RESUMEN

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. The inflammatory response is the fundamental pathologic alteration throughout AKI, regardless of the various causal factors. Macrophages are the main immune cells involved in the inflammatory microenvironment in AKI. Consequently, targeting macrophages might become a novel strategy for the treatment of AKI. In this study, we demonstrated that pseudoginsenoside-F11 (PF11), a distinctive component of Panax quinquefolius L., regulated macrophage function and protected renal tubular epithelial cells TCMK-1 from lipopolysaccharide (LPS) in vitro. PF11 also alleviated renal injuries in an LPS-induced AKI mouse model, decreased the levels of inflammatory cytokines, reduced macrophage inflammatory infiltration, and promoted the polarization of M1 macrophages to M2c macrophages with suppression of the nuclear factor-κB/NOD-like receptor thermal protein domain-associated protein 3/interleukin-1ß (NF-κB/NLRP3/IL-1ß) signaling pathway. To further investigate whether this nephroprotective effect of PF11 is mediated by macrophages, we performed macrophage depletion by injection of clodronate liposomes in mice. Macrophage depletion abolished PF11's ability to protect against LPS-induced kidney damage with downregulating the NF-κB/NLRP3/IL-1ß signaling pathway. In summary, this is the first study providing data on the efficacy and mechanism of PF11 in the treatment of AKI by regulating macrophage function.

Asunto(s)

Lesión Renal Aguda , Ginsenósidos , Interleucina-1beta , Lipopolisacáridos , Macrófagos , Ratones Endogámicos C57BL , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/metabolismo , Ginsenósidos/farmacología , Ginsenósidos/administración & dosificación , Ratones , Lipopolisacáridos/efectos adversos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Transducción de Señal/efectos de los fármacos , FN-kappa B/genética , FN-kappa B/metabolismo , FN-kappa B/inmunología , Masculino , Humanos , Panax/química

RESUMEN

Local inflammatory microenvironment in the early stage of myocardial infarction (MI) severely impaired cardiac recovery post-MI. Macrophages play a pivotal role in this process. A classical glycolytic inhibitor, 2-Deoxy-Glucose (2-DG), has been found to regulate the excessive pro-inflammatory macrophage polarization in the infarcted myocardium. This study investigated the effect of 2-DG-loaded chitosan/gelatin composite patch on the infarct microenvironment post-MI and its impact on cardiac repair. The results showed that the 2-DG patch significantly inhibited the expression of inflammatory cytokines, alleviated reactive oxygen species (ROS) accumulation, repressed the proinflammatory polarization of macrophages, attenuated local inflammatory microenvironment in the ischemic hearts, as well as improved cardiac function, reduced scar size, and promoted angiogenesis post-MI. In terms of mechanism, 2-DG exerts anti-inflammatory effects through inhibiting the NF-κB signaling pathway and reducing the assembly and activation of the NLRP3 inflammasome. These findings suggest that 2-DG composite patch may represent a promising therapeutic strategy for cardiac repair after MI.

Asunto(s)

Desoxiglucosa , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Desoxiglucosa/farmacología , Desoxiglucosa/administración & dosificación , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratones , Masculino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Transducción de Señal/efectos de los fármacos , Quitosano/farmacología , Quitosano/química , Gelatina/química , Citocinas/metabolismo , Miocardio/metabolismo , Miocardio/patología , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Ratones Endogámicos C57BL

RESUMEN

The overactivated immune cells in the infectious lesion may lead to irreversible organ damages under severe infections. However, clinically used immunosuppressive anti-inflammatory drugs will usually disturb immune homeostasis and conversely increase the risk of infections. Regulating the balance between anti-inflammation and anti-infection is thus critical in treating certain infectious diseases. Herein, considering that hydrogen peroxide (H2O2), myeloperoxidase (MPO), and neutrophils are upregulated in the inflammatory microenvironment and closely related to the severity of appendectomy patients, an inflammatory-microenvironment-responsive nanomedicine is designed by using poly(lactic-co-glycolic) acid (PLGA) nanoparticles to load chlorine E6 (Ce6), a photosensitizer, and luminal (Lum), a chemiluminescent agent. The obtained Lum/Ce6@PLGA nanoparticles, being non-toxic within normal physiological environment, can generate cytotoxic single oxygen via bioluminescence resonance energy transfer (BRET) in the inflammatory microenvironment with upregulated H2O2 and MPO, simultaneously killing pathogens and excessive inflammatory immune cells in the lesion, without disturbing immune homeostasis. As evidenced in various clinically relevant bacterial infection models and virus-induced pneumonia, Lum/Ce6@PLGA nanoparticles appeared to be rather effective in controlling both infection and inflammation, resulting in significantly improved animal survival. Therefore, the BRET-based nanoparticles by simultaneously controlling infections and inflammation may be promising nano-therapeutics for treatment of severe infectious diseases.

RESUMEN

The pro-inflammatory immune microenvironment in the localized lesion areas and the absence of DNA damage repair mechanisms in endothelial cells serve as essential accelerating factors in the development of atherosclerosis. The lack of targeted therapeutic strategies represents a significant limitation in the efficacy of therapeutic agents for atherosclerosis. In this study, Genetically engineered SNHG12-loaded cerium-macrophage exosomes (Ce-Exo) are designed as atherosclerosis-targeting agents. In vivo studies demonstrated that Ce-Exo exhibited multivalent targeting properties for macrophages, with a 4.1-fold higher atherosclerotic plaque-aggregation ability than that of the control drugs. This suggests that Ce-Exo has a higher homing capacity and deeper penetration into the atherosclerotic plaque. In apolipoprotein E-deficient mice, Ce-Exo found to effectively remodel the immune microenvironment in the lesion area, repair endothelial cell damage, and inhibit the development of atherosclerosis. This study provides a novel approach to the treatment of atherosclerosis and demonstrates the potential of cell-derived drug carriers in biomedicine.

RESUMEN

Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Asunto(s)

Fibroblastos Asociados al Cáncer , Neoplasias , Microambiente Tumoral , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Neoplasias/metabolismo , Neoplasias/patología , Animales , Reprogramación Celular , Metástasis de la Neoplasia , Reprogramación Metabólica

RESUMEN

Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.

RESUMEN

Superficial cartilage defects represent the most prevalent type of cartilage injury encountered in clinical settings, posing significant treatment challenges. Here, we fabricated a cartilage extracellular matrix mimic hydrogel (GHC, consisting of Gelatin, Hyaluronic acid, and Chondroitin sulfate) to avoid the exacerbation of cartilage deterioration, which is often driven by the accumulation of reactive oxygen species (ROS) and a pro-inflammatory microenvironment. The GHC hydrogel exhibited multifunctional properties, including in situ formation, tissue adhesiveness, anti-ROS capabilities, and the promotion of chondrogenesis. The enhancement of tissue adhesion was achieved by chemically modifying hyaluronic acid and chondroitin sulfate with o-nitrobenzene, enabling a covalent connection to the cartilage surface upon light irradiation. In vitro characterization revealed that GHC hydrogel facilitated chondrocyte adhesion, migration, and differentiation into cartilage. Additionally, GHC hydrogels demonstrated the ability to scavenge ROS in vitro and inhibit the production of inflammatory factors by chondrocytes. In the animal model of superficial cartilage injury, the hydrogel effectively promoted cartilage ECM regeneration and facilitated the interface integration between the host tissue and the material. These findings suggest that the multifunctional GHC hydrogels hold considerable promise as a strategy for cartilage defect repair. STATEMENT OF SIGNIFICANCE: Superficial cartilage defects represent the most prevalent type of cartilage injury encountered in the clinic. Previous cartilage tissue engineering materials are only suitable for full-thickness cartilage defects or osteochondral defects. Here, we developed a multifunctional GHC hydrogel composed of gelatin, hyaluronic acid, and chondroitin sulfate, which are natural cartilage extracellular matrix components. The drug-free and cell-free hydrogel not only avoids immune rejection and drug toxicity, but also shows good mechanical properties and biocompatibility. More importantly, the GHC hydrogel could adhere tightly to the superficial cartilage defects and promote cartilage regeneration while protecting against oxidation. This natural ingredients and multifunctional hydrogel is a potential material for repairing superficial cartilage defects.

RESUMEN

Ulcerative colitis is an inflammation of the colon characterized by immune dysregulation and intestinal inflammation. Developing safe oral nanomedicines that suppress intestinal inflammation, while modulating colonic inflammatory microenvironment by scavenging reactive oxygen species (ROS) and hydrogen sulfide (H2S) is crucial for the effective treatment of colitis. Here, the tofacitinib citrate and copper coordination-based nanoparticle (TF-Cu nanoparticle, T-C) to dual-scavenge ROS and H2S by coordination competition is synthesized. Moreover, the coordination of T-C using computer simulation is explored. To enhance the acid stability and inflammatory targeting of T-C, it is encapsulated with hyaluronic acid-modified chitosan, along with a calcium pectinate coating (T-C@HP). Owing to the dual pH/pectinase-responsive characteristics of T-C@HP, the nanoplatform can target inflamed colonic lesions, inhibiting phosphorylated Janus kinase 1. Furthermore, T-C@HP scavenges ROS and H2S, as well as increases NADPH levels, which is investigated by combining biosensor (HyPer7 and iNap1/c) and chemical probes. T-C@HP also alleviates colitis by regulating the colonic inflammatory microenvironment through multiple processes, including the modulation of apoptosis, macrophage polarization, tight junction, mucus layer, and intestinal flora. Complemented by satisfactory anti-inflammatory and biosafety results, this nanoplatform represents a promising, effective, and safe treatment option for colitis patients.

RESUMEN

The disturbance of the inflammatory microenvironment is a frequent pathological trait of diabetic wounds, contributing to the emergence of numerous chronic illnesses. This is crucial in both the development and recovery of wounds caused by diabetes. This study aims to perform a bibliometric analysis of research on the inflammatory microenvironment within the domain of diabetic wounds (DW) over the past 10 years. The objective is to map out the current global research landscape, pinpoint the most significant areas of study and offer guidance for future research avenues. Our research involved querying the Web of Science Core Collection (WoSCC) database for all pertinent studies on the inflammatory microenvironment in diabetic wounds (DW). We utilized bibliometric tools such as CiteSpace, VOSviewer and R (version 4.3.1) to identify and highlight the most impactful studies in the field. The study encompassed a review of 1454 articles published from 2014 to 2023, highlighting China and the United States as pivotal nations in the research of the inflammatory microenvironment in diabetic wounds (DW). Within this sphere, the University of Michigan and Harvard University in the United States, along with Shanghai Jiaotong University in China, emerged as the most prolific institutions. WANG Y from China was identified as the most productive author, while KUNKEL SL from the United States received the most citations. The research primarily focuses on topics such as wound healing, repair processes, angiogenesis, oxidative stress and macrophage activity. Additionally, "macrophage" and "delivery" were pinpointed as the leading subjects with promising research potential in this area. Research on the inflammatory microenvironment of diabetic wounds is rapidly advancing through active international collaboration. The study of new mechanisms related to the inflammatory microenvironment and the development of novel materials for repair based on this microenvironment represent emerging fields of future research, particularly in terms of translational applications. This may offer guidance and novel perspectives for further research in the area of the diabetic wound inflammatory microenvironment.

Asunto(s)

Bibliometría , Complicaciones de la Diabetes , Cicatrización de Heridas , Heridas y Lesiones , Humanos , Complicaciones de la Diabetes/inmunología , Inflamación/inmunología , Cicatrización de Heridas/inmunología , Heridas y Lesiones/inmunología

RESUMEN

Dry eye affects majority of the global population, causing significant discomfort or even visual impairment, of which inflammation plays a crucial role in the deterioration process. This highlights the need for effective and safe anti-inflammatory treatments to achieve satisfactory therapeutic outcomes. This study focuses on the potential of tetrahedral framework nucleic acids (tFNA), a self-assembled nucleic acid material, as a simple and rapid treatment for oxidative stress and inflammation-induced disorders associated with dry eye. Mechanistically, tFNA is found to effectively alleviate dry eye damage by promoting corneal epithelial healing, restoring goblet cell function, and facilitating tear secretion recovery. Through RNA-seq analysis, it is observed that tFNA treatment normalizes the expression levels of most genes. Further exploration of the mechanism reveals that tFNA reduces excessive production of reactive oxygen species and modulates the inflammatory microenvironment, especially through cGAS-STING pathway thereby levels of inflammatory cytokines, including MMP9 and IL-6, are reduced. Additionally, tFNA demonstrates excellent safety performance without causing damage to the eye. Importantly, this study represents a successful application of nanophase materials with nucleic acid biological features for the effective treatment of dry eye, highlighting the potential clinical use of tFNA in the treatment of dry eye.

RESUMEN

Periodontitis is a chronic inflammatory disease and is the primary contributor to adult tooth loss. Diabetes exacerbates periodontitis, accelerates periodontal bone resorption. Thus, effectively managing periodontitis in individuals with diabetes is a long-standing challenge. This review introduces the etiology and pathogenesis of periodontitis, and analyzes the bidirectional relationship between diabetes and periodontitis. In this review, we comprehensively summarize the four pathological microenvironments influenced by diabetic periodontitis: high glucose microenvironment, bacterial infection microenvironment, inflammatory microenvironment, and bone loss microenvironment. The hydrogel design strategies and latest research development tailored to the four microenvironments of diabetic periodontitis are mainly focused on. Finally, the challenges and potential solutions in the treatment of diabetic periodontitis are discussed. We believe this review will be helpful for researchers seeking novel avenues in the treatment of diabetic periodontitis.

Asunto(s)

Hidrogeles , Periodontitis , Humanos , Periodontitis/tratamiento farmacológico , Periodontitis/inmunología , Animales , Complicaciones de la Diabetes , Microambiente Celular , Pérdida de Hueso Alveolar

RESUMEN

Psoriasis is a chronic inflammatory disease affecting skin and joints characterized by a chronically altered immune and inflammatory response. Several factors occur from the onset to the development of this disease due to different types of cells spatially and temporally localized in the affected area, such as, keratinocytes, macrophages, neutrophils and T helper lymphocytes. This scenario leads to the chronic release of high levels of inflammatory mediators (i.e., IL-17, IL-23, IL-22, TNF-α, S100 proteins, Defensins) and lastly parakeratosis and thickening of the stratum spinosum. Extracellular vesicles (EVs) are small double membraned biological nanoparticles that are secreted by all cell types and classified, based on dimension and biogenesis, into exosomes, microvesicles and apoptotic bodies. Their role as vessels for long range molecular signals renders them key elements in the pathogenesis of psoriasis, as well as innovative platforms for potential biomarker discovery and delivery of fine-tuned anti-inflammatory therapies. In this review, the role of EVs in the pathogenesis of psoriasis and the modulation of cellular microenvironment has been summarized. The biotechnological implementation of EVs for therapy and research for new biomarkers has been also discussed.

Asunto(s)

Biomarcadores , Vesículas Extracelulares , Psoriasis , Humanos , Psoriasis/inmunología , Psoriasis/metabolismo , Psoriasis/etiología , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/inmunología , Animales , Piel/patología , Piel/inmunología , Piel/metabolismo , Microambiente Celular/inmunología

RESUMEN

Osteoporosis is the most common bone metabolic disease that affects the health of middle-aged and elderly people, which is hallmarked by imbalanced bone remodeling and a deteriorating immune microenvironment. Magnesium and calcium are pivotal matrix components that participate in the bone formation process, especially in the immune microenvironment regulation and bone remodeling stages. Nevertheless, how to potently deliver magnesium and calcium to bone tissue remains a challenge. Here, we have constructed a multifunctional nanoplatform composed of calcium-based upconversion nanoparticles and magnesium organic frameworks (CM-NH2-PAA-Ald, denoted as CMPA), which features bone-targeting and pH-responsive properties, effectively regulating the inflammatory microenvironment and promoting the coordination of osteogenic functions for treating osteoporosis. The nanoplatform can efficaciously target bone tissue and gradually degrade in response to the acidic microenvironment of osteoporosis to release magnesium and calcium ions. This study validates that CMPA possessing favorable biocompatibility can suppress inflammation and facilitate osteogenesis to treat osteoporosis. Importantly, high-throughput sequencing results demonstrate that the nanoplatform exerts a good inflammatory regulation effect through inhibition of the nuclear factor kappa-B signaling pathway, thereby normalizing the osteoporotic microenvironment. This collaborative therapeutic strategy that focuses on improving bone microenvironment and promoting osteogenesis provides new insight for the treatment of metabolic diseases such as osteoporosis.

Asunto(s)

Calcio , Magnesio , Nanopartículas , Osteogénesis , Osteoporosis , Osteogénesis/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Magnesio/farmacología , Magnesio/química , Calcio/metabolismo , Animales , Nanopartículas/química , Ratones , Inflamación/tratamiento farmacológico , Huesos/efectos de los fármacos , Huesos/metabolismo , Humanos , Microambiente Celular/efectos de los fármacos , Femenino , FN-kappa B/metabolismo

RESUMEN

BACKGROUND: Stroke is a devastating disease affecting populations worldwide and is the primary cause of long-term disability. The inflammatory storm plays a crucial role in the progression of stroke. In the acute phase of ischemic stroke, there is a transient increase in anti-inflammatory M2 microglia followed by a rapid decline. Due to the abundant phospholipid in brain tissue, lipid peroxidation is a notable characteristic of ischemia/reperfusion (I/R), constituting a structural foundation for ferroptosis in M2 microglia. Slowing down the decrease in M2 microglia numbers and controlling the inflammatory microenvironment holds significant potential for enhancing stroke recovery. RESULTS: We found that the ferroptosis inhibitor can modulate inflammatory response in MCAO mice, characterizing that the level of M2 microglia-related cytokines was increased. We then confirmed that different subtypes of microglia exhibit distinct sensitivities to I/R-induced ferroptosis. Adipose-derived stem cells derived exosome (ADSC-Exo) effectively decreased the susceptibility of M2 microglia to ferroptosis via Fxr2/Atf3/Slc7a11, suppressing the inflammatory microenvironment and promoting neuronal survival. Furthermore, through plasmid engineering, a more efficient M2 microglia-targeted exosome, termed M2pep-ADSC-Exo, was developed. In vivo and in vitro experiments demonstrated that M2pep-ADSC-Exo exhibits significant targeting specificity for M2 microglia, further inhibiting M2 microglia ferroptosis and improving neurological function in ischemic stroke mice. CONCLUSION: Collectively, we illustrated a novel potential therapeutic mechanism that Fxr2 in ADSC-Exo could alleviate the M2 microglia ferroptosis via regulating Atf3/Slc7all expression, hence inhibiting the inflammatory microenvironment, improving neurofunction recovery in cerebral I/R injury. We obtained a novel exosome, M2pep-ADSC-Exo, through engineered modification, which exhibits improved targeting capabilities toward M2 microglia. This provides a new avenue for the treatment of stroke.

Asunto(s)

Exosomas , Ferroptosis , Accidente Cerebrovascular Isquémico , Ratones Endogámicos C57BL , Microglía , Animales , Exosomas/metabolismo , Microglía/metabolismo , Ratones , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/terapia , Ferroptosis/efectos de los fármacos , Masculino , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Modelos Animales de Enfermedad , Citocinas/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia

RESUMEN

Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high mortality. The tumor microenvironment is the "soil" of its occurrence and development, and the inflammatory microenvironment is an important part of the "soil". Bile acid is closely related to the occurrence of HCC. Bile acid metabolism disorder is not only directly involved in the occurrence and development of HCC but also affects the inflammatory microenvironment of HCC. Yinchenhao decoction, a traditional Chinese medicine formula, can regulate bile acid metabolism and may affect the inflammatory microenvironment of HCC. To determine the effect of Yinchenhao decoction on bile acid metabolism in mice with HCC and to explore the possible mechanism by which Yinchenhao decoction improves the inflammatory microenvironment of HCC by regulating bile acid metabolism, we established mice model of orthotopic transplantation of hepatocellular carcinoma. These mice were treated with three doses of Yinchenhao decoction, then liver samples were collected and tested. Yinchenhao decoction can regulate the disorder of bile acid metabolism in liver cancer mice. Besides, it can improve inflammatory reactions, reduce hepatocyte degeneration and necrosis, and even reduce liver weight and the liver index. Taurochenodeoxycholic acid, hyodeoxycholic acid, and taurohyodeoxycholic acid are important molecules in the regulation of the liver inflammatory microenvironment, laying a foundation for the regulation of the liver tumor inflammatory microenvironment based on bile acids. Yinchenhao decoction may improve the inflammatory microenvironment of mice with HCC by ameliorating hepatic bile acid metabolism.

Asunto(s)

Ácidos y Sales Biliares , Carcinoma Hepatocelular , Medicamentos Herbarios Chinos , Neoplasias Hepáticas , Microambiente Tumoral , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Ratones , Ácidos y Sales Biliares/metabolismo , Microambiente Tumoral/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo

RESUMEN

The unpredictable survival rate of autologous fat grafting (AFG) seriously affects its clinical application. Improving the survival rate of AFG has become an unresolved issue in plastic surgery. Peroxisome proliferator-activated receptor-γ (PPAR-γ) regulates the adipogenic differentiation of adipocytes, but the functional mechanism in AFG remains unclear. In this study, we established an animal model of AFG and demonstrated the superior therapeutic effect of PPAR-γ regulation in the process of AFG. From day 3 after fat grafting, the PPAR-γ agonist rosiglitazone group consistently showed better adipose integrity, fewer oil cysts, and fibrosis. Massive macrophage infiltration was observed after 7 days. At the same time, M2 macrophages begin to appear. At day 14, M2 macrophages gradually became the dominant cell population, which suppressed inflammation and promoted revascularization and fat regeneration. In addition, transcriptome sequencing showed that the differentially expressed genes in the Rosiglitazone group were associated with the pathways of adipose regeneration, differentiation, and angiogenesis; these results provide new ideas for clinical treatment.

Asunto(s)

Tejido Adiposo , Macrófagos , PPAR gamma , Rosiglitazona , Trasplante Autólogo , Animales , PPAR gamma/metabolismo , PPAR gamma/genética , Macrófagos/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/citología , Rosiglitazona/farmacología , Masculino , Diferenciación Celular , Adipogénesis , Adipocitos/metabolismo , Ratones , Ratas

RESUMEN

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

Asunto(s)

Cartílago Articular , Células Madre Mesenquimatosas , Osteoartritis , Sinovitis , Ratones , Animales , Condrogénesis , Nanomedicina , Osteoartritis/tratamiento farmacológico , Diferenciación Celular , Inflamación/metabolismo , Sinovitis/metabolismo , ARN Mensajero/metabolismo

RESUMEN

Periodontitis is a chronic inflammatory disease raising the risks of tooth-supporting structures destruction and even tooth loss. The way to reconstruct periodontal bone tissues in inflammatory microenvironment has been long in demand for periodontitis treatment. In this study, the lycium barbarum glycopeptide (LbGP) loaded gelatin-based scaffolds were fabricated for periodontitis treatment. Gelatin microspheres with suitable size were prepared by emulsification and gathered by oxidized sodium alginate to prepare heterogeneous bilayer gelatin-based scaffolds, and then they were loaded with LbGP. The prepared scaffolds possessed interconnected porous microstructures, good degradation properties, sufficient mechanical properties, sustained release behavior and well biocompatibility. In vitro experiments suggested that the LbGP loaded gelatin-based scaffolds could inhibit the expression of inflammatory factors (IL-1ß, IL-6, and TNF-α), promote the expression of anti-inflammatory factor (IL-10), and the expression of osteogenic markers (BMP2, Runx2, ALP, and OCN) in PDLSCs under the LPS-stimulated inflammatory microenvironment. Moreover, in rat periodontitis models, the LbGP gelatin-based scaffolds would reduce the alveolar bone resorption of rats, increase the collagen fiber content of periodontal membrane, alleviate local inflammation and improve the expression of osteogenesis-related factors. Therefore, the LbGP loaded gelatin-based scaffolds in this study will provide a potential therapeutic strategy for periodontitis treatment.

Asunto(s)

Gelatina , Periodontitis , Andamios del Tejido , Gelatina/química , Periodontitis/tratamiento farmacológico , Periodontitis/terapia , Animales , Andamios del Tejido/química , Emulsiones/química , Ratas , Osteogénesis/efectos de los fármacos , Preparaciones de Acción Retardada/química , Humanos , Masculino , Ratas Sprague-Dawley , Porosidad , Lycium/química , Liberación de Fármacos , Microesferas , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación

RESUMEN

Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra-conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory-polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein-based conduits. Moreover, the NGC can gradually regulate the intra-conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.

Asunto(s)

Fibroínas , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos , Animales , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Ratas , Traumatismos de los Nervios Periféricos/terapia , Fibroínas/química , Fibroínas/farmacología , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Células de Schwann/metabolismo , Regeneración Tisular Dirigida/métodos , Inflamación , Andamios del Tejido/química , Nervio Ciático/lesiones

RESUMEN

Refractory diabetic wounds are associated with high incidence, mortality, and recurrence rates and are a devastating and rapidly growing clinical problem. However, treating these wounds is difficult owing to uncontrolled inflammatory microenvironments and defective angiogenesis in the affected areas, with no established effective treatment to the best of our knowledge. Herein, we optimized a dual functional therapeutic agent based on the assembly of LL-37 peptides and diblock copolymer poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS). The incorporation of PEG-PPS enabled responsive or controlled LL-37 peptide release in the presence of reactive oxygen species (ROS). LL-37@PEG-PPS nanomicelles not only scavenged excessive ROS to improve the microenvironment for angiogenesis but also released LL-37 peptides and protected them from degradation, thereby robustly increasing angiogenesis. Diabetic wounds treated with LL-37@PEG-PPS exhibited accelerated and high-quality wound healing in vivo. This study shows that LL-37@PEG-PPS can restore beneficial angiogenesis in the wound microenvironment by continuously providing angiogenesis-promoting signals. Thus, it may be a promising drug for improving chronic refractory wound healing.