Development of a new Cox model for predicting long-term survival in hepatitis cirrhosis patients underwent transjugular intrahepatic portosystemic shunts.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) placement is a procedure that can effectively treat complications of portal hypertension, such as variceal bleeding and refractory ascites. However, there have been no specific studies on predicting long-term survival after TIPS placement. AIM: To establish a model to predict long-term survival in patients with hepatitis cirrhosis after TIPS. METHODS: A retrospective analysis was conducted on a cohort of 224 patients who underwent TIPS implantation. Through univariate and multivariate Cox regression analyses, various factors were examined for their ability to predict survival at 6 years after TIPS. Consequently, a composite score was formulated, encompassing the indication, shunt reasonability, portal venous pressure gradient (PPG) after TIPS, percentage decrease in portal venous pressure (PVP), indocyanine green retention rate at 15 min (ICGR15) and total bilirubin (Tbil) level. Furthermore, the performance of the newly developed Cox (NDC) model was evaluated in an internal validation cohort and compared with that of a series of existing models. RESULTS: The indication (variceal bleeding or ascites), shunt reasonability (reasonable or unreasonable), ICGR15, postoperative PPG, percentage of PVP decrease and Tbil were found to be independent factors affecting long-term survival after TIPS placement. The NDC model incorporated these parameters and successfully identified patients at high risk, exhibiting a notably elevated mortality rate following the TIPS procedure, as observed in both the training and validation cohorts. Additionally, in terms of predicting the long-term survival rate, the performance of the NDC model was significantly better than that of the other four models [Child-Pugh, model for end-stage liver disease (MELD), MELD-sodium and the Freiburg index of post-TIPS survival]. CONCLUSION: The NDC model can accurately predict long-term survival after the TIPS procedure in patients with hepatitis cirrhosis, help identify high-risk patients and guide follow-up management after TIPS implantation.

Electrocatalytic Coenhancement of Bimetallic Polyphthalocyanine-Anchored Ru Nanoclusters Enabling Efficient Overall Water Splitting at Ampere-Level Current Densities.

Efficient electrocatalysts capable of operating continuously at industrial ampere-level current densities are crucial for large-scale applications of electrocatalytic water decomposition for hydrogen production. However, long-term industrial overall water splitting using a single electrocatalyst remains a major challenge. Here, bimetallic polyphthalocyanine (FeCoPPc)-anchored Ru nanoclusters, an innovative electrocatalyst comprising the hydrogen evolution reaction (HER) active Ru and the oxygen evolution reaction (OER) active FeCoPPc, engineered for efficient overall water splitting are demonstrated. By density functional theory calculations and systematic experiments, the electrocatalytic coenhancement effect resulting from unique charge redistribution, which synergistically boosts the HER activity of Ru and the OER activity of FeCoPPc by optimizing the adsorption energy of intermediates, is unveiled. As a result, even at a large current density of 2.0 A cm-2 , the catalyst exhibits low overpotentials of 220 and 308 mV, respectively, for HER and OER. It exhibits excellent stability, requiring only 1.88 V of cell voltage to achieve a current density of 2.0 A cm-2 in a 6.0 m KOH electrolyte at 70 °C, with a remarkable operational stability of over 100 h. This work provides a new electrocatalytic coenhancement strategy for the design and synthesis of electrocatalyst, paving the way for industrial-scale overall water splitting applications.

The p53/ZEB1-PLD3 feedback loop regulates cell proliferation in breast cancer.

Breast cancer is the most prevalent cancer globally, endangering women's physical and mental health. Phospholipase D3 (PLD3) belongs to the phosphodiesterase family (PLD). PLD3 is related to insulin-mediated phosphorylation of the AKT pathway, suggesting that it may play a role in the occurrence and development of malignant tumors. This study may further explore the molecular mechanism of PLD3 inhibiting breast cancer cell proliferation. In this study, we demonstrated that PLD3 and miR-6796 are co-expressed in breast cancer. PLD3 can bind with CDK1 and inhibit its expression, leading to mitotic arrest and inhibiting breast cancer proliferation. Wild-type p53 regulates PLD3 and miR-6796 expression by competitively binding to the PLD3 promoter with ZEB1. DNMT3B, as the target gene of miR-6796, is recruited into the PLD3 promoter by combining with ZEB1 to regulate the DNA methylation of the PLD3 promoter and ultimately affect PLD3 and miR-6796 expression. In conclusion, we revealed the role and molecular mechanism of PLD3 and its embedded miR-6796 in breast cancer proliferation, providing clues and a theoretical foundation for future research and development of therapeutic targets and prognostic markers for breast cancer.

Immunological factors in cirrhosis diseases from a bibliometric point of view.

BACKGROUND: Cirrhosis results from persistent liver injury that leads to liver fibrosis. Immunological factors play important regulatory roles in the development and progression of cirrhosis. Bibliometrics is one of the most commonly used methods for systematic evaluation of a field of study. To date, there are no bibliometric studies on the role of immunological factors in cirrhosis. AIM: To provide a comprehensive overview of the knowledge structure and research hotspots of immunological factors in cirrhosis. METHODS: We retrieved publications related to immunological factors in cirrhosis between 2003 to 2022 from the Web of Science Core Collection database on December 7, 2022. The search strategy was TS = ((Liver Cirrhosis OR hepatic cirrhosis OR liver fibrosis) AND (Immunologic* Factor* OR Immune Factor* OR Immunomodulator* OR Biological Response Modifier* OR Biomodulator*)). Only original articles and reviews were included. A total of 2873 publications were analyzed using indicators of publication and citation metrics, countries, institutes, authors, journals, references, and keywords by CiteSpace and VOSviewer. RESULTS: A total of 5104 authors from 1173 institutions across 51 countries published 2873 papers on cirrhosis and immunological factors in 281 journals. In the past 20 years, the increasing number of related annual publications and citations indicates that research on immunological factors in cirrhosis has become the focus of attention and has entered a period of accelerated development. The United States (781/27.18%), China (538/18.73%), and Germany (300/10.44%) were the leading countries in this field. Most of the top 10 authors were from the United States (4) and Germany (3), with Gershwin ME contributing the most related articles (42). World Journal of Gastroenterology was the most productive journal, whereas Hepatology was the most co-cited journal. Current research hotspots regarding immunological factors in cirrhosis include fibrosis, cirrhosis, inflammation, liver fibrosis, expression, hepatocellular carcinoma, activation, primary biliary cirrhosis, disease, and hepatic stellate cells. Burst keywords (e.g., epidemiology, gut microbiota, and pathways) represent research frontiers that have attracted the interest of researchers in recent years. CONCLUSION: This bibliometric study comprehensively summarizes the research developments and directions of immunological factors in cirrhosis, providing new ideas for promoting scientific research and clinical applications.

HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5.

Human papillomavirus (HPV) infection is a causative agent of cervical cancer (CC). N6-methyladenosine (m6A) modification is implicated in carcinogenesis and tumor progression. However, the involvement of m6A modification in HPV-involved CC remains unclear. Here we showed that HPV E6/7 oncoproteins affected the global m6A modification and E7 specifically promoted the expression of ALKBH5. We found that ALKBH5 was significantly upregulated in CC and might serve as a valuable prognostic marker. Forced expression of ALKBH5 enhanced the malignant phenotypes of CC cells. Mechanistically, we discovered that E7 increased ALKBH5 expression through E2F1-mediated activation of the H3K27Ac and H3K4Me3 histone modifications, as well as post-translational modification mediated by DDX3. ALKBH5-mediated m6A demethylation enhanced the expression of PAK5. The m6A reader YTHDF2 bound to PAK5 mRNA and regulated its stability in an m6A-dependent manner. Moreover, ALKBH5 promoted tumorigenesis and metastasis of CC by regulating PAK5. Overall, our findings herein demonstrate a significant role of ALKBH5 in CC progression in HPV-positive cells. Thus, we propose that ALKBH5 may serve as a prognostic biomarker and therapeutic target for CC patients.

Supplementation of mitochondria from endometrial mesenchymal stem cells improves oocyte quality in aged mice.

Maternal ageing is one of the major causes of reduced ovarian reserve and low oocyte quality in elderly women. Decreased oocyte quality is the main cause of age-related infertility. Mitochondria are multifunctional energy stations that determine the oocyte quality. The mitochondria in aged oocytes display functional impairments with mtDNA damage, which leads to reduced competence and developmental potential of oocytes. To improve oocyte quality, mitochondrial supplementation is carried out as a potential therapeutic approach. However, the selection of suitable cells as the source of mitochondria remains controversial. We cultivated endometrial mesenchymal stem cells (EnMSCs) from aged mice and extracted mitochondria from EnMSCs. To improve the quality of oocytes, GV oocytes were supplemented with mitochondria via microinjection. And MII oocytes from aged mice were fertilized by intracytoplasmic sperm injection (ICSI), combining EnMSCs' mitochondrial microinjection. In this study, we found that the mitochondria derived from EnMSCs could significantly improve the quality of aged oocytes. Supplementation with EnMSC mitochondria significantly increased the blastocyst ratio of MII oocytes from aged mice after ICSI. We also found that the birth rate of mitochondria-injected ageing oocytes was significantly increased after embryo transplantation. Our study demonstrates that supplementation with EnMSC-derived mitochondria can improve the quality of oocytes and promote embryo development in ageing mice, which might provide a prospective strategy for clinical treatment.

Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis potential of colorectal cancer.

BACKGROUND: Dysregulation of alternative splicing (AS) induced by serine/arginine-rich proteins has recently been linked to cancer metastasis. Nonetheless, as a member of the serine/arginine-rich protein family, the involvement of SRSF11 in colorectal cancer (CRC) is unknown. METHODS: The TCGA dataset and clinical samples were used to assess SRSF11 expression levels in CRC. For SRSF11, functional experiments were conducted both in vitro and in vivo. RNA-seq technology was used to analyze and screen SRSF11-triggered AS events, which were then confirmed by in vivo UV crosslinking and immunoprecipitation (CLIP) and mini-gene reporter assays. Jalview software was used to determine the preferential binding motif with relation to exon skipping (ES) events. Furthermore, coimmunoprecipitation (Co-IP) and Phospho-tag SDS-PAGE experiments were used to investigate PAK5-mediated phosphorylation regulation on SRSF11, and in vitro kinase experiments validated the interaction. RESULTS: In CRC, SRSF11 was discovered to be overexpressed and associated with a poor prognosis. And SRSF11 played a pro-metastatic role in vitro and in vivo. By screening SRSF11-regulated AS events, we identified the binding motif of SRSF11-triggered splicing-switching of HSPA12A AS, which specifically regulated HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the HSPA12A transcript with exon 2 retention increased N-cadherin expression by promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated SRSF11 at serine 287, protecting it from ubiquitination degradation. CONCLUSIONS: SRSF11 exerts pro-metastatic effects in CRC by inhibiting the AS of HSPA12A pre-RNA. Our findings point to SRSF11-regulated HSPA12A splicing as a novel relationship between SRSF11-regulated splicing and CRC metastasis and suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and prognostic biomarker in CRC.

Association of serum pepsinogens and gastrin-17 with Helicobacter pylori infection assessed by urea breath test.

Background: Association of gastric atrophy or cancer with levels of serum pepsinogens, gastrin-17 and anti-Helicobacter pylori IgG antibody have been extensively studied. However, the association of serum pepsinogen and gastrin-17 with H. pylori infection has not been studied in a large population. Aim: To investigate the impact of H. pylori infection on serum levels of pepsinogens and gastrin-17. Methods: A total of 354, 972 subjects who underwent health check-ups were included. Serum levels of pepsinogens and gastrin-17 were measured using the enzyme-linked immunosorbent assay. H. pylori infection was detected using 14C-urea breath test (UBT). Multivariable logistic regression analysis was used to investigate the association of serum pepsinogen and gastrin-17 with H. pylori infection. Results: H. pylori prevalence was 33.18% in this study. The mean levels of pepsinogens and gastrin-17 were higher, while the mean pepsinogen-I/II ratio were lower among H. pylori-positive than -negative subjects. In H. pylori-positive subjects, pepsinogen and gastrin-17 levels correlated positively, whereas the pepsinogen-I/II ratio correlated negatively with UBT values (e.g., the mean serum level of pepsinogen-I in subjects with UBT values in the range of 100-499dpm, 500-1499dpm, and ≥1500dpm was 94.77 ± 38.99, 102.77 ± 43.59, and 111.53 ± 47.47 ng/mL, respectively). Compared with H. pylori-negative subjects, the adjusted odds ratio (aOR) of having pepsinogen-I ≤ 70 ng/mL in the three H. pylori-positive but with different UBT value groups was 0.31 (p<0.001), 0.16 (p<0.001), and 0.08 (p<0.001), respectively; while the aOR of having G-17>5.70 pmol/L was 4.56 (p<0.001), 7.43 (p<0.001), and 7.12 (p<0.001). This suggested that H. pylori-positive subjects with higher UBT values were less likely to have pepsinogen-I ≤70 ng/mL (a serum marker for gastric atrophy), but more likely to have gastrin-17 >5.70 pmol/L (a marker for peptic ulcer). Conclusions: H. pylori-positive subjects with higher UBT values are unlikely to have gastric atrophy, but may have greater risk of severe gastritis or peptic ulcers. Our study suggests that H. pylori-positive patients with high UBT values may benefit the most from H. pylori eradication.

The Role of Alternative Splicing in Cancer: Regulatory Mechanism, Therapeutic Strategy, and Bioinformatics Application.

[Formula: see text] Alternative splicing (AS) can generate distinct transcripts and subsequent isoforms that play differential functions from the same pre-mRNA. Recently, increasing numbers of studies have emerged, unmasking the association between AS and cancer. In this review, we arranged AS events that are closely related to cancer progression and presented promising treatments based on AS for cancer therapy. Obtaining proliferative capacity, acquiring invasive properties, gaining angiogenic features, shifting metabolic ability, and getting immune escape inclination are all splicing events involved in biological processes. Spliceosome-targeted and antisense oligonucleotide technologies are two novel strategies that are hopeful in tumor therapy. In addition, bioinformatics applications based on AS were summarized for better prediction and elucidation of regulatory routines mingled in. Together, we aimed to provide a better understanding of complicated AS events associated with cancer biology and reveal AS a promising target of cancer treatment in the future.

TDP-43 upregulates lipid metabolism modulator ABHD2 to suppress apoptosis in hepatocellular carcinoma.

TAR DNA-Binding Protein 43 (TDP-43) has been well studied in neurodegenerative diseases, but its potential role in malignance is still unclear. Here, we demonstrate that TDP-43 contributes to the suppression of apoptosis by facilitating lipid metabolism in hepatocellular carcinoma (HCC). In HCC cells, TDP-43 is able to suppress apoptosis while deletion of it markedly induces apoptosis. RNA-sequencing identifies the lipid metabolism gene abhydrolase domain containing 2 (ABHD2) as the target gene of TDP-43. Tissue microarray analysis shows the positive correlation of TDP-43 and ABHD2 in HCC. Mechanistically, TDP-43 binds with the UG-rich sequence1 of ABHD2 3'UTR to enhance the mRNA stability of ABHD2, thereby upregulating ABHD2. Afterwards, TDP-43 promotes the production of free fatty acid and fatty acid oxidation-originated reactive oxygen species (ROS) in an ABHD2-dependent manner, so as to suppress apoptosis of HCC. Our findings provide insights into the mechanism of HCC progression and reveal TDP-43/ABHD2 as potential targets for the precise treatment of HCC.

A sponge heated by electromagnetic induction and solar energy for quick, efficient, and safe cleanup of high-viscosity crude oil spills.

Frequent oil spills have caused severe environmental and ecological damage. Effective cleanup has become a complex challenge owing to the poor flowability of viscous crude oils. The current method of solar heating to reduce the viscosity of heavy oil is only suitable during sunny days, while the use of Joule heating is limited by the risk of direct exposure to high-voltage electricity. Herein, we demonstrate a noncontact electromagnetic induction and solar dual-heating sponge for the quick, safe, and energy-saving cleanup of ultrahigh-viscosity heavy oil. The resulting sponge with magnetic, conductive, and hydrophobic properties can be rapidly heated to absorb heavy oil under alternating magnetic fields, solar irradiation, or both of these conditions. By constructing theoretical models and fitting the actual data, an in-depth analysis of induction and solar heating processes is carried out. The sponge has excellent resilience and stability, indicating its reusability, fast and continuous adsorption (16.17 g in 10 s), and large capacity (75-81 g/g, the highest value ever) for soft asphalt (a highly viscous crude oil). This work provides a new noncontact dual-heating strategy for heavy oil cleanup, in which absorbents use induction heating during an emergency and then switch to partial or full solar heating to save energy in sunny conditions. ENVIRONMENTAL IMPLICATION: Heavy oils stranded on the beach or floating on water can kill underwater plants by blocking sunlight, or trap water birds and other animals. Heavy oil also contains aromatic substances that are toxic to aquatic organisms. Although oil spills near shallow water cannot be cleaned up by fences or other machinery, an oil adsorbent can deal with this problem. However, common adsorbents cannot effectively absorb high-viscosity oils, such as heavy oil. In this paper, an induction and solar dual-heating sponge is developed for the effective cleanup of high-viscosity oil.

The role of surgery on locoregional treatment of patients with breast cancer newly diagnosed with ipsilateral supraclavicular lymph node metastasis.

Background: Radiotherapy is a practical locoregional treatment approach for women with breast cancer who show ipsilateral supraclavicular lymph node metastasis (ISLNM) on diagnosis. However, there is controversy around the role of supraclavicular lymph node dissection. Therefore, we aimed to study the significance of supraclavicular surgery based on radiotherapy. Patients and Methods: We retrospectively reviewed the data of 142 patients with breast cancer who presented with isolated ISLNM and received radiotherapy between the years 2000 and 2016. We also defined the effect of surgery on locoregional treatment of these patients by analyzing the prognostic factors for recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: We observed that, of the 142 patients, 104 who received radiotherapy underwent supraclavicular lymph node dissection. Also, among the study group, the progesterone receptor (PR) status (P = 0.044) and the number of axillary lymph nodes (ALNs) involved (P = 0.002) were significant independent predictors of RFS. Also, tumor size (P = 0.007), PR (P < 0.001), and number of ALNs (P < 0.001) were independent predictors of DMFS and were statistically significant. Also, PR was an independent prognostic factor of OS (P = 0.033), whereas the supraclavicular surgery was not an independent prognostic factor for RFS, DMFS, and OS. Furthermore, our study focused on 92 patients with negative estrogen receptors (ERs). The result showed that supraclavicular surgery was statistically significant for RFS (P = 0.023); no significant differences in DMFS and OS were found between patients who received supraclavicular surgery and those who did not. Conclusion: Radiotherapy may be the primary locoregional treatment approach for patients with breast cancer who present with newly diagnosed ISLNM. Additionally, supraclavicular surgery may be more appropriate for patients with negative ER who received radiotherapy.

A novel light-controlled colorimetric detection assay for nitroreductase based on p-aminophenol-catalyzed and NADH-mediated synthesis of silver nanoparticles.

A novel and efficient light-controlled colorimetric assay for the quantification and detection of nitroreductase (NTR) was constructed based on p-aminophenol (pAP)-catalyzed and nicotinamide adenine dinucleotide (NADH)-mediated generation of AgNPs. Due to the hydrolysis of p-nitrophenol by NTR in the presence of NADH, the hydrolysis product can be used as a catalyst to catalyze the reduction of Ag+ by NADH under the light. As the concentration of NTR increases, the value of absorbance at ca. 400 nm (A400) decreases and the color of the solution turns from brown to bright yellow. A linear correlation was obtained between A400 and the NTR concentration in the range from 1-50 µg mL-1 and the limit of detection (LOD) is 0.27 µg mL-1. The detection system does not respond to other common biological molecules due to the specificity of enzymes and the effect of the nitroreductase inhibitor on the NTR activity was also tested. Finally, we applied the assay to determine NTR in human serum samples by spiking different concentrations of NTR with a recovery of 85.2%-92.5%.

Shengui Sansheng Pulvis maintains blood-brain barrier integrity by vasoactive intestinal peptide after ischemic stroke.

Background Shengui Sansheng Pulvis (SSP) has about 300 years history used for stroke treatment, and evidences suggest it has beneficial effects on neuro-angiogenesis and cerebral energy metabolic amelioration post-stroke. However, its protective action and mechanisms on blood-brain barrier (BBB) is still unknown. Purpose Based on multiple neuroprotective properties of vasoactive intestinal peptide (VIP) in neurological disorders, we investigate if SSP maintaining BBB integrity is associated with VIP pathway in rat permanent middle cerebral artery occlusion (MCAo) model. Methods Three doses of SSP extraction were administered orally. Evaluations of motor and balance abilities and detection of brain edema were performed, and BBB permeability were assessed by Evans blue (EB) staining. Primary brain microvascular endothelial cells (BMECs) were subjected to oxygen-glucose deprivation, and incubated with high dose SSP drug-containing serum and VIP-antagonist respectively. Transendothelial electrical resistance (TEER) assay and Tetramethylrhodamine isothiocyanate (TRITC)-dextran (4.4 kDa) and fluorescein isothiocyanate (FITC)-dextran (70 kDa) were used to evaluate the features of paracellular junction. Western blot detected the expressions of Claudin-5, ZO-1, Occludin and VE-cadherin, matrix metalloproteinase (MMP) 2/9 and VIP receptors 1/2, and immunofluorescence staining tested VIP and Claudin-5 expressions. Results Our results show that SSP significantly reduces EB infiltration in dose-dependent manner in vivo and attenuates TRITC- dextran and FITC-dextran diffusion in vitro, and strengthens endothelial junctional complexes as represented by decreasing Claudin-5, ZO-1, Occludin and VE-cadherin degradations and MMP 2/9 expression, as well as promoting TEER in BMECs after ischemia. Moreover, it suggests that SSP notably enhances VIP and its receptors 1/2 expressions. VIP-antagonist exacerbates paracellular barrier of BMECs, while the result is reversed after incubation with high dose SSP drug-containing serum. Additionally, SSP also improve brain edema and motor and balance abilities after ischemic stroke. Conclusions we firstly demonstrate that the ameliorated efficacy of SSP on BBB permeability is related to the enhancements of VIP and its receptors, suggesting SSP might be an effective therapeutic agent on maintaining BBB integrity post-stroke.

Polyglycolic acid sutures embedded in abdominal acupoints for treatment of simple obesity in adults: a randomized control trial.

BACKGROUND: Acupoint catgut embedding therapy characterized by acupoint, needle and catgut are superior to traditional acupuncture, due to exerting more comprehensive therapeutic efficacy. However, it is still deficient in clinical evidence for polyglycolic acid sutures, a novel biodegradable material instead of catgut, embedded for the treatment of simple obesity. In our study, we investigate the efficacy and related mechanism of polyglycolic acid sutures embedded in abdominal acupoints on simple obese persons by a randomized control trial. METHODS: A total of 51 eligible participators were randomly allocated to a polyglycolic acid sutures embedding therapy (PASET) group (n = 28) or control group (n = 23). Participators in PASET group received polyglycolic acid sutures alternatively embedded in abdominal I group and II group acupoints in odd and even number therapeutic courses, and participators in control group were required to perform lifestyle modification. The duration of the study was 10 weeks. RESULTS: It suggested that PASET significantly reduced weight, body mass index, hip circumference, waist circumference, waist/hip ratio, waist-to-height ratio and thickness of abdominal subcutaneous fat tissue compared with those before treatment (p < 0.01), but lifestyle modification only illustrated downward trend of weight (p < 0.05). Moreover, PASET group also improved the evaluated scores in aspects of physical function, self-esteem, public distress and sexual life, as well as decreased blood pressure, glycemia, low density lipoprotein, uric acid and the levels of tumor necrosis factor-alpha, interleukin-1ß, and increased high density lipoprotein in comparison with those before treatment (p < 0.05), whose efficacies are superior to control group. Additionally, our results also indicate PASET is relative safe and its pain and discomfort can be tolerable. CONCLUSIONS: PASET distinctly ameliorates anthropometric data and quality of life in obese population, which associates with improvements of metabolic profile and inflammatory response. Based on the advantageous actions, we think PASET is an effective therapeutic approach to simple obesity treatment.Trial registration ChiCTR, ChiCTR1800015591. Registered 10 April 2018, http://www.chictr.org.cn/showproj.aspx?proj=23258.

SNHG5 Promotes Breast Cancer Proliferation by Sponging the miR-154-5p/PCNA Axis.

Breast cancer is the most common malignant tumor and the main cause of cancer-associated mortality in females worldwide. Long non-coding RNAs (lncRNAs) have been reported to play vital roles in breast cancer development and progression; however, our understanding of most lncRNAs in breast cancer is still limited. In this study, we demonstrated that small nucleolar RNA host gene 5 (SNHG5) promotes breast cancer cell proliferation both in vitro and in vivo, and depletion of SNHG5 significantly led to cell-cycle arrest at G1 phase. Accumulating evidence has shown that many lncRNA transcripts could function as competing endogenous RNAs (ceRNAs) by competitively binding common microRNAs (miRNAs). We found that SNHG5 acts as a sponge for miR-154-5p, reducing its ability to repress proliferating cell nuclear antigen (PCNA). SNHG5 promoted breast cancer proliferation and cell-cycle progression by upregulation of PCNA expression. Clinically, we observed an increased SNHG5 expression in breast cancer, whereas miR-154-5p was decreased in breast cancer tissues compared with the adjacent normal breast tissues. Furthermore, the SNHG5 expression was significantly negatively correlated with miR-154-5p expression. Taken together, our data uncover the SNHG5-miR-154-5p-PCNA axis and provide a novel mechanism to explain breast cancer proliferation.

Estrogen receptor-α-miR-1271-SNAI2 feedback loop regulates transforming growth factor-ß-induced breast cancer progression.

BACKGROUND: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-ß (TGF-ß) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited. METHODS: The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ERα-miR-1271-SNAI2 feedback loop. RESULTS: miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-ß-induced EMT in a miR-1271 dependent manner. Furthermore, ERα transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2. CONCLUSIONS: Our data uncover the ERα-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-ß network in breast cancer progression.

Combined treatment of sodium ferulate, n-butylidenephthalide, and ADSCs rehabilitates neurovascular unit in rats after photothrombotic stroke.

The remodelling of structural and functional neurovascular unit (NVU) becomes a central therapeutic strategy after cerebral ischaemic stroke. In the present study, we investigated the effect of combined therapy of sodium ferulate (SF), n-butylidenephthalide (BP) and adipose-derived stromal cells (ADSCs) to ameliorate the injured NVU in the photochemically induced thrombotic stroke in rats. After solely or combined treatment, the neovascularization, activation of astrocytes, neurogenesis, expressions of vascular endothelial growth factor (VEGF) and claudin-5 were assessed by immunohistochemical or immunofluorescence staining. In order to uncover the underlying mechanism of therapeutic effect, signalling of protein kinase B/mammalian target of rapamycin (AKT/mTOR), extracellular signal-regulated kinase 1/2 (ERK1/2), and Notch1 in infarct zone were analysed by western blot. 18 F-2-deoxy-glucose/positron emission tomography, magnetic resonance imaging, Evans blue staining were employed to evaluate the glucose metabolism, cerebral blood flow (CBF), and brain-blood barrier (BBB) permeability, respectively. The results showed that combined treatment increased the neovascularization, neurogenesis, and VEGF secretion, modulated the astrocyte activation, enhanced the regional CBF, and glucose metabolism, as well as reduced BBB permeability and promoted claudin-5 expression, indicating the restoration of structure and function of NVU. The activation of ERK1/2 and Notch1 pathways and inhibition of AKT/mTOR pathway might be involved in the therapeutic mechanism. In summary, we have demonstrated that combined ADSCs with SF and BP, targeting the NVU remodelling, is a potential treatment for ischaemic stroke. These results may provide valuable information for developing future combined cellular and pharmacological therapeutic strategy for ischaemic stroke.

Oncoprotein HBXIP induces PKM2 via transcription factor E2F1 to promote cell proliferation in ER-positive breast cancer.

We have reported that hepatitis B X-interacting protein (HBXIP, also termed LAMTOR5) can act as an oncogenic transcriptional co-activator to modulate gene expression, promoting breast cancer development. Pyruvate kinase muscle isozyme M2 (PKM2), encoded by PKM gene, has emerged as a key oncoprotein in breast cancer. Yet, the regulatory mechanism of PKM2 is still unexplored. Here, we report that HBXIP can upregulate PKM2 to accelerate proliferation of estrogen receptor positive (ER+) breast cancer. Immunohistochemistry analysis using breast cancer tissue microarray uncovered a positive association between the expression of HBXIP and PKM2. We also discovered that PKM2 expression was positively related with HBXIP expression in clinical breast cancer patients by real-time PCR assay. Interestingly, in ER+ breast cancer cells, HBXIP was capable of upregulating PKM2 expression at mRNA and protein levels in a dose-dependent manner, as well as increasing the activity of PKM promoter. Mechanistically, HBXIP could stimulate PKM promoter through binding to the -779/-579 promoter region involving co-activation of E2F transcription factor 1 (E2F1). In function, cell viability, EdU, colony formation, and xenograft tumor growth assays showed that HBXIP contributed to accelerating cell proliferation through PKM2 in ER+ breast cancer. Collectively, we conclude that HBXIP induces PKM2 through transcription factor E2F1 to facilitate ER+ breast cancer cell proliferation. We provide new evidence for the mechanism of transcription regulation of PKM2 in promotion of breast cancer progression.

Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism.

Aspirin can efficiently inhibit liver cancer growth, but the mechanism is poorly understood. In this study, we report that aspirin modulates glucose uptake through downregulating glucose transporter 1 (GLUT1), leading to the inhibition of hepatoma cell proliferation. Our data showed that aspirin significantly decreased the levels of reactive oxygen species (ROS) and glucose consumption in hepatoma cells. Interestingly, we identified that GLUT1 and HIF1α could be decreased by aspirin. Mechanically, we demonstrated that the -1008/-780 region was the regulatory element of transcriptional factor NF-κB in GLUT1 promoter by luciferase report gene assays. PDTC, an inhibitor of NF-κB, could suppress the expression of GLUT1 in HepG2 and H7402 cells, followed by affecting the levels of ROS and glucose consumption. CoCl2-activated HIF1α expression could slightly rescue the GLUT1 expression inhibited by aspirin or PDTC, suggesting that aspirin depressed GLUT1 through targeting NF-κB or NF-κB/HIF1α signaling. Moreover, we found that GLUT1 was highly expressed in clinical HCC tissues relating to their paired adjacent normal tissues. Importantly, we observed that high level of GLUT1 was significantly correlated with the poor relapse-free survival of HCC patients by analysis of public data. Functionally, overexpression of GLUT1 blocked the PDTC-induced or aspirin-induced inhibition of glucose metabolism in HepG2 cells. Conversely, aspirin failed to work when GLUT1 was stably knocked down in the cells. Administration of aspirin could depress the growth of hepatoma cells through controlling GLUT1 in vitro and in vivo. Thus, our finding provides new insights into the mechanism by which aspirin depresses liver cancer.