HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Secoemestrin C Ameliorates Psoriasis-like Skin Inflammation in Mice by Suppressing the TNF-α/NF-κB Signaling Pathway.

OBJECTIVE: Secoemestrin C (SC), an epitetrathiodioxopiperazine isolated from Aspergillus nidulans, has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune hepatitis. However, the effect of SC on regulating the inflammation and its underlying mechanisms in the pathogenesis of psoriasis remain unclear. This study aimed to evaluate the effects of SC on inflammatory dermatosis both in vitro and in vivo. METHODS: In vitro, HaCaT cells were induced with tumor necrosis factor-alpha (TNF-α, 10 ng/mL) to establish an inflammatory injury model, and the expression of nuclear transcription factor-κB (NF-κB) pathway components was measured using qRT-PCR and Western blotting. An in vivo mouse model of imiquimod (IMQ)-induced psoriasis-like skin inflammation was used to evaluate the effectiveness of SC in alleviating psoriasis. RESULTS: SC significantly blocked the activation of NF-κB signaling in TNF-α-stimulated HaCaT cells. In addition, systemic and local administration of SC improved psoriatic dermatitis in the IMQ-induced mouse model. SC reduced skin scale and significantly inhibited the secretion of inflammatory factors in skin lesions. CONCLUSION: The protective effect of SC against psoriatic-associated inflammation reveals its potential therapeutic value for treating psoriasis.

HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis.

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

17ß-estradiol inhibits TGF-ß-induced collagen gel contraction mediated by human Tenon fibroblasts via Smads and MAPK signaling pathways.

AIM: To investigate the impact of 17ß-estradiol on the collagen gels contraction (CGC) and inflammation induced by transforming growth factor (TGF)-ß in human Tenon fibroblasts (HTFs). METHODS: HTFs were three-dimensionally cultivated in type I collagen-generated gels with or without TGF-ß (5 ng/mL), 17ß-estradiol (12.5 to 100 µmol/L), or progesterone (12.5 to 100 µmol/L). Then, the collagen gel diameter was determined to assess the contraction, and the development of stress fibers was analyzed using immunofluorescence staining. Immunoblot and gelatin zymography assays were used to analyze matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) being released into culture supernatants. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase chain reaction (RT-PCR) were used to detect interleukin (IL)-6, monocyte chemoattractant proteins (MCP)-1, and vascular endothelial growth factor (VEGF) in HTFs at the translational and transcriptional levels. The phosphorylation levels of Sma- and Mad-related proteins (Smads), mitogen-activated protein kinases (MAPKs), and protein kinase B (AKT) were measured by immunoblotting. Statistical analysis was performed using either the Tukey-Kramer test or Student's unpaired t-test to compare the various treatments. RESULTS: The CGC caused by TGF-ß in HTFs was significantly inhibited by 17ß-estradiol (25 to 100 µmol/L), and a statistically significant difference was observed when comparing the normal control group with 17ß-estradiol concentrations exceeding 25 µmol/L (P<0.05). The suppressive impact of 17ß-estradiol became evident 24h after administration and peaked at 72h (P<0.05), whereas progesterone had no impact. Moreover, 17ß-estradiol attenuated the formation of stress fibers, and the production of MMP-3 and MMP-1 in HTFs stimulated by TGF-ß. The expression of MCP-1, IL-6, and VEGF mRNA and protein in HTFs were suppressed by 100 µmol/L 17ß-estradiol (P<0.01). Additionally, the phosphorylation of Smad2 Smad3, p38, and extracellular signal-regulated kinase (ERK) were downregulated (P <0.01). CONCLUSION: 17ß-estradiol significantly inhibits the CGC and inflammation caused by TGF-ß in HTFs. This inhibition is likely related to the suppression of stress fibers, inhibition of MMPs, and attenuation of Smads and MAPK (ERK and p38) signaling. 17ß-estradiol may have potential clinical benefits in preventing scar development and inflammation in the conjunctiva.

Transcriptome profiling Revealed the potential mechanisms of Shen Lin Bai Zhu San n-butanol extract on DSS induced Colitis in Mice and LC-MS analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disorder in gastrointestinal tract. Shen Ling Bai Zhu San (SLBZS), which has a long history of use in Traditional Chinese Medicine (TCM), has been widely used to treat gastrointestinal diseases. The isolated fractions of TCM have also been proved to possess an important potential for treating diseases, which are due to their effective components. PURPOSE: In this study, we examined the possibility that SLBZS and its isolated active fractions may prevent DSS-induced colitis, and investigated the potential mechanisms by regulating genetic profile of colon. METHODS: Colitis mice were induced by 2.5% DSS for 7 days, and then SLBZS and different SLBZS extracts were administrated to protect the mice for 7 days. Body weight, diarrhea, bleeding in stool, colon length, spleen weight, cytokines of serum and colon and pathology of colon were assessed. The level of Ginsenoside Rg1, Re and Rb1 in different SLBZS extracts and qualitative analysis of n-butanol extract of SLBZS (S-Nb) was performed by HPLC and LC-MS, respectively. And the effects of S-Nb on the transcriptome in colitis were investigated. RESULTS: Our results showed that SLBZS and S-Nb significantly regained body weight, reduced DAI, splenomegaly and the length of colon and attenuated histological damage of the colon. Meanwhile, SLBZS and S-Nb markedly reduced the levels of TNF-α, IL-1ß and IL-6 and increased the level of IL-10 in serum and colon. These effects may be associated with the high levels of Ginsenoside Rg1, Re and Rb1 and rich variety of compounds in S-Nb including 6 ginsenosides, glycyrrhizin, L-tryptophan, and so on. Transcriptome analysis revealed that S-Nb selectively regulated 103 differentially expressed genes (DEGs), 36 of which were changed in DSS-induced mice. And the genes of Per2, Per3, Npy and Serpina3m were closely related to colitis and also restored by S-Nb with different extent. Remarkably, these DEGs modulated the biological functions of colitis mice, including extracellular region, response to external stimulus, MAPK signaling pathway and arginine and proline metabolism. CONCLUSIONS: These data indicated that SLBZS and S-Nb blunted DSS-induced colitis by modulating differentially expression gene profile and biological functions based on their ginsenosides and rich compounds.

Revision and Validation of the Chinese Version of the McGill Quality of Life Questionnaire for ICU End-of-Life Patients.

BACKGROUND: Hospice care for end-of-life patients in the ICU should focus on quality of life. Currently, there are no specific quality-of-life measures for ICU end-of-life patients in China. OBJECTIVE: The aim of this study was to revise and culturally adapt the Taiwanese version of the McGill Quality of Life Questionnaire (MQOL-Taiwan) and to test its reliability and validity to provide an effective instrument for assessing the quality of life of ICU patients at the end of life. METHODS: The revision and cultural adaptation of the MQOL-Taiwan were performed to develop a Chinese version of the McGill Quality of Life Questionnaire for ICU end-of-life patients (MQOL-ICU). A total of 156 ICU doctors, 286 ICU nurses and 120 ICU family members of end-of-life patients were surveyed with the revised scale to evaluate the quality of life of ICU patients at the end of life. The content validity, construct validity, and internal consistency of the scale were measured after the revision. RESULTS: The Chinese version of the MQOL-ICU scale was formed based on the MQOL-Taiwan scale, which includes 8 items. For the Chinese version of the MQOL-ICU, the item-content validity index (I-CVI) ranged from 0.789 to 0.905, and the average scale-level content validity index (S-CVI/Ave) was 0.845. After exploratory factor analysis, the Kaiser-Meyer-Olkin (KMO) value was 0.700, and 3 dominant factors were extracted: physical and psychological symptoms, existential well-being, and support. In addition, 70.385% of the total variance was explained. The internal consistency (Cronbach's α) coefficient of the whole MQOL-ICU was 0.804, and the coefficients for the 3 domains ranged from 0.779 to 0.833. CONCLUSION: The Chinese version of the MQOL-ICU showed good reliability and validity, and it can be used to assess the quality of life of ICU patients at the end of life.

Comparison of a polyvinyl chloride tube with a wire-reinforced tube for tracheal intubation through the SaCoVLM video laryngeal mask airway: protocol for a randomised controlled study.

INTRODUCTION: The SaCoVLM is a new type of video intubating laryngeal mask airway (LMA), and it is the first LMA to realise continuous visual monitoring. There is a lack of studies on intubation using the SaCoVLM. The aim of this study is to compare the success rate of intubation with polyvinyl chloride (PVC) tubes and wire-reinforced (WR) tubes using the SaCoVLM. METHODS AND ANALYSIS: This prospective, single-centre, single-blind, parallel-arm, randomised controlled study will be conducted in a tertiary university hospital in China. We will include 104 patients undergoing elective laparoscopic surgery under general anaesthesia. Patients will be randomly assigned to the PVC tracheal tube group (n=52, PVC group) or the WR tracheal tube group (n=52, WR group). The primary outcome is the total success rate of intubation. The secondary outcomes are the first success rate of intubation, the time of tracheal intubation, the site of the first contact, the adjustment action for tracheal intubation, haemodynamic fluctuation during intubation and extubation, incidence of trauma as evidenced by blood, and the incidence rates of postoperative sore throat, hoarseness, and dysphagia. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University (YXLL-KY-2022 (008)). All participants will provide written informed consent. The results will be disseminated through peer-reviewed publications and at conferences or congresses. TRIAL REGISTRATION NUMBER: NCT05338827.

Metformin alleviates irradiation-induced intestinal injury by activation of FXR in intestinal epithelia.

Abdominal irradiation (IR) destroys the intestinal mucosal barrier, leading to severe intestinal infection. There is an urgent need to find safe and effective treatments to reduce IR-induced intestinal injury. In this study, we reported that metformin protected mice from abdominal IR-induced intestinal injury by improving the composition and diversity of intestinal flora. The elimination of intestinal microbiota (Abx) abrogated the protective effects of metformin on irradiated mice. We further characterized that treatment of metformin increased the murine intestinal abundance of Lactobacillus, which mediated the radioprotective effect. The administration of Lactobacillus or fecal microbiota transplantation (FMT) into Abx mice considerably lessened IR-induced intestinal damage and restored the radioprotective function of metformin in Abx mice. In addition, applying the murine intestinal organoid model, we demonstrated that IR inhibited the formation of intestinal organoids, and metformin alone bore no protective effect on organoids after IR. However, a combination of metformin and Lactobacillus or Lactobacillus alone displayed a strong radioprotection on the organoid formation. We demonstrated that metformin/Lactobacillus activated the farnesoid X receptor (FXR) signaling in intestinal epithelial cells and hence upregulated tight junction proteins and mucins in intestinal epithelia, increased the number of goblet cells, and augmented the mucus layer thickness to maintain the integrity of intestinal epithelial barrier, which eventually contributed to reduced radiation intestinal injury. In addition, we found that Lactobacillus abundance was significantly increased in the intestine of patients receiving metformin while undergoing abdominal radiotherapy and the abundance was negatively correlated with the diarrhea duration of patients. In conclusion, our results demonstrate that metformin possesses a protective effect on IR-induced intestinal injury by upregulating the abundance of Lactobacillus in the intestine.

Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases.

The mammalian gastrointestinal tract is colonized with a majority of gut microbes, affecting host metabolism and homeostasis. Gut microbiota plays a vital role in nutrient exchange, signaling transduction between intestinal epithelial cells, and resistance to pathogen invasion. Gut microbiota is divided into mucus layer bacteria and intestinal lumen bacteria based on the colonization distribution. Akkermansia muciniphila (A. muciniphila) prefers to colonize in the intestinal mucus layer, and specifically degrades mucins to produce short-chain fatty acids, providing energy for the host and promoting colonization of the bacterium itself. Degradation of mucins prompts the host to compensate for the production of more mucins, thereby maintaining the dynamics of these proteins. In the intestinal micro-ecosystem, A. muciniphila is non-pathogenic, and its colonization with suitable abundance contributes to the development of immune system, thus promoting intestinal health. The mechanisms by which A. muciniphila bears a protective role in the host intestine are currently unclear. In this review, we summarize the microenvironment for the colonization of A. muciniphila, physiological characteristics and pathophysiological impact of A. muciniphila on intestinal diseases, such as irritable bowel syndrome, inflammatory bowel diseases, and intestinal tumors. We also provided updates for current studies on signals that A. muciniphila enhances intestinal barrier integrity and regulates immune response. Together, we conclude that A. muciniphila is a promising probiotic, which could be a microbial target for the treatment of multiple intestinal diseases.

Long Noncoding RNA BCYRN1 Recruits BATF to Promote TM4SF1 Upregulation and Enhance HCC Cell Proliferation and Invasion.

Hepatocellular carcinoma (HCC) is a common form of cancer for which a subset of reliable clinical biomarkers has been defined. However, other factors including long noncoding RNAs (lncRNAs) can also regulate HCC development. This study was thus designed to understand how the lncRNA Brain cytoplasmic RNA 1 (BCYRN1) modulates HCC progression. Bioinformatics approaches were used to identify genes, lncRNAs, and transcription factors that were differentially expressed in the context of HCC, after which the relative expression of BCYRN1 in HCC and control tissues was assessed via qPCR. The ability of BCYRN1 to bind the transcription factor BATF was further evaluated in an RNA immunoprecipitation (RIP) assay, while chromatin immunoprecipitation (ChIP) was used to gauge the binding of the TM4SF1 promoter by BATF. Luciferase reporter assays were also used to assess the association between BCYRN1 and the TM4SF1 promoter. Subsequent loss- and gain-of-function assays were then conducted to explore the effects of altering BCYRN1 expression levels on the proliferative, invasive, and migratory activity of HCC cells. BCYRN1 upregulation was associated with poorer clinical outcomes in HCC patients, and knocking down this lncRNA impaired HCC cell migration and invasion. From a mechanistic perspective, BATF was recruited to the TM4SF1 promoter by BCYRN1, and reducing the expression of this lncRNA was sufficient to constrain xenograft tumor growth in mice. These results highlight BCYRN1 as a putative therapeutic target in HCC tumors.

Transcriptome and metabolome reveal the accumulation of secondary metabolites in different varieties of Cinnamomum longepaniculatum.

BACKGROUND: Cinnamomum longepaniculatum (Gamble) N. Chao ex H. W. Li, whose leaves produce essential oils, is a traditional Chinese medicine and economically important tree species. In our study, two C. longepaniculatum varieties that have significantly different essential oil contents and leaf phenotypes were selected as the materials to investigate secondary metabolism. RESULT: The essential oil content and leaf phenotypes were different between the two varieties. When the results of both transcriptome and metabolomic analyses were combined, it was found that the differences were related to phenylalanine metabolic pathways, particularly the metabolism of flavonoids and terpenoids. The transcriptome results based on KEGG pathway enrichment analysis showed that pathways involving phenylpropanoids, tryptophan biosynthesis and terpenoids significantly differed between the two varieties; 11 DEGs (2 upregulated and 9 downregulated) were associated with the biosynthesis of other secondary metabolites, and 12 DEGs (2 upregulated and 10 downregulated) were related to the metabolism of terpenoids and polyketides. Through further analysis of the leaves, we detected 196 metabolites in C. longepaniculatum. The abundance of 49 (26 downregulated and 23 upregulated) metabolites differed between the two varieties, which is likely related to the differences in the accumulation of these metabolites. We identified 12 flavonoids, 8 terpenoids and 8 alkaloids and identified 4 kinds of PMFs from the leaves of C. longepaniculatum. CONCLUSIONS: The combined results of transcriptome and metabolomic analyses revealed a strong correlation between metabolite contents and gene expression. We speculate that light leads to differences in the secondary metabolism and phenotypes of leaves of different varieties of C. longepaniculatum. This research provides data for secondary metabolite studies and lays a solid foundation for breeding ideal C. longepaniculatum plants.

Lactobacillus Suppresses Tumorigenesis of Oropharyngeal Cancer via Enhancing Anti-Tumor Immune Response.

Deficiency in T cell-mediated adaptive immunity, such as low CD8+ T cell infiltration, inhibits the immune surveillance, promotes malignant transformation, and facilitates tumor growth. Microbiota dysbiosis diminishes the immune system and contributes to the occurrence of cancer. However, the impact of oral dysbiosis on the occurrence and molecular mechanisms of oropharyngeal cancer (OPC) remains largely unknown. In the current study, we used 4-nitroquinoline-1-oxide (4NQO) to mimic tobacco-related carcinogenesis to generate a murine OPC model and determine the role of microbiota changes in OPC tumorigenesis. Our results showed that the oral flora composition of mice was deregulated during the tumorigenesis of OPC. The abundance of Streptococcus, Veillonella, Muribacter, Rodentibacter, and Gemella was increased, whereas the dominant genus Lactobacillus was gradually decreased with disease progression. We further demonstrated that infiltration of CD8+ T lymphocytes was markedly reduced due to the reduction of Lactobacillus. Supplementation of Lactobacillus increased the infiltration of CD8+ T cells, promoted the expression of IFN-γ and granzyme B, and lessened the OPC progression. Analyzing the metabolites of the Lactobacillus, we demonstrated that Lactobacillus enhanced the anti-tumor immune response by producing acetate in OPC development. Administration of acetate to mice could increase the expression of IFN-γ and IFN-γ-inducible chemokines in tumor tissues by activating GPR43 to promote the infiltration of CD8+ T lymphocytes and substantially delay the development of OPC. Together, our data suggest that dysbiosis of oral microbiota promotes the tumorigenesis of OPC through downregulation of cytotoxic T lymphocytes. Lactobacillus and its metabolite acetate improve the tumor microenvironment, which could be applied in the treatment of OPC.

The Application and Influence of Hospice Care Among Patients with Advanced Esophageal Cancer.

OBJECTIVE: To investigate the application effect of hospice care in patients with advanced esophageal cancer (EC), provide a practical basis for improving sleep quality, dignity, and subjective well-being, and relieving depression and anxiety in patients with advanced EC. METHODS: A randomized cluster sampling method was used to select 60 patients with advanced EC who received routine intervention (control group) and 64 patients with advanced EC who received hospice care (study group). The intervention time was three months, and the self-rated anxiety scale (SAS) before and after the interventions was compared between the two groups. The Hamilton Depression Scale (HAMD), the Pittsburgh Sleep Quality Index (PSQI), the General Well-being Scale (GWB), the Patient Dignity Scale (PDI), and patients' physical pain state were recorded. RESULTS: No significant differences were found in the HAMD, SAS, PSQI, GWB, or PDI scores between the two groups before the interventions (P > 0.05); after the interventions, the HAMD, SAS, PSQI, and PDI scores of the two groups were significantly decreased, and the HAMD, SAS, PSQI, and PDI scores of the study group were lower compared with the control group. The GWB scores of the two groups were significantly increased, and those of the study group were significantly higher compared with the control group; the difference was statistically significant (P < 0.05). After the interventions, pain grades of III and above decreased in both groups to grade II, and pain sensation in the study group was lower compared with the control group; the difference was statistically significant (P < 0.05). CONCLUSION: Hospice care can reduce the level of pain related to depression and anxiety in patients with advanced EC and improve their sleep quality, as well as their sense of dignity and subjective well-being.

Elevated RBP-Jκ and CXCL11 Expression in Colon Cancer is Associated with an Unfavorable Clinical Outcome.

INTRODUCTION: This study aims at exploring the expression and significance of recombination signal-binding protein for immunoglobulin kappa J region (RBP-Jκ) and C-X-C motif chemokine 11 (CXCL11) in human colon cancer tissues. METHODS: The RBP-Jκ and CXCL11 expression levels were assessed by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) in patients with colon cancer, and their prognostic significance was evaluated. RESULTS: Through analyzing 342 samples of colon cancer patients treated at our institution, increased expression of RBP-Jκ and CXCL11 was found in human colon cancer specimens compared with matched paratumorous normal specimens (P<0.001). A positive correlation was found between RBP-Jκ expression and CXCL11 expression (P<0.001). High RBP-Jκ expression was significantly associated with poorly differentiated tumors (P=0.005), invasion beyond propria muscularis (P=0.025), lymph node metastases (P=0.005), distant metastasis (P<0.001), advanced tumor-node-metastasis (TNM) stage (P=0.004), and a shorter overall survival (P<0.001). An increase in CXCL11 protein expression was associated with poorly differentiated tumors (P=0.015), invasion beyond propria muscularis (P=0.029), lymph node metastases (P=0.031), distant metastasis (P=0.045), advanced TNM stage (P=0.026), and a shorter overall survival of patients (P<0.001). In multivariate Cox regression analysis, RBP-Jκ protein expression (P=0.036), CXCL11 protein expression (P=0.001), differentiation (P<0.001), depth of invasion (P=0.009), distant metastasis (P<0.001), and TNM stage (P<0.001) were independent prognostic indicators of colon cancer. CONCLUSION: High expression of RBP-Jκ is closely associated with high CXCL11 expression, which represents a risk factor for the poor overall survival of colon cancer patients.

Validation of the Chinese Version of the Quality of Dying and Death Questionnaire for Family Members of ICU Patients.

CONTEXT: The quality of end-of-life care services directly affects the end-of-life quality of life of patients and their families. At present, there are no standard tools in China for assessing the quality of dying and death (QODD) of critical intensive care unit (ICU) patients. OBJECTIVES: This study aimed to introduce the Chinese version of the QODD questionnaire for family members of ICU patients, after transcultural adaptation and validation, to provide an effective instrument for assessing the quality of end-of-life care of ICU patients in China, fill the gap in the evaluation of the quality of end-of-life care of critical ICU patients in China, and offer a theoretical basis and practical guidance during purposeful intervention. METHODS: This study involved the main adult caregivers or principal family members of 149 dying critically ill patients. The original QODD scale was translated using the double forward and backward method. Nine cultural adaptation experts adapted the Chinese version of the QODD scale for completion by family members of ICU patients. Then, we carried out content validity, structural validity, internal consistency, confirmatory factors, and item correlation analysis of the modified scale. RESULTS: The Chinese version of the QODD for family members of ICU patients was developed after some items were deleted or modified. The content validity index was 0.93, indicating that all items were correlated with the measurement of death quality. The Kaiser-Meyer-Olkin value was 0.797, suggesting that the correlations between items were high. The Cronbach's α was 0.865, indicating good internal consistency. In confirmatory factor analysis, the fit indices were χ2 = 207.327, non-normed fit index = 0.916, root mean square error of approximation = 0.033, and comparative fit index = 0.93, indicating a good fit of the five-factor model of the Chinese version of the QODD questionnaire for family members of ICU patients. CONCLUSION: The Chinese version of the QODD questionnaire for family members of ICU patients is a reliable and effective instrument for evaluating the quality of death among patients who die in the ICU and can be applied to clinical practice and research.

Revealing the structure-activity relationship of two Cu-porphyrin-based metal-organic frameworks for the electrochemical CO2-to-HCOOH transformation.

The eCO2RR activity is correlated to the internal structural character of the catalyst. We employed two types of structural models of porphyrin-based MOFs of PCN-222(Cu) and PCN-224(Cu) into heterogeneous catalysis to illustrate the effect of structural factors on the eCO2RR performance. The composite catalyst PCN-222(Cu)/C displays better activity and selectivity (η = 450 mV, FEHCOOH = 44.3%, j = 3.2 mA cm-2) than PCN-224(Cu)/C (η = 450 mV, FEHCOOH = 34.1%, j = 2.4 mA cm-2) for the CO2 reduction to HCOOH in the range of -0.7--0.9 V (vs. RHE) due to its higher BET surface area, CO2 uptake, and a larger pore diameter. It is interesting that PCN-224(Cu)/C displays better performance in the range of -0.4--0.6 V (vs. RHE) due to its greater heat of adsorption, Qst and a higher affinity for CO2 molecule, which could promote the capture of CO2 onto the exposed active sites. As a result, PCN-224(Cu)/C exhibits better stability for the long-term electrolysis.

Enhanced adsorption and slow release of phosphate by dolomite-alginate composite beads as potential fertilizer.

The recovery and reuse of phosphorus (P) from wastewater treatment process is a critical and viable target for sustainable P utilization. This study explores a novel approach of integrating ultrafine mineral particles into hydrogel matrixes for enhancing the capacity of phosphate adsorption. Dolomite-alginate (DA) hydrogel beads were prepared by integrating ball-milled, ultrafine dolomite powders into calcium cross-linked alginate hydrogel matrix. The adsorption isotherms followed a Langmuir-Freundlich adsorption model with higher specific adsorption capacity than those reported in literature. The kinetics of phosphate adsorption suggest that the adsorption is diffusion controlled. Investigation of adsorption capacity at different pH showed a maximum adsorption capacity in the pH range of 7-10. Lastly, we demonstrated that the DA beads are capable of slowly releasing most of the adsorbed phosphate, which is an important criterion for them to be an effective phosphorous fertilizer. This study, using DA composite hydrogel as an example, demonstrates a promising strategy of immobilizing ultrafine mineral adsorbents into biocompatible hydrogel matrix for effective recovery of phosphorous resource from wastewater. PRACTITIONER POINTS: Integration of dolomite and alginate hydrogel beads is demonstrated using ball milling. Ball milling process increases the specific adsorption capacity of dolomite on phosphorus. Adsorption isotherms, kinetics, and pH effects of the dolomite-alginate beads are investigated. The dolomite-alginate beads can be used as slow-release phosphorus fertilizer.

Pioglitazone attenuates aging-related disorders in aged apolipoprotein E deficient mice.

Pioglitazone (Piog) activates peroxisome proliferator activated receptor-γ (PPARγ) and is widely used in clinic for the treatment of diabetes mellitus. PPARγ in various tissues has the essential regulatory role of multiple metabolic function, suggest that PPARγ signaling may contribute to aging processes. However, little is known about the consequences of Piog on aging in aged animal models. We used apolipoprotein E deficient (apoE-/-) mice model to evaluate the effects of Piog on aging-related disorders. Our results showed that long-term and low-dose Piog treatment significantly reduced aortic atherosclerosis, aging-related renal glomerulosclerosis and interstitial fibrosis, and hepatic steatosis, while improved the dermis in skin atrophy, compared to the control group. These morphological alterations were linked to the role of Piog, including regulation of plasma cholesterol and triglycerides (TG) levels, increased antioxidant superoxide dismutase (SOD) activity and decreased myeloperoxidase (MPO) activity. Moreover, accompanied with up-regulation of PPARγ expression, Piog had obviously increased the mRNA levels of anti-aging genes Sirtuin1 and Klotho, decreased the p53 protein level, and altered the expression of several genes involving cholesterol excretion, TG biosynthesis and inflammation in the liver. In conclusion, Piog treatment is effective to modulate the oxidative and inflammatory status, cell senescence, and lipid metabolism, contributing to attenuate several aging-related disorders in the aged apoE-/- mice, thereby maybe a promising protective therapy of aging and age-related diseases.

[Simultaneous determination of salidroside and tyrosol in Beagle dog plasma using UHPLC-MS/MS after pre-column dansyl chloride derivatization].

A pre-column derivatization method combined with UHPLC-MS/MS was developed for the simultaneous determination of salidroside and tyrosol in Beagle dog plasma. After protein precipitation by acetonitrile, the liquid supernatant was treated with dansyl chloride under dark conditions at 60 ℃ for 30 min, and then, the sample solution was extracted using methyl tertiary butyl ether. The multiple reaction monitoring in positive ion mode was used for MS detection of the tested analytes with the specific ion transitions of m/z 534.2→372.0 for salidroside derivative, m/z 372.0→171.0 for tyrosol derivative and m/z 506.0→171.0 for arbutin derivative. The chromatograph separation was achieved on an ACQUITY UPLC® BEH C18 column (100 mm × 2.1 mm, 1.7 µm) with a gradient mobile phase consisting of acetonitrile (0.1% formic acid)-water (10% acetonitrile, 0.1% formic acid) for 9 min. The assay showed a good linearity over the range of 0.02/0.1 − 20/10 µmol·L−1 with a lower limit of quantitation of 0.02 and 0.1 µmol·L−1 for salidroside and tyrosol in dog plasma, respectively. The intra- and inter-day precisions were all less than 8.68%, and the accuracy was within ±11.4%. The established method with a high sensitivity, good specificity and reliability was appropriate for simultaneous determination of salidroside and tyrosol in dog plasma and successfully applied to a pharmacokinetic study after intragastric administration of salidroside to Beagle dogs.

Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aß Production in Neurons from APP/PS1 Transgenic Mice.

Hydrogen sulfide (H2S) is now considered to be a gasotransmitter and may be involved in the pathological process of Alzheimer's disease (AD). A majority of APP is associated with mitochondria and is a substrate for the mitochondrial γ-secretase. The mitochondria-associated APP metabolism where APP intracellular domains (AICD) and Aß are generated locally and may contribute to mitochondrial dysfunction in AD. Here, we aimed to investigate the ability of H2S to mediate APP processing in mitochondria and assessed the possible mechanisms underlying H2S-mediated AD development. We treated neurons from APP/PS1 transgenic mice with a range of sodium hydrosulfide (NaHS) concentrations. NaHS attenuated APP processing and decreased Aß production in mitochondria. Meanwhile, NaHS did not changed BACE-1 and ADAM10 (a disintegrin and metalloprotease 10) protein levels, but NaHS (30 µM) significantly increased the levels of presenilin 1(PS1), PEN-2, and NCT, as well as improved the γ-secretase activity, while NaHS (50 µM) exhibits the opposing effects. Furthermore, the intracellular ATP and the COX IV activity of APP/PS1 neurons were increased after 30 µM NaHS treatment, while the ROS level was decreased and the MMP was stabilized. The effect of NaHS differs from DAPT (a non-selective γ-secretase inhibitor), and it selectively inhibited γ-secretase in vitro, without interacting with Notch and modulating its cleavage. The results indicated that NaHS decreases Aß accumulation in mitochondria by selectively inhibiting γ-secretase. Thus, we provide a mechanistic view of NaHS is a potential anti-AD drug candidate and it may decrease Aß deposition in mitochondria by selectively inhibiting γ-secretase activity and therefore protecting the mitochondrial function during AD conditions.