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Silver nanoparticles (AgNPs) have been one of the most attractive nanomaterials in biomedicine due to their unique physicochemical properties. In this paper, we review the state-of-the-art advances of AgNPs in the synthesis methods, medical applications and biosafety of AgNPs. The synthesis methods of AgNPs include physical, chemical and biological routes. AgNPs are mainly used for antimicrobial and anticancer therapy, and also applied in the promotion of wound repair and bone healing, or as the vaccine adjuvant, anti-diabetic agent and biosensors. This review also summarizes the biological action mechanisms of AgNPs, which mainly involve the release of silver ions (Ag+), generation of reactive oxygen species (ROS), destruction of membrane structure. Despite these therapeutic benefits, their biological safety problems such as potential toxicity on cells, tissue, and organs should be paid enough attention. Besides, we briefly introduce a new type of Ag particles smaller than AgNPs, silver Ångstrom (Å, 1 Å = 0.1 nm) particles (AgÅPs), which exhibit better biological activity and lower toxicity compared with AgNPs. Finally, we conclude the current challenges and point out the future development direction of AgNPs.

Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called “calcification paradox”. Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861. This study uncovers the role of extracellular vesicles from bone matrix as a messenger in the development of osteoporosis and vascular calcification (calcification paradox) during skeletal aging and menopause by transferring miR-483-5p and miR-2861.

Prostate cancer (PCa) is one of the most common malignancies in males. Despite the success of immunotherapy in many malignant cancers, strategies are still needed to improve therapeutic efficacy in PCa. This study aimed to investigate the effects of -derived extracellular vesicles ( -EVs) on PCa and elucidate the underlying immune-related mechanism. -EVs were isolated by ultracentrifugation and intravenously injected to treat syngeneic PCa-bearing immune-competent mice. Immunophenotypic changes in immune cells, such as cytotoxic T lymphocytes and macrophages, were measured via flow cytometry analysis. Histological examination was used to detect morphological changes in major organs after -EVs treatments. In vitro, flow cytometry was performed to confirm the effects of -EVs on the activation of CD8 T cells. Quantitative PCR and immunofluorescence staining were carried out to test the impact of -EVs on macrophage polarization. Cell counting kit-8 (CCK-8) analysis, colony formation assays, and scratch wound healing assays were conducted to assess the effects of -EVs-treated macrophages on the proliferation and invasion of PCa cells. CCK-8 assays also confirmed the impact of -EVs on the viability of normal cells. Intravenous injection of -EVs in immune-competent mice reduced the tumor burden of PCa without inducing obvious toxicity in normal tissues. This treatment elevated the proportion of granzyme B-positive (GZMB ) and interferon γ-positive (IFN-γ ) lymphocytes in CD8 T cells and caused macrophage recruitment, with increased tumor-killing M1 macrophages and decreased immunosuppressive M2 macrophages. In vitro, -EVs increased the number of GZMB CD8 and IFN-γ CD8 T cells and M1-like macrophages. In addition, conditioned medium from -EVs-treated macrophages suppressed the proliferation and invasion of prostate cells. Furthermore, the effective dose of -EVs was well-tolerated in normal cells. Our study revealed the promising prospects of -EVs as an efficient and biocompatible immunotherapeutic agent for PCa treatment.

Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ). The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2 ) and activated microglia (CD68 IBA1 ) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes ( ) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined. MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 ( ) and Optineurin ( ), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage. Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.

Although machine learning (ML) algorithms have been applied to point-of-care sepsis prognostication, ML has not been used to predict sepsis mortality in an administrative database. Therefore, we examined the performance of common ML algorithms in predicting sepsis mortality in adult patients with sepsis and compared it with that of the conventional context knowledge-based logistic regression approach. The aim of this study is to examine the performance of common ML algorithms in predicting sepsis mortality in adult patients with sepsis and compare it with that of the conventional context knowledge-based logistic regression approach. We examined inpatient admissions for sepsis in the US National Inpatient Sample using hospitalizations in 2010-2013 as the training data set. We developed four ML models to predict in-hospital mortality: logistic regression with least absolute shrinkage and selection operator regularization, random forest, gradient-boosted decision tree, and deep neural network. To estimate their performance, we compared our models with the Super Learner model. Using hospitalizations in 2014 as the testing data set, we examined the models' area under the receiver operating characteristic curve (AUC), confusion matrix results, and net reclassification improvement. Hospitalizations of 923,759 adults were included in the analysis. Compared with the reference logistic regression (AUC: 0.786, 95% CI 0.783-0.788), all ML models showed superior discriminative ability (P<.001), including logistic regression with least absolute shrinkage and selection operator regularization (AUC: 0.878, 95% CI 0.876-0.879), random forest (AUC: 0.878, 95% CI 0.877-0.880), xgboost (AUC: 0.888, 95% CI 0.886-0.889), and neural network (AUC: 0.893, 95% CI 0.891-0.895). All 4 ML models showed higher sensitivity, specificity, positive predictive value, and negative predictive value compared with the reference logistic regression model (P<.001). We obtained similar results from the Super Learner model (AUC: 0.883, 95% CI 0.881-0.885). ML approaches can improve sensitivity, specificity, positive predictive value, negative predictive value, discrimination, and calibration in predicting in-hospital mortality in patients hospitalized with sepsis in the United States. These models need further validation and could be applied to develop more accurate models to compare risk-standardized mortality rates across hospitals and geographic regions, paving the way for research and policy initiatives studying disparities in sepsis care.

Recently, the gut microbiota (GM) has been shown to be a regulator of bone homeostasis and the mechanisms by which GM modulates bone mass are still being investigated. Here, it is found that colonization with GM from children (CGM) but not from the elderly (EGM) prevents decreases in bone mass and bone strength in conventionally raised, ovariectomy (OVX)‐induced osteoporotic mice. 16S rRNA gene sequencing reveals that CGM reverses the OVX‐induced reduction of Akkermansia muciniphila (Akk). Direct replenishment of Akk is sufficient to correct the OVX‐induced imbalanced bone metabolism and protect against osteoporosis. Mechanistic studies show that the secretion of extracellular vesicles (EVs) is required for the CGM‐ and Akk‐induced bone protective effects and these nanovesicles can enter and accumulate into bone tissues to attenuate the OVX‐induced osteoporotic phenotypes by augmenting osteogenic activity and inhibiting osteoclast formation. The study identifies that gut bacterium Akk mediates the CGM‐induced anti‐osteoporotic effects and presents a novel mechanism underlying the exchange of signals between GM and host bone. Colonization with gut microbiota from children (CGM) but not from the elderly (EGM) reverses the ovariectomy (OVX)‐induced reduction of Akkermansia muciniphila (Akk) and prevents OVX‐induced osteoporosis. Direct replenishment of Akk also induces bone benefits in OVX mice. Extracellular vesicles from CGM and Akk can enter into bone to directly attenuate the OVX‐induced osteoporotic phenotypes by augmenting osteogenesis and inhibiting osteoclastogenesis.

Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout (omentin-1−/−) mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-α (TNF-α), we determined that recombinant omentin-1 reduces the production of pro-inflammatory factors in the TNF-α-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate-induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the pro-inflammatory cytokines.

Microsatellite stable (MSS) gastric cancer (GC) responds poorly to immunotherapy and exhibits heterogeneous outcomes. Histone lactylation plays a critical role in cancer progression. However, the prognostic and therapeutic potential of a lactylation-related gene signature (LRGS) in MSS GC remains largely unexplored. Data of MSS GC patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Consensus clustering based on lactylation-related gene expression profiles was performed to stratify patients. We further constructed the LRGS using machine learning algorithms. We also assessed its correlations with clinicopathological parameters, the tumor microenvironment, and chemosensitivity. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was employed to predict potential responses to immunotherapy. Single-cell analysis, cell-cell communication analysis, in silico knockout, and immunohistochemical validation were integrated to explore the functional roles of key genes. Consensus clustering uncovered two clusters with significantly different overall survival outcomes. A nine-gene LRGS was established and effectively stratified patients into high- and low-risk groups. The high-risk group displayed an immunosuppressive microenvironment, reduced chemosensitivity, and higher TIDE scores. Single-cell analysis revealed that LRGS scores were highest in cancer-associated fibroblasts (CAFs), with and highly expressed in PDGFRA+ CAFs and CA9+ CAFs, respectively. Cell-cell communication analysis showed that these two CAF subtypes exhibited distinct signaling patterns via the COLLAGEN and MIF pathways. In silico knockout further validated that and are essential for matrix remodeling and hypoxia adaptation in their respective CAF subtypes. Immunohistochemical analysis confirmed elevated protein levels of and in MSS GC. This study developed and validated a robust LRGS for MSS GC. This signature facilitates accurate prognosis prediction and shows potential to predict responses to both chemotherapy and immunotherapy.

A differentiation switch of bone marrow mesenchymal stem/stromal cells (BMSCs) from osteoblasts to adipocytes contributes to age‐ and menopause‐associated bone loss and marrow adiposity. Here it is found that osteocytes, the most abundant bone cells, promote adipogenesis and inhibit osteogenesis of BMSCs by secreting neuropeptide Y (NPY), whose expression increases with aging and osteoporosis. Deletion of NPY in osteocytes generates a high bone mass phenotype, and attenuates aging‐ and ovariectomy (OVX)‐induced bone‐fat imbalance in mice. Osteocyte NPY production is under the control of autonomic nervous system (ANS) and osteocyte NPY deletion blocks the ANS‐induced regulation of BMSC fate and bone‐fat balance. γ‐Oryzanol, a clinically used ANS regulator, significantly increases bone formation and reverses aging‐ and OVX‐induced osteocyte NPY overproduction and marrow adiposity in control mice, but not in mice lacking osteocyte NPY. The study suggests a new mode of neuronal control of bone metabolism through the ANS‐induced regulation of osteocyte NPY. Normally, norepinephrine (NE) and acetylcholine (ACh) production is maintained at a balanced level in bone, so that osteocytes cannot generate excessive neuropeptide Y (NPY) to favor bone marrow mesenchymal stem/stromal cell adipogenesis rather than osteogenesis. With aging/estrogen deficiency, sympathetic overactivity, and decreased parasympathetic activity cause NE overproduction and ACh reduction, resulting in excess osteocyte NPY generation and subsequent bone‐fat imbalance.

Background Renal erythropoietin (EPO)-producing (REP) cells produce EPO through hypoxia-inducible factor (HIF) 2α-activated gene transcription. Insufficient EPO production leads to anemia in patients with chronic kidney disease. Although recombinant EPO is effective to improve anemia, no reliable REP cell lines limit further progress of research and development of novel treatment. Methods We screened Epo mRNA expression in mouse fibroblast cell lines. Small interfering RNA specific for HIF1α or HIF2α was transfected to study Epo expression in C3H10T1/2 cells. The effect of transforming growth factor-β1 (TGF-β1) on HIF-EPO axis was studied in C3H10T1/2 cells and mice. Results Similar to mouse REP pericytes, C3H10T1/2 cells differentiated to α-smooth muscle actin + myofibroblasts after exposure to TGF-β1. Specific HIF knockdown demonstrated the role of HIF2α in hypoxia-induced Epo expression. Sustained TGF-β1 exposure increased neither DNA methyltransferase nor methylation of Epas1 and Epo genes. However, TGF-β1 repressed HIF2α-encoding Epas1 promptly through activating activin receptor-like kinase-5 (ALK5), thereby decreasing Epo induction by hypoxia and prolyl hydroxylase domain inhibitor roxadustat. In mice with pro-fibrotic injury induced by ureteral obstruction, upregulation of Tgfb1 was accompanied with downregulation of Epas1 and Epo in injured kidneys and myofibroblasts, which were reversed by ALK5 inhibitor SB431542. Conclusion C3H10T1/2 cells possessed the property of HIF2α-dependent Epo expression in REP pericytes. TGF-β1 induced not only the transition to myofibroblasts but also a repressive effect on Epas1 - Epo axis in C3H10T1/2 cells. The repressive effect of TGF-β1 on Epas1 - Epo axis was confirmed in REP pericytes in vivo. Inhibition of TGF-β1-ALK5 signaling might provide a novel treatment to rescue EPO expression in REP pericytes of injured kidney.