Ferroptosis boosted oral cancer photodynamic therapy by carrier-free Sorafenib-Ce6 self-assembly nanoparticles.

Oral cancer is a disease with high morbidity and mortality worldwide and greatly impacts the quality of life, especially in patients with advanced stages. Photodynamic therapy (PDT) is one of the most effective clinical treatments for oral cancers. However, most clinically applied photosensitizers have several deficiencies, including oxygen dependence, poor aqueous solubility, and a lack of tumor-targeting ability. Herein, the carrier-free multifunctional Sorafenib (Sor), chlorin e6 (Ce6), and Fe3+ self-assembly co-delivery nanoparticles (Sor-Ce6 NPs) were constructed via combining a ferroptosis inducer Sor and a photosensitizer Ce6 for synergetic therapy. The as-synthesized Sor-Ce6 NPs presented excellent colloidal stability and water dispersity with good in vivo tumor-targeting ability. More significantly, the low dose of Sor-Ce6 NPs had little dark toxicity but produced significantly enhanced ROS and supplied O2 sustainably to increase phototoxicity through ferroptosis pathway. Notably, the Sor-Ce6 NPs showed significantly higher in vitro and in vivo anti-tumor efficacy than the Sor/Ce6 mixture due to the improvement of cellular uptake and the incorporation of foreign Fe ions in the system, which also confer the T1 magnetic resonance-guided imaging ability to the formed Sor-Ce6 NPs. Our study demonstrates a promising self-assembled strategy for overcoming hypoxia-related PDT resistance for oral cancer treatment.

Astragaloside IV-mediated inhibition of oxidative stress by upregulation of ghrelin in type 2 diabetes-induced cognitive impairment.

This study is to observe the upregulation effect of astragaloside IV on ghrelin in diabetic cognitive impairment (DCI) rats and to investigate the pathway in prevention and treatment by reducing oxidative stress. The DCI model was induced with streptozotocin (STZ) in conjunction with a high-fat and high-sugar diet and divided into three groups: model, low-dose (40 mg/kg), and high-dose (80 mg/kg) astragaloside IV. After 30 days of gavage, the learning and memory abilities of rats, as well as their body weight and blood glucose levels, were tested using the Morris water maze and then detection of insulin resistance, SOD activity, and serum MDA levels. The whole brain of rats was sampled for hematoxylin-eosin and Nissl staining to observe pathological changes in the hippocampal CA1 region. Immunohistochemistry was used to detect ghrelin expression in the hippocampal CA1 region. A Western blot was used to determine changes in GHS-R1α/AMPK/PGC-1α/UCP2. RT-qPCR was used to determine the levels of ghrelin mRNA. Astragaloside IV reduced nerve damage, increased superoxide dismutase (SOD) activity, decreased MDA levels, and improved insulin resistance. Ghrelin levels and expression increased in serum and hippocampal tissues, and ghrelin mRNA levels increased in rat stomach tissues. According to Western blot, it increased the expression of the ghrelin receptor GHS-R1α and upregulated the mitochondrial function associated-protein AMPK-PGC-1α-UCP2. Astragaloside IV increases ghrelin expression in the brain to reduce oxidative stress and delay diabetes-induced cognitive impairment. It may be related to the promotion of ghrelin mRNA levels.

Toxicity Analysis of Mesoporous Polydopamine on Intestinal Tissue and Microflora.

As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in local temperature. Considering the importance of PTAs in the clinical application of PTT, the safety of PTAs should be carefully evaluated before their widespread use. As a promising PTA, mesoporous polydopamine (MPDA) was studied for its clinical applications for tumor photothermal therapy and drug delivery. Given the important role that intestinal microflora plays in health, the impacts of MPDA on the intestine and on intestinal microflora were systematically evaluated in this study. Through biological and animal experiments, it was found that MPDA exhibited excellent biocompatibility, in vitro and in vivo. Moreover, 16S rRNA analysis demonstrated that there was no obvious difference in the composition and classification of intestinal microflora between different drug delivery groups and the control group. The results provided new evidence that MPDA was safe to use in large doses via different drug delivery means, and this lays the foundation for further clinical applications.

Effects of the Dectin-2/TNF-α Pathway on Ventricular Arrhythmia after Acute Myocardial Infarction in Mice.

Background: Inflammatory responses are involved in ischemic injuries and cardiac repair after acute myocardial infarction (AMI). Dectin-2 is a C-type lectin receptor that induces cytokine production and promotes local inflammatory responses. Methods: Sixty C57BL/6 mice were randomly assigned to a sham-surgery group, AMI group, or AMI + etanercept group, with 20 mice in each group. Programmed electrical stimulation (PES) was used to anesthetized mice to induce ventricular tachycardia. Real-time polymerase chain reaction (PCR) and western blot analysis were adopted to determine the expression and distribution of dectin-2 in heart tissues. The tumor necrosis factor-α (TNF-α), interferon-gamma (IFN)-γ, interleukin (IL) 4, and IL-5 levels in the serum were determined using ELISAs. Results: The expression of dectin-2 and TNF-α was increased in the myocardium in AMI, and the susceptibility to ventricular arrhythmia (VA) was increased. The induction rate of VA was significantly decreased by etanercept. Compared with those in the sham-surgery group, the AMI group showed significantly higher serum TNF-α and IFN-γ levels and lower IL-4 and IL-5levels. Conclusion: Dectin-2 intensifies the activation of the TNF-α immune reaction through the Th1 differentiation, which may increase vulnerability to VA in AMI.

Drought promotes soil phosphorus transformation and reduces phosphorus bioavailability in a temperate forest.

Drought can substantially alter ecosystem functions, especially biogeochemical cycles of key nutrients. As an essential but often limiting nutrient, P plays a central role in critical ecosystem processes (i.e. primary productivity). However, little is known about how drought can affect the soil phosphorus (P) cycle and its bioavailability in forest ecosystems. Here, we conducted a four-year field drought experiment using throughfall reduction approach to examine how drought can alter soil P dynamics and bioavailability in a warm temperate forest. We found that the P held in calcium phosphate was significantly decreased under drought, which was accompanied by the increases of inorganic and organic P bound with secondary minerals (Fe/Al oxides). These drought-induced P transformations can be well explained by the soil pH. The significant decline in soil pH under drought can drive the solubilization of P held in calcium phosphate. Our study further showed that drought directly decreased soil P bioavailability and altered the potential mechanisms of the replenishment of inorganic P into the soil solution. The potential of the inorganic P release driven by protons was reduced, while inorganic P release potentials driven by enzyme and organic acid were increased under drought. Therefore, our results strongly suggested that drought can significantly alter the soil P biogeochemical cycles and change the biological mechanisms underlying P bioavailability.

Matrix Metalloproteinase Responsive Nanoparticles for Synergistic Treatment of Colorectal Cancer via Simultaneous Anti-Angiogenesis and Chemotherapy.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide, especially in developed countries. Although patients' overall survival has been improved by either conventional chemotherapy or newly developed anti-angiogenesis treatment based on its highly vascularized feature, the relatively low therapeutic efficacy and severe side effects remain big problems in clinical practice. In this study, we describe an easy method to construct a novel matrix metalloproteinase-2 (MMP-2) responsive nanocarrier, which can load hydrophobic agents (camptothecin and sorafenib) with high efficiency to exert synergistic efficacy for CRC treatment. The drug-containing nanoparticles can particularly respond to the MMP-2 and realize the controlled release of payloads at the tumor site. Moreover, both in vitro and in vivo studies have demonstrated that this responsive nanoparticle exhibits much higher therapeutic efficacy than that of single antitumor agents or combined drugs coadministrated in traditional ways.