role in regulating cell division and mitosis and are linked to tumorigenesis, metastasis, and poor prognosis in many human cancers including leukemia and lymphoma. Danusertib (Danu) is a pan-inhibitor of Aurora kinases with few data available in leukemia therapy. This study aimed to identify new molecular targets for Aurora kinase inhibition in human leukemia cells using quantitative proteomic analysis followed by verification experiments. There were at least 2932 proteins responding to Danu treatment, including AURKB, p70S6K, and RPL15, and 603 functional proteins and 245 canonical signaling pathways were involved in regulating cell proliferation, metabolism, apoptosis, and autophagy. The proteomic data suggested that Danu-regulated RPL15 signaling might contribute to the cancer cell killing effect. Our verification experiments confirmed that Danu negatively regulated AURKB/p70S6K/RPL15 axis with the involvement of PI3K/Akt/mTOR, AMPK, and p38 MAPK signaling pathways, leading to the induction of apoptosis and autophagy in human leukemia cells. Further studies are warranted to verify the feasibility via targeting AURKB/p70S6K/RPL15 axis for leukemia therapy.

CdSe/ZnS quantum dots induce photodynamic effects and cytotoxicity in pancreatic cancer cells.

AIM: To investigate the photodynamic effect of CdSe/ZnS quantum dots (QDs) on pancreatic cancer cells and elucidate the probable mechanisms. METHODS: The pancreatic cancer cell line SW1990 was treated with different concentrations of CdSe/ZnS QDs (0, 0.5, 1.0, 1.5, 2.0, 2.5 µmol/L), with or without illumination. The viability of SW1990 cells was tested using the Cell Counting Kit-8 (CCK-8) assay. The ultrastructural changes of SW1990 cells were observed by transmission electron microscopy. Apoptosis was detected by nuclear staining and flow cytometry (FCM). Reactive oxygen species (ROS) were measured by dichlorofluorescein diacetate via fluorescence microscopy. Expression of Bax, Bcl-2 and caspase-3 was measured by real-time polymerase chain reaction (PCR) and protein immunoblotting 24 h after SW1990 cells were treated with CdSe/ZnS QDs and illuminated. RESULTS: The CCK-8 assay results showed that both CdSe/ZnS QDs with and without illumination suppressed SW1990 cell proliferation. Cell viability was significantly lower when illuminated or with a longer incubation time and a higher light dose. CdSe/ZnS QDs with illumination caused ultrastructural changes in SW1990 cells, such as organelle degeneration and chromatin condensation and aggregation at the periphery of the nucleus. Fluorescence microscopy and FCM showed that CdSe/ZnS QDs (1.5 µmol/L) with illumination increased SW1990 cell apoptosis (53.2%) and ROS generation compared with no illumination. Real-time PCR showed that expression of Bax and caspase-3 was upregulated and Bcl-2 was downregulated. Immunoblotting results were consistent with real-time PCR results. Inhibition of ROS and apoptosis both attenuated QD-photodynamic-therapy-induced cell death. CONCLUSION: CdSe/ZnS QDs can be used as a photosensitizer to inhibit SW1990 cell proliferation through ROS generation and apoptotic protein expression regulation.

[Effect of Doxorubicin on abcb4 Gene Expression in Zebrafish (Danio rerio) Embryos].

OBJECTIVE: To determine the effect of doxorubicin (DOX) on abcb4 gene expression and the role of abcb4 gene in multidrug-resistance. METHODS: Zebrafish embryos were treated with 2 mL/L DMSO, 10 µmol/L DOX and 2 mL/L DMSO+10 µmol/L DOX, respectively. The zebrafish embryos treated with Eggwater served as controls. Exposures started at 4 to 16 cell stage of the embryos and terminated 120 hours post fertilization (hpf). The expression of abcb4 gene in zebrafish embryos was examined on 48, 72, 96, and 120 hpf with whole-mount in situ hybridization (WISH) and quantitative real-time PCR (qPCR). RESULTS: Compared with the controls, DOX-exposed embryos had higher level of abcb4 gene expression (P < 0.05), but not for abcb5 gene. WISH showed that abcb4 gene was expressed in the guts of zebrafish embryos. However, those exposed to DOX also showed strong WISH signals in the brain and heart. CONCLUSION: Doxorubicin increases the expression of abcb4 gene in zebrafish embryos. abcb4 gene may play an imoortant role in multidrug-resistance.