Crosstalk between circBMI1 and miR-338-5p/ID4 inhibits AML progression.

BMI1 Polycomb Ring Finger Proto-Oncogene (BMI1) is involved in the pathogenesis of different cancers, including acute myeloid leukemia (AML). However, the role of the circular RNA of BMI1 (circBMI1) has not been studied. Our study aimed to investigate the role and mechanism of circBMI1 in AML. circBMI1 was significantly decreased in bone marrow mononuclear cells aspirated from patients with AML. Receiver operating characteristic curve analysis showed that circBMI1 could distinguish patients with AML from controls. By overexpressing and knocking down circBMI1 in HL-60 cells, we found that circBMI1 inhibited cell proliferation, promoted apoptosis, and increased chemotherapeutic drug sensitivity in AML. Experiments using severe combined immune-deficient mice and circBMI1 transgenic mice showed that mice with circBMI1 overexpression had lower white blood cell counts, which suggested less severe AML invasion. RNA immunoprecipitation and dual-luciferase reporter assay revealed binding sites among circBMI1, miR-338-5p, and inhibitor of DNA binding 4 (ID4). Rescue experiments proved that circBMI1 inhibited AML progression by binding to miR-338-5p, which affected the expression of ID4. By coculturing exosomes extracted from circBMI1-HL-60 and small interfering circBMI1-HL-60 cells with HL-60 cells, we found that exosomes from circBMI1-HL-60 cells showed tumor suppressive effects, namely inhibiting HL-60 proliferation, promoting apoptosis, and increasing chemotherapeutic drug sensitivity. Exosomes from small interfering circBMI1-HL-60 cells showed the opposite effects. circBMI1 may act as an exosome-dependent tumor inhibitor. circBMI1, a potential biomarker for clinical diagnosis, acts as a tumor suppressor in AML by regulating miR-338-5p/ID4 and might affect the pathogenesis of AML by exosome secretion.

A near-infrared fluorescence probe with large Stokes shift for selectively monitoring nitroreductase in living cells and mouse tumor models.

Hypoxia is commonly regarded as a typical feature of solid tumors, which originates from the insufficient supply of oxygen. Herein, the development of an efficient method for assessing hypoxia levels in tumors is strongly desirable. Nitroreductase (NTR) is an overexpressed reductase in the solid tumors, has been served as a potential biomarker to evaluate the degrees of hypoxia. In this work, we elaborately synthesized a new near-infrared (NIR) fluorescence probe (MR) to monitor NTR activity for assessment of hypoxia levels in living cells and in tumors. Upon exposure of NTR, the nitro-unit of MR could be selectively reduced to amino-moiety with the help of nicotinamide adenine dinucleotide. Moreover, the obtained fluorophore emitted a prominent NIR fluorescence, because it possessed a classical "push-pull" structure. The MR displayed several distinguished characters toward NTR, including intense NIR fluorescent signals, large Stokes shift, high selectivity and low limit of detection (46 ng/mL). Furthermore, cellular confocal fluorescence imaging results validated that the MR had potential of detecting NTR levels in hypoxic cells. Significantly, using the MR, the elevated of NTR levels were successfully visualized in the tumor-bearing mouse models. Therefore, this detecting platform based on this probe may be tactfully constructed for monitoring the variations of NTR and estimating the degrees of hypoxia in tumors.

PLA2G2D fosters angiogenesis in non-small cell lung cancer through aerobic glycolysis.

Non-small cell lung cancer (NSCLC) stands prominent among the prevailing and formidable oncological entities. The immune and metabolic-related molecule Phospholipase A2, group IID (PLA2G2D) exerts promotional effects on tumor progression. However, its involvement in cancer angiogenesis remains elusive. Therefore, this investigation delved into the functional significance of PLA2G2D concerning angiogenesis in NSCLC. This study analyzed the expression and enriched pathways of PLA2G2D in NSCLC tissues through bioinformatics analysis, and measured the expression of PLA2G2D in NSCLC cells using qRT-PCR and western blot (WB). Subsequently, the viability and angiogenic potential of NSCLC cells were assessed employing CCK-8 and angiogenesis assays, respectively. The expression profile of angiogenic factors was analyzed through WB. Finally, the expression of glycolysis pathway-related genes, extracellular acidification rate and oxygen consumption rate, and the levels of pyruvate, lactate, citrate, and malate were analyzed in NSCLC cells using qRT-PCR, Seahorse XF 96, and related kits. Bioinformatics analysis revealed the upregulation of PLA2G2D in NSCLC tissues and its association with VEGF and glycolysis signaling pathways. Molecular and cellular experiments demonstrated that upregulated PLA2G2D promoted the viability, angiogenic ability, and glycolysis pathway of NSCLC cells. Rescue assays revealed that the effects of high expression of PLA2G2D on the viability, angiogenic ability, and glycolysis of NSCLC cells were weakened after the addition of the glycolysis inhibitor 2-DG. In summary, PLA2G2D plays a key role in NSCLC angiogenesis through aerobic glycolysis, displaying great potential as a target for anti-angiogenesis therapy.

Near-infrared light-induced photoelectrochemical biosensor based on plasmon-enhanced upconversion nanocomposites for microRNA-155 detection with cascade amplifications.

Herein, a novel near-infrared (NIR) light-driven photoelectrochemical (PEC) biosensor based on NaYF4:Yb3+, Er3+@Bi2MoO6@Bi (NYF@BMO@Bi) nanocomposites was elaborately developed to achieve highly sensitive detection of microRNA-155 (miRNA-155). To realize signal enhancement, the coupled plasmonic bismuth (Bi) nanoparticles were constructed as an energy relay to facilitate the transfer of energy from NaYF4:Yb3+, Er3+ to Bi2MoO6, ultimately enabling the efficient separation of electron-hole pairs of Bi2MoO6 under the irradiation of a 980 nm laser. For constructing biosensing system, the initial signal was firstly amplified after the addition of alkaline phosphatase (ALP) in conjunction with the biofunctionalized NYF@BMO@Bi nanocomposites, which could catalyze the conversion of ascorbic acid 2-phosphate into ascorbic acid, and then consumed the photoacoustic holes created on the surface of Bi2MoO6 for the enlarging photocurrent production. Upon addition of target miRNA-155, the cascade signal amplification process was triggered while the ALP-modified DNA sequence was replaced and then followed by the initiation of a simulated biocatalytic precipitation reaction to attenuate the photocurrent response. On account of the NIR-light-driven and cascade amplifications strategy, the as-constructed biosensor was successfully utilized for the accurate determination of miRNA-155 ranging from 1 fM to 0.1 µM with a detection limit of 0.32 fM. We believed that the proposed nanocomposites-based NIR-triggered PEC biosensor could provide a promising platform for effective monitoring other tumor biomarkers in clinical diagnostics.

Probing Iron-Mediated Synergistic Change of Cl- and HClO in Liver Cancer Cells with a Dual-Color Fluorescence Reporter.

The ambiguous molecular mechanism remains a leading cause for the high mortality rate of liver cancer. An evident iron overload has been unveiled in liver cancer cell proliferation, which is closely related to oxidative stress. However oxidative stress-regulated chloride intracellular channel protein 1 (CLIC1) obviously increases in liver cancer cells. Cl- is also involved in cell proliferation, and its downstream product, HClO, can induce cell carcinoma when over-generated. However, whether iron overload could mediate the variation of intracellular Cl- and HClO is still uncharted. Herein, we present a dual-responsive fluorescence reporter MQFL-NH2 for simultaneously visualizing the fluctuation of Cl-/HClO at the same spot in living cells. Electrostatic binding to Cl- effectively gave an attenuated signal with blue fluorescence, and HClO induced a sharp green fluorescence. In HL-7702 cells stimulated with iron, the blue/green dual fluorescence of MQFL-NH2 displayed that Cl- and HClO were elevated. In contrast, they were both reduced in iron-removed SMMC-7721 cells. Further results revealed that iron overload could promote the levels of Cl- and HClO by up-regulating CLIC1 and myeloperoxidase. Altogether, the work will energetically contribute to grasp the molecular mechanism in iron overload-mediated pathogenesis of liver cancer.

Recent Progress in Small-Molecule Fluorescence and Photoacoustic Dual-Modal Probes for the In-Vivo Detection of Bioactive Molecules.

Intracellular bioactive molecules are essential for the maintenance of homeostasis in living organisms. Abnormal levels of them are closely related to the occurrence and development of some diseases. Hence, the direct and accurate visualization of these bioactive molecules is of vital importance for exploring their pathological roles. However, the low-content, short-lived, and widely distributed properties of bioactive molecules impede the comprehensive analysis of them dramatically. Fluorescence and photoacoustic dual-mode imaging technology provides a new solution to the above issue. Specifically, the combination of fluorescence and photoacoustic, which possesses the advantages of high resolution and in-depth tissue analysis, enables a more in-depth and systematic exploration of the pathogenic mechanisms of bioactive molecules. Moreover, due to the structural tailorability of small molecule probes, numerous small molecule dual-mode probes have been developed to meet the demand for real-time tracking and visualization of bioactive molecules in living cells or in vivo. Hence, in this review, we briefly summarize the key advances in small molecule fluorescence and photoacoustic dual-modal probes within recent years (2015-2021). A particular focus is placed on the design strategies and biological applications of probes for the detection of various bioactive molecules in vivo. Furthermore, the challenges and further prospects in this hot field are highlighted.

[Cholesteatoma of the middle ear combined with intracranial and extracranial complications in children: a case report].

In this paper, a case of middle ear cholesteatoma with sigmoid sinus thrombophlebitis and retroauricular subperiosteal abscess was reported. The female patient was hospitalized with bilateral ear abscess for more than 20 days and fever with vomiting for 14 days. Anti-infection treatment after admission, emergency right mastoid radical resection and tympanoplasty were performed under general anesthesia. The patient recovered well after surgery, and there was no recurrence after in the follow-up for more than 2 years.The clinical manifestations, imaging features and prognosis of this disease were discussed and analyzed in the paper.

Demystifying Lysosomal α-l-Fucosidase in Liver Cancer-Bearing Mice by Specific Two-Photon Fluorescence Imaging.

Liver cancer is one of the most frequently diagnosed cancers and has high mortality. However, the early treatment and prognosis can greatly prolong the survival time of patients, which depends on its early detection. α-l-Fucosidase (AFU), as a vital lysosomal hydrolase, is considered to be an ideal biomarker for early stage liver cancer. So, in vivo monitoring of AFU is essential for the early and accurate diagnosis of liver cancer. Hence, we designed the first two-photon turn-on fluorescent reporter, termed HcyCl-F, which localized to lysosomes for fast imaging of AFU. The 2-chloro-4-phenyl-α-l-fucoside bond of HcyCl-F could be effectively hydrolyzed by AFU and released the hydroxyl on the benzene ring, eventually obtaining a strong conjugated compound (HcyCl-OH) with shiny fluorescence. We demonstrated that HcyCl-F was able to rapidly and accurately respond to AFU. Using a two-photon fluorescence microscope, we successfully visualized the fluctuation of AFU in lysosomes. More importantly, a fascinatingly strong fluorescence signal was observed in the tumor tissue of liver cancer-bearing mice. Of note, we confirmed that HcyCl-F could clearly detect liver tumors in stage I. Altogether, our work provides a simple and convenient method for deciphering the critical pathological function of AFU in depth and facilitates the nondestructive and effective diagnosis of liver cancer in the early stage.

Halegenticoccus tardaugens sp. nov., an extremely halophilic archaeon isolated from a saline soil.

Two extremely halophilic archaea, isolates SYSU A00711T and SYSU A00630, were isolated from a sediment soil sample collected from the Aiding lake, China. Cells of these isolates were cocci, non-motile and stained Gram-negative. They grew optimally at 37 °C, with 20-22% NaCl (w/v) and at pH 7.5-8.0. Cells lysed in distilled water. Major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, mannosyl glucosyl diether, sulfated mannosyl glucosyl diether, and two unidentified glycolipids. Pairwise sequence comparison revealed that isolates SYSU A00711T and SYSU A00630 were closely related to Halegenticoccus soli SYSU A9-0T (94.1 and 94.0% 16S rRNA gene sequence similarities; 94.0 and 94.2% rpoB' gene similarities, respectively). The overall genomic relatedness indices values between the two isolates and Halegenticocus soli SYSU A9-0 T were: AAI, both 79.6%; ANI, 84.6 and 84.5%; dDDH, 32.5 and 26.3%, respectively. Phylogenetic trees based on the 16S rRNA gene, rpoB' gene, and genome sequences demonstrated a robust clade of these two isolates with Halegenticoccus soli SYSU A9-0T. The DNA G + C contents of these two isolates are both 64.7% (genome method). Based on the differences in phenotypic, chemotaxonomic, and phylogenetic properties, isolates SYSU A00711T and SYSU A00630 are characterized to represent a novel species in the genus Halegenticoccus, for which the name Halegenticoccus tardaugens sp. nov. is proposed. The type strain of the species Halegenticoccus tardaugens is SYSU A00711T (= KCTC 4245T = CGMCC 1.15768T).

Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy.

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug's clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT2A receptor inverse agonist used for the treatment of Parkinson's disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM's antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM's side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.

[Clinical analysis of the vascular pulsatile tinnitus associated with sigmoid sinus-mastoid].

Objective:To probe the clinical characteristics of diagnosis and therapy of vascular pulsatile tinnitus（PT） associated with sigmoid sinus-mastoid. Methods:Retrospectively analyzed the clinical data of the hospitalized 45 PT patients of an ear surgeon in one hospital between January 2013 to January 2020, and observed the effectiveness with surgery and non-surgery therapy. Surgical procedures include reconstruction the bone wall of sigmoid sinus by transmastoid approach and ligation of mastoid emissary vein. Non-surgery therapy includes anti-anemia therapy and observation. All patients have been followed-up in ENT outpatient. Results: Of 45 cases, female：male was 43：2, the mean age was 42.7 years old. The other PT patients were the subjective tinnitus except two females were the objective tinnitus. Of 40 cases, 38 patients underwent transmastoid approach to reconstructed sigmoid sinus bone wall, including 6 patients with the ligated mastoid emissary vein at the same period.The other 2 cases with the ligated mastoid emissary vein only.Five cases were treated by non-surgery therapies, including 2 cases anti-anemia therapy and 3 cases observation. The longest follow-up period was seven and a half years, the shortest was six months. One case was lost to follow up. The total cure rate was 80.0%（36/45），the surgery cure rate was 82.5%（33/40）, the non-surgery cure rate was 60.0% （3/5）. Conclusion:The pathophysiologic mechanism of the PT is still complex and unclear until now. However, the following conditions probably play an important role in the etiology: female, common features of anatomy anomalies, hemodynamic variations. It is a key point to confirm the responsible site or the main cause of the PT . Although the surgery is relatively simple, the effect is remarkable and no major postoperative complications，surgery could not be a only choice.

Exploring the Changes of Peroxisomal Polarity in the Liver of Mice with Nonalcoholic Fatty Liver Disease.

Peroxisome proliferator-activated receptor alpha (PPAR-a) is a crucial nuclear transcription regulator of lipid metabolism, which is closely associated with the initiation and development of nonalcoholic fatty liver disease (NAFLD). Because PPAR-a can directly decide the level of peroxisomal metabolic enzymes, its changes might directly cause variations in peroxisomal polarity. Therefore, we developed a new two-photon fluorescence imaging probe, PX-P, in which the triphenylamine and cyanide moieties can real-time sense peroxisomal polarity changes. Using PX-P, we observed a prominent decrease in the peroxisomal polarity in the liver of mice with NAFLD for the first time. More importantly, we discovered that intracellular excessive peroxynitrite (ONOO-) and hydrogen peroxide (H2O2) underwent nitrification and oxidation, respectively, with various sites of PPAR-a. Interestingly, the key site of PPAR-a was nitrated by a low concentration of ONOO- rather than being oxidized by the high level of H2O2. These drastically reduced the activity of PPAR-a, accelerating the occurrence of NAFLD. Moreover, through activating PPARs with pioglitazone, peroxisomal polarity markedly increased compared with that of NAFLD. Altogether, our work presents a new approach for the early diagnosis of NAFLD and identifies potential therapeutic targets.

Rapid Two-Photon Fluorescence Imaging of Monoamine Oxidase B for Diagnosis of Early-Stage Liver Fibrosis in Mice.

Liver fibrosis could induce cirrhosis and liver cancer, causing serious damages to liver function and even death. Early diagnosis of fibrosis is extremely requisite for optimizing treatment schedule to improve cure rate. In early-stage fibrosis, overexpressed monoamine oxidase B (MAO-B) can serve as a biomarker, which greatly contributes to the diagnosis of early liver fibrosis. However, there is still a lack of desired strategy to precisely monitor MAO-B in situ. In this work, we established a two-photon fluorescence imaging method for in vivo detection of MAO-B activity counting on a simply prepared probe, BiPhAA. The BiPhAA could be activated by MAO-B within 10 min and fluoresced brightly. To our knowledge, this BiPhAA-based imaging platform for MAO-B is more rapid than other current detection methods. Furthermore, BiPhAA allowed the dynamic observation of endogenous MAO-B level changes in hepatic stellate cells (LX-2). Through two-photon fluorescence imaging, we observed six times higher fluorescence brightness in the liver tissue of fibrosis mice than that of normal mice, thus successfully distinguishing mice with liver fibrosis from normal mice. Our work offers a simple, fast, and highly sensitive approach for imaging MAO-B in situ and paves a way to the diagnosis of early liver fibrosis with accuracy.

ALP-Activated Chemiluminescence PDT Nano-Platform for Liver Cancer-Specific Theranostics.

Photodynamic therapy (PDT) is a promising therapeutic approach that has been extensively applied in curing cancers. However, the limited penetration depth of external light makes PDT only practical for some superficial tumor treatments. Moreover, an external light irradiation might cause damages to adjacent normal tissues. Additionally, the poor targeting ability of PDT can lead to side effects like skin phototoxicity. Therefore, a PDT strategy addressing these drawbacks is urgently exploited. Herein, we constructed a chemiluminescence theranostics platform named MSN@H6L@ß-CD@AMPPD NPs for liver cancer-specific, in situ diagnosis and therapy without an external light source. Through the interaction of host-guest, 3-[(2-spiroadamatane)-4-methoxy-4-(3-phosphoryloxy)-phenyl-1,2-dioxetane] dioxetane, a chemiluminescence substrate of the liver cancer biomarker alkaline phosphatase was integrated with ß-cyclodextrin. Then, the ß-cyclodextrin was covalently bound to the mesoporous silica loaded with (4-carboxyphenyl) porphyrin to finally obtain the MSN@H6L@ß-CD@AMPPD NPs. These NPs can be specifically hydrolyzed by the liver cancer alkaline phosphatase and lead to the liver cancer-targeting chemiluminescence. Subsequently, (4-carboxyphenyl) porphyrin was excited by the chemiluminescence through chemiluminescence resonance energy transfer and created both near-infrared fluorescence and 1O2. This strategy greatly promotes the penetration depth and targeting ability of the PDT. In brief, the platform accomplishes a PDT nano-theranostics for liver cancer and provides a method for the imaging, diagnosis, and therapy of tumors in deep tissue.

In situ visualization of peroxisomal viscosity in the liver of mice with non-alcoholic fatty liver disease by near-infrared fluorescence and photoacoustic imaging.

Non-alcoholic fatty liver disease (NAFLD) can gradually develop into hepatic failure, and early diagnosis is crucial to improve treatment efficiency. The occurrence of NAFLD is closely related to lipid metabolism. Peroxisomes act as the first and main site for lipid metabolism in the hepatocytes, so abnormal lipid metabolism might directly affect peroxisomal viscosity. Herein, we developed a new near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging probe (PV-1) for the real-time visualization of peroxisomal viscosity in vivo. This PV-1 encompasses the malononitrile group as the rotor, which emits strong NIRF (at 705 nm) and PA (at 680 nm) signals when rotation is hindered as viscosity increases. Through dual-mode imaging, we discovered distinctly higher viscosity in the liver of NAFLD mice for the first time. We further found the remarkable amelioration of NAFLD upon treatment with N-acetylcysteine (NAC). Therefore, we anticipate that the PV-1 imaging method is promising for the early diagnosis and prognostic evaluation of NAFLD.

Visualization of Dynamic Changes in Labile Iron(II) Pools in Endoplasmic Reticulum Stress-Mediated Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) can cause liver failure and even death in severe cases, gravely threatening human health. The treatment of DILI remains a clinical challenge, mainly due to the lack of efficient and accurate diagnosis. Therefore, developing an accurate diagnosis approach is imperative to boost the timely treatment for DILI. As the primary organ of iron storage, liver's functions are tightly linked to iron homeostasis. Thus, monitoring iron homeostasis is promising for the diagnosis and treatment of DILI. Hence, we reported a new near-infrared fluorescent probe (LCy7) that enables real-time and in vivo visualizing of Fe2+ in drug-induced liver injury. In this design, Fe2+ would bind to the N4O ligand in LCy7 and conduce to the C-O bond broken in the presence of O2, which restore the masked QCy7 emitting luminous near-infrared fluorescence. Utilizing LCy7, the increase in Fe2+ was distinctly witnessed in hepatocytes under endoplasmic reticulum stress by acetaminophen (APAP) stimulation. In vivo near-infrared fluorescence imaging revealed the conspicuous rise in Fe2+ in the liver of mice during APAP-induced liver injury. We further unprecedentedly disclosed that endoplasmic reticulum stress was accompanied by the overload of Fe2+ in injured liver of these mice. Collectively, this work will facilitate a greater understanding of the pathogenesis of DILI, and also provide a powerful new tool for DILI diagnosis and treatment.