Dissipation and Safety Analysis of Dimethomorph Application in Lychee by High-Performance Liquid Chromatography-Tandem Mass Spectrometry with QuEChERS.

This study presents a method for analyzing dimethomorph residues in lychee using QuEChERS extraction and HPLC-MS/MS. The validation parameters for this method, which include accuracy, precision, linearity, and recovery, indicate that it meets standard validation requirements. Following first-order kinetics, the dissipation dynamic of dimethomorph in lychee was determined to range from 6.4 to 9.2 days. Analysis of terminal residues revealed that residues in whole lychee were substantially greater than those in the pulp, indicating that dimethomorph residues are predominantly concentrated in the peel. When applied twice and thrice at two dosage levels with pre-harvest intervals (PHIs) of 5, 7, and 10 days, the terminal residues in whole lychee ranged from 0.092 to 1.99 mg/kg. The terminal residues of the pulp ranged from 0.01 to 0.18 mg/kg, with the residue ratio of whole lychee to pulp consistently exceeding one. The risk quotient (RQ) for dimethomorph, even at the recommended dosage, was less than one, indicating that the potential for damage was negligible. This study contributes to the establishment of maximum residue limits (MRLs) in China by providing essential information on the safe application of dimethomorph in lychee orchards.

Design, synthesis, and evaluation of novel arecoline-linked amino acid derivatives for insecticidal and antifungal activities.

A series of arecoline derivatives with amino acid moieties were designed and synthesised using an acylamide condensation strategy, taking arecoline as the foundational structure. The insecticidal efficacy of these compounds against Aphis craccivora and Tetranychus cinnabarinus was evaluated. Notably, derivatives 3h and 3i demonstrated superior insecticidal activity compared with arecoline. Additionally, 3h and 3i showed good fungicidal effectiveness against two types of plant fungi. Moreover, molecular docking analyses suggested that 3h and 3i could affect the nervous systems of A. craccivora and T. cinnabarinus by binding to neuronal nicotinic acetylcholine receptors. These findings suggest that compounds 3h and 3i represent promising leads for further development in insecticide and fungicide research.

New insights into the stipitate hydnoid fungi Sarcodon, Hydnellum, and the formerly informally defined Neosarcodon, with emphasis on the edible species marketed in Southwest China.

Sarcodon and Hydnellum are two ectomycorrhizal genera of important ecological and economic value in Southwest China, and they are common in the free markets in this region. It was estimated that more than 1,500 tonnes of them were sold as edible per year, but there was little information about the taxonomic placements of these edible mushrooms sold in the markets. Traditional concepts of the two genera have also been challenged recently, and circumscription of Sarcodon and the informally defined clade "Neosarcodon" remained unresolved. In the present study, specimens collected in the field and purchased from the markets in Southwest China were analyzed based on morphological characters and DNA sequences. Phylogeny of the traditional Sarcodon s. lat. and Hydnellum s. lat. was reconstructed from the combined internal transcribed spacer (ITS), nuclear large ribosomal subunit (nLSU) and RNA polymerase II second largest subunit (RPB2) dataset based on expanded samples to reevaluate the taxonomic placements of the two genera. In the present molecular analyses, four distinct clades were recovered and strongly supported: Hydnellum, Neosarcodon, Phellodon and Sarcodon. Neosarcodon is formally introduced as a generic name to include nine species previously placed in Sarcodon, and the delimitation of Sarcodon is revised based on phylogenetic and morphological studies. Phylogenetic analyses also revealed an unexpected species diversity (17 phylogenetic species) of Sarcodon and Hydnellum in the markets; nine phylogenetic species of Sarcodon and eight of Hydnellum were uncovered from the samples collected in the markets. Eight species were resolved in the traditional S. imbricatus complex, with S. imbricatus s.str. being the most common edible stipitate hydnoid fungal species. Three of the edible Hydnellum species (H. edulium, H. subalpinum, and H. subscabrosellum), and five separated from the S. imbricatus complex (Sarcodon flavidus, S. giganteus, S. neosquamosus, S. nigrosquamosus, and S. pseudoimbricatus), are described as new. Three new Chinese records (H. illudens, H. martioflavum, and H. versipelle), and the notable S. imbricatus and S. leucopus are also reported.

A pan-cancer analysis of the prognosis and immune infiltration of eEF1A2 and its potential function in thyroid carcinoma.

Purpose: Eukaryotic translation elongation factor 1α2 (eEF1A2) promotes tumour progression in various cancers. We performed a pan-cancer analysis of eEF1A2 and explored its role in thyroid carcinoma (THCA). Methods: Databases from The Cancer Genome Atlas (TCGA), the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and the Human Protein Atlas (HPA) were used to investigate the differential expression of eEF1A2 in pan-cancer. The pathological stage, prognostic characteristics, tumour microenvironment (TME), tumour mutational burden (TMB), and microsatellite instability (MSI) were analysed in diverse tumours with different expression levels of eEF1A2. The expression levels in papillary thyroid carcinoma (PTC) and its specific role in cell proliferation, migration, invasion, and cell glycolysis in PTC cells were verified by quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry, cell counting kit-8, colony formation, wound healing, Transwell assay, and lactate acid and glucose assays.Results:eEF1A2 was differentially expressed in various malignant tumour tissues compared to control tissues and was associated with poor pathological stage and prognosis in most types of tumours. Moreover, eEF1A2 expression closely correlated with the infiltration of immunosuppressive cells, TMB, and MSI in some tumour types. Expression of eEF1A2 in PTC is higher than the para-carcinoma, and eEF1A2 downregulation suppressed TPC-1 and BCPAP cell proliferation, migration, invasion, and glycolysis. Conclusion: Our study suggests that the expression of eEF1A2 is related to the prognosis and immune infiltration of some tumours and may be a predictor of prognosis and immunotherapy. eEF1A2 could promote malignant behaviour of PTC cells.

Redoxisome Update: TRX and TXNIP/TBP2-Dependent Regulation of NLRP-1/NLRP-3 Inflammasome.

Recent studies have provided evidence for the direct binding of thioredoxin-1 (TRX1) to a component of inflammasome complex NLR family pyrin domain containing 1 (NLRP-1). This interaction suggests a potential role for TRX1 in the regulation of the NLRP-1 inflammasome. Furthermore, the NLRP-3 inflammasome is known to bind TRX1 and its inhibitor, TRX-binding protein-2/TRX-interacting protein/vitamin D3 upregulated protein-1 (TBP2/TXNIP/VDUP-1). This binding forms a redox-sensitive complex, termed the "Redoxisome," as described previously. However, the specific functions of NLRP-1 within the redoxisome complex remain undefined. Antioxid. Redox Signal. 40, 595-597.

Sudden ventricular fibrillation due to absence of pericardium in left upper lobectomy: a case report.

Background: Congenital absence of the pericardium (CAP) is a rare cardiac abnormality. As pericardial defects are usually asymptomatic, most cases are diagnosed during surgery or on autopsy. The patient in this case was found to have CAP during thoracoscope. Case: We present the unusual case of a 69-year-old patient with CAP who experienced sudden ventricular arrhythmia and developed ventricular fibrillation during left upper lobectomy. Surgical operations, the lateral decubitus position, and other external stimuli may be important risk factors for ventricular fibrillation. The patient regained sinus rhythm soon after intrathoracic cardiac compression and pharmacological treatment, including lidocaine spray (2%, 10 ml) administered to the heart surface. The surgery was then completed without any additional instances of ventricular arrhythmia. Conclusion: Patients with CAP are more susceptible to cardiac-related adverse events during thoracotomy or thoracoscopy. Treatment of ventricular arrhythmias that occur during lung resection in patients with CAP should be emphasized.

Identification of immune-related signatures and pathogenesis differences between thoracic aortic aneurysm patients with bicuspid versus tricuspid valves via weighted gene co-expression network analysis.

BACKGROUND: Thoracic aortic aneurysm (TAA) occurs due to pathological aortal dilation, and both individuals with normal tricuspid aortic valves (TAV) or abnormal bicuspid aortic valves (BAV), the latter being a congenital condition, are at risk. However, some differences are present between TAA/BAV and TAA/TAV with respect to their pathophysiological processes and molecular mechanisms, but their exact nature is still mostly unknown. Therefore, it is necessary to elucidate TAA developmental differences among BAV vs. TAV patients. METHODS: Publically-available gene expression datasets, aortic tissue derived from TAA/BAV and TAA/TAV individuals, were analyzed by weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with those conditions. Gene Ontology (GO) enrichment analysis was performed on those modules to identify the enriched genes within those modules, which were verified by Gene Set Variation Analysis (GSVA) on a dataset derived from aortic smooth muscle cell gene expression between TAA/TAV and TAV/BAV patients. Immune cell infiltration patterns were then analyzed by CIBERSORT, and a protein-protein interaction (PPI) network was constructed based on WGCNA and enrichment analysis results to identify hub genes, followed by validation via stepwise regression analysis. Three signatures most strongly associated with TAA/TAV were confirmed by receiver operating characteristic (ROC) and decision curve analyses (DCA) between prior-established training and testing gene sets. RESULTS: WGCNA delineated 2 gene modules being associated with TAA/TAV vs. TAA/BAV; both were enriched for immune-associated genes, such as those relating to immune responses, etc., under enrichment analysis. TAA/TAV and TAA/BAV tissues also had differing infiltrating immune cell proportions, particularly with respect to dendritic, mast and CD4 memory T cells. Identified three signatures, CD86, integrin beta 2 (ITGB2) and alpha M (ITGAM), as yielding the strongest associations with TAA/TAV onset, which was verified by areas under the curve (AUC) at levels approximating 0.8 or above under ROC analysis, indicating their predictive value for TAA/TAV onset. However, we did not examine possible confounding variables, so there are many alternative explanations for this association. CONCLUSIONS: TAA/TAV pathogenesis was found to be more associated with immune-related gene expression compared to TAA/BAV, and the identification of three strongly-associated genes could facilitate their usage as future biomarkers for diagnosing the likelihood of TAA/TAV onset vs. TAA/BAV, as well as for developing future treatments.

Comparative transcriptome analysis of high- and low-embryogenic Hevea brasiliensis genotypes reveals involvement of phytohormones in somatic embryogenesis.

BACKGROUND: Rubber plant (Hevea brasiliensis) is one of the major sources of latex. Somatic embryogenesis (SE) is a promising alterative to its propagation by grafting and seed. Phytohormones have been shown to influence SE in different plant species. However, limited knowledge is available on the role of phytohormones in SE in Hevea. The anther cultures of two Hevea genotypes (Yunyan 73477-YT and Reken 628-RT) with contrasting SE rate were established and four stages i.e., anthers (h), anther induced callus (y), callus differentiation state (f), and somatic embryos (p) were studied. UPLC-ESI-MS/MS and transcriptome analyses were used to study phytohormone accumulation and related expression changes in biosynthesis and signaling genes. RESULTS: YT showed higher callus induction rate than RT. Of the two genotypes, only YT exhibited successful SE. Auxins, cytokinins (CKs), abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), gibberellins (GAs), and ethylene (ETH) were detected in the two genotypes. Indole-3-acetic acid (IAA), CKs, ABA, and ETH had notable differences in the studied stages of the two genotypes. The differentially expressed genes identified in treatment comparisons were majorly enriched in MAPK and phytohormone signaling, biosynthesis of secondary metabolites, and metabolic pathways. The expression changes in IAA, CK, ABA, and ETH biosynthesis and signaling genes confirmed the differential accumulation of respective phytohormones in the two genotypes. CONCLUSION: These results suggest potential roles of phytohormones in SE in Hevea.

Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System.

Geranylgeranylacetone (GGA) exerts cytoprotective activity against various toxic stressors via the thioredoxin (TRX) redox system; however, its effect on skin inflammation and molecular mechanism on inducing the TRX of GGA is still unknown. We investigated the effects of GGA in a murine irritant contact dermatitis (ICD) model induced by croton oil. Both a topical application and oral administration of GGA induced TRX production and Nrf2 activation. GGA ameliorated ear swelling, neutrophil infiltration, and inhibited the expression of TNF-α, IL-1ß, GM-CSF, and 8-OHdG. GGA's cytoprotective effect was stronger orally than topically in mice. In vitro studies also showed that GGA suppressed the expression of NLRP3, TNF-α, IL-1ß, and GM-CSF and scavenged ROS in PAM212 cells after phorbol myristate acetate stimulation. Moreover, GGA induced endogenous TRX production and Nrf2 nuclear translocation in PAM212 cells (dependent on the presence of ROS) and activated the PI3K-Akt signaling pathway. GGA significantly downregulated thioredoxin-interacting protein (TXNIP) levels in PAM212 cells treated with or without Nrf2 siRNA. After knocking down Nrf2 in PAM212 cells, the effect of GGA on TRX induction was significantly inhibited. This suggests that GGA suppress ICD by inducing endogenous TRX, which may be regulated by PI3K/Akt/Nrf2 mediation of the TRX redox system.

Roles of sulfate-reducing bacteria in sustaining the diversity and stability of marine bacterial community.

Microbes play central roles in ocean food webs and global biogeochemical processes. Yet, the information available regarding the highly diverse bacterial communities in these systems is not comprehensive. Here we investigated the diversity, assembly process, and species coexistence frequency of bacterial communities in seawater and sediment across ∼600 km of the eastern Chinese marginal seas using 16S rRNA gene amplicon sequencing. Our analyses showed that compared with seawater, bacterial communities in sediment possessed higher diversity and experienced tight phylogenetic distribution. Neutral model analysis showed that the relative contribution of stochastic processes to the assembly process of bacterial communities in sediment was lower than that in seawater. Functional prediction results showed that sulfate-reducing bacteria (SRB) were enriched in the core bacterial sub-communities. The bacterial diversities of both sediment and seawater were positively associated with the relative abundance of SRB. Co-occurrence analysis showed that bacteria in seawater exhibited a more complex interaction network and closer co-occurrence relationships than those in sediment. The SRB of seawater were centrally located in the network and played an essential role in sustaining the complex network. In addition, further analysis indicated that the SRB of seawater helped maintain the high stability of the bacterial network. Overall, this study provided further comprehensive information regarding the characteristics of bacterial communities in the ocean, and provides new insights into keystone taxa and their roles in sustaining microbial diversity and stability in ocean.

Integrating US-guided FNAB, BRAFV600E mutation, and clinicopathologic characteristics to predict cervical central lymph-node metastasis in preoperative patients with cN0 papillary thyroid carcinoma.

BACKGROUND: The prevalence of cervical central lymph-node metastasis (CLNM) is high in patients with papillary thyroid carcinoma (PTC). There is considerable controversy surrounding the benefits of prophylactic central lymph-node dissection (pCLND) in patients with clinically negative central compartment lymph nodes (cN0). Therefore, it is crucial to accurately predict the likelihood of cervical CLNM before surgery to make informed surgical decisions. METHODS: Date from 214 PTC patients (cN0) who underwent partial or total thyroidectomy and pCLND at the Guizhou Provincial People's Hospital were collected and retrospectively analyzed. They were divided into two groups in accordance with cervical CLNM or not. Their information, including clinical characteristics, ultrasound (US) features, pathological results of fine-needle aspirations biopsy (FNAB), and other characteristics of the groups, was analyzed and compared using univariate and multivariate logistic regression analyses. RESULTS: A total of 214 patients were eligible in this study. Among them, 43.5% (93/214) of PTC patients had cervical CLNM, and 56.5% (121/214) did not. The two groups were compared using a univariate analyses, and there were no significant differences between the two groups in aspect ratio, boundary, morphology, component, and BRAFV600E (P > 0.05), and there were significant differences between gender, age, maximum tumor size, tumor location, capsule contact, microcalcifications, color Doppler flow imaging (CDFI), and Hashimoto's thyroiditis (HT) (P < 0.05). A multivariate logistic regression analysis was performed to further clarify the correlation of these indices. However, only age (OR = 2.455, P = 0.009), maximum tumor size (OR = 2.586, P = 0.010), capsule contact (OR = 3.208, P = 0.001), and CDFI (OR = 2.225, P = 0.022) were independent predictors of cervical CLNM. Combining these four factors, the area under the receiver-operating characteristic (ROC) curve for the joint diagnosis is 0.8160 (95% 0.7596-0.8725). Univariate analysis indicated that capsule contact (P = 0.001) was a possible predictive factor of BRAFV600E mutation. CONCLUSIONS: In conclusion, four independent predictors of cervical CLNM, including age < 45 years, tumor size > 1.0 cm, capsule contact, and rich blood flow, were screened out. Therefore, a comprehensive assessment of these risk factors should be conducted when designing individualized treatment regimens for PTC patients.

Role of Invasive Strategy for Non-ST-Elevation Myocardial Infarction in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Patients with chronic kidney disease (CKD) have traditionally been excluded from randomized trials. We aimed to compare percutaneous coronary intervention versus conservative management, and early intervention (EI; within 24 hours of admission) versus delayed intervention (DI; after 24 to 72 hours of admission) in patients with non-ST-segment elevation myocardial infarction (NSTEMI) and concomitant CKD. An electronic literature search was performed to search for studies comparing invasive management to conservative management or EI versus DI in patients with NSTEMI with CKD. The primary outcome was all-cause mortality; secondary outcomes were acute kidney injury (AKI) or dialysis, major bleeding, and recurrent MI. Hazard ratios (HRs) for the primary outcome and odds ratios for secondary outcomes were pooled in random-effects meta-analyses. Eleven studies (140,544 patients) were analyzed. Invasive management was associated with lower mortality than conservative management (HR 0.62, 95% confidence interval 0.57 to 0.67, p <0.001, I2 = 47%), with consistent benefit across all CKD stages, except CKD 5. There was no significant mortality difference between EI and DI, but subgroup analyses showed significant benefit for EI in stage 1 to 2 CKD (HR 0.75, 95% confidence interval 0.58 to 0.97, p = 0.03, I2 = 0%), with no significant difference in stage 3 and 4 to 5 CKD. Invasive strategy was associated with higher odds of AKI or dialysis and major bleeding, but lower odds of recurrent MI compared with conservative management. In conclusion, in patients with NSTEMI and CKD, an invasive strategy is associated with significant mortality benefit over conservative management in most patients with CKD, but at the expense of higher risk of AKI and bleeding. EI appears to benefit those with early stages of CKD. Trial Registration: PROSPERO CRD42023405491.

An Updated Meta-Analysis on the Clinical Outcomes of Percutaneous Left Atrial Appendage Closure Versus Direct Oral Anticoagulation in Patients With Atrial Fibrillation.

The availability of direct oral anticoagulants (DOACs) with known lower bleeding risk compared with warfarin have raised questions about the role of left atrial appendage closure (LAAC). We aimed to perform a meta-analysis to compare the clinical outcomes for LAAC versus DOACs. All studies directly comparing LAAC with DOACs up to January 2023 were included. The outcomes studied included the combined major adverse cardiovascular (CV) events outcomes, ischemic stroke and thromboembolic events, major bleeding, CV mortality, and all-cause mortality. Hazard ratios (HRs) and their 95% confidence interval were extracted or estimated from the data and pooled together with a random-effects model. A total of 7 studies (1 randomized controlled trial, 6 propensity-matched observational studies) were finally included, with a pooled population of 4,383 patients who underwent LAAC and 4,554 patients on DOACs. There were no significant differences between patients who underwent LAAC and patients on DOACs in terms of baseline age (75.0 vs 74.7, p = 0.27), CHA2DS2-VASc score (5.1 vs 5.1, p = 0.33), or HAS-BLED score (3.3 vs 3.3, p = 0.36). After a mean weighted follow-up of 22.0 months, LAAC was associated with significantly lower rates of combined major adverse CV event outcomes (HR 0.73 [0.56 to 0.95], p = 0.02), all-cause mortality (HR 0.68 [0.54 to 0.86], p = 0.02), and CV mortality (HR 0.55 [0.41 to 0.72], p<0.01). There were no significant differences in the rates of ischemic stroke or systemic embolism (HR 1.12 [0.92 to 1.35], p = 0.25), major bleeding (HR 0.94 [0.67 to 1.32], p = 0.71), or hemorrhagic stroke (HR 1.07 [0.74 to 1.54], p = 0.74) between LAAC and DOAC. In conclusion, percutaneous LAAC was found to be as efficacious as DOACs for stroke prevention, with lower all-cause and CV mortality. The rates of major bleeding and hemorrhagic stroke were similar. LAAC has a potential role to play in stroke prevention in patients with atrial fibrillation in the era of DOACs, but further randomized data are needed.

Young human PRP promotes the rejuvenation of aged bone marrow mesenchymal stem cells and the therapeutic effect on ischemic heart disease.

Bone marrow mesenchymal stem cell (BMSC) transplantation is an effective treatment for ischemic heart disease, but its effectiveness is limited in aging populations due to decreased viability and injury resistance of autologous BMSCs. The purpose of this study was to compare the differences between platelet-rich plasma (PRP) derived from young and aged donors, and to investigate whether it is possible to enhance the viability of elderly human BMSCs (hBMSCs) using PRP, and to apply the rejuvenated hBMSCs for the treatment of ischemia. The key growth factors in PRP, including IGF-1, EGF, and PDGF-BB, were found to have significant differences between young and old individuals. Our results showed that PRP could enhance the proliferation, cloning, and rejuvenation of aged hBMSCs, with a superior effect observed when using PRP derived from younger donors. In the SD rat infarct model, the application of hBMSCs optimized with PRP resulted in a smaller infarct area compared to the control group (NC-Old). Specifically, the infarct area in the group treated with hBMSCs cultured with PRP from young donors (YPRP-Old) was smaller than that in the group treated with PRP from older donors (OPRP-Old). The survival rate of hBMSCs after transplantation, the number of neovascularization in the infarct area of SD rats and the recovery of cardiac function were all higher in the YPRP-Old group than the OPRP-Old group, and both groups were better than the group treated with aged hBMSCs alone. In conclusion, PRP may provide a new stem cell transplantation therapy option for ischemic diseases.

New abietane and tigliane diterpenoids from the roots of Euphorbia fischeriana and their cytotoxic activities.

Three new abietane and two new tigliane diterpenoids were isolated from the roots Euphorbia fischeriana. Their structures were elucidated by spectroscopic methods and quantum chemical calculation. Compounds 4 and 5 exhibited the inhibitory activities against human cancer cells HeLa and HepG2, with IC50 ranging from 3.54 to 11.45 µM.

Comprehensive analysis of transcriptome-wide expression patterns and a circRNA/lncRNA-miRNA-mRNA network in the pathogenesis of cerebral ischemia in Rattus norvegicus.

BACKGROUND: Although ischemic stroke exhibits a high prevalence in the elderly population, the involved genes and pathways are poorly understood. In this study, we proposed to identify differentially expressed genes (DEGs) and constructed a circular RAN (circRNA)/long noncoding RNA (lncRNA)/microRNA (miRNA)-mRNA network associated with the pathogenesis of ischemic stroke by using bioinformatics analysis. METHODS: We constructed a rat model of middle cerebral artery occlusion (MCAO) and conducted total RNA and microRNA sequencing in brain specimens from MCAO and normal rats. Transcriptome-wide expression patterns were analyzed and DEGs were defined by applying Ballgown and a cut of log2-transformed fold-change (log2FC) ≥ 1 (or ≤ -1) with a P value < 0.05. We exploited Pearson correlation analysis to determine the association between the circRNA/lncRNA/mRNA network and miRNAs (P < 0.05 and corr ≤ -0.6), and the competing endogenous RNAs (ceRNA) interaction network was visualized with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were implemented for the pathway analysis of DEGs. RESULTS: Upregulated DEGs were significantly enhanced in positive regulation of cell migration, response to wounding, blood vessel morphogenesis, inflammatory response, and cell activation; Downregulated DEGs were associated with control of the modulation of chemical synaptic transmission, synapse organization, regulation of membrane potential, and regulation of ion transport. KEGG-pathway analysis showed that DEG-enhanced pathways were associated with the pathways of TNF signaling pathway, Fluid shear stress and atherosclerosis, NF-kappa B signaling pathway, Lipid and atherosclerosis, Human cytomegalovirus infection, Osteoclast differentiation, Chemokine signaling pathway, IL-17 signaling pathway, Viral protein interaction with cytokine and cytokine receptor, and Cytokine-cytokine receptor interaction. We uncovered several novel lncRNAs (lnc_00231, lnc_002239, lnc_004172; and a novel_circ0001704), five miRNAs (miR-200b-3p, miR-223-3p, miR-200c-3p, miR-3084a-3p, and miR-664-2-5p), and the top-10 mRNAs (upregulated mRNAs were Pdgfa, Il1b, Gdf15, Fosl1, and Cxcl2; downregulated mRNAs were Prkar2b, Olfm3, Lrrc73, Tmem38a, and Dlgap3) that were involved in ischemic stroke. CONCLUSIONS: Through bioinformatic network analysis, we identified the underlying molecular mechanisms and key central genes that may contribute to an inflammatory response after cerebral infarction.

Circular RNA PDK1 targets miR-4731-5p to enhance TNXB expression in ligamentum flavum hypertrophy.

Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR-4731 and miR-4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound-healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis-related protein (alpha smooth muscle actin (α-SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase-2 (MMP-2) and TNXB) in LF whereas miR-4731-5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR-4731-5p. Co-overexpression of miR-4731-5p partially reversed the proliferative and fibrosis-prompting effects of circPDK1 or TNXB. The circPDK1-miR-4731-TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in-depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy-induced LSS.

Cardioprotective effect of ultrasound-targeted destruction of Sirt3-loaded cationic microbubbles in a large animal model of pathological cardiac hypertrophy.

Pathological cardiac hypertrophy occurs in response to numerous increased afterload stimuli and precedes irreversible heart failure (HF). Therefore, therapies that ameliorate pathological cardiac hypertrophy are urgently required. Sirtuin 3 (Sirt3) is a main member of histone deacetylase class III and is a crucial anti-oxidative stress agent. Therapeutically enhancing the Sirt3 transfection efficiency in the heart would broaden the potential clinical application of Sirt3. Ultrasound-targeted microbubble destruction (UTMD) is a prospective, noninvasive, repeatable, and targeted gene delivery technique. In the present study, we explored the potential and safety of UTMD as a delivery tool for Sirt3 in hypertrophic heart tissues using adult male Bama miniature pigs. Pigs were subjected to ear vein delivery of human Sirt3 together with UTMD of cationic microbubbles (CMBs). Fluorescence imaging, western blotting, and quantitative real-time PCR revealed that the targeted destruction of ultrasonic CMBs in cardiac tissues greatly boosted Sirt3 delivery. Overexpression of Sirt3 ameliorated oxidative stress and partially improved the diastolic function and prevented the apoptosis and profibrotic response. Lastly, our data revealed that Sirt3 may regulate the potential transcription of catalase and MnSOD through Foxo3a. Combining the advantages of ultrasound CMBs with preclinical hypertrophy large animal models for gene delivery, we established a classical hypertrophy model as well as a strategy for the targeted delivery of genes to hypertrophic heart tissues. Since oxidative stress, fibrosis and apoptosis are indispensable in the evolution of cardiac hypertrophy and heart failure, our findings suggest that Sirt3 is a promising therapeutic option for these diseases. STATEMENT OF SIGNIFICANCE: Pathological cardiac hypertrophy is a central prepathology of heart failure and is seen to eventually precede it. Feasible targets that may prevent or reverse disease progression are scarce and urgently needed. In this study, we developed surface-filled lipid octafluoropropane gas core cationic microbubbles that could target the release of human Sirt3 reactivating the endogenous Sirt3 in hypertrophic hearts and protect against oxidative stress in a pig model of cardiac hypertrophy induced by aortic banding. Sirt3-CMBs may enhance cardiac diastolic function and ameliorate fibrosis and apoptosis. Our work provides a classical cationic lipid-based, UTMD-mediated Sirt3 delivery system for the treatment of Sirt3 in patients with established cardiac hypertrophy, as well as a promising therapeutic target to combat pathological cardiac hypertrophy.

The combination of hand grip strength and modified Glasgow prognostic score predicts clinical outcomes in patients with liver cancer.

Purpose: Previous studies have shown that both hand grip strength (HGS) and the modified Glasgow Prognostic Score (mGPS) are associated with poor clinical outcomes in patients with liver cancer. In spite of this, no relevant studies have been conducted to determine whether the combination of HGS and mGPS can predict the prognosis of patients with liver cancer. Accordingly, this study sought to explore this possibility. Methods: This was a multicenter study of patients with liver cancer. Based on the optimal HGS cutoff value for each sex, we determined the HGS cutoff values. The patients were divided into high and low HGS groups based on their HGS scores. An mGPS of 0 was defined as low mGPS, whereas scores higher than 0 were defined as high mGPS. The patients were combined into HGS-mGPS groups for the prediction of survival. Survival analysis was performed using Kaplan-Meier curves. A Cox regression model was designed and adjusted for confounders. To evaluate the nomogram model, receiver operating characteristic curves and calibration curves were used. Results: A total of 504 patients were enrolled in this study. Of these, 386 (76.6%) were men (mean [SD] age, 56.63 [12.06] years). Multivariate analysis revealed that patients with low HGS and high mGPS had a higher risk of death than those with neither low HGS nor high mGPS (hazard ratio [HR],1.50; 95% confidence interval [CI],1.14-1.98; p = 0.001 and HR, 1.55; 95% CI, 1.14-2.12, p = 0.001 respectively). Patients with both low HGS and high mGPS had 2.35-fold increased risk of death (HR, 2.35; 95% CI, 1.52-3.63; p < 0.001). The area under the curve of HGS-mGPS was 0.623. The calibration curve demonstrated the validity of the HGS-mGPS nomogram model for predicting the survival of patients with liver cancer. Conclusion: A combination of low HGS and high mGPS is associated with poor prognosis in patients with liver cancer. The combination of HGS and mGPS can predict the prognosis of liver cancer more accurately than HGS or mGPS alone. The nomogram model developed in this study can effectively predict the survival outcomes of liver cancer.