Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice.

BACKGROUND AND AIMS: In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH. APPROACH AND RESULTS: Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs. CONCLUSIONS: LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.

Mesoporous Silica Nanoparticles as a Potential Nanoplatform: Therapeutic Applications and Considerations.

With advances in nanotechnology, nanoparticles have come to be regarded as carriers of therapeutic agents and have been widely studied to overcome various diseases in the biomedical field. Among these particles, mesoporous silica nanoparticles (MSNs) have been investigated as potential nanocarriers to deliver drug molecules to various target sites in the body. This review introduces the physicochemical properties of MSNs and synthesis procedures of MSN-based nanoplatforms. Moreover, we focus on updating biomedical applications of MSNs as a carrier of therapeutic or diagnostic cargo and review clinical trials using silica-nanoparticle-based systems. Herein, on the one hand, we pay attention to the pharmaceutical advantages of MSNs, including nanometer particle size, high surface area, and porous structures, thus enabling efficient delivery of high drug-loading content. On the other hand, we look through biosafety and toxicity issues associated with MSN-based platforms. Based on many reports so far, MSNs have been widely applied to construct tissue engineering platforms as well as treat various diseases, including cancer, by surface functionalization or incorporation of stimuli-responsive components. However, even with the advantageous aspects that MSNs possess, there are still considerations, such as optimizing physicochemical properties or dosage regimens, regarding use of MSNs in clinics. Progress in synthesis procedures and scale-up production as well as a thorough investigation into the biosafety of MSNs would enable design of innovative and safe MSN-based platforms in biomedical fields.

Combined Application of Prototype Ultrasound and BSA-Loaded PLGA Particles for Protein Delivery.

PURPOSE: To develop an in vitro culture system for tissue engineering to mimic the in vivo environment and evaluate the applicability of ultrasound and PLGA particle system. METHODS: For tissue engineering, large molecules such as growth factors for cell differentiation should be supplied in a controlled manner into the culture system, and the in vivo microenvironment need to be reproduced in the system for the regulation of cellular function. In this study, portable prototype ultrasound with low intensity was devised and tested for protein release from bovine serum albumin (BSA)-loaded poly(lactic-co-glycolic acid) (PLGA) particles. RESULTS: BSA-loaded PLGA particles were prepared using various types of PLGA reagents and their physicochemical properties were characterized including particle size, shape, or aqueous wetting profiles. The BSA-loaded formulation showed nano-ranged size distribution with optimal physical stability during storage period, and protein release behaviors in a controlled manner. Notably, the application of prototype ultrasound with low intensity influenced protein release patterns in the culture system containing the BSA-loaded PLGA formulation. The results revealed that the portable ultrasound set controlled by the computer could contribute for the protein delivery in the culture medium. CONCLUSIONS: This study suggests that combined application with ultrasound and protein-loaded PLGA encapsulation system could be utilized to improve culture system for tissue engineering or cell regeneration therapy.

BSA/Silver Nanoparticle-Loaded Hydrogel Film for Local Photothermal Treatment of Skin Cancer.

PURPOSE: To develop a hydrogel film containing bovine serum albumin (BSA)-coated silver nanoparticles (BSA/AgNP) and evaluate its applicability for topical photothermal treatment (PTT) of skin cancer. METHODS: BSA/AgNP-loaded hydrogel films were prepared and their swelling, bioadhesive, mechanical, and photothermal properties were characterized in vitro and in vivo. RESULTS: The synthesized BSA/AgNP exhibited a narrow size distribution with good size stability and, notably, possessed great photothermal activity that could stably maintain through repetitive laser irradiation. The BSA/AgNP-loaded hydrogel films showed favorable swelling, bioadhesive, tensile, and photothermal properties. Based on these results, when tested the anti-cancer effects in B16F10 s.c. tumor-bearing mice, the PTT with the topical treatment of BSA/AgNP-loaded hydrogel films could significantly inhibit the tumor growth by a single treatment with no apparent toxicity. CONCLUSIONS: Overall, the results of this study demonstrated that the BSA/AgNP-loaded hydrogel films may serve as an effective but safe topical PTT agent for the treatment of skin cancer.

Development and characterization of a superabsorbing hydrogel film containing Ulmus davidiana var. Japonica root bark and pullulan for skin wound healing.

Ulmus davidiana var. japonica (UD) has widely been used in Korean traditional medicine for the treatment of various types of diseases including inflammation and skin wounds. The UD root bark powders possess gelling activity with an excellent capacity for absorbing water. This distinct property could make the UD root bark powders to be a great material for manufacturing a gel film specifically for the healing of large and highly exudating wounds (e.g., pressure sores and diabetic ulcers). In this research, we separated the UD root bark powder into 4 different samples based on their sizes and then tested their water absorption capacity and flowability. Based on these results, 75-150 µm sized and below 75 µm sized samples of UD root bark powders were chosen, and UD gel films were prepared. The UD gel films showed good thermal stability and mechanically improved properties compared with pullulan only gel film with excellent swelling capacity and favorable skin adhesiveness. Further, in the animal studies with the skin wound mice model, the UD gel films exhibited significant therapeutic effects on accelerating wound closure and dermal regeneration. Overall, this study demonstrated the applicability of UD root bark powders for hydrogel wound dressing materials, and the potential of UD gel films to be superior wound dressings to currently available ones.

Molecular tumor targeting of gelonin by fusion with F3 peptide.

Therapeutically potent macromolecular drugs have shown great promise for overcoming the limitations of small-molecule anti-cancer drugs. But tumor cell-selective intracellular delivery of the macromolecules remains a major hurdle for their successful clinical application. To overcome this challenge, we engineered a novel genetic fusion protein (F3-Gel) that composed of F3 peptide, a tumor-homing peptide, and gelonin, a plant-derived ribosome-inactivating protein (RIP), and then evaluated its anti-cancer activity in vitro and in vivo. The F3-Gel-encoding gene was synthesized by genetic recombination, and F3-Gel was successfully expressed in E coli. The anti-cancer activity of the produced F3-Gel was evaluated by various in vitro assays, which revealed that F3-Gel maintained equipotent protein synthesis inhibition activity (IC50=11 pmol/L) as unmodified gelonin (IC50=10 pmol/L). Furthermore, F3-Gel displayed enhanced cellular uptake into cancer cells (U87 MG, HeLa, LnCaP and 9L) than noncancerous cells (293 HEK and SVGp12). Compared with gelonin, F3-Gel exerted significantly higher cytotoxicity against these cancer cells. F3-Gel displayed significantly greater inhibition of protein translation in U87 MG cells: F3-Gel (0.5 µmol/L) was able to reduce the protein level to less than 50%, while gelonin (1 µmol/L) did not affect the intracellular protein level. In a U87 MG xenograft tumor-bearing mouse model, F3-Gel was accumulated in the tumor site at much higher levels and maintained for a prolonged time compared with gelonin. Administration of F3-Gel (0.5, 0.75 mol/kg, iv) caused 36% and 66%, respectively, inhibition of tumor growth in U87 MG xenograft mice, suggesting that it is a promising candidate drug for cancer treatment. Furthermore, this study demonstrates that fusion of F3 peptide to a potent macromolecule could provides an effective method for targeting tumors and eventually could improve their druggability.

Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity.

PURPOSE: To investigate the applicability of fusion biotoxins combining pore-forming toxins (PFTs) and ribosome-inactivating proteins (RIPs) for the anti-cancer treatment. METHODS: Membrane active PFTs tend to destabilize cell membranes of tumor cells, but lack a warhead inducing significant cause of cell death. Cell-impermeable RIPs possess a powerful warhead, yet not able to enter the tumor cells. To address these challenges for anti-tumor effects, we introduced a fusion strategy of conjugating melittin (a PFT) and gelonin (a type 1 RIP) via chemical and recombinant methods, followed by in vitro assays and in vivo animal studies. RESULTS: In vitro characterization results confirmed that the chimeric gelonin-melittin fusion proteins retained equivalent intrinsic activity to that of unmodified gelonin in inhibiting protein translation. However, chemically conjugated gelonin-melittin (cGel-Mel) and recombinant chimeric gelonin-melittin fusion (rGel-Mel) exhibited greater cell uptake, yielding a significantly enhanced cytotoxic activity over treatment of gelonin, melittin or physical mixture of gelonin and melittin. Remarkably, cGel-Mel and rGel-Mel displayed 32- and 10-fold lower IC50 than gelonin in the cell lines. The superior anti-tumor efficacy of multivalent cGel-Mel to monovalent rGel-Mel suggested that valency could be a crucial factor for the extent of melittin-mediated cell uptake. Tumoricidal effects observed from animal studies were in good accordance with our findings from the cellular assays. CONCLUSIONS: This study successfully demonstrated that fusion of biotoxins could provide a simple yet effective way to synergistically augment their anti-tumor activity.

CPP-Assisted Intracellular Drug Delivery, What Is Next?

For the past 20 years, we have witnessed an unprecedented and, indeed, rather miraculous event of how cell-penetrating peptides (CPPs), the naturally originated penetrating enhancers, help overcome the membrane barrier that has hindered the access of bio-macromolecular compounds such as genes and proteins into cells, thereby denying their clinical potential to become potent anti-cancer drugs. By taking the advantage of the unique cell-translocation property of these short peptides, various payloads of proteins, nucleic acids, or even nanoparticle-based carriers were delivered into all cell types with unparalleled efficiency. However, non-specific CPP-mediated cell penetration into normal tissues can lead to widespread organ distribution of the payloads, thereby reducing the therapeutic efficacy of the drug and at the same time increasing the drug-induced toxic effects. In view of these challenges, we present herein a review of the new designs of CPP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy in combating tumor oncology.

PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof-of-Concept Study.

PURPOSE: To investigate the feasibility of applying PTD-modified ATTEMPTS (Antibody Targeted Triggered Electrically Modified Prodrug-Type Strategy) for enhanced toxin therapy for the treatment of cancer. METHODS: A heparin-functionalized murine anti-CEA monoclonal antibody (mAb), T84.66-heparin (T84.66-Hep), was chemically synthesized and characterized for specific binding to CEA overexpressed cells. The T84.66-Hep was then applied to the PTD-modified ATTEMPTS approach and the crucial features of the drug delivery system (DDS), 'antibody targeting' and 'heparin/protamine-based prodrug', were evaluated in vitro to examine whether it could selective delivery a PTD-modified toxin, recombinant TAT-gelonin chimera (TAT-Gel), to CEA high expression cancer cells (LS174T). Furthermore, the feasibility of the drug delivery system (DDS) was assessed in vivo by biodistribution and efficacy studies using LS174T s.c. xenograft tumor bearing mice. RESULTS: T84.66-Hep displayed specific binding, but limited internalization (35% after 48 h incubation) to CEA high expression LS174T cells over low expression HCT116 cells. When mixed together with TAT-Gel, the T84.66-Hep formed a strong yet reversible complex. This complex formation provided an effective means of active tumor targeting of TAT-Gel, by 1) directing the TAT-Gel to CEA overexpressed tumor cells and 2) preventing nonspecific cell transduction to non-targeted normal cells. The cell transduction of TAT-Gel could, however, be efficiently reversed by addition of protamine. Feasibility of in vivo tumor targeting and "protamine-induced release" of TAT-Gel from the T84.66-Hep counterpart was confirmed by biodistribution and preliminary efficacy studies. CONCLUSIONS: This study successfully demonstrated in vitro and in vivo the applicability of PTD-modified ATTEMPTS for toxin-based cancer therapy.

Magnetic targeting of novel heparinized iron oxide nanoparticles evaluated in a 9L-glioma mouse model.

PURPOSE: A novel PEGylated and heparinized magnetic iron oxide nano-platform (DNPH) was synthesized for simultaneous magnetic resonance imaging (MRI) and tumor targeting. METHODS: Starch-coated magnetic iron oxide nanoparticles ("D") were crosslinked, aminated (DN) and then simultaneously PEGylated and heparinized with different feed ratios of PEG and heparin (DNPH1-4). DNPH products were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and superconducting quantum interference device (SQUID). The magentic targeting of DNPH3, with appropriate amounts of conjugated PEG and heparin, in a mouse 9L-glioma subcutaneous tumor model was confirmed by magnetic resonance imaging (MRI)/electron spin resonance (ESR). RESULTS: DNPH3 showed long circulating properties in vivo (half-life >8 h, more than 60-fold longer than that of parent D) and low reticuloendothelial system (RES) recognition in liver and spleen. Protamine, a model cationic protein, was efficiently loaded onto DNPH3 with a maximum loading content of 26.4 µg/mg Fe. Magnetic capture of DNPH3 in tumor site with optimized conditions (I.D. of 12 mg/kg, targeting time of 45 min) was up to 29.42 µg Fe/g tissue (12.26% I.D./g tissue). CONCLUSION: DNPH3 showed the potential to be used as a platform for cationic proteins for simultaneous tumor targeting and imaging.

Genetically engineered long-acting Esculentin-2CHa(1-30) fusion protein with potential applicability for the treatment of NAFLD.

Esculentin-2CHa(1-30) (?ESC") has been reported as a potent anti-diabetic peptide with little toxicity. However, its very short plasma residence time severely limits the therapeutic efficacy. To address this issue, we genetically engineered a fusion protein of tandem trimeric ESC with an albumin binding domain (ABD) and a fusion partner, SUMO (named ?SUMO-3×ESC-ABD"). The SUMO-3×ESC-ABD, successfully produced from E. coli, showed low cellular and hemolytic toxicity while displaying potent activities for the amelioration of hyperglycemia as well as non-alcoholic fatty liver disease (NAFLD) in vitro. In animal studies, the estimated plasma half-life of SUMO-3×ESC-ABD was markedly longer (427-fold) than that of the ESC peptide. In virtue of the extended plasma residence, the SUMO-3×ESC-ABD could produce significant anti-hyperglycemic effects that lasted for >2 days, while both the ESC or ESC-ABD peptides elicited little effects. Further, twice-weekly treatment for 10 weeks, the SUMO-3×ESC-ABD displayed significant improvement in blood glucose control with a reduction in body weight. Most importantly, a significant improvement in the conditions of NAFLD was observed in the SUMO-3×ESC-ABD-treated mice. Along the systemic effects (by improved glucose tolerance and body weight reduction), direct inhibition of the hepatocyte lipid uptake was suggested as the major mechanism of the anti-NAFLD effects. Overall, this study demonstrated the utility of the long-acting SUMO-3×ESC-ABD as a potent drug candidate for the treatment of NAFLD.

Long-circulating heparin-functionalized magnetic nanoparticles for potential application as a protein drug delivery platform.

Starch-coated, PEGylated, and heparin-functionalized iron oxide magnetic nanoparticles (DNPH) were successfully synthesized and characterized in detail. The PEGylation (20 kDa) process resulted in an average coating of 430 PEG molecules per nanoparticle. After that, heparin conjugation was carried out to attain the final DNPH platform with 35.4 µg of heparin/mg of Fe. Commercially acquired heparin-coated magnetic nanoparticles were also PEGylated (HP) and characterized for comparison. Protamine was selected as a model protein to demonstrate the strong binding affinity and high loading content of DNPH for therapeutically relevant cationic proteins. DNPH showed a maximum loading of 22.9 µg of protamine/mg of Fe. In the pharmacokinetic study, DNPH displayed a long-circulating half-life of 9.37 h, 37.5-fold longer than that (0.15 h) of HP. This improved plasma stability enabled extended exposure of DNPH to the tumor lesions, as was visually confirmed in a flank 9L-glioma mouse model using magnetic resonance imaging (MRI). Quantitative analysis of the Fe content in excised tumor lesions further demonstrated the superior tumor targeting ability of DNPH, with up to 31.36 µg of Fe/g of tissue (13.07% injected dose (I.D.)/g of tissue) and 7.5-fold improvement over that (4.27 µg of Fe/g of tissue; 1.78% I.D./g of tissue) of HP. Overall, this study shed light on the potential of DNPH to be used as a protein drug delivery platform.

Liposomal Iron Oxide Nanoparticles Loaded with Doxorubicin for Combined Chemo-Photothermal Cancer Therapy.

Iron oxide nanoparticle (IONP) possesses unique advantages over other nanoparticles in the use of cancer imaging and therapy. Specifically, it has drawn great attention in the emerging research field of photothermal cancer therapy. Herein, we developed doxorubicin (DOX)-loaded liposomal IONP (Lipo-IONP/DOX) and evaluated in vitro and in vivo their applicability for combined chemo-photothermal cancer therapy. The Lipo-IONP was synthesized by the thin-film evaporation method. The prepared Lipo-IONP was observed as about a 240 nm-sized agglomerate of globular-shaped nanoparticles. The TEM and FT-IR data evidenced the successful formation of liposomal IONP. The superparamagnetic property of the Lipo-IONP was confirmed by the SQUID analysis. The DSC data showed a transition temperature of about 47-48 °C for the mixed lipids composing the Lipo IONP, and the DOX release studies revealed the feasibility of induced burst release of DOX by laser irradiation. The Lipo-IONP/DOX possessed a plasma half-life of 42 min, which could ensure sufficient circulation time for magnetic tumor targeting. The in vivo magnetic targeting enabled a significant increase (6.3-fold) in the tumor accumulation of Lipo-IONP/DOX, leading to greater photothermal effects. Finally, the preliminary efficacy study evidenced the applicability as well as the safety of the Lipo-IONP/DOX for use in combined chemo-photothermal cancer therapy. Overall, the study results demonstrated that the Lipo-IONP/DOX might serve as an effective and safe agent for combined chemo-photothermal cancer therapy.

Pharmaceutical Strategies to Improve Druggability of Potential Drug Candidates in Nonalcoholic Fatty Liver Disease Therapy.

Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible without medical intervention in the early stage, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. In addition, there have also been various attempts to explore pharmaceutical strategies to improve the druggability of drug candidates. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, strategies for developing better drugs are discussed.

Albumin-coated copper nanoparticles for photothermal cancer therapy: Synthesis and in vitro characterization.

Copper nanoparticles (CuNPs) have attracted great interest in various biomedical research fields due to their superior optical and plasmonic properties. In the present study, we synthesized bovine serum albumin (BSA)-coated CuNPs (BSA-CuNPs) by adopting the aqueous reduction method in 2-step procedures. The prepared BSA-CuNPs were characterized in vitro for their physical characteristics and photothermal activity. The successful synthesis of BSA-CuNPs was verified through transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), dynamic light scattering (DLS), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and ultraviolet-visible (UV-VIS) light spectroscopy. The prepared BSA-CuNPs revealed a great light-to-heat conversion capacity and good photothermal stability. Notably, accompanied by laser irradiation, the BSA-CuNPs elicited significantly higher cytotoxicity on tumor cells than the control group. Preliminary animal studies to determine the biosafety and pharmacokinetics (PK) profiles exhibited that the BSA-CuNPs have a maximum tolerable dose (MTD) of 16 mgCu/kg and a relatively long plasma half-life of 1.98 h. Overall, our findings demonstrated that BSA-CuNPs might be a potential photothermal therapeutic agent for cancer treatment.

Topical Delivery of Cell-Penetrating Peptide-Modified Human Growth Hormone for Enhanced Wound Healing.

Protein drugs have been emerging as a class of promising therapeutics. However, their topical application has been limited by their high molecular weight and poor permeability to the cell membrane. In this study, we aimed to enhance human growth hormone (hGH) permeability for topical application by conjugation of TAT peptide, a cell-penetrating peptide, to hGH via crosslinker. After TAT was conjugated to hGH, TAT-hGH was purified by affinity chromatography. TAT-hGH significantly increased cell proliferation compared with the control. Interestingly, the effect of TAT-hGH was higher than hGH at the same concentration. Furthermore, the conjugation of TAT to hGH enhanced the permeability of TAT-hGH across the cell membrane without affecting its biological activity in vitro. In vivo, the topical application of TAT-hGH into scar tissue markedly accelerated wound healing. Histological results showed that TAT-hGH dramatically promoted the re-epithelialization of wounds in the initial stage. These results demonstrate TAT-hGH as a new therapeutic potential drug for wound healing treatment. This study also provides a new method for topical protein application via enhancement of their permeability.

Lipocalin-2 promotes acute lung inflammation and oxidative stress by enhancing macrophage iron accumulation.

Lipocalin-2 (LCN2) is an acute-phase protein that regulates inflammatory responses to bacteria or lipopolysaccharide (LPS). Although the bacteriostatic role of LCN2 is well studied, the function of LCN2 in acute lung damage remains unclear. Here, LCN2 knockout (KO) mice were used to investigate the role of LCN2 in LPS-treated mice with or without recombinant LCN2 (rLCN2). In addition, we employed patients with pneumonia. RAW264.7 cells were given LCN2 inhibition or rLCN2 with or without iron chelator deferiprone. LCN2 KO mice had a higher survival rate than wild-type (WT) mice after LPS treatment. In addition to elevated LCN2 levels in serum and bronchoalveolar lavage fluid (BALF), LPS treatment also increased LCN2 protein in alveolar macrophage lysates of BALF. LCN2 deletion attenuated neutrophil and macrophage infiltration in the lungs of LPS-treated mice as well as serum and BALF interleukin-6 (IL-6). Circulating proinflammatory cytokines and LCN2-positive macrophages were prominently increased in the BALF of pneumonia patients. In addition to increase of iron-stained macrophages in pneumonia patients, increased iron-stained macrophages and oxidative stress in LPS-treated mice were inhibited by LCN2 deletion. In contrast, rLCN2 pretreatment aggravated lung inflammation and oxidative stress in LPS-treated WT mice and then resulted in higher mortality. In RAW264.7 cells, exogenous LCN2 treatment also increased inflammation and oxidative stress, whereas LCN2 knockdown markedly diminished these effects. Furthermore, deferiprone inhibited inflammation, oxidative stress, and phagocytosis in RAW264.7 cells with high LCN2 levels, as well as LPS-induced acute lung injury in WT and LCN2 KO mice. Thus, these findings suggest that LCN2 plays a key role in inflammation and oxidative stress following acute lung injury and that LCN2 is a potential therapeutic target for pneumonia or acute lung injury.

Fc Receptor Expression as a Prognostic Factor in Patients With Non-small-cell Lung Cancer.

BACKGROUND/AIM: The neonatal Fc receptor (FcRn) is a major histocompatibility class I-like molecule responsible for the transfer of passive humoral immunity from a mother to her newborn. Recent research revealed that FcRn is involved in antigen-presentation, humoral immunity and antitumor immunity of various types of cancer, such as lung, colon and breast. Lung cancer is the leading cause of cancer-related death and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer. NSCLC is a highly heterogeneous disease and this affects the prognosis. Therefore, many studies have tried to identify factors that are associated with prognosis. The lungs are a major organ expressing FcRn. We aimed to evaluate FcRn expression in surgical specimens of NSCLC and determine its correlation with patient prognosis. MATERIALS AND METHODS: We analyzed 140 NSCLC surgical specimens for FcRn expression using immunohistochemistry and correlated positivity with clinicopathology and survival of these patients. A chi-squared test and Kaplan-Meier analysis with log-rank tests were performed for statistical evaluation. RESULTS: The FcRn-positive group had a significantly higher disease-free survival and a tendency towards increased disease-specific survival in patients with tumor-node-metastasis stage I NSCLC. CONCLUSION: Our study supports the hypothesis that FcRn down-regulation is associated with NSCLC progression.

In Vitro and In Vivo Evaluation of PEGylated Starch-Coated Iron Oxide Nanoparticles for Enhanced Photothermal Cancer Therapy.

Iron oxide nanoparticles (IONPs) possess versatile utility in cancer theranostics, thus, they have drawn enormous interest in the cancer research field. Herein, we prepared polyethylene glycol (PEG)-conjugated and starch-coated IONPs ("PEG-starch-IONPs"), and assessed their applicability for photothermal treatment (PTT) of cancer. The prepared PEG-starch-IONPs were investigated for their physical properties by transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and dynamic light scattering (DLS). The pharmacokinetic study results showed a significant extension in the plasma half-life by PEGylation, which led to a markedly increased (5.7-fold) tumor accumulation. When PEG-starch-IONPs were evaluated for their photothermal activity, notably, they displayed marked and reproducible heating effects selectively on the tumor site with laser irradiation. Lastly, efficacy studies demonstrated that PEG-starch-IONPs-based PTT may be a promising mode of cancer therapy.