Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation.

Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.

Association between type 2 diabetes mellitus and body composition based on MRI fat fraction mapping.

Purpose: To explore the association between type 2 diabetes mellitus (T2DM) and body composition based on magnetic resonance fat fraction (FF) mapping. Methods: A total of 341 subjects, who underwent abdominal MRI examination with FF mapping were enrolled in this study, including 68 T2DM patients and 273 non-T2DM patients. The FFs and areas of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and abdominal muscle (AM) were measured at the level of the L1-L2 vertebral. The FF of bone marrow adipose tissue (BMAT) was determined by the averaged FF values measured at the level of T12 and L1 vertebral, respectively. The whole hepatic fat fraction (HFF) and pancreatic fat fraction (PFF) were measured based on 3D semi-automatic segmentation on the FF mapping. All data were analyzed by GraphPad Prism and MedCalc. Results: VAT area, VAT FF, HFF, PFF of T2DM group were higher than those of non-T2DM group after adjusting for age and sex (P < 0.05). However, there was no differences in SAT area, SAT FF, BMAT FF, AM area and AM FF between the two groups (P > 0.05). VAT area and PFF were independent risk factors of T2DM (all P < 0.05). The area under the curve (AUC) of the receiver operating characteristic (ROC) for VAT area and PFF in differentiating between T2DM and non-T2DM were 0.685 and 0.787, respectively, and the AUC of PFF was higher than VAT area (P < 0.05). Additionally, in seemingly healthy individuals, the SAT area, VAT area, and AM area were found to be significantly associated with being overweight and/or obese (BMI ≥ 25) (all P < 0.05). Conclusions: In this study, it was found that there were significant associations between T2DM and VAT area, VAT FF, HFF and PFF. In addition, VAT area and PFF were the independent risk factors of T2DM. Especially, PFF showed a high diagnostic performance in discrimination between T2DM and non-T2DM. These findings may highlight the crucial role of PFF in the pathophysiology of T2DM, and it might be served as a potential imaging biomarker of the prevention and treatment of T2DM. Additionally, in individuals without diabetes, focusing on SAT area, VAT area and AM area may help identify potential health risks and provide a basis for targeted weight management and prevention measures.

BACH2-mediated CD28 and CD40LG axes contribute to pathogenesis and progression of T-cell lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of ALL characterized by its high heterogeneity and unfavorable clinical features. Despite improved insights in genetic and epigenetic landscapes of T-ALL, the molecular mechanisms that drive malignant T-cell development remain unclear. BTB and CNC homology 2 (BACH2) is a lymphoid-specific transcription repressor recognized as a tumor suppressor in B-cell malignancies, but little is known about its function and regulatory network in T-ALL. Here we found extremely low levels of BACH2 in T-ALL clinical samples and cell lines compared to normal T cells. Overexpression of BACH2 in T-ALL cells not only induced cell growth retardation but also inhibited cancer progression and infiltration in xenografts. Further RNA sequencing (RNA-seq) analysis revealed significant alterations in regulation of defense and immune responses in T-ALL cells upon BACH2 overexpression. Strikingly, CD28 and CD40LG, two essential stimulatory molecules on T cells, were for the first time identified as novel downstream targets repressed by BACH2 in T-ALL cells. Interestingly, both CD28 and CD40LG were indispensable for T-ALL survival, since largely or completely silencing CD28 and CD40LG led to rapid cell death, whereas partial knockdown of them resulted in cell-cycle arrest and enhanced apoptosis. More importantly, BACH2-mediated CD28 and CD40LG signals contributed to cell migration and dissemination of T-ALL cells to the bone marrow, thus adding a new layer to the BACH2-mediated tumor immunoregulation in T-cell malignancies.

Applying RE-AIM to examine the impact of an implementation facilitation package to scale up a program for Veterans with chronic obstructive pulmonary disease.

BACKGROUND: US Veterans are four times more likely to be diagnosed with chronic obstructive pulmonary disease (COPD) compared to the civilian population with no care model that consistently improves Veteran outcomes when scaled. COPD Coordinated Access to Reduce Exacerbations (CARE) is a care bundle intended to improve the delivery of evidence-based practices to Veterans. To address challenges to scaling this program in the Veterans' Health Administration (VA), the COPD CARE Academy (Academy), an implementation facilitation package comprised of five implementation strategies was designed and implemented. METHODS: This evaluation utilized a mixed-methods approach to assess the impact of the Academy's implementation strategies on the RE-AIM framework implementation outcomes and the extent to which they were effective at increasing clinicians' perceived capability to implement COPD CARE. A survey was administered one week after Academy participation and a semi-structured interview conducted 8 to 12 months later. Descriptive statistics were calculated for quantitative items and thematic analysis was used to analyze open-ended items. RESULTS: Thirty-six clinicians from 13 VA medical centers (VAMCs) participated in the Academy in 2020 and 2021 and 264 front-line clinicians completed COPD CARE training. Adoption of the Academy was indicated by high rates of Academy session attendance (90%) and high utilization of Academy resources. Clinicians reported the Academy to be acceptable and appropriate as an implementation package and clinicians from 92% of VAMCs reported long-term utilization of Academy resources. Effectiveness of the Academy was represented by clinicians' significant increases (p < 0.05) in their capability to complete ten implementation tasks after Academy participation. CONCLUSIONS: This evaluation found that the use of implementation facilitation paired with additional strategies enhanced the capacity of clinicians to implement COPD CARE. Future assessments are needed to explore post-academy resources that would help VAMCs to strategize localized approaches to overcome barriers.

BACH1 Loss Exerts Antitumor Effects on Mantle Cell Lymphoma Cells via Inducing a Tumor-Intrinsic Innate Immune Response and Cell-Cycle Arrest.

BTB and CNC homology 1 (BACH1) is a transcription repressor that regulates multiple physiological processes, including intracellular heme homeostasis and immune responses. Increasing lines of evidence indicate that BACH1 reshapes metastasis and metabolism of human solid tumors. However, its potential roles in mantle cell lymphoma (MCL) remain largely unknown. Here, we found that silencing BACH1 in MCL cells induced markedly cell-cycle arrest and cell apoptosis, whereas overexpression of BACH1 exhibited the opposite patterns. Increased BACH1 levels not only promoted tumor growth and dispersal in xenografts, but also conferred a long-term poor prognosis in patients with MCL. Interestingly, RNA sequencing analysis revealed noncanonical function of BACH1 in regulation of type I interferon (IFNI) response, DNA replication and repair, and cell cycle. Mechanistically, zinc finger and BTB domain containing 20 (ZBTB20) and HMG-box transcription factor 1 (HBP1) were for the first time identified as two novel downstream targets repressed by BACH1 in MCL cells. Further double-knockdown functional assays confirmed that loss of BACH1 induced ZBTB20-mediated IFNα production and HBP1-mediated cell-cycle arrest, indicating that BACH1-centered regulatory network may be a novel targetable vulnerability in MCL cells. IMPLICATIONS: BACH1 serves as a pleotropic regulator of tumor-intrinsic innate immune response and cell-cycle progression, disruption of which may offer a promising therapeutic strategy for MCL treatment.

Prognostic prediction of idiopathic membranous nephropathy using interpretable machine learning.

BACKGROUND: Established prognostic models of idiopathic membranous nephropathy (IMN) were limited to traditional modeling methods and did not comprehensively consider clinical and pathological patient data. Based on the electronic medical record (EMR) system, machine learning (ML) was used to construct a risk prediction model for the prognosis of IMN. METHODS: Data from 418 patients with IMN were diagnosed by renal biopsy at the Fifth Clinical Medical College of Shanxi Medical University. Fifty-nine medical features of the patients could be obtained from EMR, and prediction models were established based on five ML algorithms. The area under the curve, recall rate, accuracy, and F1 were used to evaluate and compare the performances of the models. Shapley additive explanation (SHAP) was used to explain the results of the best-performing model. RESULTS: One hundred and seventeen patients (28.0%) with IMN experienced adverse events, 28 of them had compound outcomes (ESRD or double serum creatinine (SCr)), and 89 had relapsed. The gradient boosting machine (LightGBM) model had the best performance, with the highest AUC (0.892 ± 0.052, 95% CI 0.840-0.945), accuracy (0.909 ± 0.016), recall (0.741 ± 0.092), precision (0.906 ± 0.027), and F1 (0.905 ± 0.020). Recursive feature elimination with random forest and SHAP plots based on LightGBM showed that anti-phospholipase A2 receptor (anti-PLA2R), immunohistochemical immunoglobulin G4 (IHC IgG4), D-dimer (D-DIMER), triglyceride (TG), serum albumin (ALB), aspartate transaminase (AST), ß2-microglobulin (BMG), SCr, and fasting plasma glucose (FPG) were important risk factors for the prognosis of IMN. Increased risk of adverse events in IMN patients was correlated with high anti-PLA2R and low IHC IgG4. CONCLUSIONS: This study established a risk prediction model for the prognosis of IMN using ML based on clinical and pathological patient data. The LightGBM model may become a tool for personalized management of IMN patients.

PocketAnchor: Learning structure-based pocket representations for protein-ligand interaction prediction.

Protein-ligand interactions are essential for cellular activities and drug discovery processes. Appropriately and effectively representing protein features is of vital importance for developing computational approaches, especially data-driven methods, for predicting protein-ligand interactions. However, existing approaches may not fully investigate the features of the ligand-occupying regions in the protein pockets. Here, we design a structure-based protein representation method, named PocketAnchor, for capturing the local environmental and spatial features of protein pockets to facilitate protein-ligand interaction-related learning tasks. We define "anchors" as probe points reaching into the cavities and those located near the surface of proteins, and we design a specific message passing strategy for gathering local information from the atoms and surface neighboring these anchors. Comprehensive evaluation of our method demonstrated its successful applications in pocket detection and binding affinity prediction, which indicated that our anchor-based approach can provide effective protein feature representations for improving the prediction of protein-ligand interactions.

Applying RE-AIM to examine the impact of an implementation facilitation package to scale up a program for Veterans with Chronic Obstructive Pulmonary Disease.

Background: U.S. Veterans are four-times more likely to be diagnosed with Chronic Obstructive Pulmonary Disease (COPD) compared to the civilian population with no care model that consistently improves Veteran outcomes when scaled. COPD Coordinated Access to Reduce Exacerbations (CARE) is a care bundle intended to improve the delivery of evidence-based practices to Veterans. To address challenges to scaling this program in the Veterans' Health Administration (VA), the COPD CARE Academy (Academy), an implementation facilitation package comprised of four implementation strategies was designed and implemented. Methods: This evaluation utilized a mixed-methods approach to assess the impact of the Academy's implementation strategies on the RE-AIM framework implementation outcomes and the extent to which they were effective at increasing clinicians' perceived capability to implement COPD CARE. A survey was administered one week after Academy participation and a semi-structured interview conducted eight to 12 months later. Descriptive statistics were calculated for quantitative items and thematic analysis was used to analyze open-ended items. Results: Thirty-six clinicians from 13 VA medical centers (VAMCs) participated in the Academy in 2020 and 2021 and 264 front-line clinicians completed COPD CARE training. Adoption of the Academy was indicated by high rates of Academy completion (97%), session attendance (90%), and high utilization of Academy resources. Clinicians reported the Academy to be acceptable and appropriate as an implementation package and clinicians from 92% of VAMCs reported long-term utilization of Academy resources. Effectiveness of the Academy was represented by clinicians' significant increases (p < 0.05) in their capability to complete ten implementation tasks after Academy participation. Conclusions: This evaluation found that the use of implementation facilitation paired with additional strategies seemed to demonstrate positive implementation outcomes across all RE-AIM domains and identified areas for potential improvement. Future assessments are needed to explore post-academy resources that would help VAMCs to strategize localized approaches to overcome barriers.

Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of hematological malignancy characterized by its high heterogeneity and potentially life-threatening clinical features. Despite the advances in risk stratification and therapeutic management of T-ALL, patients often suffer from treatment failure and chemotherapy-induced toxicity, calling for greater efforts to improve therapeutic efficacy and safety in the treatment of T-ALL. During the past decades, increasing evidence has shown the indispensable effects of leukemia-initiating cells (LICs) and leukemic niches on T-ALL initiation and progression. These milestones greatly facilitate precision medicine by interfering with the pathways that are associated with LICs and leukemic niches or by targeting themselves directly. Most of these novel agents, either alone or in combination with conventional chemotherapy, have shown promising preclinical results, facilitating them to be further evaluated under clinical trials. In this review, we summarize the latest discoveries in LICs and leukemic niches in terms of T-ALL, with a particular highlight on the current precision medicine. The challenges and future prospects are also discussed.

Ferroptosis-induced anticancer effect of resveratrol with a biomimetic nano-delivery system in colorectal cancer treatment.

Ferroptosis is a novel form of programmed cell death impelled by iron-dependent lipid peroxidation, which may be a potential strategy for cancer therapy. Here we demonstrated for the first time that Resveratrol (RSV), a traditional Chinese medicine (TCM) chemical monomer, could effectually inhibit the growth of colon cancer cells through the ROS-dependent ferroptosis pathway. Mechanistically, RSV evoked the increase of reactive oxygen species and lipid peroxidation in colorectal cancer cells, and eventually lead to ferroptosis. Furthermore, RSV could promote ferroptosis by downregulating the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). To improve the delivery efficiency of RSV, a biomimetic nanocarrier was developed by coating RSV-loaded poly(ε-caprolactone)-poly(ethylene glycol) (PCL-PEG) nanoparticles with erythrocyte membrane (RSV-NPs@RBCm). The RSV-NPs@RBCm provide the possibility to escape macrophage phagocytosis and have a long circulation effect. In addition, when coupled with a tumor-penetrating peptide iRGD, which could trigger enhanced tissue penetration tumor-specifically, the delivery of RSV-NPs@RBCm into tumors would be significantly improved results from the in vivo study demonstrated an excellent treatment efficacy for CRC. Altogether, our study highlighted the therapeutic potential of RSV as a ferroptosis-inducing anticancer agent and when loaded into a biomimetic nanoplatform, it might pave the way for the application of RSV loaded nanosystems for colorectal cancer treatment.

Enhanced antitumor effect of icariin nanoparticles coated with iRGD functionalized erythrocyte membrane.

Lung cancer is the most common cause of incidence and mortality among tumor diseases. Icariin (ICA), a potential Chinese medicine monomer, has been reported to show outstanding antitumor effects. However, the hydrophobic nature and less tumor penetration limit its potential as a topical healing agent. There are few studies report the efficacy of ICA on lung cancer, moreover, there is no biomimetic targeted delivery system in the application of ICA. Herein, we firstly develop a novel ICA bionic targeted nano-preparation, camouflaged by the tumor penetrating peptide iRGD (cRGDKGPDC), functionalized red blood cell membrane (RBCM), has the increased solubility, utilized biocompatibility, and aggravated tumor penetration of ICA. In this study, we constructed the iRGD functionalized RBCM mimetic targeted ICA-loaded nanoparticles (iRINPs) and explored the anti-tumor effect of iRINPs against lung cancer with biochemical and behavioral analysis. The results suggested that iRINPs showed improved biocompatibility and stability, and reduced phagocytic uptakes by macrophages. Besides, the modification of iRGD significantly improved the targeting ability of iRINPs. In vitro and in vivo the treatment effects and safety assays showed that iRINPs attained better therapeutic effects than ICA by inhibiting A549 cell migration, proliferation and invasion, as well as reducing side effects of ICA. Overall, we expected that the new bionic nanocarriers would be a promising nano-platform for ICA in the precise therapy of lung cancer.

Apoptotic Induction of Mitochondria-Anchored Aggregation-Induced Emission Luminogens through the Intrinsic Mitochondrial Pathway.

Gastric cancer has the third highest mortality rate globally. Chemotherapy is the primary treatment used in advanced gastric cancer. Aggregation-induced emission luminogens (AIEgens) have been exploited as non-toxic and efficient chemotherapy agents for the treatment of cancer. Our previous research demonstrated that tetraphenylethene-substituted pyridinium salt (TPE-Py) is a kind of AIEgen that had the ability to lead to apoptosis in gastric cancer cells. However, it is currently unknown whether TPE-Py induced apoptosis in gastric cancer cells by the mitochondria-mediated pathway. This research confirmed that TPE-Py could target mitochondria and induce apoptotic cell death. In addition, several well-recognized indicators were detected to investigate the functional and morphological changes of mitochondria. We found that TPE-Py could diminish the mitochondrial membrane potential and increase the accumulation of reactive oxygen species and the discharge of cytochrome c, which was related to the mitochondrial apoptotic pathway. Meanwhile, morphological changes in mitochondria were also observed by transmission electron microscopy in gastric cancer cells after incubation with TPE-Py. In conclusion, we provided insights into the mechanism regulating apoptosis in gastric cancer cells and elucidated the mechanism of apoptosis induced by TPE-Py via the intrinsic mitochondrial pathway.

Superior in vitro anticancer effect of biomimetic paclitaxel and triptolide co-delivery system in gastric cancer.

As a well-known anticancer drug, paclitaxel (PTX), a first-line chemotherapeutic agent, remains unsatisfactory for gastric cancer therapy. It is reported that triptolide (TPL) could enhance the anti-gastric cancer effect of PTX. Considering the poor solubility of both drugs, we developed a red blood cell membrane-biomimetic nanosystem, an emerging tool in drug delivery, to co-load paclitaxel and triptolide (red blood cell membrane coated PTX and TPL co-loaded poly(lactic-co-glycolic acid) [PLGA] nanoparticles, RP(P/T)). The successful preparation was confirmed in terms of particle size, morphology, and surface markers assays. This biomimetic system could prolong circulation and escape immune surveillance. And these properties were verified by stability, in vitro drug release, and cellular uptake assays. Moreover, the MTT and colony formation assays demonstrated the superior anti-proliferation effect of the RP(P/T) to free drugs. The enhanced antitumor effects of RP(P/T) on migration and invasion were also evaluated by wound-healing and transwell assays. Overall, the bionic co-delivery nanoplatform with improved efficacy in vitro is a promising therapy for gastric cancer.

Evaluation of lightwand-guided endotracheal intubation for patients with missing or no teeth: a randomized controlled study.

BACKGROUND: Unhealthy teeth can seriously affect general health and increase the risk of death in elderly people. There has been no confirmation of which device is most effective for elderly patients with teeth loss. Therefore, we compared four intubation devices in elderly patients with partial and total tooth loss aiming to reduce risk during anesthesia. METHODS: Two hundred patients were randomized to undergo tracheal intubation with the Macintosh laryngoscope, the Glidescope, the Fiberoptic bronchoscope or the Lightwand as part of general anesthesia. A unified protocol of anesthetic medications was used. HR and BP were measured at T0, T1, T2, T3, T4 and T5. Catecholamine (epinephrine and norepinephrine) blood samples were drawn at T0, T1 and T2. Intubation time and postoperative complications, including dental damage and losses, were recorded. RESULTS: Reduced fluctuations in HR, DBP, and SBP were observed in the Lightwand group. Intubation time was significantly shorter in the Lightwand group (p < 0.05). There was no statistically significant difference between the groups in epinephrine levels, but norepinephrine levels were less volatile in the Fiberoptic bronchoscope and Lightwand groups. Fewer patients in the Lightwand group experienced dental damage and other postoperative complications than in the other three groups. Although a higher success rate on the first attempt was as high as in the Fiberoptic bronchoscope group, shorter intubation time was observed only in the Lightwand group. CONCLUSION: The Lightwand offers less hemodynamic stimulation than the Macintosh laryngoscope, Glidescope, and Fiberoptic bronchoscope. Because it had the shortest intubation time, the Lightwand caused the least damage to the teeth and throat of elderly patients. Our findings showed that tracheal intubation with the Lightwand was advantageous for preventing cardiovascular stress responses with short intubation times and fewer postoperative complications.

Deciphering extrachromosomal circular DNA in Arabidopsis.

Extrachromosomal circular DNA (eccDNA) is independent of the chromosome and exists in many eukaryotes. However, the nature and origin of eccDNA in plants remains unclear. In this study, we sequenced 12 samples from four tissues (leaf, flower, stem and root) with three biological replicates. In total, we found 743 eccDNAs found in at least two samples. Most of eccDNA have inverted repeats ranging from 4 to 12 bp in the boundaries. Interestingly, eccDNA is not only related to transposon activity, but also hosts tRNA genes, suggesting that the eccDNAs may be associated with tRNA abundance which controls protein synthesis under conditions of stress. Our results provide an unprecedented view of eccDNA, which is still naïve in scope.

Morphological analysis of chromium in carbon quantum dots pairs Co-doped with zirconium and nitrogen and their applications in imaging of living cells.

As a new nanomaterial in the biochemistry field, carbon quantum dots (CDs) have been widely applied by scientists. In this study, CDs co-doped with zirconium and nitrogen (Zr-N-CDs) were synthesized quickly with lemon, ethylenediamine, and zirconium chloride through a hydrothermal method. The yield of Zr-N-CDs reached as high as 82.7%. The Zr-N-CDs showed outstanding water solubility in aqueous solution. The formation of Zr-N-CDs was verified by characterization technologies, such as high-resolution transmission electron microscopy (HRTEM), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). Moreover, the optical properties of Zr-N-CDs were investigated through fluorophotometer and ultraviolet spectroscopy. The synthesized Zr-N-CDs were applied to test hexavalent chromium (Cr (VI)), which showed a good linear relationship with the fluorescence quenching of Zr-N-CDs. The limit of detection was 0.52 µM. An analytical method for Cr morphology in natural water areas was developed in this experiment. The sensor showed good stability. The results demonstrate that the sensor detected 98.35%-100.9% Cr (VI) recovery rate in water samples. Based on the cytotoxicity of Zr-N-CDs to human cervical cancer cells (HeLa cells), the Zr-N-CDs had no evident cytotoxicity. The applications of Zr-N-CDs in bioimaging of cells were determined through laser scanning confocal microscopy.

A comprehensive evaluation of single nucleotide polymorphisms associated with hepatocellular carcinoma risk in Asian populations: A systematic review and network meta-analysis.

BACKGROUND: Single nucleotide polymorphisms (SNPs) have been inconsistently associated with hepatocellular carcinoma (HCC) risk. This meta-analysis aimed to synthesize relevant data on SNPs associated with HCC in the Asian population. METHODS: Databases were searched to identify association studies of SNPs and HCC in Asians published through January 2019. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on 41 studies (13,167 patients with HCC and 15,886 noncancer controls). Network meta-analysis and Thakkinstian's algorithm were used to select the most appropriate genetic model, along with false positive report probability (FPRP) for noteworthy associations. RESULTS: Eleven SNPs meeting the inclusion criteria were tested for association with HCC, including CCND1 rs9344, PTGS2 rs689466, IL18 rs187238 and rs1946518, KIF1B rs17401966, MDM2 rs2279744, MIR146A rs2910164, MIR149 rs2292832, MIR196A2 rs11614913, MIR499A rs3746444, and TGFB1 rs1800469. A significant increase for HCC risk was observed for MDM2 rs2279744, and the dominant (pooled OR = 1.59, 95% CI: 1.26-2.00) and codominant (pooled OR = 1.37, 95% CI: 1.18-1.60) models were determined to be the most appropriate models. MIR499A rs3746444 also showed a significant association with HCC risk under the allele contrast model (pooled OR = 1.36, 95% CI: 1.05-1.77). Only the significance of MDM2 rs2279744 was noteworthy (FPRP < 0.2). CONCLUSIONS: MDM2 rs2279744 is associated with HCC susceptibility in Asians, and the dominant and codominant models are likely the most appropriate models to estimate HCC risk.

Characterization, molecular cloning, and in silico analysis of a novel mannose-binding lectin from Polygonatum odoratum (Mill.) with anti-HSV-II and apoptosis-inducing activities.

Polygonatum odoratum lectin (POL), a novel mannose-binding lectin with anti-viral and apoptosis-inducing activities, was isolated from rhizomes of Polygonatum odoratum (Mill.) Druce. POL was a homo-tetramer with molecular weight of 11953.623Da per subunits as determined by gel filtration, SDS-PAGE and mass spectrometry. Based on its N-terminal 29-amino acid sequence the full-length cDNA sequence of POL was cloned. Subsequent phylogenetic analysis and molecular modeling revealed that POL belonged to the Galanthus nivalis agglutinin (GNA)-related lectin family, which acquired unique mannose-binding specificity. The hemagglutinating activities of POL were metal ion-independent, and were stable within certain range of pH and temperature alterations. Moreover, POL showed remarkable anti-HSV-II activity towards Vero cells, cytotoxicity towards human melanoma A375 cells and induced apoptosis in a caspase-dependent manner.

Polygonatum cyrtonema lectin induces murine fibrosarcoma L929 cell apoptosis via a caspase-dependent pathway as compared to Ophiopogon japonicus lectin.

Galanthus nivalis agglutinin (GNA)-related lectin family, a superfamily of strictly mannose-binding specific lectins, has been well-known to possess several biological functions including apoptosis-inducing activities. However, the precise mechanisms of GNA-related lectins to induce apoptosis remains to be clarified. In this study, we showed that Polygonatum cyrtonema lectin (PCL) and Ophiopogon japonicus lectin (OJL), the two mannose-binding GNA-related lectins, could induce murine fibrosarcoma L929 cell apoptosis. In addition, we found that there was a close link between their sugar-binding and apoptosis-inducing activities. Interestingly, we further confirmed that the mechanism of lectin-induced apoptosis was a caspase-dependent pathway. Moreover, we found that the two lectins could amplify tumor necrosis factor α (TNFα)-induced apoptosis. Taken together, these findings would open a new perspective for GNA-related lectins as potential anti-tumor agents.

A mannose-binding lectin from Sophora flavescens induces apoptosis in HeLa cells.

The objective of this study was to investigate the anti-tumor activity of a lectin from Sophora flavescens and explore its potential apoptotic induction mechanism. Here, an elegant series of biochemical and cell biology methods were carried out in a sequential procedure (e.g., MTT, cell morphologic changes and LDH assays, DNA ladder as well as flow cytometric assay). As a result, we found that this lectin shows a strong cytotoxicity against HeLa cells and induces apoptosis in a time- and dose-dependent manner. Subsequently, according to caspase inhibition and Western blot analysis, we further demonstrated that it is a typical caspase-dependent apoptotic mechanism. Furthermore, we also exerted some bioinformatics methods to identify the mannose-binding specificity of this lectin. In conclusion, all experimental results demonstrated that this lectin seems to be a potent anti-tumor agent for its cytotoxicity and apoptosis effects on HeLa cells. Also, bioinformatics analyses showed that this lectin is speculated to bind a certain mannose-containing receptor on cancer cell surface thereby initiating downstream caspase cascade.