Chronic stress induces fur color change from dark to brown by decreasing follicle melanocytes and tyrosinase activity in female C57BL/6 mice.

Increasing evidence suggests that stress may induce changes in hair color, with the underlying mechanism incompletely understood. In this study, female C57BL/6 mice subjected to electric foot shock combined with restraint stress were used to build chronic stress mouse model. The melanin contents and tyrosinase activity were measured in mouse skin and B16F10 melanoma cells. The enzyme-linked immunosorbent assay (ELISA) was used to determine the content of tumor necrosis factor α (TNF-α), interleukin- 1ß (IL-1ß) and interleukin-6 (IL-6) in the mouse skin. The content of nuclear factor κB (NFκB)/p65 subunit in mouse skins was valued by immunofluorescence staining. The results demonstrated that under chronic stress, the fur color turned from dark to brown in C57BL/6 mice due to the decrease of follicle melanocytes and tyrosinase activity in C57BL/6 mouse skin. Simultaneously, inflammatory responses in skins were detected as shown by increased NFκB activity and TNF-α expression in stressed mouse skin. In cultured B16F10 melanoma cells, TNF-α reduced the melanogenesis and tyrosinase activity in a dose-dependent manner. These findings indicate that chronic stress induces fur color change by decreasing follicle melanocytes and tyrosinase activity in female C57BL/6 mice, and TNF-α may play an important role in stress-induced hair color change.

Ds-HMGB1 and fr-HMGB induce depressive behavior through neuroinflammation in contrast to nonoxid-HMGB1.

High mobility group box 1 (HMGB1) has been implicated as a key factor in several neuroinflammatory conditions. Our previous study suggested that the release of central HMGB1 acts as a late-phase mediator in lipopolysaccharide (LPS)-induced depression. Recent findings indicate that the redox state of HMGB1 is a critical determinant of its immunomodulatory properties. Here, we aimed to investigate the potential mechanisms that link the redox states of HMGB1 to depression in mice. Distinct redox forms of recombinant HMGB1 (rHMGB1) were used that included fully reduced HMGB (fr-HMGB1), which acted as a chemokine, and disulfide-HMGB1 (ds-HMGB1), which possessed cytokine activity. Fr-HMGB1 in vivo was partially oxidized into ds-HMGB1; thus, the mutant protein non-oxidizable chemokine-HMGB (nonoxid-HMGB1) was applied. Concurrent with depressive behavior induced by four-week stress exposure, the HMGB1 concentrations in the serum and cerebral cortex substantially increased. Therefore, a single dose of rHMGB1 (200ng/5µl/mice) or vehicle was administered to mice via intracerebroventricular (i.c.v.) injection. The receptor inhibitors of TLR4/RAGE/CXCR4 (TAK-242/FPS-ZM1/AMD3100) (3mg/kg) were intraperitoneally injected 30min prior to rHMGB1 treatment. Depressive-like behavior was measured 20h post i.c.v. injection. Administration of fr-HMGB1 prolonged the immobility duration in the tail suspension test (TST) and decreased sucrose preference. In addition to depressive behavior, the hippocampal TNF-α protein slightly increased. These depressive behaviors and upregulation of hippocampal TNF-α were alleviated or abrogated by pretreatment with the inhibitors AMD3100, FPS-ZM1, and TAK-242. Alternatively, nonoxid-HMGB1 failed to induce TNF-α protein or prolong the immobility duration. As expected, ds-HMGB1 administration substantially upregulated hippocampal TNF-α protein, increased the immobility time in the TST and decreased sucrose preference. Moreover, both glycyrrhizin and TAK-242 improved ds-HMGB1-induced depressive behavior. Furthermore, TAK-242 significantly blocked the upregulation of hippocampal TNF-α protein and protected hippocampal myelin basic protein from ds-HMGB1-induced reduction. These drugs had no effect on the total or central distance in the open field test. Collectively, this initial experiment demonstrates the role and receptor mechanisms of HMGB1 under different redox states on the induction of depressive-like behavior. Both ds-HMGB1 and fr-HMGB1 may induce depressive-like behavior in vivo mainly via neuroinflammatory response activation.

NLRP3 Inflammasome Mediates Chronic Mild Stress-Induced Depression in Mice via Neuroinflammation.

BACKGROUND: Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1ß. The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions. METHODS: To explore the role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress. RESULTS: Mice subjected to chronic mild stress for 4 weeks had significantly higher serum corticosterone levels, serum interleukin-1ß levels, and hippocampal active interleukin-1ß protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of chronic mild stress-exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and the apoptotic speck-containing protein with a card. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of interleukin-1ß protein and significantly moderated the depressive-like behaviors induced by chronic mild stress. CONCLUSIONS: These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression.

Long-term outcomes of Boston keratoprosthesis type I: the Chinese People's Liberation Army General Hospital experience.

PURPOSE: To report the long-term outcomes of Boston keratoprosthesis type I (B-KPro type I) implantation in the management of severe ocular surface disorders. METHODS: Retrospective case series. Patients who underwent B-KPro type I implantation at the People's Liberation Army General Hospital were enrolled between March 2011 and September 2019. Data regarding visual acuity (VA), B-KPro type I retention and postoperative complications were recorded and analysed. RESULTS: A total of 103 eyes of 100 patients who underwent B-KPro type I implantation were included. The main indications were chemical burn (59.2%), ocular trauma (25.2%), herpetic keratitis (11.7%) and autoimmune diseases (3.9%). The percentage of eyes with postoperative VA of 10/200 or better was 82.7% at 6 months, 82.8% at 12 months, 77.9% at 2 years, 72.4% at 3 years, 71.1% at 4 years, 69.4% at 5 years, 58.9% at 6 years, 56.8% at 7 years and 42.9% at 8 years. Preoperatively, 8.7% eyes were diagnosed with new-onset glaucoma. Retroprosthetic membrane formation occurred in 19.4% eye. Corneal melting occurred in 18.4% eyes. Sterile vitritis was diagnosed in 4.9% eyes and infectious endophthalmitis in 2.9% eyes. Retinal detachment occurred in 0.9% eyes. CONCLUSIONS: In a Chinese patient group, B-KPro type I is a viable option for treating severe ocular surface disorders in eyes where conventional keratoplasty would have a poor prognosis, especially in patients with chemical and thermal burns. Improved visual outcomes and high retention rate can be achieved and maintained in most cases.

Relative peripheral refraction and its role in myopia onset in teenage students.

AIM: To characterize peripheral refraction and its relationship with myopia development in a selected group of male teenage Chinese students. METHODS: This 2-year prospective cohort study randomly enrolled 85 non-myopic boys (age, 14-16y) from the Experimental Class of Air Force in China. Cycloplegic peripheral refraction was examined at 0°, ±10°, and ±20° along the horizontal visual field in the right eye at the baseline and 2-year follow-up. RESULTS: The incidence of myopia at the 2-year follow-up was 15.29% (13/85). The baseline central refraction (CR) and peripheral refraction at ±10° were significantly lower in students who developed myopia than in those who did not (P<0.05). Relative peripheral refraction (RPR) did not differ between students with and without myopia (P>0.05). At the 2-year follow-up, the RPR at ±10° and 20° nasal was significantly more hyperopic in the myopic group than in the non-myopic group. Multiple linear regression analysis indicated that the change in CR was significantly correlated with the changes in RPR at 20° nasal, 10° nasal, and 20° temporal. Multivariate Logistic regression analysis indicated that the baseline CR [odds ratio (OR): 0.092, 95% confidence interval (CI): 0.012-0.688, P=0.020] and the baseline RPR at 10° nasal (OR: 0.182, 95%CI: 0.042-0.799, P=0.024) were significantly correlated with incident myopia (Omnibus test, χ 2=10.20, P=0.006). CONCLUSION: CR change is significantly correlated with changes in RPR, and students who develop myopia have more relative peripheral hyperopia. More baseline CR and relative peripheral hyperopia at 10° nasal are protective of myopia onset.

Risk Factors for Incident Myopia among Teenaged Students of the Experimental Class of the Air Force in China.

BACKGROUND: In recent decades, the prevalence rate of myopia has markedly increased, especially among teenagers. Our purpose was to determine the incidence of myopia and identify the related risk factors among schoolchildren in the experimental classes of the Air Force in China. METHODS: In May 2015, this 3-year prospective cohort study enrolled 522 boys (age, 14-16 years) attending grade 10 in 16 high schools in 15 cities in China. Cycloplegic refraction was examined using retinoscopy in both eyes at the baseline and follow-up (3 years). A detailed questionnaire was completed by the students at the 3-year follow-up and included questions on parental myopia and on the total time spent doing near work and outdoor activities each week. RESULTS: The incidence of myopia at the 3-year follow-up was 27.01% (141/522, 95% confidence interval (CI): 23.38% to 30.98%). The refractive change was -0.46 D (95% CI: -0.49 to -0.42 D). More hyperopic or less myopic baseline refraction, outdoor activity time per week ≥14 h (odds ratio (OR) = 0.464, 95% CI: 0.227 to 0.950), and reading/writing distance ≥ 30 cm (OR = 0.505, 95% CI: 0.270 to 0.944) were significant protective factors against incident myopia. Near-work time ≥28 h per week was a significant risk factor (OR = 2.579, 95% CI: 1.314 to 5.061). Parental myopia, age at the start of primary school, continuous reading/writing for ≥1 h, sleep duration per week <49 h, and one or more dietary biases were not significant risk factors (P > 0.05). CONCLUSION: A more hyperopic baseline refraction, more time spent outdoors, and longer writing/reading distance were protected against myopia onset, while more near-work time was a risk factor.

Refractive Change and Incidence of Myopia Among A Group of Highly Selected Senior High School Students in China: A Prospective Study in An Aviation Cadet Prerecruitment Class.

Purpose: To assess the incidence rate of myopia, refractive change, and the effects of influencing factors on a group of highly selected senior high school students in an Aviation Cadet prerecruitment class in China. Methods: A total of 800 nonmyopic, male, Grade 9 students aged 14- to 16-years old with cycloplegic refraction of -0.25 or greater diopters (D) to 1.75 D or less in both eyes were enrolled in May 2016. During their senior high school studies, students had one 20-minute physical training period a day, and they were encouraged to participate in outdoor activities during class recess without any time limits. The first follow-up was 8 months after enrollment when they were in Grade 10, and the second follow-up was 1 year after the first follow-up when they were in Grade 11. Comprehensive ocular examinations and a detailed questionnaire, which included questions about outdoor activity time, parental myopia, and near work, were completed at each follow-up. Results: The average spherical equivalent refraction (SER) of the right eyes was 0.39 ± 0.44 D at baseline, 0.16 ± 0.41 D at the first follow-up, and -0.10 ± 0.38 D at the second follow-up. The cumulative refractive change was -0.50 D (95% confidence interval [CI], -0.53 to -0.47). The cumulative incidence rate of myopia was 15.5% (124/800). Incident myopia was significantly associated with outdoor activity for more than 1 versus less than 0.5 hr/d (odds ratio [OR] = 0.272, 95% CI, 0.132-0.560), baseline refraction (OR = 0.079, 95% CI, 0.041-0.153), maternal myopia (OR = 2.251, 95% CI, 1.160-4.368), longer class time (OR =3.215, 95% CI, 1.088-9.499), frequent, continuous, and long time reading/writing (OR = 1.620, 95% CI, 1.022-2.570), and shorter reading/writing distance (OR = 1.828, 95% CI, 1.065-3.140). In multiple linear regression model, having outdoor activity for more than 1 hr/d was protective from cumulative SER decrease. A higher baseline refraction together with longer reading/writing time, frequent, continuous, and longtime reading/writing, and shorter reading/writing distance were risk factors for SER decrease. Conclusions: In this cohort of highly selected, nonmyopic students, longer outdoor activity time was a protective factor for both incident myopia and refractive change of myopic shift. The risk factors for incident myopia included lower hyperopic baseline refraction, more near work, and maternal myopia. The risk factors for refractive change of myopic shift included more hyperopic baseline refraction and more near work.

Indirect comparison between abiraterone acetate and enzalutamide for the treatment of metastatic castration-resistant prostate cancer: a systematic review.

This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR: 0.90, 95% CI, 0.73-1.11; HR: 0.85, 95% CI, 0.68-1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR: 0.34, 95% CI, 0.28-0.42; HR: 0.40, 95% CI, 0.30-0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28-0.48; HR: 0.61, 95% CI, 0.50-0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20-29.88; OR: 10.69, 95% CI, 3.92-29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.

Effects of hydrogen-rich water on depressive-like behavior in mice.

Emerging evidence suggests that neuroinflammation and oxidative stress may be major contributors to major depressive disorder (MDD). Patients or animal models of depression show significant increase of proinflammatory cytokine interleukin-1ß (IL-1ß) and oxidative stress biomarkers in the periphery or central nervous system (CNS). Recent studies show that hydrogen selectively reduces cytotoxic oxygen radicals, and hydrogen-rich saline potentially suppresses the production of several proinflammatory mediators. Since current depression medications are accompanied by a wide spectrum of side effects, novel preventative or therapeutic measures with fewer side effects might have a promising future. We investigated the effects of drinking hydrogen-rich water on the depressive-like behavior in mice and its underlying mechanisms. Our study show that hydrogen-rich water treatment prevents chronic unpredictable mild stress (CUMS) induced depressive-like behavior. CUMS induced elevation in IL-1ß protein levels in the hippocampus, and the cortex was significantly attenuated after 4 weeks of feeding the mice hydrogen-rich water. Over-expression of caspase-1 (the IL-1ß converting enzyme) and excessive reactive oxygen species (ROS) production in the hippocampus and prefrontal cortex (PFC) was successfully suppressed by hydrogen-rich water treatment. Our data suggest that the beneficial effects of hydrogen-rich water on depressive-like behavior may be mediated by suppression of the inflammasome activation resulting in attenuated protein IL-1ß and ROS production.

High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior.

Depression disorder is a common mental illness, of which the pathogenesis is not well understood. Studies suggest that immunity imbalance and up-regulation of pro-inflammatory cytokines may be associated with the pathogenesis of depression. High-mobility group box 1 protein (HMGB1) has gained much attention as an important player in innate immune responses and an modulating factor in several inflammatory diseases. Here we sought to explore the role of HMGB1 in the development of depression. Depression model was established with low dose of lipopolysaccharide (LPS) administration. Depressive behavior was reflected with increased immobility time in tail suspension test. Accompanying with depressive-like behavior, translocation of HMGB1 from nuclei to cytoplasm was observed by immunofluorescence assays. Meanwhile, no significant necrosis was observed evaluated by hematoxylin-eosin staining. These data indicated that HMGB1 was released actively in the central nervous system. In addition, treating the mice with human recombinant HMGB1 (rHMGB1) could induce the development of depressive-like behavior. Blockage of HMGB1 with GZA abrogated the depressive-like behavior induced by LPS or rHMGB1. These results implicated that HMGB1 was involved in LPS-induced depressive-like behavior.

TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress.

Depression is often preceded by exposure to stressful life events. Chronic stress causes perturbations in the immune system, and up-regulates production of proinflammatory cytokines, which has been proposed to be associated with the pathogenesis of clinical depression. However, the potential mechanisms by which stress-induced proinflammatory cytokines lead to the development of depression are not well understood. Here, we sought to screen the main proinflammatory cytokines and the potential mechanisms linking inflammation to depression-like behavior during unpredictable, chronic, mild stress (UCMS), in vivo. Mice were allocated into four groups in each separate experiment: saline-control, saline-UCMS, drug-control and drug-UCMS. Development of depression-like behavior was reflected as a reduction in sucrose preference, and increased immobility in both the forced swim and tail suspension tests. The following drugs were administered intraperitoneally: the pan-anti-inflammatory tetracycline derivative, minocycline (30 mg/kg, daily), the tumor necrosis factor (TNF)α monoclonal antibody, infliximab (10 mg/kg, twice weekly), and the indoleamine 2, 3-dioxygenase (IDO) inhibitor, 1-methyltryptophan (1-MT, 10 mg/mouse, daily). Plasma TNFα, IL-1ß and IL-18 increased significantly after the four-week UCMS exposure. Pretreatment of mice with minocycline completely blocked any upregulation. Concurrent with development of depression-like behaviors, the concentration of TNFα in plasma and the cerebral cortex increased remarkably. The tryptophan-degrading enzyme IDO was up-regulated in the cortex following UCMS exposure. Treatment of mice with minocycline, infliximab or 1-MT prevented the development of depression-like behaviors. Furthermore, blockade of TNFα inhibited expression of IDO and protected cortical neurons from UCMS-induced damage. These results suggest that TNFα plays a critical role in mediating UCMS-induced depression through up-regulation of IDO and subsequent damage of cortical neurons.

Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors.

AIMS: The NLRP3 inflammasome is a cytoplasmic multiprotein complex of the innate immune system that regulates the cleavage of interleukin-1ß and interleukin-18 precursors. It can detect a wide range of danger signals and trigger a series of immune-inflammatory reactions. There were plenty of studies indicating that activation of the immune system played pivotal roles in depression. However, the underlying mechanisms of immune-depression interactions remained elusive and there was no report about the involvement of inflammasome activation in depression. METHODS: We established an acute depression mouse model with lipopolysaccharide to explore the involvement of inflammasome activation in depression. RESULTS: The lipopolysaccharide-treated mice displayed depressive-like behaviors and pro-inflammatory cytokine interleukin-1ß protein and mRNA levels significantly increased. The NLRP3 inflammasome mRNA expression level also significantly elevated in depressed mice brain. Pretreatment with the NLRP3 inflammasome inhibitor Ac-YVAD-CMK significantly abrogated the depressive-like behaviors induced by lipopolysaccharide. CONCLUSION: These data suggest for the first time that the NLRP3 inflammasome is involved in lipopolysaccharide-induced mice depressive-like behaviors. The NLRP3 inflammasome may be a central mediator between immune activation and depression, which raises the possibility that it may be a more specific target for the depression treatments in the near future.