The associations between sleep timing and night sleep duration with dyslipidemia in a rural population: The Henan Rural Cohort Study.

Evidence linking sleep timing and night sleep duration to dyslipidemia was limited and inconclusive, especially among low- and middle-income adults. The aims were to evaluate the associations between sleep timing, night sleep duration and dyslipidemia in a rural population. Based on the Henan Rural Cohort Study, a total of 37 164 participants were included. The Pittsburgh Sleep Quality Index was used to collect sleep information. Logistic regression and restrictive cubic splines were conducted to explore the associations. Of the 37 164 enrolled participants, 13881 suffered from dyslipidemia. Compared to the reference groups, people who went to sleep after 23:00 or woke up after 7:30 had higher prevalence of dyslipidemia, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs)were 1.30 (1.20-1.41) and 1.34 (1.19-1.50). The adjusted OR (95%CI) of participants in the Late-sleep/Late-rise category compared to the Early-sleep/Early-rise category was 1.55 (1.08-1.23). Compared to the reference (7~≤8 h), the adjusted OR (95%CI) was 1.11 (1.03-1.20) for longer (>9 h) night sleep duration. Moreover, the combined effects of sleep duration (>9 h) with sleep time (22:00~) (OR = 1.46, 95%CI: 1.16-1.84), sleep duration (>9 h) with wake-up time (≥7:30) (OR = 1.28, 95%CI: 1.08-1.51), and sleep duration (>9 h) with the Late-sleep/Late-rise category (OR = 1.41, 95%CI: 1.14-1.75) increased the prevalence of dyslipidemia. Accordingly, our results indicate that delayed sleep timing and longer night sleep duration had independent and joint effects on higher risks of dyslipidemia in rural population.

Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth.

Proteasomes are attractive emerging targets for anti-cancer therapies. Auranofin (Aur), a gold-containing compound clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer but its anti-cancer mechanism is poorly understood. Here we report that (i) Aur shows proteasome-inhibitory effect that is comparable to that of bortezomib/Velcade (Vel); (ii) different from bortezomib, Aur inhibits proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20S proteasome; (iii) inhibition of the proteasome-associated DUBs is required for Aur-induced cytotoxicity; and (iv) Aur selectively inhibits tumor growth in vivo and induces cytotoxicity in cancer cells from acute myeloid leukemia patients. This study provides important novel insight into understanding the proteasome-inhibiting property of metal-containing compounds. Although several DUB inhibitors were reported, this study uncovers the first drug already used in clinic that can inhibit proteasome-associated DUBs with promising anti-tumor effects.

[Factors influencing long-term hepatitis B virus infection of the tree shrew (Tupaia belangeri chinensis) as an in vivo model of chronic hepatitis B].

OBJECTIVE: To determine the methods for establishing an in vivo model of long-term hepatitis B virus (HBV) infection in the Chinese tree shrew (Tupaia belangeri chinensis). METHODS: Seventy-seven neonate (1-3 days old) and 49 young adult (2 weeks to 1 year old) tree shrews were inoculated with different HBV sources (chronic hepatitis B (CHB) human patient serum, single or pooled; HBV-infected tree shrew serum, single only; HBV-infected HepG2.2.15 cells' culture medium supernatant; HBV genome-transfected HepG2.2.15 cells' culture medium supernatant) through various routes of injection (subcutaneous, intraperitoneal, and direct liver via abdominal skin; adults also received intravenous and indirect liver via spleen). Serum and liver biopsies were collected from the animals at various time points post-inoculation for detection of HBV markers by fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, time-resolved immunofluorescence, Southern blotting, dot blotting, immunohistochemistry, and microscopy. RESULTS: Among the neonatal group of tree shrews, six (7.8%) were confirmed as HBV-infected for more than 72 (up to 228) weeks after inoculation and another seven (9.1%) were suspected of persistent infections. None of the young adult tree shrews developed persistent infection. Inoculation with single-source serum from either CHB humans or tree shrews were responsible for the most cases of infections, and the subcutaneous injection produced more infections than the other inoculation routes. The most reliable methods of determining HBV infection status were detection of serum HBV immunoreactive markers and intrahepatic HBV DNA. CONCLUSION: In order to establish an in vivo model of CHB in the tree shrew, the animals should be inoculated in the neonatal period using subcutaneous injection.

Factors influencing long-term hepatitis B virus infection of the tree shrew (Tupaia belangeri chinensis) as an in vivo model of chronic hepatitis B / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To determine the methods for establishing an in vivo model of long-term hepatitis B virus (HBV) infection in the Chinese tree shrew (Tupaia belangeri chinensis).</p><p><b>METHODS</b>Seventy-seven neonate (1-3 days old) and 49 young adult (2 weeks to 1 year old) tree shrews were inoculated with different HBV sources (chronic hepatitis B (CHB) human patient serum, single or pooled; HBV-infected tree shrew serum, single only; HBV-infected HepG2.2.15 cells' culture medium supernatant; HBV genome-transfected HepG2.2.15 cells' culture medium supernatant) through various routes of injection (subcutaneous, intraperitoneal, and direct liver via abdominal skin; adults also received intravenous and indirect liver via spleen). Serum and liver biopsies were collected from the animals at various time points post-inoculation for detection of HBV markers by fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, time-resolved immunofluorescence, Southern blotting, dot blotting, immunohistochemistry, and microscopy.</p><p><b>RESULTS</b>Among the neonatal group of tree shrews, six (7.8%) were confirmed as HBV-infected for more than 72 (up to 228) weeks after inoculation and another seven (9.1%) were suspected of persistent infections. None of the young adult tree shrews developed persistent infection. Inoculation with single-source serum from either CHB humans or tree shrews were responsible for the most cases of infections, and the subcutaneous injection produced more infections than the other inoculation routes. The most reliable methods of determining HBV infection status were detection of serum HBV immunoreactive markers and intrahepatic HBV DNA.</p><p><b>CONCLUSION</b>In order to establish an in vivo model of CHB in the tree shrew, the animals should be inoculated in the neonatal period using subcutaneous injection.</p>

Effects of vanadium-containing compounds on membrane lipids and on microdomains used in receptor-mediated signaling.

There is increasing evidence for the involvement of plasma membrane microdomains in insulin receptor function. Moreover, disruption of these structures, which are typically enriched in sphingomyelin and cholesterol, results in insulin resistance. Treatment strategies for insulin resistance include the use of vanadium (V) compounds which have been shown in animal models to enhance insulin responsiveness. One possible mechanism for insulin-enhancing effects might involve direct effects of V compounds on membrane lipid organization. These changes in lipid organization promote the partitioning of insulin receptors and other receptors into membrane microdomains where receptors are optimally functional. To explore this possibility, we have used several strategies involving V complexes such as [VO(2)(dipic)](-) (pyridin-2,6-dicarboxylatodioxovanadium(V)), decavanadate (V(10)O(28)(6-), V(10)), BMOV (bis(maltolato)oxovanadium(IV)), and [VO(saltris)](2) (2-salicylideniminato-2-(hydroxymethyl)-1,3-dihydroxypropane-oxovanadium(V)). Our strategies include an evaluation of interactions between V-containing compounds and model lipid systems, an evaluation of the effects of V compounds on lipid fluidity in erythrocyte membranes, and studies of the effects of V-containing compounds on signaling events initiated by receptors known to use membrane microdomains as signaling platforms.

Epilepsy and synaptic reorganization in a perinatal rat model of hypoxia-ischemia.

PURPOSE: One of the potential consequences of perinatal hypoxia-ischemia (H-I) is the development of epilepsy, and synaptic reorganization in the hippocampus has been associated with epilepsy after an injury. We tested the hypothesis that perinatal H-I will induce spontaneous motor seizures, hippocampal lesions, and synaptic reorganization in the dentate gyrus. METHODS: The right common carotid artery of 7-day-old rats was permanently ligated, and the rats were placed for 120 min into a chamber filled with 8% oxygen (37 degrees C). Animals were directly observed for chronic motor seizures for 7 to 24 months after the H-I insult. RESULTS: Nearly half of the rats (i.e., eight of 20) were seen to have spontaneous motor seizures after the H-I injury. The ipsilateral hippocampi from both the rats with seizures and the rats not seen to have seizures had hippocampal lesions and increased amounts of Timm stain in the inner molecular layer (IML) compared with controls. The contralateral hippocampi from the rats with seizures, but not the hippocampi from the rats not seen to have seizures, had significantly increased amounts of Timm stain in the IML. CONCLUSIONS: These results suggest that perinatal H-I can induce epilepsy, ipsilateral hippocampal lesions, and mossy fiber sprouting in the lesioned and contralateral hippocampus.

Reassessment of the effects of cycloheximide on mossy fiber sprouting and epileptogenesis in the pilocarpine model of temporal lobe epilepsy.

A feature of animal models of temporal lobe epilepsy and the human disorder is hippocampal sclerosis and Timm stain in the inner molecular layer (IML) of the dentate gyrus, which represents synaptic reorganization and may be important in epileptogenesis. We reassessed the hypothesis that pre-treatment with cycloheximide (CHX) prevents Timm staining in the IML following pilocarpine (PILO)-induced status epilepticus (a multifocal model of temporal lobe epilepsy), but allows epileptogenesis (i.e., chronic spontaneous seizures) after a latent period. Hippocampal slices from PILO-treated rats without Timm stain in the IML after CHX treatment were hypothesized to lack the electrophysiological abnormalities suggestive of recurrent excitation. The primary experimental groups were as follows: 1) CHX (1 mg/kg) 30-45 min prior to administration of PILO (320 mg/kg ip, 2) only PILO, and 3) only saline (0.5 ml, IP). The CHX pre-treatment significantly decreased the number of rats that responded to PILO with status epilepticus compared to rats that received only PILO. Pre-treatment with CHX did not significantly alter the spontaneous motor seizure rate post-treatment compared to treatment with PILO alone in those animals from each group that developed status epilepticus during PILO treatment. Timm stain in the IML was not significantly different between the PILO- and PILO+CHX-treated rats. Using quantitative methods, CHX did not prevent hilar, CA1, or CA3 neuronal loss compared to the PILO-treated rats. Extracellular responses to hilar stimulation in 30 microM bicuculline and 6 mM [K(+)](o) demonstrated all-or-none bursting in both the CHX+PILO- and PILO-treated rats but not in control rats. Whole cell recordings from granule cells, using glutamate flash photolysis to activate other granule cells, showed that both the CHX+PILO- and PILO-treated rats had excitatory synaptic interactions in the granule cell layer, which were not found after saline treatment. Some rats responded to PILO (with or without CHX pre-treatment) with only one or a few seizures at treatment, and some of these animals (n = 4) demonstrated spontaneous motor seizures within 2 mo after treatment. Timm staining and neuron loss in this group were not clearly different from saline-treated rats. These results suggest that in the PILO model, pre-treatment with CHX does not affect mossy fiber sprouting in the IML of epileptic rats and does not prevent the formation of recurrent excitatory circuits. However, the develoment of spontaneous motor seizures, in a small number of rats, could occur without detectable hippocampal neuron loss or mossy fiber sprouting, as assessed by the Timm stain method.