Biomedical subjects

Hua Zhu

Publications and source records attributed to Hua Zhu.

At least 19 recordsLinked to original sources

PubMed2025

A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.

Transfer RNA-derived small RNAs (tsRNAs or tDRs) perform a range of cellular functions. Here, we showed that tRNA-Asp-GTC-3'tDR, a hypoxia-induced tDR derived from the 3' end of tRNA-Asp-GTC, activated autophagic flux in kidney cells and its silencing blocked autophagic flux. Functional gain-/loss-of-function studies in murine kidney disease models demonstrated a substantial renoprotective function of tRNA-Asp-GTC-3'tDR. Mechanistically, tRNA-Asp-GTC-3'tDR assembled stable G-quadruplex structures and sequestered pseudouridine synthase 7 (PUS7), preventing catalytic pseudouridylation of histone mRNAs. The resulting pseudouridylation deficiency directed histone mRNAs to the autophagosome-lysosome pathway, triggering RNA autophagy. This tDR-induced RNA autophagy pathway was activated during murine and human kidney diseases, suggesting clinical relevance. Thus, tRNA-Asp-GTC-3'tDR plays a role in regulating RNA autophagy, which helps to maintain homeostasis in kidney cells and protects against kidney injury.

Animals↗

PubMed2025

Comprehensive assessment of genomic heterogeneity, coalterations, and outcomes of patients with colorectal cancer: An AACR GENIE project analysis.

INTRODUCTION: Colorectal cancer remains a leading cause of cancer mortality in the United States and can be characterized by racial and sex-based disparities. The objective of the current study was to characterize the genomic heterogeneity of colorectal cancer among diverse demographic groups, assess coalteration patterns and their impact on long-term outcomes among patients with colorectal cancer. METHODS: Data from the American Association for Cancer Research GENIE registry were analyzed to assess genomic alterations in colorectal cancer. The cohort included 20,542 samples from 19,542 patients, stratified by race or ethnicity, sex, and age of onset (<50 years for early-onset colorectal cancer). Genomic alterations and coalterations among the 48 most prevalent loci were evaluated for any association with overall survival in an external Memorial Sloan Kettering Cancer Center cohort. RESULTS: Among 19,542 patients, KRAS mutations were more prevalent among Black patients (57.1%) compared with White (41.8%) and Asian (43.4%) patients (P < .001), whereas TP53 alterations were more frequent among Asian (75.6%) than White (69.9%) or Black (71.9%) patients (P < .001). Coalterations with KRAS were associated with improved survival over KRAS alteration alone, a pattern less-frequently observed among Black patients. Sex-based differences were also observed, with BRAF mutations more prevalent among females (14.6% vs 9.7%; P < .001) and TP53 mutations more common among males (73% vs 70.5%;P = .009). Although KRAS alterations tended to co-occur with alterations in ATM, ARID1A, CREBBP, FAT1, KMT2B, and KMT2D genes among patients with "early onset" colorectal cancer (all p & q < 0.05), alterations of these gene pairs were mutually exclusive among individuals with late onset colorectal cancer. CONCLUSION: Genomic alterations and coalteration patterns varied relative to race/ethnicity, sex, and age at disease onset. Differences in genomic alteration patterns of colorectal cancer somatic tumor cells are an important consideration to help address disparities among different demographic groups.

Humans↗

PubMed2006

Dissecting the signaling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model.

Nicotine has a therapeutic benefit in treating Alzheimer's disease (AD). In the present study we show that nicotine decreases accumulation of beta-amyloid (Abeta) in the cortex and hippocampus of APP (V717I) transgenic mice. Nicotine prevents activation of NF-kappaB and c-Myc by inhibiting the activation of MAP kinases (MAPKs). As a result, the activity of inducible NOS and the production of NO are down-regulated. RNA interference experiments show that the above nicotine-mediated process requires alpha7 nAChR. Nicotine decreases Abeta via the activation of alpha7nAChRs through MAPK, NF-kappaB, and c-myc pathways. Nicotine also inhibits apoptosis and cell cycle progression in this mouse line. The dissected signaling pathway of nicotine-mediated neuroprotection in the present study provides a mechanistic basis for the potential development of drug targets for treating AD.

Alzheimer Disease↗

PubMed2006

Bone-marrow-derived mesenchymal stem cells as a target for cytomegalovirus infection: implications for hematopoiesis, self-renewal and differentiation potential.

Mesenchymal stem cells (MSCs) in bone marrow (BM) regulate the differentiation and proliferation of adjacent hematopoietic precursor cells and contribute to the regeneration of mesenchymal tissues, including bone, cartilage, fat and connective tissue. BM is an important site for the pathogenesis of human cytomegalovirus (HCMV) where the virus establishes latency in hematopoietic progenitors and can transmit after reactivation to neighboring cells. Here we demonstrate that BM-MSCs are permissive to productive HCMV infection, and that HCMV alters the function of MSCs: (i) by changing the repertoire of cell surface molecules in BM-MSCs, HCMV modifies the pattern of interaction between BM-MSCs and hematopoietic cells; (ii) HCMV infection of BM-MSCs undergoing adipogenic or osteogenic differentiation impaired the process of differentiation. Our results suggest that by altering BM-MSC biology, HCMV may contribute to the development of various diseases.

Bone Marrow Cells↗

PubMed2006

Activation of platelet alphaIIbbeta3 by an exogenous peptide corresponding to the transmembrane domain of alphaIIb.

A transmembrane domain heterodimer, acting in concert with a membrane-proximal cytoplasmic domain clasp, is thought to maintain integrins in a low affinity state. To test whether helix-helix interactions between the alphaIIb and beta3 transmembrane domains regulate the activity of integrin alphaIIbbeta3, we synthesized a soluble peptide corresponding to the alphaIIb transmembrane domain, designated alphaIIb-TM, and we studied its ability to affect alphaIIbbeta3 activity in human platelets. alphaIIb-TM was alpha-helical in detergent micelles and phospholipid vesicles, readily inserted into membrane bilayers, bound to intact purified alphaIIbbeta3, and specifically associated with the transmembrane domain of alphaIIb, rather than the transmembrane domains of beta3, alpha2, and beta1, other integrin subunits present in platelets. When added to suspensions of gel-filtered platelets, alphaIIb-TM rapidly induced platelet aggregation that was not inhibited by preincubating platelets with the prostaglandin E(1) or the ADP scavenger apyrase but was prevented by the divalent cation chelator EDTA. Furthermore, alphaIIb-TM induced fibrinogen binding to platelets but not the binding of osteopontin, a specific ligand for platelet alphavbeta3. The peptide also induced fibrinogen binding to recombinant alphaIIbbeta3 expressed by Chinese hamster ovary cells, confirming that its effect was independent of platelet signal transduction. Finally, transmission electron microscopy of purified alphaIIbbeta3 revealed that alphaIIb-TM shifted the integrin from a closed configuration with its stalks touching to an open configuration with separated stalks. These observations demonstrate that transmembrane domain interactions regulate integrin function in situ and that it is possible to target intra-membranous protein-protein interactions in a way that can have functional consequences.

Animals↗

PubMed2006

Regulation of A Disintegrin And Metalloproteinase with ThromboSpondin repeats-1 expression in human endometrial stromal cells by gonadal steroids involves progestins, androgens, and estrogens.

CONTEXT: Gonadal steroids are key regulators of the extracellular matrix remodeling events that occur in the human endometrium during each menstrual cycle. The spatiotemporal expression of A Disintegrin And Metalloproteinase with ThromboSpondin repeats (ADAMTS)-1 in human endometrial stroma in vivo suggests that this novel metalloproteinase may contribute to this tightly regulated developmental process. OBJECTIVE: The objective of the study was to determine whether progesterone (P4), 17beta-estradiol (E2), or the nonaromatizable androgen dihydrotestosterone (DHT), alone or in combination, is capable of regulating ADAMTS-1 mRNA and protein levels in human endometrial stromal cells in a concentration- and time-dependent manner. DESIGN: A real-time quantitative PCR strategy and Western blotting were used to examine ADAMTS-1 mRNA and protein expression levels in primary cultures of human endometrial stromal cells. RESULTS: P4 and DHT but not E2 increased the levels of the ADAMTS-1 mRNA transcript and protein species (110 kDa) present in endometrial stromal cells in vitro in a concentration- and time-dependent manner. A combination of P4 and DHT resulted in an additional increase in stromal ADAMTS-1 expression, whereas E2 attenuated the regulatory effects of P4 and DHT in a concentration-dependent manner. The antisteroidal compounds, mifepristone (RU486) and hydroxyflutamide, were also found to inhibit specifically the P4- and DHT-mediated increase in ADAMTS-1 mRNA and protein expression levels in these primary cell cultures in a concentration-dependent manner, respectively. CONCLUSIONS: These studies demonstrate that progestins, androgens, and estrogens, alone and in combination, have distinct regulatory effects on ADAMTS-1 mRNA and protein expression levels in human endometrial stromal cells in vitro.

ADAM Proteins↗

PubMed2006

Ab initio potential energy surface and predicted microwave spectra for Ar--OCS dimer and structures of Arn--OCS (n = 2-14) clusters.

An ab initio potential energy surface for the Ar--OCS dimer was calculated using the coupled-cluster singles and doubles with noniterative inclusion of connected triples [CCSD(T)] with a large basis set containing bond functions. The interaction energies were obtained by the supermolecular approach with the full counterpoise correction for the basis set superposition error. The CCSD(T) potential was found to have two minima corresponding to the T-shaped and the collinear Ar--SCO structures. The two-dimensional discrete variable representation method was employed to calculate the rovibrational energy levels for five isotopomers Ar--OCS, Ar--OC34S, Ar--O13CS, Ar--18OCS, and Ar--17OCS. The calculated pure rotational transition frequencies for the vibrational ground state of the five isotopomers are in good agreement with the observed values. The corresponding microwave spectra show that the b-type transitions (Delta Ka = +/-1) are significantly stronger than the a-type transitions (Delta Ka = 0). Minimum-energy structures of the Ar2--OCS trimer were been determined with MP2 optimization, whereas the minimum-energy structures of the Arn--OCS clusters with n = 3-14 were obtained with the pairwise additive potentials. It was found that there are two minima corresponding to one distorted tetrahedral structure and one planar structure for the ternary complex. The 14 nearest neighbor Ar atoms form the first solvation shell around the OCS molecule.

Journal Article↗

PubMed2006

JC virus detection in bodily fluids: clues to transmission.

JC virus in saliva, oropharyngeal fluid, blood, and urine samples obtained from 58 human immunodeficiency virus-infected persons and 58 matched controls was investigated by performing quantitative polymerase chain reaction. JC virus was rarely present in oropharyngeal fluid and blood samples, even in those obtained from immunosuppressed individuals, but it was commonly detected in urine samples from both groups, suggesting that urine contributes to transmission.

Adult↗

PubMed2006

Development of the human nucleus of the solitary tract: a cyto- and chemoarchitectural study.

The present study investigated the prenatal development of the cyto- and chemoarchitecture of the human nucleus of the solitary tract from 9 to 35 weeks, by using Nissl staining and immunoreactivity to calbindin, calretinin, tyrosine hydroxylase and GAP-43. The nucleus began to gain heterogeneity and show different subnuclei as early as 13 weeks, and approached cytoarchitectural maturation from 21 to 25 weeks. The subnuclear division pattern observed in the fetal nucleus of the solitary tract at 25 weeks was very similar to that of the adult. Neurons immunoreactive to calbindin first appeared in the medial gastrointestinal area of the nucleus at 13 weeks, particularly within a putative gelatinosus subnucleus, while calretinin immunoreactivity during fetal life suggested the possible presence of a central subnucleus. Tyrosine hydroxylase immunoreactive neurons were seen in the medial subdivisions of the nucleus of the solitary tract as early as 13 weeks, but the population continued to increase until 25 weeks. Strong GAP-43 immunoreactivity was also present in the nucleus of the solitary tract at 13 weeks, especially in the dorsolateral and commissural subnuclei, while at 21 weeks there was a significant decline of GAP-43 expression. Results from the chemoarchitectural study showed that the human nucleus of the solitary tract expressed various neurochemical substances at an early developmental age (13 weeks), even before cellular and neuropil maturation was fully attained. Expression of these factors may play an important role in establishment and integration of viscerosensory function in the nucleus.

Aborted Fetus↗

PubMed2006

Differential effects of interleukin-1beta and transforming growth factor-beta1 on the expression of the inflammation-associated protein, ADAMTS-1, in human decidual stromal cells in vitro.

BACKGROUND: The pro-inflammatory cytokine, interleukin-1 beta (IL-1beta) promotes the proteolytic degradation of the extracellular matrix (ECM) of maternal decidua, a critical step in pregnancy that is counterbalanced by the expression of the anti-inflammatory cytokine, transforming growth factor-beta 1 (TGF-beta1). Recently, the inflammation-associated protein, ADAMTS-1, a member of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin repeats) gene family of metalloproteinases has been assigned a central role in the formation and organization of tissues. In view of these observations, we have hypothesized that ADAMTS-1 contributes to the cytokine-mediated remodelling of decidual ECM. METHODS: The spatiotemporal expression of ADAMTS-1 in human endometrium was examined by immunohistochemistry. A quantitative-competitive (QC)-PCR strategy and western blot analysis was then employed to determine whether IL-1beta and TGF-beta1 regulate ADAMTS-1 mRNA and protein expression levels in primary cultures of stromal cells isolated from first trimester decidua. RESULTS: ADAMTS-1 expression is associated with decidualization of the endometrial stroma in vivo. IL-1beta increased whereas TGF-beta1 decreased ADAMTS-1 mRNA and protein levels in decidual stromal cell cultures in a concentration- and time-dependent manner. These regulatory effects were attenuated by function-perturbing antibodies specific for either cytokine. CONCLUSION: IL-1beta and TGF-beta1 differentially regulate ADAMTS-1 expression in human decidual stromal cells.

ADAM Proteins↗

PubMed2006

Nicotine attenuates beta-amyloid-induced neurotoxicity by regulating metal homeostasis.

Nicotine reduces beta-amyloidosis and has a beneficial effect against Alzheimer's disease (AD), but the underlying mechanism is not clear. The abnormal interactions of beta-amyloid (Abeta) with metal ions such as copper and zinc are implicated in the process of Abeta deposition in AD brains. In the present study, we investigated the effect of nicotine on metal homeostasis in the hippocampus and cortex of APP(V717I) (London mutant form of APP) transgenic mice. A significant reduction in the metal contents of copper and zinc in senile plaques and neuropil is observed after nicotine treatment. The densities of copper and zinc distributions in a subfield of the hippocampus CA1 region are also reduced after nicotine treatment. We further studied the mechanism of nicotine-mediated effect on metal homeostasis by using SH-SY5Y cells overexpressing the Swedish mutant form of human APP (APPsw). Nicotine treatment decreases the intracellular copper concentration and attenuates Abeta-mediated neurotoxicity facilitated by the addition of copper, and these effects are independent of the activation of nicotinic acetylcholine-receptor. These data suggest that the effect of nicotine on reducing beta-amyloidosis is partly mediated by regulating metal homeostasis.

Amyloid beta-Peptides↗

PubMed2006

Type III secretion system-associated toxins, proteases, serotypes, and antibiotic resistance of Pseudomonas aeruginosa isolates associated with keratitis.

The association between possession of toxin gene-related type III secretory system, protease profiles, O serotypes, and antibiotic resistance patterns was characterized genetically and phenotypically in 46 keratitis isolates of Pseudomonas aeruginosa. There was no significant difference in exoU or exoS prevalence among the keratitis strains. Distinct protease profiles were seen in isolates harboring either exoU or exoS genes. One hundred percent (13/13) of serotype E (O:11) strains contained type III secretion system-associated cytotoxin gene exoU. Multidrug resistance was identified in 4% of Australian and 29% of Indian isolates. None of the Australian isolates was resistant to ciprofloxacin. In general, the rate of multidrug resistance in the exoU positive cytotoxic and serotype E (O:11) strains was significantly higher than in exoS positive invasive strains (p < 0.01). The results suggest that multidrug resistance may be more commonly associated with the corneal isolates of P. aeruginosa having type III secretion system-associated cytotoxin gene exoU and belonging to serotype E (O:11) group.

ADP Ribose Transferases↗

PubMed2006

Protease IV production in Pseudomonas aeruginosa from the lungs of adults with cystic fibrosis.

Protease IV is important in the pathogenesis of Pseudomonas aeruginosa-induced microbial keratitis, but little is known of its role in cystic fibrosis (CF) lung infection. In this study protease IV production was examined in 43 P. aeruginosa isolates (24 non-clonal and 19 clonal) from the lungs of chronically infected adult patients attending the Royal Prince Alfred Hospital CF Clinic, Sydney, Australia. Overall, 32/43 (74 %) isolates were positive for protease IV protein by Western blotting and 22/43 (51 %) had evidence of active protease IV on gelatin zymography. Clonal strains were 1.6 times more likely than non-clonal strains to produce protease IV [18/19 (95 %) versus 14/24 (58 %), RR=1.6, CI 1.1-2.3, P=0.007] and 3 times more likely to secrete the protein [16/19 (84 %) versus 6/24 (25 %), RR=3.4, CI 1.6-6.9, P<0.001]. Nine of the ten strains negative by both Western blotting and zymography were non-clonal, and all but one of these was positive for the protease IV gene. There was a marked strain-to-strain variation in the amount of protease IV produced. Secretion of protease IV by clonal strains may enhance their infectivity and ability to adapt to the changing CF lung environment. Overall the findings suggest that protease IV plays an important role in the pathogenesis of P. aeruginosa infection in the CF lung.

Adolescent↗

PubMed2006

High prevalence of multiple human herpesviruses in saliva from human immunodeficiency virus-infected persons in the era of highly active antiretroviral therapy.

Human immunodeficiency virus (HIV) infection is associated with an increased risk for human herpesviruses (HHVs) and their related diseases. Methods for limiting the transmission of HHVs require a better understanding of the prevalence and infectiousness of oral HHVs in HIV-infected patients. We performed quantitative PCR to investigate the prevalence, quantity, risk, and correlates of salivary HHVs from 58 HIV-seropositive individuals in a case control study. HHVs were significantly more prevalent in the salivas of HIV-seropositive persons than in those of the controls (odds ratios [ORs], 4.2 to 26.2; P<or=0.008). In HIV-infected patients, Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), cytomegalovirus (CMV), and herpes simplex virus type 1 (HSV-1) were detected in 90%, 57%, 31% and 16% of samples, respectively, compared with 48%, 24%, 2%, and 2%, respectively, of samples from controls. Multiple HHVs were observed in 71% of HIV-seropositive persons and only 16% of controls (OR, 13.0; 95% confidence interval, 5.29 to 32.56). HIV-positive patients had significantly higher EBV loads than HIV-negative persons (P<0.0001). HIV-infected patients with CD4 counts above 200 cells/microl had increased probability for having HHV-8 in saliva (P=0.009) compared with patients whose counts were less than 200. In contrast, HSV-1, EBV, and CMV were detected more often when CD4 counts were low. High salivary HHV loads were detected for those (n=7) with oral lesions. These findings suggest that saliva is a potential risk factor for the acquisition of multiple HHVs, and several host factors may function to accelerate HHV reactivation or replication in patients with HIV infection.

Adult↗

PubMed2006

Salicylic acid reduces the production of several potential virulence factors of Pseudomonas aeruginosa associated with microbial keratitis.

PURPOSE: Pseudomonas aeruginosa is a common cause of contact-lens-related microbial keratitis. This bacterium is becoming increasingly resistant to antibiotics, and even if the infection can be treated with antibiotics, damage to the cornea resulting from the combined effect of bacteria and host factors can lead to loss of vision. The purpose of this study was to test the effect of salicylic acid on the production of potential virulence factors during the growth of P. aeruginosa. METHODS: Bacterial cells were grown in a subinhibitory concentration of salicylic acid, and supernatants were collected and analyzed for presence of proteases by using zymography and hydrolysis of chromogenic substrates. The supernatants were also analyzed for the amount of acetylated homoserine lactones by using bacterial reporter strains. Pseudomonas cells from salicylic acid cultures were analyzed for their twitching and swimming motility as well as their ability to invade or cause the death of corneal epithelial cells. RESULTS: Growth in a subinhibitory concentration of salicylic acid resulted in a significant reduction in the number of bacterial cells and a reduction in the rate of the number of bacteria increasing during logarithmic growth, but the time to reach the stationary phase of growth was unchanged. These changes in growth pattern affected the amount of acylated homoserine lactones produced by P. aeruginosa 6294. Also affected by growth in salicylic acid was the ability of strain 6294 to show twitching or swimming motility. Salicylic acid also reduced the invasion of strain 6294 into corneal epithelial cells and the epithelial cell death caused by strain 6206. Furthermore, production of proteases by P. aeruginosa was significantly reduced by growth in salicylic acid. CONCLUSIONS: The results of this study clearly demonstrate that salicylic acid has a significant impact on several potential virulence factors of P. aeruginosa that may be involved in the production of microbial keratitis. These effects were probably mediated by reduction in the cell density and concomitant reduction in the quorum-sensing signaling molecules, the acylated homoserine lactones, produced by P. aeruginosa.

4-Butyrolactone↗

PubMed2006

[Ecological functional regionalization of Changsha City based on RS and GIS].

A delineation method based on the idea of regarding urban-suburban-supporting area as a system was presented in this paper, with an ecological-social-economic database created. A total of five ecological suitability regions, four ecological sensitivity regions, four ecological service regions, and five economic development regions were plotted out, and the Changsha City ecosystem was divided into five ecological functional regions, according to the heterogeneity among ecological functional units and the similarity of interior units. The areas of the five functional regions accounted for 29.47%, 32.5%, 25.95%, 9.63% and 2.45% of the total area, respectively. This research method had some advantages over traditional methods. It was flexible and efficient, because it could accept any combination of parameters organized on a polygonal base map. The variables could be added, deleted, or updated to produce new thematic map products in a short period of time. Mapping procedures were quantitative and automated. With the incorporation of remote sensing data and global position system rapid positioning, the ecological and environmental changes could be detected by monitoring the changes of regional boundary patterns. Therefore, the ecological functional regionalization of Changsha City provided a fine way of integrating remote sensing data, global position system, and geographic information system.

China↗

PubMed2005

Using DNA microarray to study human cytomegalovirus gene expression.

DNA microarray technology has become one of the most widely used tools for functional genomics and is playing an ever increasing role in the study of viral infections and host-pathogen interactions. This paper describes the development of an oligonucleotide microarray representing all the predicted open reading frames of the human cytomegalovirus (HCMV) and an established protocol for simultaneously measuring the expression of all HCMV genes. To evaluate the performance of the HCMV array, human foreskin fibroblasts were either mock infected or infected with the HCMV AD169 or Toledo strains. Hybridizations were performed to determine the level of detection of HCMV transcripts from both the AD169 and Toledo strains and to assess reproducibility within and between slides. Overall, approximately 95% of the predicted HCMV genes produced detectable levels of mRNA, with median signal to noise and signal to background ratios of 41 and 14, respectively. Scatter plots of samples within an array and between two arrays resulted in average linear regressions above 0.95 and 0.9, respectively, indicating that data from the arrays are highly reproducible. In addition, transcripts from genes found in the Toledo strain but not in AD169 were specifically detected.

Cell Line↗

PubMed2005

Development of the human superior colliculus and the retinocollicular projection.

We have used carbocyanine dye tracing from the brachium of the superior colliculus in conjunction with Nissl staining and immunohistochemistry to GAP-43 and calretinin to study the development of retinal projections to the superior colliculus in 17 human embryos and fetuses aged from 8 to 28 weeks. Lamination of the superior colliculus begins to emerge by 11 weeks, and by 16 weeks all seven layers of the mature superior colliculus are visible. Fibres immunoreactive to GAP-43 were seen at 13 weeks in the most superficial layers. By 19 weeks, GAP-43 immunoreactivity was present in the stratum opticum as well as the deeper fibres layers, indicating the development of fibre pathways following those laminae. Carbocyanine dye tracing of retinocollicular projections showed extensive rostrocaudally running unbranched fibres in the superficial superior colliculus at 12 weeks. Shortly after this (13 weeks), retinocollicular fibres penetrate the deeper collicular layers and branching becomes apparent. We also saw occasional retrogradely labelled somata following DiI insertion into the superior brachium. Our findings indicate that development of the human superior colliculus and its connections is largely complete by 20 weeks. This would suggest that functional capacity of the human superior colliculus should also be mature by the middle of gestation.

Calbindin 2↗