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Biomedical subjects

M Zhong

Publications and source records attributed to M Zhong.

At least 19 recordsLinked to original sources
PubMed2006

Sex-specific regulation of growth plate chondrocytes by estrogen is via multiple MAP kinase signaling pathways.

Both male and female rat growth plate cartilage cells possess estrogen receptors (ERs), but 17beta-estradiol (E(2)) activates protein kinase C (PKC) and PKC-dependent biological responses to E(2) only in cells from female animals. PKC signaling can elicit genomic responses via mitogen activated protein kinase (MAPK) and E(2) has been shown to activate ERK MAPK in many cells, suggesting that MAPK may play a role in growth plate chondrocytes as well. We tested if E(2) increases MAPK activity and if so, whether the response is limited to female cells, if it is PKC-dependent, and if the mechanism involves traditional ER pathways. We also determined the contribution of MAPK to the biological response of growth plate chondrocytes and assessed the relative contributions of ERK, p38 and JNK MAPKs. Female rat costochondral cartilage cells were treated with E(2) and MAPK-specific activity determined in cell layer lysates. The mechanism of MAPK activation was determined by treating the cells with E(2) conjugated to bovine serum albumin (E(2)-BSA) to assess if membrane receptors were involved; stereospecificity was determined using 17alpha-estradiol; PKC and phospholipase C (PLC) dependence was determined using specific inhibitors; and the ER agonist diethylstilbestrol, the ER antagonist ICI 182780, and tamoxifen were used to assess the role of traditional ER pathways. E(2) regulation of ERK1/2 MAPK was assessed and the relative roles of ERK1/2, p38 and JNK MAPKs determined using specific inhibitors. E(2) caused a rapid dose-dependent activation of MAPK that was greatest in cells treated for 9 min with 10(-9) M hormone; activity remained elevated for 3 h. E(2)'s effect on MAPK was stereospecific and comparable to that of E(2)-BSA. It was insensitive to DES and ICI 182780, dependent on PKC and PLC, blocked by tamoxifen and it did not require gene transcription or translation. E(2) had no effect on ERK1 or ERK2 mRNA or protein but it caused a rapid phosphorylation of ERK1/2 at 9 min. Inhibition of ERK1/2 and p38 MAPK reduced the stimulatory effects of E(2) on alkaline phosphatase activity and [(35)S]-sulfate incorporation. These results suggest that E(2) regulates MAPK through a sex-specific membrane-mediated mechanism that does not involve cytosolic ERs in a traditional sense and that ERK1/2 and p38 mediate the downstream biological effects of the hormone.

Animals↗
PubMed2004

The prevalence and spectrum of alpha and beta thalassaemia in Guangdong Province: implications for the future health burden and population screening.

AIM: Thalassaemia is a good candidate disease for control by preventive genetic programmes in developing countries. Accurate population frequency data are needed for planning the control of thalassaemia in the high risk Guangdong Province of southern China. METHODS: In total, 13397 consecutive samples from five geographical areas of Guangdong Province were analysed for both haematological and molecular parameters. RESULTS: There was a high prevalence of carriers of alpha thalassaemia (8.53%), beta thalassaemia (2.54%), and both alpha and beta thalassaemia (0.26%). Overall, 11.07% of the population in this area were heterozygous carriers of alpha and beta thalassaemia. The mutation spectrum of alpha and beta thalassaemia and its constitution were fully described in this area. This study reports the true prevalence of silent alpha thalassaemia in the southern China population for the first time. In addition, two novel mutations that give rise to alpha thalassaemia, one deletion resulting in beta thalassaemia, and a rare deletion (--(THAI) allele) previously unreported in mainland China were detected. The frequency of the most common mutation, the Southeast Asian type of deletion (--(SEA), accounting for 48.54% of all alpha thalassaemias) was similar to the total of two alpha(+) thalassaemia deletions (-alpha(3.7) and -alpha(4.2), accounting for 47.49% of alpha thalassaemia). CONCLUSION: Both alpha and beta thalassaemia are widely distributed in Guangdong Province of China. The knowledge gained in this study will enable the projected number of pregnancies at risk to be estimated and a screening strategy for control of thalassaemia to be designed in this area.

Adult↗
PubMed2002

Clearance of quinupristin-dalfopristin (Synercid) and their main metabolites during continuous veno-venous hemofiltration (CVVH) with or without dialysis.

BACKGROUND: Quinupristin-dalfopristin (Q/D) is often utilized in critically ill patients, some of whom require CVVH. This study was undertaken to determine the clearance of O/D and their main active metabolites (RPR 100391, RP 69012, RP 12536) via CVVH in the swine model. METHODS: Q/D 7.5 mg/kg was intravenously administered over 0.5 h to 12 swine after induction of acute renal failure by ligation of the renal arteries. At 0.5 h post injection, the CVVH procedure was initiated and continued for 8 hours at the following pump rates: (1)100 mL/min, (2)180 rnL/min, and (3)100 mL/min with dialysis (flow rate: 1 L/h). Blood and ultrafiltrate samples were collected at 1 h intervals and assessed by a validated HPLC method. RESULTS: Plasma analysis suggests rapid metabolism to the main active metabolites which are appreciably cleared as demonstrated by high clearance and sieving coefficient estimates. Mean clearance estimates for RP 69012, RP 100391, and RP 12536 are 729, 777, and 578 mL/h in the 100 mL/min CVVH group, 772, 785, 685 mL/min in the 180 mL/min CVVH group, and 753, 791, 616 mL/min in the 100 mL/min CVVH group with 1 L/h dialysis, respectively. CONCLUSION: These data reveal that Q/D is rapidly metabolized and the metabolites are cleared to a large extent via CVVH. Due to the considerable contribution of the metabolites to overall in vivo activities, additional studies are required to fully quantify their removal before final dosage modifications for patients undergoing CVVH can be recommended.

Animals↗
PubMed2001

Transformation of cells overexpressing a tyrosine kinase by phospholipase D1 and D2.

Phospholipase D (PLD) activity is elevated in response to most mitogenic signals. Two mammalian PLD genes (PLD1 and PLD2) have been cloned and their gene products have been characterized. PLD1 is a downstream target of the Ras/RalA GTPase cascade implicated in mitogenic and oncogenic signaling. Consistent with a role in mitogenic signaling, elevated expression of PLD1 transforms cells overexpressing the epidermal growth factor (EGF) receptor (EGFR). However, PLD2 colocalizes with the EGFR in caveolin-enriched light membrane microdomains. We therefore investigated whether PLD2 could also contribute to the transformation of cells overexpressing a tyrosine kinase. We report here that elevated expression of PLD2 transforms rat fibroblasts overexpressing either the EGFR or c-Src. Since overexpression of a tyrosine kinase is a common genetic alteration in several human cancers, these data suggest that elevation of either PLD1 or PLD2 may contribute to the progression to a malignant phenotype in cells with elevated tyrosine kinase activity.

Animals↗
PubMed2001

Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver.

Human hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In this work, we report on a comprehensive characterization of gene expression profiles of hepatitis B virus-positive HCC through the generation of a large set of 5'-read expressed sequence tag (EST) clusters (11,065 in total) from HCC and noncancerous liver samples, which then were applied to a cDNA microarray system containing 12,393 genes/ESTs and to comparison with a public database. The commercial cDNA microarray, which contains 1,176 known genes related to oncogenesis, was used also for profiling gene expression. Integrated data from the above approaches identified 2,253 genes/ESTs as candidates with differential expression. A number of genes related to oncogenesis and hepatic function/differentiation were selected for further semiquantitative reverse transcriptase-PCR analysis in 29 paired HCC/noncancerous liver samples. Many genes involved in cell cycle regulation such as cyclins, cyclin-dependent kinases, and cell cycle negative regulators were deregulated in most patients with HCC. Aberrant expression of the Wnt-beta-catenin pathway and enzymes for DNA replication also could contribute to the pathogenesis of HCC. The alteration of transcription levels was noted in a large number of genes implicated in metabolism, whereas a profile change of others might represent a status of dedifferentiation of the malignant hepatocytes, both considered as potential markers of diagnostic value. Notably, the altered transcriptome profiles in HCC could be correlated to a number of chromosome regions with amplification or loss of heterozygosity, providing one of the underlying causes of the transcription anomaly of HCC.

Carcinoma, Hepatocellular↗
PubMed2001

[Molecular mechanism underlying calcium handling in diastolic heart failure].

OBJECTIVE: To elucidate the molecular mechanism underlying calcium handling in diastolic heart failure (DHF) from mRNA level and protein expression, including L-type calcium channel, sarcoplasmic reticulum (SR) Ca(2+)-ATPase, phospholamban, ryanodine receptor, calsequestrin. METHODS: DHF was produced in rabbits by abdominal aortic coarctation. The mRNA amounts of these calcium-handling genes were measured by RT-PCR, while the protein levels of SR Ca(2+)-ATPase and phospholamban were analyzed by Western blot analysis. RESULTS: The content of calcium was significantly increased in myocardium of rabbits with DHF than in the myocardium of sham-operated rabbits. The SR Ca(2+)-ATPase activity of DHF rabbits was significantly reduced compared with that in sham-operated rabbits (21.1 micromol.mg(-1).h(-1) +/- 5.7 micromol.mg(-1).h(-1) vs 10.5 micromol.mg(-1).h(-1) +/- 2.8 micromol.mg(-1).h(-1), P < 0.01). RT-PCR analyses showed that the steady-state level of mRNA encoding the L-type calcium channel and SR Ca2+-ATPase was decreased significantly in rabbits with DHF compared with that in the sham-operated rabbits (micromol.mg(-1).h(-1)): 0.75 +/- 0.11 vs 1.20 +/- 0.33; 0.76 +/- 0.12 vs 1.24 +/- 0.38, P < 0.05). The SR Ca(2+)-ATPase mRNA level correlated negatively well with left ventricular relaxation time constant and left ventricular end-diastolic pressure (r = -0.81, -0.64, respectively, P < 0.05 approximately 0.01); the mRNA level of L-type calcium channel correlated negatively with left ventricular end-diastolic pressure (r = -0.74, P < 0.05). The mRNA level of ryanodine receptor correlated negatively with the left ventricular relaxation time constant too (r = -0.71, P < 0.05). Protein level of SR Ca(2+)-ATPase was significantly lower in rabbits with DHF than in the sham-operated rabbits (0.76 +/- 0.6 vs 1.02 +/- 0.09, P < 0.05), whereas the protein level of phospholamban was unchanged. CONCLUSION: The L-type calcium channel and SR Ca(2+)-ATPase were down regulated in DHF. These changes may be a contributory factor for DHF.

Animals↗
PubMed2001

Implication of the proprotein convertases furin, PC5 and PC7 in the cleavage of surface glycoproteins of Hong Kong, Ebola and respiratory syncytial viruses: a comparative analysis with fluorogenic peptides.

Fluorogenic peptides encompassing the processing sites of envelope glycoproteins of the infectious influenza A Hong Kong virus (HKV), Ebola virus (EBOV) and respiratory syncytial virus (RSV) were tested for cleavage by soluble recombinants of the proprotein convertases furin, PC5 and PC7. Kinetic studies with these intramolecularly quenched fluorogenic peptides revealed selective cleavages at the physiological dibasic sites. The HKV peptide is cleaved by both furin and PC5 with similar efficacy; in comparison, PC7 cleaves this substrate poorly. In contrast with the basic tetrapeptide insertion within the haemagglutinin sequence of HKV, two other dipeptide insertions revealed a poorer cleavage with a similar rank order of potency. These results demonstrate that the N-terminal RERR insertion to the wild-type avian RKKR downward arrow sequence is functionally significant, and suggest that the approx. 5-fold increase in cleavage efficacy contributes to the high infectivity of the H5N1 virus subtype. With regard to RSV peptide processing, PC7 is twice as effective as PC5 and furin. The EBOV peptide was processed with similar efficiency by the three enzymes. Our observations that all of these cleavages can be effectively inhibited by a plant andrographolide derivative at 250 microM or less might aid in the design of potent convertase inhibitors as alternative antiviral therapies.

Amino Acid Sequence↗
PubMed2001

Medium-throughput pKa screening pharmaceuticals by pressure-assisted capillary electrophoresis.

A fast screening method for the determination of the dissociation constants (pKa) of acidic, basic, and multivalent compounds was developed by using pressure-assisted capillary electrophoresis (PACE). External air pressure was applied to shorten the analysis time. The separation efficiency decreases as air pressure increases. However, it was found that air pressure does not affect the measurement of electrophoretic mobility and pKa significantly when it is less than 2 psi. The method was evaluated in terms of accuracy, precision, and ruggedness by using a set of 48 compounds with literature pKa values ranging from 2 to 10. The difference between the measured pKa values and literature values is less than 0.2 units. The throughput is approximately 20 compounds per day with a 12-point measurement ranging from pH 2.5 to 11. It was demonstrated that this method is applicable for pKa screening of pharmaceuticals with diverse chemical structures.

Acetone↗
PubMed2001

Down-regulation of inducible nitric-oxide synthase (NOS-2) during parasite-induced gut inflammation: a path to identify a selective NOS-2 inhibitor.

Nitric oxide (NO) possesses potent anti-inflammatory properties; however, an over-production of NO will promote inflammation and induce cell and tissue dysfunction. Thus, the ability to precisely regulate NO production could prove beneficial in controlling damage. In this study, advantage was taken of the well characterized inflammatory response caused by an intestinal parasite, Trichinella spiralis, to study the relationship between intestinal inflammation and the regulation of nitric oxide synthase-type 2 (NOS-2) expression. Our study revealed that a specific gut inflammatory reaction results in inhibition of NOS-2 expression. Characteristics of this inhibition are: 1) local jejunal inflammation induced by T. spiralis systemically inhibits NOS-2 gene transcription, protein expression, and enzyme activity; 2) the inhibition blunts endotoxin-stimulated NOS-2 expression; 3) the inhibition does not extend to the expression of other isoforms of NOS, to paxillin, a housekeeper protein, or to cyclooxygenase-2, another protein induced by proinflammatory cytokines; 4) the inhibition is unlikely related to the formation of specific anti-parasite antibodies; and 5) the inhibition may involve substances other than stress-induced corticosteroids. Elucidation of such potent endogenous NOS-2 down-regulatory mechanisms could lead to the development of new strategies for the therapy of inflammatory conditions characterized by the overproduction of NO.

Animals↗
PubMed2001

Streptococcus pneumoniae response to repeated moxifloxacin or levofloxacin exposure in a rabbit tissue cage model.

The role of moxifloxacin and levofloxacin pharmacokinetics (PK) in antimicrobial efficacy and in the selection of fluoroquinolone-resistant Streptococcus pneumoniae strains was investigated using the rabbit tissue cage abscess model. A rabbit tissue cage was created by insertion of sterile Wiffle balls in the dorsal cervical area. Animals orally received a range of moxifloxacin or levofloxacin doses that simulate human PK for 7 days 48 h after the Wiffle balls were inoculated with fluoroquinolone-sensitive S. pneumoniae (10(7) CFU). Abscess fluid was collected on a daily basis over 14 days to measure bacterial density and MICs. Moxifloxacin regimens produced a range of area under the concentration-time curve (AUC)/MIC ratios ranging from 9.2 to 444 and peak/MIC ratios ranging from 1.3 to 102. Levofloxacin doses produced AUC/MIC ratios of 5.1 to 85.5 and peak/MIC ratio of 0.9 to 14.8. Moxifloxacin at 6.5, 26, and 42 mg/kg reduced the bacterial log CFU per milliliter in abscess fluid (percentage of that in a sterile animal) by 4.2 +/- 2.2 (20%), 5.8 +/- 0.4 (100%), and 5.4 +/- 0.4 (100%), respectively, over the dosing period. Levofloxacin at 5.5, 22, and 32 mg/kg reduced the log CFU per milliliter in abscess fluid (percentage of that in a sterile animal) by 2.8 +/- 0.7 (20%), 5.1 +/- 1.3 (80%), and 4.6 +/- 1.3 (60%), respectively. Moxifloxacin has a greater bactericidal rate as determined by regression of log CFU versus time data. The AUC/MIC and peak/MIC ratios correlated with the efficacy of both drugs (P < 0.05). Resistance to either drug did not develop with any of the doses as assessed by a change in the MIC. In conclusion, data derived from this study show that moxifloxacin and levofloxacin exhibit rapid bactericidal activity against S. pneumoniae in vivo, and moxifloxacin exhibits enhanced bactericidal activity compared to levofloxacin, with AUC/MIC and peak/MIC ratios correlated with antimicrobial efficacy for both drugs. The development of fluoroquinolone-resistant S. pneumoniae was not observed with either drug in this model.

Animals↗
PubMed2001

Lack of interaction between levofloxacin and oxycodone: pharmacokinetics and drug disposition.

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and levofloxacin. Eight healthy volunteers were randomized in an open-label, two-way crossover study to receive oxycodone, 5 mg p.o. Q4H, and levofloxacin, 500 mg p.o. 1 hour after starting the oxycodone or levofloxacin 500 mg p.o. alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours for Cmax, tmax, and AUC determinations. There was not a significant difference (p > 0.05) in AUC (48.59 +/- 8.52 vs. 49.9 +/- 9.93), Cmax (7.73 +/- 2.6 vs. 6.6 +/- 2.0), and tmax (1.1 +/- 0.6 vs. 1.6 +/- 1.1) for levofloxacin versus levofloxacin/oxycodone regimens. It was concluded that oral oxycodone and levofloxacin can be administered concomitantly without a significant decrease in AUC, Cmax, or tmax.

Adult↗
PubMed2001

Novel tumor-promoting property of tamoxifen.

The tumor-promoting phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) cooperates with c-Src overexpression to transform rat fibroblasts. TPA transforms c-Src-overexpressing cells by depleting the delta isoform of protein kinase C (PKCdelta). Tamoxifen, which has both estrogen-mimetic and estrogen-antagonist properties, has been widely used to improve the prognosis of breast cancer patients. However, with extended use, there is an increased risk for endometrial and other cancers that can be observed within 10 years of treatment. We report here that tamoxifen, similar to TPA, cooperates with c-Src overexpression to transform 3Y1 rat fibroblasts. Tamoxifen induced both DNA synthesis and anchorage-independent cell proliferation in c-Src-overexpressing, but not in parental, 3Y1 rat fibroblasts. Tamoxifen also induced an association between c-Src and PKCdelta that resulted in the tyrosine phosphorylation and down-regulation of PKCdelta. These phenotypes were not induced by estrogen, indicating that the effect of tamoxifen was in addition to any estrogen-mimetic effects. Thus, in addition to the hyperplasia-inducing capability of an estrogen-mimetic, tamoxifen has an additional tumor-promoting capability similar to that of TPA. The dual tumor-promoting capability of both estrogen- and TPA-mimetic properties for tamoxifen may contribute to the increased incidence of endometrial cancers observed in the relatively short exposure period of <10 years.

Animals↗
PubMed2001

[Rapid detection of the common alpha-thalassemia-2 determinants by PCR assay].

OBJECTIVE: Most frequent molecular lesions of alpha-thalassemia-2 determinants are deletions of one alpha-globin gene. Satisfactory PCR methodologies for detecting the deletions are required for molecular diagnosis and genetic screening since there was no internal control in most published PCR-based strategies. The purpose of this study is to develop a reliable PCR protocol specific for the two common alpha-thalassemia-2 determinants with internal control. METHODS: The multiple repeat elements and the high GC-content of the alpha-globin locus impose severe limitations on designing suitable primers and optimizing stable conditions for PCR. In this study, two multiplex PCR systems were successfully set up. One was designed to detect the rightward deletion (-alpha(3.7)/) with two pairs of primers including one newly optimized pair for amplification of the internal standard to indicate the success of failure of PCR amplification. The other, to the leftward deletion(-alpha(4.2)/) with three primers, which were designed according to the newly sequenced data of the -alpha(4.2) and HbQ-alpha(4.2) deletions in this lab(Genbank Accession No. AF221717). In the PCR system, one is used as a common upstream primer and the other two are used as specific downstream primers for typing the normal allele and the deletion one, respectively. RESULTS: Easily interpretable, unambiguous amplifications were observed by using the multiplex PCR systems for the detection of the two common alpha-thalassemia-2 determinants. The three or four primers were run in the same tube under the same condition and both of these two systems could be used at the same thermal cycle parameters. For typing the rightward deletion, a mutant-specific amplification of 1.7 kb and a 1140 bp amplified band as a normal and system control were produced. For typing the leftward deletion, two PCR-amplified bands, a 956 bp fragment specific for a -alpha(4.2) gene and a 1140 bp one for a normal allele were found. CONCLUSION: Two sets of PCR systems with internal controls for detecting the most common two alpha-thalassemia-2 determinants have been established and may be suitable for molecular diagnosis and population screening.

Base Sequence↗
PubMed2001

[Microsurgical treatment of 86 cases of intracranial aneurysms].

OBJECTIVE: To summarize the microsurgical experience in the treatment of intracranial aneurysms. METHOD: The clinical materials, surgical modes and prognosis of 86 cases of clipped intracranial aneurysms were retrospectively reviewed. RESULTS: Of the 86 cases, 69 recovered, 10 were moderately disabled, 2 severely disabled, and 5 died. CONCLUSIONS: To avoid rerupture, aneurysms should be treated as soon as possible when the diagnosis was established. Proper management of rupture of aneurysms during operation is the key of success. Multiple aneurysms are better to be clipped in one stage. "de novo" aneurysms could be detected early by long-term angiography.

Adolescent↗
PubMed2001

[Transfusion transmitted virus infection in mother-to-infant transmission].

OBJECTIVE: To investigate the perinatal infection of transfusion transmitted virus (TTV) in the mother-to-infant transmission and molecular evidence. METHODS: TTV was examined in serum from 104 mothers and umbilical blood of their infants by a semi-nested polymerase chain reaction technique. TTV nucleotide sequences isolated from two sets of mother/infant pairs were analyzed. RESULTS: The TTV detection rate was 13.46% (15/104), and it was 4.81% (5/104) in the umbilical blood of their newborns. Homology analysis was done by sequencing between positions 1,915 and 2,185 of the published TTV genome, Analysis of TTV sequences from the 2 pairs of mother and infant both infected confirmed a genetic link between the virus of the infected mother and their infected infants. CONCLUSIONS: There is a possibility of vertical maternal-fetal transmission of TTV.

Adult↗