Bioactive Compounds for Customized Brain Health: What Are We and Where Should We Be Heading?

Many strides have been made in the field of nutrition that are making it an attractive field not only to nutrition professionals but also to healthcare practitioners. Thanks to the emergence of molecular nutrition, there is a better appreciation of how the diet modulates health at the cellular and molecular levels. More importantly, the advancements in brain imaging have produced a greater appreciation of the impact of diet on brain health.

Validity and reliability of Food-Mood Questionnaire (FMQ).

Background: The need for short and validated questionnaires to evaluate dietary patterns (DPs) and mental distress in clinical and research settings is increasing.

Aim: The purpose of this study was to develop and validate a Food-Mood Questionnaire (FMQ) to assess DPs in relation to mental distress.

Method: A standard validation protocol that included item development, pilot-testing, test-retesting, and a series of statistical validation analyses was used.

Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe.

Background: Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology.

Immunogenicity and safety of the Vi-CRM197 conjugate vaccine against typhoid fever in adults, children, and infants in south and southeast Asia: results from two randomised, observer-blind, age de-escalation, phase 2 trials.

Background: Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM197 in participants of various ages in endemic countries in south and southeast Asia.

Thymocyte expansion and maturation: crosstalk of CD44v6 on thymocytes and panCD44 on stroma cells.

Re-acquisition of immunocompetence after allogeneic bone marrow cell (BMC) transplantation depends on intrathymic maturation of the allogeneic T progenitor cells. We recently reported that CD44 promotes progenitor homing into the thymus and T-cell maturation and now elucidate the molecular mechanisms of CD44-supported thymocyte maturation. Lethally irradiated, tumor-bearing mice, allogeneically reconstituted with T-cell-depleted BMC and a small number of common lymphoid progenitor 2 cells (CLP2) from transgenic (TG) mice, that express ratCD44v4-v7 under the Thy1 promoter, showed accelerated immunocompetent T-cell recovery compared with mice reconstituted with non-transgenic (NTG) CLP2.

Anti-CD44 induces apoptosis in T lymphoma via mitochondrial depolarization.

A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth.

CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance.

CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44v(kd)) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASML(wt)) were established.

CD44 and EpCAM: cancer-initiating cell markers.

Embryonic stem cells are immortal, can self renew, and differentiate into all cells of the body. The adult organism maintains adult stem cells in regenerative organs that can differentiate into all cells of the respective organ. Virchow's hypothesis that cancer may arise from embryonic-like cells has received strong support, as it was demonstrated that tumors contain few cells, known as cancer stem or cancer-initiating cells (CIC), that account for primary and metastatic tumor growth.

CD44 promotes progenitor homing into the thymus and T cell maturation.

Regain of immunocompetence after myeloablation and bone marrow cell (BMC) reconstitution essentially depends on T progenitor homing into the thymus and intrathymic T cell maturation. CD44 facilitates progenitor homing and settlement in the bone marrow and is known as a T progenitor marker. In search for improving regain of immunocompetence after BMC reconstitution, we explored whether the CD44 standard (CD44 s) and/or variant isoforms CD44v6 and CD44v7 contribute to thymus repopulation and thymocyte maturation.

Tumorigenicity of IL-1alpha- and IL-1beta-deficient fibrosarcoma cells.

Analyzing the growth of fibrosarcoma lines derived from IL-1alpha-, IL-1beta- , or IL-1alphabeta-knockout (-/-) mice in the immunocompetent host revealed that tumor-derived IL-1alpha and IL-1beta exert strong and opposing effects on immune response induction, which prohibited the evaluation of a potential impact on tumorigenicity. Therefore, in vivo growth of IL-1-deficient tumor lines was evaluated in nu/nu mice and was compared with in vitro growth characteristics. All IL-1-deficient fibrosarcoma lines grow in immunocompromised mice.

Opposing effects of fibrosarcoma cell-derived IL-1 alpha and IL-1 beta on immune response induction.

There is evidence that cell-associated IL-1 alpha supports immune response induction. Here we explored the impact of malignant cell-derived IL-1 on immunogenicity, immune response induction and tumor-induced immunosuppression using 3-methylcholanthrene-induced fibrosarcoma lines derived from wild-type (wt), IL-1 alpha-, IL-1 beta- or IL-1a beta-knockout (IL-1 alpha(-/-), IL-1 beta(-/-), IL-1 alphabeta(-/-)) C57BL6 mice. The wt, IL-1 alpha(-/-), IL-1 beta(-/-) and IL-1 alphabeta(-/-) fibrosarcoma lines express MHC class I molecules at a high level.

The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema.

Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4(+)CD25(high) lymph node cells from mice repeatedly treated with a contact sensitizer.

Anti-CD44-mediated blockade of leukocyte migration in skin-associated immune diseases.

CD44 plays an important role in leukocyte extravasation, which is fortified in autoimmune diseases and delayed-type hypersensitivity (DTH) reactions. There is additional evidence that distinct CD44 isoforms interfere with the extravasation of selective leukocyte subsets. We wanted to explore this question in alopecia areata (AA), a hair-follicle centric autoimmune disease, and in a chronic eczema.

In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance.

CD44 is involved in leukocyte migration and activation and has recently been reported to contribute to leukocyte extravasation by associating with CD49d. We explored whether similar changes in CD44 activity are seen in vivo using murine alopecia areata (AA) as a chronic, organ-related autoimmune disease model system. Expression of the activated, hyaluronan-binding form of CD44, and of CD49d, was elevated in draining lymph node cells (LNC) of AA-affected mice as compared to control mice.

A chronic contact eczema impedes migration of antigen-presenting cells in alopecia areata.

Long-lasting allergen treatment is the most efficient therapy in alopecia areata (AA). The underlying mechanism is unknown. We here asked whether treatment with a contact sensitizer influences leukocyte migration such that dendritic cell (DC) migration or the recruitment of activated T-cells towards the skin become hampered.

CD44v6 promotes proliferation by persisting activation of MAP kinases.

CD44v6 is transiently expressed during T cell activation, and constitutively CD44v4-v7 expressing transgenic T cells show accelerated responses towards nominal antigens. The underlying mechanism is unknown. The mouse thymoma EL4 was transfected with CD44 standard isoform (CD44s) or CD44v6 cDNA (EL4-s, EL4-v6).

CD44 in cancer progression: adhesion, migration and growth regulation.

It is well established that the large array of functions that a tumour cell has to fulfil to settle as a metastasis in a distant organ requires cooperative activities between the tumour and the surrounding tissue and that several classes of molecules are involved, such as cell-cell and cell-matrix adhesion molecules and matrix degrading enzymes, to name only a few. Furthermore, metastasis formation requires concerted activities between tumour cells and surrounding cells as well as matrix elements and possibly concerted activities between individual molecules of the tumour cell itself. Adhesion molecules have originally been thought to be essential for the formation of multicellular organisms and to tether cells to the extracellular matrix or to neighbouring cells.

CD44v7 interferes with activation-induced cell death by up-regulation of anti-apoptotic gene expression.

Blockade of CD44v7 was described to cure trinitrobenzene sulfonic acid-induced colitis, a disease not developed by mice with targeted deletion of the CD44v7 exon. There was evidence for a reduction in activation-induced cell death on lamina propria lymphocytes of control as compared with CD44v7-deficient mice. To elucidate the mechanism underlying the relative apoptosis resistance of CD44v7-competent as compared with CD44v7-deficient lymphocytes, T cell activation and induction of apoptosis were analyzed on mesenteric lymph node cells and Peyer's patch lymphocytes of CD44v7-deficient and CD44v4-v7-transgenic mice, which overexpress rat CD44v4-v7 on T lymphocytes.

Involvement of CD44 in cytoskeleton rearrangement and raft reorganization in T cells.

T cell activation is accompanied by actin-mediated receptor clustering and reorganization of lipid rafts. It has been suggested that costimulatory molecules might be involved in these processes. We here provide evidence that engagement of the adhesion molecule CD44 initiates cytoskeletal rearrangement and membrane reorganization in T cells.

Cloning of the human homologue of the metastasis-associated rat C4.4A.

We have previously described a rat metastasis-associated molecule, C4.4A, which has some common features with the uPAR. Because of its restricted expression in non-transformed tissues a search for the human homologue became of interest.

CD44 supports T cell proliferation and apoptosis by apposition of protein kinases.

T cell activation is supposed to require two signals via the TCR and a co-stimulatory molecule. However, the signaling cascade of co-stimulatory molecules has remained elusive. Here we provide evidence that CD44, which is constitutively associated with Ick and fyn, supports proliferation as well as apoptosis mainly, if not exclusively, by enhancing signal transduction via the TCR/CD3 complex.

Regulation of phospholipid biosynthesis by Ca(2+)-calmodulin-dependent protein kinase inhibitors.

Inhibitors of Ca(2+)-calmodulin (CaM)-dependent protein kinases strongly modify phospholipid metabolism. Two compounds, KN62 and KT5926 recognized as blockers of Ca(2+)-CaM-dependent protein kinase II, induced a specific increase in phosphatidylserine (PtdSer) synthesis without noticeable changes in phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) biosynthesis. The increase of PtdSer synthesis was dependent on the presence of Ca2+ in the incubation medium and was impaired in cells whose Ca2+ stores were depleted by pretreatment with CD3 mAb, thapsigargin or EGTA.

The protein tyrosine kinase p56(lck) regulates the serine-base exchange activity in Jurkat T cells.

Different classes of protein kinase inhibitors for protein kinase C, cAMP-dependent protein kinase or protein tyrosine kinases have been studied for their effect on phospholipid metabolism. The results show that among the compounds studied, only 4'-aminohydroxyflavone (AHF), previously described as a specific inhibitor of the protein tyrosine kinase p56(lck), markedly increased phosphatidylserine synthesis in Jurkat T cells. The biosyntheses of phosphatidylcholine and phosphatidylethanolamine were not affected.

Tyrphostin A9 inhibits calcium release-dependent phosphorylations and calcium entry via calcium release-activated channel in Jurkat T cells.

The mechanism by which calcium-depleted intracellular stores may trigger an external calcium influx through a calcium release-activated channel was investigated by analyzing the effects of several protein tyrosine kinase inhibitors on calcium movements in Jurkat T cells. Tyrphostin A9, an inhibitor of the kinase activity of the platelet-derived growth factor (PDGF) receptor, dramatically impaired the sustained elevation of cytosolic calcium concentration, induced by either CD3 mAbs, thapsigargin, ionomycin at low (10(-7) M) concentration, or passive depletion of intracellular stores; other tested tyrphostins, lavendustin, genistein, and compound 5 lacked significant effect. Tyrphostin A9, added during the plateau phase, was able to return cytosolic calcium to resting concentration.