Transition-Metal-Oxide-Based Nanozymes for Antitumor Applications.

Transition metal oxide (TMO)-based nanozymes have appeared as hopeful tools for antitumor applications due to their unique catalytic properties and ability to modulate the tumor microenvironment (TME). The purpose of this review is to provide an overview of the latest progress made in the field of TMO-based nanozymes, focusing on their enzymatic activities and participating metal ions. These nanozymes exhibit catalase (CAT)-, peroxidase (POD)-, superoxide dismutase (SOD)-, oxidase (OXD)-, and glutathione oxidase (GSH-OXD)-like activities, enabling them to regulate reactive oxygen species (ROS) levels and glutathione (GSH) concentrations within the TME. Widely studied transition metals in TMO-based nanozymes include Fe, Mn, Cu, Ce, and the hybrid multimetallic oxides, which are also summarized. The review highlights several innovative nanozyme designs and their multifunctional capabilities. Despite the significant progress in TMO-based nanozymes, challenges such as long-term biosafety, targeting precision, catalytic mechanisms, and theoretical supports remain to be addressed, and these are also discussed. This review contributes to the summary and understanding of the rapid development of TMO-based nanozymes, which holds great promise for advancing nanomedicine and improving cancer treatment.

Apathetic Graves' disease with severe hepatic and renal dysfunction induced by COVID-19 infection: Case report and literature review.

RATIONALE: A rare and intractable case of apathetic Graves' disease (GD) with severe liver and kidney damage induced by coronavirus disease 2019 (COVID-19) carries a certain risk of missing diagnosis and delayed treatment during the COVID-19 pandemic. PATIENT CONCERN: A 60-year-old female patient developed anorexia, exhaustion, jaundice, nausea, and vomiting 10 days after COVID-19 infection. She was admitted to the Infectious Diseases Department because of recurring symptoms for more than a month. DIAGNOSIS: Based on the patient's epidemiological history, clinical symptoms, and prior history, she was preliminarily diagnosed with GD induced by COVID-19 with severe hyperthyroid-related liver injury and chronic kidney disease stage 4. Drug-induced and radiation-induced liver injuries occurred sequentially throughout the therapy. INTERVENTION: Methimazole (MMI) (10 mg/d) was administered for 1 week, and the patient's symptoms, thyroid function, and liver and kidney function improved. Nevertheless, the aforementioned symptoms and liver and kidney function deteriorated 20 days after increasing the MMI dose (20 mg/d). Therefore, in the presence of an artificial liver, hemodialysis, and other medical conditions, the treatment schedule was adjusted to individualized 131I anti-hyperthyroidism therapy. OUTCOME: After 131I treatment, the patient's liver function returned to almost normal levels after a month, but worsened when the hepatoprotective drugs were stopped. Renal function did not deteriorate significantly and returned to baseline after 3 months. Thyroid function was restored to normal approximately 4 months later. CONCLUSION: COVID-19 may induce GD. Multidisciplinary collaboration can be initiated as early as possible. Individualized 131I therapy or long-term low-dose MMI (10 mg/d) can be considered to manage hyperthyroidism in GD patients with liver and kidney dysfunction and to prolong liver protection therapy appropriately.

Cascade reaction biosensor based on gold nanocluster decorated iron-cobalt oxide nanosheets as a superior peroxidase mimic for dual-mode detection of α-glucosidase and its inhibitor.

Herein, we have synthesized a novel kind of gold nanoclusters decorated iron-cobalt oxide nanosheets (His-AuNCs@FeCo-ONSs) assembled by electrostatic interaction, which possessed both outstanding peroxidase-like activity and fluorescence property. Taking advantage of our bifunctional hybrid nanozyme and enzyme cascade reactions, a sensitive dual-mode (colorimetric/fluorescent) detection method for α-glucosidase was constructed. The detection limits for α-glucosidase were 2.2 U/L and 3.3 U/L in fluorometric and colorimetric mode, respectively. This method not only provides high sensitivity, but also can correct itself to improve the accuracy of analysis due to the dual-response signals. Furthermore, it was employed for α-glucosidase determination in real samples and screening of α-glucosidase inhibitors.

Peptide OM-LV20 protects astrocytes against oxidative stress via the 'PAC1R/JNK/TPH1' axis.

Stroke can lead to severe nerve injury and debilitation, resulting in considerable social and economic burdens. Due to the high complexity of post-injury repair mechanisms, drugs approved for use in stroke are extremely scarce, and thus, the discovery of new antistroke drugs and targets is critical. Tryptophan hydroxylase 1 (TPH1) is involved in a variety of mental and neurobehavioral processes, but its effects on stroke have not yet been reported. Here, we used primary astrocyte culture, quantitative real-time PCR, double immunofluorescence assay, lentiviral infection, cell viability analysis, Western blotting, and other biochemical experiments to explore the protective mechanism of peptide OM-LV20, which previously exhibited neuroprotective effects in rats after ischemic stroke via a mechanism that may involve TPH1. First, we showed that TPH1 was expressed in rat astrocytes. Next, we determined that OM-LV20 impacted expression changes of TPH1 in CTX-TNA2 cells and exhibited a protective effect on the decrease in cell viability and catalase (CAT) levels induced by hydrogen peroxide. Importantly, we also found that TPH1 expression induced by OM-LV20 may be related to the level of change in the pituitary adenylate cyclase-activating peptide type 1 receptor (PAC1R) and to the JNK signaling pathways, thereby exerting a protective effect on astrocytes against oxidative stress. The protective effects of OM-LV20 likely occur via the 'PAC1R/JNK/TPH1' axis, thus highlighting TPH1 as a novel antistroke drug target.

Long Noncoding RNA SCIRT Promotes HUVEC Angiogenesis via Stabilizing VEGFA mRNA Induced by Hypoxia.

Ischemia-reperfusion injury (IRI) is closely associated the abnormal expression of long noncoding RNAs (lncRNAs), especially for their regulatory roles in IRI-related angiogenesis. This study applied a hypoxia-reoxygenation (HR) cell model to simulate the IRI condition, as well as RNA sequencing and RNA pull-down experiments to reveal roles of the lncRNA and Stem Cell Inhibitory RNA Transcript (SCIRT), in endothelial angiogenesis. We found that SCIRT was increased under the HR condition and exhibited a high expression correlation with angiogenesis marker VEGFA. RNA-seq data analysis further revealed that VEGFA-related angiogenesis was regulated by SCIRT in HUVECs. Gain and loss of function experiments proved that SCIRT posttranscriptionally regulated VEGFA via affecting its mRNA stability. Furthermore, HuR (ELAVL1), an RNA binding protein (RBP), was identified as a SCIRT-binding partner, which bound and stabilized VEGFA. Moreover, SCIRT promoted HuR expression posttranslationally by inhibiting its ubiquitination under the HR condition. These findings reveal that lncRNA SCIRT can mediate endothelial angiogenesis by stabilizing the VEGFA mRNA via modulating RBP HuR stability under the HR condition.

Identification of autophagy related genes in predicting the prognosis and aiding 5- fluorouracil therapy of colorectal cancer.

The emergence of 5-Fluorouracil (5-FU) resistance is the barrier to effective clinical outcomes for colorectal cancer (CRC) patients. Autophagy was found to be involved in protecting tumor cells from 5-FU. However, the specific role of autophagy-related genes in CRC 5-FU resistance remains unclear. In this study, HSPB8 among 34 differentially expressed ARGs in CRC was identified to be the hub ARGs in 5-FU resistant which was down-regulated in CRC samples when compared with normal samples but up-regulated in CRC samples with relatively higher lymphatic invasion, later stages and poor prognosis of CRC. Mechanistic analysis demonstrated that due to the recruitment of CAFs, HSPB8 expression was enhanced in CRC cells so that HSPB8 could act together with its co-chaperone BAG3 in autophagy drived 5-FU resistance. Furthermore, the augmented expression level of HSPB8 was found to be significantly correlated to the immune cell infiltration such as Treg cells, macrophages, monocyte and dendritic cells and so on. Our results suggested CAFs driving HSPB8 induced CRC 5-FU resistance by promoting tumor autophagy would provide a new strategy in seeking potential CRC therapeutic target.

METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide, and its main cause of death is distant metastasis. Methyltransferase-like 14(METTL14), a major RNA N6-adenosine methyltransferase, is involved in tumor progression via regulating RNA function. The goal of the study is to uncover the biological function and molecular mechanism of METTL14 in CRC. METHODS: Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were employed to detect METTL14 and SOX4 in CRC cell lines and tissues. The biological functions of METTL14 were demonstrated using in vitro and in vivo experiments. Chromatin immunoprecipitation (ChIP), Transcrptomic RNA sequencing (RNA-Seq), m6A-RNA immunoprecipitation sequencing (MeRIP-Seq), RNA immunoprecipitation and luciferase reporter assays were used to explore the mechanism of METTL14 action. RESULTS: METTL14 expression was significantly downregulated in CRC and decreased METTL14 was associated with poor overall survival (OS). Both the univariate and multivariate Cox regression analysis indicated that METTL14 was an independent prognostic factor in CRC. Moreover, lysine-specific histone demethylase 5C(KDM5C)-mediated demethylation of histone H3 lysine 4 tri-methylation(H3K4me3) in the promoter of METTL14 inhibited METTL14 transcription. Functionally, we verified that METTL14 inhibited CRC cells migration, invasion and metastasis through in vitro and in vivo assays, respectively. Furthermore, we identified SRY-related high-mobility-group box 4(SOX4) as a target of METTL14-mediated m6A modification. Knockdown of METTL14 markedly abolished SOX4 mRNA m6A modification and elevated SOX4 mRNA expression. We also revealed that METTL14-mediated SOX4 mRNA degradation relied on the YTHDF2-dependent pathway. Lastly, we demonstrated that METTL14 might inhibit CRC malignant process partly through SOX4-mediated EMT process and PI3K/Akt signals. CONCLUSIONS: Decreased METTL14 facilitates tumor metastasis in CRC, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for CRC.

[Choosing, Challenging, Stabilizing, and Fulfilling: The Experiences of Palliative Care at Home as Perceived by Family Caregivers].

BACKGROUND: Although the Taiwan government has subsidized the provision of palliative care at home since 2000, the utilization rate of this service has been low. PURPOSE: The purpose of this research is to explore the experiences of palliative care at home as perceived by family caregivers. METHODS: This qualitative study used semi-structured interviews to collect the data. Six family caregivers who had been providing home-based palliative care services for at least 2 weeks were invited to participate. RESULTS: Four themes related to the care experiences of the participants emerged: (1) Choosing palliative care at home for the end-of-life journey: Considering the wishes of patients and the capacities of caregivers, with hospitals providing powerful support to caregivers; (2) Facing the burdens of providing palliative care in a home setting: Determining the caring skills while feeling fear and stress, and needing to resolve this stress and achieve a respite; (3) Pursuing stable home palliative care: Relying on consultations with the professional palliative care team for information, support, and insights regarding the value of home palliative care; and (4) Fulfilling the promise of a good death at home: Preparing the patient to say goodbye and to experience a peaceful death and family members to express their sadness and adapt to a new life. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Home palliative care services help provide patients and their families convenience, intimate care, and reassurance at home. However, all caregivers must be properly trained in caring skills and the skills necessary to sustain their long-term care responsibilities. Home palliative care services have been described as the internal and external needs that patients and families require to maintain a stable quality of life and as the comfort required by the bereaved family members. The findings of this study demonstrate the value of home palliative care and of promoting home palliative care at the end of life.

Long non-coding RNA 91H contributes to the occurrence and progression of esophageal squamous cell carcinoma by inhibiting IGF2 expression.

Long non-coding RNAs (lncRNAs) have been recently recognized as a major class of regulators in mammalian systems. 91H, a novel long noncoding antisense transcripts located on the position of the H19/IGF2 locus has been suggested to play a potential tumor-suppressor role in tumor development. However, little study has proved the mechanism in esophageal squamous cell carcinoma (ESCC). We carried out this study to explore the role of lncRNA 91H in the regulation of H19 imprinting control regions (ICR) and IGF2 expression and the association between 91H and ESCC progression. The cell line TE-1, Eca-109, and 232 ESCC patients' matched sets of paraffin-embedded adjacent normal and tumor samples were obtained in this study. The results showed that 91H expression was significantly lower in patients with higher depth of invasion, neoplastic grading and TNM which usually leads to the overexpression of IGF2 in tumor progression. The expression of 91H usually decreased in TE-1 and Eca-109 when treated with demethylation agent. Further analysis revealed that, in 91H knockdown cell lines, IGF2 expression was also significantly higher than negative controls. Therefore, the results demonstrated that the lncRNA 91H was associated with H19 ICR methylation and inhibited IGF2 expression of ESCC patients which may optimize the mechanism of IGF2 regulation in tumor development. Patients with higher depth of invasion, neoplastic grading and TNM usually demonstrated lower 91H expression potentially represent a novel clinically relevant event to identify individuals at increased risk for the occurrence, progression and prognosis of ESCC.

The involvement of Kras gene 3'-UTR polymorphisms in risk of cancer and influence on patient response to anti-EGFR therapy in metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Genetic variation of the Kras oncogene is a candidate factor for increasing susceptibility to carcinoma and modulating response of metastatic colorectal cancer (mCRC) patients treated with anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR). However, results from an increasing number of studies concerning the association of Kras gene rs712 and rs61764370 polymorphisms with risk of cancer and treatment of mCRC using anti-EGFR remain equivocal. METHODS: Risk associations were evaluated in 1,661 cases and 2,139 controls from six studies concerning rs712 and 14,796 cases and 14,985 controls from 29 studies concerning rs61764370. Response association was also examined in a subset of four studies pertaining to rs61764370 and anti-EGFR treatment in mCRC. RESULTS: Results of a meta-analysis showed that allele T (P-value of heterogeneity test [P H] =0.08, odds ratio [OR] =1.33, 95% confidence interval [CI]: 1.08-1.64) and genotype GT/TT (P H=0.14, OR =1.30, 95% CI: 1.10-1.55) in rs712 were strongly associated with cancer in Chinese subjects. No evidence of association was observed between rs712 and risk of cancer in the overall population or between rs61764370 and ovarian, breast, colorectal, or non-small-cell lung cancer risk in the Caucasian population. No significant association was found between rs61764370 and patient response to anti-EGFR therapy in mCRC. CONCLUSION: The findings not only provide further evidence that allele T of rs712 increases genetic predisposition to cancer in Chinese population, but also no significant association between rs61764370 and cancer risk in Caucasian population, and suggest that genotype GT/TT of rs61764370 may not be a biomarker for predicting clinical outcome of anti-EGFR therapy in mCRC.