Whey protein powder with milk fat globule membrane attenuates Alzheimer's disease pathology in 3×Tg-AD mice by modulating neuroinflammation through the peroxisome proliferator-activated receptor γ signaling pathway.

Whey protein powder (PP), which is mainly derived from bovine milk, is rich in milk fat globule membrane (MFGM). The MGFM has been shown to play a role in promoting neuronal development and cognition in the infant brain. However, its role in Alzheimer's disease (AD) has not been elucidated. Here, we showed that the cognitive ability of 3×Tg-AD mice (a triple-transgenic mouse model of AD) could be improved by feeding PP to mice for 3 mo. In addition, PP ameliorated amyloid peptide deposition and tau hyperphosphorylation in the brains of AD mice. We found that PP could alleviate AD pathology by inhibiting neuroinflammation through the peroxisome proliferator-activated receptor γ (PPARγ)-nuclear factor-κB signaling pathway in the brains of AD mice. Our study revealed an unexpected role of PP in regulating the neuroinflammatory pathology of AD in a mouse model.

Stereoselective Synthesis of Chiral ß-Fluoro α-Amino Acids via Pd(II)-Catalyzed Fluorination of Unactivated Methylene C(sp(3))-H Bonds: Scope and Mechanistic Studies.

The synthesis of fluorinated complex molecules via direct C(sp(3))-H fluorination is attractive yet remains challenging. Here we describe the Pd(II)-catalyzed fluorination of unactivated methylene C(sp(3))-H bonds by an inner-sphere mechanism. This method allows the site- and diastereoselective fluorination of ß-methylene C(sp(3))-H bonds of α-amino acid derivatives. A range of substrates containing both aliphatic and benzylic C(sp(3))-H bonds were compatible with this protocol, leading to an array of ß-fluorinated α-amino acids. Stoichiometric fluorination of an isolated palladacycle intermediate takes place rapidly under very mild reaction conditions (room temperature, 5-10 min). Data from preliminary mechanistic studies are consistent with direct C-F reductive elimination from a high-valent intermediate.

Copper/silver-mediated direct ortho-ethynylation of unactivated (hetero)aryl C-H bonds with terminal alkyne.

A copper/silver-mediated oxidative ortho-ethynylation of unactivated aryl C-H bonds with terminal alkyne has been developed. The reaction uses the removable PIP directing group and features broad substrate scope, high functional-group tolerance, and compatibility with a wide range of heterocycles, providing an efficient synthesis of aryl alkynes. This procedure highlights the potential of copper catalysts to promote unique, synthetically enabling C-H functionalization reactions that lie outside of the current scope of precious metal catalysis.

Palladium-Catalyzed Arylation of Unactivated γ-Methylene C(sp(3) )-H and δ-C-H Bonds with an Oxazoline-Carboxylate Auxiliary.

A palladium-catalyzed arylation of unactivated γ-methylene C(sp(3) )H and remote δ-CH bonds by using an oxazoline-carboxylate directing group has been developed. Arylation occurs with a broad substrate scope and high tolerance of functional groups (i.e., halogen, nitro, cyano, ether, trifluoromethyl, amine, and ester). The oxazoline-type auxiliary can be removed under acidic conditions.

Elevated osteopontin levels in mild cognitive impairment and Alzheimer's disease.

Inflammatory mediators are closely associated with the pathogenesis of neurodegenerative changes in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Osteopontin (OPN) is a proinflammatory cytokine that has been shown to play an important role in various neuroinflammatory diseases. However, the function of OPN in AD and MCI progression is not well defined. Cerebrospinal fluid (CSF) and plasma samples were obtained from 35 AD patients, 31 MCI patients, and 20 other noninflammatory neurologic diseases (OND). Concentrations of OPN in the CSF and plasma were determined by enzyme-linked immunosorbent assay. During a 3-year clinical followup, 13 MCI patients converted to AD (MCI converters), and 18 were clinically stable (MCI nonconverters). CSF OPN concentrations were significantly increased in AD and MCI converters compared to OND, and increased levels of OPN in AD were associated with MMSE score; OPN protein levels both in the CSF and plasma of newly diagnosed AD patients were higher than that of chronical patients. In MCI converters individuals tested longitudinally, both plasma and CSF OPN concentrations were significantly elevated when they received a diagnosis of AD during followup. Further wide-scale studies are necessary to confirm these results and to shed light on the etiopathogenic role of osteopontin in AD.

Synthesis of tryptophan-containing 2,5-diketopiperazines via sequential C-H activation: total syntheses of tryprostatin A, maremycins A and B.

Indole 2,5-diketopiperazines (DKPs) are an important type of metabolic cyclic dipeptides containing a tryptophan (Trp) unit possessing a range of interesting biological activities. The intriguing structural features and divergent activities have stimulated tremendous efforts towards their efficient synthesis. Herein, we report the development of a unified strategy for the synthesis of three Trp-containing DKPs, namely tryprostatin A, and maremycins A and B, via a sequential C-H activation strategy. The key Trp skeletons were synthesized from the inexpensive, readily available alanine via a Pd(ii)-catalyzed ß-methyl C(sp3)-H monoarylation. A subsequent C2-selective prenylation of the resulting 6-OMe-Trp by Pd/norbornene-promoted C-H activation led to the total synthesis of tryprostatin A in 12 linear steps from alanine with 25% overall yield. Meanwhile, total syntheses of maremycins A and B were successfully accomplished using a sequential Pd-catalyzed methylene C(sp3)-H methylation as the key step in 15 linear steps from alanine.

[Coronary artery and myocardium lesion comparison post atrioventricular ring radiofrequency catheter ablation with different catheters].

OBJECTIVE: To analyze the extent of myocardium and coronary artery lesion post atrioventricular ring radiofrequency catheter ablation with different tip catheters. METHODS: Twenty-one healthy dogs were randomly divided into 64 degrees C/50 W/100 s, 64 degrees C/100 W/100 s, 45 degrees C/45 W/100 s groups and ablated by 4 mm tip catheter, 8 mm tip catheter and irrigated tip catheter respectively. Left atrioventricular ring and right atrioventricular ring ablation were performed in all dogs. After ablation, myocardium lesion volume was calculated as 1/6pi x length x width x depth. Histological examinations were performed at the myocardium tissue at ablation sites. RESULTS: The lesion depths post 8 mm tip catheter ablation (7.18 +/- 1.72) mm and irrigated tip catheter ablation (7.99 +/- 1.77) mm were similar and significantly deeper than that post 4 mm tip catheter ablation (4.54 +/- 1.38) mm, P < 0.01. Similar results were found in terms of lesion volume [(356.76 +/- 94.44) mm(3) post 8 mm tip catheter ablation, (391.69 +/- 109.54) mm(3) post irrigated tip catheter ablation and (191.34 +/- 74.52) mm(3) post 4 mm tip catheter ablation]. Five (5/42, 11.9%) transmural myocardium necrosis and 8 (8/42, 19%) coronary artery lesions were observed post ablations. CONCLUSION: The extents of post ablation myocardium and coronary artery lesion were significantly higher induced by 8 mm tip catheter and irrigate tip catheter compared those by 4 mm tip catheter.

Expeditious synthesis of pyrano[2,3,4-de]quinolines via Rh(iii)-catalyzed cascade C-H activation/annulation/lactonization of quinolin-4-ol with alkynes.

Rh(iii)-catalyzed cascade C-H activation/annulation/lactonization of quinoline-4-ols and alkynes has been reported. A broad range of tetracyclic pyrano[2,3,4-de]quinolines have been prepared in one-step with good functional group tolerance, excellent site selectivity, and high efficiency.

Palladium-catalyzed sequential monoarylation/amidation of C(sp3)-H bonds: stereoselective synthesis of α-amino-ß-lactams and anti-α,ß-diamino acid.

Pd-Catalyzed sequential monoarylation/amidation of C(sp3)-H bonds of alanine enabled by a removable 5-methoxyquinolin-8-amine (MQ) auxiliary is described. This process is highly efficient and compatible with a variety of functional groups, providing a general and practical access to various α-amino-ß-lactams. The synthetic potential of this protocol is further demonstrated by the stereoselective synthesis of orthogonally protected anti-α,ß-diamino acids.

Stereoselective alkoxycarbonylation of unactivated C(sp3)-H bonds with alkyl chloroformates via Pd(II)/Pd(IV) catalysis.

Several examples on Pd-catalysed carbonylation of methyl C(sp3)-H bonds with gaseous CO via Pd(II)/Pd(0) catalysis have been reported. However, methylene C(sp3)-H carbonylation remains a great challenge, largely due to the lack of reactivity of C-H bonds and the difficulty in CO migratory insertion. Herein, we report the stereoselective alkoxycarbonylation of both methyl and methylene C(sp3)-H bonds with alkyl chloroformates through a Pd(II)/Pd(IV) catalytic cycle. A broad range of aliphatic carboxamides and alkyl chloroformates are compatible with this protocol. In addition, this process is scalable and the directing group could be easily removed under mild conditions with complete retention of configuration.

Catalyst-Controlled Amino- versus Oxy-Acetoxylation of Urea-Tethered Alkenes: Efficient Synthesis of Cyclic Ureas and Isoureas.

A catalyst-controlled vicinal amino- versus oxy-acetoxylation of alkenes with PhI(OAc)2 as the oxidant is described. The divergent synthesis of cyclic ureas and isoureas was achieved in good yields under mild conditions employing ambident urea nucleophiles. Both terminal and internal alkenes are compatible with this reaction protocol.

Pd(II)-Catalyzed arylation of unactivated methylene C(sp3)-H bonds with aryl halides using a removable auxiliary.

A Pd(II)-catalyzed arylation of methylene C(sp(3))-H bonds in aliphatic amides directed by our newly developed PIP directing group with aryl iodides/bromides has been achieved. Arylation occurs efficiently with a broad range of aryl halides and amides.

[Homocysteine' s effect on tPA and PAI-1 gene expression in HUVEC].

AIM: In order to elucidate the relationship between homocysteine (Hcy) and the fibrinolytic system, we examined the effect of Hcy on tissue- type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) gene expression in human umbilical vein endothelial cells (HUVEC) in vitro. METHODS: Total RNA was extracted from HUVEC exposed to physical and pathological concentrations of Hcy (0, 10, 50, 200, 500 micromol/L ) for 24 hours, using the guanidinium isothiocyanate method. The semi-quantification of tPA and PAI-1 mRNA in HUVEC was carried out by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: PAI-1 mRNA levels was enhanced by Hcy at concentrations of 500 micromol/L of Hcy, compared with that of 0 micromol/L Hcy (P < 0.05). The mRNA expression of tPA, however, was significantly decreased at concentrations of 500 micromol/L Hcy, compared with that of 10 micromol/L Hcy (P < 0.05), but compared with the control group, the tPA level of 10 micromol/L Hcy was much higher (P < 0.05). CONCLUSION: Hyperhomocysteinemia increases the incidence of cardio cerebral vascular disease, which may be caused by decreasing the activity of fibrinolytic system, whereas, the physiological concentration of Hcy may be decreased the incidence by enhancing the activity of fibrinolytic system.