Abstract

We developed a multimodal nonlinear optical microscopy imaging (e.g., third-harmonic generation (THG) and two-photon excited fluorescence (TPEF)) platform based on a femtosecond laser pumped photonic crystal fiber to investigate the acetowhitening phenomenon induced by acetic acid in live mammalian cells without labeling. After treated by acetic acid with concentrations of higher than 0.2%, THG images show that light scattering is remarkably increased inside the nucleus and cytoplasm in cells. Co-localized TPEF and THG imaging on tryptophan and NADH in cells indicates that the change of scattering property is largely originating from the morphological change of metabolic proteins induced by acetic acids. Further TPEF imaging on NADH and FAD in cells confirms that this change is irreversible when acetic acid concentration is higher than 1.2%. These subcellular-level THG/TPEF imaging results reveal that the acetowhitening phenomenon is highly related with proteins involved in metabolic pathways in the nucleus and cytoplasm in live cells.

© 2014 Optical Society of America

Full Article  |  PDF Article
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References

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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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2013 (1)

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

2012 (1)

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

2010 (1)

T. T. Wu, T. H. Cheung, S. F. Yim, and J. Y. Qu, “Clinical study of quantitative diagnosis of early cervical cancer based on the classification of acetowhitening kinetics,” J. Biomed. Opt. 15(2), 026001 (2010).
[Crossref] [PubMed]

2007 (3)

D. Débarre and E. Beaurepaire, “Quantitative characterization of biological liquids for third-harmonic generation microscopy,” Biophys. J. 92(2), 603–612 (2007).
[Crossref] [PubMed]

T. T. Wu and J. Y. Qu, “Assessment of the relative contribution of cellular components to the acetowhitening effect in cell cultures and suspensions using elastic light-scattering spectroscopy,” Appl. Opt. 46(21), 4834–4842 (2007).
[Crossref] [PubMed]

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

2006 (1)

L. Denny, M. Quinn, and R. Sankaranarayanan, “Chapter 8: Screening for cervical cancer in developing countries,” Vaccine 24(Suppl 3), 71–77 (2006).
[Crossref] [PubMed]

2005 (2)

T. T. Wu, J. Qu, T. H. Cheung, S. F. Yim, and Y. F. Wong, “Study of dynamic process of acetic acid induced-whitening in epithelial tissues at cellular level,” Opt. Express 13(13), 4963–4973 (2005).
[Crossref] [PubMed]

K. Yagi, Y. Aruga, A. Nakamura, A. Sekine, and H. Umezu, “The study of dynamic chemical magnifying endoscopy in gastric neoplasia,” Gastrointest. Endosc. 62(6), 963–969 (2005).
[Crossref] [PubMed]

2003 (1)

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and chromoscopy with the acetic acid test,” Endoscopy 35(5), 437–445 (2003).
[Crossref] [PubMed]

2000 (1)

1999 (2)

G. B. West, J. H. Brown, and B. J. Enquist, “The fourth dimension of life: fractal geometry and allometric scaling of organisms,” Science 284(5420), 1677–1679 (1999).
[Crossref] [PubMed]

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

1998 (1)

M. Guelrud and I. Herrera, “Acetic acid improves identification of remnant islands of Barrett’s epithelium after endoscopic therapy,” Gastrointest. Endosc. 47(6), 512–515 (1998).
[Crossref] [PubMed]

Aruga, Y.

K. Yagi, Y. Aruga, A. Nakamura, A. Sekine, and H. Umezu, “The study of dynamic chemical magnifying endoscopy in gastric neoplasia,” Gastrointest. Endosc. 62(6), 963–969 (2005).
[Crossref] [PubMed]

Badizadegan, K.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

Balas, C. J.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

Beaurepaire, E.

D. Débarre and E. Beaurepaire, “Quantitative characterization of biological liquids for third-harmonic generation microscopy,” Biophys. J. 92(2), 603–612 (2007).
[Crossref] [PubMed]

Brown, J. H.

G. B. West, J. H. Brown, and B. J. Enquist, “The fourth dimension of life: fractal geometry and allometric scaling of organisms,” Science 284(5420), 1677–1679 (1999).
[Crossref] [PubMed]

Cheung, T. H.

T. T. Wu, T. H. Cheung, S. F. Yim, and J. Y. Qu, “Clinical study of quantitative diagnosis of early cervical cancer based on the classification of acetowhitening kinetics,” J. Biomed. Opt. 15(2), 026001 (2010).
[Crossref] [PubMed]

T. T. Wu, J. Qu, T. H. Cheung, S. F. Yim, and Y. F. Wong, “Study of dynamic process of acetic acid induced-whitening in epithelial tissues at cellular level,” Opt. Express 13(13), 4963–4973 (2005).
[Crossref] [PubMed]

Choi, W.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

Collier, T.

Dasari, R. R.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

de Pradier, B.

Débarre, D.

D. Débarre and E. Beaurepaire, “Quantitative characterization of biological liquids for third-harmonic generation microscopy,” Biophys. J. 92(2), 603–612 (2007).
[Crossref] [PubMed]

Denny, L.

L. Denny, M. Quinn, and R. Sankaranarayanan, “Chapter 8: Screening for cervical cancer in developing countries,” Vaccine 24(Suppl 3), 71–77 (2006).
[Crossref] [PubMed]

Eissa, N. T.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Enquist, B. J.

G. B. West, J. H. Brown, and B. J. Enquist, “The fourth dimension of life: fractal geometry and allometric scaling of organisms,” Science 284(5420), 1677–1679 (1999).
[Crossref] [PubMed]

Fang-Yen, C.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

Fattah, E. A.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Feld, M. S.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

Follen, M.

Guelrud, M.

M. Guelrud and I. Herrera, “Acetic acid improves identification of remnant islands of Barrett’s epithelium after endoscopic therapy,” Gastrointest. Endosc. 47(6), 512–515 (1998).
[Crossref] [PubMed]

Helidonis, E. S.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

Herrera, I.

M. Guelrud and I. Herrera, “Acetic acid improves identification of remnant islands of Barrett’s epithelium after endoscopic therapy,” Gastrointest. Endosc. 47(6), 512–515 (1998).
[Crossref] [PubMed]

Ishii, T.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Jagannath, C.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Ko, S.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Komatsu, M.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Koumantakis, E.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

Lambert, R.

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and chromoscopy with the acetic acid test,” Endoscopy 35(5), 437–445 (2003).
[Crossref] [PubMed]

Li, D.

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

Li, S.

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

Liu, X. D.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Lue, N.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

Malpica, A.

Nakamura, A.

K. Yagi, Y. Aruga, A. Nakamura, A. Sekine, and H. Umezu, “The study of dynamic chemical magnifying endoscopy in gastric neoplasia,” Gastrointest. Endosc. 62(6), 963–969 (2005).
[Crossref] [PubMed]

Oh, S.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[Crossref] [PubMed]

Orfanudaki, I.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

Prokopakis, E. P.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

Qu, J.

Qu, J. Y.

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

T. T. Wu, T. H. Cheung, S. F. Yim, and J. Y. Qu, “Clinical study of quantitative diagnosis of early cervical cancer based on the classification of acetowhitening kinetics,” J. Biomed. Opt. 15(2), 026001 (2010).
[Crossref] [PubMed]

T. T. Wu and J. Y. Qu, “Assessment of the relative contribution of cellular components to the acetowhitening effect in cell cultures and suspensions using elastic light-scattering spectroscopy,” Appl. Opt. 46(21), 4834–4842 (2007).
[Crossref] [PubMed]

Quinn, M.

L. Denny, M. Quinn, and R. Sankaranarayanan, “Chapter 8: Screening for cervical cancer in developing countries,” Vaccine 24(Suppl 3), 71–77 (2006).
[Crossref] [PubMed]

Rey, J. F.

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and chromoscopy with the acetic acid test,” Endoscopy 35(5), 437–445 (2003).
[Crossref] [PubMed]

Richards-Kortum, R.

Sankaranarayanan, R.

L. Denny, M. Quinn, and R. Sankaranarayanan, “Chapter 8: Screening for cervical cancer in developing countries,” Vaccine 24(Suppl 3), 71–77 (2006).
[Crossref] [PubMed]

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and chromoscopy with the acetic acid test,” Endoscopy 35(5), 437–445 (2003).
[Crossref] [PubMed]

Sekine, A.

K. Yagi, Y. Aruga, A. Nakamura, A. Sekine, and H. Umezu, “The study of dynamic chemical magnifying endoscopy in gastric neoplasia,” Gastrointest. Endosc. 62(6), 963–969 (2005).
[Crossref] [PubMed]

Shen, P.

Sung, K. B.

Teh, S. K.

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

Themelis, G. C.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

Umezu, H.

K. Yagi, Y. Aruga, A. Nakamura, A. Sekine, and H. Umezu, “The study of dynamic chemical magnifying endoscopy in gastric neoplasia,” Gastrointest. Endosc. 62(6), 963–969 (2005).
[Crossref] [PubMed]

West, G. B.

G. B. West, J. H. Brown, and B. J. Enquist, “The fourth dimension of life: fractal geometry and allometric scaling of organisms,” Science 284(5420), 1677–1679 (1999).
[Crossref] [PubMed]

Wong, Y. F.

Wu, T. T.

Xiang, Q.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Xu, Y.

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

Yagi, K.

K. Yagi, Y. Aruga, A. Nakamura, A. Sekine, and H. Umezu, “The study of dynamic chemical magnifying endoscopy in gastric neoplasia,” Gastrointest. Endosc. 62(6), 963–969 (2005).
[Crossref] [PubMed]

Yang, Y.

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

Yim, S. F.

T. T. Wu, T. H. Cheung, S. F. Yim, and J. Y. Qu, “Clinical study of quantitative diagnosis of early cervical cancer based on the classification of acetowhitening kinetics,” J. Biomed. Opt. 15(2), 026001 (2010).
[Crossref] [PubMed]

T. T. Wu, J. Qu, T. H. Cheung, S. F. Yim, and Y. F. Wong, “Study of dynamic process of acetic acid induced-whitening in epithelial tissues at cellular level,” Opt. Express 13(13), 4963–4973 (2005).
[Crossref] [PubMed]

Zeng, Y.

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

Zheng, W.

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

Appl. Opt. (1)

Biophys. J. (1)

D. Débarre and E. Beaurepaire, “Quantitative characterization of biological liquids for third-harmonic generation microscopy,” Biophys. J. 92(2), 603–612 (2007).
[Crossref] [PubMed]

Endoscopy (1)

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and chromoscopy with the acetic acid test,” Endoscopy 35(5), 437–445 (2003).
[Crossref] [PubMed]

Gastrointest. Endosc. (2)

M. Guelrud and I. Herrera, “Acetic acid improves identification of remnant islands of Barrett’s epithelium after endoscopic therapy,” Gastrointest. Endosc. 47(6), 512–515 (1998).
[Crossref] [PubMed]

K. Yagi, Y. Aruga, A. Nakamura, A. Sekine, and H. Umezu, “The study of dynamic chemical magnifying endoscopy in gastric neoplasia,” Gastrointest. Endosc. 62(6), 963–969 (2005).
[Crossref] [PubMed]

J. Biol. Chem. (1)

X. D. Liu, S. Ko, Y. Xu, E. A. Fattah, Q. Xiang, C. Jagannath, T. Ishii, M. Komatsu, and N. T. Eissa, “Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress,” J. Biol. Chem. 287(23), 19687–19698 (2012).
[Crossref] [PubMed]

J. Biomed. Opt. (2)

S. K. Teh, W. Zheng, S. Li, D. Li, Y. Zeng, Y. Yang, and J. Y. Qu, “Multimodal nonlinear optical microscopy improves the accuracy of early diagnosis of squamous intraepithelial neoplasia,” J. Biomed. Opt. 18(3), 036001 (2013).
[Crossref] [PubMed]

T. T. Wu, T. H. Cheung, S. F. Yim, and J. Y. Qu, “Clinical study of quantitative diagnosis of early cervical cancer based on the classification of acetowhitening kinetics,” J. Biomed. Opt. 15(2), 026001 (2010).
[Crossref] [PubMed]

J. Photochem. Photobiol. B (1)

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[Crossref] [PubMed]

Nat. Methods (1)

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Figures (5)

Fig. 1
Fig. 1 Schematic diagram of the multimodal nonlinear optical imaging (TPEF/THG) platform for label-free imaging of live cells. FM, flip mirror; L, lens; M, mirrors; OPO, optical parametric oscillator; MO, microscope objective; PCF, photonic crystal fiber; F1, filter set 1 (600 ± 20nm bandpass filter); F2, filter set 2 (730 nm excitation: 650 nm shortpass, 460 ± 30nm bandpass filter; 860 nm excitation: 750 nm shortpass, 540 ± 20nm bandpass filter; 600 nm excitation: 532 nm shortpass, 355 ± 20nm bandpass filter); F3, filter set 3 (650 nm shortpass filter, 390 ± 20nm bandpass filter); DM, dichroic mirror; PMT, photomultiplier tube.
Fig. 2
Fig. 2 Exemplary label-free images based on third-harmonic generation (THG) signals arising from live mammalian cells in monolayer culture after (a) 5-minutes acetic acid treatment, and (b) 5-minute acetic acid treatment followed by 5-minute washout using fresh culture medium. Images labeled with (i) to (v) are taken at different acetic acid concentrations from 0% to 0.5% (pH values from 7.56 to 4.42) for treatment and washout conditions. All images are reconstructed from raw data without any processing, and image sizes are 60 μm × 60 μm.
Fig. 3
Fig. 3 THG image (a), TPEF of tryptophan (b) and NADH (c) images taken from live mammalian cells before and after 5-minute treatment by acetic acid with 0.3% (pH value 4.84) concentration. Image sizes are 100 μm × 100 μm.
Fig. 4
Fig. 4 Representative normalized cellular TPEF images of NADH and FAD taken (a, b) after 5-minute acetic acid treatments, and (c, d) after 5-minute acetic acid treatment followed by 5-minute washout. Images labeled with (i) to (iii) are taken at different acetic acid concentrations from 0% to 1.2% (pH 7.56 - 3.86) for treatment and washout conditions, respectively. Note the excitation power used on the samples was less than 5 mW, and a total integration time of 60s per image was used. Image sizes are 50 μm x 50 μm.
Fig. 5
Fig. 5 Fractal dimensional analysis results of co-localized NADH and FAD TPEF images at baseline and 5-minute acetic acid treatment conditions. Note: Values are presented as mean ± 1 standard deviation (SD); 5 replicates are used during each acetic acid concentration testing; * denotes p<0.05 according to Wilcoxon matched pairs test.

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