Anethole mitigates H2 O2 -induced inflammation in HIG-82 synoviocytes by suppressing the aquaporin 1 expression and activating the protein kinase A pathway.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting approximately 1% of the global population, with a higher prevalence in women than in men. Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of RA. Anethole, a prominent compound derived from fennel (Foeniculum vulgare), possesses a spectrum of therapeutic properties, including anti-arthritic, anti-inflammatory, antioxidant, and tumor-suppressive effects. However, its specific impact on RA remains underexplored. This study sought to uncover the potential therapeutic value of anethole in treating RA by employing an H2 O2 -induced inflammation model with HIG-82 synovial cells. Our results demonstrated that exposure to H2 O2 induced the inflammation and apoptosis in these cells. Remarkably, anethole treatment effectively countered these inflammatory and apoptotic processes triggered by H2 O2 . Moreover, we identified the aquaporin 1 (AQP1) and protein kinase A (PKA) pathway as critical regulators of inflammation and apoptosis. H2 O2 stimulation led to an increase in the AQP1 expression and a decrease in p-PKA-C, contributing to cartilage degradation. Conversely, anethole not only downregulated the AQP1 expression but also activated the PKA pathway, effectively suppressing cell inflammation and apoptosis. Furthermore, anethole also inhibited the enzymes responsible for cartilage degradation. In summary, our findings highlight the potential of anethole as a therapeutic agent for mitigating H2 O2 -induced inflammation and apoptosis in synovial cells, offering promising prospects for future RA treatments.

Identifying High-Quality Non-Instrumental Dysphagia Screening Tools for Detection of Adult Dysphagia Case in Acute-Care Settings: A Systematic Review.

INTRODUCTION: As patients nowadays tend to have multiple diseases and complex medical histories, our aim was to identify high-quality, non-instrumental dysphagia screening tools used for the detection of adult dysphagia cases in all disease categories in acute-care settings. METHOD: A literature search was conducted in five databases from each database's earliest inception to 31 July 2021 and guided by five keywords: 'dysphagia', 'deglutition', 'screening', 'test' and 'measure'. Without limiting the search in any specific disease category, reviewers assessed original studies and identified tools if they had been validated against instrumental evaluations and if they had been designed as a pass-fail procedure to screen whether dysphagia is absent or present. We further excluded any tool if it was (1) for pediatric focus, or (2) a patient self-report questionnaire. All final tool candidates underwent a methodological quality appraisal using the Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). RESULT: Out of 195 studies with 165 tools identified, 20 tool candidates underwent QUADAS-2 review. We found six high-quality, non-instrumental screening tools for detecting adult dysphagia cases in acute-care settings, including the Yale Swallow Protocol, Gugging Swallowing Screen, Toronto Bedside Swallowing Screening Test (both English and Portuguese versions), Sapienza Global Bedside Evaluation of Swallowing and Two-Step Thickened Water Test. These high-quality tools were developed primarily for patients with stroke. Only Yale Swallow Protocol was originally tested for heterogeneous populations with stroke, multiple sclerosis, traumatic brain injury, oesophageal surgery, neurosurgery and head-and-neck cancer. CONCLUSIONS: The results highlight the gap in the unavailability of high-quality dysphagia screening tool in several emerged high-risk populations including elderly inpatients, or patients following endotracheal extubation. Further research is needed to determine whether these six tools can be effectively applied across different high-risk populations in acute-care settings to screen for cases finding.

Effects of a swallowing and oral-care program on resuming oral feeding and reducing pneumonia in patients following endotracheal extubation: a randomized, open-label, controlled trial.

BACKGROUND: The resumption of oral feeding and free from pneumonia are important therapeutic goals for critically ill patients who have been successfully extubated after prolonged (≥ 48 h) endotracheal intubation. We aimed to examine whether a swallowing and oral-care (SOC) program provided to critically ill patients extubated from prolonged mechanical ventilation improves their oral-feeding resumption and reduces 30-day pneumonia incidence. METHODS: In this randomized, open-label, controlled trial, participants were consecutively enrolled and randomized to receive the SOC program or usual care. The interventions comprised three protocols: oral-motor exercise, sensory stimulation and lubrication, and safe-swallowing education. Beginning on the day following patient extubation, an SOC nurse provided the three-protocol care for seven consecutive days or until death or hospital discharge. With independent outcome assessors, oral-feeding resumption (yes, no) corresponded to level 6 or level 7 on the Functional Oral Intake Scale (censored seven days postextubation) along with radiographically documented pneumonia (yes, no; censored 30 days postextubation), abstracted from participants' electronic medical records were coded. RESULTS: We analyzed 145 randomized participants (SOC group = 72, control group = 73). The SOC group received, on average, 6.2 days of intervention (14.8 min daily) with no reported adverse events. By day 7, 37/72 (51.4%) of the SOC participants had resumed oral feeding vs. 24/73 (32.9%) of the control participants. Pneumonia occurred in 11/72 (15.3%) of the SOC participants and in 26/73 (35.6%) of the control participants. Independent of age and intubation longer than 6 days, SOC participants were likelier than their control counterparts to resume oral feeding (adjusted hazard ratio, 2.35; 95% CI 1.38-4.01) and had lower odds of developing pneumonia (adjusted odds ratio, 0.28; 95% CI 0.12-0.65). CONCLUSIONS: The SOC program effectively improved patients' odds that oral feeding would resume and the 30-day pneumonia incidence would decline. The program might advance dysphagia care provided to critically ill patients extubated from prolonged mechanical ventilation. TRIAL REGISTRATION: NCT03284892, registered on September 15, 2017.

Zoledronate alters natural progression of tissue-engineered vascular grafts.

Macrophages are a critical driver of neovessel formation in tissue-engineered vascular grafts (TEVGs), but also contribute to graft stenosis, a leading clinical trial complication. Macrophage depletion via liposomal delivery of clodronate, a first-generation bisphosphonate, mitigates stenosis, but simultaneously leads to a complete lack of tissue development in TEVGs. This result and the associated difficulty of utilizing liposomal delivery means that clodronate may not be an ideal means of preventing graft stenosis. Newer generation bisphosphonates, such as zoledronate, may have differential effects on graft development with more facile drug delivery. We sought to examine the effect of zoledronate on TEVG neotissue formation and its potential application for mitigating TEVG stenosis. Thus, mice implanted with TEVGs received zoledronate or no treatment and were monitored by serial ultrasound for graft dilation and stenosis. After two weeks, TEVGs were explanted for histological examination. The overall graft area and remaining graft material (polyglycolic-acid) were higher in the zoledronate treatment group. These effects were associated with a corresponding decrease in macrophage infiltration. In addition, zoledronate affected the deposition of collagen in TEVGs, specifically, total and mature collagen. These differences may be, in part, explained by a depletion of leukocytes within the bone marrow that subsequently led to a decrease in the number of tissue-infiltrating macrophages. TEVGs from zoledronate-treated mice demonstrated a significantly greater degree of smooth muscle cell presence. There was no statistical difference in graft patency between treatment and control groups. While zoledronate led to a decrease in the number of macrophages in the TEVGs, the severity of stenosis appears to have increased significantly. Zoledronate treatment demonstrates that the process of smooth muscle cell-mediated neointimal hyperplasia may occur separately from a macrophage-mediated mechanism.

Improving Leadership Competence Among Undergraduate Nursing Students: Innovative Objectives Development, Implementation, and Evaluation.

AIM: The aim of the study was to identify baccalaureate nursing leadership objectives and evaluate their effectiveness when embedded into an undergraduate nursing curriculum. BACKGROUND: The objectives of nursing leadership competencies cannot be met in one semester but must be gradually developed over successive courses. METHOD: A list of learning objectives for leadership competence was generated and reviewed by 12 experts using the Delphi method. The consensuses objectives were embedded into a four-year nursing baccalaureate curriculum in Taiwan. Nursing students (N = 120) who participated in the courses evaluated the embedded objectives of leadership competency introduced in their undergraduate nursing program. Leadership competence was improved among students on nine items (t = 2.282 to 5.741, p = .001 to .030) of the Nursing Leadership Competence Assessment Scale for Undergraduate Nursing Students. CONCLUSION: The results can serve as a reference for universities seeking to promote nursing leadership education.

Appraisal and evaluation of the instruments measuring the nursing work environment: A systematic review.

AIMS: To appraise the current instruments available for measuring the nursing work environment and re-examine the definition and construct of the nursing work environment. BACKGROUND: A psychometrically sound instrument is fundamental to understanding and improving the nursing work environment. The nursing work environment is a complex construct, and its definition remains inconclusive. None of the instruments available is considered as the gold standard. EVALUATION: A comprehensive searching was undertaken in August 2021 in six databases according to PRISMA. The COSMIN and modified GRADE were applied to assess the methodological quality and measurement properties of the instruments. Instruments were categorized into three levels. The definition and construct of nursing work environment were revisited. KEY ISSUES: Forty-one studies (19 instruments) were included. One, fourteen, and four instruments are respectively appraised as A-, B- and C-level recommendation. Definition and eight labels of nursing work environment are identified. CONCLUSION: This paper provides recommendations for selecting a proper instrument for the nursing work environment. IMPLICATIONS FOR NURSING MANAGEMENT: This study helps nurse managers to select instruments and understand the construct of the nursing work environment. The eight labels can be used as a reference for tailoring policy aimed at creating a favourable nursing work environment.

[Developing and Evaluating the Effectiveness of a Leadership Integrated Educational Program for Master's Nursing Students in Taiwan].

BACKGROUND: Nursing students with master degrees have the strong potential to serve as future leaders in medical teams. Implementing a well-developed and integrated educational program for nursing leadership at the master's level can strengthen the leadership of advanced practice nurses and promote a positive nursing practice environment. PURPOSE: To develop a leadership integrated educational program for master's nursing students and conduct a preliminary evaluation of the effectiveness of this program in cultivating leadership competencies in these students. METHODS: Phase 1: A modified Delphi survey conducted on 14 experts with clinical or academic backgrounds was used to identify the teaching objectives and strategies of the leadership integrated educational program. Phase 2: These teaching objectives and strategies were embedded into nine compulsory courses within a current training program for master's nursing students at a national university. The core elements of the leadership integrated educational program were incorporated into each compulsory course. The objectives of each compulsory course directly reflected the objectives of the integrated program. The leadership integrated educational program was implemented for one academic year, and its effectiveness was evaluated using a quasi-experimental test with a single group pre- and post-test design. A self-developed, 10-item "Master Nursing Student's Leadership Competence Scale" covering four core elements was applied to measure the self-reported leadership competencies of the participants. A paired sample t-test was applied to analyze the differences in leadership competencies between pre- and post-intervention. RESULTS: A consensus on the teaching objectives and strategies of the leadership integrated educational program was achieved in the first round of the Delphi survey. The overarching teaching objective of the leadership integrated educational program was to "lead the healthcare team with the leadership and competencies, and demonstrate the advanced nursing practice skills for improving quality of care." In addition, the four core elements under the overarching goal, i.e., personal characteristics, leading people, business management, and vision building, were proposed. Forty-eight master's nursing students participated in this study. The results showed the average total score of leadership competency was 42.33 ± 12.16 (potential range: 10 - 70), indicating that the participants had a middle level of leadership competency prior to program participation. After participating in the Leadership Integrated Educational Program for one academic year, the average total score for leadership competency increased to 51.27 ± 9.74, indicating that the participants still had a middle level of leadership competency. Nevertheless, the 8.94 increase in the post-intervention score was statistically significant (p < .01). Moreover, the scores for each subscale (personal characteristics, leading people, business management, and vision building) had all increased significantly increased from 13.52 to 15.71, 12.65 to 15.35, 8.15 to 10.31, and 8.02 to 9.90, respectively (p < .01). CONCLUSIONS / IMPLICATIONS FOR PRACTICE: This study offers proactive recommendations for reforming master's degree programs in nursing. The proposed multidisciplinary-expert-informed leadership integrated educational program may be used to strengthen leadership competencies in this student population. Furthermore, the findings provide a benchmark for developing an effective nursing leadership integrated educational program that may be incorporated into domestic master's degree programs.

The impacts of maternal childhood adversity, stress, and mental health on child development at 6 months in Taiwan: A follow-up study.

Exposure to adverse childhood experiences (ACEs) is not only associated with one's adverse health outcomes in adulthood but also increases the risk of child developmental problems in offspring. However, the mechanisms involved in the transmission of the effects of maternal ACEs to the offspring largely remain unexplored. This study sought to identify possible psychosocial pathways of intergenerational effects of maternal ACEs on child development at 6 months. Data from a longitudinal study on maternal childhood adversity and maternal psychosocial risk during pregnancy as well as maternal mental health problems and child development at 6 months postnatal were used. Structural equation modeling with bootstrapping was used to estimate the indirect effects of maternal ACEs on child development at 6 months. The model showed that maternal ACEs indirectly influenced offspring's development via maternal stressful events during pregnancy and pre- and postnatal mental health problems. This finding highlights the possible interventions at the prenatal and postnatal periods. Early identification of women who have ACEs or who are at psychosocial risk during pre- and postnatal periods is critical to provide interventions to buffer those negative effects on offspring's development. Future studies are needed to longitudinally assess the effects of maternal ACEs on child development over time.

Incidence and characteristics of paediatric abusive head trauma in Taiwan, 2006-2015: a nationwide population-based study.

OBJECTIVES: To examine the incidence rate and characteristics of paediatric abusive head trauma (PAHT) among children under age 5 years in Taiwan. METHODS: The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to identify broad and narrow definitions of children aged under 5 years with PAHT from 2006 to 2015 in Taiwan using a representative national insurance research database. Medical resource utilisation was also analysed. Incidence rates per 100 000 person-years were calculated and presented with 95% CI. Joinpoint regression analysis was used to detect the changes in trends and calculate the annual percentage change in PAHT incidence over time. RESULTS: From 2006 to 2015, 479 (narrow definition) and 538 (broad definition) PAHT cases were identified. Incidence rates of PAHT by narrow and broad definitions among children under 1 year of age (18.7/100 000 and 20.0/100 000) were nearly 10-fold or 20-fold higher than for children aged 1-2 (1.7/100 000 and 2.1/100 000) and 3-5 (0.9/100 000 and 1.2/100 000) years. The PAHT incidence significantly increased since 2012, with trends varying by age and gender. Our results suggest that over 40% of the children with PAHT experienced serious injury and nearly 13% were fatal cases. For 87% (n=57) of fatal cases, this was their first ever hospitalisation. The number of fatal cases among infants was fourfold higher than that of children aged 1-5 years. CONCLUSIONS: This study provides a robust national estimate of PAHT and identifies infants as the most vulnerable group for PAHT in Taiwan. Education to enhance healthcare profession's sensitivity and competence for the early identification and diagnosis of PAHT is critical.

Current Challenges and Solutions to Tissue Engineering of Large-scale Cardiac Constructs.

PURPOSE OF REVIEW: Large-scale tissue engineering of cardiac constructs is a rapidly advancing field; however, there are several barriers still associated with the creation and clinical application of large-scale engineered cardiac tissues. We provide an overview of the current challenges and recently (within the last 5 years) described promising solutions to overcoming said challenges. RECENT FINDINGS: The five major criteria yet to be met for clinical application of engineered cardiac tissues are successful electrochemical/mechanical cell coupling, efficient maturation of cardiomyocytes, functional vascularization of large tissues, balancing appropriate immune response, and large-scale generation of constructs. Promising solutions include the use of carbon/graphene in conjunction with existing scaffold designs, utilization of biological hormones, 3D bioprinting, and gene editing. While some of the described barriers to generation of large-scale cardiac tissue have seen encouraging advancements, there is no solution that yet achieves all 5 described criteria. It is vital then to consider a combination of techniques to achieve the optimal construct. Critically, following the demonstration of a viable construct, there remain important considerations to address associated with good manufacturing practices and establishing a standard for clinical trials.

Evaluating the Longevity of the Fontan Pathway.

Children born with single ventricle physiology who undergo Fontan palliation face a diverse set of long-term complications. However, patient follow-up has in large part been limited to single institutional experiences without uniform application of diagnostic modalities to screen for relevant outcomes. Additionally, the use of different graft materials and variable surgical technique as part of the Fontan procedure has further complicated the evaluation of single ventricle patients. The purpose of this review is to define the changes in the Fontan pathway specific to the graft material used and its relationship to patient outcomes. As a means of introduction, we briefly review the historical evolution of the Fontan procedure with a focus on the intent behind design changes and incorporation of different biomaterials. We further delineate changes to the Fontan pathway which include the development of stenosis, differential growth, thrombosis, and calcification. Ultimately, the recognition of the changes noted within the Fontan pathway need to be assessed relative to their impact on patient hemodynamics, functional capacity, and Fontan-associated comorbidities.

The axis of local cardiac endogenous Klotho-TGF-ß1-Wnt signaling mediates cardiac fibrosis in human.

BACKGROUND: Cardiovascular fibrosis is a major contributor to cardiovascular disease, the primary cause of death in patients with chronic kidney disease (CKD). We previously reported expression of endogenous Klotho in human arteries, and that CKD is a state of Klotho deficiency, resulting in vascular calcification, but myocardial expression of Klotho is poorly understood. This study aimed to further clarify endogenous Klotho's functional roles in cardiac fibrosis in patients with underlying CKD. METHODS AND RESULTS: Human atrial appendage specimens were collected during cardiac surgery from individuals with or without CKD. Cardiac fibrosis was quantified using trichrome staining. For endogenous Klotho functional studies, primary human cardiomyocytes (HCMs) were treated with uremic serum from CKD patients or recombinant human TGF-ß1. The effects of endogenous Klotho in HCMs were studied using Klotho-siRNA and Klotho-plasmid transfection. Both gene and protein expression of endogenous Klotho are found in human heart, but decreased Klotho expression is clearly associated with the degree of cardiac fibrosis in CKD patients. Moreover, we show that endogenous Klotho is expressed by HCMs and cardiac fibroblasts (HCFs) but that HCM expression is suppressed by uremic serum or TGF-ß1. Klotho knockdown or overexpression aggravates or mitigates TGF-ß1-induced fibrosis and canonical Wnt signaling in HCMs, respectively. Furthermore, co-culture of HCMs with HCFs increases TGF-ß1-induced fibrogenic proteins in HCFs, but overexpression of endogenous Klotho in HCMs mitigates this effect, suggesting functional crosstalk between HCMs and HCFs. CONCLUSIONS: Our data from analysis of human hearts as well as functional in vitro studies strongly suggests that the loss of cardiac endogenous Klotho in CKD patients, specifically in cardiomyocytes, facilitates intensified TGF-ß1 signaling which enables more vigorous cardiac fibrosis through upregulated Wnt signaling. Upregulation of endogenous Klotho inhibits pathogenic Wnt/ß-catenin signaling and may offer a novel strategy for prevention and treatment of cardiac fibrosis in CKD patients.

Exploring the relationship between nursing hours per patient day and mortality rate of hospitalised patients in Taiwan.

AIM: To investigate the relationship between nursing hours per patient day and the inpatient mortality rate in Taiwan. BACKGROUND: Nursing hours per patient day has been associated with better patient outcomes. The literature is inconclusive on the relationship between nursing hours per patient day and the inpatient mortality rate, and no studies have yet examined this issue in Taiwan. METHODS: A retrospective longitudinal study analysed data from the 'Nursing Utilization of Resources, Staffing and Environment on Outcome Study: NURSE-outcome study'. Hierarchical regression estimated the relationship between nursing hours per patient day and in-hospital mortality rate after controlling for confounding variables. RESULTS: The mean nursing hours per patient day in Taiwan was 2.3, while the mean inpatient mortality rate was 0.73% higher nursing hours per patient day was associated with a lower inpatient mortality rate after controlling for confounding variables. The total explained variance of this study in inpatient mortality rate was 19.9%. Significant relationships to inpatient mortality were found in levels of hospitals, seasonal variation and nurses' work experience. CONCLUSION: Nursing hours per patient day affects the mortality rate among hospitalised patients in Taiwan. IMPLICATIONS FOR NURSING MANAGEMENT: According to the results, we suggested the government and managers in Taiwan double the nursing hours per patient day so that the inpatient mortality rate will decline by 1.1%. This might be the optimal nurse configuration that could provide a balance between cost-effectiveness and patient safety.

[A review of mixed gas detection system based on infrared spectroscopic technique].

In order to provide the experiences and references to the researchers who are working on infrared (IR) mixed gas detection field. The proposed manuscript reviews two sections of the aforementioned field, including optical multiplexing structure and detection method. At present, the coherent light sources whose representative are quantum cascade laser (QCL) and inter-band cascade laser(ICL) become the mainstream light source in IR mixed gas detection, which replace the traditional non-coherent light source, such as IR radiation source and IR light emitting diode. In addition, the photon detector which has a super high detectivity and very short response time is gradually beyond thermal infrared detector, dominant in the field of infrared detector. The optical multiplexing structure is the key factor of IR mixed gas detection system, which consists of single light source multi-plexing detection structure and multi light source multiplexing detection structure. Particularly, single light source multiplexing detection structure is advantages of small volume and high integration, which make it a plausible candidate for the portable mixed gas detection system; Meanwhile, multi light source multiplexing detection structure is embodiment of time division multiplex, frequency division multiplexing and wavelength division multiplexing, and become the leading structure of the mixed gas detection system because of its wider spectral range, higher spectral resolution, etc. The detection method applied to IR mixed gas detection includes non-dispersive infrared (NDIR) spectroscopy, wavelength and frequency-modulation spectroscopy, cavity-enhanced spectroscopy and photoacoustic spectroscopy, etc. The IR mixed gas detection system designed by researchers after recognizing the whole sections of the proposed system, which play a significant role in industrial and agricultural production, environmental monitoring, and life science, etc.

Calocedrus formosana Essential Oils Induce ROS-Mediated Autophagy and Apoptosis by Targeting SIRT1 in Colon Cancer Cells.

Colorectal cancer is the most common cancer that affects both sexes and has a poor prognosis due to aggressiveness and chemoresistance. Essential oils isolated from Calocedrus formosana (CF-EOs) have been shown to demonstrate anti-termite, antifungal, anti-mosquito, and anti-microbial activities. However, the anticancer effects of CF-EOs are not yet fully understood. Therefore, the present study aimed to explore the molecular mechanism underlying CF-EOs-mediated anti-proliferative activity in colon cancer cells. Here, cell impedance measurements showed that CF-EOs inhibit proliferation in colon cancer cells with wild-type or mutant p53. Flow cytometry revealed that CF-EOs at 20, 50 µg/mL significantly induced ROS generation and autophagy in both HCT116 p53-wt and HCT116 p53-null cell lines, whereas pretreatment with the ROS scavenger N-acetyl cysteine (NAC) markedly attenuated these changes. CF-EOs also induced apoptosis at 50 µg/mL in both lines, as determined by flow cytometry. Protein analysis showed that CF-EOs markedly induced apoptosis markers, including Trail, cleaved caspase-3, cleaved caspase-9, and cleaved PARP, as well as autophagy markers, such as the levels of ULK1, Atg5, Atg6, Atg7, and the conversion of LC3-I to LC3-II. CF-EOs were further found to inhibit the activity and expression of the NAD+-dependent deacetylase SIRT1 to increase the levels of acetylated p53 (Ac-p53) in p53-wt cells and acetylated c-Myc (Ac-c-Myc) in p53-null cells, ultimately inducing apoptosis in both lines. Interestingly, suppression of SIRT1 by CF-EOs enhanced the acetylation of ULK1, which in turn prompted ROS-dependent autophagy in colon cancer cells. The induction of apoptosis and autophagy by CF-EOs suggests that they may have potential as a promising new approach for treating cancer. Collectively, our results suggest that essential oils isolated from Calocedrus formosana act as a promising anticancer agent against colon cancer cells by targeting SIRT1 to induce ROS-mediated autophagy and apoptosis.

Local vascular Klotho mediates diabetes-induced atherosclerosis via ERK1/2 and PI3-kinase-dependent signaling pathways.

BACKGROUND AND AIMS: Diabetes is one of the major causes of cardiovascular disease (CVD). As high as 29 % of patients with diabetes develop atherosclerosis. Vascular Smooth Muscle Cells (VSMCs) are a key mediator in the pathogenesis of atherosclerosis, generating pro-inflammatory and proliferative characteristics in atherosclerotic lesions. METHODS: We used human atherosclerotic samples, developed diabetes-induced atherosclerotic mice, and generated loss of function and gain of function in Klotho human aortic smooth muscle cells to investigate the function of Klotho in atherosclerosis. RESULTS: We found that Klotho expression is decreased in smooth muscle actin-positive cells in patients with diabetes and atherosclerosis. Consistent with human data, we found that Apoe knockout mice with streptozotocin-induced diabetes fed on a high-fat diet showed decreased expression of Klotho in SMCs. Additionally, these mice showed increased expression of TGF-ß, MMP9, phosphorylation of ERK and Akt. Further, we utilized primary Human Aortic Smooth Muscle Cells (HASMCs) with d-glucose under dose-response and in time-dependent conditions to study the role of Klotho in these cells. Klotho gain of function and loss of function studies showed that Klotho inversely regulated the expression of atherosclerotic markers TGF-ß, MMP2, MMP9, and Fractalkine. Further, High Glucose (HG) induced Akt, and ERK1/2 phosphorylation were enhanced or mitigated by endogenous Klotho deficiency or its overexpression respectively. PI3K/Akt and MAPK/ERK inhibition partially abolished the HG-induced upregulation of TGF-ß, MMP2, MMP9, and Fractalkine. Additionally, Klotho knockdown increased the proliferation of HASMCs and enhanced α-SMA and TGF-ß expression. CONCLUSIONS: Taken together, these results indicate that local vascular Klotho is involved in diabetes-induced atherosclerosis, which is via PI3K/Akt and ERK1/2-dependent signaling pathways.

The Effectiveness of Parenting Programs in Preventing Abusive Head Trauma: A Systematic Review and Meta-Analysis.

Parenting programs are the most common intervention for preventing the lethal form of child maltreatment, abusive head trauma (AHT). However, certain results of the effects of these programs have not yet been compared across studies. A systematic review with meta-analysis is warranted to quantitively synthesize the available evidence to identify effective elements and strategies of the programs for preventing AHT. This review aims to estimate AHT preventive parenting programs' pooled effect on the reduction of AHT incidence, the improvement of parental knowledge, and the increased use of safe strategies in response to infants' inconsolable crying. Studies published in English and Mandarin were searched and retained if they were randomized control trials (RCTs) or with a quasi-experimental design, included an AHT preventive parenting program, and provided data that quantified targeted outcomes. Eighteen studies were included in this review. AHT preventive parenting programs had a pooled effect on improving parents' knowledge and increasing the use of safe coping strategies in response to inconsolable crying but not on the incidence of AHT and parents' emotional self-regulation. Subgroup analyses showed that the intervention effects were mostly present across study designs or measurements and emerged in the reduction of AHT incidence compared with historical controls. The findings suggest that AHT preventive parenting programs enhance parenting knowledge and skills to provide safe care for infants. Further efforts to evaluate AHT parenting programs on the reduction of AHT incidence are necessary for decision-making on allocating and disseminating interventions.

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells.

The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus, has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations to identify and validate that heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged and targeted with sirtuin-1 (SIRT1) in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. We further addressed the cellular outcome of SIRT1 inhibition by these compounds and found that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase (tNOX, ENOX2). The direct binding of 4-dmH to tNOX decreased the oxidation of NADH to NAD+ which diminished NAD+-dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types, as opposed to the parental heliomycin-induced autophagy. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, our in vitro and in vivo findings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD+-SIRT1 axis to induce apoptosis in oral cancer cells.

Aloin and CPT-11 combination activates miRNA-133b and downregulates IGF1R- PI3K/AKT/mTOR and MEK/ERK pathways to inhibit colorectal cancer progression.

CPT-11 is one of the drugs employed in colorectal cancer treatment and has faced challenges in the form of resistance. The insulin-like growth factor 1 receptor is a tyrosine kinase receptor that mediates cancer cell survival and drug resistance. It is frequently overexpressed in colorectal cancer and has previously been identified as a microRNA target. MicroRNAs are non-coding RNA molecules that regulate gene function by suppressing messenger RNA translation. Studies have demonstrated that natural compounds can regulate microRNA function and their target genes. Therefore, combining natural compounds with existing cancer drugs can enhance the therapeutic efficacy. We investigated a natural compound, Aloin, for the potential sensitization of colorectal cancer to CPT-11. We used western blot, MTT cell viability assay, flow cytometry, and microRNA/gene knockdown and overexpression experiments, as well as an in vivo mouse model. Our investigation revealed that combining Aloin with CPT-11 exerts an enhanced anti-tumor effect in colorectal cancer. This combination reduced cell viability and induced apoptosis, both in vivo and in vitro. Furthermore, this combination upregulated miRNA-133b, while downregulating the IGF1R and its downstream MEK/ERK, and PI3K/AKT/mTOR pathways. Our findings suggests that CPT-11 and Aloin are potential combination treatment partners against colorectal cancer. MicroRNA-133b may serve as a co-therapeutic target with IGF1R against colorectal cancer, which might overcome the existing treatment limitations.

Gelation behavior of poly(9,9-dioctylfluorene)/poly[9,9-di(2-ethylhexyl)-fluorenyl-2,7-diyl] blend in methylcyclohexane solutions.

We investigated the gelation behavior of the blend of two light-emitting polyfluorenes, i.e., poly(9,9-dioctylfluorene-2,7-diyl) (PF(8)) and poly[9,9-di(2-ethylhexyl)-fluorenyl-2,7-diyl] (PF(2/6)), in solutions with methylcyclohexane (MCH). Upon prolonged aging at room temperature, dynamic light scattering revealed that phase separation in the initially well-mixed solutions occurred via spinodal decomposition, yielding a PF(8)/PF(2/6)-enriched phase and an isotropic solvent-rich phase. Sheetlike aggregates in which a portion of the PF(8) chains adopted the ß conformation were formed in the polymer-enriched phase, as revealed by small-angle X-ray scattering and optical spectroscopy. Macroscopically, the phase separation transformed the original viscous liquid solution into a gel. Measurements of the gelation temperature (T(gel)), gel-to-sol transition temperature (T(g-s)), and spinodal decomposition temperature (T(SD)) indicated that gelation (and hence phase separation) became more difficult with increasing content of PF(2/6). The presence of PF(2/6) also hindered formation of the ß-phase of PF(8.) Therefore, the microstructure and photophysical properties of PF(8)/PF(2/6) in MCH solution can be tuned by the composition of the two polymers.