Signal pathways underlying homocysteine-induced production of MCP-1 and IL-8 in cultured human whole blood

Aim : To elucidate the mechanisms underlying homocysteine (Hcy)-induced chemokine production. Methods : Human whole blood was pretreated with inhibitors of calmodulin (CaM), protein kinase C (PKC), protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and NF-ΚB and activators of PPARΓ for 60 min followed by incubation with Hcy 100 Μmol/L for 32 h. The levels of mitogen chemokine protein (MCP)-1 and interleukin-8 (IL-8) were determined by enzyme-linked immunosorbant assay (ELISA). Results : Inhibitors of PKC (calphostin C, 50-500 nmol/L and RO-31-8220, 10–100 nmol/L), CaM (W7, 28–280 Μmol/L), ERK1/2 MAPK (PD 98059, 2–20 Μmol/L), p38 MAPK (SB 203580, 0.6–6 Μmol/L), JNK MAPK (curcumin, 2–10 Μmol/L), and NF-ΚB (PDTC, 10-100 nmol/L) markedly reduced Hcy 100 Μmol/L-induced production of MCP-1 and IL-8 in human cultured whole blood, but the inhibitors of PTK (genistein, 2.6–26 Μmol/L and tyrphostin, 0.5-5 Μmol/L) had no obvious effect on MCP-1 and IL-8 production. PPARΓ activators (ciglitazone 30 Μmol/L and troglitazone 10 Μmol/L) depressed the Hcy-induced MCP-1 production but not IL-8 production in the cultured whole blood. Conclusion : Hcy-induced MCP-1 and IL-8 production is mediated by activated signaling pathways such as PKC, CaM, MAPK, and NF-ΚB. Our results not only provide clues for the signal transduction pathways mediating Hcy-induced chemokine production, but also offer a plausible explanation for a pathogenic role of hyperhomocysteinemia in these diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75644/1/j.1745-7254.2005.00005.x.pd

Multiple Neural Oscillators and Muscle Feedback Are Required for the Intestinal Fed State Motor Program

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40–60 s and separated by quiescent episodes lasting 40–200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle

Improved measurement of CP violation parameters in Bs0→J/ψK+K− decays in the vicinity of the ϕ(1020) resonance

The decay-time-dependent C P asymmetry in B 0 s → J / ψ ( → μ + μ − ) K + K − decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6     fb − 1 , collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 B 0 s signal decays with an invariant K + K − mass in the vicinity of the ϕ ( 1020 ) resonance, the C P -violating phase ϕ s is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the B 0 s − ¯ B 0 s system, Δ Γ s , and the difference of the average B 0 s and B 0 meson decay widths, Γ s − Γ d . The values obtained are ϕ s = − 0.039 ± 0.022 ± 0.006     rad , Δ Γ s = 0.0845 ± 0.0044 ± 0.0024     ps − 1 , and Γ s − Γ d = − 0.005 6 + 0.0013 − 0.0015 ± 0.0014     ps − 1 , where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase ϕ s is also measured independently for each polarization state of the K + K − system and shows no evidence for polarization dependence

[Impact of menarche age on the near-term and long-term obesity of adult females]

Objective: To study the relationship between the age of menarche and the near-term/long-term obesity in adult women. Methods: We analyzed the baseline data of 30 895 women with complete data on menarche and body measurement that was from the China Kadoorie Biobank (CKB) study from 2004 to 2008. The age of menarche was divided into three groups: ≤12, 13-16 and ≥17 years old. Prematurity was set at age ≤12 years. Multivariate logistic regression was used to analyze the effects of menarche age on the near/long-term obesity in female adults. Results: The average menarche age of respondent appeared as (15.64±1.92) years old, with prematurity number as 1 421, accounting for 4.6% of the total numbers. Regarding the postponing of dates of birth, the age of menarche in women showed an advancing tendency. Among all the adult women under study, 803 developed near-term obesity, with the prevalence as 2.6%, while the number of long-term obesity was 3 738, accounting for 12.1%. Refining factors of age, lifestyle, menopausal status, hypertension and diabetes showed that the menarche age was related to the risks of both short-term and long-term obesity in women and the ORs (95%CI) were 2.45 (1.74-3.45) and 1.99 (1.69-2.34), respectively. There was no multiplicative interaction shown between the menarche age and menopausal status on long-term obesity (P=0.324). Conclusion: Premature menarche appeared a risk factor for near-term/long-term obesity in adult females

[Impact of menarche age on the near-term and long-term obesity of adult females]

Objective: To study the relationship between the age of menarche and the near-term/long-term obesity in adult women. Methods: We analyzed the baseline data of 30 895 women with complete data on menarche and body measurement that was from the China Kadoorie Biobank (CKB) study from 2004 to 2008. The age of menarche was divided into three groups: ≤12, 13-16 and ≥17 years old. Prematurity was set at age ≤12 years. Multivariate logistic regression was used to analyze the effects of menarche age on the near/long-term obesity in female adults. Results: The average menarche age of respondent appeared as (15.64±1.92) years old, with prematurity number as 1 421, accounting for 4.6% of the total numbers. Regarding the postponing of dates of birth, the age of menarche in women showed an advancing tendency. Among all the adult women under study, 803 developed near-term obesity, with the prevalence as 2.6%, while the number of long-term obesity was 3 738, accounting for 12.1%. Refining factors of age, lifestyle, menopausal status, hypertension and diabetes showed that the menarche age was related to the risks of both short-term and long-term obesity in women and the ORs (95%CI) were 2.45 (1.74-3.45) and 1.99 (1.69-2.34), respectively. There was no multiplicative interaction shown between the menarche age and menopausal status on long-term obesity (P=0.324). Conclusion: Premature menarche appeared a risk factor for near-term/long-term obesity in adult females