Inhibition of esophageal cancer progression through HACE1-TRIP12 interaction and associated RAC1 ubiquitination and degradation.

Objective: This study investigated the significance of HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) in esophageal cancer (ESCA) and its underlying mechanism in ESCA regulation through the induction of RAC1 ubiquitination and degradation. Methods: Characterization studies of HACE1 in ESCA clinical tissues and cell lines were performed. Next, the effects of HACE1 on the biological behavior of ESCA cells were examined by silencing and overexpressing HACE1. Protein-protein interactions (PPIs) involving HACE1 were analyzed using data from the String website. The function of HACE1 in RAC1 protein ubiquitination was validated using the proteasome inhibitor MG132. The effects of HACE1 on ESCA cells through RAC1 were elucidated by applying the RAC1 inhibitor EHop-016 in a tumor-bearing nude mouse model. To establish the relationship between HACE1 and TRIP12, rescue experiments were conducted, mainly to evaluate the effect of TRIP12 silencing on HACE1-mediated RAC1 regulation in vitro and in vivo. The PPI between HACE1 and TRIP12 and their subcellular localization were further characterized through co-immunoprecipitation and immunofluorescence staining assays, respectively. Results: HACE1 protein expression was notably diminished in ESCA cells but upregulated in normal tissues. HACE1 overexpression inhibited the malignant biological behavior of ESCA cells, leading to restrained tumor growth in mice. This effect was coupled with the promotion of RAC1 protein ubiquitination and subsequent degradation. Conversely, silencing HACE1 exhibited contrasting results. PPI existed between HACE1 and TRIP12, compounded by their similar subcellular localization. Intriguingly, TRIP12 inhibition blocked HACE1-driven RAC1 ubiquitination and mitigated the inhibitory effects of HACE1 on ESCA cells, alleviating tumor growth in the tumor-bearing nude mouse model. Conclusion: HACE1 expression was downregulated in ESCA cells, suggesting that it curbs ESCA progression by inducing RAC1 protein degradation through TRIP12-mediated ubiquitination.

Integrating a Biomineralized Nanocluster for H2S-Sensitized ROS Bomb against Breast Cancer.

Nanomaterial-assisted chemodynamic therapy (CDT) has received considerable attention in recent years. It outperforms other modalities by its distinctive reactive oxygen species (ROS) generation through a nonexogenous stimulant. However, CDT is limited by the insufficient content of endogenous hydrogen peroxide (H2O2). Herein, a biodegradable MnS@HA-DOX nanocluster (MnS@HA-DOX NC) was constructed by in situ biomineralization from hyaluronic acid, to enlarge the ROS cascade and boost Mn2+-based CDT. The acid-responsive NCs could quickly degrade after internalization into endo/lysosomes, releasing Mn2+, H2S gas, and anticancer drug doxorubicin (DOX). The Fenton-like reaction catalyzed by Mn2+ was amplified by both H2S and DOX, producing a mass of cytotoxic ·OH radicals. Through the combined action of gas therapy (GT), CDT, and chemotherapy, oxidative stress would be synergistically enhanced, inducing irreversible DNA damage and cell cycle arrest, eventually resulting in cancer cell apoptosis.

Glucose Oxidase Driven Hydrogen Sulfide-Releasing Nanocascade for Diabetic Infection Treatment.

Diabetic ulcers have received much attention in recent years due to their high incidence and mortality, motivating the scientific community to develop various strategies for such chronic disease treatments. However, the therapeutic outcome of these approaches is highly compromised by invasive bacteria and a severe inflammatory microenvironment. To overcome these dilemmas, microenvironment-responsive self-delivery glucose oxidase@manganese sulfide (GOx@MnS) nanoparticles (NPs) are developed by one-step biomineralization. When they encounter the high glucose level in the ulcer site, GOx particles catalyze glucose to decrease the local pH and trigger the steady release of both manganese ions (Mn2+) and hydrogen sulfide (H2S). Mn2+ reacts with hydrogen peroxide to generate hydroxyl radicals for the elimination of bacterial infection; meanwhile, H2S is able to suppress the inflammatory response and accelerate diabetic wound healing through macrophage polarization. The excellent biocompatibility, strong bactericidal activity, and considerable immunomodulatory effect promise GOx@MnS NPs have great therapeutic potential for diabetic wound treatment.

On-demand therapeutic delivery of hydrogen sulfide aided by biomolecules.

Hydrogen sulfide (H2S), known as the third gasotransmitter, exerts various physiological functions including cardiac protection, angiogenesis, anti-inflammatory, and anti-cancer capability. Given its promising therapeutic potential as well as severe perniciousness if improper use, the sustained and tunable H2S delivery systems are highly required for H2S-based gas therapy with enhanced bioactivity and reduced side effects. To this end, a series of stimuli-responsive compounds capable of releasing H2S (termed H2S donors) have been designed over the past two decades to mimic the endogenous generation of H2S and elucidate the biological functions. Further to improve the stability of H2S donors and achieve the targeted delivery, various delivery systems have been constructed. In this review, we focus on the recent advances of an emerging subset, biomolecular-based H2S delivery systems, which combine H2S donors with biomolecular vectors including polysaccharide, peptide, and protein. We demonstrated their basic structures, building strategies, and therapeutic applications respectively to unfold their inherent merits endued by biomolecules including biocompatibility, biodegradability as well as expansibility. The varied development potentials of biomolecular-based H2S delivery systems based on their specific properties are also discussed. At the end, brief future outlooks and upcoming challenges are presented as well.

Exenatide Microspheres for Monthly Controlled-Release Aided by Magnesium Hydroxide.

GLP-1 receptor agonists are a class of diabetes medicines offering self-regulating glycemic efficacy and may best be administrated in long-acting forms. Among GLP-1 receptor agonists, exenatide is the one requiring the least dose so that controlled-release poly(d, l-lactic-co-glycolic acid) (PLGA) microspheres may best achieve this purpose. Based on this consideration, the present study extended the injection interval of exenatide microspheres from one week of the current dosage form to four weeks by simply blending Mg(OH)2 powder within the matrix of PLGA microspheres. Mg(OH)2 served as the diffusion channel creator in the earlier stage of the controlled-release period and the decelerator of the self-catalyzed degradation of PLGA (by the formed lactic and glycolic acids) in the later stage due to its pH-responsive solubility. As a result, exenatide gradually diffused from the microspheres through Mg(OH)2-created diffusion channels before degradation of the PLGA matrix, followed by a mild release due to Mg(OH)2-buffered degradation of the polymer skeleton. In addition, an extruding-settling process comprising squeezing the PLGA solution through a porous glass membrane and sedimentation-aided solidification of the PLGA droplets was used to prepare the microspheres to ensure narrow size distribution and 95% encapsulation efficiency in an aqueous continuous phase. A pharmacokinetic study using rhesus monkey model confirmed the above formulation design by showing a steady blood concentration profile of exenatide with reduced CMAX and dosage form index. Mg·(OH)2.

Antiproliferative activity and SARs of caffeic acid esters with mono-substituted phenylethanols moiety.

A series of CAPE derivatives with mono-substituted phenylethanols moiety were synthesized and evaluated by MTT assay on growth of 4 human cancer cell lines (Hela, DU-145, MCF-7 and ECA-109). The substituent effects on the antiproliferative activity were systematically investigated for the first time. It was found that electron-donating and hydrophobic substituents at 2'-position of phenylethanol moiety could significantly enhance CAPE's antiproliferative activity. 2'-Propoxyl derivative, as a novel caffeic acid ester, exhibited exquisite potency (IC50=0.4±0.02 & 0.6±0.03µM against Hela and DU-145 respectively).

Flavonoid composition and antioxidant activity of tree peony (Paeonia section moutan) yellow flowers.

Tree peony flowers are edible and traditional Chinese medicine materials. In the present study, 26 flavonoids were identified and quantified in yellow flowers of tree peony by high-performance liquid chromatography with diode array detector (HPLC-DAD) and by HPLC-electrospray ionization-mass spectrometry (HPLC-ESI-MS). Seventeen of them were first reported in flowers of tree peony, and glycosides of kaempferol, luteolin, and apigenin as well as isosalipurposide were the main flavonoids investigated. Furthermore, the petal extracts showed high antioxidant activity according to DPPH*, ABTS*(+), and OH* scavenging assays and ferric reducing antioxidant power assay. There were significant correlations between antioxidant activity and both the total polyphenol content (determined by Folin-Ciocalteu method) and the total content of quercetin, kaempferol, and luteolin glycosides. This work is valuable for elucidation of phenolic composition in tree peony flowers and for further utilization of them as functional food and medicine materials.

Simultaneous analysis of anthocyanins and flavonols in petals of lotus (Nelumbo) cultivars by high-performance liquid chromatography-photodiode array detection/electrospray ionization mass spectrometry.

A fast and reliable HPLC method for the simultaneous separation of anthocyanins and flavonols in lotus petals was developed based on the study of four candidate solvent systems. Fifteen flavonoids were identified by high-performance liquid chromatography with photodiode array detection/mass spectrometry. Among them, two anthocyanins and nine flavonols were discovered in lotus petals for the first time. This work is valuable for both the hybrid breeding on lotus oriented to flower color and the utilization of lotus petals as functional food materials.