Macrophage Polarization Research Articles

Cigarette smoke-induced exosomal miR-221-3p facilitates M1 macrophage polarization via the STAT3 pathway in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is marked by irreversible airflow limitations stemming from small airway constriction and lung emphysema. The advancement of COPD is greatly influenced by the M1 polarization of macrophages. The mechanisms governing macrophage polarization in inflammation conditions in COPD are not yet fully understood. To investigate the interplay between exosomes triggered by cigarette smoke and the polarization of macrophages, we utilized a combination of flow cytometry, quantitative real-time reverse transcription PCR, and western blot analysis. Our research reveals that cigarette smoke (CS) exposure induces the secretion of exosomes from human bronchial epithelial cells, with exosomal miR-221-3p identified as a key player in modulating the polarization of M1 macrophages. The evidence indicates that cigarette smoke promotes exosome secretion in these cells, with exosomal miR-221-3p targeting SOCS3 and regulating the STAT3 signaling pathway to facilitate M1 macrophage polarization. This research delves into the molecular pathways through which miR-221-3p facilitates the polarization of M1 macrophages, presenting a groundbreaking approach for potential targeted therapy in COPD.

B10 cells regulate macrophage polarization to alleviate inflammation and bone loss in periodontitis.

The polarization of macrophages into an anti-inflammatory phenotype is crucial for resolving periodontal inflammation. It has been reported that B10 cells can regulate the immune response of macrophages during inflammation and are also able to regulate inflammation in periodontitis. However, whether B10 cells' regulation function in periodontitis is related to macrophage polarization remains unclear. This study aims to investigate whether B10 cells can regulate macrophage polarization in periodontitis. Macrophages were cocultured with B10 cells in vitro for 5days. After coculture, macrophages were obtained for analysis directly or followed by stimulation with Pg-LPS/IFN-γ or IL-4/IL-13. Flow cytometry and/or reverse transcriptase-polymerase chain reaction (RT-PCR) were employed to detect the expression of IL-1β, iNOS, TNF-α, CD206, and ARG-1 in macrophages. B10 cells were transferred on the 5th day after ligation in wild or macrophage-depletion mice. Toluidine blue and TRAP staining were used to evaluate alveolar bone resorption and osteoclast activation. Immunohistochemistry was employed to detect the expression of CD68, IL-1β, TNF-α, iNOS, ARG-1, and IL-10. Immunofluorescence was used to detect the expression of CD68+CD86+M1 macrophages and CD68+CD206+M2 macrophages. In vitro, B10 cells inhibit the expression of IL-1β, iNOS, and TNF-α in macrophages while increasing the expression of CD206 and ARG-1. In experimental periodontitis, B10 cells inhibit the polarization of CD68+CD86+M1 macrophages and iNOS expression but enhance the polarization of CD68+CD206+M2 macrophages and ARG-1 expression. Importantly, the depletion of macrophages partially weakened the regulation function of B10 cells in periodontitis. B10 cells promote M2 macrophage polarization, inhibit M1 macrophage polarization in periodontitis, and alleviate periodontitis partially by regulating macrophage polarization.

Novel insights into vancomycin-loaded calcium sulfate and negative pressure wound therapy in preventing infections in open fractures

BackgroundOpen fractures are challenging due to susceptibility to Staphylococcus aureus infections. This study examines the impact of Vancomycin-Loaded Calcium Sulfate (VLCS) and negative pressure wound therapy (NPWT) on macrophage behavior in enhancing healing and infection resistance. Both VLCS and NPWT were evaluated individually and in combination to determine their effects on macrophage polarization and infection resistance in open fractures.MethodsThrough single-cell RNA sequencing, genomic expressions in macrophages from open fracture patients treated with VLCS and NPWT were compared to a control group. The analysis focused on MBD2 gene changes related to macrophage polarization.ResultsRemarkable modifications in MBD2 expression in the treatment group indicate a shift towards M2 macrophage polarization. Additionally, the combined treatment group exhibited greater improvements in infection resistance and healing compared to the individual treatments. This shift suggests a healing-promoting atmosphere with improved infection resilience.ConclusionsVLCS and NPWT demonstrate the ability to alter macrophage behavior toward M2 polarization, which is crucial for infection prevention in open fractures. The synergistic effect of their combined use shows even greater promise in enhancing outcomes in orthopedic trauma care.

Knockdown of HM13 Inhibits Metastasis, Proliferation, and M2 Macrophage Polarization of Non-small Cell Lung Cancer Cells by Suppressing the JAK2/STAT3 Signaling Pathway.

An upregulated histocompatibility minor 13 (HM13) has been studied in various tumors, yet the exact mechanism of HM13 in non-small cell lung cancer (NSCLC) is unclear. In view of same, the present study investigates crucial role and action mechanism of HM13 in human NSCLC. HM13 expression was higher in NSCLC tissue and cells through the Western blotting technique along with qRT-PCR. As per data from The Cancer Genome Atlas (TCGA), NSCLC patients having high HM13 expression show lower overall survival. 5-ethynyl-2-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and transwell tests were assessed for NSCLC cell growth, and invasion, and we found that silencing of HM13 inhibited the NSCLC cell proliferation, invasion. Additionally, to investigate the effects of HM13 on THP-1 macrophage polarization, a co-culture model of NSCLC and THP-1 macrophages were used. The CD206 + macrophages were examined using flow cytometry. As the markers of M2 macrophage, the mRNA levels of IL-10 and TGF-β of THP-1 cells were also detected by qRT-PCR. Knockdown of HM13 could inhibit the M2 polarization. Further experiments demonstrated that downregulated HM13 could inhibit the JAK2/STAT3 signaling pathway. RO8191 (activator of JAK/STAT3 pathway) influenced the invasion, proliferation, and expression of JAK2/STAT3 signaling pathway and Epithelial-mesenchymal transition (EMT) markers induced by HM13 silencing. HM13 knockdown also inhibited the tumor growth in vivo by xenograft nude mouse model. By inhibiting JAK2/STAT3 signaling pathway, HM13 knockdown inhibited the NSCLC cell proliferation, metastasis tumor growth, and tumor-associated macrophage M2 polarization. In NSCLC, HM13 could be a therapeutic target to treat the NSCLC.

Macrophage energy metabolism in cardiometabolic disease.

In a rapidly expanding body of literature, the major role of energy metabolism in determining the response and polarization status of macrophages has been examined, and it is currently a very active area of research. The metabolic flux through different metabolic pathways in the macrophage is interconnected and complex and could influence the polarization of macrophages. Earlier studies suggested glucose flux through cytosolic glycolysis is a prerequisite to trigger the pro-inflammatory phenotypes of macrophages while proposing that fatty acid oxidation is essential to support anti-inflammatory responses by macrophages. However, recent studies have shown that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully defined yet. In this review, we systematically reviewed and summarized the literature regarding the role of energy metabolism in controlling macrophage activity and how that might be altered in cardiometabolic diseases, namely heart failure, obesity, and diabetes. We critically appraised the experimental studies and methodologies in the published studies. We also highlighted the challenging concepts in macrophage metabolism and identified several research questions yet to be addressed in future investigations.

Thermo-Responsive Hydrogel Containing Microfluidic Chitosan Nanoparticles Loaded with Opuntia ficus-indica Extract for Periodontitis Treatment.

Periodontitis is a chronic inflammatory disease resulting from the dysbiosis of periodontal bacteria and the host's immune response, leading to tissue degradation and sustained inflammation. Traditional treatments, such as mechanical debridement and antimicrobial agents, often fail to fully eradicate pathogenic bacteria, especially in deep periodontal pockets. Consequently, the need for novel therapeutic approaches has increased the interest in bioactive natural extracts, such as that of Opuntia ficus-indica, known for its anti-inflammatory, antioxidant, and antimicrobial properties. This study investigates the encapsulation of Opuntia ficus-indica extract in OFI-loaded chitosan nanoparticles (OFI-NPs) via ionotropic gelation using a microfluidic system, allowing precise control over nanoparticle characteristics and enhancing protection against enzymatic degradation. To achieve localized and sustained release in periodontal pockets, a thermo-responsive hydrogel comprising hyaluronic acid and Pluronic F127 (OFI@tgels) was developed. The transition of OFI@tgels from a solution at low temperatures to a solid at body temperature enables prolonged drug release at inflammation sites. The in vitro application of the optimized formulation eradicated biofilms of S. mutans, P. aeruginosa (PAO1), and P. gingivalis over 36 h and disrupted extracellular polymeric substance formation. Additionally, OFI@tgel modulated immune responses by inhibiting M1 macrophage polarization and promoting a shift to the M2 phenotype. These findings suggest that OFI@tgel is a promising alternative treatment for periodontitis, effectively reducing biofilm formation and modulating the immune response.

Microneedle-Delivered PDA@Exo for Multifaceted Osteoarthritis Treatment via PI3K-Akt-mTOR Pathway.

Osteoarthritis (OA) is marked by cartilage deterioration, subchondral bone changes, and an inflammatory microenvironment. The study introduces the Microneedle-Delivered Polydopamine-Exosome (PDA@Exo MN), a therapeutic that not only preserves cartilage and promotes bone regeneration but also improves localized drug delivery through enhanced penetration capabilities. PDA@Exo MN shows strong reactive oxygen species(ROS) scavenging abilities and high biocompatibility, fostering osteogenesis and balancing anabolic and catabolic processes in cartilage. It directs macrophage polarization from M0 to the anti-inflammatory M2 phenotype. RNA sequencing of treated chondrocytes demonstrates restored cellular function and activated antioxidant responses, with modulated inflammatory pathways. The PI3K-AKT-mTOR pathway's activation, essential for PDA@Exo's effects, is confirmed via bioinformatics and Western blot. In vivo assessments robustly validate that PDA@Exo MN prevents cartilage degradation and OA progression, supported by histological assessments and micro-CT analysis, highlighting its disease-modifying impact. The excellent biocompatibility of PDA@Exo MN, verified through histological (H&E) and blood tests showing no organ damage, underscores its safety and efficacy for OA therapy, making it a novel and multifunctional nanomedical approach in orthopedics, characterized by organ-friendliness and biosecurity.

Interleukin-4-Loaded Heparin Hydrogel Regulates Macrophage Polarization to Promote Osteogenic Differentiation.

In bone tissue engineering, biological scaffolds are designed with structural and functional properties that closely resemble the extracellular environment, aiming to establish a microenvironment conducive to osteogenesis. Macrophages hold significant potential for promoting osteogenesis and modulating the biological behavior of tumor cells. Multiple coculture experiments of macrophages and osteoblasts have demonstrated that macrophage polarization significantly impacts osteogenesis. Therefore, exploring bone biomaterials that can modulate macrophage polarization holds great clinical significance. In this study, heparin was modified with maleimide and was used as a raw material to form a hydrogel with 4-am-PEG-SH. The compound was used to polarize macrophages and promote osteogenesis after combining with interleukin 4 (IL-4) by taking advantage of the electronegativity of heparin. The results revealed overexpressed M2 macrophage-related phenotypic genes and cocultivation with MC3T3-E1 cells demonstrated the osteogenesis-promoting effect of the loaded IL-4 heparin hydrogel. Previous research reported that hydrogel loaded with IL-4 can be used as a biomaterial for osteogenesis promotion. Heparin materials used in this paper are derived from clinically anticoagulant drugs and feature a simple operation. The synthesized hydrogel effectively binds cytokines, regulates macrophages to induce osteogenesis and has many potential clinical applications.

Human umbilical cord mesenchymal stem cell-derived exosomes mitigate diabetic nephropathy via enhancing M2 macrophages polarization

Background and objectivesExosomes, which are small nanoscale vesicles capable of secretion, have garnered significant attention in recent years because of their therapeutic potential, particularly in the context of kidney diseases. Notably, human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) are emerging as promising targeted therapies for renal conditions. The aim of this study was to investigate the therapeutic effects of hucMSC-Exos on diabetic kidney disease (DKD) both in vivo and in vitro. Additionally, this study seeks to elucidate cellular and molecular differentials, as well as the expression of relevant signaling pathways, through single-cell RNA sequencing. This endeavor was designed to enhance our understanding of the connection between hucMSC-Exos and the pathogenesis of DKD. Methods and resultsThe study commenced with the extraction and characterization of hucMSC-Exos, including the determination of their concentrations. Animal experiments were conducted to evaluate the therapeutic potential of hucMSC-Exos in a DKD mouse model. Subsequently, single-cell sequencing was employed to investigate the molecular mechanisms underlying the efficacy of extracellular vesicles in ameliorating DKD. These findings were further substantiated by cell-based experiments. Importantly, the results indicate that hucMSC-Exos can impede the progression of DKD in mice, with macrophage activation playing a pivotal role in this process. ConclusionsThe in vivo experiments conclusively established hucMSC-Exos as a pivotal component in preserving renal function and retarding the progression of DKD. Our utilization of single-cell sequencing technology, in conjunction with in vivo and in vitro experiments, provides compelling evidence that M2 macrophages are instrumental in enhancing the amelioration of diabetic nephropathy.

3D-printed silicate porous bioceramics promoted the polarization of M2-macrophages that enhanced the angiogenesis in bone regeneration.

The failure of bone regeneration has been considered as a serious problem that troubling patients for decades, most of which was resulted by the poor angiogenesis and chronic inflammation after surgery. Among multiple materials applied in the repair of bone defect, silicate bioceramics attracted researchers because of its excellent bioactivity. The purpose of this study was to detect the effect of specific bioactive glass ceramic (AP40, based on crystalline phases of apatite and wollastonite) on angiogenesis and the subsequent bone growth through the modulation of macrophages. Two groups were included in this study: control group (macrophages without any stimulation, denominated as Control) and AP40 group (macrophages incubated on AP40). This study investigated the effect of AP40 on macrophages polarization (RAW264.7) and angiogenesis in vitro and in vivo. Additionally, the changes of angiogenic ability regulated by macrophages were explored. AP40 showed excellent angiogenesis potential and the expression of CD31 was promoted through the modulation of macrophages toward M2 subtype. Additionally, the macrophages incubated on AP40 synthesized more PDGF-BB comparing to macrophages without any stimulation, which contributed to the improved angiogenetic ability of human umbilical vein endothelial cells (HUVECs). Results of in vivo studies indicated increased bone ingrowth along the implants, which indicated the potential of bioceramics for bone defect repair clinically.

Tailoring surface stiffness to modulate senescent macrophage immunomodulation: Implications for osteo-/angio-genesis in aged bone regeneration

The application of biomaterials in bone regeneration is a prevalent clinical practice. However, its efficacy in elderly patients remains suboptimal, necessitating further advancements. While biomaterial properties are known to orchestrate macrophage (MΦ) polarization and local immune responses, the role of biomaterial cues, specifically stiffness, in directing the senescent macrophage (S-MΦ) is still poorly understood. This study aimed to elucidate the role of substrate stiffness in modulating the immunomodulatory properties of S-MΦ and their role in osteo-immunomodulation. Our results demonstrated that employing collagen-coated polyacrylamide hydrogels with varying stiffness values (18, 76, and 295 kPa) as model materials, the high-stiffness hydrogel (295 kPa) steered S-MΦs towards a pro-inflammatory M1 phenotype, while hydrogels with lower stiffness (18 and 76 kPa) promoted an anti-inflammatory M2 phenotype. The immune microenvironment created by S-MΦs promoted the bioactivities of senescent endothelial cells (S-ECs) and senescent bone marrow mesenchymal stem cells BMSCs (S-BMSCs). Furthermore, the M2 S-MΦs, particularly incubated on the 76 kPa hydrogel matrices, significantly enhanced the ability of angiogenesis of S-ECs and osteogenic differentiation of S-BMSCs, which are crucial and interrelated processes in bone healing. This modulation aided in reducing the accumulation of reactive oxygen species in S-ECs and S-BMSCs, thereby significantly contributing to the repair and regeneration of aged bone tissue.

Structural elucidation of a capsular polysaccharide from Bacteroides uniformis and its ameliorative impact on DSS-induced colitis in mice

Capsular polysaccharides derived from Bacteroides species have emerged as potential mitigators of intestinal inflammation in murine models. However, research on capsular polysaccharides from B. uniformis, a Bacteroides species with reduced abundance in colons of patients with ulcerative colitis, remains scarce. In this study, we extracted a neutral polysaccharide component from B. uniformis ATCC8492, termed BUCPS1B, using ultrasonic disruption, ethanol precipitation, and anion exchange chromatography. Structural characterization revealed BUCPS1B as a water-soluble polysaccharide with an α-1,4-glucan main chain adorned with minor substituent sugar residues. BUCPS1B alleviated intestinal inflammation in a mouse model of colitis and induced polarization of macrophages into M2-type. Furthermore, BUCPS1B modulated the gut microbiota composition, increased the abundance of the probiotic Akkermansia muciniphila and altered the gut metabolic profile to promote phenylalanine and short chain fatty acids metabolism. BUCPS1B is therefore a promising candidate to prevent inflammation and augment intestinal health.

Suspension electrospinning of decellularized extracellular matrix: A new method to preserve bioactivity

Decellularized extracellular matrices (dECM) have strong regenerative potential as tissue engineering scaffolds; however, current clinical options for dECM scaffolds are limited to freeze-drying its native form into sheets. Electrospinning is a versatile scaffold fabrication technique that allows control of macro- and microarchitecture. It remains challenging to electrospin dECM, which has led researchers to either blend it with synthetic materials or use enzymatic digestion to fully solubilize the dECM. Both strategies reduce the innate bioactivity of dECM and limit its regenerative potential. Herein, we developed a new suspension electrospinning method to fabricate a pure dECM fibrous mesh that retains its innate bioactivity. Systematic investigation of suspension parameters was used to identify critical rheological properties required to instill “spinnability,” including homogenization, concentration, and particle size. Homogenization enhanced particle interaction to impart the requisite elastic behavior to withstand electrostatic drawing without breaking. A direct correlation between concentration and viscosity was observed that altered fiber morphology; whereas, particle size had minimal impact on suspension properties and fiber morphology. The versatility of this new method was demonstrated by electrospinning dECM with three common decellularization techniques (Abraham, Badylak, Luo) and tissue sources (intestinal submucosa, heart, skin). Bioactivity retention after electrospinning was confirmed using cell proliferation, angiogenesis, and macrophage polarization assays. Collectively, these findings provide a framework for researchers to electrospin dECM for diverse tissue engineering applications.

2D Janus carrier-enabled trojan horse: Gallium delivery for the sequential therapy of biofilm associated infection

Biofilm-associated infections (BAIs) continue to pose a major challenge in the medical field. Nanomedicine, in particular, promises significant advances in combating BAIs through the introduction of a variety of nanomaterials and nano-antimicrobial strategies. However, studies to date have primarily focused on the removal of the bacterial biofilm and neglect the subsequent post-biofilm therapeutic measures for BAIs, rendering pure anti-biofilm strategies insufficient for the holistic recovery of affected patients. Herein, we construct an emerging dual-functional composite nanosheet (SiHx@Ga) that responds to pHs fluctuation in the biofilm microenvironment to enable a sequential therapy of BAIs. In the acidic environment of biofilm, SiHx@Ga employs the self-sensitized photothermal Trojan horse strategy to effectively impair the reactive oxygen species (ROS) defense system while triggering oxidative stress and lipid peroxidation of bacteria, engendering potent antibacterial and anti-biofilm effects. Surprisingly, in the post-treatment phase, SiHx@Ga adsorbs free pathogenic nucleic acids released after biofilm destruction, generates hydrogen with ROS-scavenging and promotes macrophage polarization to the M2 type, effectively mitigating damaging inflammatory burst and promoting tissue healing. This well-orchestrated strategy provides a sequential therapy of BAIs by utilizing microenvironmental variations, offering a conceptual paradigm shift in the field of nanomedicine anti-infectives.

Periplocin improves the sensitivity of oxaliplatin-resistant hepatocellular carcinoma cells by inhibiting M2 macrophage polarization.

The aim of this research was to investigate the impact of periplocin (PPLN) on oxaliplatin (OXA) resistance in hepatocellular carcinoma (HCC) cells and offer insights for improving clinical treatment of HCC. The IC50 value of HCC cell lines against OXA was detected by the CCK-8 assay, and an OXA-resistant HepG2 cell line (HepG2/OXA) was constructed. THP-1 cells were induced into M1 or M2 macrophages, and M2 macrophage-conditioned medium (M2-CM) was prepared. M1 and M2 macrophage polarization were detected using RT-qPCR and flow cytometry. CCK-8, EdU staining, clone formation assay, flow cytometry, and western blotting were used to assess the proliferation and apoptosis of HepG2/OXA cells treated with PPLN and M2-CM. Additionally, a nude mouse subcutaneous graft tumor model was constructed. PPLN enhanced the sensitivity of HepG2/OXA cells to OXA, reduced their clone-forming ability, and promoted their apoptosis. Notably, PPLN hindered M0 macrophage polarization to M2 macrophages, while M1 polarization remained unaffected. The proliferation-inhibiting and apoptosis-promoting effects of OXA+PPLN on HepG2/OXA cells were significantly attenuated by the addition of M2-CM, suggesting that PPLN improves the OXA sensitivity of HepG2/OXA cells by hindering M2 macrophage polarization. Furthermore, PPLN inhibited M2 macrophage polarization and improved the OXA sensitivity of HepG2/OXA cells in vivo. In conclusion, PPLN inhibited the proliferation of HepG2/OXA cells, promoted their apoptosis, and inhibited M2 macrophage polarization both in vivo and in vitro, which in turn enhanced the OXA sensitivity of HepG2/OXA cells.

Microcystin-LR Regulates Interaction between Tumor Cells and Macrophages via the IRE1α/XBP1 Signaling Pathway to Promote the Progression of Colorectal Cancer.

Microcystin-LR (MC-LR), a cyanobacterial toxin, is a potent carcinogen implicated in colorectal cancer (CRC) progression. However, its impact on the tumor microenvironment (TME) during CRC development remains poorly understood. This study investigates the interaction between tumor cells and macrophages mediated by MC-LR within the TME and its influence on CRC progression. CRC mice exposed to MC-LR demonstrated a significant transformation from adenoma to adenocarcinoma. The infiltration of macrophages increased, and the IRE1α/XBP1 pathway was activated in CRC cells after MC-LR exposure, influencing macrophage M2 polarization under co-culture conditions. Additionally, hexokinase 2 (HK2), a downstream target of the IRE1α/XBP1 pathway, was identified, regulating glycolysis and lactate production. The MC-LR-induced IRE1α/XBP1/HK2 axis enhanced lactate production in CRC cells, promoting M2 macrophage polarization. Furthermore, co-culturing MC-LR-exposed CRC cells with macrophages, along with the IRE1α/XBP1 pathway inhibitor 4μ8C and the hexokinase inhibitor 2-DG, suppressed M2 macrophage-induced CRC cell migration, clonogenicity, and M2 macrophage polarization. This study elucidates the mechanism by which MC-LR-mediated interactions through the IRE1α/XBP1 pathway promote CRC progression, highlighting potential therapeutic targets.

Blocking Gremlin1 inhibits M1 macrophage polarization through Notch1/Hes1 signaling pathway in apical periodontitis

Background Gremlin1 is a multifunctional protein whose expression is demonstrated to be involved in a series of physiology and pathological processes. The association between Gremlin1 and apcial periodontitis (AP) has been established. M1-polarized macrophages are crucial immune cells that exacerbate the progression of apical periodontal inflammatory response, but the function of Gremlin1 during macrophages activation in periapical lesions is still unclear. This study attempts to explore the regulatory effects of Gremlin1 on macrophage polarization on apical periodontitis microenviroment. Methods Clinical specimens were used to determine the expression of Gremlin1 in periapical tissues by immunohistochemical (IHC) staining. Then, the disease models of periapical inflammation in rats were established, and adenovirus- associated virus (AAVs) was used to blockade Gremlin1 expression. Lentivirus carrying sh-Gremlin1 particles were used to transfect THP-1 induced M1-subtype macrophages. To assess the expression of associated molecules, Western blot, immunofluorescence staining were performed. Results Gremlin1 was significantly up-regulated in the periapical tissues of subjects with AP as identified by IHC staining, and positively correlated with levels of M1 macrophage-associated genes. Rats AP model with inhibition of Gremlin1 in periapical lesions exhibited limited infiltration of macrophages and decreased expression of M1 macrophage-related genes in periapical lesions. Furthermore, Gremlin1 blockade substantially decreased the Notch1/Hes1 signaling pathway activation level. The in vitro experiments confirmed the above results. Conclusion Taken together, current study illustrated that the Gremlin1 suppression in periapical lesions inhibited M1 macrophage polarization through Notch1/Hes1 axis. Moreover, Gremlin1 may act as a potential candidate in the treatment of AP.

Boosting Ferroptosis and immunotherapy for Colorectal Cancer by Lactate‐Related Metabolic Reprogramming

AbstractAs the presence of anaerobic metabolism of glucose, solid tumors characteristically display higher levels of lactate production, which attenuate ferroptosis therapy and the subsequent anti‐tumor immune response. Herein, hyaluronic acid (HA)‐modified and lactate oxidase (LOX)‐loaded nanoscale metal organic frameworks (MOFs), termed as FCS@LOX@HA (FCSLH) is constructed, achieving tumor‐targeted metabolic combined chemo‐dynamic therapy (CDT). Notably, the high LOX‐loading capacity of MOFs is achieved by adjusting the Fe/Cu ratio. Upon internalization by cancer cells, the FCS MOFs reacted with local glutathione (GSH) to release Fe/Cu ions for CDT. Meanwhile, the LOX catalyzed endogenous lactate to pyruvate accompanied with a release of H2O2; while the latter can enhance the FCS MOFs‐mediated CDT effect. Additionally, lactate exhaustion can impair the antioxidant system by inhibiting the HIF‐1α/SLC1A1 pathway, resulting in the accumulation of lipid peroxidation, and ferroptosis occurs accompanied by immunogenic cell death. Furthermore, lactate exhaustion within tumor‐associated macrophages (TAMs) can inhibit M2 macrophage polarization by suppressing the NF‐κB/HIF‐1α pathway, thereby augmenting anti‐tumor immune response. The in vivo studies demonstrated that cooperating with PD‐L1 antibodies can achieve excellent anti‐tumor therapeutic efficacy. Taken together, FCSLH can amplify the ferroptosis‐mediated immune response through simultaneous dysfunction of cancer cells and TAMs, which provides novel insight for integrating metabolic programmed therapy and immunotherapy.

Magnetic stirring with iron oxide nanospinners accretes neurotoxic Aβ42 oligomers into phagocytic clearable plaques for Alzheimer's disease treatment

An increasing number of medications have been explored to treat the progressive and irreversible Alzheimer's disease (AD) that stands as the predominant form of dementia among neurodegenerative ailments. However, assertions about toxic side effects of these drugs are a significant hurdle to overcome, calling for drug-free nanotherapeutics. Herein, a new therapeutic strategy devoid of conventional drugs or other cytotoxic species was developed. The constructed superparamagnetic iron oxide nanoparticles (SPIONs) nanospinners can accrete neurotoxic β-amyloid 42 oligomers (oAβ42) into aggregated magnetic plaques (mpAβ) by mechanical rotating force via remote interaction between nanoparticles and the applied magnetic field. While the cellular uptake of mpAβ attained from the magnetic stirring treatment by neuronal cells is severely limited, the facile phagocytic uptake of mpAβ by microglial cells leads to the polarization of the brain macrophages to M2 phenotype and thus the increased anti-inflammatory responses to the treatment. The SPION stirring treatment protects the AD mice from memory deterioration and maintain cognitive ability as evidenced from both nesting and Barnes maze tests. The examination of the oAβ42 injected brain tissues with the stirring treatment showed significant amelioration of functional impairment of neurons, microglia, astrocytes and oligodendrocytes alongside no obvious tissue damage caused by stirring meanwhile complete degradation of SPION was observed at day 7 after the treatment. The in vitro and animal data of this work strongly corroborate that this new modality of undruggable stirring treatment with SPIONs provides a new feasible strategy for developing novel AD treatments.

Milk-Derived Extracellular Vesicles Carrying ssc-let-7c Alleviate Early Intestinal Inflammation and Regulate Macrophage Polarization via Targeting the PTEN-Mediated PI3K/Akt Pathway.

Milk-derived extracellular vesicles (mEVs) are beneficial to the health of infants. However, the effect of mEVs on early intestinal inflammation is not well established. Herein, weaned colitic mice were used to explore the potential effects and underlying mechanisms of porcine mEVs (pmEVs) on intestinal inflammation during early life. We found that pmEVs administration attenuated early life intestinal inflammation and promoted colonic barrier integrity in mice. The anti-inflammatory effect of pmEVs was achieved by shifting a proinflammatory macrophage (M1) toward an anti-inflammatory macrophage (M2). Moreover, pmEVs can be absorbed by macrophages and reduce proinflammatory polarization (stimulated by LPS) in vitro. Noteworthily, ssc-let-7c was found to be highly expressed in pmEVs that can regulate the polarization of macrophages by targeting the tensin homologue deleted on chromosome ten (PTEN), thereby activating the PI3K/Akt pathway. Collectively, our findings revealed a crucial role of mEVs in early intestinal immunity and its underlying mechanism.