Exosomes, a subset of extracellular vesicles, are released by all active cells and play a crucial role in intercellular communications. Exosomes could facilitate the transfer of various biologically active molecules, such as DNA, non-coding RNAs, and proteins, from donor to recipient cells, thereby participating in diverse biological and pathological processes. Besides, exosomes possess unique characteristics, including non-toxicity, low-immunogenicity, and stability within biological systems, rendering them highly advantageous for cancer drug development. Meanwhile, accumulating evidence suggests that exosomes originating from tumor cells and immune cells possess distinct composition profiles that play a direct role in anticancer immunotherapy. Of note, exosomes can transport their contents to specific cells, thereby exerting an impact on the phenotype and immune-regulatory functions of targeted cells. Therapeutic cancer vaccines, an emerging therapeutics of immunotherapy, could enhance antitumor immune responses by delivering a large number of tumor antigens, thereby augmenting the immune response against tumor cells. Therefore, the therapeutic rationale of cancer vaccines and exosome-based immunotherapy are almost similar to some extent, but some challenges have hindered their application in the clinical setting. Here, in this review, we first summarized the biogenesis, structure, compositions, and biological functions of exosomes. Then we described the roles of exosomes in cancer biology, particularly in tumor immunity. We also comprehensively reviewed current exosome-based anticancer vaccine development and we divided them into three types. Finally, we give some insights into clinical translation and clinical trial progress of exosome-based anticancer vaccines for future direction.
Environmental pollution management and renewable energy development are humanity's biggest issues in the 21st century. The rise in atmospheric CO2, which has surpassed 400 parts per million, has stimulated research on CO2 reduction and conversion methods. Presently, photocatalytic conversion of CO2 to valuable hydrocarbons enables the transformation of solar energy into chemical energy and offers a novel avenue for energy conversion while regulating the greenhouse effect. This is an ideal strategy for simultaneously addressing environmental issues and the energy crisis. Photocatalysts are essential to photocatalytic processes. Photocatalyst is the core of photocatalytic technology, and graphite carbon nitride (g-C3N4) has attracted much attention because of its nonmetallic characteristics, and it has the characteristics of low cost, tunable electronic structure, easy manufacture and strong reducibility. However, its activity is not only affected by external reaction conditions, but also by the band gap structure, physical and chemical stability, surface morphology and specific surface area of the photocatalyst it. In this paper, the application progress of g-C3N4-based photocatalytic materials in CO2 reduction is reviewed, and the modification strategies of g-C3N4-based catalysts to obtain better catalytic efficiency and selectivity in CO2 photocatalytic reduction are summarized, and the future development of this material is prospected.
Methamphetamine Use Disorder (MUD) is associated with substantially reduced quality of life. Yet, decisions to use persist, due in part to avoidance of anticipated withdrawal states. However, the specific cognitive mechanisms underlying this decision process, and possible modulatory effects of aversive states, remain unclear. Here, 56 individuals with MUD and 58 healthy comparisons (HCs) performed a decision task, both with and without an aversive interoceptive state induction. Computational modeling measured the tendency to test beliefs about uncertain outcomes (directed exploration) and the ability to update beliefs in response to outcomes (learning rates). Compared to HCs, those with MUD exhibited less directed exploration and slower learning rates, but these differences were not affected by aversive state induction. These results suggest novel, state-independent computational mechanisms whereby individuals with MUD may have difficulties in testing beliefs about the tolerability of abstinence and in adjusting behavior in response to consequences of continued use.
This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.
The current status of clinical trials utilizing nanoparticle drug delivery system (NDDS) for brain tumors was summarized.Image 1.
It is commonly known that different macrophage phenotypes play specific roles in different pathophysiological processes. In recent years, many studies have linked the phenotypes of macrophages to their characteristics in different metabolic pathways, suggesting that macrophages can perform different functions through metabolic reprogramming. It is now gradually recognized that lactate, previously overlooked as a byproduct of glycolytic metabolism, acts as a signaling molecule in regulating multiple biological processes, including immunological responses and metabolism. Recently, lactate has been found to mediate epigenetic changes in macrophages through a newfound lactylation modification, thereby regulating their phenotypic transformation. This novel finding highlights the significant role of lactate metabolism in macrophage function. In this review, we summarize the features of relevant metabolic reprogramming in macrophages and the role of lactate metabolism therein. We also review the progress of research on the regulation of macrophage metabolic reprogramming by lactylation through epigenetic mechanisms.
Cellular Reprogramming , Epigenesis, Genetic , Lactic Acid , Macrophages , Macrophages/metabolism , Macrophages/immunology , Humans , Animals , Lactic Acid/metabolism , Metabolic Reprogramming
Spontaneous ventilation video-assisted thoracoscopic surgery (SV-VATS) has rapidly developed in recent years. The application scope is still being continuously explored. We describe a case in which a 40-year-old woman with mixed ground-glass opacity (GGO) and an esophageal leiomyoma successfully underwent simultaneous segmentectomy and leiomyoma resection through spontaneous ventilation video-assisted thoracoscopic surgery. The perioperative course was uneventful. Postoperative pathology revealed minimally invasive adenocarcinoma and esophageal leiomyoma.
Background: This study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments. Methods: We conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1ß, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed. Results: A positive correlation was observed between g_Ruminococcus1 and the risk of osteoporosis, while O_Burkholderiales showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the O_Burkholderiales was significantly reduced, while the abundance of g_Ruminococcus was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of O_Burkholderiales is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of g_Ruminococcus shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors. Conclusion: O_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis.
AIMS: The intricate molecular mechanisms underlying estrogen receptor-positive (ER+) breast carcinogenesis and resistance to endocrine therapy remain elusive. In this study, we elucidate the pivotal role of GPR81, a G protein-coupled receptor, in ER+ breast cancer (BC) by demonstrating low expression of GPR81 in tamoxifen (TAM)-resistant ER+ BC cell lines and tumor samples, along with the underlying molecular mechanisms. MAIN METHODS: Fatty acid oxidation (FAO) levels and lipid accumulation were explored using MDA and FAßO assay, BODIPY 493/503 staining, and Lipid TOX staining. Autophagy levels were assayed using CYTO-ID detection and Western blotting. The impact of GPR81 on TAM resistance in BC was investigated through CCK8 assay, colony formation assay and a xenograft mice model. RESULTS: Aberrantly low GPR81 expression in TAM-resistant BC cells disrupts the Rap1 pathway, leading to the upregulation of PPARα and CPT1. This elevation in PPARα/CPT1 enhances FAO, impedes lipid accumulation and lipid droplet (LD) formation, and subsequently inhibits cell autophagy, ultimately promoting TAM-resistant BC cell growth. Moreover, targeting GPR81 and FAO emerges as a promising therapeutic strategy, as the GPR81 agonist and the CPT1 inhibitor etomoxir effectively inhibit ER+ BC cell and tumor growth in vivo, re-sensitizing TAM-resistant ER+ cells to TAM treatment. CONCLUSION: Our data highlight the critical and functionally significant role of GPR81 in promoting ER+ breast tumorigenesis and resistance to endocrine therapy. GPR81 and FAO levels show potential as diagnostic biomarkers and therapeutic targets in clinical settings for TAM-resistant ER+ BC.
BACKGROUND AND AIMS: Chemotherapy resistance in colorectal cancer have been faced with significant challenges in recent years. Particular interest is directed to tumor microenvironment function. Recent work has, identified a small molecule named Divertin that prevents myosin light chain kinase 1(MLCK1) recruitment to the perijunctional actomyosin ring(PAMR), restores barrier function after tumor necrosis factor(TNF)-induced barrier loss and prevents disease progression in experimental inflammatory bowel disease. Studies have shown that MLCK is a potential target for affecting intestinal barrier function, as well as for tumor therapy. However, the relative contributions of MLCK expression and chemotherapy resistance in colorectal cancers have not been defined. METHODS: Statistical analysis of MYLK gene expression differences in colorectal cancer patients and normal population and prognosis results from The Cancer Genome Atlas(TCGA) data. Cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. Determine the role of MLCK1 in inducing 5-Fluorouracil(5-Fu) resistance in colorectal cancer cells was detected by overexpression of MLCK1 and knock-down expression of MLCK1. RESULTS: MLCK1 is expressed at different levels in different colorectal cancer cells, high MLCK1 expressing cell lines are less sensitive to 5-Fu, and low MLCK1 expressing cell lines are more sensitive to 5-Fu. MLCK1 high expression enhances resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway. CONCLUSIONS: MLCK1 high expression can enhance resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway, which will provide a new method for the treatment of colorectal cancer patients who are resistant to 5-Fu chemotherapy.
It is very important to choose a suitable method and catalyst to treat coking wastewater. In this study, Fe-Ce-Al/MMT catalysts with different Fe/Ce molar ratios were prepared, characterized by XRD, SEM, and N2 adsorption/desorption, and treated with coking wastewater. The results showed that the optimal Fe-Ce-Al/MMT catalyst with a molar ratio of Fe/Ce of 7/3 has larger interlayer spacing, specific surface area, and pore volume. Based on the composition analysis of real coking wastewater and the study of phenol simulated wastewater, the response surface test of the best catalyst for real coking wastewater was carried out, and the results are as follows: initial pH 3.46, H2O2 dosage 19.02 mL/L, Fe2+ dosage 5475.39 mL/L, reaction temperature 60 °C, and reaction time 248.14 min. Under these conditions, the COD removal rate was 86.23%.
In order to search for high specific activity and the resistant xylanases to XIP-I and provide more alternative xylanases for industrial production, a strain of Fusarium graminearum from Triticum aestivum grains infected with filamentous fungus produced xylanases was isolated and identified. Three xylanase genes from Fusarium graminearum Z-1 were cloned and successfully expressed in E. coli and P. pastoris, respectively. The specific activities of Fgxyn1, EFgxyn2 and EFgxyn3 for birchwood xylan were 38.79, 0.85 and 243.83 U/mg in E. coli, and 40.11, 0 and 910.37 U/mg in P. pastoris, respectively. EFgxyn3 and PFgxyn3 had the similar optimum pH at 6.0 and pH stability at 5.0-9.0. However, they had different optimum temperature and thermal stability, with 30 °C for EFgxyn3 and 40 °C for PFgxyn3, and 4-35 °C for EFgxyn3 and 4-40 °C for PFgxyn3, respectively. The substrate spectrum and the kinetic parameters showed that the two xylanases also exhibited the highest xylanase activity and catalytic efficiency (kcat/km) toward birchwood xylan, with 243.83 U/mg and 61.44 mL/mg/s for EFgxyn3 and 910.37 U/mg and 910.37 mL/mg/s for PFgxyn3, respectively. This study provided a novel mesophilic xylanase with high specific activity and catalytic efficiency, thus making it a promising candidate for extensive applications in animal feed and food industry. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03973-0.
Given the extremely high inter-patient heterogeneity among acute myeloid leukemia (AML), identifying biomarkers for prognostic assessment and therapeutic guidance is crucial. Cell surface markers (CSMs) have been shown to play an important role in AML leukemogenesis and progression. In this study, we evaluate the prognostic potential of all human CSMs in AML patients based on differential gene expression analysis and univariate Cox regression analysis. Utilizing multi-model analysis, including Adaptive LASSO regression, LASSO regression, and Elastic Net, we construct a 9-CSMs prognostic model for risk stratification of AML patients. The predictive value of the 9-CSMs risk score is further confirmed in three independent datasets. Multivariate Cox regression analysis shows that the risk score is an independent prognostic factor for AML patients. AML patients with high 9-CSMs risk scores have shorter overall and event-free survival time than those with lower scores. Notably, our single-cell RNA-seq analysis indicates that patients with high 9-CSMs risk scores exhibit chemotherapy resistance. Further, PI3K inhibitors are identified as potential treatments for these high-risk patients. In conclusion, we construct a 9-CSMs prognostic model which is an independent prognostic factor for the survival of AML patients and has the potential to guide drug therapy.
Lung cancer is one of the top 10 causes of death in the world today, and it is a great concern worldwide for its high mortality rate. Currently, the researchers are digging into various factors influencing the occurrence and development of lung cancer in order to increase the odds for curing lung cancer, improve the prognosis of lung cancer patients as well as reduce its morbidity. The Mediterranean diet (MD) is a special dietary structure that is based on eating vegetables, fruits, coarse grains, legumes and low-fat fish, which have anti-inflammatory, antioxidant and lipid-lowering effects. Recent studies have revealed that the MD may prevent lung cancer occurrence to some extent and inhibit its development. The purpose of this paper is to summarize and analytically discuss the effects of the MD on the oncogenesis and development of lung cancer through a review of the relevant literatures, thus to provide references for MD to prevent and treat lung cancer.â©.
Diet, Mediterranean , Lung Neoplasms , Humans , Lung Neoplasms/diet therapy , Lung Neoplasms/prevention & control , Animals
Sepsis-associated encephalopathy (SAE) is a severe complication that affects the central nervous system and is a leading cause of increased morbidity and mortality in intensive care units. Psoralidin (PSO), a coumarin compound isolated from the traditional Chinese medicine Psoralea corylifolia L., can penetrate the blood-brain barrier and has various pharmacological activities, including anti-inflammation, anti-oxidation and anti-depression. This study aims to explore whether PSO alleviates SAE and delve into the underlying mechanisms. We found that PSO treatment significantly reduced sepsis scores, aspartate transaminase (AST) and aspartate transaminase (LDH), while increased anal temperature and neurological scores in CLP-injured mice. Moreover, PSO treatment ameliorated sepsis-associated cognitive impairment, mood, anxiety disorders, inhibited inflammatory responses, as well as attenuated endoplasmic reticulum stress (ERS). These results were also validated in vitro experiments, PSO treatment reduced ROS, inflammation response, and attenuated ERS in LPS-injured N2a cells. Importantly, tunicamycin (TUN), as ERS agonist, significantly reversed the protective effect of PSO on LPS-injured N2a cells, as evidenced by increased expression levels of IL-6, NLRP3, CHOP, and ATF6. Likewise, ATF6 overexpression also reversed the protective effect of PSO. In conclusion, these results confirmed that PSO has a protective effect on SAE, which was largely attributed to neuroinflammation and ERS. These findings provide new insights into the neuroprotective role of PSO and suggest that PSO is a new therapeutic intervention of SAE.
Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.
Mitochondria , Mitophagy , Humans , Mitochondria/metabolism , Mitochondria/physiology , Mitophagy/physiology , Mitophagy/drug effects , Mitochondrial Dynamics/physiology
OBJECTIVE: To evaluate the impact of previous poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy on the effectiveness of secondary cytoreductive surgery (SCS) in patients with platinum-sensitive recurrent ovarian cancer (PSROC). METHODS: We identified patients with PSROC who underwent SCS at the Cancer Hospital, Chinese Academy of Medical Science, between January 2010 and December 2022. Postoperative complications within 30 days were categorized using the Accordion Severity Grading System. The KaplanâMeier method was used to estimate both overall survival (OS) and progression-free survival (PFS), and multivariate analysis was used to identify independent prognostic factors. RESULTS: Of the 265 patients included, 39 received prior PARP inhibitor therapy (Group A), and 226 did not (Group B). The rates of complete resection after SCS did not significantly differ between the two groups (79.5 % for Group A vs. 81.0 % for Group B; p = 0.766). As of December 2023, Group A exhibited a significantly shorter median PFS (14.2 months) than Group B (22.5 months; p = 0.002). Furthermore, the 3-year OS rate was lower in Group A (72.5 %) than in Group B (82.7 %; p = 0.015). The incidence of severe postoperative complications was comparable between Groups A and B (7.7 % vs. 1.8 %; p = 0.061). Multivariate analysis revealed that prior PARP inhibitor therapy significantly reduced the median PFS (hazard ratio (HR) = 4.434; p = 0.021) and OS (HR = 2.076; p = 0.010). CONCLUSIONS: SCS for PSROC demonstrated reduced efficacy in patients previously treated with PARP inhibitors compared to those without prior PARP inhibitor treatment.
Persistent activation of estrogen receptor alpha (ERα)-mediated estrogen signaling plays a pivotal role in driving the progression of estrogen receptor positive (ER+) breast cancer (BC). In the current study, LINC00173, a long non-coding RNA, was found to bind both ERα and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα) factor (LITAF), then cooperatively to inhibit ERα protein degradation by impeding the nuclear export of ERα. Concurrently, LITAF was found to attenuate TNFα transcription after binding to LINC00173, and this attenuating transcriptional effect was quite significant under lipopolysaccharide stimulation. Distinct functional disparities between estrogen subtypes emerge, with estradiol synergistically promoting ER+ BC cell growth with LINC00173, while estrone (E1) facilitated LITAF-transcriptional activation. In terms of therapeutic significance, silencing LINC00173 alongside moderate addition of E1 heightened TNFα and induced apoptosis, effectively inhibiting ER+ BC progression.
Introduction: The need for effective balance control in lower limb rehabilitation exoskeletons is critical for ensuring stability and safety during rehabilitation training. Current research into specialized balance recovery strategies is limited, highlighting a gap in biomechanics-inspired control methods. Methods: We introduce a new metric called "Orbit Energy" (OE), which assesses the balance state of the human-exoskeleton system based on the dynamics of the overall center of mass. Our control framework utilizes OE to choose appropriate balance recovery strategies, including torque controls at the ankle and hip joints. Results: The efficacy of our control algorithm was confirmed through Matlab Simulink simulations, which analyzed the recovery of balance under various disturbance forces and conditions. Further validation came from physical experiments with human subjects wearing the exoskeleton, where a significant reduction in muscle activation was observed during balance maintenance under external disturbances. Discussion: Our findings underscore the potential of biomechanics-inspired metrics like OE in enhancing exoskeleton functionality for rehabilitation purposes. The introduction of such metrics could lead to more targeted and effective balance recovery strategies, ultimately improving the safety and stability of exoskeleton use in rehabilitation settings.
Lenvatinib is a commonly used first-line drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is limited due to the drug resistance. EVA1A was a newly identified tumor suppressor, nevertheless, the impact of EVA1A on resistance to lenvatinib treatment in HCC and the potential molecular mechanisms remain unknown. In this study, the expression of EVA1A in HCC lenvatinib-resistant cells is decreased and its low expression was associated with a poor prognosis of HCC. Overexpression of EVA1A reversed lenvatinib resistance in vitro and in vivo, as demonstrated by its ability to promote cell apoptosis and inhibit cell proliferation, invasion, migration, EMT, and tumor growth. Silencing EVA1A in lenvatinib-sensitive parental HCC cells exerted the opposite effect and induced resistance to lenvatinib. Mechanistically, upregulated EVA1A inhibited the PI3K/AKT/MDM2 signaling pathway, resulting in a reduced interaction between MDM2 and p53, thereby stabilizing p53 and enhancing its antitumor activity. In addition, upregulated EVA1A suppressed the PI3K/AKT/mTOR signaling pathway and promoted autophagy, leading to the degradation of mutant p53 and attenuating its oncogenic impact. On the contrary, loss of EVA1A activated the PI3K/AKT/MDM2 signaling pathway and inhibited autophagy, promoting p53 proteasomal degradation and mutant p53 accumulation respectively. These findings establish a crucial role of EVA1A loss in driving lenvatinib resistance involving a mechanism of modulating PI3K/AKT/p53 signaling axis and suggest that upregulating EVA1A is a promising therapeutic strategy for alleviating resistance to lenvatinib, thereby improving the efficacy of HCC treatment.
