A Novel Bioswitchable miRNA Mimic Delivery System: Therapeutic Strategies Upgraded from Tetrahedral Framework Nucleic Acid System for Fibrotic Disease Treatment and Pyroptosis Pathway Inhibition.

There has been considerable interest in gene vectors and their role in regulating cellular activities and treating diseases since the advent of nucleic acid drugs. MicroRNA (miR) therapeutic strategies are research hotspots as they regulate gene expression post-transcriptionally and treat a range of diseases. An original tetrahedral framework nucleic acid (tFNA) analog, a bioswitchable miR inhibitor delivery system (BiRDS) carrying miR inhibitors, is previously established; however, it remains unknown whether BiRDS can be equipped with miR mimics. Taking advantage of the transport capacity of tetrahedral framework nucleic acid (tFNA) and upgrading it further, the treatment outcomes of a traditional tFNA and BiRDS at different concentrations on TGF-ß- and bleomycin-induced fibrosis simultaneously in vitro and in vivo are compared. An upgraded traditional tFNA is designed by successfully synthesizing a novel BiRDS, carrying a miR mimic, miR-27a, for treating skin fibrosis and inhibiting the pyroptosis pathway, which exhibits stability and biocompatibility. BiRDS has three times higher efficiency in delivering miRNAs than the conventional tFNA with sticky ends. Moreover, BiRDS is more potent against fibrosis and pyroptosis-related diseases than tFNAs. These findings indicate that the BiRDS can be applied as a drug delivery system for disease treatment.

The effectiveness of exercise on the symptoms in breast cancer patients undergoing adjuvant treatment: an umbrella review of systematic reviews and meta-analyses.

Background: Exercise has the potential to reduce symptoms for breast cancer patients during adjuvant treatment, and high-quality systematic reviews are essential for guiding clinical practice. The objective of this umbrella review is to examine current research evidence concerning the effectiveness of exercise on symptom management in breast cancer patients undergoing adjuvant treatment. Methods: An umbrella review was conducted. We searched for eligible systematic reviews through 11 databases until August 13rd, 2023. Two authors independently screened titles and abstracts, assessing the full-text studies based on inclusion criteria. We used AMSTAR-2 to appraise the quality of the meta-analyses. The results would be presented with narrative summaries if the replication rate of the original study for a symptom was higher than 5% (calculated via the Corrected Covered Area, CCA). The protocol was documented in the PROSPERO registry (CRD42023403990). Results: Of the 807 systematic reviews identified, 15 met the inclusion criteria, and 7 symptoms were the main focus. The main form of exercise mentioned was aerobic combined resistance exercise. The results of the quality assessment were mostly critically low (10/15). The repetition rate calculated by CCA showed moderate to very high repetition rates (10% to 18.6%). The findings of the included reviews indicated that the effects of exercise on relieving symptoms during breast cancer adjuvant treatment were mixed. Conclusions: Research is still needed to confirm the majority of studies' recommendations for exercise during adjuvant treatment for breast cancer patients, as it is crucial for managing symptoms in the rehabilitation process. To increase the efficiency of exercise in symptom management, future studies may focus more on the application of bridge symptoms, symptom networks, and ecological instantaneous assessment.

Exploring the relationship between self-management behaviour, family function and health information adoption behaviour in Chinese diabetic foot patients: a mixed-methods study protocol.

INTRODUCTION: Diabetic foot is a major burden and threat to individuals, families and society, making it imperative to promote good self-management behaviour. However, although nurses have provided these patients with excellent health knowledge, their self-management remains unsatisfactory. Although researches have shown that self-management requires family involvement, no research has been conducted in China on family function, specifically in the diabetic foot. Therefore, this study aimed to explore the relationship between self-management, family functioning, and health information adoption behaviour and explain the formation's reason. METHOD AND ANALYSIS: We will conduct a mixed-methods study using an exploratory sequential study design in Zhejiang, China. In the first phase, cross-section research will be conducted using a convenient sampling strategy on 225 diabetic foot patients. SPSS V.26 was used for correlation and multiple stepwise regression analyses. Structural equation modelling will be performed by using AMOS V.24. The researchers will conduct a semistructured interview to collect qualitative data and use NVivo to analyse. Ultimately, we will 'triangulate' to integrate quantitative and qualitative data. ETHICS AND DISSEMINATION: This study received ethical clearance from the Ethics Review Committee, the affiliated Sir Run Run Shaw Hospital of Medicine School, Zhejiang University (approval no: 2023-0145). All data collection processes will abide by health and safety measures required by the national government. Written informed consent will be obtained from all participants. The study will produce one paper that will be disseminated, to local stakeholders and participants, via local and international conferences and publications in peer-reviewed journals.

Effects of Puerarin-Loaded Tetrahedral Framework Nucleic Acids on Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is recognized as a common refractory orthopedic disease that causes severe pain and poor quality of life in patients. Puerarin (Pue), a natural isoflavone glycoside, can promote osteogenesis and inhibit apoptosis of bone mesenchymal stem cells (BMSCs), demonstrating its great potential in the treatment of osteonecrosis. However, its low aqueous solubility, fast degradation in vivo, and inadequate bioavailability, limit its clinical application and therapeutic efficacy. Tetrahedral framework nucleic acids (tFNAs) are promising novel DNA nanomaterials in drug delivery. In this study, tFNAs as Pue carriers is used and synthesized a tFNA/Pue complex (TPC) that exhibited better stability, biocompatibility, and tissue utilization than free Pue. A dexamethasone (DEX)-treated BMSC model in vitro and a methylprednisolone (MPS)-induced ONFH model in vivo is also established, to explore the regulatory effects of TPC on osteogenesis and apoptosis of BMSCs. This findings showed that TPC can restore osteogenesis dysfunction and attenuated BMSC apoptosis induced by high-dose glucocorticoids (GCs) through the hedgehog and Akt/Bcl-2 pathways, contributing to the prevention of GC-induced ONFH in rats. Thus, TPC is a promising drug for the treatment of ONFH and other osteogenesis-related diseases.

Expression and correlation of the Pi3k/Akt pathway and VEGF in oral submucous fibrosis.

Oral submucous fibrosis (OSF) has a high incidence in Asia countries, but its underlying molecular mechanism was not exploited completely. In this research, we investigated the expression of the phosphatidyl inositol 3-kinase (Pi3k)/protein kinase B (Akt) pathway and vascular endothelial growth factor (VEGF) in oral submucosal fibrosis, explore the correlation between the Pi3k/Akt pathway and VEGF, and identify the mechanisms involved in OSF. The pathological changes and fibrosis stages of OSF tissues (n = 30, 10 each of early, moderate and advanced OSF) were determined using Haematoxylin-eosin staining (HE) and Masson staining, respectively. Collagen type I (Col-I), Pi3k, Akt, VEGF, TGF-ß and p-Akt expression was detected using immunohistochemistry, qPCR and WB. The correlation between Pi3k, Akt and VEGF was analysed. Col-I expression increased as OSF progressed. However, their expression was downregulated in normal and moderate to advanced OSF tissues. VEGF expression positively correlated with Pi3k and Akt expression. VEGF expression correlated positively and negatively with the Pi3k inhibitor, LY294002 below and above a concentration of 10 µM, respectively. VEGF expression correlated positively with the Pi3k/Ak activator, IGF-1. Due to the synergistic effect between Pi3k/Akt pathway and VEGF on OSF lesions and fibrosis process, targeted Pi3k/Akt pathway regulation can induce VEGF expression and improve ischemia, ultimately treating OSF.

Myelosuppression Alleviation and Hematopoietic Regeneration by Tetrahedral-Framework Nucleic-Acid Nanostructures Functionalized with Osteogenic Growth Peptide.

As major complications of chemoradiotherapy, myelosuppression and hematopoietic-system damage severely affect immunologic function and can delay or even terminate treatment for cancer patients. Although several specific cytokines have been used for hematopoiesis recovery, their effect is limited, and they may increase the risk of tumor recurrence. In this study, osteogenic growth peptide functionalized tetrahedral framework nucleic-acid nanostructures (OGP-tFNAs) are prepared; they combine the positive hematopoiesis stimulating effect of OGP and the drug carrying function of tFNAs. The potential of OGP-tFNAs for hematopoietic stimulation and microenvironment regulation is investigated. It is shown that OGP-tFNAs can protect bone marrow stromal cells from 5-fluorouracil (5-FU)-induced DNA damage and apoptosis. OGP-tFNAs pretreatment activates the extracellularly regulated protein kinase signal and downregulates apoptosis-related proteins. OGP-tFNAs also alleviate the chemotherapy-induced inhibition of hematopoiesis-related cytokine expression, which is crucial for hematopoiesis reconstitution. In conclusion, OGP-tFNAs can protect hematopoietic cells and their microenvironment from chemotherapy-induced injuries and myelosuppression, while promoting hematopoiesis regeneration.

Tetrahedral Framework Nucleic Acids Inhibit Skin Fibrosis via the Pyroptosis Pathway.

The skin is the first line of defense for the human body and is vulnerable to injury. Various topical or systemic diseases facilitate skin inflammation, and when the intensity or duration of skin injury exceeds the ability of tissue repair, fibrosis, an outcome of a dysregulated tissue-repair response, begins to dominate the repair process. However, existing methods for reducing skin fibrosis are insufficient and cause side effects, highlighting the need for drugs that effectively inhibit skin fibrosis and reduce immunogenicity, inflammation, apoptosis, and pyroptosis. Tetrahedral framework nucleic acids (tFNAs) are DNA nanomaterials that have a unique spatial structure, demonstrate excellent biosecurity, and promote anti-inflammatory, antioxidative, antifibrotic, angiogenic, and skin-wound-healing activities with almost no toxicity. Here, we explored the potential of tFNAs in skin fibrosis therapy in vitro and in vivo. After incubating cells or injecting mice with profibrogenic molecules and tFNAs, we found that the tFNAs inhibited the epithelial-mesenchymal transition, reduced inflammatory factor levels, decreased skin collagen content, and inhibited the pyroptosis pathway. These findings suggest the potential of tFNAs in treating pyroptosis-related diseases.

Tangnaikang improves insulin resistance and ß-cell apoptosis by ameliorating metabolic inflammation in SHR.Cg-Leprcp/NDmcr rats.

OBJECTIVE: To investigate the effects of Tangnaikang (TNK), a mixture of five herbal plant extracts, on inflammation-mediated insulin resistance and B-cell apoptosis in SHR.Cg-Leprcp/NDmcr (SHR-cp) rats. METHODS: Seven-week-old SHR-cp rats were randomly divided into a control (CON) group and a TNK (3.24 g/kg) group. Wistar-Kyoto rats at the same age were used as the normal control group. After 7 weeks of continuous intragastric administration of TNK, the glucose metabolic status and insulin sensitivity of the rats were evaluated by assessing fasting serum glucose (FBG), the oral glucose tolerance test (OGTT), fasting serum insulin (FINS), and the insulin sensitivity index (ISI). Serum tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), C-reactive protein (CRP) and adiponectin were measured via enzyme-linked immunosorbent assays. Macrophage infiltration and apoptosis in adipose tissues were detected through F4/80 immunohistochemistry and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Islet morphology and B-cell apoptosis were investigated using double immunofluorescence staining and the TUNEL assay. The expression of cytokine genes in adipose tissue, the liver, and the pancreas was detected in real-time polymerase chain reaction assays. The expression and phosphorylation levels of insulin signaling-, inflammation-, and B-cell survival-related proteins in the liver and pancreas of SHR-cp rats were detected by western blotting. RESULTS: TNK (3.24 g/kg) treatment significantly decreased body weight, FBG and FINS; improved impaired glucose tolerance; increased the ISI; reduced serum levels of TNF-a, CRP and IL-6; and increased serum adiponectin. The mRNA expression of inflammatory markers was markedly reduced in the liver, pancreas, and adipose tissue. F4/80- and TUNEL-positive cells in adipose tissues were decreased, as was the number of TUNEL-positive B-cells. The phosphorylation of c-Jun N-terminal kinase and that of insulin receptor substrate-1 at serines 307 and 1101 was significantly decreased. In the pancreas, the expression of nuclear factor kappa-light chain-enhancer of activated B cells-p65 was significantly decreased, and phosphoinositide 3-kinase and IRS-2 were significantly increased. CONCLUSION: TNK was able to improve insulin resistance and B-cell apoptosis in SHR-cp rats, which might be associated with its ability to relieve the overall and local metabolic inflammatory responses observed in SHR-cp rats.

Mixture of five herbal extracts ameliorates pioglitazone-induced aggravation of hepatic steatosis via activating the adiponectin receptor 2/AMP-activated protein kinase signal pathway in diabetic KKAy mice.

OBJECTIVE: To assess the effect of a mixture of five herbal extracts (FT-5) on insulin resistance, glucose/lipid metabolism, hepatic steatosis, and to investigate whether the combination of FT-5 and pioglitazone would provide a robust effect on diabetes treatment, while may minimize undesirable side-effects of pioglitazone in diabetic Ay gene (KKAy) mice. METHODS: Seven-week-old KKAy mice were randomly divided into five groups: control (CON) group, FT-5 (2.0 g/kg) group, pioglitazone (20 mg/kg) (PIO) group, pioglitazone (20 mg/kg) + FT-5 (2.0 g/kg) (P + F) group. Age-matched C57BL/6J mice were used as the control group. After seven weeks of continuous intragastric administration of medication, the glucose metabolism, insulin sensitivity and lipid metabolism of KKAy mice were evaluated by assessing the fasting blood glucose (FBG), oral glucose tolerance test (OGTT), fasting serum insulin (FINS), insulin tolerance test (ITT), homeostasis model of assessment-insulin resistance index (HOMA-IR), total cholesterol (TC), total triglycerides (TG), and free fatty acids (FFA) in plasma and liver. Plasma and hepatic adiponectin were measured via enzyme-linked immunosorbent assays. Genes related to adipogenesis and lipolysis in white adipose tissues (WAT) and liver were examined by real-time polymerase chain reaction. Lipid metabolism-related protein expression in the liver of KKAy mice were detected by Western blotting. RESULTS: PIO treatment remarkably improved insulin resistance. However, it also showed substantial side effects. FT-5 group exhibited no significant decrease in serum glucose. However, it reduced fasting plasma TG levels and improved hepatic steatosis of KKAy mice. P + F group showed improved insulin resistance and similar body weight gain, as compared with control group. The mRNA expression of genes related to fatty acid oxidation was markedly up-regulated in the liver of P + F group. Pioglitazone administration markedly decreased the phosphorylation levels of AMPK, as compared with all other groups. Besides, even though plasma adiponectin increased in PIO, FT-5, P + F group, adipoR2 gene expression significantly decreased in the liver of PIO group. CONCLUSION: FT-5 decreased plasma TG and alleviated aggravating hepatic steatosis induced by pioglitazone in KKAy mice. FT-5's mechanism might be associated with its ability to activate the AdipoR2/AMPK pathway.

Associations between work stress and suicidal ideation: Individual-participant data from six cross-sectional studies.

OBJECTIVE: Epidemiological evidence suggests that work stress is associated with suicidal ideation (SI). However, only few studies in this area have drawn on well-established theoretical work stress models (i.e., the job-demand-control [JDC] model, the effort-reward-imbalance [ERI] model, and the model of organizational injustice [OJ]). Utilization of such models allows though for theory-based assessments and workplace interventions. Since evidence on those models' relationship with suicide-related outcomes is currently inconclusive (with regard to JDC), markedly sparse (OJ) or lacking (ERI), we aimed to provide additional or initial evidence. METHODS: We drew on original data from six cross-sectional studies, which were conducted in four countries (i.e., South Korea, China, Australia, and Germany). Work stress was measured by established questionnaires and was categorized into tertiles. In each study, SI was assessed by either one or two items taken from validated scales. Associations of work stress with SI were estimated for each study and were pooled across studies using multivariate random-effects logistic modeling. RESULTS: In the pooled analyses (n=12,422) all three work stress models were significantly associated with SI with odds ratios fluctuating around 2. For instance, the pooled odds ratios for highest versus lowest work stress exposure in terms of job strain, OJ, and ERI equalled 1.91 (95% confidence interval [CI]=1.52, 2.41), 1.98 (95% CI=1.48, 2.65), and 2.77 (95% CI=1.57, 4.88), respectively. Patterns of associations were largely consistent across the individual studies. CONCLUSION: Our study provides robust evidence of a positive association between work stress and SI.