Hierarchical Hollow Carbon Particles with Encapsulation of Carbon Nanotubes for High Performance Supercapacitors.

A novel and sustainable carbon-based material, referred to as hollow porous carbon particles encapsulating multi-wall carbon nanotubes (MWCNTs) (CNTs@HPC), is synthesized for use in supercapacitors. The synthesis process involves utilizing LTA zeolite as a rigid template and dopamine hydrochloride (DA) as the carbon source, along with catalytic decomposition of methane (CDM) to simultaneously produce MWCNTs and COx -free H2 . The findings reveal a distinctive hierarchical porous structure, comprising macropores, mesopores, and micropores, resulting in a total specific surface area (SSA) of 913 m2  g-1 . The optimal CNTs@HPC demonstrates a specific capacitance of 306 F g-1 at a current density of 1 A g-1 . Moreover, this material demonstrates an electric double-layer capacitor (EDLC) that surpasses conventional capabilities by exhibiting additional pseudocapacitance characteristics. These properties are attributed to redox reactions facilitated by the increased charge density resulting from the attraction of ions to nickel oxides, which is made possible by the material's enhanced hydrophilicity. The heightened hydrophilicity can be attributed to the presence of residual silicon-aluminum elements in CNTs@HPC, a direct outcome of the unique synthesis approach involving nickel phyllosilicate in CDM. As a result of this synthesis strategy, the material possesses excellent conductivity, enabling rapid transportation of electrolyte ions and delivering outstanding capacitive performance.

Tetrahydrocurcumin (THC) enhanced the clearance of Cryptococcus deneoformans during infection in vivo.

Cryptococcal species often cause lung infections and are the main cause of fungal meningitis. Claudin-4 appears to be a major structural component that maintains a tight alveolar barrier and prevents fluid and electrolyte leakage into the alveolar space. We aimed to determine whether S7-tetrahydrocurcumin (THC) could clearance of C. deneoformans and regulate claudin-4 expression during C. deneoformans infection. We investigated the effect of THC on C. deneoformans infection and its possible mechanism in vivo. Transmission electron microscopy was used to observe the ultrastructure of the lung tissue and the invasion of Cryptococcus. To clarify the effect of THC, we examined claudin-4, c-Jun, and Smad2 expression. We also measured claudin-4 expression in pulmonary specimens from clinical patients. THC reduced cryptococcal cell invasion in the lungs, improved alveolar exudation, and reduced inflammation. Pretreatment with THC suppressed c-Jun and Smad2 expression, resulting in significantly increased claudin-4 levels. In contrast, the expression of claudin-4 in clinical specimens from patients with cryptococcal infection was higher than that in normal specimens. THC enhanced the clearance of C. deneoformans during infection in vivo. We investigated the expression of claudin-4 and the possible mechanism of THC against C. deneoformans infection.

Two effective clinical prediction models to screen for obstructive sleep apnoea based on body mass index and other parameters.

BACKGROUND AND OBJECTIVE: The diagnosis of obstructive sleep apnea (OSA) relies on polysomnography which is time-consuming and expensive. We therefore aimed to develop two simple, non-invasive models to screen adults for OSA. METHODS: The effectiveness of using body mass index (BMI) and a new visual prediction model to screen for OSA was evaluated using a development set (1769 participants) and confirmed using an independent validation set (642 participants). RESULTS: Based on the development set, the best BMI cut-off value for diagnosing OSA was 26.45 kg/m2, with an area under the curve (AUC) of 0.7213 (95% confidence interval (CI), 0.6861-0.7566), a sensitivity of 57% and a specificity of 78%. Through forward conditional logistic regression analysis using a stepwise selection model developed from observed data, seven clinical variables were evaluated as independent predictors of OSA: age, BMI, sex, Epworth Sleepiness Scale score, witnessed apnoeas, dry mouth and arrhythmias. With this new model, the AUC was 0.7991 (95% CI, 0.7668-0.8314) for diagnosing OSA (sensitivity, 75%; specificity, 71%). The results were confirmed using the validation set. A nomogram for predicting OSA was generated based on this new model using statistical software. CONCLUSIONS: BMI can be used as an indicator to screen for OSA in the community. We created an internally validated, highly distinguishable, visual and parsimonious prediction model comprising BMI and other parameters that can be used to identify patients with OSA among outpatients. Use of this prediction model may help to improve clinical decision-making.

[Big Data Management and Application: Specialty Construction Overview and Exploration of Personnel Training System in Medical Schools].

Focusing on the undergraduate specialty construction of big data management and application in medical colleges and universities in the context of New Medical Education, we first analyzed, in this paper, the demand for trained personnel of this specialization and the status of program construction at the national and regional levels. Then, taking Anhui Medical University as an example, a key medical university in Anhui Province, we introduced the preparations made by medical colleges and universities to set up big data management and application specialty. Finally, from the perspectives of the objectives of personnel training, curriculum system, and practical teaching system, we presented in detail the exploratory efforts made by Anhui Medical University to construct a training system for personnel specializing in big data management and application. In this paper, we reported mainly the work done on the exploration of the personnel training curriculum system, covering general education, professional education, and extracurricular activities, highlighting the interdisciplinary characteristics of a personnel training curricular system that integrates medicine, engineering, and management. We also reported on a practice teaching system that combined in-class practical teaching and extracurricular activities, and that incorporated tiered contents of increasing challenge--basic practice level, cognitive practice level, comprehensive practice level, and innovative practice level. This study is expected to provide useful references for the training of personnel specializing in medical big data in the context of New Medical Education.

[A new phloroglucinol from Dryopteris fragrans and its antibacterial activity in vitro].

A new phloroglucinol was isolated from 50% ethanol extract of Dryopteris fragrans by silica gel column chromatography, Sephadex LH-20 gel column chromatography, thin-layer chromatography(TLC), and preparative liquid column chromatography. On the basis of MS, ~1H-NMR, ~(13)C-NMR, and reference materials, compound 1 was identified as 2,5-cyclohexadien-1-one, 2-{[2,6-dihydroxy-4-methoxy-3-methyl-5-(1-isobutyl)phenyl]methyl}-3,5-dihydroxy-4,4-dimethyl-6-(1-oxobutyl)(1), and named disaspidin BB. Compound 1 was evaluated for its antibacterial activity. The experimental results showed that compared with the commonly used topical antibiotics erythromycin or mupirocin, disaspidin BB exhibited significant antibacterial activities against Staphylococcus epidermidis(SEP), S. haemolyticus(SHA), and methicillin-resistant S. aureus(MRSA)(P<0.05). Additionally, disaspidin BB was sensitive to ceftazidime-resistant SEP1-SEP4, SHA5-SHA7, MRSA8, and MRSA9. The MIC values of disaspidin BB against SEP and SHA were 1.67-2.71 µg·mL~(-1) and 10.00-33.33 µg·mL~(-1) respectively. Disaspidin BB has good antibacterial activities and deserves development as a new anti-infective drug for external use.

miR-363-3p induces EMT via the Wnt/ß-catenin pathway in glioma cells by targeting CELF2.

In our previous study, we reported that CELF2 has a tumour-suppressive function in glioma. Here, we performed additional experiments to elucidate better its role in cancer. The expression profile of CELF2 was analysed by the GEPIA database, and Kaplan-Meier curves were used to evaluate the overall survival rates. Four different online databases were used to predict miRNAs targeting CELF2, and the luciferase assay was performed to identify the binding site. The biological effects of miR-363-3p and CELF2 were also investigated in vitro using MTT, Transwell, and flow cytometry assays. Western blotting, qPCR, and TOP/FOP flash dual-luciferase assays were performed to investigate the impact of miR-363-3p and CELF2 on epithelial-to-mesenchymal transition (EMT) and the Wnt/ß-catenin pathway. The effect of miR-363-3p was also tested in vivo using a xenograft mouse model. We observed an abnormal expression pattern of CELF2 in glioma cells, and higher CELF2 expression correlated with better prognosis. We identified miR-363-3p as an upstream regulator of CELF2 and confirmed its direct binding to the 3'-untranslated region of CELF2. Cell function experiments showed that miR-363-3p affected multiple aspects of glioma cells. Suppressing miR-363-3p expression inhibited glioma cell proliferation and invasion, as well as promoted cell death via attenuating EMT and blocking the Wnt/ß-catenin pathway. These effects could be abolished by the downregulation of CELF2. Treatment with ASO-miR-363-3p decreased tumour size and weight in nude mice. In conclusion, miR-363-3p induced the EMT, which resulted in increased migration and invasion and reduced apoptosis in glioma cell lines, via the Wnt/ß-catenin pathway by targeting CELF2.

Rolipram plays an anti-fibrotic effect in ligamentum flavum fibroblasts by inhibiting the activation of ERK1/2.

BACKGROUND: Fibrosis is an important factor and process of ligamentum flavum hypertrophy. The expression of phosphodiesterase family (PDE) is related to inflammation and fibrosis. This article studied the expression of PDE in hypertrophic ligamentum flavum fibroblasts and investigated whether inhibition of PDE4 activity can play an anti-fibrotic effect. METHODS: Samples of clinical hypertrophic ligamentum flavum were collected and patients with lumbar disc herniations as a control group. The collagenase digestion method is used to separate fibroblasts. qPCR is used to detect the expression of PDE subtypes, type I collagen (Col I), type III collagen (Col III), fibronectin (FN1) and transforming growth factor ß1 (TGF-ß1). Recombinant TGF-ß1 was used to stimulate fibroblasts to make a fibrotic cell model and treated with Rolipram. The morphology of the cells treated with drugs was observed by Sirius Red staining. Scratch the cells to observe their migration and proliferation. WB detects the expression of the above-mentioned multiple fibrotic proteins after drug treatment. Finally, combined with a variety of signaling pathway drugs, the signaling mechanism was studied. RESULTS: Multiple PDE subtypes were expressed in ligamentum flavum fibroblasts. The expression of PDE4A and 4B was significantly up-regulated in the hypertrophic group. Using Rolipram to inhibit PDE4 activity, the expression of Col I and TGF-ß1 in the hypertrophic group was inhibited. Col I recovered to the level of the control group. TGF-ß1 was significantly inhibited, which was lower than the control group. Recombinant TGF-ß1 stimulated fibroblasts to increase the expression of Col I/III, FN1 and TGF-ß1, which was blocked by Rolipram. Rolipram restored the increased expression of p-ERK1/2 stimulated by TGF-ß1. CONCLUSION: The expressions of PDE4A and 4B in the hypertrophic ligamentum flavum are increased, suggesting that it is related to the hypertrophy of the ligamentum flavum. Rolipram has a good anti-fibrosis effect after inhibiting the activity of PDE4. This is related to blocking the function of TGF-ß1, specifically by restoring normal ERK1/2 signal.

Design, Synthesis, and Biological Evaluation of Novel 6H-Benzo[c]chromen-6-one Derivatives as Potential Phosphodiesterase II Inhibitors.

Urolithins (hydroxylated 6H-benzo[c]chromen-6-ones) are the main bioavailable metabolites of ellagic acid (EA), which was shown to be a cognitive enhancer in the treatment of neurodegenerative diseases. As part of this research, a series of alkoxylated 6H-benzo[c]chromen-6-one derivatives were designed and synthesized. Furthermore, their biological activities were evaluated as potential PDE2 inhibitors, and the alkoxylated 6H-benzo[c]chromen-6-one derivative 1f was found to have the optimal inhibitory potential (IC50: 3.67 ± 0.47 µM). It also exhibited comparable activity in comparison to that of BAY 60-7550 in vitro cell level studies.

Isoliquiritigenin inhibits melanogenesis, melanocyte dendricity and melanosome transport by regulating ERK-mediated MITF degradation.

Isoliquiritigenin (ISL), a flavonoid component from the hydrolysis products of licorice root. It has been reported that ISL inhibited melanogenesis by suppressing the tyrosinase activity in human melanocytes. Recently, ISL was found to induce melanin degradation in human epidermal keratinocytes. However, the role of ISL in pigmentation is not fully understood. In the current study, we aimed to investigate the effects of ISL on pigmentation, and further explored the underlying mechanism. Our results suggested that ISL suppressed basal and α-MSH-, ACTH- and UV-induced melanin synthesis, in addition to inhibiting melanocyte dendricity and melanosome transport. ISL played these roles mainly by activating the extracellular signal-regulated protein kinase pathway. Once activated, it induced microphthalmia-associated transcription factor degradation and decreased the expression of tyrosinase, TRP-1, DCT, Rab27a and Cdc42, finally inhibited melanogenesis, melanocyte dendricity and melanosome transport. Our findings suggested that ISL exhibited no cytotoxicity in our research, it may prove quite useful as a safer natural skin-whitening agent.

Novel PDE5 inhibitors derived from rutaecarpine for the treatment of Alzheimer's disease.

A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure-activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC50 values about 0.086 µM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitors derived from rutaecarpine as a good candidate drug for the treatment of Alzheimer's disease.

Design, synthesis of novel purin-6-one derivatives as phosphodiesterase 2 (PDE2) inhibitors: The neuroprotective and anxiolytic-like effects.

Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders. Herein, based on the existing PDE2 inhibitors and their binding modes, a series of purin-6-one derivatives were designed, synthesized and evaluated for PDE2 inhibitory activities, which led to the discovery of the best compounds 6p and 6s with significant inhibitory potency (IC50: 72 and 81 nM, respectively). Docking simulation was performed to insert compound 6s into the crystal structure of PDE2 at the active site to determine the binding mode. Furthermore, compound 6s significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cAMP and cGMP levels. It also produced anxiolytic-like effect in the elevated plus-maze test and exhibited favorable pharmacokinetic properties in vivo. These results might bring significant instruction for further development of potent PDE2 inhibitors.

Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors.

Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.

An Ontology-Driven Approach for Integrating Intelligence to Manage Human and Ecological Health Risks in the Geospatial Sensor Web.

Due to the rapid installation of a massive number of fixed and mobile sensors, monitoring machines are intentionally or unintentionally involved in the production of a large amount of geospatial data. Environmental sensors and related software applications are rapidly altering human lifestyles and even impacting ecological and human health. However, there are rarely specific geospatial sensor web (GSW) applications for certain ecological public health questions. In this paper, we propose an ontology-driven approach for integrating intelligence to manage human and ecological health risks in the GSW. We design a Human and Ecological health Risks Ontology (HERO) based on a semantic sensor network ontology template. We also illustrate a web-based prototype, the Human and Ecological Health Risk Management System (HaEHMS), which helps health experts and decision makers to estimate human and ecological health risks. We demonstrate this intelligent system through a case study of automatic prediction of air quality and related health risk.

Advancing Catalysts by Stacking Fault Defects for Enhanced Hydrogen Production: A Review.

Green hydrogen, derived from water splitting powered by renewable energy such as solar and wind energy, provides a zero-emission solution crucial for revolutionizing hydrogen production and decarbonizing industries. Catalysts, particularly those utilizing defect engineering involving the strategical introduction of atomic-level imperfections, play a vital role in reducing energy requirements and enabling a more sustainable transition toward a hydrogen-based economy. Stacking fault (SF) defects play an important role in enhancing the electrocatalytic processes by reshaping surface reactivity, increasing active sites, improving reactants/product diffusion, and regulating electronic structure due to their dense generation ability and profound impact on catalyst properties. This review explores SF in metal-based materials, covering synthetic methods for the intentional introduction of SF and their applications in hydrogen production, including oxygen evolution reaction, photo- and electrocatalytic hydrogen evolution reaction, overall water splitting, and various other electrocatalytic processes such as oxygen reduction reaction, nitrate reduction reaction, and carbon dioxide reduction reaction. Finally, this review addresses the challenges associated with SF-based catalysts, emphasizing the importance of a detailed understanding of the properties of SF-based catalysts to optimize their electrocatalytic performance. It provides a comprehensive overview of their various applications in electrocatalytic processes, providing valuable insights for advancing sustainable energy technologies.

MOF-derived high oxygen vacancies CuO/CeO2 catalysts for low-temperature CO preferential oxidation.

The CO preferential oxidation reaction (CO-PROX) is an effective strategy to remove residual poisonous CO in proton exchange membrane fuel cells, in which oxygen vacancies play a critical role in CO adsorption and activation. Herein, a series of CuO/CeO2 catalysts derived from Ce-MOFs precursors were synthesized using different organic ligands via the hydrothermal method and the CO-PROX performance was investigated. The CuO/CeO2-135 catalyst derived from homophthalic tricarboxylic acid (1,3,5-H3BTC) exhibited superior catalytic performance with 100 % CO conversion at a relatively low temperature (T100% = 100 °C), with a wide reaction temperature range and excellent stability. The superior catalytic properties were attributed to the structural improvements provided by the 1,3,5-H3BTC precursors and the promotional effects of oxygen vacancies. Additionally, in-situ Raman spectroscopy was performed to verify the dynamic roles of oxygen vacancies for CO adsorption and activation, while in-situ DRIFTS analysis revealed key intermediates in the CO-PROX reaction, shedding light on the mechanistic aspects of the catalytic process. This work not only demonstrates insights into the effective CuO/CeO2 catalysts for CO preferential oxidation, but also provides a feasible way to synthesize MOF-derived catalysts.

Prognostic significance of CTNNB1 mutation in hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUNDS: Hepatocellular Carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. In recent years, researchers have verified that the Wnt/ß-catenin signaling pathway affects the clinicopathological features and prognosis of patients with HCC. Although many studies have investigated the relationship between Wnt/ß-catenin signaling pathway and HCC, the prognostic value of ß-catenin in HCC remains inconclusive. CTNNB1 (Catenin Beta-1) is an important factor in the Wnt/ß-catenin signaling pathway. However, no consensus has been reached on the clinical and prognostic significance of CTNNB1 mutations in HCCs. METHODS: Eligible studies and relevant data were obtained from PubMed, Web of Science, Elsevier, Cochrane Library, Ovid, and Embase databases. The correlation between CTNNB1 mutations and clinical/prognosis of patients were evaluated. A fixed- or random-effects model was used to calculate pooled odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Seventeen studies matched the selection criteria, and 1828 patients were included. This meta-analysis demonstrated that patients with HCC with CTNNB1 mutations had favorable clinicopathological features and survival. The combined ORs of 1-, 3- and 5-year overall survival were0.52 (n = 6 studies, 95% CI: 0.34-0.81, Z = 2.89, P =0.004, 0.28 (n =6 studies, 95% CI: 0.18-0.42, Z = 6.03, P<0.00001), -0.22 (n = 6 studies, 95% CI: 0.37-0.06, Z = 2.78, P = 0.005), respectively. Additionally, CTNNB1 mutation might be significantly associated with differentiation (OR = 0.54, 95% CI:0.36-0.81, Z = 2.98, P = 0.003), TMN stages (Tumor, Node, Metastasis staging classification) (OR = -0.25, 95% CI:-0.33--0.18, Z = 6.60, P<0.00001), liver cirrhosis (OR = 0.21, 95% CI:0.11-0.39, Z = 4.94, P< = 0.00001), and HBV (Hepatitis B Virus) infection (OR = 0.44, 95% CI:0.31-0.64, Z = 4.37, P<0.0001), but not with tumor size, metastasis, vascular invasion, and HCV infection. CONCLUSIONS: CTNNB1 mutation can serve as an indicator of favorable prognosis as well as a novel target for treatment in HCC.

Case Report: A rare case of non-small cell lung cancer with STRN-ALK fusion in a patient in very poor condition treated with first-line ensartinib.

Several cases of STRN-ALK fusion have been reported, and some anaplastic lymphoma kinase (ALK) inhibitors have been shown to be effective for treatment. Nevertheless, no cases of COVID-19 leading to heart failure and respiratory failure have been reported in people older than 70 years treated with ALK inhibitors. The present case report describes a 70-year-old patient with usual chronic obstructive pulmonary disease, diabetes, depression, and carotid plaque disease. Next-generation sequencing of tissue obtained by puncture biopsy revealed a STRN-ALK mutation accompanied by a TP53 mutation. The patient was treated with ensartinib and developed COVID-19 leading to heart failure and respiratory failure; nevertheless, he had a good clinical outcome and exhibited high treatment tolerability.

The differential impact of air pollutants on acute urticaria and chronic urticaria: a time series analysis.

Several studies have revealed a relationship between short-term exposure to air pollution and the exacerbation of certain skin conditions. This study was developed to expand on these findings by exploring the potential association between exposure to air pollutants including particulate matter, sulfur dioxide, and ozone and the incidence of acute and chronic urticaria in Shenyang, China, from 2016 to 2018. Exposure-response relationships between daily mean concentrations of these airborne pollutants and visits to outpatient dermatological clinics for acute urticaria and chronic urticaria were evaluated via a time series analysis approach using a generalized additive model. This analysis revealed that a 10 µg/m3 increase in daily mean O3_8h concentrations was associated with a 0.36% (95% CI, 0.31-0.41%), 0.35% (95% CI, 0.30-0.40%), and 0.34% (95% CI, 0.29-0.39%) increase in the number of outpatient visits for acute urticaria on that day (lag0), lagging day 1 (lag1), and lagging day 2 (lag2), respectively. O3 levels also had a similar but weaker effect on the frequency of patients seeking outpatient care for chronic urticaria. These analyses also revealed that estimated 0.47% (95% CI, 0.41-0.52%) and 0.46% (95% CI, 0.40-0.51%) increases in dermatological outpatient acute urticaria visits were observed for every 10µg/m3 rise in O3_8h concentrations on cumulative lagging days (lag01 and lag02). Increases in particulate matter (PM2.5, PM10) levels had a similar cumulative effect on patients with chronic urticaria. In summary, these results suggest that short-term O3, PM2.5, and PM10 exposure can increase the risk of acute urticaria and chronic urticaria.

Overexpression of the lncRNA HOTAIRM1 promotes lenvatinib resistance by downregulating miR-34a and activating autophagy in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. Despite pharmacological advances such as sorafenib and lenvatinib approval, responses are seen only in a limited fraction of HCCs, and the majority of HCC patients do not benefit from this treatment. In recent years, researchers have verified that the long noncoding RNAs (lncRNAs) impact the efficiency of lenvatinib and the prognosis of patients with HCC. MATERIALS AND METHODS: This work obtained gene expression profile from an Arraystar lncRNA microarray. Expression of HOTAIRM1, Beclin-1, and p62 in HCC was characterized in clinical HCC tissues of 24 patients with HCC. Overexpression and knockdown experiments were performed in HCC cells to examine the effects of the HOTAIRM1 on lenvatinib sensitivity. The interactions between HOTAIRM1, miR-34a and Beclin-1 were predicted according to GSEA and CNC network. The effects of HOTAIRM1, autophagy and lenvatinib on tumor inhibit were validated in orthotopic tumor-bearing nude mouse model. RESULTS: Lenvatinib-resistant HCC cell lines were established using the concentration gradient method. Data from an Arraystar lncRNA microarray indicated that HOTAIRM1, a specific lncRNA located in an evolutionarily highly conserved HOX gene cluster, was differentially expressed between lenvatinib-resistant HCC cells and their parental cells. Expression of HOTAIRM1 and Beclin-1 in HCC was characterized in clinical HCC tissues of 24 patients who have different sensitivity to lenvatinib. Knocking down of HOTAIRM1 decreased the autophagy level in lenvatinib-resistant HCC cells and increased their sensitivity to lenvatinib, especially when combined with autophagy inhibitors both in vitro and in vivo. Further study indicated that knocking down HOTAIRM1 in lenvatinib-resistant cell lines increased the level of miR-34a and inhibited the expression of Beclin-1 in Huh7-R and HepG2-R cells. Investigation according to GSEA and CNC network, lncRNA and nearby coding gene and lncRNA-miRNA analyses demonstrated that the resistance of HCC to lenvatinib was affected by the HOTAIRM1-miR-34a-Beclin-1 regulatory axis. CONCLUSION: HOTAIRM1 is an independent drug resistance factor which significantly associated with the efficacy of lenvatinib in HCC. HOTAIRM1 may downregulation of miR-34a and upregulation of Beclin-1, leading to activation of autophagy, thereby inducing lenvatinib resistance in HCC.

Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS.

Human cancers typically express a high level of tumor-promoting mutant p53 protein (Mutp53) with a minimal level of tumor-suppressing wild-type p53 protein (WTp53). In this regard, inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy. Herein, a new carrier-free nanoprodrug (i.e., Mn-ZnO2 nanoparticles) was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species (ROS) within tumor to regulate the p53 protein for high anti-tumor efficacy. In response to the mild tumor acidic environment, the released Zn2+ and H2O2 from Mn-ZnO2 NPs induced ubiquitination-mediated proteasomal degradation of Mutp53, while the liberative Mn2+ and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level. Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical (•OH) through the Fenton-like reaction. With the integration of multiple functions (i.e., carrier-free ion and ROS delivery, tumor accumulation, p53 protein modulation, toxic •OH generation, and pH-activated MRI contrast) in a single nanosystem, Mn-ZnO2 NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.