New perspectives on the therapeutic potential of quercetin in non-communicable diseases: Targeting Nrf2 to counteract oxidative stress and inflammation.

Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, metabolic diseases, and skeletal diseases, pose significant challenges to public health worldwide. The complex pathogenesis of these diseases is closely linked to oxidative stress and inflammatory damage. Nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcription factor, plays an important role in regulating antioxidant and anti-inflammatory responses to protect the cells from oxidative damage and inflammation-mediated injury. Therefore, Nrf2-targeting therapies hold promise for preventing and treating NCDs. Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation. Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs. Here, we discussed, for the first time, the close association between NCD pathogenesis and the Nrf2 signaling pathway, involved in neurodegenerative diseases (NDDs), cardiovascular disease, cancers, organ damage, and bone damage. Furthermore, we reviewed the availability, pharmacokinetics, pharmaceutics, and therapeutic applications of Que in treating NCDs. In addition, we focused on the challenges and prospects for its clinical use. Que represents a promising candidate for the treatment of NCDs due to its Nrf2-targeting properties.

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

SUMO Promotes DNA Repair Protein Collaboration to Support Alterative Telomere Lengthening in the Absence of PML.

Alternative lengthening of telomeres (ALT) pathway maintains telomeres in a significant fraction of cancers associated with poor clinical outcomes. A better understanding of ALT mechanisms can provide a basis for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins plays a critical role in the formation of ALT telomere-associated PML bodies (APBs), where telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, whether and how SUMO contributes to ALT beyond APB formation remains elusive. Here, we report that SUMO promotes collaboration among DNA repair proteins to achieve APB-independent telomere maintenance. By using ALT cancer cells with PML protein knocked out and thus devoid of APBs, we show that sumoylation is required for manifesting ALT features, including telomere clustering and telomeric DNA synthesis, independent of PML and APBs. Further, small molecule-induced telomere targeting of SUMO produces signatures of phase separation and ALT features in PML null cells in a manner depending on both sumoylation and SUMO interaction with SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are linked to the enrichment of DNA repair proteins, including Rad52, Rad51AP1, and BLM, to the SUMO-containing telomere foci. Finally, we find that Rad52 can undergo phase separation, enrich SUMO on telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that, in addition to forming APBs, SUMO also promotes collaboration among DNA repair proteins to support telomere maintenance in ALT cells. Given the promising effects of sumoylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

Ameliorative effect of anisodamine (654-1/654-2) against myocardial dysfunction induced by septic shock via the NF-κB/NLRP-3 or the PI3K-AKT/NF-κB pathway.

BACKGROUND: Septic shock, an extremely dangerous condition that causes impairment of organ function, always largely contributes to mortality in intensive care units. The impact of septic shock-induced organ damage on morbidity and mortality is substantially influenced by myocardial dysfunction. However, it remains unclear whether and in what manner anisodamine (654-1/654-2) ameliorates myocardial dysfunction caused by septic shock. PURPOSE: This study is the pioneering investigation and validation about the protective efficacy of anisodamine (654-1/654-2) against LPS-induced myocardial dysfunction in septic shock rats. It also aims to explore the differences in the underlying molecular mechanisms of both drugs. METHODS: A septic shock model was established in SD rats by after tail vein administration of LPS. 64 rats were distributed into eight groups, such as LPS group, control group, LPS+654-1 group (1.25, 2.5, and 5 mg/kg), and LPS+654-2 group (1.25, 2.5, and 5 mg/kg). The hemodynamics, echocardiography, immunohistochemical analysis, TEM, TUNEL assay, and H&E staining were utilized to assess the septic shock model and myocardial function. Lactic acid, inflammatory markers (IL-1ß, IL-6, and TNF-α), endothelial injure markers (SDC-1, HS and TM) and myocardial injury markers (CK, c-TNT and NT-pro BNP) were assessed using ELISA or biochemical kits. Additionally, the mechanisms of 654-1/654-2 were analyzed using RNA-seq and bioinformatics, and validated using western blotting and RT-PCR. RESULTS: Administration of 654-1/654-2 significantly restored hemodynamics and improved myocardial and endothelial glycocalyx injury in septic shock rats. Furthermore, 654-1/654-2 dose-dependently reduced plasma levels of lactic acid, inflammatory cytokines, and markers of endothelial and myocardial injury. Analyses using RNA-seq, WB and RT-PCR techniques indicated that 654-1/654-2 could mitigate myocardial and endothelial injury by inhibiting the NF-κB and NLRP-3 pathways, and activating the PI3K-AKT pathway. CONCLUSIONS: These findings demonstrated that 654-1/654-2 could alleviate myocardial damage in septic shock rats. Specifically, 654-1 inhibited the NF-κB/NLRP-3 pathway, whereas 654-2 promoted the PI3K-AKT pathway and inhibited the NF-κB pathway, effectively mitigating the inflammatory response and cell apoptosis.

Molecular basis for Nse5-6 mediated regulation of Smc5/6 functions.

The Smc5/6 complex (Smc5/6) is important for genome replication and repair in eukaryotes. Its cellular functions are closely linked to the ATPase activity of the Smc5 and Smc6 subunits. This activity requires the dimerization of the motor domains of the two SMC subunits and is regulated by the six non-SMC subunits (Nse1 to Nse6). Among the NSEs, Nse5 and Nse6 form a stable subcomplex (Nse5-6) that dampens the ATPase activity of the complex. However, the underlying mechanisms and biological significance of this regulation remain unclear. Here, we address these issues using structural and functional studies. We determined cryo-EM structures of the yeast Smc5/6 derived from complexes consisting of either all eight subunits or a subset of five subunits. Both structures reveal that Nse5-6 associates with Smc6's motor domain and the adjacent coiled-coil segment, termed the neck region. Our structural analyses reveal that this binding is compatible with motor domain dimerization but results in dislodging the Nse4 subunit from the Smc6 neck. As the Nse4-Smc6 neck interaction favors motor domain engagement and thus ATPase activity, Nse6's competition with Nse4 can explain how Nse5-6 disfavors ATPase activity. Such regulation could in principle differentially affect Smc5/6-mediated processes depending on their needs of the complex's ATPase activity. Indeed, mutagenesis data in cells provide evidence that the Nse6-Smc6 neck interaction is important for the resolution of DNA repair intermediates but not for replication termination. Our results thus provide a molecular basis for how Nse5-6 modulates the ATPase activity and cellular functions of Smc5/6.

Alpinia katsumadai Hayata Volatile Oil Is Effective in Treating 5-Fluorouracil-Induced Mucositis by Regulating Gut Microbiota and Modulating the GC/GR Pathway and the mPGES-1/PGE2/EP4 Pathways.

This study was aimed to investigate the therapeutic effect and mechanism of AKHO on 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Mouse body weight, diarrhea score, and H&E staining were applied to judge the therapeutic effect of AKHO. 16S rDNA and nontargeted metabolomics have been used to study the mechanism. WB, ELISA, and immunohistochemistry were adopted to validate possible mechanisms. The results demonstrated that AKHO significantly reduced diarrhea scores and intestinal damage induced by 5-FU in mice. AKHO lowered the serum levels of LD and DAO, and upregulated the expressions of ZO-1 and occludin in the ileum. Also, AKHO upregulated the abundance of Lactobacillus in the gut and suppressed KEGG pathways such as cortisol synthesis and secretion and arachidonic acid metabolism. Further validation studies indicated that AKHO downregulated the expressions of prostaglandin E2 (PGE2), microsomal prostaglandin E synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. Taken together, AKHO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway, providing novel insights into the utilization and development of this pharmaceutical/food resource.

Structural insights into Rad18 targeting by the SLF1 BRCT domains.

Rad18 interacts with the SMC5/6 localization factor 1 (SLF1) to recruit the SMC5/6 complex to DNA damage sites for repair. The mechanism of the specific Rad18 recognition by SLF1 is unclear. Here, we present the crystal structure of the tandem BRCT repeat (tBRCT) in SLF1 (SLF1tBRCT) bound with the interacting Rad18 peptide. Our structure and biochemical studies demonstrate that SLF1tBRCT interacts with two phosphoserines and adjacent residues in Rad18 for high-affinity and specificity Rad18 recognition. We found that SLF1tBRCT utilizes mechanisms common among tBRCTs as well as unique ones for Rad18 binding, the latter include interactions with an α-helical structure in Rad18 that has not been observed in other tBRCT-bound ligand proteins. Our work provides structural insights into Rad18 targeting by SLF1 and expands the understanding of BRCT-mediated complex assembly.

A blend of formic acid, benzoic acid, and tributyrin alleviates ETEC K88-induced intestinal barrier dysfunction by regulating intestinal inflammation and gut microbiota in a murine model.

This study aimed to investigate the effects of an organic acid (OA) blend on intestinal barrier function, intestinal inflammation, and gut microbiota in mice challenged with enterotoxigenic Escherichia coli K88 (ETEC K88). Ninety female Kunming mice (7 weeks old) were randomly allotted to five treatments with six replicates per treatment and three mice per replicate. The five treatments were composed of the non-ETEC K88 challenge group and ETEC K88 challenge + OA blend groups (0, 0.6 %, 1.2 %, and 2.4 % OA blend). The OA blend consisted of 47.5 % formic acid, 47.5 % benzoic acid, and 5 % tributyrin. The feeding trial lasted for 15 days, and mice were intraperitoneally injected with PBS or ETEC K88 solution on day 15. At 24 h post-challenge, one mouse per replicate was selected for sample collection. The results showed that a dosage of 0.6 % OA blend alleviated the ETEC K88-induced intestinal barrier dysfunction, as indicated by the elevated villus height and the ratio of villus height to crypt depth of jejunum, and the reduced serum diamine oxidase (DAO) and D-lactate levels, as well as the up-regulated mRNA levels of ZO-1, Claudin-1, and Occludin in jejunum mucosa of mice. Furthermore, dietary addition with 0.6 % OA blend decreased ETEC K88-induced inflammation response, as suggested by the decreased TNF-α and IL-6 levels, and the increased IgA level in the serum, as well as the down-regulated mRNA level of TNF-α, IL-6, IL-1ß, TLR-4, MyD88, and MCP-1 in jejunum mucosa of mice. Regarding gut microbiota, the beta-diversity analysis revealed a remarkable clustering between the 0.6 % OA blend group and the ETEC K88 challenge group. Supplementation of 0.6 % OA blend decreased the relative abundance of Firmicutes, and increased the relative abundance of Bacteroidota, Desulfobacterota, and Verrucomicrobiota of colonic digesta in mice. Also, the butyric acid content in the colonic digesta of mice was increased by dietary 0.6 % OA blend supplementation. Collectively, a dosage of 0.6 % OA blend could alleviate the ETEC K88-induced intestinal barrier dysfunction by regulating intestinal inflammation and gut microbiota of mice.

Association of Urinary Zinc Concentrations with Dyslipidemia and Its Subtypes: Baseline Data from the Chinese Multi-Ethnic Cohort (CMEC) Study.

This study elucidates the association between urinary zinc concentration and the risk of developing dyslipidemia and its subtypes in China's ethnic minority residents. Based on the baseline survey data of the Chinese Multi-Ethnic Cohort (CMEC) study, 10,620 subjects were included in the study. Logistic regression analysis evaluated the relationship between urinary zinc concentration and dyslipidemia and its subtypes. After adjustment, compared with urinary zinc concentration quartile 1 (Q1), the odds ratios (ORs) and 95% confidence intervals (95% CIs) of dyslipidemia participants in the quartile 2 (Q2), quartile 3 (Q3), and quartile 4 (Q4) groups were 1.091 (0.963, 1.237), 1.151 (1.051, 1.304), and 1.393 (1.230, 1.579), respectively (P for trend < 0.001). While that of hypertriglyceridemia participants in the Q2, Q3, and Q4 groups were 1.130 (0.979, 1.306), 1.283 (1.113, 1.480), and 1.483 (1.287, 1.709), respectively (P for trend < 0.001). Lastly, the ORs and 95% CIs of hyperbetalipoproteinemia participants in the Q2, Q3, and Q4 groups were 1.166 (0.945, 1.439), 1.238 (1.007, 1.522), and 1.381 (1.126, 1.695), respectively (P for trend < 0.002). This study found that urinary zinc concentrations were not associated with hypercholesterolemia and hypoalphalipoproteinemia. The dose-response relationship was non-linear between urinary zinc concentration and dyslipidemia, hypertriglyceridemia and hyperbetalipoproteinemia (P for trend < 0.001). In the stratified analysis, urinary zinc levels were positively associated with the risk of dyslipidemia, hypertriglyceridemia, and hyperbetalipoproteinemia in male, ≥ 60 years old, Miao nationality, hypertension, diabetes, and BMI ≥ 24.0 kg/m2 subgroups. Our study provides some possible evidence that elevated urinary zinc concentrations are associated with an increased risk of dyslipidemia, hypertriglyceridemia, hyperbetalipoproteinemia.

Smc5/6's multifaceted DNA binding capacities stabilize branched DNA structures.

Smc5/6 is an evolutionarily conserved SMC complex with roles in DNA replication and repair, as well as in viral DNA restriction. Understanding its multiple functions has been hampered by a lack of mechanistic studies on how the Smc5/6 complex associates with different types of DNA. Here we address this question by simultaneously visualizing the behavior of Smc5/6 on three types of DNA, namely double-stranded (ds) DNA, single-stranded (ss) DNA, and junction DNA formed by juxtaposed ss- and dsDNA, using correlative single-molecule fluorescence and force microscopy. We find that Smc5/6 displays distinct behaviors toward different types of DNA, dynamically associating with dsDNA while stably binding to junction DNA. Mechanistically, both the Nse1-3-4 subcomplex and ATP binding enhance the complex's dsDNA association. In contrast, Smc5/6's assembly onto ssDNA emanating from junction DNA, which occurs even in the presence high-affinity ssDNA binders, is aided by Nse1-3-4, but not by ATP. Moreover, we show that Smc5/6 protects junction DNA stability by preventing ssDNA annealing. The multifaceted DNA association behaviors of Smc5/6 provide a framework for understanding its diverse functions in genome maintenance and viral DNA restriction.

Transient inhibition of p53 enhances prime editing and cytosine base-editing efficiencies in human pluripotent stem cells.

Precise gene editing in human pluripotent stem cells (hPSCs) holds great promise for studying and potentially treating human diseases. Both prime editing and base editing avoid introducing double strand breaks, but low editing efficiencies make those techniques still an arduous process in hPSCs. Here we report that co-delivering of p53DD, a dominant negative fragment of p53, can greatly enhance prime editing and cytosine base editing efficiencies in generating precise mutations in hPSCs. We further apply PE3 in combination with p53DD to efficiently create multiple isogenic hPSC lines, including lines carrying GBA or LRRK2 mutations associated with Parkinson disease and a LMNA mutation linked to Hutchinson-Gilford progeria syndrome. We also correct GBA and LMNA mutations in the patient-specific iPSCs. Our data show that p53DD improves PE3 efficiency without compromising the genome-wide safety, making it feasible for safe and routine generation of isogenic hPSC lines for disease modeling.

Integrating Choline and Specific Intestinal Microbiota to Classify Type 2 Diabetes in Adults: A Machine Learning Based Metagenomics Study.

Emerging evidence is examining the precise role of intestinal microbiota in the pathogenesis of type 2 diabetes. The aim of this study was to investigate the association of intestinal microbiota and microbiota-generated metabolites with glucose metabolism systematically in a large cross-sectional study in China. 1160 subjects were divided into three groups based on their glucose level: normal glucose group (n=504), prediabetes group (n=394), and diabetes group (n=262). Plasma concentrations of TMAO, choline, betaine, and carnitine were measured. Intestinal microbiota was measured in a subgroup of 161 controls, 144 prediabetes and 56 diabetes by using metagenomics sequencing. We identified that plasma choline [Per SD of log-transformed change: odds ratio 1.36 (95 confidence interval 1.16, 1.58)] was positively, while betaine [0.77 (0.66, 0.89)] was negatively associated with diabetes, independently of TMAO. Individuals with diabetes could be accurately distinguished from controls by integrating data on choline, and certain microbiota species, as well as traditional risk factors (AUC=0.971). KOs associated with the carbohydrate metabolism pathway were enhanced in individuals with high choline level. The functional shift in the carbohydrate metabolism pathway in high choline group was driven by species Ruminococcus lactaris, Coprococcus catus and Prevotella copri. We demonstrated the potential ability for classifying diabetic population by choline and specific species, and provided a novel insight of choline metabolism linking the microbiota to impaired glucose metabolism and diabetes.

Long non-coding RNA OIP5-AS1 suppresses microRNA-92a to augment proliferation and metastasis of ovarian cancer cells through upregulating ITGA6.

OBJECTIVE: Recently, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as essential biomarkers during development of malignancies. This study was performed to study the roles of lncRNA opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) and miR-92a in ovarian cancer (OC). METHODS: OIP5-AS1, miR-92a and integrin alpha 6 (ITGA6) expression in OC tissues and cells was assessed. The screened OC cells were respectively with OIP5-AS1-, miR-92a- and ITGA6-related vectors or oligonucleotides . The viability, migration, invasion and apoptosis of the cells were determined and the levels of epithelial-mesenchymal transition (EMT)-related proteins were also measured. The interactions between OIP5-AS1 and miR-92a, and between miR-92a and ITGA6 were confirmed. RESULTS: OIP5-AS1 and ITGA6 were upregulated while miR-92a was downregulated in OC. Inhibited OIP5-AS1 or downregulated ITGA6 or elevated miR-92a repressed EMT, viability, migration and invasion, and promoted apoptosis of OC cells. OIP5-AS1 as a competing endogenous RNA interacted with miR-92a to regulate ITGA6. These effects that induced by silenced OIP5-AS1 could be reversed by miR-92a inhibition while those that induced by up-regulated miR-92a were reduced by restored ITGA6. CONCLUSION: OIP5-AS1 silencing promoted miR-92a to repress proliferation and metastasis of OC cells through inhibiting ITGA6.

Chromosome-level assembly of the Neolamarckia cadamba genome provides insights into the evolution of cadambine biosynthesis.

Neolamarckia cadamba (Roxb.), a close relative of Coffea canephora and Ophiorrhiza pumila, is an important traditional medicine in Southeast Asia. Three major glycosidic monoterpenoid indole alkaloids (MIAs), cadambine and its derivatives 3ß-isodihydrocadambine and 3ß-dihydrocadambine, accumulate in the bark and leaves, and exhibit antimalarial, antiproliferative, antioxidant, anticancer and anti-inflammatory activities. Here, we report a chromosome-scale N. cadamba genome, with 744.5 Mb assembled into 22 pseudochromosomes with contig N50 and scaffold N50 of 824.14 Kb and 29.20 Mb, respectively. Comparative genomic analysis of N. cadamba with Co. canephora revealed that N. cadamba underwent a relatively recent whole-genome duplication (WGD) event after diverging from Co. canephora, which contributed to the evolution of the MIA biosynthetic pathway. We determined the key intermediates of the cadambine biosynthetic pathway and further showed that NcSTR1 catalyzed the synthesis of strictosidine in N. cadamba. A new component, epoxystrictosidine (C27H34N2O10, m/z 547.2285), was identified in the cadambine biosynthetic pathway. Combining genome-wide association study (GWAS), population analysis, multi-omics analysis and metabolic gene cluster prediction, this study will shed light on the evolution of MIA biosynthetic pathway genes. This N. cadamba reference sequence will accelerate the understanding of the evolutionary history of specific metabolic pathways and facilitate the development of tools for enhancing bioactive productivity by metabolic engineering in microbes or by molecular breeding in plants.

Efficacy Evaluation on the Color Doppler Ultrasound, Multislice Spiral CT Combined with Serum Markers in Diagnosis of Primary Hepatic Carcinoma.

BACKGROUND: The efficacy of color Doppler ultrasound, multislice spiral CT combined with serum alpha-fetoprotein (AFP) and alpha-fetoprotein heterogeneity (AFP-L3) in the diagnosis of primary hepatic carcinoma was evaluated. METHODS: Seventy-nine patients with primary hepatic carcinoma (PHC group) and 50 patients with benign liver lesions (benign control group) admitted in Yantaishan Hospital (Yantai, China) from January 2016 to December 2018 were selected. The liver was scanned by color Doppler ultrasound and multiple multislice spiral CT. The serum AFP and AFP-L3 levels were detected by electrochemiluminescence. The value of color Doppler ultrasound, multislice spiral CT combined with serum AFP and AFP-L3 in diagnosis of primary liver cancer was retrospectively analyzed. RESULTS: The color Doppler flow imaging (CDFI) showed a high-speed and high-resistance spectrum. The serum AFP and AFP-L3 levels of patients with primary hepatic carcinoma were significantly higher than those of the benign control group were (U=138.000 and 155.500, P=0.000 and 0.000), P<0.01. The sensitivity, accuracy and negative predictive value of color Doppler ultrasound, multislice spiral CT combined with serum AFP and AFP-L3 examinations for diagnosis of primary hepatic carcinoma were 96.20, 90.70 and 93.18%, which was significantly improved compared with each single examination (X2=27.888, 17.511 and 16.202, P=0.000, 0.002 and 0.003), P<0.01. CONCLUSION: Color Doppler ultrasound, multislice spiral CT combined with AFP and AFP-L3 examination could significantly improve the diagnosis efficiency of primary hepatic carcinoma, which was beneficial to early clinical diagnosis and early treatment.

A narrative review of the relationship between TGF-ß signaling and gynecological malignant tumor.

OBJECTIVE: This paper reviews the association between transforming growth factor-ß (TGF-ß) and its receptor and tumor, focusing on gynecological malignant tumors. we hope to provide more methods to help increase the potential of TGF-ß signaling targeted treatment of specific cancers. BACKGROUND: The occurrence of a malignant tumor is a complex process of multi-step, multi-gene regulation, and its progression is affected by various components of the tumor cells and/or tumor microenvironment. The occurrence of gynecological diseases not only affect women's health, but also bring some troubles to their normal life. Especially when gynecological malignant tumors occur, the situation is more serious, which will endanger the lives of patients. Due to differences in environmental and economic conditions, not all women have access to assistance and treatment specifically meeting their needs. TGF-ß is a multi-potent growth factor that maintains homeostasis in mammals by inhibiting cell growth and promoting apoptosis in vivo. TGF-ß signaling is fundamental to inflammatory disease and favors the emergence of tumors, and it also plays an important role in immunosuppression in the tumor microenvironment. In the early stages of the tumor, TGF-ß acts as a tumor inhibitor, whereas in advanced tumors, mutations or deletion of the TGF-ß signaling core component initiate neogenesis. METHODS: Literatures about TGF-ß and gynecological malignant tumor were extensively reviewed to analyze and discuss. CONCLUSIONS: We discussed the role of TGF-ß signaling in different types of gynecological tumor cells, thus demonstrating that targeted TGF-ß signaling may be an effective tumor treatment strategy.

Expression and significance of serum soluble fms-like tyrosine kinase 1 (sFlt-1), CXC chemokine ligand 16 (CXCL16), and lipocalin 2 (LCN-2) in pregnant women with preeclampsia.

BACKGROUND: To explore the value of serum soluble fms-like tyrosine kinase 1 (sFlt-1), CXC chemokine ligand 16 (CXCL16), and lipocalin 2 (LCN-2) in the diagnosis and grading of preeclampsia (PE). METHODS: A total of 186 patients with PE diagnosed and treated in our hospital were included. According to the disease severity, the patients were divided into the mild PE group (99 cases) and the severe PE group (87 cases). A total of 72 healthy pregnant women who underwent antenatal care were selected as the healthy control group. The levels of serum sFlt-1, CXCL16, and LCN-2 before medication were compared among the patients, and the diagnosis and grading value of the above 3 indicators were analyzed. RESULTS: For PE patients vs. healthy controls, the levels of sFlt-1 (132.71±14.49 vs. 68.43±9.28 µg/L), CXCL16 (2.15±0.35 vs. 0.61±0.12 µg/L), and LCN-2 (70.81±8.25 vs. 19.22±3.14 µg/L) were all significantly higher in PE patients than in the healthy controls (P<0.05). For severe PE vs. mild PE, the levels of sFlt-1 (142.16±20.23 vs. 124.41±10.36 µg/L), CXCL16 (2.87±0.59 vs. 1.51±0.28 µg/L), and LCN-2 (90.76±10.16 vs. 53.27±6.19 µg/L) in the severe PE group were higher than those in the mild PE group (P<0.05). Receiver operating characteristic curve (ROC) analysis showed that when the cut-off values of sFlt-1, CXCL16, and LCN-2 were 99.65, 1.36, and 0.84 µg/L, respectively, the diagnostic efficacy of PE was the highest. With these cut-off values, the diagnostic sensitivities of sFlt-1, CXCL16, and LCN-2 were 86.67%, 73.33%, and 93.33%, respectively. The specificities of sFlt-1, CXCL16, and LCN-2 were 80.00%, 86.67%, and 60.00%, respectively. The areas under the curves (AUC) of sFlt-1, CXCL16, and LCN-2 were 0.764, 0.769, and 0.831, respectively. When the cut-off values for sFlt-1, CXCL16, and LCN-2 were 135.16, 2.24, and 70.38 µg/L, respectively, the efficacy was the highest in distinguishing mild and severe PE. With these cut-off values, the AUC values of sFlt-1, CXCL16, and LCN-2 were 0.837, 0.808, and 0.869, respectively. CONCLUSIONS: sFlt-1, CXCL16, and LCN-2 have certain significance in the diagnosis and grading of PE. Among them, LCN-2 has the highest correlation with the diagnosis and grading of PE.

Structure of Rad5 provides insights into its role in tolerance to replication stress.

The Rad5 family of proteins are critical genome maintenance factors, with helicase-like transcription factor (HLTF) and SNF2 histone linker PHD RING helicase (SHRPH) in humans implicated in several types of cancer. How their multiple activities coordinate has been unclear. Our recent study on Rad5 shed light on this question.