Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.

The Predictive Factors of Combined Implant Application for Breast Cancer Patients Receiving Immediate Breast Reconstruction with a Pedicled Omental Flap.

BACKGROUND: Whether a laparoscopically harvested omental flap is adequate for total breast reconstruction could not be determined preoperativaly due to lack of reliable assessment methods. This study aimed to establish a statistical model to predict the probability of omental flap insufficiency. METHODS: In this study, 200 female patients with breast cancer receiving immediate breast reconstruction with pure pedicled omental flaps or pedicled omental flaps combined with implants after nipple-areolar complex-sparing mastectomy were divided into two groups depending on whether implants were needed or not. The clinical characteristics of these two groups were compared. Correlation of body mass index (BMI) and omental volume was analyzed. Binary logistic regression was performed to predict the probability of implant requirement based on clinical parameters, showing significant differences between the two groups. RESULTS: The patients who needed implants in adjunct treatment were younger. In addition, they had larger breast specimens and smaller omental volumes than the others whose omental flaps were sufficient for total breast reconstruction. Body mass index and omental volume showed a moderately positive correlation. Age, specimen volume, and BMI all were entered into the logistic regression equation. For the patients with a BMI lower than 24.0 kg/m2, the probability of requiring implants was 5.467 times that of comparable patients with a BMI of 24.0 kg/m2 or higher. At the cutoff of 0.61, the regression equation yielded a sensitivity of 84.2% and a specificity of 72.1% in recognizing subjects with the necessity of implant application. CONCLUSION: The combination of BMI, age, and volume of breast specimen could predict with high accuracy whether implants are required for breast cancer patients receiving pedicled omental flap-based breast reconstruction.

LncRNA-MM2P regulates retinal neovascularization through M2 macrophage polarization.

The study aims to investigate the effects and potential mechanisms of lncRNA-MM2P on retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). The OIR model was established in C57BL/6J mice. RAW264.7 cell line and bone marrow-derived macrophages (BMDMs) from mice were used for in vitro studies. RT-qPCR was used to analyze the expressions of lncRNA and mRNAs. The protein expression levels were determined by western blotting. The size of avascular areas and neovascular tufts were assessed based on isolectin B4 immunofluorescence staining images. The human retinal endothelial cells (HRECs) were used to evaluate the proliferation, migration, and tube formation of endothelial cells. The expression of lncRNA-MM2P was significantly upregulated from P17 to P25 in OIR retinas. Knockdown of lncRNA-MM2P levels in vivo led to a significant reduction in the neovascular tufts and avascular areas in the retinas of OIR mice. Knockdown of lncRNA-MM2P levels in vitro suppressed the expression of M2 markers in macrophages. Moreover, we found a significant inhibition of avascular areas and neovascular tufts in OIR mice injected intravitreally with M2 macrophages treated by shRNA-MM2P. The cellular functions of proliferation, migration, and tube formation were significantly attenuated in HRECs cultured with a supernatant of shRNA-MM2P-treated M2 macrophages. Our results indicate that lncRNA-MM2P regulates retinal neovascularization by inducing M2 polarization of macrophages in OIR mice. Therefore, lncRNA-MM2P may be a potential molecular target for immunoregulation of retinal neovascularization.

Comparative proteomic analysis of retinal hypoxia-ischemia in an acute ocular hypertension model using tandem mass tag-based quantitative proteomics.

The main symptom of acute glaucoma is acute ocular hypertension (AOH), which leads to the death of retinal ganglion cells (RGCs) and permanent loss of vision. However, effective treatments for these conditions are lacking. This study aimed to identify major regulators and overall protein changes involved in AOH-induced RGC death. Proteomic patterns of the retinal protein extracts from the AOH and sham groups were analyzed using mass spectrometry (MS), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Proteomic analysis revealed 92 proteins in the AOH group compared to the control group; 58 proteins were upregulated and 34 were downregulated. Alterations in fatty acid-binding protein 7 (FABP7) and caveolin-1 (Cav-1), which are related to fatty acid metabolism and ocular inflammatory signaling, were detected using western blotting and biochemical assays. Variations in the expression of galectin-1 (Gal-1), S100 calcium-binding protein A6 (S100a6), and visinin-like protein-1 (VILIP) have been associated with neuronal ischemia. Our investigation demonstrates that neuroinflammation and fatty acid metabolism are involved in retinal impairment following AOH, suggesting a possible treatment approach for acute glaucoma.

RhoA/ROCK Signaling Is Involved in Pathological Retinal Neovascularization.

OBJECTIVE: The aim of the study was to evaluate the effect of the RhoA/ROCK inhibitor Fasudil on retinal neovascularization (NV) in vivo and angiogenesis in vitro. METHODS: C57BL/6 was used to establish an OIR model. First, RhoA/ROCK expression was first examined and compared between OIR and healthy controls. Then, we evaluated the effect of Fasudil on pathological retinal NV. Whole-mount retinal staining was performed. The percentage of NV area, the number of neovascular tufts (NVT), and branch points (BP) were quantified. Finally, human umbilical vein endothelial cells (HUVECs) were used to investigate the effect of Fasudil on angiogenesis. RESULTS: Real-time PCR and Western blotting showed that ROCK expression in retinal tissue was statistically upregulated in OIR. Furthermore, we found that Fasudil attenuated the percentage of NV area, the number of NVT, and BP significantly. In addition, Fasudil could suppress the proliferation and migration of HUVECs induced by VEGF. CONCLUSIONS: RhoA/ROCK might be involved in the pathogenesis of OIR. And its inhibitor Fasudil could suppress retinal NV in vivo and angiogenesis in vitro. Fasudil may be a potential treatment strategy for retinal vascular diseases.

Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection.

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor ß-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.

PPAR-γ promotes the polarization of rat retinal microglia to M2 phenotype by regulating the expression of CD200-CD200R1 under hypoxia.

BACKGROUND: Recent reports suggest that peroxisome proliferator-activated receptor-γ (PPAR-γ) could promote microglial M2 polarization to inhibit inflammation. However, the specific molecular mechanisms that trigger PPAR-γ's anti-inflammatory ability in microglia are yet to be expounded. Thus, in this study, we aimed to explore the molecular mechanisms behind the anti-inflammatory effects of PPAR-γ in hypoxia-stimulated rat retinal microglial cells. METHODS AND RESULTS: We used shRNA expressing lentivirus to knock down PPAR-γ and CD200 genes, and we assessed hypoxia-induced polarization markers release - M1 (iNOS, IL-1ß, IL-6, and TNF-α) and M2 (Arg-1, YM1, IL-4, and IL-10) by RT-PCR. We also monitored PPAR-γ-related signals (PPAR-γ, PPAR-γ in cytoplasm or nucleus, CD200, and CD200Rs) by Western blot and RT-PCR. Our results showed that hypoxia enhanced PPAR-γ and CD200 expressions in microglial cells. Moreover, PPAR-γ agonist 15d-PGJ2 elevated CD200 and CD200R1 expressions, whereas sh-PPAR-γ had the opposite effect. Following hypoxia, expressions of M1 markers increased significantly, while those of M2 markers decreased, and the above effects were attenuated by 15d-PGJ2. Conversely, knocking down PPAR-γ or CD200 inhibited the polarization of microglial cells to M2 phenotype. CONCLUSION: Our findings demonstrated that PPAR-γ performed an anti-inflammatory function in hypoxia-stimulated microglial cells by promoting their polarization to M2 phenotype via the CD200-CD200R1 pathway.

Influence of decentration of plate-haptic toric intraocular lens on postoperative visual quality.

BACKGROUND: To evaluate the influence of decentration of plate-haptic toric intraocular lens (IOLs) on visual quality. METHODS: This study enrolled 78 eyes of 78 patients. Patients in group A were implanted with toric IOLs, and patients in group B were implanted with monofocal IOLs. All patients were divided into group A1 and B1 (decentration below 0.3 mm) and group A2 and B2 (decentration above 0.3 mm). The uncorrected distance visual acuity (UDVA), best corrected visual acuity (BCVA), modulation transfer function cutoff (MTF cutoff), objective scatter index (OSI), strehl ratio (SR), optical interference and patients' satisfaction were measured in different pupils at three months postoperatively. The associations between decentration and visual quality were analyzed by Spearman correlation. RESULTS: There were no significant differences in UDVA, BCVA, MTF cutoff, OSI, SR, optical interference and patients' satisfaction among subgroups. The differences in decentration between groups A and B were not statistically significant. In group A2, the total higher order aberrations (tHOAs) at pupil sizes of 3 mm (P = 0.046), 5 mm (P = 0.014), spherical aberrations at pupil sizes of 3 mm (P = 0.011), 4 mm (P = 0.014), 5 mm (P = 0.000), secondary astigmatism at pupil sizes of 3 mm (P = 0.002), 4 mm (P = 0.005) were higher than in group B2. Compared to group A1, group A2 had higher spherical aberrations at pupil sizes of 4 mm (P = 0.042), 5 mm (P = 0.001), 6 mm (P = 0.038), secondary astigmatism at pupil sizes of 3 mm (P = 0.013), 4 mm (P = 0.005), 6 mm (P = 0.013). Group B2 has higher coma and secondary astigmatism than group B1 at 6-mm pupil (P = 0.014, P = 0.045). Significant positive correlations were found between spherical aberrations and the decentration of group A1 and A2 at 6-mm pupils. CONCLUSION: The decentration above 0.3 mm negatively affected visual quality due to increased tHOAs, spherical aberrations, coma and secondary astigmatism aberrations, the influence become larger with increasing pupil diameter. And toric IOLs are more affected by decentration than monofocal IOLs.

An artificial intelligence approach to classify pathogenic fungal genera of fungal keratitis using corneal confocal microscopy images.

PURPOSE: Fungal keratitis is a common cause of blindness worldwide. Timely identification of the causative fungal genera is essential for clinical management. In vivo confocal microscopy (IVCM) provides useful information on pathogenic genera. This study attempted to apply deep learning (DL) to establish an automated method to identify pathogenic fungal genera using IVCM images. METHODS: Deep learning networks were trained, validated, and tested using a data set of 3364 IVCM images that collected from 100 eyes of 100 patients with culture-proven filamentous fungal keratitis. Two transfer learning approaches were investigated: one was a combined framework that extracted features by a DL network and adopted decision tree (DT) as a classifier; another was a complete supervised DL model which used DL-based fully connected layers to implement the classification. RESULTS: The DL classifier model revealed better performance compared with the DT classifier model in an independent testing set. The DL classifier model showed an area under the receiver operating characteristic curves (AUC) of 0.887 with an accuracy of 0.817, sensitivity of 0.791, specificity of 0.831, G-mean of 0.811, and F1 score of 0.749 in identifying Fusarium, and achieved an AUC of 0.827 with an accuracy of 0.757, sensitivity of 0.756, specificity of 0.759, G-mean of 0.757, and F1 score of 0.716 in identifying Aspergillus. CONCLUSION: The DL model can classify Fusarium and Aspergillus by learning effective features in IVCM images automatically. The automated IVCM image analysis suggests a noninvasive identification of Fusarium and Aspergillus with clear potential application in early diagnosis and management of fungal keratitis.

CT Scans and Cancer Risks: A Systematic Review and Dose-response Meta-analysis.

BACKGROUND: There is still uncertainty on whether ionizing radiation from CT scans can increase the risks of cancer. This study aimed to identify the association of cumulative ionizing radiation from CT scans with pertaining cancer risks in adults. METHODS: Five databases were searched from their inception to November 15, 2020. Observational studies reporting cancer risks from CT scans in adults were included. The main outcome included quantified cancer risks as cancer case numbers in exposed/unexposed adult participants with unified converted measures to odds ratio (OR) for relative risk, hazard ratio. Global background radiation (2.4 mSv per year) was used as control for lifetime attribution risk (LAR), with the same period from incubation after exposure until survival to 100 years. RESULTS: 25 studies were included with a sum of 111,649,943 participants (mean age: 45.37 years, 83.4% women), comprising 2,049,943 actual participants from 6 studies with an average follow-up period as 30.1 years (range, 5 to 80 years); 109,600,000 participants from 19 studies using LAR. The cancer risks for adults following CT scans were inordinately increased (LAR adults, OR, 10.00 [95% CI, 5.87 to 17.05]; actual adults, OR, 1.17 [95%CI, 0.89 to 1.55]; combined, OR, 5.89 [95%CI, 3.46 to 10.35]). Moreover, cancer risks elevated with increase of radiation dose (OR, 33.31 [95% CI, 21.33 to 52.02]), and multiple CT scan sites (OR, 14.08 [95% CI, 6.60 to 30.05]). The risk of solid malignancy was higher than leukemia. Notably, there were no significant differences for age, gender, country, continent, study quality and studying time phrases. CONCLUSIONS: Based on 111.6 million adult participants from 3 continents (Asia, Europe and America), this meta-analysis identifies an inordinately increase in cancer risks from CT scans for adults. Moreover, the cancer risks were positively correlated with radiation dose and CT sites. The meta-analysis highlights the awareness of potential cancer risks of CT scans as well as more reasonable methodology to quantify cancer risks in terms of life expectancy as 100 years for LAR. PROSPERO TRIAL REGISTRATION NUMBER: CRD42019133487.

Cavin-1 promotes M2 macrophages/microglia polarization via SOCS3.

PURPOSE: Our study aimed to investigate the function of Cavin-1 and SOCS3 in macrophages/microglia M2 polarization and further explored the relevant mechanism. METHODS: Expression levels of Cavin-1 and SOCS3 in macrophages/microglia were measured by western blotting and RT-PCR, respectively. Then, Cavin-1 or SOCS3 was gene silenced by a siRNA approach, and gene silencing efficiency was determined by western blotting. Next, co-immunoprecipitation (Co-IP) was employed to further analyze the interaction between Cavin-1 and SOCS3. Finally, the activation of STAT6/PPAR-γ signaling was evaluated using western blotting, and the M2 macrophages/microglia polarization was validated by measuring the mRNA expression of M2 markers by RT-PCR. RESULTS: In the polarization process of macrophages/microglia to M2 phenotype, both Cavin-1 and SOCS3 increased synchronously at protein and mRNA level, reached the peak at the 6 h, and then decreased. After Cavin-1 or SOCS3 silencing, the expression of Cavin-1 and SOCS3 declined. These results suggested that Cavin-1 and SOCS3 were positively correlated in macrophages/microglia, and this conjecture was verified by Co-IP. Besides, Cavin-1 silencing not only suppressed the activation of STAT6/PPAR-γ pathway, but also suppressed the release of anti-inflammatory factors. Finally, we found that SOCS3 overexpression reversed the inhibitory effect of Cavin-1 silencing on the release of anti-inflammatory factors in M2 macrophages/microglia. CONCLUSIONS: Cavin-1 and SOCS3 are actively involved in the process of M2 macrophages/microglia polarization. As a SOCS3 interacting protein, Cavin-1 can promote M2 macrophages/microglia polarization via SOCS3.

New Function of Cholesterol Oxidation Products Involved in Osteoporosis Pathogenesis.

Osteoporosis (OP) is a systemic bone disease characterized by decreased bone strength, microarchitectural changes in bone tissues, and increased risk of fracture. Its occurrence is closely related to various factors such as aging, genetic factors, living habits, and nutritional deficiencies as well as the disturbance of bone homeostasis. The dysregulation of bone metabolism is regarded as one of the key influencing factors causing OP. Cholesterol oxidation products (COPs) are important compounds in the maintenance of bone metabolic homeostasis by participating in several important biological processes such as the differentiation of mesenchymal stem cells, bone formation in osteoblasts, and bone resorption in osteoclasts. The effects of specific COPs on mesenchymal stem cells are mainly manifested by promoting osteoblast genesis and inhibiting adipocyte genesis. This review aims to elucidate the biological roles of COPs in OP development, starting from the molecular mechanisms of OP, pointing out opportunities and challenges in current research, and providing new ideas and perspectives for further studies of OP pathogenesis.

Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity?-A Case-Control Study.

BACKGROUND: As effective medication to treat COVID-19 is currently unavailable, preventive remedies may be particularly important. OBJECTIVE: To examine the relationship between serum 25-hydroxy vitamin D (25(OH)D) level and COVID-19 infection, its severity, and its clinical case characteristics. METHODS: This case-control study compared serum 25(OH)D levels and rates of vitamin D deficiency (VDD) between 80 healthy controls and 62 patients diagnosed with COVID-19 and admitted to Guangxi People's Hospital, China, 2/16/2020-3/16/2020. Cases were categorized into asymptomatic, mild/moderate, and severe/critical disease. Logistic regression analysis was conducted to examine the associations between 25(OH)D level, or VDD, and case status/severity of COVID-19 while controlling for demographics and comorbidities. A threshold level of vitamin D for conveying COVID-19 risk was estimated. RESULTS: Severe/critical COVID-19 cases were significantly older and had higher percentages of comorbidity (renal failure) compared to mild cases. The serum 25(OH)D concentration in COVID-19 patient was much lower than that in healthy control. And 25(OH)D level was the lowest in severe/critical cases, compared with mild cases. In further, significantly higher rates of VDD were found in COVID-19 cases (41.9%) compared to healthy controls (11.1%). And VDD was the greatest in severe/critical cases (80%), compared with mild cases (36%). These statistically significant associations remained even after controlling for demographics and comorbidities. A potential threshold of 25(OH)D (41.19 nmol/L) to protect against COVID-19 was identified. CONCLUSION: Elderly and people with comorbidities were susceptible to severe COVID-19 infection. VDD was a risk factor for COVID-19, especially for severe/critical cases. While further confirmation is needed, vitamin D supplementation may have prevention or treatment potential for COVID-19 disease.

Identification and functional analysis of a novel missense mutation of PAX3 associated with Waardenburg syndrome type I.

PURPOSE: Waardenburg syndrome type 1 (WS1) is a rare genetic disorder characterized by dystopia canthorum, abnormal iris pigmentation, and congenital hearing loss with variable penetrance.WS1 is caused by mutations in paired box gene 3 (PAX3). The current study aimed to investigate the genetic cause of hearing loss in a four-generation Chinese WS1 family. METHODS: The phenotype of the study family was characterized using clinical evaluation and pedigree analysis. Target region high-throughput sequencing system was designed to screen the all coding exons and flanking intronic sequences of the six WS-associated genes. Sanger sequencing was used to identify the causative nucleotide changes and perform the co-segregating analysis. The expression, subcellular distribution, and transcriptional activity of the mutant PAX3 protein were analysis to reveal the functional consequences of the mutation. RESULTS: Based on diagnostic criteria, the proband of this pedigree classified as WS1. We identified a novel missense mutation (c.117 C > A, p. Asn39Lys) in exon 2 of the PAX3 gene. In vitro, the Asn39Lys PAX3 retained nuclear distribution ability. However, it failed to activate the melanocyte inducing transcription factor (MITF) promoter and impaired the function of WT PAX3. CONCLUSIONS: Our study reports a novel missense PAX3 mutation in a Chinese family and shows haploinsufficiency may be the underlying mechanism for the WS1 phenotype.

Fasudil attenuates glial cell-mediated neuroinflammation via ERK1/2 and AKT signaling pathways after optic nerve crush.

To investigate the functional role of fasudil in optic nerve crush (ONC), and further explore its possible molecular mechanism. After ONC injury, the rats were injected intraperitoneally either with fasudil or normal saline once a day until euthanized. RGCs survival was assessed by retrograde labeling with FluoroGold. Retinal glial cells activation and population changes (GFAP, iba-1) were measured by immunofluorescence. The expressions of cleaved caspase 3 and 9, p-ERK1/2 and p-AKT were detected by western blot. The levels of the pro-inflammatory cytokines were determined using real-time polymerase chain reaction. Fasudil treatment inhibited RGCs apoptosis and reduced RGCs loss demonstrated by the decreased apoptosis-associated proteins expression and the increased fluorogold labeling of RGCs after ONC, respectively. In addition, the ONC + fasudil group compared had a significantly lower expression of GFAP and iba1 compared with the ONC group. The levels of pro-inflammatory cytokines were significantly reduced in the ONC + fasudil group than in the ONC group. Furthermore, the phosphorylation levels of ERK1/2 and AKT (p-ERK1/2 and p-AKT) were obviously elevated by the fasudil treatment. Our study demonstrated that fasudil attenuated glial cell-mediated neuroinflammation by up-regulating the ERK1/2 and AKT signaling pathways in rats ONC models. We conclude that fasudil may be a novel treatment for traumatic optic neuropathy.

Anti-secretogranin III therapy of oxygen-induced retinopathy with optimal safety.

Retinopathy of prematurity (ROP) with pathological retinal neovascularization is the most common cause of blindness in children. ROP is currently treated with laser therapy or cryotherapy, both of which may adversely affect the peripheral vision with limited efficacy. Owing to the susceptibility of the developing retina and vasculatures to pharmacological intervention, there is currently no approved drug therapy for ROP in preterm infants. Secretogranin III (Scg3) was recently discovered as a highly disease-restricted angiogenic factor, and a Scg3-neutralizing monoclonal antibody (mAb) was reported with high efficacy to alleviate oxygen-induced retinopathy (OIR) in mice, a surrogate model of ROP. Herein we independently investigated the efficacy of anti-Scg3 mAb in OIR mice and characterized its safety in neonatal mice. We developed a new Scg3-neutralizing mAb recognizing a distinct epitope and independently established the therapeutic activity of anti-Scg3 therapy to alleviate OIR-induced pathological retinal neovascularization in mice. Importantly, anti-Scg3 mAb showed no detectable adverse effects on electroretinography and developing retinal vasculature. Furthermore, systemic anti-Scg3 mAb induced no renal tubular injury or abnormality in kidney vessel development and body weight gain of neonatal mice. In contrast, anti-vascular endothelial growth factor drug aflibercept showed significant side effects in neonatal mice. These results suggest that anti-Scg3 mAb may have the safety and efficacy profiles required for ROP therapy.

Antiapoptotic properties of MALT1 protease are associated with redox homeostasis in ABC-DLBCL cells.

Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) protease presents crucial antiapoptotic properties in activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL); however, the mechanism is unclear. Here, we reported that inhibition of MALT1 protease in ABC-DLBCL cells led to cell apoptosis, along with elevated mitochondrial reactive oxygen species production and a reduced oxygen consumption rate. These alterations induced by MALT1 protease inhibition were associated with reduced expression of glutaminase (GLS1) and glutathione levels. We further show that MALT1 protease was required for the activation and nuclear translocation of c-Jun, which functions as a transcription factor of the GLS1 gene by binding directly to its promoter region. Taken together, MALT1 protease maintained mitochondrial redox homeostasis and mitochondrial bioenergetics through the MALT1-c-Jun-GLS1-coupled metabolic pathway to defend against apoptosis in ABC-DLBCL cells, which raises exciting possibilities regarding targeting of the MALT1-c-Jun-GLS1 axis as a potential therapeutic strategy against ABC-DLBCL.

MiR-591 functions as tumor suppressor in breast cancer by targeting TCF4 and inhibits Hippo-YAP/TAZ signaling pathway.

BACKGROUND: MicroRNAs have been involved in regulating crucial biological function in some tumors. However, the clinical role and functional effects of miR-591 in breast cancer remain unknown. METHODS: The expression of miR-591 was detected in breast cancer tissues and their paired normal tissues by qRT-PCR. Functional assays were performed to confirm the effects of miR-591 on the proliferation and invasion of breast cancer. Bioinformatics analysis, luciferase reporter assays, western blot and in vitro assays were used to confirm that TCF4 was a target gene of miR-591. Western blot analysis was carried out to analyze the relationship between miR-591 expression and YAP1 expression in breast cancer. RESULTS: We found that miR-591 expression levels were significantly downregulated in breast cancer tissues compared to adjacent normal tumor tissues. Lower miR-591 expression notably related to lymph node metastasis and advanced TNM stage in patients with breast cancer. In vitro, cell proliferation and invasion were inhibited by transfection of miR-591 mimic in breast cancer cells, but were promoted by transfection of miR-591 inhibitor, compared to the controls. In vivo, we also found that miR-591 mimic significantly inhibited cell proliferation ability. Moreover, we identified that TCF4 was a direct target of miR-591 in breast cancer. TCF4 mediated the inhibiting effects of miR-591 on cell proliferation and invasion in breast cancer cells. In additional, we revealed that miR-591 overexpression significantly inhibited the Hippo-YAP/TAZ signaling pathway in breast cells by downregulated YAP1 expression in breast cells. CONCLUSION: Together, these results indicated that miR-591 is downregulated in breast cancer and could act as a potential target of breast cancer treatment.

Comparison of subfoveal choroidal thickness in eyes with CRVO and BRVO.

BACKGROUND: To evaluate the subfoveal choroidal thickness (SFCT) in eyes with macular edema (ME) secondary to retinal vein occlusion(RVO), and to investigate the short term response after a single intravitreal ranibizumab (IVR) injection. What is more, to compare SFCT and SFCT change between central RVO (CRVO) and branch RVO (BRVO). METHODS: In the retrospective study, we had collected 36-six treatment-naïve patients with unilateral ME secondary to RVO (including 19 CRVO and 17 BRVO). All patients had received IVR injection after newly diagnosed. The SFCT was measured at the onset and after 2 weeks of IVR injection. Paired t test was performed to compare the SFCT of RVO eyes and fellow eyes, as well as the SFCT of pre-injection and post-injection. In further, independent t test was used to compare SFCT and SFCT change between CRVO eyes and BRVO eyes. RESULTS: The mean SFCT at the onset was 326.03 ± 30.86 µm in CRVO eyes, which was significantly thicker than that in contralateral fellow eyes (p < 0.01, paired t test), and reduced to 294.15 ± 30.83 µm rapidly after 2 weeks of IVR injection (p < 0.01, paired t test). Similarly, the SFCT in BRVO eyes was significantly thicker than that in contralateral eyes at the onset, and decreased significantly after IVR injection. However, our findings showed that there was no statistically significant difference in SFCT and SFCT reduction after IVR injection between CRVO eyes and BRVO eyes. CONCLUSIONS: The SFCT in eyes with ME secondary to CRVO and BRVO was significantly thicker than that in fellow eyes, and decreased significantly within a short time in response to a single IVR injection. In further, the study showed that SFCT and SFCT change had no correlation with RVO subtypes.

Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway.

Secretogranin III (Scg3) was recently discovered as the first highly diabetic retinopathy-associated angiogenic factor, and its neutralizing antibody alleviated the disease with high efficacy in diabetic mice. Investigation of its molecular mechanisms will facilitate the translation of this novel therapy. Scg3 was reported to induce the phosphorylation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Here we characterized the importance of MEK/ERK activation to Scg3 angiogenic activity. Our results showed that MEK inhibitor PD98059 blocked Scg3-induced proliferation of human umbilical vein endothelial cells (HUVECs). This finding was corroborated by PD98059 inhibition of HUVEC migration and tube formation. Furthermore, ERK inhibitor SCH772984 also suppressed Scg3-induced proliferation and migration of HUVECs. Taken together, these findings suggest that MEK-ERK pathway plays an important role in Scg3-induced angiogenesis.