Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation. 相似文献
Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-β (Aβ) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of Aβ deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain—effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble Aβ is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble Aβ. Failure of perivascular drainage of Aβ and deposition of Aβ in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of Aβ-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, Aβ and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of Aβ and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease. 相似文献
Fibroblast strains derived from six patients with maple syrup urine disease have been investigated for their requirements of the cofactors NAD, CoASH, Mg++ and TPP in comparison with 10 normal control strains. The reconstitution of the decarboxylase function of branched chain α-keto acid (BCKA) dehydrogenase complex in lysed cells was studied with respect to the substrates u-keto-isocaproic acid, α-keto-isovaleric acid, and α-keto-β-methylvaleric acid (KIC, KIVA, MEVA). The enzyme activity of all normal control strains for the substrates KIC and KIVA was not reconstituted by TPP + Mg++ alone, but CoASH + NAD could reconstitute the enzyme activity with KIC and KIVA in different degrees. Only two control strains were tested with MEVA as substrate, and these showed in contrast that TPP + Mg++ could partly reconstitute the enzyme activity. In contrast to the relative homogeneiy in the reconstitution profiles of normal strains, the five classical and one intermittent MSUD strains showed heterogeneity in cofactor requirements. Complementation analysis using heterokaryons prepared from fibroblasts of four patients with classical MSUD and one patient with intermittent MSUD showed, in contrast to experiments with normal controls, a partial amelioration of the defect in two combinations; it is suggested that the defect in these strains is located at different functional subunits of the multienzyme complex. 相似文献
The effect of total body irradiation on the development of delayed hypersensitivity and on the febrile response to specific antigen has been studied in guinea-pigs with the following results:
1. 200 R. whole body irradiation in guinea-pigs, while suppressing circulating antibody response, did not prevent the development of delayed hypersensitivity.
2. Irradiated and non-irradiated hypersensitive animals had an equal febrile response to systemic challenge with specific antigen.
3. Serum from antigen-challenged, irradiated, hypersensitive animals contained a pyrogenic factor of the endogenous serum type capable of producing fever in normal recipients.
These results support the conclusion that production of circulating specific antibody is not essential either for development of delayed hypersensitivity or for the febrile response of the hypersensitive animal to specific antigen.
Intercellular gap-junctional communication was measured using[14C]citrulline incorporation in co-cultures of argininosuccinatelyase-deficient human fibroblasts and argininosuccinate synthetase-deficientChinese Hamster V79 cells. As previously shown, in this systemjunctional communication is completely inhibited by the tumorpromoting phorbol ester 12-O-tetra-decanoylphorbol-13-acetate(TPA). In the absence of extracellular calcium, TPA inhibitionwas less pronounced. However, synergism with calcium ionophoreA23187 could not be demonstrated. Chlorpromazine, trifluoperazineand 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl esterpartially antagonised the effect of TPA. No antagonism was demonstrablebetween calmidazolium and TPA. Treatment of co-cultures withexogenous phospholipase C or 1-oleoyl-2-acetylglycerol (OAG)resulted in communication inhibition, suggesting that proteinkinase C activation is involved in the mechanism of phorbolester-mediated communication inhibition. However co-cultureswhich had been made refractory to TPA by prolonged exposureto high concentrations remained sensitive to inhibition by phospholipaseC and OAG. These results suggest either that diacylglycerolcan produce other effects independent of protein kinase C activation,or that refractoriness to phorbol esters is not simply due toa decrease in the amount of protein kinase C. 相似文献
The essential oil of OCIMUM KILIMANDSCHARICUM Guerke, growing wild in Rwanda, was investigated by LSC, GLC and GC-MS. The oil contained 62% 1.8-cineole, indicating the occurrence of a new chemotype of the species concerned. In addition to 1.8-cineole, 16 oxygen-containing compounds and 14 monoterpene hydrocarbons were identified, of which limonene and beta-pinene were the main components. Most of the constituents were not previously known to be present in the essential oil of O. KILIMANDSCHARICUM. 相似文献
The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction. 相似文献
Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. 相似文献