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PubMed2006

Impaired downregulation following erythropoietin receptor activation in non-small cell lung carcinoma.

Recent evidence confirms the presence of erythropoietin receptors on a variety of cancer cells. This has raised concerns about the use of erythropoiesis-stimulating agents in the treatment of cancer-related anemia. Having previously identified expression of functional erythropoietin receptors in a non-small cell lung carcinoma cell line, H838, which activated key signaling pathways in response to erythropoietin stimulation, we now demonstrate impaired downregulation of the erythropoietin receptor in these tumor cells. The erythropoietin receptor is not ubiquitinated following erythropoietin stimulation in this cancer cell line, and there is no turnover of the receptor in either unstimulated or stimulated cells. Compounding this blunted response is impaired SOCS3 induction downstream of erythropoietin stimulation and an extremely delayed SOCS1 response. If this finding in non-small cell lung carcinoma is a widespread phenomenon, then impaired erythropoietin receptor downregulation and degradation in tumor cells has clinical implications for those patients receiving erythropoiesis-stimulating agents for cancer-related anemia.

Carcinoma, Non-Small-Cell Lung↗

PubMed2004

Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications.

Carcinogenesis is a multistep process characterized by genetic alterations that influence key cellular pathways involved in growth and development. Oncogenes refer to those genes whose alterations cause gain-of-function effects, while tumor suppressor genes cause loss-of-function effects that contribute to the malignant phenotype. The effects of these alterations are complex due to the high number of changes in a typical case of breast cancer and the interactions of the biological pathways involved. This review focuses on the more common abnormalities in oncogenes and tumor suppressor genes in human breast cancer and their known associations with clinical outcome in terms of tumor classification, prognosis, and response to specific therapies. A better understanding of these relationships has led to new therapeutic applications. Agents that target oncogenes and their associated pathways are now in clinical use, with many more undergoing preclinical and clinical testing. The availability of antibodies, small synthetic molecules, cyotokines, gene therapy techniques, and even natural compounds that are screened for specific biological properties has greatly increased the number of candidate drugs. Nevertheless, clinical successes have been limited because of the redundancy of many cancer-related pathways as well as the high degree of variability in genotype and phenotype among individual tumors. Likewise, strategies to replace tumor suppressor gene functions face numerous technical hurdles. This review summarizes the current achievements and future prospects for the therapeutic targeting of oncogenes and tumor suppressor genes and new technology to better classify tumors and accurately predict responses to standard and novel agents.

Breast Neoplasms↗

PubMed2026

Exploring the potential mechanism of Huang'e capsule against spontaneous benign prostatic hyperplasia in beagle dogs using high-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry, gas chromatography-mass spectrometry, and network pharmacology.

OBJECTIVE: To investigate the therapeutic efficacy and potential mechanisms of Huang'e capsule (, HEC) against benign prostatic hyperplasia (BPH). METHODS: The chemical profile of HEC was characterized using high-performance liquid chromatographyquadrupole-time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS) and gas chromatography-mass spectrometry (GC-MS) techniques. Network pharmacology was employed to analyze potential active compounds, core targets, and key signaling pathways. A spontaneous canine BPH model was used to evaluate the efficacy of HEC and to validate the predictions from network pharmacology. RESULTS: A total of 51 chemical components of HEC were identified, comprising 19 from HPLC-Q-TOF-MS/MS and 32 from GC-MS analyses. The "components-targets-pathways-disease" network analysis predicted active compounds including (s)-coriolic acid, ethyl linoleate, peroxysimulenoline, physcion, and kaempferol. Core targets identified included cytochrome P450 family 19 subfamily A member 1, estrogen receptor 2 (ESR2), ESR1, and androgen receptor (AR). Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that HEC's effects on BPH involve pathways related to cancer, phosphatidylinositol 3-kinase (PI3K) -protein kinase B (Akt)-signaling, proteoglycans in cancer, and prostate cancer signaling. Animal experiments showed that HEC significantly improved maximum urinary flow rates, reduced prostate weight, volume, and prostate index, and ameliorated histopathological changes. HEC regulated the balance between apoptosis and proliferation by downregulating AR and estrogen receptor alpha expression, while upregulating estrogen receptor beta expression. CONCLUSION: These findings indicate that HEC effectively ameliorates spontaneous BPH in beagle dogs, likely by regulating the balance between cell apoptosis and proliferation through multiple signaling pathways.

Animals↗

PubMed2026

MS4A3 as a potential prognostic biomarker for colon cancer: integrated analysis of expression patterns and immune cell infiltration.

BACKGROUND: Membrane Spanning 4-Domains A3 (MS4A3) has been confirmed to possess significant tumor-suppressive potential in various malignancies. However, its expression characteristics and clinical prognostic value in colon cancer (CC) still lack systematic and in-depth investigation. This study aimed to systematically investigate the expression pattern, prognostic value, immune microenvironment association, and biological function of MS4A3 in CC through integrated bioinformatics analyses and experimental validation. METHODS: This study utilized The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) cohort to screen for genes significantly associated with CC and combined multiple independent Gene Expression Omnibus (GEO) datasets to validate the expression patterns and prognostic significance of MS4A3. Key biological pathways were identified through gene set enrichment analysis (GSEA), and tumor immune infiltration characteristics were evaluated using the CIBERSORT algorithm. Additionally, the expression of MS4A3 and its impacts on cellular functions were validated at the cellular level through quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, Cell Counting Kit-8 (CCK-8), EdU, Transwell, and TUNEL assays. RESULTS: Analysis of public datasets revealed that MS4A3 is significantly downregulated in CC tissues, and its low expression is an independent risk factor for shortened overall survival (OS). GSEA indicated that MS4A3 downregulation is closely associated with the aberrant activation of the pentose phosphate pathway. Immune infiltration analysis showed that low MS4A3 expression is closely linked to the enrichment of M2 macrophages and neutrophils, as well as the upregulation of multiple immune checkpoint genes. In vitro experiments further confirmed that MS4A3 was lowly expressed in CC cell lines. Its overexpression significantly inhibited CC cell viability, proliferation, migration, and invasion, while simultaneously promoting cell apoptosis. CONCLUSIONS: MS4A3 expression is significantly decreased in CC tissues and is significantly correlated with poor prognosis, suggesting that this gene may serve as a potential prognostic biomarker.

MS4A3↗

PubMed1998

Drug administration in patients with diabetes mellitus. Safety considerations.

Diabetes mellitus is associated with alterations in a number of key metabolic pathways. Despite theoretical concerns, clinically significant alterations in the pharmacokinetic properties of commonly prescribed drugs are relatively uncommon. Indeed, dose adjustment is rarely required in the setting of well controlled diabetes mellitus. However, significant alterations in drug handling may occur in the context of poor metabolic control or in the presence of complications such as nephropathy. Metformin use may be complicated by lactic acidosis. Fortunately, this is a rare occurrence providing that the agent is not used in circumstances in which it is contraindicated. Indeed, the risk of death from metformin-related lactic acidosis is similar in magnitude to the risk of death related to hypoglycaemia in sulphonylurea-treated patients. The novel hypoglycaemic agent troglitazone may be associated with abnormalities in liver function in approximately 2% of patients. Discontinuation of treatment is followed by normalisation of liver enzyme levels. Current prescribing information recommends frequent monitoring of liver function tests and immediate cessation of therapy if abnormalities develop. In addition to disturbances in intermediary metabolism, diabetes mellitus may also lead to chronic microvascular and marcovascular complications. Thus, in addition to the use of drugs for the control of blood glucose, patients with diabetes mellitus are likely to be prescribed medication for associated conditions such as cardiovascular disease. Such medication includes the ACE inhibitors which are contraindicated in patients with bilateral renal artery stenosis. This complication may be theoretically more common in patients with diabetes mellitus because of accelerated atherosclerosis. However, in clinical practice this is an uncommon occurrence in the absence of clinical features that should alert the treating clinician that an individual patient might be at high risk. Although caution should also be used with beta-blocker therapy in patients with diabetes mellitus, current evidence suggests that, like ACE inhibitors, these drugs may be particularly useful in this patient group.

Acarbose↗

PubMed2002

Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications.

Cardiovascular disease is the major cause of morbidity and mortality in Westernised societies. It is well known that the aetiology of this devastating disorder involves both genetic and environmental factors. Sequence variants of the components of the renin-angiotensin-aldosterone system and the kallikrein-kinin system are suggested to have significant influences on cardiovascular homeostasis. Both gene targeting and transgenic studies in mice have clearly suggested a critical role of the angiotensin converting enzyme (ACE) gene in blood pressure regulation. Furthermore, an up-regulation of myocardial ACE gene expression has been observed in patients with heart failure. Thus, the ACE gene has been recognised as a top candidate gene for cardiovascular research. Over the past decade, the insertion/deletion (I/D) polymorphism of a 287-bp Alu element in intron 16 of the ACE gene has attracted significant attention and has been extensively investigated in a spectrum of cardiovascular phenotypes, because of its correlation with serum ACE activity. A large majority of previous studies have shown a positive association between the DD genotype and an increased risk of myocardial infarction, but results in hypertension, left ventricular hypertrophy, cardiomyopathy and restenosis after percutaneous transluminal coronary angioplasty remain quite controversial. Since ACE inhibitors are widely used in hypertension and congestive heart failure, we also review the literature on the relationship of ACE I/D polymorphism with ACE inhibitor response. It appears that this polymorphism has some moderate impact on the cardiovascular response to ACE inhibitors but there is no consensus as to which allele confers a more pronounced effect. In addition, previous data are suggestive of an association between the ACE I allele and a greater risk of increased occurrence of ACE inhibitor-induced cough, but such a relationship needs further confirmation. Overall, since ACE I/D is only an intronic marker, the true locus that controls the ACE enzyme activity remains to be identified, and could be located within either the ACE gene or another nearby gene such as the human growth hormone gene. We note that since associations tend to vary across different gender or ethnic groups, or across different socio-ecological settings, consideration of potential gene-gene and gene-environment interactions should be made. Furthermore, the dissection of the genetic underpinning of cardiovascular disease needs delineation of all molecular variants of the key physiological pathways that influence cardiovascular function.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2006

Monoclonal antibody-based targeted therapy in breast cancer: current status and future directions.

The recent development of monoclonal antibodies targeting growth factor receptors in cancer treatment represents a milestone for both researchers and physicians. Advances in the understanding of key molecular pathways for tumour growth and survival have facilitated the development of these targeted therapies, in particular in breast cancer. This review focuses on the three most important recombinant humanised monoclonal antibodies that have shown activity in women with breast cancer: trastuzumab, pertuzumab and bevacizumab. Trastuzumab, an anti-erbB2 (human epidermal growth factor receptor) monoclonal antibody, is currently routinely used in both the metastatic and adjuvant settings for patients with erbB2-positive tumours. Pertuzumab, a monoclonal antibody binding to a different epitope on erbB2 than trastuzumab, is under early clinical evaluation. This drug has been developed for breast cancer patients, whether overexpressing erbB2 or not. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A, is being evaluated in the metastatic setting for its antiangiogenic properties, and is showing promising results.

Antibodies, Monoclonal↗

PubMed2003

Cost evaluation of basiliximab treatment for renal transplant patients in Japan.

BACKGROUND: International phase III studies (CHIB 201 and 352) showed that basiliximab, a high affinity chimeric monoclonal antibody interleukin-2 receptor antagonist, is highly effective in preventing acute rejection when used as immunoprophylaxis in patients receiving cyclosporin (Neoral). We conducted a cost evaluation by applying international clinical results to standard Japanese medical practice. OBJECTIVE: To evaluate the impact of basiliximab in renal transplant patients receiving conventional immunosuppressive therapy using cyclosporin and corticosteroids from the perspective of the healthcare payer in Japan. STUDY DESIGN: A decision tree model was developed, comprising seven pathways with key clinical events identified after the transplantation. The average first-year treatment costs after transplantation for patients treated with and without basiliximab were calculated using the model. A sensitivity analysis was done to measure the degree of influence of several criteria including the incidences of rejection, and rejection responding to steroid pulse therapy and antibody therapy. METHODS: Estimates of key clinical events were derived from the international studies. Calculation of direct medical costs were made from the payers' perspective, based on the Social Insurance Medical Fee Table in Japan. The cost of basiliximab was assumed as zero. MAIN OUTCOME MEASURES AND RESULTS: Basiliximab use produced an estimated saving of 315,807 yen (2000 values) during the first year after transplantation. Reduced acute rejection treatment and dialysis most influenced the cost saving. The sensitivity analysis showed that the average cost for a patient was lower in the basiliximab group and that the model was effective within the plausible range of each criterion that would reflect renal transplantation in Japan. CONCLUSIONS: If the cost of basiliximab is less than 315,807 yen, the clinical and economic benefits of basiliximab in the first year after transplantation support the routine use of basiliximab in renal transplantation in Japan.

Adult↗

PubMed2026

Gut Microbiota, Lipidome, and Metabolites Mediate Immune Dysregulation in Diabetic Microvascular Disease: A Two-sample Mendelian Randomization and Mediation Analysis.

INTRODUCTION: Diabetic microvascular disease (DMiVD) involves dysregulated immune cell function, but the precise pathogenic mechanisms remain unclear. MATERIALS AND METHODS: We conducted a two-sample Mendelian randomization (MR) study using comprehensive GWAS and FinnGen summary statistics, encompassing 731 immune cell phenotypes, 473 gut microbial taxa, 91 inflammatory proteins, 179 lipid types, 1,400 plasma metabolites, 20 micronutrients, and DMiVD cases. The analysis aimed to evaluate causal associations between these variables and DMiVD. We further explored potential mediating roles of gut microbiota, plasma lipidome, and metabolites using mediation analysis, with multiple sensitivity tests confirming the robustness of our findings. RESULTS: We identified 20 immune cell phenotypes, 33 gut microbial taxa, 31 lipid types, and 83 plasma metabolites with significant causal associations with DMiVD. Mediation analysis revealed that the risk effect of CD3+ resting Tregs on diabetic nephropathy was partly mediated by phosphatidylcholine (16:0_18:2) (10.7%). Additionally, the protective effect of CX3CR1 on monocytes against DMiVD was partly mediated by Unclassified Bacilli A (35%), Species CAG-177 sp003538135 (22.6%), and triacylglycerol (52:6) (25.5%). DISCUSSION: These findings advance understanding of DMiVD pathogenesis, highlighting that modulation of key metabolic pathways and immune regulatory nodes may represent promising therapeutic strategies. Further experimental studies are needed to validate these potential causal relationships. CONCLUSION: Using causal inference approaches, this study identifies immune cell-mediated mechanisms underlying DMiVD, involving gut microbiota, plasma lipids, and metabolites. The results suggest potential intervention targets for mechanistic studies and therapeutic development.

Mendelian Randomization Analysis↗

PubMed2004

Ubiquitin-protein ligases--novel therapeutic targets?

Intracellular protein degradation is a tightly regulated process that in many cases is controlled by protein ubiquitylation. The ubiquitin pathway is a major route by which cells not only remove normal proteins at the appropriate time but also abnormally folded normal or mutant, cytoplasmic and membrane, proteins. This has led to a major impetus to identify constituents of the pathway. The key components that regulate substrate ubiquitylation are the ubiquitin-protein ligases. Ligases come in many forms, from single proteins to very large multiprotein complexes. Specificity of targeting can be modulated by the requirement for post-translational modifications such as phosphorylation, hydroxylation or oxidation of the substrate and, in some cases, the ligase itself. The requirement for substrate modification prior to ubiquitylation allows the same ligase to target different substrates within the same cell at different times. Abnormal intracellular protein processing is a common feature of many human diseases including neurodegenerative diseases and cancer. It may not represent the causative factor that initiates the disease process but may be a downstream regulator of the toxic effect. These abnormalities often arise from the loss of a key protein-protein interaction. As a consequence, mutated proteins can have very different half-lives from their normal counterparts. This can affect the levels of their activity and/or lead to the formation of protein aggregates (inclusion bodies/aggresomes). In this review, we aim to highlight examples of diseases where abnormal protein ubiquitylation is proposed to be a key regulator of the disease process. The recent success of the proteasome inhibitor Bortezomib (PS-341) for treatment of relapsed, refractory myeloma suggests that the modulation of individual ubiquitin-protein ligase activities with synthetic agents may represent a novel approach that has enormous potential for the treatment of a wide range of diseases.

Cysteine Endopeptidases↗

PubMed2001

Gene therapy to overcome drug resistance in cancer: targeting key regulators of the apoptotic pathway.

A better understanding of the molecular events responsible for the development of drug resistance in cancer cells has emerged in recent years. It is now established that tumor cells can acquire drug resistance by alterations of pathways involved in the regulation of apoptosis and that failure to activate this pathway in cancer cells may confer resistance to chemotherapy. This resistance to drug-induced apoptosis is likely to play an important role in tumors that are refractory to chemotherapy. The identification of points in the apoptotic pathway at which dysregulation occurs opens up new therapeutic opportunities in situations where conventional cytotoxic chemotherapy approaches fail. Although these gene therapy-based strategies are still in their infancy they will likely lead to more effective treatments for human cancers. This review will focus on gene therapy strategies developed to specifically target the apoptotic pathway and how these strategies can affect the sensitivity of tumor cells to chemotherapy.

Antibodies↗

PubMed2003

High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells.

Monocyte activation and adhesion to the endothelium play important roles in inflammatory and cardiovascular diseases. These processes are further aggravated by hyperglycemia, leading to cardiovascular complications in diabetes. We have previously shown that high glucose (HG) treatment activates monocytes and induces the expression of tumor necrosis factor (TNF)-alpha via oxidant stress and nuclear factor-kB transcription factor. To determine the effects of HG on the expression of other inflammatory genes, in the present study, HG-induced gene profiling was performed in THP-1 monocytes using cytokine gene arrays containing 375 known genes. HG treatment upregulated the expression of 41 genes and downregulated 15 genes that included chemokines, cytokines, chemokines receptors, adhesion molecules, and integrins. RT-PCR analysis further confirmed that HG significantly increased the expression of monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, beta(2)-integrin, interleukin-1beta, and others. HG treatment increased transcription of the MCP-1 gene, MCP-1 protein levels, and adhesion of THP-1 cells to endothelial cells. HG-induced MCP-1 mRNA expression and monocyte adhesion were blocked by specific inhibitors of oxidant stress, protein kinase C, ERK1/2, and p38 mitogen-activated protein kinases. These results show for the first time that multiple inflammatory cytokines and chemokines relevant to the pathogenesis of diabetes complications are induced by HG via key signaling pathways.

Acetylcysteine↗

PubMed2026

Discovery and validation of a multi-protein panel for predicting non-fatal major adverse cardiovascular events in diabetic kidney disease.

OBJECTIVE: To identify plasma protein biomarkers associated with incident non-fatal major adverse cardiovascular events (MACE) in diabetic kidney disease (DKD) patients. RESEARCH DESIGN AND METHODS: We analyzed 317 DKD patients from the UK Biobank. Plasma proteomics and clinical data (demographics, metabolism, renal function) were integrated. In an exploratory discovery phase, three sequential Cox regression models (crude, socio-demographic-adjusted, socio-demographic-metabolic adjusted) screened non-fatal MACE-associated proteins. To prevent information leakage, the cohort was then randomly split into training (70%) and testing (30%) sets; machine-learning feature selection, hyperparameter optimization, and final model development were performed exclusively within the training set. The associated proteins were input into the four-step machine-learning pipeline (LASSO-Cox, random survival forest, Boruta, XGBoost-Cox). Predictive performance was validated using Kaplan-Meier survival analyses, longitudinal trajectory modeling, and ROC benchmarking. An interactive web application was deployed for clinical implementation. RESULTS: Of 1,463 plasma proteins, 561 were associated with non-fatal MACE across Cox models, with 14 overlapping proteins. Nine core proteins (ANG, IL1R1, CXCL14, ESAM, PTGDS, HAVCR1, FGFR2, IGSF8, CCL3) were validated: ANG showed the strongest non-fatal MACE association (HR = 3.88, 95%CI 2.33-6.48, p<0.001), and all high-expression groups had elevated non-fatal MACE risk. GO/KEGG enrichment highlighted inflammatory-immune pathways like positive regulation of MAPK cascade, Cytokine-cytokine receptor interaction and PI3K-Akt signaling pathway as key mechanisms. The model integrating proteins, demographic factors, and clinical variables achieved the highest predictive performance across non-fatal MACE (AUC = 0.768), myocardial infarction (MI) (0.808), and stroke (0.816) outcomes, with superior stability in cross-validation. CoxBoost + Elastic Net framework was selected as the optimal framework via benchmarking of 101 algorithms. The model demonstrated favorable calibration in high-risk patients and yielded positive net clinical benefit across decision thresholds of 5% to 45%. The web tool (https://jiangli2941.github.io/MACE-prediction-v2/) enables input of 28 variables, outputs non-fatal MACE risk status, risk probability, and highlights abnormal indicators. CONCLUSION: Plasma proteomics combined with machine learning identifies robust non-fatal MACE predictors in DKD.

Humans↗

PubMed2006

Novel treatment approaches for patients with multiple myeloma.

Treatment options for patients with multiple myeloma are a rapidly progressing area of clinical and scientific development. The discovery of key signaling pathways needed for myeloma cell growth and proliferation has resulted in a plethora of new and different treatment options. Chief among these new agents are the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide and lenalidomide. Efficacy for these agents has been extensively studied in the relapsed and refractory states, and more recently in induction therapy. Impressive responses have been observed in the induction and relapsed disease states, completely changing the disease treatment paradigms. Building on these successes and strong preclinical work, other signal transduction inhibitors are being tested in phase I and phase II clinical trials. These include agents that target histone acetylation, farnesylation, heat shock proteins, and direct AKT-targeting agents. Additionally, monoclonal antibody targets are being developed in an effort to target the tumor cells extracellularly. Clinical trial development based on preclinically designed rational combinations and targets have the potential to rapidly translate these findings into meaningful clinical responses.

Angiogenesis Inhibitors↗

PubMed2002

An aspirin-triggered lipoxin A4 stable analog displays a unique topical anti-inflammatory profile.

Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to LTB(4). A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA(4) analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.

Administration, Cutaneous↗

PubMed2006

Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis.

Although IL-12 and IL-23 share the common p40 subunit, IL-23, rather than IL-12, seems to drive the pathogenesis of experimental autoimmune encephalomyelitis and arthritis, because IL-23/p19 knockout mice are protected from disease. In contrast, we describe in this study that newly created LacZ knockin mice deficient for IL-23 p19 were highly susceptible for the development of experimental T cell-mediated TNBS colitis and showed even more severe colitis than wild-type mice by endoscopic and histologic criteria. Subsequent studies revealed that dendritic cells from p19-deficient mice produce elevated levels of IL-12, and that IL-23 down-regulates IL-12 expression upon TLR ligation. Finally, in vivo blockade of IL-12 p40 in IL-23-deficient mice rescued mice from lethal colitis. Taken together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis.

Animals↗

PubMed1999

Ethanol and protein kinase C.

Protein kinase C (PKC) is involved in the control of many key signaling pathways in cells. Investigations over the past decade have shown that many effects of ethanol on cell function are closely interconnected with PKC. Three distinct areas of investigation have emerged; they are reviewed in this article. In vitro studies show that ethanol and higher alcohols can both inhibit or enhance PKC activity, depending on the experimental conditions. These studies show that alcohols interact directly with PKC, suggesting at least some role of this interaction in intoxication and anesthesia. Most ion channel systems are modulated by ethanol to varying degrees, and inhibition of PKC attenuates this effect; however, the mechanism by which ethanol brings about this effect is not known. Lastly, prolonged or chronic ethanol exposure up-regulates PKC, an effect that has important consequences, for example, in neuronal development; again, the mechanism leading to this process is not understood. The current consensus is that PKC is intimately involved in acute and chronic ethanol action, and the challenge now is to determine the mechanisms involved so that strategies can be developed to control these effects.

Animals↗

PubMed2001

Association of ARNT splice variants with estrogen receptor-negative breast cancer, poor induction of vascular endothelial growth factor under hypoxia, and poor prognosis.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix transcription factor that forms heterodimers with the aryl hydrocarbon receptor (AhR) or hypoxia inducible factor-1alpha to activate transcription via xenobiotic response element or hypoxia response element, respectively. Thus, it plays a major role in two key biochemical pathways involved in tumor growth. We previously showed that estrogen receptor (ER)-negative breast cancer cell lines expressed a splice variant of ARNT that was associated with Ah nonresponsiveness. We have now used a sensitive PCR method to analyze the expression of the variant in a series of 92 breast cancers to assess interactions with the ER and prognosis. The splice variant could be detected in all of the cases examined, with high ratios of variant:full-length ARNT (> or =10) characterized in 10 cases. When the patient group was split into quartiles by increasing splice variant ratios, there was an inverse relationship of ER status to ARNT splice-variant ratios (P = 0.01, chi(2)). Univariate analysis showed that cases with high ARNT splice-variant ratios > or =10 had a worse relapse-free and overall survival (P > or = 0.03; hazard ratio, 2.7; and P = 0.006; hazard ratio, 3.9, respectively). In multivariate analysis for relapse-free and overall survival, ARNT splice-variant ratio was the strongest independent factor and, although inversely related to ER, remained a separate risk factor. At least two potential mechanisms could explain this phenomenon: the loss of aryl hydrocarbon receptor-mediated antiestrogenic activity or the blockade of a proapoptotic pathway induced by hypoxia. Because several enzymes involved in drug resistance are induced through a xenobiotic response element, the tumors presenting high ARNT splice-variant ratios may be specifically targeted by drugs normally degraded or inactivated. This study shows the biological importance of ARNT splice variants in the behavior of human breast cancer and suggests that the breast cell lines in which the splice variant was discovered may be useful models for further investigation.

Adult↗