CPT1A Protects Podocytes From Lipotoxicity and Apoptosis In Vitro and Alleviates Diabetic Nephropathy In Vivo.

Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from patients with diabetes. We further evaluated the function of CPT1A in diabetic models. Overexpression of CPT1A exhibited protective effects in diabetic conditions, improving albuminuria and glomerular sclerosis as well as mitigating glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice. Mechanistically, CPT1A not only fostered lipid consumption via fatty acid metabolism pathways, thereby reducing lipotoxicity, but also anchored Bcl2 to the mitochondrial membrane, thence preventing cytochrome C release and inhibiting the mitochondrial apoptotic process. Furthermore, a novel transcription factor of CPT1A, FOXA1, was identified. We elucidate the crucial role of CPT1A in mitigating podocyte injury and the progression of DKD, indicating that targeting CPT1A may be a promising avenue for DKD treatment.

Deficiency of Nuclear Receptor Coactivator 3 Aggravates Diabetic Kidney Disease by Impairing Podocyte Autophagy.

Nuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR-γ dependent way. Podocyte-specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.

DNA methylation profiling reveals novel pathway implicated in cardiovascular diseases of diabetes.

Objective: Epigenetics was reported to mediate the effects of environmental risk factors on disease pathogenesis. We intend to unleash the role of DNA methylation modification in the pathological process of cardiovascular diseases in diabetes. Methods: We screened differentially methylated genes by methylated DNA immunoprecipitation chip (MeDIP-chip) among the enrolled participants. In addition, methylation-specific PCR (MSP) and gene expression validation in peripheral blood of participants were utilized to validate the DNA microarray findings. Results: Several aberrantly methylated genes have been explored, including phospholipase C beta 1 (PLCB1), cam kinase I delta (CAMK1D), and dopamine receptor D5 (DRD5), which participated in the calcium signaling pathway. Meanwhile, vascular endothelial growth factor B (VEGFB), placental growth factor (PLGF), fatty acid transport protein 3 (FATP3), coagulation factor II, thrombin receptor (F2R), and fatty acid transport protein 4 (FATP4) which participated in vascular endothelial growth factor receptor (VEGFR) signaling pathway were also found. After MSP and gene expression validation in peripheral blood of participants, PLCB1, PLGF, FATP4, and VEGFB were corroborated. Conclusion: This study revealed that the hypomethylation of VEGFB, PLGF, PLCB1, and FATP4 might be the potential biomarkers. Besides, VEGFR signaling pathway regulated by DNA methylation might play a role in the cardiovascular diseases' pathogenesis of diabetes.

Introducing surface-to-surface matching technique to evaluate mandibular symmetry: A retrospective study.

Objectives: This study introduced a three-dimensional (3D) surface-to-surface matching technique to evaluate the mandibular symmetry of teenagers and adults with unilateral second molar scissor bite. Methods: The targets came from 73 cone-beam computed tomography (CBCT) images with unilateral second molar scissor bite, including teenagers (n = 30) and adults (n = 43). 73 images without scissor bite and matched in sex and age were selected as controls. The scans were developed into 3D mandible models and seven mandibular functional unit models, including condylar process (Co), coronoid process (Cr), mandibular ramus (Ra), mandibular angle (Ma), alveolar process (Ap), mandibular body (Mb) and chin process (Ch). The surface-to-surface matching technique was introduced. 3D deviation analysis and matching percentages calculation were performed and compared to evaluate the symmetry of the mandible. Results: Comparisons were made between the study samples and control samples. For teenagers, the matching percentages of the entire mandible (55.31 ± 7.24%), Mb (69.04 ± 9.22%) and Co (65.19 ± 10.67%) in the study group were lower than that of the entire mandible (60.87 ± 6.38%) (P <0.01), Mb (75.0 ± 8.71%) (P <0.05) and Co (70.25 ± 8.20%) (P <0.05) in the control group. While Ap, Ra, Ch, Cr and Ma showed no statistically significant differences (P >0.05). For adults, the matching percentages of the entire mandible (48.88 ± 9.77%), Ap (65.83 ± 11.21%), Mb (64.43 ± 12.03%), Ch (79.17 ± 10.29%), Ra (64.11 ± 9.84%) and Co (61.08 ± 11.64%) in the study group were lower than the entire mandible (59.28 ± 5.49%) (P <0.01), Ap (73.65 ± 9.10%) (P <0.01), Mb (71.66 ± 8.40%) (P <0.01), Ch (83.86 ± 5.59%) (P <0.05), Ra (68.54 ± 7.87%) (P <0.05) and Co (66.20 ± 10.62%) (P <0.05) of the control group. Only Cr and Ma showed no statistically significant differences (P >0.05). Conclusion: Mandibular asymmetry was observed in both teenagers and adults with unilateral second molar scissor bite. Moreover, compared with teenagers, more mandibular units of adult patients were affected. Clinical significance: Based on the surface-to-surface matching technique, the symmetric and morphological information of the mandible can be converted into visual color maps and quantitative descriptions. This method can bring convenience to the study of the growth of mandible, orthodontic treatment and orthognathic surgery design.

The Role of Long Non-Coding RNAs in the Tumor Immune Microenvironment.

Tumorigenesis is a complicated process caused by successive genetic and epigenetic alterations. The past decades demonstrated that the immune system affects tumorigenesis, tumor progression, and metastasis. Although increasing immunotherapies are revealed, only a tiny proportion of them are effective. Long non-coding RNAs (lncRNAs) are a class of single-stranded RNA molecules larger than 200 nucleotides and are essential in the molecular network of oncology and immunology. Increasing researches have focused on the connection between lncRNAs and cancer immunotherapy. However, the in-depth mechanisms are still elusive. In this review, we outline the latest studies on the functions of lncRNAs in the tumor immune microenvironment. Via participating in various biological processes such as neutrophil recruitment, macrophage polarization, NK cells cytotoxicity, and T cells functions, lncRNAs regulate tumorigenesis, tumor invasion, epithelial-mesenchymal transition (EMT), and angiogenesis. In addition, we reviewed the current understanding of the relevant strategies for targeting lncRNAs. LncRNAs-based therapeutics may represent promising approaches in serving as prognostic biomarkers or potential therapeutic targets in cancer, providing ideas for future research and clinical application on cancer diagnosis and therapies.

Natural Killer-Like B Cells Secreting Interleukin-18 Induces a Proinflammatory Response in Periodontitis.

Natural killer-like B (NKB) cells, which are newly identified immune subsets, reveal a critical immunoregulatory property in the eradication of microbial infection via the secretion of interleukin (IL)-18. For the first time, this study investigated the role of NKB cells in secreting IL-18 in the pathogenesis of periodontitis. In this study, NKB cells' percentage and IL-18 concentration in peripheral blood and periodontium in periodontitis patients was measured using flow cytometry and ELISA. The role of IL-18 in regulating periodontal inflammation was examined in a Porphyromonas gingivalis (P. gingivalis)-induced periodontitis murine model. Peripheral and periodontal-infiltrating CD3-CD19+NKp46+ NKB cells, which were the main source of IL-18, were elevated and correlated with attachment loss in periodontitis patients. In vitro IL-18 stimulation promoted proinflammatory cytokine production in periodontal ligament cells. P. gingivalis infection induced elevation of IL-18 receptor in periodontium in a periodontitis murine model. IL-18 neutralization not only suppressed P. gingivalis-induced alveolar bone resorption, but also inhibited recruitment of antigen-non-specific inflammatory cells into the periodontium, probably via dampening expressions of cytokines, chemokines, and matrix metalloproteinases. NKB cells secreting IL-18 appeared to be an important mediator in the inflammatory response following intraoral P. gingivalis infection. These findings might be relevant to the development of immunotherapies for periodontitis.

Effects of soluble fiber supplementation on glycemic control in adults with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND & AIMS: Soluble dietary fiber is prompted as an important part of reducing blood glucose, ameliorating insulin resistance and controlling body weight. Thus, we performed this systematic review and meta-analysis of randomized controlled trials (RCTs) to quantify and synthesize the effects of soluble fiber supplementation on glycemic control and BMI modification in adults with type 2 diabetes. METHODS: We searched MEDLINE, Embase, Web of Science, ClinicalTrials.gov, and Cochrane databases until February 13, 2020 to identify RCTs that detected the effects of soluble fiber supplementation on glycemic control in adults with type 2 diabetes. A random-effects model with the generic inverse variance method was used to analyze the pooled data. The meta-regression and subgroup analyses were conducted to identify the variables that influenced the pooled results. The robust error meta-regression model was used to conduct the dose-response test. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was undertaken to evaluate the overall quality of the evidence. RESULTS: A total of 29 RCTs (33 comparisons) involving 1517 participants were identified in this meta-analysis. Results showed that supplemental soluble dietary fiber significantly reduced glycosylated hemoglobin (HbA1c, MD -0.63%, 95% CI [-0.90, -0.37]; P < 0.00001), fasting plasma glucose (FPG, MD -0.89 mmol/L, 95% CI [-1.28, -0.51]; P < 0.00001), fasting insulin (SMD -0.48, 95% CI [-0.80, -0.17]; P = 0.003), homeostatic model assessment of insulin resistance (HOMA-IR, SMD -0.58, 95% CI [-0.86, -0.29], P < 0.0001), fructosamine (SMD -1.03, 95% CI [-1.51, -0.55]; P < 0.0001), 2-h postprandial plasma glucose (SMD -0.74, 95% CI [-1.00, -0.48]; P < 0.00001), and BMI (SMD -0.31, 95% CI [-0.61, -0.00], P = 0.05) compared with control diets in patients with type 2 diabetes. Specifically, dose-response meta-analyses presented that a daily dosage of 7.6-8.3 g was recommended. CONCLUSION: Intake of soluble fiber supplementation is effective in improving glycemic control and BMI level in type 2 diabetes and is also a convenient way to help individuals meet standard dietary fiber needs. But due to the evidence of substantial heterogeneity in most pooled estimates, further long-term and high-quality RCTs are needed.

Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration.

Biomaterials as bone substitutes are always considered as foreign bodies that can trigger host immune responses. Traditional designing principles have been always aimed at minimizing the immune reactions by fabricating inert biomaterials. However, clinical evidence revealed that those methods still have limitations and many of which were only feasible in the laboratory. Currently, osteoimmunology, the very pioneering concept is drawing more and more attention-it does not simply regard the immune response as an obstacle during bone healing but emphasizes the intimate relationship of the immune and skeletal system, which includes diverse cells, cytokines, and signaling pathways. Properties of biomaterials like topography, wettability, surface charge, the release of cytokines, mediators, ions and other bioactive molecules can impose effects on immune responses to interfere with the skeletal system. Based on the bone formation mechanisms, the designing methods of the biomaterials change from immune evasive to immune reprogramming. Here, we discuss the osteoimmunomodulatory effects of the new modification strategies-adjusting properties of bone biomaterials to induce a favorable osteoimmune environment. Such strategies showed potential to benefit the development of bone materials and lay a solid foundation for the future clinical application.

Using Deep Learning to Forecast Maritime Vessel Flows.

Forecasting vessel flows is important to the development of intelligent transportation systems in the maritime field, as real-time and accurate traffic information has favorable potential in helping a maritime authority to alleviate congestion, mitigate emission of GHG (greenhouse gases) and enhance public safety, as well as assisting individual vessel users to plan better routes and reduce additional costs due to delays. In this paper, we propose three deep learning-based solutions to forecast the inflow and outflow of vessels within a given region, including a convolutional neural network (CNN), a long short-term memory (LSTM) network, and the integration of a bidirectional LSTM network with a CNN (BDLSTM-CNN). To apply those solutions, we first divide the given maritime region into M × N grids, then we forecast the inflow and outflow for all the grids. Experimental results based on the real AIS (Automatic Identification System) data of marine vessels in Singapore demonstrate that the three deep learning-based solutions significantly outperform the conventional method in terms of mean absolute error and root mean square error, with the performance of the BDLSTM-CNN-based hybrid solution being the best.

Gestational Perfluorooctanoic Acid Exposure Inhibits Placental Development by Dysregulation of Labyrinth Vessels and uNK Cells and Apoptosis in Mice.

Perfluorooctanoic acid (PFOA) is a widely used perfluorinated compound and known to cause developmental toxicity which includes the increase of resorbed embryo, decrease of fetal survival, and fetal growth retardation. Nevertheless, whether it is associated with alteration of placental development remains unknown. Pregnant mice were gavaged with 0, 2.5, 5, 10 mg PFOA /kg/day from pregnancy day (PD) 1 to PD 13. Results showed that PFOA exposure markedly decreased the placental weight and caused interstitial edema of placenta. Laminin staining indicated that blood sinusoids area was shrunken in placenta of PFOA-exposed mice. Furthermore, PFOA treatment significantly reduced numbers of uNK cells. Western blot analysis revealed that levels of Bax and cleaved-caspase 3 proteins were markedly up-regulated in PFOA-treated groups. In addition, TEM examination showed that PFOA treatment caused rupture of nuclear membrane and nuclear pyknosis and fragmentation. Thus, our results suggested that gestational PFOA exposure significantly inhibited development of early placenta through shrinkage of labyrinth vessels and downregulation of uNK cells and apoptosis induction, which may result in adverse gestational outcomes.

Novel chitosan hydrogels reinforced by silver nanoparticles with ultrahigh mechanical and high antibacterial properties for accelerating wound healing.

Poor mechanical properties of chitosan hydrogels limit their applications as the wound dressing. To overcome this drawback, we abandoned the traditional glacial acetic acid method but adopted a LiOH/urea solvent system to synthesize chitosan hydrogel. Then reductive Ag nanoparticles were integrated into the chitosan hydrogel networks, aiming at reinforcing the mechanical properties and improving the antibacterial properties of chitosan hydrogel. The synthesized hydrogels were subsequently characterized using the FTIR, XRD, SEM, and TEM. In addition, swelling characteristics, mechanical properties, antibacterial abilities as well as wound healing efficacy on Sprague-Dawley rats were evaluated. The results showed that the novel hydrogel exhibited porous three-dimensional network and ultrahigh mechanical properties due to the inter-molecular and intra-molecular interactions. The compressive strength was 15.95 ±â€¯1.95 MPa, >100 times stronger than that of the control group. Meanwhile, the hydrogels still remained structural integrity even if the strain exceeded 90%. Furthermore, compared with the controls, the hydrogels exhibited more excellent antibacterial performance and significantly (p < 0.05) increased the rate of the re-epithelialization and collagen deposition, effectively accelerating the wound healing. Therefore, the synthesized hydrogel with ultrahigh mechanical properties will be found potential applications in the fields of biomedicine.

Maternal exposure to perfluorooctanoic acid inhibits luteal function via oxidative stress and apoptosis in pregnant mice.

Perfluorooctanoic acid (PFOA) is a synthetic perfluorinated compound, which has been reported to exert adverse effect on the pregnancy. However, whether it is associated with alteration of luteal function remains unknown. Mice were administered PFOA by gavage from gestational days (GD) 1-7 or 13. PFOA treatment did not significantly affect numbers of embryo implantation. Nevertheless, on GD 13, 10mg/kg PFOA treatment significantly increased numbers of resorbed embryo. Furthermore, PFOA exposure markedly reduced serum progesterone levels but did not affect estradiol levels. Treatment also showed concomitant decreases in transcript levels for key steroidogenic enzymes, and reduced numbers and sizes of corpora lutea. In addition, PFOA administration inhibited activities of superoxide dismutase and catalase, and increased generation of hydrogen peroxide and malondialdehyde, and down-regulated level of Bcl-2 and up-regulated p53 and BAX proteins. In conclusion, PFOA exposure significantly inhibits luteal function via oxidative stress and apoptosis in pregnant mice.

Effects of recombinated Anabaena sp. lipoxygenase on the protein component and dough property of wheat flour.

The improvement effect of recombinated Anabaena sp. lipoxygenase (ana-rLOX) on the rheological property of dough was investigated with a farinograph and an extensograph. When 30 U/g ana-rLOX was added to wheat flour, the dough stability time extended from 7 to 9.5 min, the degree of softening increased about 31.1%, and the farinograph index also ascended. The dough with added ana-rLOX showed stronger resistance to extension throughout 135 min of resting time as compared to the dough without ana-rLOX. In addition, the protein component in the dough was varied with ana-rLOX. The glutenin in the dough was increased, whereas the gliadin, albumin, and globulin were decreased after the additino of ana-rLOX to the flours. Ana-rLOX could make globulin-3A, globulin 1a, and S48186 grain softness protein cross-link with gliadin and low-molecular-weight (LMW) glutenin, leading to the formation of the protein polymer. These results based on proteomic analysis might provide evidence that ana-rLOX could affect the gluten protein component and explain why it improved the farinograph and extensograph parameters of wheat flour.

Releasing polysaccharide and protein from yeast cells by ultrasound: selectivity and effects of processing parameters.

A 20 kHz high-intensity ultrasound was employed for the selective release of polysaccharide and protein from yeast cells. While the release of polysaccharide and protein was affected by most of the processing parameters, the release selectivity, which is the ratio of the amount of polysaccharide released to that of protein, designated as T/P value, was only influenced by sonication time, temperature and ionic strength, among which temperature had the greatest influence. The T/P value at 85 °C was a factor of 9.3 of the one at 25 °C. The underlying mechanism of this selectivity is speculated to be thermal denaturation and aggregation of protein within yeast cells at elevated temperatures leading to the decrease of protein release by ultrasound. This finding may be useful in exploring a novel selective process for producing polysaccharide and protein fractions from yeast biomass.