Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Fumarates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources
PubMedDate not supplied

Effect of transforming growth factor beta 2 on marrow-infused foam poly(propylene fumarate) tissue-engineered constructs for the repair of critical-size cranial defects in rabbits.

This study investigates the osseointegration of poly(propylene fumarate) (PPF) with beta-tricalcium phosphate (beta-TCP) scaffolds in a critical-size (diameter, 1.6 cm), cranial defect in 4-month-old rabbits (n = 51), killed at 6 or 12 weeks. Two molecular weights of PPF were used to produce bilayer scaffolds with 0.5-mm solid external and 2.0-mm porous internal layers. The porous layer was infused with bone marrow aspirate, with half the animals receiving 0.8 microg of transforming growth factor beta2 (TGF-beta2). No foreign body or inflammatory response was observed externally or on histological examination of explants. Statistical analysis of histological areal and linear measures of new bone formation found significantly more bone at the later sacrifice time, followed by implants receiving TGF-beta2, followed by low molecular weight PPF implants. Approximately 40% of the explants were tested for incorporation strength with a one-point "push-in" test. Because no permanent fixation was used, implant strength (28.37-129.03 N; range, 6.4 to 29.0 lb of resistance) was due entirely to new bone formation. The strongest bone was seen in implants receiving TGF-beta2-infused marrow in animals killed at 12 weeks. These results support the use of PPF as an osteogenic substrate and future research into preoperative fabrication of critical size and supercritical-size cranial prosthetic implants.

Animals↗
PubMed2003

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

Amino Acid Metabolism, Inborn Errors↗
PubMed1983

The electron transport chain of Escherichia coli grown anaerobically with fumarate as terminal electron acceptor: an electron paramagnetic resonance study.

The electron transport chain of Escherichia coli grown anaerobically on glycerol with fumarate as terminal electron acceptor, has been studied using electron paramagnetic resonance (EPR) spectroscopy. The analysis did not include cytochromes, but was confined to the lower potential (dehydrogenase) section of the electron transport chain. Several ferredoxin-type centres were detected and partially characterized, and the possible presence of iron-sulphur centres paramagnetic in their oxidized form ('HiPIP-type') was also noted. An EPR-detectable signal that may have been due to the presence of molybdenum in the electron transport chain is described and assessed. Most of the centres detected were reducible by substrate in the absence of oxidant and some were found to be wholly or partly reduced during steady state oxidation of substrates in the presence of oxygen.

Anaerobiosis↗
PubMed2004

Phosphorylation and DNA binding of the regulator DcuR of the fumarate-responsive two-component system DcuSR of Escherichia coli.

The function of the response regulator DcuR of the DcuSR fumarate two-component sensory system of Escherichia coli was analysed in vitro. Isolated DcuR protein was phosphorylated by the sensory histidine kinase, DcuS, and ATP, or by acetyl phosphate. In gel retardation assays with target promoters (frdA, dcuB, dctA), phosphoryl DcuR (DcuR-P) formed a high-affinity complex, with an apparent K(D) (app. K(D)) of 0.2-0.3 microM DcuR-P, and a low-affinity (app. K(D) 0.8-2 microM) complex. The high-affinity complex was formed only with promoters transcriptionally-regulated by DcuSR, whereas low-affinity binding was seen also with some DcuSR-independent promoters. The binding site of DcuR-P at the dcuB promoter was determined by DNase I footprinting. One binding site of 42-52 nt (position -359 to -400/-410 nt upstream of the transcriptional start) was identified in the presence of low and high concentrations of DcuR-P. Non-phosphorylated DcuR, or DcuR-D56N mutated in the phosphoryl-accepting Asp56 residue, showed low-affinity binding to target promoters. DcuR-D56N was still able to interact with DcuS. DcuR-D56N increased the phosphorylation of DcuS and competitively inhibited phosphoryl transfer to wild-type DcuR.

Base Sequence↗
PubMed2004

Fumaric acid esters in severe psoriasis, including experience of use in combination with other systemic modalities.

BACKGROUND: Fumaric acid esters (FAE) are used as a systemic treatment for severe psoriasis in Germany but there has been only very little published experience from the U.K. The potential for use in combination with other systemic drugs has not been explored. OBJECTIVES: To present data relating to the efficacy of FAE in severe psoriasis and to examine the potential dose-sparing effect and safety issues when FAE are combined with other systemic agents. METHODS: We retrospectively analysed the records of patients who had received FAE for severe psoriasis either alone (in two cases) or along with other systemic medications (in 10 cases). We reviewed the efficacy of FAE and assessed whether dose reductions were achieved for other systemic drugs. Patients were monitored carefully for possible adverse effects. RESULTS: Of 12 patients treated with FAE one discontinued the drug very early, due to flushing, while on a very low dose. The other 11 patients all demonstrated an improvement in psoriasis after starting FAE. Nine patients received FAE in combination with other systemic therapies including ciclosporin, acitretin, hydroxyurea and methotrexate. Seven achieved useful overall reductions in the dose of the other drugs. In two patients severe psoriasis was controlled using FAE alone. The side-effect profile of FAE was similar to that previously reported. There was no evidence of drug interactions. CONCLUSIONS: FAE appear effective and less toxic than other systemic treatments for psoriasis. FAE were used successfully in combination with other systemic agents and generally enabled the doses of the more hazardous drugs to be reduced. Extremely careful monitoring is required when using FAE in such combined regimens as experience is currently very limited.

Adult↗
PubMed2005

Therapy of noninfectious granulomatous skin diseases with fumaric acid esters.

BACKGROUND: Noninfectious granulomatous skin diseases are inflammatory disorders of unknown aetiology which are often recalcitrant to common anti-inflammatory treatment regimens. Recently, in several case reports, fumaric acid esters (FAE) have proved beneficial in granulomatous skin diseases, but studies on a larger collection of consecutive patients have not yet been performed. OBJECTIVES: To investigate the therapeutic efficacy of FAE for the treatment of granulomatous skin diseases. PATIENTS AND METHODS: The therapeutic efficacy and side-effects of FAE were analysed retrospectively in 32 patients with disseminated granuloma annulare (n = 13), annular elastolytic giant cell granuloma (n = 3), sarcoidosis (n = 11), necrobiosis lipoidica (n = 4), or granulomatous cheilitis (n = 1). RESULTS: Three patients discontinued treatment within 4 weeks because of side-effects. Of the remaining 29 patients, 18 patients responded to treatment with FAE. Marked improvement or complete clearance was seen in seven patients. We observed a slight to moderate improvement in 11 patients, and 11 patients did not respond. In patients showing a complete remission, the maximum effect was observed after 8.5 months (SD +/-6 months, range 3-20 months). In two patients with systemic sarcoidosis, the pulmonary changes improved in parallel with the skin. Side-effects were usually mild and resolved spontaneously upon dose reduction or discontinuation of the therapy. CONCLUSIONS: The data presented here indicate that FAE may be considered for the treatment of recalcitrant granulomatous skin disease.

Adolescent↗
PubMed2005

Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer.

Germline heterozygous loss-of-function mutations of fumarate hydratase (FH) predispose to the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL). Forty-five distinct FH mutations have been identified in 76 of 89 (85%) reported probands with skin leiomyomas. This suggests that MCUL is a genetically homogeneous condition and that most patients presenting with skin leiomyomas will have underlying FH mutations. FH mutations identified include 26/45 (58%) missense; 12/45 (27%) frameshift, 4/45 (9%) nonsense changes and 3/45 (7%) different whole gene deletions. In MCUL kindreds, the majority of females with FH mutations have both skin and uterine leiomyomas. A proportion of individuals with FH mutations have associated renal cancer, a variant known as hereditary leiomyomatosis and renal cell cancer (HLRCC). If selection bias is removed, the prevalence of renal cancer in MCUL lies between one of 46 (2%) families who were not radiologically screened, and two of 32 (6%) families who were radiologically screened. Truncating, particularly frameshift, mutations appear to be significantly associated with renal cancer (P = 0.003), suggesting a possible basis for selective screening. There may also be a significantly increased rate of renal cancer in females (P = 0.004), suggesting a possible role for hormonal factors. Review of the literature suggests that, unlike most individuals presenting with skin leiomyomas, the majority of patients presenting with uterine leiomyomas or renal cancer will not have underlying FH mutations.

Female↗
PubMed2006

Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene.

Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3-43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL.

Adult↗
PubMed2006

The syndrome of hereditary leiomyomatosis and renal cell cancer (HLRCC): The clinical features of an individual with a fumarate hydratase gene mutation.

A 55-year-old woman presented with multiple cutaneous leiomyomas and multiple uterine leiomyomas (fibroids). The clinical diagnosis of the autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome was confirmed by identification of a fumarate hydratase gene mutation. This case highlights the need to consider the possibility of renal and uterine cancer in members of cutaneous leiomyomatosis families.

Carcinoma, Renal Cell↗
PubMed2006

Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature.

Multiple cutaneous and uterine leiomyomatosis (MCUL; OMIM 150800) is an autosomal dominantly inherited disease characterized by leiomyomas of the skin and uterine leiomyomas. Recently, association of MCUL with different forms of renal cancer has been described. This syndrome is referred to as hereditary leiomyomatosis and renal cell cancer (OMIM 605839). Both disorders result from heterozygous germline mutations in the fumarate hydratase (FH) gene that may function as a tumor suppressor. Interestingly, cutaneous leiomyomas do not only manifest in a diffuse and symmetric fashion. Rather frequently, a segmental or band-like manifestation pattern can be observed, usually following the lines of Blaschko. Here, we sought to elucidate the molecular basis of diffuse and segmental cutaneous leiomyomatosis in six unrelated Dutch and Spanish patients and their families. We identified six novel FH mutations, including one missense and one nonsense mutation, two deletions and two splice-site mutations. The segmental phenotype that was observed in various patients with FH mutations most likely reflects a type 2 segmental manifestation of cutaneous leiomyomatosis as previously also described for other autosomal dominantly inherited skin diseases. The results presented here extend the current data on the molecular basis of familial cutaneous leiomyomatosis and comprise, to the best of our knowledge, the first genetic study in Dutch and Spanish patients with this disorder. In addition, we review the clinical and molecular aspects of the disease.

Amino Acid Sequence↗
PubMed2006

Antinociceptive pharmacology of N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]-N-methylacetamide, fumarate (LF22-0542), a novel nonpeptidic bradykinin B1 receptor antagonist.

The antinociceptive pharmacology of N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]-N-methylacetamide fumarate (LF22-0542), a novel nonpeptidic B1 antagonist, was characterized. LF22-0542 showed high affinity for human and mouse B1 receptors with virtually no affinity for the human B2 receptor; a selectivity index of at least 4000 times was obtained when LF22-0542 was profiled throughout binding or cell biology assays on 64 other G-protein-coupled receptor, 10 ion channels, and seven enzymes. LF22-0542 was a competitive B1 receptor antagonist and elicited significant antinociceptive actions in the mouse acetic acid-induced writhing assay, as well as in the second phases of formalin-induced nociception in mice and in both the first and second phases of the formalin response in rats. LF22-0542 was active after s.c. but not p.o. administration. In B1 receptor knockout (KO) mice, acetic acid and formalin responses were significantly reduced and LF22-0542 had no additional effects in these animals. LF22-0542 alleviated thermal hypersensitivity in both acute (carrageenan) and persistent inflammatory (complete Freund's adjuvant) pain models in rats. LF22-0542 produced a full reversal of experimental neuropathic thermal hypersensitivity but was inactive in reversing nerve injury-induced tactile hypersensitivity in rats. In agreement with this observation, B1 KO mice subjected to peripheral nerve injury did not show thermal hypersensitivity but developed nerve injury-induced tactile hypersensitivity normally. The data demonstrate the antihyperalgesic actions of a selective systemically administered B1 receptor antagonist and suggest the utility of this class of agents for the treatment of inflammatory pain states and for some aspects of neuropathic pain.

Acrylamides↗
PubMed1973

Factors affecting virulence of Shigella flexneri: avirulent strain with altered metablism of succinate, fumarate, and malate.

It has been found that a mutation of Shigella flexneri 2a to avirulence can result in altered metabolism of tricarboxylic acid cycle acids, but the effect is strongly dependent on growth conditions. Mutant cells harvested from stationary-phase cultures grown with vigorous shaking in nutrient broth oxidize succinate, fumarate, and malate much more slowly than do wild-type cells. Cell-free extracts from such cells show similar differences in oxidative ability. These differences were less pronounced when cells were harvested from the exponential phase of growth and were nonexistent when the cells were grown without shaking. When tricarboxylic acid cycle acids were used as carbon sources with shaking, mutant cells from exponential phase cultures oxidized tricarboxylic cycle acids almost to the same extent as the wild type. Stationary-phase cells grown on succinate lost succinoxidase activity, but wild-type cells retained more than twice the activity of mutant cells. The effect of growth conditions on oxidative differences between the two strains was similar to the differences in succinate uptake observed under similar conditions.

Azides↗
PubMed2005

Increased risk of cancer in patients with fumarate hydratase germline mutation.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15-29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.

Adolescent↗
PubMed2006

Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus. OBJECTIVE: To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes. METHODS: FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations. RESULTS: Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p<0.05). The enzyme activity in lymphoblastoid cell lines from three individuals with mutations in R190 was not significantly different from individuals with other missense mutations. The cytosolic and mitochondrial FH activity of cell lines from individuals with HLRCC was reduced compared with those from control cell lines (p<0.05). There was no significant difference in enzyme activity between control cell lines (n = 4) and cell lines from affected individuals with other hereditary renal cancer syndromes (n = 22). CONCLUSIONS: FH enzyme activity testing provides a useful diagnostic method for confirmation of clinical diagnosis and screening of at-risk family members.

Amino Acid Sequence↗
PubMed1994

The risk of sensibilization and contact urticaria upon topical application of fumaric acid derivatives.

Systemic and sometimes topical therapy with fumaric acid (FA) and its derivatives is used in the treatment of psoriasis. Scattered data show that the topical application of these derivatives elicits side effects. Application of FA and some derivatives on the skin was accompanied by perilesional skin irritation, macular papular rashes and urticarial reactions. In order to determine the irritating and sensitizing properties of FA derivatives we used a cytotoxicity, flank irritation, ear swelling and guinea pig maximization test. The results of the cytotoxicity test demonstrated that dimethylfumarate (DMF) was the most toxic derivative. DMF induced also contact-urticarial reactions in contrast to mono-ethylfumarate (MEF). Challenge experiments with FA, MEF and DMF in MEF- and DMF-sensitized guinea pigs demonstrated that both MEF and DMF are moderate contact sensitizers. In DMF-sensitized animals cross-reactions with MEF were found. As DMF and MEF have cytotoxic, contact-urticarial and/or sensitizing properties, topical application should be avoided.

Administration, Topical↗
PubMed1975

Studies on the latency of rat liver fumarate hydratase.

A hypotonic medium and nonionic detergents Triton X-100 and digitonin have no influence on the activity of fumarase in the homogenate or in the mitochondrial fraction either. Ionic detergents of deoxycholate, cholate and sodium dodecyl sulphate exert an inhibiting influence. The activity of enzyme was determined in an L-malate-fumarate system. 1 h of incubation and the original Racker's method gave similar results. The lack of 'latency', found for the mitochondrial fumarase, was discussed basing on the data concerned with the penetration of metabolites through the inner mitochondrial membrane.

Animals↗
PubMed2001

Synthesis and properties of photocross-linked poly(propylene fumarate) scaffolds.

The photocross-linking of poly(propylene fumarate) (PPF) to form porous scaffolds for bone tissue engineering applications was investigated. PPF was cross-linked using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and exposure to 30 min of long wavelength ultraviolet (UV) light. The porous photocross-linked PPF scaffolds (6.5 mm diameter cylinders) were synthesized by including a NaCl porogen (70, 80, and 90 wt% at cross-linking) prior to photocross-linking. After UV exposure, the samples were placed in water to remove the soluble porogen, revealing the porous PPF scaffold. As porogen leaching has not been used often with cross-linked polymers, and even more rarely with photoinitiated cross-linking, a study of the efficacy of this strategy and the properties of the resulting material was required. Results show that the inclusion of a porogen does not significantly alter the photoinitiation process and the resulting scaffolds are homogeneously cross-linked throughout their diameter. It was also shown that porosity can be generally controlled by porogen content and that scaffolds synthesized with at least 80 wt% porogen possess an interconnected pore structure. Compressive mechanical testing showed scaffold strength to decrease with increasing porogen content. The strongest scaffolds with interconnected pores had an elastic modulus of 2.3+/-0.5 MPa and compressive strength at 1% yield of 0.11+/-0.02 MPa. This work has shown that a photocross-linking/porogen leaching technique is a viable method to form porous scaffolds from photoinitiated materials.

Biophysical Phenomena↗
PubMed2003

Macular exanthema due to fumaric acid esters.

OBJECTIVE: To report a case of an unusual skin reaction to fumaric acid esters (FAE). CASE SUMMARY: A 68-year-old white woman who was treated with FAE for 4 days for lichen planus developed generalized pruritic exanthema. This was suspected to be an allergic drug reaction to FAE, and the treatment was discontinued. After 48-72 hours, the exanthema resolved completely. An objective causality assessment revealed that the adverse drug event was probable. As skin testing for diagnostic purposes is not feasible with FAE, the drug-related origin of the exanthema was confirmed by oral rechallenge with FAE. DISCUSSION: The effectiveness of FAE in the systemic treatment of psoriasis vulgaris has been proven by controlled clinical trials. The compound has been shown to be tolerable and safe even during prolonged treatment. The most frequent adverse effects are gastrointestinal symptoms and flushing, which typically occur 4-6 hours after administration of the drug. Allergic reactions to FAE have not yet been reported. Since the patient was rechallenged with the suspected drug, we could confirm the allergic origin of the exanthema. CONCLUSIONS: The occurrence of allergic skin reaction should be considered in patients receiving treatment with FAE.

Aged↗