Amentoflavone reverses epithelial-mesenchymal transition in hepatocellular carcinoma cells by targeting p53 signalling pathway axis.

Epithelial-mesenchymal transition (EMT) and its reversal process are important potential mechanisms in the development of HCC. Selaginella doederleinii Hieron is widely used in Traditional Chinese Medicine for the treatment of various tumours and Amentoflavone is its main active ingredient. This study investigates the mechanism of action of Amentoflavone on EMT in hepatocellular carcinoma from the perspective of bioinformatics and network pharmacology. Bioinformatics was used to screen Amentoflavone-regulated EMT genes that are closely related to the prognosis of HCC, and a molecular prediction model was established to assess the prognosis of HCC. The network pharmacology was used to predict the pathway axis regulated by Amentoflavone. Molecular docking of Amentoflavone with corresponding targets was performed. Detection and evaluation of the effects of Amentoflavone on cell proliferation, migration, invasion and apoptosis by CCK-8 kit, wound healing assay, Transwell assay and annexin V-FITC/propidium iodide staining. Eventually three core genes were screened, inculding NR1I2, CDK1 and CHEK1. A total of 590 GO enrichment entries were obtained, and five enrichment results were obtained by KEGG pathway analysis. Genes were mainly enriched in the p53 signalling pathway. The outcomes derived from both the wound healing assay and Transwell assay demonstrated significant inhibition of migration and invasion in HCC cells upon exposure to different concentrations of Amentoflavone. The results of Annexin V-FITC/PI staining assay showed that different concentrations of Amentoflavone induces apoptosis in HCC cells. This study revealed that the mechanism of Amentoflavone reverses EMT in hepatocellular carcinoma, possibly by inhibiting the expression of core genes and blocking the p53 signalling pathway axis to inhibit the migration and invasion of HCC cells.

Molecular pathogenesis of subretinal fibrosis in neovascular AMD focusing on epithelial-mesenchymal transformation of retinal pigment epithelium.

Age-related macular degeneration (AMD) is a leading cause of vision loss among elderly people in developed countries. Neovascular AMD (nAMD) accounts for more than 90% of AMD-related vision loss. At present, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is widely used as the first-line therapy to decrease the choroidal and retinal neovascularizations, and thus to improve or maintain the visual acuity of the patients with nAMD. However, about 1/3 patients still progress to irreversible visual impairment due to subretinal fibrosis even with adequate anti-VEGF treatment. Extensive literatures support the critical role of epithelial-mesenchymal transformation (EMT) of retinal pigment epithelium (RPE) in the pathogenesis of subretinal fibrosis in nAMD, but the underlying mechanisms still remain largely unknown. This review summarized the molecular pathogenesis of subretinal fibrosis in nAMD, especially focusing on the transforming growth factor-ß (TGF-ß)-induced EMT pathways. It was also discussed how these pathways crosstalk and respond to signals from the microenvironment to mediate EMT and contribute to the progression of nAMD-related subretinal fibrosis. Targeting EMT signaling pathways might provide a promising and effective therapeutic strategy to treat subretinal fibrosis secondary to nAMD.

Aquaporin 11 alleviates retinal Müller intracellular edema through water efflux in diabetic retinopathy.

Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME.

An in vitro cell model to study microglia activation in diabetic retinopathy.

Microglial activation has been studied extensively in diabetic retinopathy. We have previously detected activation and migration of microglia in 8-week-old diabetic rat retinas. It is widely acknowledged that microglia-mediated inflammation contributes to the progression of diabetic retinopathy. However, existing cell models do not explore the role of activated microglia in vitro. In this study, microglia were subject to various conditions mimicking diabetic retinopathy, including high glucose, glyoxal, and hypoxia. Under high glucose or glyoxal treatment, microglia demonstrated only partially functional changes, while under hypoxia, microglia became fully activated showing enlarged cell bodies, enhanced migration and phagocytosis as well as increased production of pro-inflammatory factors such as cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), and inducible nitric oxide synthase (iNOS). The data indicate that hypoxia-treated microglia is an optimal in vitro model for exploration of microglia activation in diabetic retinopathy.

Maintenance of Germinal Center B Cells by Caspase-9 through Promotion of Apoptosis and Inhibition of Necroptosis.

In response to T cell-dependent Ag encounter, naive B cells develop into germinal center (GC) B cells, which can further differentiate into Ab-secreting plasma cells or memory B cells. GC B cells are short lived and are prone to caspase-mediated apoptosis. However, how apoptotic caspases regulate GC B cell fate has not been fully characterized. In this study, we show that mice with B cell-specific knockout of caspase-9 had decreases in GC B cells and Ab production after immunization. Caspase-9-deficient B cells displayed defects in caspase-dependent apoptosis but increases in necroptosis signaling. Additional deletion of Ripk3 restored GC B cells and Ab production in mice with B cell-specific knockout of caspase-9. Our results indicate that caspase-9 plays an important role in the maintenance of Ab responses by promoting apoptosis and inhibiting necroptosis in B cells.

Increased greenhouse gas emissions intensity of major croplands in China: Implications for food security and climate change mitigation.

Balancing crop production and greenhouse gas (GHG) emissions from agriculture soil requires a better understanding and quantification of crop GHG emissions intensity, a measure of GHG emissions per unit crop production. Here we conduct a state-of-the-art estimate of the spatial-temporal variability of GHG emissions intensities for wheat, maize, and rice in China from 1949 to 2012 using an improved agricultural ecosystem model (Dynamic Land Ecosystem Model-Agriculture Version 2.0) and meta-analysis covering 172 field-GHG emissions experiments. The results show that the GHG emissions intensities of these croplands from 1949 to 2012, on average, were 0.10-1.31 kg CO2 -eq/kg, with a significant increase rate of 1.84-3.58 × 10-3  kg CO2 -eq kg-1  year-1 . Nitrogen fertilizer was the dominant factor contributing to the increase in GHG emissions intensity in northern China and increased its impact in southern China in the 2000s. Increasing GHG emissions intensity implies that excessive fertilizer failed to markedly stimulate crop yield increase in China but still exacerbated soil GHG emissions. This study found that overfertilization of more than 60% was mainly located in the winter wheat-summer maize rotation systems in the North China Plain, the winter wheat-rice rotation systems in the middle and lower reaches of the Yangtze River and southwest China, and most of the double rice systems in the South. Our simulations suggest that roughly a one-third reduction in the current N fertilizer application level over these "overfertilization" regions would not significantly influence crop yield but decrease soil GHG emissions by 29.60%-32.50% and GHG emissions intensity by 0.13-0.25 kg CO2 -eq/kg. This reduction is about 29% and 5% of total agricultural soil GHG emissions in China and the world, respectively. This study suggests that improving nitrogen use efficiency would be an effective strategy to mitigate GHG emissions and sustain China's food security.

The assessment of 8th edition AJCC prognostic staging system and a simplified staging system for breast cancer: The analytic results from the SEER database.

The prognostic value of the prognostic staging system that incorporated estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor-2 (Her-2), and histological grade has been validated in breast cancer (BC) patients, but the staging system seems to be somewhat complex. Recently, an updated bioscore system based on these tumor biological factors was proposed. The purpose of this study was to compare the prognostic stratification between prognostic staging system of American Joint Commission on Cancer (AJCC) and a simplified staging system based on the bioscore system and anatomic TNM staging for BC patients. A total of 44 593 patients with invasive ductal carcinoma who underwent radical resection between 2010 and 2011 were reviewed using the SEER database. The patients were reclassified into different groups according to the anatomic staging system, prognostic staging system, risk bioscore system, and simplified staging system, respectively. The prognostic differences between different groups were compared and clinicopathologic features were analyzed. The anatomic TNM staging failed to clearly distinguish the prognostic difference between stage IIIB and stage IIIC. Therefore, we proposed an adjusted anatomic staging, in which T1N3 and T2N3 were downstaged from stage IIIC to stage IIIB, and T4N2 was upstaged from stage IIIB to stage IIIC. Histological grade III, ER(-), PR(-), and Her-2(-) were identified as independent prognostic factors in the multivariate analysis, and these factors were separately marked as 1 point. There were significant survival differences among different risk points except for the comparison between 0 and 1 point. The higher the risk points, the poorer the prognosis of BC patients. In addition, the curve distance between stage IIA and stage IIB was not significantly broaden according to the prognostic staging system. However, the prognostic stratification for BC patients could be significantly improved by the simplified staging system incorporated the bioscore system and adjusted anatomic staging. Several drawbacks may still exist in the prognostic staging system of AJCC. A simplified staging system that incorporated risk score system and the anatomic staging could provide more accurate prognostic information for BC patients.

The Impact of Preoperative Underweight Status on Postoperative Complication and Survival Outcome of Gastric Cancer Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: In this study, we performed a systematic review and meta-analysis to evaluate the impact of preoperative underweight status on postoperative complications and survival outcome of gastric cancer (GC) patients. METHODS: The related studies were identified by searching PubMed and Embase databases. According to the body mass index (BMI), all patients were classified into underweight group (<18.5 kg/m2) and normal weight group (≥18.5 kg/m2, <25 kg/m2). The relevant data were extracted and pooled effect size were assessed using a fixed effect model or random effect model. RESULTS: A total of 12 studies were included in this meta-analysis. The results indicated that underweight patients had a higher risk of postoperative complications than normal weight patients (RR: 1.28, 95% CI: 1.01-1.61, P < 0.05; I2 = 57.3%), especially for pulmonary infection (RR: 1.58, 95% CI: 1.03-2.43, P < 0.05; I2 = 47.7%). However, there was no significant difference between underweight and normal weight patients for major surgery-related complications such as anastomotic leakage, wound infection, and intra-abdominal infection. In addition, the short-term (RR: 2.12, 95% CI: 1.47-3.06, P < 0.001; I2 = 0%) and long-term survival (HR: 1.53, 95% CI: 1.14-2.07, P < 0.01; I2 = 64.0%) of underweight patients was significantly poorer than that of normal weight patients. CONCLUSION: Preoperative underweight status was significantly associated with unfavorable postoperative outcome of GC patients. The status may represent excessive nutritional consumption and malnutrition resulting from aggressive tumor.

The assessment of different risk classification systems for gastrointestinal stromal tumors (GISTs): the analytic results from the SEER database.

BACKGROUND: Although various risk classification systems for GISTs have been proposed, the optimum one remains uncertain. In the present study, we compared the prognostic stratification of different risk classification systems for GIST patients. METHODS: We reviewed those patients who were pathologically diagnosed with GISTs in the SEER database between 2009 and 2014. All patients were classified into different risk groups according to the NIH criteria, AFIP criteria and AJCC staging system, respectively. The prognostic differences between different risk groups were compared and clinicopathologic features were analyzed. RESULTS: The prognosis of small intestinal GISTs was not significantly different from that of gastric GISTs. For gastric GIST patients, there was no significant prognostic difference between very low risk and low risk group according to the NIH and AFIP criteria. However, the prognostic stratification for two groups could be improved by the AJCC staging system. For small intestinal GIST patients, the prognostic difference between low risk and intermediate risk group was not stratified properly by the NIH and AFIP criteria. However, the prognostic difference between two groups could reach statistical significance according to the AJCC staging system. Unlike gastric GISTs, tumor size was not identified as an independent factor influencing the prognosis of small intestinal GISTs. CONCLUSIONS: The AJCC staging system could provide a better prognostic stratification for GIST patients compared with the NIH and AFIP criteria, regardless of gastric or small intestinal tumor. However, primary tumor location and tumor size may be reconsidered and revised in the risk classification system.

Anatomical location of metastatic lymph nodes: an indispensable prognostic factor for gastric cancer patients who underwent curative resection.

BACKGROUND: Although the numeric-based lymph node (LN) staging was widely used in the worldwide, it did not represent the anatomical location of metastatic lymph nodes (MLNs) and not reflect extent of LN dissection. Therefore, in the present study, we investigated whether the anatomical location of MLNs was still necessary to evaluate the prognosis of node-positive gastric cancer (GC) patients. METHODS: We reviewed 1451 GC patients who underwent radical gastrectomy in our institution between January 1986 and January 2008. All patients were reclassified into several groups according to the anatomical location of MLNs and the number of MLNs. The prognostic differences between different patient groups were compared and clinicopathologic features were analyzed. RESULTS: In the present study, both anatomical location of MLNs and the number of MLNs were identified as the independent prognostic factors (p < .01). The patients with extraperigastric LN involvement showed a poorer prognosis compared with the perigastric-only group (p < .001). For the N1-N2 stage patients, the prognostic discrepancy was still observed among them when the anatomical location of MLNs was considered (p < .05). For the N3-stage patients, although the anatomical location of MLNs had no significant effect on the prognosis of these patients, the higher number of MLNs in the extraperigastric area was correlated with the unfavorable prognosis (p < .05). CONCLUSION: The anatomical location of MLNs was an important factor influencing the prognostic outcome of GC patients. To provide more accurate prognostic information for GC patients, the anatomical location of MLNs should not be ignored.

Assessment of the 8th edition of TNM staging system for gastric cancer: the results from the SEER and a single-institution database.

AIM: To investigate whether the 8th edition of Tumor, Node, Metastasis (TNM) staging could properly evaluate the prognosis of gastric cancer patients. METHODS: The prognostic performance between the 7th and 8th edition of TNM staging was compared and clinicopathologic features were analyzed. RESULTS: The stage shifts in the 8th edition staging resulted in the increased numbers of stage IIIA patients and decreased numbers of stage IIB, stage IIIB and stage IIIC patients. Compared with the previous edition, the 8th edition of TNM staging provided a better prognostic stratification for stage III patients. However, whether it is reasonable to incorporate T4aN2, T4aN3a and T4bN3b into stage IIIA, stage IIIB and stage IIIC respectively, which still need further validation. CONCLUSION: Despite the obvious superiority, several deficiencies may still exist in the new edition staging. To better provide prognostic information and therapeutic guidance for gastric cancer patients, the TNM staging system should be further improved in the future.

Sheng-ji Hua-yu formula promotes diabetic wound healing of re-epithelization via Activin/Follistatin regulation.

BACKGROUND: Sheng-ji Hua-yu(SJHY) formula is one of the most useful Traditional Chinese medicine (TCM) in the treatment of the delayed diabetic wound. However, elucidating the related molecular biological mechanism of how the SJHY Formula affects excessive inflammation in the process of re-epithelialization of diabetic wound healing is a task urgently needed to be fulfilled. The objectives of this study is to evaluate the effect of antagonisic expression of pro-/anti-inflammatory factors on transforming growth factor-ß(TGF-ß) superfamily (activin and follistatin) in the process of re-epithelialization of diabetic wound healing in vivo, and to characterize the involvement of the activin/follistatin protein expression regulation, phospho-Smad (pSmad2), and Nuclear factor kappa B p50 (NF-kB) p50 in the diabetic wound healing effects of SJHY formula. METHODS: SJHY Formula was prepared by pharmaceutical preparation room of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine. Diabetic wound healing activity was evaluated by circular excision wound models. Wound healing activity was examined by macroscopic evaluation. Activin/follistatin expression regulation, protein expression of pSmad2 and NF-kB p50 in skin tissue of wounds were analyzed by Real Time PCR, Western blot, immunohistochemistry and hematoxylin and eosin (H&E) staining. RESULTS: Macroscopic evaluation analysis showed that wound healing of diabetic mice was delayed, and SJHY Formula accelerated wound healing time of diabetic mice. Real Time PCR analysis showed higher mRNA expression of activin/follistatin in diabetic delayed wound versus the wound in normal mice. Western Blot immunoassay analysis showed reduction of activin/follistatin proteins levels by SJHY Formula treatment 15 days after injury. Immunohistochemistry investigated the reduction of pSmad2 and NF-kB p50 nuclear staining in the epidermis of diabetic SJHY versus diabetic control mice on day 15 after wounding. H&E staining revealed that SJHY Formula accelerated re-epithelialization of diabetic wound healing. CONCLUSION: The present study found that diabetic delayed wound healing time is closely related to the high expression level of activin/follistatin, which leads to excessive inflammation in the process of re-epithelization. SJHY Formula accelerates re-epithelialization and healing time of diabetic wounds through decreasing the high expression of activin/follistatin.

N2O emission characteristics and its affecting factors in rain-fed potato fields in Wuchuan County, China.

Representing an important greenhouse gas, nitrous oxide (N2O) emission from cultivated land is a hot topic in current climate change research. This study examined the influences of nitrogen fertilisation, temperature and soil moisture on the ammonia monooxygenase subunit A (amoA) gene copy numbers and N2O emission characteristics. The experimental observation of N2O fluxes was based on the static chamber-gas chromatographic method. The ammonia-oxidising bacteria (AOB) and ammonia-oxidising archaea (AOA) gene copy numbers in different periods were measured by real-time polymerase chain reaction (PCR). The results indicated that rain-fed potato field was a N2O source, and the average annual N2O emission was approximately 0.46 ± 0.06 kgN2O-N/ha/year. N2O emissions increased significantly with increase in fertilisation, temperatures below 19.6 °C and soil volumetric water content under 15%. Crop rotation appreciably decreases N2O emissions by 34.4 to 52.4% compared to continuous cropping in rain-fed potato fields. The significant correlation between N2O fluxes and AOB copy numbers implied that N2O emissions were primarily controlled by AOB in rain-fed potato fields. The research has important theoretical and practical value for understanding N2O emissions from rain-fed dry farmland fields.

PCVMZM: Using the Probabilistic Classification Vector Machines Model Combined with a Zernike Moments Descriptor to Predict Protein-Protein Interactions from Protein Sequences.

Protein-protein interactions (PPIs) are essential for most living organisms' process. Thus, detecting PPIs is extremely important to understand the molecular mechanisms of biological systems. Although many PPIs data have been generated by high-throughput technologies for a variety of organisms, the whole interatom is still far from complete. In addition, the high-throughput technologies for detecting PPIs has some unavoidable defects, including time consumption, high cost, and high error rate. In recent years, with the development of machine learning, computational methods have been broadly used to predict PPIs, and can achieve good prediction rate. In this paper, we present here PCVMZM, a computational method based on a Probabilistic Classification Vector Machines (PCVM) model and Zernike moments (ZM) descriptor for predicting the PPIs from protein amino acids sequences. Specifically, a Zernike moments (ZM) descriptor is used to extract protein evolutionary information from Position-Specific Scoring Matrix (PSSM) generated by Position-Specific Iterated Basic Local Alignment Search Tool (PSI-BLAST). Then, PCVM classifier is used to infer the interactions among protein. When performed on PPIs datasets of Yeast and H. Pylori, the proposed method can achieve the average prediction accuracy of 94.48% and 91.25%, respectively. In order to further evaluate the performance of the proposed method, the state-of-the-art support vector machines (SVM) classifier is used and compares with the PCVM model. Experimental results on the Yeast dataset show that the performance of PCVM classifier is better than that of SVM classifier. The experimental results indicate that our proposed method is robust, powerful and feasible, which can be used as a helpful tool for proteomics research.

Integrated transcriptome and metabolome study reveal the therapeutic effects of nicotinamide riboside and nicotinamide mononucleotide on nonalcoholic fatty liver disease.

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.

An ERP study on the late stage of Chinese metaphor processing.

Psycholinguistic models of metaphor processing remain a subject of debate. A prime-probe design using Chinese materials with a specific time span (300 ms) was applied to test the mechanisms of metaphor processing. Conventional and familiarized metaphors were designed as primes, followed by a probe word semantically related to the prime metaphor (MT), a probe word related to the literal meaning of the final word of the prime metaphor (LT), control/unrelated probe word (UT), or non-word. Event-related potentials (ERPs) elicited by the probes were recorded to examine metaphor processing. In N400, results revealed that UT and LT elicited significantly more negative waveforms than MT in both primes. MTs and LTs showed no difference between conventional and familiarized metaphors, suggesting that metaphorical meaning may be accessed directly, regardless of whether conventional or familiarized metaphors. The results were generally compatible with the direct processing model.

A highly biocompatible and bioactive transdermal nano collagen for enhanced healing of UV-damaged skin.

Skin damage caused by excessive UV radiation has gradually become one of the most prevalent skin diseases. Collagen has gradually found applications in the treatment of UV-damaged skin; however, their high molecular weight greatly limits their capacity to permeate the skin barrier and repair the damaged skin. Nano collagen has garnered growing attentions in the mimicking of collagen; while the investigation of its skin permeability and wound-healing capability remains vacancies. Herein, we have for the first time created a highly biocompatible and bioactive transdermal nano collagen demonstrating remarkable transdermal capacity and repair efficacy for UV-damaged skin. The transdermal nano collagen exhibited a stable triple-helix structure, effectively promoting the adhesion and proliferation of fibroblasts. Notably, the transdermal nano collagen displayed exceptional penetration capabilities, permeating fibroblast and healthy skin. Combo evaluations revealed that the transdermal nano collagen contributed to recovering the intensity and TEWL values of UV-damaged skin to normal level. Histological analysis further indicated that transdermal nano collagen significantly accelerated the repair of damaged skin by promoting the collagen regeneration and fibroblasts activation. This highly biocompatible and bioactive transdermal nano collagen provides a novel substituted strategy for the transdermal absorption of collagen, indicating great potential applications in cosmetics and dermatology.

Glucose transport, transporters and metabolism in diabetic retinopathy.

Diabetic retinopathy (DR) is the most common reason for blindness in working-age individuals globally. Prolonged high blood glucose is a main causative factor for DR development, and glucose transport is prerequisite for the disturbances in DR caused by hyperglycemia. Glucose transport is mediated by its transporters, including the facilitated transporters (glucose transporter, GLUTs), the "active" glucose transporters (sodium-dependent glucose transporters, SGLTs), and the SLC50 family of uniporters (sugars will eventually be exported transporters, SWEETs). Glucose transport across the blood-retinal barrier (BRB) is crucial for nourishing the neuronal retina in the context of retinal physiology. This physiological process primarily relies on GLUTs and SGLTs, which mediate the glucose transportation across both the cell membrane of retinal capillary endothelial cells and the retinal pigment epithelium (RPE). Under diabetic conditions, increased accumulation of extracellular glucose enhances the retinal cellular glucose uptake and metabolism via both glycolysis and glycolytic side branches, which activates several biochemical pathways, including the protein kinase C (PKC), advanced glycation end-products (AGEs), polyol pathway and hexosamine biosynthetic pathway (HBP). These activated biochemical pathways further increase the production of reactive oxygen species (ROS), leading to oxidative stress and activation of Poly (ADP-ribose) polymerase (PARP). The activated PARP further affects all the cellular components in the retina, and finally resulting in microangiopathy, neurodegeneration and low-to-moderate grade inflammation in DR. This review aims to discuss the changes of glucose transport, glucose transporters, as well as its metabolism in DR, which influences the retinal neurovascular unit (NVU) and implies the possible therapeutic strategies for treating DR.

Versatile triblock peptides mimicking ABC-type heterotrimeric collagen with stabilizing salt bridges.

Type IV collagen, a principal constituent of basement membranes, consists of six distinct α chains that assemble into both ABC and AAB-type heterotrimers. While collagen-like peptides have been investigated for heterotrimer formation, the construction of ABC-type heterotrimeric collagen mimetic peptides remains a formidable challenge, primarily due to the intricate composition and arrangement of the chains. We have herein for the first time reported the development of a versatile triblock peptide system to mimic ABC-type heterotrimeric collagen stabilized by salt bridges. The triblock peptides A, B, and C incorporate functional natural type IV collagen sequences in the center, along with charged amino acids at their N and C-terminals. By leveraging electrostatic repulsion at these charged termini, the formation of homotrimers is effectively inhibited, while stable ABC-type heterotrimers are generated through the establishment of salt bridges between oppositely charged terminals. Circular dichroism (CD) spectroscopy demonstrated that peptides A, B, and C existed as individual monomers, while they effectively formed stable ABC-type heterotrimers upon being mixed at a molar ratio of 1:1:1. Additionally, fluorescence quenching results indicated that fluorescence-labeled peptides A', B', and C' formed ABC-type heterotrimer, exhibiting comparable thermal stability as determined by CD spectroscopy. Molecular dynamics simulations elucidated the role of salt bridges between arginine and aspartic acid residues at N- and C-terminals in maintaining a unique chain register in the ABC-type heterotrimers. These triblock peptides offer a robust approach for replicating the structural and functional characteristics of type IV collagen, with promising applications in elucidating the biological roles and pathologies associated with heterotrimeric collagen.

Efficacy, Safety and the Lymphocyte Subset Changes of Low-Dose IL-2 in Patients with Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis.

INTRODUCTION: Current therapies for autoimmune rheumatic diseases (ARDs) have limited efficacy in certain patients, highlighting the need for the development of novel treatment approaches. This meta-analysis aims to assess the efficacy and safety of low-dose interleukin-2 (LD-IL-2) and evaluate the alterations in lymphocyte subsets in various rheumatic diseases following administration of different dosages of LD-IL-2. METHODS: A comprehensive search was conducted in PubMed, Web of Science, the Cochrane Library, Embase databases and CNKI to identify relevant studies. A total of 31 trials were included in this meta-analysis. The review protocols were registered on PROSPERO (CRD42022318916), and the study followed the PRISMA guidelines. RESULTS: Following LD-IL-2 treatment, patients with ARDs exhibited a significant increase in the number of Th17 cells and Tregs compared to their pre-treatment levels [standardized mean difference (SMD) = 0.50, 95% confidence interval (CI) (0.33, 0.67), P < 0.001; SMD = 1.13, 95% CI (0.97, 1.29), P < 0.001]. Moreover, the Th17/Tregs ratio showed a significant decrease [SMD = - 0.54, 95% CI (- 0.64, - 0.45), P < 0.001]. In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), LD-IL-2 injection led to a significant increase in Treg numbers, and the Th17/Tregs ratio and disease activity scores, including Disease Activity Score-28 joints (DAS28), Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), were all significantly reduced. No serious adverse events were reported in any of the included studies. Additionally, 54.8% of patients with lupus nephritis achieved distinct clinical remission following LD-IL-2 treatment. Injection site reactions and fever were the most common side effects of LD-IL-2, occurring in 33.1% and 14.4% of patients, respectively. CONCLUSION: LD-IL-2 treatment showed promise and was well tolerated in the management of ARDs, as it effectively promoted the proliferation and functional recovery of Tregs. TRIAL REGISTRATION: Retrospectively registered (CRD42022318916, 21/04/2022).