Differential cytokine expression in gastric tissues highlights helicobacter pylori's role in gastritis.

Helicobacter pylori (H. pylori), known for causing gastric inflammation, gastritis and gastric cancer, prompted our study to investigate the differential expression of cytokines in gastric tissues, which is crucial for understanding H. pylori infection and its potential progression to gastric cancer. Focusing on Il-1ß, IL-6, IL-8, IL-12, IL-18, and TNF-α, we analysed gene and protein levels to differentiate between H. pylori-infected and non-infected gastritis. We utilised real-time quantitative polymerase chain reaction (RT-qPCR) for gene quantification, immunohistochemical staining, and ELISA for protein measurement. Gastric samples from patients with gastritis were divided into three groups: (1) non-gastritis (N-group) group, (2) gastritis without H. pylori infection (G-group), and (3) gastritis with H. pylori infection (GH-group), each consisting of 8 samples. Our findings revealed a statistically significant variation in cytokine expression. Generally, cytokine levels were higher in gastritis, but in H. pylori-infected gastritis, IL-1ß, IL-6, and IL-8 levels were lower compared to H. pylori-independent gastritis, while IL-12, IL-18, and TNF-α levels were higher. This distinct cytokine expression pattern in H. pylori-infected gastritis underscores a unique inflammatory response, providing deeper insights into its pathogenesis.

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification.

Cognitive impairment is a common feature among patients with diffuse glioma. The objective of the study is to investigate the relationship between preoperative cognitive function and clinical as well as molecular factors, firstly based on the new 2021 World Health Organization's updated classification of central nervous system tumors. A total of 110 diffuse glioma patients enrolled underwent preoperative cognitive assessments using the Mini-Mental State Examination and Montreal Cognitive Assessment. Clinical information was collected from medical records, and gene sequencing was performed to analyze the 18 most influenced genes. The differences in cognitive function between patients with and without glioblastoma were compared under both the 2016 and 2021 WHO classification of tumors of the central nervous system to assess their effect of differentiation on cognition. The study found that age, tumor location, and glioblastoma had significant differences in cognitive function. Several genetic alterations were significantly correlated with cognition. Especially, IDH, CIC, and ATRX are positively correlated with several cognitive domains, while most other genes are negatively correlated. For most focused genes, patients with a low number of genetic alterations tended to have better cognitive function. Our study suggested that, in addition to clinical characteristics such as age, histological type, and tumor location, molecular characteristics play a crucial role in cognitive function. Further research into the mechanisms by which tumors affect brain function is expected to enhance the quality of life for glioma patients. This study highlights the importance of considering both clinical and molecular factors in the management of glioma patients to improve cognitive outcomes.

Photo-responsive hydrogel facilitates nutrition deprivation by an ambidextrous approach for preventing cancer recurrence and metastasis.

Postoperative recurrence at the primary site and distant metastasis remains the challenge in treating triple-negative breast cancer due to its unpredictable invasion into adjacent tissues. Although systemic chemotherapy has been extensively adopted to attenuate the recurrence and metastasis, the abundant nutrition supply by blood vessels would promote the rapid proliferation of tumor cells and angiogenesis. Herein, we reported a nutrition deprivation strategy by ambidextrously blocking the residual blood vessels and inhibiting angiogenesis to realize efficient treatment of triple-negative breast cancer. To this end, an injectable hydrogel with photo-responsive property was prepared by using polydopamine crosslinked collagen/silk fibroin composite to deliver thrombin for blocking blood vessels and angiogenesis. In the presence of NIR light, the locked thrombin was released into the blood vessels in the adjacent tissues to promote blood coagulation. In addition, the photothermal effect would reduce the secreting of VEGF for preventing angiogenesis in the adjacent tissues. The in vitro and in vivo results demonstrated that the permanent interruption of nutrient supply by blocking the blood vessels adjacent to the resected tumor and preventing angiogenesis is a promising strategy to prevent the recurrence and metastasis of TNBC.

A comparison of passive and active wall mechanics between elastic and muscular arteries of juvenile and adult rats.

The elastic abdominal aorta and muscular femoral artery are susceptible to aneurysm and atherosclerosis, respectively. The vessel wall mechanics should be an important element for the difference. The objective of the study is to demonstrate a comparison of vessel wall mechanics between elastic and muscular arteries of juvenile and adult rats to show the changes of mechanical properties relevant to aging. The passive and active mechanical tests, theoretical analysis, and histological evaluation were carried out to investigate mechanical properties of vessel walls in the abdominal aorta and carotid and femoral arteries of young and adult rats. There are stiffening femoral artery, unchanged carotid artery, and distensible abdominal aorta in adult rats as compared with the young. The opening angle has values of 54 ± 13°, 82 ± 13°, and 94 ± 13° in the abdominal aorta and carotid and femoral arteries of adult rats, respectively, as well as 80 ± 22°, 93 ± 19°, and 100 ± 23° in the young. The findings are explained by the significantly reduced width of collagen fibers in the abdominal aorta, relatively unchanged width in the carotid artery, and significantly increased width in the femoral artery of adult rats as compared with the young. In conjunction with available literatures, we concluded that inconsistency for nonlinear age-related changes of artery wall mechanics occurs between arteries of different types, which may be a risk factor for the occurrence of abdominal aorta aneurysm and femoral artery atherosclerosis.

Short-Term Inhalation of Ultrafine Zinc Particles Could Alleviate Cardiac Dysfunctions in Rats of Myocardial Infarction.

It is not clear for inhalation of ultrafine metal particles in air pollution to impair human health. In the study, we aimed to investigate whether short-term (4 weeks) inhalation of ultrafine zinc particles could deteriorate the cardiac and hemodynamic functions in rats of myocardial infarction (MI). MI was induced in Wistar rats through coronary artery ligation surgery and given an inhalation of ultrafine zinc particles for 4 weeks (post-MI 4 weeks, 4 days per week, and 4 h per day). Cardiac strain and strain rate were quantified by the speckle tracking echocardiography. The pressure and flow wave were recorded in the carotid artery and analyzed by using the Womersley model. Myocardial infarction resulted in the LV wall thinning, LV cavity dilation, remarkable decrease of ejection fraction, dp/dt Max, -dp/dt Min, myocardial strain and strain rates, and increased LV end-diastolic pressure, as well as impaired hemodynamic environment. The short-term inhalation of ultrafine zinc particles significantly alleviated cardiac and hemodynamic dysfunctions, which could protect from the MI-induced myocardial and hemodynamic impairments albeit it is unknown for the long-term inhalation.

Mechanical difference of left ventricle between rabbits of myocardial infarction and hypertrophy.

The analysis of cardiac wall stress is of importance to understand the development of heart failure (HF). The aim of the study is to carry out the cardiac mechanics analysis to show the changes of left ventricular (LV) wall stresses after LV hypertrophy (LVH) and myocardial infarction (MI). Here, LVH and MI were generated in rabbit hearts through the transverse aortic constriction (TAC) and the distal left circumflex (LCx) artery ligation operations, respectively. Physiological and CT measurements were carried out at postoperative 2 and 4 weeks, based on which a finite element (FE) model was developed to perform the mechanics computation. We found a gradual increase of end-diastolic myofiber stress in free wall and interventricular septum of LVH and MI (higher stress in the free wall than the septum). In the interventricular septum, the 4-weeks LVH group has the highest ED myofiber stresses (11.378 ± 3.022 kPa), while the 4-weeks MI group has the highest ED myofiber stresses (13.494 ± 2.835 kPa) in the free wall. LVH increased myocardial volume (3.49 ± 0.07 and 4.52 ± 0.26 ml at postoperative 2 and 4 weeks) while MI increased LV volume (from 2.75 ± 0.29 to 4.19 ± 0.27 ml). LVH and MI had different distributions of local myofiber stress.

Morphometric, Hemodynamic, and Multi-Omics Analyses in Heart Failure Rats with Preserved Ejection Fraction.

(1) Background: There are no successive treatments for heart failure with preserved ejection fraction (HFpEF) because of complex interactions between environmental, histological, and genetic risk factors. The objective of the study is to investigate changes in cardiomyocytes and molecular networks associated with HFpEF. (2) Methods: Dahl salt-sensitive (DSS) rats developed HFpEF when fed with a high-salt (HS) diet for 7 weeks, which was confirmed by in vivo and ex vivo measurements. Shotgun proteomics, microarray, Western blot, and quantitative RT-PCR analyses were further carried out to investigate cellular and molecular mechanisms. (3) Results: Rats with HFpEF showed diastolic dysfunction, impaired systolic function, and prolonged repolarization of myocytes, owing to an increase in cell size and apoptosis of myocytes. Heatmap of multi-omics further showed significant differences between rats with HFpEF and controls. Gene Set Enrichment Analysis (GSEA) of multi-omics revealed genetic risk factors involved in cardiac muscle contraction, proteasome, B cell receptor signaling, and p53 signaling pathway. Gene Ontology (GO) analysis of multi-omics showed the inflammatory response and mitochondrial fission as top biological processes that may deteriorate myocyte stiffening. GO analysis of protein-to-protein network indicated cytoskeleton protein, cell fraction, enzyme binding, and ATP binding as the top enriched molecular functions. Western blot validated upregulated Mff and Itga9 and downregulated Map1lc3a in the HS group, which likely contributed to accumulation of aberrant mitochondria to increase ROS and elevation of myocyte stiffness, and subsequent contractile dysfunction and myocardial apoptosis. (4) Conclusions: Multi-omics analysis revealed multiple pathways associated with HFpEF. This study shows insight into molecular mechanisms for the development of HFpEF and may provide potential targets for the treatment of HFpEF.

Speckle tracking echocardiography could detect the difference of pressure overload-induced myocardial remodelling between young and adult rats.

The assessment by speckle tracking echocardiography (STE) provides useful information on regional and global left ventricular (LV) functions. The aim of the study is to investigate if STE-based strain analysis could detect the difference of pressure overload-induced myocardial remodelling between young and adult rats. Physiological, haemodynamic, histological measurements were performed post-operatively in young and adult rats with transverse aortic constriction (TAC) as well as the age-matched shams. Two-way ANOVA was used to detect the statistical difference of various measured parameters. Pressure overload decreased the ejection fraction, fractional shortening, dp/dtmax and |dp/dtmin|, but increased the LV end-diastolic (ED) pressure in adult rat hearts for nine weeks after TAC operation than those in young rat hearts. Pressure overload also resulted in different changes of peak strain and strain rate in the free wall, but similar changes in the interventricular septum of young and adult rat hearts. The changes in myocardial remodelling were confirmed by the histological analysis including the increased apoptosis rate of myocytes and collagen area ratio in the free wall of adult rat hearts of LV hypertrophy when compared with the young. Pressure overload alters myocardial components in different degrees between young and adult animals. STE-based strain analysis could detect the subtle difference of pressure overload-induced myocardial remodelling between young and adult rats.

Inhalation of Ultrafine Zinc Particles Impaired Cardiovascular Functions in Hypertension-Induced Heart Failure Rats With Preserved Ejection Fraction.

Although it is possible for inhalation of ultrafine particles to impair human health, its effect is not clear in patients with HFpEF. This study investigated cardiac and hemodynamic changes in hypertension-induced rats of HFpEF after inhaling ultrafine zinc particles for a while. Multiple experimental measurements were carried out in DSS rats fed with high salt (HS) and low salt (LS) diets as well as HS diet with the inhalation of ultrafine zinc particles (defined as HP). Cardiac strain and strain rate were quantified by the speckle tracking echocardiography. The pressure and flow waves were recorded in the carotid artery and abdominal aorta and analyzed by the models of Windkessel and Womersley types. HS and HP rats were found to show lower strains on endocardium and epicardium than LS rats. The inhalation of ultrafine zinc particles further reduced the strain in the longitudinal direction on the endocardium of rats with HFpEF, but had relatively small effects on the epicardium. The inhalation of ultrafine zinc particles resulted in the increase of systemic resistance and the decrease of total vascular compliance as well as the increased PWV and induced more severe vascular stiffening in rats with HFpEF. In summary, the inhalation of ultrafine zinc particles deteriorated local myocardial dysfunctions in the LV and the hemodynamic environment in peripheral arteries in rats of HFpEF. This study is of importance to understand the mechanisms of cardiovascular impairments owing to air pollution.

Contribution of genetic polymorphism of methylene tetrahydrofolate reductase on the effect of methotrexate in ectopic pregnancy patients.

BACKGROUND: Methotrexate (MTX) is the prior drug in ectopic pregnancy (EP). However, approximately 10% of patients suffer from failure by MTX therapy. Reduced folate carrier 1 (RFC1), methylene tetrahydrofolate reductase (MTHFR), and dihydrofolate reductase (DHFR) are involved in the transport and effects of MTX in vivo. In the present study, we aim to investigate the relationship between the genetic polymorphisms of RFC1, MTHFR, and DHFR and the clinical efficacy of MTX in tubal pregnancies. METHODS: 100 patients of EP were enrolled in this study. Polymorphisms of RFC1 G80A, MTHFR C677T, and DHFR A-317G were genotyped. ß-hCG level was detected in day 0, 4, and 7 after MTX injection. Association of MTX efficacy and genetic polymorphisms was analyzed. RESULTS: Methylene tetrahydrofolate reductase C677T was associated with MTX treatment (P = .017). The success rate of first MTX injection was superior in patients with harboring mutation allele of MTHFR gene than that in patients with wild-type gene (P = .001). However, there was no significant association between the polymorphisms of RFC1 G80A, DHFR A-317G, and surgical treatment (P = .709 and .476, respectively). In addition, ß-hCG level decrement was not significantly changed by MTX injection with different polymorphisms of RFC1, MTHFR, and DHFR on either day 4 (P = .214, 0.197 and 0.270, respectively) or day 7 (P = .172, .554, and .726, respectively). CONCLUSION: Our results suggested that the reliable indicator was polymorphism of MTHFR C677T in failure by MTX injection.

Viral and Bacterial Etiology of Acute Febrile Respiratory Syndrome among Patients in Qinghai, China.

OBJECTIVE: This study was conducted to investigate the viral and bacterial etiology and epidemiology of patients with acute febrile respiratory syndrome (AFRS) in Qinghai using a commercial routine multiplex-ligation-nucleic acid amplification test (NAT)-based assay. METHODS: A total of 445 nasopharyngeal swabs specimens from patients with AFRS were analyzed using the RespiFinderSmart22kit (PathoFinder BV, Netherlands) and the LightCycler 480 real-time PCR system. RESULTS: Among the 225 (225/445, 51%) positive specimens, 329 positive pathogens were detected, including 298 (90.58%) viruses and 31 (9%) bacteria. The most commonly detected pathogens were influenza virus (IFV; 37.39%; 123/329), adenovirus (AdV; 17.02%; 56/329), human coronaviruses (HCoVs; 10.94%; 36/329), rhinovirus/enterovirus (RV/EV; 10.03%; 33/329), parainfluenza viruses (PIVs; 8.51%; 28/329), and Mycoplasma pneumoniae (M. pneu; 8.51%; 28/329), respectively. Among the co-infected cases (17.53%; 78/445), IFV/AdV and IFV/M. pneu were the most common co-infections. Most of the respiratory viruses were detected in summer and fall. CONCLUSION: In our study, IFV-A was the most common respiratory pathogen among 22 detected pathogens, followed by AdV, HCoV, RV/EV, PIV, and M. pneu. Bacteria appeared less frequently than viruses, and co-infection was the most common phenomenon among viral pathogens. Pathogens were distributed among different age groups and respiratory viruses were generally active in July, September, and November. Enhanced surveillance and early detection can be useful in the diagnosis, treatment, and prevention of AFRS, as well as for guiding the development of appropriate public health strategies.

In-hospital, short-term and long-term adverse clinical outcomes observed in patients with type 2 diabetes mellitus vs non-diabetes mellitus following percutaneous coronary intervention: A meta-analysis including 139,774 patients.

BACKGROUND: Several studies have shown that patients with type 2 diabetes mellitus (T2DM) have worse clinical outcomes in comparison to patients without diabetes mellitus (DM) following Percutaneous Coronary Intervention (PCI). However, the adverse clinical outcomes were not similarly reported in all the studies. Therefore, in order to standardize this issue, a meta-analysis including 139,774 patients was carried out to compare the in-hospital, short-term (<1 year) and long-term (≥1 year) adverse clinical outcomes in patients with and without T2DM following PCI. METHODS: Electronic databases including MEDLINE, EMBASE, and the Cochrane Library were searched for Randomized Controlled Trials (RCTs) and observational studies. The adverse clinical outcomes which were analyzed included mortality, myocardial infarction (MI), major adverse cardiac events (MACEs), stroke, bleeding, target vessel revascularization (TVR), target lesion revascularization (TLR), and stent thrombosis. Risk Ratios (RR) with 95% confidence intervals (CI) were used to express the pooled effect on discontinuous variables and the analysis was carried out by RevMan 5.3 software. RESULTS: A total number of 139,774 participants were assessed. Results of this analysis showed that in-hospital mortality and MACEs were significantly higher in patients with T2DM (RR 2.57; 95% CI: 1.95-3.38; P = .00001) and (RR: 1.38; 95% CI: 1.10-1.73; P = .005) respectively. In addition, majority of the short and long-term adverse clinical outcomes were also significantly higher in the DM group as compared to the non-DM group. Stent thrombosis was significantly higher in the DM compared to the non-DM group during the short term follow-up period (RR 1.59; 95% CI: 1.16-2.18;P = .004). However, long-term stent thrombosis was similarly manifested. CONCLUSION: According to this meta-analysis including a total number of 139,774 patients, following PCI, those patients with T2DM suffered more in-hospital, short as well as long-term adverse outcomes as reported by most of the Randomized Controlled Trials and Observational studies, compared to those patients without diabetes mellitus.

Detection of six common human paramyxoviruses in patients with acute febrile respiratory symptoms using a novel multiplex real-time RT-PCR assay.

Human metapneumovirus (hMPV), respiratory syncytial virus type A (RSV-A), RSV-B, and human parainfluenza viruses 1, 2, and 3 (HPIV-1, HPIV-2, and HPIV-3) are common respiratory paramyxoviruses. Here, we developed a two-tube triplex one-step real-time reverse-transcription polymerase chain reaction (real-time RT-PCR) and evaluated its performance using clinical samples. The data showed that this novel assay was 100% consistent with the monoplex real-time RT-PCR assay (in-house), which was superior to the commercial routine multiplex-ligation-NAT-based assay. Meanwhile, the clinical nasopharyngeal swabs of 471 patients with the acute febrile respiratory syndrome (AFRS) were analyzed using the established method. The results showed that 52 (11.7%) cases were positive for paramyxovirus. Among them, HPIVs and RSV-A had the highest detection rate. The age and seasonal distribution of human paramyxovirus infection were analyzed. In conclusion, we developed a novel multiplex real-time RT-PCR assay for the rapid detection of six common human paramyxoviruses, which were dominant in patients with AFRS in Qinghai.

Adverse clinical outcomes associated with double dose clopidogrel compared to the other antiplatelet regimens in patients with coronary artery disease: a systematic review and meta-analysis.

BACKGROUND: Recently, several newer antiplatelet treatment strategies have been used in patients with coronary artery disease (CAD). Apart from the dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel, double dose clopidogrel (DDC), triple antiplatelet therapy (TAPT) consisting of aspirin, clopidogrel and cilostazol and other newer antiplatelet agents have shown to be effective in different ways. In this analysis, we aimed to systematically compare the adverse clinical outcomes and the bleeding events which were observed when DDC was compared to the other antiplatelet regimens in patients with CAD. METHODS: English publications comparing DDC with other antiplatelet regimens were searched from MEDLARS/MEDLINE, EMBASE, www.ClinicalTrials.gov and Google Scholar. Adverse cardiovascular outcomes and bleeding events were the study endpoints. Statistical analysis was carried out by the RevMan 5.3 software whereby odds ratios (OR) with 95% confidence intervals (CIs) were calculated. RESULTS: A total number of 23,065 participants were included. Results of this analysis showed major adverse cardiac events (MACEs), all-cause mortality, cardiac death, stroke, stent thrombosis, revascularization and myocardial infarction (MI) to have been similarly manifested in patients who were treated with DDC versus the control group with OR: 0.98, 95% CI: 0.78-1.22; p = 0.83, OR: 0.95, 95% CI: 0.77-1.17; p = 0.62, OR: 0.97, 95% CI: 0.79-1.20; p = 0.81, OR: 0.98, 95% CI: 0.65-1.48; p = 0.94, OR: 0.84, 95% CI: 0.40-1.75; p = 0.64, OR: 0.88, 95% CI: 0.52-1.49; p = 0.63, and OR: 0.89, 95% CI: 0.65-1.21; p = 0.45 respectively. Any minor and major bleedings were also similarly manifested. When DDC was compared to DAPT, no significant difference was observed in any bleeding event with OR: 1.58, 95% CI: 0.86-2.91; p = 0.14. Even when DDC was compared with either ticagrelor or prasugrel or TAPT, still no significant difference was observed in terms of bleeding outcomes. CONCLUSIONS: In patients with CAD, adverse clinical outcomes were not significantly different when DDC was compared to the other antiplatelet regimens. In addition, bleeding events were also similarly manifested when DDC was compared to DAPT, TAPT or ticagrelor/prasugrel.

Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors.

BACKGROUND/AIMS: Unlike other organs, which only have one set of capillary network, the renal microvasculature consists of two sets of capillary network series connected by efferent arterioles. Angiotensin II constricts the efferent glomerular artery. Hence, renal tumor blood flow (BF) distribution may be different from tumors in other organs. This study aims to investigate the effects of angiotensin II on the hemodynamics of intrarenal VX2 tumors using perfusion computed tomography(CT). METHODS: Twenty-four male New Zealand white rabbits were randomly divided into three groups: groups A (blank controls), group B (negative controls), and group C (angiotensin II-treated animals). Group B and C were established to the model of intrarenal VX2 tumors. Furthermore, perfusion CT of the kidney was performed in each group. Prior to perfusion CT scan in group C, the mean arterial blood was elevated to 150-160 mmHg by angiotensin II. The BF, blood volume (BV), mean transit time (MTT), capillary permeability-surface area product (PS), and relative permeability-surface area product (RPS) of tumors and renal tissues were calculated. RESULTS: Compared with normal renal cortex tissues in group A, the BF, BV and PS values of tumors in group B were significantly lower, MTT was prolonged and RPS increased. Compared with group B, only the RPS of these tumors increased from 83.23 ± 29.17% to 120.94 ± 31.84% by angiotensin II infusion. Angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor (CDT) and the right renal cortex (RRC). CONCLUSIONS: Perfusion CT can accurately observe the influence of angiotensin II on normal and tumor BF in kidneys. This clarifies the effect of angiotensin II on intrarenal tumor hemodynamics.

Hepatic Hemangiomas Alter Morphometry and Impair Hemodynamics of the Abdominal Aorta and Primary Branches From Computer Simulations.

Background: The formation of hepatic hemangiomas (HH) is associated with VEGF and IL-7 that alter conduit arteries and small arterioles. To our knowledge, there are no studies to investigate the effects of HH on the hemodynamics in conduit arteries. The aim of the study is to perform morphometric and hemodynamic analysis in abdominal conduit arteries and bifurcations of HH patients and controls. Methods: Based on morphometry reconstructed from CT images, geometrical models were meshed with prismatic elements for the near wall region and tetrahedral and hexahedral elements for the core region. Simulations were performed for computation of the non-Newtonian blood flow using the Carreau-Yasuda model, based on which multiple hemodynamic parameters were determined. Results: There was an increase of the lumen size, diameter ratio, and curvature in the abdominal arterial tree of HH patients as compared with controls. This significantly increased the surface area ratio of low time-averaged wall shear stress (i.e., SAR-TAWSS [Formula: see text] 100%) (24.1 ± 7.9 vs. 5 ± 6%, 11.6 ± 12.8 vs. < 0.1%, and 44.5 ± 9.2 vs. 21 ± 24% at hepatic bifurcations, common hepatic arteries, and abdominal aortas, respectively, between HH and control patients). Conclusions: Morphometric changes caused by HH significantly deteriorated the hemodynamic environment in abdominal conduit arteries and bifurcations, which could be an important risk factor for the incidence and progression of vascular diseases.

Surface-adaptive zwitterionic nanoparticles for prolonged blood circulation time and enhanced cellular uptake in tumor cells.

Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems. STATEMENT OF SIGNIFICANCE: Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.

The effect of shear on the cytoskeleton remodeling and physiological performance of myocardium cells through Tmod1.

Objective: mechanical stimulation alters cell metabolism, but little is known about the effects of mechanical strain on the cytoskeleton of myocardium cells. This study was to investigate the changes of F-actin, a cytoskeleton protein of myocardium cells, and to provide a theoretical basis for further investigation of the mechanism of myocardium-remodeling. Methods: we examined the effects of fluid shear stress on the Tmod1 expression and F-actin cytoskeleton remodeling. Then, after myocardial cells, silenced by si-Tmod1, were treated by fluid shear stress, the change of intracellular calcium ion concentration, ROS in myocardial cells, cytochrome C, and the amount of F-actin, LDH and T-SOD MDA were evaluated with laser light confocal microscopy, western blot, and ELISA, respectively. Results: fluid shear stress can induce F-actin cytoskeleton remodeling and upregulate Tmod1 expression. After myocardial cells were under the conditions of Tmod1 inhibition, shear stress can significantly reduce the increase of ROS levels and calcium content, decrease the release of cells cytochrome C and LDH, decrease the MDA content, and increase the level of T-SOD. Conclusion: in conclusion, shear treatment can remodel the cytoskeleton through Tmod1, and its mechanism may be related to scavenging oxidative stress products, ROS and MDA, the increase of intracellular antioxidant enzyme activity of SOD and improvement in mitochondrial dysfunction.

The Structure-function remodeling in rabbit hearts of myocardial infarction.

Animal models are of importance to investigate basic mechanisms for ischemic heart failure (HF). The objective of the study was to create a rabbit model through multiple coronary artery ligations to investigate the postoperative structure-function remodeling of the left ventricle (LV) and coronary arterial trees. Here, we hypothesize that the interplay of the degenerated coronary vasculature and increased ventricle wall stress relevant to cardiac fibrosis in vicinity of myocardial infarction (MI) precipitates the incidence and progression of ischemic HF Echocardiographic measurements showed an approximately monotonic drop of fractional shortening and ejection fraction from 40% and 73% down to 28% and 58% as well as persistent enlargement of LV cavity and slight mitral regurgitation at postoperative 12 weeks. Micro-CT and histological measurements showed that coronary vascular rarefaction and cardiac fibrosis relevant to inflammation occurred concurrently in vicinity of MI at postoperative 12 weeks albeit there was compensatory vascular growth at postoperative 6 weeks. These findings validate the proposed rabbit model and prove the hypothesis. The post-MI rabbit model can serve as a reference to test various drugs for treatment of ischemic HF.