Pseudomonas aeruginosa two-component system LadS/PA0034 regulates macrophage phagocytosis via fimbrial protein cupA1.

Pseudomonas aeruginosa is one of the most common nosocomial pathogens worldwide, known for its virulence, drug resistance, and elaborate sensor-response network. The primary challenge encountered by pathogens during the initial stages of infection is the immune clearance arising from the host. The resident macrophages of barrier organs serve as the frontline defense against these pathogens. Central to our understanding is the mechanism by which bacteria modify their behavior to circumvent macrophage-mediated clearance, ensuring their persistence and colonization. To successfully evade macrophage-mediated phagocytosis, bacteria must possess an adaptive response mechanism. Two-component systems provide bacteria the agility to navigate diverse environmental challenges, translating external stimuli into cellular adaptive responses. Here, we report that the well-documented histidine kinase, LadS, coupled to a cognate two-component response regulator, PA0034, governs the expression of a vital adhesin called chaperone-usher pathway pilus cupA. The LadS/PA0034 system is susceptible to interference from the reactive oxygen species likely to be produced by macrophages and further lead to a poor adhesive phenotype with scantily cupA pilus, impairing the phagocytosis efficiency of macrophages during acute infection. This dynamic underscores the intriguing interplay: as macrophages deploy reactive oxygen species to combat bacterial invasion, the bacteria recalibrate their exterior to elude these defenses. IMPORTANCE: The notoriety of Pseudomonas aeruginosa is underscored by its virulence, drug resistance, and elaborate sensor-response network. Yet, the mechanisms by which P. aeruginosa maneuvers to escape phagocytosis during acute infections remain elusive. This study pinpoints a two-component response regulator, PA0034, coupled with the histidine kinase LadS, and responds to macrophage-derived reactive oxygen species. The macrophage-derived reactive oxygen species can impair the LadS/PA0034 system, resulting in reduced expression of cupA pilus in the exterior of P. aeruginosa. Since the cupA pilus is an important adhesin of P. aeruginosa, its deficiency reduces bacterial adhesion and changes their behavior to adopt a planktonic lifestyle, subsequently inhibiting the phagocytosis of macrophages by interfering with bacterial adhesion. Briefly, reactive oxygen species may act as environmental cues for the LadS/PA0034 system. Upon recognition, P. aeruginosa may transition to a poorly adhesive state, efficiently avoiding engulfment by macrophages.

Molecular mechanisms involved in regulating protein activity and biological function of MST3.

Mammalian sterile 20-like (Ste20-like) protein kinase 3 (MST3) or serine/threonine-protein kinase 24 (STK24) is a serine/threonine protein kinase that belongs to the mammalian STE20-like protein kinase family. MST3 is a pleiotropic protein that plays a critical role in regulating a variety of events, including apoptosis, immune response, metabolism, hypertension, tumor progression, and development of the central nervous system. The MST3-mediated regulation is intricately related to protein activity, post-translational modification, and subcellular location. Here, we review the recent progress on the regulatory mechanisms against MST3 and its-mediated control of disease progression.

Comparative genomics studies on the stk gene family in vertebrates: From the bighead carp (Hypophthalmichthys nobilis) genome.

The mammalian sterile 20-like (MST) family belongs to the serine/threonine protein kinase (STK) superfamily and participates in a variety of biological processes, such as cell apoptosis, polarity, migration, immune regulation, inflammatory responses, and cancer. In the economically important bighead carp (Hypophthalmichthys nobilis), the STK gene family and immune-related biological functions may be helpful in increasing its economic yield. However, the comprehensive role of STKs in the bighead carp remains unclear. In this study, the five stk sequences from the bighead carp were divided into two classes: stk3/4 and stk24/25/26. Gene structure and motif prediction analyses confirmed that stk is conserved in the bighead carp. Compared to 26 other vertebrate species, teleosts (including bighead carp) possess more stk members because of teleost-specific whole-genome duplication. Synteny analysis revealed that stk3, stk24, stk25, and stk26 have been relatively conserved in bighead carp during evolution. Meanwhile, stk4 was lost in most Cyprinid species, including bighead carp, during evolution. RNA-seq data revealed that STK expression was associated with various pathogens, and the expression of these STKs (Hnstk3, Hnstk24a, Hnstk24b, Hnstk25, and Hnstk26) was different in seven tissues of bighead carp. In addition, we showed that STK expression levels were dramatically altered in the head kidney and that stk24 was involved in defense against Aeromonas hydrophila. This study provides a molecular basis for the analysis of stk function in bighead carp, and can be used as a reference for further phylogenomics.

Recent progress of biocompatible carbon dots in hypoxia-related fields.

Almost all eukaryotes need oxygen to maintain regular physiological activities. When the organism is under hypoxic situation for a persistent or periodic, it will induce irreversible physiological disorders and even pathological results. Hypoxia is closely related to the pathogenesis of metabolic diseases, cancer, chronic heart disease and kidney disease, myocardial ischemia, as well as reproductive diseases like preeclampsia and endometriosis. Therefore, monitoring and treatment of hypoxia have important implications for the pathophysiology of human-related diseases. Carbon dots (CDs) are emerging nanomaterials developed after 2004 with excellent performance, and have broad application potential in variousdomains likeoptical, biomedicine, energy. Advanced hypoxia therapeutics should be integrated with monitoring and treatment, and CDs with excellent performance are good potential options when sensing is combined with various therapeutic methods. Some researchers have also begun to carry out research in related fields and achieved some results. This article aims to clarify the various applications of CDs in hypoxia-related fields in recent years, including hypoxia sensing and hypoxia tumor theranostics. Finally, the possible challenges and prospects for the application of CDs in hypoxia-related fields are discussed.

6'-O-Galloylpaeoniflorin attenuates Helicobacter pylori-associated gastritis via modulating Nrf2 pathway.

As a common disease of the digestive system, chronic gastritis is inflammation of the gastric mucosa caused by various factors. Helicobacter pylori (H. pylori) is one of the main causes of chronic gastritis, which can lead to gastric mucosal damage and gland atrophy, thereby promoting gastrocarcinogenesis. Oxidative stress and the inflammatory response are important mechanisms of H. pylori-induced gastritis. 6'-O-Galloylpaeoniflorin (GPF) is a substance isolated from peony root with antioxidant and anti-inflammatory activities. However, its role and mechanism in the pathogenesis of H. pylori-induced chronic gastritis remain unclear. This study explored the effects of GPF on H. pylori-induced gastric mucosal oxidative stress and inflammation using flow cytometry, western blotting, real-time quantitative PCR, and immunohistochemistry. We found that H. pylori infection increased oxidative stress and expression of inflammatory cytokines in vitro and in vivo and that these outcomes were inhibited by GPF. Furthermore, GPF activated nuclear factor erythroid-related factor-2 (Nrf2) and its downstream target genes in H. pylori-infected GES-1 cells and mice. The anti-inflammatory and antioxidant effects of GPF on H. pylori-infected cells were attenuated by an Nrf2 inhibitor. Taken together, these data suggest that GPF reduces H. pylori-induced gastric mucosa injury by activating Nrf2 signaling and that GPF is a potential candidate for the treatment of H. pylori-associated gastritis.

Penetration and Cratering of Steel Target by Jets from Titanium Alloy Shaped Charge Liners.

In order to enlarge the crater diameter of shaped charge jet penetration into steel targets, this paper investigates the penetration and cratering characteristics of steel targets by shaped charge jets from titanium alloy liners. Titanium alloy shaped charge liners are prepared separately with mechanical processing and selective laser melting (SLM), and pulsed X-ray radiography is used to identify jet formation characteristics. Jet formation is numerically simulated by AUTODYN-3D, and steel target penetration tests are carried out at a short jet stand-off distance. The results show that AUTODYN-3D can realistically simulate jet formation from titanium alloy liners and that the SLM-processed liner exhibits better penetration performance than the mechanically processed liner. The existing cratering formula of jet penetration is modified to make it consistent with the aperture variations of jet penetration from titanium alloy-lined shaped charges at a short stand-off distance. The findings of this study are expected to provide technical and theoretical support for research on the penetration characteristics of the jets from titanium alloy-lined shaped charges.

[Responses of spatial distribution pattern of the dominant population Artemisia ordosica to enclosure restoration in desert steppe.] / è’æ¼ è‰åŽŸä¼˜åŠ¿ç§ç¾¤æ²¹è’¿ç©ºé—´åˆ†å¸ƒæ ¼å±€å¯¹å°è‚²æ¢å¤çš„å“åº”.

Shrubs play an important role in maintaining biodiversity, stability and ecological service in grassland. Exploring the effects of enclosure on dominant shrub population can provide scientific guidance for grassland restoration and tending management. In this study, we investigated main growth characteristics and spatial distribution pattern of Artemisia ordosica population in four enclosed grasslands with duration of 0, 5, 15, and 25 years. The results showed that population density increased first and then decreased with time extension, and peaked after enclosed for 15 years, which was 3.7 times that of unenclosed plot. The crown and projected area showed opposite responses trend to that of density, which decreased by 31.7% and 52.3% after enclosed 15 years, respectively. The height decreased by 25.3% after 5 years of enclosure, and then increased gradually. Semi-variance function analysis showed that population distribution in all grasslands conformed to Gaussian model. The spatial variation decreased gradually in the early stage of enclosure, and then increased after enclosed for 15 years. Structure ratio in each plot was higher than 0.75, but nugget was relatively small, indicating that spatial autocorrelation of population was mainly affected by structural factors rather than random factors. Spatial distribution of A. ordosica population was patchy and striped. Enclosure reduced spatial variation of population at small scale. However, spatial heterogeneity and scale dependence of population enhanced after enclosed 25 years as plaque dissociating. Our findings suggest that enclosure duration is the key factor affecting plant growth and spatial distribution of dominant population in desert steppe. Long-term fencing enhances the spatial heterogeneity of dominant population. Appropriate human intervention should be carried out after 15 years of enclosure.

Pseudomonas aeruginosa PcrV Enhances the Nitric Oxide-Mediated Tumoricidal Activity of Tumor-Associated Macrophages via a TLR4/PI3K/AKT/mTOR-Glycolysis-Nitric Oxide Circuit.

Tumor-associated macrophages (TAMs), which display a tumor-supportive M2 phenotype, are closely related to tumor growth and metastasis. The reprogramming of TAMs toward a tumoricidal M1 profile has emerged as an attractive strategy for cancer immunotherapy. In this study, we found that the intratumoral injection of PcrV protein, a component of the Pseudomonas aeruginosa type 3 secretion system, suppressed tumor growth and increased apoptosis, inducible nitric oxide synthase (iNOS) expression, and the percentage of M1-polarized TAMs in tumor tissues. Furthermore, the intratumoral injection of PcrV-primed macrophages exerted a similar tumoricidal effect. In vitro analyses revealed that PcrV reeducated TAMs toward an antitumoral M1 phenotype and augmented their nitric oxide (NO)-mediated cytotoxicity against cancer cells. Mechanistically, we found that these effects were dependent on the activation of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated regulation of a PI3K/AKT/mTOR-glycolysis-NO feedback loop via direct interaction with TLR4. Collectively, these results revealed a potential role for PcrV in cancer immunotherapy through the targeting of TAM plasticity.

Berberine mitigates nonalcoholic hepatic steatosis by downregulating SIRT1-FoxO1-SREBP2 pathway for cholesterol synthesis.

OBJECTIVE: To investigate effects of berberine (BBR) on cholesterol synthesis in HepG2 cells with free fatty acid (FFA)-induced steatosis and to explore the underlying mechanisms. METHODS: A steatosis cell model was induced in HepG2 cell line fed with FFA (0.5 mmol/L, oleic acid:palmitic acid = 2:1), and then treated with three concentrations of BBR; cell viability was assessed with cell counting kit-8 assays. Lipid accumulation in cells was observed through oil red O staining and total cholesterol (TC) content was detected by TC assay. The effects of BBR on cholesterol synthesis mediators were assessed by Western blotting and quantitative polymerase chain reaction. In addition, both silent information regulator 1 (SIRT1) and forkhead box transcription factor O1 (FoxO1) inhibitors were employed for validation. RESULTS: FFA-induced steatosis was successfully established in HepG2 cells. Lipid accumulation and TC content in BBR groups were significantly lower (P < 0.05, P < 0.01), associated with significantly higher mRNA and protein levels of SIRT1(P < 0.05, P < 0.01), significantly lower sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy 3-methylglutaryl-CoA reductase levels (P < 0.05, P < 0.01), as well as higher Acetyl-FoxO1 protein level (P < 0.05, P < 0.01) compared to the FFA only group. Both SIRT1 inhibitor SIRT1-IN-1 and FoxO1 inhibitor AS1842856 blocked the BBR-mediated therapeutic effects. Immunofluorescence showed that the increased SIRT1 expression increased FoxO1 deacetylation, and promoted its nuclear translocation. CONCLUSION: BBR can mitigate FFA-induced steatosis in HepG2 cells by activating SIRT1-FoxO1-SREBP2 signal pathway. BBR may emerge as a potential drug candidate for treating nonalcoholic hepatic steatosis.

Compressive Properties and Constitutive Model of Semicrystalline Polyethylene.

The mechanical properties of polyethylene (PE) materials are greatly influenced by their molecular structures, environmental temperature, and strain rate. In this study, static and dynamic compression tests were performed on two semicrystalline PE materials-ultrahigh molecular weight polyethylene (UHMWPE) and high-density polyethylene (HDPE). The stress-strain curves of HDPE and UHMWPE under uniaxial compression at temperatures of -40-120 °C and strain rates of 0.001-5500 s-1 were obtained. The research findings suggest that both the UHMWPE and HDPE showed significant strain rate-strengthening effect and temperature-softening effect. In particular, HDPE exhibited better compression resistance and high-temperature resistance. The relationships between the yield stress and temperature and between the yield stress and strain rate for both materials were fitted, and the Cowper-Symonds constitutive model was built while considering the temperature effect. The parameters of the constitutive model were obtained and input into LS-DYNA software to simulate the dynamic compression process of HDPE. The simulation result was consistent with the test result, validating the accuracy of the constitutive parameters.

Metformin Targets Foxo1 to Control Glucose Homeostasis.

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.

The Associations of Genital Mycoplasmas with Female Infertility and Adverse Pregnancy Outcomes: a Systematic Review and Meta-analysis.

The roles of genital mycoplasmas including Mycoplasma genitalium (M. genitalium), Mycoplasma hominis (M. hominis), Ureaplasma urealyticum (U. urealyticum), and Ureaplasma parvum (U. parvum) in reproductive diseases are equivocal. To investigate whether genital mycoplasmas are risk factors of female infertility and adverse pregnancy outcomes, we performed a systematic review and meta-analysis. Electronic databases were searched for related studies. A random-effects model or fixed-effects model was employed to generate forest plots. Pooled odd ratios (ORs) with 95% confidence intervals (CIs) were applied to measure the strength of associations. Meanwhile, heterogeneity was evaluated by H statistic and I2 statistic, and publication bias was explored by funnel plots based on Egger's test and Begg's test. The search yielded 2054 relevant records, and 35 articles were ultimately included for meta-analysis. M. genitalium was a significant risk factor for female infertility (OR, 13.03 [95% CI, 3.46-48.98]) and preterm birth (PTB) (OR, 1.81 [95% CI, 1.17-2.80]), but not for spontaneous abortion (SA) (OR, 0.58 [95% CI, 0.25-1.35]). M. hominis can significantly increase the potential risk of female infertility (OR, 1.56 [95% CI, 1.02-2.38]), SA (OR, 9.14 [95% CI, 4.14-20.18]), stillbirth (OR, 3.98 [95% CI, 1.39-11.36]), and premature rupture of membranes (PROM) (OR, 1.79 [95% CI, 1.26-2.55]), but was not associated with PTB (OR, 1.29 [95% CI, 0.78-2.15]). U. urealyticum had no significant risk effect on female infertility (OR, 0.68 [95% CI, 0.42-1.11]). Coinfections of M. hominis and Ureaplasma were significantly associated with female infertility, SA, and stillbirth, but not with PROM. On the basis of current evidences, this meta-analysis supports that M. genitalium is a risk factor for female infertility and PTB; M. hominis is a potential risk factor for female infertility, SA, stillbirth, and PROM; U. urealyticum has no significant association with female infertility; and the relationship of U. parvum with female infertility and adverse pregnancy outcomes needs to be paid more attention to and remains to be further revealed.

Berberine impairs coxsackievirus B3-induced myocarditis through the inhibition of virus replication and host pro-inflammatory response.

Berberine (BBR), an isoquinoline alkaloid isolated from Rhizoma coptidis, is reported to possess antiviral activity. Our previous study has shown that BBR alleviates coxsackievirus B3 (CVB3) replication in HeLa cells. However, the anti-CVB3 activity of BBR is still unclear in vivo. In this study, we explored the effect of BBR on CVB3-induced viral myocarditis in mice. These results demonstrated the beneficial effect of BBR on alleviating CVB3-induced myocarditis in vivo, which sheds new light on the utility of BBR as a therapeutic strategy against CVB3-induced viral myocarditis.

Simulation study on modified coil configuration used for shrink fitting of semi-built-up crankshaft and parameters influencing the thermal distribution.

Semi-built-up crankshafts are universally manufactured by shrink-fitting process with induction heating device. The configurations of induction coil have a great impact on the distributions of eddy current and temperature of crankthrows. Most induction devices are apt to cause some undesirable phenomena such as uneven temperature distribution and irregular deformation after induction heating. This article proposes a modified configuration of induction heating coil according to the crankthrow geometry. By combining the heat conduction equation and the heat boundary conditions, a three-dimensional finite element model, which takes into account the nonlinearity of the material's electromagnetic and thermal physical properties in the heating process, was developed. The influence of several parameters, such as position and curvature of the arc coil, the current frequency and density, coaxiality of crankweb hole and coil, influencing the temperature distribution inside the crankthrow was also analyzed. The comparison with the numerical simulation results of the original configuration indicates that the modified configuration has better adaptability to the crankthrow. Also, it can help to improve the temperature distribution, and reduce the deformation of the shrink-fitting hole. This exploration provide an effective way for the enterprise to further enhance the shrink-fitting quality of crankshaft.

Type III Secretion Protein, PcrV, Impairs Pseudomonas aeruginosa Biofilm Formation by Increasing M1 Macrophage-Mediated Anti-bacterial Activities.

Pseudomonas aeruginosa biofilms employ a variety of strategies to hijack the host immune defense system to achieve chronic infection. However, the bacterial components that are involved in this process are not yet fully understood. PcrV, a needle tip protein of the P. aeruginosa type III secretion system (T3SS), was downregulated during P. aeruginosa biofilm infection. The impaired expression of the P. aeruginosa pcrV gene is associated with attenuated immune activation and an increased percentage of M2 macrophages following P. aeruginosa biofilm infection. Treatment with exogenous PcrV produced from Escherichia coli elevated tissue inflammation and the percentage of M1 macrophages, resulting in reduction in the biofilm burden. Further analyses demonstrated that the potential of PcrV to induce classically activated M1 macrophages as evidenced by the increased production of proinflammatory cytokines and anti-bacterial mediators, including inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS), as well as increased phagocytosis of bacteria. Mechanistically, PcrV-mediated promotion of macrophage M1 polarization and phagocytosis occurs through the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. Collectively, these findings reveal a potential role of PcrV in skewing host immune defense to promote P. aeruginosa biofilm infection and provide new insights into the therapeutic strategies for P. aeruginosa biofilm infection.

Hyperoside Alleviates High Glucose-Induced Proliferation of Mesangial Cells through the Inhibition of the ERK/CREB/miRNA-34a Signaling Pathway.

PURPOSE: Hyperoside, a flavonoid isolated from conventional medicinal herbs, has been demonstrated to exert a significant protective effect in diabetic nephropathy. This study aimed to determine the underlying mechanisms, by which hyperoside inhibits high glucose-(HG-) induced proliferation in mouse renal mesangial cells. METHODS: Mouse glomerular mesangial cells line (SV40-MES13) was used to study the inhibitory effect of hyperoside on cell proliferation induced by 30 mM glucose, which was used to simulate a diabetic condition. Viable cell count was assessed using the Cell Counting Kit-8 and by the 5-ethynyl-20-deoxyuridine incorporation assay. The underlying mechanism involving miRNA-34a was further investigated by quantitative RT-PCR and transfection with miRNA-34a agomir. The phosphorylation levels of extracellular signal-regulated kinases (ERKs) and cAMP-response element-binding protein (CREB) were measured by Western blotting. The binding region and the critical binding sites of CREB in the miRNA-34a promoter were investigated by the chromatin immunoprecipitation assay and luciferase reporter assay, respectively. RESULTS: We found that hyperoside could significantly decrease HG-induced proliferation of SV40-MES13 cells in a dose-dependent manner, without causing obvious cell death. In addition, hyperoside inhibited the activation of ERK pathway and phosphorylation of its downstream transcriptional factor CREB, as well as the miRNA-34a expression. We further confirmed that CREB-mediated regulation of miRNA-34a is dependent on the direct binding to specific sites in the promoter region of miRNA-34a. CONCLUSION: Our cumulative results suggested that hyperoside inhibits the proliferation of SV40-MES13 cells through the suppression of the ERK/CREB/miRNA-34a signaling pathway, which provides new insight to the current investigation on therapeutic strategies for diabetic nephropathy.

[N2 O Emissions from Tea Plantations with Sorghum Intercropping and Application of Big Urea Pills].

A large amount of fertilizers are applied to the tea plantations resulting in high nitrous oxide (N2O) emissions. The area of Chinese tea plantations has been expanding in recent years, making them an important source of agricultural N2O emissions. There is an urgent need for effective mitigation measures for N2O emissions from tea plantations. In this study, the N2O emission flux and related environmental factors are measured in Chinese mid-subtropical typical hilly tea plantation under three kinds of management measures, namely intercropping sorghum, applying big urea pills, and under conventional fertilization conditions. The aim of this experiment is to determine the main factors controlling N2O emissions from the soils of the tea plantation and confirm the true effectiveness of the proposed N2O emission mitigation measures. The results of a 2-year field experiment show that:① N2O emissions were significantly correlated with soil chemical properties, temperature and rainfall, interaction between soil physical and chemical properties; soil chemical properties have the greatest impact on soil N2O emissions. The concentration of soil NO3--N is the most important factor determining the size of N2O flux in the tea plantation. The most important task of N2O emission mitigation research in the tea plantation is to reduce the concentration of soil NO3--N; ② sorghum intercropping reduces N2O emissions by 51.2% while not affecting the tea yield. From the perspective of mitigating global warming, sorghum intercropping is the best tea plantation management measure per the results of this study; ③ applying big urea pills effectively increases tea yield while simultaneously reducing the N2O emissions by 34.7%. From the perspective of balancing economic benefits as well as mitigating global warming, application of big urea pills is undoubtedly the best tea plantation management measure as indicated by this study.

Dynamic Constitutive Model of Ultra-High Molecular Weight Polyethylene (UHMWPE): Considering the Temperature and Strain Rate Effects.

The temperature and strain rate significantly affect the ballistic performance of UHMWPE, but the deformation of UHMWPE under thermo-mechanical coupling has been rarely studied. To investigate the influences of the temperature and the strain rate on the mechanical properties of UHMWPE, a Split Hopkinson Pressure Bar (SHPB) apparatus was used to conduct uniaxial compression experiments on UHMWPE. The stress-strain curves of UHMWPE were obtained at temperatures of 20-100 °C and strain rates of 1300-4300 s-1. Based on the experimental results, the UHMWPE belongs to viscoelastic-plastic material, and a hardening effect occurs once UHMWPE enters the plastic zone. By comparing the stress-strain curves at different temperatures and strain rates, it was found that UHMWPE exhibits strain rate strengthening and temperature softening effects. By modifying the Sherwood-Frost model, a constitutive model was established to describe the dynamic mechanical properties of UHMWPE at different temperatures. The results calculated using the constitutive model were in good agreement with the experimental data. This study provides a reference for the design of UHMWPE as a ballistic-resistant material.

Mibefradil Alleviates High-Glucose-induced Cardiac Hypertrophy by Inhibiting PI3K/Akt/mTOR-mediated Autophagy.

Cardiac hypertrophy causes heart failure and is associated with hyperglycemia in patients with diabetes mellitus. Mibefradil, which acts as a T-type calcium channel blocker, exerts beneficial effects in patients with heart failure. In this study, we explored the effects and mechanism of mibefradil on high-glucose-induced cardiac hypertrophy in H9c2 cells. H9c2 cells were incubated in a high-glucose medium and then treated with different concentrations of mibefradil in the presence or absence of the Akt inhibitor MK2206 or mTOR inhibitor rapamycin. Cell size was evaluated through immunofluorescence, and mRNA expression of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain) was assessed by using quantitative real-time polymerase chain reaction. Changes in the expression of p-PI3K, p-Akt, and p-mTOR were evaluated using Western blotting, and autophagosome formation was detected using transmission electron microscopy. Our results indicate that mibefradil reduced the size of H9c2 cells, decreased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain, and decreased the level of autophagic flux. However, MK2206 and rapamycin induced autophagy and reversed the effects of mibefradil on high-glucose-induced H9c2 cells. In conclusion, mibefradil ameliorated high-glucose-induced cardiac hypertrophy by activating the PI3K/Akt/mTOR pathway and inhibiting excessive autophagy. Our study shows that mibefradil can be used therapeutically to ameliorate cardiac hypertrophy in patients with diabetes mellitus.

CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification.

BACKGROUND: Aberrant expression of circular RNAs contributes to the initiation and progression of cancers, but the underlying mechanism remains elusive. METHODS: RNA-seq and qRT-PCR were performed to screen differential expressed circRNAs between gastric cancer tissues and adjacent normal tissues. Candidate circRNA (circMRPS35) was screened out and validated by qRT-PCR. Cell proliferation and invasion ability were determined by CCK-8 and cell invasion assays. RNA-seq, GO-pathway, RNA pull-down and ChIRP were further applied to search for detailed mechanism. RESULTS: Here, a novel circRNA named circMRPS35, was screened out by RNA-seq in gastric cancer tissues, whose expression is related to clinicopathological characteristics and prognosis in gastric cancer patients. Biologically, circMRPS35 suppresses the proliferation and invasion of gastric cancer cells in vitro and in vivo. Mechanistically, circMRPS35 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of FOXO1 and FOXO3a genes, which elicits acetylation of H4K5 in their promoters. Particularly, circMRPS35 specifically binds to FOXO1/3a promoter regions directly. Thus, it dramatically activates the transcription of FOXO1/3a and triggers subsequent response of their downstream target genes expression, including p21, p27, Twist1 and E-cadherin, resulting in the inhibition of cell proliferation and invasion. Moreover, circMRPS35 expression positively correlates with that of FOXO1/3a in gastric cancer tissues. CONCLUSIONS: Our findings not only reveal the pivotal roles of circMRPS35 in governing histone modification in anticancer treatment, but also advocate for triggering circMRPS35/KAT7/FOXO1/3a pathway to combat gastric cancer.