Synthesis and biological evaluation of new chlorin derivatives as potential photosensitizers for photodynamic therapy

Three new water-soluble chlorin derivatives 3, 5 and 8 for potential use as photosensitizers in photodynamic therapy (PDT) for cancer were synthesized from photoprotoporphyrin IX dimethyl ester (1). The in vivo biodistribution and clearance of chlorin derivatives 3, 5 and 8 were investigated in tumor-bearing mice. Iminodiacetic acid derivative 8 showed the greatest tumor-selective accumulation among the new chlorin derivatives with maximum accumulation in tumor tissue at 3 h after intravenous injection and rapid clearance from normal tissues within 24 h after injection. The in vivo therapeutic efficacy of PDT using 8 was evaluated by measuring tumor growth rates in tumor-bearing mice with 660 nm light-emitting diode irradiation at 3 h after injection of 8. Tumor growth was significantly inhibited by PDT using 8. These results indicate that iminodiacetic acid derivative 8 is useful as a new photosensitizer to overcome the disadvantages of photosensitizers that are currently in clinical use.     

A peptide receptor-based bioelectronic nose for the real-time determination of seafood quality

We herein report a peptide receptor-based bioelectronic nose (PRBN) that can determine the quality of seafood in real-time through measuring the amount of trimethylamine (TMA) generated from spoiled seafood. The PRBN was developed using single walled-carbon nanotube field-effect transistors (SWNT-FETs) functionalized with olfactory receptor-derived peptides (ORPs) which can recognize TMA and it allowed us to sensitively and selectively detect TMA in real-time at concentrations as low as 10fM. Utilizing these properties, we were able to not only determine the quality of three kinds of seafood (oyster, shrimp, and lobster), but were also able to distinguish spoiled seafood from other types of spoiled foods without any pretreatment processes. Especially, the use of small synthetic peptide rather than the whole protein allowed PRBNs to be simply manufactured through a single-step process and to be reused with high reproducibility due to no requirement of lipid bilayers. Furthermore, the PRBN was produced on a portable scale making it effectively useful for the food industry where the on-site measurement of seafood quality is required.     

Purification and Properties of Allothreonine Aldolase from Maise Seedlings

In order to elucidate the structure-activity relationship of griseofulvin (1), (±)-6′-demethyl analog (3), 2′-demethoxy-6′-demethyldihydro analog (4), (±)-dechloro-6′-ethyl analog (5), (±)-dechloro-6′-epi-ethyl analog (6), (±)-6′-ethyl analog (7) and (±)-6′-epi-ethyl analog (8) were synthesized by a Diels-Alder cycloaddition of alkylidene ketones (16, 17, 18, 19 and 20) with modified 1,3-butadienes (21 or 22). Their biological activities were examined against fungi.     

Notch Pathway Activation Contributes to Inhibition of C2C12 Myoblast Differentiation by Ethanol

The loss of muscle mass in alcoholic myopathy may reflect alcohol inhibition of myogenic cell differentiation into myotubes. Here, using a high content imaging system we show that ethanol inhibits C2C12 myoblast differentiation by reducing myogenic fusion, creating smaller and less complex myotubes compared with controls. Ethanol administration during C2C12 differentiation reduced MyoD and myogenin expression, and microarray analysis identified ethanol activation of the Notch signaling pathway target genes Hes1 and Hey1. A reporter plasmid regulated by the Hes1 proximal promoter was activated by alcohol treatment in C2C12 cells. Treatment of differentiating C2C12 cells with a gamma secretase inhibitor (GSI) abrogated induction of Hes1. On a morphological level GSI treatment completely rescued myogenic fusion defects and partially restored other myotube parameters in response to alcohol. We conclude that alcohol inhibits C2C12 myoblast differentiation and the inhibition of myogenic fusion is mediated by Notch pathway activation.     

Bioelectronic nose and its application to smell visualization

There have been many trials to visualize smell using various techniques in order to objectively express the smell because information obtained from the sense of smell in human is very subjective. So far, well-trained experts such as a perfumer, complex and large-scale equipment such as GC-MS, and an electronic nose have played major roles in objectively detecting and recognizing odors. Recently, an optoelectronic nose was developed to achieve this purpose, but some limitations regarding the sensitivity and the number of smells that can be visualized still persist. Since the elucidation of the olfactory mechanism, numerous researches have been accomplished for the development of a sensing device by mimicking human olfactory system. Engineered olfactory cells were constructed to mimic the human olfactory system, and the use of engineered olfactory cells for smell visualization has been attempted with the use of various methods such as calcium imaging, CRE reporter assay, BRET, and membrane potential assay; however, it is not easy to consistently control the condition of cells and it is impossible to detect low odorant concentration. Recently, the bioelectronic nose was developed, and much improved along with the improvement of nano-biotechnology. The bioelectronic nose consists of the following two parts: primary transducer and secondary transducer. Biological materials as a primary transducer improved the selectivity of the sensor, and nanomaterials as a secondary transducer increased the sensitivity. Especially, the bioelectronic noses using various nanomaterials combined with human olfactory receptors or nanovesicles derived from engineered olfactory cells have a potential which can detect almost all of the smells recognized by human because an engineered olfactory cell might be able to express any human olfactory receptor as well as can mimic human olfactory system. Therefore, bioelectronic nose will be a potent tool for smell visualization, but only if two technologies are completed. First, a multi-channel array-sensing system has to be applied for the integration of all of the olfactory receptors into a single chip for mimicking the performance of human nose. Second, the processing technique of the multi-channel system signals should be simultaneously established with the conversion of the signals to visual images. With the use of this latest sensing technology, the realization of a proper smell-visualization technology is expected in the near future.     

Fill Factor Losses in Cu2ZnSn(SxSe1−x)4 Solar Cells: Insights from Physical and Electrical Characterization of Devices and Exfoliated Films

Besides the open circuit voltage (V_OC) deficit, fill factor (FF) is the second most significant parameter deficit for earth‐abundant kesterite solar cell technology. Here, various pathways for FF loss are discussed, with focus on the series resistance issue and its various contributing factors. Electrical and physical characterizations of the full range of bandgap (E_g = 1.0–1.5 eV) Cu₂ZnSn(S_xSe_1?x)₄ (CZTSSe) devices, as well as bare and exfoliated films with various S/(S + Se) ratios, are performed. High intensity Suns‐V_OC measurement indicates a nonohmic junction developing in high bandgap CZTSSe. Grazing incidence X‐ray diffraction, Raman mapping, field emission scanning electron microscopy, and X‐ray photoelectron spectroscopy indicate the formation of Sn(S,Se)₂, Mo(S,Se)₂, and Zn(S,Se) at the high bandgap CZTSSe/Mo interface, contributing to the increased series resistance (R_S) and nonohmic back contact characteristics. This study offers some clues as to why the record‐CZTSSe solar cells occur within a bandgap range centered around 1.15 eV and offers some direction for further optimization.     

Skin aging caused by intrinsic or extrinsic processes characterized with functional proteomics

The skin provides protection against environmental stress. However, intrinsic and extrinsic aging causes significant alteration to skin structure and components, which subsequently impairs molecular characteristics and biochemical processes. Here, we have conducted an immunohistological investigation and established the proteome profiles on nude mice skin to verify the specific responses during aging caused by different factors. Our results showed that UVB‐elicited aging results in upregulation of proliferating cell nuclear antigen and strong oxidative damage in DNA, whereas chronological aging abolished epidermal cell growth and increased the expression of caspase‐14, as well as protein carbonylation. Network analysis indicated that the programmed skin aging activated the ubiquitin system and triggered obvious downregulation of 14‐3‐3 sigma, which might accelerate the loss of cell growth capacity. On the other hand, UVB stimulation enhanced inflammation and the risk of skin carcinogenesis. Collectively, functional proteomics could provide large‐scale investigation of the potent proteins and molecules that play important roles in skin subjected to both intrinsic and extrinsic aging.     

Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence

Anti-tumor CD8⁺ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing melanoma tumor-associated antigen (TAA)—dopachrome tautomerase (AdDCT) and resection resulting in major surgical stress (abdominal nephrectomy), we demonstrate that surgical stress results in a reduction in the number of CD8⁺ T cell that produce cytokines (IFNγ, TNFα, Granzyme B) in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC) population numbers and functional impairment of TAA-specific CD8⁺ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8⁺ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients.     

Paternal B Vitamin Intake Is a Determinant of Growth,Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring

Background

The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well.

Objective

In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content.

Methods

Male Apc^1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B₂, B₆, B₁₂, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc^1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden.

Results

No differences in intestinal tumor incidence or burden were found between male Apc^1638N offspring of different paternal diet groups. Although in female Apc^1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid-metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring.

Conclusions

In this animal model, modulation of paternal B vitamin intake prior to mating alters offspring weight gain, lipid metabolism and tumor growth in a sex-specific fashion. These results highlight the need to better define how paternal nutrition affects the health of offspring.