OBJECTIVES: To analyze the differentially expressed exosomal miRNAs in patients with chronic heart failure (CHF) complicated by hyperuricemia (HUA) and explore their potential as novel diagnostic molecular markers and their target genes. METHODS: This study was conducted among 30 CHF patients with HUA (observation group) and 30 healthy volunteers (control group) enrolled between September, 2020 and September, 2023. Peripheral blood samples were collected from 6 CHF patients with HUA for analyzing exosomal miRNAs by high-throughput sequencing, and the results were validated in the remaining 24 patients using qRT-PCR. GO and KEGG enrichment analyses were performed to predict the the target genes of the identified differential miRNAs. We also validated the differentially expressed miRNAs by animal experiment. RESULTS: A total of 42 differentially expressed exosomal miRNAs were detected in observation group by high-throughput sequencing; among them, miR-27a-5p was significantly upregulated (P=0.000179), and miR-139-3p was significantly downregulated (P=0.000058). In the 24 patients with both CHF and PUA, qRT-PCR validated significant upregulation of miR-27a-5p (P=0.004) and downregulation of miR-139-3p (P=0.005) in serum exosomes. When combined, miR-27a-5p and miR-139-3p had a maximum area under the curve (AUC) of 0.899 (95% CI: 0812-0.987) for predicting CHF complicated by HUA. GO and KEGG enrichment analyses suggested that the differential expressions of miR-27a-5p and miR-139-3p was associated with the activation of the AMPK-mTOR signaling pathway to activate the autophagic response. We obtained the same conclusion from animal experiment. CONCLUSIONS Upregulated exosomal miR-27a-5p combined with downregulated exosomal miR-139-3p expression can serve as a novel molecular marker for diagnosis of CHF complicated by HUA, and their differential expression may promote autophagy in cardiomyocytes by activating the AMPK-mTOR signaling pathway.
Humans ; Hyperuricemia/diagnosis* ; Heart Failure/genetics* ; MicroRNAs/metabolism* ; Exosomes/metabolism* ; Chronic Disease ; Male ; Female ; Middle Aged ; Animals

One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
Animals ; Mice ; RNA, Untranslated/metabolism* ; Aging/genetics* ; Mice, Transgenic ; Telomerase/metabolism* ; RNA/genetics* ; Hippocampus/metabolism* ; Humans ; Mice, Inbred C57BL

Purpose: Vaccinia virus is widely used as an oncolytic agent for human cancer therapy, and several versions of vaccinia virus have demonstrated robust antitumor effects in breast cancer. Most vaccinia viruses are modified by thymidine kinase (TK) deletion. The function of the cyclin-dependent kinase inhibitor p21 in breast cancer remains controversial. We explored the impact of p21 gene knockdown (KD) on breast cancer cells and whether p21 KD interferes with the antitumor effect of TK-negative vaccinia virus. Methods: p21 KD MDA-MB-231 and p21 KD MCF-7 cells were prepared, and cell proliferation and migration rates were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch healing assays. The tumor growth of xenografts originating from p21KD MDA-MB-231 cells and control cells was compared in a mouse model. The colony formation and sphere-forming abilities of p21 KD breast cancer cells were also determined using low-melting agarose and serum-free culture. The tumorkilling effect of the vaccinia virus was determined in breast cancer cells and mouse models using an MTT assay and tumor cell xenografts. Results: p21 KD increased the growth and migration of MDA-MB-231 and MCF-7 cells and promoted the cell growth of MDA-MB-231 cells in mice, while decreasing the colony formation and sphere formation abilities. Expression of TK was reduced in p21 KD MDAMB-231 cells. Oncolytic effects of both wild-type and TK-deleted vaccinia viruses were attenuated in p21KD MDA-MB-231 cells. The tumor-killing effect of TK-deleted vaccinia virus was also weakened in xenografted mice bearing p21 KD MDA-MB-231 cells. Conclusion Targeted inhibition of p21 accelerates the proliferation and migration of breast cancer cells and impairs the tumor-killing effect of vaccinia virus, suggesting that p21 levels in cancer cells interfere with vaccinia virus oncolytic therapy.

Purpose: Vaccinia virus is widely used as an oncolytic agent for human cancer therapy, and several versions of vaccinia virus have demonstrated robust antitumor effects in breast cancer. Most vaccinia viruses are modified by thymidine kinase (TK) deletion. The function of the cyclin-dependent kinase inhibitor p21 in breast cancer remains controversial. We explored the impact of p21 gene knockdown (KD) on breast cancer cells and whether p21 KD interferes with the antitumor effect of TK-negative vaccinia virus. Methods: p21 KD MDA-MB-231 and p21 KD MCF-7 cells were prepared, and cell proliferation and migration rates were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch healing assays. The tumor growth of xenografts originating from p21KD MDA-MB-231 cells and control cells was compared in a mouse model. The colony formation and sphere-forming abilities of p21 KD breast cancer cells were also determined using low-melting agarose and serum-free culture. The tumorkilling effect of the vaccinia virus was determined in breast cancer cells and mouse models using an MTT assay and tumor cell xenografts. Results: p21 KD increased the growth and migration of MDA-MB-231 and MCF-7 cells and promoted the cell growth of MDA-MB-231 cells in mice, while decreasing the colony formation and sphere formation abilities. Expression of TK was reduced in p21 KD MDAMB-231 cells. Oncolytic effects of both wild-type and TK-deleted vaccinia viruses were attenuated in p21KD MDA-MB-231 cells. The tumor-killing effect of TK-deleted vaccinia virus was also weakened in xenografted mice bearing p21 KD MDA-MB-231 cells. Conclusion Targeted inhibition of p21 accelerates the proliferation and migration of breast cancer cells and impairs the tumor-killing effect of vaccinia virus, suggesting that p21 levels in cancer cells interfere with vaccinia virus oncolytic therapy.

The purpose of this paper is to systematically summarize the gene polymorphisms associated with osteoporosis(OP)susceptibility in Zhuang ethnic group in Guangxi.These genes mainly encode vitamin D receptor,estrogen receptor,calcitonin receptor,and adiponectin.The genotype and allele distribution frequency were compared between Zhuang ethnic group and other ethnic groups,which can clarify the existing genes and the potential gene polymorphism associated with OP in Zhuang ethnic group.The findings provide a representative solution for the subsequent research on the genes associated with OP susceptibility in ethnic minorities.

Objective To standardize nursing management on postoperative patients with a left ventricular assist-ant device(LVAD).Methods The first draft of the Consensus was formed on the basis of literature review.2 rounds of expert consultations and a round of online meeting discussion were held for adjustments and modifications the draft of the Consensus.Results The recovery rate of the inquiry questionnaire was 93.75%.The authority coefficients of the 2 rounds of inquiry experts were 0.927 and 0.920.The concentration degree of expert opinions for each indicator was greater than 3.5 score,and the coefficient of variation was less than 0.25.The Kendall harmony coefficients for 2 rounds of correspondence were 0.402 and 0.407(P<0.01).The final Consensus formed through expert consultations and meetings includes 7 themes:hemodynamic monitoring,LVAD function monitoring,coagulation function monitoring,percutaneous cable and wound care,exercise rehabilitation care,health education and guidance,and pre-discharge assessment.Conclusion The Consensus is scientific,rigorous,and authoritative.The Consensus covers all aspects of postoperative care for patients with LVAD,and it will benefit to clinical practice.

OBJECTIVE To investigate the effect of Jianpi Yangzheng(JPYZ)formula regulating tumor-associated macrophage(TAM)exosomes on anoikis in gastric cancer and its mechanism.METHODS TAM model was established by inducing human mononuclear THP-1 cells in vitro;M0,TAM and TAM+JPYZ formula exosomes were extracted by ultracentrifugation and co-incuba-ted with gastric cancer cells.Flow cytometry was used to detect the effect of exosomes in each group on anoikis in gastric cancer cells.A BALB/c transplanted tumor mouse model was constructed,and the expression level of apoptotic proteins in transplanted tumors was detected by Western blot.Label-free mass spectrometry proteomics and bioinformatics were used to analyze the differential proteins in gastric cancer cells before and after intervention;Western blot and qPCR experiments were used to detect the expression level of dif-ferential protein isocitrate dehydrogenase 1(IDH1),and ubiquitination experiments were used to detect the ubiquitination level of IDH1;kits were used to detect the levels of α-ketoglutarate(α-KG),NADPH/NADP+,glutathione(GSH/GSSG)and reactive oxy-gen species(ROS)content.RESULTS The anoikis rate of gastric cancer cells was reduced after TAM exosomes intervention(P<0.05,P<0.01),while it was significantly increased after TAM+JPYZ exosomes intervention(P<0.05,P<0.01).In the in vivo mouse experiment,the ratio of Cleaved Caspase-3/Caspase-3 in the tumor of the TAM exosome group was reduced(P<0.05),while the ra-tio was significantly increased after TAM+JPYZ exosome intervention(P<0.05).Proteomic analysis showed that IDH1 was significant-ly different after intervention,and was related to tricarboxylic acid cycle metabolism.Compared with the M0 group,the IDH1 ubiquiti-nation level of gastric cancer cells in the TAM group with exosome intervention was increased,the levels of α-KG,NADPH/NADP+and GSH/GSSG were significantly increased,and the ROS content was reduced(P<0.05),while TAM+JPYZ exosomes could reverse the above phenomenon.CONCLUSION JPYZ Formula can regulate TAM exosomes to cause ubiquitin degradation of IDH1 in gas-tric cancer cells,reduce the level of tricarboxylic acid cycle metabolism in gastric cancer cells,promote ROS accumulation,induce anoikis in gastric cancer,and thus inhibit the development of gastric cancer.

Objective To explore the value of lipoprotein-associated phospholipase A2(Lp-PLA2)in the diagnostic grading and prog-nostic assessment of pneumonia-associated acute respiratory distress syndrome(p-ARDS).Methods The study was a prospective ob-servational study.Fifty-seven patients with p-ARDS admitted to the ICU ward of Tianjin Hospital from January 2022 to August 2023 were included as the research subjects.Twenty-six pneumonia patients admitted to the general respiratory ward during the same period and 10 healthy individuals undergoing medical examinations were selected as the control group.Their serum samples were collected,and the samples from p-ARDS and pneumonia patients were obtained within 24 hours of admission.The levels of serum Lp-PLA2,in-terleukin 6(IL-6),and IL-8 were detected using the Luminex? multiplex test kit.The baseline data and laboratory test results,inclu-ding routine blood parameters,biochemical markers,C-reactive protein(CRP),procalcitonin(PCT),and D-dimer at admission,were collected from the patients with p-ARDS or pneumonia.The levels of serum Lp-PLA2 were compared by grouping based on clinical diagnosis,severity of ARDS,and clinical outcomes on day 28 after admission.The diagnostic and prognostic value of serum Lp-PLA2 in p-ARDS was evaluated by plotting the receiver operating characteristic(ROC)curve,Spearman correlation analysis,and Logistic regression analysis.Results The levels of serum Lp-PLA2 in the p-ARDS group([233.67±83.49]ng/mL)were significantly higher than that in the pneumonia group([150.86±39.48]ng/mL,P＜0.05),while those in the pneumonia group were significantly higher than that in the healthy control group([150.86±39.48]ng/mL vs[92.07±12.89]ng/mL,P＜0.05).The analysis results of the ROC curve showed that serum Lp-PLA2 had a better ability to distinguish p-ARDS from pneumonia than indicators such as IL-6,IL-8,CRP,and PCT,with an area under the ROC curve(AUCROC)of 0.781(95％CI:0.685-0.878).The diagnostic value of serum Lp-PLA2 combined with D-dimer was higher,with an AUCROC of 0.897(95％CI:0.832-0.963).Subgroup analysis found that as lung inju-ry worsened,the levels of serum Lp-PLA2 increased,and that serum Lp-PLA2 levels were negatively correlated with the PaO2/FiO2 ra-tio in p-ARDS patients(r=-0.549)and positively correlated with the sequential organ failure assessment(SOFA)scores at admission(r=0.412).The levels of serum Lp-PLA2 in the death group of p-ARDS were significantly higher than that in the survival group([314.5±43.1]ng/mL vs[174.9±48.9]ng/mL,P＜0.001).Logistic regression analysis showed that after adjusting for the SOFA score,serum Lp-PLA2 was independently associated with the mortality risk on day 28 after admission(OR=1.099,95％CI:1.026-1.178,P=0.007).Similar results were obtained after adjusting for IL-8 or the PaO2/FiO2 ratio.Conclusion Serum Lp-PLA2 may be used as a biomarker to aid in the diagnostic grading and prognostic assessment of p-ARDS.

Objective To minimize variations in treatment outcomes of L5/S1 percutaneous intervertebral radiofrequency thermocoagulation(PIRFT)arising from physician proficiency and achieve precise quantitative risk assessment of the puncture paths.Methods We used a self-developed deep neural network DWT-UNet for automatic segmentation of the magnetic resonance(MR)images of the L5/S1 segments into 7 key structures:L5,S1,Ilium,Disc,N5,Dura mater,and Skin,based on which a needle insertion path planning environment was modeled.Six hard constraints and 6 soft constraints were proposed based on clinical criteria for needle insertion,and the physician's experience was quantified into weights using the analytic hierarchy process and incorporated into the risk function for needle insertion paths to enhance individual case adaptability.By leveraging the proposed skin entry point sampling sub-algorithm and Kambin's triangle projection area sub-algorithm in conjunction with the analytic hierarchy process,and employing various technologies such as ray tracing,CPU multi-threading,and GPU parallel computing,a puncture path was calculated that not only met clinical hard constraints but also optimized the overall soft constraints.Results A surgical team conducted a subjective evaluation of the 21 needle puncture paths planned by the algorithm,and all the paths met the clinical requirements,with 95.24%of them rated excellent or good.Compared with the physician's planning results,the plans generated by the algorithm showed inferior DIlium,DS1,and Depth(P<0.05)but much better DDura,DL5,DN5,and AKambin(P<0.05).In the 21 cases,the planning time of the algorithm averaged 7.97±3.73 s,much shorter than that by the physicians(typically beyond 10 min).Conclusion The multi-constraint optimal puncture path planning algorithm offers an efficient automated solution for PIRFT of the L5/S1 segments with great potentials for clinical application.

Objective To minimize variations in treatment outcomes of L5/S1 percutaneous intervertebral radiofrequency thermocoagulation(PIRFT)arising from physician proficiency and achieve precise quantitative risk assessment of the puncture paths.Methods We used a self-developed deep neural network DWT-UNet for automatic segmentation of the magnetic resonance(MR)images of the L5/S1 segments into 7 key structures:L5,S1,Ilium,Disc,N5,Dura mater,and Skin,based on which a needle insertion path planning environment was modeled.Six hard constraints and 6 soft constraints were proposed based on clinical criteria for needle insertion,and the physician's experience was quantified into weights using the analytic hierarchy process and incorporated into the risk function for needle insertion paths to enhance individual case adaptability.By leveraging the proposed skin entry point sampling sub-algorithm and Kambin's triangle projection area sub-algorithm in conjunction with the analytic hierarchy process,and employing various technologies such as ray tracing,CPU multi-threading,and GPU parallel computing,a puncture path was calculated that not only met clinical hard constraints but also optimized the overall soft constraints.Results A surgical team conducted a subjective evaluation of the 21 needle puncture paths planned by the algorithm,and all the paths met the clinical requirements,with 95.24%of them rated excellent or good.Compared with the physician's planning results,the plans generated by the algorithm showed inferior DIlium,DS1,and Depth(P<0.05)but much better DDura,DL5,DN5,and AKambin(P<0.05).In the 21 cases,the planning time of the algorithm averaged 7.97±3.73 s,much shorter than that by the physicians(typically beyond 10 min).Conclusion The multi-constraint optimal puncture path planning algorithm offers an efficient automated solution for PIRFT of the L5/S1 segments with great potentials for clinical application.