Biomedical subjects

Wenhua Liu

Publications and source records attributed to Wenhua Liu.

At least 19 recordsLinked to original sources

PubMed2006

Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin.

The noradrenergic system in the prefrontal cortex (PFC) is involved in many physiological and psychological processes, including working memory and mood control. To understand the functions of the noradrenergic system, we examined the regulation of NMDA receptors (NMDARs), key players in cognition and emotion, by alpha1- and alpha2-adrenergic receptors (alpha1-ARs, alpha2-ARs) in PFC pyramidal neurons. Applying norepinephrine or a norepinephrine transporter inhibitor reduced the amplitude but not paired-pulse ratio of NMDAR-mediated excitatory postsynaptic currents (EPSC) in PFC slices. Specific alpha1-AR or alpha2-AR agonists also decreased NMDAR-EPSC amplitude and whole-cell NMDAR current amplitude in dissociated PFC neurons. The alpha1-AR effect depended on the phospholipase C-inositol 1,4,5-trisphosphate-Ca(2+) pathway, whereas the alpha2-AR effect depended on protein kinase A and the microtubule-based transport of NMDARs that is regulated by ERK signaling. Furthermore, two members of the RGS family, RGS2 and RGS4, were found to down-regulate the effect of alpha1-AR on NMDAR currents, whereas only RGS4 was involved in inhibiting alpha2-AR regulation of NMDAR currents. The regulating effects of RGS2/4 on alpha1-AR signaling were lost in mutant mice lacking spinophilin, which binds several RGS members and G protein-coupled receptors, whereas the effect of RGS4 on alpha2-AR signaling was not altered in spinophilin-knockout mice. Our work suggests that activation of alpha1-ARs or alpha2-ARs suppresses NMDAR currents in PFC neurons by distinct mechanisms. The effect of alpha1-ARs is modified by RGS2/4 that are recruited to the receptor complex by spinophilin, whereas the effect of alpha2-ARs is modified by RGS4 independent of spinophilin.

Animals↗

PubMed2006

Expression of vitamin D3 receptor in kidney tumors.

The kidney is not only a primary vitamin D target organ but also is a key site of vitamin D metabolism. Recent studies have shown that vitamin D has important physiologic effects on proliferation and differentiation in a variety of benign and malignant cells. Our preliminary immunohistochemical study showed that vitamin D receptor (VDR) was highly expressed in renal distal tubules and collecting ducts, whereas the renal proximal tubules and glomeruli did not express VDR. These observations led us to study the expression of VDR in various kidney tumors to determine the possible diagnostic utility of VDR. Paraffin tissue microarray (TMA) blocks were constructed containing core cylinders from clear cell (52), papillary (35), chromophobe (20), sarcomatoid (20), and metastatic (59) renal cell carcinomas (RCCs). Oncocytomas (20), normal adult kidneys (12), and normal adult adrenals (6) were also included. In addition, 30 clear cell RCCs and 3 collecting duct carcinomas were also studied using conventional sections. Furthermore, VDR messenger RNA and protein expression was also quantified using real-time reverse transcriptase-polymerase chain reaction and Western blot analysis. Vitamin D receptor was strongly positive in collecting duct carcinomas (100% [3/3], cytoplasmic), papillary RCCs (94% [33/35], cytoplasmic), chromophobe RCCs (85% [17/20], membranous), and oncocytomas (90% [18/20], cytoplasmic with perinuclear accentuation). In contrast, VDR expression was focal/weak and present only in the peripheral regions of clear cell RCCs. Vitamin D receptor was weakly positive in sarcomatoid variant RCCs (88% [14/16]) regardless of the type of associated original RCC. Overall, VDR is a discriminative marker for renal cell tumors. The preferential expression of VDR in chromophobe RCCs, oncocytomas, and collecting duct carcinomas is in agreement with the concept that these tumors differentiate toward epithelium lining the distal convoluted tubules and collecting ducts. Considering the different VDR expression patterns, VDR is a useful ancillary tool in distinguishing chromophobe RCCs from oncocytomas. In addition, the focal and much weaker VDR expression in clear cell RCCs makes VDR valuable in distinguishing clear cell RCC from other types of RCCs.

Adenoma, Oxyphilic↗

PubMed2006

Inhibition of Th2-mediated allergic airway inflammatory disease by CD137 costimulation.

The engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8(+) T cells and stimulate IFN-gamma production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN-gamma and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion.

Animals↗

PubMed2006

Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen.

Ectopic expression of peripherally restricted Ags by medullary thymic epithelial cells (mTECs) is associated with negative selection. Autoimmune regulator (AIRE) is considered to be the master regulator of these Ags. We show in this study that the ectopic expression of type II collagen (CII) in mTECs and the corresponding central tolerance to CII are AIRE independent but lymphotoxin dependent. The failure to properly express CII in mTECs of Lta(-/-) and Ltbr(-/-) mice leads to overt autoimmunity to CII and exquisite susceptibility to arthritis. These findings define the existence of additional pathways of ectopic peripheral Ag expression, parallel to and independent of AIRE, which may cover an extended spectrum of peripheral Ags in the thymus.

Animals↗

PubMed2006

Parkin suppresses the expression of monoamine oxidases.

Mutations of parkin are linked to early onset Parkinson disease. Here we show that stable transfection of parkin in the human dopaminergic neuroblastoma cell line SH-SY5Y markedly reduced the activities of both monoamine oxidase (MAO) A and B. The amount of 3,4-dihydroxyphenylacetic acid, which is produced during dopamine oxidation by MAO, was greatly reduced by parkin overexpression. Radioligand binding assays showed that MAO binding sites were decreased accordingly. Consistent with these, MAO-B protein level was much lower, whereas the amount of MAO-A protein was not determined due to the lack of a suitable antibody. Co-transfection of either MAO with parkin in HEK293 cells did not significantly alter ubiquitination and degradation of each MAO. When we measured MAO expression by real-time quantitative reverse transcription-PCR, marked reductions were seen in SH-SY5Y cells stably expressing parkin compared with the parental cells or a control line stably transfected with luciferase. In addition, parkin mutants defective in E3 ligase activity exhibited different effects on MAO expression. We found that parkin also significantly decreased mRNA levels of both MAOs in the mouse fibroblast cell line NIH3T3. Furthermore, MAO expression was significantly increased in human B lymphocyte cell lines derived from Parkinson disease patients with homozygous but not heterozygous deletion of exon 4 of parkin. Together these results suggest that parkin suppresses MAO expression. This function may limit the production of reactive oxygen species generated by MAO in dopamine oxidation and would, thus, be beneficial to the survival of dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Exposure of spermatozoa to duroquinone may impair reproduction of the common carp (Cyprinus carpio) through oxidative stress.

Toxicity of many waterborne organic contaminants to aquatic organisms is mediated through oxidative damages resulting from the production of reactive oxygen species (ROS). Using duroquinone as a model ROS inducer, we carried out in vitro and in vivo experiments to test the hypothesis that reproduction in common carp (Cyprinus carpio) can be impaired through oxidative damage of their spermatozoa. In vitro exposure of fish spermatozoa to 0, 12.5, 25, 50, 100 and 200 microM duroquinone for 2 h showed a significant increase in the level of ROS in a dose-dependant manner. Sperm motility was significantly reduced in all exposure groups, but lipid peroxidation (LPO) and DNA strand break (measured by comet assay) were only enhanced at 50 microM and above. A significant decrease in subsequent hatching rate was recorded in all the exposure groups, despite fertilization rate was not affected. In the in vivo experiment, spermatozoa were collected 24 and 72 h after fish received intra-peritoneal injections of 1.0 and 10 mg kg(-1) body weight duroquinone. DNA damage was clearly evident in spermatozoa of all treatment groups after 72 h exposure, and ROS was significantly enhanced in the high concentration group. LPO however, remained unchanged in both treatment groups. The overall results of both our in vitro and in vivo experiments demonstrated that duroquinone can induce ROS production in spermatozoa, which may impair sperm quality and subsequently reproductive success through oxidative stress.

Animals↗

PubMed2006

KSHV/HHV8-associated primary cutaneous plasmablastic lymphoma in a patient with Castleman's disease and Kaposi's sarcoma.

We report a unique case of Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)/human herpesvirus (HHV)8-associated lymphoma in a 56-year-old man with a history of acquired immune deficiency syndrome, Castleman's disease, KS, and idiopathic thrombocytopenic purpura. Three months following the diagnosis of KS affecting a left cervical lymph node and Castleman's disease with bone marrow involvement, he presented with a subcutaneous, tender lesion on his left arm. A skin biopsy demonstrated a superficial and deep, interstitial-nodular infiltrate of severely atypical lymphoid cells showing plasmacytoid features, numerous mitotic figures, and frequent individual apoptotic tumor cells. The morphologic features were those of plasmablastic lymphoma (PBL). Immunohistochemical study showed that the lymphoma cells strongly expressed CD45, CD30, and KSHV/HHV8 latency-associated nuclear antigen. KSHV/HHV8 was also detected in the biopsy sections of the patient's KS and Castleman's disease. Epstein-Barr virus in situ hybridization was diffusely positive. In situ hybridization demonstrated kappa-light chain restriction. Although KSHV/HHV8 has been individually associated with KS, Castleman's disease, and PBL, this appears to be the first reported case in which all three entities were present simultaneously in one person, suggesting a critical role of KSHV/HHV8 as a common denominator in the pathogenesis of these diseases.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Fulminant liver failure after radical prostatectomy in the hyperlordotic position.

In the hyperlordotic position, the patient's hips are above the feet and head. This position has previously been associated with partial vena caval occlusion, increased venous pressures, and spinal cord infarction. We describe a case of fulminant hepatic failure after radical retropubic prostatectomy performed in the hyperlordotic position.

Fatal Outcome↗

PubMed2006

[Egg cluster pattern of two coexisting melitaeine butterfly species and oviposition site selection of their adult females].

In this study, the oviposition sites of Euphydryas aurinia and Meiltaea phoebe adult females in the same habitat network were investigated, aimed to identify the factors affecting the patch quality. The results showed that the egg-laying females of both melitaeine butterfly species preferred to oviposit in the open areas with large-sized host plants and surrounded by short vegetations, especially on warm and sunny slopes. For E. aurinia, most of its egg clusters were concentrated within the area less than 3 m to the edge of cropland, and the average distance from each egg cluster to the edge of nearest cropland was 3.55 +/- 0.33 m (n = 246); but for M. phoebe, a few of its egg clusters distributed in the area less than 3 m to the edge, and the average distance was 7.43 +/- 1.53 m (n = 25). It was suggested that the criteria to evaluate the patch quality and the conservation strategies for the two butterfly species should be different, due to their special habitat requirements of ovipositing females.

Animals↗

PubMed2005

NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors.

Natural killer (NK) cells are generally reported as innate effector cells for killing virally infected and transformed cells. It is unclear how NK cells evoke adaptive immunity to eradicate tumors. We now demonstrate that the TNF superfamily member, LIGHT, known as TNFSF14 and a T-cell costimulatory molecule, is a critical ligand for the activation of NK cells. Herpesvirus entry mediator (HVEM) is expressed on NK cells, and its engagement with LIGHT mediates NK-cell activation. The expression of LIGHT inside tumors leads to rapid rejection in a NK-dependent manner. Both NK and CD8+ cells are essential but not sufficient for the rejection of tumors because mice lacking either population fail to reject the tumor. Interestingly, activated NK cells do not kill tumors directly but can facilitate the priming of tumor-specific CD8+ T cells in an IFN-gamma-dependent manner. Conversely, intratumor depletion of either NK cells or IFN-gamma during tumor progression disrupts CD8+ cell-mediated tumor rejection, suggesting that the tumor is the essential site for the crosstalk between NK and CD8+ cells. Furthermore, IFNG-deficient NK cells fail to effectively activate CD8+ T cells, suggesting IFN-gamma plays an important role in NK-mediated activation of cytotoxic T lymphocytes (CTLs). Our findings establish a direct role for LIGHT in NK activation/expansion and a critical helper role of activated NK cells in priming CD8+ T cells and breaking T-cell tolerance at the tumor site.

Animals↗

PubMed2005

Selective vulnerability of dopaminergic neurons to microtubule depolymerization.

Parkinson disease (PD) is characterized by the specific degeneration of dopaminergic (DA) neurons in substantia nigra and has been linked to a variety of environmental and genetic factors. Rotenone, an environmental PD toxin, exhibited much greater toxicity to DA neurons in midbrain neuronal cultures than to non-DA neurons. The effect was significantly decreased by the microtubule-stabilizing drug taxol and mimicked by microtubule-depolymerizing agents such as colchicine or nocodazole. Microtubule depolymerization disrupted vesicular transport along microtubules and caused the accumulation of dopamine vesicles in the soma. This led to increased oxidative stress due to oxidation of cytosolic dopamine leaked from vesicles. Inhibition of dopamine metabolism significantly reduced rotenone toxicity. Thus, our results suggest that microtubule depolymerization induced by PD toxins such as rotenone plays a key role in the selective death of dopaminergic neurons.

Cell Death↗

PubMed2005

Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors.

Tumor environment can be critical for preventing the immunological destruction of antigenic tumors. We have observed a selective accumulation of CD4(+)CD25(+) T cells inside tumors. In a murine fibrosarcoma L(d)-expressing Ag104, these cells made up the majority of tumor-infiltrating lymphocytes at the late stage of tumor progression, and their depletion during the effector phase, rather than priming phase, successfully enhanced antitumor immunity. We show here that CD4(+)CD25(+) T cells suppressed the proliferation and interferon-gamma production of CD8(+) T cells in vivo at the local tumor site. Blockade of the effects of IL-10 and TGF-beta partially reversed the suppression imposed by the CD4(+) cells. Furthermore, local depletion of CD4(+) cells inside the tumor resulted in a change of cytokine milieu and led to the eradication of well-established highly aggressive tumors and the development of long-term antitumor memory. Therefore, CD4(+)CD25(+) T cells maintained an environment in the tumor that concealed the immunogenicity of tumor cells to permit progressive growth of antigenic tumors. Our study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.

Adoptive Transfer↗

PubMed2005

Cultured gill epithelial cells from tilapia (Oreochromis niloticus): a new in vitro assay for toxicants.

A culture gill epithelium from seawater-adapted tilapia (Oreochromis niloticus) was developed for testing PAHs and dioxin-like contaminants in seawater. The epithelia consists two to three layers of epithelial cells incorporating both pavement cells and mitochondria-rich cells (MRCs). Polarity and a stable transepithelial resistance (TER) were maintained, and closely resembled those in fish gills in vivo. The tightness (integrity) of the epithelia remained unchanged upon exposure to benzo[a]pyrene (B[a]P), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3,3',4,4',5-pentachlorobiphenyl (PCB#126), while a concentration-dependent response of EROD activity in the epithelia was induced within 18-24 h when the apical side was exposed to these toxicants. The 24 h EC50 of EROD activity was 2.77x10(-7) M for PCB#126, 1.85x10(-7) M for B[a]P and 7.38x10(-10) M for TCDD, showing that the preparation was not only sensitive to PAHs and dioxin-like compounds, but also able to produce inductive potency of AhR agonists that generally agreed with those derived from other established in vitro and in vivo systems. The results suggest that the cultured gill epithelia from seawater-adapted tilapia may serve as a simple, rapid and cost-effective tool for assessing exposure and potential effects of toxicants in marine waters.

Animals↗

PubMed2005

[Analysis on the role and endowment of virtual water in agricultural ecosystem].

Water is one of the most important components of agricultural ecosystem, and also a source of food security, which plays an essential role in ensuring sustainable food resources for a growing population. In this study, the policy relevancy of virtual water was addressed, with food production, alternative trend of import, and product condition analyzed. The results showed that an average of 10.2 x 10(9) m3 water and 27.7 x 10(6) hm2 land was transferred by imported wheat, while an average of 0.3 x 10(9) m3 water and 1.6 x 10(6) hm2 land was transferred by imported maize. The sum of virtual water equivalent was 10.5 x 10(9) m3. It's of significance to alleviate the pressure of water stress in agriculture and arable land, help to resolve water predication of food production by food imports, and compensate water endowment.

Agriculture↗

PubMed2004

Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems.

Our recent studies suggest that 1,25-dihydroxyvitamin D3 functions as an endocrine suppressor of renin biosynthesis. Genetic disruption of the vitamin D receptor (VDR) results in overstimulation of the renin-angiotensin system (RAS), leading to high blood pressure and cardiac hypertrophy. Consistent with the higher heart-to-body weight ratio, the size of left ventricular cardiomyocytes in VDR knockout (KO) mice was markedly increased compared with wild-type (WT) mice. As expected, levels of atrial natriuretic peptide (ANP) mRNA and circulating ANP were also increased in VDRKO mice. Treatment of VDRKO mice with captopril reduced cardiac hypertrophy and normalized ANP expression. To investigate the role of the cardiac RAS in the development of cardiac hypertrophy, the expression of renin, angiotensinogen, and AT-1a receptor in the heart was examined by real-time RT-PCR and immunostaining. In VDRKO mice, the cardiac renin mRNA level was significantly increased, and this increase was further amplified by captopril treatment. Consistently, intense immunostaining was detected in the left ventricle of captopril-treated WT and VDRKO mice by use of an anti-renin antibody. Levels of cardiac angiotensinogen and AT-1a receptor mRNAs were unchanged in the mutant mice. These data suggest that the cardiac hypertrophy seen in VDRKO mice is a consequence of activation of both the systemic and cardiac RAS and support the notion that 1,25-dihydroxyvitamin D(3) regulates cardiac functions, at least in part, through the RAS.

Animals↗

PubMed2004

Critical role of vitamin D in sulfate homeostasis: regulation of the sodium-sulfate cotransporter by 1,25-dihydroxyvitamin D3.

As the fourth most abundant anion in the body, sulfate plays an essential role in numerous physiological processes. One key protein involved in transcellular transport of sulfate is the sodium-sulfate cotransporter NaSi-1, and previous studies suggest that vitamin D modulates sulfate homeostasis by regulating NaSi-1 expression. In the present study, we found that, in mice lacking the vitamin D receptor (VDR), NaSi-1 expression in the kidney was reduced by 72% but intestinal NaSi-1 levels remained unchanged. In connection with these findings, urinary sulfate excretion was increased by 42% whereas serum sulfate concentration was reduced by 50% in VDR knockout mice. Moreover, levels of hepatic glutathione and skeletal sulfated proteoglycans were also reduced by 18 and 45%, respectively, in the mutant mice. Similar results were observed in VDR knockout mice after their blood ionized calcium levels and rachitic bone phenotype were normalized by dietary means, indicating that vitamin D regulation of NaSi-1 expression and sulfate metabolism is independent of its role in calcium metabolism. Treatment of wild-type mice with 1,25-dihydroxyvitamin D3 or vitamin D analog markedly stimulated renal NaSi-1 mRNA expression. These data provide strong in vivo evidence that vitamin D plays a critical role in sulfate homeostasis. However, the observation that serum sulfate and skeletal proteoglycan levels in normocalcemic VDR knockout mice remained low in the absence of rickets and osteomalacia suggests that the contribution of sulfate deficiency to development of rickets and osteomalacia is minimal.

Animals↗

PubMed2004

Priming of naive T cells inside tumors leads to eradication of established tumors.

The tumor barrier comprised of nonantigenic stromal cells may contribute to the failure of tumor rejection. The tumor-necrosis factor superfamily member LIGHT (also known as TNFSF-14) is a ligand of stromal cell-expressed lymphotoxin-beta receptor and T cell-expressed herpes viral entry mediator (HVEM). Here we show that forced expression of LIGHT in the tumor environment induces a massive infiltration of naive T lymphocytes that correlates with an upregulation of both chemokine production and expression of adhesion molecules. Activation of these infiltrating T cells, possibly through HVEM, leads to the rejection of established, highly progressive tumors at local and distal sites. Our study indicates that targeting the tumor barrier may be an effective strategy for cancer immunotherapy.

Animals↗

PubMed2004

Functional expression and characterization of four novel neurotoxins from sea anemone Anthopleura sp.

The genes of four novel neurotoxins, named Hk2a, Hk7a, Hk8a, and Hk16a, were obtained from sea anemone Anthopleura sp. All four neurotoxins were composed of 47 amino acid residues and the variable residues among them were found in positions 14, 22, 25, and 37. To study their activities, the four toxins fused to the Escherichia coli thioredoxin were overexpressed by BL21 (DE3), cleaved off from the fusion partner, purified, and characterized with MALDI-TOF and CD assays. Contractile force studies of isolated SD atria indicated that rHk2a had the strongest and rHk7a the longest heart stimulation effect. Consequently, the Arg14, a highly conserved residue in various sea anemone neurotoxins, can be inferred to contribute to the duration but not the intensity of contraction-stimulating activity. Our work renders useful information to studies of sea anemone neurotoxins, especially to the clarification of the function of the disputative Arg14.

Amino Acid Sequence↗