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Now you can search all such registers to identify clinical trial research around the world!






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No dirivative works may be made or used for commercial purposes.

 

Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development




 

Can we now turn off allergy-sensitive cells?

Research suggests blocking transcription factors from turning genes "on" helps aleviate severe lung reactions. RCM-1 is a newly developed, nontoxic small molecule that stops mucus production in mice exposed to allergens.


Transcription factors are tiny proteins that switch genes on and off in the nucleus of a cell. But, they are considered unreachable targets with medicinal drugs because of their small size and precarious location. Now, researchers at Cincinnati Children's Hospital Medical Center have discovered a small molecular compound that can block these gene switches, and help elimate allergy generated inflammation and mucous.

Published online April 18 in Science Signaling, scientists tested a new compound they call RCM-1. It appears to stop the transcription factor FOXM1 and a long series of chain reactions leading to cell inflammation and asthma. The scientists show that RMC-1 prevents overproduction of mucous in goblet cells that line the lungs of mice with asthma, and in cell cultures of the human airway.

"Traditional targets for drugs are receptors on cell surfaces, which are easy to reach. Transcription factors are inside cell nuclei and difficult to reach," said Vladimir Kalinichenko, MD, PhD, the study's lead investigator and a member of the Division of Pulmonary Biology. "RCM-1 keeps FOXM1 from entering the cell nucleus by activating cell machinery called proteasomes that degrade the transcription factor. This was very efficient at reducing lung inflammation and production of mucous-generating goblet cells in our tests."


RCM-1 restricts the copying (transcription) of a critical factor that distinguishes between goblet cells and airway progenitor cells. RCM-1 increases the breakdown of a proteasome called Forkhead box M1 (FOXM1).


RCM-1 went on to improve lung function by decreasing inflammatory cytokine production in those mice exposed to (1) house dust mites and (2) interleukin-13 (IL-13). Both trigger goblet cells to swell in an attempt to push offending allergens out through the nuclear cell wall.

Airway epithelial cells from mice were first cultured in the lab in petri dishes. Then RCM-1 was injected into each cell nucleus. RCM-1 reduced the amount of IL-13 and STAT6 (an activator of transcription 6), preventing the function of the STAT6 target genes Spdef and Foxa3. Both genes are key transcriptional regulators of goblet cell differentiation.


These results suggest that RCM-1 inhibits goblet cells, column-shaped cells lining both respiratory and intestinal tracts, from secreting mucus — providing a new therapeutic target for patients with asthma or chronic airway diseases.


Calling their compound a new therapeutic candidate for severe asthma and other chronic airway diseases, researchers believe with additional research and development their discovery could lead to future clinical trials for asthma, Cystic Fibrosis and Chronic Obstructive Pulmonary Disease (COPD). All severe pulmonary diseases associated with increased inflammation and mucous hyper-secretion.

Leveraging the ongoing research into FOXM1 by his laboratory - FOXM1 also plays a key role in lung cancer - Kalinichenko's team identified the RCM-1 compound during a computer-supported biological imaging screen of 50,000 small compounds stored at the University of Cincinnati Genome Research Center. The scientists searched specifically for compounds that would target FOXM1 and inhibit its activation of downstream pro-inflammatory molecules that drive overproduction of mucous-generating goblet cells.

The research team then tested RMC-1 in cultured human airway epithelial cells and mouse models of asthma (via injection into the animals' peritoneal cavities). The mice were either sensitized with house dust mite allergens or treated with a pro-inflammatory molecule called interleukin 13 (IL-13), to induce mucous production found in airway diseases.

Microscopic images not only show that RMC-1 prevented FOXM1 from entering the nucleus in cultured human airway epithelial cells and in mouse allergen-sensitized respiratory airways — it also reduced lung inflammation and improved lung function in mice sensitized to house dust mite allergens. FOXM1 also prevented IL-13 from causing goblet cell expansion in mice given the pro-inflammatory molecule intra-nasally.

Before the research team's identification of RMC-1 could eventually lead to clinical trials, Kalinichenko's researchers will first need to test RCM-1 in more sophisticated animal models of respiratory diseases. This will help address issues related to dosage, toxicity, optimal methods of therapeutic delivery, etc.

In their future work, researchers also want to refine the chemical structure of RCM-1 to make it more efficient and improve the method of therapeutic delivery. This includes seeing if the compound can be packaged into nanoparticles for intravenous injection. The researchers have applied for a patent on RCM-1, working through the Cincinnati Children's Center for Technology Commercialization.

Abstract
Goblet cell metaplasia and excessive mucus secretion associated with asthma, cystic fibrosis, and chronic obstructive pulmonary disease contribute to morbidity and mortality worldwide. We performed a high-throughput screen to identify small molecules targeting a transcriptional network critical for the differentiation of goblet cells in response to allergens. We identified RCM-1, a nontoxic small molecule that inhibited goblet cell metaplasia and excessive mucus production in mice after exposure to allergens. RCM-1 blocked the nuclear localization and increased the proteasomal degradation of Forkhead box M1 (FOXM1), a transcription factor critical for the differentiation of goblet cells from airway progenitor cells. RCM-1 reduced airway resistance, increased lung compliance, and decreased proinflammatory cytokine production in mice exposed to the house dust mite and interleukin-13 (IL-13), which triggers goblet cell metaplasia. In cultured airway epithelial cells and in mice, RCM-1 reduced IL-13 and STAT6 (signal transducer and activator of transcription 6) signaling and prevented the expression of the STAT6 target genes Spdef and Foxa3, which are key transcriptional regulators of goblet cell differentiation. These results suggest that RCM-1 is an inhibitor of goblet cell metaplasia and IL-13 signaling, providing a new therapeutic candidate to treat patients with asthma and other chronic airway diseases.

Funding support for this research came in part from: the National Institutes of Health (HL84151, HL123490, HL132849, CA142724); a Research Scholar Grant (RSG-13-325) from the American Cancer Society; the National Health Research Institutes of Taiwan (NHRI-EX105-10309BC); and from the Ministry of Science and Technology of Taiwan (MOST102-2628-B-007-003-MY3).
Return to top of page

Apr 27, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



This microscopic image shows human lung epithelial cells treated with an experimental molecular compound called RCM-1. RCM-1 treatment removes a transcription factor called FOXM1 (GREEN) from the nucleus of cells (BLUE) placing it into the cell's cytoplasm. FOXM1 triggers excess inflammation and mucous in diseases like asthma and COPD. Researchers at Cincinnati Children's report in Science Signaling how RMC-1 prevents excess inflammation and mucous in mouse and human respiratory cells.
Image Credit: Cincinnati Children's Hospital

 


Phospholid by Wikipedia lor: #000; } -->
  o
 
The Visible Embryo Home
   
Google  
Home--- -History-----Bibliography-----Pregnancy Timeline-----Prescription Drugs in Pregnancy---- Pregnancy Calculator----Female Reproductive System----News----Contact

   
WHO International Clinical Trials Registry Platform

The World Health Organization (WHO) has a Web site to help researchers, doctors and patients obtain information on clinical trials.

Now you can search all such registers to identify clinical trial research around the world!






Home

History

Bibliography

Pregnancy Timeline

Prescription Drug Effects on Pregnancy

Pregnancy Calculator

Female Reproductive System

News

Disclaimer: The Visible Embryo web site is provided for your general information only. The information contained on this site should not be treated as a substitute for medical, legal or other professional advice. Neither is The Visible Embryo responsible or liable for the contents of any websites of third parties which are listed on this site.


Content protected under a Creative Commons License.
No dirivative works may be made or used for commercial purposes.

 

Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development




 

Can we now turn off allergy-sensitive cells?

Research suggests blocking transcription factors from turning genes "on" helps aleviate severe lung reactions. RCM-1 is a newly developed, nontoxic small molecule that stops mucus production in mice exposed to allergens.


Transcription factors are tiny proteins that switch genes on and off in the nucleus of a cell. But, they are considered unreachable targets with medicinal drugs because of their small size and precarious location. Now, researchers at Cincinnati Children's Hospital Medical Center have discovered a small molecular compound that can block these gene switches, and help elimate allergy generated inflammation and mucous.

Published online April 18 in Science Signaling, scientists tested a new compound they call RCM-1. It appears to stop the transcription factor FOXM1 and a long series of chain reactions leading to cell inflammation and asthma. The scientists show that RMC-1 prevents overproduction of mucous in goblet cells that line the lungs of mice with asthma, and in cell cultures of the human airway.

"Traditional targets for drugs are receptors on cell surfaces, which are easy to reach. Transcription factors are inside cell nuclei and difficult to reach," said Vladimir Kalinichenko, MD, PhD, the study's lead investigator and a member of the Division of Pulmonary Biology. "RCM-1 keeps FOXM1 from entering the cell nucleus by activating cell machinery called proteasomes that degrade the transcription factor. This was very efficient at reducing lung inflammation and production of mucous-generating goblet cells in our tests."


RCM-1 restricts the copying (transcription) of a critical factor that distinguishes between goblet cells and airway progenitor cells. RCM-1 increases the breakdown of a proteasome called Forkhead box M1 (FOXM1).


RCM-1 went on to improve lung function by decreasing inflammatory cytokine production in those mice exposed to (1) house dust mites and (2) interleukin-13 (IL-13). Both trigger goblet cells to swell in an attempt to push offending allergens out through the nuclear cell wall.

Airway epithelial cells from mice were first cultured in the lab in petri dishes. Then RCM-1 was injected into each cell nucleus. RCM-1 reduced the amount of IL-13 and STAT6 (an activator of transcription 6), preventing the function of the STAT6 target genes Spdef and Foxa3. Both genes are key transcriptional regulators of goblet cell differentiation.


These results suggest that RCM-1 inhibits goblet cells, column-shaped cells lining both respiratory and intestinal tracts, from secreting mucus — providing a new therapeutic target for patients with asthma or chronic airway diseases.


Calling their compound a new therapeutic candidate for severe asthma and other chronic airway diseases, researchers believe with additional research and development their discovery could lead to future clinical trials for asthma, Cystic Fibrosis and Chronic Obstructive Pulmonary Disease (COPD). All severe pulmonary diseases associated with increased inflammation and mucous hyper-secretion.

Leveraging the ongoing research into FOXM1 by his laboratory - FOXM1 also plays a key role in lung cancer - Kalinichenko's team identified the RCM-1 compound during a computer-supported biological imaging screen of 50,000 small compounds stored at the University of Cincinnati Genome Research Center. The scientists searched specifically for compounds that would target FOXM1 and inhibit its activation of downstream pro-inflammatory molecules that drive overproduction of mucous-generating goblet cells.

The research team then tested RMC-1 in cultured human airway epithelial cells and mouse models of asthma (via injection into the animals' peritoneal cavities). The mice were either sensitized with house dust mite allergens or treated with a pro-inflammatory molecule called interleukin 13 (IL-13), to induce mucous production found in airway diseases.

Microscopic images not only show that RMC-1 prevented FOXM1 from entering the nucleus in cultured human airway epithelial cells and in mouse allergen-sensitized respiratory airways — it also reduced lung inflammation and improved lung function in mice sensitized to house dust mite allergens. FOXM1 also prevented IL-13 from causing goblet cell expansion in mice given the pro-inflammatory molecule intra-nasally.

Before the research team's identification of RMC-1 could eventually lead to clinical trials, Kalinichenko's researchers will first need to test RCM-1 in more sophisticated animal models of respiratory diseases. This will help address issues related to dosage, toxicity, optimal methods of therapeutic delivery, etc.

In their future work, researchers also want to refine the chemical structure of RCM-1 to make it more efficient and improve the method of therapeutic delivery. This includes seeing if the compound can be packaged into nanoparticles for intravenous injection. The researchers have applied for a patent on RCM-1, working through the Cincinnati Children's Center for Technology Commercialization.

Abstract
Goblet cell metaplasia and excessive mucus secretion associated with asthma, cystic fibrosis, and chronic obstructive pulmonary disease contribute to morbidity and mortality worldwide. We performed a high-throughput screen to identify small molecules targeting a transcriptional network critical for the differentiation of goblet cells in response to allergens. We identified RCM-1, a nontoxic small molecule that inhibited goblet cell metaplasia and excessive mucus production in mice after exposure to allergens. RCM-1 blocked the nuclear localization and increased the proteasomal degradation of Forkhead box M1 (FOXM1), a transcription factor critical for the differentiation of goblet cells from airway progenitor cells. RCM-1 reduced airway resistance, increased lung compliance, and decreased proinflammatory cytokine production in mice exposed to the house dust mite and interleukin-13 (IL-13), which triggers goblet cell metaplasia. In cultured airway epithelial cells and in mice, RCM-1 reduced IL-13 and STAT6 (signal transducer and activator of transcription 6) signaling and prevented the expression of the STAT6 target genes Spdef and Foxa3, which are key transcriptional regulators of goblet cell differentiation. These results suggest that RCM-1 is an inhibitor of goblet cell metaplasia and IL-13 signaling, providing a new therapeutic candidate to treat patients with asthma and other chronic airway diseases.

Funding support for this research came in part from: the National Institutes of Health (HL84151, HL123490, HL132849, CA142724); a Research Scholar Grant (RSG-13-325) from the American Cancer Society; the National Health Research Institutes of Taiwan (NHRI-EX105-10309BC); and from the Ministry of Science and Technology of Taiwan (MOST102-2628-B-007-003-MY3).
Return to top of page

Apr 27, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



This microscopic image shows human lung epithelial cells treated with an experimental molecular compound called RCM-1. RCM-1 treatment removes a transcription factor called FOXM1 (GREEN) from the nucleus of cells (BLUE) placing it into the cell's cytoplasm. FOXM1 triggers excess inflammation and mucous in diseases like asthma and COPD. Researchers at Cincinnati Children's report in Science Signaling how RMC-1 prevents excess inflammation and mucous in mouse and human respiratory cells.
Image Credit: Cincinnati Children's Hospital

 


Phospholid by Wikipedia