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BACKGROUND: The nutrient-absorbing villi of small intestines are renewed and repaired by intestinal stem cells (ISCs), which reside in a well-organized crypt structure. Genetic studies have shown that Wnt molecules secreted by telocytes, Gli1+ stromal cells, and epithelial cells are required for ISC proliferation and villus homeostasis. Intestinal stromal cells are heterogeneous and single-cell profiling has divided them into telocytes/subepithelial myofibroblasts, myocytes, pericytes, trophocytes, and Pdgfralow stromal cells. Yet, the niche function of these stromal populations remains incompletely understood. RESULTS: We show here that a Twist2 stromal lineage, which constitutes the Pdgfralow stromal cell and trophocyte subpopulations, maintains the crypt structure to provide an inflammation-restricting niche for regenerating ISCs. Ablating Twist2 lineage cells or deletion of one Wntless allele in these cells disturbs the crypt structure and impairs villus homeostasis. Upon radiation, Wntless haplo-deficiency caused decreased production of anti-microbial peptides and increased inflammation, leading to defective ISC proliferation and crypt regeneration, which were partially rescued by eradication of commensal bacteria. In addition, we show that Wnts secreted by Acta2+ subpopulations also play a role in crypt regeneration but not homeostasis. CONCLUSIONS: These findings suggest that ISCs may require different niches for villus homeostasis and regeneration and that the Twist2 lineage cells may help to maintain a microbe-restricted environment to allow ISC-mediated crypt regeneration.
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Linaje de la Célula , Homeostasis , Intestinos , Nicho de Células Madre , Células Madre , Células Madre/citología , Células Madre/metabolismo , Intestinos/citología , Intestinos/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Animales , RatonesRESUMEN
BACKGROUND: Preliminary evidence demonstrates that visit-to-visit systolic blood pressure (SBP) variability is a prognostic factor of TBI. However, literature regarding the impact of initial blood pressure management on the outcomes of TBI patients is limited. We aimed to further validate the clinical significance of BPV on the prognostic outcomes of patients with TBI. METHODS: We performed the analysis by using individual patient-level data acquired from the eICU-CRD, which collected 200,859 ICU admissions of 139,367 patients in 2014 and 2015 from 208 US hospitals. Adult patients with traumatic intraparenchymal hemorrhage or contusion were included. The primary outcome was in-hospital mortality and the secondary outcome was discharge-home rate. Blood pressure variability (BPV) was calculated according to standard criteria: at least six measurements were taken in the first 24 h (hyperacute group) and 36 over days 2-7 (acute group). We estimated the associations between BPV and outcomes with logistic and proportional odds regression models. The key parameter for BPV was standard deviation (SD) of SBP, categorized into quintiles. We also calculated the average real variability (ARV), as well as maximum, minimum, and mean SBP for comparison in our analysis. RESULTS: We studied 1486 patients in the hyperacute group and 857 in the acute group. SD of SBP had a significant association with the in-hospital mortality for both the hyperacute group (highest quintile adjusted OR 2.28 95% CI 1.18-4.42; ptrend<0.001) and the acute group (highest quintile adjusted OR 2.17, 95% CI 1.08-4.36; ptrend<0.001). The strongest predictors of primary outcome were SD of SBP in the hyperacute phase and minimum SBP in the acute phase. Associations were similar for the discharge-home rate (for the hyperacute group, highest quintile adjusted OR 0.58, 95% CI 0.37-0.89; ptrend<0.001; for the acute group OR 0.55, 95% CI 0.32-0.95; ptrend<0.001). CONCLUSION: Systolic BPV seems to predict a poor outcome in patients with TBI. The benefits of early treatment to maintain appropriate SBP level might be enhanced by smooth and sustained control.
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Presión Sanguínea , Lesiones Traumáticas del Encéfalo , Mortalidad Hospitalaria , Humanos , Masculino , Femenino , Lesiones Traumáticas del Encéfalo/mortalidad , Lesiones Traumáticas del Encéfalo/fisiopatología , Pronóstico , Persona de Mediana Edad , Adulto , Anciano , Unidades de Cuidados Intensivos/estadística & datos numéricos , Estados Unidos/epidemiología , Bases de Datos FactualesRESUMEN
BACKGROUND: Septic shock is one of the leading causes of mortality in intensive care units. This retrospective study was carried out to evaluate the association of clinical available factors with 28-day mortality. PATIENTS AND METHOD: In this observational study, patients with perioperative septic shocks secondary to intra-abdominal infection caused by enteric perforation were included. A total of 328 sepsis patients were admitted to the surgical intensive care units from January 2012 to December 2016. A total of 138 patients met the enrolment criteria and were included in the study. The data of demographic, clinical and laboratory were all recorded. RESULT: All these 138 patients received abdominal surgery prior to surgical intensive care units caused by acute enteric perforation. These patients were all met the diagnostic criteria of septic shock according to Sepsis-3. Statistical analysis showed that lactic acid, blood platelet, fibrinogen, creatinine and activated partial thromboplastin time were found to be associated with 28-day mortality. A combination of serum activated partial thromboplastin time combined with fibrinogen and creatinine could predict in-hospital 28-day mortality. The area under the curve of serum activated partial thromboplastin time combined with fibrinogen and creatinine is 0.875 (0.806-0.944). CONCLUSION: In conclusion, this pilot study demonstrated that these factors can predict the prognosis of septic shock caused by enteric perforation. In order to reduce the mortality, surgeons and intensive care units physician may consider these data in perioperative period.
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Hemostáticos , Sepsis , Choque Séptico , Humanos , Fibrinógeno , Tiempo de Tromboplastina Parcial , Creatinina , Choque Séptico/complicaciones , Proyectos Piloto , Pronóstico , Estudios RetrospectivosRESUMEN
Obesity is common in the middle aged population and it increases the risks of diabetes, cardiovascular diseases, certain cancers, and dementia. Yet, its etiology remains incompletely understood. Here, we show that ectopic expression of HB-EGF, an important regulator of neurogenesis, in Nestin+ neuroepithelial progenitors with the Cre-LoxP system leads to development of spontaneous middle age obesity in male mice accompanied by hyperglycemia and insulin resistance. The Nestin-HB-EGF mice show decreases in food uptake, energy expenditure, and physical activity, suggesting that reduced energy expenditure underlies the pathogenesis of this obesity model. However, HB-EGF expression in appetite-controlling POMC or AgRP neurons or adipocytes fails to induce obesity. Mechanistically, HB-EGF suppresses expression of Hypocretin/Orexin, an orexigenic neuropeptide hormone, in the hypothalamus of middle aged Nestin-HB-EGF mice. Hypothalamus Orexin administration alleviates the obese and hyperglycemic phenotypes in Nestin-HB-EGF mice. This study uncovers an important role for HB-EGF in regulating Orexin expression and energy expenditure and establishes a midlife obesity model whose pathogenesis involves age-dependent changes in hypothalamus neurons.
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Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Nestina/metabolismo , Células-Madre Neurales/metabolismo , Obesidad/metabolismo , Orexinas/metabolismo , Adiponectina/sangre , Envejecimiento , Animales , Composición Corporal , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Humanos , Insulina/sangre , Leptina/sangre , Ratones , Nestina/genética , Orexinas/genéticaRESUMEN
Inflammation is a key regulator in the progression of atherosclerosis (AS) which extremely affects people's health. Secoisolariciresinol diglucoside (SDG), a plant lignan, is relevant to angiogenesis and cardioprotection against ischemia-reperfusion injury and improves vascular disorders. However, the effect of SDG on cardiovascular disorder is not clear. In the present study, we aimed to investigate the effects of SDG on lipopolysaccharide- (LPS-) stimulated Human Umbilical Vein Endothelial Cells (HUVECs) and elucidate the underlying mechanism. The LPS-stimulated HUVEC cellular model was established. The cell viability, the cell tube formation activity, the nitric oxide (NO) release, the levels of inflammatory cytokine interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), the activation of nuclear factor kappa-B (NF-κB) pathway, and the expression of protein kinase B (Akt) were determined using Cell Counting Kit-8, cell tube-formation assay, western blotting, and enzyme-linked immunosorbent assay. Our results revealed that SDG reduces the angiogenic capacity of HUVECs and inhibited LPS-mediated HUVEC injury and apoptosis. In addition, SDG increased NO release and decreased the levels of IL-1ß, IL-6, and TNF-α in LPS-treated HUVECs. Meanwhile, SDG inhibited the NF-κB pathway and downregulated Akt expression in LPS-induced HUVECs. Our results indicated that SDG relieves LPS-mediated HUVEC injury by inhibiting the NF-κB pathway which is partly dependent on the disruption of Akt activation. Therefore, SDG exerts its cytoprotective effects in the context of LPS-treated HUVECs via regulation of the Akt/IκB/NF-κB pathway and may be a potential treatment drug for cardiovascular disease.
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Butileno Glicoles/farmacología , Glucósidos/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteínas I-kappa B/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We report a facile and low-cost method to synthesize Si/Cu2O heterojunction nanowire arrays, without SiOx, at the Si/Cu2O interface. The reductive Si-H bonds on the surface of Si nanowires plays a key role in situ by reducing Cu(II) ions to Cu2O nanocubes and avoiding the SiOx interface layer. Different pH values would vary the electrochemical potential of reactions and as a result, different products would be formed. Utilized as a photoanode for water splitting, Si/Cu2O nanowire arrays exhibit good photoelectrochemical performance.
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Soil pathogens play important roles in shaping soil microbial diversity and controlling ecosystem functions. Though climate and local environmental factors and their influences on fungal pathogen communities have been examined separately, few studies explore the relative contributions of these factors. This is particularly crucial in eco-fragile regions, which are more sensitive to environmental changes. Herein we investigated the diversity and community structure of putative soil fungal pathogens in cold and dry grasslands on the Tibetan Plateau, using high-throughput sequencing. The results showed that steppe soils had the highest diversity of all pathogens and plant pathogens; contrastingly, meadow soils had the highest animal pathogen diversity. Structural equation modelling revealed that climate, plant, and soil had similar levels of influence on putative soil fungal pathogen diversity, with total effects ranging from 52% to 59% (all p < 0.001), with precipitation exhibiting a stronger direct effect than plant and soil factors. Putative soil fungal pathogen community structure gradually changed with desert, steppe, and meadow, and was primarily controlled by the interactions of climate, plant, and soil factors rather than by distinct factors individually. This finding contrasts with most studies of soil bacterial and fungal community structure, which generally report dominant roles of individual environmental factors.
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Ecosistema , Pradera , Suelo/química , Microbiología del Suelo , PlantasRESUMEN
Background: Due to scarce therapeutic options, hospital-acquired infections caused by Klebsiella pneumoniae (KP), particularly carbapenem-resistant KP (CRKP), pose enormous threat to patients' health worldwide. This study aimed to characterize the epidemiology and risk factors of CRKP among nosocomial KP infections. Method: MEDLINE, Embase, PubMed, and Google Scholar were searched for studies reporting CRKP prevalence from inception to 30 March 2023. Data from eligible publications were extracted and subjected to meta-analysis to obtain global, regional, and country-specific estimates. To determine the cause of heterogeneity among the selected studies, prespecified subgroup analyses and meta-regression were also performed. Odds ratios of CRKP-associated risk factors were pooled by a DerSimonian and Laird random-effects method. Results: We retained 61 articles across 14 countries and territories. The global prevalence of CRKP among patients with KP infections was 28.69% (95% CI, 26.53%-30.86%). South Asia had the highest CRKP prevalence at 66.04% (95% CI, 54.22%-77.85%), while high-income North America had the lowest prevalence at 14.29% (95% CI, 6.50%-22.0%). In the country/territory level, Greece had the highest prevalence at 70.61% (95% CI, 56.77%-84.45%), followed by India at 67.62% (95% CI, 53.74%-81.79%) and Taiwan at 67.54% (95% CI, 58.65%-76.14%). Hospital-acquired CRKP infections were associated with the following factors: hematologic malignancies, corticosteroid therapies, intensive care unit stays, mechanical ventilations, central venous catheter implantations, previous hospitalization, and antibiotic-related exposures (antifungals, carbapenems, quinolones, and cephalosporins). Conclusions: Study findings highlight the importance of routine surveillance to control carbapenem resistance and suggest that patients with nosocomial KP infection have a very high prevalence of CRKP.
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Osteoarthritis affects 15% of people over 65 years of age. It is characterized by articular cartilage degradation and inflammation, leading to joint pain and disability. Osteoarthritis is incurable and the patients may eventually need joint replacement. An emerging treatment is mesenchymal stromal cells (MSCs), with over two hundred clinical trials being registered. However, the outcomes of these trials have fallen short of the expectation, due to heterogeneity of MSCs and uncertain mechanisms of action. It is generally believed that MSCs exert their function mainly by secreting immunomodulatory and trophic factors. Here we used knee osteoarthritis mouse model to assess the therapeutic effects of MSCs isolated from the white adipose or dermal adipose tissue of Prrx1-Cre; R26tdTomato mice and Dermo1-Cre; R26tdTomato mice. We found that the Prrx1-lineage MSCs from the white adipose tissues showed the greatest in vitro differentiation potentials among the four MSC groups and single cell profiling showed that the Prrx1-lineage MSCs contained more stem cells than the Dermo1 counterpart. Only the Prrx1-lineage cells isolated from white adipose tissues showed long-term therapeutic effectiveness on early-stage osteoarthritis models. Mechanistically, Prrx1-lineage MSCs differentiated into Col2+ chondrocytes and replaced the damage cartilage, activated Col1 expressing in resident chondrocytes, and inhibited synovial inflammation. Transcriptome analysis showed that the articular chondrocytes derived from injected MSCs expressed immunomodulatory cytokines, trophic factors, and chondrocyte-specific genes. Our study identified a MSC population genetically marked by Prrx1 that has great multipotentiality and can differentiate into chondrocytes to replace the damaged cartilage.
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Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1-/- mice (Ackr1-/- chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.
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Movimiento Celular , Macrófagos , Regeneración , Humanos , Animales , Macrófagos/metabolismo , Ratones , Tendones/metabolismo , Tendones/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/genética , Proteómica , Femenino , MultiómicaRESUMEN
Aims: Retinal ischemia/reperfusion (I/R) injury is implicated in the etiology of various ocular disorders. Prior research has demonstrated that bone marrow tyrosine kinase on chromosome X (BMX) contributes to the advancement of ischemic disease and inflammatory reactions. Consequently, the current investigation aims to evaluate BMX's impact on retinal I/R injury and clarify its implied mechanism of action. Main methods: This study utilized male and female systemic BMX knockout (BMX-/-) mice to conduct experiments. The utilization of Western blot assay and immunofluorescence labeling techniques was employed to investigate variations in the expression of protein and tissue localization. Histomorphological changes were observed through H&E staining and SD-OCT examination. Visual function changes were assessed through electrophysiological experiments. Furthermore, apoptosis in the retina was identified using the TUNEL assay, as well as the ELISA technique, which has been utilized to determine the inflammatory factors level. Key findings: Our investigation results revealed that the knockdown of BMX did not yield a significant effect on mouse retina. In mice, BMX knockdown mitigated the negative impact of I/R injury on retinal tissue structure and visual function. BMX knockdown effectively reduced apoptosis, suppressed inflammatory responses, and decreased inflammatory factors subsequent to I/R injury. The outcomes of the current investigation revealed that BMX knockdown partially protected the retina through downregulating phosphorylation of AKT/ERK/STAT3 pathway. Significance: Our investigation showed that BMX-/- reduces AKT, ERK, and STAT3 phosphorylation, reducing apoptosis and inflammation. Thus, this strategy protected the retina from structural and functional damage after I/R injury.
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Mg2Y8Si6O26 : Ce3+, Mn2+ phosphor was synthesized by the high temperature solid-state reaction, and the structure and luminescence properties were characterized by X-ray diffraction (XRD) and fluorescence spectrophotometer. The XRD pattern demonstrated that the synthetic material belongs to the hexagonal phase of Mg2Y8Si6O26 crystal without detectable impurity and space group P6(3)/m. The excitation and emission spectrum showed that there exist two lattice positions for Ce3+ in Mg2Y8Si6O26 crystal and their luminescence properties were compared. There are two emission peaks at 400 and 600 nm in the emission spectra under excitation at 286 nm, which come from Ce3+ and Mn2+ emission, respectively. It was demonstrated that there exists energy transfer between Ce3+ and Mn2+. The white light can be achieved by changing Mn2+ concentration. It can be used as a potential single-phased white phosphor excited by ultraviolet light.
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BaIn6 Y2O13 phosphors with different doping concentrations of Yb3+ and Er3+ were prepared via the high temperature solid-state reaction method. XRD data showed that BaIn6 Y2O13 phosphors belong to hexagonal system and the introduction of doping agent Yb3+ and Er3+ did not change the lattice structure of the host. The upconversion emission spectrum and power were measured by 971 nm LD laser with different excitation powers and the energy efficiencies of the samples were calculated. The obtained data showed that the ratio of green power to red power kept decreasing with the increase in doping agent concentration when the excitation density remains constant, increasing with the increase in the excitation density at the same concentration of doping agent. The analyses revealed that the former was attributed to the increasing cross relaxation between Er3+ ions, while the latter came from the raise of the energy transfer between Yb3+ and Er3+ ions and the excited state absorption of Er3+ ions due to the higher excitation density. With the increase in the excitation density, at the beginning the green luminescence power was proportional to the square of the excitation power, which agrees with the reported result. The maximum values of the fluorescence efficiencies of the samples were obtained as 0.38% (the doping concentrations of Yb3+ and Er3+ are 3%, 1%)and 0.06% (the doping concentrations of Yb3+ and Er3+ are 9%, 3%). It can be attributed to the long lifetime of 4 I13/2 energy level so it can gather a large number of electrons and reduce the population of ground state, resulting in lower pump efficiency.
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BACKGROUND: Road collisions are a significant source of traumatic brain injury (TBI). We aimed to determine the pattern of road injury related TBI (RI-TBI) incidence, as well as its temporal trends. METHODS: We collected detailed information on RI-TBI between 1990 and 2019, derived from the Global Burden of Disease Study 2019. Estimated annual percentage changes (EAPCs) of RI-TBI age standardized incidence rate (ASIR), by sex, region, and cause of road injuries, were assessed to quantify the temporal trends of RI-TBI burden. RESULTS: Globally, incident cases of RI-TBI increased 68.1% from 6,900,000 in 1990 to 11,600,000 in 2019. The overall ASIR increased by an average of 0.43% (95% CI 0.30%-0.56%) per year during this period. The ASIR of RI-TBI due to cyclist, motorcyclist and other road injuries increased between 1990 and 2019; the corresponding EAPCs were 0.56 (95% CI 0.37-0.75), 1.60 (95% CI 1.35-1.86), and 0.75 (95% CI 0.59-0.91), respectively. In contrast, the ASIR of RI-TBI due to motor vehicle and pedestrian decreased with an EAPC of -0.12 and -0.14 respectively. The changing pattern for RI-TBI was heterogeneous across countries and regions. The most pronounced increases were observed in Mexico (EAPC = 3.74), followed by China (EAPC = 2.45) and Lesotho (EAPC = 1.91). CONCLUSIONS: RI-TBI remains a major public health concern worldwide, although road safety legislations have contributed to the decreasing incidence in some countries. We found an unfavorable trend in several countries with a relatively low socio-demographic index, suggesting that much more targeted and specific approaches should be adopted in these areas to forestall the increase in RI-TBI.
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Lesiones Traumáticas del Encéfalo , Carga Global de Enfermedades , Humanos , Incidencia , Lesiones Traumáticas del Encéfalo/epidemiología , China , México , Salud Global , Años de Vida Ajustados por Calidad de VidaRESUMEN
PREMISE OF THE STUDY: In Chinese bayberry (Myrica rubra), the available simple sequence repeat (SSR) markers are insufficient to meet the developing demand for genetic and molecular breeding research. This study was aimed at developing a large number of polymorphic expressed sequence tag (EST)-SSRs from the transcriptome of Chinese bayberry. ⢠METHODS AND RESULTS: Five hundred ninety-four compound EST-SSRs and 5557 noncompound ones were identified from 41239 unigene sequences generated from the transcriptome of M. rubra cv. Biqi. Using 10 Chinese bayberry cultivars, 109 polymorphic EST-SSRs were screened from 412 selected. In total, they generated 389 alleles, with a polymorphism ratio of 93.8%. In addition, it was observed that the polymorphism levels of compound EST-SSRs were somewhat lower than those of noncompound ones. ⢠CONCLUSIONS: The 109 polymorphic EST-SSRs developed from the Chinese bayberry transcriptome should greatly promote the development of genetic and molecular breeding studies in this as well as other Myricaceae species.
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Cartilla de ADN/genética , ADN de Plantas/genética , Etiquetas de Secuencia Expresada , Repeticiones de Microsatélite , Myrica/genética , Polimorfismo Genético , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , TranscriptomaRESUMEN
BACKGROUND: Acute kidney injury caused by sepsis has become a hotspot of scientific research in recent years. Since the kidney is the most abundant of all organs with vascular endothelium, activation and injury of vascular endothelial cells is a main reason to renal dysfunction. In our research, we identify that miRNA-449c-5p can alleviate HUVECs injury through inhibiting the NF-κb signaling pathway activation by targeting TAK1 with the method of bioinformatics and in vitro experiment. METHODS: Datasets of GSE28750 and GSE94717 were obtained from the GEO database. Differential analysis was performed on the two data sets using the GEO2R tool of the GEO database, and the miRNA-mRNA network was further constructed. Lipopolysaccharide (LPS) against Human umbilical vein endothelial cells induced an in vitro model of AKI were used for verification. RT-PCR, Western blotting, ELISA, CCK8, EDU and luciferase reporter genes were used to verify whether miR-449c-5p could alleviate the apoptosis of vascular endothelial cells and the release of inflammatory factors during the progression of sepsis by inhibiting the expression of TAK1. RESULTS: TAK1 was identified as a direct target of miR-449c-5p by luciferase reporter gene assay, and TAK1 expression was negatively regulated by miR-449c-5p. Overexpression of miR-449c-5p promoted cell viability, inhibited apoptosis rate and inhibited the expression of inflammatory cytokines in HUVECs after LPS stimulation. Moreover, miR-449c-5p deactivated NF-κB signaling by targeting TAK1. CONCLUSION: In cell model experiments, it was found that miRNA-449c-5p could inhibit the release of LPS induced inflammatory cytokine, inhibit the occurrence of apoptosis and promote cell proliferation by inhibiting the expression of TAK1. Therefore, thus miRNA-449c-5p played a protective role on vascular endothelial cells.
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Quinasas Quinasa Quinasa PAM/genética , MicroARNs , Sepsis , Apoptosis/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Lipopolisacáridos/farmacología , MicroARNs/genética , FN-kappa B/metabolismo , Sepsis/genética , Sepsis/metabolismo , Transducción de SeñalRESUMEN
Specialized connective tissues, including bone and adipose tissues, control various physiological activities, including mineral and energy homeostasis. However, the identity of stem cells maintaining these tissues throughout adulthood remains elusive. By conducting genetic lineage tracing and cell depletion experiments in newly generated knock-in Cre/CreERT2 lines, we show here that rare Prrx1-expressing cells act as stem cells for bone, white adipose tissue and dermis in adult mice, which are indispensable for the homeostasis and repair of these tissues. Single-cell profiling reveals the cycling and multipotent nature of Prrx1-expressing cells and the stemness of these cells is further validated by transplantation assays. Moreover, we identify the cell surface markers for Prrx1-expressing stem cells and show that the activities of these stem cells are regulated by Wnt signaling. These findings expand our knowledge of connective tissue homeostasis/regeneration and may help improve stem-cell-based therapies.
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Tejido Adiposo Blanco , Células Madre , Ratones , AnimalesRESUMEN
Acquired chemotherapy resistance is one of the main culprits in the relapse of breast cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small adaptor protein, SH3BGRL, is not only elevated in the majority of breast cancer patients but also has relevance with the relapse and poor prognosis of breast cancer patients. Functionally, SH3BGRL upregulation enhances the chemoresistance of breast cancer cells to the first-line doxorubicin treatment through macroautophagic/autophagic protection. Mechanistically, SH3BGRL can unexpectedly bind to ribosomal subunits to enhance PIK3C3 translation efficiency and sustain ATG12 stability. Therefore, inhibition of autophagy or silence of PIK3C3 or ATG12 can effectively block the driving effect of SH3BGRL on doxorubicin resistance of breast cancer cells in vitro and in vivo. We also validate that SH3BGRL expression is positively correlated with that of PIK3C3 or ATG12, as well as the constitutive occurrence of autophagy in clinical breast cancer tissues. Taken together, our data reveal that SH3BGRL upregulation would be a key driver to the acquired chemotherapy resistance through autophagy enhancement in breast cancer while targeting SH3BGRL could be a potential therapeutic strategy against breast cancer.Abbreviations: ABCs: ATP-binding cassette transporters; Act D: actinomycin D; ACTB/ß-actin: actin beta; ATG: autophagy-related; Baf A1: bafilomycin A1; CASP3: caspase 3; CHX: cycloheximide; CQ: chloroquine; Dox: doxorubicin; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GEO: gene expression omnibus; GFP: green fluorescent protein; G6PD: glucose-6-phosphate dehydrogenase; GSEA: gene set enrichment analysis; IHC: immunochemistry; KEGG: Kyoto Encyclopedia of Genes and Genomes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; 3-MA: 3-methyladenine; mRNA: messenger RNA; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; SH3BGRL: SH3 domain binding glutamate-rich protein-like; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.
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Proteína 12 Relacionada con la Autofagia , Autofagia , Neoplasias de la Mama , Fosfatidilinositol 3-Quinasas Clase III , Autofagia/fisiología , Proteína 12 Relacionada con la Autofagia/genética , Proteína 12 Relacionada con la Autofagia/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Recurrencia Local de Neoplasia , ProteínasRESUMEN
Umbilical cord mesenchymal stem cells (UC-MSCs) have certain advantages over other MSCs and about 300 clinical trials have been registered using UC-MSCs to treat diseases such as osteoarthritis, autoimmune diseases, and degenerative disorders, yet, only limited success has been achieved. One reason is that in vitro expanded UC-MSCs show tremendous heterogeneity and their relationship to in vivo UC-MSCs remains unknown. Here, we investigated freshly isolated, uncultured UC-MSCs by single-cell RNA sequencing (scRNA-seq) and found two populations of UC-MSCs. Although UC-MSCs share many expressed genes and may have the same origin, they can be clearly separated based on differentially expressed genes including CD73 and other markers. Moreover, group 1 MSCs are enriched in expression of genes in immune response/regulatory activities, muscle cell proliferation and differentiation, stemness, and oxidative stress while group 2 MSCs are enriched with gene expression in extracellular matrix production, osteoblast and chondrocytes differentiation, and bone and cartilage growth. These findings suggest that UC-MSCs should be separated right after isolation and individually expanded in vitro to treat different diseases.
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Células Madre Mesenquimatosas , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Perfilación de la Expresión Génica , Humanos , Análisis de la Célula Individual , Cordón UmbilicalRESUMEN
Metastatic recurrence is still a major challenge in breast cancer treatment, but the underlying mechanisms remain unclear. Here, we report that a small adaptor protein, SH3BGRL, is upregulated in the majority of breast cancer patients, especially elevated in those with metastatic relapse, indicating it as a marker for the poor prognosis of breast cancer. Physiologically, SH3BGRL can multifunctionally promote breast cancer cell tumorigenicity, migration, invasiveness, and efficient lung colonization in nude mice. Mechanistically, SH3BGRL downregulates the acting-binding protein profilin 1 (PFN1) by accelerating the translation of the PFN1 E3 ligase, STUB1 via SH3BGRL interaction with ribosomal proteins, or/and enhancing the interaction of PFN1 with STUB1 to accelerate PFN1 degradation. Loss of PFN1 consequently contributes to downstream multiple activations of AKT, NF-kB, and WNT signaling pathways. In contrast, the forced expression of compensatory PFN1 in SH3BGRL-high cells efficiently neutralizes SH3BGRL-induced metastasis and tumorigenesis with PTEN upregulation and PI3K-AKT signaling inactivation. Clinical analysis validates that SH3BGRL expression is negatively correlated with PFN1 and PTEN levels, but positively to the activations of AKT, NF-kB, and WNT signaling pathways in breast patient tissues. Our results thus suggest that SH3BGRL is a valuable prognostic factor and a potential therapeutic target for preventing breast cancer progression and metastasis.