A Universal Strategy for Synthesis of 2D Ternary Transition Metal Phosphorous Chalcogenides.

The 2D ternary transition metal phosphorous chalcogenides (TMPCs) have attracted extensive research interest due to their widely tunable band gap, rich electronic properties, inherent magnetic and ferroelectric properties. However, the synthesis of TMPCs via chemical vapor deposition (CVD) is still challenging since it is difficult to control reactions among multi-precursors. Here, a subtractive element growth mechanism is proposed to controllably synthesize the TMPCs. Based on the growth mechanism, the TMPCs including FePS3 , FePSe3 , MnPS3 , MnPSe3 , CdPS3 , CdPSe3 , In2 P3 S9 , and SnPS3 are achieved successfully and further confirmed by Raman, second-harmonic generation (SHG), and scanning transmission electron microscopy (STEM). The typical TMPCs-SnPS3 shows a strong SHG signal at 1064 nm, with an effective nonlinear susceptibility χ(2) of 8.41 × 10-11  m V-1 , which is about 8 times of that in MoS2 . And the photodetector based on CdPSe3 exhibits superior detection performances with responsivity of 582 mA W-1 , high detectivity of 3.19 × 1011  Jones, and fast rise time of 611 µs, which is better than most previously reported TMPCs-based photodetectors. These results demonstrate the high quality of TMPCs and promote the exploration of the optical properties of 2D TMPCs for their applications in optoelectronics.

Sevelamer arsenite nanoparticle as a Pi-responsive drug carrier and embolic agent for chemoembolization.

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

Pi-inducedin-situaggregation of sevelamer nanoparticles for vascular embolization.

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives,in situgelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackablein vivo. In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic.

Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin.

It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.

Ultrasound-Guided Percutaneous Ethanol-Paclitaxel Combined Therapy for Rabbit VX2 Liver Tumors.

BACKGROUND: It is difficult to achieve whole tumor ablation using percutaneous ethanol ablation therapy (PEAT) due to the limited diffusion of ethanol. PURPOSE: To determine whether chemotherapy can be an adjuvant therapy to benefit PEAT, we investigated ultrasound-guided percutaneous ethanol-paclitaxel combined therapy (PEPCT) of VX2 carcinoma, a rabbit liver cancer model. MATERIALS AND METHODS: A six-arm study was designed to quantify the correlation between paclitaxel (PTX) dose and tumor necrosis or cell proliferation, including sham group (2 mL saline, n=6), incremented dose of PTX (0, 12.5, 25, 37.5 mg) in 2.0 mL ethanol (n=6) and a conventional PEAT group (n=6) as comparison. The test was followed by contrast-enhanced ultrasonic (CEUS) before 7-day sacrifice, tumor harvest, and sectioning. Tumor necrosis ratio was radiologically and histologically quantified; modified proliferation index (m-PI) was proposed to quantify the PTX's pharmacological effects. A linear regression model was set to correlate the PTX dose with tumor necrosis ratio or cell proliferation index. The difference of radiological, histological necrosis ratio (HNR) and modified PI in six groups was analyzed via Kruskal-Wallis H-test, Welch analysis of variance and one-way ANOVA. RESULTS: Incremental increases of PTX (0, 12.5, 25, 37.5 mg) correlated with greater fraction of tumor necrosis (R2 = 0.946, P<0.001 for radiological necrosis ratio [RNR], R2 = 0.843, P<0.001 forHNR), indicating that one week after procedure PTX's anti-proliferation and ethanol's dehydration co-induced severe tumor necrosis. Correlation analysis further testified a significant association between PTX dose and m-PI (R2 = 0.860, P<0.001). CONCLUSION: These results suggest a clear role for PTX-induced cytotoxicity and support the use of chemotherapeutic drugs in ablation therapy.

Nanosized drug-eluting bead for transcatheter arterial chemoembolization (ND-TACE).

Commercially available drug-eluting embolization beads (100-500 µm) reduced the occurrence of adverse events related to an anticancer drug, but were unascertained to remarkably benefit the transcatheter arterial chemoembolization (TACE) treatment of intermediate-stage liver cancer. Dextran-coated arsenite nanoparticles with the size ranging from 400 to 600 nm were developed as a nanosized drug-eluting bead (NDEB) for chemoembolization therapy of the rabbit VX2 liver tumor. We fully characterized their relevant physicochemistry and drug release properties. Their hemolysis was investigated before vessel embolization. The introduction of the NDEB allowed continuous embolization of tumor feeding vessels and sustained release of arsenic trioxide, thereby causing severe tumor necrosis and reduced vascularity. Sonography including B mode ultrasound, color Doppler flow imaging (CDFI) and dynamic contrast-enhanced ultrasound (CEUS) were performed to evaluate the tumor vascularity and viability. Additionally, its hepatotoxicity was tolerable at a medium dose. NDEB-TACE might be an effective therapeutic strategy for interventional therapy.

Intratumoral inorganic phosphate deprivation: A new anticancer strategy?

Tumor epidemiology, as well as tumor microenvironments and cancer cell signaling study, has been presented with statistical relevance of inorganic phosphate (Pi) to tumorigenesis. Although serum Pi is still not acknowledged as a clinical tumor biomarker, abnormally high Pi concentration in serum or tumor lesions is gradually recognized as a characteristic of malignancy. On the other hand, phosphate binder (e.g. La2 (CO3)3, Fosrenols) has been clinically approved to treat hyperphosphatemia, a metabolic disease characterized by a high serum phosphate level. We hypothesize that, if reducing phosphate burden comes to benefit tumor therapy, could systemic or intratumoral administration of phosphate binder effectively deprive tumor Pi concentration, and then inhibit tumor growth and metastases? From the past clinical and preclinical outcomes, we'd conclude that Pi is not only a metabolite during tumor growth but also a force to trigger tumor progression and metastases. Two types of cancer models were developed to initiate this study. Firstly, a patient-derived xenograft mouse model of colorectal cancer was designed, where mice were administered systemically or intratumorally with lanthanum acetate (a molecular phosphate binder), and the serum or intratumoral Pi concentration levels were found to a dropdown. Secondly, a rabbit VX2 liver tumor was set up for the local-regional therapy model, where lanthanum acetate was intratumorally administered by the standard transcatheter arterial chemoembolization procedure, and it significantly reduced intratumoral Pi concentration. Therefore, Pi deprivation by phosphate binder might be a new anticancer strategy if reducing phosphate burden could effectively arrest tumor growth and delay metastatic progression.

Will Arsenic Trioxide Benefit Treatment of Solid Tumor by Nano- Encapsulation?

Arsenic trioxide (ATO) has remarkably enhanced therapeutic efficacy in treating both newly diagnosed and relapsed patients suffering from Acute Promyelocytic Leukemia (APL). Unfortunately, whether as a single agent, component of combined chemotherapy, or as a chemosensitizer or radiosensitizer combined with interventional therapy/radiotherapy, it did not benefit treatment of solid tumor (liver cancer, bladder cancer, glioma, breast cancer, cervical cancer, colorectal cancer, lung cancer, and melanoma) as seen from the clinical trials reported from the published journals or FDA-approved trials in the past decades. The clinical outcome failed to live up to our expectations, which was attributed to severe systemic toxicity and inappropriate pharmacokinetic such as low delivery efficiency and rapid renal elimination. Nanomedicine is designed to fuel up pharmaceuticals and polish off adverse effects by the moderation of their absorption, distribution, metabolism, and excretion. Nevertheless, quite a few nanodrugs (such as Doxil, Abraxane) were approved to be used clinically, and "from bench to bedside" it seems to be no easy way for most of them, such as nano-ATO. Encapsulating ATO into several types of nano-vehicles (liposome, polymer micelle, porous silicon, etc.), nano-TO can improve pharmacokinetic and become a prominent candidate to penetrate into tumor tissue, but so far no nano- ATO clinical trials have been approved around the world. On summarizing the clinical trials of ATO on solid tumor and preclinical study of nano-ATO, it is believed there is still a chance for ATO to play a critical co-helper in a comprehensive therapy to fight with solid tumor.

Sustained release of arsenic trioxide benefits interventional therapy on rabbit VX2 liver tumor.

The benefit of chemotherapy as a constituent of transcatheter arterial chemoembolization (TACE) is still in debate. Recently we have developed arsenic trioxide nanoparticle prodrug (ATONP) as a new anticancer drug, but its systemic toxicity is a big issue. In this preclinical TACE study, ATONP emulsified in lipiodol behaved as drug-eluting bead manner. Sustained release of arsenic from ATONP within occluded tumor caused very low arsenic level in plasma, avoiding the "rushing out" effect as ATO did. Correspondingly, intratumoral arsenic accumulation and inorganic phosphate deprivation were simultaneously observed, and arsenic concentration was much higher as ATONP was transarterially administered than ATO, or intravenously injected. Tumor necrosis and apoptosis were remarkably more severe in ATONP group than ATO, but no significant hepatic and renal toxicity was perceived. In brief, ATONP alleviated arsenic toxicity and boosted the therapeutic effect of TACE via Pi-activated drug sustainable release.

Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia.

BACKGROUND: Excessive binge alcohol drinking has acute cardiac arrhythmogenic effects, including promotion of atrial fibrillation (AF), which underlies "Holiday Heart Syndrome." The mechanism that couples binge alcohol abuse with AF susceptibility remains unclear. We previously reported stress-activated c-Jun N-terminal kinase (JNK) signaling contributes to AF development. This is interesting because JNK is implicated in alcohol-caused organ malfunction beyond the heart. OBJECTIVES: The purpose of this study was to detail how JNK promotes binge alcohol-evoked susceptibility to AF. METHODS: The authors found binge alcohol-exposure leads to activated JNK, specifically JNK2. Furthermore, binge alcohol induces AF (24- vs. 1.8-Hz burst pacing-induced episodes per attempt per animal), higher incidence of diastolic intracellular Ca2+ activity (Ca2+ waves, sarcoplasmic reticulum [SR] Ca2+ leakage), and membrane voltage (Vm) and systolic Ca2+ release spatiotemporal heterogeneity (ΔtVm-Ca). These changes were completely eliminated by JNK inhibition both in vivo and in vitro. calmodulin kinase II (CaMKII) is a proarrhythmic molecule known to drive SR Ca2+ mishandling. RESULTS: The authors report for the first time that binge alcohol activates JNK2, which subsequently phosphorylates the CaMKII protein, enhancing CaMKII-driven SR Ca2+ mishandling. CaMKII inhibition eliminates binge alcohol-evoked arrhythmic activities. CONCLUSIONS: Our studies demonstrate that binge alcohol exposure activates JNK2 in atria, which then drives CaMKII activation, prompting aberrant Ca2+ waves and, thus, enhanced susceptibility to atrial arrhythmia. Our results reveal a previously unrecognized form of alcohol-driven kinase-on-kinase proarrhythmic crosstalk. Atrial JNK2 function represents a potential novel therapeutic target to treat and/or prevent AF.

The stress kinase JNK regulates gap junction Cx43 gene expression and promotes atrial fibrillation in the aged heart.

BACKGROUND: The stress kinase c-jun N-terminal kinase (JNK) is critical in the pathogenesis of cardiac diseases associated with an increased incidence of atrial fibrillation (AF), the most common arrhythmia in the elderly. We recently discovered that JNK activation is linked to the loss of gap junction connexin43 (Cx43) and enhanced atrial arrhythmogenicity. However, direct evidence for JNK-mediated impairment of intercellular coupling (cell-cell communication) in the intact aged atrium is lacking, as is evidence for whether and how JNK suppresses Cx43 in the aged human atrium. METHODS AND RESULTS: JNK activity in human atrial samples is correlated with both reduced Cx43 expression and increasing age. Using a unique technique of optical mapping space constant measurement, we found that impaired intercellular coupling and reduced Cx43 were linked to enhanced activation of JNK in intact aged rabbit atria. These JNK-associated alterations were further confirmed in naturally JNK activated aged mice and in cardiac-specific inducible MKK7D (JNK upstream activator) young mice. Moreover, JNK inhibition, using either JNK specific inhibitors in aged wild-type (WT) mice and JNK activator anisomycin-treated young WT mice or JNK1/2 dominant-negative mice with genetically inhibited cardiac JNK activity, completely eliminated these functional abnormalities. Furthermore, we discovered for the first time that long-term JNK activation downregulates Cx43 expression via c-jun suppressed transcriptional activity of the Cx43 gene promoter. CONCLUSION: Our results demonstrate that JNK is a critical regulator of Cx43 expression, and that augmented JNK activation in aged atria downregulates Cx43 to impair cell-cell communication and promote the development of AF. JNK inhibition may represent a promising therapeutic approach to prevent or treat AF in the elderly.

Identification of flavonoids and their glycosides by high-performance liquid chromatography with electrospray ionization mass spectrometry and with diode array ultraviolet detection.

Identification of flavonoids and flavonoid glycosides was carried out on Psidium guajava Linn leaves by means of high-performance liquid chromatography ultraviolet (HPLC-UV) analysis and HPLC mass spectrometry. By using HPLC-UV, two known phenolics (gallic acid and quercetin) and five newly reported ones (procatechuic acid, chlorogenic acid, caffeic acid, kaempferol and ferulic acid) were identified in alcohol guava leaf extract. Structural information about the compounds was obtained from the retention times, the UV spectra and mass spectra without the need to isolate the individual compounds. Two flavonoids (quercetin and kaempferol) and four flavonoid glycosides (three known components, quercetin 3-O-alpha-L-arabinoside, quercetin 3-O-beta-D-glucoside and quercetin 3-O-beta-D-galactoside, along with one novel compound, kaempferol-glycoside) and three other unknown compounds have been identified in the fractions.