Induction chemotherapy regimes in first-line treatment for locoregionally advanced nasopharyngeal carcinoma: A network meta-analysis and cost-effectiveness analysis.

OBJECTIVE: The aim of this study is to evaluate the efficacy and cost-effectiveness of various induction chemotherapy (IC) regimens as first-line treatment for Locoregionally advanced nasopharyngeal carcinoma (LA-NPC), aiming to provide clinicians and patients with informed insights to aid in treatment decision-making. PATIENTS AND METHODS: We conducted a network meta-analysis (NMA) and cost-effectiveness analysis (CEA) based on data from 10 clinical trials investigating IC regimens for the treatment of LA-NPC. A Bayesian NMA was performed, with the primary outcomes being hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS). To model the disease progression of LA-NPC, we developed a dynamic partitioned survival model consisting of three disease states: progression-free survival (PFS), progression disease (PD), and death. The model was run on a 3-week cycle for a research period of 10 years, with quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) serving as outcome measures. RESULTS: According to the surface under the cumulative ranking curve (SUCRA) estimates derived from the NMA, TPC and TP, as IC regimens, appear to exhibit superior efficacy compared to other treatment modalities. In terms of CEA, concurrent chemoradiotherapy (CCRT), TPF + CCRT, and GP + CCRT were found to be dominated (more costs and less QALYs). Comparatively, TPC + CCRT emerged as a cost-effective option with an ICER of $1260.57/QALY when compared to PF + CCRT. However, TP + CCRT demonstrated even greater cost-effectiveness than TPC + CCRT, with an associated increase in costs of $3300.83 and an increment of 0.1578 QALYs per patient compared to TPC + CCRT, resulting in an ICER of $20917.62/QALY. CONCLUSION: Based on considerations of efficacy and cost-effectiveness, the TP + CCRT treatment regimen may emerge as the most favorable first-line therapeutic approach for patients with LA-NPC.

A probe for NIR-II imaging and multimodal analysis of early Alzheimer's disease by targeting CTGF.

To date, earlier diagnosis of Alzheimer's disease (AD) is still challenging. Recent studies revealed the elevated expression of connective tissue growth factor (CTGF) in AD brain is an upstream regulator of amyloid-beta (Aß) plaque, thus CTGF could be an earlier diagnostic biomarker of AD than Aß plaque. Herein, we develop a peptide-coated gold nanocluster that specifically targets CTGF with high affinity (KD ~ 21.9 nM). The probe can well penetrate the blood-brain-barrier (BBB) of APP/PS1 transgenic mice at early-stage (earlier than 3-month-old) in vivo, allowing non-invasive NIR-II imaging of CTGF when there is no appearance of Aß plaque deposition. Notably, this probe can also be applied to measuring CTGF on postmortem brain sections by multimodal analysis, including fluorescence imaging, peroxidase-like chromogenic imaging, and ICP-MS quantitation, which enables distinguishment between the brains of AD patients and healthy people. This probe possesses great potential for precise diagnosis of earlier AD before Aß plaque formation.

A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

The current standard treatment for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) comprises concurrent radiotherapy (CRT) alongside platinum-based chemotherapy. However, innovative therapeutic alternatives are being evaluated in phase II/III randomized trials. This study employed a Bayesian network meta-analysis (NMA) using fixed effects to provide both direct and indirect comparisons of all existing treatment modalities for unresectable LASCCHN. METHODS: We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. RESULTS: Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. CONCLUSION: Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

The current standard treatment for advanced head and neck cancer involves combining radiation therapy with chemotherapy. However, there are ongoing trials exploring alternative therapies. In this study, we conducted a comprehensive analysis of existing treatments using a statistical method called network meta-analysis. Our analysis included data from randomized controlled trials published between January 2000 and July 2023. We focused on overall survival and progression-free survival as key outcome measures. The results of our analysis showed that none of the alternative treatments demonstrated significant advantages over the standard concurrent chemoradiotherapy. Nevertheless, there is potential for improved outcomes when targeted therapy or induction chemotherapy is combined with concurrent chemoradiotherapy.

Comamonas endophytica sp. nov., a novel indole acetic acid producing endophyte isolated from bamboo in China.

Two novel indole acetic acid-producing strains, 5MLIRT and D4N7, were isolated from Indosasa shibataeoides in Yongzhou, Hunan province, and Phyllostachys edulis in Hangzhou, Zhejiang province, respectively. Based on their 16S rRNA sequences, strains 5MLIRT and D4N7 were closely related to Comamonas antarcticus 16-35-5T (98.4 % sequence similarity), and the results of 92-core gene phylogenetic trees showed that strains 5MLIRT and D4N7 formed a phylogenetic lineage within the clade comprising Comamonas species. The complete genome size of strain 5MLIRT was 4.49 Mb including two plasmids, and the DNA G+C content was 66.5 mol%. The draft genome of strain D4N7 was 4.26 Mb with 66.7 mol% G+C content. The average nucleotide identity and digital DNA-DNA hybridization values among strain 5MLIRT and species in the genus Comamonas were all below the species delineation threshold. The colonies of strain 5MLIRT and D4N7 were circular with regular margins, convex, pale yellow and 1.0-2.0 mm in diameter when incubated at 30 °C for 3 days. Strains 5MLIRT and D4N7 grew optimally at 30 °C, pH 7.0 and 1.0 % NaCl. The respiratory isoprenoid quinone was ubiquinone-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Polyphasic analyses indicated that strains 5MLIRT and D4N7 could be distinguished from related validly named Comamonas species and represent a novel species of the genus Comamonas, for which the name Comamonas endophytica sp. nov. is proposed. The type strain is 5MLIRT (=ACCC 62069T=GDMCC 1.2958T=JCM 35331T).

Characterization of color variation in bamboo sheath of Chimonobambusa hejiangensis by UPLC-ESI-MS/MS and RNA sequencing.

BACKGROUND: Chimonobambusa hejiangensis (C.hejiangensis) is a high-quality bamboo species native to China, known for its shoots that are a popular nutritional food. Three C.hejiangensis cultivars exhibit unique color variation in their shoot sheaths, however, the molecular mechanism behind this color change remains unclear. METHODS: We investigated flavonoid accumulation in the three bamboo cultivar sheaths using metabolomics and transcriptomics. RESULTS: UPLC-MS/MS identified 969 metabolites, with 187, 103, and 132 having differential accumulation in the yellow-sheath (YShe) vs. spot-sheath (SShe)/black-sheath (BShe) and SShe vs. BShe comparison groups. Flavonoids were the major metabolites that determined bamboo sheath color through differential accumulation of metabolites (DAMs) analysis. Additionally, there were 33 significantly differentially expressed flavonoid structural genes involved in the anthocyanin synthesis pathway based on transcriptome data. We conducted a KEGG analysis on DEGs and DAMs, revealing significant enrichment of phenylpropanoid and flavonoid biosynthetic pathways. Using gene co-expression network analysis, we identified nine structural genes and 29 transcription factors strongly linked to anthocyanin biosynthesis. CONCLUSION: We identified a comprehensive regulatory network for flavonoid biosynthesis which should improve our comprehension of the molecular mechanisms responsible for color variation and flavonoid biosynthesis in bamboo sheaths.

A MRI-based radiomics model for predicting the response to anlotinb combined with temozolomide in recurrent malignant glioma patients.

OBJECTIVE: Anlotinib is a multitarget anti-angiogenic drug that combined with temozolomide (TMZ) can effectively prolongs the overall survival (OS) of recurrent malignant glioma(rMG),but some patients do not respond to anlotinib combined with TMZ. These patients were associated with a worse prognosis and lack effective identification methods. Therefore, it is necessary to differentiate patients who may have good response to anlotinb in combination with TMZ from those who are not, in order to provide personalized targeted therapies. METHODS: Fifty three rMG patients (42 in training cohort and 11 in testing cohort) receiving anlotinib combined with TMZ were enrolled. A total of 3668 radiomics features were extracted from the recurrent MRI images. Radiomics features are reduced and filtered by hypothesis testing and Least Absolute Shrinkage And Selection (LASSO) regression. Eight machine learning models construct the radiomics model, and then screen out the optimal model. The performance of the model was assessed by its discrimination, calibration, and clinical usefulness with validation. RESULTS: Fifty three patients with rMG were enrolled in our study. Thirty four patients displayed effective treatment response, showed a higher survival benefits than non-response group, the median progression-free survival(PFS) was 8.53 months versus 5.33 months (p = 0.06) and the median OS was 19.9 months and 7.33 months (p = 0.029), respectively. Three radiomics features were incorporated into the model construction as final variables after LASSO regression analysis. In testing cohort, Logistic Regression (LR) model has the best performance with an Area Under the Curve (AUC) of 0.93 compared with other models, which can effectively predict the response of rMG patients to anlotinib in combination with TMZ. The calibration curve confirmed the agreement between the observed actual and prediction probability. Within the reasonable threshold probability range (0.38-0.88), the radiomics model shows good clinical utility. CONCLUSIONS: The above-described radiomics model performed well, which can serve as a clinical tool for individualized prediction of the response to anlotinb combined with TMZ in rMG patients.

MRI-based clinical radiomics nomogram may predict the early response after concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma.

Objective: Tumor residue after concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients often predicts poor prognosis. Thus, the objective of this retrospective study is to develop a nomogram that combines magnetic resonance (MRI) radiomics features and clinical features to predict the early response of locally advanced nasopharyngeal carcinoma (LA-NPC). Methods: A total of 91 patients with LA-NPC were included in this study. Patients were randomly divided into training and validation cohorts at a ratio of 3:1. Univariate and multivariate analyses were performed on the clinical parameters of the patients to select clinical features to build a clinical model. In the training cohort, the Least Absolute Shrinkage and Selection Operator (LASSO) regression model was used to select radiomics features for construction of a radiomics model. The logistic regression algorithm was then used to combine the clinical features with the radiomics features to construct the clinical radiomics nomogram. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were drawn to compare and verify the predictive performances of the clinical model, radiomics model, and clinical radiomics nomogram. Results: Platelet lymphocyte ratio (PLR) and nasopharyngeal tumor volume were identified as independent predictors of early response in patients with locally advanced nasopharyngeal carcinoma. A total of 5502 radiomics features were extracted, from which 25 radiomics features were selected to construct the radiomics model. The clinical radiomics nomogram demonstrated the highest AUC in both the training and validation cohorts (training cohort 0.975 vs 0.973 vs 0.713; validation cohort 0.968 vs 0.952 vs 0.706). The calibration curve and DCA indicated good predictive performance for the nomogram. Conclusion: A clinical radiomics nomogram, which combines clinical features with radiomics features based on MRI, can predict early tumor regression in patients with LA-NPC. The performance of the nomogram is superior to that of either the clinical model or radiomics model alone. Therefore, it can be used to identify patients without CR at an early stage and provide guidance for personalized therapy.

[Retracted] MicroRNA­199a­3p inhibits ovarian cancer cell viability by targeting the oncogene YAP1.

Following the publication of the above article, the authors have submitted a request that it be retracted on account of the fact that, when requested to do so, the first author was unable to provide the original data for this article. The Editor of Molecular Medicine Reports has agreed with the request that this article be retracted. Note that all the authors agree with the decision to retract this article. The Editor and the authors regret any inconvenience that this retraction will cause to the readership of the Journal. [Molecular Medicine Reports 23: 237, 2021; DOI: 10.3892/mmr.2021.11876].

Massilia phyllostachyos sp. nov., Isolated from the Roots of Moso Bamboo in China.

A Gram-negative, strictly aerobic, motile, and rod-shaped bacterial strain G4R7T was isolated from the roots of moso bamboo (Phyllostachys edulis) in Zhejiang, Hangzhou Province, China. After comparing 16S rRNA gene sequences, strain G4R7T exhibited the highest similarities with Massilia neuiana PTW21T (98.3%), followed by M. agri K-3-1T (98.3%), M. consociate CCUG 58010T (97.7%), M. niastensis 5516S-1T (97.7%) and M. yuzhufengensis ZD1-4T (97.6%). The phylogenetic analysis revealed that strain G4R7T belonged to the genus Massilia. The draft genome of strain G4R7T was 5.81 Mb, and the G+C content was 64.4%. The average nucleotide identity values between G4R7T and another related member of the genus Massilia ranged from 76.6 to 87.2%, and the digital DNA-DNA hybridization ranged from 20.7 to 27.9%. Strain G4R7T grew at 15-37 °C (optimum 25-30 °C) and pH 6.0-9.0 (optimum pH 7.0) in the presence of 0-3% (w/v) NaCl (optimum 0%). The respiratory quinone was Q-8, and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, and aminophospholipid. The major cellular fatty acids were C10:0 3OH, C12:0, C12:0 2OH, and C16:0, summed feature 3 (C16:1 ω6c and/or C16:1 ω7c). As per the data from chemotaxonomic, phylogenetic, and phenotypic evidence, strain G4R7T represents a new species of genus Massilia, for which the name Massilia phyllostachyos sp. nov. is proposed. The type strain is G4R7T (=ACCC 61911T=GDMCC 1.2961T=JCM 35225T).

Retraction Note: MicroRNA-199a-5p suppresses the cell growth of colorectal cancer by targeting oncogene Caprin1.

[This retracts the article DOI: 10.1007/s13205-020-02433-9.].

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions.

The δ-opioid receptor (δOR) has been considered as a therapeutic target in multiple neurological and neuropsychiatric disorders particularly as δOR agonists are deemed safer alternatives relative to the more abuse-liable µ-opioid receptor drugs. Clinical development of δOR agonists, however, has been challenging in part due to the seizure-inducing effects of certain δOR agonists. Especially agonists that resemble the δOR-selective agonist SNC80 have well-established convulsive activity. Close inspection suggests that many of those seizurogenic δOR agonists efficaciously recruit ß-arrestin, yet surprisingly, SNC80 displays enhanced seizure activity in ß-arrestin 1 knockout mice. This finding led us to hypothesize that perhaps ß-arrestin 1 is protective against, whereas ß-arrestin 2 is detrimental for δOR-agonist-induced seizures. To investigate our hypothesis, we characterized three different δOR agonists (SNC80, ADL5859, ARM390) in cellular assays and in vivo in wild-type and ß-arrestin 1 and ß-arrestin 2 knockout mice for seizure activity. We also investigated downstream kinases associated with ß-arrestin-dependent signal transduction. We discovered that δOR agonist-induced seizure activity strongly and positively correlates with ß-arrestin 2 efficacy for the agonist, but that indirect inhibition of ERK activation using the MEK inhibitor SL327 did not inhibit seizure potency and duration. Inhibition of the PI3K/AKT/mTOR signaling with honokiol but not PQR530, attenuated SNC80 seizure duration in ß-arrestin 1 knockout, but honokiol did not reduce SNC80-induced seizures in wild-type mice. Ultimately, our results indicate that ß-arrestin 2 is correlated with δOR agonist-induced seizure intensity, but that global ß-arrestin 1 knockout mice are a poor model system to investigate their mechanism of action.

Sex- and ß-arrestin-dependent effects of kappa opioid receptor-mediated ethanol consumption.

The kappa opioid receptor is a known regulator of ethanol consumption, but the molecular mechanisms behind its actions have been underexplored. The scaffolding protein ß-arrestin 2 has previously been implicated in driving ethanol consumption at the related delta opioid receptor and has also been suggested to be a driver behind other negative kappa opioid receptor mediated effects. Here, we used kappa opioid agonists with different efficacies for recruiting ß-arrestin 2 and knockout animals to determine whether there is a role for ß-arrestin 2 in the modulation of voluntary ethanol consumption by the kappa opioid receptor. We find that an agonist with low ß-arrestin 2 efficacy more consistently lowers ethanol consumption than agonists with high efficacy for ß-arrestin 2. However, knockdown of ß-arrestin 2 amplifies the ethanol consumption-promoting effects of the arrestin-recruiting kappa agonists U50,488 and nalfurafine. We control for potentially confounding sedative effects at the kappa opioid receptor and find that ß-arrestin 2 is not necessary for kappa opioid receptor-mediated sedation, and that sedation does not correlate with effects on ethanol consumption. Overall, the results suggest a complex relationship between agonist profile, sex, and kappa opioid receptor modulation of ethanol consumption, with little role for kappa opioid receptor-mediated sedation.

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder.

Background and Purpose: Mitragyna speciosa extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder. Experimental Approach: We characterized paynantheine, speciociliatine, and four novel kratom-derived analogs for their ability to bind and activate δOR, µOR, and κOR. Select opioids were assessed in behavioral assays in male C57BL/6N WT and δOR knockout mice. Key Results: Paynantheine (10 mg∙kg-1, i.p.) produced aversion in a limited conditioned place preference (CPP) paradigm but did not produce CPP with additional conditioning sessions. Paynantheine did not produce robust antinociception but did block morphine-induced antinociception and hyperlocomotion. Yet, at 10 and 30 mg∙kg-1 doses (i.p.), paynantheine did not counteract morphine CPP. 7-hydroxypaynantheine and 7-hydroxyspeciogynine displayed potency at δOR but limited µOR potency relative to 7-hydroxymitragynine in vitro, and dose-dependently decreased voluntary alcohol consumption in WT but not δOR in KO mice. 7-hydroxyspeciogynine has a maximally tolerated dose of at least 10 mg∙kg-1 (s.c.) at which it did not produce significant CPP neither alter general locomotion nor induce noticeable seizures. Conclusion and Implications: Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window.

Protoplasts: From Isolation to CRISPR/Cas Genome Editing Application.

In the clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR associated protein (Cas) system, protoplasts are not only useful for rapidly validating the mutagenesis efficiency of various RNA-guided endonucleases, promoters, sgRNA designs, or Cas proteins, but can also be a platform for DNA-free gene editing. To date, the latter approach has been applied to numerous crops, particularly those with complex genomes, a long juvenile period, a tendency for heterosis, and/or self-incompatibility. Protoplast regeneration is thus a key step in DNA-free gene editing. In this report, we review the history and some future prospects for protoplast technology, including protoplast transfection, transformation, fusion, regeneration, and current protoplast applications in CRISPR/Cas-based breeding.

microRNA-23a promotes cell growth and metastasis in gastric cancer via targeting SPRY2-mediated ERK signaling.

[This retracts the article DOI: 10.3892/ol.2018.8374.].

MicroRNA­199a­3p inhibits ovarian cancer cell viability by targeting the oncogene YAP1.

MicroRNA­199a­3p (miR­199a­3p) is aberrantly expressed in various types of cancer where it exhibits a tumor suppressive role. However, the biological role of miR­199a­3p in ovarian cancer (OC) remains unclear. The present study aimed to investigate whether miR­199a­3p was a tumor suppressor in OC and to identify the possible mechanisms. It was found that miR­199a­3p expression was significantly downregulated in the tumor tissues and blood samples of patients with OC, as well as in three OC cell lines. In addition, its low expression was closely associated with International Federation of Gynecology and Obstetrics disease stage, histological grade and lymph node metastasis. It was demonstrated that overexpression of miR­199a­3p inhibited the viability and promoted apoptosis of OV90 and SKOV­3 cells. In addition, Yes­associated protein 1 (YAP1), a well­known oncogene, was identified as a direct target of miR­199a­3p in OC cells. Additionally, it was observed that YAP1 was significantly increased and inversely correlated with miR­199a­3p expression in OC tissues. Notably, YAP1 overexpression abrogated the tumor suppressive effects of miR­199a­3p in vitro. Collectively, the present results indicated that miR­199a­3p suppressed viability in OC cells, at least partly via inhibiting the YAP1 oncogene, suggesting that miR­199a­3p may act as a biomarker and therapeutic target for patients with OC.

MicroRNA-199a-5p suppresses the cell growth of colorectal cancer by targeting oncogene Caprin1.

MicroRNAs-199a-5p (miR-199a-5p) plays critical regulatory roles in various types of human cancers. However, the biological function and regulatory mechanisms of miR-199a-5p in colorectal cancer (CRC) remain unclear. The aim of this study was to investigate the role of miR-199a-5p in CRC and possible mechanisms of its action. The expression of miR-199a-5p in CRC tumor tissues was validated using quantitative real-time PCR (qRT-PCR). The effects of miR-199a-5p on cell proliferation and apoptosis were evaluated in vitro. Then, the association of miR-199a-5p and its downstream target was investigated in both cell line and clinical specimens. Furthermore, gain- and loss-of-function studies of cytoplasmic activation/proliferation-associated protein-1 (Caprin1) were performed to assess whether the suppressive effect of on CRC cells were via targeting Caprin1. Using a microarray platform, we focused on miR-199a-5p for further research, which was one of the most markedly downregulated miRNAs in CRC tumor tissues. Functionally, the overexpression of miR-199a-5p inhibited proliferation and induced apoptosis in both HTC116 and SW480 cells. Furthermore, cytoplasmic activation/proliferation-associated protein-1 (Caprin1), a well-known oncogene, was directly targeted by miR-199a-5p. It was also observed that Caprin1 was upregulated, and inversely correlated with miR-199a-5p levels in CRC tissues. Further investigations revealed that knockdown of Caprin1 by siRNA has similar role with miR-199a-5p overexpression in CRC cells, suggesting the oncogenic role of Caprin1 in CRC. In the contrast, we found that overexpression of Caprin1 reversed the suppressive effects of miR-199a-5p on CRC cells. Collectively, our study suggests that miR-199a-5p/Caprin1 axis may serve as potential therapeutic targets for the treatment of CRC.

Gold Clusters Attenuate Inflammation in Rat Mesangial Cells via Inhibiting the Activation of NF-κB Pathway.

Sepsis-induced acute kidney injury (AKI) with high incidence and mortality rates remains a great challenge in the clinic; thus, novel therapies need to be developed urgently. This complication is associated with an overwhelming systemic inflammatory response. The aim of this study was to evaluate the potential effects and possible mechanisms of gold clusters on septic AKI in vitro. Rat mesangial HBZY-1 cells were treated with peptide-templated gold clusters under lipopolysaccharide (LPS) stimulation. The LPS-induced expression of pro-inflammatory cytokines was measured, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6). Our data showed that the LPS-induced transcription and secretion of these cytokines were suppressed by pretreatment of gold clusters in a dose-dependent manner. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) also play key roles in septic AKI and both of them are induced upon LPS-stimulation in mesangial cells. Our results further showed that pretreatment with gold clusters dramatically inhibited the LPS-stimulated transcription and expression of COX2 and iNOS, and the subsequent prostaglandin E2 (PGE2) and nitric oxide (NO) production in HBZY-1 cells. Since these factors are involved in the NF-κB pathway upon LPS stimulation, the potential roles of gold clusters on the NF-κB pathway were further determined. We found that LPS-induced NF-κB activation was suppressed in gold clusters-pretreated HBZY-1 cells. These results demonstrated that gold clusters can attenuate LPS-induced inflammation in mesangial cells, probably via inhibiting the activation of the NF-κB pathway, suggesting a potential therapeutic approach for septic AKI.

Gold clusters prevent breast cancer bone metastasis by suppressing tumor-induced osteoclastogenesis.

Rationale: Bone is the most frequent site for breast cancer metastasis, which accounts for the leading cause of death in advanced breast cancer patients. Serious skeletal-related events (SREs) caused by bone metastasis have a decisive impact on the life expectancy of breast cancer patients, making breast cancer almost incurable. Metastatic breast cancer cell induced pathological osteoclastogenesis is a key driver of bone metastasis and osteolytic bone lesions. We previously reported that gold clusters can prevent inflammation induced osteoclastogenesis and osteolysis in vivo. In this study, we investigated the effects of a BSA-coated gold cluster on metastatic breast cancer-induced osteoclastogenesis in vitro and tumor-induced osteolysis in vivo, and elucidated its possible mechanism. Methods: Breast cancer cell line MDA-MB-231 was used to evaluate the regulatory effects of gold clusters on breast cancer metastasis and tumor induced osteoclastogenesis in vitro. Cell counting kit-8, transwell, wound-healing and colony formation assays were performed to evaluate the effect of gold clusters on proliferation and metastasis of MDA-MB-231 cells. Tartrate-resistant acid phosphatase (TRAP) staining and filamentous-actin rings analysis were used to detect the regulatory effects of gold clusters on MDA-MB-231 cell-conditioned medium (MDA-MB-231 CM) triggered and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in mouse bone marrow-derived mononuclear cells (BMMs). A mouse model of breast cancer bone metastasis was used to evaluate the in vivo activity of the gold cluster on the tumor induced osteolysis. Results: The gold clusters suppressed the migration, invasion and colony formation of MDA-MB-231 cells in a dose-dependent manner in vitro. The gold clusters strongly inhibited both MDA-MB-231 CM triggered and RANKL-induced osteoclast formation from BMMs in vitro. Cell studies indicated that the gold clusters suppressed the expression of osteolysis-related factors in MDA-MB-231 cells and inhibited the subsequent activation of NF-κB pathway in BMMs. Treatment with the clusters at a dose of 10 mg Au/kg.bw significantly reduces the breast cancer cell induced osteolysis in vivo. Conclusion: Therefore, the gold clusters may offer new therapeutic agents for preventing breast cancer bone metastasis and secondary osteolysis to improve patient outcomes.

MicroRNA-7 inhibits hepatocellular carcinoma cell invasion and metastasis by regulating Atg5-mediated autophagy.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, with a low 5-year survival rate (5-9%). The abnormal expression of miRNA in liver cancer cells may play an important role in the pathophysiology of liver cancer. The ability of tumor invasion and metastasis is an important indicator to evaluate the degree of malignancy of HCC. Autophagy may affect the ability of tumor cells to invade and metastasize. Autophagy-related genes and proteins (Atg) are the core and key to regulating autophagy. The purpose of this study was to investigate the effect of microRNA-7 (miR-7) on targeting autophagy-related protein Atg5 to inhibit the effect of autophagy on the invasion and metastasis ability of liver cancer cells. METHODS: The content of miR-7 and Atg5 in normal liver tissue and HCC tissues was detected by quantitative real-time polymerase chain (qRT-PCR). SMMC-7721 hepatoma cells were cultured in vitro, a starvation environment was simulated to activate autophagy, and transfection of cells was carried out by using miR-7 mimic, inhibitor, and autophagic inhibitor 3-MA. The RFP-GFP-LC3 double-labeled adenovirus infected hepatoma cells, and autophagy was detected by fluorescence microscopy. Western blot was used to detect the expression of LC3, Atg5, and the epithelial-mesenchymal transition (EMT)-related proteins (N-cadherin, vimentin, and snail). Transwell and plate cloning were used to detect the proliferation, invasion, and metastasis of hepatocarcinoma cells. RESULTS: Expression of miR-7 (16.72±4.71, P<0.05) in HCC tissues was low, but the expression of Atg5 (13.70±2.80, P<0.05)was high. MiR-7 and Atg5 were highly negatively correlated in hepatoma tissues (r=-0.97). With the overexpression of hepatoma cells, the expression of Atg5 (0.49±0.07, F=395.26) and LC3II (0.51±0.06, F=23.58) was increased (P<0.05), and the autophagy was enhanced. As a result, the proliferation of hepatocarcinoma cells was decreased (t=3.22, P<0.05), the expression of EMT-related protein [N-cadherin (0.37±0.04), vimentin (0.60±0.07), snail (0.54±0.07)] was decreased (P<0.05), and hepatoma cell invasion and metastasis were decreased (n=6, F=162.28, P<0.05). CONCLUSIONS: MiR-7 can inhibit the invasion and metastasis of hepatoma cells by targeting Atg5 to regulate autophagy.