Natural Products for Pancreatic Cancer Treatment: From Traditional Medicine to Modern Drug Discovery.

Pancreatic cancer, the seventh most lethal cancer around the world, is considered complicated cancer due to poor prognosis and difficulty in treatment. Despite all the conventional treatments, including surgical therapy and chemotherapy, the mortality rate is still high. Therefore, the possibility of using natural products for pancreatic cancer is increasing. In this study, 68 natural products that have anti-pancreatic cancer effects reported within five years were reviewed. The mechanisms of anti-cancer effects were divided into four types: apoptosis, anti-metastasis, anti-angiogenesis, and anti-resistance. Most of the studies were conducted for natural products that induce apoptosis in pancreatic cancer. Among them, plant extracts such as Eucalyptus microcorys account for the major portion. Some natural products, including Moringa, Coix seed, etc., showed multi-functional properties. Natural products could be beneficial candidates for treating pancreatic cancer.

Repeated Use of the Psychoactive Substance Ethylphenidate Impacts Neurochemistry and Reward Learning in Adolescent Male and Female Mice.

Schedule II prescription psychostimulants, such as methylphenidate (MPH), can be misused as nootropic drugs, i.e., drugs that enhance focus and cognition. When users are unable to obtain these prescribed medications, they may seek out novel psychoactive substances (NPSs) that are not yet scheduled. An example of a NPS reportedly being abused is ethylphenidate (EPH), a close analog of MPH but with a higher preference for the dopamine transporter compared with the norepinephrine transporter. Therefore, based upon this pharmacological profile and user self-reports, we hypothesized that repeated EPH exposure in adolescent mice may be rewarding and alter cognition. Here, we report that repeated exposure to 15 mg/kg EPH decreased spatial cognitive performance as assessed by the Barnes maze spatial learning task in adolescent male C57Bl/6 mice; however, male mice did not show alterations in the expression of mature BDNF - a protein associated with increased cognitive function - in key brain regions. Acute EPH exposure induced hyperlocomotion at a high dose (15 mg/kg, i.p.), but not a low dose (5 mg/kg, i.p.). Interestingly, mice exhibited significant conditioned place preference at the low EPH dose, suggesting that even non-stimulating doses of EPH are rewarding. In both males and females, repeated EPH exposure increased expression of deltaFosB - a marker associated with increased risk of drug abuse - in the dorsal striatum, nucleus accumbens, and prefrontal cortex. Overall, our results suggest that repeated EPH use in adolescence is psychostimulatory, rewarding, increases crucial brain markers of reward-related behaviors, and may negatively impact spatial performance.

Behavioral Characterization of ß-Arrestin 1 Knockout Mice in Anxiety-Like and Alcohol Behaviors.

ß-Arrestin 1 and 2 are highly expressed proteins involved in the desensitization of G protein-coupled receptor signaling which also regulate a variety of intracellular signaling pathways. Gene knockout (KO) studies suggest that the two isoforms are not homologous in their effects on baseline and drug-induced behavior; yet, the role of ß-arrestin 1 in the central nervous system has been less investigated compared to ß-arrestin 2. Here, we investigate how global ß-arrestin 1 KO affects anxiety-like and alcohol-related behaviors in male and female C57BL/6 mice. We observed increased baseline locomotor activity in ß-arrestin 1 KO animals compared with wild-type (WT) or heterozygous (HET) mice with a sex effect. KO male mice were less anxious in a light/dark transition test, although this effect may have been confounded by increased locomotor activity. No differences in sucrose intake were observed between genotypes or sexes. Female ß-arrestin 1 KO mice consumed more 10% alcohol than HET females in a limited 4-h access, two-bottle choice, drinking-in-the-dark model. In a 20% alcohol binge-like access model, female KO animals consumed significantly more alcohol than HET and WT females. A significant sex effect was observed in both alcohol consumption models, with female mice consuming greater amounts of alcohol than males relative to body weight. Increased sensitivity to latency to loss of righting reflex (LORR) was observed in ß-arrestin 1 KO mice although no differences were observed in duration of LORR. Overall, our efforts suggest that ß-arrestin 1 may be protective against increased alcohol consumption in females and hyperactivity in both sexes.

Odontogenic infection involving the secondary fascial space in diabetic and non-diabetic patients: a clinical comparative study.

OBJECTIVES: This retrospective study was performed to evaluate the clinical impact of diabetes mellitus on the prognosis in secondary space infection. MATERIALS AND METHODS: Medical records, radiographic images, computed tomography, and microbial studies of 51 patients (25 diabetic patients and 26 non-diabetic patients) were reviewed. Patients were diagnosed as secondary fascial space infections with odontogenic origin and underwent treatment at Chonnam National University Hospital, in Department of Oral and Maxillofacial Surgery, from January 2007 to February 2009. RESULTS: COMPARED TO PATIENTS WITHOUT DIABETES, PATIENTS WITH DIABETES WERE PRESENTED WITH THE FOLLOWING CHARACTERISTICS: older age (diabetic patients: 62.9 years, non-diabetic patients, 47.8 years), more spaces involved (diabetic patients, 60%; non-diabetic patients, 27.3%), more intense treatment, longer hospitalization (diabetic patients, 28.9 days; non-diabetic patients, 15.4 days), higher white blood cell and C-reactive protein values, higher incidence of complication (diabetic patients, 40%; non-diabetic patients, 7.7%), and distinctive main causative microorganisms. CONCLUSION: These results suggest that the prognosis of diabetic patients is poorer than that of non-diabetic patients in secondary space infections since they had greater incidence rates of involved spaces, abnormal hematologic findings, more complications, and additional procedures, such as tracheostomy.

Evolution of H5N1 influenza virus through proteotyping of hemagglutinin with high resolution mass spectrometry.

The evolution of the major surface hemagglutinin (HA) antigen of type A H5N1 influenza viruses is explored at the amino acid level using a new proteotyping approach. Alignments of translated hemagglutinin gene sequences of all characterised type A H5N1 strains, or subsets thereof, has enabled the presence of signature peptides of conserved sequence and unique mass to be investigated from the perspective of the host, period and region from which strains were isolated. Consistent with the rapid, cross species transmission of H5N1 strains among migratory birds, poultry and humans throughout south-east Asia, no signatures unique to the host or region were found. Nevertheless, several period-specific signature peptides were identified that enable strains associated with the 1997 H5N1 pandemic to be rapidly differentiated from those in circulation across the subsequent decade.

Proteotyping to establish gene origin within reassortant influenza viruses.

The application of a rapid and direct proteotyping approach with which to identify the gene origin of viral antigens in a reassortant influenza strain is demonstrated. The reassortant strain, constructed for a vaccine against type A 2009 H1N1 pandemic influenza, contains genes derived from a wild-type pandemic strain (A/California/7/2009) and an egg adapted high-growth strain (denoted NYMC X-157) derived from an earlier A/Puerto Rico/8/34 strain. The proteotyping approach employs modern proteomics methods and high resolution mass spectrometry to correctly establish that the genes of the surface antigens, hemagglutinin and neuraminidase, are derived from the A/California/7/2009 strain while those for nucleoprotein and matrix protein M1 antigens are derived from the NYMC X-157 strain. This is achieved for both gel-separated antigens and those from a whole vaccine digest. Furthermore, signature peptides detected in the mass spectra of the digested antigens enable the engineered reassortant strain to be identified as a type A virus of the H1N1 subtype in accord with earlier studies. The results demonstrate that proteotyping approach provides a more direct and rapid approach over RT-PCR with which to characterize reassortant strains of the influenza virus at the molecular protein level. Given that these strains pose the greatest risk to human and animal health and have been responsible for all human pandemics of the 20th and 21st centuries, there is a vital need for the origins and evolutionary history of these strains to be rapidly established.

Ability of N-acetylcarnosine to protect lens crystallins from oxidation and oxidative damage by radical probe mass spectrometry (RP-MS).

The application of Radical Probe Mass Spectrometry based on protein footprinting studies is described to investigate the effectiveness of the antioxidant N-acetylcarnosine (NAC) in preventing oxidative damage to lens crystallins present in the eye of mammals. Despite separate clinical trials which have reported the benefit of administering NAC to the eye as a 1% topical solution for the treatment of human cataract, no evidence was found to suggest that the antioxidant had any significant direct effect on reducing the levels of oxidation within the most abundant lens crystallins, α and ß-crystallin, at the molecular level at increasing concentrations of NAC. The results of this laboratory study suggest that the therapeutic benefit demonstrated in clinical trials is associated with the nature or formulation of the topical solution and/or that the mode of action of NAC as an antioxidant is not a direct one.

Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration.

Amyloid precursor protein (APP) has eight potential phosphorylation sites in its cytoplasmic domain. Recently, it has demonstrated that the constitutive phosphorylation of APP at T668 (APP695 isoform numbering) was observed specifically in the brain. Neuron-specific phosphorylation of APP at T668 is thought to be important for neuronal functions of APP, although its exact physiological significance remains to be clarified. In this study, we show that the phosphorylation of the APP intracellular domain (AICD) at T668 is essential for its binding to Fe65 and its nuclear translocation and affects the resultant neurotoxicity, possibly mediated through the induction of glycogen synthase kinase 3beta and tau phosphorylation by enhancing the formation of a ternary complex with Fe65 and CP2 transcription factor. Taken together, these results suggest that the phosphorylation of AICD at T668 contributes to the neuronal degeneration in Alzheimer's disease (AD) by regulating its translocation into the nucleus and then affects neurodegeneration; therefore, the specific inhibitor of T668 phosphorylation might be the target of AD therapy.