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Double-arch tunnels, as one of the popular forms of tunnels, might be exposed to boiling liquid expanding vapour explosions (BLEVEs) associated with transported liquified petroleum gas (LPG), which could cause damage to the tunnel and even catastrophic collapse of the tunnel in extreme cases. However, very limited study has investigated the performance of double-arch tunnels when exposed to internal BLEVEs and in most analyses of tunnel responses to accidental explosions. The TNT-equivalence method was used to approximate the explosion load, which may lead to inaccurate tunnel response predictions. This study numerically investigates the response of typical double-arch tunnels to an internal BLEVE resulting from the instantaneous rupture of a 20 m3 LPG tank. Effects of various factors, including in-situ stresses, BLEVE locations, and lining configurations on tunnel responses are examined. The results show that the double-arch tunnels at their early-operation ages are more vulnerable to severe damage when exposed to the BLEVE due to the low action of in-situ stress of rock mass on the response of early-age tunnels. It is also found that directing the LPG tank to different driving lanes inside tunnels can affect the BLEVE-induced tunnel response more significantly than varying the configurations of tunnel lining. Moreover, installing section-steel arches in the mid-wall can effectively improve the blast resistance of the double-arch tunnels against the internal BLEVE. In addition, the prediction models based on multi-variate nonlinear regressions and machine learning methods are developed to predict the BLEVE-induced damage levels of the double-arch tunnels without and with section-steel arches.

Abstract The human gastrointestinal tract is populated with a diverse microbial community. The vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect of human biology, including health maintenance, development, aging, and disease. The advent of new sequencing technologies and culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations to shed light on microbiome–host interactions. Evidence has unveiled the bidirectional communication between the gut microbiome and the central nervous system, referred to as the “microbiota–gut–brain axis”. The microbiota–gut–brain axis represents an important regulator of glial functions, making it an actionable target to ameliorate the development and progression of neurodegenerative diseases. In this review, we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases. As the gut microbiome provides essential cues to microglia, astrocytes, and oligodendrocytes, we examine the communications between gut microbiota and these glial cells during healthy states and neurodegenerative diseases. Subsequently, we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases using a metabolite-centric approach, while also examining the role of gut microbiota-related neurotransmitters and gut hormones. Next, we examine the potential of targeting the intestinal barrier, blood–brain barrier, meninges, and peripheral immune system to counteract glial dysfunction in neurodegeneration. Finally, we conclude by assessing the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. A thorough comprehension of the microbiota–gut–brain axis will foster the development of effective therapeutic interventions for the management of neurodegenerative diseases.

Abstract Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity globally. Studies have shown that infections especially bacteraemia and sepsis are associated with increased risks for endothelial dysfunction and related CVDs including atherosclerosis. Extracellular vesicles (EVs) are small, sealed membrane‐derived structures that are released into body fluids and blood from cells and/or microbes and are critically involved in a variety of important cell functions and disease development, including intercellular communications, immune responses and inflammation. It is known that EVs‐mediated mechanism(s) is important in the development of endothelial dysfunction in infections with a diverse spectrum of microorganisms including Escherichia coli, Candida albicans, SARS‐CoV‐2 (the virus for COVID‐19) and Helicobacter pylori. H. pylori infection is one of the most common infections globally. During H. pylori infection, EVs can carry H. pylori components, such as lipopolysaccharide, cytotoxin‐associated gene A, or vacuolating cytotoxin A, and transfer these substances into endothelial cells, triggering inflammatory responses and endothelial dysfunction. This review is to illustrate the important role of EVs in the pathogenesis of infectious diseases, and the development of endothelial dysfunction in infectious diseases especially H. pylori infection, and to discuss the potential mechanisms and clinical implications.

Iron tailing porous concrete (ITPC) is a new foamed concrete material that using iron ore tailing powder to partially replace the cement. Previous investigations on ITPC primarily focused on its mechanical properties under static loads or low strain rate conditions, leaving a significant gap in its impact resistance performance at high strain rates. This study employed the split Hopkinson pressure bar (SHPB) to test ITPC specimens under impact loading with strain rate around 120 s−1. Density, water-binder (W/B) ratio, iron tailing powder content, polypropylene fiber length and content were taken as key design variables to prepare the ITPC specimens with different mix ratios and study their effects on the dynamic material properties of ITPC. Specifically, the failure modes, stress-strain relations, elastic moduli, compressive strengths and energy dissipation densities of the ITPC specimens with various design variables were recorded and compared. The test results indicate that the material density, fiber length and content have strong influences on the impact failure modes of ITPC. The elastic modulus, compressive strength and energy dissipation density of ITPC exhibit exponential growth with the material density. These parameters, however, show an initial growth followed by a decrease with the rising W/B ratio, fiber length and fiber content, and they reach the peak values at around 0.70, 9 mm and 2.0%, respectively. Moreover, the iron tailing powder content of 25% is recommended for ITPC for maintaining good impact resistance.

Accidental boiling liquid expansion vapour explosions (BLEVEs) caused by the bursting of liquified petroleum gas (LPG) tank inside a tunnel can induce vibrations of its surrounding geological media and threaten the stability of adjacent tunnels and structures. Therefore, it is essential to understand the characteristics of vibrations induced by LPG BLEVEs inside the tunnel for the safety design of its adjacent structures. Owing to the difficulty in effectively predicting the LPG BLEVE loads, the current practice usually employs equivalent methods, e.g., the TNT-equivalency method, in LPG BLEVE load predictions for structural response analysis, which may lead to inaccurate response predictions. This study compares ground vibrations induced by a BLEVE inside an arched road tunnel with those induced by its equivalent TNT explosion via high-fidelity numerical simulations. The results demonstrate that the frequency of BLEVE-induced vibrations is lower than that induced by the TNT explosion at the same scaled distance. The intensity of LPG BLEVE-induced vibrations at relatively small-scaled distances is lower than that of TNT explosion-induced vibrations at the same scaled distance, but becomes higher after a certain scaled distance because of the relatively low attenuation rate. In addition, parametric analysis is conducted to evaluate the effects of various factors on the characteristics of LPG BLEVE-induced ground vibrations. It is found that the surrounding rock type, the rock porosity, and the cover depth of the tunnel have more significant influences than the concrete grade of the tunnel lining. The recommendation for the tunnel design is also given based on the intensity and frequency characteristics of BLEVE-induced vibrations.

This study aims to investigate the behaviour of reinforced concrete (RC) beams strengthened by Carbon Fibre-Reinforced Polymer (CFRP) under static and impact loads. A series of RC beams were tested and categorized into four groups, namely, unstrengthened RC beams (B1), RC beams strengthened with a CFRP longitudinal strip in the tension zone (B2), RC beams wrapped with CFRP fabric (B3), and RC beams strengthened with a combination of both CFRP longitudinal strips and wraps (B4). The results show that the average load–displacement capacity of RC beam group (B4) was improved by 84.88% as compared with the unstrengthened beam (B1) under static loads. The dynamic test results demonstrated an increase in the deflection resistance of RC beam group (B4) by −57.89% as compared with unstrengthened RC beam group (B1) under identical drop weights of 1 m. In addition, a collapse failure mode was noticed in the unstrengthened beams, while minor damage was recorded mainly in the case of RC beam group (B4). Furthermore, the numerical analysis conducted using LS-DYNA software (V 971 R6.0.0) proved that the adopted numerical models can efficiently predict the behaviour of RC beams under dynamic loads, with maximum differences reaching up to −12.5% compared with the experimental test results.

As a green environmentally-friendly material, rubberised concrete (RuC), which has the characteristics of low elastic modulus, large deformation capacity, high damping, good energy dissipation and good crack resistance, has attracted extensive attention and research in the civil engineering discipline. However, most of existing studies are based on experimental tests on RuC material properties, and there has been no numerical study based on meso-scale modelling of RuC yet. To more comprehensively investigate the RuC dynamic material properties without conducting intensive experimental tests, this study developed a high-fidelity meso-scale model considering coarse and fine aggregates and rubber crumbs to numerically investigate the mechanical properties of rubberised concrete under different strain rates. The meso-scale model was verified against both quasi-static compressive testing data and Split Hopkinson Pressure Bar (SHPB) dynamic testing data. Using the verified numerical model, the dynamic properties of rubberised concrete with various rubber content (0%–30%) under different strain rates were studied. The numerical results show that the developed meso-scale model can use to predict the static and dynamic properties of rubberised concrete with high accuracy. The dynamic compressive strength of the rubberised concrete increases with the increment of the strain rate, and the strain rate sensitivity increases with the rubber content ranging from 0 to 30%. Based on intensive numerical simulation data, empirical DIFs is used as a function of strain rate and rubber content to predict the dynamic strength of rubberised concrete.

Abstract Prefabricated construction is attracting increasing interest in recent years, since this construction method has various advantages as compared to the cast-in-situ construction method, such as less construction time, higher quality control and reduced environmental impact. As a typical type of prefabricated structures, precast segmental column (PSC) has been used as the substructure to accelerate the construction speed of bridges. This paper reviews the performances of the PSCs under seismic loadings. In particular, the seismic performances of the PSC itself under cyclic loading and real earthquake ground motions, the seismic behaviours of PSC-supported bridge structures, and the responses of precast rocking column (PRC)-supported bridges, are comprehensively reviewed and their pros and cons are discussed. For the completeness of the paper, the performances of the PSCs under multiple dynamic hazards, namely impact and blast loadings here are also briefly summarized at the end of this paper.

BackgroundSubstantial sex differences exist in atherosclerosis. Excessive reactive oxygen species (ROS) formation could lead to endothelial dysfunction which is critical to atherosclerosis development and progression. Helicobacter pylori (H. pylori) infection has been shown to attenuate endothelial function via exosomes-mediated ROS formation. We have demonstrated that H. pylori infection selectively increases atherosclerosis risk in males with unknown mechanism(s). The present study was to test the hypothesis that H. pylori infection impaired endothelial function selectively in male mice through exosome-mediated ROS formation.Methods and resultsAge-matched male and female C57BL/6 mice were infected with CagA+ H. pylori to investigate sex differences in H. pylori infection-induced endothelial dysfunction. H. pylori infection attenuated acetylcholine (ACh)-induced endothelium-dependent aortic relaxation without changing nitroglycerine-induced endothelium-independent relaxation in male but not female mice, associated with increased ROS formation in aorta compared with controls, which could be reversed by N-acetylcysteine treatment. Treatment of cultured mouse brain microvascular endothelial cells with exosomes from H. pylori infected male, not female, mice significantly increased intracellular ROS production and impaired endothelial function with decreased migration, tube formation, and proliferation, which could be prevented with N-acetylcysteine treatment.ConclusionsH. pylori infection selectively impairs endothelial function in male mice due to exosome-mediated ROS formation.

Atherosclerosis remains a leading cause of cardiovascular diseases. Although the mechanism for atherosclerosis is complex and has not been fully understood, inflammation and oxidative stress play a critical role in the development and progression of atherosclerosis. N-acetylcysteine (NAC) has been used as a mucolytic agent and an antidote for acetaminophen overdose with a well-established safety profile. NAC has antioxidant and anti-inflammatory effects through multiple mechanisms, including an increase in the intracellular glutathione level and an attenuation of the nuclear factor kappa-B mediated production of inflammatory cytokines like tumor necrosis factor-alpha and interleukins. Numerous animal studies have demonstrated that NAC significantly decreases the development and progression of atherosclerosis. However, the data on the outcomes of clinical studies in patients with atherosclerosis have been limited and inconsistent. The purpose of this review is to summarize the data on the effect of NAC on atherosclerosis from both pre-clinical and clinical studies and discuss the potential mechanisms of action of NAC on atherosclerosis, as well as challenges in the field.

BackgroundExposure to fine particulate matter (PM) is a significant risk for cardiovascular diseases largely due to increased reactive oxygen species (ROS) production and inflammation. Caspase recruitment domain (CARD)9 is critically involved in innate immunity and inflammation. The present study was designed to test the hypothesis that CARD9 signaling is critically involved in PM exposure-induced oxidative stress and impaired recovery of limb ischemia.Methods and resultsCritical limb ischemia (CLI) was created in male wildtype C57BL/6 and age matched CARD9 deficient mice with or without PM (average diameter 2.8 μm) exposure. Mice received intranasal PM exposure for 1 month prior to creation of CLI and continued for the duration of the experiment. Blood flow and mechanical function were evaluated in vivo at baseline and days 3, 7, 14, and 21 post CLI. PM exposure significantly increased ROS production, macrophage infiltration, and CARD9 protein expression in ischemic limbs of C57BL/6 mice in association with decreased recovery of blood flow and mechanical function. CARD9 deficiency effectively prevented PM exposure-induced ROS production and macrophage infiltration and preserved the recovery of ischemic limb with increased capillary density. CARD9 deficiency also significantly attenuated PM exposure-induced increase of circulating CD11b+/F4/80+ macrophages.ConclusionThe data indicate that CARD9 signaling plays an important role in PM exposure-induced ROS production and impaired limb recovery following ischemia in mice.

Abstract Currently, the relationship of bifurcation morphology and aneurysm presence at the major cerebral bifurcations is not clear. This study was to investigate cerebral arterial bifurcation morphology and accompanied hemodynamic stresses associated with cerebral aneurysm presence at major cerebral arterial bifurcations. Cerebral angiographic data of major cerebral artery bifurcations of 554 anterior cerebral arteries, 582 internal carotid arteries, 793 middle cerebral arteries and 195 basilar arteries were used for measurement of arterial diameter, lateral and bifurcation angles and aneurysm deviation. Hemodynamic stresses were analyzed using computational fluid dynamic simulation. Significantly (P

Cylindrical specimens are commonly used in Split Hopkinson pressure bar (SHPB) tests to study the uniaxial dynamic properties of concrete-like materials. In recent years, true tri-axial SHPB equipment has also been developed or is under development to investigate the material dynamic properties under tri-axial impact loads. For such tests, cubic specimens are needed. It is well understood that static material strength obtained from cylinder and cube specimens are different. Conversion factors are obtained and adopted in some guidelines to convert the material strength obtained from the two types of specimens. Previous uniaxial impact tests have also demonstrated that the failure mode and the strain rate effect of cubic specimens are very different from that of cylindrical ones. However, the mechanical background of these findings is unclear. As an extension of the previous laboratory study, this study performs numerical SHPB tests of cubic and cylindrical concrete specimens subjected to uniaxial impact load with the validated numerical model. The stress states of cubic specimens in relation to its failure mode under different strain rates is analyzed and compared with cylindrical specimens. The detailed analyses of the numerical simulation results show that the lateral inertial confinement of the cylindrical specimen is higher than that of the cubic specimen under the same strain rates. For cubic specimen, the corners are more severely damaged because of the lower lateral confinement and the occurrence of the tensile radial stress which is not observed in cylindrical specimens. These results explain why the dynamic material strengths obtained from the two types of specimens are different and are strain rate dependent. Based on the simulation results, an empirical formula of conversion factor as a function of strain rate is proposed, which supplements the traditional conversion factor for quasi-static material strength. It can be used for transforming the dynamic compressive strength from cylinders to cubes obtained from impact tests at different strain rates.

Genomic instability is a prominent hallmark of cancer, however the mechanisms that drive and sustain this process remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability ectopically express meiosis-specific genes and undergo meiomitosis, the clash of mitotic and meiotic processes. These meiotic genes may represent novel therapeutic targets for the treatment of cancer. We studied the relationship between the expression of the meiosis protein HORMAD1 and genomic instability in squamous cell carcinomas (SCCs). First, we assessed markers of DNA damage and genomic instability following knockdown and overexpression of HORMAD1 in different cell lines representing SCCs and epithelial cancers. shRNA-mediated depletion of HORMAD1 expression resulted in increased genomic instability, DNA damage, increased sensitivity to etoposide, and decreased expression of DNA damage response/repair genes. Conversely, overexpression of HORMAD1 exhibited protective effects leading to decreased DNA damage, enhanced survival and decreased sensitivity to etoposide. Furthermore, we identified a meiotic molecular pathway that regulates HORMAD1 expression by targeting the upstream meiosis transcription factor STRA8. Our results highlight a specific relationship between HORMAD1 and genomic instability in SCCs, suggesting that selectively inhibiting HORMAD1, possibly, through STRA8 signaling, may provide a new paradigm of treatment options for HORMAD1-expressing SCCs.

Heat shock protein 90 (Hsp90) has evolved as a cancerous cell growth regulator by stabilising various oncogenic kinases. Upon the Hsp90 inhibition, the expression of its client proteins is downregulated and thus leads to denaturation of cellular proteins and cancer cell death. Hsp90 inhibitors, particularly those naturally derived from plants, fungi and bacteria, have gained substantial interest as a feasible therapeutic approach for cancer treatment due to their diverse pharmacological properties. In order to gain insights into the potential development of more efficacious Hsp90 inhibitors for cancer treatment, this review is conducted to analyse both in vitro and in vivo data on the chemical and biological activities of natural Hsp90 inhibitors. The systematic search was conducted in databases (PubMed, Scopus and Web of Science) with terms “Hsp90 inhibitor” and “cancer”, prompting a total of 61 articles after screening with inclusion criteria. This comprehensive review systematically summarised the efficacy of 14 different classes of naturally derived Hsp90 inhibitors in cancerous cell and animal tumour models by consolidating the primary outcomes in terms of IC50, reduction of tumour size and physicochemical properties. The detailed pharmacodynamic (the structure-activity relationship, mechanism of action) and pharmacokinetics (toxicity, oral bioavailability) of these Hsp90 inhibitors together with the study limitations were discussed. Collectively, these findings emphasise the necessity of comprehending the molecular mechanisms as well as the correlation of Hsp90 and its relative client proteins to drive the generation of viable Hsp90 inhibitors with improved pharmacodynamic and pharmacokinetic profiles.

ObjectivesTo explore the associations between posterior communicating artery (PComA) aneurysms and morphological characteristics of arteries upstream of and around the PComA bifurcation site.MethodsIn this study, fifty-seven patients with PComA aneurysms and sixty-two control subjects without aneurysms were enrolled. The centerlines of the internal carotid artery (ICA) and important branches were generated for the measurement and analysis of morphological parameters, such as carotid siphon types, diameters of two fitting circles, and the angle formed by them (D1, D2, and ϕ), length (L) and tortuosity (TL) of ICA segment between an ophthalmic artery and PComA bifurcations, bifurcation angle (θ), tortuosity (TICA and TPComA), and flow direction changes (θICA and θPComA) around the PComA bifurcation site.ResultsNo significant difference (p > 0.05) was found in the siphon types (p = 0.467) or L (p = 0.114). Significant differences (p < 0.05) were detected in D1 (p = 0.036), TL (p < 0.001), D2 (p = 0.004), ϕ (p = 0.008), θ (p = 0.001), TICA (p < 0.001), TPComA (p = 0.012), θICA (p < 0.001), and θPComA (p < 0.001) between the two groups. TICA had the largest area under the curve (AUC) (0.843) in the receiver operating characteristic (ROC) analysis in diagnosing the probability of PComA aneurysms presence and was identified as the only potent morphological parameter (OR = 11.909) associated with PComA aneurysms presence.ConclusionsThe high tortuosity of the ICA segment around the PComA bifurcation is associated with PComA aneurysm presence.

Background and ObjectiveInflammatory bowel disease (IBD) produces significant local and systemic inflammation with increased reactive oxygen species (ROS) formation. IBD Patients are at an increased risk for developing endothelial dysfunction and cardiovascular diseases. The present study tested the hypothesis that IBD impairs aortic endothelial function via ROS formation and investigate potential sex-related differences.Methods and ResultsAcute and chronic colitis models were induced in male and female C57BL/6 mice with dextran sodium sulfate (DSS) treatment. Aortic wall stiffness, endothelial function, and ROS levels, as well as serum levels of pro-inflammatory cytokines were evaluated. Acetylcholine (Ach)-induced endothelium-dependent relaxation of abdominal aorta without perivascular adipose tissue (PVAT) was significantly reduced in female mice, not males, with chronic colitis without a change in nitroglycerin-induced endothelium-independent relaxation. PVAT effectively preserved Ach-induced relaxation in abdominal aorta of female mice with chronic colitis. Aortic peak velocity, maximal intraluminal diameters, pulse wave velocity, distensibility and radial strain were preserved in mice with both acute and chronic colitis. Although pro-inflammatory cytokines levels were increased in mice with acute and chronic colitis, aortic ROS levels were not increased.ConclusionThe data demonstrate that abdominal aortic endothelial function was attenuated selectively in female mice with chronic colitis independent of ROS formation. Further, PVAT played an important role in preserving endothelial function in female mice with chronic colitis.

BackgroundHelicobacter pylori (H. pylori) infection increases the risk for atherosclerosis, and ROS are critical to endothelial dysfunction and atherosclerosis. CagA is a major H. pylori virulence factor associated with atherosclerosis. The present study aimed to test the hypothesis that CagA+H. pylori effectively colonizes gastric mucosa, and CagA+H. pylori, but not CagA–H. pylori, infection impairs endothelial function through exosomes-mediated ROS formation.MethodsC57BL/6 were used to determine the colonization ability of CagA+H. pylori and CagA–H. pylori. ROS production, endothelial function of thoracic aorta and atherosclerosis were measured in CagA+H. pylori and CagA–H. pylori infected mice. Exosomes from CagA+H. pylori and CagA–H. pylori or without H. pylori infected mouse serum or GES-1 were isolated and co-cultured with bEND.3 and HUVECs to determine how CagA+H. pylori infection impairs endothelial function. Further, GW4869 was used to determine if CagA+H. pylori infection could lead to endothelial dysfunction and atherosclerosis through an exosomes-mediated mechanism.ResultsCagA+H. pylori colonized gastric mucosa more effectively than CagA–H. pylori in mice. CagA+H. pylori, not CagA–H. pylori, infection significantly increased aortic ROS production, decreased ACh-induced aortic relaxation, and enhanced early atherosclerosis formation, which were prevented with N-acetylcysteine treatment. Treatment with CagA-containing exosomes significantly increased intracellular ROS production in endothelial cells and impaired their function. Inhibition of exosomes secretion with GW4869 effectively prevented excessive aortic ROS production, endothelial dysfunction, and atherosclerosis in mice with CagA+H. pylori infection.ConclusionThese data suggest that CagA+H. pylori effectively colonizes gastric mucosa, impairs endothelial function, and enhances atherosclerosis via exosomes-mediated ROS formation in mice.

Caspase-recruitment domain 9 (CARD9) protein is expressed in many cells especially in immune cells, and is critically involved in the function of the innate and adaptive immune systems through extensive interactions between CARD9 and other signaling molecules including NF-κB and MAPK. CARD9-mediated signaling plays a central role in regulating inflammatory responses and oxidative stress through the productions of important cytokines and chemokines. Abnormalities of CARD9 and CARD9 signaling or CARD9 mutations or polymorphism are associated with a variety of pathological conditions including infections, inflammation, and autoimmune disorders. This review focuses on the function of CARD9 and CARD9-mediated signaling pathways, as well as interactions with other important signaling molecules in different cell types and the relations to specific disease conditions including inflammatory diseases, infections, tumorigenesis, and cardiovascular pathologies.

Background Therapy with mesenchymal stem cells remains a promising but challenging approach to critical limb ischemia in diabetes because of the dismal cell survival. Methods and Results Critical limb ischemia in type 2 diabetes mouse model was used to explore the impact of diabetic limb ischemia on the survival of bone marrow mesenchymal stromal cells (bMSCs). Inhibition of intracellular reactive oxygen species was achieved with concomitant overexpression of superoxide dismutase (SOD)‐1 and glutathione peroxidase‐1 in the transplanted bMSCs, and extracellular reactive oxygen species was attenuated using SOD‐3 overexpression and N‐acetylcysteine treatment. In vivo optical fluorescence imaging and laser Doppler perfusion imaging were used to track cell retention and determine blood flow in diabetic ischemic limb, respectively. Survival of the transplanted bMSCs was significantly decreased in diabetic ischemic limb compared with the control. In vitro study indicated that advanced glycation end products, not high glucose, significantly decreased the proliferation of bMSCs and increased their apoptosis associated with increased reactive oxygen species production and selective reduction of SOD‐1 and SOD‐3. In vivo study demonstrated that concomitant overexpression of SOD‐1, SOD‐3, and glutathione peroxidase‐1, or host treatment with N‐acetylcysteine, significantly enhanced in vivo survival of transplanted bMSCs, and improved critical limb ischemia in diabetic mice. Combination of triple antioxidant enzyme overexpression in bMSCs with host N‐acetylcysteine treatment further improved bMSC survival with enhanced circulatory and functional recovery from diabetic critical limb ischemia. Conclusions Simultaneous suppression of reactive oxygen species from transplanted bMSCs and host tissue could additively enhance bMSC survival in diabetic ischemic limb with increased therapeutic efficacy in diabetes.

Inflammatory bowel disease (IBD) produces significant systemic inflammation and increases the risk of endothelial dysfunction and peripheral artery disease. Our recent study demonstrated that abdominal aortic endothelial cell function was impaired selectively in female mice with chronic colitis. This study aimed to test the hypothesis that experimental colitis leads to femoral artery endothelial cell dysfunction and impairs limb ischemia recovery in female mice. An experimental chronic colitis model was created in female C57BL/6 mice with dextran sodium sulfate (DSS) treatment. Unilateral hind limb ischemia was produced by femoral artery ligation. Limb blood perfusion, vascular density, tissue ROS levels, and plasma levels of proinflammatory cytokines were assessed. Femoral artery endothelium-dependent and -independent vasodilation of the contralateral limb were evaluated ex vivo using acetylcholine and nitroglycerin, respectively. As expected, the plasma levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-17, were significantly increased in the DSS-induced colitis model. However, ROS levels in the ischemic muscle tissues were not significantly increased in colitis model as compared to the controls. There were no significant changes in endothelium-dependent or -independent vasodilation of the femoral artery between colitis model and the control. Recovery of function and blood flow in the ischemic limb and capillary density in the ischemic gastrocnemius muscle were preserved in the colitis model as compared with the control. The data demonstrated that DSS-induced chronic colitis had no significant impact on femoral artery endothelial function or ischemic limb recovery in female mice.

Objective To investigate the relationship between tumor markers of lung cancer and bone metastasis of whole body bone imaging in lung adenocarcinoma. Methods The whole body bone imaging of 278 patients diagnosed as lung adenocarcinoma in our hospital was retrospectively analyzed. One-factor Pearson chi-square analysis and Logistic binary regression were used to analyze the relevant factors of bone metastasis of lung adenocarcinoma. Results (1) One-factor chi-square analysis results showed that CA125, CYFRA21-1, NSE, SCC, CEA, ALP and hilar lymph nodes were risk factors for bone metastasis(all P < 0.05); (2) Binary Logistic analysis results showed that CA125, NSE, ALP, CEA and hilar lymph nodes were risk factors for bone metastasis(all P < 0.05, OR > 1); SCC and ProGRP were risk factors for bone metastasis, but without statistical significance(P > 0.05, OR > 1). Conclusion CA125, NSE, ALP, CEA and hilar lymph nodes are risk factors for bone metastasis. SCC and ProGRP are risk factors for bone metastasis, but without statistically significance; CYFRA21-1 is not a risk factor for bone metastasis in lung adenocarcinoma.

Population-based studies have suggested that patients with inflammatory bowel disease (IBD) might be at an increased risk for cardiovascular diseases. A meta-analysis was performed on clinical studies to evaluate endothelial function, arterial stiffness, and carotid intima-media thickness (cIMT) in patients with IBD, after searching PubMed, Embase, Cochrane library, and Web of Science databases. A random-effects model was used to allow for the pooling of studies and for determination of the overall effect. After exclusion, a total of 41 eligible studies with 2330 patients with IBD and 2032 matched controls were identified and included for the analysis. It was found that cIMT was significantly increased in patients with IBD as compared with that in matched controls (Cohen’s d: 0.63; 95% CI: 0.34, 0.93; I2 = 91.84%). The carotid–femoral pulse wave velocity was significantly higher in patients with IBD compared to that in matched controls (Cohen’s d: 0.76; 95% CI: 0.54, 0.98; I2 = 70.03%). The augmentation index was also significantly increased in patients with IBD compared to matched control subjects (Cohen’s d: 0.35; 95% CI: 0.08, 0.63; I2 = 61.37%). Brachial artery flow-mediated dilatation was significantly decreased in patients with IBD than that in matched controls (Cohen’s d: −0.73; 95% CI: −1.10, −0.36; I2 = 81.02%). Based on the meta-analysis, it was found that patients with IBD exhibit significant endothelial dysfunction, increased arterial stiffness, and cIMT. Thus, patients with IBD may benefit from aggressive risk stratification for cardiovascular diseases.

Critical limb ischemia (CLI) is a severe complication of diabetes mellitus that occurs without effective therapy. Excessive reactive oxygen species (ROS) production and oxidative stress play critical roles in the development of diabetic cardiovascular complications. N-acetylcysteine (NAC) reduces ischemia-induced ROS production. The present study aimed to investigate the effect of NAC on the recovery of ischemic limb in an experimental model of type-2 diabetes. TALLYHO/JngJ diabetic and SWR/J non-diabetic mice were used for developing a CLI model. For NAC treatment, mice received NAC (1 mg/mL) in their drinking water for 24 h before initiating CLI, and continuously for the duration of the experiment. Blood flow, mechanical function, histology, expression of antioxidant enzymes including superoxide dismutase (SOD)-1, SOD-3, glutathione peroxidase (Gpx)-1, catalase, and phosphorylated insulin receptor substrate (IRS)-1, Akt, and eNOS in ischemic limb were evaluated in vivo or ex vivo. Body weight, blood glucose, plasma advanced glycation end-products (AGEs), plasma insulin, insulin resistance index, and plasma TNF-a were also evaluated during the experiment. NAC treatment effectively attenuated ROS production with preserved expressions of SOD-1, Gpx-1, catalase, phosphorylated Akt, and eNOS, and enhanced the recovery of blood flow and function of the diabetic ischemic limb. NAC treatment also significantly decreased the levels of phosphorylated IRS-1 (Ser307) expression and plasma TNF-α in diabetic mice without significant changes in blood glucose and AGEs levels. In conclusion, NAC treatment enhanced the recovery of blood flow and mechanical function in ischemic limbs in T2D mice in association with improved tissue redox/inflammatory status and insulin resistance.

Formononetin (FMNT) is a major bioactive compound from Astragalus membranaceus (Fisch.) Bunge, and has been widely used to treat conditions related to vascular insufficiency. However, the molecular mechanism for the therapeutic effect has not been well defined. This study aimed to investigate the effect and mechanism of FMNT on endothelial function. The potential targets and signaling pathways of FMNT in the setting of ischemia were predicted using network pharmacology analysis. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro studies and C57BL/6 mice were used for in vivo experiments. The results of the network pharmacology analysis showed that multiple signaling molecules including MAPK and PI3K-Akt pathways could be involved in the pharmacological actions of FMNT against ischemic diseases. The experimental validation data showed that FMNT significantly promoted the growth, proliferation, migration and tube formation of HUVECs in association with activation of endothelial nitric oxide synthase (eNOS) and promotion of intracellular nitric oxide (NO) production. FMNT also markedly activated Erk1/2 and Akt signaling in HUVECs. The enhanced endothelial function by FMNT was abolished when the cells were pre-treated with eNOS inhibitor. FMNT-induced eNOS/NO activation, endothelial function and angiogenesis was also effectively attenuated when Erk1/2 or Akt signaling pathway was inhibited. In addition, FMNT significantly promoted wound healing in C57BL/6 mice associated with activation of Erk1/2 and Akt signaling. Enhanced wound healing by FMNT in mice was prevented when eNOS-, Erk1/2, or Akt-medicated signaling was inhibited. Moreover, when Akt signaling was inhibited in HUVECs, FMNT was still able to activate Erk1/2 signaling without promotion of endothelial function. Similarly, FMNT could activate Akt signaling with no change in endothelial function when Erk1/2 signaling was attenuated in HUVECs. Conclusively, the present study demonstrated that FMNT significantly enhanced endothelial function and promoted angiogenesis in vitro and in vivo through activating Erk1/2- and Akt-mediated eNOS/NO signaling pathway. The data also suggested that simultaneous activation of Erk1/2 and Akt signaling was required for FMNT-induced promotion of endothelial function. Results from the present study might provide support and evidence for the application of FMNT during the clinical treatment of conditions related to vascular insufficiency.

Background and purpose: Early neurological deterioration (END) is associated with poor outcome for patients with acute ischemic stroke (AIS). Patients with hyperglycemia have increased risk for stroke and tend to have poor outcome with and without diabetes after stroke. The present study aimed to determine if blood glucose was associated with END and if sex difference was present in the development of END in AIS patients.Methods: A total of 220 consecutive patients (both males and females) with AIS between 2012 and 2015 were screened for this retrospective study. After exclusion, 213 patients were included for analysis. Propensity-score matching was used for normalization of variables including stroke severity, time from symptom onset to treatment, and treatment methods.Results: END was present in 68 patients (31.9%). Multivariate regression analysis showed that the risk of END was significantly higher in males with AIS than in females (P < 0.001), and admission blood glucose level was independently associated with END (P < 0.001). However, subgroup analysis demonstrated that admission glucose levels were significantly associated with increased risk for END only in females, but not in males (P = 0.008). When the cutoff value of 107.1 mg/dL was used, the admission blood glucose level had a significant predictive value for END prediction with a sensitivity of 100% and a specificity of 53% in female patients.Conclusions: The data demonstrated that sex difference was present for the development of END in AIS patients with an increased risk for males. The present study also showed that admission glucose level could be an important predicting factor for END in female patients with AIS.

This paper proposes using neutral axis locations to monitor and quantify the prestress force in post-tensioned precast segmental beams. Strain measurements are used to obtain the neutral axis locations of specific cross-sections of the precast prestressed segmental beams, based on the plane–remains–plane and linear strain distribution assumption. A theoretical calculation method based on the static equilibrium of a specific cross-section is developed to calculate the prestress force in segmental beams based on the neutral axis location. To verify the accuracy of the proposed method, a post-tensioned prestressed segmental beam is built and tested in the laboratory. A corresponding high-fidelity finite element model is also developed based on the beam design and material properties. Experimental studies and numerical simulations are conducted to verify the feasibility and accuracy of the proposed method in quantifying the prestress force in precast segmental beams. Both experimental and numerical results demonstrate that the proposed method can reliably estimate the prestress force, which can be used to monitor the prestress force loss in post-tensioned structures.

Background Epidemiological studies have suggested an association between Helicobacter pylori (H pylori) infection and atherosclerosis through undefined mechanisms. Endothelial dysfunction is critical to the development of atherosclerosis and related cardiovascular diseases. The present study was designed to test the hypothesis that H pylori infection impaires endothelial function through exosome‐mediated mechanisms. Methods and Results Young male and female patients (18‐35 years old) with and without H pylori infection were recruited to minimize the chance of potential risk factors for endothelial dysfunction for the study. Endothelium‐dependent flow‐mediated vasodilatation of the brachial artery was evaluated in the patients and control subjects. Mouse infection models with CagA+ H pylori from a gastric ulcer patient were created to determine if H pylori infection‐induced endothelial dysfunction could be reproduced in animal models. H pylori infection significantly decreased endothelium‐dependent flow‐mediated vasodilatation in young patients and significantly attenuated acetylcholine‐induced endothelium‐dependent aortic relaxation without change in nitroglycerin‐induced endothelium‐independent vascular relaxation in mice. H pylori eradication significantly improved endothelium‐dependent vasodilation in both patients and mice with H pylori infection. Exosomes from conditioned media of human gastric epithelial cells cultured with CagA+ H pylori or serum exosomes from patients and mice with H pylori infection significantly decreased endothelial functions with decreased migration, tube formation, and proliferation in vitro. Inhibition of exosome secretion with GW4869 effectively preserved endothelial function in mice with H pylori infection. Conclusions H pylori infection impaired endothelial function in patients and mice through exosome‐medicated mechanisms. The findings indicated that H pylori infection might be a novel risk factor for cardiovascular diseases.

Ambient fine particulate matter (PM) exposure associates with an increased risk of cardiovascular diseases (CVDs). Major sex differences between males and females exist in epidemiology, pathophysiology, and outcome of CVDs. Endothelial progenitor cells (EPCs) play a vital role in the development and progression of CVDs. PM exposure-induced reduction of EPCs is observed in male, not female, mice with increased reactive oxygen species (ROS) production and oxidative stress. The lung is considered an important source of ROS in mice with PM exposure. The aim of the present study was to investigate the sex differences in pulmonary superoxide dismutase (SOD) expression and ROS production, and to test the effect of SOD mimic Tempol on the populations of EPCs in mice with PM exposure. Both male and female C57BL/6 mice (8–10 weeks) were exposed to intranasal PM or vehicle for 6 weeks. Flow cytometry analysis demonstrated that PM exposure significantly decreased the levels of EPCs (CD34+/CD133+) in both blood and bone marrow with increased ROS production in males, but not in females. ELISA analysis showed higher levels of serum IL-6 and IL-1βin males than in females. Pulmonary expression of the antioxidant enzyme SOD1 was significantly decreased in males after PM exposure, but not in females. Administration of the SOD mimic Tempol in male mice with PM exposure attenuated the production of ROS and inflammatory cytokines, and preserved EPC levels. These data indicated that PM exposure-induced reduction of EPC population in male mice may be due to decreased expression of pulmonary SOD1 in male mice.

Males have a higher risk for cardiovascular diseases (CVDs) than females. Ambient fine particulate matter (PM) exposure increases CVD risk with increased reactive oxygen species (ROS) production and oxidative stress. Endothelial progenitor cells (EPCs) are important to vascular structure and function and can contribute to the development of CVDs. The aims of the present study were to determine if sex differences exist in the effect of PM exposure on circulating EPCs in mice and, if so, whether oxidative stress plays a role. Male and female C57BL/6 mice (8–10 weeks old) were exposed to PM or a vehicle control for six weeks. ELISA analysis showed that PM exposure substantially increased the serum levels of IL-6 and IL-1β in both males and females, but the concentrations were significantly higher in males. PM exposure only increased the serum levels of TNF-α in males. Flow cytometry analysis demonstrated that ROS production was significantly increased by PM treatment in males but not in females. Similarly, the level of circulating EPCs (CD34+/CD133+ and Sca-1+/Flk-1+) was significantly decreased by PM treatment in males but not in females. Antioxidants N-acetylcysteine (NAC) effectively prevented PM exposure-induced ROS and inflammatory cytokine production and restored circulating EPC levels in male mice. In sharp contrast, circulating EPC levels remained unchanged in female mice with PM exposure, an effect that was not altered by ovariectomy. In conclusion, PM exposure selectively decreased the circulating EPC population in male mice via increased oxidative stress without a significant impact on circulating EPCs in females independent of estrogen.

High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53−/− mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.