The primary purpose of this study was to investigate the effects of aerobic and resistance training on BDNF and IGF-I expression in a 3xTg-AD mouse model of Alzheimer’s disease. Twenty-four 3xTg-AD mice were randomly assigned to either an aerobic (AT, n=8), resistance (RT, n=8), or control (CNT, n=8) group. Intervention groups underwent 9 weeks of exercise training. Motor behavior and grip strength were measured pre- and post- intervention. Our results showed a significant increase in hippocampal BDNF expression in AT mice after a 9-week intervention. Further, AT mice were found to have higher concentrations of IGF-I, and improved motor behavior when compared to RT and CNT. No significant differences were observed in IGF-I concentration between RT and other groups. RT improved grip strength after nine weeks of training. These findings support the use of AT and RT as a tool to improve comorbidities found in Alzheimer’s disease. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

1 v. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1994

xxiii, 222 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Insulin-like growth factor-I circulates at high concentrations in blood, mainly complexed with IGF-binding proteins. The main objective of the thesis is to determine the general role played by plasma IGF-binding proteins in the regulation of IGF transfer from blood to tissues. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Science, 1994

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 117-126).

Το συμπλήρωμα είναι βασικός παράγοντας της φυσικής ανοσίας (innate immunity) και αποτελεί γέφυρα για την ενεργοποίηση της ειδικής ανοσίας (adaptive immunity). Αποτελείται από ένα σύστημα πρωτεϊνών, που συναντώνται ως ανενεργά προένζυμα και ενεργοποιούνται μέσω πρωτεόλυσης πυροδοτώντας έναν καταρράκτη αντιδράσεων. Οι οδοί ενεργοποίησης του συμπληρώματος καταλήγουν στον σχηματισμό ενός λυτικού συμπλόκου (Membrane Attack Complex – MAC) που καταστρέφει τους παθογόνους μικροοργανισμούς. Οι πρωτεΐνες, συστατικά του συμπλόκου, ανήκουν στην οικογένεια MACPF (MAC – Perforin). Σημαντικό ρόλο στη λειτουργία τους παίζει η πρωτεϊνική περιοχή (module) FIMAC (Factor I Membrane Attack Complex). Η περιοχή αυτή υπάρχει στα συστατικά C6 (Complement component 6) και C7 (Complement component 7) του συμπλόκου MAC και φαίνεται να είναι η περιοχή πρόσδεσής τους με την περιοχή C345C του C5b. Επιπλέον, η περιοχή FIMAC υπάρχει και στον παράγοντα Ι του Συμπληρώματος (Complement Factor I, CFI), ο οποίος συμμετέχει στην αποσταθεροποίηση της κομβερτάσης C3/C5, μέσω του καρβοξυτελικού άκρου της FIMAC που φαίνεται να συνδέεται αλλοστερικά με την πρωτεϊνική περιοχή SP (Serine Protease), που αποτελεί την ενεργή του περιοχή. Το μοντέλο, για την ανάλυση της περιοχής FIMAC βασίστηκε στην περιοχή της πρωτεΐνης φολιστατίνη (follistatin, FS) FD (follistatin Domain), η οποία αναλύθηκε πρόσφατα κρυσταλλογραφικά και με την οποία εμφανίζει ομοιότητα στην αλληλουχία της. Η δομή FD αποτελεί ένα υβρίδιο μιας αμινοτελικής περιοχής EGF (Epidermal Growth Factor) και μίας καρβοξυτελικής περιοχής του ωοβλεννοειδούς (ovomucoid) που ομοιάζουν με τις πρωτεϊνικές περιοχές KAZAL και συναντώνται σε πολλούς αναστολείς σερινικών πρωτεασών. Η περιοχή FD περιέχεται, επίσης, στην πρωτεΐνη αγκρίνη (agrin, AGRN) που αποτελεί συστατικό της βασικής μεμβράνης και παίζει σημαντικό ρόλο στην νευρομυϊκή σύναψη. Η μελέτη των πρωτεϊνικών περιοχών FIMAC και KAZAL αναφορικά με την λειτουργία, την δομή και την εξέλιξή τους αποτέλεσε το αντικείμενο της παρούσας εργασίας. Για την εκπόνηση αυτής της μελέτης χρησιμοποιήθηκαν δεδομένα από βάσεις βιολογικών δεδομένων και εργαλεία βιοπληροφορικής ανάλυσης. Πρωτογενές υλικό της μελέτης αποτέλεσαν οι νουκλεοτιδικές και αμινοξικές αλληλουχίες των γονιδίων C6, C7, CFI, AGRN και FS σε όλους τους οργανισμούς που βρέθηκαν (σπονδυλωτά και ασπόνδυλα), και πιο συγκεκριμένα οι αλληλουχίες που αντιστοιχούν στις πρωτεϊνικές περιοχές FIMAC και KAZAL. Οι πρωτοταγείς δομές των FIMAC ( ̴ 78αα) και KAZAL ( ̴ 55αα) διαφέρουν ως προς το μήκος τους, με μερικές εξαιρέσεις που αφορούν περιοχές KAZAL των πρωτεϊνών AGRN και FS (>80αα). Οι δευτεροταγείς δομές των FIMAC και KAZAL παρουσιάζουν μεγάλη ομοιότητα, φέροντας δομές α – έλικας και β – πτυχωτής επιφάνειας στην αλληλουχία τους. Τέλος, τα μοντέλα προσομοίωσης τριτοταγούς δομής και των δύο περιοχών FIMAC και KAZAL οπτικοποιούν τη διαμόρφωση των δομών της α – έλικας και των β – πτυχωτών επιφανειών στον χώρο. Αξιοσημείωτη είναι η παρουσία σημαντικού αριθμού κυστεϊνικών καταλοίπων στις αλληλουχίες των περιοχών FIMAC (8 – 10 Cys), με μεγαλύτερη συγκέντρωση στο αμινοτελικό άκρο, και KAZAL (4 – 6 Cys) με ομοιόμορφη κατανομή. Εξελικτικά, η εμφάνιση γονιδίων που συμμετέχουν και στις τρεις οδούς ενεργοποίησης του συμπληρώματος και καταλήγουν στη διαμόρφωση του συμπλόκου MAC συνοδεύεται με την εμφάνιση των χονδριχθύων. Πιο συγκεκριμένα, όσον αφορά τα γονίδια του συμπληρώματος που περιλαμβάνουν τις περιοχές FIMAC και KAZAL, ο CFI πρωτοεμφανίζεται στα άγναθα, το C6 στους χονδριχθείς και το C7 στους οστεϊχθείς. Η παρουσία των γονιδίων AGRN και FS έχει πιστοποιηθεί νωρίτερα εξελικτικά στο στάδιο των κεφαλοχορδωτών καθώς και στους πλατυέλμινθες των πρωτοστομίων. Έτσι, φαίνεται ότι η περιοχή KAZAL στις πρωτεΐνες AGRN και FS στα ασπόνδυλα αποτελεί προγονική περιοχή όλων των FIMAC και KAZAL που υπάρχουν σήμερα. Ωστόσο, νέες πρωτεϊνικές περιοχές KAZAL εμφανίστηκαν και αργότερα κατά την εξέλιξη των ειδών. Η συντηρητικότητα και των δύο περιοχών FIMAC και KAZAL στο επίπεδο της γονιδιακής τους κληρονόμησης είναι μεγάλη. Όλα τα intron phases των εξονίων που κωδικοποιούν τις περιοχές KAZAL και FIMAC σε όλα τα γονίδια όπου συναντώνται είναι 1, εκτός από τα αντίστοιχα εξόνια για την περιοχή FIMAC της γραμμικής θέσης 1 στις πρωτεΐνες C6 και C7 (intron phase 2), που φαίνεται να είναι εξελικτικά μεταγενέστερες περιοχές, και δημιουργήθηκαν με διπλασιασμό εξονίου, σε μεταγενέστερα εξελικτικά στάδια. / The complement system is a key component of the innate immune system and links the innate and adaptive immunity. It consists of more than 35 soluble and membrane proteins that initially are found as inactivated proenzymes and they can be activated by a proteolytic cascade. All three pathways that activate the complement leads to the formation of a Membrane Attack Complex (MAC) that lyses the pathogenic microorganisms. Proteins that participate in the formation of MAC, belongs to the MACPF (MAC – Perforin) family. The FIMAC (Factor I Membrane Attack Complex) module plays significant role in the function of MACPF proteins. The Complement proteins 6 (C6) and 7 (C7) that are components of the MAC, include the FIMAC module in their sequences and it seems that this module is their binding region with C345C of C5b. Moreover, the FIMAC module exists in Complement Factor I (CFI), which is a serine protease (SP) and degrades C4b and C3b molecules. The carboxyl - terminal of FIMAC module binds allosteric with the SP region in CFI and seems to be important for the function of CFI as a serine protease. The model for the analysis of FIMAC module was based in Follistatin Domain (FD) of follistatin (FS) protein, which has been analyzed by crystallography. FIMAC and FD modules seem to have homologous sequences. The FD structure is a hybrid of an amino – terminal EGF (Epidermal Growth Factor) subdomain and of a carboxyl – terminal similar to ovomucoid subdomain, which is called KAZAL and is present in many serine protease inhibitors. The FD module is also present in the Agrin (AGRN) protein. AGRN is an extracellular matrix molecule released by the nerve and is critical for the formation of the neuromuscular junction. The subject of this work was the study of FIMAC and KAZAL modules concerning their function, structure and evolution. There were used data from biological databases and bioinformatic tools for analysis. The nucleotide and amino acid sequences of C6, C7, CFI, AGRN and FS genes from the organisms that were found (vertebrates and invertebrates), and more specific, FIMAC and KAZAL sequences, were the primary material of this study. There are differences in the length of the primary structures of FIMAC ( ̴ 78aa) and KAZAL ( ̴ 55aa) modules, except for some KAZAL modules of AGRN and FS proteins (>80aa). The secondary structures of FIMAC and KAZAL modules seem to be similar as both of them contain α-helix and β-sheet conformations. Simulation models of tertiary structure of both FIMAC and KAZAL modules revealed a common conformation of α-helix and β-sheet in space. The presence of cysteine residues are very conserved and seem to be important in FIMAC (8 – 10 Cys) and KAZAL (4 – 6 Cys) modules, although the concentration of cysteine residues in FIMAC modules are denser in amino – terminal region compared with their corresponding concentration in KAZALs, where they follow an equable distribution. Evolutionary, the genes that participate in all three pathways of complement activation and result in MAC formation, first appeared on chondrichthyes. Moreover, FIMAC and KAZAL modules included in CFI sequence found firstly on agnatha, on chondrichthyes in C6 sequences and on osteichthyes in C7 sequences. The presence of AGRN and FS genes were certified earlier in evolution on cephalochordates and platyelminthes of protostomes. As a result, it seems that the KAZAL modules of AGRN and FS proteins in invertebrates are the ancestors of all FIMAC and KAZAL modules. Nevertheless, new KAZAL modules appeared later during evolution of species. At the genomic level, exons corresponding to the FIMAC and KAZAL modules are highly conserved in different taxa. Intron phases of all exons corresponding to the FIMAC and KAZAL modules in all genes are 1, except for exons of FIMAC modules in first position of C6 and C7 genes (phase 2) that seem to be evolutionary posterior and were emerged by exon duplication, later in evolution.

Deoxycholic acid (DCA) is a secondary bile acid postulated to be involved in the etiology and the progression of colorectal cancer, but its specific mechanisms are not fully understood. DCA has been shown to induce apoptosis allowing selection for apoptosis-resistant cells, which highlights the importance of understanding the mechanisms of action of DCA. Previously, it has been demonstrated that DCA perturbs the plasma membrane, leading to the activation of receptor tyrosine kinases. Because the insulin-like growth factor-1 receptor (IGF-IR), a receptor tyrosine kinase, is demonstrated to play a significant role in protecting colorectal cancer cells from apoptosis, we hypothesized that DCA modulates IGF-IR functions in colorectal cancer cells. We demonstrated that DCA induced the dynamin-dependent endocytosis of IGF-IR through both clathrin-mediated and caveolin-1-dependent mechanisms. Endocytosis of IGF-IR sensitized cells to DCA-induced apoptosis, which demonstrated that IGF-IR played a role in protecting cells against DCA-induced apoptosis. Since DCA-induced endocytosis of IGF-IR was determined to be a caveolin-1 dependent process, caveolin-1 knockdown in HCT116 (HCT116-Cav1-AS) prevented the DCA-mediated endocytosis of IGF-IR. However, we observed an increased sensitivity of DCA-induced apoptosis in the Cav1-AS cells. This suggested that caveolin-1 knockdown altered the plasma membrane dynamics such that although IGF-IR was maintained at the plasma membrane, it facilitated a pro-apoptotic signal. We demonstrated that DCA induced the activation of the pro-apoptotic p38 signaling pathway in HCT116-Cav1-AS, but not in HCT116-Mock, via IGF-IR. Inhibition of both the IGF-IR and p38 independently in HCT116-Cav1-AS significantly decreased their sensitivity to DCA-induced apoptosis. These observations demonstrated that, in a caveolin-1 dependent manner, IGF-IR played a dynamic role in the DCA-mediated apoptosis. Finally, we provided preliminary evidence demonstrating that autophagy played a central role in protecting DCA-resistant cells from DCA-induced apoptosis.Since resistance to DCA also confers apoptosis-resistance, understanding the mechanisms that lead to or prevent DCA-induced cell death is significant, since they can lead to the development of novel therapeutic strategies to sensitize apoptosis-resistant colorectal cancer cells to undergo cell death.

Insulin-like growth factor-1 (IGF-1) is essential for oligodendrocyte (OL) development, promoting their survival, proliferation and differentiation. Furthermore, IGF-1 null mutant mice have a decrease in CNS myelination and in the number of OL progenitors (OLPs). IGF-1 interacts with the Type I IGF receptor to activate two main downstream signalling pathways, the PI3K/Akt and the Ras-Raf-MEK/ERK cascades, which mediate survival or proliferation of OLPs. The objective of this study is to elucidate the transduction pathways involved in IGF-I-stimulated protein synthesis, important for growth and differentiation of OLs. In other cellular systems, the PI3K/Akt pathway is involved in protein translation. mTOR and the p70 S6 kinase are downstream effectors that phosphorylate translation initiation factors (e.g. eIF-4E) and their regulators (e.g. 4E-BP1). OLPs were obtained from primary cultures and were treated with IGF-1 with or without inhibitors LY294002 or wortmannin (PI3K), rapamycin (mTOR), Akt III or IV, an adenovirus with a dominant negative form of Akt or PD98059 (ERK). Protein synthesis was assessed by metabolic labeling with [35S]-methionine, and protein phosphorylation by Western blotting. Results from the former showed that IGF-1 stimulates protein synthesis in a dose-dependent manner. Moreover, IGF-1 increases protein synthesis in OLPs through PI3K, mTOR, Akt and ERK activation. Concordantly, Western blot analysis reveals that IGF-1 stimulates phosphorylation of Akt, mTOR, ERK, S6 and 4E-BP 1. Activation of S6 and inactivation of 4E-BP1 occur through phosphorylation and are required for protein synthesis to take place. These events are dependent on the upstream activation of PI3K, Akt and mTOR.

The study of diabetes mellitus is vital in this day and age because its incidence is increasing at an alarming rate. Diabetes results in the loss of function of beta-cells within the pancreas. Insulin resistance contributes to diabetes but the human body can compensate in various ways such as increasing the islet cell mass, glucose disposal and insulin secretion, in order to prevent the onset of diabetes. Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are two integral hormones important in both glucose homeostasis and islet cell growth. Early studies using cultured islet cells have demonstrated positive regulation of beta-cell growth by both GH and IGF-I. To evaluate their relevance on normal beta-cell growth, compensatory growth, as well as in insulin responsiveness, we have used two mouse models that represent opposite manipulations of the GH/IGF-I axis. Specifically, the growth hormone receptor gene deficient (GHR-/-) and the IGF-I overexpression (MT-IGF) mice, to help understand the role of glucose homeostasis and islet cell growth in the GH/IGF-I axis. GH is essential for somatic growth and development as well as maintaining metabolic homeostasis. It is known that GH stimulates normal islet cell growth. Moreover, GH may also participate in islet cell overgrowth and compensate for insulin resistance induced by obesity. To determine whether the islet cell overgrowth is dependent on GH signaling, we studied the response of GHR-/- mice to high-fat diet (HFD)-induced obesity. We also studied the insulin responsiveness in GHR-/- mice. On the other hand, IGF-I promotes embryonic development, postnatal growth and the maturation of various organ systems. The notion that IGF-I stimulates islet cell growth has been challenged in recent years by results from IGF-I and receptor gene targeted models. We have characterized MT-IGF mice which overexpress the IGF-I gene. / The results of our studies indicate that (1) GH is essential for normal islet cell growth, but not required for compensatory overgrowth of the islets in response to obesity, (2) GHR gene deficiency caused delayed insulin responsiveness in skeletal muscle; in contrast to elevated insulin sensitivity in the liver; (3) although overexpression does not stimulate islet cell growth, a chronic IGF-I elevation caused significant hypoglycemia, hypoinsulinemia, and improved glucose tolerance, (4) finally IGF-I overexpression mice are resistant to experimental diabetes.

Bibliography :leaves 250-302. / xix, 302, [19] leaves, [4] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Results suggest that IGF-I peptides significantly influence gastrointestinal growth in normal adult and suckling rats and indicate they may have therapeutic implications both in conditions of impaired gut function in the adult gastrointestinal tract and in the treatment of gut disease in the immature intestine. / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics & Gynaecology, 1995?

Thesis (Ph.D.) -- University of Adelaide, Department of Animal Science, 1992.