Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice.

Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPARγ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPARγ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPARγ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.

Talin-1 inhibits Smurf1-mediated Stat3 degradation to modulate ß-cell proliferation and mass in mice.

Insufficient pancreatic ß-cell mass and reduced insulin expression are key events in the pathogenesis of diabetes mellitus (DM). Here we demonstrate the high expression of Talin-1 in ß-cells and that deficiency of Talin-1 reduces ß-cell proliferation, which leads to reduced ß-cell mass and insulin expression, thus causing glucose intolerance without affecting peripheral insulin sensitivity in mice. High-fat diet fed exerbates these phenotypes. Mechanistically, Talin-1 interacts with the E3 ligase smad ubiquitination regulatory factor 1 (Smurf1), which prohibits ubiquitination of the signal transducer and activator of transcription 3 (Stat3) mediated by Smurf1, and ablation of Talin-1 enhances Smurf1-mediated ubiquitination of Stat3, leading to decreased ß-cell proliferation and mass. Furthermore, haploinsufficiency of Talin-1 and Stat3 genes, but not that of either gene, in ß-cell in mice significantly impairs glucose tolerance and insulin expression, indicating that both factors indeed function in the same genetic pathway. Finally, inducible deletion Talin-1 in ß-cell causes glucose intolerance in adult mice. Collectively, our findings reveal that Talin-1 functions as a crucial regulator of ß-cell mass, and highlight its potential as a therapeutic target for DM patients.

Natural products modulate NLRP3 in ulcerative colitis.

Ulcerative colitis (UC) is a clinically common, progressive, devastating, chronic inflammatory disease of the intestine that is recurrent and difficult to treat. Nod-like receptor protein 3 (NLRP3) is a protein complex composed of multiple proteins whose formation activates cysteine aspartate protease-1 (caspase-1) to induce the maturation and secretion of inflammatory mediators such as interleukin (IL)-1ß and IL-18, promoting the development of inflammatory responses. Recent studies have shown that NLRP3 is associated with UC susceptibility, and that it maintains a stable intestinal environment by responding to a wide range of pathogenic microorganisms. The mainstay of treatment for UC is to control inflammation and relieve symptoms. Despite a certain curative effect, there are problems such as easy recurrence after drug withdrawal and many side effects associated with long-term medication. NLRP3 serves as a core link in the inflammatory response. If the relationship between NLRP3 and gut microbes and inflammation-associated factors can be analyzed concerning its related inflammatory signaling pathways, its expression status as well as specific mechanism in the course of IBD can be elucidated and further considered for clinical diagnosis and treatment of IBD, it is expected that the development of lead compounds targeting the NLRP3 inflammasome can be developed for the treatment of IBD. Research into the prevention and treatment of UC, which has become a hotbed of research in recent years, has shown that natural products are rich in therapeutic means, and multi-targets, with fewer adverse effects. Natural products have shown promise in treating UC in numerous basic and clinical trials over the past few years. This paper describes the regulatory role of the NLRP3 inflammasome in UC and the mechanism of recent natural products targeting NLRP3 against UC, which provides a reference for the clinical treatment of this disease.

Knowledge and Practice Behaviors Toward the Care of the Dying Among Chinese Oncology Nurses: A Cross-Sectional Survey.

The quality of care provided to patients with cancer at the end of their lives remains unsatisfactory, especially during their last days and hours of life. This study aimed to investigate knowledge and practice behaviors of oncology nurses in relation to the care of the dying and to analyze the influencing factors. A convenience sample of 222 oncology nurses was recruited from 14 hospitals in Beijing, China, in January 2022. These nurses completed an online survey that included a demographic and work characteristics questionnaire and knowledge and practice behavior questionnaires regarding the care needs of dying cancer patients. The self-perceived knowledge and practice behavior of oncology nurses toward the care of the dying were found to be moderate. However, their understanding of airway management, restlessness, and delirium management was insufficient. In addition, their ability to effectively communicate recommendations for discontinuing unnecessary procedures, medications, treatments, and monitoring was inadequate. Nurses' previous end-of-life care education and experience of caring for dying patients influenced their knowledge. Nurses' practice settings, experience of caring for dying patients, and their knowledge were key factors in shaping their behaviors. Providing targeted continuing education for nurses in hospital settings and exploring the nursing pathway may be important ways to bridge their knowledge gap and enhance their practice behaviors toward caring for dying patients.

Kindlin-2 controls angiogenesis through modulating Notch1 signaling.

Kindlin-2 is critical for development and homeostasis of key organs, including skeleton, liver, islet, etc., yet its role in modulating angiogenesis is unknown. Here, we report that sufficient KINDLIN-2 is extremely important for NOTCH-mediated physiological angiogenesis. The expression of KINDLIN-2 in HUVECs is significantly modulated by angiogenic factors such as vascular endothelial growth factor A or tumor necrosis factor α. A strong co-localization of CD31 and Kindlin-2 in tissue sections is demonstrated by immunofluorescence staining. Endothelial-cell-specific Kindlin-2 deletion embryos die on E10.5 due to hemorrhage caused by the impaired physiological angiogenesis. Experiments in vitro show that vascular endothelial growth factor A-induced multiple functions of endothelial cells, including migration, matrix proteolysis, morphogenesis and sprouting, are all strengthened by KINDLIN-2 overexpression and severely impaired in the absence of KINDLIN-2. Mechanistically, we demonstrate that KINDLIN-2 inhibits the release of Notch intracellular domain through binding to and maintaining the integrity of NOTCH1. The impaired angiogenesis and avascular retinas caused by KINDLIN-2 deficiency can be rescued by DAPT, an inhibitor of γ-secretase which releases the intracellular domain from NOTCH1. Moreover, we demonstrate that high glucose stimulated hyperactive angiogenesis by increasing KINDLIN-2 expression could be prevented by KINDLIN-2 knockdown, indicating Kindlin-2 as a potential therapeutic target in treatment of diabetic retinopathy. Our study for the first time demonstrates the significance of Kindlin-2 in determining Notch-mediated angiogenesis during development and highlights Kindlin-2 as the potential therapeutic target in angiogenic diseases, such as diabetic retinopathy.

The gut microbes in inflammatory bowel disease: Future novel target option for pharmacotherapy.

Gut microbes constitute the main microbiota in the human body, which can regulate biological processes such as immunity, cell proliferation, and differentiation, hence playing a specific function in intestinal diseases. In recent years, gut microbes have become a research hotspot in the pharmaceutical field. Because of their enormous number, diversity, and functional complexity, gut microbes have essential functions in the development of many digestive diseases. Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease with a complex etiology, the exact cause and pathogenesis are unclear. There are no medicines that can cure IBD, and more research on therapeutic drugs is urgently needed. It has been reported that gut microbes play a critical role in pathogenesis, and there is a tight and complex association between gut microbes and IBD. The dysregulation of gut microbes may be a predisposing factor for IBD, and at the same time, IBD may exacerbate gut microbes' disorders, but the mechanism of interaction between the two is still not well defined. The study of the relationship between gut microbes and IBD is not only important to elucidate the pathogenesis but also has a positive effect on the treatment based on the regimen of regulating gut microbes. This review describes the latest research progress on the functions of gut microbes and their relationship with IBD, which can provide reference and assistance for further research. It may provide a theoretical basis for the application of probiotics, fecal microbiota transplantation, and other therapeutic methods to regulate gut microbes in IBD.

Corrigendum to "Evaluation of a whole process management model based on an information system for cancer patients with pain: A prospective nonrandomized controlled study" [Asia-Pacific J Oncol Nurs 9 (2022) 88-96].

[This corrects the article DOI: 10.1016/j.apjon.2021.12.017.].

Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function.

Inflammatory liver diseases are a major cause of morbidity and mortality worldwide; however, underlying mechanisms are incompletely understood. Here we show that deleting the focal adhesion protein Kindlin-2 expression in hepatocytes using the Alb-Cre transgenic mice causes a severe inflammation, resulting in premature death. Kindlin-2 loss accelerates hepatocyte apoptosis with subsequent compensatory cell proliferation and accumulation of the collagenous extracellular matrix, leading to massive liver fibrosis and dysfunction. Mechanistically, Kindlin-2 loss abnormally activates the tumor necrosis factor (TNF) pathway. Blocking activation of the TNF signaling pathway by deleting TNF receptor or deletion of Caspase 8 expression in hepatocytes essentially restores liver function and prevents premature death caused by Kindlin-2 loss. Finally, of translational significance, adeno-associated virus mediated overexpression of Kindlin-2 in hepatocytes attenuates the D-galactosamine and lipopolysaccharide-induced liver injury and death in mice. Collectively, we establish that Kindlin-2 acts as a novel intrinsic inhibitor of the TNF pathway to maintain liver homeostasis and may define a useful therapeutic target for liver diseases.

The role and mechanism of flavonoid herbal natural products in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine that presents clinically with abdominal pain, mucopurulent stools, and posterior urgency. The lesions of UC are mainly concentrated in the rectal and colonic mucosa and submucosa. For patients with mild to moderate UC, the best pharmacological treatment includes glucocorticoids, immunosuppressants, antibiotics, and biologics, but the long-term application can have serious toxic side effects. Currently, nearly 40% of UC patients are treated with herbal natural products in combination with traditional medications to reduce the incidence of toxic side effects. Flavonoid herbal natural products are the most widely distributed polyphenols in plants and fruits, which have certain antioxidant and anti-inflammatory activities. Flavonoid herbal natural products have achieved remarkable efficacy in the treatment of UC. The pharmacological mechanisms are related to anti-inflammation, promotion of mucosal healing, maintenance of intestinal immune homeostasis, and regulation of intestinal flora. In this paper, we summarize the flavonoid components of anti-ulcerative colitis and their mechanisms reported in the past 10 years, to provide a basis for rational clinical use and the development of new anti-ulcerative colitis drugs.

Stem Cell-Based Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients' quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.

Traditional Chinese Medicine and Natural Products: Potential Approaches for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a rare, recurrent, and intractable inflammation obstruction of the stomach tract, usually accompanied by inflammation of cell proliferation and inflammation of the colon and carries a particular cause of inflammation. The clinical use of drugs in western countries affects IBD treatment, but various adverse effects and high prices limit their application. For these reasons, Traditional Chinese Medicine (TCM) is more advantageous in treating IBD. This paper reviews the mechanism and research status of TCM and natural products in IBD treatment by analyzing the relevant literature to provide a scientific and theoretical basis for IBD treatment.

Inflammatory bowel disease: an overview of Chinese herbal medicine formula-based treatment.

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the intestine, including Crohn's disease (CD) and ulcerative colitis (UC), whose etiology and pathogenesis have not been fully understood. Due to its prolonged course and chronic recurrence, IBD imposes a heavy economic burden and psychological stress on patients. Traditional Chinese Herbal Medicine has unique advantages in IBD treatment because of its symptomatic treatment. However, the advantages of the Chinese Herbal Medicine Formula (CHMF) have rarely been discussed. In recent years, many scholars have conducted fundamental studies on CHMF to delay IBD from different perspectives and found that CHMF may help maintain intestinal integrity, reduce inflammation, and decrease oxidative stress, thus playing a positive role in the treatment of IBD. Therefore, this review focuses on the mechanisms associated with CHMF in IBD treatment. CHMF has apparent advantages. In addition to the exact composition and controlled quality of modern drugs, it also has multi-component and multi-target synergistic effects. CHMF has good prospects in the treatment of IBD, but its multi-agent composition and wide range of targets exacerbate the difficulty of studying its treatment of IBD. Future research on CHMF-related mechanisms is needed to achieve better efficacy.

Evaluation of a whole process management model based on an information system for cancer patients with pain: A prospective nonrandomized controlled study.

Objective: The aim of this study was to evaluate the effects of whole process management model interventions based on information system benefits reported by patients with cancer pain. Methods: We performed a quantitative, prospective nonrandomized controlled design from June to October 2020. A total of 124 cancer patients with pain were enrolled. Patients in the experimental group received a whole process management model intervention based on an information system compared to the control group who received routine cancer pain management. Data were collected at baseline and after a four-week follow-up, acting as a test-retest control. The primary outcome was pain management quality, which was measured using the American Pain Society Patient Outcome Questionnaire-Chinese version (APS-POQ-C). Secondary outcomes were patient-related attitudinal barriers and analgesic adherence. The Barrier Questionnaire (BQ) and a single-item questionnaire were used. Chi-square tests were used to compare the pain intensity and analgesic adherence, independent sample t-test and Mann-Whitney U test were performed to test the differences in the pain management quality and patient-related attitudinal barriers between control and experimental groups. Results: Baseline characteristics and outcomes of the participants did not differ significantly (P â€‹> â€‹0.05). Primary outcomes were changes in four aspect of the quality of pain management (APS-POQ-C) between the two groups (P â€‹< â€‹0.05). Patients in the whole process management group reported significantly better pain control and perception of care than the control group. With respect to secondary endpoints, a significant difference in favor of the experimental group was found for barriers (P â€‹< â€‹0.05) and medication adherence (60.0% vs. 40.0%; P â€‹< â€‹0.05) after the interventions. Conclusions: The whole process management of patients with cancer pain effectively improves patient-reported quality of pain management, reduces patient-perceived barriers, enhances patient adherence to analgesic drugs and is worthy of clinical application.

Structural Equation Model of Factors Related to Death Anxiety for Chinese Patients with Cancer.

This study aimed to develop a model that specifies the predictive effects of factors on death anxiety among Chinese patients with cancer using structural equation modeling. Using convenience sampling, data were collected from 353 cancer patients. Self-administered questionnaires included Social Support Rating Scale, Rosenberg Self-Esteem Scale, Connor Davidson Resilience Scale, Templer's Death Anxiety Scale, and socio-demographic factors. The results showed that social support, self-esteem, and resilience significantly impacted death anxiety. The final model fitted the data acceptably (χ2 = 37.319, df =31, p = 0.201). Social support mediated death anxiety through self-esteem and resilience. Resilience mediated the buffer effect of self-esteem on death anxiety as an intermediary factor. Findings suggest the need for further studies to explore effective interventions to provide social support and improve self-esteem and resilience among patients with cancer to alleviate death anxiety.

Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice.

Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Here we report that Kindlin-2 is dramatically up-regulated in livers in obese mice and patients with NAFLD. Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. In contrast, Kindlin-2 overexpression in liver exacerbates NAFLD and promotes lipid metabolism disorder and inflammation in hepatocytes. A C-terminal region (aa 570-680) of Kindlin-2 binds to and stabilizes Foxo1 by inhibiting its ubiquitination and degradation through the Skp2 E3 ligase. Kindlin-2 deficiency increases Foxo1 phosphorylation at Ser256, which favors its ubiquitination by Skp2. Thus, Kindllin-2 loss down-regulates Foxo1 protein in hepatocytes. Foxo1 overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. Finally, AAV8-mediated shRNA knockdown of Kindlin-2 in liver alleviates NAFLD in obese mice. Collectively, we demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation.

Migration and transformation of heavy metals in Chinese medicine residues during the process of traditional pyrolysis and solar pyrolysis.

Chinese medicine residues (CMRs) have always been considered difficult to realize resource treatment because of the possible residual heavy metals (HMs). In this study, CMRs containing HMs (Cu, Cd and Pb) were pyrolized in the tube furnace and the solar pyrolysis equipment. The ratio of HMs entering the pyrolysis products (bio-gas, bio-oil and bio-char) and the stability of HMs in biochar were analyzed. A comparative analysis showed that the less volatile HMs were basically concentrated in the biochar after the pyrolysis treatment, indicating that pyrolysis could enrich the HMs in the biochar. The leaching experiments showed that the leaching rates of Cu, Cd and Pb from biochar were 0-0.41%, 0-3.03% and 0.09-0.86% respectively, while the leaching rates of CMR were as high as 18.85, 10.98 and 2.52%, indicating that the pyrolysis process could improve the fixation effect of HMs in biomass to a greater extent and reduce the leaching toxicity of HMs. Compared with the traditional pyrolysis method, the solar pyrolysis had the same effect on the enrichment and stabilization of heavy metals in CMRs, which means that it is possible to realize the resource treatment of CMR through a renewable green energy (solar energy).

Preferences for a good death: a cross-sectional survey in advanced cancer patients.

OBJECTIVE: The aim of this study was to describe preferences for a good death among Chinese patients with advanced cancer and then to explore factors contributing to their preferences including patient demographics and disease variables. METHODS: A convenience sample of 275 patients with advanced cancer was recruited from a tertiary cancer hospital in Beijing, China, between February and December 2017. A Chinese version of the Good Death Inventory (GDI) was used to measure patients' preferences for dying and death. Besides, data were collected using a multi-itemed questionnaire focusing on demographic and disease characteristics of patients. RESULTS: Of the 275 questionnaires returned, 248 responses were analysed (effective response rate 90.2%). According to the total scores for each of the 20 domains, the five most important domains of a good death were: good relationship with family (19.80±2.39), independence (19.66±2.56), maintaining hope and pleasure (19.56±2.55), good relationship with medical staff (18.92±3.73), not being a burden to others (18.89±3.30). Patients' characteristics including age, educational status, religious belief, medical payment types, family economic status, past experiences of the death of others, the period since cancer diagnosis, past experiences of hospitalisation and subjective physical condition influenced their preferences for a good death (all p<0.05). CONCLUSIONS: We had an in-depth knowledge and understanding of their preferences for good death among Chinese patients with advanced cancer. Meanwhile, we found some patients' factors contributed to different preferences for a good death. These findings have the potential to guide hospice care services aimed at achieving a good death for patients with advanced cancer.

Application of microbial immobilization technology for remediation of Cr(VI) contamination: A review.

The discharge of chromium (Cr) contaminated wastewater is creating a serious threat to aquatic environment due to the rapid pace in agricultural and industrial activities. Particularly, the long-term exposure of Cr(VI) polluted wastewater to the environment is causing serious harm to human health. Therefore, the treatment of Cr(VI) contaminated wastewater is demanding widespread attention. Regarding this, the bioremediation is being considered as a reliable and feasible option to handle Cr(VI) contaminated wastewater because of having low technical investment and operating costs. However, certain factors such as loss of microorganisms, toxicity to microorganisms and uneven microbial growth cycle in the presence of high concentrations of Cr(VI) are hindering its commercial applications. Regarding this, microbial immobilization technology (MIT) is getting great research interest because it could overcome the shortcomings of bioremediation technology's poor tolerance against Cr. Therefore, this review is the first attempt to emphases recent research developments in the remediation of Cr(VI) contamination via MIT. Starting from the selection of immobilized carrier, the present review is designed to critically discuss the various microbial immobilizing methods i.e., adsorption, embedding, covalent binding and medium interception. Further, the mechanism of Cr(VI) removal by immobilized microorganism has also been explored, precisely. In addition, three kinds of microorganism immobilization devices have been critically examined. Finally, knowledge gaps/key challenges and future perspectives are also discussed that would be helpful for the experts in improving MIT for the remediation of Cr(VI) contamination.

Active biochar-supported iron oxides for Cr(VI) removal from groundwater: Kinetics, stability and the key role of FeO in electron-transfer mechanism.

Chromium (Cr), especially in forms of hexavalent chromium (Cr(VI)) remains a serious threat to public health and environmental safety for its high toxicity. Herein, two types of iron-modification methods adopting co-pyrolysis and surface-deposition respectively were carried out to prepare active Fe-biochar composites (FeBC) for Cr(VI) removal in the simulated groundwater environment. The systematic characterization demonstrated that larger BET surface area and diversified iron oxides of FeBC-1 obtained from the co-pyrolysis method contributed to higher adsorption and reduction activity towards Cr(VI) degradation in comparison with FeBC-2 produced from surface-deposition method. Further, FeO was evidenced to be a main active component for transforming Cr(VI) to lower-toxicity Cr(III) uniting XRD and XPS analysis. Also, the designed batch experiments aiming at deeper clarifying FeBC-1 revealed that the pseudo-second-order kinetic and intra-particle diffusion model could well describe the Cr(VI) sorption behaviors, suggesting that a single-layer, chemical adsorption process as well as internal particle diffusion both controlled the removal process of Cr(VI) using FeBC-1. Finally, the stability experiments stated that FeBC-1 was basically stable at acidic and neutral conditions. Thus, it was found that co-pyrolysis of FeBC-1 is a potential technology for Cr(VI) remediation.