Effects of non-pharmacological interventions on depressive symptoms and risk of major depressive disorder in adults with subthreshold depression: A systematic review and meta-analysis.

Subthreshold depression (StD) is a condition that significantly reduces the quality of life and increases the risk of developing major depressive disorder (MDD). In order to investigate the effectiveness of non-pharmacological interventions (NPIs) in preventing the onset of MDD and improving depressive symptoms in adults with StD (AStDs), we conducted a systematic search of nine databases and included a total of 15 studies. Standardized mean differences (SMDs) were calculated using random effects models. RoB2 tool and GRADEpro software were used to assess the methodological quality and evidence. Funnel plots, Egger's, and Begg's tests were used to analyze publication bias. Sensitivity, subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity. The results showed that NPIs had a significant effect in preventing the onset of MDD and improving depressive symptoms. Subgroup analysis revealed that NPIs were particularly effective in general adult populations, during short-term follow-up (FU) periods, among pregnant women, and in universal prevention programs. The results were found to be robust and credible, as they were less sensitive to changes in the analysis method. Timely detection and treatment of StD is feasible and important, as it can effectively delay or prevent the onset of MDD.

Retinal Proteomic Analysis in a Mouse Model of Endotoxin-Induced Uveitis Using Data-Independent Acquisition-Based Mass Spectrometry.

Uveitis is a group of sight-threatening ocular inflammatory diseases, potentially leading to permanent vision loss in patients. However, it remains largely unknown how uveitis causes retinal malfunction and vision loss. Endotoxin-induced uveitis (EIU) in rodents is a good animal model to study uveitis and associated acute retinal inflammation. To understand the pathogenic mechanism of uveitis and screen potential targets for treatment, we analyzed the retinal proteomic profile of the EIU mouse model using a data-independent acquisition-based mass spectrometry (SWATH-MS). After systemic LPS administration, we observed activation of microglial cells accompanied with the elevation of pro-inflammatory mediators and visual function declines. In total, we observed 79 upregulated and 90 downregulated differentially expressed proteins (DEPs). Among the DEPs, we found that histone family members (histone H1, H2A, H2B) and blood proteins including haptoglobin (HP), hemopexin (HPX), and fibrinogen gamma chain (FGG) were dramatically increased in EIU groups relative to those in control groups. We identified phototransduction and synaptic vesicle cycle as the top two significant KEGG pathways. Moreover, canonical pathway analysis on DEPs using Ingenuity Pathway Analysis revealed top three most significant enriched pathways related to acute phase response signaling, synaptogenesis signaling, and eif2 signaling. We further confirmed upregulation of several DEPs associated with the acute phase response signaling including HP, HPX, and FGG in LPS-treated retinas by qPCR and Western blot. In summary, this study serves as the first report to detect retinal proteome changes in the EIU model. The study provides several potential candidates for exploring the mechanism and novel therapeutic targets for uveitis and other retinal inflammatory diseases.

MED1 Downregulation Contributes to TGFß-Induced Metastasis by Inhibiting SMAD2 Ubiquitination Degradation in Cutaneous Melanoma.

Metastasis is the main reason for the high mortality of patients and indeed a difficult task in the treatment of cutaneous melanoma. Therefore, it is of great clinical value to explore the molecular mechanism of cutaneous metastatic melanoma and develop novel therapies. MED1, acting as a factor required for activator-dependent transcription, is reported to be involved in carcinogenesis and progression. In this study, we found that MED1 was highly expressed in patients with cutaneous melanoma. MED1 downregulation could induce cellular epithelial-to-mesenchymal transition and promote migration, invasion, and metastasis of cutaneous melanoma in vivo and in vitro. Further analysis showed that in Med1 knockdown cells, the TGFß/SMAD2 signaling pathway mediated an increase in epithelial-to-mesenchymal transition phenotype and migration. The opposite results were observed after treatment with TGFß inhibitors. To further explore the mechanism, we found that MED1 interacted with SMAD2, and MED1 downregulation could protect SMAD2 from degradation by inhibiting SMAD2 ubiquitination. Together, these results suggest that MED1 inhibited TGFß signaling pathway to reduce cell epithelial-to-mesenchymal transition phenotype and migration through SMAD2 ubiquitination in the metastasis of cutaneous melanoma. Our findings elucidated the role of MED1 in the metastasis of cutaneous melanoma and provided a target for the therapeutic strategies of cutaneous melanoma.

Aberrant HO-1/NQO1-Reactive Oxygen Species-ERK Signaling Pathway Contributes to Aggravation of TPA-Induced Irritant Contact Dermatitis in Nrf2-Deficient Mice.

NF-erythroid 2-related factor 2 (Nrf2) is a major transcription factor to protect cells against reactive oxygen species (ROS) and reactive toxicants. Meanwhile, Nrf2 can inhibit contact dermatitis through redox-dependent and -independent pathways. However, the underlying mechanisms of how Nrf2 mediates irritant contact dermatitis (ICD) are still unclear. In this article, we elucidated the role of Nrf2 in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute ICD. Our study demonstrated that the ear thickness, redness, swelling, and neutrophil infiltration were significantly increased, accompanied by increased expression of inflammatory cytokines (IL-1α, IL-1ß, IL-6, etc.) and decreased expression of antioxidant genes (HO-1 and NQO1) in Nrf2 knockout mice. Moreover, ERK phosphorylation was elevated in mouse embryonic fibroblasts (MEFs) from Nrf2 knockout mouse. Inhibition of ERK significantly alleviated TPA-induced cutaneous inflammation and ROS accumulation in MEFs derived from mouse. Conversely, ROS scavenging inhibited the ERK activation and TPA-induced inflammation in MEFs. Taken together, the findings illustrate the key role of the Nrf2/ROS/ERK signaling pathway in TPA-induced acute ICD.

Topical Applications of a Heparinoid-Containing Product Attenuate Glucocorticoid-Induced Alterations in Epidermal Permeability Barrier in Mice.

INTRODUCTION: Either systemic or topical glucocorticoids (GCs) can cause significant adverse effects on cutaneous structure and function. Although some products and ingredients can improve GC-induced abnormalities in epidermal permeability barrier, the efficacy is moderate. Prior studies in normal mice showed that topical applications of a heparinoid-containing product, Hirudoid® cream, improve epidermal barrier function by upregulation of epidermal proliferation, expression of mRNA for epidermal differentiation, and lipid production. OBJECTIVE: The objective of this study was to assess whether topical applications of this product could prevent GC-induced changes in epidermal function in murine skin. MATERIALS AND METHODS: One group of C57BL/6J mice was treated topically with 0.05% clobetasol propionate twice daily for 6 days, while another group was treated topically with Hirudoid® cream 30 min after each application of clobetasol propionate. Untreated mice served as normal controls. Transepidermal water loss (TEWL) rates, stratum corneum hydration, and skin surface pH were measured using respective probes connected to an MPA5 physiology monitor. qPCR was used to measure the expression levels of mRNA for keratinocyte differentiation-related proteins and lipid synthetic enzymes. RESULTS: Co-applications of Hirudoid® cream with GC minimally, but significantly, increased skin thickness in comparison to GC treatment alone (p < 0.05), in parallel with increased expression levels of mRNA for PCNA in both the dermis and the epidermis. Moreover, Hirudoid® cream largely prevented GC-induced elevation in basal TEWL (p < 0.001) and delay in barrier recovery (p < 0.05), accompanied by upregulation in the expression levels of mRNA for epidermal involucrin, HMGCoA, and SPT1. However, both stratum corneum hydration and skin surface pH were comparable in the skin treated with GC alone versus GC + Hirudoid® cream. CONCLUSION: Topical heparinoid-containing product can partially prevent GC-induced alterations in some epidermal functions.

Phospholipase C epsilon mediates cytokine cascade induced by acute disruption of epidermal permeability barrier in mice.

Disruption of epidermal barrier is an important trigger in abnormal cutaneous inflammation. Phospholipase C epsilon (PLCε), a Ras/Rap1 effector, is essential for regulating cytokines production in different types of skin inflammation. Our previous studies have demonstrated that elevated expression of PLCε participates in the psoriasis-like inflammation in PLCε overexpressing transgenic mice model, while the reduction in PLCε expression attenuates inflammatory responses in either TPA- or DNFB-induced cutaneous inflammation. Here, we determined the role of PLCε in cutaneous inflammation induced by acute abrogation of epidermal permeability barrier. In comparison to wild type controls, PLCε KO mice exhibited reduced ear swelling and infiltration of granulocytes after tape-stripping. Moreover, expression levels of pro-inflammatory cytokines (IL-1α, IL-1ß), chemokines (CXCL-1, CXCL-2, CCL20), and antimicrobial peptides (S100 proteins, MBD3) were lower in PLCε-deficient versus wild type mice. Likewise, expression levels of cytokines and chemokines were also lower in PLCε deficient keratinocytes and fibroblasts following IL-22 stimulation in vitro. Furthermore, knockdown of PLCε with its siRNA decreased expression of IL-1α, CCL20, and S100 proteins, and MBD3 in HEK cultures. Collectively, these results suggested that PLCε mediated cytokine cascade induced by acute barrier disruption. IL-22 is likely the upstream of PLCε-mediated cytokine cascade following acute barrier disruption.

The Potential Roles of Exosomal miR-214 in Bone Metastasis of Lung Adenocarcinoma.

Bone metastasis is closely related to the alterations of bone microenvironment. In this article, we hypothesize that exosomes may be involved in the "vicious circle" by transferring miR-214. miR-214 is highly expressed in lung adenocarcinoma, and is closely related to the degree of lung cancer progression. As a key regulator of bone homeostasis, miR-214 promotes osteoclast differentiation and mediates intercellular communication between osteoclasts and osteoblasts via the way of exosomal miRNA. Therefore, it is highly probable that exosomal miR-214 derived from lung adenocarcinoma may disrupt bone homeostasis by enhancing bone resorption. Exosomal miR-214 can be released by lung adenocarcinoma cells, enters peripheral circulation, and is taken up by osteoclasts, consequently stimulating osteoclast differentiation. The enhanced bone resorption alters the bone microenvironment by releasing multiple cytokines and growth factors favoring cancer cells. The circulating cancer cells migrate to bone, proliferate, and colonize, resulting in the formation of metastasis. Furthermore, osteoclasts derived exosomal miR-214 may in turn contribute to cancer progression. In this way, the exosomal miR-214 from osteoclasts and lung adenocarcinoma cells mediates the positive interaction between bone resorption and bone metastasis. The levels of exosomal miR-214 in the peripheral circulation may help predict the risk of bone metastasis. The exosomal miR-214 may be a potential therapeutic target for both prevention and treatment of bone metastasis in patients with lung adenocarcinoma.

Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.

INTRODUCTION: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV. PURPOSE: We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in-vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti-angiogenic consequences in a murine CNV model. MATERIALS AND METHODS: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. RESULTS: Mice treated with PPP, administered intraperitoneally or orally, showed 22-32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter. CONCLUSIONS: PPP reduces IGF-1 dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD.

Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.

INTRODUCTION: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1 and its receptor, IGF-1R, have been implicated in CNV. PURPOSE: A prior study has shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in vivo model. In this study we investigated the effect of PPP on VEGF expression, both in vitro and in vivo, and whether this effect has antiangiogenic consequences in a murine CNV model. METHODS: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in the choroid and retinal pigment epithelial cells (ARPE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. RESULTS: Mice treated with PPP, administered intraperitoneally or orally, showed a 22% to 32% (P = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroid were significantly reduced. In cultured ARPE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. PPP reduced the level of transcriptional activity of the VEGF promoter. CONCLUSIONS: PPP reduces IGF-1-dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the treatment of conditions associated with CNV, including neovascular AMD.

Photochemical damage of the retina.

Visual perception occurs when radiation with a wavelength between 400 and 760 nm reaches the retina. The retina has evolved to capture photons efficiently and initiate visual transduction. The retina, however, is vulnerable to damage by light, a vulnerability that has long been recognized. Photochemical damage has been widely studied, because it can cause retinal damage within the intensity range of natural light. Photochemical lesions are primarily located in the outer layers at the central region of the retina. Two classes of photochemical damage have been recognized: Class I damage, which is characterized by the rhodopsin action spectrum, is believed to be mediated by visual pigments, with the primary lesions located in the photoreceptors; whereas Class II damage is generally confined to the retinal pigment epithelium. The action spectrum peaks in the short wavelength region, providing the basis for the concept of blue light hazard. Several factors can modify the susceptibility of the retina to photochemical damage. Photochemical mechanisms, in particular mechanisms that arise from illumination with blue light, are responsible for solar retinitis and for iatrogenic retinal insult from ophthalmological instruments. Further, blue light may play a role in the pathogenesis of age-related macular degeneration. Laboratory studies have suggested that photochemical damage includes oxidative events. Retinal cells die by apoptosis in response to photic injury, and the process of cell death is operated by diverse damaging mechanisms. Modern molecular biology techniques help to study in-depth the basic mechanism of photochemical damage of the retina and to develop strategies of neuroprotection.

Involvement of caspase-3 in photoreceptor cell apoptosis induced by in vivo blue light exposure.

PURPOSE: To investigate the potential role of caspase-3 in blue light-induced apoptosis in photoreceptor cells. METHODS: Cyclic light-raised Sprague-Dawley rats were exposed to 400 to 480 nm light for 6 hours at an irradiance of 0.64 W/m(2). The rats were then kept in darkness for recovery and killed at scheduled time points from 0 hours up to 24 hours after exposure to light. The unexposed rats were used as the control. Apoptosis was marked with in situ terminal dUTP nick end labeling (TUNEL). Caspase-3 expression was explored using immunohistochemistry, Western blot analysis, real-time RT-PCR, and enzyme activity assay. RESULTS: Exposure to blue light resulted in photoreceptor cell apoptosis, mostly in the superior temporal area of the retina. TUNEL-positive cells were highest during 8 to 16 hours of recovery in darkness. Procaspase-3 protein was constitutively expressed in the rat retina and was apparently upregulated after exposure to light, with expression peaking at 8 to 16 hours and subsiding at 24 hours. The upregulation was further supported by enhanced transcription of caspase-3 in the postexposure retina. Meanwhile, increased cleavage of caspase-3 into its active fragments of 17 and 19 kDa was detected after exposure to light, peaking at 16 hours. Activation of caspase-3 was subsequently located in the photoreceptor cells and predominantly in the superior part of the temporal quadrant. This coincided with elevated caspase-3-like activity at 16 hours after exposure to light. CONCLUSIONS: Procaspase-3 protein is temporally upregulated in the retina after in vivo exposure to blue light, and the upregulation is coupled to activation of caspase-3 and concomitant induction of apoptosis in the photoreceptor cells.