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At least 199 records · Page 11Linked to original sources
PubMed1999

A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects.

Microdeletions of chromosome 22q11 are the most common genetic defects associated with cardiac and craniofacial anomalies in humans. A screen for mouse genes dependent on dHAND, a transcription factor implicated in neural crest development, identified Ufd1, which maps to human 22q11 and encodes a protein involved in degradation of ubiquitinated proteins. Mouse Ufd1 was specifically expressed in most tissues affected in patients with 22q11 deletion syndrome. The human UFD1L gene was deleted in all 182 patients studied with 22q11 deletion, and a smaller deletion of approximately 20 kilobases that removed exons 1 to 3 of UFD1L was found in one individual with features typical of 22q11 deletion syndrome. These data suggest that UFD1L haploinsufficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion.

Adaptor Proteins, Vesicular Transport↗
PubMed1988

Independent molecular pathways in initiation and loss of hormone responsiveness of breast carcinomas.

These studies were set up to determine whether those oncogenes participating in the initiation of mammary carcinogenesis (for example, ras oncogenes) play a direct role in the outcome of events associated with the late stages of tumor development such as loss of hormone dependency. Mammary carcinomas induced by a single carcinogenic insult in pubescent rats was selected as an in vivo model system with direct relevance to human breast cancer. Acquisition of hormone-independent growth in these carcinogen-induced tumors was found to be independent of the activation of ras oncogenes during the early stages of carcinogenesis. In agreement with these observations, introduction of a human ras oncogene into human MCF-7 breast carcinoma cells did not abrogate their hormonal dependency for growth in vivo. These findings suggest that those events responsible for the critical stages of breast cancer development occur independently and in an uncoordinated manner.

Animals↗
PubMed2005

Molecular pathways leading to cancer cachexia.

Loss of body weight in cancer patients strongly influences morbidity and mortality. Recent studies have suggested that both tumor and host factors play a major role in tissue catabolism in cachexia, leading to upregulation of degradative pathways in both skeletal muscle and adipose tissue.

Adipose Tissue↗
PubMed2005

Hereditary hormone excess: genes, molecular pathways, and syndromes.

Hereditary origin of a tumor helps toward early discovery of its mutated gene; for example, it supports the compilation of a DNA panel from index cases to identify that gene by finding mutations in it. The gene for a hereditary tumor may contribute also to common tumors. For some syndromes, such as hereditary paraganglioma, several genes can cause a similar syndrome. For other syndromes, such as multiple endocrine neoplasia 2, one gene supports variants of a syndrome. Onset usually begins earlier and in more locations with hereditary than sporadic tumors. Mono- or oligoclonal ("clonal") tumor usually implies a postnatal delay, albeit less delay than for sporadic tumor, to onset and potential for cancer. Hormone excess from a polyclonal tissue shows onset at birth and no benefit from subtotal ablation of the secreting organ. Genes can cause neoplasms through stepwise loss of function, gain of function, or combinations of these. Polyclonal hormonal excess reflects abnormal gene dosage or effect, such as activation or haploinsufficiency. Polyclonal hyperplasia can cause the main endpoint of clinical expression in some syndromes or can be a precursor to clonal progression in others. Gene discovery is usually the first step toward clarifying the molecule and pathway mutated in a syndrome. Most mutated pathways in hormone excess states are only partly understood. The bases for tissue specificity of hormone excess syndromes are usually uncertain. In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter. Polyclonal excess of a hormone is usually from a defect in the sensor system for an extracellular ligand (e.g., calcium, glucose, TSH). The final connections of any of these polyclonal or clonal pathways to hormone secretion have not been identified. In many cases, monoclonal proliferation causes hormone excess, probably as a secondary consequence of accumulation of cells with coincidental hormone-secretory ability.

Endocrine Gland Neoplasms↗
PubMed2002

Cellular and molecular pathways regulating mammalian sex determination.

In mammals, sex is determined by the presence or absence of a single gene on the Y chromosome, Sry. Sry, a member of the high mobility group family of transcription factors, is required to initiate male-specific pathways and repress female-specific pathways. Expression of Sry in the gonad, beginning at 10.5 days postcoitum, leads to the differentiation of the somatic supporting cell precursors as Sertoli cells. These cells direct the other cells of the gonad into their respective lineages. Currently, no direct targets of Sry are known. A number of cellular pathways initiated by Sry are required for testis development. These include the proliferation of pre-Sertoli cells and commitment to the Sertoli lineage, migration of cells from the adjacent mesonephros, and formation of a male-specific vasculature. Work is underway to identify genes controlling these processes. These genes will then be linked to Sry.

Animals↗
PubMedDate not supplied

Molecular pathways of anxiety revealed by knockout mice.

Anxiety is a normal reaction to threatening situations, and serves a physiological protective function. Pathological anxiety is characterized by a bias to interpret ambiguous situations as threatening, by avoidance of situations that are perceived to be harmful, and/or by exaggerated reactions to threat. Although much evidence indicates the involvement of the gamma-aminobutyric acid, serotonin, norepinephrine, dopamine, and neuropeptide transmitter systems in the pathophysiology of anxiety, little is known about how anxiety develops and what genetic/environmental factors underlie susceptibility to anxiety. Recently, inactivation of several genes, associated with either chemical communication between neurons or signaling within neurons, has been shown to give rise to anxiety-related behavior in knockout mice. Apart from confirming the involvement of serotonin, gamma-aminobutyric acid, and corticotrophin-releasing hormone as major mediators of anxiety and stress related behaviors, two novel groups of anxiety-relevant molecules have been revealed. The first group consists of neurotrophic-type molecules, such as interferon gamma, neural cell adhesion molecule, and midkine, which play important roles in neuronal development and cell-to-cell communication. The second group comprises regulators of intracellular signaling and gene expression, which emphasizes the importance of gene regulation in anxiety-related behaviors. Defects in these molecules are likely to contribute to the abnormal development and/or function of neuronal networks, which leads to the manifestation of anxiety disorders.

Animals↗
PubMed2003

Molecular pathways in cerebral ischemia: cues to novel therapeutic strategies.

Stroke is one of the leading causes of death and severe disability in most industrialized countries. Despite the extensive research efforts of both academic and industrial laboratories during the last few decades, no changes have been brought about by the design of neuroprotective therapies. The progressive decrease of stroke-induced death and disability is entirely attributable to improvements in the identification and reduction of risk factors. Over the past few years, experimental research has led to the emergence of a wealth of information regarding the complex and interrelated processes of neuronal degeneration and death triggered by ischemia. This unprecedented insight has led to new theories on the mechanisms of ischemic damage, and has suggested new targets and strategies for therapeutic intervention designed to reduce the clinical consequences of stroke. Among current developments, three strategies seem particularly appealing namely, the limitation of initial or secondary neuronal death by inhibition of apoptotic mechanisms, the enhancement of the endogenous capacity of nervous structures to restore lost function, and the replacement of lost cells by transplantation therapy.

Animals↗
PubMed2004

The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression.

The p16INK4a tumor suppressor protein functions as an inhibitor of CDK4 and CDK6, the D-type cyclin-dependent kinases that initiate the phosphorylation of the retinoblastoma tumor suppressor protein, RB. Thus, p16INK4a has the capacity to arrest cells in the G1-phase of the cell cycle and its probable physiological role is in the implementation of irreversible growth arrest termed cellular senescence. Cellular senescence is a state of permanent growth arrest that can be induced by a variety of stresses such as DNA-damage and aberrant mitogenic signaling in human primary cells. In contrast to normal cells, the function of the p16INK4a gene or its downstream mediators is frequently deregulated in many types of human cancers, illustrating the importance of cellular senescence in tumor suppression. Here we discuss the molecular mechanisms that direct cellular senescence and reveal its potential for tumor suppression.

Cell Cycle↗
PubMed2005

Molecular pathways of endothelial cell activation for (targeted) pharmacological intervention of chronic inflammatory diseases.

In chronic inflammatory conditions, endothelial cells actively recruit immune cells from the circulation into the underlying tissue and participate in angiogenesis to support the continuous demand for oxygen and nutrients. They do so in response to activation by cytokines and growth factors such as tumour necrosis factor alpha (TNFalpha), interleukin-1 (IL-1), vascular endothelial growth factor (VEGF), and fibroblast growth factors (FGFs). Receptor triggering initiates intracellular signal transduction leading to activation of nuclear factor kappaB (NFkappaB), mitogen activated protein kinase (MAPK) activity, and nitric oxide and reactive oxygen species production, among others. As a result, adhesion molecules, cytokines and chemokines, and a variety of other genes are being expressed that mediate and control the inflammatory process. In recent years, different classes of drugs have been developed that interfere with selected enzymes involved in the intracellular signalling cascades. In endothelial cell cultures, they exert potent inhibitory effects on the expression of genes, while several studies also report on in vivo effectiveness to confine the inflammatory responses. To prevent undesired toxicity and to improve drug behaviour and efficacy, drug carrier systems have been developed that selectively deliver the therapeutics into the activated endothelial cells. The above subjects are recapitulated to give an overview on the status of development of endothelial cell directed therapeutic strategies to pharmacologically interfere with chronic inflammatory diseases.

Animals↗
PubMed2025

Interconnected study of molecular pathways: miR-137 as a central element at the intersection of lipid metabolism and prostate carcinogenesis.

OBJECTIVE: To evaluate the roles of miR-137 and its target genes in lipid metabolism and prostate tumorigenesis. METHODS: We used a series of bioinformatic approaches to establish the relationship between miR-137 and its target genes. We mapped the metabolic pathways of interest in the Reactome database and identified the central target genes of miR-137 in this pathway using four platforms: Reactome, miRDB, miRmap, and TargetScan. To assess the expression and association with clinical parameters, we obtained information from the UALCAN, OncoDB, and GEPIA2 databases using a dataset of patients with prostate cancer from The Cancer Genome Atlas. For functional enrichment analysis and construction of the protein-protein interaction network, we used the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and STRING. RESULTS: Our in silico study of The Cancer Genome Atlas database revealed that miR-137 is underexpressed in tumor tissues, and its reduction is associated with poor prognosis. An intriguing set of eight genes within the PPARα pathway: PPARGC1A, PPARGC1B, NCOA1, NCOA2, NCOA3, MED1, MED27, and ESRRA displayed synergy, positive correlations, and synchronized expression patterns in adipose, hepatic, and prostatic tissues, all linked to the enigmatic processes of metabolic regulation. Among the highlighted genes, ESRRA was overexpressed in the malignant environment, whereas its counterparts remained underexpressed. The plot was thickened with associations between the expression of NCOA1, NCOA3, and MED27, lymph node involvement, and the overexpression of several genes linked to advanced prostate cancer stages. An intriguing pattern emerged, with patients exhibiting reduced disease-free survival overexpressing NCOA2, NCOA3, MED27, and ESRRA. CONCLUSION: This study elucidates the possibility that miR-137 subtly modulates metabolic genes in prostate cancer, suggesting its latent therapeutic potential as a biomarker for disease progression. BACKGROUND: ■ The reduction of miR-137 in tumor tissues is associated with a worse prognosis. BACKGROUND: ■ miR-137 has eight oncogenically relevant target genes acting in the PPARα lipid pathway. BACKGROUND: ■ NCOA1, NCOA3, MED27, and ESRRA are associated with advanced prostate cancer. BACKGROUND: ■ miR-137 exhibits significant clinical potential by repressing the activation of pathways that influence prostate tumorigenesis in hyperstimulated metabolic environments. BACKGROUND: Prostate cancer progression is sustained by the simultaneous activation of pathways involving lipid uptake and de novo synthesis. In this context, miR-137 inhibits adipogenic differentiation and may reduce lipid uptake by tumor cells by modulating the PPAR/ p160/ESRRA axis, considerably attenuating metabolic effects and suppressing prostate tumorigenesis.

Male↗
PubMed2026

Molecular Pathways, Target Landscape, and Translational Models in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a substantial global health burden and the greatest unmet medical need for cardiovascular diseases. It is marked by pronounced clinical heterogeneity and complex multi-system pathophysiology with limited therapeutic options. Progress in developing effective therapeutics is constrained by the inadequacy of experimental models to fully recapitulate the multifactorial nature of the disease. Recent evidence underscores the significant involvement of inflammatory, oxidative, and mitochondrial pathways in the pathogenesis of HFpEF, with non-coding RNAs and epigenetic regulation serving as crucial modulators and prospective therapeutic targets. This review maps the HFpEF target landscape, while critically assessing the mechanistic contributions, translational fidelity, and limitations of existing in vivo and in vitro models. Further, advances are noted among the in vitro technologies, including human cardiac organoids and engineered heart tissues integrated with high-throughput multi-omics and computational modeling, enabling in-depth examination of HFpEF mechanisms. Finally, we underscore the necessity of integrative, systems-level approaches and multi-marker strategies to enhance translational relevance, improve risk stratification, and accelerate development of mechanism-based therapies. Collectively, this review supports phenotypic-guided and mechanism-informed therapeutic development for HFpEF, and provides a roadmap for next generation model development and therapeutic innovation.

Humans↗
PubMed2005

Molecular pathways in the chemosensitization of cisplatin by quercetin in human head and neck cancer.

The aim of this study was to develop novel and less toxic therapy for human head and neck squamous cell carcinoma (HNSCCs) and to investigate the mechanism of quercetin-induced apoptosis in human laryngeal HeP2 cells and its effect on cisplatin induced apoptosis. Priming the cells with quercetin (40 microM) increased the apoptosis induced by cisplatin alone from 18.7% to 42.2% in HeP2 cells. Quercetin induced apoptosis via inhibition of Akt/PKB phosphorylation, an upstream kinase of pro-survival protein kinase cascade. Inhibition of Akt phosphorylation was coupled with a significant decrease of anti-apoptotic Bcl-2 and Bcl-XL. Quercetin caused a downregulation of Cu-Zn Superoxide Dismutase which perhaps led to an increase of reactive oxidative stress (ROS). The decrease of Bcl-2 and Bcl-XL along with this oxidative stress caused release of mitochondrial cytochrome c into the cytosol and subsequent induction of pro-caspase-9 processing. Inhibition of heat shock proteins may be another mechanism for the pro-apoptotic activity of quercetin. Cisplatin induced apoptosis appears to be partly due to induction of JNK activity which leads to the activation of endonucleases. Increased JNK activity led to increased phosphorylation of c-Fos. Cisplatin additionally appears to induce apoptosis by down-regulating the enzyme Nitric Oxide Synthase (NOS). Cisplatin also acts by increasing pro-apoptotic Bax concentration in the cells thereby leading to caspase-9 activation via the mitochondrial pathway. These results support the fact that quercetin and cisplatin act by separate pathways and demonstrate interactions between the pathways that result in synergistic actions. Possibly of greater potential value is the interaction of a conventional cytotoxic drug (cisplatin) and a nontoxic chemopreventive agent (quercetin) thereby allowing the use of less toxic doses of chemotherapy for treatment of HNSCCs.

Apoptosis↗
PubMed2005

From immature lamin to premature aging: molecular pathways and therapeutic opportunities.

Accelerated aging or progeria has been a puzzling disease for many years. The recent findings involving the lamin A/FACE-1 (substrate/protease) system in the etiology of Hutchinson-Gilford progeria syndrome and related pathologies have shed some light on the mechanisms underlying the development of these devastating conditions. Thus, genetic defects in the nuclear envelope protein prelamin A or in the FACE-1 metalloprotease (also called Zmspte24) involved in prelamin A proteolytic maturation, cause the accumulation of an abnormal form of this protein and the subsequent disruption of nuclear envelope integrity. Recently, we and others have observed how this disruption leads to alterations in chromatin organization, genomic instability, transcriptional changes, and activation of a p53-linked signaling pathway. By using genetic manipulation approaches in mouse, we have shown that lowering prelamin A levels results in a total recovery of Zmpste24-deficient mice from the accelerated aging process. Moreover, p53 nullizygosity allows a modest but significant improvement in the premature aging phenotype, and contributes to delaying the onset of the progeroid condition. On the basis of these results, we propose different potential therapeutic approaches that could be tested in Zmpste24-deficient mice. These strategies, some of which are based on existing drugs, might contribute to the development of effective treatments for these dramatic pathologies.

Aging, Premature↗
PubMed2002

Cellular and molecular pathways of ischemic neuronal death.

Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of Ca2+ and Na+ that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.

Animals↗
PubMedDate not supplied

[Molecular pathways of T lymphocyte activation].

TRIGGERING T CELL ACTIVATION: A quiescent T cell must encounter an antigen presenting cell to become activated. The T receptor for the antigen delivers a first specific signal which alone is insufficient to trigger total T cell activation. A second signal independent of antigen recognition is furnished by the antigen presenting cell, leading to total activation. PATHWAYS CAPABLE OF DELIVERING THE SECOND SIGNAL: CD28 and CTLA-4 are two molecules capable of playing a powerful role in regulating immune response. The fate of B cells depends on the CD40 molecule they carry on their surface as well as on T cells which express its ligand. Adherence molecules CD11a/CD18 induce tight adherence between T cells and antigen presenting cells by binding their CD50 ligand (ICAM-3); this bond activates the T cell, completing the first signal. The CD2 pathway and its ligands, a constitutional expression on two partner cells, is a strong adherence pathway which also transmits two powerful activation signals for T cells. SEVERAL FUNCTIONAL STATES: These different activation pathways illustrate the subtle interaction between surface molecules, capable of inducing different functional states depending on the environment.

Antigens↗
PubMed2003

Molecular pathways of endoplasmic reticulum dysfunctions: possible cause of cell death in the nervous system.

This review summarizes recent information on the role of calcium in the process of neuronal injury with special attention to the role of calcium stores in the endoplasmic reticulum (ER). Experimental results present evidence that ER is the site of complex processes such as calcium storage, synthesis and folding of proteins and cell response to stress. ER function is impaired in many acute and chronic diseases of the brain which in turn induce calcium store depletion and conserved stress responses. Understanding the mechanisms leading to ER dysfunction may lead to recognition of neuronal protection strategies.

Animals↗