Bilirubin ameliorates osteoarthritis via activating Nrf2/HO-1 pathway and suppressing NF-κB signalling.

Osteoarthritis (OA) is a chronic degenerative joint disease that affects worldwide. Oxidative stress plays a critical role in the chronic inflammation and OA progression. Scavenging overproduced reactive oxygen species (ROS) could be rational strategy for OA treatment. Bilirubin (BR) is a potent endogenous antioxidant that can scavenge various ROS and also exhibit anti-inflammatory effects. However, whether BR could exert protection on chondrocytes for OA treatment has not yet been elucidated. Here, chondrocytes were exposed to hydrogen peroxide with or without BR treatment. The cell viability was assessed, and the intracellular ROS, inflammation cytokines were monitored to indicate the state of chondrocytes. In addition, BR was also tested on LPS-treated Raw264.7 cells to test the anti-inflammation property. An in vitro bimimic OA microenvironment was constructed by LPS-treated Raw264.7 and chondrocytes, and BR also exert certain protection for chondrocytes by activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. An ACLT-induced OA model was constructed to test the in vivo therapeutic efficacy of BR. Compared to the clinical used HA, BR significantly reduced cartilage degeneration and delayed OA progression. Overall, our data shows that BR has a protective effect on chondrocytes and can delay OA progression caused by oxidative stress.

The impact of oxygen on Ga doped ZnO film.

The Ga doped ZnO (GZO) film is one of the promising alternative films to replace ITO film, but its properties suffer from degradation when it is deposited under oxygen-rich conditions. This degradation has been investigated by depositing the films under different oxygen partial pressures. XRD results showed that all GZO films had wurtzite structure and the lattice parameter-c contracted when oxygen was introduced into the argon deposition atmosphere, but the parameter-c nearly remained constant when oxygen partial pressures were further increased. The contraction of parameter-c was caused by the increasing concentrations of VZn (Zn vacancy). It was the first time to observe that the impurity phase of Ga2Zn6O9 appeared and disappeared in GZO films during the increase of oxygen partial pressures. Analogously, conductivity decayed and optical bandgap decreased abruptly as oxygen was introduced, which enhanced self-compensation of donors and acceptors. The energy band structures of GZO and ZnO films were determined by using UPS, and the results showed that oxygen had little effect on the electron affinity of the GZO film, but a significant difference in electron affinity between the ZnO and GZO films was observed. This result indicated that although the electron affinity of ZnO could be effectively tuned by doping with Ga, it remained quite stable for GZO under oxygen-rich conditions.

Matrix Metalloproteinase Inspired Therapeutic Strategies for Bone Diseases.

Matrix Metalloproteinases (MMPs), as a family of zinc-containing enzymes, show the function of decomposing Extracellular Matrix (ECM) and participate in the physiological processes of cell migration, growth, inflammation, and metabolism. Clinical and experimental studies have indicated that MMPs play an essential role in tissue injury and repair as well as tumor diagnosis, metastasis, and prognosis. An increasing number of researchers have paid attention to their functions and mechanisms in bone health and diseases. The present review focuses on MMPs-inspired therapeutic strategies for the treatment of bone-related diseases. We introduce the role of MMPs in bone diseases, highlight the MMPs-inspired therapeutic options, and posit MMPs as a trigger for smart cell/drug delivery.

Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells.

Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.

The role of transporters in cancer redox homeostasis and cross-talk with nanomedicines.

Tumor cell usually exhibits high levels of reactive oxygen species and adaptive antioxidant system due to the metabolic, genetic, and microenvironment-associated alterations. The altered redox homeostasis can promote tumor progression, development, and treatment resistance. Several membrane transporters are involved in the resetting redox homeostasis and play important roles in tumor progression. Therefore, targeting the involved transporters to disrupt the altered redox balance emerges as a viable strategy for cancer therapy. In addition, nanomedicines have drawn much attention in the past decades. Using nanomedicines to target or reset the redox homeostasis alone or combined with other therapies has brought convincing data in cancer treatment. In this review, we will introduce the altered redox balance in cancer metabolism and involved transporters, and highlight the recent advancements of redox-modulating nanomedicines for cancer treatment.

Nanoparticle mediated codelivery of nifuratel and doxorubicin for synergistic anticancer therapy through STAT3 inhibition.

Chemotherapy is one of the most potent strategies to treat gastric cancer in clinic. However, the resistance of cancer cells to chemotherapeutics is a remarkable impediment to the treatment. Moreover, signal transducer and activator of transcription 3 (STAT3) is a critical transcriptional factor that over-activated in gastric cancer, and highly involved in the induction of chemoresistance. In this study, we developed poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the simultaneous codelivery of doxorubicin (DOX) and nifuratel (NIF, a novel STAT3 inhibitor) for enhanced cancer therapy. The synergistic effect of DOX and NIF against cancer cells was evaluated in gastric cancer cells. PLGA nanoparticles with an optimal ratio of DOX and NIF (DNNPs) were prepared and characterized. The cellular uptake and anticancer effects of DNNPs were investigated, and the underlying mechanisms were further explored. DNNPs presented as a spherical shape, provided sustained release profiles, and exhibited significantly increased uptake and cytotoxicity in gastric cancer cells. Mechanism studies showed that DNNPs significantly induced mitochondrial-dependent apoptosis and inhibited STAT3 phosphorylation, explaining the enhanced anticancer effect. These results suggested that DNNPs represented a promising strategy against gastric cancer by inhibiting the STAT3 pathway and amplifying apoptosis.

Tumor Microenvironment-Responsive, Multistaged Liposome Induces Apoptosis and Ferroptosis by Amplifying Oxidative Stress for Enhanced Cancer Therapy.

Tumor cells usually display metabolic, genetic, and microenvironment-related alterations, which are beneficial to tumor proliferation, tumor development, and resistance occurrence. Many transporters and enzymes, including ATB0,+, xCT, and matrix metalloproteinases (MMPs), are involved in the altered cell metabolism and tumor microenvironment and often abnormally upregulated in malignant tumors. Meanwhile, these dysregulated transporters and enzymes provide targets not only for a pharmacological blockage to suppress tumor progress but also for tumor-specific delivery. Although transporters and MMPs have been widely reported for antitumor drug delivery, the feasibility of utilizing two strategies has never been elucidated yet. Herein, we developed an MMP2-activated and ATB0,+-targeted liposome with doxorubicin and sorafenib (DS@MA-LS) loaded for optimal tumor drug delivery for cancer therapy. DS@MA-LS was designed to prolong blood circulation and deshield the PEG shell from MMP2 cleavage to expose lysine and target overexpressed ATB0,+ for enhanced tumor distribution and cancer cellular uptake. Besides the anticancer effects of loaded drugs, the endocytosed liposomes could further increase ROS production and suppress the antioxidant system to amplify oxidative stress. As expected, DS@MA-LS displayed enhanced targeted drug delivery to tumor sites with the MMP2-controlled ligand exposure and ATB0,+-mediated uptake. More importantly, DS@MA-LS successfully inhibited the tumor growth and cancer cell proliferation both in vitro and in vivo by enhancing apoptosis and ferroptosis, which thanks to the increased ROS generation and impaired GSH synthesis synergistically amplified oxidative stress. Our results suggested that the tumor microenvironment-responsive, multistaged nanoplatform, DS@MA-LS, has excellent potential for optimal drug delivery and enhanced cancer treatment.

Endocytosis of ATB0,+(SLC6A14)-targeted liposomes for drug delivery and its therapeutic application for pancreatic cancer.

Background: SLC6A14 (ATB0,+), a Na+/Cl-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.Research design and methods: Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na+ and Cl-, and inhibitable by ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions: We conclude that ATB0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.