Biomedical subjects
Publications and source records attributed to Hailing Zhang.
A compound was synthesized that binds to a phospholipid bilayer via a hydrophobic steroid thereby projecting a strong multi-hydrogen bonding unit into the surrounding water. As shown by light scattering, light microscopy, and cryo-HRSEM, this latter unit self-adheres and induces membrane-membrane attachments, as found in many biological systems.
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Eleven triamides bearing long alkyl chains have been synthesized to produce a new class of amphiphilic compounds (dubbed "peptoad"). The properties of these molecules have been investigated by X-ray analysis, solubility studies, light and electron microscopy, surface tensiometry, light scattering, drug dissolution, and molecular dynamics. In the solid state, the peptoads assemble in layers with both intra- and interlayer hydrogen bonding coupled to side-by-side proximity of the hydrocarbon chains. Peptoads with a terminal primary amide and a total of three amide NH sites are water-insoluble owing presumably to attractive forces in the solid state. However, peptoads with terminal -CONMe(2) groups and two internal amide NH sites are water-soluble at room temperature. This solubility is critically dependent upon the chain length. For example, a C(7)-chained peptoad is 1600 times more soluble than its C(9) analogue. High concentrations (6-8 M) of C(7) peptoads in water are clear and do not gel. Light microscopy shows long fibers floating in an isotropic liquid. Water-soluble peptoads are highly surface-active, lowering water's surface tension as effectively as a soap with a much longer chain. Surface tension plots show a "critical aggregation concentration", but it is believed from light scattering and molecular dynamics that the aggregates grow continuously as more peptoad is added to the water. In answer to the inevitable (but valid) question, "What possible good are they?", it can be pointed out that a peptoad solubilizes a water-insoluble drug, paclitaxel (Taxol), as efficiently as does Cremophor EL, a commercial excipient widely used with paclitaxel and other nonpolar drugs. Peptoads, being small molecules and consisting of hydrolyzable amide groups, are likely biodegradable and less prone to the hypersensitivity and neurotoxicity found with Cremophor EL.
The objectives of the present study were to determine the effect of nicotine on MAPK signaling and on the proliferation of AR42J cells as well as to assess the relationship between MAPK activation and exocrine secretion in these cells. AR42J cells were incubated with nicotine and analyzed for the activation of MAPK by Western blot analysis using their respective antibodies and confirmed by immunohistochemistry. The effect of nicotine on cell proliferation was determined by the spectrophotometric method, and cell function was assessed by cholecystokinin (CCK)-stimulated amylase release into the culture medium. Nicotine at a dose of 100 microM induced phospho-ERK1/2 activation maximally in 3 min compared with untreated cells. Furthermore, immunofluorescence study confirmed the nicotine-induced increase in translocation of phospho-ERK1/2 to the nucleus. Activation of phospho-ERK1/2 was inhibited by an ERK1/2 pathway inhibitor but not by a nicotine receptor antagonist. At the same dose, there was significantly enhanced proliferation of AR42J cells until 72 h without toxic effect, as the percentage of lactate dehydrogenase release remained unchanged. Other MAPKs, c-Jun NH2-terminal kinase 1/2 and p38 MAPK, were not affected by nicotine treatment. At a nicotine dose of 100 microM, the CCK-stimulated release of amylase was maximal at 6 min, and, although a nicotinic receptor antagonist inhibited this response, it was not inhibited by the ERK1/2 pathway inhibitor. We conclude that nicotine treatment induced activation of ERK1/2 and increased the proliferation of AR42J cells. The data further indicate that MAPK signaling by nicotine is independent of the secretory response.
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Though the etiology of hemifacial atrophy is still unknown, the aim of its reconstruction is cosmetic amelioration of the defect. Among many techniques introduced, microsurgical reconstruction has become the gold standard to restore the symmetry of the face. Seven free anterolateral thigh adipofascial flaps were used to reconstruct hemifacial atrophy between September 1999 and May 2005. There were 1 male and 6 females in the series. All the patients had unilateral disease (6 right and 1 left). The average age of onset of disease was 11.9 years. The average duration of atrophy was 6.7 years. The patients' average age was 25 years (range, 21 to 32 years), and the average follow-up period was 12.6 months (range, 6 to 36). The size of the transferred flap ranged from 8 x 6 cm to 12 x 13 cm. All adipofascial flaps survived completely. No complications occurred. The result is stable, and no recurrence of facial atrophy was seen in the patients after follow-up. One patient received minor revision because of the bulky reconstructed face. The esthetic appearance of the reconstructed face was acceptable. Despite a variable vascular anatomy that can give rise to some surgical challenge in raising the anterolateral thigh adipofascial flap, the authors conclude that this is a safe and reliable adipofascial flap for hemifacial atrophy.
The preparation and cell transfection of chitosan-DNA nanoparticles were studied. The TFPI (tissue factor pathway inhibitor) or EGFP (enhanced green fluorescent protein) plasmid DNA was encapsulated with chitosan to form gene nanoparticles. The results with TEM showed that the nanoparticles were of sphere shape. The mean diameter of the nanoparticles was 149 nm and the diameter ranged from 80-250 nm, which were measured by the photo related spectrometry (PCS). The encapsulation efficiency of DNA was 96% +/- 1.38% and the DNA content in the nanoparticles was 37% +/- 3.0%. The encapsulated DNA could be protected from the degradation by DNase I. The transfection efficiency of chitosan nanoparticles were about equivalent to that of the LipofectAMINETM reagent. Our results also showed that chitosan nanoparticles were nontoxic to cultured cells.
Increased flux of glucose through the hexosamine biosynthetic pathway has been implicated in insulin resistance, altered insulin secretion, and diabetic nephropathy. Glutamine:fructose-6-phosphate amidotransferase (GFPT), the rate limiting enzyme in hexosamine biosynthesis, is encoded by the unlinked but highly homologous genes GFPT1 and GFPT2. We tested the hypothesis that GFPT2 sequence variation contributed to the susceptibility to type 2 diabetes mellitus (T2DM) and diabetic nephropathy in Caucasian and African-American individuals. We identified 11 single nucleotide polymorphisms (SNPs), of which seven were common. A single variant in exon 14, I471V, altered the amino acid sequence, is conserved between human and mouse genes, and was associated with T2DM among Caucasians (P = 0.05). A trend to an association was noted with diabetic nephropathy among African-American individuals (P = 0.15). Several variants in the 3' untranslated region (UTR) and exon 18 were also associated with T2DM in Caucasian individuals (P < 0.05), and the SNP in the 3' UTR was associated with diabetic nephropathy in African-American subjects (P = 0.047). GFPT2 mRNA levels in transformed lymphocytes from study subjects were significantly increased among African-American subjects compared with Caucasian individuals, regardless of diagnosis. Furthermore, the associated allele of the 3' UTR SNP was approximately 2-fold overexpressed. We propose that the 3' UTR variant results in increased GFPT2 mRNA levels with resultant increased hexosamine flux. The I471V variant may contribute to altered protein function or may simply be in linkage disequilibrium with the 3' UTR.
Considerable data support adiponectin as an important adipose-derived insulin sensitizer that enhances fatty acid oxidation and alters hepatic gluconeogenesis. Adiponectin acts by way of two receptors, ADIPOR1 and ADIPOR2. ADIPOR1 is widely expressed in tissues, including muscle, liver, and pancreas, and binds the globular form of adiponectin with high affinity. To test the hypothesis that sequence variations in or near the ADIPOR1 gene contribute to the risk of developing type 2 diabetes and the metabolic syndrome, we screened the eight exons (including the untranslated exon 1) of the ADIPOR1 gene with flanking intronic sequences and the 5' and 3' flanking sequences. We identified 22 single nucleotide polymorphisms (SNPs) in Caucasian and African-American subjects, of which a single nonsynonymous SNP (N44K) in exon 2 was present only in African-American subjects. We typed 14 sequence variants that had minor allele frequencies >5%. No SNP was associated with type 2 diabetes in Caucasians or African Americans, and no SNP was a determinant of insulin sensitivity or insulin secretion among nondiabetic members of high-risk Caucasian families. However, the two alleles of a SNP in the 3' untranslated region were expressed unequally, and ADIPOR1 mRNA levels were significantly lower among transformed lymphocytes from diabetic African-American individuals than among control cell lines. This altered gene expression might suggest a role for ADIPOR1 in the metabolic syndrome.
L7/Pcp-2 is a GoLoco domain protein that modulates the activation of Galpha(i) and Galpha(o). We have previously described the Purkinje cell-specific expression of the Pcp-2(L7) gene and the abundant localization of its mRNA in mouse cerebellar Purkinje cell dendrites. Here we report on two alternative cerebellar forms of the L7/Pcp-2 mRNA and protein by examination of the gene structures and cDNA sequences of the mouse, rat, and human genes. The structures of the rodent and human genes are very similar with the most notable difference in the genomic configuration of the first exon. Despite this difference, the human and rodent genes both encode two alternative mRNAs due to the choice of two transcriptional start positions. The two mRNA forms, in turn, predict two forms of the L7/Pcp-2 protein, which are both highly conserved across species. These two protein forms differ with respect to the number of GoLoco domains. Lastly we examined the issue of mRNA localization in dendrites. In mouse both mRNA forms are detectable in dendrites but their relative proportions change during development. In addition we performed in situ hybridization on a developmental series of human cerebellar sections and demonstrate that the L7/Pcp-2 mRNA is also localized in dendrites of humans. As previously described in the mouse the dendritic localization in humans is developmentally regulated being most prominent during the peak phase of synaptogenesis and decreasing dramatically with age. The conservation of all of these properties of both the L7/Pcp-2 protein and mRNA highlights their likely importance in controlling the development and/or motor control function of Purkinje cells.
We studied the changes of met-enkephalin (Met-Enk) content and preproenkephalin (PPE) mRNA in the striatum in a mouse model of nicotine abstinence. Nicotine, 2 mg/kg, s.c., was administered four times daily for 14 days and Met-Enk and PPE mRNA evaluated at various times (4-96 h) following drug discontinuation. Met-Enk, assayed by radioimmunoassay, was increased in the ventral (nucleus accumbens) but not dorsal (putamen/caudate) striatum, while PPE mRNA, assayed in whole striatum by Northern blotting was elevated. Both changes were seen early during withdrawal and lasted over 72 h. In situ hybridization revealed enhanced signal in the dorsal striatum, mostly laterally, and smaller increases in the rostral pole, core and shell of the nucleus accumbens. These observations indicate that during nicotine withdrawal, striatal enkephalinergic neurons undergo adaptative responses, which might contribute to the abstinence behavioral syndrome.