Aptamer and DNAzyme-Functionalized Cu-MOF Hybrid Nanozymes for the Monitoring and Management of Bacteria-Infected Wounds.

Metal-organic frameworks (MOFs) with peroxidase (POD)-like activity have great potential for combating drug-resistant bacterial infections. However, the use of POD-like activities is severely limited by low oxygen levels and high levels of glutathione (GSH) within the microenvironment of bacterial infection. Herein, G-quadruplex/hemin DNAzyme-aptamer probes and tannic acid-chelated Au nanoparticle (Au-TA)-decorated Cu-based MOF nanosheets (termed GATC) with triple-enzyme activities were developed for visual detection and efficient antibacterial therapy. First, the monometallic MOFs (Cu-ZIF) showed the best catalytic and loading capacity performance compared with the bimetallic MOFs (CoCu-ZIF and ZnCu-ZIF). Then, Cu-MOFs, Au-TA, and DNAzyme improve the POD-like activity to generate more hydroxyl radicals (•OH) to kill bacteria. GATC can bind to bacteria through aptamer recognition, increasing the bacterial surface contact area for efficient antibacterial activity. GATC can decompose H2O2 into O2 to alleviate hypoxia and improve the microenvironment due to its catalase (CAT)-like activity. In addition, GATC exhibited GSH peroxidase-like activity, which can avoid the loss of •OH and result in bacterial death more easily. Compared with previous studies, GATC exhibited extraordinary bactericidal ability at an extremely low dosage of 3 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA). Notably, the GATC-catalyzed chromogenic reaction could accurately monitor the MRSA infection treatment process. Overall, this work could establish a therapeutic platform for the monitoring and management of bacteria-infected wounds.

Construction of Smart Biomaterials for Promoting Diabetic Wound Healing.

Diabetes mellitus is a complicated metabolic disease that has become one of the fastest-growing health crises in modern society. Diabetic patients may suffer from various complications, and diabetic foot is one of them. It can lead to increased rates of lower-extremity amputation and mortality, even seriously threatening the life and health of patients. Because its healing process is affected by various factors, its management and treatment are very challenging. To address these problems, smart biomaterials have been developed to expedite diabetic wound closure and improve treatment outcomes. This review begins with a discussion of the basic mechanisms of wound recovery and the limitations of current dressings used for diabetic wound healing. Then, the categories and characteristics of the smart biomaterial scaffolds, which can be utilized as a delivery system for drugs with anti-inflammatory activity, bioactive agency, and antibacterial nanoparticles for diabetic wound treatment were described. In addition, it can act as a responsive system to the stimulus of the pH, reactive oxygen species, and glucose concentration from the wound microenvironment. These results show that smart biomaterials have an enormous perspective for the treatment of diabetic wounds in all stages of healing. Finally, the advantages of the construction of smart biomaterials are summarized, and possible new strategies for the clinical management of diabetic wounds are proposed.

Recent Advances in Nanozymes for Bacteria-Infected Wound Therapy.

Bacterial-infected wounds are a serious threat to public health. Bacterial invasion can easily delay the wound healing process and even cause more serious damage. Therefore, effective new methods or drugs are needed to treat wounds. Nanozyme is an artificial enzyme that mimics the activity of a natural enzyme, and a substitute for natural enzymes by mimicking the coordination environment of the catalytic site. Due to the numerous excellent properties of nanozymes, the generation of drug-resistant bacteria can be avoided while treating bacterial infection wounds by catalyzing the sterilization mechanism of generating reactive oxygen species (ROS). Notably, there are still some defects in the nanozyme antibacterial agents, and the design direction is to realize the multifunctionalization and intelligence of a single system. In this review, we first discuss the pathophysiology of bacteria infected wound healing, the formation of bacterial infection wounds, and the strategies for treating bacterially infected wounds. In addition, the antibacterial advantages and mechanism of nanozymes for bacteria-infected wounds are also described. Importantly, a series of nanomaterials based on nanozyme synthesis for the treatment of infected wounds are emphasized. Finally, the challenges and prospects of nanozymes for treating bacterial infection wounds are proposed for future research in this field.

Ultrathin trimetallic metal-organic framework nanosheets for accelerating bacteria-infected wound healing.

Bacteria-infected wounds are commonly regarded as a hidden threat to human health that can create persistent infection and even bring about amputation or death. Two-dimensional metal-organic frameworks (2D MOFs) with biomimetic enzyme activity have been used to reduce the huge harm caused by antibiotic resistance due to their massive active sites and ultralarge specific surface area. However, their therapeutic efficiency is unsatisfactory because of their relatively low catalytic activity and poor productivity. In this paper, we presented a simple and mild one-pot solution phase method for the large-scale synthesis of NiCoCu-based MOF nanosheets. The NiCoCu nanosheets (denoted as (Ni2Co1)1-xCux) with controlled molar ratios have different morphologies and sizes. Specifically, the (Ni2Co1)0.5Cu0.5 nanosheets showed the best catalytic performance toward the reduction of H2O2 and H2O2 was efficiently catalyzed to generate toxic •OH in the presence of MOF nanosheets with peroxidase-like activity. (Ni2Co1)0.5Cu0.5 exhibited the best antibacterial activity against gram-positive Escherichia coli and methicillin-resistant Staphylococcus aureus bacteria. Animal wound healing experiments demonstrate that ultrathin trimetallic nanosheets can effectively contribute to wound healing with excellent biocompatibility. This study reveals the immense potential of ultrathin trimetallic MOF nanosheets for clinical antibacterial therapy for future pragmatic clinical applications.

Promoting enteral tube feeding safety and performance in preterm infants: A systematic review.

BACKGROUND: Enteral tube feeding is commonly used in preterm infants to provide enteral nutrition. Nurses play a crucial role in promoting feeding safety and performance. OBJECTIVES: The aims of this systematic review were to identify nursing practices regarding feeding safety and performance promotion in preterm infants with enteral tube feeding and summarize evidence on the effectiveness of these practices. METHODS: A comprehensive search was performed in six databases (MEDLINE, EMBASE, CINAHL, Web of Science, Cochrane Library, and Scopus). Studies on nursing practices aimed at promoting feeding safety and performance in preterm infants with enteral tube feeding were included. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) for randomized controlled studies and the tool of risk-of-bias in non-randomized studies of interventions (ROBINS-I) for non-randomized studies of interventions. A narrative synthesis strategy was employed to gather evidence and analyze data. RESULTS: 61 studies (47 randomized controlled studies and 14 quasi-experimental studies) covering seven categories of practices were included. The identified nursing practices included controlling feeding interval, selecting feeding position, monitoring gastric residual, disposing of gastric residual, managing feeding temperature, feeding promotion stimulation, and supplementary methods during the transition from tube to oral feeding. Evidence supported the effectiveness of oro-motor stimulation and non-nutritive sucking as feeding performance promotion strategies in preterm infants. Other practices were suggested to be used cautiously or recommended to be further studied due to limited evidence. CONCLUSIONS: The review identified seven categories of nursing practices in promoting feeding safety and performance in preterm infants receiving enteral tube feeding. Oro-motor stimulation and non-nutritive sucking can be used in clinical settings to promote feeding performance in preterm infants with enteral tube feeding. Other practices will continue to be dictated by local preferences and cost factors until more robust evidence becomes available. REGISTRATION: PROSPERO database (CRD42020196256).

Persistence of Symptoms After Discharge of Patients Hospitalized Due to COVID-19.

Many patients who had coronavirus disease 2019 (COVID-19) had at least one symptom that persisted after recovery from the acute phase. Our purpose was to review the empirical evidence on symptom prevalence, complications, and management of patients with long COVID. We systematically reviewed the literature on the clinical manifestations of long COVID-19, defined by the persistence of symptoms beyond the acute phase of infection. Bibliographic searches in PubMed and Google Scholar were conducted to retrieve relevant studies on confirmed patients with long COVID that were published prior to August 30, 2021. The most common persistent symptoms were fatigue, cough, dyspnea, chest pains, chest tightness, joint pain, muscle pain, loss of taste or smell, hair loss, sleep difficulties, anxiety, and depression. Some of the less common persistent symptoms were skin rash, decreased appetite, sweating, inability to concentrate, and memory lapses. In addition to these general symptoms, some patients experienced dysfunctions of specific organs, mainly the lungs, heart, kidneys, and nervous system. A comprehensive understanding of the persistent clinical manifestations of COVID-19 can improve and facilitate patient management and referrals. Prompt rehabilitative care and targeted interventions of these patients may improve their recovery from physical, immune, and mental health symptoms.

2D/3D Copper-Based Metal-Organic Frameworks for Electrochemical Detection of Hydrogen Peroxide.

Metal-organic frameworks (MOFs) have been extensively used as modified materials of electrochemical sensors in the food industry and agricultural system. In this work, two kinds of copper-based MOFs (Cu-MOFs) with a two dimensional (2D) sheet-like structure and three dimensional (3D) octahedral structure for H2O2 detection were synthesized and compared. The synthesized 2D and 3D Cu-MOFs were modified on the glassy carbon electrode to fabricate electrochemical sensors, respectively. The sensor with 3D Cu-MOF modification (HKUST-1/GCE) presented better electrocatalytic performance than the 2D Cu-MOF modified sensor in H2O2 reduction. Under optimal conditions, the prepared sensor displayed two wide linear ranges of 2 µM-3 mM and 3-25 mM and a low detection limit of 0.68 µM. In addition, the 3D Cu-MOF sensor exhibited good selectivity and stability. Furthermore, the prepared HKUST-1/GCE was used for the detection of H2O2 in milk samples with a high recovery rate, indicating great potential and applicability for the detection of substances in food samples. This work provides a convenient, practical, and low-cost route for analysis and extends the application range of MOFs in the food industry, agricultural and environmental systems, and even in the medical field.

A Synthetic Curcuminoid Analog, (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone, Ameliorates Impaired Wound Healing in Streptozotocin-Induced Diabetic Mice by Increasing miR-146a.

The impairment in diabetic wound healing represents a significant clinical problem, with no efficient targeted treatments for these wound disorders. Curcumin is well confirmed to improve diabetic wound healing, however, its low bioavailability and poor solubility severely limit its clinical application. This study aims to provide the pharmacological basis for the use of (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66). The results showed that topically applied C66 improved cutaneous wound healing in vivo. Further studies showed that C66 treatment increased the level of microRNA-146a (miR-146a) in the wounds in streptozotocin (STZ)-induced diabetic mice, downregulated the expression of interleukin-1 receptor-associated kinase 1 (IRAK1) and phosphorylated nuclear factor-κB (NF-κB) p65 subunit (p-p65) (both p < 0.05), and suppressed the mRNA expression of inflammation-related cytokines, tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6). The in vitro data obtained in human umbilical vein endothelial cells (HUVECs) showed that C66 could reverse high glucose (HG)-induced NF-κB activation due to upregulation of miR-146a expression, which matched the in vivo findings. In conclusion, the present study indicates that C66 exerts anti-inflammation activity and accelerates skin wound healing of diabetic mice, probably via increasing miR-146a and inhibiting the NF-κB-mediated inflammation pathway. Therefore, C66 may be a promising alternative for the treatment of diabetic wounds.

Quercetin Promotes Diabetic Wound Healing via Switching Macrophages From M1 to M2 Polarization.

BACKGROUND: For patients with diabetes mellitus, excessive and long-lasting inflammatory reactions at the wound site commonly lead to the delayed refractory wound healing. The polarization of macrophages in terms of M1 and M2 phenotypes is closely related to the production of inflammatory cytokines. Quercetin is traditionally recognized to have anti-inflammatory effect; however, whether quercetin modulates macrophage polarization from M1 to M2 and thus promotes diabetic wound healing remain unknown. MATERIALS AND METHODS: Wounded male diabetic rats were equally divided into five groups: model group, solvent control group (10% DMSO), and three drug groups treated with quercetin (Q) at concentrations of 10 mg/mL (Q-LD [low dose]), 20 mg/mL (Q-MD [medium dose]), and 40 mg/mL (Q-HD [high dose]), respectively. The anti-inflammatory effect of quercetin on diabetic wounds was observed. Immunohistochemistry and quantificational real-time polymerase chain reaction were applied to test the changes in macrophage polarization and inflammatory responses. RESULTS: The wound contraction was fastest in Q-HD group. Hematoxylin and eosin (H&E) and Masson's trichrome staining revealed that fibroblast distribution and collagen deposition in quercetin-treated groups were significantly higher than those in the model group. Immunohistochemistry tests showed more CD206-positive cells and less iNOS-positive cells in quercetin-treated groups. Furthermore, the levels of proinflammatory factors in quercetin-treated groups were lower than those in the model group, whereas the levels of the anti-inflammatory factors and angiogenesis-related factors were relatively higher. CONCLUSIONS: In short, quercetin inhibits inflammatory reactions via modulating macrophage polarization switching from M1 to M2 phenotype, thereby accelerating the diabetic wound repair.

Trend in the nutritional status of children aged 2-7 years in Luoding city, China: A panel study from 2004 to 2013.

To examine trends in the prevalence of wasting, stunting, overweight, and obesity among children in Luoding, a lower-middle-income city in southern China, we collected height, weight and other information on 65,908 pre-school children aged 2 to 7 years from 23 kindergartens, in which health examinations were conducted annually between 2004 and 2013. We used the growth standards of the World Health Organization (WHO) to calculate Z-scores for height and body mass index (BMI), and used the cut-offs recommended by WHO to define wasting, stunting, overweight, and obesity for each child. From 2004 to 2013, the prevalence of overweight increased from 3.70% to 7.27% and of obesity increased from 1.04% to 2.08%. Meanwhile, the prevalence of wasting decreased from 0.91% to 0.72% and of stunting decreased from 9.29% to 5.22%. These trends suggest there was still a double burden of nutritional status there. The nutritional interventions focusing on pre-school children should be comprehensively elaborated in lower-middle-income areas such as Luoding.

Quercetin improves postpartum hypogalactia in milk-deficient mice via stimulating prolactin production in pituitary gland.

Postpartum dysgalactia is a common clinical problem for lactating women. Seeking out the safe and efficient phytoestrogens will be a promising strategy for postpartum dysgalactia therapy. In this study, the postpartum mice within four groups, including control group, the model group, and the treatment groups intragastrically administrated with normal saline, bromocriptine, bromocriptine plus 17α-ethinyl estradiol, and bromocriptine plus quercetin, respectively, were used. The results showed that quercetin, a kind of natural phytoestrogen, could efficiently promote lactation yield and mammary gland development in the agalactosis mice produced by bromocriptine administration. Mechanically, quercetin, such as 17α-ethinyl estradiol, significantly stimulated prolactin (PRL) production and deposition in the mammary gland in the agalactosis mice determined by western blotting, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Furthermore, quercetin could increase the expression of ß-casein, stearoyl-CoA desaturase, fatty acid synthase, and α-lactalbumin in the breast tissues that are responsible for the production of fatty acid, lactose, and galactose in the milk at the transcriptional level determined by quantitative polymerase chain reaction. Specifically, quercetin promoted primary mammary epithelial cell proliferation and stimulated prolactin receptor (PRLR) expression probably via AKT activation in vitro. In conclusion, this study indicates that estrogen-like quercetin promotes mammary gland development and lactation yield in milk-deficient mice, probably via stimulating PRL expression and release from the pituitary gland, as well as induces PRLR expression in primary mammary epithelial cells.

Copeptin in heart failure: Review and meta-analysis.

BACKGROUND: The aim of this study was to explore the prognostic value of copeptin for predicting all-cause mortality in heart failure (HF). METHODS: PubMed, Embase and Cochrane databases were systematically searched to identify if a 2×2 contingency table could be constructed based on both the copeptin level and the all-cause mortality in patients diagnosed with HF. The characteristics of test performance were summarized using forest plots and summary receiver operating characteristic curves (SROC). Q-test and I2 index were used to evaluate heterogeneity. RESULTS: Ten prospective cohort studies comprising 4473 patients were eligible in this meta-analysis. An elevated copeptin level was associated with an increased risk of all-cause mortality in HF patients (Relative risk (RR) was 2.64 (95% CI, 2.09-3.32)). The pooled sensitivity (SEN) and specificity (SPE) of copeptin were 0.57 (95% CI, 0.50-0.63) and 0.74 (95% CI, 0.69-0.79), respectively. The positive likelihood ratio was 2.2 (95% CI, 1.90-2.60) and the negative likelihood ratio was 0.58 (95% CI, 0.52-0.66). Furthermore, the summary Diagnostic Odds Ratio (DOR) was 4.00 (95% CI, 3.00-5.00) and the AUC was 0.70 (95% CI, 0.66-0.74) similar to the AUC of NT-proBNP 0.71 (95% CI, 0.67-0.75). CONCLUSIONS: Elevated levels of copeptin are associated with all-cause mortality in HF patients. The predictive value of copeptin is comparable with NT-proBNP for all-cause mortality in HF patients. Further studies are warranted to explore the prognostic value of copeptin in conjunction with other biomarkers and to determine an optimal cut-off level.

Determination of risk factors affecting the in-hospital prognosis of patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention.

BACKGROUND: To determine the factors affecting the in-hospital prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI), and to establish its prognostic discriminant model. METHODS: A total of 701 consecutive STEMI patients undergoing PCI were enrolled in this study. The patients were divided into two groups, good prognosis and poor prognosis, based on whether the patient had adverse outcomes (death or heart function ≥ grade III) at discharge. Demographic and basic clinical characteristics, diagnosis at admission (e.g., ventricular function, complications, or hyperlipidemia), and biomedical indicators (e.g., blood count, basal metabolism and biochemical composition, blood lipid and glucose levels, myocardial biomarkers, and coagulation) were collected and analyzed. RESULTS: We determined 22 factors as risk factors for the in-hospital prognosis of STEMI patients after PCI: age, cardiac function during hospitalization, complications, history of diabetes mellitus, et al., among which the history of diabetes, uric acid, urea nitrogen, and activated partial thromboplastin time (APTT) were independent risk factors. CONCLUSION: We identified four independent risk factors for the in-hospital prognosis of STEMI patients after PCI and generated a prognostic model to predict the adverse outcomes of these patients.

Diagnostic accuracy of ultrasonography for detecting nasogastric tube (NGT) placement in adults: A systematic review and meta analysis.

OBJECTIVE: To review the evidence on diagnostic accuracy of ultrasonography for detecting correct nasogastric tube (NGT) placement in adults compared to X-ray as the reference standard. METHODS: This is a systematic review and meta-analysis of observational studies, searched in the literature between 1961 and 2015. We included studies which compared the diagnostic accuracy of ultrasonography detection for NGT placement with X-ray in adult patients who were undergoing NGT placement for any reason in any care setting. We searched published studies in the following electronic databases: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Web of Science, WanFang Data, China Journal Net, and the Chinese Biomedical Literature Database. Both English and non-English-language articles were retrieved. Risk of bias was assessed using a standard procedure according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. RESULTS: We included five studies involving a total of 420 adult patients undergoing nasogastric tube placement: three trials were undertaken in mechanically ventilated patients in prehospital settings and two involved participants with comma or severe trauma in emergency room or intensive care unit (ICU). Pooled results showed that ultrasonography had a sensitivity of 0.93 (95% CI 0.87 to 0.97), and specificity of 0.97 (95% CI 0. 23 to 1.00), suggesting that diagnostic performance of ultrasound is useful to confirm correct NGT placement, but not optimal to detect incorrect NGT position. This was confirmed through a summary receiver operator characteristics (SROC) curve that showed the area under the curve was 0.96 (95% CI 0.94 to 0.98). DISCUSSION: The main limitation of the review is the relatively moderate level of heterogeneity of included studies which may partially undermine the reliability and reproducibility of results. The insufficient studies included did not allow identification of possible sources of heterogeneity and exploration of reporting bias. Due to heterogeneity of studies, the diagnostic performance of ultrasonography could only be drawn cautiously. Physicians and nurses should perform routine X-ray if visualization of NGT is not possible. More well designed studies exploring ultrasound as a diagnostic tool for accuracy of NGT placement are needed to strengthen the current evidence.

Prevalence of prehypertension and associated risk factors among health check-up population in Guangzhou, China.

The authors aimed to investigate the prevalence and risk factors of prehypertension among a cohort of patients presenting for a health check-up in Guangzhou. Using an age-and gender-stratified random sample method, 5170 urban adults aged 18-70 years undergoing health examination in Guangzhou were selected. Prehypertension was defined as systolic blood pressure (SBP) of 120-139 mmHg or diastolic blood pressure (DBP) of 80-89 mmHg. Overall prevalence of prehypertension in our study population was 35.15% (43.75% in men, 23.56% in women; P<0.05). Multivariate logistic regression analysis indicated that age (odds ratio [OR] =1.257), female (OR=0.437), fasting blood glucose (OR=1.514), total cholesterol (OR=1.241), triglycerides (OR=1.236), uric acid (OR=1.222), and body mass index (OR=1.778) were risk factors for prehypertension. The prevalence of prehypertension was reported to be higher among men in our study population in Guangzhou.

Sirtuin-6 inhibits cardiac fibroblasts differentiation into myofibroblasts via inactivation of nuclear factor κB signaling.

Differentiation of cardiac fibroblasts (CFs) into myofibroblasts represents a key event in cardiac fibrosis that contributes to pathologic cardiac remodeling. However, regulation of this phenotypic transformation remains elusive. Here, we show that sirtuin-6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent histone deacetylase, plays a role in the regulation of myofibroblast differentiation. SIRT6 expression was upregulated under pathologic conditions in angiotensin II (Ang II)-stimulated CFs and in myocardium of rat subjected to abdominal aortic constriction surgery. SIRT6 depletion by RNA interference (small interfering RNA [siRNA]) in CFs resulted in increased cell proliferation and extracellular matrix deposition. Further examination of SIRT6-depleted CFs demonstrated significantly higher expression of α-smooth muscle actin (α-SMA), the classical marker of myofibroblast differentiation, and increased formation of focal adhesions. Notably, SIRT6 depletion further exacerbated Ang II-induced myofibroblast differentiation. Overexpression of SIRT6 restored α-SMA expression in SIRT6-depleted or Ang II-treated CFs. Moreover, SIRT6 depletion induced the DNA binding activity and transcriptional activity of nuclear factor κB (NF-κB). Importantly, using an NF-κB p65 siRNA or pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB activity, reversed the expression of phenotypic markers of myofibroblasts. Our findings unravel a novel role of SIRT6 as a key modulator in the phenotypic conversion of CFs to myofibroblasts.

Carotid proliferative plaque formation in a canine model of chronic hypertension.

BACKGROUND: There are few reports describing arterial plaque formation induced by hypertension alone. The aim of this study was to establish a canine model of chronic hypertension and investigate carotid plaque development. METHODS: Ten beagles were studied; 5 underwent bilateral renal artery constriction via a novel vascular clip, and 5 sham-operated animals served as controls. Systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid values, the intima-media thickness, and the carotid artery plaque score were investigated during 1 year after placement of the clips. RESULTS: The mean SBP and DBP over time were significantly greater in the constriction group (P < 0.001 for SBP, P < 0.01 for DBP). There were no significant differences in blood lipid levels or other biochemical parameters. Carotid plaques were demonstrated at 4 months postoperation in the constriction group; and in the constriction group, intima-media thickness became significantly greater at 4 months (P < 0.05), and plaque scores became significantly higher at 8 months (P = 0.034) after clip placement. Carotid stenosis was proved by digital subtraction angiography 1 year after clip placement, and histological examination revealed that the plaques were mainly comprised of smooth muscle cells, proteoglycans, and collagen fibers, but few macrophages and little lipid. CONCLUSIONS: Carotid proliferative plaques were developed in a canine model of chronic hypertension induced by a novel vascular clip. The plaques were mainly comprised of smooth muscle cells, proteoglycans, and collagen fibers.

Cisplatin and oxaliplatin inhibit gap junctional communication by direct action and by reduction of connexin expression, thereby counteracting cytotoxic efficacy.

Cisplatin [cis-diamminedichloroplatinum(II)]/oxaliplatin [1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II)] toxicity is enhanced by functional gap junctions between treated cells, implying that inhibition of gap junctions may decrease cytotoxic activity of these platinum-based agents. This study investigates the effect of gap junction modulation by cisplatin/oxaliplatin on cytotoxicity in a transformed cell line. The effects were explored using junctional channels expressed in transfected HeLa cells and purified hemichannels. Junctional channels showed a rapid, dose-dependent decrease in dye coupling with exposure to cisplatin/oxaliplatin. With longer exposure, both compounds also decreased connexin expression. Both compounds inhibit the activity of purified connexin hemichannels, over the same concentration range that they inhibit junctional dye permeability, demonstrating that inhibition occurs by direct interaction of the drugs with connexin protein. Cisplatin/oxaliplatin reduced the clonogenic survival of HeLa cells at low density and high density in a dose-dependent manner, but to a greater degree at high density, consistent with a positive effect of gap junctional intercellular communication (GJIC) on cytotoxicity. Reduction of GJIC by genetic or pharmacological means decreased cisplatin/oxaliplatin toxicity. At low cisplatin/oxaliplatin concentrations, where effects on connexin channels are minimal, the toxicity increased with increased cell density. However, higher concentrations strongly inhibited GJIC, and this counteracted the enhancing effect of greater cell density on toxicity. The present results indicate that inhibition of GJIC by cisplatin/oxaliplatin decreases their cytotoxicity. Direct inhibition of GJIC and reduction of connexin expression by cisplatin/oxaliplatin may thereby compromise the effectiveness of these compounds and be a factor in the development of resistance to this class of chemotherapeutic agents.

[Correlation between myocardial ischemia and carotid atherosclerosis in hypertensive patients].

OBJECTIVE: To analyze the correlation between myocardial ischemia and carotid atherosclerosis in hypertensive patients. METHODS: The clinical data were collected from 85 hospitalized hypertensive patients admitted between May 2005 and September 2008 without the complication of coronary artery disease as confirmed by cardiac computed tomographic angiography (CTA). According to the results of treadmill exercise test, the patients were divided myocardial ischemia group and ischemia-free group. Univariate and multivariate analyses were used to screen the risk factors of myocardial ischemia. The correlations were analyzed between myocardial ischemia, common carotid artery intima-media thickness (IMT), Crouse score of the carotid plaque, thickness of the intraventricular septum and left artrium. The receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of IMT and Crouse score in predicting the presence of myocardial ischemia in hypertensive patients. RESULTS: Carotid plaque formation was identified as the major risk factor of myocardial ischemia in hypertensive patients (OR=4.982, P=0.004). The incidence of myocardial ischemia in the hypertensive patients with carotid plaques was significantly higher than that in the patients without the plaque (Chi2=9.317, P=0.002). Myocardial ischemia in hypertensive patients was positively correlated to the thickness of the intraventricular septum (r=0.362, P=0.001) and left artrium (r=0.298, P=0.009), and the IMT of the common carotid artery was positively correlated to the thickness of the intraventricular septum (r=0.231, P=0.045). The area under cure (AUC) of the ROC curve of Crouse score was 0.726-/+0.061 in predicting the presence of myocardial ischemia in the hypertensive patients (P=0.001), and that of IMT was 0.682-/+0.061 (P=0.006). CONCLUSION: Carotid plaque formation is the major risk factor of myocardial ischemia in hypertensive patients and shows a positive correlation to the onset of myocardial ischemia, but both the common carotid artery IMT and the Crouse score of the carotid plaque are not accurate markers for predicting myocardial ischemia in patients with hypertension.