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Mesenchymal stem cells (MSCs) are adult stromal cells with the capacity to differentiate into multiple types of cells. MSCs represent an attractive option in regenerative medicine due to their multifaceted abilities for tissue repair, immunosuppression, and anti-inflammation. Recent studies demonstrate that MSCs exert their effects via paracrine activity, which is at least partially mediated by extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) could mimic the function of parental MSCs by transferring their components such as DNA, proteins/peptides, mRNA, microRNA (miRNA), lipids, and organelles to recipient cells. In this review, we aim to summarize the mechanism and role of miRNA transfer in mediating the effects of MSC-EVs in the models of human diseases. The first three sections of the review discuss the sorting of miRNAs into EVs, uptake of EVs by target cells, and functional transfer of miRNAs via EVs. Then, we describe the composition of miRNAs in MSC-EVs. Next, we provide the existing evidence that MSC-EVs affect the outcomes of renal, liver, heart, and brain diseases by transferring their miRNA contents. In conclusion, EV-mediated miRNA transfer plays an important role in disease-modulating capacity of MSCs.

Extracellular vesicles (EVs) contain proteins, microRNAs, mRNAs, long non-coding RNAs, and phospholipids, and are a novel mechanism of intercellular communication. It has been proposed that the immunomodulatory and regenerative effects of mesenchymal stem/stromal cells (MSCs) are mainly mediated by soluble paracrine factors and MSC-derived EVs (MSC-EVs). Recent studies suggest that MSC-EVs may serve as a novel and cell-free alternative to whole-cell therapies. The focus of this review is to discuss the functional proteins which facilitate the effects of MSC-EVs. The first section of the review discusses the general functions of EV proteins. Next, we describe the proteomics of MSC-EVs as compared with their parental cells. Then, the review presents the current knowledge that protein contents of MSC-EVs play an essential role in immunomodulation and treatment of various diseases. In summary, functional protein components are at least partially responsible for disease-modulating capacity of MSC-EVs.

Background Identifying the past and future burden of kidney cancer (KC) and its temporal trends among older adults (≥ 65 years) at global, regional, and national levels is critical for effective prevention strategies. Methods The age-standardized incidence, prevalence, mortality, and disability-adjusted life years (DALYs) were calculated using data from the Global Burden of Disease (GBD) study from 1990 to 2021. These indicators were stratified by sex, age, and socio-demographic index (SDI). The correlation between these indicators and SDI was assessed. Temporal trends were quantified using the annual average percentage change (AAPC), and future trends from 2022 to 2040 were predicted using the Bayesian age-period-cohort (BAPC) model. Results The global age-standardized incidence rate (ASIR) of KC among older adults increased from 21.73 per 100,000 people in 1990 to 26.74 per 100,000 people in 2021, with an AAPC of 0.67%. Age-standardized DALYs rate (ASDR) remained stable, while significant increases were observed in age-standardized prevalence (AAPC = 1.24%, 95%CI: 1.14–1.34%) and mortality rate (AAPC = 0.13%, 95%CI: 0.05–0.22%). From 1990 to 2021, males consistently exhibited a higher disease burden than females, additionally, the ASIR of KC increased significantly in all age subgroups. Regions with higher SDI levels also showed a greater disease burden, while Oceania had the lowest burden of KC in 2021. The ASIR increased in almost all countries and territories. Czechia showed the highest ASIR (92.25 per 100,000 people) and ASDR (819.88 per 100,000 people). Smoking and high body mass index (BMI) remained significant risk factors for DALYs and mortality in the older population, and their effects were greatest in high SDI region. Furthermore, the burden of KC is expected to continue to decline through 2040. Conclusions The global burden of KC among older adults increased from 1990 to 2021, with notable regional and national variations. However, it is projected to continue to decline through 2040. The management of smoking and high BMI remain major challenges for people with KC, necessitating targeted clinical guidelines, particularly focusing on males and the older adults.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus to cause acute respiratory distress syndrome (ARDS) and contains four structural proteins: spike, envelope, membrane, and nucleocapsid. An increasing number of studies have demonstrated that all four structural proteins of SARS-CoV-2 are capable of causing lung injury, even without the presence of intact virus. Therefore, the topic of SARS-CoV-2 structural protein-evoked lung injury warrants more attention. In the current article, we first synopsize the structural features of SARS-CoV-2 structural proteins. Second, we discuss the mechanisms for structural protein-induced inflammatory responses in vitro . Finally, we list the findings that indicate structural proteins themselves are toxic and sufficient to induce lung injury in vivo . Recognizing mechanisms of lung injury triggered by SARS-CoV-2 structural proteins may facilitate the development of targeted modalities in treating COVID-19.

Background Traditional Chinese medicine (TCM) is an important source of bioactive compounds, hence enjoying a wide application in clinical treatment, while its pharmacodynamic material basis remains difficult to elucidate as it has a complex chemical composition. Piper longum L is a commonly used herbal medicine in prescriptions for chronic kidney disease (CKD), yet its key active ingredients responsible for anti-renal fibrosis effects remain unclear. This study aimed to establish a novel and efficient strategy for the screening and identification of anti-fibrotic compounds from Piper longum L. Methods HK-2 cells with fibrotic features induced by transforming growth factor-β (TGF-β) were used to develop a hollow fiber cell fishing coupled with high-performance liquid chromatography (HFCF-HPLC) mode. This model was integrated with network pharmacology and molecular biology techniques to screen and validate active anti-fibrotic compounds in Piper longum L. The in vivo efficacy of the identified compounds was further evaluated by a unilateral ischemia–reperfusion injury (uIRI) model with delayed contralateral nephrectomy in C57BL/6 J mice. Serum creatinine (SCr) and blood urea nitrogen (BUN) levels were taken into account to assess the renal function, while immunohistochemistry and western blot served for analyzing the fibrosis markers α-SMA and collagen-I. Results HFCF-HPLC screening identified two key active compounds from Piper longum L: piperlongumine (PIPA) and piperlonguminine (PLG). Among them, PIPA exhibited the strongest inhibitory effect on the expression of fibrosis markers in vitro. In vivo studies demonstrated that PIPA significantly reduced renal fibrosis in the uIRI model, as indicated by lower SCr and BUN levels, improved renal histopathology, and reduced extracellular matrix deposition. Conclusions A novel HFCF-HPLC model was successfully established to screen active compounds from TCM against renal fibrosis. PIPA was identified as a promising anti-fibrotic agent from Piper longum L, demonstrating significant renoprotective effects in in vitro and in vivo models. This work advances the modernization of herbal medicine research by offering a integrated strategy for identifying bioactive TCM components.

Background Macrophages have heterogeneous phenotypes and complex functions within both innate and adaptive immune responses. To date, most experimental studies have been performed on macrophages derived from bone marrow, spleen and peritoneum. However, differences among macrophages from these particular sources remain unclear. In this study, the features of murine macrophages from bone marrow, spleen and peritoneum were compared. Results We found that peritoneal macrophages (PMs) appear to be more mature than bone marrow derived macrophages (BMs) and splenic macrophages (SPMs) based on their morphology and surface molecular characteristics. BMs showed the strongest capacity for both proliferation and phagocytosis among the three populations of macrophage. Under resting conditions, SPMs maintained high levels of pro-inflammatory cytokines expression (IL-6, IL-12 and TNF-α), whereas BMs produced high levels of suppressive cytokines (IL-10 and TGF-β). However, SPMs activated with LPS not only maintained higher levels of (IL-6, IL-12 and TNF-α) than BMs or PMs, but also maintained higher levels of IL-10 and TGF-β. Conclusions Our results show that BMs, SPMs and PMs are distinct populations with different biological functions, providing clues to guide their further experimental or therapeutic use.

Mitochondria-associated membranes (MAMs), the specialized contact regions linking the endoplasmic reticulum (ER) and mitochondria, have emerged as dynamic communication hubs critical for preserving cellular homeostasis. These structures are crucial for controlling a range of essential cellular processes, such as calcium (Ca 2+ ) signaling, lipid metabolism, autophagy, apoptosis, and inflammatory response. Increasing evidence connects MAM dysfunction to various inflammatory conditions, such as metabolic disorders, neurodegenerative diseases, and antiviral response. In the context of acute lung injury, altered ER–mitochondria interactions can result in mitochondria Ca 2+ overload, heightened oxidative stress, and augmented inflammatory response. Together, these pathological processes enhance endothelial permeability and exacerbate pulmonary inflammation. This review highlights the structural and functional attributes of MAMs, the mechanisms underlying MAM-mediated inflammation, and the roles of MAMs in metabolic, neurological, and antiviral inflammation. It also delves into the role of MAMs in acute lung injury, unveiling fresh insights that may pave the way for innovative therapies targeting ER–mitochondria crosstalk.

Background: TGF-β1 is a key cytokine involved in both airway inflammation and airway remodeling in asthma because of its anti-inflammatory and profibrotic effect. In our previous study, we found that knockdown of cytosolic β-catenin alleviated the profibrogenic effect of TGF-β1 without influencing its anti-inflammatory effect. However, the exact role of targeting β-catenin in asthma is not yet fully demonstrated. In the present study, we investigated the effect and mechanism of targeting β-catenin in OVA-challenged asthmatic rats with airway inflammation and remodeling features. Methods: We integrated experimental asthma model and asthma related cell model to explore the effect of targeting β-catenin on airway inflammation and remodeling of asthma. Results: Blocking β-catenin with ICG001, a small molecule inhibitor of β-catenin/TCF via binding to cAMP-response elementbinding protein, attenuated airway inflammation by increasing levels of anti-inflammation cytokines IL-10, IL-35 and decreasing levels of T helper (Th)2 cells and Th17 cytokine. Suppressing β-catenin by ICG001 inhibited airway remodeling via reducing the level of TGF-β1 and the expressions of Snail, MMP-7, MMP-9 and, up-regulating expression of E-cadherin, down-regulating expressions of α-SMA and Fn. Inhibition of β-catenin with ICG001 suppressed TGF-β1 induced proliferation and activation of CCC-REPF-1, blocked TGF-β1 induced epithelial–mesenchymal transition (EMT) of RLE-6TN. Conclusion: Blockade of β-catenin/TCF not only prevents TGF-β1 induced EMT and profibrogenic effects involved in pathological remodeling of airway, but also alleviates airway inflammation in asthma by balancing pro-inflammatory and anti-inflammatory cytokine. In conclusion, targeting β-catenin specifically via inhibition of β-catenin/TCF might be a new therapeutic strategy for asthma. The reviews of this paper are available via the supplemental material section.

Background Sepsis is a common indirect insult leading to acute respiratory distress syndrome (ARDS). Circulating extracellular vesicles (EVs) have been reported to participate in the pathogenesis of sepsis. However, the alteration of EV-bound S100A8/A9 during septic shock, along with the role of S100A8/A9 in driving acute lung injury, remains unexplored. Methods EVs were isolated from the plasma of patients upon admission with sepsis or septic shock, as well as from healthy controls. Levels of EV S100A8/A9 were assayed via ELISA. To examine the effects and underlying mechanisms of septic shock EVs in acute lung injury, these EVs were administered intratracheally into wild-type C57BL/6 mice or mice with a deficiency of advanced glycation end-products (RAGE). In addition, a mouse model of polymicrobial sepsis was introduced using cecal ligation and puncture (CLP). Results Levels of EV S100A8/A9 were significantly elevated in patients with sepsis or septic shock compared to healthy controls. Receiver operating characteristic (ROC) analysis demonstrated that EV S100A8/A9 effectively distinguished between septic shock and sepsis and had predictive potential for the development of ARDS. Notably, the levels of S100A8/A9 in EVs and alveolar macrophages from CLP mice were significantly higher than those in sham mice. Intratracheal administration of septic shock EVs directly induced acute lung injury and M1 macrophage polarization in a lipopolysaccharide-independent manner. Septic shock EVs were efficiently taken up by alveolar macrophages in vivo, leading to a significant increase in S100A8/A9 levels, which was inhibited by preincubating the EVs with an S100A8/A9 neutralizing antibody. Additionally, mice with deficiency in RAGE, a receptor for S100A8/A9, were partially protected from acute lung injury induced by septic shock EVs. In vitro, septic shock EVs prompted a proinflammatory response in bone marrow-derived macrophages. This response was blocked by preincubating the EVs with the S100A8/A9 neutralizing antibody. Conclusions Our results suggested that EV S100A8/A9 has potential value in distinguishing septic shock from sepsis and predicting the development of ARDS. Septic shock EVs-induced lung injury is at least partially mediated through S100A8/A9-RAGE pathway, involving the activation of alveolar macrophages.

Our study aimed at assessing the impact of β-blocker treatment on the mortality of patients with sepsis-associated acute kidney injury (SA-AKI). Clinical data for patients with SA-AKI were collected from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Baseline characteristics between β-blocker users and non-users were adjusted through propensity score matching (PSM). Kaplan-Meier curves and the Cox proportional hazards model were employed to analyze the relationship between β-blocker use and mortality, with the primary outcome being 30-day mortality. This study included data from 8,620 patients, with 3,159 receiving treatment and 5,461 not. After PSM, 2,896 matched pairs were created. The analysis revealed that 30-day (hazard ratio [HR]: 0.58, 95% CI: 0.52-0.65;  < 0.001), 90-day (HR: 0.55, 95% CI: 0.50-0.61;  < 0.001), and 365-day mortality (HR: 0.59, 95% CI: 0.54-0.64;  < 0.001) were significantly reduced in β-blocker users. Treatment with long-acting β-blockers was linked to notable improvement in 30-day (17.0 29.2%;  < 0.001), 90-day (24.1 36.0%;  < 0.001), and 365-day survival (31.9 45.0%;  < 0.001). In contrast, short-acting β-blockers showed no significant effect on 30-day (33.8 28.3%;  = 0.08), 90-day (37.5 34.2%;  = 0.07), or 365-day mortality (46.3 38.8%;  = 0.14). β-blocker therapy was associated with reduced mortality rates at 30, 90, and 365 days in SA-AKI patients. Long-acting β-blockers have demonstrated significant protective effects, while short-acting β-blockers, like esmolol, failed to improve patient survival in SA-AKI.