The Experts below are selected from a list of 60126 Experts worldwide ranked by ideXlab platform
Joshua J Jacobs - One of the best experts on this subject based on the ideXlab platform.
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chemokines associated with pathologic responses to orthopedic implant debris
Frontiers in Endocrinology, 2017Co-Authors: Nadim J Hallab, Joshua J JacobsAbstract:Despite the success in returning people to health saving mobility and high quality of life, the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after approximately 15-25 years of use, due to slow progressive subtle inflammation to implant debris compromising the bone implant interface. This local inflammatory pseudo disease state is primarily caused by implant debris interaction with innate immune cells, i.e. macrophages. This implant debris can also activate an adaptive immune reaction giving rise to the concept of implant related Metal Sensitivity. However, a consensus of studies agree the dominant form of this response is due to innate reactivity by macrophages to implant debris danger signaling (DAMP) eliciting cytokine-based and chemokine inflammatory responses. This review covers implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and how this leads to subsequent implant failure through loosening and osteolysis, i.e what is known of central chemokines (e.g. IL-8, MCP-1, MIP-1, CCL9, CCL10, CCL17, CCL22) associated with implant-debris reactivity as related to the innate immune system activation/cytokine expression, e.g. danger signaling (e.g. IL-1beta, IL-18, IL-33 etc), toll-like receptor activation (e.g. IL-6, TNF-alpha etc), bone catabolism (e.g. TRAP5b) and hypoxia responses (Hif1-alpha). More study is needed however, to fully understand these interactions to effectively counter cytokine and chemokine based orthopedic implant related inflammation.
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the pathology of orthopedic implant failure is mediated by innate immune system cytokines
Mediators of Inflammation, 2014Co-Authors: Stefan Landgraeber, Marcus Jager, Joshua J Jacobs, Nadim J HallabAbstract:All of the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after 15–25 years of use, due to slow progressive subtle inflammation at the bone implant interface. This inflammatory disease state is caused by implant debris acting, primarily, on innate immune cells, that is, macrophages. This slow progressive pathological bone loss or “aseptic loosening” is a potentially life-threatening condition due to the serious complications in older people (>75 yrs) of total joint replacement revision surgery. In some people implant debris (particles and ions from Metals) can influence the adaptive immune system as well, giving rise to the concept of Metal Sensitivity. However, a consensus of studies agrees that the dominant form of this response is due to innate reactivity by macrophages to implant debris where both danger (DAMP) and pathogen (PAMP) signalling elicit cytokine-based inflammatory responses. This paper discusses implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and the subsequent formation of osteolysis. Different mechanisms of implant-debris reactivity related to the innate immune system are detailed, for example, danger signalling (e.g., IL-1
, IL-18, IL-33, etc.), toll-like receptor activation (e.g., IL-6, TNF- , etc.), apoptosis (e.g., caspases 3–9), bone catabolism (e.g., TRAP5b), and hypoxia responses (Hif1- ). Cytokine-based clinical and basic science studies are in progress to provide diagnosis and therapeutic intervention strategies. -
Metal Sensitivity in patients with orthopaedic implants
Journal of Bone and Joint Surgery American Volume, 2001Co-Authors: Nadim J Hallab, Katharine Merritt, Joshua J JacobsAbstract:All Metals in contact with biological systems undergo corrosion. This electrochemical process leads to the formation of Metal ions, which may activate the immune system by forming complexes with endogenous proteins. Implant degradation products have been shown to be associated with dermatitis, urticaria, and vasculitis. If cutaneous signs of an allergic response appear after implantation of a Metal device, Metal Sensitivity should be considered. Currently, there is no generally accepted test for the clinical determination of Metal hyperSensitivity to implanted devices. The prevalence of dermal Sensitivity in patients with a joint replacement device, particularly those with a failed implant, is substantially higher than that in the general population. Until the roles of delayed hyperSensitivity and humoral immune responses to Metallic orthopaedic implants are more clearly defined, the risk to patients may be considered minimal. It is currently unclear whether Metal Sensitivity is a contributing factor to implant failure. Implant-related Metal Sensitivity has been well documented in case and group studies; however, overall it remains a relatively unpredictable and poorly understood phenomenon in the context of orthopaedic implant materials1-3. Dermal hyperSensitivity to Metal is common, affecting about 10% to 15% of the population1,2,4,5. Dermal contact with and ingestion of Metals have been reported to cause immune reactions, which most typically manifest as hives, eczema, redness, and itching1,6,7. Historically, the ability of implant materials to demonstrate appropriate host and material responses has resulted in the elimination of candidate materials based on observation of adverse host responses. However, some adverse responses are difficult to characterize in preclinical and clinical settings because of their infrequent or subtle nature. In vivo Metal hyperSensitivity or hyperSensitivity-like reactivity to Metallic biomaterials is one such response. Although little is known …
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a triple assay technique for the evaluation of Metal induced delayed type hyperSensitivity responses in patients with or receiving total joint arthroplasty
Journal of Biomedical Materials Research, 2000Co-Authors: Nadim J Hallab, Katalin Mikecz, Joshua J JacobsAbstract:The determination of biocompatibility has been dominated historically by the characterization of candidate materials based upon the observation of adverse host responses. However, some adverse responses are subtle in clinical settings and continue to foster debate and investigation. One of these responses is “Metal allergy” or hyperSensitivity to Metallic biomaterials. Current methods used to diagnose hyperSensitivity reactions, such as dermal patch testing and migration inhibition assays, are not well accepted in orthopedic practice as a means for the characterization of hyperSensitivity to Metallic joint-replacement components. An increasing need to resolve whether Metal Sensitivity may be a significant and/or predisposing factor for eliciting an over-aggressive immune response in patients with Metallic implant components requires improved and standardized widespread study. Here we present three in vitro methodologies: (1) a proliferation assay, (2) cytokine analysis using ELISA, and (3) a migration inhibition assay. When in conjunction with one another, these assays may be used to more comprehensively quantify Metal-induced hyperSensitivity responses. Therefore, these methodologies are detailed with the intent of facilitating multi-center large-scale studies. In the following cases, a multi-assay approach for measuring the prevalence of delayed-type hyperSensitivity in orthopedic patients shows the propensity to yield a more comprehensive and, therefore, more conclusive determination than currently employed patch testing or single assay techniques. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res (Appl Biomater) 53: 480–489, 2000
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hyperSensitivity to Metallic biomaterials a review of leukocyte migration inhibition assays
Biomaterials, 2000Co-Authors: Nadim J Hallab, Joshua J Jacobs, Jonathan BlackAbstract:Abstract Metal hyperSensitivity is a well-established phenomenon occurring in a variety of domestic and workplace settings. Degradation products of Metallic biomaterials may mediate Metal hyperSensitivity. However, little is known about the short- and long-term pharmacodynamics and bioavailability of circulating Metal degradation products in vivo. Mechanisms by which in vivo Metal Sensitivity reactions occur have not been well characterized and the degree to which Metal Sensitivity may be a predisposing factor for eliciting an overaggressive immune response remains clinically unpredictable. In vitro leukocyte migration inhibition assays have been used for investigating cell-mediated hyperSensitivity reactions to biomaterial and biomaterial degradation products. This review provides a historical and technical summary of four in vitro techniques used for determination of leukocyte migration activity: (1) membrane migration or Boyden chamber, (2) capillary tube, (3) leukocyte migration using agarose technique, and (4) collagen gels. It is difficult to determine which, if any, of these techniques is singularly best suited for the investigation of suspected biomaterial-related symptoms in patients. However, Boyden chamber membrane migration testing is recommended for clinical investigations, principally because a high degree of standardized investigator independent materials and methodologies is necessary for compiling and comparing the results of patients tested at various times over the length of an extended study. Ultimately, in vitro migration inhibition testing has the potential to provide a reliable means for predicting some complications and thus enhancing the outcome for patients receiving Metallic implants. Continuing improvements in migration inhibition testing methods, used alone or in combination with other immunologic assays, will likely improve assessment of patients susceptible to biomaterial antigen-induced delayed-type hyperSensitivity responses.
Nadim J Hallab - One of the best experts on this subject based on the ideXlab platform.
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chemokines associated with pathologic responses to orthopedic implant debris
Frontiers in Endocrinology, 2017Co-Authors: Nadim J Hallab, Joshua J JacobsAbstract:Despite the success in returning people to health saving mobility and high quality of life, the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after approximately 15-25 years of use, due to slow progressive subtle inflammation to implant debris compromising the bone implant interface. This local inflammatory pseudo disease state is primarily caused by implant debris interaction with innate immune cells, i.e. macrophages. This implant debris can also activate an adaptive immune reaction giving rise to the concept of implant related Metal Sensitivity. However, a consensus of studies agree the dominant form of this response is due to innate reactivity by macrophages to implant debris danger signaling (DAMP) eliciting cytokine-based and chemokine inflammatory responses. This review covers implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and how this leads to subsequent implant failure through loosening and osteolysis, i.e what is known of central chemokines (e.g. IL-8, MCP-1, MIP-1, CCL9, CCL10, CCL17, CCL22) associated with implant-debris reactivity as related to the innate immune system activation/cytokine expression, e.g. danger signaling (e.g. IL-1beta, IL-18, IL-33 etc), toll-like receptor activation (e.g. IL-6, TNF-alpha etc), bone catabolism (e.g. TRAP5b) and hypoxia responses (Hif1-alpha). More study is needed however, to fully understand these interactions to effectively counter cytokine and chemokine based orthopedic implant related inflammation.
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the pathology of orthopedic implant failure is mediated by innate immune system cytokines
Mediators of Inflammation, 2014Co-Authors: Stefan Landgraeber, Marcus Jager, Joshua J Jacobs, Nadim J HallabAbstract:All of the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after 15–25 years of use, due to slow progressive subtle inflammation at the bone implant interface. This inflammatory disease state is caused by implant debris acting, primarily, on innate immune cells, that is, macrophages. This slow progressive pathological bone loss or “aseptic loosening” is a potentially life-threatening condition due to the serious complications in older people (>75 yrs) of total joint replacement revision surgery. In some people implant debris (particles and ions from Metals) can influence the adaptive immune system as well, giving rise to the concept of Metal Sensitivity. However, a consensus of studies agrees that the dominant form of this response is due to innate reactivity by macrophages to implant debris where both danger (DAMP) and pathogen (PAMP) signalling elicit cytokine-based inflammatory responses. This paper discusses implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and the subsequent formation of osteolysis. Different mechanisms of implant-debris reactivity related to the innate immune system are detailed, for example, danger signalling (e.g., IL-1
, IL-18, IL-33, etc.), toll-like receptor activation (e.g., IL-6, TNF- , etc.), apoptosis (e.g., caspases 3–9), bone catabolism (e.g., TRAP5b), and hypoxia responses (Hif1- ). Cytokine-based clinical and basic science studies are in progress to provide diagnosis and therapeutic intervention strategies. -
Metal Sensitivity in patients with orthopaedic implants
Journal of Bone and Joint Surgery American Volume, 2001Co-Authors: Nadim J Hallab, Katharine Merritt, Joshua J JacobsAbstract:All Metals in contact with biological systems undergo corrosion. This electrochemical process leads to the formation of Metal ions, which may activate the immune system by forming complexes with endogenous proteins. Implant degradation products have been shown to be associated with dermatitis, urticaria, and vasculitis. If cutaneous signs of an allergic response appear after implantation of a Metal device, Metal Sensitivity should be considered. Currently, there is no generally accepted test for the clinical determination of Metal hyperSensitivity to implanted devices. The prevalence of dermal Sensitivity in patients with a joint replacement device, particularly those with a failed implant, is substantially higher than that in the general population. Until the roles of delayed hyperSensitivity and humoral immune responses to Metallic orthopaedic implants are more clearly defined, the risk to patients may be considered minimal. It is currently unclear whether Metal Sensitivity is a contributing factor to implant failure. Implant-related Metal Sensitivity has been well documented in case and group studies; however, overall it remains a relatively unpredictable and poorly understood phenomenon in the context of orthopaedic implant materials1-3. Dermal hyperSensitivity to Metal is common, affecting about 10% to 15% of the population1,2,4,5. Dermal contact with and ingestion of Metals have been reported to cause immune reactions, which most typically manifest as hives, eczema, redness, and itching1,6,7. Historically, the ability of implant materials to demonstrate appropriate host and material responses has resulted in the elimination of candidate materials based on observation of adverse host responses. However, some adverse responses are difficult to characterize in preclinical and clinical settings because of their infrequent or subtle nature. In vivo Metal hyperSensitivity or hyperSensitivity-like reactivity to Metallic biomaterials is one such response. Although little is known …
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a triple assay technique for the evaluation of Metal induced delayed type hyperSensitivity responses in patients with or receiving total joint arthroplasty
Journal of Biomedical Materials Research, 2000Co-Authors: Nadim J Hallab, Katalin Mikecz, Joshua J JacobsAbstract:The determination of biocompatibility has been dominated historically by the characterization of candidate materials based upon the observation of adverse host responses. However, some adverse responses are subtle in clinical settings and continue to foster debate and investigation. One of these responses is “Metal allergy” or hyperSensitivity to Metallic biomaterials. Current methods used to diagnose hyperSensitivity reactions, such as dermal patch testing and migration inhibition assays, are not well accepted in orthopedic practice as a means for the characterization of hyperSensitivity to Metallic joint-replacement components. An increasing need to resolve whether Metal Sensitivity may be a significant and/or predisposing factor for eliciting an over-aggressive immune response in patients with Metallic implant components requires improved and standardized widespread study. Here we present three in vitro methodologies: (1) a proliferation assay, (2) cytokine analysis using ELISA, and (3) a migration inhibition assay. When in conjunction with one another, these assays may be used to more comprehensively quantify Metal-induced hyperSensitivity responses. Therefore, these methodologies are detailed with the intent of facilitating multi-center large-scale studies. In the following cases, a multi-assay approach for measuring the prevalence of delayed-type hyperSensitivity in orthopedic patients shows the propensity to yield a more comprehensive and, therefore, more conclusive determination than currently employed patch testing or single assay techniques. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res (Appl Biomater) 53: 480–489, 2000
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hyperSensitivity to Metallic biomaterials a review of leukocyte migration inhibition assays
Biomaterials, 2000Co-Authors: Nadim J Hallab, Joshua J Jacobs, Jonathan BlackAbstract:Abstract Metal hyperSensitivity is a well-established phenomenon occurring in a variety of domestic and workplace settings. Degradation products of Metallic biomaterials may mediate Metal hyperSensitivity. However, little is known about the short- and long-term pharmacodynamics and bioavailability of circulating Metal degradation products in vivo. Mechanisms by which in vivo Metal Sensitivity reactions occur have not been well characterized and the degree to which Metal Sensitivity may be a predisposing factor for eliciting an overaggressive immune response remains clinically unpredictable. In vitro leukocyte migration inhibition assays have been used for investigating cell-mediated hyperSensitivity reactions to biomaterial and biomaterial degradation products. This review provides a historical and technical summary of four in vitro techniques used for determination of leukocyte migration activity: (1) membrane migration or Boyden chamber, (2) capillary tube, (3) leukocyte migration using agarose technique, and (4) collagen gels. It is difficult to determine which, if any, of these techniques is singularly best suited for the investigation of suspected biomaterial-related symptoms in patients. However, Boyden chamber membrane migration testing is recommended for clinical investigations, principally because a high degree of standardized investigator independent materials and methodologies is necessary for compiling and comparing the results of patients tested at various times over the length of an extended study. Ultimately, in vitro migration inhibition testing has the potential to provide a reliable means for predicting some complications and thus enhancing the outcome for patients receiving Metallic implants. Continuing improvements in migration inhibition testing methods, used alone or in combination with other immunologic assays, will likely improve assessment of patients susceptible to biomaterial antigen-induced delayed-type hyperSensitivity responses.
Yoshiaki Toyama - One of the best experts on this subject based on the ideXlab platform.
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five types of inflammatory arthritis following total knee arthroplasty
Journal of Biomedical Materials Research Part A, 2007Co-Authors: Yasuo Niki, Hideo Matsumoto, Toshiro Otani, Taisuke Tomatsu, Yoshiaki ToyamaAbstract:Joint effusion after total knee arthroplasty (TKA) is considered as a manifestation of certain inflammatory reactions within prosthetic joints. This study investigated causes of joint effusion following TKA and analyzed phenotypic characteristics of synovial fluid leukocytes for each cause. Forty-six TKAs for rheumatoid arthritis (RA) and 49 TKAs for osteoarthritis (OA) displaying joint effusion were investigated. Causes of joint effusion were clinically identified and frequencies of each cause were compared between RA and OA. Synovial fluid cell phenotypes were analyzed using a fluorescence-activated cell sorter. Clinical diagnoses for joint effusion were classified into five different groups: deep infection (DI); increased activity of RA (IRA); particle-induced synovitis (PS); Metal Sensitivity (MS); and nonspecific synovitis (NS). The most frequent cause of post-TKA effusion was IRA in RA, and NS in OA. Biomaterial-related arthritis such as PS and MS were more frequent with OA than with RA. Analysis of synovial fluid cell phenotypes revealed that the characteristic cells for each diagnosis were CD16(+)CD14(-) neutrophils in IRA and DI, CD14(+) macrophages in PS, and CD3(+)CD45RO(+) T cells in MS. Post-TKA joint effusion is clinically caused by five different types of arthritis. Phenotypic characteristics of synovial fluid leukocytes reflect joint pathology and contribute to diagnosis and exclusion of biomaterial-related arthritis.
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screening for symptomatic Metal Sensitivity a prospective study of 92 patients undergoing total knee arthroplasty
Biomaterials, 2004Co-Authors: Yasuo Niki, Hideo Matsumoto, Toshiro Otani, Taku Yatabe, Makoto Kondo, Fumihiro Yoshimine, Yoshiaki ToyamaAbstract:Abstract Metal Sensitivity (MS) reactions to implant Metals represent a rare but well-documented complication following total joint arthroplasty (TJA). Although 20–25% of post-TJA patients develop MS, only a few highly susceptible patients ( P
Robert L Barrack - One of the best experts on this subject based on the ideXlab platform.
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Metal Sensitivity in total knee arthroplasty doc am i allergic to my implant
Orthopaedic Proceedings, 2018Co-Authors: Robert L BarrackAbstract:The role of Metal Sensitivity or allergy in causing persistent symptoms or failure and need for a revision of a total joint replacement has been the topic of debate and controversy for decades. There was renewed interest in this area with the rise of Metal-on-Metal hip arthroplasty and the advent of adverse local tissue reactions. This led to an increase in Metal ion testing as well as Metal Sensitivity testing. With the decline of the use of Metal-on-Metal hip components, this is now mostly an issue in knee arthroplasty. It is well known that a substantial percentage of patients have persistent symptoms following knee replacement. What remains in question is whether allergy to Metal or other materials such as PMMA may be a contributing factor. It is accepted that the incidence of positive skin patch tests is higher in symptomatic failed joint replacements. Nickel Sensitivity is most common as a positive skin test with up to 15% of patients demonstrating this followed by chromium and cobalt. A recent revi...
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Metal Sensitivity in total knee arthroplasty doc am i allergic to my implant
Journal of Bone and Joint Surgery-british Volume, 2017Co-Authors: Robert L BarrackAbstract:The role of Metal Sensitivity or allergy in causing persistent symptoms or failure and need for a revision of a total joint replacement has been the topic of debate and controversy for decades. There was renewed interest in this area with the rise of Metal-on-Metal hip arthroplasty and the advent of adverse local tissue reactions. This led to an increase in Metal ion testing as well as Metal Sensitivity testing. With the decline of the use of Metal-on-Metal hip components, this is now mostly an issue in knee arthroplasty. It is well known that a substantial percentage of patients have persistent symptoms following knee replacement. What remains in question is whether allergy to Metal or other materials such as PMMA may be a contributing factor. It is accepted that the incidence of positive skin patch tests is higher in symptomatic failed joint replacements. Nickel Sensitivity is most common as a positive skin test with up to 15% of patients demonstrating this followed by chromium and cobalt. A recent review by Lachiewicz et al. concluded that there was insufficient evidence to recommend routine or widespread cutaneous or in vitro hyperSensitivity testing before primary TKA, that there is no evidence-based rationale to recommend a routine Metal allergy screening questionnaire, that there is only anecdotal support for Ni-free implants, and that local dermatitis should be treated with topical steroids. In another article, routine screening for Metal allergy was not recommended, however, selective screening for history of Sensitivity or unexplained pain or early loosening was suggested. Other experts have recommended a role for utilizing a commercially available alternative to components containing nickel or cobalt in patients thought to be hypersensitive. A recent study, however, concluded that there was no difference in complications, revisions, or reoperations among patients who tested positive with patch testing whether they were treated with standard components or nickel free components. Likewise, a consensus panel published results from the United Kingdom in which cobalt chrome implants were recommended regardless of the patients Metal allergy status. Patient perception is important, however, and among patients who report multiple allergies of any kind, a higher percentage are likely to be dissatisfied with their knee replacement. Of more importance are those reporting a specific allergy to Metal are substantially more likely to express some dissatisfaction with their components. Metal allergy as a cause of chronic pain and/or early failure of joint replacement is rare if it exists at all. It is always a diagnosis of exclusion. Patients who think they are allergic are probably more likely to be more symptomatic following joint replacement. Whether or not to use a nickel free or hypoallergenic component in such patients remains an area of controversy.
Li Zhang - One of the best experts on this subject based on the ideXlab platform.
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predicting cadmium toxicity with the kinetics of phytochelatin induction in a marine diatom
Aquatic Toxicology, 2019Co-Authors: Yue Yuan, Wei Zhang, Hezhong Yuan, Li ZhangAbstract:Phytochelatin (PC) synthesis is thought to be a rapid and specific response to Metal exposure in marine phytoplankton, but its potential as a predictor of Metal toxicity is far from conclusive. Thus this research examines the bioaccumulation, PC induction, and toxicity of Cadmium (Cd) in Thalassiosira weissflogii, a coastal diatom under varying nutrient conditions. Nitrogen limitation strongly inhibited Cd uptake and PC induction at the same [Cd2+] level, and increased Metal Sensitivity. Conversely, phosphorus limitation had little influence on Cd accumulation and PC induction, yet also enhanced Metal effect on growth. Differential growth inhibitions were correlated with [Cd2+], intracellular Cd concentration, PC concentration, the kinetics of Cd uptake and PC induction, respectively. It was found that stronger interrelations existed between kinetic rates (both Cd uptake and PC synthesis) and Cd Sensitivity than between the static concentrations (Cd and PC) and growth inhibition. Moreover, according to the calculated median inhibition concentration (IC50), median effective uptake rate of Cd, as well as median effective induction rate of PCs, the latter two showed the smallest variation when nutrients were varied (1.4-1.9 fold). Our study set out the first step toward considering the use of PC synthesis kinetics to predict Metal toxicity for phytoplankton.
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quantitative relationship between cadmium uptake and the kinetics of phytochelatin induction by cadmium in a marine diatom
Scientific Reports, 2016Co-Authors: Zhiqiang Guo, Wei Zhang, Qiaoguo Tan, Li Zhang, Mindong ChenAbstract:Heavy Metals activate the synthesis of phytochelatins (PCs), while the induced PCs might affect Metal uptake via chelating intracellular free Metals. However, the relationship of PCs to Metal uptake is poorly understood. In this study, we examined the kinetics of cadmium (Cd) accumulation and the synthesis of PCs in a marine diatom, Thalassiosira weissflogii, under different irradiance levels. Irradiance alone could not change the concentrations of PCs in the Cd-free treatments, while higher irradiance accelerated the induction of intracellular PCs at the same [Cd2+] level. PC-SH (2 × PC2 + 3 × PC3 + 4 × PC4) was bound with Cd at a stoichiometric ratio of 2 to 49 in our short-term uptake experiments, indicating that PC induction is sufficient to serve as the first line of defense against Cd stress. A positive linear correlation between the induction rate of PCs and the Cd uptake rate was observed, while the ratio of the PC content to intracellular Cd varied greatly when the irradiance was increased several fold. Because Metal uptake has been successfully used in predicting acute Metal toxicity, our findings are helpful for understanding the role of PCs in Metal detoxification and developing PCs as biomarkers for Metal Sensitivity.