La ciclorreversión (CR) oxidativa ó reductiva de oxetanos por transferencia electrónica fotoinducida (TEF), no ha sido estudiada en profundidad, a pesar de que este proceso ha despertado un gran interés en la última década en relación con la exploración de nuevas rutas sintéticas y con la reparación fotoquímica del ADN. Respecto a la via fotooxidativa, teniendo en cuenta los cálculos teóricos y los datos experimentales ya publicados sobre su naturaleza se ha considerado interesante realizar un estudio experimental que aporte nuevos conocimientos acerca del mecanismo de reacción. En este contexto, se ha elegido como sustrato modelo el trans,trans-2-ciclopropil-3-fenil-4-metiloxetano (1) que ha permitido aclarar aspectos mecanísticos de la CR oxidativa de oxetanos. La escisión de 1 por ruptura inicial del enlace C2-C3 da lugar a los compuestos utilizados en la fotocicloadición de Patero-Büchi para la síntesis de 1. Por el contrario, la formación de un fotoproducto nuevo debido a la captura nucleofílica intermolecular del intermedio resultante de la fragmentación al enlace O-C2 por acetonitrilo está de acuerdo con un mecanismo por pasos. Respecto a la via fotorreductiva, se ha estudiado la CR del sustrato modelo trans,trans-2-(4-cianofenil)-3-fenil-4-metiloxetano (4) usando el 1-metoxinaftaleno como fotosensibilizador. Los datos experimentales son consistentes con que la reacción tiene lugar desde el estado singlete del sensibilizador. La fragmentación del anión radical de 4 ocurre por ruptura de los enlaces O-C2 y C3-C4 dando lugar a productos (acetaldehído y 4-cianoestilbeno) diferentes a los usados para la síntesis de 4 por medio de la fotociloadición de Paterno-Büchi. El proceso transcurre a través del anión radical del trans-4-cianoestilbeno, que se ha detectado mediante FDL (?max = 500 nm). Además, se ha estudiado la CR reductiva intramolecular utilizando como sustratos el (2S)-2-(6-metoxinaft-2-il)propanoato de (2R,3S,4S)-[2-(4-cianofenil)-3-feniloxetano-4-il / Pérez Ruiz, R. (2006). Ciclorreversión de iones radicales de oxetanos [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/1925 / Palancia

<p>According to the Global Cancer Incidence, Mortality, and Prevention (GLOBOCAN) study for 2018, 2,089,000 women will have been diagnosed with breast cancer worldwide, with 627,000 breast cancer-related mortalities. It is estimated that between 15 – 20 % of breast cancer diagnoses are of the triple-negative subtype. Triple-negative breast cancers (TNBCs) do not express the receptors for estrogen, progesterone, and human epidermal growth factor 2, and hence cannot be treated using hormone receptor-targeted therapy. </p> <p>TNBCs are commonly of the basal-like phenotype, with high expression levels of proteins involved in epithelial-mesenchymal transition, extracellular-matrix (ECM) remodeling, cell cycle progression, survival and drug resistance, invasion, and metastasis. 5-year survival rates are significantly lower for TNBC patients, and the disease is characterized by poorer grade at the time of diagnosis as well as higher 5-year distant relapse rates, with a greater chance of lung and CNS metastases. Current treatments for TNBC take the form of aggressive cytotoxic chemotherapy regimens with multiple adverse side-effects. An important goal of on-going studies is to identify new compounds with significant TNBC-specificity, in order to improve patient survival outcomes while preserving a high quality of life during treatment.</p> <p> For several decades, compounds originally isolated from bioactive natural extracts, such as the taxanes and vinca<i> </i>alkaloids, have been at the forefront of chemotherapy. However, due to their non -specific mechanisms of action, treatment with these compounds eventually leads to significant toxicity to normal cells and tissues. Modern transcriptomics, metabolomics, and proteomics tools have greatly improved our understanding of the mechanisms governing cancer initiation and progression, and revealed the considerable heterogeneity of tumor cells. This has allowed for the identification of potential vulnerabilities in multiple cancers, including TNBCs. By leveraging these new technologies and insights with the tremendous diversity of bioactive compounds from organisms that remain unstudied, new classes of onco-drugs targeting pathways specific to TNBC cells could be identified in the near future.</p> <p>Here, we describe the cytotoxic effects of extracts from <i>Lippia origanoides </i>- a species of medicinal shrub native to Central and South America - on TNBC cells. We report that these extracts induce rapid, sustained, and irreversible apoptosis in TNBC cells <i>in vitro</i>, with significantly reduced cytotoxicity against normal mammary epithelial cells. The <i>L. origanoides </i>extracts LOE and L42 exploited two TNBC-specific characteristics to induce apoptosis in these cells: i) inhibiting the constitutively active survival and inflammatory NF-kB signaling pathway, and ii) significantly dysregulating the expression levels of mitochondrial enzymes required to maintain the TCA cycle and oxidative phosphorylation; metabolic pathways that are required for the maintenance of TNBC cell growth and proliferation.</p> <p>Finally, to lay the foundations for future studies on the abilities of these extracts to prevent tumor initiation and inhibit tumor growth <i>in vivo</i>, we also show that the <i>L. origanoides </i>extract, L42, is non-toxic<i> </i>to immunocompetent C57BL/6 mice, and have developed an <i>in vivo </i>model of human TNBC in athymic <i>nu/nu</i> mice. </p> <p>Collectively, our studies are the first to identify the anti-TNBC-specific properties of bioactive extracts from the <i>Lippia </i>species, and reveal that targeting NF-kB signaling and mitochondrial metabolism are potential avenues to new therapeutics against this subtype of breast cancer. Future work in our lab will focus on identifying the bioactive components (BACs) of the extract mediating its apoptotic effects, and shedding light on their protein binding partners within the cell.</p>

<div>The use of computational approaches to understand kinase substrate preference has been a powerful tool in the search to develop artificial peptide probes to monitor kinase activity, however, most of these efforts focus on a small portion of the human kinome. The use of high throughput techniques to identify known kinase substrates plays an important role in development of sensitive protein kinase activity assays.</div><div>The KINATEST-ID pipeline is an example of a computational tool that uses known kinase substrate sequence information to identify kinase substrate preference. This approach was used to design three artificial substrates for ABL, JAK2 and SRC family kinases. These biosensors were used to design ELISA and lanthanide-based assays to monitor in vitro kinase activity. The KINATEST-ID pipeline relies on a high number of reported kinase substrates to predict artificial substrate sequences, however, not all kinases have the sufficient number of known substrates to make an accurate prediction. </div><div>The adaptation of kinase assay linked with phosphoproteomics technique was used to increase the number of known FLT3 kinase variant substrate sequences. Subsequently, a set of data formatting tools were developed to curate the mass spectrometry data to become compatible with a command line version of the KINATEST-ID pipeline modules. This approach was used to design seven pan-FLT3 artificial substrate (FAStides) sequences. The pair of FAStides that were deemed the most sensitive toward FLT3 kinase phosphorylation were assayed in increasing concentrations of clinically relevant tyrosine kinase inhibitors. </div><div>To improve the automation of the mass spectrometry data analysis and formatting for use with the KINATEST-ID pipeline, a streamlined process was developed within a bioinformatic platform, GalaxyP. The data formatting tools used to process the FLT3 mass spectrometry data were converted into compatible versions to execute within the GalaxyP framework. This process was used to design four BTK artificial substrates (BAStide) to monitor kinase activity. Additionally, one of the BAStide sequences was designed in the lanthanide chelating motif to develop an antibody-free activity assay for BTK. </div><div>Lastly, a multicolored time resolved lanthanide assay was designed by labeling SYK artificial substrate and a SRC family artificial substrate to measure the activity of both kinases in the same kinase reaction. This highlighted the functionality of lanthanide-based time resolved assays for potential multiplexing assay development. </div><div><br></div>

<p>  </p> <p>Cyclic dinucleotides (CDNs) such as the bacterial CDNs (cyclic-di-AMP, cyclic-di-GMP and 3’3’cyclic GMP-AMP) and mammalian CDN, 2’3’-cGAMP, are essential immune response second messenger signaling molecules. These CDNs act via Stimulator of interferon genes (STING)-TANK Binding Kinase 1 (TBK1)-Interferon Regulatory Factor 3 (IRF3) pathway. However, data from our lab and others indicate that beyond the classical STING-TBK1-IRF3 pathway, CDNs also regulate other signaling axes related to both inflammatory and non-inflammatory pathways. But, a global view of how these CDNs affect signaling in diverse cells or through non-STING pathways is lacking. There is also paucity of data on CDN modulated kinases and no global assessment of phosphorylation events that follow cyclic GMP AMP synthase (cGAS)-STING axis stimulation in immune cells. Herein, I have used a proteomics approach to determine signaling pathways regulated by bacterial CDNs, c-di-GMP and c-di-AMP in human gingival fibroblasts such as pathways related to nucleotide excision repair (NER) which ordinarily do not channel through STING (Chapter 3). Additionally, with the use of phosphoproteomics and bioinformatics, this project accomplished a system-wide phosphorylation analyses of T cells treated with 2’3’cGAMP and showed that 2’3’cGAMP impact various, yet unreported critical kinases (E.g. LCK, ZAP70, ARG2) and signaling pathways important for T cell function (Chapter 4). Asides known interferon signaling, these differentially phosphorylated kinases were involved in T cell receptor (TCR) signaling, myeloid cell differentiation, cell cycle regulation, and regulation of double strand break repair. </p> <p>Another area of interest addressed by this project is the discovery of novel antibacterial agents against multi-drug resistant (MDR) bacteria. Thus, in Chapters 5 and 6, I show the identification, antibacterial activity and characterization of <strong>HSD1835</strong> and <strong>HSD1919 </strong>as novel SF5 and SCF-containing membrane active compounds, highly potent against preformed MDR biofilms with fast bactericidal activity against persister bacteria. Plus, an exciting addition to the fight against MDR bacteria in Chapter 7, the discovery of <strong>HSD1624</strong> and analogs, which are able to re-sensitize MDR and colistin resistant bacteria such as <em>Pseudomonas aeruginosa</em> from a colistin MIC of 1024 μg/mL to 0.03 μg/mL (64000-fold reduction). Ultimately, these compounds could be translated into anti-biofilm and, anti-MDR bacteria therapeutics, preventing repeated surgeries due to infections, and saving lives. </p>

No description available.

M. Tech. (Department of Chemistry, Faculty of Applied and Computer Sciences) Vaal University of Technology. / The polymer and their blended fibres provide good surface and intermolecular chemistry that bring additional functionalities and structural changes that can be adapted for new usages. Natural polymers are known to possess desirable qualities in terms of biocompatibility and biodegradability. The natural polymers are chosen due to their abundance but have difficulties in the preparations hence the addition of a synthetic polymer is vital. An important property of the polymer blended fibres is its miscibility which affects the mechanical properties, the morphology and degradation. Metal oxide nanoparticles embedded into polymer blended fibres enhances the performances of the polymer blended fibre permeability, selectivity, strength, and hydrophilicity. This study reports on the synthesis and characterization of zein, collagen nanofibres, zein/PVA fibre blends, iron oxide, manganese oxide nanoparticles, Fe2O3/zein /PVA and Mn2O3/zein/PVA fibre nanocomposite blends. The zein nanofibres and zein/PVA fibre blends were electrospun using electrospinning technique. Parameters such as the concentration and voltage were investigated. These parameters had an effect on the fibre morphology. The electrospun zein nanofibres and zein/PVA fibre blends were characterized using scanning electron microscopy (SEM), UV-Visible spectroscopy, Photoluminescence (PL), X-ray diffraction (XRD), Fourier transformer infrared (FTIR) spectroscopy and Thermal gravimetric analysis (TGA). The SEM results illustrated that an increase in the concentration of zein nanofibres improved the morphology of the fibres into ribbon like shape and had an effect on the average diameter size. The addition of PVA into zein nanofibres enhanced electrospinnabilty and the mechanical strength of zein was dependent on the presence of PVA. The optical properties, XRD, FTIR and thermal studies confirmed that zein/PVA (80/20) blend weight ratio was miscible and the other blend weight ratios remained immiscible, this was due to stronger interaction of hydrophilic performance of zein and PVA through hydrogen bonding. Therefore, fibre blend weight ratios of zein/PVA (90/10, 80/20, 70/30, 60/40 and 50/50) were successfully fabricated. The optimisation of collagen nanofibres favoured electrospraying instead of electrospinning hence collagen nanofibres could not be fabricated. Iron oxide nanoparticles was synthesized using hydrothermal method and manganese oxide nanoparticles was synthesized through co-precipitation method. The TEM results revealed well defined shapes of metal oxide nanoparticles illustrating that the increment of temperature had an influence on the crystallinity and particle size of 𝛼-Fe2O3 , 𝛼-MnO2 and 𝛼-Mn2O3 nanoparticles. The XRD confirmed the crystalline pattern of the metal oxide nanoparticles were of rhombohedral 𝛼-Fe2O3 structures (JCPDS 00-033-0664), cryptomelane phase 𝛼-MnO2 (JCPDS No. 29-1020) and orthorhombic crystalline phase of 𝛼-Mn2O3 (JCPDS No. 04-007-088). The metal oxide nanoparticles were thermally stable. Three different concentrations (4.25 wt%, 4.75 wt% and 5.25 wt %) of 𝛼-Fe2O3 and 𝛼- Mn2O3 were embedded onto zein/PVA (80/20) fibre blends and electrospun. The SEM, optical properties, XRD and TGA confirmed that the embedment of metal oxide nanoparticles enhanced the zein/PVA fibre blends performance, mechanical strength and resistance to wear therefore 5.25 wt% of 𝛼-Fe2O3/zein/PVA and 𝛼-Mn2O3/zein/PVA were explored further for the adsorption of chrysoidine G removal from wastewater. The adsorption studies of zein/PVA (80/20), 𝛼-Fe2O3/zein/PVA and 𝛼-Mn2O3/zein/PVA were carried out in a batch system on the effects of contact time, pH, initial concentration and adsorbent dosage. All the nanoadsorbents could rapidly reach adsorption equilibrium within 30 min at room temperature. The maximum removal efficiency of chrysoidine G of zein/PVA, 𝛼-Mn2O3/zein/PVA was higher than 𝛼-Fe2O3/zein/PVA. The dye adsorption equilibrium data were well-fit with Langmuir isotherm rather than Freundlich isotherm. The comparison of kinetic models revealed that the overall adsorption process was described well by pseudo second-order kinetics. The polymeric materials were cost effective hence regeneration studies were implemented for three cycles. These nanoadsorbents are easily available and are expected to be economical.

<p dir="ltr">Adipose tissue is characterized by the dominant presence of adipocytes, specialized cells adept at lipid metabolism. These adipocytes act as critical nodes, coordinating the complex processes of energy storage and mobilization according to the body's metabolic requirements. Within the adipocyte population of mammals, there are three main subtypes: white, beige, and brown adipocytes. White adipocytes are primarily dedicated to the sequestration of energy in the form of triglycerides. Conversely, beige and brown adipocytes are distinguished by their capacity for thermogenesis, the process of dissipating nutritional energy as heat. The contemporary challenge of chronic overnutrition has precipitated a global surge in obesity and cardiometabolic diseases. Addressing this issue necessitates the maintenance of white adipocyte homeostasis and the enhancement of the quantity and function of thermogenic adipocytes, which are imperative for mitigating the global obesity epidemics.</p><p dir="ltr">Mitochondrion, a multifunctional organelle, is integral to a broad spectrum of cellular processes, including anabolic and catabolic metabolism, bioenergetics, and signal transduction, all of which are essential for maintaining cellular functions and homeostasis. The efficacy of mitochondrial operations is intrinsically linked to their membrane dynamics. In this study, transmission electron microscopy and mass spectrometry were employed to investigate the proteins implicated in the cold-induced mitochondrial membrane remodeling in brown adipocytes. Through this approach, a poorly characterized protein, Family with Sequence Similarity 210 Member A (FAM210A), was identified as a mitochondrial inner membrane protein that is induced by cold stimulation. Subsequent loss-of-function experiments were conducted to elucidate the role of FAM210A in adipocytes. Mice with adipose-specific deletion of <i>Fam210a</i> (<i>Fam210a</i>^<em>AKO</em>) exhibited compromised mitochondrial cristae structure and a reduced thermogenic capacity in brown adipose tissue (BAT), resulting in an increased susceptibility to lethal hypothermia during acute cold challenge. Moreover, in mice with inducible ablation of <i>Fam210a</i> in adipocytes (<i>Fam210</i>^{<em>iAKO</em>}), mitochondrial alterations in BAT were negligible at thermoneutral conditions; however, they exhibited defective cold-induced mitochondrial cristae remodeling, culminating in a progressive loss of cristae and diminished mitochondrial density. Mechanistically, it was determined that FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage, thus compromising cold-induced mitochondrial remodeling in BAT.</p><p dir="ltr">Additionally, this research delved into the role of FAM210A in adipocytes in response to dietary stress by feeding mice with high-fat diet (HFD). The study found a consistent correlation between FAM210A expression and OPA1 cleavage in adipocytes under HFD challenge. Mice lacking FAM210A in all adipocytes and subjected to HFD exhibited lipoatrophy in white adipose tissue (WAT) and a downregulation of genes associated with adipogenesis and lipid metabolism. In contrast, mice with a brown adipocyte-specific ablation of <i>Fam210a </i>(<i>Fam210a</i>^<em>UKO</em>) displayed no significant change in WAT mass but had enlarged livers. Crucially, both <i>Fam210a</i>^<em>AKO</em> and <i>Fam210a</i>^<em>UKO</em> mice presented increased WAT inflammation, deteriorated glucose tolerance, and exacerbated insulin resistance. These findings underscore the pivotal role of FAM210A in brown adipose tissue (BAT) in the preservation of WAT homeostasis and the regulation of systemic glucose clearance in diet-induced obesity.</p><p dir="ltr">In summary, these studies characterize the mitochondrial dynamics in brown adipocytes in response to cold stress, identify a new cold-induced mitochondrial protein, FAM210A, and uncover its functions in adipocytes under cold and dietary stresses. These findings highlight the importance of mitochondrial remodeling in the adaptive response of adipocytes to evolving metabolic demands. This work establishes FAM210A as a key regulator of mitochondrial cristae remodeling, shedding light on the mechanisms that govern mitochondrial plasticity in adipocytes.</p>

Ziel dieser Arbeit war es, den grundlegenden Mechanismus des Ladungstransfers bei molekularer Dotierung an organisch-organischen Grenzflächen besser zu verstehen. Es wurde eine Vielfalt modernster spektroskopischer Methoden eingesetzt, um die elektronische Struktur und neue dotierungsinduzierte CT-Übergänge zu ergründen. Dazu gehören UPS und XPS für Valenzsignaturen und Kernniveauzustände. Absorptionsspektroskopie im UV-vis-NIR und Röntgenbereich wurde zur Bestimmung der Übergangsenergien eingesetzt. Schwingungsspektroskopie wurde eingesetzt, um den CT-Grad in DA-Systemen für gestapelte und gemischte Heteroübergänge zu quantifizieren. Strom-Spannungs-Messungen wurden zur Bestimmung der elektrischen Leitfähigkeit und Rasterkraftmikroskopie zur Charakterisierung der Oberflächenmorphologie eingesetzt. Die in dieser Arbeit behandelten Themen sind: (1) Planare Heteroübergänge aus DIP und F6TCNNQ wurden hergestellt. Sie wurden im Hinblick auf CT-Komplexbildung, Grenzflächendotierung und Exzitonenbindungsenergien an der D|A-Grenzfläche untersucht. (2) DBTTF wurde mit TCNNQ und F6TCNNQ in Lösung und in dünnen Filmen gemischt. Daraus wurde der Zusammenhang zwischen Dotierungsmechanismen, CTC- und IPA-Bildung, mit dem Aggregatzustand hergeleitet. (3.1) Rubren-Einkristalle wurden mit Mo(tfd)3 und CoCp2 p- und n-dotiert. Nach der Dotierung verschiebt sich die Banddispersion entsprechend, wohingegen die effektive Masse der Löcher konstant bleibt. (3.2) DBTTF-Einkristalle wurden mit TCNNQ, F6TCNNQ und Mo(tfd)3 dotiert. Aus den Änderungen der elektronischen Struktur wurden der CT über die D|A-Grenzfläche sowie die Dichte der Oberflächenzustände quantifiziert. (4) Von drei DA-Systemen mit unterschiedlicher GS-Wechselwirkungsstärke, DIP:C60, DIP:PDIR-CN2 und DIP|F6TCNNQ, wurden die Grenzflächenexzitonen charakterisiert. Ein Vergleich verschiedener Modelle, die die optische CTC Absorption aus dem DA-Energieniveauoffset beschreiben und abschätzen können, rundet die Ergebnisse ab. / The aim of this thesis was to enhance the understanding of the charge transfer mechanism during molecular doping at organic-organic interfaces. A wide range of state-of-the-art spectroscopic methods was employed to unravel the electronic structure and new CT transitions resulting from doping. This includes UPS and XPS for valence signatures and core level states. Absorption spectroscopies in the UV-vis-NIR and X-ray regions were used to determine transition energies. Vibrational spectroscopy was employed to quantify the CT degree in DA systems for stacked and mixed heterojunctions. Current-voltage measurements were used for the determination of electrical conductivities and scanning force microscopy for surface morphology characterization. The topics covered in this thesis are: (1) Planar heterojunctions of DIP and F6TCNNQ were fabricated. They were studied with regard to CT complex formation, interface doping and exciton binding energies at the D|A interface. (2) DBTTF was blended with TCNNQ and F6TCNNQ in solution and in thin films. From this, the connection of the two doping mechanisms, CTC and IPA formation, to the state of matter was derived. (3.1) Rubrene single crystals were p- and n-doped with Mo(tfd)3 and CoCp2. After doping, the band dispersion shifts accordingly, while the hole effective mass stays constant. (3.2) DBTTF single crystals were doped with TCNNQ, F6TCNNQ and Mo(tfd)3. From changes in the electronic structure, the CT across the D|A interface as well as the density of surface states were quantified. (4) From three DA systems with varying GS interaction strength, DIP:C60, DIP:PDIR–CN2 and DIP|F6TCNNQ, the interfacial excitons were characterized. A comparison of different models, which describe and allow to estimate the optical absorption in CTCs from the DA energy level offset, concludes the results.

<p dir="ltr">Obesity is a worldwide epidemic that is partially linked to changing lifestyles within the modern world, including increased access to calorically dense foods and decreased energy output due to more sedentary jobs. Obesity can lead to many different health complications, such as cardiovascular diseases or Type 2 Diabetes (T2D). Obesity-induced T2D is caused by dysfunction of the insulin-producing beta cells of the pancreas. However, mechanisms that promote obesity and the mechanisms by which obesity leads to beta cell dysfunction are not fully known.</p><p dir="ltr">Spinophilin is a filamentous (F)-actin binding, protein scaffolding, and protein phosphatase 1 (PP1)-targeting protein that can regulate protein. Spinophilin has multiple actions. Spinophilin can bundle filamentous actin to modulate the cellular cytoskeleton. Spinophilin also mediates substrate phosphorylation by targeting and modulating PP1 activity. In addition, spinophilin interacts with multiple proteins, including certain G-protein coupled receptors and can scaffold them with F-actin and/or PP1. Previous studies established that spinophilin KO mice have decreased fat mass, increased lean mass, and improved glucose tolerance. Yet, how spinophilin modulates the above metabolic parameters is unclear. We found that spinophilin is expressed in hypothalamic tissue and appears to also be expressed in the feeding center of the hypothalamus, as well as in other glucose-sensing cells known as tanycytes that neighbor the arcuate nucleus and the third ventricle. We found that loss of spinophilin limited weight gain observed in both a leptin receptor db/db mouse line (Leprdb/db<i>)</i> and mice fed a high-fat diet. Moreover, we found that the decreased fat mass seen in global spinophilin KO mice, at least in the Leprdb/db mice, was not due to major differences in feeding behaviors, consistent with what was observed by other groups using high-fat diet-fed mice. </p><p dir="ltr">As spinophilin was not associated with alterations in feeding, we posited that its ability to modulate glucose homeostasis may be linked to non-neuronal actions of the protein. Previous studies have found that spinophilin may regulate adipose tissue function and <i>in vitro</i> pancreatic beta cell function; however, its role in the pancreas and beta cells <i>in vivo</i> is not well characterized. We found that spinophilin is expressed in mouse pancreas. Using proteomics-based approaches we identified multiple putative spinophilin interacting proteins isolated from intact pancreas, including: PP1, the spinophilin homolog neurabin, and myosin-9. KEGG pathway analysis of proteomic proteins identified multiple pathways regulating ER stress, such as the unfolded protein response, and cytoskeletal arrangement. We observed decreased associations of spinophilin with PP1 and neurabin and increased association with myosin-9 in obese, Leprdb/db mice as early as 6 weeks, as well as significant decreases in body weight when spinophilin was knocked out in Leprdb/db mice. Moreover, we confirmed a robust and specific increased interaction of spinophilin with myosin-9, and other cytoskeletal proteins. Additionally, we found specific spinophilin interactions with ribosomal proteins, and exocrine and digestion proteins in high-fat diet-fed mice. Using our recently generated pancreatic beta cell-specific spinophilin KO mice, we found that loss of spinophilin in mice on a high-fat diet significantly reduces weight gain and improves whole- body glucose tolerance, and loss of spinophilin specifically within the beta cells also improves whole-body glucose tolerance, with no effect on body weight, further suggesting cell type-specific and independent roles for spinophilin on body weight and glucose homeostasis.</p>

No description available.