What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

Background

Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingør, Denmark.

Methodology

Literature search in databases as PubMed and ISI Web of Science in combination with manual search was used to answer the following five questions: ¹Can resveratrol be recommended in the prevention or treatment of human diseases?; ²Are there observed “side effects” caused by the intake of resveratrol in humans?; ³What is the relevant dose of resveratrol?; ⁴What valid data are available regarding an effect in various species of experimental animals?; ⁵Which relevant (overall) mechanisms of action of resveratrol have been documented?

Conclusions/Significance

The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.     

Efficacy and Safety of Anthelmintics Tested against Taenia solium Cysticercosis in Pigs

Porcine cysticercosis, an infection caused by Taenia solium metacestodes, is continuously being reported in low-income countries of Latin America, Asia, and sub-Saharan Africa. The disease was declared eradicable by the International Task Force for Diseases Eradication (ITFDE) in 1993, and it is listed among the 17 WHO Neglected Tropical Diseases and Neglected Zoonoses that are potentially eradicable. In view of that, WHO has proposed a step-wise approach to its elimination, including chemotherapy of infected pigs. Different drugs have been tested on porcine cysticercosis with varying efficacies. These include flubendazole, fenbendazole, albendazole, albendazole sulphoxide, oxfendazole, praziquantel, and nitazoxanide. This review summarises available information on the efficacies and adverse effects shown by these drugs in pigs. Oxfendazole has shown to be effective for the control of porcine cysticercosis; however, it needs to be integrated with other control approaches. There is a need for standardised guidelines for evaluating the efficacy of anthelmintics against porcine cysticercosis, and more efficacy studies are needed since the conclusions so far are based on a limited number of studies using few infected pigs.

Key Learning Points

• Among the anthelmintics evaluated, oxfendazole has proven to be safe and efficacious against porcine cysticercosis.
• Limited intervention trials have shown oxfendazole to be effective for control of porcine cysticercosis; however, it needs to be integrated with other control approaches.
• Standardised protocols for assessment of anthelmintic efficacy and effectiveness for control of porcine cysticercosis are lacking, making inter-study comparison difficult.
• More studies are needed to fully assess the efficacy and effectiveness of oxfendazole and other anthelmintics against T. solium cysticercosis and other pig parasitoses.

Key References

• Gonzales AE, Garcia HH, Gilman RH, Gavidia CM, Tsang VCW, et al. (1996) Effective, single-dose treatment of porcine cysticercosis with oxfendazole. Am J Trop Med Hyg 54: 391-394.
• Gonzalez AE, Falcon N, Gavidia C, Garcia HH, Tsang VCW, et al. (1997) Treatment of porcine cysticercosis with oxfendazole: a dose-response trial. Vet Rec 141: 420-422.
• Moreno L, Lopez-Urbina MT, Faras C, Domingue G, Donadeu M, et al. (2012) A high oxfendazole dose to control porcine cysticercosis: Pharmacokinetics and tissue residue profiles. Food Chem Toxicol 50: 3819 – 3825.
• Sikasunge CS, Johansen MV, Willingham AL, III, Leifsson PS, Phiri IK (2008) Taenia solium porcine cysticercosis: viability of cysticerci and persistency of antibodies and cysticercal antigens after treatment with oxfendazole. Vet Parasitol 158: 57-66.
• Torres A, Plancarte A, Villalobos ANM, Aluja ASd, Navarro R, et al. (1992) Praziquantel treatment of porcine brain and muscle Taenia solium cysticercosis. 3. Effect of 1-day treatment. Parasitol Res 78: 161-164.

     

Mechanisms of Topoisomerase I (TOP1) Gene Copy Number Increase in a Stage III Colorectal Cancer Patient Cohort

Background

Topoisomerase I (Top1) is the target of Top1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH).

Methods

Nine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined.

Results

TOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20<2.0) showed a trend towards shorter TTR (univariate HR: 1.57, p = 0.07).

Conclusions

TOP1 gene copy number increase occurs frequently in stage III CRC in a mechanism that often includes CEN-20. Using CEN-2 as a measurement for tumor ploidy levels, we were able to discriminate between different mechanisms of gene gain, which appeared to differ in prognostic impact. TOP1 FISH guidelines have been updated.     

Peroxisome proliferator-activated receptor gamma is required for CD4+ T cell-mediated lymphopenia-associated autoimmunity

The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) was shown to play an immunoregulatory role in many immune-related cell types, and activation of PPARγ was reported to be an effective therapeutic approach in murine and human autoimmune disease. However, despite an association between lymphopenia and autoimmunity, there has been no study on the role of T cell PPARγ in lymphopenia-associated autoimmunity. In the present studies, we examined the role of PPARγ in CD4(+) T cells in two murine models of lymphopenia-associated autoimmunity. Surprisingly, we found that PPARγ expression in CD4(+) CD25(-) T cells (T effector cells [Teffs]) is actually required for development of autoimmunity under lymphopenic conditions. Mechanistically, the inability of PPARγ-deficient (T-PPAR) Teffs to mediate lymphopenic autoimmunity is associated with a significant decrease in accumulation of Teffs in the spleen, lymph nodes, and tissues after adoptive transfer. This abnormal accumulation of T-PPAR Teffs was associated with defects in both in vivo proliferation and survival. Additionally, T-PPAR Teffs demonstrated decreased cytokine production in inflammatory sites and decreased expression of the homing receptor α4β7. Finally, these abnormalities in T-PPAR Teff function were not elicited by lymphopenia alone but also required the additional activation involved in the mediation of autoimmunity. Thus, in contrast to its documented immunosuppressive role, we identified an unexpected function for PPARγ in Teffs: a role in Teff proliferation and survival in lymphopenia-associated autoimmunity. These findings highlight both the multifunctional role of PPARγ in T cells and the complexity of PPARγ as a potential therapeutic target in autoimmunity.     

T cell-signaling network analysis reveals distinct differences between CD28 and CD2 costimulation responses in various subsets and in the MAPK pathway between resting and activated regulatory T cells

To uncover signaling system differences between T cell stimuli and T cell subsets, phosphorylation status of 18 signaling proteins at six different time points following TCR triggering and CD28/CD2 costimulation was examined in human T cell subsets by phospho-epitope-specific flow cytometry of fluorescent cell barcoded samples, thereby providing a high-resolution signaling map. Compared with effector/memory T cells, naive T cells displayed stronger activation of proximal signaling molecules after TCR triggering alone. Conversely, distal phosphorylation events, like pErk and pS6-ribosomal protein, were stronger in effector/memory subsets. CD28 costimulation specifically induced signaling necessary for proper NF-κB activation, whereas CD2 signaled more strongly to S6-ribosomal protein. Analysis of resting regulatory T cells (rTregs; CD4(+)CD45RA(+)FOXP3(+)) and activated regulatory T cells (actTregs; CD4(+)CD45RA(-)FOXP3(++)) revealed that, although rTregs had low basal, but inducible, Erk activity, actTregs displayed high basal Erk phosphorylation and little or no Akt activation. Interestingly, the use of Mek inhibitors to block Erk activation inhibited activation-dependent FOXP3 upregulation in rTregs, their transition to actTregs, and the resulting increase in suppressive capacity. In summary, our systems approach unraveled distinct differences in signaling elicited by CD28 and CD2 costimulation and between rTregs and actTregs. Blocking rTreg transition to highly suppressive actTregs by Mek inhibitors might have future therapeutic applications.     

Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development.     

Di‐ and tri‐nucleotide repeat microsatellites for the mealy plum aphid,Hyalopterus pruni

Hyalopterus pruni is an invasive aphid pest in California. To study the population biology of this pest both in California and its native Mediterranean region, we have developed 11 di‐ and tri‐nucleotide repeat microsatellite markers. Each locus amplified in individuals representing the full range of geographical regions and host plants where Hyalopterus is found. Polymorphism was high, ranging from six to 22 alleles per locus in the individuals screened. These loci represent the first microsatellites developed for Hyalopterus and they should be of great value in studying the invasion biology and population structure of this insect pest.     

The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an inherited disorder of mitochondrial fatty acid oxidation associated with variations in the ACADS gene and variable clinical symptoms. In addition to rare ACADS inactivating variations, two common variations, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser), have been identified in patients, but these are also present in up to 14% of normal populations leading to questions of their clinical relevance. The common variant alleles encode proteins with nearly normal enzymatic activity at physiological conditions in vitro. SCAD enzyme function, however, is impaired at increased temperature and the tendency to misfold increases under conditions of cellular stress. The present study examines misfolding of variant SCAD proteins identified in patients with SCAD deficiency. Analysis of the ACADS gene in 114 patients revealed 29 variations, 26 missense, one start codon, and two stop codon variations. In vitro import studies of variant SCAD proteins in isolated mitochondria from SCAD deficient (SCAD−/−) mice demonstrated an increased tendency of the abnormal proteins to misfold and aggregate compared to the wild-type, a phenomenon that often leads to gain-of-function cellular phenotypes. However, no correlation was found between the clinical phenotype and the degree of SCAD dysfunction. We propose that SCAD deficiency should be considered as a disorder of protein folding that can lead to clinical disease in combination with other genetic and environmental factors. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.