Chemokines in diabetic eye disease.

BACKGROUND: Diabetic eye disease is a common micro-vascular complication of diabetes and a leading cause of decreased vision and blindness in people of working age worldwide.Although previous studies have shown that chemokines system may be a player in pathogenesis of diabetic eye disease, it is unclear which chemokines play the most important role.To date, there is no meta-analysis which has investigated the role of chemokines in diabetic eye disease.We hope this study will contribute to a better understanding of both the signaling pathways of the chemokines in the pathophysiological process, and more reliable therapeutic targets for diabetic eye disease. METHODS: Embase, PubMed, Web of Science and Cochrane Library systematically searched for relevant studies from inception to Sep 1, 2023. A random-effect model was used and standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated to summarize the associated measure between chemokines concentrations and diabetic eye disease. Network meta-analysis to rank chemokines-effect values according to ranked probabilities. RESULTS: A total of 33 different chemokines involving 11,465 subjects (6559 cases and 4906 controls) were included in the meta-analysis. Results of the meta-analysis showed that concentrations of CC and CXC chemokines in the diabetic eye disease patients were significantly higher than those in the controls. Moreover, network meta-analysis showed that the effect of CCL8, CCL2, CXCL8 and CXCL10 were ranked highest in terms of probabilities. Concentrations of CCL8, CCL2, CXCL8 and CXCL10 may be associated with diabetic eye disease, especially in diabetic retinopathy and diabetic macular edema. CONCLUSION: Our study suggests that CCL2 and CXCL8 may play key roles in pathogenesis of diabetic eye disease. Future research should explore putative mechanisms underlying these links, with the commitment to develop novel prophylactic and therapeutic for diabetic eye disease.

A PARP14/TARG1-Regulated RACK1 MARylation Cycle Drives Stress Granule Dynamics in Ovarian Cancer Cells.

Mono(ADP-ribosyl)ation (MARylation), a post-translational modification (PTM) of proteins, is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, a member of the tryptophan-aspartate repeat (WD-repeat) family of proteins and an integral component of the ribosome, is MARylated by the mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. We mapped and confirmed the sites of MARylation, which occur on three acidic residues within blades 4 and 5 of ß-propeller domain of RACK1, a chaperone that shuttles and anchors proteins where needed. Site-specific MARylation of RACK1 is required for stress granule formation and promotes the colocalization of RACK1 to stress granules with key components, such as G3BP1, eIF3η, and 40S ribosomal proteins. In parallel, we observed reduced translation of a subset of mRNAs, including those encoding key cancer regulators (e.g., AKT). Treatment with a PARP14 inhibitor or mutation of the sites of MARylation on RACK1 blocks these outcomes. To re-set the system after prolonged stress and recovery, the ADP-ribosyl hydrolase TARG1 deMARylates RACK1 to dissociate the stress granules and return RACK1 and the 40S ribosomal subunit to the cytoplasm, allowing for a restoration of translation. Collectively, our results highlight the discovery of a PARP14/TARG1-regulated RACK1 MARylation cycle that controls stress granule assembly and disassembly in ovarian cancer cells.

Comparative effectiveness of oseltamivir versus peramivir for hospitalized children (aged 0-5 years) with influenza infection.

OBJECTIVES: The effectiveness of oseltamivir versus peramivir in children infected with influenza remains unclear. This study aimed to evaluate their effectiveness in young children (aged 0-5 years) infected with severe influenza A virus (IAV) or influenza B virus (IBV). METHODS: We analyzed a cohort of 1662 young children with either IAV (N = 1095) or IBV (N = 567) who received oseltamivir or peramivir treatment from January 1, 2018 to March 31, 2022. Propensity score matching methods were applied to match children who were oseltamivir-treated versus peramivir-treated. RESULTS: Children who were IAV-infected and IBV-infected shared similar features, such as influenza-associated symptoms and comorbidities at baseline. Among children infected with IAV with bacterial coinfection, the recovery rate was significantly greater in children treated with oseltamivir than in children treated with peramivir (15.6% vs 4.4%, P = 0.01). The median duration of hospitalization was also shorter in children treated with oseltamivir. Among children infected with IAV without bacterial coinfection, the recovery rate was greater in children treated with oseltamivir than in children treated with peramivir (21.1% vs 3.7%, P = 0.002). However, oseltamivir and peramivir offered similar recovery rates and duration of hospitalization (P >0.05 for both) among children infected with IBV. CONCLUSION: Oseltamivir and peramivir exhibit similar effectiveness in young children with severe influenza B, whereas oseltamivir demonstrated improved recovery and shorter hospitalization in the treatment of severe influenza A in hospitalized children.

Glucagon-like peptide-1 receptor agonists as add-on therapy to insulin for type 1 diabetes mellitus.

Background: To assess the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) used as an adjunct to insulin therapy in adults with type 1 diabetes. Methods: A search of electronic databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) from 1 January 1950 to 23 May 2021 was conducted to find randomized controlled trials. The primary outcome was the change in HbA1c. Eight efficacy and six safety secondary endpoints were evaluated via meta-analysis. Weighted mean difference (WMD) and odds ratio (OR), alongside 95% confidence interval (CI), were calculated using the random effects model. Results: Among 1,379 candidate studies, 11 trials comprising 2,856 participants satisfied the inclusion criteria. Overall, GLP-1 RA adjunctive therapy reduced HbA1c by -0.21% (95% CI, -0.33 to -0.10), weight by -4.04 kg (-4.8 to -3.27), systolic pressure by -2.57 mmHg (-4.11 to -1.03), and diastolic blood pressure by -1.02 mmHg (-1.99 to -0.06). In addition, there was a decrease in prandial insulin dose (WMD, -4.23 IU; 95% CI, -5.26 to -3.20), basal insulin dose (-2.40 IU; -3.93 to -0.87), and total insulin dose (-5.73 IU; -10.61 to -0.86). Moreover, GLP-1 RAs did not increase the incidence of severe hypoglycemia, diabetic ketoacidosis, or severe adverse events. However, GLP-1 RAs increased the incidence of gastrointestinal adverse events (OR, 2.96; 95% CI, 2.33-3.77). Conclusion: Our meta-analysis of randomized clinical trials suggests moderate beneficial effects of GLP-1 RAs on the metabolic profile in patients with type 1 diabetes, without an increased risk of serious adverse events. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO; Identifier: CRD 42020199840.

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In order to explore the mechanism underlying zinc (Zn) accumulation and tolerance in woody garden species, the effects of different Zn concentrations (0, 250, 500, 1000, 2000 mg·kg-1) on leaf, branch, root biomass and leaf ultrastructure of Koelreuteria paniculata, Ailanthus altissima, and Ginkgo biloba were studied in a pot pollution simulation experiment. The concentration of Zn in plant organs, the subcellular distribution and chemical forms of Zn in leaves and roots were further analyzed. The results showed that all the three species could survive under diffe-rent Zn concentrations, but the biomass of leaves, stems and roots decreased compared with the control. Excessive Zn could lead to cell deformation, cell wall rupture and organelle disintegration of leaves in K. paniculata and A. altissima, while the cells in leaves of G. biloba could maintain normal morphology, indicating that G. biloba had a better tolerance to Zn than K. paniculata and A. altissima. With the increases of Zn concentration, Zn concentration in the organs of the three species showed an increasing trend, and the Zn concentration in K. paniculata and A. altissima was significantly higher than that in G. biloba, indicating that the Zn accumulation ability of K. paniculata and A. altissima was stronger than that of G. biloba. Zn was mainly distributed in the cell walls of leaves and roots, accounting for 26.9%-71.8% and 28.1%-82.6%, respectively. Under the treatment with the highest Zn concentration (2000 mg·kg-1), Zn concentration in the soluble components (mainly vacuoles) could be higher than that in the cell walls. In addition, Zn mainly existed in NaCl-, HAc- and HCl-extracted forms in leaves, accounting for 57.4%-82.7%, and Zn mainly existed in NaCl- and HAc-extracted forms in roots, accounting for 42.8%-67.2%, all of which were forms with relatively low activity. Therefore, cell wall retention, vacuoles segregation and accumulating Zn in less active forms might be important mechanisms underlying Zn accumulation and tolerance in the three trees.

Circ_0057558 promotes nonalcoholic fatty liver disease by regulating ROCK1/AMPK signaling through targeting miR-206.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver disorders that is featured by the extensive deposition of fat in the hepatocytes. Current treatments are very limited due to its unclear pathogenesis. Here, we investigated the function of circ_0057558 and miR-206 in NAFLD. High-fat diet (HFD) feeding mouse was used as an in vivo NAFLD model and long-chain-free fatty acid (FFA)-treated liver cells were used as an in vitro NAFLD model. qRT-PCR was used to measure levels of miR-206, ROCK1 mRNA, and circ_0057558, while Western blotting was employed to determine protein levels of ROCK1, p-AMPK, AMPK, and lipogenesis-related proteins. Immunohistochemistry were performed to examine ROCK1 level. Oil-Red O staining was used to assess the lipid deposition in cells. ELISA was performed to examine secreted triglyceride (TG) level. Dual-luciferase assay was used to validate interactions of miR-206/ROCK1 and circ_0057558/miR-206. RNA immunoprecipitation was employed to confirm the binding of circ_0057558 with miR-206. Circ_0057558 was elevated while miR-206 was reduced in both in vivo and in vitro NAFLD models. miR-206 directly bound with ROCK1 3'-UTR and suppressed lipogenesis and TG secretion through targeting ROCK1/AMPK signaling. Circ_0057558 directly interacted with miR-206 to disinhibit ROCK1/AMPK signaling. Knockdown of circ_0057558 or overexpression of miR-206 inhibited lipogenesis, TG secretion and expression of lipogenesis-related proteins. ROCK1 knockdown reversed the effects of circ_0057558 overexpression. Injection of miR-206 mimics significantly ameliorated NAFLD progression in vivo. Circ_0057558 acts as a miR-206 sponge to de-repress the ROCK1/AMPK signaling and facilitates lipogenesis and TG secretion, which greatly contributes to NAFLD development and progression.

Chemokines in Type 1 Diabetes Mellitus.

BACKGROUND: Previous studies suggested that chemokines may play an important role in the formation and mediation of immune microenvironments of patients affected by Type 1 Diabetes Mellitus (T1DM). The aim of this study was to summarise available evidence on the associations of different chemokines with T1DM. METHODS: Following PRISMA guidelines, we systematically searched in PubMed, Web of Science, Embase and Cochrane Library databases for studies on the associations of different chemokines with T1DM. The effect size of the associations were the standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) of the chemokines concentrations, calculated as group differences between the T1DM patients and the controls. These were summarized using network meta-analysis, which was also used to rank the chemokines by surface under cumulative ranking curve (SUCRA) probabilities. RESULTS: A total of 32 original studies on the association of different chemokines with T1DM were identified. Fifteen different chemokine nodes were compared between 15,683 T1DM patients and 15,128 controls, and 6 different chemokine receptor nodes were compared between 463 T1DM patients and 460 controls. Circulating samples (blood, serum, and plasma) showed that concentrations of CCL5 and CXCL1 were significantly higher in the T1DM patients than in the controls (SMD of 3.13 and 1.50, respectively). On the other hand, no significant difference in chemokine receptors between T1DM and controls was observed. SUCRA probabilities showed that circulating CCL5 had the highest rank in T1DM among all the chemokines investigated. CONCLUSION: The results suggest that circulating CCL5 and CXCL1 may be promising novel biomarkers of T1DM. Future research should attempt to replicate these findings in longitudinal studies and explore potential mechanisms underlying this association.

[Adenovirus pneumonia with hemophagocytic lymphohistiocytosis in children: a clinical analysis of 7 children].

OBJECTIVE: To study the clinical features of children with adenovirus pneumonia and hemophagocytic lymphohistiocytosis (HLH). METHODS: A retrospective analysis was performed on the mediacal data of 7 children with adenovirus pneumonia and HLH from March to September, 2019. RESULTS: The age of these children ranged from 11 months to 5 years, and among these children, 5 were aged <2 years and 5 were boys. None of these children had underlying diseases. All children were hospitalized due to persistent high fever and cough, and the peak temperature of fever was 39°C to 41°C. With disease progression, 7 children developed hepatomegaly and 6 developed splenomegaly. Routine blood test results showed reductions in two or three lineages of blood cells, with increases in serum ferritin (SF), C-reactive protein (CRP), procalcitonin (PCT), and lactate dehydrogenase (LDH). Phagocytosis of blood cells was observed in 6 children. Radiological examination of lungs showed pneumonia changes. All 7 children were diagnosed with human adenovirus type 7 infection based on pathogenic metagenome detection. No abnormality was found by HLH gene detection and the children were diagnosed with secondary HLH. All children received intravenous immunoglobulin. Among these children, 4 received dexamethasone and etoposide chemotherapy, 3 received dexamethasone alone, and 4 received plasma exchange. Of the 7 children, 2 died and 5 were recovered. Compared with those who survived, the children who died had significantly greater reductions in the three lineages of blood cells and significantly greater increases in serum levels of CRP, PCT, SF, and LDH. CONCLUSIONS: The children with adenovirus pneumonia and HLH have main clinical features of persistent high fever, progressive reductions in two or three lineages of peripheral blood cells, and involvement of other organ systems, including hepatosplenomegaly. Significant increases in serum levels of CRP, PCT, SF, and LDH may suggest a poor prognosis.

LncRNA NEAT1 promotes hepatic lipid accumulation via regulating miR-146a-5p/ROCK1 in nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease, which influences the health of people worldwide. However, the specific mechanism of the disease remains unknown, and effective treatments are still lacking. It was reported that Nuclear enriched abundant transcript 1 (NEAT1) obviously was up-regulated in NAFLD model. But the role and underlying mechanism of NEAT1 in NAFLD is unclear. METHODS: HepG2 cells were treated by free fatty acids (FFA) and C57BL/6J mice were treated by high-fat diet to establish NAFLD in vitro and in vivo models, respectively. Cell transfection was applied to regulate the expression of NEAT1, ROCK1, and miR-146a-5p. Western blotting and qRT-PCR were used for measuring expression of protein and mRNA level, respectively. Dual luciferase assay was used to detect the target relationship. Oil Red O staining was used to measure the lipid accumulation. HE staining was used for observing pathological feature of liver tissues. RESULTS: High levels of NEAT1 and ROCK1, and low level of miR-146a-5p were identified in NAFLD models. NEAT1 could target miR-146a-5p to promote ROCK1 expression. Knockdown of NEAT1, overexpression of miR-146a-5p and knockdown of ROCK1 inhibited lipid accumulation through activating AMPK pathway. CONCLUSION: NEAT1 may regulate NAFLD through miR-146a-5p targeting ROCK1, and further affect AMPK/SREBP pathway. This study may provide a new thought for the treatment of NAFLD.

Aromatase excess syndrome in a Chinese boy due to a novel duplication at 15q21.2.

Background Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder caused by CYP19A1 overexpression. Clinical manifestations of AEXS include pre- or peri-pubertal gynecomastia, advanced bone age and compromised adult height. Case presentation Here we report an 8-year-old boy diagnosed with AEXS by chromosomal array that revealed a 1.1 Mb novel de novo duplication at 15q21.2, with a predicted final height of 157.4 cm. We prescribed letrozole and growth hormone (GH) to maximize his linear growth. Without further bone age advancement, his height increased from 137.7 cm to 144 cm after an 8-month treatment period. Conclusions We identified a novel duplication at 15q21.2 in AEXS, and found that aromatase inhibitor (AI) plus GH might provide a better growth-promoting approach for AEXS patients.

Serum levels of omentin-1 are increased after weight loss and are particularly associated with increases in obese children with metabolic syndrome.

AIM: There have been very few paediatric studies on omentin-1, an anti-inflammatory adipokine that provides a link between adiposity, insulin resistance and metabolic syndrome. This Chinese study evaluated the association between omentin-1 and metabolic syndrome and analysed the effect of a six-month lifestyle intervention on the levels in obese children. METHODS: We recruited 119 obese outpatients (75% boys) aged 7-18 years from the Second Affiliated Hospital of Xi'an Jiaotong University, who underwent a six- month lifestyle intervention. Our controls were 55 matched children with normal weight. Anthropometric parameters, biochemical data and circulating omentin-1 levels were measured at baseline and after six months. RESULTS: Of the 119 obese children, 32 (27%) had metabolic syndrome. The obese children, particularly those with metabolic syndrome, had significantly lower serum omentin-1 levels at baseline than the controls. We also found that the omentin-1 levels were negatively associated with their body mass index, waist circumference and homoeostasis model assessment of insulin resistance. After the six-month lifestyle intervention, the obese children showed significant weight loss and their omentin-1 levels increased. CONCLUSION: Serum omentin-1 was regulated by weight and seemed to be associated with children's metabolic disorders. A six-month lifestyle intervention significantly increased serum omentin-1 levels.

Metformin ameliorates hepatic steatosis and improves the induction of autophagy in HFD­induced obese mice.

The present study aimed to investigate the effect of metformin on the induction of autophagy in the liver and adipose tissues of a mouse model of obesity. C57BL/6J mice were fed a high­fat diet (HFD) for 12 weeks to induce obesity­associated hepatic steatosis, and treated with metformin (150 mg/kg/d) by intraperitoneal injection for the final 4 weeks of HFD feeding. Body weight was recorded weekly, and the food intake of the mice was recorded daily during the treatment period. Liver and adipose tissues were harvested for histological and molecular analyses. The results revealed that metformin significantly reduced body weight without altering food intake in the HFD mice, particularly in the epididymal white adipose tissue (eWAT). Metformin treatment ameliorated HFD­induced hepatic steatosis and serum levels of triglycerides, which was consistent with a marked increase in the expression levels of microtubule­associated protein 1 light chain 3 (LC3) and AMP­activated protein kinase (AMPK) in the liver following metformin treatment. However, metformin suppressed the expression of LC3 in the eWAT without altering the expression of AMPK, compared with that in the HFD mice. In conclusion, metformin reduced the body weight and hepatic steatosis of the HFD­induced obese mice, without altering food intake. The effects of metformin treatment may be attributable to the improved induction of hepatic autophagy and the inhibited induction of adipose tissue autophagy.

TNF-α downregulates CIDEC via MEK/ERK pathway in human adipocytes.

OBJECTIVE: Cell death-inducing DFF45-like effector C (CIDEC) is a lipid droplet-coating protein that promotes triglyceride accumulation and inhibits lipolysis. TNF-α downregulates CIDEC levels to enhance basal lipolysis, whereas CIDEC overexpression could block this effect. This study aimed to investigate the signaling pathway of TNF-α-mediated CIDEC downregulation in human adipocytes. METHODS: First CIDEC expression was detected in adipose tissue of lean and human subjects with obesity. Next, the temporal- and dose-dependent effects of TNF-α on CIDEC expression in human SW872 adipocytes were investigated. Selective inhibitors or RNAi or constitutively active MEK1 mutant was used to suppress or stimulate MEK/ERK cascade. Immunofluorescence and subcellular fractionation technique were used to study PPARγ redistribution after TNF-α treatment. Reporter assay was performed to confirm the direct effects of TNF-α on CIDEC transcription. RESULTS: CIDEC expression decreased in adipose tissue of subjects with obesity and negatively correlated with adipose TNF-α levels and systemic lipolysis. TNF-α reduced CIDEC expression in vitro, but suppression of MEK/ERK cascade prevented TNF-α-mediated CIDEC downregulation. PPARγ, the transcription factor of CIDEC, was phosphorylated and redistributed by TNF-α in a MEK/ERK-dependent manner. Reporter assay confirmed that TNF-α reduced CIDEC transcription. CONCLUSIONS: TNF-α downregulates CIDEC expression through phosphorylation and nuclear export of PPARγ by MEK/ERK cascade.

[Association between acanthosis nigricans and metabolic syndrome in children with obesity].

OBJECTIVE: To investigate adipokines levels in obese children with acanthosis nigricans (AN) and to explore the relationship between AN and metabolic syndrome (MS). METHODS: A cross-sectional study was performed on 109 obese children and 47 age- and gender-matched normal controls. The obese children were divided into two groups with AN and without AN. Serum levels of adiponectin, leptin, TNF-α and retinol-binding protein 4 (RBP4) were measured using ELISA. Multiple logistic regression analysis was performed to estimate the association of clinical parameters with MS. RESULTS: Waist-hip ratio, systolic blood pressure, triglyceride, fasting insulin and insulin resistance index (HOMA-IR) were significantly higher in obese children with AN than in those without AN and normal controls (P<0.05). The obese children with AN and without AN had lower adiponectin levels than normal controls (P<0.05), on the contrary, the obese children with AN had higher leptin levels than those without AN and normal controls (P<0.05). Multiple logistic regression analysis revealed that AN (OR=3.469, 95%CI: 1.518-7.929) and BMI (OR=7.108, 95%CI: 2.359-21.416) were independent risk factors for MS. CONCLUSIONS: As a visible marker of insulin resistance, AN is associated with abnormal adipokines secretion. Reducing the incidence of AN and losing weight may prevent obesity associated MS.

SFRP5 correlates with obesity and metabolic syndrome and increases after weight loss in children.

OBJECTIVE: Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine, which has been shown as a mediator between obesity and its comorbidities. The aim of this study was to evaluate the associations of SFRP5 with metabolic syndrome (MetS) and the effects of lifestyle interventions on circulating SFRP5 levels in children. DESIGN: A cross-sectional study was conducted among 111 obese children and 49 lean controls, and a lifestyle intervention was performed in a subgroup of 31 obese children for 6 months. Anthropometric parameters, clinical data and circulating SFRP5 levels were measured at baseline and after lifestyle intervention. RESULTS: Secreted frizzled-related protein 5 was significantly lower in obese children, especially in those with MetS, and negatively correlated with body mass index (BMI), waist circumference and homeostasis model assessment of insulin resistance. Independent of other well-known risk factors, SFRP5 was a significant predictor of MetS in children. In the longitudinal study, lifestyle intervention led to significant weight loss and higher SFRP5 levels. Furthermore, changes in BMI significantly correlated with the rising magnitude of SFRP5. CONCLUSIONS: Serum SFRP5 is regulated by weight status and seems to be correlated with metabolic disorders in children.

[Research advances on CIDEC in insulin resistance].

Childhood obesity has been rising dramatically in recent years and most patients are insulin resistant. Recent studies have indicated that cell death-inducing DFF45-like effector C (CIDEC) is responsible for the development of insulin resistance. CIDEC regulates adipogenesis, lipid storage and lipolysis, thus protecting insulin target tissues from lipotoxity. This paper reviews current findings on the structure and function of CIDEC, its transcriptional and post-translational regulations, and the underlying mechanism of CIDEC causing insulin resistance. As a novel lipid droplet protein, CIDEC may be a drug target for treatment of insulin resistance and relevant metabolic disorders.