Targeting mitochondrial quality control for diabetic cardiomyopathy: Therapeutic potential of hypoglycemic drugs.

Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.

Perinatal risk factors for neonatal early-onset sepsis: a meta-analysis of observational studies.

OBJECTIVE: Early-onset neonatal sepsis (EONS) remains an important cause of neonatal mortality and has many risk factors, therefore, this study aimed to investigate the perinatal risk factors for EONS. METHODS: We searched CNKI, Wan Fang, VIP, CBM, PubMed, Embase, and Web of Science to compile studies regarding the incidence of neonatal early-onset sepsis, published up to 1 May 2022. To evaluate the quality of the included studies, we used the Newcastle-Ottawa Scale, and the RevMan5.3 software was used for meta-analysis. RESULTS: A total of 17 studies were included, with 1987 cases in the case group and 4814 cases in the control group. Meta-analysis showed that perinatal asphyxia or intrauterine distress (OR = 3.00, 95% CI: 2.18-4.13), amniotic fluid meconium contamination (OR = 4.51, 95% CI: 2.31-8.81), group B streptococcal (GBS) colonization in pregnant women (OR = 2.13, 95% CI: 1.48-3.05), chorioamnionitis (OR = 4.58, 95% CI: 2.61-8.05), premature rupture of membranes (OR = 2.63, 95% CI: 2.09-3.30), lower gestational age (OR = 1.31, 95% CI: 1.18-1.44), maternal urinary or reproductive tract infection (OR = 3.61, 95% CI: 2.14-6.11), perinatal fever (OR = 3.59, 95% CI: 2.25-5.71), very low birth weight (OR = 3.79, 95% CI: 2.14-6.73), and vaginal examination ≥3 times (OR = 7.95, 95% CI: 4.04-15.64) were the perinatal risk factors for EONS. CONCLUSION: Perinatal asphyxia or intrauterine distress, meconium contamination in amniotic fluid, GBS colonization in pregnant women, chorioamnionitis, premature rupture of membranes, lower gestational age, maternal urinary tract or reproductive tract infection, perinatal fever, very low birth weight, and vaginal examinations ≥3 times may increase the risk of EONS.

Spin-dependent and tunable perfect absorption in a Fabry-Perot cavity containing a multi-Weyl semimetal.

Spin-dependent absorption has been widely studied in metamaterials and metasurfaces with chirality since it develops significant applications in multiplexed holograms, photodection, and filtering. Here, the one-dimensional photonic crystal Fabry-Perot (FP) cavity containing a multi-Weyl semimetal (mWSM) defect is proposed to investigate the spin-dependent perfect absorption. Results denote that the distinct refractive indices of right hand circularly polarized (RCP) and left hand circularly polarized (LCP) waves are present due to the nonzero off-diagonal term of mWSM, thus supporting the perfect absorption of RCP and LCP waves at distinct resonant wavelengths. The different perfect absorption wavelengths of RCP and LCP waves reveal the spin-dependent perfect absorption. By altering the Fermi energy, tilt degree of Weyl cones, Weyl nodes separation, topological charge, and thickness of the mWSM layer, the perfect absorption wavelength of RCP and LCP waves can be regulated conveniently. Particularly, the linear tunable perfect absorption wavelength with thickness of the mWSM layer supports the accurate determination of perfect absorption wavelength at distinct mWSM thicknesses. Our studies develop simple and effective approaches to acquire the spin-dependent and adjustable perfect absorption without the external magnetic field, and can find practical applications in spin-dependent photonic devices.

Inhibition of CK2α accelerates skin wound healing by promoting endothelial cell proliferation through the Hedgehog signaling pathway.

Diabetes is a chronic disease characterized by perturbed glucose and lipid metabolism, resulting in high blood glucose levels. Many complications induced by endothelial dysfunction can cause disability and even death of diabetic patients. Here, we found that the protein level of casein kinase 2α (CK2α) was increased in the endothelium of mice with type I diabetes (T1D) induced by streptozotocin (STZ) injection. Although a potential correlation between the protein level of CK2α and endothelial dysfunction in diabetes was established, the contribution of CK2α to the progression of endothelial dysfunction in diabetes remained largely unknown. By using CX4945 (a selective CK2α antagonist) and Si-csnk2a1 (small interfering RNA targeting CK2α), we found that inhibition of CK2α accelerated skin wound healing in T1D mice by promoting proliferation of endothelial cells. Administration of CX4945 or Si-csnk2a1 rescued the impaired Hedgehog signaling pathway in high glucose-treated human umbilical vein endothelial cells (HUVECs). Exploration of the underlying molecular mechanism revealed that the protective effect of CK2α inhibition on angiogenesis, which contributes to skin wound healing in diabetic mice, was blocked by administration of GANT61 (an inhibitor targeting the Hedgehog signaling pathway). Our findings establish CK2α as a regulator of endothelial dysfunction in diabetes and demonstrate that inhibition of CK2α accelerates skin wound healing in T1D mice by promoting endothelial cell proliferation via the Hedgehog signaling pathway.

Probing the Effect of Photovoltaic Material on Voc in Ternary Polymer Solar Cells with Non-Fullerene Acceptors by Machine Learning.

The power conversion efficiency (PCE) of ternary polymer solar cells (PSCs) with non-fullerene has a phenomenal increase in recent years. However, improving the open circuit voltage (Voc) of ternary PSCs with non-fullerene still remains a challenge. Therefore, in this work, machine learning (ML) algorithms are employed, including eXtreme gradient boosting, K-nearest neighbor and random forest, to quantitatively analyze the impact mechanism of Voc in ternary PSCs with the double acceptors from the two aspects of photovoltaic materials. In one aspect of photovoltaic materials, the doping concentration has the greatest impact on Voc in ternary PSCs. Furthermore, the addition of the third component affects the energy offset between the donor and acceptor for increasing Voc in ternary PSCs. More importantly, to obtain the maximum Voc in ternary PSCs with the double acceptors, the HOMO and LUMO energy levels of the third component should be around (-5.7 ± 0.1) eV and (-3.6 ± 0.1) eV, respectively. In the other aspect of molecular descriptors and molecular fingerprints in the third component of ternary PSCs with the double acceptors, the hydrogen bond strength and aromatic ring structure of the third component have high impact on the Voc of ternary PSCs. In partial dependence plot, it is clear that when the number of methyl groups is four and the number of carbonyl groups is two in the third component of acceptor, the Voc of ternary PSCs with the double acceptors can be maximized. All of these findings provide valuable insights into the development of materials with high Voc in ternary PSCs for saving time and cost.

MiRNAs as biomarkers for diagnosis of neonatal sepsis: a systematic review and meta-analysis.

BACKGROUND: The relationship between circulating miRNAs and neonatal sepsis and the mechanism of action are still unclear at this time. Therefore, the potential diagnostic role of miRNAs in neonatal sepsis (NS) was studied through meta-analysis. METHOD: Web of Science, Cochrane Library, PubMed, and Embase are retrieved, supplemented by manual search, and the search was conducted to find related studies without time limit until May 2022.The quality of the literature was assessed via QUADAS criteria and meta-analyzed via Stata 11.0 software, including the assessment of specificity, sensitivity, likelihood ratio and diagnostic odds ratio. Then, sensitivity analysis and heterogeneity testing were conducted, and finally, the summary receiver operating characteristics (SROC) curve was drawn. RESULT: This study included 14 articles, including 20 miRNAs and 1597 newborns(control group: 727 and case group: 870). Among them, one article was of low quality, three articles were of high quality, and the rest were of medium quality. According to the results of random effects model analysis, the pooled specificity and sensitivity of miRNA for the diagnosis of NS were 0.83 (95%CI: 0.79-0.87) and 0.76 (95%CI: 0.72-0.80), respectively. And negative likelihood ratio, positive likelihood ratio, and diagnostic odds ratio were 0.29 (95%CI: 0.24-0.34), 4.51 (95%CI: 3.52-5.78), and 15.81 (95%CI: 10.71-23.35), respectively. The area under the SROC curve was 0.86, and there was no evidence publication bias detected in the funnel plot. CONCLUSION: Circulating miRNAs may be very useful in the development of early diagnostic strategies for neonatal sepsis.

The accuracy of soluble urokinase-type plasminogen activator receptor for the diagnosis of neonatal sepsis: a meta-analysis.

Background: Neonatal sepsis is one of the major causes of morbidity and mortality in newborns. However, atypical clinical manifestations and symptoms make the early diagnosis of neonatal sepsis a challenge. Relatively high-serum soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated as a diagnostic biomarker for adult sepsis. Therefore, the meta-analysis is intended to explore the diagnostic value of suPAR for neonatal sepsis. Methods: The PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, China Biological Medicine Disk, and Wanfang databases were retrieved from inception to 31 December 2022 to collect diagnostic accuracy studies about suPAR for neonatal sepsis. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias in the included studies using the quality assessment of diagnostic accuracy studies-2 (QUADAS-2) tool. Then, a meta-analysis was performed using Stata 15.0 software. Results: A total of six articles involving eight studies were included. The results of the meta-analysis showed that the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.89 [95%CI (0.83-0.93)], 0.94 [95%CI (0.77-0.98)], 14 [95%CI (3.5-55.2)], 0.12 [95%CI (0.08-0.18)], and 117 [95%CI (24-567)], respectively. The area under the curve (AUC) of summary receiver operator characteristic (SROC) curves was 0.92 [95%CI (0.90-0.94)]. Sensitivity analysis confirmed the stability of the results, and publication bias was not observed. Fagan's nomogram results demonstrated the clinical availability of the findings. Conclusion: Current evidence suggests that suPAR has potential diagnostic value for neonatal sepsis. Owing to the limited quality of the included studies, more high-quality studies are needed to verify the above conclusion.

The association between mannose binding lectin gene polymorphisms and the risk of neonatal sepsis: an updated meta-analysis.

Objectives: To evaluate the relationship between mannose-binding lectin (MBL) polymorphism and neonatal sepsis to provide ideas for early diagnosis and control of neonatal sepsis using meta-analysis. Methods: The China National Knowledge Infrastructure, WanFang Data, China Biological Medicine Disc, PubMed, Embase, Cochrane Library, and Web of Science databases were electronically searched to collect studies on the association between the MBL gene variants and the risk of neonatal sepsis. Original articles from case-control and cohort studies on the relationship between MBL polymorphisms and neonatal sepsis were considered eligible. Meta-analysis was performed using Stata 15.0 software. The chi-square-based Q test and I2 statistics were used to assess heterogeneity. Forest plots were used to display the results graphically. Potential publication bias was assessed using the Egger and Begg tests and funnel plots. Results: Twenty-two studies, including 4565 cases and 12,746 controls, were included in this meta-analysis. Meta-analysis showed a significant relationship between MBL rs1800450 (codon 54, G > A) and neonatal sepsis in the variant vs. wild types. However, the analysis showed MBL exon 1 gene polymorphism (A/O), MBL rs5030737 (codon 52, C > T), and rs1800451 (codon 57, G > A), involved in existing research, were not associated with the risk of sepsis in neonates. Conclusions: Current evidence shows that MBL rs1800450 is associated with neonatal culture-proven sepsis. Owing to the limited quantity and quality of the included studies, more high-quality studies are required to verify the above conclusion.

Analysis of influencing factors associated with the time between cataract surgery and Nd:YAG laser posterior capsulotomy.

PURPOSE: To retrospectively analyze the clinical data of large samples of YAG laser posterior capsulotomy, and to explore the influencing factors of time from cataract surgery to YAG laser capsulotomy (TFCSTLC), so as to provide reference for the occurrence and treatment of real-world posterior capsular opacification (PCO). METHODS: 1093 patients (1093 eyes) with PCO who underwent YAG laser posterior capsulotomy from 2014 to 2019 in the largest eye center of northwest China were analyzed retrospectively. The gender, age, systemic complications, material, and design of intraocular lens (IOL) and TFCSTLC were recorded. The test and Wilcoxon rank sum test were applied to analyze and compare the average TFCSTLC values under different factors, and the relationship between each factor and TFCSTLC was analyzed by multiple linear regression. RESULTS: The average TFCSTLC was 19.2 (range, 7.9 ∼ 31.2) months. There were significant statistical differences in TFCSTLC among the implanted single focus versus multifocal IOLs (P < 0.001), diabetic versus non-diabetic patients (P < 0.001), high myopia versus non-high myopia patients (P = 0.003). Multiple linear regression analysis demonstrated that TFCSTLC was negatively correlated in patients with diabetes mellitus versus with no history of diabetes mellitus (coefficient, -5.36; 95% confidence interval [CI], -8.30 to -2.41; P < 0 .001), and multifocal IOL versus a single focus IOL implanted (coefficient, -5.56 ; 95% CI, -9.01 to -2.11; P = 0.002). CONCLUSIONS: TFCSTLC may be affected by many factors in the real world. The YAG laser posterior capsulotomy time was sooner in patients with a history of diabetes mellitus and multifocal IOL implanted.

Beneficial effects of Lactobacillus rhamnosus hsryfm 1301 fermented milk on rats with nonalcoholic fatty liver disease.

A growing stream of research suggests that probiotic fermented milk has a good effect on nonalcoholic fatty liver disease. This work aimed to study the beneficial effects of Lactobacillus rhamnosus hsryfm 1301 fermented milk (fermented milk) on rats with nonalcoholic fatty liver disease induced by a high-fat diet. The results showed that the body weight and the serum levels of total cholesterol, total glyceride, low-density lipoprotein, alanine transaminase, aspartate aminotransferase, free fatty acid, and reactive oxygen species were significantly increased in rats fed a high-fat diet (M) for 8 wk, whereas high-density lipoprotein cholesterol and superoxide dismutase were significantly decreased. However, the body weight and the serum levels of total cholesterol, total glyceride, alanine transaminase, aspartate aminotransferase, free fatty acid, reactive oxygen species, interleukin-8, tumor necrosis factor-α, and interleukin-6 were significantly decreased with fermented milk (T) for 8 wk, and the number of fat vacuoles in hepatocytes was lower than that in the M group. There were significant differences in 19 metabolites in serum between the M group and the C group (administration of nonfermented milk) and in 17 metabolites between the T group and the M group. The contents of 7 different metabolites, glycine, glycerophosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, thioetheramide-PC, d-aspartic acid, oleic acid, and l-glutamate, were significantly increased in the M group rat serum, and l-palmitoyl carnitine, N6-methyl-l-lysine, thymine, and 2-oxadipic acid were significantly decreased. In the T group rat serum, the contents of 8 different metabolites-1-O-(cis-9-octadecenyl)-2-O-acetyl-sn-glycero-3-phosphocholine, acetylcarnitine, glycine, glycerophosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, d-aspartic acid, oleic acid, and l-glutamate were significantly decreased, whereas creatinine and thymine were significantly increased. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that 50 metabolic pathways were enriched in the M/C group and T/M group rat serum, of which 12 metabolic pathways were significantly different, mainly distributed in lipid metabolism, amino acid, and endocrine system metabolic pathways. Fermented milk ameliorated inflammation, oxygenation, and hepatocyte injury by regulating lipid metabolism, amino acid metabolic pathways, and related metabolites in the serum of rats with nonalcoholic fatty liver disease.

Nobiletin as a chemopreventive natural product against cancer, a comprehensive review.

As a leading cause of death, second only to heart disease, cancer has always been one of the burning topics in medical research. When targeting multiple signal pathways in tumorigenesis chemoprevention, using natural or synthetic anti-cancer drugs is a vital strategy to reduce cancer damage. However, toxic effects, multidrug resistance (MDR) as well as cancer stem cells (CSCs) all prominently limited the clinical application of conventional anticancer drugs. With low side effects, strong biological activity, unique mechanism, and wide range of targets, natural products derived from plants are considered significant sources for new drug development. Nobiletin is one of the most attractive compounds, a unique flavonoid primarily isolated from the peel of citrus fruits. Numerous studies in vitro and in vivo have suggested that nobiletin and its derivatives possess the eminent potential to become effective cancer chemoprevention agents through various cellular and molecular levels. This article aims to comprehensively review the anticancer efficacy and specific mechanisms of nobiletin, enhancing our understanding of its chemoprevention properties and providing the latest research findings. At the end of this review, we also give some discussion and future perspectives regarding the challenges and opportunities in nobiletin efficient exploitation.

IL-6 upregulates the expression of IL-6R through the JAK2/STAT3 signalling pathway to promote progression of hepatocellular carcinoma.

The progression of hepatocellular carcinoma (HCC) involves multifactor, multistep interactions. High expression of interleukin-6 receptor (IL-6R) plays an important role in the occurrence and development of tumours, but the regulatory mechanism of IL-6R expression and its function in HCC have not been fully defined. Western blot was used to evaluate the phosphorylation of key kinases in the JAK2/STAT3 pathway and the protein expression levels of related proliferation molecules, migration molecules and apoptotic molecules. The antiapoptosis, migration and proliferation of cells of each group were analysed with JC-1 to judge the cell apoptosis rate, the EdU method to determine the proliferation vitality of the cells, clone formation experiments and Transwell experiments. High expression of IL-6R in cell lines, lower protein levels of the apoptotic molecules c-Caspase7 and c-Caspase3 and higher protein levels of the proliferative molecules p-P70S6K and migration molecules MMP9 and MMP2 were consistent with stronger antiapoptosis, proliferation and migration. Interestingly, IL-6 upregulated the expression of IL-6R by activating the JAK2/STAT3 signalling pathway. Also, the expression of IL-6R protein was downregulated after lentivirus knockdown of STAT3. In nude mice bearing subcutaneous tumours, upregulation of IL-6R expression after activation of the JAK2/STAT3 signalling pathway by IL-6 significantly increased tumour growth. Moreover, the expression of IL-6R protein was downregulated, and the terminal tumour volume was significantly downregulated in the lentiviral STAT3 knockdown group. IL-6 regulated the transcription of IL-6R through the activation of the JAK2/STAT3 signalling pathway.

Coal dust nanoparticles induced pulmonary fibrosis by promoting inflammation and epithelial-mesenchymal transition via the NF-κB/NLRP3 pathway driven by IGF1/ROS-mediated AKT/GSK3ß signals.

Pneumoconiosis is the most common and serious disease among coal miners. In earlier work on this subject, we documented that coal dust (CD) nanoparticles (CD-NPs) induced pulmonary fibrosis (PF) more profoundly than did CD micron particles (CD-MPs), but the mechanism has not been thoroughly studied. Based on the GEO database, jveen, STRING, and Cytoscape tools were used to screen hub genes regulating PF. Particle size distribution of CD were analyzed with Malvern nanoparticle size potentiometer. Combining 8 computational methods, we found that IGF1, POSTN, MMP7, ASPN, and CXCL14 may act as hub genes regulating PF. Based on the high score of IGF1 and its important regulatory role in various tissue fibrosis, we selected it as the target gene in this study. Activation of the IGF1/IGF1R axis promoted CD-NPs-induced PF, and inhibition of the axis activation had the opposite effect in vitro and in vivo. Furthermore, activation of the IGF1/IGF1R axis induced generation of reactive oxygen species (ROS) to promote epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) to accelerate PF. High-throughput gene sequencing based on lung tissue suggested that cytokine-cytokine receptor interaction and the NF-kB signaling pathway play a key role in PF. Also, ROS induced inflammation and EMT by the activation of the NF-kB/NLRP3 axis to accelerate PF. ROS can induce the activation of AKT/GSK3ß signaling, and inhibition of it can inhibit ROS-induced inflammation and EMT by the NF-kB/NLRP3 axis, thereby inhibiting PF. CD-NPs induced PF by promoting inflammation and EMT via the NF-κB/NLRP3 pathway driven by IGF1/ROS-mediated AKT/GSK3ß signals. This study provides a valuable experimental basis for the prevention and treatment of coal workers' pneumoconiosis. Illustration of the overall research idea of this study: IGF1 stimulates coal dust nanoparticles induced pulmonary fibrosis by promoting inflammation and EMT via the NF-κB/NLRP3 pathway driven by ROS-mediated AKT/GSK3ß signals.

Accelerated exploration of efficient ternary solar cells with PTB7:PC71BM:SMPV1 using machine-learning methods.

Machine learning (ML) provides an efficient tool for predicting the photoelectric conversion efficiency (PCE) of organic solar cells (OSCs). In this paper, random forest (RF), K-nearest neighbors, and support vector machine are used to predict the PCE for ternary OSCs with PC71BM. The results of ML show that RF has the best PCE prediction accuracy. Therefore, RF is chosen to predict the champion PCE of ternary OSCs with PTB7:PC71BM:SMPV1, which is around 8.01% in ternary OSCs with a doping ratio of around 6 wt% of SMPV1. To check the prediction, ternary OSCs with PTB7:PC71BM:SMPV1 were fabricated, and the experimental results show that the best PCE of 8.83% is obtained in ternary OSCs with 7.5 wt% of SMPV1 introduced. The experiments verify the feasibility of ML in predicting the PCE of ternary OSCs, and its great potential in predicting the doping concentration of the third component for ternary OSCs. Moreover, the working mechanism of the performance enhancement in the ternary OSCs is further researched and demonstrated as the following: (i) an increase in photon capture in the visible light spectrum to enhance the short circuit current density (Jsc); (ii) high priority charge transport to boost the fill factor and Jsc.

Differences in the characteristics and pulmonary toxicity of nano- and micron-sized respirable coal dust.

BACKGROUND: The characteristics of coal dust (CD) particles affect the inhalation of CD, which causes coal worker's pneumoconiosis (CWP). CD nanoparticles (CD-NPs, < 500 nm) and micron particles (CD-MPs, < 5 µm) are components of the respirable CD. However, the differences in physicochemical properties and pulmonary toxicity between CD-NPs and CD-MPs remain unclear. METHODS: CD was analyzed by scanning electron microscopy, Malvern nanoparticle size potentiometer, energy dispersive spectroscopy, infrared spectroscopy, and electron paramagnetic resonance spectroscopy. CCK-8 assay, ELISA, transmission electron microscope, JC-1 staining, reactive oxygen species activity probe, calcium ion fluorescent probe, AO/EB staining, flow cytometry, and western blot were used to determine the differences between CD-NPs and CD-MPs on acute pulmonary toxicity. CCK-8, scratch healing and Transwell assay, hematoxylin-eosin and Masson staining, immunohistochemistry, immunofluorescence, and western blot were applied to examine the effects of CD-NPs and CD-MPs on pneumoconiosis. RESULTS: Analysis of the size distribution of CD revealed that the samples had been size segregated. The carbon content of CD-NPs was greater than that of CD-MPs, and the oxygen, aluminum, and silicon contents were less. In in vitro experiments with A549 and BEAS-2B cells, CD-NPs, compared with CD-MPs, had more inflammatory vacuoles, release of pro-inflammatory cytokines (IL-6, IL-1ß, TNFα) and profibrotic cytokines (CXCL2, TGFß1), mitochondrial damage (reactive oxygen species and Ca2+ levels and decreased mitochondrial membrane potential), and cell death (apoptosis, pyroptosis, and necrosis). CD-NPs-induced fibrosis model cells had stronger proliferation, migration, and invasion than did CD-MPs. In in vivo experiments, lung coefficient, alveolar inflammation score, and lung tissue fibrosis score (mean: 1.1%, 1.33, 1.33) of CD-NPs were higher than those of CD-MPs (mean: 1.3%, 2.67, 2.67). CD-NPs accelerated the progression of pulmonary fibrosis by upregulating the expression of pro-fibrotic proteins and promoting epithelial-mesenchymal transition. The regulatory molecules involved were E-cadherin, N-cadherin, COL-1, COL-3, ZO-1, ZEB1, Slug, α-SMA, TGFß1, and Vimentin. CONCLUSIONS: Stimulation with CD-NPs resulted in more pronounced acute and chronic lung toxicity than did stimulation with CD-MPs. These effects included acute inflammatory response, mitochondrial damage, pyroptosis, and necrosis, and more pulmonary fibrosis induced by epithelial-mesenchymal transition.

ASIC1α up-regulates MMP-2/9 expression to enhance mobility and proliferation of liver cancer cells via the PI3K/AKT/mTOR pathway.

A major challenge in the treatment of liver cancer is that a large proportion of patients fail to achieve long-term disease control, with death from liver cancer cell migration and invasion. Acid-sensitive ion channel 1α (ASIC1α) is involved in the migration, invasion, and proliferation of liver cancer cells. Therefore, we explored the mechanism of ASIC1α-mediated liver cancer cell migration and invasion. We determined the levels of ASIC1α by western blotting and immunofluorescence in HepG2 and SK-Hep1 cells cultured in various acidic conditions. In addition, wound healing assay, transwell invasion assay, and MTT assay were conducted to assess the migration, invasion, and proliferation abilities of liver cancer cells. Western blotting was conducted to determine the levels of MMP2, MMP9, ASIC1α, p-PI3Kp85, t-PI3Kp85, p-AKT(Ser473), t-AKT, p-mTOR (Ser2448), t-mTOR. We first found that the levels of ASIC1α in the HepG2 and SK-Hep1 cells in acidic conditions (pH 6.5) were significantly increased. Inhibition and knockdown of ASIC1α down-regulated MMP-2/9 expression and inhibited the migration, invasion, and proliferation of HepG2 and SK-Hep1 cells; overexpression of ASIC1α had the opposite effect. We further demonstrated that ASIC1α up-regulates MMP-2/9 via activation of the PI3K/AKT/mTOR pathway, thereby promoting migration, invasion, and proliferation of liver cancer cells. Overexpression of MMP-2/9 and activation of AKT reversed these effects on liver cancer cells caused by inhibition of ASIC1α. We conclude that ASIC1α can regulate migration, invasion, and proliferation of liver cancer cells through the MMP-2/9/PI3K/AKT/mTOR pathway. These observations may provide a new reference for liver cancer chemotherapy.

ASIC1a stimulates the resistance of human hepatocellular carcinoma by promoting EMT via the AKT/GSK3ß/Snail pathway driven by TGFß/Smad signals.

Multidrug resistance is the main obstacle to curing hepatocellular carcinoma (HCC). Acid-sensing ion channel 1a (ASIC1a) has critical roles in all stages of cancer progression, especially invasion and metastasis, and in resistance to therapy. Epithelial to mesenchymal transition (EMT) transforms epithelial cells into mesenchymal cells after being stimulated by extracellular factors and is closely related to tumour infiltration and resistance. We used Western blotting, immunofluorescence, qRT-PCR, immunohistochemical staining, MTT, colony formation and scratch healing assay to determine ASIC1a levels and its relationship to cell proliferation, migration and invasion. ASIC1a is overexpressed in HCC tissues, and the amount increased in resistant HCC cells. EMT occurred more frequently in drug-resistant cells than in parental cells. Inactivation of ASIC1a inhibited cell migration and invasion and increased the chemosensitivity of cells through EMT. Overexpression of ASIC1a upregulated EMT and increased the cells' proliferation, migration and invasion and induced drug resistance; knocking down ASIC1a with shRNA had the opposite effects. ASIC1a increased cell migration and invasion through EMT by regulating α and ß-catenin, vimentin and fibronectin expression via the AKT/GSK-3ß/Snail pathway driven by TGFß/Smad signals. ASIC1a mediates drug resistance of HCC through EMT via the AKT/GSK-3ß/Snail pathway.

c-Met up-regulates the expression of PD-L1 through MAPK/NF-κBp65 pathway.

Sorafenib acquired drug resistance during the treatment of hepatocellular carcinoma (HCC) reduces the efficacy of the drug. The immune escape effect induced by PD-L1 is largely associated with drug resistance of HCC. However, the regulated mechanism of PD-L1 is unclear. This research aimed to clarify the control mechanism of PD-L1. c-Met was found abnormally highly expressed in Huh-7SR with high PD-L1 expression. In addition, c-Met, as the upstream target molecule of PD-L1, promoted the proliferation and migration of HCC in vitro and in vivo. We also found that c-Met activated the MAPK signaling pathway and the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression. In conclusion, c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC. The role of c-Met and PD-L1 in HCC needs to be further studied, but it is a potential target for the treatment of HCC. KEY MESSAGES: In the study, it was found that c-Met is also abnormally highly expressed in Huh-7SR with high PD-L1 expression and can promote the development of HCC in vitro and in vivo. PD-L1 and c-Met expression levels are positively correlated. In the follow-up mechanism study, we found that c-Met activated the MAPK signaling pathway and subsequently activated the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression. Our study found that c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC.

Autophagy up-regulated by MEK/ERK promotes the repair of DNA damage caused by aflatoxin B1.

Aflatoxin B1 (AFB1), a kind of mycotoxin, exerts its cytotoxicity by increasing the oxidative damage of target organs, especially the liver. In vivo and in vitro experiments were carried out to elucidate the toxic mechanism of AFB1. The results of MTT, cloning-formation, flow cytometry, immunocytochemistry, Reverse transcription PCR (RT-PCR) and western blot showed that AFB1 activated NOX2 gp91 phox, inhibited proliferation and migration, and blocked cell cycle at G0/G1 period of HHL-5 cells. Autophagy promoted the repair of NOX2-dependent DNA damage. NOX2/gp91 phox mainly activates MEK/ERK pathway and then up-regulates autophagy. In vivo experiments have shown that AFB1 (0.75 mg/kg daily orally, 4 weeks) had no significant changes in the size and shape of the liver in mice. However, these treatments lead to structural abnormalities of hepatocytes and DNA damage. In summary, AFB1 caused intracellular oxidative stress and DNA damage, NOX2/gp91-phox activates the MEK/ERK pathway, and upregulated autophagy to promote the repair of DNA damage. We concluded that by increasing the level of autophagy, the ability of anti-AFB1 toxicity of liver can be increased.

Risk factors for necrotizing enterocolitis in neonates: A meta-analysis.

Objective: The objective is to identify the risk factors for necrotizing enterocolitis (NEC) in neonates by a meta-analysis, and to provide a reference for the prevention of NEC. Methods: The databases, including Chinese Biomedical Literature Datebase, China National Knowledge Infrastructure, Wanfang database, and Weipu Periodical database, PubMed, Web of Science, Embase, Cochrane Library, were searched for studies on the risk factors for NEC in neonates. The meta-analysis was carried out with the aid of Stata software. Results: A total of 52 studies were included, with 48 case-control studies and 4 cohort studies. There were 166,580 neonates in total, with 33,522 neonates in the case group and 133,058 neonates in the control group. The meta-analysis showed that gestational diabetes (OR = 3.62, 95% CI:1.77-7.41), premature rupture of membranes (OR = 3.81, 95% CI:1.16-12.52), low birth weight (OR = 3.00, 95% CI:2.26-3.97), small for gestational age (OR = 1.85, 95% CI:1.15-2.97), septicemia (OR = 4.34, 95% CI:3.06-6.15), blood transfusion (OR = 3.08, 95% CI:2.16-4.38), congenital heart disease (OR = 2.73, 95% CI:1.10-6.78), respiratory distress syndrome (OR = 2.12, 95% CI:1.24-3.63), premature birth (OR = 5.63, 95% CI:2.91-10.92), pneumonia (OR = 4.07, 95% CI:2.84-5.82) were risk factors for NEC in neonates. Breastfeeding (OR = 0.37, 95% CI:0.23-0.59), take probiotics (OR = 0.30, 95% CI:0.22-0.40), prenatal use of glucocorticoids (OR = 0.39, 95% CI:0.30-0.50), Hyperbilirubinemia (OR = 0.28, 95% CI:0.09-0.86) were protective factors for NEC in neonates. Conclusions: Gestational diabetes, premature rupture of membranes, low birth weight, small for gestational age, septicemia, blood transfusion, congenital heart disease, respiratory distress syndrome, premature birth, and pneumonia may increase the risk of NEC in neonates. Breastfeeding, taking probiotics, prenatal use of glucocorticoids, and Hyperbilirubinemia may reduce the risk of NEC in neonates.