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Tong Zhou

Publications and source records attributed to Tong Zhou.

At least 19 recordsLinked to original sources
PubMed2026

Redox Rewiring in Nicotine-Driven Gastric Carcinogenesis: Uncovering ROS-Dependent Oncogenic Circuits.

SIGNIFICANCE: Nicotine from tobacco products, secondhand smoke, and emerging delivery systems remains a major but underappreciated driver of gastric carcinogenesis (GC). Although reactive oxygen species (ROS) have long been implicated in tumor biology, current models incompletely explain how chronic nicotine selectively reprograms gastric epithelial signaling. This review advances the concept of redox rewiring, whereby nicotine establishes a persistent oxidative state that orchestrates multiple oncogenic programs via spatially compartmentalized NOX signaling. RECENT ADVANCES: We synthesize evidence for a unified model wherein nicotine activates nAChR/β-AR signaling, Ca2+ influx, PKC, and compartmentalized NOX-derived ROS to generate distinct oncogenic outputs. Beyond the established NOX/ROS/NF-κB/MAPK-driven IL-8 and MMP-9 axes, we integrate emerging evidence into three interconnected modules governing EMT/metastasis (ABL1/STAT3/COX-2/periostin), survival/chemoresistance (ERK/GLI1/Bcl-2), and invasion/immune evasion (miR-21/PDCD4). Collectively, these circuits suggest that ROS function not merely as damaging byproducts but as spatially organized signaling mediators dictating tumor behavior. CRITICAL ISSUES: A major challenge is distinguishing established mechanisms from incompletely validated models. The three proposed axes are testable hypotheses requiring experimental validation. Most data derive from in vitro studies with nonphysiologic nicotine concentrations, and artifacts from nonspecific ROS probes are common. Compensatory pathway activation and multi-target effects of natural products remain underexplored. FUTURE DIRECTIONS: We outline a precision-redox oncology roadmap linking pathway-specific biomarkers, mechanistically matched natural products, and biomarker-enriched trials. Priorities include genetic validation of the three axes, time-resolved ROS imaging, and pulsed natural product regimens. By reframing nicotine-driven GC as adaptive redox network remodeling, this review provides a framework for prevention, stratification, and next-generation therapy. Antioxid. Redox Signal. 00, 000-000.

gastric cancer↗
PubMed2026

Modtector: ultra-fast modification signal mining on mapped sequencing reads.

SUMMARY: Existing tools for RNA epitranscriptomic modification and structural signal analysis are often fragmented, inefficiency, and limited to single signal types. We developed Modtector, an unified tool for extracting mutation and reverse-transcription stop signals from aligned sequencing reads. By using a "count-then-correct" strategy, Modtector reduces computational complexity and enables efficient dual-signal analysis. It achieves multi-fold speedups on large-genome and high-coverage datasets, including completing HEK293 22G data analysis in 5 minutes, and show strong scalability on single-cell datasets with speedups exceeding 50-fold. AVAILABILITY: The source code is available at GitHub (https://github.com/TongZhou2017/modtector) and Crates.io (https://crates.io/crates/modtector). The archived source-code snapshot used in this study is available at Zenodo (DOI: 10.5281/zenodo.20967747), corresponding to GitHub commit 7c60e9d. Workflow examples, datasets, and analysis scripts are available at Zenodo (DOI: 10.5281/zenodo.17316476 and 10.5281/zenodo.18523297).

Humans↗
PubMed2025

Identification and validation of prognostic genes associated with mitochondrial nuclear genes in gastric cancer.

Mitochondrial-related nuclear genes (MNGs) have shown great importance in cancer diagnosis and prognosis, but their role in gastric cancer (GC) remains unclear. GC-related transcriptome data from the gene expression omnibus and cancer genome atlas databases were analyzed to identify differentially expressed MNGs. A prognostic risk model was constructed through univariate Cox and least absolute shrinkage and selection operator regression, validated by Kaplan-Meier (K-M) survival curve and receiver operating characteristic curve. This was followed by immune infiltration analysis, independent prognostic analysis, functional enrichment analysis, drug sensitivity analysis, drug prediction, molecular docking and construction of regulatory networks. Three prognostic genes (ATP8A2, COX15 and TARS2) were identified. The expression of TARS2 and COX15 was positively correlated with CNV, while ATP8A2 was unaffected. The risk model and nomogram, integrating risk score and clinicopathological factors, exhibited excellent predictive performance. A significant correlation was observed between prognostic genes and differential immune cells, such as T cells, B cells, and NK cells. BMS-754807, Gefitinib, JQ1, Lapatinib, and Sapitinib exhibited significant differences in sensitivity between the high-risk group and the low-risk group. The results of molecular docking showed TP8A2 has stable binding ability with cytosine, COX15 with indomethacin, and TARS2 with bisacodyl. RT-qPCR revealed downregulation of ATP8A2 and upregulation of COX15 and TARS2 in GC samples. MNGs, including ATP8A2, COX15, and TARS2, demonstrated significant associations with immune infiltration, CNV, and prognostic outcomes of GC.

Humans↗
PubMed2003

TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis.

TRAIL has been proposed as an anti-inflammatory cytokine in animal models of rheumatoid arthritis (RA). Using two agonistic mAbs specific for TRAIL-R1 (DR4) and TRAIL-R2 (DR5), we examined the expression and function of these death receptors in RA synovial fibroblast cells. The synovial tissues and primary synovial fibroblast cells isolated from patients with RA, but not those isolated from patients with osteoarthritis, selectively expressed high levels of cell surface DR5 and were highly susceptible to anti-DR5 Ab (TRA-8)-mediated apoptosis. In contrast, RA synoviocytes did not show increased expression of TRAIL-R1 (DR4), nor was there any difference in expression of Fas between RA and osteoarthritis synovial cells. In vitro TRA-8 induced apoptosis of RA synovial cells and inhibited production of matrix metalloproteinases induced by pro-inflammatory cytokines. In vivo TRA-8 effectively inhibited hypercellularity of a SV40-transformed RA synovial cell line and completely prevented bone erosion and cartilage destruction induced by these cells. These results indicate that increased DR5 expression and susceptibility to DR5-mediated apoptosis are characteristic of the proliferating synovial cells in RA. As highly proliferative transformed-appearing RA synovial cells play a crucial role in bone erosion and cartilage destruction in RA, the specific targeting of DR5 on RA synovial cells with an agonistic anti-DR5 Ab may be a potential therapy for RA.

Adult↗
PubMed2003

Fc gamma Rs modulate cytotoxicity of anti-Fas antibodies: implications for agonistic antibody-based therapeutics.

Development of anti-Fas Abs to treat diseases with insufficient Fas-mediated apoptosis has been limited by concern about hepatotoxicity. We report here that hepatotoxicity elicited by anti-Fas Ab Jo2 is dependent on FcgammaRIIB. Thus, following Jo2 treatment, all FcgammaRIIB(-/-) mice survived while 80% of wild-type and all FcR-gamma(-/-) mice died from acute liver failure. Microscopic examination suggests that FcgammaRIIB deficiency protects the hepatic sinusoidal endothelium, a cell type that normally coexpresses Fas and FcgammaRIIB. In vitro studies showed that FcgammaRIIB, but not FcgammaRI and FcgammaRIII, on neighboring macrophages substantially enhanced Jo2 mediated apoptosis of Fas expressing target cells. However, FcgammaRI and FcgammaRIII appeared essential for apoptosis-inducing activity of a non-hepatotoxic anti-Fas mAb HFE7A. These findings imply that by interacting with the Fc region of agonistic Abs, FcgammaRs can modulate both the desired and undesired consequences of Ab-based therapy. Recognizing this fact should facilitate development of safer and more efficacious agonistic Abs.

Animals↗
PubMed2003

Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway.

Using two agonistic monoclonal antibodies specific for each death receptor of TRAIL, 2E12 (anti-human DR4) and TRA-8 (anti-human DR5), we examined the signal transduction of the death receptors in combination with or without chemotherapy agents such as Adriamycin (doxorubicin hydrochloride) and Cisplatin. Our results demonstrated that chemotherapy agents were able to enhance apoptosis-inducing activity of these antibodies against several different types of tumor cell lines through enhanced caspase activation. The combination of the antibodies and chemotherapy agents led to a synergistical activation of the JNK/p38 MAP kinase, which was mediated by MKK4. The combination also caused an increased release of cytochrome c and Smac/DIABLO from mitochondria in parallel with the profound loss of mitochondrial membrane potential. These results suggest that the enhanced activation of the JNK/p38 kinase and the mitochondrial apoptosis pathways play a crucial role in synergistic induction of the death receptor-mediated apoptosis by chemotherapy agents. Thus, the simultaneous targeting of cell surface death receptors with agonistic antibodies and the intracellular JNK/p38 and the mitochondrial death pathways with chemotherapy agents would enhance the efficacy and selectivity of both agents in cancer therapy.

Acetylcysteine↗
PubMed2003

Evaluating prey capture by larval mummichogs (Fundulus heteroclitus) as a potential biomarker for contaminants.

We evaluated larval prey capture as a "behavioral biomarker" of contamination by examining feeding behavior of larval mummichogs (Fundulus heteroclitus) from many different sites, including a severely contaminated "Superfund" site, moderately contaminated sites, and reference areas. Prey capture ability was related to sediment contaminant levels. The levels of contaminants at a site were highly correlated with each other, so that the impact of individual contaminants was confounded. The number of captures of brine shrimp by mummichog larvae from all sites was highly variable, but significant negative correlations of prey capture were seen with mercury, lead, zinc, cadmium, and PCBs. As observed previously with adults, polyaromatic hydrocarbons (PAHs) did not appear to impair prey capture ability. The only site in which prey capture rates of 8-day old larvae were severely affected was the most highly contaminated Superfund site, Berry's Creek, NJ. This implies that larval prey capture is not as sensitive a behavioral biomarker for contamination as adult behavior studied previously.

Animals↗
PubMed2003

Effect of tetramethylpyrazine on P-selectin and hepatic/renal ischemia and reperfusion injury in rats.

AIM: To investigate the effect of tetramethylpyrazine on hepatic/renal ischemia and reperfusion injury in rats. METHODS: Hepatic/renal function, histopathological changes, and hepatic/renal P-selectin expression were studied with biochemical measurement and immunohistochemistry in hepatic/renal ischemia and reperfusion injury in rat models. RESULTS: Hepatic/renal insufficiency and histopathological damage were much less in the tetramethylpyrazine-treated group than those in the saline-treated groups. Hepatic/renal P-selectin expression was down regulated in the tetramethylpyrazine-treated group. CONCLUSION: P-selectin might mediate neutrophil infiltration and contribute to hepatic/renal ischemia and reperfusion injury. Tetramethylpyrazine might prevent hepatic/renal damage induced by ischemia and reperfusion injury through inhibition of P-selectin.

Animals↗
PubMed2003

Effect of P-selectin monoclonal antibody on metastasis of gastric cancer and immune function.

AIM: To investigate the effect of cell adhesion molecule P-selectin monoclonal antibody (Mab) on metastasis and immune function of mice orthototopically implanted with human gastric cancer tissue. METHODS: SCID mice were implanted orthotopically with SGC-7901 human gastric carcinoma tissue. Starting from day 3 after operation, animals were given intravenously PBS or P-selectin Mab (100 microg/injection) (for both normal mice and tumor-implanted mice with tumors), twice weekly for 3 weeks. Two animals in each group were sacrificed randomly at the 1st, 2nd, 4th week and 6th week. While T cell and B cell transformation indices were determined with the (3)H TdR infiltration method, the NK cell activity was detected by the LDH release method. RESULTS: The metastatic rate in the P-selectin Mab treated group was lower than that in the PBS treated group (with tumors). The NK activity of normal mice increased over time. The immune functions (T, B cell function, NK activity) of the tumor group in the 6th week were significantly lower than those in the 4th week, but the change was attenuated by P-selectin Mab. CONCLUSION: P-selectin Mab could suppress the metastasis of gastric cancer with no adverse effect on host immune function.

Animals↗
PubMed2003

[Cloning, expression of the lectin-EGF domain of P-selectin, and preparation of its monoclonal antibody].

To prepare monoclonal antibody specific to P-selectin lectin-EGF domain, the gene for lectin-EGF domain of P-selectin L-EGF was amplified from normal human platelets by RT-PCR, then was cloned into prokaryotic vector pET42b(+). The recombinant plasmid was transformed into E. coli DH5 alpha strain for further screening and characterization, and was expressed in E. coli BL21 strain. Expressed protein was purified by chromatography on a Ni(2+)-NTA superflow agarose column and eluted with pH 8.0-4.5 urea gradient. Then the mAb anti-lectin-EGF was prepared with classical hybridoma technique, and 3 hybridoma cell lines (B10, F3 and H5) were obtained with Ig subclasses of these mAbs were IgG(2), IgG(1), and IgG(3) respectively, and their light chains were all kappa chain. Immuofluorescence and FACS assays demonstrated that mAbs could specifically recognize P-selectin expressed on ECV (endothelial cell line) stimulated by LPS. Meanwhile, the role of mAbs to P-selectin lectin-EGF domain was studied, and it was proved that the mAbs markedly inhibited adhesion between platelets and neutrophils in vitro. These monoclonal antibodies can specifically recognize the natural P-selectin and markedly inhibit adhesion between platelets and neutrophils in vitro.

Animals↗
PubMed2002

Bisindolylmaleimide VIII enhances DR5-mediated apoptosis through the MKK4/JNK/p38 kinase and the mitochondrial pathways.

Bisindolylmaleimide VIII (Bis VIII) has been previously shown to enhance Fas-mediated apoptosis through a protein kinase C-independent mechanism. In the present study, we examined the effect of Bis VIII on apoptosis induced by DR5 (TRAIL-R2), using an agonistic anti-human DR5 monoclonal antibody, TRA-8. Our results demonstrated that Bis VIII was able to enhance the apoptosis-inducing activity of TRA-8 both in vitro and in vivo. The combination of TRA-8 and Bis VIII led to a synergistic and sustained activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase, which was mediated by MAPK kinase 4 and was caspase-8-dependent. The mitochondrial pathway is involved in the synergistic induction of apoptosis by Bis VIII and TRA-8. Bis VIII alone induced the loss of mitochondrial membrane potential in a caspase-independent fashion without subsequent release of cytochrome c. However, in the presence of Bis VIII, TRA-8 induced more profound loss of mitochondrial membrane potential and release of cytochrome c. These results suggest that the enhanced and persistent activation of the JNK/p38 and the decreased mitochondrial membrane potential play a crucial role in synergistic induction of the death receptor-mediated apoptosis by Bis VIII. The unique ability of Bis VIII to enhance DR5-mediated apoptosis signal transduction discloses a potential utility of this compound in combination with anti-DR5 antibody in cancer therapy.

Apoptosis↗
PubMed2002

Conversion of phosphoglycolate to phosphate termini on 3' overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1.

Mammalian cells contain potent activity for removal of 3'-phosphoglycolates from single-stranded oligomers and from 3' overhangs of DNA double strand breaks, but no specific enzyme has been implicated in such removal. Fractionated human whole-cell extracts contained an activity, which in the presence of EDTA, catalyzed removal of glycolate from phosphoglycolate at a single-stranded 3' terminus to leave a 3'-phosphate, reminiscent of the human tyrosyl-DNA phosphodiesterase hTdp1. Recombinant hTdp1, as well as Saccharomyces cerevisiae Tdp1, catalyzed similar removal of glycolate, although less efficiently than removal of tyrosine. Moreover, glycolate-removing activity could be immunodepleted from the fractionated extracts by antiserum to hTdp1. When a plasmid containing a double strand break with a 3'-phosphoglycolate on a 3-base 3' overhang was incubated in human cell extracts, phosphoglycolate processing proceeded rapidly for the first few minutes but then slowed dramatically, suggesting that the single-stranded overhangs gradually became sequestered and inaccessible to hTdp1. The results suggest a role for hTdp1 in repair of free radical-mediated DNA double strand breaks bearing terminally blocked 3' overhangs.

Base Sequence↗
PubMed2002

Depletion of collagen II-reactive T cells and blocking of B cell activation prevents collagen II-induced arthritis in DBA/1j mice.

Collagen II (CII)-induced arthritis in DBA/1j mice is mediated by both CII-reactive T cells and anti-CII Ab-producing B cells. To determine the relative role of these processes in the development of arthritis, we specifically eliminated CII-reactive T cells by treating the mice with CII-pulsed syngeneic macrophages that had been transfected with a binary adenovirus system. These macrophages express murine Fas ligand in a doxycycline-inducible manner with autocrine suicide inhibited by concomitant expression of p35. The mice were treated i.v. with four doses of CII-APC-AdFasLp35Tet or a single dose of AdCMVsTACI (5 x 10(9) PFU), or both simultaneously, beginning 2 wk after priming with CII in CFA. Treatment with CII-APC-AdFasLp35Tet alone or in combination with a single dose of AdCMVsTACI prevented the development of CII-induced arthritis and T cell infiltration in the joint. The elimination of T cells was specific in that a normal T cell response was observed on stimulation with OVA after treatment with CII-APC-AdFasLp35Tet. Treatment with AdCMVsTACI alone prevented production of detectable levels of circulating anti-CII autoantibodies and reduced the severity of arthritis but did not prevent its development. These results indicate that the CII-reactive T cells play a crucial role in the development of CII-induced arthritis and that the anti-CII Abs act to enhance the development of CII-induced arthritis.

Adenoviridae↗
PubMed2002

Mutation, specialization, and hypersensitivity in highly optimized tolerance.

We introduce a model of evolution in which competing organisms are represented by percolation lattice models. Fitness is based on the number of occupied sites remaining after removing a cluster connected to a randomly selected site. High-fitness individuals arising through mutation and selection must trade off density versus robustness to loss, and are characterized by cellular barrier patterns that prevent large cascading losses to common disturbances. This model shows that Highly Optimized Tolerance (HOT), which links complexity to robustness in designed systems, arises naturally through Darwinian mechanisms. Although the model is a severe abstraction of biology, it produces a surprisingly wide variety of micro- and macroevolutionary features strikingly similar to real biological evolution.

Biological Evolution↗
PubMed2002

Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses.

Marginal zone (MZ) and B1 B lymphocytes participate jointly in the early immune response against T-independent (TI) particulate antigens. Here we show that blood-derived neutrophil granulocytes and CD11c(lo) immature dendritic cells (DC) are the primary cells that efficiently capture and transport particulate bacteria to the spleen. In a systemic infection, CD11c(lo) DC, but not neutrophils, provide critical survival signals, which can be inhibited by TACI-Fc, to antigen-specific MZ B cells and promote their differentiation into IgM-secreting plasmablasts. In a local TI response, peritoneal cavity macrophages provide similar support to B1 B-derived Ag-specific blasts. In the absence of soluble TACI ligands, Ag-activated MZ- and B1-derived blasts lack survival signals and undergo apoptosis, resulting in severely impaired antibody responses.

Adoptive Transfer↗
PubMed2002

Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption.

The objective of the current study was to characterize the effects of DE-71 (a commercial polybrominated diphenyl ether mixture containing mostly tetra- and penta-bromodiphenyl ethers) on thyroid hormones and hepatic enzyme activity in offspring, following perinatal maternal exposure. Primiparous Long-Evans rats were orally administered DE-71 (0, 1, 10, and 30 mg/kg/day) in corn oil from gestation day (GD) 6 to postnatal day (PND) 21. Serum and liver samples obtained from dams (GD 20 and PND 22), fetuses (GD 20), and offspring (PNDs 4, 14, 36, and 90) were analyzed for circulating total serum thyroxine (T(4)) and triiodothyronine (T(3)), or hepatic microsomal ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD), and uridine diphosphoglucuronosyl transferase (UDPGT) activity. There were no significant effects of treatment on maternal body weight gain, litter size, or sex ratio, nor were there any effects on any measures of offspring viability or growth. Serum T(4) was reduced in a dose-dependent manner in fetuses on GD 20 (at least 15%) and offspring on PND 4 and PND 14 (50 and 64% maximal in the 10 and 30 mg/kg/day groups, respectively), but recovered to control levels by PND 36. Reduction in serum T(4) was also noted in GD 20 dams (48% at highest dose), as well as PND 22 dams (44% at highest dose). There was no significant effect of DE 71 on T(3) concentrations at any time in the dams or the offspring. Increased liver to body weight ratios in offspring were consistent with induction of EROD (maximal 95-fold), PROD (maximal 26-fold) or UDPGT (maximal 4.7-fold). Induction of PROD was similar in both dams and offspring; however, EROD and UDPGT induction were much greater in offspring compared to dams (EROD = 3.8-fold; UDPGT = 0.5-fold). These data support the conclusion that DE-71 is an endocrine disrupter in rats during development.

Animals↗
PubMed2002

Tumor necrosis factor-related apoptosis-inducing ligand induces caspase-dependent interleukin-8 expression and apoptosis in human astroglioma cells.

Among the tumor necrosis factor (TNF) family of cytokines, FasL and TNF-related apoptosis-inducing ligand (TRAIL) are known to induce cell death via caspase activation. Recently, other biological functions of these death ligands have been postulated in vitro and in vivo. It was previously shown that Fas ligation induces chemokine expression in human glioma cells. In this study, we investigated whether the TRAIL-DR5 system transduces signals similar to those induced by other TNF family ligands and receptors. To address this issue, two human glioma cell lines, CRT-MG and U87-MG, were used, and an agonistic antibody against DR5 (TRA-8) and human recombinant TRAIL were used to ligate DR5. We demonstrate that DR5 ligation by either TRAIL or TRA-8 induces two functional outcomes, apoptosis and expression of the chemokine interleukin-8 (IL-8); the nonspecific caspase inhibitor Boc-D-Fmk blocks both TRAIL-mediated cell death and IL-8 production; the caspase 3-specific inhibitor z-DEVD-Fmk suppresses TRAIL-mediated apoptosis but not IL-8 induction; caspase 1- and 8-specific inhibitors block both TRAIL-mediated cell death and IL-8 production; and DR5 ligation by TRAIL mediates AP-1 and NF-kappaB activation, which can be inhibited by caspase 1- and 8-specific inhibitors. These findings collectively indicate that DR5 ligation on human glioma cells leads to apoptosis and that the activation of AP-1 and NF-kappaB leads to the induction of IL-8 expression; these responses are dependent on caspase activation. Therefore, the TRAIL-DR5 system has a role not only as an inducer of apoptotic cell death but also as a transducer for proinflammatory and angiogenic signals in human brain tumors.

Antibodies, Monoclonal↗