Association of Valproic Acid and Its Main Metabolites' Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring.

Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 µg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 µg/mL versus 4.83 µg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.

Prevalence and risk factors of depression among elderly people in nursing homes from 2012 to 2022: a systematic review and meta-analysis.

OBJECTIVES: To determine a pooled prevalence of depression and its influencing factors among nursing home residents. METHOD: PsycINFO, PubMed, Embase, and Web of Science were searched for studies investigating the prevalence and risk factors of late-life depression among nursing home residents between January 2012 and November 2022. Two reviewers independently completed the literature screening, data extraction and quality assessment. A random-effects model was utilized to pool the prevalence of depression and summarize the influencing factors. RESULTS: This meta-analysis included 48 studies involving 28,501 participants. The pooled prevalence of depressive mood and major depressive disorder was 53% and 27%, respectively. The rate of depressive mood is higher in lower-middle-income countries (60.0%), compared with high- (53.0%) and upper-middle-income countries (44.0%). The rate of depressive mood (35.0%) is higher among females than male (19.0%). Depression was influenced by factors, including male (OR = 0.28), insufficient income (OR = 3.53), comorbidities (OR = 2.66), pain (OR = 2.67; r = 0.31), functional disability (r = 0.33), loneliness (r = 0.43), number of chronic health problems (r = 0.18), social support (r = -0.28), activities of daily living (r = -0.43), subjective health (r = -0.28), autonomy (r = -0.41), environment (r = -0.50) and physical (r = -0.57) and psychological health (r = -0.65). CONCLUSION: The prevalence of depressive mood is high among nursing home residents, especially in lower-middle-income countries. It is influenced by factors including gender, income, social support, daily activities, environment, physical and psychological health and autonomy. Understanding those factors can provide evidence-based recommendations for improved awareness, prevention and better management of late-life depression.

Taraxerone exerts antipulmonary fibrosis effect through Smad signaling pathway and antioxidant stress response in a Sirtuin1-dependent manner.

Idiopathic pulmonary fibrosis treatments are limited, often with severe side effects, highlighting the need for novel options. Taraxerone has diverse biomedical properties, but its mechanism remains unclear. This study investigates taraxerone's impact and the mechanisms involved in bleomycin-induced pulmonary fibrosis in mice. After establishing a pulmonary fibrosis mouse model, taraxerone was intraperitoneally injected continuously for 14-28 days. The in vivo antifibrotic and antioxidative stress effects of taraxerone were assessed. In vitro, the influence of taraxerone on transforming growth factor-ß1-induced myofibroblast transformation and oxidative stress was investigated. Subsequently, quantitative polymerase chain reaction screened the histone deacetylase and Sirtuin family, and taraxerone's effects on SIRT1 were assessed. After SIRT1 siRNA treatment, changes in myofibroblast transformation and antioxidant capacity in response to taraxerone were observed. Acetylation and phosphorylation levels of Smad3 were evaluated. We also examined the binding levels of SIRT1 with Pho-Smad3 and Smad3, as well as the nuclear localization of Smad2/3. EX527 confirmed SIRT1's in vivo action in response to taraxerone. In vitro experiments suggested that taraxerone inhibited myofibroblast differentiation by activating SIRT1 and reducing oxidative stress. We also observed a new interaction between SIRT1 and the Smad complex. Taraxerone activates SIRT1, enabling it to bind directly to Smad3. This leads to reduced Smad complex phosphorylation and limited nuclear translocation. As a result, the transcription of fibrotic factors is reduced. In vivo validation confirms taraxerone's SIRT1-mediated antifibrotic effectiveness. This suggests that targeting SIRT1-mediated inhibition of myofibroblast differentiation could be a key strategy in taraxerone-based therapy for pulmonary fibrosis.

Perceptions of primary health care nurses and general practitioners in the care of older people with urinary incontinence.

AIMS: To identify the challenges and opportunities among primary health care nurses and general practitioners (GPs) in the care of older people with urinary incontinence (UI) and other chronic conditions in China. BACKGROUND: UI is highly prevalent among community-dwelling older people with chronic conditions but is underreported and poorly managed. Understanding the factors that affect primary health care professionals' practices in their care for this population is imperative to foster nurse-led UI care services. DESIGN: A qualitative descriptive study. METHODS: Four focus groups were held with 24 primary health care nurses and GPs in Changsha, Hunan Province, China, between July and September 2021. A reflective thematic analysis was used to identify themes. RESULTS: This study revealed misconceptions regarding older people living with UI and other chronic conditions in primary care health professional participants. Moreover, primary health care nurses had very limited autonomy in UI diagnosis and initiating care interventions for this patient population. By reflecting on practices, participants recognized various practical solutions to improve the detection and management of UI. Participants also identified barriers to accessing care services in older people with UI. They suggested changes in the health care system to achieve universal access to UI care services for older people. CONCLUSION: Nurse-led UI care services in primary health care for community-dwelling older people with chronic conditions are in high demand but are underdeveloped due to professional and health care system factors. IMPACT: Findings from this study provide new insights into challenges faced by primary health care professionals and illuminate practical solutions to address these challenges. REPORTING METHODS: Adherence to COREQ guidelines was maintained. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Barriers and facilitators to patient education provided by nurses: A mixed-method systematic review.

AIM: To investigate the factors that facilitate or hinder nurses in providing patient education. DESIGN: A mixed-method systematic review. DATA SOURCES: Six databases (Cochrane Library, PubMed, EMBASE, Web of Science, MEDLINE and ERIC) were systematically searched for relevant publications. METHODS: The study was conducted following the JBI for mixed-method systematic reviews, and the reporting followed the PRISMA guideline. Two researchers independently performed literature screening, literature evaluation, data extraction and synthesis. PROSPERO registration number: CRD42023427451. RESULTS: Twenty-six eligible articles were included, including 15 quantitative articles, 10 qualitative articles and 2 mixed-methods articles. The resultant synthesis of key findings led to the identification of these barriers and facilitators, categorised into five distinct levels: nurse-related factors, organisational factors, patient-related factors, the nurse-patient relationship and interdisciplinary collaboration. CONCLUSIONS: The findings highlight the factors that facilitate or hinder nurses in providing patient education, suggesting that multifaceted interventions can enhance the practice of patient education in nursing and support the development of appropriate patient education guidelines or public policies. RELEVANCE TO CLINICAL PRACTICE: This review delineates the facilitators and barriers influencing nurses' provision of patient education, offering an initial framework for nursing managers to craft interventions aimed at enhancing the quality of patient education provided by nurses, consequently elevating the overall quality of nursing.

Psychometric validation of the Chinese versions of the quality of communication questionnaires for cancer patients and their family caregivers.

BACKGROUND: Given the lack of valid and reliable instruments for evaluating the quality of communication between physicians and cancer patients and their family caregivers in China, this study translated and culturally adapted the Quality of Communication questionnaires for cancer patients (QOC-P) and their family caregivers (QOC-F) for use in the Chinese context and evaluated their psychometric properties. METHODS: The QOC-P and QOC-F were translated following an adapted version of Brislin's translation model and culturally adapted according to a Delphi expert panel. We pretested and refined the Chinese versions of the QOC-P and QOC-F among 16 dyads of patients and their family caregivers. Subsequently, we administered the questionnaires to 228 dyads of patients and their family caregivers who were recruited from six tertiary hospitals. The content validity, construct validity, convergent validity, and reliability of the QOC-P and QOC-F were examined. RESULTS: Through exploratory factor analysis, The QOC-P and QOC-F were divided into two dimensions: general communication and end-of-life communication. The Cronbach's coefficients ranged from 0.905 to 0.907 for the two subscales of the QOC-P and from 0.908 to 0.953 for the two subscales of the QOC-F. The two-week test-retest reliability was acceptable for both the QOC-P and QOC-F, with intraclass correlation coefficients of 0.993 and 0.991, respectively. The scale content validity index (QOC-P: 0.857, QOC-F: 1.0) and split-half reliability (QOC-P: 0.833, QOC-F: 0.935) were satisfactory. There was a negative correlation with anxiety and depression for both the QOC-P (r = -0.233 & -0.241, p < 0.001) and QOC-F (r = -0.464 & -0.420, p<0.001). The QOC-P showed a negative correlation with decision regret (r = -0.445, p<0.001) and a positive correlation with shared decision-making (r = 0.525, p<0.001), as hypothesized. CONCLUSION: The QOC-P and QOC-F show acceptable psychometric properties for evaluating the quality of communication between physicians and cancer patients and their family caregivers in both clinical and research contexts. Future studies should use more diverse and inclusive samples to test the structure of the Chinese version of the QOC-P and QOC-F with confirmatory factor analysis.

Academic-practice partnerships in evidence-based nursing practice: A theory-guided scoping review.

BACKGROUND: Academic-practice partnerships have the potential to solve many challenges in evidence-based nursing practice which is crucial for high-quality care. AIMS: To identify the existing knowledge on academic-practice partnerships in evidence-based nursing practice. METHODS: We conducted this review following the Joanna Briggs Institute scoping review methodology. We performed a comprehensive literature search of nine databases as well as five websites for gray literature. Two researchers independently conducted literature screening and data extraction and analysis. A third researcher was involved when needed. RESULTS: Dedicated time, dedicated resources, and compatible goals were found to be the top three inputs in academic-practice partnerships for evidence-based nursing practice. Meeting and discussion were the most popular forms of activities. Sufficient resources were the most important facilitators. Insufficient resources, insufficient time, and communication issues were the top three barriers. CONCLUSIONS: The assumption proposed in the practice-academic partnership logic model (i.e., inputs plus activities can lead to outputs and outcomes) was preliminarily verified by the results of this review in the context of evidence-based nursing practice. Academic-practice partnerships can leverage the advantages of both sides to overcome barriers and promote evidence-based nursing practice. However, it is essential to conduct a broader range of high-quality studies. Such endeavors could offer more comprehensive evidence for refining the framework of academic-practice partnerships in evidence-based nursing practice. IMPLICATIONS FOR NURSING EDUCATION, PRACTICE, POLICY AND RESEARCH: The "theoretical framework of academic-practice partnerships in evidence-based nursing practice" could theoretically guide academic and clinical nursing staff to collaborate on evidence-based nursing practice and related research and education programs. The academic-practice partnerships in evidence-based nursing practice could lead to a win-win situation for both the academic and the clinical sides. Furthermore, the results of this study provide an evidence-based foundation for policymakers to develop supportive policies for academic-practice partnerships in evidence-based nursing practice.

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Advance care planning (ACP) is designed to ensure that patients lacking autonomous decision-making capacity receive medical services in accordance with their expectations and preferences. Individuals with advanced cancer are a crucial target for ACP implementation. However, the current practice of ACP in this group in China is suboptimal, demanding high-quality implementation evidence to strengthen ACP in the clinical practice of patients with advanced cancer. The existing literature can be summarized into 27 pieces of evidence across 7 dimensions, including initiation time, intervention content, intervention providers, intervention modalities, communication skills, outcome indicators, and environmental support. The aforementioned evidence could provide crucial support for improving ACP implementation for patients with advanced cancer. Subsequent research efforts should integrate patient preferences and explore the most suitable implementation strategies for ACP in the Chinese population with advanced cancer, considering diverse aspects such as traditional culture, ACP education and training, legislative support, and healthcare system refinement.

Symptom clusters among breast cancer patients in relation to chemotherapy cycles: a longitudinal study.

PURPOSE: The aim of this study was to identify symptom clusters in breast cancer patients undergoing adjuvant chemotherapy. METHODS: A prospective longitudinal study was conducted. And a sample of 620 breast cancer patients receiving adjuvant chemotherapy was recruited using convenience sampling from May 20, 2020, to March 31, 2021. Data were collected eight times: the first chemotherapy cycle (T1) to the eighth cycle of chemotherapy (T8). Exploratory factor analysis was used to explore the composition of symptom clusters. RESULTS: Symptoms with an incidence of less than 20% were deleted and the remaining symptoms were included in the factor analysis. Three common factors were extracted in T1, including gastrointestinal symptom cluster, emotional and psychological symptom cluster, and menopausal symptom cluster. Five common factors were extracted from T2 to T7, including gastrointestinal symptom cluster, emotional and psychological symptom cluster, neurological symptom cluster, menopausal symptom cluster, and self-image disorder symptom cluster. Four common factors were extracted at T8, including gastrointestinal symptom cluster, emotional and psychological symptom cluster, neurological symptom cluster, and menopausal symptom cluster. CONCLUSION: Breast cancer patients undergoing adjuvant chemotherapy experience multiple symptoms and different symptom clusters in different chemotherapy cycles. It is a benefit for health care providers to better understand and care for breast cancer patients. It will also help such women to manage concurrent symptoms ahead to promote their quality of life.

Isobavachalcone inhibits RANKL-induced osteoclastogenesis via miR-193-3p/NF-κB/NFATc1 signaling pathway in BMMs cells.

Inhibition of extensive osteoclastogenesis and bone resorption is considered a potential therapeutic target for the treatment of osteoporosis. Isobavachalcone (IBC) is derived from the traditional Chinese herb Psoralea corylifolia Linn. We showed that IBC dose-dependently suppressed receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis in bone marrow monocyte/macrophage (BMMs) and osteoclastic bone-resorption function without cytotoxicity at a dose of no more than 8 µmin vitro. Mechanistically, the results of western blot and quantitative real-time polymerase chain reaction (qRT-PCR) indicated that IBC inhibited the RANKL-induced degradation of IκBα and phosphorylation of nuclear factor kappa B (NF-κB) in BMMs, and subsequently downregulated the expression of osteoclastic-specific genes and osteoclastogenesis-related proteins. TRAP staining and qRT-PCR showed that IBC can inhibit osteoclast differentiation by down-regulating the expression of miR-193-3p on osteoclast differentiation. Overall, our findings suggest that IBC may serve as a promising compound for the treatment of osteoporosis and other metabolic bone diseases.

Differences in evidence-based nursing practice competencies of clinical and academic nurses in China and opportunities for complementary collaborations: A cross-sectional study.

AIMS AND OBJECTIVES: To explore the evidence-based nursing practice (EBNP) competencies of clinical and academic nurses and their collaboration needs for supporting EBNP. BACKGROUND: Academic-practice partnerships have strong potential to overcome the key barriers to EBNP. However, there is little known about the collaboration needs of clinical and academic nurses for EBNP. DESIGN: A cross-sectional study. METHODS: We recruited clinical and academic nurses online during November 2021 to January 2022. Using a reliable and validated scale and adapted questionnaires, data were collected relating to demographic information, EBNP-related resources availability, EBNP competencies and EBNP collaboration needs. These data were described using descriptive statistical methods. The t test, χ2 test and Mann-Whitney U test were used to evaluate if the different responses between clinical and academic nurses were statistically significant. This study was reported following the STROBET checklist. RESULTS: Two 240 clinical nurses and 232 academic nurses submitted questionnaires. There was no difference in overall EBNP competence between clinical and academic nurses. However, clinical nurses reported lower levels of competence and stronger intentions to collaborate with academic nurses when searching for, appraising, and synthesising evidence. Academic nurses reported lower levels of competence and stronger intentions to collaborate with clinical nurses for disseminating and implementing evidence. CONCLUSION: Clinical and academic nurses both reported high needs for collaborating to overcome their perceived role limitations. Clinical and academic nurses have different strengths and limitations in EBNP. These role differences and intentions to collaborate for different dimensions of EBNP competence suggest that clinical and academic nursing roles could be complementary to each other, offering opportunities for synergistic collaborations to better support overall EBNP. RELEVANCE TO CLINICAL PRACTICE: Healthcare and academic institutions should promote academic-practice partnerships as opportunities to gain complementary expertise on different dimensions of EBNP, and to improve nurses' competencies and confidence in EBNP overall.

Instruments for measuring nursing research competence: a COSMIN-based scoping review.

AIM: The aim of this scoping review was to evaluate and summarise the measurement properties of nursing research competence instruments and provide a summary overview of the use of nursing research competence instruments. BACKGROUND: Increasing nursing research competence instruments have been developed. However, a systematic review and evaluation of nursing research competence instruments is lacking. METHOD: This scoping review was conducted following the Joanna Briggs Institute updated methodology for scoping reviews and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. Reviewers searched articles in Eight English databases and two Chinese databases between April 1st, 2022, and April 30th, 2022. An updated literature search was conducted between March 1st and March 4th, 2023. The literature screening and data extraction were conducted by two reviewers, independently. A third reviewer was involved when consensus was needed. The COnsensus-based Standards for the selection of health Measurement Instruments methodology was used to evaluate the methodological quality and measurement properties of the nursing research competence instruments. RESULTS: Ten studies involving eight nursing research competence instruments were included. None of the existing instruments have assessed all measurement properties. A total of 177 empirical studies have utilized a nursing research competence instrument with tested measurement properties. CONCLUSION: 'Self-evaluated Nursing Research Capacity of Questionnaire (refined)' was identified as the most appropriate nursing research competence instrument in existing instruments. However, reviewers need to conduct further measurement properties studies on the existing nursing research competence instruments. IMPLICATIONS FOR THE NURSING POLICY: This study could guide the selection of appropriate nursing research competence instruments which could help to evaluate the nursing research competence of nurses and inform the development of intervention plans to enhance nursing research competence.

Perceived patient safety culture and its associated factors among clinical managers of tertiary hospitals: a cross-sectional survey.

BACKGROUND: Patient safety is a global challenge influenced by perceived patient safety culture. However, limited knowledge exists regarding the patient safety culture perceived by hospital clinical managers and its associated factors. This study aims to investigate the perceptions of patient safety culture and associated factors among clinical managers of tertiary hospitals in China. METHODS: A cross-sectional survey was conducted from June 19 to July 16, 2021, involving 539 clinical managers from four tertiary hospitals in Changsha City of Hunan Province. The Hospital Survey on Patient Safety Culture (HSOPSC) was utilized to assess perceived patient safety culture. Bivariate, multivariable linear regression, and logistic regression analyses were performed. RESULTS: The mean score for the total HSOPSC was 72.5 ± 7.6, with dimensional scores ranging from 62.1 (14.9) to 86.6 (11.7). Three dimensions exhibited positive response rates (PRRs) < 50%, indicating areas that need to be improved: "nonpunitive response to errors" (40.5%), "staffing" (41.9%), and "frequency of events reported" (47.4%). Specialized hospitals (ß = 1.744, P = 0.037), female gender (ß = 2.496, P = 0.003), higher professional title (ß = 1.413, P = 0.049), a higher education level (ß = 1.316, P = 0.001), and shorter time delays per shift (ß=-1.13, P < 0.001) were correlated with higher perceived patient safety culture. Education level, work department, "teamwork within a unit", "management support for patient safety", "communication openness", and "staffing" dimensions were associated with patient safety grades (all P < 0.05). Years worked in hospitals, occupation, education level, work department, hospital nature, professional title, "communication openness", and "handoffs & transitions" were associated with the number of adverse events reported (all P < 0.05). CONCLUSIONS: Our study revealed a generally low level of patient safety culture perceived by clinical managers and identified priority areas requiring urgent improvement. The associated factors of patient safety culture provide important guidance for the development of targeted interventions in the future. Promoting patient safety by optimizing the patient safety culture perceived by clinical managers should be prioritized.

Caregiving burden and positive aspects of caregiving in schizophrenia: Mediating roles of hope and social support.

Caring for an ill relative with schizophrenia can lead to both negative and positive experiences. The study aimed to determine the relationship between caregiving burden and positive caregiving experiences and evaluate the roles of hope and social support as possible mediators in this relationship. This study included 344 Chinese family caregivers of adults with schizophrenia. Instruments included Positive Aspects of Caregiving, Herth Hope Index, Caregiver Burden Inventory, and Multidimensional Scale of Perceived Social Support. Data was analysed by Mann-Whitney U tests, Kruskal-Wallis H tests, Spearman correlation, and a serial mediation model. Results showed that hope and social support separately and serially mediated the relationship between caregiving burden and positive caregiving experiences. The mediation effect of hope was stronger than that of social support and their serial mediation effect. Increasing hope and social support of family caregivers may alleviate caregiving burden and improve positive caregiving experiences.

Bidirectional relationship between fear of falling and frailty among community-dwelling older adults: A longitudinal study.

This study aims to examine the bidirectional association between fear of falling (FOF) and frailty among community-dwelling older adults. Longitudinal analyses were conducted over a representative sample of 5,829 community-dwelling individuals ≥65 years from the National Health and Aging Trends Study. FOF was ascertained by asking participants whether they worried about falling and if this worry ever limited their activities. Frailty status was assessed based on frailty phenotype. At baseline, 71.4% of participants reported no FOF, 16.7% reported FOF without fear-related activity restriction (FAR), and 11.9% reported FOF with FAR. The proportion of robust, pre-frail and frail respondents at baseline was 36.1%, 48.7% and 15.2%, respectively. Multinomial logistic regression models indicated FOF with and without FAR predicted pre-frailty and frailty. Pre-frailty predicted FOF with and without FAR, while frailty only predicted FOF with FAR. Tailored intervention strategies are needed for preventing adverse outcomes of FOF and frailty among the older population.

Relationships among social support, coping style, self-stigma, and quality of life in patients with diabetic foot ulcer: A multicentre, cross-sectional study.

Patients with diabetic foot ulcer have a significantly lower quality of life. Quality of life could be connected to other psychological or social processes. The purpose of this study was to examine the relationships between social support, decision regret, self-stigma, and quality of life in patients with diabetic foot ulcers. The sample of the study consisted of 229 diabetic foot ulcer patients. Data were collected from September 2019 to March 2020. The demographic and clinical information, the Stigma Scale for Chronic Illness, Medical Coping Scale, Social Support Scale, and Quality of Life scale were used to assess the quality life for diabetic foot ulcer. Pearson correlation coefficient and structural equation modelling were used for data analysis. The quality of life was negatively correlated with self-stigma, positively correlated with social support, giving up coping, and not significantly correlated with confrontation coping and avoidance coping. Self-stigma has significant indirect effects on quality of life through social support and coping style. Further clinical intervention strategies for decreasing self-stigma as well as strengthening social support and positive coping styles are needed to inform diabetic foot ulcer patients, thus improving their quality of life.

Kindlin-2 protects pancreatic ß cells through inhibiting NLRP3 inflammasome activation in diabetic mice.

Diabetes mellitus has been a major public health problem worldwide, characterized by insulin resistance and dysfunction of ß-cells. A previous study showed that Kindlin-2 loss in ß-cells dramatically reduces insulin secretion and decreases ß-cell mass, resulting in severe diabetes-like phenotypes. It suggests that Kindlin-2 in ß-cells play an important role in regulating glucose homeostasis. However, the effect of Kindlin-2 on the function of ß-cells under chronic hyperglycemia in diabetes has not been explored. Here we report that Kindlin-2 overexpression ameliorates diabetes and improves insulin secretion in mice induced by streptozocin. In contrast, Kindlin-2 insufficiency exacerbates diabetes and promotes ß-cells dysfunction and inflammation in ß-cells induced by a high-fat diet (HFD). In vitro, Kindlin-2 overexpression prevented high-glucose (HG)-induced dysfunction in ß-cells. Kindlin-2 overexpression also decreased the expression of pro-inflammatory cytokines and NLRP3 inflammasome expression in ß-cells exposed to HG. Furthermore, the loss of Kindlin-2 aggravates the expression of inflammatory cytokines and NLRP3 induced by HG in ß-cells. Collectively, we demonstrate that Kindlin-2 protects against diabetes by inhibiting NLRP3 inflammasome activation.

Novel Clinical Biomarkers for Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) remains a critical clinical issue and has been a treatment challenge today as it was in the past. However, the traditional biomarkers or indicators are insufficient to predict the risks and outcome of patients with DILI due to its poor specificity and sensitivity. Recently, the development of high-throughput technologies, especially omics and multiomics has sparked growing interests in identification of novel clinical DILI biomarkers, many of which also provide a mechanistic insight. Accordingly, in this minireview, we summarize recent advances in novel clinical biomarkers for DILI prediction, diagnosis, and prognosis and highlight the limitations or challenges involved in biomarker discovery or its clinical translation. Although huge work has been done, most reported biomarkers lack comprehensive information and more specific DILI biomarkers are still needed to complement the traditional biomarkers such as alanine aminotransferase (ALT) or aspartate transaminase (AST) in clinical decision-making. SIGNIFICANCE STATEMENT: This current review outlines an overview of novel clinical biomarkers for drug-induced liver injury (DILI) identified in clinical retrospective or prospective clinical analysis. Many of these biomarkers provide a mechanistic insight and are promising to complement the traditional DILI biomarkers. This work also highlights the limitations or challenges involved in biomarker discovery or its clinical translation.

Polymeric Chloroquine as an Effective Antimigration Agent in the Treatment of Pancreatic Cancer.

Hydroxychloroquine (HCQ) has been the subject of multiple recent preclinical and clinical studies for its beneficial use in the combination treatments of different types of cancers. Polymeric HCQ (PCQ), a macromolecular multivalent version of HCQ, has been shown to be effective in various cancer models both in vitro and in vivo as an inhibitor of cancer cell migration and experimental lung metastasis. Here, we present detailed in vitro studies that show that low concentrations of PCQ can efficiently inhibit cancer cell migration and colony formation orders of magnitude more effectively compared to HCQ. After intraperitoneal administration of PCQ in vivo, high levels of tumor accumulation and penetration are observed, combined with strong antimetastatic activity in an orthotopic pancreatic cancer model. These studies support the idea that PCQ may be effectively used at low doses as an adjuvant in the therapy of pancreatic cancer. In conjunction with previously published literature, these studies further undergird the potential of PCQ as an anticancer agent.

Study of Renal Accumulation of Targeted Polycations in Acute Kidney Injury.

Acute kidney injury (AKI) is a global healthcare burden characterized by rapid loss of renal function and high morbidity and mortality. Chemokine receptor CXCR4 participates in the renal infiltration of immune cells following injury and in local inflammatory enhancement. Injured renal tubule cells overexpress CXCR4, which could be used as a target for improved drug delivery in AKI. Plerixafor is a small-molecule CXCR4 antagonist that has shown beneficial effects against AKI and has been previously developed into a polymeric analog (polymeric plerixafor, PP). With the goal of gaining a better understanding of how overall charge and hydrophilicity affect renal accumulation of PP, we have synthesized PP copolymers containing hydroxyl, carboxyl, primary amine, and alkyl moieties using Michael-type addition copolymerization. All synthesized copolymers showed excellent CXCR4-binding and inhibiting ability in vitro and improved cellular uptake in hypoxia-reoxygenation stimulated mouse tubule cells. Analysis of serum protein binding revealed that polymers with hydroxyl group modification showed the least amount of protein binding. Biodistribution of the polymers was tested in a unilateral ischemia reperfusion-induced AKI mouse model. The results showed significant differences in accumulation in the injured kidneys depending on the net charge and hydrophilicity of the polymers. The findings of this study will guide the development of polymeric drug carriers for targeted delivery to injured kidneys for better AKI therapy.