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Mifepristone, a progesterone receptor antagonist, was initially used to terminate early pregnancy. As scientific research advanced, it emerged to be effective in the treatment of various tumors and tumor-like conditions such as endometriosis. Despite the therapeutic potential of mifepristone, its therapeutic effect is still far from ideal because the drug is difficult to dissolve and to accumulate in the target tissue sites. To address this issue, mifepristone-loaded nanostructured lipid carriers (Mif-NLC) were prepared by a simple solvent diffusion method and their anti-endometriosis performance and mechanisms were initially investigated. By optimizing the preparation protocol, we obtained uniform and spheroidal Mif-NLC with an average particle size of 280 nm. The encapsulation rate and drug loading capacity were 64.67% ± 0.15% and 2.7% ± 0.014%, respectively, as measured by UV spectrophotometry. The in vitro release kinetics indicated that mifepristone was released from NLC in a sustained-release manner. Compared with free mifepristone, Mif-NLC exhibited enhanced cellular uptake and inhibition of invasion activity in primary mesenchymal cells of endometriosis. A certain reduction in the size of endometriotic cysts was observed in animals compared to controls. The induction of autophagy via Mif-NLC may serve as the molecular mechanism underlying this effect. Furthermore, observation of uterine structures showed negligible toxic effects. This suggested that mifepristone encapsulated in NLC can improve its bioavailability and anti-endometriosis efficacy, which provided a new strategy for the treatment of endometriosis.
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For the efficient degradation of organic pollutants with the goal of reducing the water environment pollution, we employed an alkaline hydrothermal treatment on primeval g-C3N4 to synthesize a hydroxyl-grafted g-C3N4 (CN-0.5) material, from which we engineered a novel Fenton-like catalyst, known as Cu-CN-0.5. The introduction of numerous hydroxyl functional groups allowed the CN-0.5 substrate to stably fix active copper oxide particles through surface complexation, resulting in a low Cu leaching rate during a Cu-CN-0.5 Fenton-like process. A sequence of characterization techniques and theoretical calculations uncovered that interfacial complexation induced charge redistribution on the Cu-CN-0.5 surface. Specifically, some of the π electrons in the tris-s-triazine units were transferred to the copper oxide particles along the newly formed chemical bonds (C(π)-O-Cu), forming a π-deficient area on the tris-s-triazine plane near the complexation site. In a typical Cu-CN-0.5 Fenton-like process, a stable π-π interaction was established due to the favorable positive-negative match of electrostatic potential between the aromatic pollutants and π-deficient areas, leading to a significant improvement in Cu-CN-0.5's adsorption capacity for aromatic pollutants. Furthermore, pollutants also delivered electrons to the Cu-CN-0.5 Fenton-like system via a "through-space" approach, which suppressed the futile oxidation of H2O2 in reducing the high-valent Cu2+ and significantly improved the generation efficiency of â¢OH with high oxidative capacity. As expected, Cu-CN-0.5 not only exhibited an efficient Fenton degradation for several typical aromatic organic pollutants, but also demonstrated both a low metal leaching rate (0.12 mg/L) and a H2O2 utilization rate exceeding 80%. The distinctive Fenton degradation mechanism substantiated the potential of the as-prepared material for effective wastewater treatment applications.
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Cobre , Peróxido de Hidrógeno , Hierro , Contaminantes Químicos del Agua , Catálisis , Contaminantes Químicos del Agua/química , Peróxido de Hidrógeno/química , Hierro/química , Cobre/química , Grafito/química , Oxidación-Reducción , Nitrilos/química , Compuestos de Nitrógeno/químicaRESUMEN
Recurrent Spontaneous Abortion (RSA) is a common pregnancy complication, that has multifactorial causes, and currently, 40%-50% of cases remain unexplained, referred to as Unexplained RSA (URSA). Due to the elusive etiology and mechanisms, clinical management is exceedingly challenging. In recent years, with the progress in reproductive immunology, a growing body of evidence suggests a relationship between URSA and maternal-fetal immunology, offering hope for the development of tailored treatment strategies. This article provides an immunological perspective on the pathogenesis, diagnosis, and treatment of RSA. On one hand, it comprehensively reviews the immunological mechanisms underlying RSA, including abnormalities in maternal-fetal interface immune tolerance, maternal-fetal interface immune cell function, gut microbiota-mediated immune dysregulation, and vaginal microbiota-mediated immune anomalies. On the other hand, it presents the diagnosis and existing treatment modalities for RSA. This article offers a clear knowledge framework for understanding RSA from an immunological standpoint. In conclusion, while the "layers of the veil" regarding immunological factors in RSA are gradually being unveiled, our current research may only scratch the surface. In terms of immunological etiology, effective diagnostic tools for RSA are currently lacking, and the efficacy and safety of immunotherapies, primarily based on lymphocyte immunotherapy and intravenous immunoglobulin, remain contentious.
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Aborto Habitual , Humanos , Femenino , Embarazo , Aborto Habitual/inmunología , Tolerancia Inmunológica , Intercambio Materno-Fetal/inmunología , Microbioma Gastrointestinal/inmunología , Inmunoterapia/métodosRESUMEN
Purpose: Preoperative oral carbohydrate (CHO) is a rapid postoperative rehabilitation protocol that improves perioperative outcomes and is widely used in adult surgical patients. However, pregnant women are excluded because of the possibility of aspiration due to delayed gastric emptying. This meta-analysis was conducted to evaluate the efficacy of preoperative oral CHO in elective cesarean section. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to July 2023. Randomized controlled trials were included. The risk of bias was assessed using the Cochrane tool. Risk ratios and 95% confidence intervals were calculated. Meta-analysis was performed using random-effects models to estimate risk ratios and mean differences (MDs) with 95% confidence intervals (CIs). The outcomes included thirst and hunger scores, incidence of vomiting and nausea, time to flatus, and homeostatic model assessment of insulin resistance (HOMA-IR). Results: A total of nine studies with 1211 patients were included in the analysis. The levels of thirst and hunger were evaluated using a 10-point visual analog scale, with 0 representing the best and 10 representing the worst. The severity of hunger (weighted mean difference (WMD: -2.34, 95% CI: -3.13 to -1.54), time to flatus (WMD: -3.51 hours, 95% CI: -6.85 to -0.17), and HOMA-IR (WMD: -1.04, 95% CI: -1.31 to -0.77) were significantly lower in the CHO group compared to the control group. However, there were no significant differences in the severity of thirst or the incidence of vomiting and nausea between the CHO and control groups. Conclusion: Preoperative oral CHO during cesarean section alleviates thirst and hunger, shortens the time of postoperative flatus, and reduces HOMA-IR. However, the available evidence is insufficient to reach a clear consensus on the benefits or harms of preoperative oral CHO during cesarean section. Therefore, it is premature to make a definitive recommendation for or against its routine use.
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In recent studies, carbon nanotube (CNTs) materials and their composites have demonstrated remarkable catalytic activity in the activation of persulfate (PS), facilitating the efficient degradation of organic pollutants. In this study, a novel Co loaded carbon nanotubes (CoO@CNT) catalyst was prepared to promote PDS activation for the degradation of sulfafurazole (SIZ). Experimental results, the CNT as a carrier effectively reduces the leaching of cobalt ions and improves the electron transport capacityï¼whereas the introduced Co effectively activates the PDS, promoting the generation of highly reactive radicals to degrade SIZ. Under optimized conditions (a catalyst dose of 0.2 g/L, a PDS dose of 1 g/L and an initial pH = 9.0), the obtained CoO@CNT demonstrated favorable Fenton-like performance, reaching a degradation efficiency of 95.55% within 30 min. Furthermore, density functional theory (DFT) calculations demonstrate that the introduction of cobalt (Co) accelerates electron transfer, promoting the decomposition of PDS while facilitating the Co2+/Co3+ redox cycling. We further employed the environmental chemistry and risk assessment system (ECOSAR) to evaluate the ecological toxicity of intermediate products, revealing a significant reduction in ecological toxicity associated with this degradation process, thereby confirming its environmental harmlessness. Through batch experiments and studies, we gained a comprehensive understanding of the mechanism and influencing factors of CoO@CNT in the role of SIZ degradation, and provided robust support for evaluating the ecological toxicity of degradation products. This study provides a significant strategy for the development of efficient catalysts incorporating Co for the environmentally friendly degradation of organic pollutants.
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Cobalto , Nanotubos de Carbono , Nanotubos de Carbono/química , Cobalto/química , Catálisis , Sulfatos/química , Óxidos/química , Contaminantes Químicos del Agua/química , Oxidación-ReducciónRESUMEN
Chronic postsurgical pain (CPSP) with high incidence negatively impacts the quality of life. X-C motif chemokine 13 (CXCL13) has been associated with postsurgery inflammation and exacerbates neuropathic pain in patients with CPSP. This study was aimed to illustrate the relationship between CXCL13 and nod-like receptor protein-3 (NLRP3), which is also involved in CPSP. A CPSP model was constructed by skin/muscle incision and retraction (SMIR) in right medial thigh, and the rats were divided into three groups: Sham, SMIR, and SMIRâ +â anti-CXCL13 (intrathecally injected with anti-CXCL13 antibody). Then, the paw withdrawal threshold (PWT) score of rats was recorded. Primary rat astrocytes were isolated and treated with recombinant protein CXCL13 with or without NLRP3 inhibitor INF39. The expressions of CXCL13, CXCR5, IL-1ß, IL-18, GFAP, NLRP3, and Caspase-1 p20 were detected by real-time quantitative reverse transcription PCR, western blot, ELISA, immunocytochemistry, and immunofluorescence analyses. The anti-CXCL13 antibody alleviated SMIR-induced decreased PWT and increased expression of GFAP, CXCL13, CXCR5, NLRP3, and Caspase-1 p20 in spinal cord tissues. The production of IL-1ß, IL-18, and expression of CXCL13, CXCR5, GFAP, NLRP3, and Caspase-1 p20 were increased in recombinant protein CXCL13-treated primary rat astrocytes in a dose-dependent manner. Treatment with NLRP3 inhibitor INF39 inhibited the function of recombinant protein CXCL13 in primary rat astrocytes. The CXCL13/CXCR5 signaling could promote neuropathic pain, astrocytes activation, and NLRP3 inflammasome activation in CPSP model rats by targeting NLRP3. NLRP3 may be a potential target for the management of CPSP.
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Quimiocina CXCL13 , Proteína con Dominio Pirina 3 de la Familia NLR , Neuralgia , Dolor Postoperatorio , Receptores CXCR5 , Animales , Ratas , Astrocitos/metabolismo , Caspasas , Quimiocina CXCL13/metabolismo , Interleucina-18 , Neuralgia/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Dolor Postoperatorio/metabolismo , Ratas Sprague-Dawley , Receptores CXCR5/metabolismo , Proteínas RecombinantesRESUMEN
Physiological or pathological hypoperfusion of the placenta is one of the main causes of intrauterine growth restriction (IUGR) which poses a significant risk to the health of the fetus and newborn. Tadalafil, a 5-type phosphodiesterase inhibitor, has previously been found to improve the symptoms of IUGR in various clinical studies. Unfortunately, its clinical utility is hindered by its limited water solubility, rapid metabolism, and lack of specific distribution in target tissues rendering tadalafil unable to maintain long-term placental perfusion. In this study, iRGD-modified tadalafil-loaded liposomes (iRGD-lipo@Tad) featuring a size of approximately 480 nm were designed to rectify the shortcomings of tadalafil. The prepared iRGD-lipo@Tad exhibited superior stability, sustained drug release capacity, and low cytotoxicity. The fluorescence study, tissue slice study, and drug biodistribution study together demonstrated the placenta-anchored ability of iRGD-modified liposomes. This was achieved by a dual approach consisting of the iRGD-mediated placenta-targeting effect and special particle size-mediated placenta resident effect. The pharmacokinetic study revealed a significant improvement in the in vivo process of tadalafil encapsulated by the iRGD-modified liposomes. In comparison to the tadalafil solution, the peak plasma concentration of iRGD-lipo@Tad was significantly increased, and the area under the curve was increased by about 7.88 times. In the pharmacodynamic study, iRGD-lipo@Tad achieved a continuous and efficient improvement of placental blood perfusion. This was achieved by decreasing the ratio of plasma soluble fms-like tyrosine kinase to placental growth factor and increasing the levels of cyclic guanosine monophosphate and nitric oxide. Consequently, iRGD-lipo@Tad resulted in a significant increase in embryo weight and a reduction in the miscarriage rate of N-Nitro-L-arginine methyl ester-induced IUGR pregnant mice without detectable toxicity. In summary, the nanotechnology-assisted therapy strategy presented here not only overcomes the limitations of tadalafil in the clinical treatment of IUGR but also offers new avenues to address the treatment of other placenta-originated diseases.
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Liposomas , Placenta , Humanos , Femenino , Embarazo , Animales , Ratones , Liposomas/metabolismo , Tadalafilo/uso terapéutico , Tadalafilo/metabolismo , Placenta/metabolismo , Placenta/patología , Retardo del Crecimiento Fetal/tratamiento farmacológico , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , Distribución Tisular , Factor de Crecimiento Placentario/metabolismo , PerfusiónRESUMEN
Currently, the precise causes of over 40 % of recurrent spontaneous abortion (RSA) cases cannot be identified, leading to the term "unexplained RSA" (URSA). Through an exploration of the gut microbiota, metabolites, and immune cell subsets in URSA, this study establishes a link between gut microbiota-derived metabolites and immune cells. The results indicate reduced diversity in the gut microbiota of URSA. Targeted metabolomic analyses reveal decreased levels of gut microbiota-derived deoxycholic acid (DCA), glycolithocholic acid (GLCA), acetate, propionate, and butyrate in URSA. Furthermore, elevated frequencies of Th1, Th17, and plasma B cells, along with decreased frequencies of Tregs and Bregs, are observed in the peripheral blood of URSA. The results demonstrate correlations between the levels of gut microbiota-derived bile acids and short-chain fatty acids and the frequencies of various immune cell subsets in circulation. Collectively, this study uncovers an association between gut microbiota-derived metabolites and circulating immune cell subsets in URSA.
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Two-dimensional organic-inorganic hybrid perovskites (2D HOIPs) have been widely used for various optoelectronics applications owing to their excellent photoelectric properties. However, the selection of organic spacer cations is mostly qualitative without quantitative guidance. Meanwhile, the fundamental mechanism of the carrier transport across the organic spacer layer is still unclear. Here, by using the first-principles nonadiabatic molecular dynamics (NAMD) method, we have studied the transport process of excited carriers between 2D HOIPs separated by a spacer cation layer in real time at atomic levels. We find that the excited electrons and holes can transfer from single-inorganic-layer 2D HOIP to bi-inorganic-layer 2D HOIP on a subpicosecond to picosecond scale. Moreover, we have developed a new method to capture the electron-hole interaction in the frame of NAMD. This work provides a promising direction to design new materials toward high-performance optoelectronics.
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Osteogenic differentiation, proliferation, and/or apoptosis of bone marrow mesenchymal stem cells (BMSCs) are involved in the progression of postmenopausal osteoporosis (PMO). However, circular RNA (circRNA)-mediated changes in the cellular function of BMSCs in PMO are still unclear. This study revealed the excellent ability of circ-Plod2 to promote osteogenic differentiation of BMSCs and its molecular mechanisms. In this study, ovariectomized (OVX) rats and control (Sham) rats were used to simulate PMO. Initially, we found that the expression of circ-Plod2 in OVX BMSCs is down-regulated and the expression of the Mpo gene is up-regulated by sequencing and verification. Further, we confirmed that circ-Plod2 is located in the cytoplasm and belongs to exon-type circRNA. Interestingly, circ-Plod2 promotes Mpo-dependent osteogenic differentiation of BMSCs without affecting proliferation, apoptosis, adipogenic differentiation, or chondrogenic differentiation of BMSCs. Mechanistically, we demonstrated that circ-Plod2 specifically binds IGF2BP2 to form an RNA-protein complex that destabilizes Mpo mRNA. Overexpression of circ-Plod2 in the bone marrow cavity effectively alleviated osteoporosis in OVX rats and inhibited the expression of MPO in BMSCs. Together, this study reveals that circ-Plod2 destabilizes Mpo mRNA by binding to IGF2BP2 to promote osteogenic differentiation of BMSCs to alleviate osteoporosis. The findings of this study may provide biomarkers for the diagnosis of PMO, and may also provide potential strategies for the clinical treatment of PMO.
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Células Madre Mesenquimatosas , MicroARNs , Osteoporosis Posmenopáusica , Osteoporosis , Peroxidasa , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa , Animales , Femenino , Humanos , Ratas , Células de la Médula Ósea , Diferenciación Celular , Células Cultivadas , MicroARNs/genética , Osteogénesis/genética , Osteoporosis/tratamiento farmacológico , Osteoporosis Posmenopáusica/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/metabolismo , Peroxidasa/metabolismoRESUMEN
Background: Male breast cancer (MBC) is a rare disease, accounting for <1% of all male carcinomas. Lack of prospective data, the current therapy for MBC is based on retrospective analysis or information that is extrapolated from studies of female patients. We constructed a nomogram model for predicting the overall survival (OS) of MBC patients and verify its feasibility using data from China. Methods: Constructed a predictive model using 1224 MBC patients from the Surveillance, Epidemiology and End Results (SEER) registry between 2010 and 2015. The performance of the model was externally validated between 2002 to 2021 using 44 MBC patients from the Fujian Medical University Union Hospital. The independent prognostic factors were selected by univariate and multivariate Cox regression analyses. The nomogram was constructed to predict individual survival outcomes for MBC patients. The discriminative power, calibration, and clinical effectiveness of the nomogram were evaluated by the receiver operating characteristic (ROC) curve, and the decision curve analysis (DCA). Results: A total of 1224 male breast cancer patients were in the training cohort and 44 in the validation cohort. T status (p<0.001), age at diagnosis (p<0.001), histologic grade (p=0.008), M status (p<0.001), ER status (p=0.001), Her2 status (p=0.019), chemotherapy (p=0.015) were independently associated with OS. The diagnostic performance of this model was evaluated and validated using ROC curves on the training and validation datasets. In the training cohort, the nomogram-predicted AUC value was 0.786 for 3-year OS and 0.767 for 5-year OS. In the validation cohort, the nomogram-predicted AUC value was 0.893 for 3-year OS and 0.895 for 5-year OS. Decision curve analysis demonstrated that the nomogram was more benefit than the AJCC stage. Conclusions: We developed a nomogram that predicts 3-year and 5-year survival in MBC patients. Validation using bootstrap sampling revealed optimal discrimination and calibration, suggesting that the nomogram may have clinical utility. The results remain reproducible in the validation cohort which included Chinese data. The model was superior to the AJCC stage system as shown in the decision curve analysis (DCA).
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Somatic cell nuclear transfer (SCNT) can reprogram differentiated somatic cells into totipotency. Although pre-implantation development of SCNT embryos has greatly improved, most SCNT blastocysts are still arrested at the peri-implantation stage, and the underlying mechanism remains elusive. Here, we develop a 3D in vitro culture system for SCNT peri-implantation embryos and discover that persistent Wnt signals block the naïve-to-primed pluripotency transition of epiblasts with aberrant H3K27me3 occupancy, which in turn leads to defects in epiblast transformation events and subsequent implantation failure. Strikingly, manipulating Wnt signals can attenuate the pluripotency transition and H3K27me3 deposition defects in epiblasts and achieve up to a 9-fold increase in cloning efficiency. Finally, single-cell RNA-seq analysis reveals that Wnt inhibition markedly enhances the lineage developmental trajectories of SCNT blastocysts during peri-implantation development. Overall, these findings reveal diminished potentials of SCNT blastocysts for lineage specification and validate a critical peri-implantation barrier for SCNT embryos.
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Purpose: Paclitaxel-induced peripheral neuropathy (PIPN) constitutes a refractory and progressive adverse consequence of paclitaxel treatment, causing pain and sensory anomalies in cancer survivors. Although the gut-brain axis is involved in multiple disorders including cancer, its impact on peripheral pain conditions remains elusive. Thus, we assessed the importance of gut microbiota and related mechanisms in PIPN. Methods: By implementing fecal microbiota transplantation (FMT) in a rat PIPN model (ie, rats treated with paclitaxel; hereafter as PIPN rats), we explored the effect of gut microbiota on PIPN rats using multiple methods, including different behavioral tests, 16S ribosomal DNA (rDNA) sequencing, and biochemical techniques. Results: Sequencing of 16S rDNA revealed that the abundance of genera Bacteroides and UCG-005 increased, while that of genera Turicibacter, Clostridium sensu stricto 1 and Corynebacterium decreased in the PIPN rats. However, when treated with FMT using fecal from normal rats, the mechanical allodynia and thermal hyperalgesia in PIPN rats were significantly alleviated. In addition, FMT treatment reduced the expression of toll-like receptor 4 (TLR4), phospho-p38 mitogen-activated protein kinase (p-p38MAPK), and the astrocytic marker glial fibrillary acidic protein in the colon and spinal dorsal horn. TAK242 (a TLR4 inhibitor) significantly alleviated the behavioral hypersensitivity of PIPN rats and inhibited the TLR4/p38MAPK pathway in astrocytes in these rats. Conclusion: The gut microbiota played a critical role in PIPN. Future therapies treating PIPN should consider microbe-based treatment as an option.
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Colorectal cancer (CRC) therapy is a big challenge, and seeking an effective and safe drug is a pressing clinical need. Gambogic acid is a potent antineoplastic agent without the drawback of bone marrow suppression. To improve its druggability (e.g., poor water solubility and tumor delivery), a lactoferrin-modified gambogic acid liposomal delivery system (LF-lipo) was developed to enhance the treatment efficacy of CRC. The LF-lipo can specifically bind LRP-1 expressed on colorectal cancer cells to enhance drug delivery to the tumor cells and yield enhanced therapeutic efficacy. The LF-lipo promoted tumor cell apoptosis and autophagy, reduced reactive oxygen species (ROS) levels in tumor cells, and inhibited angiogenesis; moreover, it could also repolarize tumor-associated macrophages from the M2 to M1 phenotype and induce ICD to activate T cells, exhibiting the capability of remodeling the tumor immune microenvironment. The liposomal formulation yielded an efficient and safe treatment outcome and has potential for clinical translation.
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Neoplasias Colorrectales , Liposomas , Humanos , Liposomas/uso terapéutico , Lactoferrina , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Microambiente TumoralRESUMEN
Understanding the atomistic mechanisms of non-equilibrium processes during solid-state synthesis, such as nucleation and grain structure formation of a layered oxide phase, is a critical challenge for developing promising cathode materials such as Ni-rich layered oxide for Li-ion batteries. In this study, we found that the aluminum oxide coating layer transforms into lithium aluminate as an intermediate, which has favorable low interfacial energies with the layered oxide to promote the nucleation of the latter. The fast and uniform nucleation and formation of the layered oxide phase at relatively low temperatures were evidenced using solid-state nuclear magnetic resonance and in situ synchrotron X-ray diffraction. The resulting Ni-rich layered oxide cathode has fine primary particles, as visualized by three-dimensional tomography constructed using a focused-ion beam and scanning electron microscopy. The densely packed fine primary particles enable the excellent mechanical strength of the secondary particles, as demonstrated by in situ compression tests. This strategy provides a new approach for developing next-generation, high-strength battery materials.
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Cancer is generally considered a result of genetic mutations that cause epigenetic changes, leading to anomalous cellular behavior. Since 1970s, an increasing understanding of the plasma membrane and specifically the lipid alterations in tumor cells have provided novel insights for cancer therapy. Moreover, the advances in nanotechnology offer a potential opportunity to target the tumor plasma membrane while minimizing side effects on normal cells. To further develop membrane lipid perturbing tumor therapy, the first section of this review demonstrates the association between plasma membrane physicochemical properties and tumor signaling, metastasis, and drug resistance. The second section highlights existing nanotherapeutic strategies for membrane disruption, including lipid peroxide accumulation, cholesterol regulation, membrane structure disruption, lipid raft immobilization, and energy-mediated plasma membrane perturbation. Finally, the third section evaluates the prospects and challenges of plasma membrane lipid perturbing therapy as a therapeutic strategy for cancers. The reviewed membrane lipid perturbing tumor therapy strategies are expected to bring about necessary changes in tumor therapy in the coming decades.
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Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Lípidos de la Membrana/análisis , Membrana Celular/metabolismo , Microdominios de Membrana/química , Microdominios de Membrana/metabolismo , NanotecnologíaRESUMEN
Alleviating immunosuppression of the tumor microenvironment is an important strategy to improve immune checkpoint therapy. It is an urgent but unmet need to develop adjuvant therapeutics for assisting the mainstay immunotherapies. Trichosanthin is an approved gynecology drug in China and its immunomodulatory effects have drawn much attention as an old drug for new applications in cancer. In this work, a recombinant cell-penetrating trichosanthin (rTCS-LMWP) was prepared via genetic fusion of a cell-penetrating peptide sequence (LMWP) to trichosanthin aiming to overcome the intratumoral penetration and intracellular delivery challenges. The potential of trichosanthin as an adjuvant therapy was explored, including its effects on tumor cells, antigen-presenting cells, tumor immune microenvironment, and the synergistic effect in combination with anti-PD-1. The results revealed that rTCS-LMWP can stimulate the maturation of dendritic cells via activating the STING-TBK1-IRF3 pathway, repolarize the protumor M2-type macrophages, and upregulate the pro-inflammatory cytokine expression. Moreover, rTCS-LMWP can enhance anti-PD-1 therapeutic efficacy in a CT26-bearing mouse model. The synergistic effect involved the induction of immunogenic cell death in the tumors, the proliferation and functionalization of cytotoxic T cells, and the suppression of the immunosuppressive regulatory T cells. These findings indicate that trichosanthin can be developed as an immunomodulator to facilitate cancer immunotherapy.
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Neoplasias Colorrectales , Tricosantina , Animales , Ratones , Células Presentadoras de Antígenos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Citocinas , Tricosantina/farmacología , Tricosantina/uso terapéutico , Microambiente TumoralRESUMEN
Background: Metaplastic breast cancer (MBC) is a rare breast tumor and the prognostic factors for survival in patients still remain controversial. This study aims to develop and validate a nomogram to predict the overall survival (OS) of patients with MBC. Methods: We searched the Surveillance, Epidemiology, and End Results (SEER) database for data about patients including metaplastic breast cancer and infiltrating ductal carcinoma (IDC) from 2010 to 2018. The survival outcomes of patients between MBC and IDC were analyzed and compared with the Kaplan-Meier (KM) method. MBC patients were randomly allocated to the training set and validation I set by a ratio of eight to two. Meanwhile, the performance of this model was validated again by the validation II set, which consisted of MBC patients from the Union Hospital of Fujian Medical University between 2010 and 2018. The independent prognostic factors were selected by univariate and multivariate Cox regression analyses. The nomogram was constructed to predict individual survival outcomes for MBC patients. The discriminative power, calibration, and clinical effectiveness of the nomogram were evaluated by the concordance index (C-index), the receiver operating characteristic (ROC) curve, and the decision curve analysis (DCA). Results: MBC had a significantly higher T stage (T2 and above accounting for 75.1% vs 39.9%), fewer infiltrated lymph nodes (N0 accounted for 76.2% vs 67.7%), a lower proportion of ER (22.2% vs 81.2%), PR (13.6% vs 71.4%), and HER-2(6.7% vs 17.7%) positive, radiotherapy(51.6% vs 58.0%) but more chemotherapy(67.5% vs 44.7%), and a higher rate of mastectomy(53.2% vs 36.8%), which was discovered when comparing the clinical baseline data between MBC and IDC. Age at diagnosis, T, N, and M stage, as well as surgery and radiation treatment, were all significant independent prognostic factors for overall survival (OS). In the validation I cohort, the nomogram's C-index (0.769 95% CI 0.710 -0.828) was indicated to be considerably higher than the standard AJCC model's (0.700 95% CI 0.644 -0.756). Nomogram's great predictive capability capacity further was supported by the comparatively high C-index of the validation II sets (0.728 95%CI 0.588-0.869). Conclusions: Metaplastic breast cancer is more aggressive, with a worse clinical prognosis than IDC. This nomogram is recommended for patients with MBC, both American and Chinese, which can help clinicians make more accurate individualized survival analyses.
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In the therapy of placenta-originated diseases during pregnancy, the main challenges are fetal exposure to drugs, which can pass through the placenta and cause safety concerns for fetal development. The design of placenta-resident drug delivery system is an advantageous method to minimize fetal exposure as well as reduce adverse maternal off-target effects. By utilizing the placenta as a biological barrier, the placenta-resident nanodrugs could be trapped in the local placenta to concentrate on the treatment of this abnormal originated tissue. Therefore, the success of such systems largely depends on the placental retention capacity. This paper expounds on the transport mechanism of nanodrugs in the placenta, analyzes the factors that affect the placental retention of nanodrugs, and summarizes the advantages and concerns of current nanoplatforms in the treatment of placenta-originated diseases. In general, this review aims to provide a theoretical basis for the construction of placenta-resident drug delivery systems, which will potentially enable safe and efficient clinical treatment for placenta-originated diseases in the future.