No abstract

Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus poses risk to 2.5 billion people worldwide and causes 50 to 100 million human infections each year. Neither a vaccine nor an antiviral therapy is currently available for prevention and treatment of DENV infection. Here, we report a previously undescribed adenosine analog, NITD008, that potently inhibits DENV both in vitro and in vivo. In addition to the 4 serotypes of DENV, NITD008 inhibits other flaviviruses, including West Nile virus, yellow fever virus, and Powassan virus. The compound also suppresses hepatitis C virus, but it does not inhibit nonflaviviruses, such as Western equine encephalitis virus and vesicular stomatitis virus. A triphosphate form of NITD008 directly inhibits the RNA-dependent RNA polymerase activity of DENV, indicating that the compound functions as a chain terminator during viral RNA synthesis. NITD008 has good in vivo pharmacokinetic properties and is biologically available through oral administration. Treatment of DENV-infected mice with NITD008 suppressed peak viremia, reduced cytokine elevation, and completely prevented the infected mice from death. No observed adverse effect level (NOAEL) was achieved when rats were orally dosed with NITD008 at 50 mg/kg daily for 1 week. However, NOAEL could not be accomplished when rats and dogs were dosed daily for 2 weeks. Nevertheless, our results have proved the concept that a nucleoside inhibitor could be developed for potential treatment of flavivirus infections.

No abstract

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.

No abstract

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.

We have synthesized high-quality, micrometer-sized, single-crystal GeSe nanosheets using vapor transport and deposition techniques. Photoresponse is investigated based on mechanically exfoliated GeSe nanosheet combined with Au contacts under a global laser irradiation scheme. The nonlinearship, asymmetric, and unsaturated characteristics of the I-V curves reveal that two uneven back-to-back Schottky contacts are formed. First-principles calculations indicate that the occurrence of defects-induced in-gap defective states, which are responsible for the slow decay of the current in the OFF state and for the weak light intensity dependence of photocurrent. The Schottky photodetector exhibits a marked photoresponse to NIR light illumination (maximum photoconductive gain ∼5.3 × 10(2) % at 4 V) at a wavelength of 808 nm. The significant photoresponse and good responsitivity (∼3.5 A W(-1)) suggests its potential applications as photodetectors.

No abstract