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PubMed2025

Identifying key palmitoylation-associated genes in endometriosis through genomic data analysis.

BACKGROUND: Palmitoylation, a post-translational lipid modification, has garnered increasing attention for its role in inflammatory processes and tumorigenesis. Emerging evidence suggests a potential association between palmitoylation and inflammatory responses in the pathogenesis of endometriosis. However, the precise mechanistic interplay remains elusive, necessitating further investigation. METHODS: This study integrated transcriptomic analysis and Mendelian randomization (MR) to identify a causal gene set implicated in endometriosis. Differentially expressed genes (DEGs) were first identified in the training dataset using the limma package in R. Weighted gene co-expression network analysis (WGCNA) was subsequently performed, leveraging Single Sample Gene Set Enrichment Analysis (ssGSEA)-derived scores of palmitoylation-related genes (PRGs) as phenotypic traits to identify key modular genes. The intersection of these key modular genes with DEGs yielded a refined gene set. Machine learning algorithms were then applied to further optimize gene selection, followed by external validation, immune infiltration analysis, RNA network construction, and exploration of potential targeted drug candidates. RESULTS: Through a rigorous screening process, VRK1, GALNT12, and RMI1 emerged as key genes associated with palmitoylation, exhibiting significant downregulation in endometriosis samples (P < 0.05), indicative of a potential protective role. Immune infiltration analysis further revealed strong correlations between these genes and M2 macrophages as well as resting Natural Killer (NK) cells. Additionally, investigations into the targeted RNA network and drug association profiling provided novel insights, laying the groundwork for future high-quality validation studies. CONCLUSIONS: This study employed a comprehensive analytical framework to identify palmitoylation-associated key genes in endometriosis. The integration of immunoinfiltration analysis, RNA network construction, and drug association profiling offers valuable insights for advancing clinical diagnostics, disease monitoring, and therapeutic development in endometriosis.

Humans↗

PubMed2002

Delayed short-term secretory regulation of ghrelin in obese animals: evidenced by a specific RIA for the active form of ghrelin.

Ghrelin is an acylated peptide, whose lipid modification is essential for its biological activities. Previous studies demonstrated that it strongly stimulates GH release and has a potent orexigenic action. Meanwhile, there is enough evidence showing that feeding states influence plasma ghrelin levels. Fasting stimulates ghrelin secretion, and feeding reduces plasma ghrelin levels. In this study we examined the regulation of plasma ghrelin by fasting in genetically obese animals considering its molecular forms. Plasma levels of active form of ghrelin as well as those of total ghrelin were reduced in ob/ob and db/db mice compared with those in their control mice. Zucker fatty (fa/fa) rats also showed lower plasma ghrelin levels by fasting than the control rats. Insulin-induced hypoglycemia, however, stimulated ghrelin secretion in the fasted fatty rats. Moreover, glucose injection was revealed to reduce plasma ghrelin levels in rats. The effect of the severity of obesity on secretory regulation of ghrelin was also studied. Older fatty rats showed low plasma ghrelin levels even after 48-h fasting. These data suggest that the short-term secretory regulation of total ghrelin and the active form of ghrelin is delayed in obese animals and that blood glucose levels may be involved in the delayed regulation.

Aging↗

PubMed2002

Genomic and nongenomic mechanisms of nitric oxide synthesis induction in human endothelial cells by a fourth-generation selective estrogen receptor modulator.

Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. EM-652 (acolbifene) is a fourth-generation selective ER modulator (SERM) exerting complete antiestrogenic effects on the breast and uterus. EM-652 potently inhibits bone resorption and induces positive lipid modifications in estrogen-deficient animals. As most of the cardioprotective actions of estrogen are exerted directly at the vascular level, we studied the effects of EM-652 on endothelial production of nitric oxide (NO) in vitro and in vivo. EM-652 triggers NO release by human umbilical vein endothelial cells through nongenomic mechanisms, rapidly activating endothelial nitric oxide synthase (eNOS) via an ER-dependent sequential activation of MAPKs and PI3K/Akt pathways independently from gene transcription or protein synthesis. Moreover, EM-652 increases eNOS protein levels during prolonged treatments. Upon pharmacological comparison, EM-652 is markedly more potent than the SERMs raloxifene and tamoxifen in increasing NO synthesis from endothelial cells. In ovariectomized and fertile rats, EM-652 increases aortic eNOS expression and enzymatic activity at low, but not at higher, dosages. The present data show that EM-652 (acolbifene) has estrogen-like activity on the vascular wall, directly increasing NO production through genomic and nongenomic mechanisms in vitro and in vivo.

Animals↗

PubMed2006

Signal dynamics in Sonic hedgehog tissue patterning.

During development, secreted signaling factors, called morphogens, instruct cells to adopt specific mature phenotypes. However, the mechanisms that morphogen systems employ to establish a precise concentration gradient for patterning tissue architecture are highly complex and are typically analyzed only at long times after secretion (i.e. steady state). We have developed a theoretical model that analyzes dynamically how the intricate transport and signal transduction mechanisms of a model morphogen, Sonic hedgehog (Shh), cooperate in modular fashion to regulate tissue patterning in the neural tube. Consistent with numerous recent studies, the model elucidates how the dynamics of gradient formation can be a key determinant of cell response. In addition, this work yields several novel insights into how different transport mechanisms or ;modules' control pattern formation. The model predicts that slowing the transport of a morphogen, such as by lipid modification of the ligand Shh, by ligand binding to proteoglycans, or by the moderate upregulation of dedicated transport molecules like Dispatched, can actually increase the signaling range of the morphogen by concentrating it near the secretion source. Furthermore, several transcriptional targets of Shh, such as Patched and Hedgehog-interacting protein, significantly limit its signaling range by slowing transport and promoting ligand degradation. This modeling approach elucidates how individual modular elements that operate dynamically at various times during patterning can shape a tissue pattern.

Animals↗

PubMed2003

Nitric oxide signaling specificity--the heart of the problem.

Nitric oxide (NO) is a gaseous free radical that functions as an endogenous mediator in numerous tissues. Because NO is both reactive and highly diffusible, its formation must be tightly regulated to control its synthesis and to specify its signaling. Indeed, molecular studies of the NO synthase (NOS) family of enzymes have elaborated a variety of mechanisms, including protein interactions, lipid modifications and protein phosphorylation cascades that spatially and temporally control NO biosynthesis. These mechanisms determine both the upstream cellular signals that stimulate NO formation and the downstream molecular targets for NO. Understanding these cellular pathways that control NOS will help us to elucidate the functional roles of NO and provide novel strategies to treat diseases associated with NO abnormalities.

Animals↗

PubMed2006

Key role of local regulation in chemosensing revealed by a new molecular interaction-based modeling method.

The signaling network underlying eukaryotic chemosensing is a complex combination of receptor-mediated transmembrane signals, lipid modifications, protein translocations, and differential activation/deactivation of membrane-bound and cytosolic components. As such, it provides particularly interesting challenges for a combined computational and experimental analysis. We developed a novel detailed molecular signaling model that, when used to simulate the response to the attractant cyclic adenosine monophosphate (cAMP), made nontrivial predictions about Dictyostelium chemosensing. These predictions, including the unexpected existence of spatially asymmetrical, multiphasic, cyclic adenosine monophosphate-induced PTEN translocation and phosphatidylinositol-(3,4,5)P3 generation, were experimentally verified by quantitative single-cell microscopy leading us to propose significant modifications to the current standard model for chemoattractant-induced biochemical polarization in this organism. Key to this successful modeling effort was the use of "Simmune," a new software package that supports the facile development and testing of detailed computational representations of cellular behavior. An intuitive interface allows user definition of complex signaling networks based on the definition of specific molecular binding site interactions and the subcellular localization of molecules. It automatically translates such inputs into spatially resolved simulations and dynamic graphical representations of the resulting signaling network that can be explored in a manner that closely parallels wet lab experimental procedures. These features of Simmune were critical to the model development and analysis presented here and are likely to be useful in the computational investigation of many aspects of cell biology.

Animals↗

PubMed2006

Secretion of pro- and mature Rhizopus arrhizus lipases by Pichia pastoris and properties of the proteins.

The lipases of Rhizopus spp. share a high 1,3-regiospecificity toward triacylglycerols, which makes them important enzymes in lipid modification. In the present study, the extracellularly active production of recombinant Rhizopus arrhizuslipase was carried out with genes encoding the mature region (mRAL) and the mRAL having the prosequence (ProRAL) in Pichia pastoris. Two transformed P. pastoris clones containing the multicopy of mRAL and ProRAL genes were separately selected for the production of recombinant enzymes. In a fed-batch cultivation, where methanol feeding was controlled by an on-line methanol analyzer, the supernatant contained 91 mg/L recombinant pro-form lipase (rProRAL) and 80 mg/L recombinant mature lipase (rRAL) after 92 h of cultivation. rProRAL and rRAL were purified by ultrafiltration, SP-Sepharose Fast Flow chromatography, and Butyl-Sepharose Fast Flow chromatography. Molecular weights of rProRAL and rRAL are 32 kDa and 29 kDa, respectively. The amino-terminal analysis showed that the 32-kDa protein was mRAL attached with 28 amino acids of the carboxy-terminal part of the prosequence (rPro28RAL). The specific lipase activities of mRAL attached with 28 amino acids of the carboxy-terminal part of the prosequence (rPro28RAL) and rRAL were 1543 U/mg and 2437 U/mg. The rPro28RAL was more stable than rRAL at pH 4.0-7.0, whereas rRAL was more stable at pH 7.0-10.0. The rPro28RAL had the highest lipase activity toward tributyrin (C4), whereas rRAL had the highest lipase activity toward tricaprylin (C8).

Amino Acid Sequence↗

PubMedDate not supplied

Upstream and downstream of ran GTPase.

Among the Ras family, Ran is a unique small G protein. It does not have a lipid modification motif at the C-terminus to bind to the membrane, which is often observed within the Ras family. Ran may therefore interact with a wide range of proteins in various intracellular locations. This means that Ran could play many different roles like nucleocytoplasmic transport, microtubule assembly and so on. All of the Ran functions should be regulated by RanGEF and RanGAP. It is an interesting issue why RCC1, a RanGEF, is localized in the nucleus and RanGAP1/Ran1p in the cytoplasm. It is possible that RCC1 checks the state of chromosomal DNA replication and transfers it to the downstream events through Ran; thereby, RCC1 would be involved in coupling the spatial localization of cellular macromolecules with the cell cycle progression. In this context, Ran will be a very important cell cycle mediator. There is yet another G protein cascade, Gtr1-Gtr2, which interacts with the Ran cycle.

Cell Cycle↗

PubMed2003

Protein prenyltransferases: anchor size, pseudogenes and parasites.

Lipid modification of eukaryotic proteins by protein prenyltransferases is required for critical signaling pathways, cell cycle progression, cytoskeleton remodeling, induction of apoptosis and vesicular trafficking. This review analyzes the influence of distinct states of sequential posttranslational processing that can be obtained after single or double prenylation, reversible palmitoylation, proteolytic cleavage of the C-terminus and possible reversible carboxymethylation. This series of modifications, as well as the exact length of the prenyl anchor, are determinants in protein-membrane and specific protein-protein interactions of protein prenyltransferase substrates. Furthermore, the occurrence and distribution of pseudogenes of protein prenyltransferase subunits are discussed. Besides being developed as anti-cancer agents, prenyltransferase inhibitors are effective against an increasing number of parasitic diseases. Extensive screens for protein prenyltransferases in genomic data of fungal and protozoan pathogens unveil a series of new pharmacologic targets for prenyltransferase inhibition, including the parasites Brugia malayi, Onchocerca volvulus, Aspergillus nidulans, Pneumocystis carinii, Entamoeba histolytica, Strongyloides stercoralis, Trichinella spiralis and Cryptosporidium parvum.

Animals↗

PubMed2004

The effect of risk factor changes on peripheral arterial disease and cardiovascular risk.

Peripheral arterial disease (PAD) due to atherosclerosis, although frequently ignored in clinical practice, results in significant cardiovascular morbidity and mortality and may progress due to uncontrolled atherosclerotic risk factors. Although treatment of claudication symptoms is important for improved lifestyle, treatment of risk factors will prolong life. Smoking cessation, blood pressure control, lipid modification and strict control of diabetes mellitus will reduce the risk of both macro and micro vascular disease progression. Risk factor modification in conjunction with antiplatelet treatment results in decreased heart attack, stroke and peripheral vascular events in patients with PAD.

Arteriosclerosis↗

PubMed2001

Dimerization of small GTPase Rab5.

Rab proteins are small GTPases, localized to distinct cellular compartments, regulating specific steps of intracellular membrane trafficking. One member of the Rab family, Rab5, consists of three isoforms, Rab5a, Rab5b, and Rab5c, which have been shown to play an important role in early events of endocytosis. Using the yeast two-hybrid system, we have identified several cytosolic proteins that interact with the Rab5b Q79L (decreasing intrinsic and GTPase-activating protein-stimulated GTPase activities). Surprisingly, most positive clones were Rab5b or Rab5c, indicating that Rab5 could dimerize among extra-isoforms in the yeast two-hybrid system. In vitro and in vivo chemical cross-linking assays demonstrated that lipid-unmodified wild-type Rab5b purified from Escherichia coli, wild-type Rab5b, or a dominant active form Rab5b Q79L expressed in human 293T cells dimerized. Furthermore, the same assays using a Rab5b R81A substitution mutant showed that the Arg81 in the Switch II region [the second GTP/GDP binding motif (residues 74-93)] was essential for Rab5b dimerization. These results suggest that Rab5 isoforms can be dimerized depending upon the GTP-bound conformation, but independent upon a lipid modification.

Amino Acid Sequence↗

PubMed2000

Serological cloning of a melanocyte rab guanosine 5'-triphosphate-binding protein and a chromosome condensation protein from a melanoma complementary DNA library.

Characterization of immunogenic human melanoma antigens has been a major focus of tumor immunologists over the past two decades, and a broad array of antigens recognized by antibodies and T cells in the autologous host has been defined. In the present study, a melanoma library was screened by SEREX (serological analysis of cDNA expression libraries), and 43 genes were isolated, 2 of which, NY-MEL-1 and NY-MEL-3, encode novel gene products with differential tissue expression. NY-MEL-1 encodes a new rab GTP-binding protein, rab38. Among >40 rab proteins, rab38 has a unique COOH terminus which would allow posttranslational farnesylation and palmitoylation, lipid modifications normally occurring in ras proteins but not in other rab proteins. It is also the only rab gene showing a predominant mRNA expression in melanocytes, a cell-specific expression pattern likely related to melanosomal transport and docking. Northern blot analysis showed no detectable expression in other normal tissues. Consistent with this lineage specificity, rab38 mRNA is expressed in 80-90% of melanoma (17 of 19), but rarely in nonmelanocytic malignancies (1 of 16). The second novel gene isolated, NY-MEL-3, encodes a mitotic protein highly homologous to the Xenopus chromosome condensation protein XCAP-G, designated hCAP-G. Analysis of hCAP-G mRNA expression showed highest expression in the testis among normal tissues and variable expression in tumor cells, reflecting the proliferative activity in these cells. This mitosis-related expression suggests hCAP-G as a possible proliferation marker and a potential prognostic indicator in cancer. These findings provide further support that SEREX can define biologically significant molecules in cancer.

Animals↗

PubMed2001

Assessment and management of intermittent claudication: importance of secondary prevention.

Atherosclerotic peripheral arterial disease (PAD) is a common disorder with a steep age-related incidence that affects 5-10% of the over 55-year age group. Because of the association with atherosclerotic disease elsewhere, particularly coronary heart disease (CHD), the ankle-brachial pressure index (ABPI) correlates inversely with survival. Clinical management centres around detection, assessment, symptom relief and prevention of secondary cardiovascular complications. Non-invasive ultrasound and colour duplex techniques have revolutionised the detection of PAD, and the long-term surveillance of disease progression, while antiplatelet therapy coupled with risk factor modification (lipids, blood pressure and glycaemic control and smoking cessation) are aimed at reducing direct or indirect vascular complications, e.g. amputation or CHD death. The natural history of intermittent claudication, although troublesome and disabling, often runs a stable, fairly benign course, so the majority of patients (73%) are treated medically. Selecting patients for surgical revascularisation (angioplasty, bypass or endarterectomy) is guided principally by the severity of clinical symptoms, but discrete, proximal, short-segmental lesions are the most amenable to surgical intervention. In general, surgery is indicated to relieve disabling symptoms when medical therapy had failed; for treatment of symptoms of limb-threatening ischaemia, including rest pain, ischaemic ulceration and gangrene; and to remove or bypass sources of thrombo-embolism. Thus, medical therapies for symptom relief and secondary prevention of complications form the mainstay of treatment for three-quarters of patients with uncomplicated intermittent claudication.

Angioplasty, Balloon↗

PubMed1992

Multidrug resistance: prospects for clinical management.

Clinical success in the treatment of tumors with chemotherapy has significantly improved over the past several years. However, treatment failures due to drug resistance of cancer cells has remained a major problem. The classical form of multiple drug resistance is perhaps also the most common type of drug resistance, and represents the overexpression of a transmembrane glycoprotein pump (P-170) that mediates the efflux of a spectrum of structurally and functionally unrelated drugs. Here, we discuss recent evidence that support the concept that the total phenomenon of multiple drug resistance (MDR) involves several other mechanisms in addition to that underlying "classical" MDR. These include the action of other energy-dependent membrane efflux pumps, elevated levels of GSH for drug conjugation and detoxification to facilitate export, enhanced DNA repair facility, gene amplification and oncogene activation. The combination of mechanisms used by any particular cell line is variable and suggests that many of these mechanisms are independent. Successful reversal of drug resistance appears to require the identification of relevant operative resistance mechanisms. An example is the competitive inhibition of P-170 with verapamil, quinine and tamoxifen. A broadly successful strategy for killing drug-resistant cancer cells, however, could be based on either selective energy depletion of cancer cells or the permeabilization of tumor cells with an effective bypass of efflux pumps, since many mechanisms of drug resistance entail the energy-dependent export of toxins. The latter approach may be achieved via membrane lipid modifications or the introduction of membrane pores by biological or physical (electroporation) means.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

HMG-CoA reductase inhibitors (statins) as anticancer drugs (review).

Apart from their lipid lowering activity, HMG-CoA reductase inhibitors (statins) impair numerous cellular functions associated with metastasis, e.g. gene expression, angiogenesis, cell adhesion, cell motility and invasiveness. Furthermore, statins have impact on apoptotic cell death and modulate cellular susceptibility to cell killing by anticancer drugs and ionizing radiation. Part of the effects provoked by statins are due to the inhibition of the prenylation of low molecular weight GTPases, in particular Ras and Rho, which play key roles in signaling evoked by stimulation of cell surface receptors. C-terminal lipid modification of Ras/Rho GTPases is essential for their correct intracellular localization and function. By depletion of the cellular pool of isoprene precursor molecules, statins reduce the level of membrane-bound active Ras/Rho proteins, thereby impairing corresponding functions. Since broad clinical experience already exists for statins, their incorporation into established tumor-therapeutic regimens would be realizable in a rather short period of time. Here, data available at present arguing for the usefulness of statins in anticancer therapy are summarized and discussed.

Cell Adhesion↗

PubMedDate not supplied

Rhodiola rosea as antioxidant in red blood cells: ultrastructural and hemolytic behaviour.

Rhodiola rosea L. (Crassulaceae) is a plant that lives at high altitude in Europe and Asia, widely used for its high capacity to increase the organism resistance to different stress conditions. Although a few international literature supports these effects, today R. rosea has become a common component of many dietary supplements also in the Western world. The aim of the present study was to investigate the effect of the R. rosea roots aqueous extract on in vitro human erythrocytes exposed to hypochlorous acid (HOCl)-oxidative stress. Several damages occur in human erythrocytes exposed in vitro to HOCl, among these membrane protein and lipid modifications, shifting from the discocyte shape to the echinocyte one, and determining lysis ultimately. Therefore, in the present work, the evaluation of the antioxidant capacity of the Rhodiola extract has been carried out by means of scanning electron microscopy and of hemolytic behaviour on human erythrocytes exposed to HOCl in the presence of increasing doses of the aqueous extract in different experimental environments (co-incubation and subsequent incubations). The results obtained are consistent with a significant protection of the extract in presence of the oxidative agent, but a cautionary note emerges from the analysis of the data related to the cell exposition to the plant extract in the absence of any induced oxidative stress. In fact, the addition to erythrocyte of high doses of R. rosea extract always determines severe alterations of the cell shape.

Antioxidants↗

PubMed2006

Rho GTPases: promising cellular targets for novel anticancer drugs.

Ras-homologous (Rho) GTPases play a pivotal role in the regulation of numerous cellular functions associated with malignant transformation and metastasis. Rho GTPases are localized at membranes and become activated upon stimulation of cell surface receptors. In their GTP-bound (=active) state, Rho proteins bind to effector proteins, thereby triggering specific cellular responses. Members of the Rho family of small GTPases are key regulators of actin reorganization, cell motility, cell-cell and cell-extracellular matrix (ECM) adhesion as well as of cell cycle progression, gene expression and apoptosis. Each of these functions is of importance for the development and progression of cancer. Furthermore, Rho guanine exchange factors (GEFs) are often oncogenic and the expression level of Rho GTPases frequently increases with malignancy. Rho proteins also affect cellular susceptibility to DNA damaging agents, including antineoplastic drugs and ionizing radiation (IR). Thus, modulation of Rho driven mechanisms may influence the therapeutic efficiency and/or the side effects of conventional antineoplastic therapy. Because of their pleiotropic functions, Rho proteins appear to be promising targets for the development of novel anticancer drugs. Experimental approaches to inhibit Rho (and Ras) have focused on the attenuation of their C-terminal isoprenylation. This is because C-terminal lipid modification is required for correct intracellular localization and function of Rho/Ras. Inhibitors of farnesyltransferase (FTI), geranylgeranyltransferase (GGTI) as well as of HMG-CoA-reductase (i. e. statins) have been investigated with respect to their usefulness in tumor therapy. The studies showed that these compounds affect tumor progression and furthermore have impact on the frequency of cell death induced by tumor therapeutics. A possible drawback of inhibitors of isoprenylation is their poor selectivity for individual Rho GTPases. Therefore, specific inhibitors of individual Rho functions (notably RhoA-, RhoB-, Rac1- or Cdc42-related functions) are predicted to be of great therapeutic benefit. Indeed, compounds developed as specific inhibitors of the RhoA-effector molecule Rho-kinase (ROK) have been demonstrated to exert anti-metastatic activity in vivo.

Animals↗

PubMed1990

Alpha 1-adrenoreceptor blockade and the molecular basis of lipid metabolism alterations.

For the past 40 years, adrenoreceptors have been studied as the biomolecular mediators of tissue response to catecholamines. An expanded role of alpha-adrenoreceptors in the regulation of risk factors for coronary heart disease (CHD) has recently emerged. Hypercholesterolaemia, hypertension, and cigarette smoking are the major risk factors and their interactions are associated with increased mortality. Control of hypertension alone has failed to reduce the risk of CHD. Conversely, reduction of elevated total cholesterol and low density lipoprotein (LDL)-cholesterol has been shown to lower the risk of CHD. As a result, multiple risk factor approaches to the management of patients have evolved in attempts to reduce deaths from CHD. Selective alpha 1-adrenoreceptor antagonists appear to have a dual function in CHD risk management since they control elevated blood pressure by peripheral vasodilatation and reduce atherogenic lipids by several mechanisms. With selective alpha 1-blockade, the number of LDL-cholesterol receptors is up-regulated and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG Co-A reductase) activity is suppressed causing reductions in total cholesterol, LDL-cholesterol, and apoprotein B levels. Effects on intermediary metabolism reduce synthesis of very low density lipoprotein (VLDL) which contributes to a reduction of total triglyceride levels and, to a lesser extent, to a reduction of total cholesterol levels. Increased lipoprotein lipase activity leads to reduced total triglyceride and VLDL levels and to increased high density lipoprotein (HDL)-cholesterol levels. As demonstrated by the initial prospective data from Phase I of the Treatment of Mild Hypertension Study (TOMHS), both reduction of raised blood pressure and beneficial lipid modifications are sustained (1 year) with selective alpha 1-blockade. The prospective benefits on morbidity and mortality from CHD of such favourable changes in these two major risk factors remain to be quantified.

Adrenergic alpha-Antagonists↗