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Eric Block Seogjoo Jang Hiroaki Matsunami Sivakumar Sekharan Bérénice Dethier Mehmed Z. Ertem Sivaji Gundala Yi Pan Shengju Li Zhen Li Stephene N. Lodge Mehmet Ozbil Huihong Jiang Sonia F. Penalba Victor S. Batista Hanyi Zhuang 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(21):E2766-E2774
The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and 13C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d30 lacks the 1,380- to 1,550-cm−1 IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.In 1870, the British physician William Ogle wrote: “As in the eye and the ear the sensory impression is known to result not from the contact of material particles given off by the object seen or heard, but from waves or undulations of the ether or the air, one cannot but suspect that the same may be true in the remaining sense, and that the undulatory theory of smell… [may be] the true one” (1, 2). Of the 29 different “theories of odour” listed in the 1967 edition of The Chemical Senses (3), nine associate odor with vibrations, particularly those theories championed by Dyson (4, 5) and Wright (6–8). However, the premise that olfaction involves detection of vibrational frequencies of odorants remains highly speculative because neither the structures of the odorant receptors (ORs) nor the binding sites or the activation mechanisms triggered upon odorant binding to ORs have been established. In 1996–1997, Turin (9–12) elaborated on the undulatory theory of smell, as considered in more detail below, and suggested that a mechanism analogous to inelastic electron tunneling spectroscopy (13) may be involved, where tunneling electrons in the receptor probe the vibrational frequencies of odorants. In 2013, Gane et al. (14) commented that “whether olfaction recognizes odorants by their shape, their molecular vibrations, or both remains an open and controversial question” and that “a convenient way to address [this question] is to test for odor character differences between deuterated and nondeuterated odorant isotopomers since these have identical ground-state conformations but different vibrational modes.” Gane et al. (14) also stated that a particularly appropriate test case would involve odorants containing “more CH group… [such as] musks [which] are among the largest odorants and typically contain 15–18 carbons and 28 or more hydrogens.”In judging the plausibility of the vibration theory, we use a multipronged approach:
- i)We consider the concepts of shape vs. vibration theory and odorant perception vs. reception.
- ii)As a test of the vibration theory, we have prepared a series of isotopomers of musks and other compounds, containing up to 30 C–H or C–D bonds as test odorants, which are evaluated using in vitro activation of receptors identified by us and other groups as being highly responsive to these isotopomers.
- iii)We consider the confounding effects of impurities and isotope effects in interpreting odorant perception, as well as the validity of requirements for specific IR bands for recognition of musks by their receptors.
- iv)We examine the physical validity of the models developed to support the vibration theory.
- v)We consider the specific limitations of our in vitro approach using isotopomers to evaluate the vibration theory, based primarily on results obtained with a single identified human musk OR, in addition to other OR/ligand pairs.
- vi)We consider plausible nonvibration theory models for docking of musks to the human musk receptor, OR5AN1, where the musk carbonyl group functions as a hydrogen bond acceptor.
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Ultrastructural localization of factor XIIIa 总被引:1,自引:0,他引:1
Gundala Schaumburg-Lever Birgitte Gehring Edwin Kaiserling 《Journal of cutaneous pathology》1994,21(2):129-134
Thin sections of dermatofibromas, of a basal cell epithelioma, a patch stage lesion of Kaposi's sarcoma, a case of angiolymphoid hyperplasia with eosinophilia, and one case of malignant mastocytosis were incubated with antibody to factor XIIIa (FXIIIa). Regardless whether the tissue had been embedded in Lowicryl K4M, Epon, or Araldite, labeling was found in dermal dendrocytes, mast cells, and endothelial cells. In dermal dendrocytes, the reaction product was seen in dilated cisternae of the rough endoplasmic reticulum as well as free within the cytoplasm. In endothelial cells, FXIIIa was localized within Weibel Palade bodies, free within the cytoplasm, and in villous projections into the vasucular lumen. In mast cells, the reaction was found in mast cell granules exclusively. Mast cells, dermal dendrocytes, and endothelial cells have in common that all three express FXIIIa, belong to the microvascular unit, and are increased in number during angiogenesis and in fibrovascular processes. It thus seems that these cells are functionally related. 相似文献
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Gundala S Wells LD Milliano MT Talkad V Luxon BA Neuschwander-Tetri BA 《Archives of toxicology》2004,78(2):68-73
Hepatotoxicity caused by the mushroom poison -amanitin is an unusual but serious cause of death and liver transplantation. Understanding the mechanisms of -amanitin uptake may lead to rational therapeutic approaches. Because older data suggested that a sodium-dependent bile acid transporter is responsible for -amanitin uptake, we tested the hypothesis that Na+-taurocholate cotransporter polypeptide (Ntcp) facilitates hepatocellular -amanitin uptake. Human hepatoblastoma cells (HepG2), cells that have lost native Ntcp expression, were stably transfected with the rat Ntcp gene. Taurocholate uptake by the transfected cells exhibited a physiologically normal K
m and V
max. A toxicologically relevant functional assay for -amanitin uptake was developed by measuring its ability to block cytokine-induced synthesis of interleukin-1 receptor antagonist (IL-1Ra) mRNA. Treatment with interleukin-1 (10 ng/ml) and interleukin-6 (100 ng/ml) increased IL-1Ra mRNA abundance 8.6-fold and 15.6-fold in HepG2 cells and Ntcp-transfected cells, respectively. Pretreatment of transfected cells with 1 µM -amanitin for 6–10 h almost completely blocked induction of IL-1Ra mRNA (1.9-fold induction) whereas pretreatment of non-transfected cells did not block induction of IL-1Ra mRNA (21.6-fold induction, P<0.02 compared with stimulated transfected cells without -amanitin). These findings demonstrate that Ntcp may be an important mediator of -amanitin uptake by the liver. 相似文献
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Maged Henary Lakshminarayana Narayana Shazia Ahad Sushma R. Gundala Rao Mukkavilli Vibhuti Sharma Eric A. Owens Yogesh Yadav Mulpuri Nagaraju Donald Hamelberg Vibha Tandon Dulal Panda Ritu Aneja 《Biochemical pharmacology》2014
Noscapine, an opium-derived ‘kinder-gentler’ microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a–c; 8a–c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and 8c strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and 8c treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and 8c revealed at least 1–2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development. 相似文献
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Background: Serum leptin concentrations are reported to be elevated in patients with periodontal diseases and may have a modulating role in cardiovascular diseases. Serum leptin concentrations have not been assessed in periodontitis associated with acute myocardial infarction (AMI) to date. The purpose of this study was to assess the concentration of serum leptin in periodontitis associated with AMI. Methods: A cross‐sectional clinical study was conducted comprising a sample size of 120 participants divided into four groups (n = 30 each) based on their clinical signs: 1) control; 2) AMI; 3) generalized chronic periodontitis (GCP); and 4) GCP + AMI. Body mass index (BMI) was calculated and recorded for all the subjects based on BMI chart of the World Health Organization. After thorough clinical and oral examination, plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment loss (AL) were recorded. In addition, 2 mL venous blood was collected by venipuncture from all participants to determine serum leptin concentration using the enzyme‐linked immunosorbent assay method. Results: A strong correlation of serum leptin concentration to BMI was observed in AMI, GCP, and GCP + AMI groups. Serum leptin levels were significantly elevated in AMI, GCP, and GCP + AMI groups compared to the control group. Significant associations between serum leptin concentration and PI, GI, PD, and AL were also seen in the GCP group. PI, GI, PD, and AL were statistically significantly elevated in GCP + AMI and AMI groups. Conclusion: Elevated serum leptin concentration was associated with increased BMI, GCP, and AMI and may serve as a risk marker for these conditions. 相似文献
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Muthyala Venkateswar Reddy Gundala Philip H. 《Proceedings of the National Academy of Sciences, India. Section B.》2019,89(2):631-637
Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - The recombinant organophosphate hydrolase (OPH) purified from E. coli was used to encapsulate in nonionic... 相似文献
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Gundala Venkata Naveen Kumar Keito Hoshitsuki Sanjay Rathod Manda J. Ramsey Lauren Kokai Erin E. Kershaw Wen Xie Christian A. Fernandez 《药学学报(英文版)》2021,11(12):3779-3790
PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver. 相似文献
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Mishra RC Karna P Gundala SR Pannu V Stanton RA Gupta KK Robinson MH Lopus M Wilson L Henary M Aneja R 《Biochemical pharmacology》2011,(2):110-121
Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in the clinic, these drugs are associated with severe toxicity and drug resistance problems. Noscapinoids represent an emerging class of microtubule-modulating anticancer agents based upon the parent molecule noscapine, a naturally occurring non-toxic cough-suppressant opium alkaloid. Here we report in silico molecular modeling, chemical synthesis and biological evaluation of novel analogs derived by modification at position-7 of the benzofuranone ring system of noscapine. The synthesized analogs were evaluated for their tubulin polymerization activity and their biological activity was examined by their antiproliferative potential using representative cancer cell lines from varying tissue-origin [A549 (lung), CEM (lymphoma), MIA PaCa-2 (pancreatic), MCF-7 (breast) and PC-3 (prostate)]. Cell-cycle studies were performed to explore their ability to halt the cell-cycle and induce subsequent apoptosis. The varying biological activity of these analogs that differ in the nature and bulk of substituent at position-7 was rationalized utilizing predictive in silico molecular modeling. 相似文献