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Abnormal tumor metabolism creates a complex tumor immune microenvironment that plays a dominant role in the metastasis of triple-negative breast cancer (TNBC). TNBC is insensitive to immune checkpoint blockade (ICB) therapy because of insufficient cytotoxic T lymphocyte (CTL) infiltration and a hyper-lactic acid-suppressive immune microenvironment caused by abnormal glycolysis. Herein, we propose an amplified strategy based on lactic acid regulation to reprogram the immunosuppressive tumor microenvironment (ITM) and combine it with ICB therapy to achieve enhanced antitumor immunotherapy effects. Specifically, we constructed CASN, a carrier-free photodynamic bioregulator, through the self-assembly of the photosensitizer Chlorin e6 and monocarboxylate transporter 1 (MCT1) inhibitor AZD3965. CASN exhibited a uniform structure, good stability, and drug accumulation at the tumor site. CASN-mediated photodynamic therapy following laser irradiation inhibited primary tumor growth and induced immunogenic cell death. Furthermore, CASN reduced lactic acid-mediated regulatory T cell generation and M2 tumor-associated macrophage polarization by blocking MCT1-mediated lactic acid efflux to attenuate immune suppression, inducing the recruitment and activation of CTLs. Ultimately, CASN-mediated immunopotentiation combined with ICB therapy considerably strengthened tumor immunotherapy and effectively inhibited tumor growth and metastasis of TNBC. This synergistic amplification strategy overcomes the limitations of an acidic ITM and presents a potential clinical treatment option for metastatic tumors.
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Accurate quantification of flow dynamics during reservoir ecological scheduling hinders the maintenance of normal reproductive activities in downstream riverine fish. This study proposed a quantitative method for determining the flow rate changes in reservoir ecological scheduling. The approach utilized the daily flow rate and daily flow-rate increment to characterize the flow process. Adopting the perspective of shifting spawning grounds of adhesive egg-laying fish species in response to flow rate variations, we introduced the Spawning Ground Overlap Rate as an indicator and utilized it to determine flow rate changes. Focusing on the downstream area of the Yangqu Hydropower Station in the upper reaches of the Yellow River, we calculated the distribution of spawning grounds and the Spawning Ground Overlap Rate in the region. We set a threshold for the Spawning Ground Overlap Rate to restrict the flow rate changes. The results indicated that during the fish spawning period, the ecological flow range in the downstream area of the Yangqu Dam was 480-1200 m3/s. It was required to maintain a daily flow rate change of less than 49.45 m3/(s·d) and a maximum seven-day flow difference of less than 227.76 m3/s to maintain the optimal level of spawning ground overlap rate. Additionally, it was necessary to keep the daily flow rate change below 123.83 m3/(s·d) and the maximum seven-day flow difference below 368.84 m3/s to maintain the minimum spawning ground overlap rate. The findings provide foundational data for determining flow dynamics during the ecological scheduling of the spawning period for viscous-spawning fish.
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Ríos , Animales , Peces/fisiología , Reproducción , Ecosistema , Ecología , China , Movimientos del AguaRESUMEN
BACKGROUND: Some recent studies have shown that female subclinical hypothyroidism (SCH) is associated with diminished ovarian reserve (DOR). In this study, we aimed to investigate whether serum-free thyroxine (fT4) concentrations within the reference range are associated with ovarian reserve in women. METHODS: This cross-sectional study included 4933 infertile women with normal-range fT4 concentrations who received assisted reproductive technology treatment in our clinic. The data of women in different fT4 concentration tertiles (namely 12-15.33, 15.34-18.67, and 18.68-22 pmol/L) were compared with ovarian reserve markers, namely the anti-Müllerian hormone (AMH) concentration, the antral follicle count (AFC), and the number of aspirated oocytes. The primary outcomes were the AMH concentration and the risk of DOR, diagnosed as an AMH concentration < 1.1 ng/mL. RESULTS: The average ages of women in the low-normal, middle-normal, and high-normal fT4 tertiles were 33.20 (standard deviation [SD]: 5.11), 32.33 (SD: 5.13), and 31.61 (SD: 5.10) years, respectively (p < 0.0001). AMH concentrations (adjusted mean: 3.32 [95% confidence interval {CI}: 3.16 to 3.50] vs. 3.51 [3.40 to 3.62] vs. 3.64 [3.50 to 3.80] ng/mL, p = 0.022) were significantly different between the fT4 concentration tertiles. The risk of DOR was significantly increased in the low-normal (adjusted odds ratio: 1.61 [95% CI: 1.01 to 2.58]) and middle-normal (1.47 [95% CI: 1.00 to 2.16]) tertiles compared with the high-normal tertile. Subgroup analysis showed that AMH concentrations were significantly different among the fT4 concentration tertiles in women aged < 35 years (adjusted mean: 3.94 [95% CI: 3.70 to 4.20] vs. 4.25 [4.11 to 4.39] vs. 4.38 [4.18 to 4.58], p = 0.028), whereas this difference was not significant in women aged ≥ 35 years (p = 0.534). The general additive models using fT4 as a continuous variable indicated that a lower fT4 concentration within the normal range was significantly associated with a lower AMH concentration (p = 0.027), a lower AFC (p = 0.018), a lower number of aspirated oocytes (p = 0.001), and a higher risk of DOR (p = 0.007). CONCLUSION: Low-normal fT4 concentrations are associated with lower ovarian reserve in infertile women.
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Hormona Antimülleriana , Infertilidad Femenina , Reserva Ovárica , Técnicas Reproductivas Asistidas , Tiroxina , Humanos , Femenino , Reserva Ovárica/fisiología , Adulto , Estudios Transversales , Infertilidad Femenina/sangre , Infertilidad Femenina/terapia , Infertilidad Femenina/diagnóstico , Tiroxina/sangre , Hormona Antimülleriana/sangre , Valores de Referencia , Hipotiroidismo/sangreRESUMEN
BACKGROUND: Nauclea officinalis (Pierre ex Pit.) Merr. & Chun (Rubiaceae) is widely used to treat respiratory diseases in China. Strictosamide is its main active component and has significant anti-inflammatory activity. However, the effects and molecular mechanisms of strictosamide in the treatment of acute lung injury (ALI) remain largely unknown. PURPOSE: This study aimed to examine the regulatory effects of strictosamide on T helper 17 cells (Th17 cells)/Regulatory T cells (Treg cells) and gut microbiota in ALI-affected mice. MATERIALS AND METHODS: The ALI model was induced using lipopolysaccharide (LPS) intraperitoneal injection. Hematoxylin-eosin (H&E) staining, the number of inflammatory cells in broncho-alveolar lavage fluid (BALF), the Wet/Dry (W/D) ratio, and myeloperoxidase (MPO) activity were utilized as evaluation indices for the therapeutic efficacy of strictosamide on ALI. Flow cytometry (FCM), enzyme-linked immune sorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to determine the regulation of strictosamide on the Th17/Treg cells and the STAT3/STAT5 signaling pathway. The analysis of gut microbiota was conducted using 16S rDNA sequencing. The verification of the relationship between the gut microbiome and immune function was conducted using Spearman analysis. RESULTS: Strictosamide attenuated inflammation on ALI induced by LPS, which reduced the levels of Th17-related factors interleukin (IL)-6 and IL-17 and increased Treg-related factors IL-10 and transforming growth factor (TGF)-ß. In the spleens and whole blood, strictosamide reduced the proportion of Th17 cells and increased the proportion of Treg cells. Furthermore, strictosamide increased Forkhead/winged helix transcription factor 3 (Foxp3) and p-STAT5 protein expression while inhibiting Retinoid-related orphan nuclear receptors-γt (RORγt) and p-STAT3 expression. Moreover, strictosamide reshaped the diversity and structure of the gut microbiota, and influence the associations between immune parameters and gut microbiota in ALI mice. CONCLUSIONS: In summary, the results of the current investigation showed that strictosamide has a therapeutic impact on LPS-induced ALI. The mechanism of action of this effect may be associated with the modulation of Th17 and Treg cells differentiation via the SATA signaling pathway, as well as the impact of the gut microbiota.
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Lesión Pulmonar Aguda , Microbioma Gastrointestinal , Lipopolisacáridos , Factor de Transcripción STAT3 , Linfocitos T Reguladores , Células Th17 , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Células Th17/efectos de los fármacos , Masculino , Ratones , Factor de Transcripción STAT3/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/citologíaRESUMEN
Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.
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Antineoplásicos , Fibroblastos Asociados al Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Interleucina-8 , Neoplasias Pulmonares , Animales , Ratones , Antígenos CD , Antígenos de Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Interleucina-8/genética , Interleucina-8/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , FN-kappa B , HumanosRESUMEN
Traumatic brain injury (TBI) can induce systemic coagulopathy and inflammation, thereby increasing the risk of mortality and disability. However, the mechanism causing systemic coagulopathy and inflammation following TBI remains unclear. In prior research, we discovered that brain-derived extracellular vesicles (BDEVs), originating from the injured brain, can activate the coagulation cascade and inflammatory cells. In this study, we primarily investigated how BDEVs affect systemic coagulopathy and inflammation in peripheral circulation. The results of cytokines and coagulation function indicated that BDEVs can lead to systemic coagulopathy and inflammation by influencing inflammatory factors and chemokines within 24 h. Furthermore, according to flow cytometry and blood cell counter results, we found that BDEVs induced changes in the blood count such as a reduced number of platelets and leukocytes and an increased percentage of neutrophils, macrophages, activated platelets, circulating platelet-EVs, and leukocyte-derived EVs. We also discovered that eliminating circulating BDEVs with lactadherin helped improve coagulopathy and inflammation, relieved blood cell dysfunction, and decreased the circulating platelet-EVs and leukocyte-derived EVs. Our research provides a novel viewpoint and potential mechanism of TBI-associated secondary damage.
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Trastornos de la Coagulación Sanguínea , Lesiones Traumáticas del Encéfalo , Vesículas Extracelulares , Humanos , Lesiones Traumáticas del Encéfalo/complicaciones , Inflamación/complicaciones , Encéfalo , Trastornos de la Coagulación Sanguínea/etiologíaRESUMEN
BACKGROUND: Solar cell/supercapacitor integrated devices (SCSD) have made some progress in terms of device structure and electrode materials, but there are still many key challenges in controlling electrode performance and improving the efficiency of integrated devices. AIM OF REVIEW: It is necessary to study how to balance the photoelectric conversion process and the storage process. From the microscopic mechanism of different functional unit materials to the mechanism of macroscopic devices, it is essential to conduct in-depth research. KEY SCIENTIFIC CONCEPTS OF REVIEW: Here, the structures and preparation methods of various types of integrated SCSD were introduced. Then, the strategies for improving the overall performance of integrated devices were evaluated. Finally, the key objectives of reducing the cost of materials, increasing the stability and sustainability of devices were highlighted. Better matching of different functional units of devices was also prospected.
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BACKGROUND: Spiraea L. is a genus comprising approximately 90 species that are distributed throughout the northern temperate regions. China is recognized as the center of species diversity for this genus, hosting more than 70 species, including 47 endemic species. While Spiraea is well-known for its ornamental value, its taxonomic and phylogenetic studies have been insufficient. RESULTS: In this study, we conducted sequencing and assembly of the plastid genomes (plastomes) of 34 Asiatic Spiraea accessions (representing 27 Asiatic Spiraea species) from China and neighboring regions. The Spiraea plastid genome exhibits typical quadripartite structures and encodes 113-114 genes, including 78-79 protein-coding genes (PCGs), 30 tRNA genes, and 4 rRNA genes. Linear regression analysis revealed a significant correlation between genome size and the length of the SC region. By the sliding windows method, we identified several hypervariable hotspots within the Spiraea plastome, all of which were localized in the SC regions. Our phylogenomic analysis successfully established a robust phylogenetic framework for Spiraea, but it did not support the current defined section boundaries. Additionally, we discovered that the genus underwent diversification after the Early Oligocene (~ 30 Ma), followed by a rapid speciation process during the Pliocene and Pleistocene periods. CONCLUSIONS: The plastomes of Spiraea provided us invaluable insights into its phylogenetic relationships and evolutionary history. In conjunction with plastome data, further investigations utilizing other genomes, such as the nuclear genome, are urgently needed to enhance our understanding of the evolutionary history of this genus.
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Genoma del Cloroplasto , Genoma de Plastidios , Rosaceae , Spiraea , Filogenia , Evolución Molecular , Genoma del Cloroplasto/genéticaRESUMEN
Cancer associated fibroblasts (CAFs) are one of the main components of tumor microenvironment (TME). In TME, the interaction between tumor cells and non-tumor cells or among non tumor cells can promote the occurrence and development of tumors. CAFs can interact with a variety of immune cells and promote the occurrence and development of tumors by inhibiting the function of adaptive immune cells and reshaping the immune microenvironment in TME. The interaction between CAFs and macrophages and the induction of macrophage polarization towards M2 type play an important role in promoting tumor occurrence and development. This article reviews the research progress of CAF in promoting the polarization of M2 macrophages.
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Fibroblastos Asociados al Cáncer , Fibroblastos Asociados al Cáncer/patología , Macrófagos/patología , Microambiente TumoralRESUMEN
Background: Cyclin-dependent kinase inhibitor 3 (CDKN3) has been studied in many cancers. However, the comprehensive and systematic pancancer analysis of CDKN3 genes is still lacking. Methods: Data were downloaded from online databases. R was used for analysis of the differential expression and gene alteration of CDKN3 and of the associations between CDKN3 expression and survival, signaling pathways, and drug sensitivity. Clinical samples and in vitro experiments were selected for verification. Results: CDKN3 expression was higher in most types of cancers, and this phenotype was significantly correlated with poor survival. CDKN3 showed gene alterations and copy number alterations in many cancers and associated with some immune-related pathways and factors. Drug sensitivity analysis elucidated that CDKN3 could be a useful marker for therapy selection. Clinical samples elucidated CDKN3 expressed high in endometrial cancer tissue. In vitro studies showed that CDKN3 induced pro-tumor effect in immune environment and facilitated endometrial cancer cell proliferation and G1/S phase transition. Conclusion: CDKN3 has been shown to be highly expressed in most types of cancers and promoted cancer cell progression. CDKN3 may serve as a novel marker in clinical diagnosis, treatment, and prognosis prediction in future.
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Estrogen receptor (ER)-positive breast cancer (BRCA) is the most commonly diagnosed molecular subtype of BRCA. It is routinely treated with endocrine therapy; however, some patients relapse after therapy and develop drug resistance, resulting in treatment failure. In the present study, we identified markers of ER-positive BRCA and evaluated their putative function in immune infiltration as well as their clinicopathological significance. The ubiquitin family domain containing 1 (UBFD1) protein was associated with the prognosis of ER-positive BRCA patients. Its expression was higher in ER-positive BRCA tissues compared with adjacent nontumor tissues. Patients with higher UBFD1 expression had a poorer prognosis. UBFD1 is an independent risk factor for ER-positive BRCA patients and its function was primarily associated with hormone activity and inflammation. Taken together, UBFD1 is a potential prognostic biomarker and candidate target of ER-positive BRCA.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Pronóstico , Recurrencia Local de Neoplasia , BiomarcadoresRESUMEN
STUDY QUESTION: Does a humanin analogue (HNG) have a therapeutic effect on intrauterine adhesions (IUAs) caused by uterine cavity surgery in a rat model? SUMMARY ANSWER: HNG supplementation attenuated the development of endometrial fibrosis and IUAs, improved fertility, and contributed to the regulation of endometrial fibrosis by inhibiting endometrial ferroptosis in rats with IUAs. WHAT IS KNOWN ALREADY: IUAs, which are characterized by endometrial fibrosis, are a common cause of female infertility. Humanin (rattin in rats) is a mitochondrial-derived peptide that is widely expressed in multiple tissues. S14G-humanin (HNG) is an HNG that has been reported to have a protective effect against myocardial fibrosis. STUDY DESIGN, SIZE, DURATION: Endometrial tissues from three patients with IUAs and three controls were tested for humanin expression. Two animal models were used to evaluate the modelling effect of IUAs and the preventive effect of HNG against IUAs. In the first model, 40 rats were equally randomized to control and Day 7, 14, and 21 groups to establish the IUA model. In the second model, 66 rats were equally randomized to the control, IUA, and IUA + humanin analogue (HNG) groups. Erastin was used to induce ferroptosis in the Ishikawa cell line. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endometrium was scraped with a surgical spatula, combined with lipopolysaccharide treatment, to establish the rat model of IUAs. Rats were intraperitoneally injected with 5 mg/kg/day HNG for 21 consecutive days beginning from the day of operation to evaluate the therapeutic effect on IUAs. Haematoxylin-eosin and Masson's trichrome staining were used to assess endometrial morphology and evaluate fibrosis. Ferroptosis-related markers, namely nuclear factor E2-related factor 2 (Nrf2), acyl-CoA synthetase long-chain family member 4 (ACSL4), haeme oxygenase-1 (HO-1), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and ferritin, were measured by immunohistochemistry and western blotting to determine whether ferroptosis was involved in the development of IUAs and to assess the attenuative effect of HNG on ferroptosis. Additionally, the female rats were mated with male rats with normal fertility to assess fertility. MAIN RESULTS AND THE ROLE OF CHANCE: Humanin was widely expressed in endometrial cells, including epithelial and stromal cells, in both humans and rats. Humanin expression levels were downregulated in the endometria of patients and rats with IUAs relative to the endometria of controls. Endometrial thickness and the number of glands were significantly decreased on Day 7, 14, and 21 after endometrial scraping when compared with the controls (all P < 0.05), whereas the fibrotic area was significantly increased (P < 0.05). Among the tested ferroptosis markers, the expression levels of Nrf2, SLC7A11, and GPX4 were significantly downregulated and those of ACSL4, HO-1, and ferritin were significantly upregulated after endometrial scraping relative to their expression levels in controls (all P < 0.05). The mating rates in the control, IUA, and IUA + HNG groups were 100% (10/10), 40% (4/10), and 80% (8/10), respectively. The number of embryos in rats with IUAs (mean ± SD: 1.6 ± 2.1) was significantly less than the number in the controls (11.8 ± 1.5). HNG supplementation significantly attenuated this decrease in the number of implanted embryos (6.3 ± 4.5) (P < 0.01). Further results showed that HNG significantly attenuated the altered expression levels of proteins involved in ferroptosis in the endometria of rats with IUAs. Moreover, in vitro experiments showed that HNG significantly attenuated the erastin-induced decrease in the viability of the Ishikawa cell line and also attenuated the increase in reactive oxygen species production and the downregulation of GPX4. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: The findings of this study showed that HNG inhibited ferroptosis and reduced fibrosis in a rat model of IUAs. However, we could not establish a causal relationship between ferroptosis and the development of IUAs. WIDER IMPLICATIONS OF THE FINDINGS: HNG may be effective at alleviating fibrosis during the development of IUAs, and the inhibition of ferroptosis is a promising new strategy for IUA therapy. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (No. 82171647); the '1000 Talent Plan' of Yunnan Province (No. RLQN20200001); and the Basic Research Project of the Yunnan Province-Outstanding Youth Foundation (No. 202101AW070018). The authors declare no competing financial interests.
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Ferroptosis , Enfermedades Uterinas , Humanos , Adolescente , Ratas , Animales , Femenino , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , China , Endometrio/metabolismo , Enfermedades Uterinas/metabolismo , Células Epiteliales/metabolismo , Fibrosis , Ferritinas/metabolismo , Proteínas/metabolismoRESUMEN
Traumatic brain injury (TBI) can negatively impact systemic organs, which can lead to more death and disability. However, the mechanism underlying the effect of TBI on systemic organs remains unclear. In previous work, we found that brain-derived extracellular vesicles (BDEVs) released from the injured brain can induce systemic coagulation with a widespread fibrin deposition in the microvasculature of the lungs, kidney, and heart in a mouse model of TBI. In this study, we investigated whether BDEVs can induce heart, lung, liver, and kidney injury in TBI mice. The results of pathological staining and related biomarkers indicated that BDEVs can induce histological damage and systematic dysfunction. In vivo imaging system demonstrated that BDEVs can gather in systemic organs. We also found that BDEVs could induce cell apoptosis in the lung, liver, heart, and kidney. Furthermore, we discovered that BDEVs could cause multi-organ endothelial cell damage. Finally, this secondary multi-organ damage could be relieved by removing circulating BDEVs. Our research provides a novel perspective and potential mechanism of TBI-associated multi-organ damage.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Vesículas Extracelulares , Ratones , Animales , Encéfalo/patología , Lesiones Encefálicas/patología , Apoptosis , Vesículas Extracelulares/patologíaRESUMEN
Endothelial dysfunction is a key proponent of pathophysiological process of traumatic brain injury (TBI). We previously demonstrated that extracellular vesicles (EVs) released from injured brains led to endothelial barrier disruption and vascular leakage. However, the molecular mechanisms of this EV-induced endothelial dysfunction (endotheliopathy) remain unclear. Here, we enriched plasma EVs from TBI patients (TEVs), and detected high mobility group box 1 (HMGB1) exposure to 50.33 ± 10.17% of TEVs and the number of HMGB1+TEVs correlated with injury severity. We then investigated for the first time the impact of TEVs on endothelial function using adoptive transfer models. We found that TEVs induced dysfunction of cultured human umbilical vein endothelial cells and mediated endothelial dysfunction in both normal and TBI mice, which were propagated through the HMGB1-activated receptor for advanced glycation end products (RAGE)/Cathepsin B signaling, and the resultant NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and canonical caspase-1/gasdermin D (GSDMD)-dependent pyroptosis. Finally, von Willebrand factor (VWF) was detected on the surface of 77.01 ± 7.51% of HMGB1+TEVs. The TEV-mediated endotheliopathy was reversed by a polyclonal VWF antibody, indicating that VWF might serve a coupling factor that tethered TEVs to ECs, thus facilitating HMGB1-induced endotheliopathy. These results suggest that circulating EVs isolated from patients with TBI alone are sufficient to induce endothelial dysfunction and contribute to secondary brain injury that are dependent on immunologically active HMGB1 exposed on their surface. This finding provided new insight for the development of potential therapeutic targets and diagnostic biomarkers for TBI.
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Lesiones Traumáticas del Encéfalo , Vesículas Extracelulares , Proteína HMGB1 , Enfermedades Vasculares , Humanos , Ratones , Animales , Factor de von Willebrand , Lesiones Traumáticas del Encéfalo/complicaciones , Células Endoteliales de la Vena Umbilical HumanaRESUMEN
Objectives: To obtain the normal values of fractional concentration of nasal nitric oxide in Chinese children aged 6-18 years, so as to provide reference for clinical diagnosis. Methods: 2,580 out of 3,200 children (1,359 males and 1,221 females), whom were included from 12 centers around China were taken tests, their height and weight were also recorded. Data were used to analyze the normal range and influencing factors of fractional concentration of nasal nitric oxide values. Measurements: Data was measured using the Nano Coulomb Breath Analyzer (Sunvou-CA2122, Wuxi, China), according to the American Thoracic Society/European Respiratory Society (ATS/ERS) recommendations. Main Results: We calculated the normal range and prediction equation of fractional concentration of nasal nitric oxide values in Chinese children aged 6-18 years. The mean FnNO values of Chinese aged 6-18 yrs was 454.5 ± 176.2â ppb, and 95% of them were in the range of 134.5-844.0â ppb. The prediction rule of FnNO values for Chinese children aged 6-11 yrs was: FnNO = 298.881 + 17.974 × age. And for children aged 12-18 yrs was: FnNO = 579.222-30.332 × (male = 0, female = 1)-5.503 × age. Conclusions: Sex and age were two significant predictors of FnNO values for Chinese children(aged 12-18â yrs). Hopefully this study can provide some reference value for clinical diagnosis in children.
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Triple negative breast cancer (TNBC) is a highly aggressive subtype with a poor prognosis due to its high rates of proliferation and metastasis. Recently, hydrogen sulfide (H2S) has been recognized as a novel gasotransmitter that plays a significant role in various pathological processes, including cancer. Here, we show that exogenous H2S inhibited TNBC cancer cell proliferation, migration and invasion in vitro, and also decreased cancer malignances in the mouse model of TNBC. To investigate the underlying mechanisms of H2S's anti-cancer effects in TNBC, we performed transcriptome sequencing and bioinformatic analyses. 2121 differentially expressed genes (DEGs) were revealed, and mainly enriched in cell cycle and DNA replication pathways. Further analysis revealed changes in alternative splicing after exogenous H2S treatment. Protein-protein interaction (PPI) network analysis was performed, which identified 458 interactions among 276 DEGs enriched in cell cycle and DNA replication pathways.We identified seven hub genes (MCM3, MCM4, MCM5, MCM6, CDC6, CDC45, and GINS2) through PPI network analysis, which were up-regulated in clinical human breast cancer but down-regulated after H2S treatment. Based on the hub genes selected, we developed a model predicting that exogenous H2S mainly exerts its anti-TNBC role by delaying DNA replication. Our findings suggest that exogenous H2S has potential as a therapeutic agent in TNBC and may exert its therapeutic potential through DNA replication and the cell cycle pathway.
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Sulfuro de Hidrógeno , Neoplasias de la Mama Triple Negativas , Animales , Ratones , Humanos , Sulfuro de Hidrógeno/farmacología , Sulfuro de Hidrógeno/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Ciclo Celular , Mapas de Interacción de Proteínas , Replicación del ADN , Regulación Neoplásica de la Expresión Génica , Proteínas Cromosómicas no Histona/genéticaRESUMEN
BACKGROUND AND AIMS: The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH) and establish microbiome-based molecular subtyping of HBV-related HCC to elucidate the correlation between IMH and HCC tumorigenesis. APPROACH AND RESULTS: A case-control study was designed to investigate microbial landscape and characteristic microbial signatures of HBV-related HCC tissues adopting metagenomics next-generation sequencing. Microbiome-based molecular subtyping of HCC tissues was established by nonmetric multidimensional scaling. The tumor immune microenvironment of 2 molecular subtypes was characterized by EPIC and CIBERSORT based on RNA-seq and verified by immunohistochemistry. The gene set variation analysis was adopted to explore the crosstalk between the immune and metabolism microenvironment. A prognosis-related gene risk signature between 2 subtypes was constructed by the weighted gene coexpression network analysis and the Cox regression analysis and then verified by the Kaplan-Meier survival curve.IMH demonstrated in HBV-related HCC tissues was comparably lower than that in chronic hepatitis tissues. Two microbiome-based HCC molecular subtypes, defined as bacteria- and virus-dominant subtypes, were established and significantly correlated with discrepant clinical-pathologic features. Higher infiltration of M2 macrophage was detected in the bacteria-dominant subtype with to the virus-dominant subtype, accompanied by multiple upregulated metabolism pathways. Furthermore, a 3-gene risk signature containing CSAG4 , PIP4P2 , and TOMM5 was filtered out, which could predict the clinical prognosis of HCC patients accurately using the Cancer Genome Atlas data. CONCLUSIONS: Microbiome-based molecular subtyping demonstrated IMH of HBV-related HCC was correlated with a disparity in clinical-pathologic features and tumor microenvironment (TME), which might be proposed as a biomarker for prognosis prediction of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Estudios de Casos y Controles , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/etiología , Microambiente TumoralRESUMEN
Increasing Cashmere production can add value because it is the primary product of Cashmere goats. Recent years, peoples find miRNAs are crucial in regulating the development of hair follicle. Following Solexa sequencing, many miRNAs were distinguishingly expressed in telogen skin samples of goats and sheep in earlier study. But the method through which miR-21 controls the growth of hair follicles is still ambiguous. Bioinformatics analysis was used to predict the target genes of miR-21. The mRNA level of miR-21 in telogen Cashmere goat skins was higher than in anagen, according to the results of qRT-PCR, and the target genes expressed similarly with miR-21. Western blot showed similar trend, the protein expression of FGF18 and SMAD7 were lower in anagen samples. The Dual-Luciferase reporter assay confirmed miRNA-21's relationship with its target gene, and the consequences indicated found FGF18 and SMAD7 have positive correlations with miR-21. Western blot and qRT-PCR distinguished the expression of protein and mRNA in miR-21 and its target genes. According to the consequence, we found that target genes expression was increased by miR-21 in HaCaT cells. This study identified that miR-21 might take part in the development of Cashmere goat's hair follicles by targeting FGF18 and SMAD7.
Asunto(s)
Folículo Piloso , MicroARNs , Animales , Ovinos/genética , Folículo Piloso/metabolismo , Cabras , Perfilación de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/genéticaRESUMEN
Gastrointestinal cancers are the most common type of cancer affecting humans. High expression of HOX transcript antisense intergenic RNA (HOTAIR), a long noncoding RNA (lncRNA), in various types of different tumors may be associated with poor prognosis. In the present study, we performed a meta-analysis of the relationship between HOTAIR expression and gastrointestinal cancers. Five databases were comprehensively searched for all literature until January 2023. Moreover, the target genes of HOTAIR were predicted by coexpression analysis based on The Cancer Genome Atlas (TCGA) gene expression matrix for six gastrointestinal cancer types. Finally, the mechanism through which HOTAIR affects tumors of the digestive system was systematically reviewed. Our results showed that the high HOTAIR expression group had worse outcomes with a pooled hazard ratio (HR) of 1.56 (95% confidence interval [CI] = 1.38-1.75, P<0.001). Furthermore, HOTAIR was identified as an unfavorable prognostic factor for overall survival (OS) in the esophageal carcinoma (ESCA) and gastric cancer (GC), as the HR were 1.94 and 1.58, respectively. The high correlation between the expression of homeobox C (HOXC) family genes and HOTAIR, with correlation coefficients of 0.863 (HOXC11), 0.664 (HOXC10), 0.645 (HOXC8), and 0.581 (HOXC12). The 'cell cycle' pathway and pathways relating to infections, namely 'herpes simplex virus 1 infection' and 'complement and coagulation cascades' were significantly enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Also, we perform a systematic review to summarize the related oncogenic mechanism of HOTAIR. In conclusion, the HOTAIR has been identified as a potential prognostic factor in patients with gastrointestinal cancers.