Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system x c -. Among the existing system x c inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system x c and inducer of ferroptosis potentially suitable for in vivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system x c -, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both in vitro and in vivo. Using untargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.

Two-dimensional (2D) MXenes have recently been shown to be promising for applications in anticancer photothermal therapy (PTT), owing to their outstanding photothermal performance. However, as with the other inorganic 2D nanomaterials, the MXene-based nanoplatforms lack the appropriate biocompatibility and stability in physiological conditions, targeting capability, and controlled release of drug, for cancer therapy. Fabricating a smart MXene-based nanoplatform for the treatment of cancer therefore remains a challenge. In this work, composite hydrogels based on cellulose and TiC MXene, were synthesized for the first time. We have shown that the cellulose/MXene composite hydrogels possess rapid response near-infrared-stimulated characteristics, which present as a continuous dynamic process in water. As a result, when loaded with the anticancer drug doxorubicin hydrochloride (DOX), the cellulose/MXene hydrogels are capable of significantly accelerating the DOX release. This behavior is attributed to the expansion of the pores within the three-dimensional cellulose-based networks, triggered by illumination with an 808 nm light. Capitalizing on their excellent photothermal performance and controlled, sustained release of DOX, the cellulose/MXene hydrogels are utilized as a multifunctional nanoplatform for tumor treatment by intratumoral injection. The results showed that the combination of PTT and prolonged adjuvant chemotherapy delivered using this nanoplatform was highly efficient for instant tumor destruction and for suppressing tumor relapse, demonstrating the potential of the nanoplatform for application in cancer therapy. Our work not only opens the door for the fabrication of smart MXene-based nanocomposites, along with their promising application against cancer, but also paves the way for the development of other inorganic 2D composites for applications in biomedicine.

Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system xc – inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.

pH and glucose dual-responsive injectable hydrogels were prepared through the cross-linking of Schiff's base and phenylboronate ester using phenylboronic-modified chitosan, poly(vinyl alcohol) and benzaldehyde-capped poly(ethylene glycol). Protein drugs and live cells could be incorporated into the hydrogels during the in situ cross-linking, displaying sustained and pH/glucose-triggered drug release from the hydrogels and cell viability and proliferation in the three-dimensional hydrogel matrix as well. Hence, the hydrogels with insulin and fibroblasts were considered as bioactive dressings for diabetic wound healing. A streptozotocin-induced diabetic rat model was used to evaluate the efficacy of hydrogel dressings in wound repair. The results revealed that the incorporation of insulin and L929 in the hydrogels could promote neovascularization and collagen deposition and enhance the wound-healing process of diabetic wounds. Thus, the drug- and cell-loaded hydrogels have promising potential in wound healing as a medicated system for various therapeutic proteins and live cells.

Wound repair and tissue regeneration are complex processes that involve many physiological signals. Thus, employing novel wound dressings with potent biological activity and physiological signal response ability to accelerate wound healing is a possible solution. Herein, inspired by mussel chemistry, we developed a polydopamine (PDA)-reduced graphene oxide (pGO)-incorporated chitosan (CS) and silk fibroin (SF) (pGO-CS/SF) scaffold with good mechanical, electroactive, and antioxidative properties as an efficient wound dressing. First, pGO with good dispersibility and cell affinity was obtained upon reduction by PDA under alkali conditions. Second, pGO was dispersed into a CS/SF mixture, and then CS and SF chains were dual-cross-linked by poly­(ethylene glycol) diglycidyl ether and glutaraldehyde to obtain a pGO-incorporated gel. Finally, the gel underwent a freeze-dry process to obtain the pGO-CS/SF scaffold. Owing to PDA reduction and functionalization, pGO in the scaffold plays important roles for the performances of the scaffolds. First, the pGO acts as nanoreinforcement to enhance the mechanical properties of the scaffold by combining the dual-cross-linked CS/SF network. Second, the uniformly distributed pGO in the scaffolds comprises a well-connected electric pathway, which can provide a channel for the transmission of electrical signals in the scaffold. Moreover, pGO in the scaffolds serves as an antioxidant agent to scavenge reactive oxygen species (ROS) and therefore terminates excessive ROS oxidation. In vitro studies show that electroactive pGO-CS/SF scaffolds can respond to electrical signals and promote cytological behavior. In addition, the pGO-CS/SF scaffolds can reduce cellular oxidation by removing excessive ROS. The in vivo full-thickness skin defect model demonstrates that the electroactive and antioxidative pGO-CS/SF scaffold can efficiently enhance wound healing. In summary, the pGO-CS/SF scaffold is a promising wound dressing because of its ability to promote physiological electrical signal transmission for cell growth and reduce ROS oxidation, resulting in an improved wound regeneration effect.

Epimedium (family Berberidaceae), commonly known as Horny Goat Weed or Yin Yang Huo, is commonly used as a tonic, aphrodisiac, anti-rheumatic and anti-cancer agent in traditional herbal formulations in Asian countries such as China, Japan, and Korea. The major bioactive compounds present within this plant include icariin, icaritin and icariside II. Although it is best known for its aphrodisiac properties, scientific and pharmacological studies suggest it possesses broad therapeutic capabilities, especially for enhancing reproductive function and osteoprotective, neuroprotective, cardioprotective, anti-inflammatory and immunoprotective effects. In recent years, there has been great interest in scientific investigation of the purported anti-cancer properties of icariin and its derivatives. Data from in vitro and in vivo studies suggests these compounds demonstrate anti-cancer activity against a wide range of cancer cells which occurs through various mechanisms such as apoptosis, cell cycle modulation, anti-angiogenesis, anti-metastasis and immunomodulation. Of note, they are efficient at targeting cancer stem cells and drug-resistant cancer cells. These are highly desirable properties to be emulated in the development of novel anti-cancer drugs in combatting the emergence of drug resistance and overcoming the limited efficacy of current standard treatment. This review aims to summarize the anti-cancer mechanisms of icariin and its derivatives with reference to the published literature. The currently utilized applications of icariin and its derivatives in cancer treatment are explored with reference to existing patents. Based on the data compiled, icariin and its derivatives are shown to be compounds with tremendous potential for the development of new anti-cancer drugs.

Gelatin methacryloyl (GelMA) hydrogels are widely used for tissue regeneration.

Cardiovascular diseases (CVDs) are among the leading causes of morbidity and mortality in both the developed and developing world. Rhizoma coptidis (RC), known as Huang Lian in China, is the dried rhizome of medicinal plants from the family Ranunculaceae, such as Coptis chinensis Franch, C. deltoidea C.Y. Cheng et Hsiao, and C. teeta Wall which has been used by Chinese medicinal physicians for more than 2000 years. In China, RC is a common component in traditional medicines used to treat CVD associated problems including obesity, diabetes mellitus, hyperlipidemia, hyperglycemia and disorders of lipid metabolism. In recent years, numerous scientific studies have sought to investigate the biological properties of RC to provide scientific evidence for its traditional medical uses. RC has been found to exert significant beneficial effects on major risk factors for CVDs including anti-atherosclerotic effect, lipid-lowering effect, anti-obesity effect and anti-hepatic steatosis effect. It also has myocardioprotective effect as it provides protection from myocardial ischemia-reperfusion injury. These properties have been attributed to the presence of bioactive compounds contained in RC such as berberine, coptisine, palmatine, epiberberine, jatrorrhizine, and magnoflorine; all of which have been demonstrated to have cardioprotective effects on the various parameters contributing to the occurrence of CVD through a variety of pathways. The evidence available in the published literature indicates that RC is a herb with tremendous potential to reduce the risks of CVDs, and this review aims to summarize the cardioprotective properties of RC with reference to the published literature which overall indicates that RC is a herb with remarkable potential to reduce the risks and damage caused by CVDs.