Biomedical subjects

Jinhui Wang

Publications and source records attributed to Jinhui Wang.

15 recordsLinked to original sources

PubMed2026

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.

RATIONALE: Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the "Death-from-Cancer" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer. METHODS: A conditional Usp22 knockout (Usp22-KO) was generated in the KRASG12D; p53-/- (KP) mouse model. Cancer progression was monitored by micro-computed tomography (micro-CT). Multiplex immunofluorescence (mIF), RNA sequencing, and spatial transcriptomics profiled cancer and tumor microenvironment (TME) changes. Responses to anti-PD-1/PD-L1 therapies were compared between KP and Usp22-KO KP (KPU-) lung cancers. RESULTS: USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers. CONCLUSIONS: USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.

Animals↗

PubMed2006

A quantitative kinetic model for ATP-induced intracellular Ca2+ oscillations.

A quantitative kinetic model is proposed to simulate the ATP-induced intracellular Ca(2+) oscillations. The quantitative effect of ATP concentration upon the oscillations was successfully simulated. Our simulation results support previous experimental explanations that the Ca(2+) oscillations are mainly due to interaction of Ca(2+) release from the endoplasmic reticulum (ER) and the ATP-dependent Ca(2+) pump back into the ER, and the oscillations are prolonged by extracellular Ca(2+) entry that maintains the constant Ca(2+) supplies to its intracellular stores. The model is also able to simulate the sudden disappearance phenomenon of the Ca(2+) oscillations observed in some cell types by taking into account of the biphasic characteristic of the Ca(2+) release from the endoplasmic reticulum (ER). Moreover, the model simulation results for the Ca(2+) oscillations characteristics such as duration, peak [Ca(2+)](cyt), and average interval, etc., lead to prediction of some possible factors responsible for the variations of Ca(2+) oscillations in different types of cells.

Adenosine Triphosphate↗

PubMed2006

Phenotypic and functional status of intrahepatic T cells in chronic hepatitis C.

Polychromatic flow-cytometric assays were used to analyze paired intrahepatic and peripheral lymphocyte samples from 37 patients with chronic hepatitis C. Compared with peripheral cells, intrahepatic T cells were selectively enriched with CD45RO+ memory T cells but had a lower percentage of CD4+ T cells expressing the differentiation markers CD27 and CD28. The percentage of intrahepatic CD45RO+ and CD28+ T cells correlated with the degree of liver inflammation, which suggests that memory T cells at relatively early stages of differentiation are directly involved in liver inflammation. Despite their memory phenotype, intrahepatic T cells were defective in proliferation capability, produced less interferon- gamma in response to stimulation by T cell receptor, and contained less perforin but expressed higher levels of Fas and Fas ligand, compared with their counterparts in peripheral blood. The distinct characteristics of intrahepatic T cells suggest that they play an important role in the immunopathogenesis of chronic hepatitis C.

Adult↗

PubMed2006

Afterhyperpolarization improves spike programming through lowering threshold potentials and refractory periods mediated by voltage-gated sodium channels.

Neurons program various patterns of sequential spikes as neural codes to guide animal behavior. Studies show that spike programming (capacity and timing precision) is influenced by inhibitory synaptic inputs and membrane afterhyperpolarization (AHP). Less is clear about how these inhibitory components regulate spike programming, which we investigated at the cortical neurons. Whole-cell current-clamp recording for action potentials and single channel recording for voltage-gated sodium channels (VGSC) were conducted at regular-spiking and fast-spiking neurons in the cortical slices. With quantifying the threshold potentials and refractory periods of sequential spikes, we found that fast-spiking neurons expressing AHP possess lower threshold potentials and shorter refractory periods, and the hyperpolarization pulse immediately after each of spikes lowers threshold potentials and shortens refractory periods at regular-spiking neurons. Moreover, the hyperpolarization pulses shorten the refractory periods for VGSC reactivation and threshold potentials for its sequential activation. Our data indicate that inhibitory components immediately after spikes, such as AHP and recurrent inhibition, improve spike capacity and timing precision via lowering the refractory periods and threshold potentials mediated by voltage-gated sodium channels.

Action Potentials↗

PubMed2006

The postnatal development of refractory periods and threshold potentials at cerebellar Purkinje neurons.

Cerebellum is involved in the motion coordination and working memory, to which spike programming at Purkinje neurons are essential. The development of Purkinje neurons in the embryonic stage has been well studied. However, it is not clear about the maturation of their intrinsic property related to spike programming during postnatal period. We developed the approach to quantify the intrinsic property of sequential spikes with whole-cell recording, and analyzed the postnatal development of Purkinje neurons in cerebellar slices. Our results demonstrate that the threshold potentials shift toward more negatively than resting membrane potential, refractory periods following each of spikes decrease, as well as the relationship between refractory periods and inter-spike intervals converts to be more linear during the postnatal maturation. This postnatal plasticity of neuronal intrinsic properties enhances the firing ability and spike capacity, in turn strengthens spike programming, at cerebellar Purkinje neurons.

Action Potentials↗

PubMed2006

Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy.

Manganese superoxide dismutase (MnSOD) is a latent tumor suppressor gene. To investigate the therapeutic effect of MnSOD and its mechanisms, a replication-competent recombinant adenovirus with E1B 55-kDa gene deletion (ZD55) was constructed, and human MnSOD and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes were inserted to form ZD55-MnSOD and ZD55-TRAIL. ZD55-MnSOD exhibited an inhibition in tumor cell growth approximately 1,000-fold greater than Ad-MnSOD. ZD55-TRAIL was shown to induce the MnSOD expression in SW620 cells. Accordingly, by the combined use of ZD55-MnSOD with ZD55-TRAIL (i.e., "dual gene virotherapy"), all established colorectal tumor xenografts were completely eliminated in nude mice. The evidence exists that the MnSOD overexpression led to a slower tumor cell growth both in vitro and in vivo as a result of apoptosis caused by MnSOD and TRAIL overexpression after adenoviral transduction. Our results showed that the production of hydrogen peroxide derived from MnSOD dismutation activated caspase-8, which might down-regulate Bcl-2 expression and induce Bax translocation to mitochondria. Subsequently, Bax translocation enhanced the release of apoptosis-initiating factor and cytochrome c. Cytochrome c finally triggered apoptosis by activating caspase-9 and caspase-3 in apoptotic cascade. Bax-mediated apoptosis seems to be dependent on caspase-8 activation because the inhibition of caspase-8 prevented Bid processing and Bax translocation. In conclusion, our dual gene virotherapy completely eliminated colorectal tumor xenografts via enhanced apoptosis, and this novel strategy points toward a new direction of cancer treatment.

Adenoviridae↗

PubMed2005

The refractory periods and threshold potentials of sequential spikes measured by whole-cell recording.

Neurons in the central nervous system are thought to program neural language via firing sequential spikes for guiding animal behaviors. The quantitative profiles of spike intrinsic properties are critically important to understand spike programming. We developed approaches with whole-cell recordings to measure the threshold potentials and refractory periods (RPs) of sequential spikes, and to analyze the relationships of these factors with spike timing precision and capacity at the regular-spiking and fast-spiking neurons in cortical slice. The RPs and threshold potentials of sequential spikes at these two groups of neurons are different and are linearly correlated with spike timing precision and capacity. These data suggest that RPs and threshold potentials essentially navigate the spike programming for the precise and loyal encoding of meaningful neural signals. Our study provides the avenues for decoding the spectrum of the neural signals quantitatively.

Action Potentials↗

PubMed2005

Suppression of morphine withdrawal syndrome by interleukin-2 and its gene.

The naloxone-precipitated withdrawal syndrome in mice and rats after intrathecal injection of recombinant human interleukin-2 protein (rIL-2) or its gene was studied. The results showed that rIL-2 could significantly decrease the number of jumps in mice. In rats, rIL-2 significantly suppressed irritating, diarrhea, weight loss, abnormal posture and salivation. Tendencies towards reductions in teeth chewing and dog-shaking were also observed. Furthermore, pcDNA3-IL-2 (8 microg DNA) had a similar effect as 1x10 IU rIL-2 protein on inhibition of morphine withdrawal syndrome in mice, and the expression of rIL-2 protein in spinal cord could be detected for 6 days. These findings provided further evidence for the neuroregulatory function of an immunological molecule such as IL-2.

Animals↗

PubMed2005

Suppression of tumor growth by oncolytic adenovirus-mediated delivery of an antiangiogenic gene, soluble Flt-1.

Armed oncolytic adenoviruses represent an appealing tumor treatment approach, as they can attack tumors at multiple levels. In this study, considering that angiogenesis plays a central role in tumor growth, we inserted an antiangiogenic gene, sflt-1(1-3) (the first three extracellular domains of FLT1, the hVEGF receptor-1), into an E1B-55-kDa-deleted oncolytic adenovirus (ZD55) to construct ZD55-sflt-1. Although soluble (s) Flt-1 did not affect tumor cell growth, ZD55-sflt-1 could specifically induce a cytopathic effect in tumor cells, like ONYX-015. The secretion of sFlt-1 from ZD55-sflt-1 was much higher than that from replication-deficient Ad-sflt-1 upon infection of SW620 human colon tumor cells, leading to a stronger inhibitory effect on VEGF-induced proliferation and tube formation ability of HUVECs. Moreover, marked reduction of tumor growth and long-term survival rates were observed in ZD55-sflt-1-treated nude mice with subcutaneous SW620 tumor. Its efficacy correlated with a decrease in microvessel density and an increase in apoptotic tumor cells. In addition, ZD55-sflt-1 showed a synergic effect with the chemotherapeutic agent 5-FU. These results indicate that ZD55-sflt-1, combining the advantages of oncolytic adenovirus and antiangiogenic gene therapy, is a powerful agent for human tumor treatment.

Adenoviridae↗

PubMed2004

Expression of chemokine receptors on intrahepatic and peripheral lymphocytes in chronic hepatitis C infection: its relationship to liver inflammation.

BACKGROUND: Intrahepatic lymphocytes are believed to be directly involved in the immunopathogenesis of chronic liver diseases. Little is known about the trafficking of lymphocytes into the liver and their role in chronic hepatitis C infection. METHODS: The expression of 4 chemokine receptors and an activation marker on multiple lymphocyte subsets in paired liver biopsy and peripheral blood specimens from 23 patients with chronic hepatitis C infection were analyzed by a 6-color flow-cytometric assay. RESULTS: CCR5, CXCR3, and CXCR6 were expressed on intrahepatic CD4+ and CD8+ T cells, natural killer (NK) T cells, NK cells, and B cells at significantly higher frequencies than on peripheral lymphocyte subsets. The expression of these receptors and the activation marker CD38 tended to increase with the severity of liver inflammation. This increase was significant for several intrahepatic lymphocytes subsets. Correlations in expression differed among pairs of these extralymphoid homing receptors on the intrahepatic T cells. CONCLUSIONS: The homing program for intrahepatic lymphocytes involves multiple extralymphoid chemokine receptors that are regulated by >1 pathway. The expression of homing receptors on intrahepatic lymphocytes is associated with the immunopathogenesis of chronic hepatitis C disease. These preliminary results indicate that confirmational studies with larger sample sizes are warranted.

ADP-ribosyl Cyclase↗

PubMed2004

Combination of Targeting Gene-ViroTherapy with 5-FU enhances antitumor efficacy in malignant colorectal carcinoma.

To improve the therapeutic effect of ONYX015, an E1B55kD-deleted replication-competent adenovirus, ZD55 was constructed and armed with the therapeutic gene hTRAIL to form ZD55-hTRAIL, which was used for cancer therapy and which we call Targeting Gene-ViroTherapy. In vitro experiments with SW620, HCT116, and HT29 colorectal carcinoma cell lines demonstrated that they were all sensitive to ZD55-hTRAIL, and especially sensitive to ZD55-hTRAIL plus 5-fluorouracil (5-FU) treatment. In the SW620 xenograft tumor model, various treatment groups showed marked differences at week 11, with the tumor volume for the phosphate-buffered saline (PBS) treatment group >1700 mm3, for 5-FU > 1300 mm3, for ONYX015 1051.3 mm3, for ZD55-hTRAIL 600.05 mm3, and for ZD55-hTRAIL plus 5-FU 230.2 mm3. At the end of week 14, tumor-bearing mice in the other groups almost all died, whereas all the mice in the combined treatment group were alive, with one mouse tumor free. By transmission electron microscopy (TEM) assay, most tumor cells treated with ONYX015 or with ZD55-hTRAIL singly or in combination with 5-FU were lysed due to viral propagation. RT-PCR analysis and immunohistochemistry examination revealed that hTRAIL was expressed in ZD55-hTRAIL-treated SW620 tumor tissue. Furthermore, no detectable hepatoxicity was found by serum enzyme level analysis. These results suggest that ZD55-hTRAIL alone or in combination with 5-FU may have potential clinical implications.

Adenoviridae↗

PubMed2004

Two new lactones and one new aryl-8-oxa-bicyclo[3,2,1]oct-3-en-2-one from Descurainia sophia.

Two new lactones (1, 2), descurainolide A and B, and one new aryl-8-oxa-bicyclo[3,2,1]-oct-3-en-2-one (3), descurainin, together with five known compounds (4-8), were isolated from the seeds of Descurainia sophia (L.) WEBB ex PRANTL. The structures of the new compounds were elucidated by extensive studies of their 1D, 2D NMR and HR-MS. Compounds 4 and 5 showed cytotoxicity.

Alkenes↗

PubMed2003

Enhanced suicide gene therapy by chimeric tumor-specific promoter based on HSF1 transcriptional regulation.

Two tandem cassettes, one containing the telomerase reverse transcriptase gene (hTERT) promoter upstream of a constitutively activated form of heat shock transcription factor 1 (cHSF1) and followed by the other containing the heat shock protein 70B (hsp70B) promoter (HSE) upstream of the cytosine deaminase (CD) gene, could greatly enhance the efficiency of CD gene therapy while retaining tumor specificity in vitro and in vivo. This hTERT-cHSF1/HSE promoter could restrict gene expression in tumor cells and was about 1.5-3-fold more potent than the cytomegalovirus (CMV) promoter. hTERT-cHSF1/HSE-CD transfection led to tumor cells more sensitive to 5-fluorocytosine compared with hTERT-CD and its toxicity was comparable to that of CMV-CD. Besides enhancement of promoter activity, cHSF1 overexpression itself could enhance the bystander effect of CD gene therapy that could be reversed by anti-Fas antibody. This system also led to activation of stress-related genes such as hsp70 in tumor cells, which in the presence of cell killing by the cytotoxic gene is a highly immunostimulatory event. Furthermore, a more potent anti-tumor effect of hTERT-cHSF1/HSE-CD was observed in nude mice inoculated with Bcap37 cells. No obvious activity of the hTERT-cHSF1/HSE promoter was observed in normal tissues after intravenous administration. These results indicate that the hTERT-cHSF1/HSE promoter is highly tumor-specific and strong with potential application in targeted gene therapy, and therefore may be useful for construction of vectors for systemic therapy.

Animals↗

PubMed2003

[Ecological characteristics of Prorocentrum dentatum and the cause of harmful algal bloom formation in China Sea].

Large-scale harmful alga bloom (HAB) has been found in Changjiang River estuary and Zhoushan archipelago in recent three years, and the alga is Prorocentrum dentatum, which distributes in the sea areas with high salinity and (may) originates in outer sea area. Data from recent HAB rapid monitoring and ecological investigation were analyzed to study its ecological characteristics and forming inducement. The results showed that the most suitable temperature and salinity range for HAB forming was from 18 degrees C to 22 degrees C and from 21 to 31, respectively. The P. dentatum was motile and owned diurnal vertical migration bringing them the advantages in obtaining light and nutrients. Eutrophication was the preliminary condition, and water temperature, nitrate content, upwelling current, and strong competence on low phosphate environment were important to cause and maintain HAB.

China↗

PubMed2002

Small bowel bacterial overgrowth and endotoxemia in cirrhosis.

OBJECTIVE: To investigate the incidence of the small bowel bacterial overgrowth in cirrhotics and analyze the correlation among small bowel bacterial overgrowth (SBBO), plasma endotoxin level and plasma interleukin-2(IL-2), interleukin-6(IL-6), or tumor necrosis factor alpha(TNF-alpha) level. METHODS: Small bowel bacterial overgrowth in 71 cirrhotics was test by glucose hydrogen breath test (GHBT); plasma endotoxin in cirrhotics was measured with limilus lysate test; and plasma cytokine (IL-2, IL-6 and TNF-alpha) was measured with a solid-phase enzyme-linked immunosorbent assay; the incidence of SBBO in those 71 cirrhotics was investigated and the correlation between plasma endotoxin level and plasma IL-2, IL-6, or TNF-alpha level was analysed. RESULTS: (1)Positive GHBT were observed in 18 of 71 icrrhotics(25.3%); (2) Plasma endotoxin, IL-2, IL-6 and TNF-alpha levels were significantly higher in those cirrhotic patients with positive GHBT than in those with negative GHBT [(0.715 +/- 0.229) Eu/L versus (0.379 +/- 0.223) Eu/L, (19.15 +/- 4.60) ng/L versus (9.41 +/- 6.69) ng/L, (93.29 +/- 27.37) ng/L versus (53.22 +/- 28.31) ng/L, (42.18 +/- 16.91) ng/L versus (27.72 +/- 17.06) ng/L, respectively; P < 0.01]; (3) A significant correlation was observed between the level of plasma endotoxin and the level of plasma IL-2(r = 0.894, P < 0.001), IL-6(r = 0.857, P < 0.001) or TNF-alpha( r = 0.845,P < 0.001)in cirrhotics; CONCLUSIONS: (1)Plasma endotoxin, IL-2, IL-6,and TNF-alpha levels are increased in cirrhotic patients with SBBO, which suggests SBBO in cirrhotics may exasperated endotoxeamia;(2)Plasma endotoxin level in cirrhotics may stimulate some kinds of immune activated cells to produce IL-2, IL-6 and TNF-alpha, which may deteriorated cirrhosis or the complications.

Bacterial Infections↗