Enzyme-Empowered "Two Birds with One Stone" Strategy for Amplifying Tumor Apoptosis and Metabolic Clearance.

Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel "two birds with one stone" technique for amplifying enzyme-mediated tumor apoptosis and enzyme-promoted metabolic clearance is proposed and achieved using GOx-functionalized rhenium nanoclusters-doped polypyrrole (Re@ReP-G). Re@ReP-G reduces ATP production while increasing H2O2 concentrations in the tumor microenvironment through GOx-induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti-apoptotic Bcl-2 proteins, the upregulation of pro-apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser-induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, H2O2 catalyzes the conversion of rhenium nanoclusters in Re@ReP-G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP-G-based "two birds with one stone" therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms.

The causal effect of reproductive factors on pelvic floor dysfunction: a Mendelian randomization study.

BACKGROUND: Pelvic floor dysfunction (PFD) is an extremely widespread urogynecologic disorder, the prevalence of which increases with aging. PFD has severely affected women's quality of life and has been called a social cancer. While previous studies have identified risk factors such as vaginal delivery and obesity for PFD, other reproductive factors, including age at menarche (AAMA), have been largely overlooked. Therefore, we used a Mendelian randomization (MR) study for the first time to investigate the potential causal relationship between reproductive factors and PFD. METHODS: We obtained summary statistics from genome-wide association studies (GWAS) for female genital prolapse (FGP), stress urinary incontinence (SUI), and five reproductive factors. Two-sample Mendelian randomization analysis (TSMR) was performed to explore the causal associations between these factors. The causal effects of reproductive factors on FGP and SUI were primarily estimated using the standard inverse variance weighting (IVW) method, with additional complementary and sensitivity analyses conducted using multiple approaches. A multivariate Mendelian randomization (MVMR) study was also conducted to adjust for pleiotropic effects and possible sources of selection bias and to identify independent exposure factors. RESULTS: Our findings revealed that advanced age at first sexual intercourse (AFS) and age at first birth (AFB) exhibited negative causal effects on both FGP and SUI. AAMA showed negative causal effects solely on FGP, while age at last live birth (ALB) and age at menopause (AAMO) did not demonstrate any causal effect on either FGP or SUI. And the MVMR results showed that AFB and AFS had independent negative causal effects on FGP and SUI, respectively. CONCLUSIONS: This study, for the first time, investigates the causal relationship between reproductive factors and PFD. The results suggested a causal relationship between some reproductive factors, such as AFB and AFS, and PFD, but there were significant differences between FGPand SUI. Therefore, future studies should explore the underlying mechanisms and develop preventive measures for reproductive factors to reduce the disease burden of PFD.

A clinical study evaluating the combination of LISA and SNIPPV for the treatment of respiratory distress syndrome in preterm infants.

To compare the therapeutic effect of less invasive surfactant administration (LISA) followed by synchronized nasal intermittent positive pressure ventilation (SNIPPV) and traditional intubate-Surfactant-Extubate (InSurE) strategy for the treatment of neonatal respiratory distress syndrome (NRDS). A single-center, non-randomized and single- blinded study Tertiary neonatal intensive care unit 89 infants enrolled were preterm with gestational age < 366/7 weeks and clinically diagnosed with neonatal RDS (NRDS) Interventions: 32 infants were assigned to the LISA + SNIPPV group and 57 infants to the InSurE + nCPAP group. No statistically significant differences were noted in the baseline characteristics of the enrolled infants. A lower proportion of infants developed BPD in the LISA + SNIPPV group compared to the InSurE + CPAP group [10 (31.25%) vs. 21 (36.84%), P > 0.05]; however, there was no statistically significant difference. The number needed to treat (NNT) with LISA + SNIPPV to prevent BPD development is 18. The mortality rate was not significant between our study arms [1 (3.13%) vs 2 (3.51%), P > 0.05]. There were no statistically significant differences in the durations (days) of MV [(12.18 ± 13.89) vs. (11.35 ± 11.61), P > 0.05], oxygen therapy [(35.03 ± 19.13) vs. (39.75 ± 17.91), P > 0.05] and re-intubation rates [(0.19 ± 0.40) vs. (0.21 ± 0.45), P > 0.05] between the two study groups. In terms of complications, the incidence of patent ductus arteriosus (PDA) [24 (75.00%) vs. 27 (47.37%), P < 0.05] was higher and a lower rate of disturbed liver function [1 (3.23%) vs. 19 (33.33%), P < 0.05] were observed in the LISA + SNIPPV group. Acid-base imbalances were reportedly significantly higher in the InSurE group (P < 0.05). No significant differences in other complications were noted. In the interventional group, FiO2 requirements were significantly lower up until the 3rd week of treatment [FiO2 at day 0, (30.75 ± 4.78) vs. (34.66 ± 9.83), P < 0.05; FiO2 at day 21, (25.32 ± 3.74) vs. (29.11 ± 8.17), P < 0.05], as was RSS on days 2 [(0.77 ± 0.38) vs. (1.94 ± 0.75), P < 0.05] and 3 [(0.66 ± 0.33) vs. (1.89 ± 0.82), P < 0.05] after treatment. Additionally, infants in the standard group had a significantly prolonged hospital stay (days) [(45.97 ± 16.93) vs. (54.40 ± 16.26), P < 0.05]. The combination of LISA and SNIPPV for NRDS can potentially lower the rate of BPD, FiO2 demand and shorten the length of hospitalization.

Humoral immune response after Ad26.COV2.S vaccination in patients with multiple sclerosis treated with natalizumab.

The immunomodulatory effects of disease-modifying therapies for multiple sclerosis might affect the immune response to vaccines for severe acute respiratory syndrome coronavirus 2. We analyzed the severe acute respiratory syndrome coronavirus 2-specific antibody response and lymphocyte profile before and after Ad26.COV2.S (Johnson & Johnson) vaccination in natalizumab-treated patients with multiple sclerosis. There was a 72-fold increase in mean anti-severe acute respiratory syndrome coronavirus 2 spike immunoglobulin G levels 4 weeks after vaccination and a 137-fold increase after 6 months. Other immune signals were within normal ranges. Natalizumab-treated patients with multiple sclerosis had a robust immune response to Ad26.COV2.S vaccine, and other immune signals were not significantly affected.

Bibliometric analysis of studies on stress urinary incontinence surgery.

Background: Stress urinary incontinence (SUI) is characterized by the involuntary leakage of urine during activities that increase abdominal pressure. In recent years, a considerable number of studies on SUI surgery have been published. However, there has been a lack of systematic quantification and comprehensive summarization of these studies. Bibliometrics is a discipline that utilizes measurement methods to quantify scientific literature. Thus, this study utilized publications from the Web of Science (WOS) as a data source and conducted a comprehensive analysis and visualization of studies related to SUI surgery in recent years using bibliometric techniques. Methods: We conducted a search and retrieved information on 988 studies related to SUI surgery in the WOS Core Collection. The data covered ten years from September 7, 2013, to September 7, 2023. We employed VOSviewer software, CiteSpace software, and Bibliometrix for analysis and visualization. Results: Over the ten years, the number of publications exhibited a fluctuating trend, initially decreasing and then increasing. The United States emerged as the leading contributor in terms of both publication volume and quality. The University of Alabama Birmingham ranked as the institution with the highest number of publications, while the International Urogynecology Journal featured the most publications among journals. Conclusions: This paper presents a bibliometric analysis of publications related to SUI surgery from 2013 to 2023. The aim is to offer researchers a concise overview of the field and inspire future research directions.

The causal effect of educational attainment on stress urinary incontinence: a two-sample mendelian randomization study.

BACKGROUND: Stress urinary incontinence (SUI) is characterized by involuntary urine leakage in response to increased abdominal pressure, such as coughing, laughing, or sneezing. It significantly affects women's quality of life and imposes a substantial disease burden. While pregnancy and childbirth have been previously identified as risk factors for SUI, educational attainment may also play a role. Therefore, this paper investigates the causal relationship between educational attainment and SUI using two-sample Mendelian randomization (TSMR) analysis, years of schooling (YOS), and college or university degree (CUD) as proxies. METHODS: Summary statistics of YOS, CUD, and SUI were obtained from genome-wide association studies (GWAS), and TSMR analysis was applied to explore potential causal relationships between them. Causal effects were mainly estimated using the standard inverse variance weighting (IVW) method, and complementary and sensitivity analyses were also performed using multiple methods. RESULTS: The results indicate that both YOS (OR = 0.994, 95% CI: 0.992-0.996; P = 7.764E-10) and CUD (OR = 0.987, 95% CI: 0.983-0.991; P = 1.217E-09) may have a negative causal effect on SUI. CONCLUSIONS: Improving educational attainment may go some way towards reducing the risk of SUI. Therefore, it is important to increase efforts to improve the imbalance in educational development and safeguard women's health.

Global burden and trends of ectopic pregnancy: An observational trend study from 1990 to 2019.

BACKGROUND: Ectopic pregnancy (EP) is one of the leading causes of death in women in early pregnancy, and the mortality of EP have gradually decreased over time in developed countries such as the United Kingdom and the United States. However, epidemiological information on EP has been lacking in recent years, so we analyzed EP data over a thirty-year period from 1990-2019 with the help of Global Burden of Disease study (GBD) data to fill this gap. METHODS: According to the EP data in GBD for the three decades from 1990 to 2019, we used estimated annual percentage changes (EAPC) to assess the trend of age-standardized incidence rate (ASIR), age-standardized death rate (ASDR) and age-standardized disability adjusted life years (AS-DALYs) trends in EP and to explore the correlation between socio-demographic index (SDI) stratification, age stratification and EP. RESULTS: Global ASIR, ASDR, AS-DALYs for EP in 2019 are 170.33/100,000 persons (95% UI: 133.18 to 218.49), 0.16/100,000 persons (95% UI, 0.14 to 0.19) and 9.69/100,000 persons (95% UI, 8.27 to 11.31), respectively. At the overall level, ASDR is significantly negatively correlated with SDI values (R = -0.699, p < 0.001). Besides that, ASDR and AS-DALYs have basically the same pattern. In addition, iron deficiency is one of the risk factors for EP. CONCLUSIONS: In the past three decades, the morbidity, mortality and disease burden of EP have gradually decreased. It is noteworthy that some economically disadvantaged areas are still experiencing an increase in all indicators, therefore, it is more important to strengthen the protection of women from ethnic minorities and low-income groups.

Microneedle systems: cell, exosome, and nucleic acid based strategies.

Cells, exosomes, and nucleic acids play crucial roles in biomedical engineering, holding substantial clinical potential. However, their utility is often hindered by various drawbacks, including cellular immunogenicity, and instability of exosomes and nucleic acids. In recent years, microneedle (MN) technology has revolutionized drug delivery by offering minimal invasiveness and remarkable versatility. MN has emerged as an ideal platform for the extraction, storage, and delivery of these biological components. This review presents a comprehensive overview of the historical progression and recent advances in the field of MN. Specifically, it highlights the current applications of cell-, exosome-, and nucleic acid-based MN systems, while presenting prevailing research challenges. Additionally, the review provides insights into the prospects of MN in this area, aiming to provide new ideas for researchers and facilitate the clinical translation of MN technology.

IL-1ß-mediated inflammatory responses in intervertebral disc degeneration: Mechanisms, signaling pathways, and therapeutic potential.

Intervertebral disc degeneration (IDD) has been widely recognized as the primary cause of low back pain and is one of the major chronic diseases imposing a severe socioeconomic burden worldwide. IDD is a degenerative process characterized by inflammatory responses, and its underlying pathological mechanisms remain complex. Genetic, developmental, biochemical, and biomechanical factors contribute to the development of IDD. There is a pressing need for an effective non-surgical treatment, mainly due to the lack of comprehensive understanding of the specific mechanisms involved and the effective therapeutic targets for IDD. Recently, interleukin (IL)-1ß has been recognized as an essential inflammatory factor and a key mediator of the inflammatory process in IDD. Current studies have found that IL-1ß is mainly involved in IDD by affecting the metabolism of the extracellular matrix and regulating cell death (RCD), such as apoptosis, pyroptosis, and ferroptosis (a new form of RCD). Although analysis of clinical samples from different laboratories confirmed how IL-1ß is induced in IDD, its specific signal transduction pathway, and the inflammatory role mediated in IDD remains unclear. This review describes the molecules and mechanisms involved in IL-1ß-mediated inflammatory responses, and their roles in resolving the inflammatory process in IDD. Understanding the signaling pathways involved in IL-1ß may lead to a new class of targets that promote remission for IDD patients. This review aims to provide a framework for the treatment of IDD by analyzing the signaling mechanism and function related to IL-1ß, especially in terms of inflammation, matrix metabolism, and cell death regulation.

The mechanisms and functions of TGF-ß1 in tendon healing.

Tendon injury accounts for 30% of musculoskeletal diseases and often leads to disability, pain, healthcare cost, and lost productivity. Following injury to tendon, tendon healing proceeds via three overlapping healing processes. However, due to the structural defects of the tendon itself, the tendon healing process is characterized by the formation of excessive fibrotic scar tissue, and injured tendons rarely return to native tendons, which can easily contribute to tendon reinjury. Moreover, the resulting fibrous scar is considered to be a precipitating factor for subsequent degenerative tendinopathy. Despite this, therapies are almost limited because underlying molecular mechanisms during tendon healing are still unknown. Transforming Growth Factor-ß1 (TGF-ß1) is known as one of most potent profibrogenic factors during tendon healing process. However, blockage TGF-ß1 fails to effectively enhance tendon healing. A detailed understanding of real abilities of TGF-ß1 involved in tendon healing can bring promising perspectives for therapeutic value that improve the tendon healing process. Thus, in this review, we describe recent efforts to identify and characterize the roles and mechanisms of TGF-ß1 involved at each stage of the tendon healing and highlight potential roles of TGF-ß1 leading to the fibrotic response to tendon injury.

From fetal tendon regeneration to adult therapeutic modalities: TGF-ß3 in scarless healing.

Tendon injuries are common disorders that can significantly impact people's lives. Unfortunately, the limited regenerative ability of tendons results in tissue healing in a scar-mediated manner. The current therapeutic strategies fail to fully recover the functions of the injured tendons, and as such, the conception of 'scarless healing' has gained prominent attention in the field of regenerative medicine. Interestingly, injured fetal tendons possess the capability to heal through regeneration, which builds an ideal blueprint for adult tendon regeneration. Studies have shown that fetal biochemical cues have the potential to improve adult tendon healing. Here we review the biological factors that contribute to fetal tendon regeneration and how manipulation of these biochemical cues in the adult tendon healing process could achieve regeneration.

We reviewed the biological factors that contribute to fetal tendon regeneration and how manipulation of these biochemical cues in the adult tendon healing process could achieve regeneration. The results showed that inflammation and TGF-ß level are the main elements involved in fetal tendon regeneration. Experimental manipulation of these biochemical cues in the adult tendon healing process demonstrated that although the blockade of TGF-ß1, TGF-ß2 and inflammation reduced scar tissue in adult tendon healing, this inhibition also destroyed the mechanical properties of the tendons. An effective alternative is regulating the specific downstream profibrotic effectors of both TGF-ß1 and inflammation, which is preferable to those that completely inhibit these factors. Finally, TGF-ß3 is a master regulator allowing a shift from adult scar healing to scarless healing, and the administration of TGF-ß3 is a viable strategy to promote adult regenerative healing. In terms of mechanisms, TGF-ß3 can activate Smad7 and inhibit the JNK/c-Jun signaling pathway to promote tendon regenerative healing.

Identification of RAC1 in promoting brain metastasis of lung adenocarcinoma using single-cell transcriptome sequencing.

This study aims to give a new perspective to the biomarkers in the lung adenocarcinoma (LUAD) brain metastasis, pathways involved and potential therapeutics. We performed a comprehensive single-cell level transcriptomic analysis on one LUAD patient with circulating tumor cells (CTCs), primary tumor tissue and metastatic tumor tissue using scRNA-seq approach to identify metastasis related biomarkers. Further scRNA-seq were performed on 7 patients to validate the cancer metastatic hallmark. with single cells collected from either metastatic or primary LUAD tissues. Pathological and functional studies were also performed to evidence the critical role of RAC1 in the LUAD metastasis. Hallmark gene was verified based on immunohistochemistry staining, cytological experiment, survival information from The Cancer Genome Atlas (TCGA), and staining results from Human Protein Atlas (HPA) databases. PCA analysis revealed that CTCs were in the intermediate place between the metastatic group and primary group. In the unsupervised clustering analysis CTCs were closer to one of the metastatic tumor cells, implying heterogeneity of the metastatic tumor and origin of the CTCs were from metastatic site. Transitional phase related gene analysis identified RAC1 was enriched in metastatic tumor tissue (MTT) preferred gene set functioning as regulated cell death and apoptosis as well as promoted macromolecule organization. Compared with normal tissue, expression levels of RAC1 increased significantly in LUAD tissue based on HPA database. High expression of RAC1 predicts worse prognosis and higher-risk. EMT analysis identified the propensity of mesenchymal state in primary cells while epithelial signals were higher in the metastatic site. Functional clustering and pathway analyses suggested genes in RAC1 highly expressed cells played critical roles in adhesion, ECM and VEGF signaling pathways. Inhibition of RAC1 attenuates the proliferation, invasiveness and migration ability of lung cancer cells. Besides, through MRI T2WI results, we proved that RAC1 can promote brain metastasis in the RAC1-overexpressed H1975 cell burden nude mouse model. RAC1 and its mechanisms might promote drug design against LUAD brain metastasis.

Simultaneous determination of twenty-nine active compounds in fuzhengjiedu granules by HPLC-QQQ-MS/MS.

As an empirical medicine of traditional Chinese medicine, Fuzhengjiedu Granules have shown an effect against COVID-19 in clinical and inflammatory animal models. It is formulated with eight herbs, including Aconiti Lateralis Radix Praeparata, Zingiberis Rhizoma, Glycyrrhizae Radix Et Rhizoma, Lonicerae Japonicae Flos, Gleditsiae Spina, Fici Radix, Pogostemonis Herba, and Citri Reticulatae Pericarpium. This study established a high-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS) method by simultaneously determining 29 active compounds in the granules with significant content differences. Separation by gradient elution using acetonitrile and water (0.1% formic acid) as mobile phases was performed on a Waters Acquilty UPLC T3 column (2.1 mm × 100 mm, 1.7 µm). A triple quadrupole mass spectrometer, operating in positive and negative ionization modes, was used for multiple reaction monitoring to detect the 29 compounds. All calibration curves showed good linear regression (r2 > 0.998). RSDs of precision, reproducibility, and stability of active compounds were all lower than 5.0%. The recovery rates were 95.4-104.9%, with RSDs< 5.0%. This method was successfully used to analyze the samples, and the results showed that 26 representative active components from 8 herbs were detected in the granules. While aconitine, mesaconitine, and hypaconitine were not detected, indicating that the existing samples were safe. The granules had the maximum and minimum content of hesperidin (27.3 ± 0.375 mg/g) and benzoylaconine (38.2 ± 0.759 ng/g). To conclude, a fast, accurate, sensitive, and reliable HPLC-QQQ-MS/MS method was established, which can simultaneously detect 29 active compounds that have a considerable difference in the content of Fuzhengjiedu Granules. This study can be used to control the quality and safety of Fuzhengjiedu Granules and provide a basis and guarantee for further experimental research and clinical application.

Long-Term Effectiveness and Safety of Natalizumab in African American and Hispanic/Latino Patients with Early Relapsing-Remitting Multiple Sclerosis: STRIVE Data Analysis.

INTRODUCTION: In STRIVE, natalizumab treatment demonstrated effectiveness in clinical, magnetic resonance imaging (MRI), and patient-reported outcomes (PROs) in patients with early relapsing-remitting multiple sclerosis (RRMS). This post hoc analysis examined the effectiveness and safety of natalizumab in patients who self-identified as either Black/African American (AA) or Hispanic/Latino. METHODS: Clinical, MRI, and PROs were assessed for the Black/AA subgroup (n = 40) and compared with the non-Hispanic White subgroup (n = 158). As a result of the very small sample size, outcomes for the Hispanic/Latino subgroup (n = 18) were assessed separately, including a sensitivity analysis with Hispanic/Latino patients who completed the 4-year study on natalizumab. RESULTS: Clinical, MRI, and PROs were comparable between the Black/AA and non-Hispanic White subgroups except for MRI outcomes at year 1. A higher proportion of non-Hispanic White than Black/AA patients achieved MRI no evidence of disease activity (NEDA; 75.4% vs. 50.0%, p = 0.0121) and no new or newly enlarging T2 lesions (77.6% vs. 50.0%, p = 0.0031) at year 1; these differences were not observed in years 2-4 of the study. For the Hispanic/Latino subgroup in the intent-to-treat population, 46.2% and 55.6% achieved NEDA at years 1 and 2; 66.7% and 90.0% achieved clinical NEDA at years 3 and 4. Annualized relapse rate was reduced by 93.0% at year 1 versus the year before natalizumab initiation; this reduction was maintained throughout the study. Over 4 years, 37.5-50.0% of patients had a clinically meaningful improvement in their Symbol Digit Modalities Test score, and 81.8-100.0% and 90.9-100.0% had stable/improved Multiple Sclerosis Impact Scale-29 physical and psychological scores, respectively. Similar results were observed in the sensitivity analysis with Hispanic/Latino subgroup of the 4-year natalizumab completers. CONCLUSION: These results highlight the effectiveness and safety of natalizumab in patients with early RRMS who self-identified as Black/AA or Hispanic/Latino. CLINICALTRIALS: GOV: NCT01485003.

Ground glass opacity resection extent assessment trial (GREAT): A study protocol of multi-institutional, prospective, open-label, randomized phase III trial of minimally invasive segmentectomy versus lobectomy for ground glass opacity (GGO)-containing early-stage invasive lung adenocarcinoma.

Background: With widely use of computed tomography (CT) screening, an increasing number of early-stage lung cancers appearing as ground glass opacity (GGO) have been detected. Therefore, attempts have been made to investigate the feasibility of segmentectomy instead of lobectomy for those patients with GGO. However, the two recently released phase III trials failed to distinguish between GGO-containing lesions from pure solid nodules in the inclusion criteria, and the surgical methods did not distinguish between minimally invasive surgery and open thoracotomy. In addition, total lesion size≤ 2cm was taken as the inclusion criterion, instead of the solid part size recommended in the eighth edition of Union for International Cancer Control/International Association for the Study of Lung Cancer/American Joint Committee on Cancer (UICC/IASLC/AJCC) staging system. Hence, this present trial aims to figure out whether minimally invasive segmentectomy shows superiority in perioperative outcomes and non-inferiority in oncological prognosis over minimally invasive lobectomy among patients with GGO-containing clinical stage T1a-T1b lung invasive adenocarcinoma (IADC). Methods/design: Sample sizes are 1024 patients, who will be randomized into minimally invasive segmentectomy and lobectomy groups . Patients will be collected from 19 hospitals in China. Patients with peripheral mixed ground glass opacity (mGGO) with 0.5cm

Immunomodulatory properties of mesenchymal stromal/stem cells: The link with metabolism.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) are the most promising stem cells for the treatment of multiple inflammatory and immune diseases due to their easy acquisition and potent immuno-regulatory capacities. These immune functions mainly depend on the MSC secretion of soluble factors. Recent studies have shown that the metabolism of MSCs plays critical roles in immunomodulation, which not only provides energy and building blocks for macromolecule synthesis but is also involved in the signaling pathway regulation. AIM OF REVIEW: A thorough understanding of metabolic regulation in MSC immunomodulatory properties can provide new sights to the enhancement of MSC-based therapy. KEY SCIENTIFIC CONCEPTS OF REVIEW: MSC immune regulation can be affected by cellular metabolism (glucose, adenosine triphosphate, lipid and amino acid metabolism), which further mediates MSC therapy efficiency in inflammatory and immune diseases. The enhancement of glycolysis of MSCs, such as signaling molecule activation, inflammatory cytokines priming, or environmental control can promote MSC immune functions and therapeutic potential. Besides glucose metabolism, inflammatory stimuli also alter the lipid molecular profile of MSCs, but the direct link with immunomodulatory properties remains to be further explored. Arginine metabolism, glutamine-glutamate metabolism and tryptophan-kynurenine via indoleamine 2,3-dioxygenase (IDO) metabolism all contribute to the immune regulation of MSCs. In addition to the metabolism dictating the MSC immune functions, MSCs also influence the metabolism of immune cells and thus determine their behaviors. However, more direct evidence of the metabolism in MSC immune abilities as well as the underlying mechanism requires to be uncovered.

The role of the canonical nf-κb signaling pathway in the development of acute liver failure.

As a clinical emergency with a high mortality rate, the treatment of acute liver failure has been paid attention to by society. At present, liver transplantation is the most effective treatment for acute liver failure, but there is still an insufficient supply of liver sources and a poor prognosis. In view of the current therapeutic development of this disease, more researchers have turned their attention to the research of drugs related to the NF-κB pathway. The NF-κB canonical pathway has been proven to play a role in a variety of diseases, regulating inflammation, apoptosis, and other physiological processes. More and more evidence shows that the NF-κB canonical pathway regulates the pathogenesis of acute liver failure. In this review, we will summarize the regulation process of the NF-κB canonical pathway on acute liver failure, and develop a new way to treat acute liver failure by targeting the components of the pathway.

Targeted Wolfram-Doped Polypyrrole for Photonic Hyperthermia-Synergized Radiotherapy.

Single ionizing radiation at a tolerable dose is ineffectual in eliminating malignancies but readily generates harmful effects on surrounding normal tissues. Herein, we intelligently fabricated novel wolfram-doped polypyrrole (WPPy) through a simple oxidative polymerization method with WCl6 as an oxidizing catalyst, which possessed good biocompatibility, high photothermal conversion, and intensive radiosensitivity capacities to concurrently serve as a photothermal reagent and a radiosensitizer for hyperthermia-synergized radiotherapy (RT) against a malignant tumor. In comparison with traditional polypyrrole without noble metal doping, the innovative introduction of WCl6 not only successfully launched the polymerization of a pyrrole monomer but also endowed WPPy with additional radiosensitization. More importantly, after further decoration with an active targeted component (SP94 polypeptide), the obtained WPPy@SP94 significantly increased tumor internalization and accumulation in vitro and in vivo and induced obvious DNA damage as well as robust ROS generation under X-ray irradiation, which meanwhile synergized with strong photonic hyperthermia to effectively inhibit tumor growth by single drug injection. Moreover, such biocompatible WPPy@SP94 showed negligible adverse effects on normal cells and tissues. WPPy@SP94 developed in this study not only expands the category of polypyrrole chemical syntheses but also sheds light on WPPy@SP94-based radiosensitizers for cancer RT.

Indoleamine 2,3-dioxygenase mediates the therapeutic effects of adipose-derived stromal/stem cells in experimental periodontitis by modulating macrophages through the kynurenine-AhR-NRF2 pathway.

OBJECTIVES: Mesenchymal stromal/stem cell (MSC)-based therapy has become a promising approach to periodontal tissue repair. Adipose-derived stromal/stem cells (ASCs), compared with other dental or non-dental MSCs, serve as promising candidates for MSC therapy due to non-invasive acquisition and abundant sources. This study aimed to explore the effects of ASC therapy in experimental periodontitis and the underlying mechanism. METHODS: Micro-CT was performed to evaluate the alveolar bone parameters following local injection of ASCs. Immunohistochemistry and immunofluorescence were employed to detect the expression of IL-1ß, osteocalcin (OCN), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and surface markers of macrophage polarization. Afterward, multiple reaction monitoring (MRM)-based targeted tryptophan metabolomic analysis was used to examine the ASC metabolites. Chromatin immunoprecipitation (ChIP)-qPCR assay was performed to investigate the direct binding of aryl hydrocarbon receptor (AhR) and NRF2. RESULTS: Alveolar bone loss was reduced, and the ratio of iNOS+/CD206+ macrophages was significantly decreased after ASC injection in the rat models of periodontitis. ASCs promoted NRF2 expression and activation in macrophages, while NRF2 silencing in macrophages blocked the regulation of ASCs on macrophages. Furthermore, the expression of indoleamine 2,3-dioxygenase (IDO) of ASCs in the inflammatory condition was high. The inhibitor of IDO, 1-methyltryptophan (1-MT), impaired the therapeutic effects of ASCs in experimental periodontitis and regulation of macrophage polarization. Mechanistically, kynurenine (Kyn), a metabolite of ASCs catalyzed by IDO, activated AhR and enhanced its binding to the promoter of NRF2, which stimulated M2 macrophage polarization. CONCLUSIONS: These findings suggested that ASCs can alleviate ligature-induced periodontitis through modulating macrophage polarization by the IDO-dependent Kyn-AhR-NRF2 pathway, uncovering a novel mechanism and providing a scientific basis for ASC-based therapy in experimental periodontitis.