Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis

<p>Abstract</p> <p>Background</p> <p>In contrast to tumor-suppressive apoptosis and autophagic cell death, necrosis promotes tumor progression by releasing the pro-inflammatory and tumor-promoting cytokine high mobility group box 1 (HMGB1), and its presence in tumor patients is associated with poor prognosis. Thus, necrosis has important clinical implications in tumor development; however, its molecular mechanism remains poorly understood.</p> <p>Results</p> <p>In the present study, we show that Distal-less 2 (Dlx-2), a homeobox gene of the Dlx family that is involved in embryonic development, is induced in cancer cell lines dependently of reactive oxygen species (ROS) in response to glucose deprivation (GD), one of the metabolic stresses occurring in solid tumors. Increased Dlx-2 expression was also detected in the inner regions, which experience metabolic stress, of human tumors and of a multicellular tumor spheroid, an <it>in vitro </it>model of solid tumors. Dlx-2 short hairpin RNA (shRNA) inhibited metabolic stress-induced increase in propidium iodide-positive cell population and HMGB1 and lactate dehydrogenase (LDH) release, indicating the important role(s) of Dlx-2 in metabolic stress-induced necrosis. Dlx-2 shRNA appeared to exert its anti-necrotic effects by preventing metabolic stress-induced increases in mitochondrial ROS, which are responsible for triggering necrosis.</p> <p>Conclusions</p> <p>These results suggest that Dlx-2 may be involved in tumor progression via the regulation of metabolic stress-induced necrosis.</p

Kikuchi's Disease in Children: Clinical Manifestations and Imaging Features

Previously published studies on Kikuchi disease (KD) have frequently addressed the computed tomography (CT) findings in the adult population, however, only a few studies have been reported for the pediatric age group. The purpose of this study is to analyze the clinical characteristics and imaging features of KD in children. Fifteen children (2-14 yr) who had a neck CT and pathology diagnosis of KD were included in this study. Clinical features, including the duration of lymphadenopathy and fever, prognosis, and laboratory values, were evaluated. We analyzed the sites, size, and lymph node pattern as seen on their CT scans. The median duration of fever was 10 days. Fourteen patients experienced improvement in their condition, although four of these patients experienced recurrent episodes of KD. All patients had affected cervical nodes at level V. Perinodal infiltrates were observed in the affected cervical nodes in 14 cases (93%), and non-enhancing necrosis was also noted within the affected cervical nodes in 10 cases (63%). In conclusion, the combination of imaging findings in conjunction with clinical findings of KD may help to determine whether or not to perform pathology analysis and follow-up studies

Mitochondrial-Targeting Anticancer Agent Conjugates and Nanocarrier Systems for Cancer Treatment

The mitochondrion is an important intracellular organelle for drug targeting due to its key roles and functions in cellular proliferation and death. In the last few decades, several studies have revealed mitochondrial functions, attracting the focus of many researchers to work in this field over nuclear targeting. Mitochondrial targeting was initiated in 1995 with a triphenylphosphonium-thiobutyl conjugate as an antioxidant agent. The major driving force for mitochondrial targeting in cancer cells is the higher mitochondrial membrane potential compared with that of the cytosol, which allows some molecules to selectively target mitochondria. In this review, we discuss mitochondria-targeting ligand-conjugated anticancer agents and their in vitro and in vivo behaviors. In addition, we describe a mitochondria-targeting nanocarrier system for anticancer drug delivery. As previously reported, several agents have been known to have mitochondrial targeting potential; however, they are not sufficient for direct application for cancer therapy. Thus, many studies have focused on direct conjugation of targeting ligands to therapeutic agents to improve their efficacy. There are many variables for optimal mitochondria-targeted agent development, such as choosing a correct targeting ligand and linker. However, using the nanocarrier system could solve some issues related to solubility and selectivity. Thus, this review focuses on mitochondria-targeting drug conjugates and mitochondria-targeted nanocarrier systems for anticancer agent delivery

Effectiveness of electroacupuncture on anxiety: a systematic review and meta-analysis of randomized controlled trials

This systematic review and meta-analysis aimed to comprehensively evaluate the effectiveness of electroacupuncture (EA) for patients with anxiety. Randomized controlled trials (RCTs) on the treatment of anxiety by EA up to November 2022 were searched and collected from nine databases. Hamilton Anxiety Rating Scale (HAMA), self-rating anxiety scale (SAS), and adverse reactions were used as outcome indicators. The quality of relevant articles was evaluated using the Cochrane Collaboration’s risk of bias tool. The quality of evidence for each outcome was classified as “low risk,” “unclear risk,” or “high risk.” RevMan 5.0 was used for data analysis. A total of 633 articles were identified from nine electronic databases; 37 RCTs were included, which measured anxiety changes by using EA alone compared to the control group. For the main outcome, EA significantly reduced the HAMA score [Mean difference (MD):−1.13 (95% CI:−2.55–0.29), I2:80%], and the quality of evidence was moderate. EA significantly reduced the SAS score (MD:−3.47 (95% CI,−6.57−−0.36), I2:88%), and the quality of evidence was moderate. Our meta-analysis shows that EA reduces HAMA and SAS. This study suggests that EA can relieve anxiety. For various uses, additional research is needed on its effect when combined with other treatments.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=345658, identifier (CRD42022345658)

Impact of Non-vitamin K Antagonist Oral Anticoagulant Withdrawal on Stroke Outcomes

Introduction: Discontinuation of oral anticoagulants such as non-vitamin K antagonist oral anticoagulants (NOACs) may induce a hypercoagulable state, leading to severe stroke and poor outcomes. This study aimed to compare stroke outcomes between NOACs withdrawal and other prior medication statuses in patients with non-valvular atrial fibrillation (NVAF).Methods: Consecutive patients who had pre-existing NVAF and were admitted for an acute ischemic stroke or transient ischemic attack- at five hospitals between January 2013 and December 2016 were included. Prior medication status was categorized into seven groups such as no antithrombotics, antiplatelet-only, warfarin with subtherapeutic intensity, warfarin with therapeutic intensity, NOAC, warfarin withdrawal, and NOAC withdrawal. We compared initial National Institute of Health Stroke Scale (NIHSS) scores between groupsResults: Among 719 patients with NVAF, The median NIHSS score at admission was 5 (IQR 1-13). The NOAC withdrawal group had the highest median NIHSS scores at stroke onset [16, interquartile range, IQR (1–17)], followed by the warfarin withdrawal group [11, IQR (1–14, 18)], the no antithrombotic group [5, IQR (1–13, 18, 19)], and the warfarin with subtherapeutic intensity group [5, IQR (1–10, 18, 19)]. A Multivariable analysis demonstrated that NOAC withdrawal was independently associated with higher NIHSS scores at stroke onset (B 4.645, 95% confidence interval 0.384–8.906, P = 0.033). The median interval from drug withdrawal to ischemic stroke or TIA was 7 days (IQR 4-15) in the NOAC group.Conclusions: Stroke that occurred after stopping oral anticoagulants, especially NOAC, and was more severe at presentation and associated with poorer outcomes

Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells

Ras/Raf/MEKs/ERKs and PI3 K/Akt/mTOR signaling pathways have key roles in cancer development and growth processes, as well as in cancer malignance and chemoresistance. In this study, we screened the therapeutic potential of magnolin using 15 human cancer cell lines and combined magnolin sensitivity with the CCLE mutaome analysis for relevant mutation information. The results showed that magnolin efficacy on cell proliferation inhibition were lower in TOV‐112D ovarian cancer cells than that in SKOV3 cells by G1 and G2/M cell cycle phase accumulation. Notably, magnolin suppressed colony growth of TOV‐112D cells in soft agar, whereas colony growth of SKOV3 cells in soft agar was not affected by magnolin treatment. Interestingly, phospho‐protein profiles in the MAPK and PI3 K signaling pathways indicated that SKOV3 cells showed marked increase of Akt phosphorylation at Thr308 and Ser473 and very weak ERK1/2 phosphorylation levels by EGF stimulation. The phospho‐protein profiles in TOV‐112D cells were the opposite of those of SKOV3 cells. Importantly, magnolin treatment suppressed phosphorylation of RSKs in TOV‐112D, but not in SKOV3 cells. Moreover, magnolin increased SA‐β‐galactosidase‐positive cells in a dose‐dependent manner in TOV‐112D cells, but not in SKOV3 cells. Notably, oral administration of Shin‐Yi fraction 1, which contained magnolin approximately 53%, suppressed TOV‐112D cell growth in athymic nude mice by induction of p16Ink4a and p27Kip1. Taken together, targeting of ERK1 and ERK2 is suitable for the treatment of ovarian cancer cells that do not harbor the constitutive active P13 K mutation and the loss‐of‐function mutations of the p16 and/or p53 tumor suppressor proteins

Fargesin Inhibits EGF-Induced Cell Transformation and Colon Cancer Cell Growth by Suppression of CDK2/Cyclin E Signaling Pathway

Although the lignan compound fargesin is a major ingredient in Shin-Yi, the roles of fargesin in carcinogenesis and cancer cell growth have not been elucidated. In this study, we observed that fargesin inhibited cell proliferation and transformation by suppression of epidermal growth factor (EGF)-stimulated G1/S-phase cell cycle transition in premalignant JB6 Cl41 and HaCaT cells. Unexpectedly, we found that signaling pathway analyses showed different regulation patterns in which fargesin inhibited phosphatidylinositol 3-kinase/AKT signaling without an alteration of or increase in mitogen activated protein kinase (MAPK) in JB6 Cl41 and HaCaT cells, while both signaling pathways were abrogated by fargesin treatment in colon cancer cells. We further found that fargesin-induced colony growth inhibition of colon cancer cells was mediated by suppression of the cyclin dependent kinase 2 (CDK2)/cyclin E signaling axis by upregulation of p21WAF1/Cip1, resulting in G1-phase cell cycle accumulation in a dose-dependent manner. Simultaneously, the suppression of CDK2/cyclin E and induction of p21WAF1/Cip1 were correlated with Rb phosphorylation and c-Myc suppression. Taken together, we conclude that fargesin-mediated c-Myc suppression inhibits EGF-induced cell transformation and colon cancer cell colony growth by the suppression of retinoblastoma (Rb)-E2F and CDK/cyclin signaling pathways, which are mainly regulated by MAPK and PKB signaling pathways