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BACKGROUND: This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores (EWSs) and three shock indices in early sepsis prediction in the emergency department (ED). METHODS: We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong. The primary outcome was sepsis (Sepsis-3 definition) within 48 h of ED presentation. Using c-statistics and the DeLong test, we compared 11 EWSs, including the National Early Warning Score 2 (NEWS2), Modified Early Warning Score, and Worthing Physiological Scoring System (WPS), etc., and three shock indices (the shock index [SI], modified shock index [MSI], and diastolic shock index [DSI]), with Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) in predicting the primary outcome, intensive care unit admission, and mortality at different time points. RESULTS: We analyzed 601 patients, of whom 166 (27.6%) developed sepsis. NEWS2 had the highest point estimate (area under the receiver operating characteristic curve [AUROC] 0.75, 95%CI 0.70-0.79) and was significantly better than SIRS, qSOFA, other EWSs and shock indices, except WPS, at predicting the primary outcome. However, the pooled sensitivity and specificity of NEWS2 ≥ 5 for the prediction of sepsis were 0.45 (95%CI 0.37-0.52) and 0.88 (95%CI 0.85-0.91), respectively. The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION: NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.
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BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation is involved in many types of arterial diseases, including neointima hyperplasia, in which Ca2+ has been recognized as a key player. However, the physiological role of Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3Rs) from endoplasmic reticulum in regulating VSMC proliferation has not been well determined. METHODS AND RESULTS: Both in vitro cell culture models and in vivo mouse models were generated to investigate the role of IP3Rs in regulating VSMC proliferation. Expression of all 3 IP3R subtypes was increased in cultured VSMCs upon platelet-derived growth factor-BB and FBS stimulation as well as in the left carotid artery undergoing intimal thickening after vascular occlusion. Genetic ablation of all 3 IP3R subtypes abolished endoplasmic reticulum Ca2+ release in cultured VSMCs, significantly reduced cell proliferation induced by platelet-derived growth factor-BB and FBS stimulation, and also decreased cell migration of VSMCs. Furthermore, smooth muscle-specific deletion of all IP3R subtypes in adult mice dramatically attenuated neointima formation induced by left carotid artery ligation, accompanied by significant decreases in cell proliferation and matrix metalloproteinase-9 expression in injured vessels. Mechanistically, IP3R-mediated Ca2+ release may activate cAMP response element-binding protein, a key player in controlling VSMC proliferation, via Ca2+/calmodulin-dependent protein kinase II and Akt. Loss of IP3Rs suppressed cAMP response element-binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca2+ permeable ionophore, ionomycin, can reverse cAMP response element-binding protein phosphorylation in IP3R triple knockout VSMCs. CONCLUSIONS: Our results demonstrated an essential role of IP3R-mediated Ca2+ release from endoplasmic reticulum in regulating cAMP response element-binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.
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Proliferação de Células , Receptores de Inositol 1,4,5-Trifosfato , Músculo Liso Vascular , Miócitos de Músculo Liso , Neointima , Animais , Masculino , Camundongos , Becaplermina/farmacologia , Becaplermina/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/genética , Movimento Celular , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neointima/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
INTRODUCTION: This study explored the association between psoriasis and the weight-adjusted waist index (WWI), a newly developed measure of adiposity. The research was conducted among adults in the United States. METHODS: Utilizing survey data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2009 to 2014, the present study aimed to investigate the potential correlation between psoriasis and WWI within a sample of 15,920 adult participants. Employing multivariable logistic regression and nonlinear curve fitting techniques, we analyzed this plausible association. Additionally, a subgroup analysis was conducted to ascertain the consistency across diverse populations. RESULTS: A significant positive association was discovered between psoriasis and WWI in the investigated sample of 15,920 adults. After conducting a comprehensive adjustment of the model, it was observed that each incremental unit of WWI was significantly associated with an 14% elevated likelihood of developing psoriasis (OR = 1.16, 95% CI 1.01-1.36). Moreover, individuals belonging to the highest quartile of WWI exhibited a 47% higher risk of psoriasis compared to those in the lowest quartile (OR = 1.44, 95% CI 1.01-2.06). This positive correlation remained consistent across various subgroups. The study also compared WWI with BMI and waist circumference, finding that WWI is a more stable metric of obesity. CONCLUSIONS: Our study suggested that in US adults, there is a positive association between WWI and psoriasis. It also indicated that WWI showed potential as a valuable index of psoriasis among the general population.
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Índice de Massa Corporal , Inquéritos Nutricionais , Psoríase , Circunferência da Cintura , Humanos , Psoríase/epidemiologia , Masculino , Feminino , Estudos Transversais , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Adulto , Obesidade/epidemiologia , Fatores de Risco , Peso Corporal , AdiposidadeRESUMO
Current microbiome signatures for chronic diseases such as diabetic kidney disease (DKD) are mainly based on low-resolution taxa such as genus or phyla and are often inconsistent among studies. In microbial ecosystems, bacterial functions are strain specific, and taxonomically different bacteria tend to form co-abundance functional groups called guilds. Here, we identified guild-level signatures for DKD by performing in-depth metagenomic sequencing and conducting genome-centric and guild-based analysis on fecal samples from 116 DKD patients and 91 healthy subjects. Redundancy analysis on 1,543 high-quality metagenome-assembled genomes (HQMAGs) identified 54 HQMAGs that were differentially distributed among the young healthy control group, elderly healthy control group, early-stage DKD patients (EDG), and late-stage DKD patients (LDG). Co-abundance network analysis classified the 54 HQMAGs into two guilds. Compared to guild 2, guild 1 contained more short-chain fatty acid biosynthesis genes and fewer genes encoding uremic toxin indole biosynthesis, antibiotic resistance, and virulence factors. Guild indices, derived from the total abundance of guild members and their diversity, delineated DKD patients from healthy subjects and between different severities of DKD. Age-adjusted partial Spearman correlation analysis showed that the guild indices were correlated with DKD disease progression and with risk indicators of poor prognosis. We further validated that the random forest classification model established with the 54 HQMAGs was also applicable for classifying patients with end-stage renal disease and healthy subjects in an independent data set. Therefore, this genome-level, guild-based microbial analysis strategy may identify DKD patients with different severity at an earlier stage to guide clinical interventions. IMPORTANCE: Traditionally, microbiome research has been constrained by the reliance on taxonomic classifications that may not reflect the functional dynamics or the ecological interactions within microbial communities. By transcending these limitations with a genome-centric and guild-based analysis, our study sheds light on the intricate and specific interactions between microbial strains and diabetic kidney disease (DKD). We have unveiled two distinct microbial guilds with opposite influences on host health, which may redefine our understanding of microbial contributions to disease progression. The implications of our findings extend beyond mere association, providing potential pathways for intervention and opening new avenues for patient stratification in clinical settings. This work paves the way for a paradigm shift in microbiome research in DKD and potentially other chronic kidney diseases, from a focus on taxonomy to a more nuanced view of microbial ecology and function that is more closely aligned with clinical outcomes.
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Bactérias , Nefropatias Diabéticas , Fezes , Microbioma Gastrointestinal , Metagenoma , Metagenômica , Humanos , Microbioma Gastrointestinal/genética , Nefropatias Diabéticas/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Masculino , Feminino , Fezes/microbiologia , Pessoa de Meia-Idade , Adulto , IdosoRESUMO
Background: Epidemiological evidence suggests that there is an increased risk of coronary heart disease (CHD) related to jobs involving shift work (JSW), but the causality of and mechanism underlying such a relationship remain unclear. Therefore, we aimed to explore the relationship between JSW and CHD, investigating both causality and potential mediating factors. Methods: We performed univariate, multivariate, and mediation Mendelian randomisation (MR) analyses using data from large genome-wide association studies focussed on JSW and CHD, as well as data on some CHD risk factors (type 2 diabetes, hypertension, obesity, and lipids measurement) and 196 gut microbiota taxa. Single-nucleotide polymorphisms significantly associated with JSW acted as instrument variables. We used inverse-variance weighting as the primary method of analysis. Results: Bidirectional MR analysis indicated a robust effect of JSW on increased CHD risk; however, the existence of CHD did not affect the choice of JSW. We identified a mediating effects of type 2 diabetes and hypertension in this relationship, accounting for 11.89% and 14.80% of the total effect of JSW on CHD, respectively. JSW were also causally associated with the risk of type 2 diabetes and hypertension and had an effect on nine microbial taxa. The mediating influence of the Eubacterium brachy group at the genus level explained 16.64% of the total effect of JSW on hypertension. We found limited evidence for the causal effect of JSW on obesity and lipids measurements. Conclusions: Our findings suggest a causal effect of JSW on CHD, diabetes, and hypertension. We also found evidence for a significant connection between JSW and alterations in the gut microbiota. Considering that certain microbial taxa mediated the effect of JSW on hypertension risk, targeting gut microbiota through therapeutics could potentially mitigate high risks of hypertension and CHD associated with JSW.
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Doença das Coronárias , Microbioma Gastrointestinal , Análise da Randomização Mendeliana , Jornada de Trabalho em Turnos , Humanos , Doença das Coronárias/epidemiologia , Doença das Coronárias/microbiologia , Fatores de Risco , Jornada de Trabalho em Turnos/efeitos adversos , Estudo de Associação Genômica Ampla , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/microbiologia , Polimorfismo de Nucleotídeo Único , Análise de Mediação , Hipertensão/epidemiologiaRESUMO
In advanced batteries, interphases serve as the key component in stabilizing the electrolyte with reactive electrode materials far beyond thermodynamic equilibria. While an active interphase facilitates the transport of working ions, an inactive interphase obstructs ion flow, constituting the primary barrier to the realization of battery chemistries. Here, a successful transformation of a traditionally inactive passivating layer on Mg-metal anode, characteristic of Mg-metal batteries with typical carbonate electrolytes, into an active and robust interphase in the Li-metal scenario is presented. By further strategically designing magnesiated Li+ electrolytes, the in situ development of this resilient interphase on Li-metal anodes, imparting enduring stability to Li-metal batteries with nickel-rich cathodes is induced. It is identified that the strong affinity between Mg2+ and anions in magnesiated Li+ electrolytes assembles ionic clusters with a bias for reducibility, thereby catalyzing the creation of anion-derived interphases rich in inorganic constituents. The prevalence of ionic clusters induced by magnesiation of electrolytes has brought properties only available in high-concentration electrolytes, suggesting a fresh paradigm of tailing electrolytes for highly reversible LMBs.
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Broad cellular components-initiated efficient chemical reactions that occur in malignant cells may contribute to exploring emerging strategies for cancer treatment. Herein, an ozonated oleogel (OG(O)) was developed to achieve cancer ozone therapy (O3-T) based on intracellular Criegee's reaction. By integrating the chemo-drug, the ozone-loaded oleogel (Dox@OG(O)) was prepared as a chemotherapeutic agent for local O3-T, associated with chemotherapy (CT)/radiotherapy (RT)/immunotherapy and wound healing. The in vitro results showed that, Dox@OG(O) could achieve high ozone loading efficiency and ensure its stability. This Oleogel-mediated O3-T could directly destroy tumor cells via intracellular Criegee's reaction occurred on cell membranes, as well as the effects of tumor microenvironment (TME) regulation by the generation of oxygen/reactive oxygen species (ROS) and depletion of glutathione (GSH). Meanwhile, under the stimulation of X-ray, an accelerated free radical's production was observed, further combined with the radio-sensitivity after TME regulation, an effective anti-tumor effect would be achieved. Further on, in vivo results demonstrated that the locally implanted Dox@OG(O) could effectively inhibit the growth of both primary and secondary tumors. Considering these results above, it will serve as inspiration for future studies investigating of O3-T, especially for postoperative skin diseases.
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Doxorrubicina , Neoplasias , Compostos Orgânicos , Ozônio , Microambiente Tumoral , Ozônio/química , Animais , Humanos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Compostos Orgânicos/química , Compostos Orgânicos/farmacologia , Compostos Orgânicos/administração & dosagem , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Camundongos Nus , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Feminino , Glutationa/metabolismo , CamundongosRESUMO
Community-acquired respiratory infection is the commonest cause of sepsis presenting to emergency departments. Yet current experimental animal models simulate peritoneal sepsis with intraperitoneal (I.P.) injection of lipopolysaccharide (LPS) as the predominant route. We aimed to compare the progression of organ injury between I.P. LPS and intranasal (I.N.) LPS in order to establish a better endotoxemia murine model of respiratory sepsis. Eight weeks old male BALB/c mice received LPS-Escherichia coli doses at 0.15, 1, 10, 20, 40 and 100 mg per kg body weight (e.g. LPS-10 is a dose of 10 mg/kg body weight). Disease severity was monitored by a modified Mouse Clinical Assessment Score for Sepsis (M-CASS; range 0-21). A M-CASS score ≥ 10 or a weight reduction of ≥ 20%, was used as a criterion for euthanasia. The primary outcome was the survival rate (either no death or no need for euthanasia). The progression of disease was specified as M-CASS, body weight, blood glucose, histopathological changes to lung, liver, spleen, kidney, brain and heart tissues. Survival rate in I.P. LPS-20 mice was 0% (2/3 died; 1/3 euthanized with M-CASS > 10) at 24 h. Survival rate in all doses of I.N. LPS was 100% (20/20; 3-4 per group) at 96 h. 24 h mean M-CASS post-I.P. LPS-10 was 6.4/21 significantly higher than I.N. LPS-10 of 1.7/21 (Unpaired t test, P < 0.05). Organ injury was present at 96 h in the I.P. LPS-10 group: lung (3/3; 100%), spleen (3/3; 100%) and liver (1/3; 33%). At 24 h in the I.P. LPS-20 group, kidney injury was observed in the euthanized mouse. At 96 h in the post-I.N. LPS-20 group, only lung injury was observed in 2/3 (67%) mice (Kruskal-Wallis test with Dunn's, P < 0.01). At 24 h in the post-I.N. LPS-100 group all (4/4) mice had evidence of lung injury. Variable doses of I.N. LPS in mice produced lung injury but did not produce sepsis. Higher doses of I.P. LPS induced multi-organ injury but not respiratory sepsis. Lethal models of respiratory virus, e.g., influenza A, might provide alternative avenues that can be explored in future research.
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Cell necroptosis has presented great potential, acting as an effective approach against tumor apoptotic resistance, and it could be further enhanced via accompanying reactive oxygen species (ROS) overexpression. However, whether overproduced ROS assists the necroptotic pathway remains unclear. Thus, iron-palladium nanozyme (FePd NZ)- and shikonin (SKN)-encapsulated functional lipid nanoparticles (FPS-LNPs) were designed to investigate the ROS overexpression-enhanced SKN-induced necroptosis. In this system, SKN acts as an effective necroptosis inducer for cancer cells, and FePd NZ, a sensitive Fenton reaction catalyst, produces extra-intracellular ROS to reinforce the necroptotic pathway. Both in vitro and in vivo antitumor evaluation revealed that FPS-LNPs presented the best tumor growth inhibition efficacy compared with FP-LNPs or SKN-LNPs alone. Meanwhile, induced necroptosis by FPS-LNPs can further trigger the release of damage-associated molecular patterns (DAMPs) and antigens from dying tumor cells to activate the innate immune response. Taking biosafety into consideration, this study has provided a potential nanoplatform for cancer nanotherapy via inducing necroptosis to avoid apoptosis resistance and activate CD8+ T cell immune response.
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Lipossomos , Nanopartículas , Naftoquinonas , Necroptose , Neoplasias , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , ApoptoseRESUMO
Enlightened by the great success of the drug repurposing strategy in the pharmaceutical industry, in the current study, material repurposing is proposed where the performance of carbonyl iron powder (CIP), a nutritional intervention agent of iron supplement approved by the US FDA for iron deficiency anemia in clinic, was explored in anti-cancer treatment. Besides the abnormal iron metabolic characteristics of tumors, serving as potential targets for CIP-based cancer therapy under the repurposing paradigm, the efficacy of CIP as a catalyst in the Fenton reaction, activator for dihydroartemisinin (DHA), thus increasing the chemo-sensitivity of tumors, as well as a potent agent for NIR-II photothermal therapy (PTT) was fully evaluated in an injectable alginate hydrogel form. The CIP-ALG gel caused a rapid temperature rise in the tumor site under NIR-II laser irradiation, leading to complete ablation in the primary tumor. Further, this photothermal-ablation led to the significant release of ATP, and in the bilateral tumor model, both primary tumor ablation and inhibition of secondary tumor were observed simultaneously under the synergistic tumor treatment of nutritional-photothermal therapy (NT/PTT). Thus, material repurposing was confirmed by our pioneering trial and CIP-ALG-meditated NT/PTT/immunotherapy provides a new choice for safe and efficient tumor therapy.
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Trifosfato de Adenosina , Antineoplásicos , Raios Infravermelhos , Animais , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/química , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Imunoterapia , Reposicionamento de Medicamentos , Humanos , Lasers , Terapia Fototérmica , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Alginatos/química , Feminino , Hidrogéis/química , Hidrogéis/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Tamanho da Partícula , Artemisininas/química , Artemisininas/farmacologiaRESUMO
Purpose: This study aimed to investigate the composition of ocular surface microbiota in patients with obesity. Methods: This case-control study, spanning from November 2020 to March 2021 at Henan Provincial People's Hospital, involved 35 patients with obesity and an equivalent number of age and gender-matched healthy controls. By employing 16S rRNA sequencing, this study analyzed the differences in ocular surface microbiota between the two groups. The functional prediction analysis of the ocular surface microbiota was conducted using PICRUSt2. Results: The alpha diversity showed no notable differences in the richness or evenness of the ocular surface microbiota when comparing patients with obesity to healthy controls (Shannon index, P=0.1003). However, beta diversity highlighted significant variances in the microbiota composition of these two groups (ANOSIM, P=0.005). LEfSe analysis revealed that the relative abundances of Delftia, Cutibacterium, Aquabacterium, Acidovorax, Caulobacteraceae unclassified, Comamonas and Porphyromonas in patients with obesity were significantly increased (P<0.05). Predictive analysis using PICRUSt2 highlighted a significant enhancement in certain metabolic pathways in patients with obesity, notably xenobiotics metabolism via cytochrome P450 (CYP450), lipid metabolism, and the oligomerization domain (NOD)-like receptor signaling pathway (P<0.05). Conclusions: Patients with obesity exhibit a distinct ocular surface core microbiome. The observed variations in this microbiome may correlate with increased activity in CYP450, changes in lipid metabolism, and alterations in NOD-like receptor signaling pathways.
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Olho , Microbiota , Humanos , Estudos de Casos e Controles , RNA Ribossômico 16S , ObesidadeRESUMO
Objective: This study aimed to evaluate the effect of case-based learning (CBL) method with virtual reality (VR) simulation technology (CBL-VR) on midwifery laboratory courses. Methods: A quasi-experimental design was employed. A total of 135 midwifery students were recruited from Nursing College of Guilin Medical University in China from September 2020 to January 2022. Intervention group recruited students from the Class of 2019 (n = 59) and control group recruited students from the Class of 2018 (n = 76). The intervention group students received the CBL-VR method based on traditional laboratory teaching, the contents of course included four sections: eutocia (6 class hours), dystocia (6 class hours), umbilical cord prolapse (2 class hours), and neonatal asphyxia and resuscitation (4 class hours), 40 min per class hour. The control group students received the traditional laboratory teaching. Students' academic performance, Self-Directed Learning (SDL) Ability Questionnaire, and the education satisfaction questionnaire were used to evaluate the teaching efficacy between two groups. Results: After intervention, the intervention group students achieved higher scores than the control group in individual operation ability (90.88 ± 2.14 vs. 89.24 ± 3.15), team operation ability (90.97 ± 2.33 vs. 81.28 ± 5.45), and midwifery case analysis ability (88.64 ± 3.19 vs. 86.70 ± 2.56) (P ï¼0.01). Prior to the implementation of the course, there was no difference in the SDL ability scores between the two groups of students (P ï¼ 0.05). However, following the course intervention, the SDL ability scores of the intervention group were higher than those of the control group (94.78 ± 6.59 vs. 88.12 ± 8.36), and the scores in all dimensions of the intervention group were also higher (P < 0.05). Additionally, more than 94% of the students indicated that CBL-VR method developed comprehensive abilities, including independent-study enthusiasm, independent thinking, collaboration, and communication. Conclusion: Using the CBL-VR method in midwifery lab courses improved students' course performance, SDL ability, and comprehensive ability. Students highly recognized the effectiveness of this approach.
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Photoaging is one major exogenous factor of skin aging. Efficacy and safety of current anti-photoaging therapies remained to be improved. Our previous studies indicated that skin-derived precursors (SKPs) alleviated photodamage by early activation of TGF-ß/Smad signaling pathway via thrombospondin1 (TSP1). However, the research concerning SKP conditioned medium (SKP-CM) has never been reported. In the current study, we aimed to explore the anti-photoaging effects of SKP-CM both in vitro and in vivo, and to elucidate the possible mechanisms. Mouse SKP-CM (mSKP-CM) collection was optimized by a comparative method. The concentration of protein and growth factors in mSKP-CM was detected using BCA protein assay kit and growth factor protein chip. The anti-photoaging effects of mSKP-CM and its regulation of key factors in the TGF-ß/Smad signaling pathway were explored using UVA + UVB photoaged mouse fibroblasts (mFBs) and nude mice dorsal skin. The research revealed that mSKP-CM contained significantly higher-concentration of protein and growth factors than mouse mesenchymal stem cell conditioned medium (mDMSC-CM). mSKP-CM alleviated mFBs photoaging by restoring cell viability and relieving senescence and death. ELISA, qRT-PCR, and western blot results implied the potential mechanisms were associated with the early activation of TGF-ß/Smad signaling pathway by TSP1. In vivo experiments demonstrated that compared with the topical intradermal mDMSC-CM injection and retinoic acid cream application, the photodamaged mice dorsal skin intradermally injected with mSKP-CM showed significantly better improvement. Consistent with the in vitro results, both western blot and immunohistochemistry results confirmed that protein expression of TSP1, smad2/3, p-smad2/3, TGF-ß1, and collagen I increased, and matrix metalloproteinases decreased. In summary, both in vitro and in vivo experiments demonstrated that mSKP-CM alleviated photoaging through an early activation of TGF-ß/Smad signaling pathway via TSP1. SKP-CM may serve as a novel and promising cell-free therapeutical approach for anti-photoaging treatment and regenerative medicine.
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Envelhecimento da Pele , Animais , Camundongos , Meios de Cultivo Condicionados/farmacologia , Transdução de Sinais , Camundongos Nus , Colágeno Tipo I/metabolismo , Fibroblastos , Fator de Crescimento Transformador beta/metabolismoRESUMO
Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca2+/Cu2+ dual-ion "nano trap" to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu2+-tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca2+/Cu2+ dual-ions "nano trap". The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca2+, Cu2+, and DSF releasing simultaneously. The released Ca2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H2O2) overexpression. Meanwhile, Ca2+/reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)-copper complexes formed by the Cu2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu2+ will be reduced by intracellular glutathione to generate Cu+, which can catalyze the H2O2 to produce a toxic hydroxyl radical by a Cu+-mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.
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Neoplasias da Mama , Dissulfiram , Polifenóis , Humanos , Feminino , Dissulfiram/farmacologia , Cobre/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Peróxido de Hidrogênio/metabolismo , Paraptose , Linhagem Celular Tumoral , ApoptoseRESUMO
The therapeutic efficacy of bone tumor treatment is primarily limited by inadequate tumor resection, resulting in recurrence and metastasis, as well as the deep location of tumors. Herein, an injectable doxorubicin (DOX)-loaded magnetic alginate hydrogel (DOX@MAH) was developed to evaluate the efficacy of an alternating magnetic field (AMF)-responsive, chemothermal synergistic therapy for multimodality treatment of bone tumors. The prepared hydrogel exhibits a superior drug-loading capacity and a continuous DOX release. This multifunctionality can be attributed to the combined use of DOX for chemotherapy and iron oxide nanoparticle-containing alginate hydrogels as magnetic hyperthermia agents to generate hyperthermia for tumor elimination without the limit on penetration depth. Moreover, the hydrogel can be formed when in contact with the calcium ions, which are abundant in bone tissues; therefore, this hydrogel could perfectly fit the bone defects caused by the surgical removal of the bone tumor tissue, and the hydrogel could tightly attach the surgical margin of the bone to realize a high efficacy residual tumor tissue elimination treated by chemothermal synergistic therapy. The hydrogel demonstrates excellent hyperthermia performance, as evidenced by in vitro cytotoxicity tests on tumor cells. These tests reveal that the combined therapy based on DOX@MAH under AMF significantly induces cell death compared to single magnetic hyperthermia or chemotherapy. In vivo antitumor effects in tumor-bearing mice demonstrate that DOX@MAH injection at the tumor site effectively inhibits tumor growth and leads to tumor necrosis. This work not only establishes an effective DOX@MAH system as a synergistic chemothermal therapy platform for treating bone tumors but also sheds light on the application of alginate to combine calcium ions of the bone to treat bone defect diseases.
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Neoplasias Ósseas , Hipertermia Induzida , Animais , Camundongos , Hidrogéis/farmacologia , Cálcio , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Hipertermia , Hipertermia Induzida/métodos , Alginatos , Íons , Fenômenos MagnéticosRESUMO
Vascular neogenesis, an early event in the development of rheumatoid arthritis (RA) inflammation, is critical for the formation of synovial vascular networks and plays a key role in the progression and persistence of chronic RA inflammation. microRNAs (miRNAs), a class of single-stranded, non-coding RNAs with approximately 21-23 nucleotides in length, regulate gene expression by binding to the 3' untranslated region (3'-UTR) of specific mRNAs. Increasing evidence suggests that miRNAs are differently expressed in diseases associated with vascular neogenesis and play a crucial role in disease-related vascular neogenesis. However, current studies are not sufficient and further experimental studies are needed to validate and establish the relationship between miRNAs and diseases associated with vascular neogenesis, and to determine the specific role of miRNAs in vascular development pathways. To better treat vascular neogenesis in diseases such as RA, we need additional studies on the role of miRNAs and their target genes in vascular development, and to provide more strategic references. In addition, future studies can use modern biotechnological methods such as proteomics and transcriptomics to investigate the expression and regulatory mechanisms of miRNAs, providing a more comprehensive and in-depth research basis for the treatment of related diseases such as RA.
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Artrite Reumatoide , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Angiogênese , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Inflamação , BiotecnologiaRESUMO
Expression Atlas (www.ebi.ac.uk/gxa) and its newest counterpart the Single Cell Expression Atlas (www.ebi.ac.uk/gxa/sc) are EMBL-EBI's knowledgebases for gene and protein expression and localisation in bulk and at single cell level. These resources aim to allow users to investigate their expression in normal tissue (baseline) or in response to perturbations such as disease or changes to genotype (differential) across multiple species. Users are invited to search for genes or metadata terms across species or biological conditions in a standardised consistent interface. Alongside these data, new features in Single Cell Expression Atlas allow users to query metadata through our new cell type wheel search. At the experiment level data can be explored through two types of dimensionality reduction plots, t-distributed Stochastic Neighbor Embedding (tSNE) and Uniform Manifold Approximation and Projection (UMAP), overlaid with either clustering or metadata information to assist users' understanding. Data are also visualised as marker gene heatmaps identifying genes that help confer cluster identity. For some data, additional visualisations are available as interactive cell level anatomograms and cell type gene expression heatmaps.
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Bases de Dados Genéticas , Perfilação da Expressão Gênica , Proteômica , Genótipo , Metadados , Análise de Célula Única , Internet , Humanos , AnimaisRESUMO
A complete blood count (CBC) is routinely ordered for emergency department (ED) patients with infections. Certain parameters, such as the neutrophil-to-lymphocyte ratio (NLR), might have prognostic value. We aimed to evaluate the prognostic value of the presenting CBC parameters combined with clinical variables in predicting 30-day mortality in adult ED patients with infections using an artificial neural network (ANN). We conducted a retrospective study of ED patients with infections between 17 December 2021 and 16 February 2022. Clinical variables and CBC parameters were collected from patient records, with NLR, monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) calculated. We determined the discriminatory performance using the area under the receiver operating characteristic curve (AUROC) and performed a 70/30 random data split and supervised ANN machine learning. We analyzed 558 patients, of whom 144 (25.8%) had sepsis and 60 (10.8%) died at 30 days. The AUROCs of NLR, MLR, PLR, and their sum were 0.644 (95% CI 0.573-0.716), 0.555 (95% CI 0.482-0.628), 0.606 (95% CI 0.529-0.682), and 0.610 (95% CI 0.534-0.686), respectively. The ANN model based on twelve variables including clinical variables, hemoglobin, red cell distribution width, NLR, and PLR achieved an AUROC of 0.811 in the testing dataset.
Assuntos
Linfócitos , Sepse , Adulto , Humanos , Estudos Retrospectivos , Contagem de Células Sanguíneas , Prognóstico , Plaquetas , Neutrófilos , Sepse/diagnósticoRESUMO
Vocal communication is essential for social behaviors in humans and non-human primates. While the frontal cortex is crucial to human speech production, its role in vocal production in non-human primates has long been questioned. It is unclear whether activities in the frontal cortex represent diverse vocal signals used in non-human primate communication. Here we studied single neuron activities and local field potentials (LFP) in the frontal cortex of male marmoset monkeys while the animal engaged in vocal exchanges with conspecifics in a social environment. We found that both single neuron activities and LFP were modulated by the production of each of the four major call types. Moreover, neural activities showed distinct patterns for different call types and theta-band LFP oscillations showed phase-locking to the phrases of twitter calls, suggesting a neural representation of vocalization features. Our results suggest important functions of the marmoset frontal cortex in supporting the production of diverse vocalizations in communication.