Alpha-melanocyte stimulating hormone protects retinal pigment epithelium cells from oxidative stress through activation of melanocortin 1 receptor-Akt-mTOR signaling.

Patients with age related macular degeneration (AMD) will develop vision loss in the center of the visual field. Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is an important contributor of AMD. In this study, we explored the pro-survival effect of α-melanocyte stimulating hormone (α-MSH) on oxidative stressed RPE cells. We found that α-MSH receptor melanocortin 1 receptor (MC1R) was functionally expressed in primary and transformed RPE cells. RPE cells were response to α-MSH stimulation. α-MSH activated Akt/mammalian target of rapamycin (mTOR) and Erk1/2 signalings in RPE cells, which were inhibited by MC1R siRNA knockdown. α-MSH protected RPE cells from hydrogen peroxide (H2O2)-induced apoptosis, an effect that was almost abolished when MC1R was depleted by siRNA. α-MSH-mediated S6K1 activation and pro-survival effect against H2O2 was inhibited by Akt inhibitors (perifosine, MK-2206 and LY294002). Further, mTOR inhibition by rapamycin, or by mTOR siRNA knockdown, diminished α-MSH's pro-survival effect in RPE cells. Thus, Akt and its downstream mTOR signaling mediates α-MSH-induced survival in RPE cells. In summary, we have identified a new α-MSH-MC1R physiologic pathway that reduces H2O2-induced RPE cell damage, and might minimize the risk of developing AMD.

Squamosamide derivative FLZ protects retinal pigment epithelium cells from oxidative stress through activation of epidermal growth factor receptor (EGFR)-AKT signaling.

Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the pro-survival effect of FLZ in oxidative stressed-RPE cells and studied the underlying signaling mechanisms. Our results showed that FLZ attenuated hydrogen peroxide (H2O2)-induced viability decrease and apoptosis in the RPE cell line (ARPE-19 cells) and in primary mouse RPE cells. Western blotting results showed that FLZ activated AKT signaling in RPE cells. The AKT-specific inhibitor, MK-2206, the phosphoinositide 3-kinase (PI3K)/AKT pan inhibitor, wortmannin, and AKT1-shRNA (short hairpin RNA) depletion almost abolished FLZ-mediated pro-survival/anti-apoptosis activity. We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ-induced AKT activation and the pro-survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H2O2 was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown. In conclusion, FLZ protects RPE cells from oxidative stress through activation of EGFR-AKT signaling, and our results suggest that FLZ might have therapeutic values for AMD.

Ultraviolet (UV) and hydrogen peroxide activate ceramide-ER stress-AMPK signaling axis to promote retinal pigment epithelium (RPE) cell apoptosis.

Ultraviolet (UV) radiation and reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelium (RPE) cells by inducing cell apoptosis, which is the main cause of age-related macular degeneration (AMD). The mechanism by which UV/ROS induces RPE cell death is not fully addressed. Here, we observed the activation of a ceramide-endoplasmic reticulum (ER) stress-AMP activated protein kinase (AMPK) signaling axis in UV and hydrogen peroxide (H2O2)-treated RPE cells. UV and H2O2 induced an early ceramide production, profound ER stress and AMPK activation. Pharmacological inhibitors against ER stress (salubrinal), ceramide production (fumonisin B1) and AMPK activation (compound C) suppressed UV- and H2O2-induced RPE cell apoptosis. Conversely, cell permeable short-chain C6 ceramide and AMPK activator AICAR (5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide) mimicked UV and H2O2's effects and promoted RPE cell apoptosis. Together, these results suggest that UV/H2O2 activates the ceramide-ER stress-AMPK signaling axis to promote RPE cell apoptosis.

Rare and First Manifestation of Lupus Panniculitis as Lupus Mastitis: A Case Report and Literature Review.

INTRODUCTION: This case report presents a rare occurrence of lupus mastitis affecting the breast. CASE PRESENTATION: An induration with mild discomfort was detected in the upper inner quadrant of the right breast of a 27-year-old Chinese woman with regular menstrual cycles. The patient is currently unmarried and has no previous history of full-term pregnancies or lactation. An ill-defined, subcutaneous, hyperechoic lesion with no calcification was visualized on breast ultrasound. Peripheral and internal blood flow signals demonstrated high intensity. Pathological analysis of a breast needle biopsy revealed fat lobule necrosis accompanied by mixed lymphoplasmacytic and histiocytic aggregates. CONCLUSION: The diagnosis of lupus mastitis necessitates a comprehensive evaluation of the patient's medical history, serological testing, imaging studies, and histopathological analysis.

Targeting Keap1 by miR-626 protects retinal pigment epithelium cells from oxidative injury by activating Nrf2 signaling.

Activation of the NF-E2-related factor 2 (Nrf2) cascade can offer significant protection against oxidative stress in retinal pigment epithelium (RPE) cells. Here, we identified a novel kelch-like ECH-associated protein 1 (Keap1)-targeting microRNA, microRNA-626 (miR-626) that activates Nrf2 signaling. In ARPE-19 cells and primary human RPE cells, ectopic overexpression of miR-626 targeting the 3'-UTR (3'-untranslated region) of Keap1 downregulated its expression, promoting Nrf2 protein stabilization and nuclear translocation, leading to expression of ARE-dependent genes (HO1, NOQ1 and GCLC). Functional studies showed that miR-626 protected RPE cells from hydrogen peroxide (H2O2)-induced oxidative injury. Conversely, miR-626 inhibition induced Keap1 upregulation and Nrf2 cascade inhibition, exacerbating oxidative injury in RPE cells. Further studies demonstrated that miR-626 was ineffective in Keap1-knockout or Nrf2-knockout RPE cells. Importantly, miR-626 also activated Keap1-Nrf2 signaling cascade in human lens epithelial cells (HLECs) and primary human retinal ganglion cells (RGCs), providing protection from H2O2. At last, we show that plasma miR-626 levels are significantly downregulated in age-related macular degeneration (AMD) patients than those in the healthy donors. We conclude that targeting Keap1 by miR-626 protects RPE cells and other ophthalmic cells from oxidative injury via activation of Nrf2 signaling cascade.

AMPKα phosphatase Ppm1E upregulation in human gastric cancer is required for cell proliferation.

Activation of AMP-activated protein kinase (AMPK) is a valuable anti-cancer strategy. In the current study, we tested expression and potential function of Ca2+/calmodulin-dependent protein kinase phosphatase (Ppm1E), an AMPKα phosphatase, in human gastric cancers. Ppm1E expression was elevated in human gastric cancer tissues (vs. normal tissues), which was correlated with AMPK (p-AMPKα, Thr-172) dephosphorylation and mTOR complex 1 (mTORC1) activation. Ppm1E upregulation, AMPK inhibition and mTORC1 activation were also observed in human gastric cancer cell lines (AGS, HGC-27, and SNU601). Intriguingly, Ppm1E knockdown by shRNA induced AMPK activation, mTORC1 inactivation, and proliferation inhibition in AGS cells. On the other hand, forced over-expression of Ppm1E induced further AMPK inhibition and mTORC1 activation to enhance AGS cell proliferation. Remarkably, microRNA-135b-5p ("miR-135b-5p"), an anti-Ppm1E microRNA, was downregulated in both human gastric cancer tissues and cells. Reversely, miR-135b-5p exogenous expression caused Ppm1E depletion, AMPK activation, and AGC cell proliferation inhibition. Together, Ppm1E upregulation in human gastric cancer is important for cell proliferation, possible via regulating AMPK-mTOR signaling.

miRNA-141 attenuates UV-induced oxidative stress via activating Keap1-Nrf2 signaling in human retinal pigment epithelium cells and retinal ganglion cells.

Activation of NF-E2-related factor 2 (Nrf2) signaling could protect cells from ultra violet (UV) radiation. We aim to provoke Nrf2 activation via downregulating its inhibitor Keap1 by microRNA-141 ("miR-141"). In both human retinal pigment epithelium cells (RPEs) and retinal ganglion cells (RGCs), forced-expression of miR-141 downregulated Keap1, causing Nrf2 stabilization, accumulation and nuclear translocation, which led to transcription of multiple antioxidant-responsive element (ARE) genes (HO1, NOQ1 and GCLC). Further, UV-induced reactive oxygen species (ROS) production and cell death were significantly attenuated in miR-141-expressing RPEs and RGCs. On the other hand, depletion of miR-141 via expressing its inhibitor antagomiR-141 led to Keap1 upregulation and Nrf2 degradation, which aggravated UV-induced death of RPEs and RGCs. Significantly, Nrf2 shRNA knockdown almost abolished miR-141-mediated cytoprotection against UV in RPEs. These results demonstrate that miR-141 targets Keap1 to activate Nrf2 signaling, which protects RPEs and RGCs from UV radiation.