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Primary liver cancer (PLC) is one of the most common malignant gastrointestinal tumors worldwide. Limited by the shortage of liver transplantation donors and the heterogeneity of tumors, patients with liver cancer lack effective treatment options, which leads to rapid progression and metastasis. Currently, preclinical models of PLC fall short of clinical reality and are limited in their response to disease progression and the effectiveness of drug therapy. Organoids are in vitro three-dimensional cultured preclinical models with a high degree of heterogeneity that preserve the histomorphological and genomic features of primary tumors. Liver cancer organoids have been widely used for drug screening, new target discovery, and precision medicine; thus representing a promising tool to study PLC. Here, we summarize the progress of research on liver cancer organoids and their potential application as disease models. This review provides a comprehensive introduction to this emerging technology and offers new ideas for researchers to explore in the field of precision medicine.
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Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.
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Disfunción Cognitiva , Estrés del Retículo Endoplásmico , Ferroptosis , Hipoxia , Neuronas , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Hipoxia/metabolismo , Hipoxia/complicaciones , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Ciclohexilaminas/farmacología , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/metabolismo , Humanos , Quinoxalinas , Compuestos de Espiro , Sistema de Transporte de Aminoácidos y+RESUMEN
OBJECTIVE: Obstructive Sleep Apnea (OSA) during pregnancy is characterized by intermittent hypoxia (IH) during sleep and will lead to the rise of oxidative stress in the fetal body. Pyroptosis, a type of inflammatory and programmable cell death mediated by Gasdermin D (GSDMD), plays a substantial role in oxygen deprivation's contribution to neural system damage. Existing research shows that Nicotinamide Adenine Dinucleotide Phosphate (NADPH) plays a protective role in alleviating brain tissue pyroptosis. We speculate that exogenous NADPH may play a protective role in OSA during pregnancy. METHODS: A model of GIH group was established to simulate the pathophysiological mechanisms of OSA during pregnant and AIR group was established by giving the same frequency. Sham group was established by injecting NS and the NADPH group was established and given exogenous NADPH. We utilized the Morris Water Maze to assess cognitive function impairment, Luxol Fast Blue (LBF) staining to confirm myelin sheath formation, TUNEL staining to examine cell death in fetal mice brain tissue, and Western blotting to detect pertinent protein expressions. RESULTS: The GIH group offspring exhibited decreases in spatial learning and memory abilities, reduced numbers of oligodendrocytes and formed myelin, as well as increased expression of pyroptosis-related proteins. The NADPH group offspring showed restoration in spatial learning and memory abilities increased counts of oligodendrocytes and formed myelin sheaths, in addition to decreased expression of pyroptosis-related. CONCLUSIONS: This study demonstrates that early injection of exogenous NADPH can alleviate the damage to fetal brain development caused by gestational intermittent hypoxia (GIH).
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NADP , Piroptosis , Animales , Embarazo , Femenino , Ratones , NADP/metabolismo , Lesiones Encefálicas/patología , Lesiones Encefálicas/metabolismo , Hipoxia/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Efectos Tardíos de la Exposición PrenatalRESUMEN
Purpose: Human umbilical cord mesenchymal stem cell (hucMSC)-derived small extracellular vesicles (sEVs) are natural nanocarriers with promising potential in treating liver fibrosis and have widespread applications in the fields of nanomedicine and regenerative medicine. However, the therapeutic efficacy of natural hucMSC-sEVs is currently limited owing to their non-specific distribution in vivo and partial removal by mononuclear macrophages following systemic delivery. Thus, the therapeutic efficacy can be improved through the development of engineered hucMSC-sEVs capable to overcome these limitations. Patients and Methods: To improve the anti-liver fibrosis efficacy of hucMSC-sEVs, we genetically engineered hucMSC-sEVs to overexpress the anti-fibrotic gene bone morphogenic protein 7 (BMP7) in parental cells. This was achieved using lentiviral transfection, following which BMP7-loaded hucMSC-sEVs were isolated through ultracentrifugation. First, the liver fibrosis was induced in C57BL/6J mice by intraperitoneal injection of 50% carbon tetrachloride (CCL4) twice a week for 8 weeks. These mice were subsequently treated with BMP7+sEVs via tail vein injection, and the anti-liver fibrosis effect of BMP7+sEVs was validated using small animal in vivo imaging, immunohistochemistry (IHC), tissue immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Finally, cell function studies were performed to confirm the in vivo results. Results: Liver imaging and liver histopathology confirmed that the engineered hucMSC-sEVs could reach the liver of mice and aggregate around activated hepatic stellate cells (aHSCs) with a significantly stronger anti-liver fibrosis effect of BMP7-loaded hucMSC-sEVs compared to those of blank or negative control-transfected hucMSC-sEVs. In vitro, BMP7-loaded hucMSC-sEVs promoted the phenotypic reversal of aHSCs and inhibited their proliferation to enhance the anti-fibrotic effects. Conclusion: These engineered BMP7-loaded hucMSC-sEVs offer a novel and promising strategy for the clinical treatment of liver fibrosis.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Animales , Ratones , Humanos , Células Estrelladas Hepáticas/patología , Ratones Endogámicos C57BL , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/terapia , Cirrosis Hepática/metabolismo , Fibrosis , Vesículas Extracelulares/patología , Células Madre Mesenquimatosas/metabolismo , Cordón Umbilical , Proteína Morfogenética Ósea 7/genética , Proteína Morfogenética Ósea 7/metabolismoRESUMEN
BACKGROUND: The use of umbilical cord mesenchymal stem cells (UC-MSCs) is a burgeoning method for the treatment of liver cirrhosis. However, the secretory phenotype and regulatory ability of UC-MSCs are easily affected by their microenvironment. Ensuring a specific microenvironment to enhance the UC-MSCs phenotype is a potential strategy for improving their therapeutic efficacy. The aim of this study was to explore therapeutic UC-MSCs phenotypes for improving liver fibrosis. METHODS: RNA-sequencing was used to analyze the response pattern of UC-MSCs after exposure to the serum of cirrhotic patients with HBV. Using immunohistochemistry, quantitative polymerase chain reaction, and immunofluorescence techniques, we evaluated the therapeutic effect of UC-MSCs pretreated with interferon alpha 2 (IFN-α2) (pre-MSCs) in an animal model of cirrhosis. Immunoblotting, ELISA, and other techniques were used to analyze the signaling pathways underlying the IFN-induced changes in UC-MSCs. RESULTS: UC-MSCs exposed to the serum of patients with hepatitis B-induced cirrhosis showed an enhanced response to type I IFN. The activated type I IFN signal induced the highest secretion of colony-stimulating factor 3 (CSF-3), interleukin (IL)-8, and chemokine (C-C motif) ligand 20 (CCL20) by the UC-MSCs. Pre-MSCs showed a higher therapeutic efficacy than untreated UC-MSCs in an animal model of liver fibrosis. Immunohistochemical analysis revealed that pre-MSCs could recruit neutrophils resulting in an increase in the secretion of matrix metalloprotease 8 that alleviated fibrosis. When neutrophils in animals were depleted, the therapeutic effect of pre-MSCs on fibrosis was inhibited. IFN-α2 altered the secretory phenotype of UC-MSCs by activating phosphorylated signal transducer and activator of transcription 1 and 2 (p-STAT1 and p-STAT2). CONCLUSIONS: Pre-MSCs exhibited enhanced secretion of CSF-3, IL-8, and CCL20 and recruited neutrophils to alleviate fibrosis. This new strategy can improve cell therapy for liver cirrhosis.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Humanos , Animales , Interferón alfa-2/farmacología , Neutrófilos , Cirrosis Hepática/terapia , Cirrosis Hepática/metabolismo , Fibrosis , Células Madre Mesenquimatosas/metabolismo , Cordón Umbilical , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
Objective: Obstructive sleep apnea (OSA) seriously affects the children's cognitive functions, but the neuroimaging mechanism of cognitive impairment is still unclear. The purpose of our study was to explore the difference in brain local gray matter volume (GMV) between children with OSA and non-OSA, and the correlation between the difference regions of brain gray matter volume and cognitive, the severity of OSA. Method: Eighty-three children aged 8-13 years were recruited in our study, 52 children were diagnosed as OSA by polysomnography, and 31 as the non-OSA. All the subjects were underwent high-resolution 3-dimensional T1-weighted magnetic resonance images. The voxel-based morphometry (VBM) was be used to analyse the local GMV. The Das-Naglieri cognitive assessment system (DN: CAS) was used to assess the subjects' cognitive. The difference of local GMV between the two groups was analyzed by two-sample T-test. The PSG variables and the scores of DN: CAS between the OSA group and non-OSA group were compared by independent samples t-tests. Pearson correlation was used to calculate the association between the difference areas of gray matter volumes in brain and DN: CAS scores, obstructive apnea/hypopnea index (OAHI, an index of the severity of OSA). Results: The gray matter volume of the right Middle Frontal Gyrus (MFG_R) in OSA children were larger than the non-OSA children, and the OSA children had lower scores of the Word Series in DN: CAS. There was negative correlation between the scores of Expressive Attention in DN: CAS and the gray matter volume of the right middle frontal gyrus, and it was no significantly correlation between OAHI and the gray matter volume of the right middle frontal gyrus. Conclusion: Our results suggest that the development of gray matter volume in frontal cortex, which associated with attention, were sensitive to the effects of OSA, provides neuroimaging evidence for cognitive impairment in children with OSA.
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Androgenetic alopecia is the most common cause of hair loss aggravated by increased life pressure, tension, and anxiety. Although androgenetic alopecia (AGA) does not significantly effect physical health, it can have serious negative impact on the mental health and quality of life of the patient. Currently, the effect of medical treatment for AGA is not idealistic, stem cell-based regenerative medicine has shown potential for hair regrowth and follicle repair, but the long-term effect and mechanism of stem cell therapy is not quite explicit. In this review, we summarize the methods, efficacy, mechanism, and clinical progress of stem cell therapies for AGA by now, hope it will present a more comprehensive view in this topic.
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Alopecia , Calidad de Vida , Humanos , Alopecia/terapia , Cabello , Tratamiento Basado en Trasplante de Células y Tejidos , Células MadreRESUMEN
OBJECTIVE: Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) is a sleep respiratory disease associated with cognitive impairment, The nuclear factor erythroid 2 related factor 2 (Nrf2) plays a neuroprotective role. This study was designed to investigate the mechanism of Nrf2 protecting neural cells from endoplasmic reticulum stress (ERS), induced by chronic intermittent hypoxia (CIH) and sleep fragmentation (SF) which caused cognitive impairment in mice. METHODS: Establishment of CIH and SF mice to simulate OSAHS mouse model. An eight-arm maze behavior test measured the cognitive function of mice, and Nissl staining and TUNEL staining were used to detect pathological changes in hippocampal neurons. The expression of ERS and Nrf2 and its downstream related mRNAs and proteins were detected by qRT-PCR and Western blotting. RESULTS: CIH and SF lead to cognitive impairment in mice, and Sulforaphane (SFN, Nrf2 agonist) plays a protective role, while Nrf2-KO aggravates the cognitive impairment. CIH and SF reduced the number of Nissl bodies in neurons and induced apoptosis. The mRNA levels of BiP, CHOP, Nrf2, GCLC and Prdx1 in CIH, SF and CIH + SF groups were increased (p = 0.001), whereas the mRNA levels of BiP and CHOP in the CIH + SF + SFN group were decreased (p = 0.02) while those of Nrf2 and Prdx1 were increased (p = 0.005). The CIH + SF + Nrf2-KO group, the mRNA levels of CHOP were increased (p = 0.001) while Nrf2, GCLC and Prdx1 were decreased (p = 0.001). The protein levels of CHOP and active Caspase-12 in CIH, SF, CIH + SF and CIH + SF + Nrf2-KO groups were increased (p = 0.03), while those of Prdx1 and Nrf2 were increased (p = 0.03) in the CIH + SF + SFN group, while decreased (p = 0.02) in the Nrf2-KO group. CONCLUSIONS: Chronic intermittent hypoxia(CIH) and sleep fragmentation(SF) could aggravate the inflammatory response of nerve cells through endoplasmic reticulum stress, leading to apoptosis of nerve cells, and causing cognitive impairment in mice.Nrf2 alleviates cognitive impairment induced by chronic intermittent hypoxia and sleep fragmentation by modulating endoplasmic reticulum stress. Activation of Nrf2 protects cognitive impairment through the Nrf2-Prdx1 signaling pathway.
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Disfunción Cognitiva , Factor 2 Relacionado con NF-E2 , Apnea Obstructiva del Sueño , Animales , Ratones , Modelos Animales de Enfermedad , Hipoxia/complicaciones , Factor 2 Relacionado con NF-E2/genética , Apnea Obstructiva del Sueño/complicaciones , Privación de Sueño/complicacionesRESUMEN
BACKGROUND: Tumor cell density is a basic pathological feature of solid tumors. Chemotherapy, radiotherapy, and targeted therapy reduce tumor cell density, whereas unrestricted tumor cell proliferation promotes this feature. The impact of tumor cells on the microenvironment following changes in tumor cell density is still unclear. In this study, we focused on the response of key immune cell subsets to tumor cell density in hepatocellular carcinoma (HCC). METHODS: We determined the density of tumor and immune cells in the same area by section staining. We then identified potential mediators using polymerase chain reaction (PCR), enzyme-linked immunofluorescence assay (ELISA), 3D and co-culture, flow cytometry, and lentivirus intervention. The mechanism of lactate promotion was verified using lactate tests, bioinformatics, western blotting, and the above methods. The IL-8/DAPK1/lactate/regulatory T cell (Treg) axis was verified using a mouse liver cancer model. Tumor mutation burden was calculated using maftools in R. RESULTS: We found that the Treg/CD8 + T cell ratio is not consistent with tumor cell density in HCC, and a decreased Treg/CD8 + T cell ratio in the range of 5000-6000 cells/mm2 may elicit the possibility for immunotherapy in an immunosuppressive microenvironment. We showed that IL-8 mediates this immune fluctuation and promotes the infiltration of Tregs through the DAPK1/pyruvate kinase activity/lactate axis in HCC. Based on tumor ploidy and mutation burden data, we discussed the potential significance of immune fluctuation in the homeostasis of HCC mutation burden and proposed a "density checkpoint" and "entropy model" to describe this phenomenon. CONCLUSIONS: In summary, we report the mode of infiltration of Tregs/CD8 + T cells in response to tumor cell density and provide a new theoretical basis for IL-8 as a therapeutic target and the selection of an immunotherapy window in HCC.
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Carcinoma Hepatocelular , Interleucina-8 , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Linfocitos T CD8-positivos , Recuento de Células , Interleucina-8/metabolismo , Lactatos/uso terapéutico , Neoplasias Hepáticas/genética , Linfocitos T Reguladores , Microambiente Tumoral , Animales , RatonesRESUMEN
Carfentanil, as a fentanyl analogue, is a potent synthetic opioid. It has been controlled in many countries, and its emergence has been highlighted by many recent reports. However, although discriminative stimulus effects of carfentanil in rats had been reported, its abuse potential has not been fully evaluated. In this study, we evaluated the abuse potential of carfentanil via the tests of conditioned place preference (CPP), drug self-administration and naloxone-precipitated opioid withdrawal assay, compared with fentanyl and heroin. Carfentanil exhibited significant place preference at a minimum dose of 1 µg/kg in mice, whereas fentanyl and heroin induced significant place preference at the minimum doses of 100 µg/kg and 1000 µg/kg, respectively. In the drug-substitution test in heroin self-administered rats (50 µg/kg/infusion), carfentanil and fentanyl acquired significant self-administrations above saline levels from 0.05-0.1 and 0.1-10.0 µg/kg/infusion, respectively. Carfentanil induced the maximum number of infusions at 0.1 µg/kg, whereas fentanyl and heroin at 1 and 25 µg/kg, respectively. In short, carfentanil showed the highest potency to induce CPP and self-administration. Furthermore, repeated treatment with escalating doses of carfentanil, fentanyl or heroin induced typical withdrawal symptoms in mice, including a greater number of jumping and weight loss than saline group. This indicated that carfentanil could produce physical dependence similar to fentanyl and heroin. Taken together, the present study demonstrated the higher abuse potential of carfentanil compared with fentanyl and heroin. The rank order of abuse potential for these compounds is carfentanil > fentanyl > heroin.
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Analgésicos Opioides , Síndrome de Abstinencia a Sustancias , Ratas , Ratones , Animales , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Heroína/farmacología , Fentanilo/farmacología , Naloxona/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológicoRESUMEN
BACKGROUND: Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction. METHODS: First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results. RESULTS: AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin-yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness. CONCLUSIONS: Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/genética , Mecanotransducción Celular , Neoplasias Hepáticas/genética , Fenotipo , Hidrogeles , Microambiente TumoralRESUMEN
Introduction: Bone marrow mesenchymal stem cells (BMSCs) are a promising cell type for tissue engineering, however, the application of BMSCs is largely hampered by the limited number harvested from bone marrow cells. The methods or strategies that focused on promoting the capacity of BMSCs expansion ex vivo become more and more important. Tanshinone IIA (Tan IIA), the main active components of Danshen, has been found to promote BMSCs proliferation, but the underlying mechanism is still unclear. The aim of this study is to explore the effect and underlying mechanism of Tan IIA on the expansion capacity of hBMSCs ex vivo. Methods: In this present study, the effect of Tan IIA on the expansion capacity of BMSCs from human was investigated, and quantitative proteome analysis was applied furtherly to identify the differentially expressed proteins (DEPs) and the molecular signaling pathways in Tan IIA-treated hBMSCs. Finally, molecular biology skills were employed to verify the proposed mechanism of Tan IIA in promoting hBMSCs expansion. Results: The results showed that a total of 84 DEPs were identified, of which 51 proteins were upregulated and 33 proteins were downregulated. Besides, Tan IIA could promote hBMSCs proliferation by regulating the progression of S phase via increasing the release of fibroblast growth factor 2 (FGF2), FGF-mediated PI3K/AKT signaling pathways may play an important role in Tan IIA's effect on hBMSCs expansion. Conclusions: This study employed molecular biology skills combined with quantitative proteome analysis, to some extent, clarified the mechanism of Tan IIA's effect on promoting hBMSCs proliferation, and will give a hint that Tan IIA may have the potential to be used for BMSCs applications in cell therapies in the future.
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In recent years, Pb-free CsSnI3 perovskite materials with excellent photoelectric properties as well as low toxicity are attracting much attention in photoelectric devices. However, deep level defects in CsSnI3, such as high density of tin vacancies, structural deformation of SnI6- octahedra and oxidation of Sn2+ states, are the major challenge to achieve high-performance CsSnI3-based photoelectric devices with good stability. In this work, defect passivation method is adopted to solve the above issues, and the ultra-stable and high-performance CsSnI3 nanowires (NWs) photodetectors (PDs) are fabricated via incorporating 1-butyl-2,3-dimethylimidazolium chloride salt (BMIMCl) into perovskites. Through materials analysis and theoretical calculations, BMIM+ ions can effectively passivate the Sn-related defects and reduce the dark current of CsSnI3 NW PDs. To further reduce the dark current of the devices, the polymethyl methacrylate is introduced, and finally, the dual passivated CsSnI3 NWPDs show ultra-high performance with an ultra-low dark current of 2 × 10-11 A, a responsivity of up to 0.237 A W-1, a high detectivity of 1.18 × 1012 Jones and a linear dynamic range of 180 dB. Furthermore, the unpackaged devices exhibit ultra-high stability in device performance after 60 days of storage in air (25 °C, 50% humidity), with the device performance remaining above 90%.
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BACKGROUND: Effective therapeutics to stop or reverse liver fibrosis have not emerged, because these potential agents cannot specifically target activated hepatic stellate cells (aHSCs) or are frequently toxic to parenchymal cells. Human umbilical cord mesenchymal stem cell (Huc-MSC)-derived exosomes show promise in nanomedicine for the treatment of liver fibrosis. However, systemic injection showed that unmodified exosomes were mainly taken up by the mononuclear phagocyte system. The discovery of ligands that selectively bind to a specific target plays a crucial role in clinically relevant diagnostics and therapeutics. Herein, we aimed to identify the targeting peptide of aHSCs by screening a phage-displayed peptide library, and modify Huc-MSC-derived exosomes with the targeting peptide. RESULTS: In this study, we screened a phage-displayed peptide library by biopanning for peptides preferentially bound to HSC-T6 cells. The identified peptide, HSTP1, also exhibited better targeting ability to aHSCs in pathological sections of fibrotic liver tissues. Then, HSTP1 was fused with exosomal enriched membrane protein (Lamp2b) and was displayed on the surface of exosomes through genetic engineering technology. The engineered exosomes (HSTP1-Exos) could be more efficiently internalized by HSC-T6 cells and outperformed both unmodified exosomes (Blank-Exos) and Lamp2b protein overexpressed exosomes (Lamp2b + Exos) in enhancing the ability of exosomes to promote HSC-T6 reversion to a quiescent phenotype. In vivo results showed HSTP1-Exos could specifically target to the aHSC region after intravenous administration, as demonstrated by coimmunofluorescence with the typical aHSCs marker α-SMA, and enhance the therapeutic effect on liver fibrosis. CONCLUSION: These results suggest that HSTP1 is a reliable targeting peptide that can specifically bind to aHSCs and that HSTP1-modified exosomes realize the precise treatment for aHSCs in complex liver tissue. We provide a novel strategy for clinical liver fibrosis therapy.
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Exosomas , Células Estrelladas Hepáticas , Exosomas/metabolismo , Células Estrelladas Hepáticas/metabolismo , Humanos , Cirrosis Hepática/terapia , Proteínas de la Membrana/metabolismo , Biblioteca de Péptidos , Péptidos/metabolismo , Cordón Umbilical/metabolismoRESUMEN
The tumor microenvironment (TME) is a complex macromolecular network filled with a series of stromal cells. It plays an important role in tumorigenesis, development, immune escape, drug resistance, and other processes and has received increasing attention in recent years. Currently, tumor cell-centered treatments are insufficient to eradicate malignancies, and researchers are constantly searching for better treatments. Over the past decade, the TME has been recognized as a rich resource for anti-cancer drug development. As a significant mechanical feature in the microenvironment of solid tumors, matrix stiffness is increased owing to stromal deposition and remodeling. The effect of matrix stiffness on cancer cells has been described in many studies, whereas its effect on cancer stromal cell fate has rarely been summarized. Therefore, this review discusses the relevant content and drug treatment studies targeting matrix stiffness. STATEMENT OF SIGNIFICANCE: Biochemical and biophysical interactions between tumor cells, stromal cells, and the extracellular matrix (ECM) co-create a distinct tumor microenvironment (TME), which impacts disease outcome. In recent years, there has been a greater emphasis on the physical properties of the ECM, with matrix stiffness being one of the most thoroughly investigated. The matrix stiffness of solid tumors is now commonly acknowledged to be greater than that of normal tissues. Cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and endothelial cells (ECs) can all respond to matrix stiffness. At the same time, our current understanding of the TME is insufficient, and an in-depth examination of interactions between ECM and cells could lead to the development of more efficient and specialized treatments.
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Fibroblastos Asociados al Cáncer , Neoplasias , Células Endoteliales/patología , Matriz Extracelular/patología , Humanos , Neoplasias/patología , Neoplasias/terapia , Células del Estroma/patología , Microambiente TumoralRESUMEN
Cost-effective treatment strategies for liver fibrosis or cirrhosis are limited. Many clinical trials of stem cells for liver disease shown that stem cells might be a potential therapeutic approach. This review will summarize the published clinical trials of stem cells for the treatment of liver fibrosis/cirrhosis and provide the latest overview of various cell sources, cell doses, and delivery methods. We also describe the limitations and strengths of various stem cells in clinical applications. Furthermore, to clarify how stem cells play a therapeutic role in liver fibrosis, we discuss the molecular mechanisms of stem cells for treatment of liver fibrosis, including liver regeneration, immunoregulation, resistance to injury, myofibroblast repression, and extracellular matrix degradation. We provide a perspective for the prospects of future clinical implementation of stem cells.
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Trasplante de Células Madre Mesenquimatosas , Fibrosis , Humanos , Hígado/metabolismo , Cirrosis Hepática/patología , Regeneración Hepática/fisiología , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
2-Fluorodeschloroketamine (2-FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2-FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2-FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self-administration and drug discrimination using ketamine as a reference. 2-FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2-FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2-FDCK and ketamine induced locomotor sensitization after withdrawal. 2-FDCK readily induced self-administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2-FDCK dose-dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2-FDCK has an abuse potential comparable with ketamine.