P-aminobenzoic acid promotes retinal regeneration through activation of Ascl1a in zebrafish.

JOURNAL/nrgr/04.03/01300535-202408000-00040/figure1/v/2023-12-16T180322Z/r/image-tiff The retina of zebrafish can regenerate completely after injury. Multiple studies have demonstrated that metabolic alterations occur during retinal damage; however to date no study has identified a link between metabolites and retinal regeneration of zebrafish. Here, we performed an unbiased metabolome sequencing in the N-methyl-D-aspartic acid-damaged retinas of zebrafish to demonstrate the metabolomic mechanism of retinal regeneration. Among the differentially-expressed metabolites, we found a significant decrease in p-aminobenzoic acid in the N-methyl-D-aspartic acid-damaged retinas of zebrafish. Then, we investigated the role of p-aminobenzoic acid in retinal regeneration in adult zebrafish. Importantly, p-aminobenzoic acid activated Achaetescute complex-like 1a expression, thereby promoting Müller glia reprogramming and division, as well as Müller glia-derived progenitor cell proliferation. Finally, we eliminated folic acid and inflammation as downstream effectors of PABA and demonstrated that PABA had little effect on Müller glia distribution. Taken together, these findings show that PABA contributes to retinal regeneration through activation of Achaetescute complex-like 1a expression in the N-methyl-D-aspartic acid-damaged retinas of zebrafish.

Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.

The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.

Spatio-temporal Analysis of Demand for Elderly Care Services and Its Key Influencing Factors in Chinese Cities: A Web Search Engine Approach.

The demand for elderly care services (DECS) in Chinese Cities is one of the most concerned issues. The aim of this study was to understand the spatial and temporal evolution and external factors of DECS in Chinese cities and support the formulation of elderly care policies. We collected Baidu Index data for 287 prefecture-level and above cities and 31 provinces in China from January 1, 2012 to December 31, 2020. The Thiel Index was employed to describe the differences of DECS at different regional levels, and multiple linear regression was used to explore the external factors affecting DECS by calculating the variance inflation factor (VIF) to identify multicollinearity. The DECS of Chinese cities increased from 0.48 million in 2012 to 0.96 million in 2020, and the Thiel Index decreased from 0.5237 in 2012 to 0.2211 in 2020. Per capital GDP, number of primary beds, proportion of population aged 65 and over, number of primary care visits, and proportion of illiterate population over the age of 15 have significant influences on DECS (P < .05). DECS was on the rise in Chinese cities, with significant regional differences. At the provincial level, regional differences were influenced by level of economic development, primary care provision, aging population, educational attainment, and health status. It is suggested to pay more attention to DECS in small and medium-sized cities or regions, to strengthen primary care, and to improve the health literacy and health status of the elderly population.

Research on the Current Situation and Countermeasures of Inpatient Cost and Medical Insurance Payment Method for Rehabilitation Services in City S.

Objective: This study aimed to introduce bed-day payment for rehabilitation services in City S, China, and analyze the cost of inpatient rehabilitation services. Key issues were defined and relevant countermeasures were discussed. Methods: The data about the rehabilitation cost of 3,828 inpatient patients from June 2018 to December 2019 was used. Descriptive statistics and the Kruskal-Wallis test were employed to describe sample characteristics and clarify the comparity of cost and length of stay (LOS) across different groups. After normalizing the distribution of cost and LOS by Box-Cox transformation, multiple linear regression was used to explore the factors influencing cost and LOS by calculating the variance inflation factor (VIF) to identify multicollinearity. Finally, 20 senior and middle management personnel of the hospitals were interviewed through a semi-structured interview method to further figure out the existing problems and countermeasures. Results: (1) During 2015-2019: both discharges and the cost of rehabilitation hospitalization in City S rose rapidly. (2) The highest number of discharges were for circulatory system diseases (57.65%). Endocrine, nutritional, and metabolic diseases were noted to have the longest average length of stay (ALOS) reaching 105.8 days. The shortest ALOS was found to be 24.2 days from the diseases of the musculoskeletal system and connective tissue. Neurological, circulatory, urological, psychiatric, infectious, and parasitic diseases were observed to be generally more costly. (3) The cost of rehabilitation was determined to mainly consist of the rehabilitation fee (23.63%), comprehensive medical service fee (22.61%), and treatment fee (19.03%). (4) Type of disease, age, nature of the hospital, and grade of the hospital have significant influences both on cost and LOS (P < 0.05). The most critical factor affecting the cost was found to be the length of stay (standardized coefficient = 0.777). (5) The key issues of City S's rehabilitative services system were identified to be the incomplete criteria, imperfections in the payment system, and the fragmentation of services. Conclusions: Bed-day payment is the main payment method for rehabilitation services, but there is a conflict between rapidly rising costs and increasing demand for rehabilitation. The main factors affecting the cost include the length of stay, type of disease, the grade of the hospital, etc. Lack of criteria, imperfections in the payment system, and the fragmentation of services limit sustainability. The core approach is to establish a three-tier rehabilitative network and innovate the current payment system.

From Bench to Bed: The Current Genome Editing Therapies for Glaucoma.

Glaucoma is a group of optic neuropathies featured by degeneration of retinal ganglion cells and loss of their axons in the optic nerve. The only currently approved therapies focus on lowering intraocular pressure with medication and surgery. Over the previous few decades, technological advances and research progress regarding pathogenesis has brought glaucomatous gene therapy to the forefront. In this review, we discuss the three current genome editing methods and potential disease mechanisms of glaucoma. We further summarize different genome editing strategies that are being developed to target a number of glaucoma-related genes and pathways from four aspects including strategies to lower intraocular pressure, neuroprotection, RGC and optic nerve neuro-regeneration, and other strategies. In summary, genome therapy is a promising therapy for treating patients with glaucoma and has great potential to be widely applied in clinical practice.

Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1.

BACKGROUND: Despite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years. METHODS: Using multiple human ovarian cancer cell lines, a transwell co-culture system of the carboplatin or VP-16-challenged feeder and receptor cells was established to demonstrate the chemotherapy-exacerbated migration. The migration and cancer stem cell (CSC)-like characteristics were determined by wound healing, transwell migration, flow cytometry and sphere formation. mRNA and protein expression were identified by qPCR and western blot. Bioinformatics analysis was used to investigate the differentially expressed genes. GLI1 expression in tissue samples was analysed by immunohistochemistry. RESULTS: Chemotherapy was found to not only kill tumour cells, but also trigger the induction of CSC-like traits and the migration of ovarian cancer cells. EMT markers Vimentin and Snail in receptor cells were upregulated in the microenvironment of chemotherapy-challenged feeder cells. The transcription factor GLI1 was upregulated by chemotherapy in both clinical samples and cell lines. Follow-up functional experiments illustrated that inhibiting GLI1 reversed the chemotherapy-exacerbated CSC-like traits, including CD44 and CD133, as well as prevented the migration of ovarian cancer cells. CONCLUSIONS: Targeting GLI1 may improve clinical benefits in the chemotherapy-exacerbated metastasis in ovarian cancer treatment.

5-FU preferably induces apoptosis in BRAF V600E colorectal cancer cells via downregulation of Bcl-xL.

Fluorouracil (5-FU) which has been widely used in postoperative adjuvant therapy in patients with colon cancer, remains the main backbone of combination treatment of patients with colon cancer. However, the efficacy of 5-FU alone in colorectal cancer patients with BRAFV600E is not clear. In this study, we demonstrated that BRAFV600E confers sensitivity to 5-FU in vitro and in vivo xenograft model, using the paired isogenic colorectal cancer cell lines RKO with either BRAF Wild Type (WT)(+/-) or mutant (Mut) (600E/-). Our results revealed 5-FU preferably induces marked apoptosis in BRAF-mutant colorectal cancer cells, through attenuating expression of Bcl-xL and activation caspase-3/9 pathway, eventually conferring the anti-tumor efficacy of 5-FU in vitro and in vivo. Meanwhile, expression of Bcl-xL remained unchanged in BRAF WT group after treatment of 5-FU, although low extent of anti-tumor activity of 5-FU still being observed. In conclusion, these results provided a better understanding of clinical outcome of 5-FU between BRAF WT and mutant colorectal cancer patients, and suggested the inhibition of Bcl-xL might present an alternative strategy to enhance the therapeutic efficacy of 5-FU in colorectal cancer patients with BRAF mutation.

Correlated overexpression of metadherin and SND1 in glioma cells.

Glioma is the most common primary brain tumor with poor prognosis. Effective treatment of glioma remains a big challenge due to complex pathogenic mechanisms. Previous studies have shown that metadherin (MTDH) and its interacting protein staphylococcal nuclease domain containing 1 (SND1) are overexpressed in many solid tumors. To elucidate the role of MDTH and SND1 in the pathogenesis of glioma, we examined the expression of MTDH and SND1 in primary glioma tissues and found that both MTDH and SND1 were highly expressed, with similar expression patterns. Co-expression of MTDH and SND1 was associated with advanced glioma grades. In addition, we detected the interaction between MTDH and SND1 in cultured glioma cell lines. MTDH could promote the expression of p65 and SND1 in glioma cells. However, enhanced SND1 expression by MTDH was abolished by the inhibition of p65. In conclusion, we demonstrated high expression levels MTDH and SND1 in primary glioma tissues. MTDH might promote glioma by inducing SND1 expression through the activation of NF-κB pathway. MTDH and SND1 may serve as the indicator of malignancy and prognosis as well as therapeutic targets for patients with glioma.

Prognostic significance of astrocyte elevated gene-1 in human astrocytomas.

Astrocyte Elevated Gene-1 (AEG-1) has been proposed as a biomarker for a variety of cancers. This study aimed to investigate the expression of AEG-1 in human astrocytomas and the correlation between AEG-1 expression and clinicopathologic variables of astrocytomas. AEG-1 expression in four pairs of matched astrocytomas tissues and 5 cell lines was detected by immunohistochemical and Western blot analysis. In addition, AEG-1 protein expression was examined by immunohistochemical staining in 204 cases, including 32 normal brain tissues, 80 Low-malignant astrocytomas (LMAs) and 92 High-Malignant astrocytomas (HMAs). AEG-1 expression in 31 LMAs and 29 HMAs samples was detected by RT-PCR and Western blot analysis. We detected AEG-1 expression in normal neurons and glioma cell lines U87, U251 and M059K, but not in normal glial cells. Immunohistochemical analysis showed that 128 of 172 (74.4%) paraffin-embedded archival astrocytomas samples exhibited positive AEG-1 expression. Statistical analysis suggested that higher AEG-1 level was significantly correlated with histological grade of astrocytomas. In addition, AEG-1 mRNA and protein expression was higher in HMAs than in LMAs. AEG-1 expression had no correlation with the gender or age of astrocytoma patients. In summary, our data suggest that AEG-1 may represent a novel prognostic marker for astrocytomas.

Prevalence and genotype distribution of human papillomavirus infection in Harbin, Northeast China.

This study aimed to investigate the overall prevalence of human papillomavirus (HPV) infection among women examined at a hospital in Harbin and to evaluate the impact of HPV types on the natural outcome and state of cervical cytology. A total of 2,938 female outpatients from the affiliated hospital of Harbin Medical University were enrolled. Rapid hybridization gene chip and liquid-based cytology tests were used to detect HPV genotypes and cervical cytology. The overall prevalence of HPV in women who came to this hospital was 36.45 %. The majority were infected with a single strain, and the high-risk HPV (HR-HPV) type constituted the largest proportion. HPV16 and 58 were the most common types, while the genotypes of single low-risk HPV (LR-HPV) were not the same in different age groups. HPV53, 16 and 81 were the most common types in multiple HR-HPV infection; HR-HPV16, 33, 81 and LR-HPV 6, 44, 43 were the most common in HR and LR-HPV infection. In total, 44.1 % of the women with HSIL and 44.0 % with ASCUS were positive for HR-HPV16. Multiple HPV infections and single HPV infections had no effect on the natural outcome after half a year. HPV16, 81 and 35 had a better natural outcome, followed by HPV52 and 53, but HPV58, 59 and 18 had a bad outcome after half a year. This is the first study to show that the distribution of HPV types is different in Harbin than it is in other regions. These findings will provide guidance for the vaccination program in this area.