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1.
Molecular mimicry, the concept that antigenic determinants of microorganisms resemble antigenic determinants of the host,
is frequently cited as a plausible mechanism to account for the association of infection and autoimmune disease. Based on
analogous sequences of amino acids or on cross-reactions of monoclonal antibodies, numerous examples of such mimicry have
been reported. There are, however, no clear examples of a human disease caused by molecular mimicry. 相似文献
2.
Di Francesco AM Ruggiero A Riccardi R 《Cellular and molecular life sciences : CMLS》2002,59(11):1914-1927
Oxaliplatin (Eloxatine) is a third-generation platinum compound which has shown a wide antitumour effect both in vitro and
in vivo, a better safety profile than cisplatin and a lack of cross-resistance with cisplatin and carboplatin. In this scenario,
oxaliplatin may represent an innovative and challenging drug extending the antitumour activity in diseases such as gastrointestinal
cancer that are not usually sensitive to these coordination complexes. Oxaliplatin has a non-hydrolysable diaminocyclohexane
(DACH) carrier ligand which is maintained in the final cytotoxic metabolites of the drug. Like cisplatin, oxaliplatin targets
DNA producing mainly 1,2-GG intrastrand cross-links. The cellular and molecular aspects of the mechanism of action of oxaliplatin
have not yet been fully elucidated. However, the intrinsic chemical and steric characteristics of the DACH-platinum adducts
appear to contribute to the lack of cross-resistance with cisplatin. To date, mismatch repair and replicative bypass appear
to be the processes most likely involved in differentiating the molecular responses to these agents.
Received 15 March 2002; received after revision 13 May 2002; accepted 21 May 2002
RID="*"
ID="*"Corresponding author. 相似文献
3.
No Abstract.
Received 21 February 2002; received after revision 16 May 2002; accepted 14 June 2002 相似文献
4.
Both philosophers and scientists have recently promoted transparency as an important element of responsible scientific practice. Philosophers have placed particular emphasis on the ways that transparency can assist with efforts to manage value judgments in science responsibly. This paper examines a potential challenge to this approach, namely, that efforts to promote transparency can themselves be value-laden. This is particularly problematic when transparency incorporates second-order value judgments that are underwritten by the same values at stake in the desire for transparency about the first-order value judgments involved in scientific research. The paper uses a case study involving research on Lyme disease to illustrate this worry, but it responds by elucidating a range of scenarios in which transparency can still play an effective role in managing value judgments responsibly. 相似文献
5.
Cellular and molecular aspects of drugs of the future: meropenem 总被引:1,自引:0,他引:1
Cottagnoud P 《Cellular and molecular life sciences : CMLS》2002,59(11):1928-1933
Meropenem, first synthesized in the late eighties, has become one of the most important beta-lactam antibiotics of the carbapenem subclass used for the treatment of a variety of life-threatening infections. Due to its unique chemical structure, meropenem is not inactivated by the kidney dehydropeptidase I and the majority of microbial beta-lactamases. Its antimicrobial activity is based on its high affinity for the majority of cell wall-synthesizing enzymes, the so-called penicillin-binding proteins, of Gram-positive and -negative bacteria. However, bacteria have evolved several approaches to resist meropenem: (i) by reducing the affinity of the penicillin-binding proteins for the antibiotics, (ii) by decreasing the permeability of the outer membrane of Gram-negative bacteria, (iii) by using efflux pumps, and (iv) by activating zinc-dependent carbapenemases. Meropenem has a low toxicity profile and, in contrast to imipenem, no central nervous system toxicity. 相似文献
6.
E. S. Güner 《Cellular and molecular life sciences : CMLS》1996,52(4):364-372
The effectiveness of complement-mediated killing ofBorrelia burgdorferi, the causative agent of Lyme disease, in the presence of host-derived tissues was studied. Second and high passage forms ofB. burgdorferi 297 isolate were grown in a LEW/N rat joint tissue co-culture system and in artificial BSK medium. Guinea pig complement and third week immune serum from hamsters with experimental Lyme disease were added to the cultures. Both high and low passage borrelia grown in BSK medium died and did not revive after 3 weeks incubation in BSK medium. However, 5–12% of tissue co-cultured borrelia survived the first complement-mediated lysis. Repeated re-growth and lysis cycles in tissue co-culture resulted in isolation of an 85% complement-resistant population ofB. burgdorferi. Joint tissue culture supernatant collected on the third day of tissue culture, and fibronectin (25 g/ml), also protected spirochetes from complement-mediated lysis in contrast to BSK or fresh co-culture medium. Complement-mediated lysis may not be an effective mechanism in eradication of borrelia, and the chronicity of Lyme disease may be due to resistance ofB. burgdorferi variants to host immune defense mechanisms in the presence of host-derived tissues. 相似文献
7.
Anti-DNA antibodies: aspects of structure and pathogenicity 总被引:4,自引:0,他引:4
Anti-DNA antibodies contribute to the pathology of systemic lupus erythematosus. Their depositon in tissue lesions could
result from localization of preformed immune complexes of antibodies with DNA or nucleosomes, or from cross-reaction of anti-DNA
antibodies directly with tissue proteins. Structural analyses contribute to understanding their pathogenic potential. Primary
structures of lupus immunoglobulin G double-stranded DNA-binding autoantibodies are determined by immunoglobulin genes with
mutated variable region segments, indicative of selection by immunizing antigen. Arginine, lysine and asparagine residues
in complementarity-determining region favor DNA binding. Heavy-chain variable regions make major contributions to DNA binding;
affinity and specificity of binding are modulated or can be abrogated by the light-chain variable domain. Crytallographic
structure is known for a few antibody-DNA complexes and several ligand-free Fab fragments. Computer modeling supplements this
limited information. Structural information of lupus antibody interactions with both DNA and cross-reacting molecules will
support use of ligands to inhibit tissue deposition of the antibodies and prevent lesion formation in lupus.
Received 4 July 2002; accepted 23 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
8.
A. Hemminki 《Cellular and molecular life sciences : CMLS》1999,55(5):735-750
Peutz-Jeghers syndrome (PJS) is a classic, but not widely known hereditary trait. Its clinical hallmarks are intestinal hamartomatous polyposis and melanin pigmentation of the skin and mucous membranes. In addition, PJS predisposes to cancer . The most common malignancies are small intestinal, colorectal, stomach and pancreatic adenocarcinomas. Other cancer types that probably occur in excess in PJS families include breast and uterine cervical cancer, as well as testicular and ovarian sex cord tumors. The relative risk of cancer may be as high as 18 times that of the general population, and the cancer patients' prognosis is reduced. Recently, the predisposing locus was mapped to 19p13.3 using a novel method. Subsequently, the causative gene was shown to be LKB1 (a.k.a. STK11), a serine/threonine kinase of unknown function. Although preliminary reports seem to suggest a minor role for LKB1 in sporadic tumorigenesis, further investigations are needed. Received 12 October 1998; received after revision 30 November 1998; accepted 30 November 1998 相似文献
9.
J. R. Regueiro A. Arnaiz-Villena J. L. Vicario J. Martinez-Laso A. Pacheco J. M. Rivera-Guzman 《Cellular and molecular life sciences : CMLS》1993,49(6-7):553-556
Extended HLA haplotypes frequencies were estimated from the HLA, C2, Bf and C4 phenotypes of 74 patients with non-insulin-dependent diabetes (NIDD), 92 with juvenile rheumatoid arthritis (JRA), 44 with Berger's disease (BD), 83 with insulin-dependent diabetes (IDD), and 140 healthy controls. The extended HLA haplotype B18 CF130 DR3 DQw2, which is common (around 10% phenotype frequency) in healthy Spaniards and in other populations of paleo-North African origin, was found to be significantly less frequent in NIDD, JRA and BD, whereas its frequency was normal in IDD (although DR3 DQw2 haplotypes were increased in the latter disease). These data support the existence of a common HLA-linked pathogeneic mechanism in NIDD, JRA and BD, and point to a genetic difference between IDD and NIDD at the HLA level. This effect is readily detectable in our population because the uncommon BfF1 allele marks that haplotype instead of the more common BfS, which marks B8 CS01 DR3 DQw2 in other Caucasians. Our results support the hypothesis of strong selective pressures operating at the HLA level to preserve extended HLA haplotypes with advantageous gene sets from dilution by crossing-over. Imbalanced incomplete haplotypes may give rise to inappropriate T-cell repertoire selection in the thymus and/or antigen handling in the periphery, and be partly responsible for the pathogenesis of certain HLA-linked diseases (i.e. NIDD, JRA, and BD). 相似文献
10.
Zhenhua Luo Yao Liu Yitong Liu Hui Chen Songtao Shi Yi Liu 《Cellular and molecular life sciences : CMLS》2017,74(24):4443-4453
Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs. 相似文献
11.
Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling
pathways and protein catalysts. Ferritin, a protein nanocage around an iron/oxy mineral, centralizes the control. Complementary
DNA (antioxidant responsive element/Maf recognition element) and mRNA (iron responsive element) responses regulate ferritin
synthesis rates. Multiple iron-protein interactions control iron and oxygen substrate movement through the protein cage, from
dynamic gated pores to catalytic sites related to di-iron oxygenase cofactor sites. Maxi-ferritins concentrate iron for the
bio-synthesis of iron/heme proteins, trapping oxygen; bacterial mini-ferritins, DNA protection during starvation proteins,
reverse the substrate roles, destroying oxidants, trapping iron and protecting DNA. Ferritin is nature’s unique and conserved
approach to controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA and mRNA
sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant
metabolism.
Received 25 June 2005; received after revision 17 October 2005; accepted 25 November 2005 相似文献
12.
Comparison of the growing number of disorders known to be associated with triplet repeat expansions reveals both common features
and a diversity of molecular pathways. Despite significant progress towards the characterization of proteins coded by the
mutant genes, the complex nature of these disorders requires identification of all molecular components of the triplet repeat
pathways. In this brief review we will discuss recent progress in determining the molecular mechanisms of disorders with unstable
trinucleotide mutations.
Received 13 January 1999; received after revision 8 March 1999; accepted 9 March 1999 相似文献
13.
Type 1A diabetes is an organ-specific autoimmune disease resulting from destruction of insulin-producing pancreatic beta-cells. The main susceptibility genes code for polymorphic HLA molecules and in particular alleles of class II MHC genes (DR, DQ and DP). Polymorphisms of individual genes outside the MHC also contribute to diabetes risk but recent evidence suggests that there are additional non-HLA genes determining susceptibility linked to the MHC. It is now possible using genetic and autoantibody assays to predict the development of type 1A diabetes in the majority of individuals, and trials of diabetes prevention are underway. 相似文献
14.
15.
Hsp70 chaperones: Cellular functions and molecular mechanism 总被引:36,自引:0,他引:36
Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.Received 21 October 2004; received after revision 24 November 2004; accepted 6 December 2004 相似文献
16.
Maneuf YP Gonzalez MI Sutton KS Chung FZ Pinnock RD Lee K 《Cellular and molecular life sciences : CMLS》2003,60(4):742-750
Gabapentin was originally designed as an anti-convulsant gamma-aminobutyric acid (GABA) mimetic capable of crossing the blood-brain barrier. In the present review we show that although gabapentin is not a GABA mimetic, it has great utility as an add-on therapy for epilepsy and as a first-line treatment for neuropathic pain. We summarise the studies that have been performed which demonstrate that gabapentin appears to interact with a novel binding site expressed at high density within the central nervous system (CNS), namely the alpha2delta voltage-dependent calcium channel subunit. The review continues by examining the effects of gabapentin on calcium channel function and neurotransmitter release before, in the latter part of the review, summarising the more recently discovered actions of gabapentin in relation to intracellular signalling. 相似文献
17.
Congenital muscular dystrophy: molecular and cellular aspects 总被引:8,自引:0,他引:8
Jimenez-Mallebrera C Brown SC Sewry CA Muntoni F 《Cellular and molecular life sciences : CMLS》2005,62(7-8):809-823
The congenital muscular dystrophies are a clinically and genetically heterogeneous group of neuromuscular disorders. Each form has a characteristic phenotype, but there is overlap between some entities and their classification is based on a combination of clinical features and the primary or secondary protein defect. Recent studies have identified the genetic basis of a number of congenital muscular dystrophies (11 genes in total) and have recognised a novel pathological mechanism that highlights the importance of the correct posttranslational processing of proteins, in particular -dystroglycan. Diagnosis of these conditions has been aided by the availability of specific antibodies for each protein and a better understanding of the protein changes that accompany each condition. In this review we present the major molecular, clinical and diagnostic aspects of each group of congenital muscular dystrophy with an emphasis in the more recent developments.Received 11 December 2004; accepted 15 December 2004 相似文献
18.
Activation of cytotoxic T cells by solid tumours? 总被引:2,自引:0,他引:2
Tumour-specific cytotoxic T cells (CTLs) are among the best-defined biological anticancer weapons. Nevertheless, they often fail to control tumour growth in vivo. Many reasons for this have been evoked tumours may actively inhibit CTLs, or may protect them selves from CTL recognition by various means. However, one does not necessarily need to postulate such active immune evasion mechanisms specifically acquired by tumour cells. In this review we argue that the failure of immune protection is due to the intrinsic inability of tumours to activate an effective immune response, and that many tumours are similar to normal issues in this respect. It is striking to see that the majority of the so-called immune escape mechanisms are not specifically acquired by selected tumour cells, but are common mechanisms shared between solid tumours and normal, healthy tissues. Immune responses are poor because tumour antigens do not efficiently localize to lymph follicles in lymphoid tissues, and are not efficiently presented to CTLs in an immunogenic context. The fact that tumours do not induce CTLs but are often susceptible to lymphocyte-mediated cytotoxicity indicates that more intensified immunization protocols should result in improved clinical outcome. 相似文献
19.
Cellular and molecular mechanism of low-turnover osteopenia in the klotho-deficient mouse 总被引:3,自引:0,他引:3
Kawaguchi H Manabe N Chikuda H Nakamura K Kuroo M 《Cellular and molecular life sciences : CMLS》2000,57(5):731-737
The mouse homozygous for a disruption of the klotho locus (KL-/- or klotho mouse) exhibited multiple pathological conditions resembling human aging. We observed osteopenia in KL-/- mice with a low bone turnover, in which the decrease in bone formation exceeded the decrease in bone resorption and resulted in net bone loss. This pathophysiology resembles closely that of senile osteoporosis in humans. Osteoblastic cells from KL-/- mice proliferated normally in vitro; however, they showed much lower alkaline phosphatase activity and mineralized matrix formation than those from control mice. Cultured osteoclastic cells from KL-/- mice had normal resorbing activity and survival rate, but the differentiation of osteoclastic cells from their precursors was significantly disturbed: in the co-culture of osteoblastic cells and osteoclast precursor cells, the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclastic cells was extremely poor only when osteoclast precursor cells originated from KL-/- mice independently of the origin of the osteoblastic cells. In addition, we found that osteoprotegerin a secreted factor which inhibits osteoclastogenesis, was up-regulated in KL-/- mice. We conclude that a defect in klotho gene expression leads to the independent impairment of osteoblast and osteoclast differentiation, which can be a cause of low-turnover osteoporosis. 相似文献
20.
Summary Conformational analysis and molecular graphics are used to model a representative melanin structure to estimate a chemical's in vitro affinity for melanin. The modelling data fit to a simple linear equation relative to a logarithmic transformation of the experimentally-derived binding data (r=0.901). The goodnes of fit, as evidenced by the F-statistic, F(1, 14)=60.09 (p=0.000002), for the regression indicates that this technique gives an accurate representation of the interaction of these chemicals with melanin in vitro. 相似文献