Ferroptosis-related metabolic mechanism and nanoparticulate anticancer drug delivery systems based on ferroptosis.

Ferroptosis is a new type of cell death discovered in recent years that distinguishes from apoptosis and necrosis, mainly caused by the imbalance between the production and degradation of lipid reactive oxygen species in cells. Although the mechanism of ferroptosis is not yet clear, the phenomenon of ferroptosis has attracted widespread attention from researchers and has become a new hotspot in anti-tumor research. Studies have shown that ferroptosis is involved in the occurrence and development of a variety of diseases such as nervous system diseases, cardiovascular diseases and cancer. And inhibiting or inducing the occurrence of ferroptosis can effectively intervene in related diseases. At the same time, nanotechnology, by virtue of its distinct advantages, has been widely used in the development of nanodrug delivery systems. This review outlines current the advance on the intersection of ferroptosis and biomedical nanotechnology. In this review, the discovery and characteristics of ferroptosis, the mechanism of occurrence and the relationship with disease are summarized. More importantly, we summarized the strategies for inducing ferroptosis based on nanoparticulate drug delivery systems for cancer treatment.

Mefloquine as a dual inhibitor of glioblastoma angiogenesis and glioblastoma via disrupting lysosomal function.

Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment development. Given potent anti-cancer efficacy of mefloquine, FDA-approved anti-malarial drug, there is increasing interest in repurposing mefloquine for treatment of cancers, including glioblastoma. In line with these efforts, our work is the first to demonstrate that mefloquine is also an inhibitor of glioblastoma angiogenesis. Using glioblastoma microvascular endothelial cell (GMEC) isolated from glioblastoma patients, we show that mefloquine at clinically achievable concentration inhibits GMEC differentiation, capillary network formation, adhesion to Matrix, growth and survival. Mefloquine also inhibits growth and induces apoptosis in glioblastoma cells regardless of cellular origin and genetic background. We further show that mefloquine significantly inhibits glioblastoma growth but not formation, and this is associated with decreased glioblastoma angiogenesis in mice. Mechanistically, mefloquine disrupted lysosomal integrity and function in GMECs, leading to oxidative stress and lysosomal lipid damage. Rescue studies confirm that mefloquine acts on GMECs in a lysosomal disruption-dependent manner. Our findings demonstrate the anti-angiogenic activity of mefloquine via disrupting lysosomal function. The dual inhibitory role of mefloquine in glioblastoma angiogenesis and glioblastoma displays its advantage over other anti-cancer drugs for glioblastoma treatment. Our work also highlights the essential role of lysosome in both glioblastoma and its angiogenesis.

Formulation optimization of solid self-microemulsifying pellets for enhanced oral bioavailability of curcumin.

Solidification of self-microemulsifying drug delivery systems (SMEDDS) is one of the major trends to promote the transformation of self-microemulsion technology into industrialization. Here, a preliminary curcumin SMEDDS formulation was constructed to improve the druggability of curcumin, through the determination of equilibrium solubility determination, self-emulsifying grading assessment, and pseudo-ternary phase diagrams drafting. Furthermore, the optimal curcumin SMEDDS formulation consisted of 10% Ethyl oleate, 57.82% Cremophor RH 40, and 32.18% Transcutol P was obtained by the simplex lattice design. Besides, curcumin solid self-microemulsifying drug delivery system (S-SMEDDS) was developed by the extrusion and spheronization process to achieve the solidification of SMEDDS. The formulation of curcumin S-SMEDDS pellets was screened by the single factor experiment and the process parameters were investigated using the orthogonal optimization method. Subsequently, curcumin S-SMEDDS pellets were evaluated by apparent morphology characterization, redispersibility study, drug release behavior, and pharmacokinetic evaluation. Results from the pharmacokinetic study in rabbits showed that the AUC0-τ of the curcumin S-SMEDDS pellets and curcumin suspension were 5.91 ± 0.28 µg/mL·h and 2.05 ± 0.04 µg/mL·h, while the relative bioavailability was 289.30%. These studies demonstrated that S-SMEDDS pellets can be a promising strategy for curcumin industrialized outputs.

ATP responsive DNA nanogels grown on biocompatible branches for anticancer drug delivery.

We developed biocompatible ATP responsive DNA nanogels, by grafting DNA strands on carboxymethyl chitosan polymer chains, and then hybridizing with ATP aptamers to form core-shell nanogels. The DNA duplex structure could embed DOX in the G-C sequences, and realize simultaneous sol-gel transition and DOX release when suffering enrich ATP in tumor cells.

Pea-like nanocabins enable autonomous cruise and step-by-step drug pushing for deep tumor inhibition.

Pea-like nanocabins (HA@APT§DOX) were designed for deep tumor inhibition. The AS1411 aptamer (APT) constituted "core shelf" which guaranteed DOX "beans" could be embedded, while the outer HA acted as "pea shell" coating. During the circulation (primary orbit), HA@APT§DOX could autonomously cruise until leak through tumor vasculature. Upon tumor superficial site, the "pea shell" could be degraded by highly expressed hyaluronic acid enzymes (HAase) and peel-off, resulting in orbit changing of released APT§DOX to reach the deep tumor tissue. Furthermore, APT§DOX could be specifically uptaken into A549 tumor cells (secondary orbit). Finally, DOX was released under the acidic environment of lysosome, and delivered into nuclear (targeting orbit) to achieve drug pushing for deep tumor inhibition. More importantly, the in vivo imaging and anti-tumor effects evaluations showed that these nanocabins could effectively enhance drugs accumulation in tumor sites and inhibit tumor growth, with reduced systemic toxicity in 4T1 tumor-bearing mice.

Chemical Compositions of Propolis from China and the United States and their Antimicrobial Activities Against Penicillium notatum.

The chemical compositions of ethanol extracts of propolis from China (EEP-C) and the United States (EEP-A) and their antifungal activity against Penicillium notatum were determined. The result showed that a total of 49 compounds were detected by UPLC-Q-TOF-MS, 30 of which were present in samples from two regions. The major compounds of EEP-C and EEP-A were similar, including pinocembrin, pinobanksin-3-O-acetate, galanin, chrysin, pinobanksin, and pinobanksin-methyl ether, and both of them showed antifungal activity against P. notatum with same minimum inhibitory concentration (MIC) value of 0.8 mg·mL-1. In the presence of propolis, the mycelial growth was inhibited, the hyphae became shriveled and wrinkled, the extracellular conductivities were increased, and the activities of succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) were decreased. In addition, iTRAQ-based quantitative proteomic analysis of P. notatum in response to propolis revealed that a total of 341 proteins were differentially expressed, of which 88 (25.8%) were upregulated and 253 (74.2%) were downregulated. Meanwhile, the differentially expressed proteins (DEPs) involved in energy production and conversion, carbohydrate transport and metabolism, and the sterol biosynthetic pathway were identified. This study revealed that propolis could affect respiration, interfere with energy metabolism, and influence steroid biosynthesis to inhibit the growth of P. notatum.

Experimental study and performance analysis of solar-driven exhaust air thermoelectric heat pump recovery system.

Exhaust air heat recovery is of great significance for building energy conservation. Since passive heat recovery systems use temperature or enthalpy difference between outdoor air and indoor air to drive the system, the temperature of fresh air supply cannot meet indoor requirements and the exhaust heat is not fully recovered. In this study, a solar-driven exhaust air thermoelectric heat pump recovery (SDEATHP) system is tested and evaluated for its ability to recover thermal energy from exhaust air to cool or heat fresh air. An experimental platform was established to test its performance. Results show that the SDEATHP system can obtain higher fresh air supply temperature in winter and lower fresh air supply temperature in summer. The system requires only 3.12 W of power for the fans, and the average relative cooling coefficient in summer and the average relative heating coefficient can reach 50.6 and 57.9, respectively. The optimal operating current and voltage of TE modules and photovoltaic system is analyzed, and then the number and types of electrical connections for the TE modules in SDEATHP system are discussed. The SDEATHP system provides a new method for building energy recovery and fresh air supply.

Thermo-sensitive hydrogels for delivering biotherapeutic molecules: A review.

To date, a variety of delivery systems based on organic or inorganic materials have been investigated. Among them, hydrogels have become one of the most promising field in drug delivery system due to their unique properties. Temperature-sensitive hydrogels, which gelation at physiological temperature, gift the delivery system with excellent spatial and temporal control, and have a widely application in drug delivery, tissue engineering, imaging, and wound dressing. This review provides a brief overview on the concept and classification of temperature-sensitive hydrogels, and covers the application of temperature-sensitive gel systems in delivery of biotherapeutic molecules.

NMR-based serum metabolomics study reveals a innovative diagnostic model for missed abortion.

A missed abortion (MA) is an in-utero death of the embryo or fetus before the 20th week of gestation with retained products of conception. In order to discover novel biomarkers for MA, a 1H NMR spectroscopy-based metabolomics approach was applied to detect human MA serum metabolic profiles. Serum samples were obtained from patients with MA (n = 15) and healthy controls (n = 9) for study. The NOESYPR1D spectrum combined with multi-variate pattern recognition analysis was used to cluster the groups and establish a disease-specific metabolites phenotype. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) models were capable of distinguishing MA patients from healthy subjects. The results revealed that 24 metabolites altered in MA patients compared with the control population. Metabolomic pathway analysis demonstrated that alanine, aspartate and glutamate metabolism, citrate cycle (TCA cycle), taurine and hypotaurine metabolism were significantly altered in MA. The results indicated that serum NMR-based metabolomic profiling method is sensitive and specific enough to distinguish MA and from healthy controls, this method could be developed as a clinically useful diagnostic tool for MA. The finding from the MA serum metabolic profiling shed a new light on further understanding of MA disease mechanisms.

Disseminators or silencers: The effect of information diffusion intensity on cooperation in public goods game.

In the Network Era, with the emergence of various instant communication tools, the public are easier to be disseminators than ever. But we have often heard that silence is golden. Inspired by this fact, we investigate that whether the existence of disseminators is beneficial to promote cooperation in the provision of public culture services. To answer this interesting question, we classify disseminators as neutral disseminators, positive disseminators and negative disseminators. And four models are set up, namely, neutral disseminator model (MBD), positive disseminator model (MPD), negative disseminator model (MND) and silencer model (MS). By numerical simulations, it is observed that MND, MBD, MPD and MS perform best in 70%, 25%, 5% and 0% of cases, respectively. And the advantage of the best model is different in various situations. Our work highlights that criticizing instead of tolerating defection is always the best choice to promote cooperation, except the population is relatively large or the agent's reference range fluctuates violently. Besides, under the mechanisms of reputation and conformity, the organizer can not play a significant role on promoting cooperation by intervening information transfer in some conditions, especially when the link-neighbor degree is very low.

Angiotensin II Type I Receptor Agonistic Autoantibody Induces Podocyte Injury via Activation of the TRPC6- Calcium/Calcineurin Pathway in Pre-Eclampsia.

BACKGROUND/AIMS: Angiotensin II type I receptor agonistic autoantibody (AT1-AA) is closely related to pre-eclampsia, which is characterized by proteinuria and hypertension. AT1-AA has been shown to enhance the effect of AngII in pre-eclampsia, such as production of endothelin-1, activation of ROS, and vasoconstriction, which are considered to be associated with hypertension; however, whether or not AT1-AA participates in podocyte damage leading to the generation of proteinuria has not been reported. In this study we investigated the role of pre-eclamptic serum AT1-AA on podocytes and the mechanism underlying the generation of proteinuria. METHODS: The levels of AT1-AA isolated from pre-eclamptic sera were determined by an enzyme-linked immunosorbent assay. Human podocytes were cultured in vitro and treated with various concentrations of AT1-AA. Whether or not an ERK1/2 inhibitor and TRPC6 siRNA inhibit the effect of AT1-AA on podocytes was determined. Western blot was used to detect the expression of podocyte-specific proteins (nephrin, synaptopodin, and podocin) and the phosphorylation of ERK1/2 and TRPC6. The arrangement of F-actin was observed by immunofluorescence. A Calcineurin Cellular Activity Assay Kit was used to detect calcineurin activity. Changes in the intracellular Ca2+ concentration was determined by confocal laser. RESULTS: AT1-AA induced a decrease in podocyte-specific protein expression and calcineurin activity and increased expression of p-ERK1/2 and TRPC6 protein and the intracellular Ca2+ concentration. Immunofluorescence revealed rearrangement of F-actin. PD98059, an inhibitor of ERK1/2, and TRPC6 siRNA attenuated the decreased expression of podocyte-specific proteins and decreased intracellular Ca2+ concentration. The expression of TRPC6 was reduced following the addition of ERK1/2 inhibitor. CONCLUSION: AT1-AA induced podocyte damage in a dose-dependent manner. The underlying mechanism might involve activation of the TRPC6 -calcium/calcineurin pathway. This study provides new details regarding podocyte injury and the mechanism underlying the generation of proteinuria in pre-eclampsia.

Microenvironmental Control of MUC1 Aptamer-Guided Acid-Labile Nanoconjugate within Injectable Microporous Hydrogels.

Although aptamers are well-known as cell-specific membrane biomarkers for tumor-targeted therapy, it is important to avoid their degradation by nucleases in vivo. In this study, we developed a MUC1 aptamer-doxorubicin nanoconjugate (APT-DOX) through an acid-labile linkage and embedded APT-DOX into a thermosensitive hydrogel for antitumor therapy. The hydrogels exhibit a sol-gel transition upon intratumoral injection, resulting in the protection and controlled release control of APT-DOX with the shielding of the gel network. Moreover, the released APT-DOX was prone to be enriched at the tumor cells due to specific intracellular transport by the overexpressing MUC1 protein; however, APT-DOX regained the free DOX form via the rupture of the linkage under tumor cells lysosome acidic conditions and achieved increased concentration in the nucleus for antitumor treatment.

Spatial controlled multistage nanocarriers through hybridization of dendrimers and gelatin nanoparticles for deep penetration and therapy into tumor tissue.

Most nanoparticles (NPs) have difficulty deeply penetrating into tumor tissues. Here, we designed a spatially controlled multistage nanocarrier by encapsulating small polyamidoamine (PAMAM) dendrimers (~5 nm) within large gelatin NPs (~200 nm). This multistage nanocarrier is meant to be stable during systemic circulation and to leak through tumor vasculature walls by the enhanced permeation and retention (EPR) effect. Afterwards, this multistage nanocarrier release PAMAM dendrimers in response to the high matrix metalloproteinase-2 (MMP-2) enzymes in the tumor microenvironment, and further transport into tumor cells. In this study, the demonstrated high intracellular uptake and deep penetration into tumor model verified the effective enzymes-responsively and spatially controlled multistage penetration of these combined nanocarriers. In addition, these multistage nanocarrier were further loaded with anti-tumor drug methotrexate (MTX) and evaluated both in vitro and in vivo to investigate their anti-tumor effect, which demonstrated that this multistage nanocarrier hold great potential in improving anti-tumor efficiency.

Self-assembled polyelectrolyte complexes films as efficient compression coating layers for controlled-releasing tablets.

Currently, polysaccharide-based hydrogels are widely studied macromolecular networks to modify drug dissolution from controlled-releasing matrix tablets. Among them, polyelectrolyte complexes (PEC) films consisted of chitosan (CS) and sodium alginate (SA) could be obtained via spontaneously assembling under physiological gastrointestinal environment. Here, we utilized these self-assembled PEC films as an efficient coating materials to develop controlled-released matrix tablets through compression coating process, with paracetamol (APAP) as model drug. The constitutive and morphology characteristic studies on these PEC films illustrated that the mixture of CS and SA with the weight ratio of 1:1 would be an promising outer layer for compression-coating tablets. In addition, the in vitro drug releasing behavior experiments demonstrated that the optimized compression coating tablets displayed satisfied zero-order drug releasing profits. Furthermore, the in vivo pharmacokinetic studies of these APAP loaded compression-coated tablets in New Zealand rabbits gave that the Tmax (12.32 ± 1.05 h) was significantly prolonged (p < 0.01), compared to that (0.89 ± 0.26 h) of common APAP tablets (Jinfuning®) after oral administration. These studies suggest that the compression-coated tablets with self-assembled PEC film as coating outer layer may be a promising strategy for peroral controlled release delivery system of water soluble drugs.

Plasma metabolomic profile and potential biomarkers for missed abortion.

A missed abortion (MA) is an in utero death of the embryo or fetus before the 20th week of gestation with retained products of conception, and this condition is currently common in China. In order to discover novel biomarkers for MA, ultrahigh performance liquid chromatography was applied to study plasma metabolite profiles for 33 patients with MA and 29 control subjects. Thirty-seven differential plasma metabolites were found to discriminate between the two groups in the initial cohort (15 subjects with MA and 15 healthy controls). The feasibility of using these potential biomarkers to predict MA was further evaluated in the validation cohort (18 subjects with MA and 14 healthy controls) and 15 had an area under the receiver operating characteristic curve of >0.80, making them satisfactory. Tryptophan metabolism and sphingolipid metabolism were identified as important potential target pathways for MA using metabolic pathway impact analysis. Furthermore, three of the 15 satisfactory metabolites (glyceric acid, indole and sphingosine) were combined to establish a predictive model with 100% sensitivity and 100% specificity in the validation cohort. Taken together, these results suggest that MA results in significant disturbance of metabolism and those various novel biomarkers have satisfactory diagnostic and predictive power for MA.

Topotecan hydrochloride liposomes incorporated into thermosensitive hydrogel for sustained and efficient in situ therapy of H22 tumor in Kunming mice.

Topotecan hydrochloride (TPT) has potential for the treatment of ovarian cancer, but the activity of TPT tends to decrease due to the ring-opening at physiological pH. In this study, we proposed to incorporate TPT liposomes into injectable thermosensitive in situ hydrogel, consisting of chitosan (CS) and ß-glycerophosphate (ß-GP), for sustained release and preservation of active lactone form of TPT. The rheology studies were carried out to investigate the sol-gel temperature, flow behavior and viscosity of these CS/ß-GP systems. The optimized formulation exhibited sol-gel transition at 40.2 ± 0.4 °C, with pseudoplastic flow behavior. The drug release rate of TPT liposomes loaded CS/ß-GP hydrogel in phosphate buffer saline (pH = 7.4) was found to be slowed down, and the lactone fraction of TPT in the hydrogel matrix was maintaining 40% after 50 h. In addition, the antitumor efficacy in Kunming mice bearing Hepatoma-22 tumor, after intratumoral injection of TPT liposomes loaded CS/ß-GP hydrogel, was higher than that of TPT in saline and TPT in CS/ß-GP hydrogel. Those results demonstrated that TPT liposomes loaded CS/ß-GP hydrogel could become a potential formulation for improving the antitumor efficacy of TPT and suggested an important technology platform for intratumoral administration of derivative of camptothecin-family drugs.

Encapsulation of acetylshikonin by polyamidoamine dendrimers for preparing prominent nanoparticles.

Acetylshikonin (AS) has demonstrated antitumor potential. However, the development of therapeutic applications utilizing AS is inhibited by its poor solubility in water. In the present work, polyamidoamine (PAMAM) dendrimers and their PEGylated derivatives were employed to increase the solubility of AS. A distinct color transition was observed during the encapsulation of AS suggesting strong intermolecular forces between PAMAM and AS. Ultraviolet-visible, high-performance liquid chromatography, and (1)H NMR were used to verify the interaction between PAMAM and AS. The maximum amount of combined AS to each PAMAM molecule was determined. The cytotoxicity of AS nanoparticles was evaluated against leukemia (K562) and breast cancer (SK-BR-3) cell lines; the AS nanoparticles were shown to effectively inhibit tumor cells.

Advanced strategies for CRISPR/Cas9 delivery and applications in gene editing, therapy, and cancer detection using nanoparticles and nanocarriers.

Cancer remains one of the deadliest diseases, and is characterised by the uncontrolled growth of modified human cells. Unlike infectious diseases, cancer does not originate from foreign agents. Though a variety of diagnostic procedures are available; their cost-effectiveness and accessibility create significant hurdles. Non-specific cancer symptoms further complicate early detection, leading to belated recognition of certain cancer. The lack of reliable biomarkers hampers effective treatment, as chemotherapy, radiation therapy, and surgery often result in poor outcomes and high recurrence rates. Genetic and epigenetic mutations play a crucial role in cancer pathogenesis, necessitating the development of alternate treatment methods. The advent of CRISPR/Cas9 technology has transformed molecular biology and exhibits potential for gene modification and therapy in various cancer types. Nonetheless, obstacles such as safe transport, off-target consequences, and potency must be overcome before widespread clinical use. Notably, this review delves into the multifaceted landscape of cancer research, highlighting the pivotal role of nanoparticles in advancing CRISPR/Cas9-based cancer interventions. By addressing the challenges associated with cancer diagnosis and treatment, this integrated approach paves the way for innovative solutions and improved patient outcomes.

A nomogram to predict severe COVID-19 patients with increased pulmonary lesions in early days.

Objectives: This study aimed to predict severe coronavirus disease 2019 (COVID-19) progression in patients with increased pneumonia lesions in the early days. A simplified nomogram was developed utilizing artificial intelligence (AI)-based quantified computed tomography (CT). Methods: From 17 December 2019 to 20 February 2020, a total of 246 patients were confirmed COVID-19 infected in Jingzhou Central Hospital, Hubei Province, China. Of these patients, 93 were mildly ill and had follow-up examinations in 7 days, and 61 of them had enlarged lesions on CT scans. We collected the neutrophil-to-lymphocyte ratio (NLR) and three quantitative CT features from two examinations within 7 days. The three quantitative CT features of pneumonia lesions, including ground-glass opacity volume (GV), semi-consolidation volume (SV), and consolidation volume (CV), were automatically calculated using AI. Additionally, the variation volumes of the lesions were also computed. Finally, a nomogram was developed using a multivariable logistic regression model. To simplify the model, we classified all the lesion volumes based on quartiles and curve fitting results. Results: Among the 93 patients, 61 patients showed enlarged lesions on CT within 7 days, of whom 19 (31.1%) developed any severe illness. The multivariable logistic regression model included age, NLR on the second time, an increase in lesion volume, and changes in SV and CV in 7 days. The personalized prediction nomogram demonstrated strong discrimination in the sample, with an area under curve (AUC) and the receiver operating characteristic curve (ROC) of 0.961 and a 95% confidence interval (CI) of 0.917-1.000. Decision curve analysis illustrated that a nomogram based on quantitative AI was clinically useful. Conclusion: The integration of CT quantitative changes, NLR, and age in this model exhibits promising performance in predicting the progression to severe illness in COVID-19 patients with early-stage pneumonia lesions. This comprehensive approach holds the potential to assist clinical decision-making.

Urease catalyzed high-density sodium alginate microspheres enable high oral bioavailability of macromolecular drugs.

Destruction of insulin caused by the gastric microenvironment and rapid deactivation pose inevitable barriers to oral macromolecular absorption, especially for most peptide and protein drugs. In this study, we developed high-density sodium alginate microspheres composed of magnesium oxide and urease to address these challenges. These microspheres aim to anchor the gastric mucus layer and induce microenvironmental liquefaction, thereby enhancing gastric retention and the protection of insulin. The sedimentation test confirmed the capability of the Ins/Ur/MgO@SA microsphere to rapidly traverse the gastric juice under the influence of gravity. Additionally, the urease immobilized on the Ins/Ur/MgO@SA microspheres catalyzes the hydrolysis of urea in the gastric mucus and promotes the liquefaction of mucus, which is beneficial for microsphere retention. The inclusion of MgO particles and urease, acting as pHM modifiers, helps in adjusting the local pH to avoid gastric acid-induced damage. Subsequently, an in vivo pharmacokinetic experiment verified that the relative bioavailability of the p.o. Ins/Ur/MgO@SA treated group was 15-fold higher than that of the p.o.insulin treated group. Meanwhile, satisfactory blood glucose level (BGL) reduction was observed in diabetic animals. In conclusion, Ins/Ur/MgO@SA microspheres demonstrate high biocompatibility as insulin carriers with prolonged drug release time and increased gastric retention properties, showing a far-reaching strategy for oral macromolecular drug delivery.