Dry eye and decreased tear film stability in primary acquired nasolacrimal duct obstruction patients.

PURPOSE: Exploring the prevalence of dry eye (DE) and the changes of tear film stability in patients with primary acquired obstruction of the nasolacrimal duct (PANDO). METHODS: In this cross-sectional, observational study, 370 eyes in 223 patients with PANDO were assessed. The ocular surface disease index (OSDI) was used to evaluate ocular surface symptoms, and the Keratograph 5M non-invasive ocular surface analyser was used to assess ocular surface parameters. According to the TFOS DEWS II criteria, patients with OSDI ≥ 13 and NIKBUT < 10 s were diagnosed with DE. RESULTS: Of the 223 PANDO patients, 65 (29.1%) met the diagnostic criteria for DE. Compared with patients without DE, PANDO patients with DE were significantly older (p < 0.001), had a longer duration of epiphora (p = 0.023), and more likely to have a positive regurgitation on pressure over the lacrimal sac (ROPLAS) sign (p = 0.003). Multifactorial analysis showed that older age, positive ROPLAS and hypertension were significant independent predictors of DE (p < 0.05). Among the 147 unilateral PANDO patients without DE, the TMH, NIKBUT-first, NIKBUT-average and bulbar erythema scores were significantly higher in the PANDO sides. CONCLUSIONS: This study illustrated the prevalence of DE in PANDO patients was 29.1% and DE is more likely to occur in those who are older, have hypertension and are positive for ROPLAS. In addition, in patients with unilateral nasolacrimal duct obstruction, a decrease in tear film stability was observed in the healthy eye.

Microbial distributions in the conjunctiva and lacrimal sacs of patients with chronic dacryocystitis in a tertiary hospital.

BACKGROUND: The aim was to clarify the distributions of bacteria in the conjunctival sac and lacrimal sac in patients with chronic dacryocystitis. METHODS: In total, 297 (322 eyes) chronic dacryocystitis patients who underwent nasal endoscopic dacryocystorhinostomy (EN-DCR) were included. Conjunctival sac secretions from the affected eye were collected preoperatively, and lacrimal sac retention fluid from the affected side in the same patient was collected intraoperatively. Bacterial culture and drug sensitivity testing were performed to determine bacterial distributions. RESULTS: In total, 127 bacterial isolates (49 species) were detected in 123 eyes in the conjunctival group, with a positivity rate of 38.2% (123/322); 85 bacterial isolates (30 species) were detected in 85 eyes in the lacrimal sac group, with a positivity rate of 26.4% (85/322). The positivity rates were significantly different (P = 0.001) between two groups. The gram-negative bacilli proportion in the lacrimal sac group (36/85, 42.4%) was significantly higher than that in the conjunctival sac group (37/127, 29.2%) ( P = 0.047). Positive conjunctival sac secretion culture (123/322) was significantly associated with increased ocular secretion (281/322, 87.3%) (P = 0.002). Among the culture-positive bacteria in the conjunctival sac group and the lacrimal sac group, 30/127, 23.6% and 43/127, 26.7% and 21/85, 24.7% and 20/85, 23.5% were resistant to levofloxacin and tobramycin, respectively. CONCLUSIONS: This study illustrated differences in bacterial distributions between conjunctival sac secretions and retained lacrimal sac fluid in chronic dacryocystitis patients, with a higher proportion of gram-negative bacilli in lacrimal sac secretions. The ocular surface flora in chronic dacryocystitis patients is partially resistant to levofloxacin and tobramycin, which need to be considered by ophthalmologists.

Role of PGC-1α in fiber type conversion in the palatopharyngeus muscle of OSA patients.

BACKGROUND: Obstructive sleep apnea (OSA) has a high incidence and is harmful to health. It is characterized by repeated collapse of the upper airway. However, the mechanism underlying upper airway collapse is unclear. METHODS: Patients with OSA and chronic tonsillitis were studied. Pathological changes in palatopharyngeus muscle were detected. The expression of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) and nuclear respiratory factor-1 (NRF-1) in muscles was detected by PCR and Western blotting. Immunofluorescence staining was used to detect the expression of type I and type II myofibril. RESULTS: The structure of the palatopharyngeus muscle was changed, and the expression of PGC-1α and NRF-1 was decreased in the OSA group compared with that in the control group. The expression of PGC-1α, NRF-1, and type I myofibril in C2C12 myoblasts was decreased by intermittent hypoxia exposure. The expression of type I myofibril was decreased when knocking down PGC-1α. CONCLUSION: OSA patients exhibited pathological damage in palatopharyngeus muscle. PGC-1α was involved in the fiber type conversion in palatopharyngeus muscle caused by intermittent hypoxia.

Sophocarpine Attenuates Cognitive Impairment and Promotes Neurogenesis in a Mouse Model of Alzheimer's Disease.

INTRODUCTION: Alzheimer's disease (AD), which is characterized by abnormal deposition of amyloid-ß (Aß) plaques and impaired neurogenesis and cognition, still lacks an optimally effective therapeutic agent for its management, and mounting evidence has shown that inflammatory processes are implicated in AD. Sophocarpine has been reported to exert inflammation-regulating effects in various diseases. However, whether sophocarpine can exert anti-neuroinflammatory and neuroprotective effects in AD remains unclear. This study investigated whether sophocarpine could ameliorate the pathological features and potential mechanisms in a mouse AD model. METHODS: APP/PS1 mice were treated with sophocarpine for 8 weeks. We quantified the effects of sophocarpine treatment on cognitive performance using a behavioral test. Brain Aß deposits and neurogenesis were evaluated using immunofluorescence staining. We also assessed the morphology and inflammatory changes induced by sophocarpine administration and its expression in the hippocampus. RESULTS: Administration of sophocarpine significantly alleviated cognitive impairment and reduced neural loss. APP/PS1 mice treated with sophocarpine showed reduced Aß plaque deposits and enhanced neurogenesis. Sophocarpine markedly decreased the expression of inflammation markers and inhibited microglial activation. CONCLUSIONS: Sophocarpine could potentially alleviate cognitive impairment and brain damage in APP/PS1 mice with its neuroprotective effects via modulation of the inflammatory pathway.

Clinicians versus patients subjective adverse events assessment: based on patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).

PURPOSE: Adverse events (AEs) assessment by clinicians is a standard practice in a clinical setting. However, studies have found clinicians tend to report fewer AEs, especially subjective AEs. We aimed to explore the difference of subjective AEs assessment between clinicians and patients based on PRO-CTCAE, and to discuss the necessity of incorporating patient into the evaluation of AEs. METHODS: Between April and July 2019, two different questionnaires with the same subjective AEs were given to patients and clinicians in the Day Chemotherapy ward of Breast Center in the Fourth Hospital of HeBei Medical University. Patients completed a Simplified Chinese version of PRO-CTCAE, including six common subjective AEs of chemotherapy: nausea, vomiting, diarrhea, fatigue, pain, and constipation. Clinicians completed the common terminology criteria for adverse events (CTCAE) with the same AEs. General information of enrolled patients and results from the questionnaires were collected and analyzed. RESULTS: 384 paired questionnaires were collected. Clinicians reported less subjective AEs than patients, and the general agreement between patients and clinicians was poor. When considering the grade difference, we utilize weighted kappa coefficient to analysis, and agreement between patients and clinicians was poor (k < 0.4) regardless of the frequency, the severity and interfering with daily life of AEs, and the most discrepancies were within one point. Patients tended to grade severer than the clinician. CONCLUSIONS: The results of this study showed that there were differences between clinicians and patients in subjective adverse events evaluation. Patient reporting of symptoms can be used as a supplementary method to incorporate the current approach to monitor subjective AEs, to improve the timeliness and accuracy of clinical evaluation of subjective AEs.

Histone demethylase KDM6B regulates 1,25-dihydroxyvitamin D3-induced senescence in glioma cells.

Vitamin D is a fat-soluble vitamin and plays an important role in calcium absorption and bone development, whose lack can cause a variety of diseases, including cancer. Human epidemiological studies suggested that vitamin D3 deficiency might increase glioma incidence, but molecular mechanism is less understood. In this study, we show that 1,25-dihydroxyvitamin D3 (the active form of vitamin D3) induces senescence of glioma cells and increases the expression of senescence markers, INK4A and cyclin-dependent kinase inhibitor 1A (CDKN1A). 1,25-Dihydroxyvitamin D3 also upregulates the expression of histone demethylase, KDM6B. Knockdown of KDM6B attenuates 1,25-dihydroxyvitamin D3-induced senescence and upregulation of INK4A and CDKN1A. KDM6B promotes the transcription of INK4A by eliminating the trimethylation of repressive marker H3K27me3 near its promoter. This study reveals a new regulatory mechanism involved in vitamin D3 inhibition on gliomas, which is beneficial to prevention and adjuvant therapy of glioma.

Regulation of histone demethylase KDM6B by hypoxia-inducible factor-2α.

Lysine (K)-specific demethylase 6B (KDM6B) is a histone H3K27 demethylase, which specifically catalyzes the demethylation of H3 lysine-27 tri/dimethylation (H3K27me3/2). KDM6B can activate gene transcription by promoting transcriptional elongation which is associated with RNA polymerase II and related elongation factors. So KDM6B is important for the regulation of gene expression. Previous studies have indicated that several histone demethylases such as KDM3A, KDM4B, and KDM4C are regulated by hypoxia-inducible factor (HIF). But, the effect of hypoxia on KDM6B is not fully understood. In this study, we found that the expression levels of KDM6B mRNA and protein are modestly up-regulated under hypoxia (1% O2) or mimic hypoxia (desferrioxamine mesylate or CoCl2 treatment) (P<0.05). The result of RNAi shows that the up-regulation of KDM6B is dependent on HIF-2α, but not on HIF-1α. The result of chromatin immunoprecipitation assay indicates that there is a hypoxia response element in KDM6B promoter (-4041 to -4037). The result of Co-IP assay indicates that KDM6B can form complex with HIF-2α or HIF-1α. The knockdown experiment implies that KDM6B is a potential regulator for HIF-2α target genes. These data demonstrate that KDM6B is a new hypoxia response gene regulated by HIF-2α. Our results also show that KDM6B is a potential co-activator of HIF-α, which is important for the activation of hypoxia response genes.

Curcumin combined with oxaliplatin effectively suppress colorectal carcinoma in vivo through inducing apoptosis.

Studies have shown chemopreventive and/or chemotherapeutic effects of several curcumin-based combinatorial treatments on colorectal cancer cells. However, their in vivo effects remain unclear. This study has demonstrated the therapeutic effect of curcumin and oxaliplatin, alone or in combination, on subcutaneously xenografted LoVo human colorectal cancer cells in immunodeficient (nu/nu) mice in vivo. Combinatorial administration of curcumin and oxaliplatin evidently inhibited the growth of colorectal cancer in nude mice, which was significantly more effective than either agent alone. Curcumin combined with oxaliplatin treatment induced apoptosis, accompanied by ultrastructural changes and cell cycle arrest in S and G2/M phases. Further mechanism analysis indicated that while the number of apoptotic tumor cells and the expression of Bax, caspase-3, and poly (ADP-ribose) polymerase (PARP) increased significantly, the expression of Bcl-2, survivin, HSP70, pro-caspase-3, and pro-PARP were dramatically suppressed in tumor cells after the treatment with combinatorial curcumin and oxaliplatin for 22 days. Taken together, the present study has demonstrated that administration of combined curcumin and oxaliplatin effectively suppressed colorectal carcinoma in vivo through inducing apoptosis and thus may provide an effective treatment for colorectal carcinoma.

The challenges and benefits of public health in smart cities from a 4 M perspective.

Introduction: With the acceleration of urbanization, public health issues have become increasingly prominent in smart city construction, especially in the face of sudden public health crises. A deep research method for public health management based on a 4M perspective (human, machine, materials, methods) is proposed to effectively address these challenges. Methods: The method involves studying the impact of human factors such as population age, gender, and occupation on public health from a human perspective. It incorporates a machine perspective by constructing a public health prediction model using deep neural networks. Additionally, it analyzes resource allocation and process optimization in public health management from the materials and methods perspectives. Results: The experiments demonstrate that the public health prediction model based on deep neural networks achieved a prediction accuracy of 98.6% and a recall rate of 97.5% on the test dataset. In terms of resource allocation and process optimization, reasonable adjustments and optimizations increased the coverage of public health services by 20% and decreased the response time to public health events by 30%. Discussion: This research method has significant benefits for addressing the challenges of public health in smart cities. It can improve the efficiency and effectiveness of public health services, helping smart cities respond more quickly and accurately to potential large-scale public health events in the future. This approach holds important theoretical and practical significance.

Gene expression profiles of sodium-dependent vitamin C transporters in mice after alcohol consumption.

Alcoholic liver disease (ALD) is a serious liver problem in western countries. Our previous study has demonstrated that vitamin C plays a protective role in ALD. The vitamin C homeostasis is tightly regulated by sodium-dependent vitamin C transporters (SVCTs) 1 and 2. But the role of two SVCTs in ALD is less understood. In this study, we examined the expression patterns of two SVCTs in mice after alcohol consumption. Our results suggested that alcohol consumption obviously increased the expression of two SVCTs in liver and SVCT1 in kidney and intestine, which is important for vitamin C absorption. Vitamin C supplement increased the sera vitamin C content and ameliorated the symptom of ALD. Intestinal absorption and renal re-absorption mediated by SVCT1 are key factors to increase the sera vitamin C content after alcohol consumption. We proposed that both reactive oxygen species and low vitamin C concentration regulate the expression of SVCTs, and the protective role of vitamin C is mediated by suppressing the stability of hypoxia-inducible factor-1α. Thus, our study is significant for the understanding of vitamin C homeostasis in ALD and for better use of other antioxidants in ALD therapy.

Acceptance of Advance Care Planning Among Young Adults in Shijiazhuang, China: A Mixed-Methods Study.

Context: In the event of accidental trauma, incurable disease and public health emergencies, young adults are unable to participate in their own medical decisions, family members face the huge decision-making pressure and medical resources of the society were unevenly distributed. Objective: The purposes of this study is to investigate the Advanced Care Planning (ACP) acceptance and examine its influencing factors using sequential explanatory mixed methods in order to provide a basis for the formulation of later interventions. Methods: A cross-sectional study of young adults (N = 785) and 12 other young adults from two other communities were investigated from January 2021 to February 2022. Descriptive statistics and multiple linear regressions were conducted. Content analysis was performed on the qualitative data. Results: The primary factors that contributed to the acceptance of ACP were the natural acceptance of death, being female, having a high level of education, having a loved one diagnosed with a chronic disease, and having heard of ACP. Among young adults, the acceptance of ACP may be impeded by a fear of the unknown nature of death, a poor understanding of ACP, and family-led decision-making. Discussion: Our study found that 77.1% had not heard of ACP before participating in the study and showed potential to accept ACP-related interventions. The study highlighted the importance of implementing regular young adult education courses, promoting routine ACP knowledge, individualized education, discussing family member's disease experiences, conducting family meetings, and identifying young adult responsibilities and roles in implement ACP for young adults in China.

Expression and significance of histone H3K27 demethylases in renal cell carcinoma.

BACKGROUND: The histone H3K27 demethylases UTX and JMJD3 are important regulatory factors that modulate gene expression by altering the physical state of chromatin. Previous studies have indicated an abnormal H3K27 methylation status in carcinogenesis. We therefore investigated the expression patterns of UTX and JMJD3 in renal cell carcinoma (RCC) and their roles in cancer development. METHODS: The mRNA expression levels of the UTX and JMJD3 genes were determined in cancer tissues and adjacent normal tissues in 36 patients with primary RCC, using quantitative real-time-polymerase chain reaction. The UTX and JMJD3 protein contents were measured by western blotting and immunohistochemical analysis. RESULTS: UTX and JMJD3 transcripts were significantly increased in cancer tissues compared to normal tissues (P < 0.05). mRNA levels of the inhibitor of cyclin-dependent kinases 4 and 6 p16INK4a were also increased in cancer tissues (P < 0.001). Western blotting indicated that levels of both demethylases were increased in cancer tissues. The level of tri-methylated H3K27 (H3K27me3) was lower in cancer tissues compared to normal tissues, but expression of the H3K27 methyltransferase EZH2 was increased (P < 0.05). These results suggest that the two H3K27 demethylases may play critical roles in the regulation of H3K27 methylation status in RCC. Immunohistochemical analysis confirmed that UTX and JMJD3 expression were upregulated in cancer tissues compared to adjacent tissues. CONCLUSIONS: This study demonstrated that UTX and JMJD3 were upregulated in cancer tissues, suggesting that they may be involved in the development of primary RCC. The potential roles of H3K27 demethylases as biomarkers in the early diagnosis of RCC need to be further explored.

Calcitonin increases hepatic hepcidin expression through the BMP6 of kidney in mice.

BACKGROUND: Osteoporosis is frequently accompanied by iron disorders. Calcitonin (CT) was approved as a clinical drug to treat osteoporosis. Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin deficiency leads to iron overload diseases. This study was aimed at investigating the effect of CT on hepatic hepcidin and the mechanism by which CT modulates hepatic hepcidin pathways and iron metabolism. METHOD: RT-PCR, Western blot, ELISA and siRNA were used to detect the effect of CT on iron metabolism in vivo and in vitro. In addition, the regulatory signal molecules of hepcidin were measured to explore the molecular mechanism of its regulation. RESULTS: The results showed that CT strongly increased hepcidin expression and altered iron homeostasis, after mice were intraperitoneal injection of CT. In response to CT administration, BMP6 level in kidney and the serum BMP6 was increased significantly. The phosphorylation of Smad1/5/8 proteins in liver was increased at 3 h and 6 h. Moreover, the Bmp inhibitor LDN-193,189 pretreatment significantly attenuated the CT-mediated increases in phosphorylated Smad1/5/8 and Hamp1 mRNA levels. Calcitonin receptor (CTR) siRNA transfection significant suppressed the role of CT on BMP6 expression in Caki-1 cells. CONCLUSION: Our results suggest that CT strongly induces hepcidin expression and affected iron metabolism. It will provide a new strategy for the treatment of calcium iron related diseases.

Histone H3K9 demethylase JMJD1A is a co-activator of erythropoietin expression under hypoxia.

Erythropoietin (EPO) is a secreted hormone that stimulates the production of red blood cells, and the level of EPO is increased under hypoxia. The expression of EPO is regulated not only by the hypoxia-inducible factor (HIF) but also partly through epigenetic modifications, including histone acetylation and methylation. In this study, we report that histone H3K9 demethylase JMJD1 A is regulated by HIF-2α in HepG2 cells under hypoxia. Knockdown or over-expression of JMJD1 A can decrease or increase EPO expression, respectively. JMJD1 A can interact with HIF-2α to form a co-activator complex, which binds to the hypoxia response elements of EPO and increases EPO expression by catalyzing demethylation of H3K9me2, a transcription suppression marker. The results demonstrate that JMJD1 A is a co-activator of EPO expression.

The histone H3 Lys 27 demethylase KDM6B promotes migration and invasion of glioma cells partly by regulating the expression of SNAI1.

The histone demethylase KDM6B, also known as jumonji domain-containing protein 3 (JMJD3), is an epigenetic regulator which plays important roles in immune activation, tissue regeneration, cellular senescence and cancer metastasis. But, the role of KDM6B in glioma metastasis is poorly understood. In this study, we achieved transcriptional regulation of KDM6B in glioma cells using CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa). Our results showed that KDM6B promotes the proliferation, migration and invasion of human glioblastoma cells U87 and U251 using CCK8, scratch and transwell assays. Further results indicated that KDM6B increases the expression of SNAI1, a key factor of epithelial-mesenchymal transition (EMT). KDM6B catalyzes the demethylation of histone H3 Lys 27 trimethylation (H3K27me3) in the promoter of SNAI1, which is important for SNAI1 upregulation. Taken together, these findings provide new insight into the mechanism by which KDM6B promotes glioma metastasis.

Calcitriol induces cell senescence of kidney cancer through JMJD3 mediated histone demethylation.

Calcitriol, also known as 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3), is a biologically active form of vitamin D and has a wide range of anticancer activity against various cancer cell lines. However, the mechanism of calcitriol remains to be further studied. In this study, the biological effect and epigenetic regulation of calcitriol on kidney cancer cells were investigated. Calcitriol can significantly inhibit cell proliferation of kidney cancer cell lines 786-O (P<0.05). Calcitriol also induced cell apoptosis and senescence of 786-O and ACHN (P<0.05). Calcitriol can increase the expression of histone demethylase JMJD3 and cell senescence marker p16INK4A (P<0.05). Knockdown of JMJD3 decreased p16INK4A upregulation after calcitriol treatment (P<0.05), and also reduced calcitriol-induced cell senescence (P<0.05). This study reveals a new mechanism of anticancer activity of calcitriol by showing that histone demethylase JMJD3 induced by calcitriol increases p16INK4A expression and cell senescence. Therefore, these results provide new strategy for treatment and prevention of kidney cancer.

Effects of moderate exercise over different phases on age-related physiological dysfunction in testes of SAMP8 mice.

Oxidative stress and chronic inflammation have been implicated in the testicular aging process. Different types and moderate-intensity of regular exercise may reduce age-related physiological dysfunction associated with inflammation and oxidative stress, but such effects of moderate-intensity of exercise over different phases of life in testes have not been reported. In this study, male SAMP8 mice, a senescence-accelerated strain, were maintained as sedentary (sed) or subjected to daily 15-min periods of swimming exercise between ages of 2-7 months (lifelong), 2-4 months (earlier) or 5-7 months (late). Age-related changes, including serum testosterone levels and biomarkers of inflammation and oxidative stress were analyzed at the end of the experiment. All exercise groups showed significantly greater serum testosterone levels and decreased age-related inflammation and oxidative stress compared with the sedentary group. Exercise also increased expression and activity of the nuclear factor erythroid 2-related factor (Nrf2), a transcriptional regulator of the cellular anti-oxidant system, and decreased expression and activity of nuclear factor kappa beta (NF-κB), a mediator of inflammatory molecules, in the nucleus of testicular cells. However, lifelong and earlier groups generally showed significantly better protective effects than the late group against age-related physiological dysfunction in testes. Thus, lifelong exercise and earlier phase exercise were most effective in counteracting oxidative stress and inflammation and in preserving testes function through regulation of Nrf2 and NF-κB. These results advocate the benefits of lifelong exercise and emphasize a greater protection against male aging by instituting exercise earlier rather than late in life.

Demethoxycurcumin inhibits cell proliferation, migration and invasion in prostate cancer cells.

Curcumin (CUR) is a natural agent that has been demonstrated to effectively inhibit prostate cancer growth. However, natural CUR is relatively unstable and can be easily degraded in vivo. Therefore, it is essential to develop other stable curcuminoids. Demethoxycurcumin (DMC) is a candidate that has been verified in several tumor types and has potential for the treatment of prostate cancer. In the present study, we investigated the effects of DMC on proliferation, apoptosis and migration of PC-3 cells. MTT assay results indicated that DMC inhibited PC-3 cell viability in a dose- and time-dependent manner, and DMC induced G2/M phase arrest. Furthermore, PC-3 cells in DMC-treated groups had a higher apoptotic rate compared with DMSO-treated control. This effect may be due to the activation of the caspase-3 pathway. In DMC-treated groups, migrating and invasive cells were dramatically reduced (P<0.05). The activity of MMP-2, which is correlated with migration and invasion was also suppressed by DMC. These results indicated that DMC may inhibit PC-3 cell migration and invasion partially by affecting MMP-2 activity. In conclusion, DMC significantly inhibits proliferation, migration and invasion of cultured PC-3 cells, and this study may provide evidence for future in vivo studies and clinical use.