Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy.

Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.

Chiral Skeletons of Mesoporous Silica Nanospheres to Mitigate Alzheimer's ß-Amyloid Aggregation.

Chiral mesoporous silica (mSiO2) nanomaterials have gained significant attention during the past two decades. Most of them show a topologically characteristic helix; however, little attention has been paid to the molecular-scale chirality of mSiO2 frameworks. Herein, we report a chiral amide-gel-directed synthesis strategy for the fabrication of chiral mSiO2 nanospheres with molecular-scale-like chirality in the silicate skeletons. The functionalization of micelles with the chiral amide gels via electrostatic interactions realizes the growth of molecular configuration chiral silica sols. Subsequent modular self-assembly results in the formation of dendritic large mesoporous silica nanospheres with molecular chirality of the silica frameworks. As a result, the resultant chiral mSiO2 nanospheres show abundant large mesopores (∼10.1 nm), high pore volumes (∼1.8 cm3·g-1), high surface areas (∼525 m2·g-1), and evident CD activity. The successful transfer of the chirality from the chiral amide gels to composited micelles and further to asymmetric silica polymeric frameworks based on modular self-assembly leads to the presence of molecular chirality in the final products. The chiral mSiO2 frameworks display a good chiral stability after a high-temperature calcination (even up to 1000 °C). The chiral mSiO2 can impart a notable decline in ß-amyloid protein (Aß42) aggregation formation up to 79%, leading to significant mitigation of Aß42-induced cytotoxicity on the human neuroblastoma line SH-ST5Y cells in vitro. This finding opens a new avenue to construct the molecular chirality configuration in nanomaterials for optical and biomedical applications.

Roles and regulation of histone acetylation in hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC) is the most frequent malignant tumor of the liver, but its prognosis is poor. Histone acetylation is an important epigenetic regulatory mode that modulates chromatin structure and transcriptional status to control gene expression in eukaryotic cells. Generally, histone acetylation and deacetylation processes are controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Dysregulation of histone modification is reported to drive aberrant transcriptional programmes that facilitate liver cancer onset and progression. Emerging studies have demonstrated that several HDAC inhibitors exert tumor-suppressive properties via activation of various cell death molecular pathways in HCC. However, the complexity involved in the epigenetic transcription modifications and non-epigenetic cellular signaling processes limit their potential clinical applications. This review brings an in-depth view of the oncogenic mechanisms reported to be related to aberrant HCC-associated histone acetylation, which might provide new insights into the effective therapeutic strategies to prevent and treat HCC.

Invention of a non-invasive intracranial pressure (ICP) monitoring system - an enlightenment from a hydrocephalus study.

BACKGROUND: Mechanical obstruction is the most common cause of shunt failure for hydrocephalic patients. However, the diagnosis is extremely challenging and often requires invasive testing methods. Thus, a simple and non-invasive technique is in urgent need to predict the intracranial pressure (ICP) of hydrocephalic patients during their post-surgical follow-up, which could help neurosurgeons to determine the conditions of the shunt system. MATERIALS AND METHODS: Two groups of patients were enrolled in the current study. In group I, patients were enrolled as they were diagnosed with high ICP hydrocephalus and received shunt surgery. The shunt valve pressures were taken for their post-surgical ICP. Meanwhile, the participants of group II exhibited abnormally increased lumbar puncture opening pressure (LPOP; from 180 to 400 mmH2O). Both the ICP and LPOP were used to match with their corresponding tympanic membrane temperature (TMT). RESULTS: When patients' ICP were in the normal range (group I, from 50 to 180 mmH2O), the TMT correlated with ICP in a linear regression model (R2 = 0.59, p < 0.001). Interestingly, when patients exhibited above-normal ICP (LPOP was from 180 to 400 mmH2O), their TMT fit well with the ICP in a third-order polynomial regression (R2 = 0.88). When the ICP was 287.98 mmH2O, the TMT approached the vertex, which was 38.54 °C. Based on this TMT-ICP algorithm, we invented a non-invasive ICP monitor system. Interestingly, a tight linear correlation was detected between the ICP data drawn from the non-invasive device and Codman ICP monitoring system (R2 = 0.93, p < 0.01). CONCLUSIONS: We believe the TMT-ICP algorithm (the Y-Jiang model) could be used for preliminary prediction of shunt malfunction as well as monitoring ICP changes.

Introduction of a Novel, Continuous, Noninvasive Estimation of Intracranial Pressure and Cerebral Perfusion Pressure Based on Tympanic Membrane Temperature.

OBJECTIVE: Hydrocephalus is a common but potentially life-threatening condition. However, valve malfunction makes further diagnosis difficult. Thus, we tried to develop a noninvasive method to detect the hydrocephalus intracranial pressure (ICP) during routine follow-up. METHODS: In group I, the patient was recruited because a spinal tap test was necessary for either disease diagnosis or treatment. In group II, patients were diagnosed with high ICP hydrocephalus and received shunt surgery. The tympanic membrane temperatures (TMTs) were recorded and plotted against the spinal tap pressure (STP) and shunt valve pressures. RESULTS: All patients in group I showed an above-normal STP (from 180 to 400 mm H2O). The STP presents with an inverted U-shaped curve when it is plotted against TMT (R2 = 0.9). When the STP was 286.1 mm H2O, the TMT approached its peak value, which was 38.61°C (101.5°F). However, when ICP was in the normal range (50-200 mm H2O), the TMT correlated with ICP in a linear regression model (R2 = 0.69; P < 0.001). In addition, the cerebral perfusion pressure (CPP) was calculated and plotted against TMT. The TMT-CPP was also shown as a parabola (R2 = 0.74). Based on the TMT-ICP algorithm, we invented a noninvasive ICP monitor system, which performs in a manner comparable to the Codman ICP Transducer (R2 = 0.9; P < 0.01). CONCLUSIONS: Both Y-Jiang TMT-ICP and TMT-CPP algorithms are useful to monitor the shunt outcomes and identify potential shunt failure. More importantly, these algorithms open the possibility for the rational acquisition of ICP and CPP noninvasively.

Machine learning predictive models for acute pancreatitis: A systematic review.

INTRODUCTION: Acute pancreatitis (AP) is a common clinical pancreatic disease. Patients with different severity levels have different clinical outcomes. With the advantages of algorithms, machine learning (ML) has gradually emerged in the field of disease prediction, assisting doctors in decision-making. METHODS: A systematic review was conducted using the PubMed, Web of Science, Scopus, and Embase databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Publication time was limited from inception to 29 May 2021. Studies that have used ML to establish predictive tools for AP were eligible for inclusion. Quality assessment of the included studies was conducted in accordance with the IJMEDI checklist. RESULTS: In this systematic review, 24 of 2,913 articles, with a total of 8,327 patients and 47 models, were included. The studies could be divided into five categories: 10 studies (42%) reported severity prediction; 10 studies (42%), complication prediction; 3 studies (13%), mortality prediction; 2 studies (8%), recurrence prediction; and 2 studies (8%), surgery timing prediction. ML showed great accuracy in several prediction tasks. However, most of the included studies were retrospective in nature, conducted at a single centre, based on database data, and lacked external validation. According to the IJMEDI checklist and our scoring criteria, two studies were considered to be of high quality. Most studies had an obvious bias in the quality of data preparation, validation, and deployment dimensions. CONCLUSION: In the prediction tasks for AP, ML has shown great potential in assisting decision-making. However, the existing studies still have some deficiencies in the process of model construction. Future studies need to optimize the deficiencies and further evaluate the comparability of the ML systems and model performance, so as to consequently develop high-quality ML-based models that can be used in clinical practice.

Anatomic versus non-anatomic resection of hepatocellular carcinoma with microvascular invasion: A systematic review and meta-analysis.

The efficacy of anatomical resection (AR) and non-anatomical resection (NR) in the treatment of hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) remains unknown. This study compared the safety and outcomes of these surgical procedures. A systematic literature search was conducted. The main outcomes were overall survival (OS), disease-free survival (DFS). Overall hazard ratio (HR) was calculated from Kaplan-Meier plots and outcomes using random-effects models. There was no significant difference in postoperative complications between the AR and NR groups (risk ratio [RR]: 0.92, 95% confidence interval [CI]: 0.72-1.17, p = 0.496). OS was higher with AR at 1 year (RR: 0.66, 95% CI: 0.45-0.98, p = 0.037), 3 years (RR: 0.64, 95% CI: 0.50-0.82, p = 0.000), and 5 years (RR: 0.76, 95% CI: 0.65-0.89, p = 0.001). AR was associated with a higher OS rate (HR: 0.62, 95% CI: 0.47-0.82, p = 0.001). AR was associated with improved DFS at 1 year (RR: 0.65, 95% CI: 0.52 to 0.82, p = 0.000), 3 years (RR: 0.75, 95% CI: 0.66 to 0.86, p = 0.000), and 5 years (95% CI: 0.75 to 0.94, p = 0.002). Compared with NR, AR had significant advantages on overall HR of DFS (HR: 0.64, 95% CI: 0.45 to 0.91, p = 0.012). In conclusion, AR was associated with higher rates of OS and DFS in HCC patients with MVI. Thus, for well-presented liver function HCC patients which are predicted to have positive MVI, AR is recommended.

Mesenchymal stem cells ameliorate lipid metabolism through reducing mitochondrial damage of hepatocytes in the treatment of post-hepatectomy liver failure.

Hepatectomy is an effective therapeutic strategy for many benign and malignant liver diseases, while the complexity of liver anatomy and the difficulty of operation lead to complications after hepatectomy. Among them, post-hepatectomy liver failure (PHLF) is the main factor threatening the life of patients. At present, liver transplantation is an effective approach for PHLF. However, the application of liver transplantation has been largely limited due to the shortage of donors and the high cost of such operation. Therefore, it is urgently necessary to develop a new treatment for PHLF. Mesenchymal stem cells (MSCs) have become a new treatment regimen for liver diseases because of their easy access and low immunogenicity. Our study found that there were some subtle connections between MSCs and liver lipid metabolism in the PHLF model. We used MSC transplantation to treat PHLF induced by 90% hepatectomy. MSC transplantation could restore the mitochondrial function, promote the ß-oxidation of fatty acid (FA), and reduce the lipid accumulation of hepatocytes. In addition, interleukin 10 (IL-10), a cytokine with immunoregulatory function, had an important role in lipid metabolism. We also found that MSCs transplantation activated the mammalian target of rapamycin (mTOR) pathway. Therefore, we explored the relationship between mitochondrial damage and lipid metabolism abnormality or PHLF. MSCs improved mitochondrial function and corrected abnormal lipid metabolism by affecting the mTOR pathway in the treatment of PHLF. Collectively, MSC transplantation could be used as a potential treatment for PHLF.

Comprehensive Pan-Cancer Genomic Analysis Reveals PHF19 as a Carcinogenic Indicator Related to Immune Infiltration and Prognosis of Hepatocellular Carcinoma.

Background: As a crucial constituent part of Polycomb repressive complex 2, PHD finger protein 19 (PHF19) plays a pivotal role in epigenetic regulation, and acts as a critical regulator of multiple pathophysiological processes. However, the exact roles of PHF19 in cancers remain enigmatic. The present research was primarily designed to provide the prognostic landscape visualizations of PHF19 in cancers, and study the correlations between PHF19 expression and immune infiltration characteristics in tumor microenvironment. Methods: Raw data in regard to PHF19 expression were extracted from TCGA and GEO data portals. We examined the expression patterns, prognostic values, mutation landscapes, and protein-protein interaction network of PHF19 in pan-cancer utilizing multiple databases, and investigated the relationship of PHF19 expression with immune infiltrates across TCGA-sequenced cancers. The R language was used to conduct KEGG and GO enrichment analyses. Besides, we built a risk-score model of hepatocellular carcinoma (HCC) and validated its prognostic classification efficiency. Results: On balance, PHF19 expression was significantly higher in cancers in comparison with that in noncancerous samples. Increased expression of PHF19 was detrimental to the clinical prognoses of cancer patients, especially HCC. There were significant correlations between PHF19 expression and TMB or MSI in several cancers. High PHF19 levels were critically associated with the infiltration of myeloid-derived suppressor cells (MDSCs) and Th2 subsets of CD4+ T cells in most cancers. Enrichment analyses revealed that PHF19 participated in regulating carcinogenic processes including cell cycle and DNA replication, and was correlated with the progression of HCC. Intriguingly, GSEA suggested that PHF19 was correlated with the cellular components including immunoglobulin complex and T cell receptor complex in HCC. Based on PHF19-associated functional gene sets, an eleven-gene prognostic signature was constructed to predict HCC prognosis. Finally, we validated pan-cancer PHF19 expression, and its impacts on immune infiltrates in HCC. Conclusion: The epigenetic related regulator PHF19 participates in the carcinogenic progression of multiple cancers, and may contribute to the immune infiltration in tumor microenvironment. Our study suggests that PHF19 can serve as a carcinogenic indicator related to prognosis in pan-cancer, especially HCC, and shed new light on therapeutics of cancers for clinicians.

Puerarin protects against high-fat high-sucrose diet-induced non-alcoholic fatty liver disease by modulating PARP-1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis.

As yet, there was no effective pharmacological therapy approved for non-alcoholic fatty liver disease (NAFLD). Here, we aimed to evaluate the therapeutic potential of puerarin against NAFLD and explored the underlying mechanisms. C57BL/6J mice were fed with a high-fat high-sucrose (HFHS) diet with or without puerarin coadministration intragastrically. The levels of hepatocellular injury, steatosis, fibrosis, and mitochondrial and metabolism alteration were detected. First, puerarin ameliorated histopathologic abnormalities due to HFHS. We observed a marked increase in hepatic lipid content, inflammation, and fibrosis level, which were attenuated by puerarin. Possible mechanisms were related to puerarin-mediated activation of PI3K/AKT pathway and further improvement in fatty acid metabolism. Puerarin restored the NAD+ content and beneficially affected the hepatic mitochondrial function, which attenuated HFHS-induced steatosis and metabolic disturbances. Finally, hepatic PARP-1 was activated due to excessive fat intake. Puerarin attenuated the PARP-1 expression in HFHS-fed mice, and PJ34, the PARP inhibitor, could mimic these protections of puerarin. However, pharmacological inhibition of PI3K disabled the protection of puerarin or PJ34 toward NAD+ refilling and mitochondrial homeostasis. In conclusion, our findings indicated that puerarin could be a promising and practical therapeutic strategy in NAFLD through modulating PARP-1/PI3K/AKT signaling pathway and further facilitating mitochondrial function.

Mesenchymal Stem Cells Improve Glycometabolism and Liver Regeneration in the Treatment of Post-hepatectomy Liver Failure.

BACKGROUND: The mortality rate of post-hepatectomy liver failure (PHLF) remains very high, and liver transplantation is the only effective treatment regimen for PHLF. Cell transplantation is a potential treatment for liver diseases. Previous studies have proved that mesenchymal stem cells (MSCs) have immunomodulatory functions. In the present study, we found that MSCs promoted glycogen synthesis and liver regeneration in the treatment of PHLF. MSC transplantation also improved the survival rate of rats after 90% partial hepatectomy (PH). In our current study, we aimed to determine the efficacy and mechanism of MSC transplantation in the treatment of PHLF. METHODS: Mesenchymal stem cells were isolated from Sprague-Dawley rats and cultured using a standardized protocol. The MSCs were transplanted to treat acute liver failure induced by 90% PH. The therapeutic efficacy of MSCs on PHLF was verified through measuring alanine transaminase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), serum ammonia, liver weight to body weight ratio, blood glucose, and histology. To further study the mechanism of MSC transplantation in treatment for PHLF, we assessed the changes in the AKT/glycogen synthase kinase-3ß (GSK-3ß)/ß-catenin pathway. A-674563 (AKT inhibitor) and SB216763 (GSK-3ß inhibitor) were employed to validate our findings. SPSS version 19.0 was used for statistical analysis, and the independent-samples t-test was carried out to analyze the collected data. RESULTS: Mesenchymal stem cell transplantation attenuated the liver injury in acute liver failure induced by 90% PH. MSC transplantation improved the glucose metabolism and survival rate in the PHLF model. The effect of MSC transplantation on hepatocyte proliferation might be related to AKT/GSK-3ß/ß-catenin pathway. CONCLUSION: Mesenchymal stem cell transplantation could be use as a potential treatment for PHLF.

Identification of a novel and heterozygous LMF1 nonsense mutation in an acute pancreatitis patient with severe hypertriglyceridemia, severe obesity and heavy smoking.

BACKGROUND: Hypertriglyceridemia (HTG) is one of the most common etiologies of acute pancreatitis (AP). Variants in five genes involved in the regulation of plasma lipid metabolism, namely LPL, APOA5, APOC2, GPIHBP1 and LMF1, have been frequently reported to cause or predispose to HTG. METHODS: A Han Chinese patient with HTG-induced AP was assessed for genetic variants by Sanger sequencing of the entire coding and flanking sequences of the above five genes. RESULTS: The patient was a 32-year-old man with severe obesity (Body Mass Index = 35) and heavy smoking (ten cigarettes per day for more than ten years). At the onset of AP, his serum triglyceride concentration was elevated to 1450.52 mg/dL. We sequenced the entire coding and flanking sequences of the LPL, APOC2, APOA5, GBIHBP1 and LMF1 genes in the patient. We found no putative deleterious variants, with the exception of a novel and heterozygous nonsense variant, c.1024C > T (p.Arg342*; rs776584760), in exon 7 of the LMF1 gene. CONCLUSIONS: This is the first time that a heterozygous LMF1 nonsense variant was found in a HTG-AP patient with severe obesity and heavy smoking, highlighting an important interplay between genetic and lifestyle factors in the etiology of HTG.

Mesenchymal stem cells increase heme oxygenase 1-activated autophagy in treatment of acute liver failure.

In recent years, transplantation of mesenchymal stem cells (MSCs) has attracted much attention as a potential cell-based therapy for acute liver failure (ALF). As an inducible enzyme, heme oxygenase 1 (HO-1) has been reported to have cytoprotective, anti-apoptotic and immunoregulatory effects. Autophagy, a conserved catabolic process in cells, may be an important pathway for MSCs to treat ALF. In this study, we aimed to explore whether MSCs treat ALF by regulating autophagy and whether HO-1 was involved in the same pathway. Bone marrow-derived MSCs were isolated from Sprague-Dawley rats and cultured according to an established protocol. Co-culture systems of MSCs and hepatocytes were used to assess autophagy in the treatment of ALF. Meanwhile, MSCs were transplanted into rats with d-galactosamine (Gal)-induced ALF. Autophagy inhibitor (3-methyladenine, 3-MA), HO-1 inhibitor (zinc protoporphyrin, ZnPP) and PI3K specific inhibitor (LY294002) were employed in the study. Blood samples and liver tissues were collected before euthanasia. Survival rate, liver function, inflammatory factors, histology, Ki67 and TUNEL staining were determined. MSCs transplantation alleviated ALF both in vivo and in vitro. Autophagy and autophagy-related proteins were significantly up-regulated during MSCs treatment. 3-MA attenuated the therapeutic effect of MSCs. Administration of LY294002 before ALF induction inhibited hepatocyte autophagy. During the MSCs treatment, the HO-1 expression was increased, while inhibiting HO-1 attenuated the therapeutic effect of MSCs as well as hepatocyte autophagy. These findings suggested MSCs could alleviate ALF by increasing the HO-1 expression, which played an important role in activating autophagy through PI3K/AKT signaling pathway.

Delivery of MTH1 inhibitor (TH287) and MDR1 siRNA via hyaluronic acid-based mesoporous silica nanoparticles for oral cancers treatment.

Oral cancer accounts for 95% of all maxillofacial malignant neoplasm. Presently, surgery and radiation (with and without chemotherapy) are the major treatments for oral cancer; however it met with limited therapeutic outcome. Overcoming the multidrug resistance and finding new therapeutic agents for oral cancer treatment are some of the serious challenges. Small molecule, TH287 potently and selectively inhibits the MTH1 protein in cells and could act as a new chemotherapeutic agent. The study reports the successful loading and delivery of MTH1 inhibitor - TH287 and MDR1 siRNA in oral squamous cell carcinoma. Our results showed that HA-assembled mesoporous silica nanoparticles were effective in controlling the drug release and internalization in CAL27 cancer cells. Cytotoxicity and apoptosis assay showed that combination of TH287 + MDR1 siRNA was significantly more effective in inducing the anticancer effect compared to that of TH287 (MTH1 inhibitor) alone. SiTMSN and HA-siTMSN significantly reduced the tumor burden compared to that of untreated control and free TH287. The study strongly supports the fact that the HA-siTMSN plays dual of inhibiting the MDR1 function and enhancing the cell killing effect of TH287 in the cancer tissues. Overall, results suggest that the HA-siTMSN platform is a promising vector the systemic delivery of MDR1 siRNA/TH287 and combinational therapeutics could be a viable solution for treatment of cancer of oral cavity.

Sorafenib inhibits caspase-1 expression through suppressing TLR4/stat3/SUMO1 pathway in hepatocellular carcinoma.

Sorafenib has been demonstrated to be a beneficial treatment for advanced hepatocellular carcinoma (HCC). Emerging evidence indicates that caspase-1 activation plays a crucial role in HCC progression. However, the relationship between caspase-1 and sorafenib has rarely been reported. In this study, we showed that caspase-1 was essential for lipopolysaccharide (LPS)-induced epithelial-mesenchymal transition (EMT). Moreover, sorafenib treatment could inhibit LPS-stimulated caspase-1 overexpression through restricting the nuclear transport of p65, which contributed to inactivation of NF-κB. Co-immunoprecipitation (Co-IP) experiments and immunoblot analysis indicated that sorafenib treatment decreased the SUMOylation of p65 via inhibiting TLR4/stat3/SUMO1 signaling cascades. In conclusion, the results of this study suggest that sorafenib inhibits caspase-1 expression through suppressing the nuclear translocation of p65 and provide new insights into the mechanisms of sorafenib treatment in HCC.

BM­MSCs protect against liver ischemia/reperfusion injury via HO­1 mediated autophagy.

Ischemia/reperfusion (I/R) injury is considered to be a contributing factor in liver injury following major hepatic resection or liver transplantation. Bone marrow mesenchymal stem cells (BM­MSCs) have the potential to protect against liver I/R injury; however, the precise mechanisms have not been completely elucidated. Autophagy serves an important role in protecting against various injuries, including I/R injury. The present study aimed to determine the role of autophagy and its potential regulatory mechanism in BM­MSC­mediated protection against liver I/R injury in rats. The results demonstrated that BM­MSCs mitigated I/R injury and enhanced autophagy in vivo. In addition, inhibition of autophagy by 3­methyladenine reversed the positive effects of BM­MSCs. Furthermore, heme oxygenase­1 (HO­1) expression was promoted by BM­MSCs. Using zinc protoporphyrin IX to inhibit HO­1 demonstrated that HO­1 was important for the promotion of autophagy. In conclusion, the present study revealed that BM­MSCs protected against liver I/R injury via the promotion of HO­1­mediated autophagy.

Rage induces hepatocellular carcinoma proliferation and sorafenib resistance by modulating autophagy.

The receptor for advanced glycation end products (Rage) is involved in the development of various tumors and acts as an oncogenic protein. Rage is overexpressed in tumors including hepatocellular carcinoma (HCC). However, the molecular mechanism of Rage in HCC progression and sorafenib resistance remains unclear. In this study, enhanced Rage expression is highly associated proliferation and contributes to sorafenib resistance. Rage deficiency contributed to autophagy induction through activating AMPK/mTOR signaling pathway, which is important for sorafenib response. Moreover, the interactions between Rage and Rage ligands such as high mobility group box 1 (HMGB1) and s100a4 positively increased Rage expression. Our data indicate that Rage may be a potential target for therapeutic intervention in HCC and biomarker for sorafenib resistance.

PARP-1 promotes tumor recurrence after warm ischemic liver graft transplantation via neutrophil recruitment and polarization.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a crucial contributor to exacerbate ischemia and reperfusion (IR) injury and cancer process. However, there is little research into whether PARP-1 affects the hepatocellular carcinoma (HCC) recurrence after liver transplantation. In this study, we investigated the influence of PARP-1 on hepatic neutrophil mobilizing and phenotype shifting which may lead to HCC recurrence after liver transplantation. We found that rats received the grafts with warm ischemic injury had higher risk of HCC recurrence, which was markedly prevented by pharmacological inhibition of PARP-1 after liver transplantation. In mouse models, the up-regulation of PARP-1 was closely related to the greater tumor burden and increased hepatic susceptibility to recurrence after IR injury. The reason was that high hepatic PARP-1 led to increased liver CXCL1 levels, which in turn promoted recruitment of neutrophils. Both blocking CXCL1/CXCR2 signaling pathway and depleting neutrophils decreased tumor burden. Moreover, these infiltrating neutrophils were programmed to a proangiogenic phenotype under the influence of PARP-1 in vivo after hepatic IR injury. In conclusion, IR-induced PARP-1 up-regulation increased the hepatic recruitment of neutrophils through regulation of CXCL1/CXCR2 signaling and polarized hepatic neutrophils to proangiogenic phenotype, which further promoted HCC recurrence after transplantation.

Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure.

BACKGROUND: Mesenchymal stem cells (MSCs) have been studied for the treatment of acute liver failure (ALF) for several years. MSCs may exert their effect via complex paracrine mechanisms. Heme oxygenase (HO) 1, a rate-limiting enzyme in heme metabolism, exerts a wide range of anti-inflammatory, anti-apoptotic and immunoregulatory effects in a variety of diseases. However, the relationship between MSCs and HO-1 in the treatment of ALF is still unclear. We investigated the preventive and therapeutic potential of intravenously administered BMSCs. METHODS: Bone marrow-derived mesenchymal stem cells (BMSCs) obtained from Sprague-Dawley rats were isolated and cultured. We employed BMSCs, hemin (a HO-1 inducer) and zinc protoporphyrin (ZnPP, the HO-1 activity inhibitor) in D-galactosamine (D-Gal)/lipopolysaccharides (LPS)-induced ALF rats. Rats were sacrificed at days 1, 3, 5, and 7 post-transfusion, respectively. Blood samples and liver tissues were collected. Hepatic injury, HO-1 activity, chemokines, inflammatory cytokines, the number and oxidative activity of neutrophils, ki67, and TUNEL-positive cells were evaluated. RESULTS: HO-1 induction or BMSCs transplantation attenuated D-galactosamine/lipopolysaccharide-induced increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin (TBIL), ammonia, and inflammatory cytokines. Treatment with hemin or BMSCs also inhibited neutrophil infiltration, oxidative activity, and hepatocyte apoptosis. The protective effect of BMSCs was partially neutralized by ZnPP, suggesting the key role of HO-1 in the process. CONCLUSIONS: These findings may correlate with inhibition of nuclear factor-κ B activation. BMSCs ameliorated ALF by increasing the HO-1 expression, which reduced PMN infiltration and function, and played an important anti-inflammatory and anti-apoptotic role. Proposed mechanism by which BMSCs reduce inflammation, neutrophil activation, and hepatocyte apoptosis and promote hepatocyte proliferation via HO-1. BMSCs increase HO-1 expression in liver via Nrf2. HO-1 protects against LPS/D-Gal-induced ALF by inhibiting neutrophil infiltration and inflammatory burst, and hepatocyte apoptosis and necrosis. HO-1 also promotes hepatocyte proliferation.

Prostate cancer antigen 3 moderately improves diagnostic accuracy in Chinese patients undergoing first prostate biopsy.

Prostate cancer antigen 3 (PCA3) is a biomarker for diagnosing prostate cancer (PCa) identified in the Caucasian population. We evaluated the effectiveness of urinary PCA3 in predicting the biopsy result in 500 men undergoing initial prostate biopsy. The predictive power of the PCA3 score was evaluated by the area under receiver operating characteristic (ROC) curve (AUC) and by decision curve analysis. PCA3 score sufficed to discriminate positive from negative prostate biopsy results but was not correlated with the aggressiveness of PCa. The ROC analysis showed a higher AUC for the PCA3 score than %fPSA (0.750 vs 0.622, P = 0.046) in patients with a PSA of 4.0-10.0 ng ml-1 , but the PCA3-based model is not significantly better than the base model. Decision curve analysis indicates the PCA3-based model was superior to the base model with a higher net benefit for almost all threshold probabilities, especially the threshold probabilities of 25%-40% in patients with a PSA of 4.0-10.0 ng ml-1 . However, the AUC of the PCA3 score (0.712) is not superior to %fPSA (0.698) or PSAD (0.773) in patients with a PSA >10.0 ng ml-1 . Our results confirmed that the RT-PCR-based PCA3 test moderately improved diagnostic accuracy in Chinese patients undergoing first prostate biopsy with a PSA of 4.0-10.0 ng ml-1 .