Discovery of Pharmacological Compounds that Stimulate Renal Mitochondrial Biogenesis and Restore Kidney Function

Dysfunctional mitochondria are a primary pathological consequence of acute kidney injury (AKI). Mitochondrial homeostasis is disrupted up to 144 h after ischemia-reperfusion (I/R) induced-AKI in the renal cortical tissue of mice. Stimulation of mitochondrial biogenesis in renal cells after oxidant injury restores mitochondrial function. The primary goals of this project were to identify novel pharmacological compounds capable of inducing mitochondrial biogenesis in the renal proximal tubule and evaluate if this induction would promote the recovery of mitochondrial and/or renal function after in vivo AKI. The secondary goal was to employ our mitochondrial approach for drug discovery towards identifying a novel treatment for a different disease state, skeletal muscle atrophy. Stimulation of the G-protein couple receptor (GPCR) family in response to physiological stress results in the downstream activation of effectors, which upregulates the expression and activity of PGC-1α and subsequently activates the mitochondrial biogenic program. Pharmacological agonism of both the stimulatory GPCR (β2-AR) and the inhibitory (A1AR) GPCR family via full and partial agonists resulted in the stimulation of mitochondrial biogenesis in the renal proximal tubule. The A1AR partial agonist CVT-2759 was superior to the full agonist CCPA in stimulating mitochondrial biogenesis in the proximal tubule. Acute kidney injury (AKI), by induction of ischemia-reperfusion (I/R), in mice produced persistent proximal tubule damage, which resulted in minimal recovery of kidney and mitochondrial function at 144 h post injury. Tubule pathology was characterized histologically by the presence of presence of necrosis. Renal dysfunction and injury was evidence by robust increases in serum creatinine and KIM-1 expression. In addition, mitochondrial OXPHOS proteins were suppressed and dysfunctional. Treatment with formoterol, a potent, highly specific, and long-acting -β2-AR agonist, restored renal function, rescued renal tubules from injury, and diminished necrosis after I/R-induced AKI. Concomitantly, formoterol stimulated mitochondrial biogenesis and restored the expression and function of mitochondrial proteins. Skeletal muscle atrophy remains a clinical problem in numerous pathological conditions. β2-AR receptor agonists, such as formoterol, are capable of inducing mitochondrial biogenesis and skeletal muscle hypertrophy. Recently, atomoxetine, an FDA approved norepinephrine reuptake inhibitor, was positive in a cellular assay for mitochondrial biogenesis. Using a mouse model of dexamethasone-induced skeletal muscle atrophy we determined that atomoxetine prevents skeletal muscle atrophy via a non-canonical PGC-1α signaling mechanism. In addition, we determined that formoterol selectively induces the PGC-1α4 splice variant, which initiates a discrete gene program resulting in skeletal muscle hypertrophy. Taken together, we determined that pharmacological stimulation of mitochondrial biogenesis via formoterol is capable of promoting faster recovery of mitochondrial function, which is associated with accelerated recovery of overall kidney function after maximal kidney dysfunction is established. Overall, we have demonstrated that our drug discovery approach is effective in identifying pharmacological compounds capable of inducing mitochondrial biogenesis and other nuclear regulators of metabolism. This approach proves beneficial in defining novel therapies for disease states that are characterized by dysfunctional mitochondria

New Late Permian paleomagnetic data from Argentina: Refinement of the apparent polar wander path of Gondwana

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95004/1/ggge1994.pd

Hur upplever personal kulturkrockar på kortareaffärsresor?

I den allt mer globaliserade värld vi lever i blir det vanligare att göra affärer mellanolika länder. Sverige räcker inte till för alla varor och tjänster som produceras här ochlandet behöver därför hitta nya marknader för sina produkter. Sverige exporterar årligenvaror och tjänster som motsvarar 50 % av Sveriges BNP. Med andra ord görs det väldigtmycket affärer med andra länder. Men hur väl förberedda är medarbetarna på desvenska företagen för att göra affärer med främmande kulturer? Detsamma gällerföretagen, hur väl förberedda är de på denna utveckling? Vad gör de av den kunskapoch kompetens som finns på så många företag?I dagsläget är Tyskland vårt största exportland och även om det ligger Sverige närakulturellt så är de affärsmässiga kulturskillnaderna större. De har en mycket tydligarehierarki, är raka på sak och diskuterar inte mer än nödvändigt. Det land som är mest påuppåtgående vad gäller export är Kina, där Sverige har ökat sin export med 260 % sedan1998. Därför är det viktigt att lära sig göra affärer med de länder som vi ännu inte har så etablerad kontakt med. Genom en empirisk undersökning i form av intervjuer skapades en bild av hur det ser utpå företag idag. Något förvånansvärt är att det var så många företag som helt eller delvissaknade rutiner för att utbilda personalen innan en resa, samt för återkoppling efterresor.Den empiriska undersökningen tydliggjorde bristerna i flödet av kunskap omutlandsaffärer. Det var inte bara spridningen av kunskap som var dålig på de olikaföretagen, utan även utbildningen inför en resa. En del av dem som intervjuades vardock öppna för en lösning då de själva ansåg att kunskap och kompetens gick till spillo.Empirin visade även på att skillnaderna mellan kön, ålder och bransch var nästintillobefintlig. För att lösa problemet med den bristande spridningen av kunskap har författarna tilldenna rapport utvecklat en lösning i form av en hemsida. Företagen köper en licens föratt få tillgång till hemsidan och kan sen sprida kunskapen både internt och till andraföretag.In the increasingly globalized world we live in, it is more and more common to dobusiness across borders. Sweden is not a big enough country to make use of all thegoods and services produced here. Therefore the country needs to find new markets fortheir products. Sweden annually exports products and services that meet 50% of Sweden's GNP. But how well prepared are the employees of the Swedish companies todo business with foreign cultures? The same applies to businesses, how well preparedthey are for this development? Also, what do they do with the knowledge and expertisethat exists in so many companies?Currently Germany is the country Sweden exports the most products to. Even thoughGermany is culturally close to Sweden, the business cultures differ. Germans have avery set hierarchy and they cut straight to the chase at meetings. The country most onthe rise when it comes to Swedish export is China. Sweden has increased its exports toChina by 260 % since 1998. Therefore it is also important to learn to do business withcountries that we don’t yet have such an established contact with. Through an empirical study in the form of interviews, an idea of what the situation istoday was formed. It was somewhat surprising to find that there were so manycompanies that partially or completely lacked procedures to train staff before a trip andgive feedback after travelling.The empirical study demonstrated the limitations of knowledge about foreign affairs incompanies. However, most of those who were interviewed were open to the idea ofsome kind of solution to the problem. The empirical study also showed that thedifferences between gender, age and industry were almost non-existent.To solve the problem of lack of sharing knowledge on these topics, the authors of thisreport developed a solution in the form of a website. The companies buy a license toaccess the website, and can then share knowledge both internally and with othercompanies

Latvia’s taxes system

Diplomdarba mērķis ir izpētīt Latvijas nodokļu sistēmu, tās sastāvdaļas, normatīvo bāzi, ietekmējošos faktorus, paralēli tam skatīt kā pēdējos gados ir mainījušās nodokļu likmes un kā tas ir ietekmējis nodokļu ieņēmumus, izteikt secinājumus un izstrādāt priekšlikumus par nodokļu sistēmas uzlabošanu. Darbā tiks skatīts katrs nodokļa veids, tā objekts, likme un atvieglojumi, uzsverot būtiskās nianses katrā nodoklī. Darba temats ir aktuāls ar to, ka pašlaik sabiedrībā ir ļoti aktuāls jautājums par inflācijas samazināšanu Latvijā un izmaiņas nodokļos ir viens no instrumentiem kā to ietekmēt. Diplomdarbs sastāv no četrām daļām. Pirmajā daļā tiks apskatīta nodokļu sistēmas teorētiskā puses un raksturota Latvijas nodokļu sistēma, skatīti kopējiem nodokļu ieņēmumi Latvijā no 2001. – 2006. gadam. Darba otrajā daļā tiks skatīti tieši nodokli Latvijā, trešajā daļā – netiešie nodokļi, savukārt ceturtajā daļā - pārējie nodokļi Latvijā. Visās trīs daļas detalizēti tiks skatīts katrs nodokļu veids, to likmes, ietekmējošie faktori, analizējot pēdējā gada tendences un izmaiņas nodokļos. Tiks veikta ieņēmumu analīze par pēdējiem pieciem gadiem. Darbā sīkāk tiks apskatītas to nodokļu attīstības iespējas, kuri pēdējā gada laikā sabiedrība izraisījuši vislielākās diskusijas – iedzīvotāju ienākuma nodoklis, akcīzes nodoklis, nekustamā īpašuma nodoklis, pievienotās vērtības nodoklis, automobiļu un motociklu nodoklis. Diplomdarbā ir izmantoti dažādi informācijas avoti: LR likumdošanas akti, mācību grāmatas, ministriju mājas lapas, kā arī preses un interneta portālos pieejamā informācija.The objective of diploma work is to research Latvia’s taxes system, its components, legal base, influence factors, to prepare an overview on tax rates changes in the last years and how those changes have influenced taxes incomes and give conclusions and proposals in order to improve the taxes system in Latvia. In the diploma work is overviewed each kind of taxes, its object, rate, preference and most important aspects. The theme of diploma work is very actual because the question about reducing the inflation level in Latvia is very actual in the society and changes in tax system is one of the instruments in order to reduce inflation level The diploma work consists from four parts. In the first part is overviewed the taxes system theory, characterized current tax system in Latvia and researched taxes incomes in Latvia during 2001 - 2006. In the second part of diploma work is researched the direct taxes, in the third part – indirect taxes, but in the fourth part - an other taxes in Latvia. Research of every kind of taxes, its rates, influence factors, analyse of tendencies and changes in tax system last year and taxes incomes during last five years is included in all four parts. More detailed research was done on analyzing the development of taxes, especially inhabitant income tax, excise duty, real estate tax, value added tax, tax of auto and motorcycle. Different kind of information resources were used in preparation the diploma work: legal acts of the Republic of Latvian, textbooks, Internet home pages and mass media materials

A Novel Class of Small Molecule Inhibitors of HDAC6

Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor’s selective toxicity against leukemia

A Novel Class of Small Molecule Inhibitors of HDAC6

Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor’s selective toxicity against leukemia