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At least 253 records · Page 14Linked to original sources

PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8⁺ effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗

PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗

PubMed1998

Subtracted, unique-sequence, in situ hybridization: experimental and diagnostic applications.

Nonrandom chromosomal aberrations, particularly in cancer, identify pathogenic biological pathways and, in some cases, have clinical relevance as diagnostic or prognostic markers. Fluorescence and colorimetric in situ hybridization methods facilitate identification of numerical and structural chromosome abnormalities. We report the development of robust, unique-sequence in situ hybridization probes that have several novel features: 1) they are constructed from multimegabase contigs of yeast artificial chromosome (YAC) clones; 2) they are in the form of adapter-ligated, short-fragment, DNA libraries that may be amplified by polymerase chain reaction; and 3) they have had repetitive sequences (eg, Alu and LINE elements) quantitatively removed by subtractive hybridization. These subtracted probes are labeled conveniently, and the fluorescence or colorimetric detection signals are extremely bright. Moreover, they constitute a stable resource that may be amplified through at least four rounds of polymerase chain reaction without diminishing signal intensity. We demonstrate applications of subtracted probes for the MYC and EWS oncogene regions, including 1) characterization of a novel EWS-region translocation in Ewing's sarcoma, 2) identification of chromosomal translocations in paraffin sections, and 3) identification of chromosomal translocations by conventional bright-field microscopy.

Burkitt Lymphoma↗

PubMed1977

Reductive dechlorination of DDT by haem proteins.

DDT1 is converted to DDD by reduced myoglobin (rapidly), cytochrome c oxidase, and a haem-containing undecapeptide derived from cytochrome c. Cytochrome c itself is inactive. This demonstrates that an accessible haem site is necessary for the reaction. Spectrophotometric evidence is presented for an interaction between DDT and the undecapeptide. These results cast light on one of the biological pathways for the breakdown of DDT.

Animals↗

PubMed1999

Transition metal ion-catalyzed oxygen activation during pathogenic processes.

Most pathological processes include the production of activated oxygen species augmented or attenuated by transition metal ions catalyzing one electron transitions. Inhalation of airborne particles, infections, ingestion of toxins or liberation from endogenous stores represent biological pathways for the induction of pathogenic processes by these metal ions. In this short review basic reactions involving transition metal ions operating during oxidative stress in certain diseases will be discussed.

Catalysis↗

PubMed2003

Monoamines stimulate sex reversal in the saddleback wrasse.

Monoamine neurotransmitters (norepinephrine, dopamine, and serotonin) play an important role in reproduction and sexual behavior throughout the vertebrates. They are the first endogenous chemical signals in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis. In teleosts with behavioral sex determination, much is known about behavioral cues that induce sex reversal. The cues are social, processed via the visual system and depend on the ratio of females to males in the population. The mechanisms by which these external behavioral cues are converted to an internal chemical regulatory process are largely unknown. The protogynous Hawaiian saddleback wrasse, Thalassoma duperrey, was used to investigate the biological pathway mediating the conversion of a social cue into neuroendocrine events regulating sex reversal. Because monoamines play an important role in the regulation of the HPG axis, they were selected as likely candidates for such a conversion. To determine if monoamines could affect sex reversal, drugs affecting monoamines were used in an attempt to either induce sex reversal under non-permissive conditions, or prevent sex reversal under permissive conditions. Increasing norepinephrine or blocking dopamine or serotonin lead to sex reversal in experimental animals under non-permissive conditions. Increasing serotonin blocked sex reversal under permissive conditions, while blocking dopamine or norepinephrine retarded the process. The results presented here demonstrate that monoamines contribute significantly to the control sex reversal. Norepinephrine stimulates initiation and completion of gonadal sex of reversal as well as color change perhaps directly via its effects on the HPG axis. Dopamine exercises inhibitory action on the initiation of sex reversal while 5-HT inhibits both initiation and completion of sex reversal. The serotonergic system appears to be an integral part of the pathway mediating the conversion of a social cue into a neuroendocrine event. The complex organization of neurochemical events controlling the psychosocial, physiological, and anatomical events that constitute reversal of sexual identity includes monoamine neurotransmitters.

Adaptation, Physiological↗

PubMed2003

Crystal structure of the alpha1beta1 integrin I domain in complex with an antibody Fab fragment.

The alpha1beta1 (VLA-1) integrin is a cell-surface receptor for collagen and laminin and has been implicated in biological pathways involved in several pathological processes. These processes may be inhibited by the monoclonal antibody AQC2, which binds with high affinity to human alpha1beta1 integrin. To understand the structural basis of the inhibition we determined the crystal structure of the complex of a chimeric rat/human I domain of the alpha1beta1 integrin and the Fab fragment of humanized AQC2 antibody. The structure of the complex shows that the antibody blocks the collagen binding site of the I domain. An aspartate residue, from the CDR3 loop of the antibody heavy chain, coordinates the MIDAS metal ion in a manner similar to that of a glutamate residue from collagen. Substitution of the aspartate residue by alanine or arginine results in significant reduction of antibody binding affinity. Interestingly, although the mode of metal ion coordination resembles that of the open conformation, the I domain maintains an overall closed conformation previously observed only for unliganded I domains.

Crystallography, X-Ray↗

PubMed2003

[Fish omega-3 fatty acids and risk of coronary heart disease].

A great amount of evidence from epidemiological studies and clinical trials supports a protective effect against coronary heart disease for fish consumption and intake of marine omega-3 fatty acids. Biological pathways for this risk reduction include membrane stabilization in the cardiac myocite, inhibition of platelet aggregation, favourable modifications of the lipid profile, decrease in blood pressure and reduction of the inflammatory response of the endothelium. Results from epidemiological studies suggest a threshold effect for the consumption of fish and omega-3 fatty acids. Risk reduction is especially important for cardiac sudden death. Nevertheless, protection against non-fatal coronary heart disease has also been observed. Recently published studies have shown that mercury intake, present in high concentrations in fish, could counteract the beneficial effect from fish consumption.

Clinical Trials as Topic↗

PubMed1998

Some aspects on radiation induced transmissible genomic instability.

The early observations on the possible induction of transmissible genomic instability after exposure to ionising radiation has received a strong support in the literature during the last 10 years. Aided by new research tools in biology, the better understanding of the mechanisms behind genomic instability leads to conclusions which are challenging the existing views on the interaction and response of the genome to radiation or chemicals. It has become commonly accepted that the full revelation of biological pathways leading to the loss of stability of the genome will also be a major step in the understanding of carcinogenesis. In this short review, some aspects of the recent knowledge and their implications are discussed.

Cell Death↗

PubMed2001

The role of fat cell derived peptides in age-related metabolic alterations.

Aging in humans is associated with alterations in body fat distribution and a parallel gradual increase in the prevalence of atherosclerotic cardiovascular disease, as well as mortality of all causes. Because of nutrient cost, availability, and the sedentary life-style, half of the western world population has fat mass in excess of 30% of the body weight that weighs 3-4 times more than the fat mass of lean subjects. Recent discoveries of various hormones, cytokines and complement factors secreted by adipose cells opened a new avenue of research, looking at the role of these fat derived peptides in different conditions. We will focus here on the potential role of fat tissue in different physiological and physiopathological conditions associated with age-related metabolism and risk factors for diseases. We will also exemplify how body fat capacity, distribution and function can be directly linked, and may play a central role in energy metabolism and homeostasis, atherosclerosis, and possibly in the defense against cancer. We hypothesize that biological pathways involved in nutrient regulation in fat tissue may be important in inducing longevity in calorie restricted animals.

Adipocytes↗

PubMed1996

Childhood social circumstances and psychosocial and behavioural factors as determinants of plasma fibrinogen.

BACKGROUND: High plasma fibrinogen concentration is associated with an increased risk of coronary heart disease. We have investigated associations between plasma fibrinogen and factors operating in childhood and in adulthood, including the psychosocial characteristics. METHODS: In a cross-sectional study of Civil Servants in London, UK, 2095 men and 1202 women aged 45-55 years provided blood samples for fibrinogen measurement at the time of the Whitehall II study baseline. The participants completed a questionnaire on demographic characteristics, education, employment grade, parents' occupation, health behaviours, and work characteristics. FINDINGS: Measures of childhood environment (adult height, father's social class, and participant's education) were inversely associated with adult plasma fibrinogen concentration in both sexes. Lower socioeconomic status (as shown by employment grade) was associated with higher fibrinogen concentrations, with differences from top to bottom grade of 0.22 g/L (95% Cl 0.13-0.31) in men and 0.37 g/L (0.18-0.56) in women (p<0.0001, both sexes). This association was not accounted for by measures of childhood circumstances. Control over work, assessed by personnel managers, was inversely related to fibrinogen in both sexes, and a similar relation was seen for self-rated control over work among men but not women. Men in the bottom third of the distribution for self-rated and externally assessed control over work had higher fibrinogen concentrations than those in the top third for both measures (difference 0.16 g//L [0.07-0.26]; p<0.001.) There was no difference between these extremes among women (0.02 g/L [0.16 to 0.19]). Current smokers had higher fibrinogen concentrations than non-smokers, and moderate alcohol consumers had lower concentrations than those who drank occasionally or never. INTERPRETATION: Although our study was cross-sectional, it provides evidence that adult fibrinogen concentration is determined by factors operating throughout life. Fibrinogen may be a marker of the biological pathways that mediate the inverse socioeconomic gradient in coronary disease.

Adult↗

PubMed2001

Stearyl poly(ethylene oxide) grafted surfaces for preferential adsorption of albumin.

An ideal surface for many biomedical applications would resist non-specific protein adsorption while at the same time triggering a specific biological pathway. Based on the approach of selectively binding albumin to free fatty acids, stearyl groups were immobilized onto poly(styrene) backbone via poly(ethylene oxide) side chains. X-ray photoelectron spectroscopy (XPS) analysis indicates substantial surface enrichment of the stearyl poly(ethylene oxide) (SPEO). In an aqueous environment, the surface rearrangement is limited, as proved by dynamic contact angle tests. The comb-like copolymer presents a special hydrophobic surface with high SPEO surface density, which may be due to the 'tail like' SPEO architecture at the copolymer/water interface. Protein adsorption tests confirm that the comb-like surfaces adsorb high levels of albumin and resist fibrinogen adsorption very significantly. The surfaces prepared in this research attract and reversibly bind albumin due to the synergistic action of the PEO chains and the stearyl end groups.

Adsorption↗

PubMed2002

Complex regulation of thyroid hormone action: multiple opportunities for pharmacological intervention.

The thyroid hormone (TH; 3,3',5,5'-tetra-iodothyronine and 3,3',5'-triiodothyronine) regulates growth, development, and critical metabolic functions. Thyroid diseases are among the most prevalent group of metabolic disorders in the Western world. TH exerts effects through complex biological pathways, which offer a wealth of opportunities to pharmacologically intervene in TH signalling at numerous steps. These include biosynthesis, cell-specific uptake or export (involving L-type amino acid transporter, organic anion transporter, organic cation transporter, or multidrug resistance transporter), as well as nuclear targeting and actions (the latter including TH receptor binding and histone acetylation/deacetylation). Such processes represent potentially important pharmacological targets for the design of novel or improved therapies for TH disorders, obesity, and cardiovascular diseases.

Receptors, Thyroid Hormone↗

PubMed2002

Targeted therapy in non-small cell lung cancer.

Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) offers only modest benefits over best supportive care alone by modestly prolonging survival, reducing symptoms, and improving quality of life. Despite the introduction of a number of new agents over the past decade, we have seen no convincing improvements in efficacy and safety with platinum-based regimens. It appears that a plateau has been reached in the development of traditional cytotoxic chemotherapy and a new paradigm is needed. Novel treatment modalities have emerged from advances in the understanding of tumor cell biology. These sophisticated new agents home in on and neutralize specific targets in the biologic pathway of cancer. This "targeted therapy" represents a new generation of anticancer treatment and a chance to revitalize the moribund state of NSCLC treatment.

Angiogenesis Inhibitors↗

PubMed2003

Understanding the mechanisms of action of EGFR inhibitors in NSCLC: what we know and what we do not know.

The development of rationally designed agents targeting specific biological pathways in tumor development has been heralded as a major paradigm shift in the approach to the treatment of cancer. The application of these agents has lead to promising pre-clinical findings in a variety of human cancer pre-clinical models including lung cancer. Results from initial clinical trials employing targeted agents have shown that in contrast to what was expected, only selected patients may benefit. Determining which patients will benefit remains a major challenge. Findings from the 'Iressa' Dose Evaluation in Lung Cancer and INTACT trials for non-small cell lung cancer (NSCLC) require investigators to return to the laboratory to design relevant pre-clinical studies that improve our ability to predict response to targeted agents in the clinic.

Antineoplastic Agents↗

PubMed2003

Genetics of psoriasis: the potential impact on new therapies.

There is considerable epidemiologic evidence that genes play a key role in the pathogenesis of psoriasis. It is also clear that multiple genes are involved and that the disease is genetically heterogeneous. Important interactions with the environment are also implicated in its development. A number of genetic loci have been identified by genome wide linkage scans and two loci have been replicated: PSORS1 on chromosome 6, within the major histocompatibility complex, and PSORS2 on chromosome 17q. Understanding the genetic basis of psoriasis will represent a major advance in our understanding of the disease and will reveal novel disease-specific biologic pathways. This information will be used to develop more specific diagnostic and prognostic tools and also lead to the development of individualized treatment plans. Benefits of the latter include more effective and safer treatments and potentially major pharmaco-economic gain.

Chromosome Mapping↗

PubMed2001

Hypoglycaemia-induced cell death: features of neuroprotection by the P2 receptor antagonist basilen blue.

Our previous work in neuronal cultures has shown that several antagonists of P2 ATP receptors prevent cell death evoked by hypoglycaemia, chemical hypoxia, mitochondria dysfunction, as well as glutamate-dependent excitotoxicity and low potassium-induced apoptosis. Experiments are now designed to examine which biological pathway contributes to cell death/survival under glucose starvation. We show here that, consequently to hypoglycaemic insults, cerebellar granule neurones undergo a combination of apoptosis and necrosis both inhibited by the P2 receptor antagonist basilen blue. This is demonstrated by morphological and biochemical features, such as TdT-mediated dUTP-biotin nick end-labelling, fluorescent staining of nuclear chromatin using Hoechst 33258, direct counting of intact viable nuclei and extracellular releasing of the cytosolic enzyme LDH. Furthermore, we show that hypoglycaemia induces outflow of cytochrome c from mitochondria and it up-regulates heat-shock proteins HSP70, but not HSP90, glucose-regulated proteins GRP75 and GRP78, as well as expression and activity of the enzyme caspase-2. Basilen blue can modulate only some of these effects. Our data contribute to dissect the role played by P2 receptor antagonism in sustaining neuroprotection against metabolic stresses.

Animals↗

PubMed2002

Molecular biology of lung cancer: clinical implications.

This review summarizes the rapidly expanding knowledge of the molecular pathogenesis of lung cancer. It is clear that respiratory epithelial cells require many genetic alterations to become invasive and metastatic cancer. Much more is to be learned, but with modern technology. Clinicians can detect "field cancerized" regions and preneoplastic and malignant cells, therefore offering the opportunity to intercede with biomarker-monitored prevention and early detection efforts. Such molecular screening and detection efforts will likely be coupled to advances in low-dose computed tomographic imaging, positron emission tomography scans, and other imaging modalities. Although this molecular marker approach has great potential, there is not yet a molecular marker validated in large prospective trials that has major independent predictive prognostic value. There is an urgent need for large, adequately powered, carefully designed prospective studies to identify clinically useful new biomarkers. Finally, new therapeutic strategies with genetic manipulation, small molecules, antibodies, vaccines, and, particularly, new drugs targeting specific biologic pathways found to be abnormal in lung provide for future optimism. Researchers need to define their individual value, especially when integrated with standard therapies.

Biomarkers, Tumor↗