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.

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.

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.

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.

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.

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.

[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.

Angiotensin II prompts heart cell apoptosis via AT1 receptor-augmented phosphatase and tensin homolog and miR-320-3p functions to enhance suppression of the IGF1R-PI3K-AKT survival pathway.

BACKGROUND: Hypertension is a severe public health risk factor worldwide. Elevated angiotensin II (Ang II) produced by the renin-angiotensin-aldosterone system can lead to hypertension and its complications. METHOD: In this study, we addressed the cardiac-injury effects of Ang II and investigated the signaling mechanism induced by Ang II. Both H9c2 cardiomyoblast cells and neonatal rat cardiomyocytes were exposed to Ang II to observe hypertension-related cardiac apoptosis. RESULTS: The results of western blotting revealed that Ang II significantly attenuated the IGF1R-PI3K-AKT pathway via the Ang II-AT1 receptor axis and phosphatase and tensin homolog expression. Furthermore, real-time PCR showed that Ang II also activated miR-320-3p transcription to repress the PI3K-Akt pathway. In the heart tissue of spontaneously hypertensive rats, activation of the IGF1R survival pathway was also reduced compared with that in Wistar-Kyoto rats, especially in aged spontaneously hypertensive rats. CONCLUSION: Hence, we speculate that the Ang II-AT1 receptor axis induces both phosphatase and tensin homolog and miR-320-3p expression to downregulate the IGF1R-PI3K-AKT survival pathway and cause cell apoptosis in the heart.

Daidzein Synergizes with Gefitinib to Induce ROS/JNK/c-Jun Activation and Inhibit EGFR-STAT/AKT/ERK Pathways to enhance Lung Adenocarcinoma cells chemosensitivity.

Lung cancer is the major cause of cancer associated mortality. Mutations in EGFR have been implicated in lung cancer pathogenesis. Gefitinib (GF) is a RTKI (receptor tyrosine kinase inhibitor) first-choice drug for EGFR mutated advanced lung cancer. However, drug toxicity and cancer cell resistance lead to treatment failure. Consequently, new therapeutic strategies are urgently required. Therefore, this study was aimed at identifying tumor suppressive compounds that can synergistically improve Gefitinib chemosensitivity in the lung cancer treatment. Medicinal plants offer a vast platform for the development of novel anticancer agents. Daidzein (DZ) is an isoflavone compound extracted from soy plants and has been shown to possess many medicinal benefits. The anticancer potential of GF and DZ combination treatment was investigated using MTT, western blot, fluorescent microscopy imaging, flow cytometry and nude mice tumor xenograft techniques. Our results demonstrate that DZ synergistically induces c-Jun nuclear translocation through ROS/ASK1/JNK and downregulates EGFR-STAT/AKT/ERK pathways to activate apoptosis and a G0/G1 phase cell cycle blockade. In in-vivo, the combination treatment significantly suppressed A549 lung cancer cells tumor xenograft growth without noticeable toxicity. Daidzein supplements with current chemotherapeutic agents may well be an alternative strategy to improve the treatment efficacy of lung adenocarcinoma.

Calreticulin nuclear translocalization alleviates CaM/CaMKII/CREB signaling pathway to enhance chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells.

Calreticulin (CRT) is located in the endoplasmic reticulum (ER), it helps proteins fold correctly inside the ER, and acts as a modulator of Ca2+ homeostasis. Aberrant expression of CRT is implicated in several cancer types, qualifying CRT as a potential therapeutic target. However, it remains unclear how CRT affects specific oncogenic pathways. In this study, we used histone deacetylase inhibitors (HDACis) to establish drug-resistant liver cancer cells and further analyzed the molecular mechanism of development of drug resistance in those cells. The 2D gel electrophoresis and RT-PCR data showed that CRT was downregulated in HDACis-resistant cells by comparing with HA22T parental cells. We previously elucidated the development of drug-resistance in HCC cells via activation of PP1-eIF2α pathway, but not via ER stress pathway. Here, we show that thapsigargin induced ER stress through mechanism other than ER stress downstream protein GRP78-PERK to regulate CRT expression in HDACis-R cells. Moreover, the expression level of CRT was not the main cause of apoptosis in HDACis-resistant cells. Mechanistic studies identified the apoptosis factors in the nucleus-the HDACis-mediated overexpression of CRT, CRT translocation to the cell nucleus, and reduced CaM/CaMKII/CREB pathway-that led to chemosensitivity in HDACis-R HCC cells.

Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth.

Background: Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods: Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results: Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid-structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions: These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

Health services utilization and cost of abusive head trauma in Taiwan: A population-based retrospective matched cohort study.

BACKGROUND: Abusive head trauma (AHT) is a serious health problem that results the highest mortality among children who are maltreated. Many AHT survivors suffer from long-term sequelae and require medical treatment. However, the knowledge of AHT-attributable health services utilization and costs at national level are limited. OBJECTIVE: To estimate health services utilization and costs attributable to AHT among children aged 0-4 years in Taiwan. PARTICIPANTS AND SETTING: Sixty-three fatal and 664 survival AHT cases were identified using Taiwan national population database between 2003 and 2015. A total of 2656 non-AHT children were exactly 4:1 matched to the survival cases based on their birth year, gender, the calendar year of the index date, insured location, and health insurance premium (social economic status indicator). METHODS: Health services utilization and costs were calculated on an annual basis for 3 years after the index date. AHT-attributable health services utilization and costs during 3-year follow-up period was evaluated by regression models. RESULTS: AHT diagnosis was positively associated with inpatient admissions, length of stay, emergency room (ER) visits, and outpatient visits. AHT-attributable medical costs were 1.64-17.27 times, 1.25-5.22 times, and 1.77-2.36 times greater for inpatient, ER, and outpatient during 3-year period than matched controls, respectively. Fatal AHT cases had higher inpatient utilization and greater medical costs than AHT survivors. CONCLUSIONS: Children with AHT had greater health services utilization and higher costs for years. Strategies to reduce the burden of AHT on health care system are imperative.

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.

Characterization of exopolysaccharide-producing lactic acid bacteria from Taiwanese ropy fermented milk and their application in low-fat fermented milk.

OBJECTIVE: The aim of this study was to characterize the exopolysaccharides (EPS)-producing lactic acid bacteria from Taiwanese ropy fermented milk (TRFM) for developing a clean label low-fat fermented milk. METHODS: Potential isolates from TRFM were selected based on the Gram staining test and observation of turbid suspension in the culture broth. Random amplified polymorphic DNA-polymerase chain reaction, 16S rRNA gene sequencing, and API CHL 50 test were used for strain identification. After evaluation of EPS concentration, target strains were introduced to low-fat milk fermentation for 24 h. Fermentation characters were checked: pH value, acidity, viable count, syneresis, and viscosity. Sensory evaluation of fermented products was carried out by 30 volunteers, while the storage test was performed for 21 days at 4°C. RESULTS: Two EPS-producing strains (APL15 and APL16) were isolated from TRFM and identified as Lactococcus (Lc.) lactis subsp. cremoris. Their EPS concentrations in glucose and lactose media were higher than other published strains of Lc. lactis subsp. cremoris. Low-fat fermented milk separately prepared with APL15 and APL16 reached pH 4.3 and acidity 0.8% with a viable count of 9 log colony-forming units/mL. The physical properties of both products were superior to the control yogurt, showing significant improvements in syneresis and viscosity (p<0.05). Our low-fat products had appropriate sensory scores in appearance and texture according to sensory evaluation. Although decreasing viable cells of strains during the 21-day storage test, low-fat fermented milk made by APL15 exhibited stable physicochemical properties, including pH value, acidity, syneresis and sufficient viable cells throughout the storage period. CONCLUSION: This study demonstrated that Lc. lactis subsp. cremoris APL15 isolated from TRFM had good fermentation abilities to produce low-fat fermented milk. These data indicate that EPS-producing lactic acid bacteria have great potential to act as natural food stabilizers for low-fat fermented milk.

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.

Rapid Detection of Gut Microbial Metabolite Trimethylamine N-Oxide for Chronic Kidney Disease Prevention.

The gut microbiota plays a critical role in chronic kidney disease (CKD) and hypertension. Trimethylamine-N-oxide (TMAO) and trimethylamine (TMA) are gut microbiota-derived metabolites, and both are known uraemic toxins that are implicated in CKD, atherosclerosis, colorectal cancer and cardiovascular risk. Therefore, the detection and quantification of TMAO, which is a metabolite from gut microbes, are important for the diagnosis of diseases such as atherosclerosis, thrombosis and colorectal cancer. In this study, a new "colour-switch" method that is based on the combination of a plasma separation pad/absorption pad and polyallylamine hydrochloride-capped manganese dioxide (PAH@MnO2) nanozyme was developed for the direct quantitative detection of TMAO in whole blood without blood sample pretreatment. As a proof of concept, a limit of quantitation (LOQ) of less than 6.7 µM for TMAO was obtained with a wide linear quantification range from 15.6 to 500 µM through quantitative analysis, thereby suggesting potential clinical applications in blood TMAO monitoring for CKD patients.

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.

Formation and Near-Infrared Emission of CsPbI3 Nanoparticles Embedded in Cs4PbI6 Crystals.

Cs4PbI6, as a rarely investigated member of the Cs4PbX6 (X is a halogen element) family, has been successfully synthesized at low temperatures, and the synthetic conditions have been optimized. Metal iodides such as LiI, KI, NiI2, CoI2, and ZnI2, as additives, play an important role in enhancing the formation of the Cs4PbI6 microcrystals. ZnI2 with the lowest dissociation energy is the most efficient additive to supply iodide ions, and its amount of addition has also been optimized. Strong red to near-infrared (NIR) emission properties have been detected, and its optical emission centers have been identified to be numerous embedded perovskite-type α-CsPbI3 nanocrystallites (∼5 nm in diameter) based on investigations of temperature- and pressure-dependent photoluminescent properties. High-resolution transmission electron microscopy was used to detect these hidden nanoparticles, although the material was highly beam-sensitive and confirmed a "raisin bread"-like structure of the Cs4PbI6 crystals. A NIR mini-LED for the biological application has been successfully fabricated using as-synthesized Cs4PbI6 crystals. This work provides information for the future development of infrared fluorescent nanoscale perovskite materials.

Sex and Tamoxifen confound murine experimental studies in cardiovascular tissue engineering.

Tissue engineered vascular grafts hold promise for the creation of functional blood vessels from biodegradable scaffolds. Because the precise mechanisms regulating this process are still under investigation, inducible genetic mouse models are an important and widely used research tool. However, here we describe the importance of challenging the baseline assumption that tamoxifen is inert when used as a small molecule inducer in the context of cardiovascular tissue engineering. Employing a standard inferior vena cava vascular interposition graft model in C57BL/6 mice, we discovered differences in the immunologic response between control and tamoxifen-treated animals, including occlusion rate, macrophage infiltration and phenotype, the extent of foreign body giant cell development, and collagen deposition. Further, differences were noted between untreated males and females. Our findings demonstrate that the host-response to materials commonly used in cardiovascular tissue engineering is sex-specific and critically impacted by exposure to tamoxifen, necessitating careful model selection and interpretation of results.

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.