Potential osteoporosis-blocker Sparassis crispa polysaccharide: Isolation, purification and structure elucidation.

This study aimed to investigate the structural characterization of water-soluble polysaccharides from Sparassis crispa and their effects on the proliferation and differentiation of mouse osteoblasts. Three fractions (F-1, F-2, and F-3) were obtained from crude polysaccharides by a DEAE-52 cellulose column. The main fraction (F-1) was further purified by polysaccharide gel purification systems to obtain purified water-soluble Sparassis crispa polysaccharide (SCPS). The chemical structure of SCPS was analyzed by gas chromatography, Fourier transform infrared spectroscopy, methylation analysis, and nuclear magnetic resonance spectroscopy. The monosaccharide compositional analysis revealed that SCPS consisted of fucose, arabinose, galactose, glucose, xylose, mannose, ribose, galacturonic acid, glucuronic acid, and mannuronic acid in a molar ratio of 17.37:1.94:25.52:30.83:1.14:0.30:4.98:2.87:2.65. Moreover, the backbone of SCPS was composed of →3)-ß-d-Glcp-(1→4)-ß-d-Glcp-(1→, with side chains attached to the backbone at the O-6 positions through the →3,6)-ß-d-Glcp-(1→ linkage. The in vitro experiments were conducted to investigate the effects of SCPS on the proliferation and differentiation of mouse osteoblasts. The results showed that SCPS significantly enhanced the proliferation and differentiation of mouse osteoblasts, indicating their potential as a pharmaceutical agent for promoting osteoblast proliferation and differentiation.

Analysis of bioactive components and synergistic action mechanism of ShuGan-QieZhi Capsule for treating non-alcoholic fatty liver disease.

BACKGROUND: ShuGan-QieZhi capsule (SGQZC) is a traditional Chinese preparation used to treat hyperlipidemia and obesity, even non-alcoholic fatty liver disease (NAFLD). However, its therapeutic effects, main bioactive ingredients, as well as potential mechanisms for NAFLD are still unclear. PURPOSE: To investigate the pharmacological effect, main active ingredients, and mechanisms of SGQZC against high-fat diet (HFD)-induced NAFLD in mice. METHODS: NAFLD models were established by feeding C57BL/6 J mice an HFD for 24 weeks. From the 12th week, HFD-fed mice received daily gavage of either SGQZC or silibinin for 12 weeks. Hepatic hypertrophy parameters, along with hepatic and systemic lipid metabolism changes in NAFLD mice, were assessed. Oil red O and histopathological staining techniques determined lipid accumulation and liver injury severity. qRT-PCR analysis measured the expression of genes tied to liver lipid metabolism and inflammation. HPLC-MS/MS identified the primary components of SGQZC in the serum. Human normal hepatocytes (LO2) and hepatic stellate cells (LX-2) were used to screen SGQZC's bioactive ingredients. Network pharmacological analysis, transcriptomics, and western blotting delved into SGQZC's synergistic mechanisms against NAFLD. RESULTS: SGQZC ameliorated abnormal lipid metabolism and liver hypertrophy in mice with HFD-induced NAFLD, consequently reducing hepatic lipid accumulation, inflammatory cell infiltration, and liver impairment. Eight crucial components of SGQZC were detected in serum using HPLC-MS/MS and were found to effectively attenuate lipid accumulation and inflammation in liver cells. Further investigation indicated that SGQZC modulates MAPK pathway and AKT/NF-κB pathway, subsequently improving lipid metabolism and inflammation. CONCLUSION: SGQZC alleviates NAFLD by synergistically modulating the MAPK-mediated lipid metabolism and inhibiting AKT/NF-κB pathways-mediated inflammation. Our findings reveal the enormous potential of SGQZC for the treatment of NAFLD, providing a possible new clinical therapeutic strategy.

NSUN5-FTH1 Axis Inhibits Ferroptosis to Promote the Growth of Gastric Cancer Cells.

Recent studies revealed that NOP2/Sun RNA methyltransferase 5 (NSUN5) - ferritin heavy chain (FTH1) pathway is associated with ferroptosis in stem cells, whereas its roles in gastric cancer are still unclear. Our study aims to investigate the roles of the NSUN5-FTH1 axis in gastric cancer (GC) and its molecular mechanisms. Stable cell lines were constructed on SGC7901 cells by using shRNAs and pcDNA3.1 expression vectors, respectively. CCK-8 kits were used to determine cell viability. Biochemicals assays were used to detect lipid reactive oxygen species (ROS) and intracellular Fe2+ levels. RNA immunoprecipitation assay, qPCR, and Western blotting were used to determine the changes in biomarkers. GC xenograft mouse model was established to confirm the observation in vivo. An elevation of NSUN5 was observed in GC tumor tissues. NSUN5 inhibited ferroptosis including decreasing cell viability and increasing levels of lipid ROS and Fe2+ in GC cells. Besides, a positive correlation was also observed between NSUN5 and FTH1. Interestingly, NSUN5 regulated the levels of FTH1, instead of FTH1 regulating NSUN5 in GC cells. NSUN5-FTH1 axis regulated erastin-induced ferroptosis in SGC7901 cells. Consistently, silencing NSUN5 or FTH1 inhibited the growth of the SGC7901 tumor in vivo. NSUN5-FTH1 axis promoted the growth of GC cells in part by the regulation of ferroptosis.

Vancomycin population pharmacokinetics analysis in Chinese paediatric patients with varying degrees of renal function and ages: development of new practical dosing recommendations.

OBJECTIVES: To describe the pharmacokinetics of vancomycin in a large Chinese paediatric cohort with varying degrees of renal function and ages and to develop practical dosing guidelines. PATIENTS AND METHODS: We conducted a retrospective population pharmacokinetic study using data from paediatric patients who received vancomycin between June 2013 and June 2022. A non-linear mixed-effect modelling approach with a one-compartment model structure was applied. Monte Carlo simulations were used to stimulate an optimal dosage regimen to achieve the target of AUC24/MIC between 400 and 650. RESULTS: We analysed a total of 673 paediatric patients and 1547 vancomycin serum concentrations. Covariate analysis revealed that physiological maturation, renal function, albumin and cardiothoracic surgery (CTS) significantly affected vancomycin pharmacokinetics. The typical clearance and volume of distribution, standardized to 70 kg, were 7.75 L/h (2.3% relative standard error, RSE) and 36.2 L (1.7% RSE), respectively. Based on the model, we proposed an optimal dosing regimen that considers the patient's age and estimate glomerular filtration rate (eGFR) to achieve a target AUC24/MIC for CTS and non-CTS patients. We also found that a loading dose of 20 mg/kg can help patients with an eGFR of <60 mL/min/1.73 m2 achieve the target AUC on the first day of treatment. CONCLUSIONS: We established vancomycin pharmacokinetic parameters in Chinese paediatric patients and proposed a dosing guideline integrating eGFR, age and CTS status, potentially improving clinical outcomes and reducing nephrotoxicity risk.

Prognostic immunogenic characteristics of iron pendant disease modifiers in colon cancer.

Background: We explored the prognostic and immunogenic characteristics of iron pendant disease regulators in colon cancer to provide a scientific basis for the prediction of tumor prognosis-related markers and potential immunotherapeutic drug targets. Methods: RNA sequencing and matched complete clinical information of colon cancer (COAD) were retrieved from the UCSC Xena database, and genomic and transcriptomic data of colon cancer from the TCGA database were downloaded. Then univariate and multifactorial Cox regression were used to process these data. The prognostic factors were analyzed by single-factor and multi-factor Cox regression, followed by Kaplan-Meier survival curves with the aid of R software "survival" package. Then we use FireBrowse online analysis tool to analyze the expression variation of all cancer genes, and draw a histogram according to the influencing factors to predict the 1, 3, and 5 year survival rates of patients. Results: The results show that age, tumor stage and iron death score were significantly correlated with prognosis (p<0.05). Further multivariate cox regression analysis confirmed that age, tumor stage and iron death score were still significantly correlated with prognosis (p<0.05); The calibration curve results show that the deviation between the predicted values of 1 year, 3 years and 5 years and the diagonal of the figure is very small; the ROC curve results show that the AUC values of the 1-year and 5-year ROC curves of the bar graph are high; the DCA curve results show that the net yield of the bar graph is the largest; The scores of T cells and B cells in the high iron death score group were significantly lower than those in the low iron death score group, and the activities of immune related pathways were significantly reduced. There was a significant difference in the iron death score between the iron death molecular subtype and the gene cluster subtype. Conclusions: The model showed a superior response to immunotherapy in the high-risk group, revealing a potential relationship between iron death and tumor immunotherapy, which will provide new ideas for the treatment and prognostic assessment of colon cancer patients.

Prognostic value of the S100 calcium-binding protein family members in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a crucial public health problem around the world, and the outlook remains bleak. More accurate prediction models are urgently needed because of the great heterogeneity of HCC. The S100 protein family contains over 20 differentially expressed members, which are commonly dysregulated in cancers. In the present study, we analyzed the expression profile of S100 family members in patients with HCC based on the TCGA database. A novel prognostic risk score model, based on S100 family members, was developed using the least absolute shrinkage and selection operator regression algorithm, to analyze the clinical outcome. Our prediction model showed a powerful predictive value (1-year AUC: 0.738; 3-year AUC: 0.746; 5-year AUC: 0.813), while two former prediction models had less excellent performances than ours. And the S100 family members-based subtypes reveal the heterogeneity in many aspects, including gene mutations, phenotypic traits, tumor immune infiltration, and predictive therapeutic efficacy. We further investigated the role of S100A9, one member with the highest coefficient in the risk score model, which was mainly expressed in para-tumoral tissues. Using the Single-Sample Gene Set Enrichment Analysis algorithm and immunofluorescence staining of tumor tissue sections, we found that S100A9 may be associated with macrophages. These findings provide a new potential risk score model for HCC and support further study of S100 family members in patients, especially S100A9.

Tumor malignancy by genetic transfer between cells forming cell-in-cell structures.

Cell-in-cell structures (CICs) refer to a type of unique structure with one or more cells within another one, whose biological outcomes are poorly understood. The present study aims to investigate the effects of CICs formation on tumor progression. Using genetically marked hepatocellular cancer cell lines, we explored the possibility that tumor cells might acquire genetic information and malignant phenotypes from parental cells undergoing CICs formation. The present study showed that the derivatives, isolated from CICs formed between two subpopulations by flow cytometry sorting, were found to inherit aggressive features from the parental cells, manifested with increased abilities in both proliferation and invasiveness. Consistently, the CICs clones expressed a lower level of E-cadherin and a higher level of Vimentin, ZEB-1, Fibronectin, MMP9, MMP2 and Snail as compared with the parental cells, indicating epithelial-mesenchymal transition. Remarkably, the new derivatives exhibited significantly enhanced tumorigenicity in the xenograft mouse models. Moreover, whole exome sequencing analysis identified a group of potential genes which were involved in CIC-mediated genetic transfer. These results are consistent with a role of genetic transfer by CICs formation in genomic instability and malignancy of tumor cells, which suggest that the formation of CICs may promote genetic transfer and gain of malignancy during tumor progression.

m6A mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer.

N6-methyladenosine (m6A) mRNA methylation has been considered a gene modulatory mechanism involved in disease progression and carcinogenesis. Herein, we aimed to explore the specific mechanism of m6A mRNA methylation in endometrial cancer. RT-qPCR was implemented to test the clinical correlation between m6A methylation and endometrial cancer. Bioinformatics analysis was performed to screen the genes related to endometrial cancer, and SRAMP was utilized for the prediction of m6A targets. Western blot assay and MeRIP-qPCR experiments were conducted to verify the effect of m6A methylation on the candidate genes and the signaling pathways involved in the occurrence of endometrial cancer. m6A-seq, RT-qPCR, and polysome profiling were used to confirm the mechanisms of m6A methylation in modulating related genes and pathways. The levels of m6A methylation, METTL3, and IGFBP4 were reduced in tumor tissues of patients with endometrial cancer, and SRAMP analysis confirmed that IGFBP4 and PAPPA had m6A methylation sites. Reduced m6A methylation promoted endometrial cancer cell progression and tumor formation in vivo. m6A methylation of RNA in endometrial cancer cells directly modulated IGFBP4 and PAPPA expression. m6A methylation regulated the PAPPA/IGFBP4 axis, thereby influencing endometrial cancer through the NF-κB and ERK signaling pathways. Knockdown of PAPPA or overexpression of IGFBP4 in endometrial cancer cells partially reduced disease progression caused by reduced m6A methylation. This research suggests that m6A mRNA methylation modulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to induce cell proliferation and tumor formation in endometrial cancer. 1. METTL3 expressed modestly and m6A methylation of IGFBP4 and PAPPA mRNAs decreased in endometrial cancer; 2. YTHDF1-mediated IGFBP4 translation was reduced in HEC-1-A and AN3CA cells, and YTHDF2-mediated PAPPA mRNA degradation was blunted but its protein expression increased; 3. Increased PAPPA and reduced IGFBP4 activated IGF1-induced ERK, AKT, and NF-κB pathways by binding IGFR, thereby promoting cancer cell malignancy.

Case report: Successful management of Parvimonas micra pneumonia mimicking hematogenous Staphylococcus aureus pneumonia.

Parvimonas micra is an anaerobic Gram-positive coccus frequently found in the oral cavity and gastrointestinal tract, but rarely in the lung. Therefore, pneumonia caused by P. micra is also rare. Although there are some reports of P. micra related pneumonia due to aspiration or blood-borne infection with definite remote infection source, there are no reported cases of hematogenous P. micra pneumonia in healthy adults lacking a remote source of infection. Herein, we described the intact disease of P. micra-related pneumonia mimicking hematogenous Staphylococcus aureus pneumonia in terms of chest imagery and diagnosed via metagenomic next-generation sequencing (mNGS). Interestingly, there was no clear remote pathogenic source identified in the patient. Microbiome analysis revealed dysbiosis of the oral flora possibly related to poor oral hygiene and a long history of smoking. The patient was treated with moxifloxacin for 3 months. Ultimately, computed tomography (CT) of the chest showed total resolution of the lung lesion. Clinicians need to update the etiology of community-acquired pneumonia. When antibiotic therapy is not effective, pathogen examination becomes very important. New methods of pathogen detection such as mNGS should be employed to this end. For the treatment of P. micra pneumonia, no standardized course of treatment was reported. Imaging absorption of lung infections may provide a more objective guidance for the duration of antibiotics in P. micra pneumonia.

Homoharringtonine Attenuates Dextran Sulfate Sodium-Induced Colitis by Inhibiting NF-κB Signaling.

Homoharringtonine (HHT) exhibits an anti-inflammatory activity. The potential protective effects and mechanisms of HHT on dextran sulfate sodium- (DSS-) induced colitis were investigated. DSS-induced colitis mice were intraperitoneally injected with HHT. Body weight, colon length, disease activity index (DAI), and histopathological change were examined. The relative contents of interleukin- (IL-) 1ß, tumor necrosis factor- (TNF-) α, IL-6, and the chemokine (C-C motif) ligand 2 (CCL2) in the colon tissues and HHT-treated RAW264.7 cells were detected with the enzyme-linked immunosorbent assay. In the meantime, the levels of p-p65 and p-IκBα were detected by Western blot. The proportion of macrophages (CD11b+F4/80+) in the colon tissues was detected by flow cytometry. HHT alleviated DSS-induced colitis with downregulated TNF-α, IL-1ß, IL-6, and CCL2 expression; reduced activation of nuclear factor-kappa B (NF-κB) signaling; and diminished proportion of recruited macrophages in colon tissues. It was further testified that HHT inhibited lipopolysaccharide-induced macrophage activation with reduced activation of NF-κB signaling. In addition, HHT inhibited the M1 polarization of both human and mouse macrophages, while HHT did not affect the differentiation of human CD4 T cells into Th17, Th1, or Treg cells and did not affect the proliferation and migration of human colon epithelial cells. In summary, HHT attenuates DSS-induced colitis by inhibiting macrophage-associated NF-κB activation and M1 polarization, which could be an option for the treatment of ulcerative colitis.

Circular RNA circ_0006089 regulates the IGF1R expression by targeting miR-143-3p to promote gastric cancer proliferation, migration and invasion.

Circular RNAs (circRNAs) figure prominently in regulating the progression of a variety of human malignancies. This study was performed to probe how circ_0006089 functioned in gastric cancer (GC). CircRNA expression profile GSE83521 was downloaded from Gene Expression Omnibus (GEO) database, and circRNAs and analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure circ_0006089, microRNA-143-3p (miR-143-3p) and insulin-like growth factor 1 receptor (IGF1R) mRNA expressions in GC tissues and cell lines. Kaplan-Meier curves were used to detect the relationship between circ_0006089 expression and overall survival time of GC patients. Cell counting kit-8 (CCK-8) and 5-bromo-2-deoxyuridine (BrdU) assays were employed to detect the proliferative ability of GC cells after circ_0006089 was overexpressed or knocked down. Wound healing assay and Transwell assay were executed to examine the migration and invasion ability of GC cells. Western blot was adopted to detect IGF1R protein expressions. Circ_0006089 expression was up-regulated in GC samples and cell lines. And high circ_0006089 expression was associated with shorter survival time in GC patients. Circ_0006089 overexpression in GC cells significantly accelerated GC cell proliferation, migration and invasion, whereas circ_0006089 knockdown resulted in the opposite effects. Additionally, miR-143-3p was validated as a downstream target of circ_0006089, and circ_0006089 could positively regulate IGF1R expression via repressing miR-143-3p. Circ_0006089 is highly expressed in GC, and it promotes the malignancy of GC cells via modulating miR-143-3p/IGF1R axis, suggesting that circ_0006089 may serve as a promising therapeutic target for GC.

The Cropping Obstacle of Garlic Was Associated With Changes in Soil Physicochemical Properties, Enzymatic Activities and Bacterial and Fungal Communities.

Aims: In garlic cultivation, long-time monoculture has resulted in continuous-cropping obstacles. However, the cause has not been studied to date. Methods: We analyzed soils from garlic fields in Pengzhou, China, to determine continuous-cropping obstacle related changes in soil physicochemical properties and enzyme activities, and in the diversity and composition of bacterial and fungal communities. Furthermore, we examined the relationships between soil properties and the bacterial and fungal communities. Results: The soil pH and the soil catalase, urease, invertase, and polyphenol oxidase activities were lower in the cropping obstacle soil than in the healthy control soil. The richness and diversity of the bacteria were lower in the cropping obstacle soil than in the control. The bacterial and fungal communities in the cropping obstacle soil were clearly different from those in the control soil. The differences in bacterial communities between the cropping obstacle soil and the control soil were associated with differences in pH and available potassium content. The taxa with higher relative abundances in the cropping obstacle soils included potential plant pathogens and the taxa with lower relative abundances included potential plant growth promoters. Conclusion: The enrichment of plant pathogens and the depletion of plant growth promoting fungi may have contributed to the poor growth of garlic in the cropping obstacle soil. The enzyme activity and microbial community differences were associated with acidification that was likely an important factor in the deterioration of the soil ecological environment and the garlic cropping obstacle. The results provide information to guide agricultural practices in cultivating garlic.

Perforating and nonperforating indications in repeated surgeries for Crohn's disease.

BACKGROUND: Despite advances in medical therapy for Crohn's disease (CD), most patients with CD require repeated resection surgeries. AIM: To analyze the perforating and nonperforating indications of repeated CD operations and identify the anastomosis characteristics for postoperative CD. METHODS: We retrospectively reviewed 386 patients who underwent at least one resection for CD between 2003 and 2013.Clinical characteristics of each surgery were collected. Univariate and multivariate analyses were performed to determine risk factors for recurrence. RESULTS: The indication for reoperation in CD tends to be the same as that for primary operation, i.e., perforating disease tends to represent as perforating disease and nonperforating as nonperforating. Concordance was found between the first surgery and second surgery in terms of the indication for the operation (P = 0.006), and the indication for the third surgery was also correlated with that for the second surgery (P = 0.033). Even if the correlation of surgical indications between repeated operations, the rate of perforating indication for the second and third surgeries was significantly higher than that of the first surgery. In addition, the presence of perforating CD was a predictor of recurrence for both the first and second surgeries. Moreover, anastomotic lesions were the most common sites of recurrence after the operation. Based on the importance of anastomosis, anastomosis might be a new type of disease location for the classification of postoperative CD. CONCLUSION: CD not only has stable characteristics but also progresses chronically. Perforation is a progressive surgical indication for Crohn's disease. For CD after surgery, anastomosis may be a new classification of disease location.

Identification and external validation of the hub genes associated with cardiorenal syndrome through time-series and network analyses.

Cardiorenal syndrome (CRS), defined as acute or chronic damage to the heart or kidney triggering impairment of another organ, has a poor prognosis. However, the molecular mechanisms underlying CRS remain largely unknown. The RNA-sequencing data of the left ventricle tissue isolated from the sham-operated and CRS model rats at different time points were downloaded from the Gene Expression Omnibus (GEO) database. Genomic differences, protein-protein interaction networks, and short time-series analyses, revealed fibronectin 1 (FN1) and periostin (POSTN) as hub genes associated with CRS progression. The transcriptome sequencing data of humans obtained from the GEO revealed that FN1 and POSTN were both significantly associated with many different heart and kidney diseases. Peripheral blood samples from 20 control and 20 CRS patients were collected from the local hospital, and the gene expression levels of FN1 and POSTN were detected by real-time quantitative polymerase chain reaction. FN1 (area under the curve [AUC] = 0.807) and POSTN (AUC = 0.767) could distinguish CRS in the local cohort with high efficacy and were positively correlated with renal and heart damage markers, such as left ventricular ejection fraction. To improve the diagnostic ability, diagnosis models comprising FN1 and POSTN were constructed by logistic regression (F-Score = 0.718), classification tree (F-Score = 0.812), and random forest (F-Score = 1.000). Overall, the transcriptome data of CRS rat models were systematically analyzed, revealing that FN1 and POSTN were hub genes, which were validated in different public datasets and the local cohort.

Crown Ether-Based Supramolecular Polymers: From Synthesis to Self-Assembly.

Supramolecular polymers not only possess many advantages of traditional polymers, but also have many unique characteristics. Supramolecular polymers can be constructed by self-assembly of various noncovalent interactions. Host-guest interaction, as one important type of noncovalent interactions, has been widely applied to construct supramolecular polymers. From the perspective of classification of the recognition system motifs, host-guest recognition motifs mainly include crown ether, cyclodextrin, calixarene, cucurbituril, and pillararene-based host-guest recognition pairs. Crown ethers, as the first-generation macrocyclic hosts, have played a very important part in the development of supramolecular chemistry. Due to the easy modification of crown ethers, various crown ether derivatives have been prepared by attaching some functional groups to the edges of crown ethers, which endowed them with some interesting properties and made them ideal candidates for the fabrication of supramolecular polymers. This review gives a review of the preparation of crown ether-based supramolecular polymers (CSPs) and summarizes crown ether-based recognition pairs, organization methods, topological structures, stimuli-responsiveness, and functional characteristics.

SFRP2 Improves Mitochondrial Dynamics and Mitochondrial Biogenesis, Oxidative Stress, and Apoptosis in Diabetic Cardiomyopathy.

BACKGROUND: The mitochondrial dynamics and mitochondrial biogenesis are essential for maintaining the bioenergy function of mitochondria in diabetic cardiomyopathy (DCM). Previous studies have revealed that secreted frizzled-related protein 2 (SFRP2) is beneficial against apoptosis and oxidative stress. However, no research has confirmed whether SFRP2 regulates oxidative stress and apoptosis through mitochondrial function in DCM. METHODS: Exposure of H9C2 cardiomyocytes in high glucose (HG) 25 mM and palmitic acid (PAL) 0.2 mM was used to simulate DCM in vitro. H9C2 cells with SFRP2 overexpression or SFRP2 knockdown were constructed and cultured under glucolipotoxicity or normal glucose conditions. An SD rat model of type 2 diabetes mellitus (T2DM) was generated using a high-fat diet combined with a low-dose STZ injection. Overexpression of SFRP2 in the rat model was generated by using an adeno-associated virus approach. CCK-8, TUNEL assay, and DHE staining were used to detect cell viability, and MitoTracker Red CMXRos was used to detect changes in mitochondrial membrane potential. We used qRT-PCR and western blot to further explore the mechanisms of SFRP2 regulating mitochondrial dynamics through the AMPK/PGC1-α pathway to improve diabetic cardiomyocyte injury. RESULTS: Our results indicated that SFRP2 was significantly downregulated in H9C2 cells and cardiac tissues in T2DM conditions, accompanied by decreased expression of mitochondrial dysfunction. The mitochondrial membrane potential was reduced, and the cells were led to oxidative stress injury and apoptosis. Furthermore, the overexpression of SFRP2 could reverse apoptosis and promote mitochondrial function in T2DM conditions in vitro and in vivo. We also found that silencing endogenous SFRP2 could further promote glucolipotoxicity-induced mitochondrial dysfunction and apoptosis in cardiomyocytes, accompanied by downregulation of p-AMPK. CONCLUSION: SFRP2 exerted cardioprotective effects by salvaging mitochondrial function in an AMPK-PGC1-α-dependent manner, which modulates mitochondrial dynamics and mitochondrial biogenesis, reducing oxidative stress and apoptosis. SFRP2 may be a promising therapeutic biomarker in DCM.

AKR1C3 and Its Transcription Factor HOXB4 Are Promising Diagnostic Biomarkers for Acute Myocardial Infarction.

Background: A recent study disclosed that ferroptosis was an important myocyte death style in myocardial infarction (MI). However, the diagnostic value of ferroptosis regulators and correlated underlying mechanisms in acute myocardial infarction (AMI) remain unknown. Methods: Bioinformatical analyses were conducted to identify the candidate biomarkers for AMI, and the collected local samples were used to validate the findings via real-time quantitative PCR. Bioinformatical analysis and luciferase reporter assay were implemented to identify the transcriptional factor. Transient transfection and ferroptosis characteristic measurement, including glutathione peroxidase 4, malondialdehyde, iron, and glutathione, was performed to verify the ability of the candidate gene to regulate the ferroptosis of cardiomyocytes. A meta-analysis was conducted in multiple independent cohorts to clarify the diagnostic value. Results: A total of 121 ferroptosis regulators were extracted from previous studies, and aldo-keto reductase family 1 member C3 (AKR1C3) was significantly downregulated in the peripheral blood samples of AMI cases from the analysis of GSE48060 and GSE97320. HOXB4 served as a transcriptional activator for AKR1C3 and could suppress the ferroptosis of the H9C2 cells treated with erastin. Besides this, peripheral blood samples from 16 AMI patients and 16 patients without coronary atherosclerotic disease were collected, where AKR1C3 and HOXB4 both showed a high diagnostic ability. Furthermore, a nomogram including HOXB4 and AKR1C3 was established and successfully validated in six independent datasets. A clinical correlation analysis displayed that AKR1C3 and HOXB4 were correlated with smoking, CK, CK-MB, and N-terminal-pro-B-type natriuretic peptide. Conclusion: Taken together, this study demonstrates that AKR1C3 and HOXB4 are promising diagnostic biomarkers, providing novel insights into the ferroptosis mechanisms of AMI.

Diagnostic and prognostic factors, and two nomograms for endometrial cancer patients with bone metastasis: A large cohort retrospective study.

ABSTRACT: Patients with endometrial cancer (EC) who develop bone metastasis (BM) always imply a poorer prognosis. However, reliable predictive models associated with BM from EC are currently limited.We retrospectively analyzed data on 54,077 patients diagnosed with primary EC in the Surveillance, Epidemiology, and End Results database. Multivariate logistic regression analysis was used to determine independent predictors of BM from EC. Univariate and multivariate Cox regression analyses were used to determine independent prognostic factors for EC with BM. Based on independent predictors and prognostic factors, we constructed a diagnostic nomogram and prognostic nomogram separately. Besides, calibration curves, receiver operating characteristic curves, and decision curve analysis were used to evaluate the models.A total of 54,077 patients with EC from the Surveillance, Epidemiology, and End Results database were included in this study, 364 of whom had BM. Multivariate analysis in the logistic model showed that lung metastasis, liver metastasis, brain metastasis, N stage, T stage, histologic grade, and race were risk factors for BM from EC. Multivariate analysis in the Cox model showed that liver metastasis, brain metastasis, chemotherapy, surgery, and histologic type had a significant effect on overall survival. Moreover, the receiver operating characteristic curve, calibration curve, and decision curve analysis indicated the good performance of both diagnostic and prognostic nomograms.Two clinical prediction model was constructed and validated to predict individual risk and overall survival for EC with BM, respectively. Diagnostic nomogram and prognostic nomogram are complementary, improving the clinician's ability to assess the patient's prognosis and enhancing prognosis-based decision making.

Sites of Synchronous Distant Metastases, Prognosis, and Nomogram for Small Cell Lung Cancer Patients with Bone Metastasis: A Large Cohort Retrospective Study.

BACKGROUND: Small cell lung cancer (SCLC) is often associated with metastases at the time of diagnosis, and the bone is one of the most common sites. The primary aim of this study was to investigate the site of synchronous distant metastasis to other organs in SCLC patients with bone metastasis (BM) and develop a robust predictive prognostic model. METHODS: We retrospectively analyzed the data from patients diagnosed with SCLC with BM in the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox analyses were used to identify independent prognostic factors. A prognostic nomogram was constructed and evaluated by calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Then, according to the sites of metastasis and treatment modality, all patients were stratified into several subgroups. The relationship among sites of metastasis, treatment modality, and overall survival was then analyzed. RESULTS: A total of 6253 patients were included. Independent prognostic factors for SCLC with BM were age, sex, primary site, radiotherapy, chemotherapy, brain metastasis, liver metastasis, and marital status. Calibration, ROC curves, and DCA indicated the excellent performance of the prognostic nomogram. The liver is the most common organ for extraskeletal metastases, followed by the lung. Patients with only BM had the longest mean survival time (9.30 ± 0.31 months). In the subgroup analysis, chemotherapy was an independent prognostic factor for all subgroups. In contrast, radiotherapy showed a positive effect on the prognosis of patients in all subgroups except those with bone and brain metastases and those with bone, lung, and brain metastases. CONCLUSIONS: The prognostic nomogram is expected to be an accurate and personalized tool for predicting the prognosis of SCLC patients with BM. Additionally, the determination of the sites of synchronous extraskeletal metastases and the associated prognosis helps in treatment selection.