Seeking Cells, Targeting Bacteria: A Cascade-Targeting Bacteria-Responsive Nanosystem for Combating Intracellular Bacterial Infections.

Intracellular bacteria pose a great challenge to antimicrobial therapy due to various physiological barriers at both cellular and bacterial levels, which impede drug penetration and intracellular targeting, thereby fostering antibiotic resistance and yielding suboptimal treatment outcomes. Herein, a cascade-target bacterial-responsive drug delivery nanosystem, MM@SPE NPs, comprising a macrophage membrane (MM) shell and a core of SPE NPs. SPE NPs consist of phenylboronic acid-grafted dendritic mesoporous silica nanoparticles (SP NPs) encapsulated with epigallocatechin-3-gallate (EGCG), a non-antibiotic antibacterial component, via pH-sensitive boronic ester bonds are introduced. Upon administration, MM@SPE NPs actively home in on infected macrophages due to the homologous targeting properties of the MM shell, which is subsequently disrupted during cellular endocytosis. Within the cellular environment, SPE NPs expose and spontaneously accumulate around intracellular bacteria through their bacteria-targeting phenylboronic acid groups. The acidic bacterial microenvironment further triggers the breakage of boronic ester bonds between SP NPs and EGCG, allowing the bacterial-responsive release of EGCG for localized intracellular antibacterial effects. The efficacy of MM@SPE NPs in precisely eliminating intracellular bacteria is validated in two rat models of intracellular bacterial infections. This cascade-targeting responsive system offers new solutions for treating intracellular bacterial infections while minimizing the risk of drug resistance.

Advances in reparative materials for infectious bone defects and their applications in maxillofacial regions.

Infectious bone defects are characterized by the partial loss or destruction of bone tissue resulting from bacterial contaminations subsequent to diseases or external injuries. Traditional bone transplantation and clinical methods are insufficient in meeting the treatment demands for such diseases. As a result, researchers have increasingly focused on the development of more sophisticated biomaterials for improved therapeutic outcomes in recent years. This review endeavors to investigate specific reparative materials utilized for the treatment of infectious bone defects, particularly those present in the maxillofacial region, with a focus on biomaterials capable of releasing therapeutic substances, functional contact biomaterials, and novel physical therapy materials. These biomaterials operate via heightened antibacterial or osteogenic properties in order to eliminate bacteria and/or stimulate bone cells regeneration in the defect, ultimately fostering the reconstitution of maxillofacial bone tissue. Based upon some successful applications of new concept materials in bone repair of other parts, we also explore their future prospects and potential uses in maxillofacial bone repair later in this review. We highlight that the exploration of advanced biomaterials holds promise in establishing a solid foundation for the development of more biocompatible, effective, and personalized treatments for reconstructing infectious maxillofacial defects.

A macrophage cell membrane-coated cascade-targeting photothermal nanosystem for combating intracellular bacterial infections.

Current antibacterial interventions encounter formidable challenges when confronting intracellular bacteria, attributable to their clustering within phagocytes, particularly macrophages, evading host immunity and resisting antibiotics. Herein, we have developed an intelligent cell membrane-based nanosystem, denoted as MM@DAu NPs, which seamlessly integrates cascade-targeting capabilities with controllable antibacterial functions for the precise elimination of intracellular bacteria. MM@DAu NPs feature a core comprising D-alanine-functionalized gold nanoparticles (DAu NPs) enveloped by a macrophage cell membrane (MM) coating. Upon administration, MM@DAu NPs harness the intrinsic homologous targeting ability of their macrophage membrane to infiltrate bacteria-infected macrophages. Upon internalization within these host cells, exposed DAu NPs from MM@DAu NPs selectively bind to intracellular bacteria through the bacteria-targeting agent, D-alanine present on DAu NPs. This intricate process establishes a cascade mechanism that efficiently targets intracellular bacteria. Upon exposure to near-infrared irradiation, the accumulated DAu NPs surrounding intracellular bacteria induce local hyperthermia, enabling precise clearance of intracellular bacteria. Further validation in animal models infected with the typical intracellular bacteria, Staphylococcus aureus, substantiates the exceptional cascade-targeting efficacy and photothermal antibacterial potential of MM@DAu NPs in vivo. Therefore, this integrated cell membrane-based cascade-targeting photothermal nanosystem offers a promising approach for conquering persistent intracellular infections without drug resistance risks. STATEMENT OF SIGNIFICANCE: Intracellular bacterial infections lead to treatment failures and relapses because intracellular bacteria could cluster within phagocytes, especially macrophages, evading the host immune system and resisting antibiotics. Herein, we have developed an intelligent cell membrane-based nanosystem MM@DAu NPs, which is designed to precisely eliminate intracellular bacteria through a controllable cascade-targeting photothermal antibacterial approach. MM@DAu NPs combine D-alanine-functionalized gold nanoparticles with a macrophage cell membrane coating. Upon administration, MM@DAu NPs harness the homologous targeting ability of macrophage membrane to infiltrate bacteria-infected macrophages. Upon internalization, exposed DAu NPs from MM@DAu NPs selectively bind to intracellular bacteria through the bacteria-targeting agent, enabling precise clearance of intracellular bacteria through local hyperthermia. This integrated cell membrane-based cascade-targeting photothermal nanosystem offers a promising avenue for conquering persistent intracellular infections without drug resistance risks.

Impact of intelligent information-based perioperative care on postoperative rehabilitation, complications, and quality of life of patients undergoing gastrointestinal surgery.

To investigate the impact of perioperative intelligent information-based care on postoperative rehabilitation, complications, and quality of life of patients in the operating room. Retrospective analysis of information on 84 patients who underwent gastrointestinal surgery in our hospital from May 2021 to May 2022 were divided into to control group (n = 42) and observation group (n = 42) according to different care modalities. The control group received conventional care, while the observation group received intelligent information-based perioperative care. The total postoperative treatment time, length of stay, Pittsburgh Sleep Quality Index score, Pain Numerical Rating Scale score, Hamilton Anxiety Scale score, Hamilton Depression Scale score, complication rate, quality of life score, and nursing satisfaction were observed. The total postoperative treatment time and total hospital stay in the observation group were significantly shorter than that of the control group (P < .05). After care, the Pittsburgh Sleep Quality Index and Numerical Rating Scale scores in the observation group were significantly lower than that of the control group (P < .05). After care, Hamilton Anxiety Scale and Hamilton Depression Scale scores were significantly lower in both groups, and the observation group was lower than the control group (P < .05). The complication rate in the observation groups was 11.9% (5/42), which was significantly lower than that of 47.62% (20/42) in the control group (P < .001). The quality of life of patients such as physical ability, pain, mood, sleep, social activity, and physical activity scores in the observation group were significantly lower than that of the control group after care (P < .05). The nursing satisfaction rate of patients in the observation group was 95.27% (40/42), which was significantly higher than that of 78.57% (33/42) in the control group (P = .024). Intelligent information-based perioperative care can promote the postoperative recovery of patients undergoing gastrointestinal surgery, can successfully improve patients' sleep quality and pain level, alleviate negative emotions, reduce the risk of postoperative complications, and improve patients' quality of life and satisfaction, which is worthy of clinical promotion.

A multifunctional polymeric coating with self-adsorbed, antifouling and in situ remineralization properties for caries management.

Dental caries is a biofilm-induced bacterial infectious oral disease, where the early attachment of proteins and pathogenic bacteria to tooth surfaces has been known as the main cause of biofilm formation. Typically, dental caries is commonly accompanied by mineral depletion of enamels, thus causing dental demineralization. Multifunctional materials are highly attractive candidates for treating dental caries. Herein, we successfully synthesized diblock copolymers poly(ethylene glycol)-b-poly(aspartic acid) (PEG-PAsp) and modified them with alendronate sodium (ALN) to serve as bioactive bifunctional coatings (PEG-PAsp-ALN) on teeth. The PEG segments are employed for inhibiting proteins and bacterial adhesion. In addition, due to the presence of both PAsp and ALN, a synergistically strong binding capacity could be achieved with the tooth surface, thus promoting rapid and thorough remineralization in situ, while maintaining excellent safety. The combination treatment can significantly suppress the biofilm formation, which is beneficial for alleviating the demineralization of enamels caused by bacteria, and further, facilitate remineralization in situ. This approach thus demonstrates the potential of the copolymer PEG-PAsp-ALN coating as a multifunctional protecting layer on the tooth surface for high-efficiency prevention and treatment of dental caries.

The Impact of Illness Perceptions on Depressive Symptoms Among Benign Prostatic Hyperplasia Patients with Lower Urinary Tract Symptom.

OBJECTIVE: This study aimed at exploring whether illness perceptions may mediate the relationship between depressive symptoms and lower urinary tract symptoms (LUTS) among benign prostatic hyperplasia (BPH) patients. METHODS: The Patient Health Questionnaire (PHQ-9) for depression, the International Prostate Symptom Score (IPSS) for the severity of LUTS and the brief Illness Perception Questionnaire (B-IPQ) for illness perceptions (IPs) were used among the 157 BPH patients with LUTS. Pearson's correlation test and hierarchical regression analyses were used to assess the correlations between LUTS, depressive symptoms and IPs. RESULTS: Our study found that the severity of LUTS was associated with depressive symptoms and subscales of illness perception; meanwhile, IPs were associated with the level of education. A positive relationship was found between the scores of PHQ9 and the B-IPQ subscales of illness consequences, identity, timeline, concern and emotion; thus, a negative correlation was found between scores of PHQ9 and the B-IPQ subscales of illness coherence, personal control and treatment control. The hierarchical regression analysis showed IPSS and the B-IPQ subscales of illness consequences, concern and emotion were significantly associated with depression, and explained 85.1% of the variance in depressive symptoms (R2 = 0.851, p < 0.05). CONCLUSION: The relationship between LUTS and depressive symptoms may be mediated by the negative IPs, including consequences, concern and emotions. Clinicians should not only focus on the LUTS but also on the IPs to improve depressive symptoms among BPH patients.

Effects of perioperative rosuvastatin on postoperative delirium in elderly patients: A randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Experimental evidence has indicated the benefits of statins for the treatment of postoperative delirium. Previously, clinical trials did not reach definite conclusions on the effects of statins on delirium. Some clinical trials have indicated that statins reduce postoperative delirium and improve outcomes, while some studies have reported negative results. AIM: To evaluate whether perioperative rosuvastatin treatment reduces the incidence of delirium and improves clinical outcomes. METHODS: This randomized, double-blind, and placebo-controlled trial was conducted in a single center in Jiangsu, China. This study enrolled patients aged greater than 60 years who received general anesthesia during elective operations and provided informed consent. A computer-generated randomization sequence (in a 1:1 ratio) was used to randomly assign patients to receive either rosuvastatin (40 mg/d) or placebo. Participants, care providers, and investigators were all masked to group assignments. The primary endpoint was the incidence of delirium, which was assessed twice daily with the Confusion Assessment Method during the first 7 postoperative days. Analyses were performed on intention-to-treat and safety populations. RESULTS: Between January 1, 2017 and January 1, 2020, 3512 patients were assessed. A total of 821 patients were randomly assigned to receive either placebo (n = 411) or rosuvastatin (n = 410). The incidence of postoperative delirium was significantly lower in the rosuvastatin group [23 (5.6%) of 410 patients] than in the placebo group {42 (13.5%) of 411 patients [odds ratios (OR) = 0.522, 95% confidence interval (CI): 0.308-0.885; P < 0.05]}. No significant difference in 30-d all-cause mortality (6.1% vs 8.7%, OR = 0.67, 95%CI: 0.39-1.2, P = 0.147) was observed between the two groups. Rosuvastatin decreased the hospitalization time (13.8 ± 2.5 vs 14.2 ± 2.8, P = 0.03) and hospitalization expenses (9.3 ± 2.5 vs 9.8 ± 2.9, P = 0.007). No significant differences in abnormal liver enzymes (9.0% vs 7.1%, OR = 1.307, 95%CI: 0.787-2.169, P = 0.30) or rhabdomyolysis (0.73% vs 0.24%, OR = 3.020, 95%CI: 0.31-29.2, P = 0.37) were observed between the two groups. CONCLUSION: The current study suggests that perioperative rosuvastatin treatment reduces the incidence of delirium after an elective operation under general anesthesia. However, the evidence does not reveal that rosuvastatin improves clinical outcomes. The therapy is safe. Further investigation is necessary to fully understand the potential usefulness of rosuvastatin in elderly patients.

Increased Circulating Osteoprotegerin Levels in Type 1 Diabetes Mellitus: A Systematic Review and Meta-analysis Based on Observational Studies.

Objectives: Type 1 diabetes mellitus (T1D) has been disclosed to be associated with an elevated risk of cardiovascular disease (CVD), as well as increased risks of losing bone mass and progression of osteoporosis (OP). Osteoprotegerin (OPG), as a decoy receptor, has been demonstrated to play a critical role in bone metabolism homeostasis and vascular atherosclerotic diseases. This meta-analysis aimed to investigate the associations between OPG levels and T1D. Methods: Related literatures were searched and identified from the database of the Cochrane Library database, PubMed and EMbase inception to August 3, 2019 in English. The pooled standard mean difference (SMD) with its 95% confidence interval (CI) was calculated in using random-effect model analysis. Chi-square Q statistic and I2 test were performed to evaluate and quantified the presence of heterogeneity. Results: Twelve studies with 1288 subjects (794 T1D patients and 494 healthy controls) were finally included. The incorporated results indicated that T1D patients have higher plasma/serum OPG levels than in healthy individuals (SMD = 0.64, 95% CI: 0.06, 1.22). Subgroup analyses suggested that Caucasian and glycosylated hemoglobin A1c (HbA1c) <8.5% groups showed higher OPG levels, however, there was no significant differences of OPG levels regarding subgroups of BMI ≥ or <25, children-adolescents or adults and HbA1c ≥8.5%. Conclusions: The current evidence suggested that circulating OPG levels are significantly higher in T1D than in healthy controls, and the increase of OPG levels are influenced by factors of race and HbA1c.

Association of circulating cystatin C levels with type 2 diabetes mellitus: a systematic review and meta-analysis.

INTRODUCTION: This study aimed to systemically summarize the present literature about circulating cystatin C (Cys C) levels in type 2 diabetes mellitus (T2DM) and provide a more precise evaluation of Cys C levels in T2DM. MATERIAL AND METHODS: Relevant studies about Cys C concentrations in T2DM were searched in PubMed, EMBASE and the Cochrane Library database (up to Oct 31 2018). We computed the pooled standard mean difference (SMD) with its 95% confidence interval (CI) of Cys C levels through a random-effect model. The Q test and the I2 statistic were used to assess and quantify between-study heterogeneity; publication bias was evaluated through a funnel plot and Egger's linear regression test. RESULTS: After the literature search and screening process, 14 studies with 723 T2DM patients and 473 healthy controls were finally included in the meta-analysis. The results showed that T2DM patients had significantly higher Cys C levels compared to healthy controls (SMD = 1.39, 95% CI: 0.92-1.86, p < 0.001). Publication bias was not detected based on the symmetrical shape of the funnel plot and the results of Egger's test (p = 0.452). Subgroup analyses suggested that variables of human race, age, gender, study sample size and disease duration have a relationship with Cys C level in T2DM patients. CONCLUSIONS: Overall, our study suggests that patients with T2DM have an elevated circulating Cys C level compared to healthy controls, and it is associated with race, age, gender, study sample size and disease duration. Further investigations are still needed to explore the causal relationship of aberrant Cys C concentrations in T2DM.

No association between low-dose reserpine use and depression in older hypertensive patient: result of a multicenter, cross-sectional study.

BACKGROUND: Reserpine is currently used by millions of Chinese hypertensive patients, in spite of the continued concern of its depressogenic effect, even when used in low dose. This study aimed to investigate the association between low-dose reserpine use and depression in older Chinese hypertensive patient. METHODS: In this cross-sectional, case-control study, we recruited patient aged 60 years or over who had regularly taken one or two tables of "compound reserpine and triamterene tablets (CRTTs)" for more than one year (reserpine user) from 26 community health centers located in 10 provinces in China. For each patient who took CRTTs, we selected an age (within five years) and sex matched hypertensive patient who had never taken any drugs containing reserpine (non-reserpine user) as control. Depressive symptoms were evaluated using a Chinese depression scale adapted from the Zung Self-Rating Depression Scale. Demographic, clinical data and laboratory examination results within six months were collected. RESULTS: From August 2018 to December 2018, 787 reserpine user and 787 non-reserpine user were recruited. The mean age of all study subjects was 70.3 years, with about equal numbers of males and females. The mean depression score was 40.4 in reserpine users and 40.6 in non-reserpine users (P = 0.7). The majority of study subject had a depression score < 53 (87.6% in reserpine users and 88.2% in non-reserpine users, respectively). There were no significant differences in the prevalence of mild, moderate or severe depression in reserpine users and non-reserpine users. CONCLUSIONS: There is no association between low-dose reserpine use and depression in older hypertensive patient. The role of reserpine in the treatment and control of hypertension should be reconsidered; and further studies, especially randomized, controlled clinical trials to compare efficacy and safety of reserpine and other widely recommended anti-hypertensive agents are needed.

Glucagon-like peptide-1 attenuates endothelial barrier injury in diabetes via cAMP/PKA mediated down-regulation of MLC phosphorylation.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) showed protective effects on endothelium-dependent dilatation. Since endothelial barrier dysfunction also plays a pivotal role in atherosclerosis, this study was designed to investigate the effects of GLP-1 on endothelial barrier function in diabetic aortic endothelium and explore the underlying mechanism. METHODS: For in vivo studies, diabetic rats were established and subjected to 12- and 24-week treatment of exenatide. The morphological changes of aortic endothelium were observed with transmission electron microscope. A permeability assay of aortic endothelium was performed using the surface biotinylation technique. Protein expression was detected by immunohistochemical analysis and Western blots. For in vitro studies, human umbilical vein endothelial cells (HUVECs) were cultured in medium enriched with advanced glycation end products (AGEs) or AGEs plus GLP-1 and other reagents. The integrity of endothelium was evaluated by endothelial monolayer permeability assay and transendothelial resistance. The in vitro expressions of relevant proteins in signaling pathways were also detected by immunofluorescence and Western blots. RESULTS: In vivo, the enhanced aortic endothelial permeability in diabetic aortas were attenuated by exenatide treatment. Additionally, myosin light chain (MLC) phosphorylation, related to actomyosin contractility, and activation of its upstream targets in diabetic aorta were inhibited after administration of exenatide. In vitro, the endothelial monolayer permeability and the assembly of stress fibers were reduced by GLP-1 intervention under diabetic condition. Meanwhile, AGE-induced MLC phosphorylation mediating ECs contractility was inhibited by GLP-1. Furthermore, GLP-1 down-regulated the upstream targets of MLC phosphorylation, including RAGE, Rho/ROCK and MAPK signaling pathways. Intriguingly, the effects of GLP-1 elicited on ECs contractility and barrier function in diabetes were blunted by inhibition of GLP-1R, cAMP or PKA and stimulation of Rho/ROCK and MAPK signaling pathways. CONCLUSION: The findings of this study suggest that the stabilizing effect of GLP-1 on the endothelial barrier and contraction of AGE-treated ECs is caused by GLP-1R/cAMP/PKA activation and the subsequent inactivation of RAGE/Rho/ROCK as well as MAPK signaling pathways.

Cardiac rehabilitation in acute myocardial infarction patients after percutaneous coronary intervention: A community-based study.

BACKGROUND: Acute myocardial infarction (AMI) is one of the leading causes of death and physical disability worldwide. However, the development of community- based cardiac rehabilitation (CR) in AMI patients is hysteretic. Here, we aimed to evaluate the safety and efficacy of CR applied in the community in AMI patients who underwent percutaneous coronary intervention (PCI). METHODS: A total of 130 ST-segment elevated myocardial infarction (STEMI) patients after PCI were randomly divided into 2 groups in the community, rehabilitation group (n = 65) and control group (n = 65). Cardiac function, a 6-minute walk distance, exercise time and steps, cardiovascular risk factors were monitored respectively and compared before and after the intervention of 2 groups. The software of EpiData 3.1 was used to input research data and SPSS16.0 was used for statistical analysis. RESULTS: After a planned rehabilitation intervention, the rehabilitation group showed better results than the control group. The rehabilitation group had a significant improvement in recurrence angina and readmission (P < .01). Left ventricular ejection fraction (LVEF) of rehabilitation group showed improvement in phase II (t = 4.963, P < .01) and phase III (t = 11.802, P < .01), and the New York Heart Association (NYHA) classification was recovered within class II. There was a significant difference compared with before (Z = 7.238, P < .01). Six minutes walking distance, aerobic exercise time, and steps all achieved rehabilitation requirements in rehabilitation group in phase II and III, there existed distinct variation between 2 phases. Rehabilitation group had a better result in cardiovascular risk factors than control group (P < .05). CONCLUSION: Community-based CR after PCI through simple but safe exercise methods can improve the AMI patient's living quality, which includes increasing cardiac ejection fraction, exercise tolerance, and physical status. It must be emphasized that the good result should be established by the foundation of close cooperation between cardiologists and general practitioners, also the importance of cooperation of patients and their families should not be ignored. The rehabilitation program we used is feasible, safe, and effective.

PXR polymorphisms have impact on the clinical efficacy of clopidogrel in patients undergoing percutaneous coronary intervention.

BACKGROUNDS: Clopidogrel is widely used in Coronary Heart Disease (CHD) patients undergoing percutaneous coronary intervention (PCI) to prevent thrombotic events. However, clopidogrel response variability (CRV) may affect the patients' clinical outcomes. The current data have shown that genetic factors play an important role in CRV. The aim of this research is to investigate the association of pregnane X receptor (PXR, also called NR1I2) genetic polymorphisms with the clinical efficacy of clopidogrel in patients undergoing PCI. METHODS: A total of 384 patients undergoing PCI were recruited and treated with dual antiplatelet therapy (DAPT) for 12 months. The plasma concentration of clopidogrel carboxylic acid metabolites (CLPM) was measured by High Performance Liquid Chromatography (HPLC). The maximum aggregation rate (MAR) of platelet were measured by PL-11 analyzer. PXR genetic polymorphisms were determined by Sequenom MassArray system. The clinical outcomes were observed by readmission, outpatient and calling back interview within 12 months after PCI. RESULTS: Among all 384 patients, a total of 153 patients were occurred with major adverse cardiovascular events (MACE), 29 patients were occurred with bleeding events, the other patients had a favorable prognosis. The polymprphisms of PXR rs3814057A > C [OR(95%CI): 0.71(0.527-0.957), P = 0.024], rs3814058T > C [OR (95%CI): 1.395(1.034-1.883), P = 0.029] and rs6785049 A > G [OR(95%CI): 0.724 (0.535-0.979), P = 0.036] were significantly associated with MACE. The haplotype h1 (GCC) was associated with a higher risk of MACE [OR (95%CI): 1.385 (1.028-1.866), P = 0.031]. Whereas, the haplotype h2 (AAT) was associated with a lower risk of MACE [OR (95%CI): 0.711(0.525-0.962), P = 0.027]. CONCLUSIONS: The genotypes and haplotypes of PXR rs3814057, rs3814058 and rs6785049 have impact on the MACE in clopidogrel treated patients after PCI.

Melatonin ameliorates myocardial apoptosis by suppressing endoplasmic reticulum stress in rats with long­term diabetic cardiomyopathy.

The effects of melatonin (MLT), which exerts cardioprotective effects against myocardial apoptosis, in long­term diabetic cardiomyopathy are not currently well defined. The present study aimed to investigate how MLT protects the heart through modulating myocardial apoptosis in rats with type 2 diabetes mellitus (DM). In total, 36 rats were randomly divided into three groups, including control (n=12), DM (n=12) and DM + MLT (n=12) groups. The results demonstrated that, in DM rats, a significant increase was observed in the serum fasting blood glucose and lipid levels, in addition to insulin resistance and cardiac dysfunction, which were attenuated in DM rats treated with MLT. Additionally, cellular apoptosis in rats with DM was increased, and the expression of Bcl­2 was downregulated, while levels of Bcl­2­associated X and caspase­3 were upregulated, and these observations were reversed by MLT, as determined by TUNEL and western blot analysis, respectively. As increased endoplasmic reticulum (ER) stress induced by hyperglycemia is reported to be a factor for apoptosis, the present study also determined the expression of proteins associated with ER stress in cardiac tissues following MLT treatment by western blotting. The results further indicated that MLT decreased the expression of ER stress hallmarks, including CCAAT/enhancer­binding protein homologous protein, glucose­regulated protein 78, protein kinase RNA­like endoplasmic reticulum kinase (PERK) and activating transcription factor 6α in cardiac tissues. In conclusion, the results of the present study indicate that MLT may protect heart by ameliorating cardiac ER stress­induced apoptosis in diabetic cardiomyopathy.

Sitagliptin inhibits endothelin-1 expression in the aortic endothelium of rats with streptozotocin-induced diabetes by suppressing the nuclear factor-κB/IκBα system through the activation of AMP-activated protein kinase.

Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin, exert favourable effects on the vascular endothelium. DPP-4 inhibitors suppress the degradation of glucagon-like peptide-1 (GLP­1), which has been reported to enhance nitric oxide (NO) production. However, the effects of DPP-4 inhibitors on endothelin-1 (ET-1) expression in the aorta, as well as the underlying mechanisms responsible for these effects, have yet to be investigated in animal models of diabetes mellitus (DM). In the present study, the rats were randomly divided into the following four groups: i) control; ii) DM; iii) DM + low­dose sitagliptin (10 mg/kg); and iv) DM + high­dose sitagliptin (30 mg/kg). Apart from the control group, all the rats received a high-fat diet for 8 weeks prior to the induction of diabetes with an intraperitoneal injection of streptozotocin. The treatments were then administered for 12 weeks. The serum levels of ET-1, NO, GLP-1 and insulin were measured as well as endothelial function. The expression of ET-1, AMP-activated protein kinase (AMPK) and nuclear factor (NF)-κB/IκBα were determined. After 12 weeks of treatment, the diabetic rats receiving sitagliptin showed significantly elevated serum levels of GLP-1 and NO, and reduced levels of ET-1. Moreover, sitagliptin significantly attenuated endothelial dysfunction as well as the remodeling of the aortic wall. Notably, sitagliptin inhibited ET-1 expression at the transcriptional and translational level in the aorta, which may have been mediated by the suppression of the NF-κB/IκBα system induced by AMPK activation. The majority of the above-mentioned effects were dose dependent. Taken together, the findings of the present study indicate that sitagliptin inhibits ET-1 expression in the aortic endothelium by suppressing the NF-κB/IκBα system through the activation of the AMPK pathway in diabetic rats. These findings further demonstrate some of the vasoprotective properties of DPP-4 inhibitors in vivo.

Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor κB signaling pathways.

Interaction between advanced glycation endproducts (AGEs) and receptor for AGEs (RAGE) as well as downstream pathways leads to vascular endothelial dysfunction in diabetes. Glucagon-like peptide-1 (GLP-1) has been reported to attenuate endothelial dysfunction in the models of atherosclerosis. However, whether GLP-1 exerts protective effects on aortic endothelium in diabetic animal model and the underlying mechanisms are still not well defined. Experimental diabetes was induced through administration with combination of high-fat diet and intraperitoneal injection of streptozotocin. Rats were randomly divided into four groups, including controls, diabetes, diabetes + sitagliptin (30 mg/kg/day), diabetes + exenatide (3 µg/kg/12 h). Eventually, endothelial damage, markers of inflammation and oxidative stress, were measured. After 12 weeks administration, diabetic rats received sitagliptin and exenatide showed significant elevation of serum NO level and reduction of ET-1 as well as inflammatory cytokines levels. Moreover, sitagliptin and exenatide significantly inhibited aortic oxidative stress level and improved aortic endothelial function in diabetic rats. Importantly, these drugs inhibited the protein expression level in AGE/RAGE-induced RhoA/ROCK/NF-κB/IκBα signaling pathways and activated AMPK in diabetic aorta. Finally, the target proteins of p-eNOS, iNOS, and ET-1, which reflect endothelial function, were also changed by these drugs. Our present study indicates that sitagliptin and exenatide administrations can improve endothelial function in diabetic aorta. Of note, RAGE/RhoA/ROCK and AMPK mediated NF-κB signaling pathways may be the intervention targets of these drugs to protect aortic endothelium.

Temporal changes of symbiont density and host fitness after rifampicin treatment in a whitefly of the Bemisia tabaci species complex.

Microbial symbionts are essential or important partners to phloem-feeding insects. Antibiotics have been used to selectively eliminate symbionts from their host insects and establish host lines with or without certain symbionts for investigating functions of the symbionts. In this study, using the antibiotic rifampicin we attempted to selectively eliminate certain symbionts from a population of the Middle East-Asia Minor 1 whitefly of the Bemisia tabaci species complex, which harbors the primary symbiont "Candidatus Portiera aleyrodidarum" and two secondary symbionts "Candidatus Hamiltonella defensa" and Rickettsia. Neither the primary nor the secondary symbionts were completely depleted in the adults (F0) that fed for 48 h on a diet treated with rifampicin at concentrations of 1-100 µg/mL. However, both the primary and secondary symbionts were nearly completely depleted in the offspring (F1) of the rifampicin-treated adults. Although the F1 adults produced some eggs (F2), most of the eggs failed to hatch and none of them reached the second instar, and consequently the rifampicin-treated whitefly colony vanished at the F2 generation. Interestingly, quantitative polymerase chain reaction assays showed that in the rifampicin-treated whiteflies, the density of the primary symbiont was reduced at an obviously slower pace than the secondary symbionts. Mating experiments between rifampicin-treated and untreated adults demonstrated that the negative effects of rifampicin on host fitness were expressed when the females were treated by the antibiotic, and whether males were treated or not by the antibiotic had little contribution to the negative effects. These observations indicate that with this whitefly population it is not feasible to selectively eliminate the secondary symbionts using rifampicin without affecting the primary symbiont and establish host lines for experimental studies. However, the extinction of the whitefly colony at the second generation after rifampicin treatment indicates the potential of the antibiotic as a control agent of the whitefly pest.

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs.

1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin-aspirin therapy, the safety and side effect of combined therapy remains unclear. 2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses. 3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC(0-t)) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC(0-t) and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC(0-t) and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin. 4. Coadministration of warfarin had no markedly effects on the AUC(0-t) and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC(0-t) and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin. 5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug-drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin-aspirin drug interactions in healthy volunteers or patients.

Melatonin Attenuates Aortic Endothelial Permeability and Arteriosclerosis in Streptozotocin-Induced Diabetic Rats: Possible Role of MLCK- and MLCP-Dependent MLC Phosphorylation.

The development of diabetic macrovascular complications is a multifactorial process, and melatonin may possess cardiovascular protective properties. This study was designed to evaluate whether melatonin attenuates arteriosclerosis and endothelial permeability by suppressing the myosin light-chain kinase (MLCK)/myosin light-chain phosphorylation (p-MLC) system via the mitogen-activated protein kinase (MAPK) signaling pathway or by suppressing the myosin phosphatase-targeting subunit phosphorylation (p-MYPT)/p-MLC system in diabetes mellitus (DM). Rats were randomly divided into 4 groups, including control, high-fat diet, DM, and DM + melatonin groups. Melatonin was administered (10 mg/kg/d) by gavage for 12 weeks. The DM significantly increased the serum fasting blood glucose and lipid levels, as well as insulin resistance and endothelial dysfunction, which were attenuated by melatonin therapy to various extents. Importantly, the aortic endothelial permeability was significantly increased in DM rats but was dramatically reversed following treatment with melatonin. Our findings further indicated that hyperglycemia and hyperlipidemia enhanced the expressions of MLCK, p-MYPT, and p-MLC, which were partly associated with decreased membrane type 1 expression, increased extracellular signal-regulated kinase (ERK) phosphorylation, and increased p38 expression. However, these changes in protein expression were also significantly reversed by melatonin. Thus, our results are the first to demonstrate that the endothelial hyperpermeability induced by DM is associated with increased expressions of MLCK, p-MYPT, and p-MLC, which can be attenuated by melatonin at least partly through the ERK/p38 signaling pathway.

Serum biomarkers VEGF-C and IL-6 are associated with severe human Peripheral Artery Stenosis.

BACKGROUND: Emerging reports propose possible biomarkers that are related to inflammation, nutrition and lipid parameters for detection of the progression of atherosclerotic plaques, peripheral artery disease (PAD) and particularly peripheral artery stenosis (PAS). However, it remains unclear which biomarkers in serum are associated with the severity of PAS. FINDINGS: In this study, we measured serum levels of inflammatory biomarkers along with lipid and nutritional parameters in 53 patients who suffered different degrees of PAS. Serum concentrations of vascular endothelial growth factor-c (VEGF-C) and IL-6 (Interleukin 6) were significantly increased in patients showing moderate or severe PAS. Furthermore, the number of blood monocytes from PAS patients was significantly increased, which showed elevated adhesion to plate-coated fibrinogen. Compared to healthy subjects, freshly isolated or LPS (lipopolysaccharide)-stimulated blood monocytes from PAS patients could produce VEGF-C and IL-6 at higher levels. CONCLUSIONS: Our study suggests that the increased number of blood monocytes might play key roles during the development of severe PAS, which enhance adhesion at the local narrowed peripheral artery and secret high levels of VEGF-C and IL-6. We suggest that serum concentrations of VEGF-C and IL-6 might be used as biomarkers for diagnosis severe PAS in combination with clinical imaging examination.