Integrin α6 targeted cancer imaging and therapy

Integrins represent ideal targets for molecular imaging and targeted therapy of cancer and their role in cancer has been reviewed extensively elsewhere. Except for αVβ3 and αVβ5, the remaining integrins were not systematically considered and tested as potential therapeutic targets. In recent years, the studies on integrin α6 as a cancer imaging and therapeutic target are increasing, due to their highly expressed in several cancers, and their expression has been associated with poor survival. Integrin α6 appears to be a particularly attractive target for cancer imaging and therapy, and therefore we have developed a wide array of integrin α6-target molecular probes for molecular imaging and targeted therapy of different cancers. Despite the studies on integrin α6 as a cancer imaging and therapeutic target increasing in recent years, most of them were derived from preclinical mouse models, revealing that much more can be done in the future. The development of integrin α6 drugs may now be at an important point, with opportunities to learn from previous research, to explore new approaches. In this review, we will briefly introduce integrin α6 and highlighted the recent advances in integrin α6 targeted imaging and therapeutics in cancer

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Background: Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods: A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results: PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion: This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI

Nanoscale Zero-Valent Iron Modified by Bentonite with Enhanced Cr(VI) Removal Efficiency, Improved Mobility, and Reduced Toxicity

The aggregation of nanoscale zero-valent iron (nZVI) particles and their limited transport ability in environmental media hinder their application in environmental remediation. In this study, the Cr(VI) removal efficiency, transport performance, and toxicity of nZVI and bentonite-modified nZVI (B-nZVI) were investigated. Compared with nZVI, B-nZVI improved the removal efficiency of Cr(VI) by 10%, and also significantly increased the transport in quartz sand and soil. Increasing the flow rate can enhance the transport of nZVI and B-nZVI in the quartz sand columns. The transport of the two materials in different soils was negatively correlated with the clay composition. Besides, modification of nZVI by bentonite could reduce toxicity to luminous bacteria (Photobacterium phosphereum T3) and ryegrass (Lolium perenne L.). Compared with Fe-EDTA, the transfer factors of nZVI and B-nZVI were 65.0% and 66.4% lower, respectively. This indicated that although iron nanoparticles accumulated in the roots of ryegrass, they were difficult to be transported to the shoots. The results of this study indicate that B-nZVI has a strong application potential in in situ environmental remediation

Integrin α6 targeted cancer imaging and therapy

Integrins represent ideal targets for molecular imaging and targeted therapy of cancer and their role in cancer has been reviewed extensively elsewhere. Except for αVβ3 and αVβ5, the remaining integrins were not systematically considered and tested as potential therapeutic targets. In recent years, the studies on integrin α6 as a cancer imaging and therapeutic target are increasing, due to their highly expressed in several cancers, and their expression has been associated with poor survival. Integrin α6 appears to be a particularly attractive target for cancer imaging and therapy, and therefore we have developed a wide array of integrin α6-target molecular probes for molecular imaging and targeted therapy of different cancers. Despite the studies on integrin α6 as a cancer imaging and therapeutic target increasing in recent years, most of them were derived from preclinical mouse models, revealing that much more can be done in the future. The development of integrin α6 drugs may now be at an important point, with opportunities to learn from previous research, to explore new approaches. In this review, we will briefly introduce integrin α6 and highlighted the recent advances in integrin α6 targeted imaging and therapeutics in cancer

The involvement of sirtuins during optic nerve injury of rats

Sirtuins, comprised of seven members, protect cells from injury, possibly through different roles. In this study, we used two young rat optic nerve injury models to analyze the changes in Sirts 1-7 at different time points to better understand the role of sirtuins during optic nerve injury. Twelve-week-old adult male F344 rats (total n=42) were divided randomly into two groups. One group was subjected to optic nerve cut (ON-cut) and the other group was subjected to a peripheral nerve-optic nerve graft (PN-ON graft) on the left eye. At 1 and 3 days and 1, 2, and 4 weeks, rats were euthanized and retinas of both eyes were removed. Total RNA was extracted and first-strand cDNA was synthesized. Sirts 1-7 and housekeeping -actin quantitative real-time PCR were performed. The quantitative real-time PCR profile showed that sirtuin mRNAs in both groups increased following optic nerve injury with and without peripheral nerve grafting. Sirt1 mRNA increased rapidly, reaching its peak at 3 days after surgery. Sirts 2-7 showed an increasing trend and remained high through 4 weeks after surgery. Sirts 4 and 6 were the only Sirts that increased in number in the PN-graft group at 4 weeks after surgery, where neuronal survival should be higher. Our data indicate that Sirt1 and Sirts 2-7 may play different or complementary roles in optic nerve injury and that Sirts 4 and 6 may play a greater role than the remaining Sirts in axon regeneration

A novel selenium-containing glutathione transferase zeta1-1, the activity of which surpasses the level of some native glutathione peroxidases

Glutathione peroxidase (GPX) is a critical antioxidant selenoenzyme in organisms that protects cells against oxidative damage by catalyzing the reduction of hydroperoxides by glutathione (GSH). Thus, some GPX mimics have been generated because of their potential therapeutic value. The generation of a semisynthetic selenoenzyme with peroxidase activity, which matches the catalytic efficiencies of naturally evolved GPX, has been a great challenge. Previously, we semisynthesized a GPX mimetic with high catalytic efficiency using a rat theta class glutathione transferase (rGST T2-2) as a scaffold, in which the highly specific GSH-binding site is adjacent to an active site serine residue that can be chemically modified to selenocysteine (Sec). In this study, we have taken advantage of a new scaffold, hGSTZ1-1, in which there are two serine residues in the active site, to achieve both high thiol selectivity and highly catalytic efficiency. The GPX activity of Se-hGSTZ1-1 is about 1.5 times that of rabbit liver GPX, indicating that the selenium content at the active site plays an important role in enhancement of catalytic performance. Kinetic studies revealed that the catalytic mechanism of Se-hGSTZ1-1 belong in a ping-pong mechanism similar to that of the natural GPX

Automated Synthesis and Preclinical Evaluation of Optimized Integrin α6-Targeted Positron Emission Tomography Imaging of Pancreatic Cancer

Integrin α6 has been considered a promising biomarker, is overexpressed in many tumors, and plays a vital role in tumor formation, recurrence, and metastasis. In this study, we identified a novel high-affinity integrin α6-targeted peptide named RD2 (Arg-Trp-Tyr-Asp-PEG4)2-Lys-Lys and developed a 18F-radiolabeled peptide tracer ([18F]-AlF-NOTA-RD2) and evaluated its potential application in positron emission tomography (PET) imaging of pancreatic cancer. [18F]-AlF-NOTA-RD2 was produced using GMP (Good Manufacturing Practice of Medical Products)-compliant automatic radiosynthesis on a single GE FASTLab2 cassette-type synthesis module. The stability of [18F]-AlF-NOTA-RD2 was analyzed in phosphate-buffered saline (PBS) and fetal bovine serum (FBS). The cell uptake assay of the tracer was assessed using PANC-1 cells. In addition, small-animal PET imaging and biodistribution studies of [18F]-AlF-NOTA-RD2 were performed in pancreatic cancer subcutaneous tumor-bearing mice. The PET tracer [18F]-AlF-NOTA-RD2 was obtained with a radiochemical yield of 23.7 ± 4.7%, radiochemical purity of >99%, and molar activity of 165.7 ± 59.1 GBq/μmol. [18F]-AlF-NOTA-RD2 exhibited good in vitro stability in PBS and FBS. LogP octanol water value for the tracer was −2.28 ± 0.05 (n = 3). The binding affinity of RD2 to the integrin α6 protein (Kd = 0.13 ± 3.65 μM, n = 3) was significantly higher than that of the RWY (CRWYDENAC) (Kd = 6.97 ± 1.44 μM, n = 3). Small-animal PET imaging and biodistribution also revealed that [18F]-AlF-NOTA-RD2 displayed rapid and good tumor uptake and lower liver background uptake in PANC-1 tumor-bearing mice. [18F]-AlF-NOTA-RD2 showed significant radioactivity accumulation in tumors and was successfully blocked by NOTA-RD2. Compared with [18F]-FDG, [18F]-AlF-NOTA-RD2 PET imaging and biodistribution studies in PANC-1 xenograft tumor-bearing mice confirmed a good tumor-to-muscle ratio (8.69 ± 2.03 vs 1.41 ± 0.23, respectively) at 0.5 h and (2.99 ± 3.02 vs 1.43 ± 0.17, respectively) at 1 h post injection. Autoradiography of human pancreatic cancer tumor tissues further confirmed high accumulation of [18F]-AlF-NOTA-RD2. In summary, we developed an optimized integrin α6-targeted imaging tracer and obtained high radioactivity products with a cassette-type synthesis module; moreover, the tracer exhibited good binding affinity with integrin α6 and good target specificity for PANC-1 cells in xenograft pancreatic tumor-bearing mice, demonstrating its promising application as a noninvasive PET radiotracer of integrin α6 expression in pancreatic cancer