Factors Influencing the Self-management of Breast Cancer-Related Lymphedema: A Meta-synthesis of Qualitative Studies.

BACKGROUND: Patients with breast cancer have an estimated 14% to 60% risk of developing lymphedema after treatment. Self-management behavior strategies regarding lymphedema are essential in preventing and alleviating the severity of lymphedema. OBJECTIVE: The aim of this study was to evaluate qualitative research evidence on the potential influencing factors for self-management behaviors of lymphedema in patients with breast cancer. METHODS: A systematic search of 10 electronic databases was conducted to identify qualitative studies on patient experience of lymphedema self-management. The following databases were included and appraised using the Joanna Briggs Institute Critical Appraisal Checklist: Cochrane Library, PubMed, EMBASE, Web of Science, PsycINFO, Scopus, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, Wanfang Med Online, and Chinese Biomedical Database. RESULTS: The literature search yielded 5313 studies, of which only 22 qualitative studies fulfilled the eligibility criteria. Five synthesized findings were derived encompassing personal characteristics, personal knowledge and experience, personal health beliefs, self-regulation skills and abilities, and social influences and support. CONCLUSIONS: Patients with breast cancer are confronted with many challenges when performing self-management of lymphedema. Therefore, it is important to recognize potential facilitators and barriers to further offer practical recommendations that promote self-management activities for lymphedema. IMPLICATIONS FOR PRACTICE: Healthcare professionals should receive consistent training on lymphedema management. On the basis of individual patient characteristics, tailored education and support should be provided, including transforming irrational beliefs, and improving related knowledge and skills, with the aim to promote self-management behaviors with respect to lymphedema.

Advances in the application of extracellular vesicles derived from three-dimensional culture of stem cells.

Stem cells (SCs) have been used therapeutically for decades, yet their applications are limited by factors such as the risk of immune rejection and potential tumorigenicity. Extracellular vesicles (EVs), a key paracrine component of stem cell potency, overcome the drawbacks of stem cell applications as a cell-free therapeutic agent and play an important role in treating various diseases. However, EVs derived from two-dimensional (2D) planar culture of SCs have low yield and face challenges in large-scale production, which hinders the clinical translation of EVs. Three-dimensional (3D) culture, given its ability to more realistically simulate the in vivo environment, can not only expand SCs in large quantities, but also improve the yield and activity of EVs, changing the content of EVs and improving their therapeutic effects. In this review, we briefly describe the advantages of EVs and EV-related clinical applications, provide an overview of 3D cell culture, and finally focus on specific applications and future perspectives of EVs derived from 3D culture of different SCs.

Durable transgene expression and efficient re-administration after rAAV2.5T-mediated fCFTRΔR gene delivery to adult ferret lungs.

The dosing interval for effective recombinant adeno-associated virus (rAAV)-mediated gene therapy of cystic fibrosis lung disease remains unknown. Here, we assessed the durability of rAAV2.5T-fCFTRΔR-mediated transgene expression and neutralizing antibody (NAb) responses in lungs of adult wild-type ferrets. Within the first 3 months following rAAV2.5T-fCFTRΔR delivery to the lung, CFTRΔR transgene expression declined ∼5.6-fold and then remained stable to 5 months at ∼26% the level of endogenous CFTR. rAAV NAbs in the plasma and bronchoalveolar lavage fluid (BALF) peaked at 21 days, coinciding with peak ELISpot T cell responses to AAV capsid peptides, after which both responses declined and remained stable at 4-5 months post dosing. Administration of reporter vector rAAV2.5T-gLuc (gaussia luciferase) at 5 months following rAAV2.5T-fCFTRΔR dosing gave rise to similar levels of gLuc expression in the BALF as observed in age-matched reporter-only controls, demonstrating that residual BALF NAbs were functionally insignificant. Notably, the second vector administration led to a 2.6-fold greater ELISpot T cell response and ∼2.3-fold decline in fCFTRΔR mRNA and vector genomes derived from the initial rAAV2.5T-fCFTRΔR administration, suggesting selective destruction of transduced cells from the first vector dose. These findings provide insights into humoral and cellular immune response to rAAV that may be useful for optimizing gene therapy to the cystic fibrosis lung.

In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF. Using primary intestinal organoids and air-liquid interface cultures of airway epithelia, we demonstrate that the F508del mutation in ferret CFTR results in a severe folding and trafficking defect, which can be partially restored by treatment with CFTR modulators. In utero treatment of pregnant jills with ivacaftor/lumacaftor prevented meconium ileus at birth in F508del kits and sustained postnatal treatment of CF offspring improved survival and partially protected from pancreatic insufficiency. Withdrawal of ivacaftor/lumacaftor treatment from juvenile CF ferrets reestablished pancreatic and lung diseases, with altered pulmonary mechanics. These findings suggest that in utero intervention with a combination of CFTR modulators may provide therapeutic benefits to individuals with F508del. This CFTR-F508del ferret model may be useful for testing therapies using clinically translatable endpoints.

A Dual Role of Mesenchymal Stem Cell Derived Small Extracellular Vesicles on TRPC6 Protein and Mitochondria to Promote Diabetic Wound Healing.

Diabetic wounds exhibit delayed and incomplete healing, usually due to vascular and nerve damage. Dysregulation of cellular Ca2+ homeostasis has recently been shown to be closely related to insulin resistance and type 2 diabetes mellitus. However, the involvement of this dysregulation in diabetic wound complications remains unknown. In this study, we found calcium dysregulation in patients with diabetic ulcers via tissue protein profiling. High glucose and glucometabolic toxicant stimulation considerably impaired the function of TRPC6, a pore subunit of transient receptor potential channels mediating Ca2+ influx, and mitochondria, which regulate calcium cycling and metabolism. Furthermore, we found that mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) could play a dual role in restoring the function of TRPC6 and mitochondria by delivering transcription factor SP2 and deubiquitinating enzyme USP9, respectively. MSC-sEVs could transfer SP2 that activated TRPC6 expression by binding to its specific promoter regions (-1519 to -1725 bp), thus recovering Ca2+ influx and downstream pathways. MSC-sEVs also promoted mitophagy to restore mitochondrial function by transporting USP9 that stabilized the expression of Parkin, a major player in mitophagy, thereby guaranteeing Ca2+ efflux and avoidance of Ca2+ overload. Targeting the regulation of calcium homeostasis provides a perspective for understanding diabetic wound healing, and the corresponding design of MSC-sEVs could be a potential therapeutic strategy.

Prognostic nomogram for patients with tongue squamous cell carcinoma: A SEER-based study.

OBJECTIVES: In order to predict the patients' prognosis with tongue squamous cell carcinoma (SCC), this study set out to develop a clinically useful and trustworthy prognostic nomogram. SUBJECTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program was used to compile clinical information on patients with tongue SCC between 2010 and 2015. The likelihood of Cancer-Specific Survival (CSS) and Overall Survival (OS) for specific patients was predicted using a prognostic nomogram created with the help of the RStudio software. The nomogram's predictive ability was evaluated using the consistency index (C-index) and decision curve analysis, and the nomogram was calibrated for 1-, 2-, 3-, 5-, and 10-year CSS and OS. RESULTS: Patients numbering 6453were enrolled in this study. The primary cohort (3895) and validation cohort (2558) were each randomly assigned. Sex, age, tumor-node-metastasis (TNM) stage, surgery, chemotherapy, and radiation were significant risk factors for OS, whereas age, TNM stage, surgery, chemotherapy, and radiotherapy were significant risk factors for CSS. Additionally, C-index and calibration curves indicated that the prognostic nomogram prediction and the actual observation in both cohorts would be very coherent. CONCLUSIONS: The predictive nomogram created in this study can offer patients with tongue SCC customized treatment and survival risk assessment.

Micro electrical fields induced MSC-sEVs attenuate neuronal cell apoptosis by activating autophagy via lncRNA MALAT1/miR-22-3p/SIRT1/AMPK axis in spinal cord injury.

Spinal cord injury (SCI) is a traumatic condition of the central nervous system that causes paralysis of the limbs. Micro electric fields (EF) have been implicated in a novel therapeutic approach for nerve injury repair and regeneration, but the effects of human umbilical cord mesenchymal stem cell-derived small extracellular vesicles that are induced by micro electric fields (EF-sEVs) stimulation on SCI remain unknown. The aim of the present study was to investigate whether EF-sEVs have therapeutic effects a rat model of SCI. EF-sEVs and normally conditioned human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (CON-sEVs) were collected and injected intralesionally into SCI model rats to evaluate the therapeutic effects. We detect the expression of candidate long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA-MALAT1) in EF-sEVs and CON-sEVs. The targets and downstream effectors of lncRNA-MALAT1 were investigated using luciferase reporter assays. Using both in vivo and in vitro experiments, we demonstrated that EF-sEVs increased autophagy and decreased apoptosis after SCI, which promoted the recovery of motor function. We further confirmed that the neuroprotective effects of EF-sEVs in vitro and in vivo correlated with the presence of encapsulated lncRNA-MALAT1 in sEVs. lncRNA-MALAT1 targeted miR-22-3p via sponging, reducing miR-22-3p's suppressive effects on its target, SIRT1, and this translated into AMPK phosphorylation and increased levels of the antiapoptotic protein Bcl-2. Collectively, the present study identified that the lncRNA-MALAT1 in EF-sEVs plays a neuroprotective role via the miRNA-22-3p/SIRT1/AMPK axis and offers a fresh perspective and a potential therapeutic approach using sEVs to improve SCI.

Breast cancer survivors' experiences of barriers and facilitators to lymphedema self-management behaviors: a theory-based qualitative study.

PURPOSE: Lifelong self-management plays a critical role in the prevention and management of lymphedema among breast cancer survivors. However, adherence to lymphedema self-management behaviors has remained suboptimal. Hence, we adopted a theory-informed method to elucidate the facilitators and barriers of lymphedema self-management for breast cancer survivors. METHODS: In-depth semi-structured interviews were conducted between August and October 2022 in the lymphedema nursing clinic of a tertiary cancer hospital. The maximum variation sampling technique was used to ensure a diverse sample. The ITHBC (Integrated Theory of Health Behavior Change) framework was used to inform the interview outline and data analysis. Interview transcripts were coded line-by-line and mapped to domains in accordance with the ITHBC, using both deductive and inductive content analysis. RESULTS: A total of 16 participants were interviewed (aged 35 to 67). Twenty-three themes (12 facilitators and 11 barriers) were mapped onto the three domains (knowledge and belief, social facilitation, and self-regulation skill and ability) of ITHBC as facilitators and barriers to lymphedema self-management. Three additional themes including limited treatment resources for lymphedema, inconvenience of lymphedema management, boredom and tedium of lymphedema self-management were categorized under the domain of other barriers. CONCLUSIONS: Incorporating these findings into the ITHBC framework allows for a more systematic selection of theory-based strategies that may improve the design of effective lymphedema self-management interventions for breast cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Elucidating impact factors, especially facilitators and barriers, for lymphedema self-management adherence is essential for developing effective intervention programs to enhance breast cancer survivors' lymphedema self-management behaviors.

Characterization of histone chaperone MCM2 as a key regulator in arsenic-induced depletion of H3.3 at genomic loci.

Arsenic exposure is associated with an increased risk of many cancers, and epigenetic mechanisms play a crucial role in arsenic-mediated carcinogenesis. Our previous studies have shown that arsenic exposure induces polyadenylation of H3.1 mRNA and inhibits the deposition of H3.3 at critical gene regulatory elements. However, the precise underling mechanisms are not yet understood. To characterize the factors governing arsenic-induced inhibition of H3.3 assembly through H3.1 mRNA polyadenylation, we utilized mass spectrometry to identify the proteins, especially histone chaperones, with reduced binding affinity to H3.3 under conditions of arsenic exposure and polyadenylated H3.1 mRNA overexpression. Our findings reveal that the interaction between H3.3 and the histone chaperon protein MCM2 is diminished by both polyadenylated H3.1 mRNA overexpression and arsenic treatment in human lung epithelial BEAS-2B cells. The increased binding of MCM2 to H3.1, resulting from elevated H3.1 protein levels, appears to contribute to the reduced availability of MCM2 for H3.3. To further investigate the role of MCM2 in H3.3 deposition during arsenic exposure and H3.1 mRNA polyadenylation, we overexpressed MCM2 in BEAS-2B cells overexpressing polyadenylated H3.1 or exposed to arsenic. Our results demonstrate that MCM2 overexpression attenuates H3.3 depletion at several genomic loci, suggesting its involvement in the arsenic-induced displacement of H3.3 mediated by H3.1 mRNA polyadenylation. These findings suggest that changes in the association between histone chaperone MCM2 and H3.3 due to polyadenylation of H3.1 mRNA may play a pivotal role in arsenic-induced carcinogenesis.

Factors associated with lymphedema self-management behaviours among breast cancer survivors: A cross-sectional study.

AIMS AND OBJECTIVES: The purpose of this empirical study was to explore the current status and associated factors of lymphedema self-management behaviours among Chinese breast cancer survivors. BACKGROUND: Breast cancer-related lymphedema is a lifetime concern for survivors and is currently incurable. Lifetime lymphedema self-management takes a significant role in preventing development and progression of lymphedema. Understanding influencing factors of lymphedema self-management behaviours can help to develop targeted intervention programs. DESIGN: A multicentre cross-sectional study. METHODS: From December 2021 to April 2022, a convenience sample of 586 participants were recruited at four tertiary hospitals in four cities in China. Self-reported questionnaires were used to measure socio-demographic characteristics, disease-and treatment-related characteristics, lymphedema self-management behaviours, lymphedema knowledge, illness perception, self-efficacy, self-regulation and social support. Descriptive analysis, bivariate analysis and hierarchical multiple regression were conducted. This study was registered at Chinese Clinical Trial Registry (ChiCTR2200057084), and was reported followed the STROBE checklist. RESULTS: Breast cancer survivors reported moderate level of lymphedema self-management behaviours. Promotion of lymph reflux management was ranked the least performed self-management behaviours, while the affected limb protection management ranked the most. 36.2% of self-management behaviours was explained by exercise regularly, level of attention on lymphedema prevention, unclear about the tumour stage (vs. stage I), knowledge, self-efficacy, emotional illness representation and social support. CONCLUSIONS: Lymphedema self-management behaviours of breast cancer survivors was insufficient. Performance of lymphedema self-management varied with different socio-demographic characteristics, along with different levels of knowledge, self-efficacy, perception and social support. All these identified predictors should be reckoned in assessment and intervention of lymphedema self-management behaviours. RELEVANCE TO CLINICAL PRACTICE: This study addressed that breast cancer survivors' lymphedema self-management behaviours should be promoted. Focusing on identified predictors, further lymphedema surveillance, knowledge education or social facilitation programs are recommended to enhance their self-management performance and adherence.

Predicting lymphedema self-management behaviours in breast cancer patients: A structural equation model with the Integrated Theory of Health Behaviour Change.

AIMS: To explore predictors of lymphedema self-management behaviours among Chinese breast cancer survivors based on the Integrated Theory of Health Behaviour Change, and to clarify the interrelationship among these variables. DESIGN: Further analysis of a multicentre cross-sectional and survey-based study. METHODS: A total of 586 participants with breast cancer were recruited from December 2021 to April 2022 in different cities in China. We used self-reported questionnaires to collect data. Descriptive analysis, bivariate analysis and structural equation model were performed. RESULTS: The Integrated Theory of Health Behaviour Change is suitable for predicting lymphedema self-management behaviours. The final structural model showed good model fit. Social support, self-efficacy and lymphedema knowledge positively affected lymphedema self-management behaviours, directly and indirectly. Self-regulation acted as a crucial mediator between these variables and self-management. The direct path between social support and self-regulation was not significant. Lymphedema knowledge and social support also influenced self-management via illness perception, self-efficacy and self-regulation, sequentially. These variables explained 55.9% of the variance in lymphedema self-management behaviours. CONCLUSIONS: The modified model based on the Integrated Theory of Health Behaviour Change fitted well in predicting lymphedema self-management behaviours among breast cancer patients. Lymphedema knowledge, illness perception, self-efficacy, social support and self-regulation directly and indirectly influenced lymphedema self-management behaviours. IMPACT: This study provides a theoretical basis for the assessment and interventions of lymphedema self-management behaviours in breast cancer patients. Lymphedema self-management behaviours should be assessed regularly and comprehensively, taking these predictors into consideration to identify potential barriers. Further research is needed to explore effective interventions integrating these significant predictors. REPORTING METHOD: This study was reported following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cross-sectional studies. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contributed to the design or conduct of the study, analysis or interpretation of the data, or in the preparation of the manuscript. WHAT DOES THIS PAPER CONTRIBUTE TO THE WIDER GLOBAL CLINICAL COMMUNITY?: This study focused on identifying and predicting mechanism of self-management based on a theory of behaviour change. The results can be applied among patients with other chronic diseases or high-risk populations, and inspire the assessment and interventions facilitating self-management behaviours. STUDY REGISTRATION: This study was registered as an observational study at Chinese Clinical Trial Registry: http://www.chictr.org.cn (ChiCTR2200057084). IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: For breast cancer patients with poor lymphedema self-management behaviour, attention should be raised among nurses and involved healthcare staffs that lymphedema self-management is multi-faced. Strategies targeted at improving social support, self-regulation, knowledge, self-efficacy and illness perception should be also addressed in lymphedema self-management programs, to facilitate more effective improvement of lymphedema self-management behaviours.

Systematic pan-cancer analysis identifies cuproptosis-related gene DLAT as an immunological and prognostic biomarker.

Lipoylated dihydrolipoamide S-acetyltransferase (DLAT), the component E2 of the multi-enzyme pyruvate dehydrogenase complex, is one of the key molecules of cuproptosis. However, the prognostic value and immunological role of DLAT in pan-cancer are still unclear. Using a series of bioinformatics approaches, we studied combined data from different databases, including the Cancer Genome Atlas, Genotype Tissue-Expression, the Cancer Cell Line Encyclopedia, Human Protein Atlas, and cBioPortal to investigate the role of DLAT expression in prognosis and tumor immunity response. We also reveal the potential correlations between DLAT expression and gene alterations, DNA methylation, copy number variation (CNV), tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), immune infiltration levels, and various immune-related genes across different cancers. The results show that DLAT displays abnormal expression within most malignant tumors. Through gene set enrichment analysis (GSEA), we found that DLAT was significantly associated with immune-related pathways. Further, the expression of DLAT was also confirmed to be correlated with the tumor microenvironment and diverse infiltration of immune cells, especially tumor-associated macrophages (TAMs). In addition, we found that DLAT is co-expressed with genes encoding major histocompatibility complex (MHC), immunostimulators, immune inhibitors, chemokines, and chemokine receptors. Meanwhile, we demonstrate that DLAT expression is correlated with TMB in 10 cancers and MSI in 11 cancers. Our study reveals that DLAT plays an essential role in tumorigenesis and cancer immunity, which may be used to function as a prognostic biomarker and potential target for cancer immunotherapy.

Immunosuppression reduces rAAV2.5T neutralizing antibodies that limit efficacy following repeat dosing to ferret lungs.

The efficacy of redosing the recombinant adeno-associated virus (rAAV) vector rAAV2.5T to ferret lung is limited by AAV neutralizing antibody (NAb) responses. While immunosuppression strategies have allowed for systemic rAAV repeat dosing, their utility for rAAV lung-directed gene therapy is largely unexplored. To this end, we evaluated two immunosuppression (IS) strategies to improve repeat dosing of rAAV2.5T to ferret lungs: (1) a combination of three IS drugs (Tri-IS) with broad coverage against cellular and humoral responses (methylprednisolone [MP], azathioprine, and cyclosporine) and (2) MP alone, which is typically used in systemic rAAV applications. Repeat dosing utilized AAV2.5T-SP183-fCFTRΔR (recombinant ferret CFTR transgene), followed 28 days later by AAV2.5T-SP183-gLuc (for quantification of transgene expression). Both the Tri-IS and MP strategies significantly improved transgene expression following repeat dosing and reduced AAV2.5T NAb responses in the bronchioalveolar lavage fluid (BALF) and plasma, while AAV2.5T binding antibody subtypes and cellular immune responses by ELISpot were largely unchanged by IS. One exception was the reduction in plasma AAV2.5T binding immunoglobulin G (IgG) in both IS groups. Only the Tri-IS strategy significantly suppressed splenocyte expression of IFNA (interferon α [IFN-α]) and IL4. Our studies suggest that IS strategies may be useful in clinical application of rAAV targeting lung genetic diseases such as cystic fibrosis.

Development and validation of a risk prediction model for breast cancer-related lymphedema in postoperative patients with breast cancer.

OBJECTIVE: Breast cancer-related lymphedema (BCRL) is a common post-operative complication in patients with breast cancer. Here, we sought to develop and validate a predictive model of BCRL in Chinese patients with breast cancer. METHODS: Clinical and demographic data on patients with breast cancer were collected between 2016 and 2021 at a Cancer Hospital in China. A nomogram for predicting the risk of lymphedema in postoperative patients with breast cancer was constructed and verified using R 3.5.2 software. Model performance was evaluated using area under the ROC curve (AUC) and goodness-of-fit statistics, and the model was internally validated. RESULTS: A total of 1732 postoperative patients with breast cancer, comprising 1212 and 520 patients in the development and validation groups, respectively, were included. Of these 438 (25.39%) developed lymphedema. Significant predictors identified in the predictive model were time since breast cancer surgery, level of lymph node dissection, number of lymph nodes dissected, radiotherapy, and postoperative body mass index. At the 31.9% optimal cut-off the model had AUC values of 0.728 and 0.710 in the development and validation groups, respectively. Calibration plots showed a good match between predicted and observed rates. In decision curve analysis, the net benefit of the model was better between threshold probabilities of 10%-80%. CONCLUSION: The model has good discrimination and accuracy for lymphedema risk assessment, which can provide a reference for individualized clinical prediction of the risk of BCRL. Multicenter prospective trials are required to verify the predictive value of the model.

Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy.

Increasing evidences show that unmodified extracellular vesicles (EVs) derived from various cells can effectively inhibit the malignant progression of different types of tumors by delivering the bioactive molecules. Therefore, EVs are expected to be developed as emerging anticancer drugs. Meanwhile, unmodified EVs as an advanced and promising nanocarrier that is frequently used in targeted delivery therapeutic cargos and personalized reagents for the treatment and diagnosis of cancer. To improve the efficacy of EV-based treatments, researchers are trying to engineering EVs as an emerging nanomedicine translational therapy platform through biological, physical and chemical approaches, which can be broaden and altered to enhance their therapeutic capability. EVs loaded with therapeutic components such as tumor suppressor drugs, siRNAs, proteins, peptides, and conjugates exhibit significantly enhanced anti-tumor effects. Moreover, the design and preparation of tumor-targeted modified EVs greatly enhance the specificity and effectiveness of tumor therapy, and these strategies are expected to become novel ideas for tumor precision medicine. This review will focus on reviewing the latest research progress of functionalized EVs, clarifying the superior biological functions and powerful therapeutic potential of EVs, for researchers to explore new design concepts based on EVs and build next-generation nanomedicine therapeutic platforms.

Mesenchymal Stem Cells and Their Small Extracellular Vesicles as Crucial Immunological Efficacy for Hepatic Diseases.

Mesenchymal stem cell small extracellular vesicles (MSC-sEVs) are a priority for researchers because of their role in tissue regeneration. sEVs act as paracrine factors and carry various cargos, revealing the state of the parent cells and contributing to cell-cell communication during both physiological and pathological circumstances. Hepatic diseases are mainly characterized by inflammatory cell infiltration and hepatocyte necrosis and fibrosis, bringing the focus onto immune regulation and other regulatory mechanisms of MSCs/MSC-sEVs. Increasing evidence suggests that MSCs and their sEVs protect against acute and chronic liver injury by inducing macrophages (MΦ) to transform into the M2 subtype, accelerating regulatory T/B (Treg/Breg) cell activation and promoting immunosuppression. MSCs/MSC-sEVs also prevent the proliferation and differentiation of T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells. This review summarizes the potential roles for MSCs/MSC-sEVs, including immunomodulation and tissue regeneration, in various liver diseases. There is also a specific focus on the use of MSC-sEVs for targeted drug delivery to treat hepatitis.

Parkinson's Disease Dementia: Synergistic Effects of Alpha-Synuclein, Tau, Beta-Amyloid, and Iron.

Parkinson's disease dementia (PDD) is a common complication of Parkinson's disease that seriously affects patients' health and quality of life. At present, the process and pathological mechanisms of PDD remain controversial, which hinders the development of treatments. An increasing number of clinical studies have shown that alpha-synuclein (α-syn), tau, beta-amyloid (Aß), and iron are closely associated with PDD severity. Thus, we inferred the vicious cycle that causes oxidative stress (OS), due to the synergistic effects of α-syn, tau, Aß, and, iron, and which plays a pivotal role in the mechanism underlying PDD. First, iron-mediated reactive oxygen species (ROS) production can lead to neuronal protein accumulation (e.g., α-syn andAß) and cytotoxicity. In addition, regulation of post-translational modification of α-syn by iron affects the aggregation or oligomer formation of α-syn. Iron promotes tau aggregation and neurofibrillary tangles (NFTs) formation. High levels of iron, α-syn, Aß, tau, and NFTs can cause severe OS and neuroinflammation, which lead to cell death. Then, the increasing formation of α-syn, Aß, and NFTs further increase iron levels, which promotes the spread of α-syn and Aß in the central and peripheral nervous systems. Finally, iron-induced neurotoxicity promotes the activation of glycogen synthase kinase 3ß (GSK3ß) related pathways in the synaptic terminals, which in turn play an important role in the pathological synergistic effects of α-syn, tau and Aß. Thus, as the central factor regulating this vicious cycle, GSK3ß is a potential target for the prevention and treatment of PDD; this is worthy of future study.

Anti-cataract effects of coconut water in vivo and in vitro.

OBJECTIVE: To determine the anti-cataract effects of coconut water (CW) in vivo and in vitro, and to explore the potential pathogenic mechanism. METHODS: In this study, 48 male Sprague-Dawley rats were randomly divided into 4 groups: control (CO), diabetic (DM), diabetic treated with CW (DM + CW), and diabetic treated with Glibenclamide (DM + Gli). Except for the CO group, in the other three groups, intraperitoneal injection of STZ (60 mg/kg) was conducted to establish diabetic models. The experiment was conducted for 20 weeks. The slit-lamp examination was undertaken during the period of experiment (20 weeks), and then, all rats were sacrificed. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the left lens were measured by using biochemical assays. The right lens was used for pathological analysis. The rat lens epithelial cells (LECs) were cultured in vitro and the subcultured cell were divided into four groups, namely the normal glucose group (5 mmol /L glucose, Group I), the high glucose group (40 mmol/L glucose, Group II), high glucose +5% CW group (Group III), and high glucose +10% CW group (Group IV). LECs were cultured under the conditions as described above for 48 h. Cell proliferation and the morphological changes were observed with interted phase contrast microscope.The level of cell apoptosis was determined by flow cytometry. the level of SOD, MDA and GSH-Px were also detected. RESULTS: The lens opacity index decreased in diabetic rats, and LECs apoptosis ratio also decreased in high glucose environments that received CW. Under treatment with CW, reduced MDA level and elevated activities of SOD and GSH-Px were detected, both in vivo and in vitro experiments. The increased severity of cataract and LECs apoptosis were noted in diabetic rats that received normal water, while CW markedly mitigated the enhanced cataract severity and the reduction of LECs induced by diabetes mellitus. CONCLUSION: CW is a functional food that can protect the lens from diabetic cataract. The possible underlying mechanism may be partly explained via the decreased oxidative stress in lens. However, further research needs to be conducted to indicate the pathogenic mechanism of anti-diabetic effects of CW.

Exosomes: Emerging Therapy Delivery Tools and Biomarkers for Kidney Diseases.

Exosomes are nanometer-sized small EVs coated with bilayer structure, which are released by prokaryotic and eukaryotic cells. Exosomes are rich in a variety of biologically active substances, such as proteins, nucleotides, and lipids. Exosomes are widely present in various body fluids and cell culture supernatants, and it mediates the physiological and pathological processes of the body through the shuttle of these active ingredients to target cells. In recent years, studies have shown that exosomes from a variety of cell sources can play a beneficial role in acute and chronic kidney disease. In particular, exosomes derived from mesenchymal stem cells have significant curative effects on the prevention and treatment of kidney disease in preclinical trials. Besides, some encapsulated substances are demonstrated to exert beneficial effects on various diseases, so they have attracted much attention. In addition, exosomes have extensive sources, stable biological activity, and good biocompatibility and are easy to store and transport; these advantages endow exosomes with superior diagnostic value. With the rapid development of liquid biopsy technology related to exosomes, the application of exosomes in the rapid diagnosis of kidney disease has become more prominent. In this review, the latest development of exosomes, including the biosynthesis process, the isolation and identification methods of exosomes are systematically summarized. The utilization of exosomes in diagnosis and their positive effects in the repair of kidney dysfunction are discussed, along with the specific mechanisms. This review is expected to be helpful for relevant studies and to provide insight into future applications in clinical practice.

Roles of Mesenchymal Stem Cell-Derived Exosomes in Cancer Development and Targeted Therapy.

Exosomes have emerged as a new drug delivery system. In particular, exosomes derived from mesenchymal stem cells (MSCs) have been extensively studied because of their tumor-homing ability and yield advantages. Considering that MSC-derived exosomes are a double-edged sword in the development, metastasis, and invasion of tumors, engineered exosomes have broad potential use. In this review, we focused on the latest development in the treatment of tumors using engineered and nonengineered MSC-derived exosomes (MSC-EXs). Nonengineered MSC-EXs exert an antitumor effect on several well-studied tumors by affecting tumor growth, angiogenesis, metastasis, and invasion. Furthermore, engineered exosomes have promising research prospects as drug-carrying tools for the transport of miRNAs, small-molecule drugs, and proteins. Although exosomes lack uniform standards in terms of definition, separation, and purification, they still have great research value because of their unique advantages, such as high biocompatibility and low toxicity. Future studies on MSC-EXs should elucidate the mechanisms underlying their anticancer effect and the safety of their application.