A review of the flavor profile of metal salts: understanding the complexity of metallic sensation

2021 ◽  
Author(s):  
Michelle J Y Ecarma ◽  
Alissa A Nolden
Keyword(s):  
Treatment Options ◽  
Metal Salts ◽  
In Vitro Assays ◽  
Knock Out ◽  
Anion Complex ◽  
Knock Out Mice ◽  
Definition Of ◽  
Psychophysical Studies ◽  
Chemosensory Systems

Abstract The oral sensation of metallic is a complex experience. Much of our current understanding of metallic sensation is from the investigation of metal salts, which elicit diverse sensations, including taste, smell, and chemesthetic sensations, and therefore meet the definition of a flavor rather than a taste. Due to the involvement of multiple chemosensory systems, it can be challenging to define and characterize metallic sensation. Here, we provide a comprehensive review of the psychophysical studies quantifying and characterizing metallic sensation, focusing on metal salts. We examine the factors that impact perception, including anion complex, concentration, nasal occlusion, and pH. In addition, we summarize the receptors thought to be involved in the perception of metallic sensation (i.e., TRPV1, T1R3, TRPA1, and T2R7) either as a result of in vitro assays or from studies in knock-out mice. By enhancing our scientific understanding of metallic sensation and its transduction pathways, it has the potential to improve food, pharmaceuticals, help identify suppression or masking strategies, and improve the ability to characterize individual differences in metallic sensation. It also has the potential to translate to clinical populations by addressing the disparities in knowledge and treatment options for individuals suffering from metallic taste disorder (i.e., phantom taste or “metal mouth”). Future psychophysical studies investigating the sensory perception of metal salts should include a range of compounds and diverse food matrices, coupled with modern sensory methods, which will help to provide a more comprehensive understanding of metallic sensation.

FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 3997-4002 ◽  
Author(s):  
Dirk Meyer ◽  
Carsten Schiller ◽  
Jürgen Westermann ◽  
Shozo Izui ◽  
Wouter L. W. Hazenbos ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Knock Out ◽  
Effector Cells ◽  
Igg Isotypes ◽  
Knock Out Mice ◽  
Deficient Mice ◽  
Experimental Autoimmune

Abstract In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcγRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.

In Vitro and In Vivo Characterization of Full-Length rFVIII Modified with PEG Via Coupling to Primary Amino Groups.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3147-3147 ◽  
Author(s):  
Peter L. Turecek ◽  
Jürgen Siekmann ◽  
Herbert Gritsch ◽  
Katalin Váradi ◽  
Rafi-Uddin Ahmad ◽  
...  
Keyword(s):  
Half Life ◽  
Hemophilia A ◽  
Specific Activity ◽  
Exchange Chromatography ◽  
Full Length ◽  
Thrombin Inhibitor ◽  
Knock Out ◽  
Knock Out Mice

Abstract Chemical modification of recombinant therapeutic proteins with PEG has been shown to enhance the biological half-life. Here we assess the effect of PEGylation on FVIII. Full-length rFVIII bulk drug substance from protein-free fermentation (Advate process, Baxter) was conditioned into a buffer suitable for coupling to polyethylene glycol succinimidyl succinate (linear PEG, 5 kDa PEG chain length). PEG was covalently bound by amine coupling preferentially to lysine residues of FVIII at neutral pH. PEG was removed by ion-exchange chromatography and the PEG-FVIII derivative was concentrated by ultra-diafiltration. The conjugates thus obtained retained about 30–40% of the activity of non-modified rFVIII. The specific activity decreased with the amount of PEG linked to the FVIII molecule. In SDS-PAGE and immunoblot studies PEGylated rFVIII showed a band pattern similar to unmodified FVIII with full-length, heavy chain fragments of 180 kDa and 120 kDa and the light chain fragment of 80 kDa. PEGylation also occurred to a high extent in the B domain of FVIII. All bands appeared broadened due to the attachment of polymeric PEG. The maintenance of functionality of FVIII was demonstrated by its potential to be activated and inactivated by thrombin. In the assay PEGylated and unmodified FVIII were incubated with 1 nM thrombin. Sub-samples were drawn at intervals up to 40 minutes and added to a mixture of FIXa, FX, phospholipid vesicles and Ca2+ containing a thrombin inhibitor. After 3 minutes incubation at 37°C the amount of activated FX (FXa) was measured using a FXa-specific chromogenic substrate. Unmodified rFVIII showed a typical picture of an immediate increase in FXa activity and a subsequent decline with no further FXa generation after 15 minutes. PEGylated rFVIII was activated to the same extent as unmodified FVIII but the decay in FXa generation was slower and did not reach the zero level, even 40 minutes after incubation. The formation of the typical thrombin cleavage fragments, with unmodified as well as PEGylated rFVIII, was demonstrated in a Western blot analysis. The slower inactivation by thrombin was also seen there. The pharmacokinetic properties of PEGylated rFVIII compared with rFVIII were investigated in hemophilia A knock-out mice. Both preparations were applied at a dose of 200 IU rFVIII/kg and groups of mice (n=5) were exsanguinated at several time points up to 24 hours. Terminal half-life for PEGylated rFVIII was calculated at 4.9 hours compared with 1.9 hours for unmodified rFVIII in hemophilia A knock-out mice. AUC was approximately doubled. These results indicate that rFVIII can be biochemically modified with PEG whilst at least partly retaining its major functions, but at the same time prolonging its survival in the circulation of hemophilic mice.

FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 3997-4002 ◽  
Author(s):  
Dirk Meyer ◽  
Carsten Schiller ◽  
Jürgen Westermann ◽  
Shozo Izui ◽  
Wouter L. W. Hazenbos ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Knock Out ◽  
Effector Cells ◽  
Igg Isotypes ◽  
Knock Out Mice ◽  
Deficient Mice ◽  
Experimental Autoimmune

In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcγRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.

scholarly journals Activation of GPR116/ADGRF5 by its tethered agonist requires key amino acids in extracellular loop 2 of the transmembrane domain

2021 ◽  
Author(s):  
James P Bridges ◽  
Caterina Safina ◽  
Bernard Picard ◽  
Kari Brown ◽  
Alyssa Filuta ◽  
...  
Keyword(s):  
Amino Acids ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Site Directed Mutagenesis ◽  
Peptide Sequence ◽  
Knock Out ◽  
Autocatalytic Cleavage ◽  
Knock Out Mice

The mechanistic details of the tethered agonist mode of activation for adhesion GPCRs has not been completely deciphered. We set out to investigate the physiologic importance of autocatalytic cleavage upstream of the agonistic peptide sequence, an event necessary for NTF displacement and subsequent receptor activation. To examine this hypothesis, we characterized tethered agonist-mediated activation of GPR116 in vitro and in vivo. A knock-in mouse expressing a non-cleavable GPR116 mutant phenocopies the pulmonary phenotype of GPR116 knock-out mice, demonstrating that tethered agonist-mediated receptor activation is indispensable for function in vivo. Using site-directed mutagenesis and species swapping approaches we identified key conserved amino acids for GPR116 activation in the tethered agonist sequence and in extracellular loops 2/3 (ECL2/3). We further highlight residues in transmembrane7 (TM7) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model supporting tethered agonist:ECL2 interactions for GPR116 activation.

Bcr-Abl Directly Activates Stat5 Independent of Jak2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 511-511
Author(s):  
Oliver D. Hantschel ◽  
Eva Eckelhart ◽  
Ines Kaupe ◽  
Florian Grebien ◽  
Kay-Uwe Wagner ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Lines ◽  
Tyrosine Kinases ◽  
Functional Role ◽  
Kinase Inhibitors ◽  
Knock Out ◽  
Kinase Substrate ◽  
Knock Out Mice

Abstract Abstract 511 Persistent activation of the transcription factor Stat5 is a signaling hallmark of Chronic Myelogenous Leukemia (CML). In mouse models, Stat5 was required for initial myeloid and lymphoid transformation (by Bcr-Abl p210 or p185 and v-Abl). Most importantly, we and others recently showed that Stat5 was also required for maintenance of Bcr-Abl-dependent leukemia in vivo and for engraftment and reconstitution of Bcr-Abl p210-positive leukemia in secondary recipients. Therefore, Stat5 is of central functional importance in the Bcr-Abl signaling network and represents a possible critical vulnerable node in CML. In contrast to the well-studied functional role of Stat5 in disease models, the molecular mechanism of Bcr-Abl dependent Stat5 activation, including the tyrosine kinase(s) that phosphorylate and activate Stat5, remain only partially understood. In particular, conflicting views on the involvement of the Jak2 kinase and its potential role as a drug target in CML exist. We used conditional Jak2 knock-out mice to study the contribution of Jak2 in Bcr-Abl-dependent transformation and leukemogenicity. Jak2 ablation did not compromise the Bcr-Abl p210-mediated transforming capability in primary murine bone marrow- or fetal liver-derived hematopoietic cells in vitro. In contrast, initial lymphoid transformation by v-abl and Bcr-Abl p185 was abolished in Jak2 knock-out mice. Jak2 deletion did not have an effect on maintenance of lymphoid leukemia cells in vitro, whereas deletion of Stat5 induced a G1 arrest and subsequent apoptosis. In line with this, ablation of Jak2 expression after leukemia induction did not alter disease latency or disease phenotype. Consistently, we did not observe a decrease in Stat5 activation upon siRNA-mediated knock-down of Jak2 alone or all four Jak kinases (Jak1, Jak2, Jak3 and Tyk2) in CML cell lines. Using a panel of pharmacological inhibitors, we found that neither Jak2-selective, nor pan-Jak kinase inhibitors or Src family kinase-selective inhibitors led to a decrease in Stat5 phosphorylation, while the highly selective Bcr-Abl inhibitor nilotinib completely abrogated Stat5 phosphorylation. To study possible contributions of other tyrosine kinases in the Bcr-Abl dependent activation of Stat5, we used Ba/F3 cells expressing the TKI-resistant Bcr-Abl mutant T315I in combination with different broad-specificity tyrosine kinase inhibitors, like dasatinib. At dasatinib concentrations that inhibited several dozens of tyrosine kinases, Stat5 phosphorylation in Ba/F3 Bcr-Abl T315I cells was unaffected, excluding a role for most tyrosine kinases other than Bcr-Abl in Stat5 activation and pointing towards a direct phosphorylation of Stat5 by Bcr-Abl. Together, this data excludes a role of Jak and Src kinases in the activation of Stat5 in Bcr-Abl positive cell lines. Finally, in comprehensive enzyme kinetic analysis experiments using recombinant kinase, Stat5 had a similar KM value for Bcr-Abl as the canonical direct Bcr-Abl substrate CrkL and displayed only mildly lower kinase substrate parameters (vmax, kcat) than CrkL, fully compatible with direct phosphorylation of Stat5 by Bcr-Abl. Together with our earlier data on the pivotal role of Stat5 in the transcriptional and signaling network of Bcr-Abl, we propose a hypersensitive switch-like behavior of the Bcr-Abl-Stat5 kinase substrate pair that mechanistically rationalizes the central functional role of Stat5 in the signaling of CML cells. In summary, we provide compelling evidence that activation of Stat5 by Bcr-Abl is likely to be direct and that targeting of Jak2 in CML may not be of therapeutic benefit, as Jak2 is not required for CML initiation or maintenance. Disclosures: Hantschel: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria.

P2-291 ABCA1 knock-out mice have decreased apoeinbrainand CSF and secrete cholesterol poor apoE-containing HDL from astrocytes in vitro

2004 ◽  
Vol 25 ◽  
pp. S315-S316
Author(s):  
Suzanne E. Wahrle ◽  
Hong Jiang ◽  
Maia Parsadanian ◽  
Justin Legleiter ◽  
Tomasz Kowaleski ◽  
...  
Keyword(s):  
Knock Out ◽  
Knock Out Mice

scholarly journals Changes in Liver Gene Expression of Azin1 Knock-out Mice

2010 ◽  
Vol 65 (7-8) ◽  
pp. 519-527 ◽  
Author(s):  
Tao Wan ◽  
Yuan Hu ◽  
Ailong Huang ◽  
Ken-ichi Yamamura ◽  
Hua Tang
Keyword(s):  
Ornithine Decarboxylase ◽  
Regulatory Protein ◽  
Fold Change ◽  
Oligonucleotide Array ◽  
Wild Type ◽  
Polyamine Biosynthesis ◽  
Knock Out ◽  
Knock Out Mice

The ornithine decarboxylase antizyme inhibitor (AZI) was discovered as a protein that binds to the regulatory protein antizyme and inhibits the ability of antizyme to interact with the enzyme ornithine decarboxylase (ODC). Several studies showed that the AZI protein is important for cell growth in vitro. However, the function of this gene in vivo remained unclear. In our study, we analyzed the transcriptional profiles of livers on the 19th day of pregnancy of Azin1 knock-out mice and wild-type mice using the Agilent oligonucleotide array. Compared to the wild-type mice, in the liver of Azin1 knock-out mice 1812 upregulated genes (fold change ≥ 2) and 1466 downregulated genes (fold change ≤ 0.5) were showed in the microarray data. Altered genes were then assigned to functional categories and mapped to signaling pathways. These genes have functions such as regulation of the metabolism, transcription and translation, polyamine biosynthesis, embryonic morphogenesis, regulation of cell cycle and proliferation signal transduction cascades, immune response and apoptosis. Real-time PCR was used to confirm the differential expression of some selected genes. Overall, our study provides novel understanding of the biological functions of AZI in vivo.

In vivo and in vitro investigations of heterozygous nebulin knock-out mice disclose a mild skeletal muscle phenotype

2013 ◽  
Vol 23 (4) ◽  
pp. 357-369 ◽  
Author(s):  
C. Gineste ◽  
J.M. De Winter ◽  
C. Kohl ◽  
C.C. Witt ◽  
B. Giannesini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knock Out ◽  
Knock Out Mice

scholarly journals The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Long Gao ◽  
Yuan Liu ◽  
Xiaohong Du ◽  
Sai Ma ◽  
Minmin Ge ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Enzymatic Activity ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
In Vitro Assays ◽  
Knock Out

AbstractIt has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

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