Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling
It has been well established that radiation-induced gastrointestinal injury is manifested through loss of intestinal crypt stem cells and disruption of the mucosal layers, resulting in diarrhoea, weight loss, electrolyte imbalance, infection and mortality. Podophyllotoxin and rutin in combination (G...
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| Veröffentlicht in: | Apoptosis (London) 2019-04, Vol.24 (3-4), p.326-340 |
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| description | It has been well established that radiation-induced gastrointestinal injury is manifested through loss of intestinal crypt stem cells and disruption of the mucosal layers, resulting in diarrhoea, weight loss, electrolyte imbalance, infection and mortality. Podophyllotoxin and rutin in combination (G-003M) has been reported to regulate endogenous cellular antioxidant defense systems and inflammatory response. However, the mechanism by which G-003M ameliorates radiation-induced intestinal stem cell (ISC) injury remains unclear. Here, we hypothesize the radioprotective potential of G-003M would amplify the intestinal crypt stem cells through upregulation of Wnt/β-catenin signaling and accelerate the reconstitution of the irradiated intestine. Our results showed significant functional and structural intestine regeneration in irradiated animals following G-003M treatment which resulted in improved animal survival. Immunohistochemical examination revealed an enhancement in Lgr5
+ ve
crypt stem cells. Increased β-catenin nuclear translocation resulted in upregulation of β-catenin target genes that supported ISC renewal and expansion in G-003M-treated mice, as compared to IR-treated mice. However, G-003M could not rescue the Wnt knockdown cohorts (XAV939 treated) which exhibited greater incidence of intestinal apoptosis, DNA damage and crypt depopulation upon radiation exposure. These findings suggest the involvement of Wnt pathway during G-003M mediated amelioration of IR-induced ISC injury. G-003M also minimised acute inflammation by restricting the infiltration of immune cells into the intestinal venules. Furthermore, G-003M treated animals showed improved anti-tumor response compared to FDA approved Amifostine. Taken together, our findings suggest that G-003M may be used as a potential countermeasure for radiation injuries as well as an adjuvant during anti-cancer therapy. |
| doi_str_mv | 10.1007/s10495-019-01519-x |
| format | Article |
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+ ve
crypt stem cells. Increased β-catenin nuclear translocation resulted in upregulation of β-catenin target genes that supported ISC renewal and expansion in G-003M-treated mice, as compared to IR-treated mice. However, G-003M could not rescue the Wnt knockdown cohorts (XAV939 treated) which exhibited greater incidence of intestinal apoptosis, DNA damage and crypt depopulation upon radiation exposure. These findings suggest the involvement of Wnt pathway during G-003M mediated amelioration of IR-induced ISC injury. G-003M also minimised acute inflammation by restricting the infiltration of immune cells into the intestinal venules. Furthermore, G-003M treated animals showed improved anti-tumor response compared to FDA approved Amifostine. Taken together, our findings suggest that G-003M may be used as a potential countermeasure for radiation injuries as well as an adjuvant during anti-cancer therapy.</description><identifier>ISSN: 1360-8185</identifier><identifier>EISSN: 1573-675X</identifier><identifier>DOI: 10.1007/s10495-019-01519-x</identifier><identifier>PMID: 30725351</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Amifostine ; Animals ; Antioxidants ; Antiviral drugs ; Apoptosis ; beta Catenin - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Cancer Research ; Cell Biology ; Deoxyribonucleic acid ; Diarrhea ; DNA ; DNA damage ; DNA Damage - drug effects ; Drug Therapy, Combination - methods ; Electrolytic cells ; Immune system ; Infiltration ; Inflammation ; Inflammation - metabolism ; Inflammatory response ; Intestinal Mucosa - drug effects ; Intestinal Mucosa - metabolism ; Intestine ; Intestines - drug effects ; Male ; Metastases ; Mice ; Mice, Inbred C57BL ; Mucosa ; Nuclear transport ; Oncology ; Podophyllotoxin ; Podophyllotoxin - physiology ; Radiation damage ; Radiation effects ; Radiation injuries ; Radiation Injuries - drug therapy ; Radiation Injuries - metabolism ; Radiation-Protective Agents - pharmacology ; Receptors, G-Protein-Coupled - metabolism ; Regeneration ; Rutin ; Rutin - physiology ; Signaling ; Stem cell transplantation ; Stem cells ; Stem Cells - drug effects ; Stem Cells - metabolism ; Structure-function relationships ; Survival ; Translocation ; Up-Regulation - drug effects ; Virology ; Weight loss ; Wnt protein ; Wnt Signaling Pathway - drug effects ; β-Catenin</subject><ispartof>Apoptosis (London), 2019-04, Vol.24 (3-4), p.326-340</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2019</rights><rights>Apoptosis is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c220x-6cf6511b8885ff2e5e8ce597322f819626e4fae004aab364ecf14ed42dc9cca03</citedby><cites>FETCH-LOGICAL-c220x-6cf6511b8885ff2e5e8ce597322f819626e4fae004aab364ecf14ed42dc9cca03</cites><orcidid>0000-0002-3096-5044</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10495-019-01519-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10495-019-01519-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30725351$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kalita, Bhargab</creatorcontrib><creatorcontrib>Ranjan, Rajiv</creatorcontrib><creatorcontrib>Gupta, Manju Lata</creatorcontrib><title>Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling</title><title>Apoptosis (London)</title><addtitle>Apoptosis</addtitle><addtitle>Apoptosis</addtitle><description>It has been well established that radiation-induced gastrointestinal injury is manifested through loss of intestinal crypt stem cells and disruption of the mucosal layers, resulting in diarrhoea, weight loss, electrolyte imbalance, infection and mortality. Podophyllotoxin and rutin in combination (G-003M) has been reported to regulate endogenous cellular antioxidant defense systems and inflammatory response. However, the mechanism by which G-003M ameliorates radiation-induced intestinal stem cell (ISC) injury remains unclear. Here, we hypothesize the radioprotective potential of G-003M would amplify the intestinal crypt stem cells through upregulation of Wnt/β-catenin signaling and accelerate the reconstitution of the irradiated intestine. Our results showed significant functional and structural intestine regeneration in irradiated animals following G-003M treatment which resulted in improved animal survival. Immunohistochemical examination revealed an enhancement in Lgr5
+ ve
crypt stem cells. Increased β-catenin nuclear translocation resulted in upregulation of β-catenin target genes that supported ISC renewal and expansion in G-003M-treated mice, as compared to IR-treated mice. However, G-003M could not rescue the Wnt knockdown cohorts (XAV939 treated) which exhibited greater incidence of intestinal apoptosis, DNA damage and crypt depopulation upon radiation exposure. These findings suggest the involvement of Wnt pathway during G-003M mediated amelioration of IR-induced ISC injury. G-003M also minimised acute inflammation by restricting the infiltration of immune cells into the intestinal venules. Furthermore, G-003M treated animals showed improved anti-tumor response compared to FDA approved Amifostine. Taken together, our findings suggest that G-003M may be used as a potential countermeasure for radiation injuries as well as an adjuvant during anti-cancer therapy.</description><subject>Amifostine</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Antiviral drugs</subject><subject>Apoptosis</subject><subject>beta Catenin - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Deoxyribonucleic acid</subject><subject>Diarrhea</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Damage - drug effects</subject><subject>Drug Therapy, Combination - methods</subject><subject>Electrolytic cells</subject><subject>Immune system</subject><subject>Infiltration</subject><subject>Inflammation</subject><subject>Inflammation - metabolism</subject><subject>Inflammatory response</subject><subject>Intestinal Mucosa - drug effects</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestine</subject><subject>Intestines - drug effects</subject><subject>Male</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mucosa</subject><subject>Nuclear transport</subject><subject>Oncology</subject><subject>Podophyllotoxin</subject><subject>Podophyllotoxin - physiology</subject><subject>Radiation damage</subject><subject>Radiation effects</subject><subject>Radiation injuries</subject><subject>Radiation Injuries - drug therapy</subject><subject>Radiation Injuries - metabolism</subject><subject>Radiation-Protective Agents - pharmacology</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Regeneration</subject><subject>Rutin</subject><subject>Rutin - physiology</subject><subject>Signaling</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Stem Cells - drug effects</subject><subject>Stem Cells - metabolism</subject><subject>Structure-function relationships</subject><subject>Survival</subject><subject>Translocation</subject><subject>Up-Regulation - drug effects</subject><subject>Virology</subject><subject>Weight loss</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway - drug effects</subject><subject>β-Catenin</subject><issn>1360-8185</issn><issn>1573-675X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9Ucuu0zAQtRCI-4AfYIEssUFCAT9iJ1mi6sJFqsQGBLvITcapq8QutlO1O7Z8Br_GlzAlF5BYsLA9Mz5zZo4OIU84e8kZq14lzspGFYw3eBTex3vkkqtKFrpSn-9jLDUral6rC3KV0o4xJmtZPiQXklVCScUvyfdVmDbOm-yCpzmCyRP4TIOl-9CH_fY0jiGHo_PU-J7GOWO0j2EKGRKdwpyAroeoXvz4-u0A1HksI8SMNGWYaAfjmGia48EdsGYG43zKdIS8xTSa3i2Dnd_N8UTzNoZ52NJPuEFyA9I4PzwiD6wZEzy-e6_Jxzc3H1a3xfr923er1-uiE4IdC91ZrTjf1HWtrBWgoO5ANZUUwta80UJDaQ0wVhqzkbqEzvIS-lL0XdN1hslr8nzhRXlfZpTRTi6dBRgPqLMVgmvRNBUrEfrsH-guzBHXRRSvtKoUV2dCsaC6GFKKYNt9dJOJp5az9mxguxjYooHtLwPbIzY9vaOeNxP0f1p-O4YAuQASfvkB4t_Z_6H9Cd94rIM</recordid><startdate>201904</startdate><enddate>201904</enddate><creator>Kalita, Bhargab</creator><creator>Ranjan, Rajiv</creator><creator>Gupta, Manju Lata</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7RQ</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>U9A</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3096-5044</orcidid></search><sort><creationdate>201904</creationdate><title>Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling</title><author>Kalita, Bhargab ; Ranjan, Rajiv ; Gupta, Manju Lata</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c220x-6cf6511b8885ff2e5e8ce597322f819626e4fae004aab364ecf14ed42dc9cca03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Amifostine</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Antiviral drugs</topic><topic>Apoptosis</topic><topic>beta Catenin - metabolism</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Cell Biology</topic><topic>Deoxyribonucleic acid</topic><topic>Diarrhea</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA Damage - drug effects</topic><topic>Drug Therapy, Combination - methods</topic><topic>Electrolytic cells</topic><topic>Immune system</topic><topic>Infiltration</topic><topic>Inflammation</topic><topic>Inflammation - metabolism</topic><topic>Inflammatory response</topic><topic>Intestinal Mucosa - drug effects</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestine</topic><topic>Intestines - drug effects</topic><topic>Male</topic><topic>Metastases</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mucosa</topic><topic>Nuclear transport</topic><topic>Oncology</topic><topic>Podophyllotoxin</topic><topic>Podophyllotoxin - physiology</topic><topic>Radiation damage</topic><topic>Radiation effects</topic><topic>Radiation injuries</topic><topic>Radiation Injuries - drug therapy</topic><topic>Radiation Injuries - metabolism</topic><topic>Radiation-Protective Agents - pharmacology</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Regeneration</topic><topic>Rutin</topic><topic>Rutin - physiology</topic><topic>Signaling</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Stem Cells - drug effects</topic><topic>Stem Cells - metabolism</topic><topic>Structure-function relationships</topic><topic>Survival</topic><topic>Translocation</topic><topic>Up-Regulation - drug effects</topic><topic>Virology</topic><topic>Weight loss</topic><topic>Wnt protein</topic><topic>Wnt Signaling Pathway - drug effects</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kalita, Bhargab</creatorcontrib><creatorcontrib>Ranjan, Rajiv</creatorcontrib><creatorcontrib>Gupta, Manju Lata</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Career & Technical Education Database</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Apoptosis (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kalita, Bhargab</au><au>Ranjan, Rajiv</au><au>Gupta, Manju Lata</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling</atitle><jtitle>Apoptosis (London)</jtitle><stitle>Apoptosis</stitle><addtitle>Apoptosis</addtitle><date>2019-04</date><risdate>2019</risdate><volume>24</volume><issue>3-4</issue><spage>326</spage><epage>340</epage><pages>326-340</pages><issn>1360-8185</issn><eissn>1573-675X</eissn><abstract>It has been well established that radiation-induced gastrointestinal injury is manifested through loss of intestinal crypt stem cells and disruption of the mucosal layers, resulting in diarrhoea, weight loss, electrolyte imbalance, infection and mortality. Podophyllotoxin and rutin in combination (G-003M) has been reported to regulate endogenous cellular antioxidant defense systems and inflammatory response. However, the mechanism by which G-003M ameliorates radiation-induced intestinal stem cell (ISC) injury remains unclear. Here, we hypothesize the radioprotective potential of G-003M would amplify the intestinal crypt stem cells through upregulation of Wnt/β-catenin signaling and accelerate the reconstitution of the irradiated intestine. Our results showed significant functional and structural intestine regeneration in irradiated animals following G-003M treatment which resulted in improved animal survival. Immunohistochemical examination revealed an enhancement in Lgr5
+ ve
crypt stem cells. Increased β-catenin nuclear translocation resulted in upregulation of β-catenin target genes that supported ISC renewal and expansion in G-003M-treated mice, as compared to IR-treated mice. However, G-003M could not rescue the Wnt knockdown cohorts (XAV939 treated) which exhibited greater incidence of intestinal apoptosis, DNA damage and crypt depopulation upon radiation exposure. These findings suggest the involvement of Wnt pathway during G-003M mediated amelioration of IR-induced ISC injury. G-003M also minimised acute inflammation by restricting the infiltration of immune cells into the intestinal venules. Furthermore, G-003M treated animals showed improved anti-tumor response compared to FDA approved Amifostine. Taken together, our findings suggest that G-003M may be used as a potential countermeasure for radiation injuries as well as an adjuvant during anti-cancer therapy.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>30725351</pmid><doi>10.1007/s10495-019-01519-x</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-3096-5044</orcidid></addata></record> |
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| ispartof | Apoptosis (London), 2019-04, Vol.24 (3-4), p.326-340 |
| issn | 1360-8185 1573-675X |
| language | eng |
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| subjects | Amifostine Animals Antioxidants Antiviral drugs Apoptosis beta Catenin - metabolism Biochemistry Biomedical and Life Sciences Biomedicine Cancer Cancer Research Cell Biology Deoxyribonucleic acid Diarrhea DNA DNA damage DNA Damage - drug effects Drug Therapy, Combination - methods Electrolytic cells Immune system Infiltration Inflammation Inflammation - metabolism Inflammatory response Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Intestine Intestines - drug effects Male Metastases Mice Mice, Inbred C57BL Mucosa Nuclear transport Oncology Podophyllotoxin Podophyllotoxin - physiology Radiation damage Radiation effects Radiation injuries Radiation Injuries - drug therapy Radiation Injuries - metabolism Radiation-Protective Agents - pharmacology Receptors, G-Protein-Coupled - metabolism Regeneration Rutin Rutin - physiology Signaling Stem cell transplantation Stem cells Stem Cells - drug effects Stem Cells - metabolism Structure-function relationships Survival Translocation Up-Regulation - drug effects Virology Weight loss Wnt protein Wnt Signaling Pathway - drug effects β-Catenin |
| title | Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling |
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