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Biomedical subjects

P Fan

Publications and source records attributed to P Fan.

At least 37 records · Page 2Linked to original sources
PubMed2001

[Serum apolipoprotein A I, B100 and E levels and apolipoprotein E polymorphism in patients with Alzheimer's disease and multiple infarction dementia in Chinese population].

OBJECTIVE: To investigate the relationship of serum apolipoprotein (apo) A I, B100 and E levels and apo E polymorphism to Alzheimer's disease (AD) and multiple infarction dementia (MID) in Chinese population. METHODS: The apoE phenotypes were assayed by isoelectric focusing and immunoblotting, and apolipoproteins were determined by radial immunodiffusion assay in 75 patients with AD, 36 patients with MID and 60 control subjects. RESULTS: The frequency of apo E4 allele (epsilon 4) was significantly higher and the frequency of epsilon 2 allele was lower in AD group, compared with those in the control group (0.2333 vs 0.0666, 0.0467 vs 0.0833, P < 0.05). The frequency of epsilon 4 allele in MID group was also higher than that in the control group (0.2083 vs 0.0666, P < 0.05). The fasting serum apoA 1 and E levels in AD and MID groups were remarkably lower than those in the control group (P < 0.001 and P < 0.05). CONCLUSION: Apo E4 allele epsilon 4 was associated with AD and MID. ApoE4 might be a risk factor for AD and MID, and apo E2 might be a protective factor for AD. The serum apo A I and apoE levels were significantly decreased in patients with Alzheimer's disease and multiple infarction dementia.

Aged↗
PubMed2001

[Study of blood dynamics of ophthalmic artery in patients with sudden sensorineural hearing loss using color Doppler flow imaging].

OBJECTIVE: To investigate the relationship between the pathogenesis of sudden sensorineural hearing loss (SSHL) and the disorder of blood circulation in inner ear. METHOD: Blood dynamics of the ophthalmic artery were studied quantitatively using color doppler imaging in 34 patients with SSHL. RESULT: Compared with 34 self-controls and 15 normal controls, 28 patients (82.4%) with SSHL had significantly lower blood flow velocities and higher resistance indices (P < 0.05), and there was no significant difference between the self-control group and the normal control group (P > 0.05). CONCLUSION: The study suggested that the blood situations--the decreased blood flow velocities and perfusion and increased resistance of ophthalmic artery in patients with SSHL maybe play a role in the pathogenesis of SSHL.

Adolescent↗
PubMed2001

[Study on apoE gene polymorphism in Chinese type II b hyperlipidemia].

OBJECTIVE: To study apolipoprotein(apo) E polymorphism and its relationship with plasma lipids and apolipoproteins levels in Chinese patients with type II b hyperlip oproteinemia. METHODS: apoE genotypes were assayed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method, serum lipids were determined by enzyme method, and apolipoproteins were measured by radial immunodiffusion assay in 74 type II b hyperlipidemia patients whose fasting serum lipids levels were TG > or = 2.26 mmol/L, TC > or = 6.21 mmol/L and in 230 healthy subjects whose fasting serum lipids levels were TG < 1.82 mmol/L, TC < 6.21 mmol/L from a population of Chinese Han nationality in Chengdu area. RESULTS: Compared with the control group, the serum TG, TC, LDLC, nHDLC, apoA II, apoB100, apoC II, apoC III, apoE levels and TG/HDLC ratio in patients with type II b hyperlipidemia were significantly increased(P < 0.001), and the serum HDLC levels and apoE/apoC III ratio were significantly decreased (P < 0.05). ApoE3/3 genotype and allele epsilon 3 frequency in type II b hyperlipidemia group and control group were both the highest. In type II b hyperlipidemia group, allele epsilon 2 frequency tended to increase and allele epsilon 4 frequency tended to decrease as compared with those in the control group (P > 0.05). In type II b hyperlipidemia group the genotype of apoE2 was associated with higher serum TG, apoC II, apoE levels and apoE/apoC III ratio when compared with the genotype of apoE3; the genotype of apoE4 was associated with higher serum TC, nHDLC and apoE levels when compared with the genotypes E3 and E2 (P < 0.001). CONCLUSION: The alleles epsilon 2 and epsilon 4 are associated with serum TG, TC, nHDLC, apoC II and apoE levels to some extent in type II b hyperlipide in Chinese population.

Adult↗
PubMed2000

Degradation of transcription factor RFX5 during the inhibition of both constitutive and interferon gamma-inducible major histocompatibility complex class I expression in chlamydia-infected cells.

We have previously shown that the obligate intracellular pathogen chlamydia can suppress interferon (IFN)-gamma-inducible major histocompatibility complex (MHC) class II expression in infected cells by degrading upstream stimulation factor (USF)-1. We now report that chlamydia can also inhibit both constitutive and IFN-gamma-inducible MHC class I expression in the infected cells. The inhibition of MHC class I molecule expression correlates well with degradation of RFX5, an essential downstream transcription factor required for both the constitutive and IFN-gamma-inducible MHC class I expression. We further demonstrate that a lactacystin-sensitive proteasome-like activity identified in chlamydia-infected cell cytosolic fraction can degrade both USF-1 and RFX5. This proteasome-like activity is dependent on chlamydial but not host protein synthesis. Host preexisting proteasomes may not be required for the unique proteasome-like activity. These observations suggest that chlamydia-secreted factors may directly participate in the proteasome-like activity. Efforts to identify the chlamydial factors are underway. These findings provide novel information on the molecular mechanisms of chlamydial evasion of host immune recognition.

Bacterial Proteins↗
PubMed2000

Dominant negative down-regulation of endotoxin-induced tumor necrosis factor alpha production by Lps(d)/Ran.

We recently showed that adenoviral transfer and expression of the Lps(d)/Ran gene isolated from endotoxin-resistant C3H/HeJ mice could protect endotoxin-sensitive mice from endotoxic shock. Elevation of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), is thought to be essential for the development of septic shock. To investigate the extent to which Lps(d)/Ran affects TNF-alpha production, we transduced primary macrophages from endotoxin-sensitive and -resistant mice with adenoviral vectors expressing the wild-type and the mutant Lps/Ran cDNAs and other control genes, and compared the amount of TNF-alpha produced by these various transduced macrophages. Successful transfer and expression of Lps(d)/Ran cDNA in endotoxin-sensitive C3H/HeOuJ macrophages reduced TNF-alpha production upon lipopolysaccharide (LPS) stimulation, as compared with macrophages transduced with vectors expressing the wild-type Lps(n)/Ran cDNA, the green fluorescent protein gene, or the lacZ gene. On the other hand, successful transfer and expression of the wild-type Lps(n)/Ran cDNA in primary macrophages from endotoxin-resistant C3H/HeJ mice failed to induce TNF-alpha production to any significant extent unless a very high LPS concentration was used. Given our previous demonstration that Lps(n)/Ran functions effectively in restoring LPS responsiveness in B cells from C3H/HeJ mice, we conclude that Lps/Ran is involved in a CD14-independent signal transduction pathway. This dominant negative down-regulation by Lps(d)/Ran on TNF-alpha production by macrophages and probably other innate immune responses may be key to the development of an effective gene therapy for endotoxic or septic shock.

Adenoviridae↗
PubMed2000

Endothelial dysfunction associated with left ventricular diastolic dysfunction in patients with coronary heart disease.

OBJECTIVE: We sought to assess the correlation between endothelial vasodilation and left ventricular diastolic function. BACKGROUND: Previous studies have demonstrated that similar neurohumoral factors are involved in myocardial and vascular endothelial impairment. The degree of endothelial dysfunction is related to the clinical severity of the heart failure. However, it is not clear whether endothelial dysfunction develops with the progression of left ventricular diastolic dysfunction. We hypothesize that the endothelial dysfunction is associated with left ventricular diastolic dysfunction. METHODS: Using high-resolution ultrasound, we measured the dilator response of the brachial artery to hyperemia (endothelium-dependent vasodilation) and to 0.5 mg nitroglycerin (endothelium-independent vasodilation), and measured peak velocities of the early wave (Evmax) and the atrial wave (Avmax) in 40 coronary heart disease (CHD) patients and 20 normal subjects. We analyzed the relationship between the Evmax/Avmax ratio and endothelium-dependent vasodilation. RESULTS: The results showed that endothelium-dependent and endothelium-independent vasodilation as well as the Evmax/Avmax ratio were lower in the CHD group than those in the control group (4.29%+/-1.42%, 17.58%+/-2.99%, 0.81+/-0.24 vs. 9.62%+/-2.34%, 24.18%+/-3.15%, 1.07+/-0.29, respectively, P<0.01). The Evmax/Avmax ratio was related to endothelium-dependent vasodilation (r=0.45, P<0.01). CONCLUSIONS: Our results showed that the development of endothelial dysfunction was associated with the progression of myocardial diastolic dysfunction, which suggests that the same mechanisms may be involved in the impairment of endothelium and myocardium.

Brachial Artery↗
PubMed2000

Oxidative modification of lipoproteins in hypertriglyceridemic patients and hypercholesterolemic rabbits in vivo.

Many lines of evidence suggest that LDL is oxidized in vivo and that Ox-LDL is present in the artery wall. But the oxidation of VLDL and HDL in vivo has not yet been reported. In this study, the oxidative modification of serum LDL, VLDL, and HDL in patients with endogenous hypertriglyceridemia (HTG) and in serum of rabbits fed on high cholesterol diet were made. The serum LDL, VLDL and HDL were isolated by the density gradient ultracentrifugation. The oxidative modification of LDL, VLDL and HDL were identified by agarose eletrophoresis, absorbance at 234 nm and fluorescence of TBARS. The results showed that serum TC, TG and TBARS in the HTG group (n = 25) and in rabbits fed with a high fat diet (for 12 weeks, n = 8) were significantly higher than those of the corresponding control groups (normal subjects, n = 25; rabbits fed with a normal diet, n = 8; p < 0.01). The electrophoretic mobilities of LDL, VLDL and HDL were increased when compared with the controls, and absorbance at 234 nm and TBARS of LDL, VLDL and HDL in the HTG group and in the high fat diet rabbits were significantly higher than those of the controls (p < 0.01). These results suggest that not only LDL but also VLDL and HDL were oxidatively modified in vivo in the patients with HTG and in the rabbits fed with a high cholesterol diet.

Adult↗
PubMed1999

Fast repair of deoxynucleotide radical cations by phenylpropanoid glycosides (PPGs) and their analogs.

The repair effects on deoxynucleotide radical cations of phenylpropanoid glycosides (PPGs) and their analogs, isolated from a Chinese folk medicinal herb, were studied using the pulse radiolysis technique. The radical cations of deoxynucleotides were formed by the reaction of SO4*- with deoxynucleotides. On pulse irradiation of a nitrogen saturated deoxynucleotide aqueous solution containing 20 mM K2S2O8, 200 mM t-BuOH and one of the PPGs or their analogs, the transient absorption spectra of the radical cations of nucleotide decayed with the formation of those of the radical cation of PPGs or their analogs within several tens of microseconds after electron pulse irradiation. The result indicates that deoxynucleotide radical cations can be repaired by PPGs or their analogs. The rate constants of the repair reactions were determined to be 0.48-1.1 x 10(9), 0.64-1.80 x 10(9) and 2.12-4.4 x 10(9) M(-1) s(-1) for dAMP, dGMP and dCMP radical cations respectively. It is obvious that the rate constants of the repair reaction depend on the number of phenolic hydroxyl groups contained in the PPGs and their analogs. A deeper understanding of this new repair mechanism will undoubtedly help researchers design strategies to prevent and/or intervene more effective in free radical related diseases.

Cations↗
PubMed1999

Lps(d)/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses.

C3H/HeJ inbred mice are defective in that they are highly resistant to endotoxic shock as compared with normal responder mice. Their B cells and macrophages do not respond significantly when exposed to lipopolysaccharide (LPS), whereas cells from the responder mice do. Using a functional assay, we previously isolated a cDNA, which encodes for Ran/TC4 GTPase. We now show that this gene is mutated in C3H/HeJ mice, which accounts for their resistance to endotoxin stimulation. Sequence analysis of independent mutant Lps(d)/Ran cDNAs isolated from splenic B cells of C3H/HeJ mice reveals a consistent single base substitution at position 870, where a thymidine is replaced with a cytidine. In situ hybridization maps the Lps(d)/Ran cDNA to mouse chromosome 4. By retroviral gene transfer, the wild-type Lps(n)/Ran cDNA but not the mutant Lps(d)/Ran cDNA can restore LPS responsiveness of C3H/HeJ cells. Adenoviral gene transfer in vivo with the mutant Lps(d)/Ran cDNA but not the wild-type Lps(n)/Ran cDNA rescues endotoxin-sensitive mice from septic shock. Thus Lps/Ran is an important target for LPS-mediated signal transduction, and the Lps(d)/Ran gene may be useful as a therapeutic sequence in gene therapy for endotoxemia and septic shock.

3' Untranslated Regions↗
PubMed1999

Novel conformationally restricted tetracyclic analogs of delta8-tetrahydrocannabinol.

Novel analogs of (-)-delta8-tetrahydrocannabinol (delta8-THC) in which the conformation of the side chain was restricted by incorporating the first one or two carbons into a six membered ring fused with the aromatic phenolic A ring were synthesized. The affinities of the novel ligands for CB1 and CB2 indicated that the "southbound" chain conformer retained the highest affinity for both receptors.

Animals↗
PubMed1999

Substrate specificity and stereoselectivity of rat brain microsomal anandamide amidohydrolase.

Anandamide amidohydrolase (AAH) catalyzes the hydrolysis of arachidonylethanolamide (anandamide), an endogenous cannabinoid receptor ligand. To delineate the structural requirements of AAH substrates, rat brain microsomal AAH hydrolysis of a series of anandamide congeners was studied using two reverse-phase high-performance liquid chromatography (RP-HPLC) assays developed in our laboratory. Arachidonamide (1) was found to be the best substrate with an apparent Km of 2.34 mM and a Vmax of 2.89 nmol/min/mg of protein. Although anandamide (2) has a similar Km value, its Vmax is approximately one-half that of arachidonamide. N, N-Bis(2-hydroxyethyl)arachidonamide (3) was not hydrolyzed, suggesting specificity for unsubstituted or mono-N-substituted arachidonamides. Analogues with a methyl group at the 1'-position of the ethanolamido headgroup were also found to have greater resistance to enzymatic turnover and therefore increased metabolic stability. The enzyme exhibited high stereoselectivity as the rate of hydrolysis of (R)-alpha-methanandamide (2.4%) (anandamide = 100%) was about 10-fold lower than that of its (S)-enantiomer (23%). In contrast, (R)-beta-methanandamide was 6-times more susceptible (121%) than the (S)-beta-enantiomer (21%). Interestingly, an inverse correlation was shown between AAH stereoselectivity and the brain cannabinoid receptor affinity as the enantiomers with high receptor affinity displayed low susceptibility to hydrolysis by AAH. Metabolic stability is also imparted to analogues with a short hydrocarbon headgroup as well as to those possessing 2-monomethyl or 2,2-dimethyl substituents. 2-Arachidonylglycerol and racemic 1-arachidonylglycerol were shown to be excellent AAH substrates. To identify AAH inhibitors, hydrolysis of anandamide was also studied in the presence of a select group of cannabimimetics. Of these, (-)-Delta8-THC and SR141716A, a biarylpyrazole CB1 antagonist, were found to inhibit enzymatic activity. These newly defined enzyme recognition parameters should provide a foundation for the rational development of stable, therapeutically useful anandamide analogues with high receptor affinity.

Amidohydrolases↗
PubMed1999

Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists.

As a potent, specific antagonist for the brain cannabinoid receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compound for initiating studies designed to examine the structure-activity relationships of related compounds and to search for more selective and potent cannabimimetic ligands. A series of pyrazole derivatives was designed and synthesized to aid in the characterization of the cannabinoid receptor binding sites and also to serve as potentially useful pharmacological probes. Therapeutically, such compounds may have the ability to antagonize harmful side effects of cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain cannabinoid CB1 receptor antagonistic activity included (a) a para-substituted phenyl ring at the 5-position, (b) a carboxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this series contained a p-iodophenyl group at the 5-position, a piperidinyl carboxamide at the 3-position, and a 2,4-dichlorophenyl group at the 1-position of the pyrazole ring. The iodinated nature of this compound offers additional utility as a gamma-enriching SPECT (single photon emission computed tomography) ligand that may be useful in characterizing brain CB1 receptor binding in vivo.

Animals↗
PubMed1999

Morphological evaluation of a regurgitant orifice by 3-D echocardiography: applications in the quantification of valvular regurgitation.

The clinical evaluation of blood flow regurgitation through a heart valve or stenotic lesion is an unresolved problem. The proximal flowfield region has been the study focus in the last few years; however, investigators have failed to identify an accurate and reliable calculation scheme due to lack of geometric information about the shape and size of the regurgitating or stenotic orifice. Presented here is a superior method of calculation, by using three-dimensional (3-D) echocardiography combined with Doppler velocimetry. The geometric structure of the orifice in a regurgitating porcine prosthetic valve in vitro was formulated by 3-D image construction of sequentially obtained 2-D images. The velocity flowfield was accessed by color Doppler flow mapping (CD) and continuous-wave Doppler (CW). Two accurate methods of calculation of regurgitant variables were developed. The first method calculated peak regurgitant flow rate from CD and the second method calculated regurgitant flow volume from CW. Both methods showed excellent correlation with the corresponding true values from an electromagnetic flowmeter. The promising preliminary results in such a realistic porcine model indicate the possibility of establishing a routine procedure to be tested in the clinical setting.

Animals↗
PubMed1999

Probing the N-5 region of the indoloquinoline alkaloid, cryptolepine for anticryptococcal activity.

N-5 Alkylated analogues of cryptolepine were synthesized and tested for anticryptococcal activity. Evidence provided in this study suggests that the active form of cryptolepine consists of the flat tetracyclic aromatic ring with the methyl group on the N-5 atom. It was also found that changes in the electronic density around the N-5 atom do not appear to affect activity. Steric hindrance of the N-5 substituents seems to decrease activity. Through systematic modification of the N-5 alkyl groups, o-phenylpentyl group was shown to possess the highest potency thus far.

Alkaloids↗
PubMed1999

Efficient CFTR expression from AAV vectors packaged with promoters--the second generation.

Gene therapy studies of cystic fibrosis (CF) have shown that AAV-based vector was efficient in transferring but not in expressing the CFTR cDNA in the target cells. The levels of CFTR gene expression were limited by the small packaging capacity of AAV because it had been difficult to package the CFTR cDNA with an efficient promoter. In the present study we have developed a new generation of AAV/CFTR vectors which contain efficient short promoters to express the CFTR gene in target cells. To do so, we reduced the size of the CFTR cDNA by determining the minimal untranslated regions required for expression of CFTR cDNA. We also identified short and efficient promoters that could be packaged with the down-sized CFTR cDNA into a novel AAV vector that had a maximal packaging capacity. Functional analyses showed that the new vectors were packaged efficiently and expressed higher levels of CFTR than a vector in which the CFTR gene was driven by the ITR sequence of AAV. Transduction of airway epithelial cells containing [symbol: see text] 508 mutation with the new vectors demonstrated efficient expression of the wild-type CFTR and correction of the CF phenotype. In contrast, no significant CFTR expression was detected in cells infected with the vector that express the CFTR gene from the ITR. These findings support the notion that the AAV can be developed into an efficient vector to transduce the CFTR gene and vectors expressing higher levels of CFTR from an efficient promoter should provide better efficacy for gene therapy of cystic fibrosis.

Cystic Fibrosis↗
PubMed1999

Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand.

In the search for a radioligand capable of imaging cannabinoid CB1 receptors in the living human brain by SPECT (single photon emission computed tomography),N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) was synthesized. This compound is an analog of the potent, CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]. AM281 bound to brain and spleen membrane preparations (CB1 and CB2 receptors, respectively) with K(i) values of 12 nM and 4200 nM, respectively. AM281 also inhibited the response of guinea-pig small intestine preparation to a cannabinoid receptor agonist. Thus, AM281 behaves as a CB1 receptor selective antagonist. Methods for the rapid, high-yield synthesis and purification of [123I]AM281 were developed, and transaxially reconstructed brain SPECT images obtained after continuous infusion of [123I]AM281 in baboons. Thus [123I]AM281 may be suitable for imaging CB1 receptors in humans.

Animals↗
PubMed1999

Systemic antifungal agents against AIDS-related opportunistic infections: current status and emerging drugs in development.

No effective drug was available for the treatment of systemic fungal infections until the discovery of Amphotericin B in 1953. Since then flucytosine, azoles and later the triazoles, have now become available. The current interest in the development of new antifungal agents can partially be explained by the dramatic rise in the number of AIDS cases and the subsequent suppression of the immune system in patients with the disease. For example, over 90% of those diagnosed to be HIV-positive contract a fungal infection during the course of their illness. Other conditions that have spurred the development of new systemic antifungal agents include the increase in the frequency of bone marrow and organ transplants, the use of antineoplastic agents, long-term use of corticosteroids and even the indiscriminate use of antibiotics. The emergence of fungi resistant to currently available agents, especially the azoles, has made the need for new and effective antifungal agents more urgent. This review article focuses on agents targeted against opportunistic fungal infections, i.e., fungal infections which, in contrast to immunocompetent individuals, may cause serious life-threatening illness in immunocompromised individuals. Agents currently on the market or undergoing clinical development, as well as potential new agents that have been discovered, are discussed.

AIDS-Related Opportunistic Infections↗