| 1. |
- Dominguez, Cecilia A, et al.
(författare)
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Genetic analysis of neuropathic pain-like behavior following peripheral nerve injury suggests a role of the major histocompatibility complex in development of allodynia
- 2008
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 1872-6623 .- 0304-3959. ; 136:3, s. 313-319
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Tidskriftsartikel (refereegranskat)abstract
- Neuropathic pain is a common consequence of damage to the nervous system. We here report a genetic analysis of development of neuropathic pain-like behaviors after unilateral photochemically-induced ischemic sciatic nerve injury in a panel of inbred rat strains known to display different susceptibility to autoimmune neuroinflammation. Pain behavior was initially characterized in Dark-Agouti (DA; RT1(avl)), Piebald Virol Glaxo (PVG; RT1(c)), and in the major histocompatibility complex (MHC)-congenic strain PVG-RT1(avl). All strains developed mechanical hypersensitivity (allodynia) following nerve injury. However, the extent and duration of allodynia varied significantly among the strains, with PVG displaying more severe allodynia compared to DA rats. Interestingly, the response of PVG-RT1(avR1) was similar to that of DA, suggesting regulation by the MHC locus. This notion was subsequently confirmed in an F2 cohort derived from crossing of the PVG and PVG-RT1(avl) strains, where allodynia was reduced in homozygous or heterozygous carriers of the RT1(avl) allele in comparison to rats homozygous for the RT1(c) allele. These results indicate that certain allelic variants of the MHC could influence susceptibility to develop and maintain neuropathic pain-like behavior following peripheral nerve injury in rats.
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| 2. |
- He, Lu-Jun, et al.
(författare)
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Genetic polymorphisms of N-acetyltransferase 2 and colorectal cancer risk.
- 2005
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Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 11:27, s. 4268-4271
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To identify the distribution of N-acetyltrasferase 2(NAT2) polymorphism in Hebei Han Chinese and the effects of the polymorphism on the development of colorectal cancer. METHODS: We performed a hospital-based case-control study of 237 healthy individuals and 83 colorectal cancer patients of Hebei Han Chinese. DNA was extracted from peripheral blood and cancer tissues. The genotypes of the polymorphisms were assessed by PCR-restriction fragment length polymorphism (RFLP). RESULTS: There were four NAT2 alleles of WT, M1, M2, and M3 both in the healthy subjects and in the patients, and 10 genotypes of WT/WT, WT/M1, WT/M2, WT/M3, M1/M1, M1/M2, M1/M3, M2/M2, M2/M3, M3/M3. M2 allele was present in 15.61% of healthy subjects and 29.52% of patients (chi(2) = 15.31, P<0.0001), and M3 allele was present in 30.59% of healthy subjects and 16.87% of patients (chi(2) = 25.33, P<0.0001). There were more WT/M2 (chi(2) = 34.42, P<0.0001, odd ratio = 4.99, 95%CI = 2.27-9.38) and less WT/M3 (chi(2) = 3.80, P = 0.03) in the patients than in the healthy subjects. In 70.3% of the patients, there was a difference in NAT2 genotype between their tumors and blood cells. Patients had more WT/M2 (chi(2) = 5.11, P = 0.02) and less M2/M3 (chi(2) = 4.27, P = 0.039) in their blood cells than in the tumors. Furthermore, 53.8% (7/13) of M2/M3 in tumors were from WT/M2 of blood cells. CONCLUSION: There is a possible relationship between the NAT2 polymorphisms and colorectal cancer in Hebei Han Chinese. The genotype WT/M2 may be a risk factor for colorectal cancer.
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| 3. |
- Hu, Xiao Jing
(författare)
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Modulation of acetylcholine release by serotonergic 5-HT1A and 5-HT1B receptors : a microdialysis study in the awake rat
- 2007
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the thesis was to investigate the effects of the 5-HT1A receptor antagonist robalzotan (NAD-299) and the 5-HT1B receptor antagonist NAS-181 ((R)-(+)-2-(3-morpholinomethyl-2Hchromen-8-yl) oxymethyl-morpholine methanesulfonate) on cholinergic, glutamatergic and GABAergic neurotransmission in the rat brain in vivo. The extracellular levels of acetylcholine (ACh), glutamate (Glu) and GABA were monitored by microdialysis in the frontal cortex (FC) and ventral hippocampus (VHipp) in separate groups of awake rats. Robalzotan (0.3; 1 and 3 µmol/kg s.c.) caused a dose-dependent increase of extracellular ACh levels in the rat FC to a maximal value of about 210-280% of controls at the highest dose. ACh concentrations returned to the normal levels within 120 min. Similarly, in the VHipp, both robalzotan given at a dose of 3 µmol/kg s.c., and to a lesser extent another 5-HT1A receptor antagonist, WAY 100635 (1.5 µmol/kg s.c), elevated the ACh levels to about 220% and 160%, respectively. Further, the potency of robalzotan to increase cholinergic transmission in the FC was compared to that of a reversible acetylcholinesterase inhibitor donepezil (Aricept, E2020). Donepezil, given at it dose of I mg/kg s.c., increased the cortical extracellular levels of ACh to a maximum of about 350% of the control values, thereafter the ACh concentrations returned to the normal levels within 80 min. The AUCs calculated for 80 min after the administration of robalzotan (3 µmol/kg) or donepezil (1 mg/kg) indicated that cortical ACh levels increased by a similar degree, although the effective time-course of donepezil was somewhat shorter. In the following microdialysis study, the effects of local administrations of robalzotan into the nucleus basalis magnocellularis (NBM) on the frontocortical ACh release were examined in the awake rats. Robalzotan, injected locally into the NBM at doses of 6 and 18 nmol/rat caused a dose-dependent increase of cortical extracellular ACh concentrations. The maximal ACh increase was observed between 20-40 min after the drug administration, reaching 217 % of control values at a higher dose. However, the ACh levels maintained elevated during the entire post-injection sampling period (180 min). Robalzotan (75 or 100 µM perfused locally into the FC or VHipp showed only a moderate and delayed effect, increasing the ACh levels by about 30%. These results suggest that cholinergic afferents to the FC are under tonic inhibitory control of 5-HT1A heteroreceptors in the NBM and the cholinomimetic effect of robalzotan is probably associated with increased firing rates of cortical (and possibly also hippocampal) afferents. Additionally, the effect of locally perfused robalzotan on ACh release in the frontal cortex could be indirectly mediated, for example via the blockade of inhibitory 5HT1A heteroreceptors located on the pyramidal cells projecting in a feedback loop to the NBM. The purpose of the final study was to investigate the effects of the 5-HT1B receptor antagonist NAS181 ((R)-(+)-2(3-morpholinomethyl-2H-chromen-8-yl) oxymethyl-morpholine methanesulfonate) on cholinergic, glutamatergic and GABA-ergic neurotransmission in the rat brain in vivo. NAS- 181 (1; 5 or 10 mg/kg, s.c.) caused a dose-dependent increase in ACh levels, reaching the maximal values of 500% (FC) and 230% (VHipp) of controls at 80 min postinjection. On the contrary, NAS-181 injected at doses of 10 or even 20 mg/kg s.c. had no effect on basal extracellular levels of Glu and GABA in these areas. In summary, the present findings indicate that ACh neurotransmission in the frontal cortex and ventral hippocampus, the brain structures strongly implicated in cognitive function, is under tonic inhibitory control of the 5-HT1A heteroreceptors in the nucleus basalis and medial septum/diagonal band areas and the 5-HT1B heteroreceptors most likely localized at the terminal areas. It is concluded that the selective or combined 5-HT1A and 5-HT1B receptor antagonists may represent a potentially new alternative in the treatment of pathologies characterized by a cholinergic deficit in the central -nervous system.
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| 4. |
- Hua, Dong, et al.
(författare)
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Small interfering RNA-directed targeting of toll-like receptor 4 inhibits human prostate cancer cell invasion, survival, and tumorigenicity
- 2009
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 46:15, s. 2876-2884
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Tidskriftsartikel (refereegranskat)abstract
- A major cause of tumor treatment failure is cancer cell metastasis. Toll-like receptor 4 (TLR4)-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. In this study, we investigated the biological roles of TLR4 in prostate metastatic cell invasion and survival, and the potential of gene silencing of TLR4 using small interfering RNA (siRNA) for treatment of cancer. In cultured human prostate cancer cell lines, TLR4 were higher PC3 and DU145 as compared with the poorly metastatic LNCaP indicating that up-regulation of TLR4 was positively correlated with metastasis of tumor cell. In the highly metastatic cancer cell PC3, gene silencing of TLR4 using siRNA significantly inhibited TLR4 mRNA expression and protein level. Knockdown of TLR4 in PC3 cells resulted in a dramatic reduction of tumor cell migration and invasion as indicated by a Matrigel invasion assay. Furthermore, TLR4 siRNA suppressed cell viability and ultimately caused the induction of apoptotic cell death. The effects were associated with abrogating TLR4-mediated signaling to downstream target molecules such as myeloid differentiation factor 88 (MyD88), adaptor-inducing IFN-beta (TRIF), and interferon regulatory factor-1 (IRF-1). In a mouse prostate cancer model, administration with the plasmid construct expressing siRNA for TLR4 obviously inhibited established tumor growth and survival. These studies revealed evidence of a multifaceted signaling network operating downstream of TLR4-mediated tumor cell invasion, proliferation, and survival. Thus, RNA interference-directed targeting of TLR4 may raise the potential of its application for cancer therapy.
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| 5. |
- Jiang, Jing-Ting, et al.
(författare)
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Lipids changes in liver cancer
- 2007
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Ingår i: Journal of Zhejiang University-Science B. - 1862-1783. ; 8:6, s. 398-409
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Forskningsöversikt (refereegranskat)abstract
- Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer.
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| 6. |
- Lan, Ting, et al.
(författare)
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Extensive functional diversification of the Populus glutathione S-transferase supergene family
- 2009
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Ingår i: The Plant Cell. - : Oxford University Press (OUP). - 1040-4651 .- 1532-298X. ; 21:12, s. 3749-3766
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Tidskriftsartikel (refereegranskat)abstract
- Identifying how genes and their functions evolve after duplication is central to understanding gene family radiation. In this study, we systematically examined the functional diversification of the glutathione S-transferase (GST) gene family in Populus trichocarpa by integrating phylogeny, expression, substrate specificity, and enzyme kinetic data. GSTs are ubiquitous proteins in plants that play important roles in stress tolerance and detoxification metabolism. Genome annotation identified 81 GST genes in Populus that were divided into eight classes with distinct divergence in their evolutionary rate, gene structure, expression responses to abiotic stressors, and enzymatic properties of encoded proteins. In addition, when all the functional parameters were examined, clear divergence was observed within tandem clusters and between paralogous gene pairs, suggesting that subfunctionalization has taken place among duplicate genes. The two domains of GST proteins appear to have evolved under differential selective pressures. The C-terminal domain seems to have been subject to more relaxed functional constraints or divergent directional selection, which may have allowed rapid changes in substrate specificity, affinity, and activity, while maintaining the primary function of the enzyme. Our findings shed light on mechanisms that facilitate the retention of duplicate genes, which can result in a large gene family with a broad substrate spectrum and a wide range of reactivity toward different substrates.
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| 7. |
- Rutqvist, Jonny, et al.
(författare)
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A multiple-code simulation study of the long-term EDZ evolution of geological nuclear waste repositories
- 2009
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Ingår i: Environmental Geology. - : Springer Science and Business Media LLC. - 0943-0105 .- 1432-0495. ; 57:6, s. 1313-1324
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Tidskriftsartikel (refereegranskat)abstract
- This simulation study shows how widely different model approaches can be adapted to model the evolution of the excavation disturbed zone (EDZ) around a heated nuclear waste emplacement drift in fractured rock. The study includes modeling of coupled thermal-hydrological-mechanical (THM) processes, with simplified consideration of chemical coupling in terms of time-dependent strength degradation or subcritical crack growth. The different model approaches applied in this study include boundary element, finite element, finite difference, particle mechanics, and elasto-plastic cellular automata methods. The simulation results indicate that thermally induced differential stresses near the top of the emplacement drift may cause progressive failure and permeability changes during the first 100 years (i.e., after emplacement and drift closure). Moreover, the results indicate that time-dependent mechanical changes may play only a small role during the first 100 years of increasing temperature and thermal stress, whereas such time-dependency is insignificant after peak temperature, because of decreasing thermal stress.
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| 8. |
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