Advertisements
Feeds:
Posts
Comments

Archive for the ‘Biochemical pathways’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Over the past 20 years, studies have shown that girls and possibly boys have been experiencing puberty at progressively younger ages. This is troubling news, as earlier age at puberty has been linked with increased risk of mental illness, breast and ovarian cancer in girls and testicular cancer in boys. Researchers found that daughters of mothers who had higher levels of diethyl phthalate and triclosan in their bodies during pregnancy experienced puberty at younger ages. The same trend was not observed in boys. So, researchers suspected that girls exposed to chemicals commonly found in toothpaste, makeup, soap and other personal care products before birth may hit puberty earlier.

 

Diethyl phthalate is often used as a stabilizer in fragrances and cosmetics. The antimicrobial agent triclosan — which the FDA banned from use in hand soap in 2017 because it was shown to be ineffective — is still used in some toothpastes. Researchers suspected that many chemicals in personal care products can interfere with natural hormones in human bodies, and studies have shown that exposure to these chemicals can alter reproductive development in rats. Chemicals that have been implicated include phthalates, which are often found in scented products like perfumes, soaps and shampoos; parabens, which are used as preservatives in cosmetics; and phenols, which include triclosan.

 

However, few studies have looked at how these chemicals might affect the growth of human children. This present study at UC Berkeley, USA recruited pregnant women living in the farm-working, primarily Latino communities of Central California’s Salinas Valley between 1999 and 2000. While the primary aim of the study was to examine the impact of pesticide exposure on childhood development, the researchers used the opportunity to examine the effects of other chemicals as well. The scientists measured concentrations of phthalates, parabens and phenols in urine samples taken from mothers twice during pregnancy, and from children at the age of 9. They then followed the growth of the children — 159 boys and 179 girls — between the ages of 9 and 13 to track the timing of developmental milestones marking different stages of puberty.

 

The vast majority — more than 90 percent — of urine samples of both mothers and children showed detectable concentrations of all three classes of chemicals, with the exception of triclosan which was present in approximately 70 percent of samples. The researchers found that every time the concentrations of diethyl phthalate and triclosan in the mother’s urine doubled, the timing of developmental milestones in girls shifted approximately one month earlier. Girls who had higher concentrations of parabens in their urine at age 9 also experienced puberty at younger ages. However, it is unclear if the chemicals were causing the shift, or if girls who reached puberty earlier were more likely to start using personal care products at younger ages.

 

The limitations are that these chemicals are quickly metabolized and one to two urinary measurements per developmental point may not accurately reflect usual exposure. The study population was limited to Latino children of low socioeconomic status living in a farmworker community and may not be widely generalizable. But, this study contributes to a growing literature that suggests that exposure to certain endocrine disrupting chemicals may impact timing of puberty in children.

 

References:

 

https://www.universityofcalifornia.edu/news/prenatal-exposure-chemicals-personal-care-products-may-speed-puberty-girls?utm_source=fiat-lux

 

https://www.ncbi.nlm.nih.gov/pubmed/30517665

 

https://www.ncbi.nlm.nih.gov/pubmed/24781428

 

https://www.ncbi.nlm.nih.gov/pubmed/30203993

 

https://www.ncbi.nlm.nih.gov/pubmed/25173057

 

Advertisements

Read Full Post »


Lesson 9 Cell Signaling:  Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBiol3373

Stephen J. Wiilliams, Ph.D: Curator

The following contain curations of scientific articles from the site https://pharmaceuticalintelligence.com  intended as additional reference material  to supplement material presented in the lecture.

Wnts are a family of lipid-modified secreted glycoproteins which are involved in:

Normal physiological processes including

A. Development:

– Osteogenesis and adipogenesis (Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes)

  – embryogenesis including body axis patterning, cell fate specification, cell proliferation and cell migration

B. tissue regeneration in adult tissue

read: Wnt signaling in the intestinal epithelium: from endoderm to cancer

And in pathologic processes such as oncogenesis (refer to Wnt/β-catenin Signaling [7.10]) and to your Powerpoint presentation

 

The curation Wnt/β-catenin Signaling is a comprehensive review of canonical and noncanonical Wnt signaling pathways

 

To review:

 

 

 

 

 

 

 

 

 

 

 

Activating the canonical Wnt pathway frees B-catenin from the degradation complex, resulting in B-catenin translocating to the nucleus and resultant transcription of B-catenin/TCF/LEF target genes.

Fig. 1 Canonical Wnt/FZD signaling pathway. (A) In the absence of Wnt signaling, soluble β-catenin is phosphorylated by a degradation complex consisting of the kinases GSK3β and CK1α and the scaffolding proteins APC and Axin1. Phosphorylated β-catenin is targeted for proteasomal degradation after ubiquitination by the SCF protein complex. In the nucleus and in the absence of β-catenin, TCF/LEF transcription factor activity is repressed by TLE-1; (B) activation of the canonical Wnt/FZD signaling leads to phosphorylation of Dvl/Dsh, which in turn recruits Axin1 and GSK3β adjacent to the plasma membrane, thus preventing the formation of the degradation complex. As a result, β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it promotes the expression of target genes via interaction with TCF/LEF transcription factors and other proteins such as CBP, Bcl9, and Pygo.

NOTE: In the canonical signaling, the Wnt signal is transmitted via the Frizzled/LRP5/6 activated receptor to INACTIVATE the degradation complex thus allowing free B-catenin to act as the ultimate transducer of the signal.

Remember, as we discussed, the most frequent cancer-related mutations of WNT pathway constituents is in APC.

This shows how important the degradation complex is in controlling canonical WNT signaling.

Other cell signaling systems are controlled by protein degradation:

A.  The Forkhead family of transcription factors

Read: Regulation of FoxO protein stability via ubiquitination and proteasome degradation

B. Tumor necrosis factor α/NF κB signaling

Read: NF-κB, the first quarter-century: remarkable progress and outstanding questions

1.            Question: In cell involving G-proteins, the signal can be terminated by desensitization mechanisms.  How is both the canonical and noncanonical Wnt signal eventually terminated/desensitized?

We also discussed the noncanonical Wnt signaling pathway (independent of B-catenin induced transcriptional activity).  Note that the canonical and noncanonical involve different transducers of the signal.

Noncanonical WNT Signaling

Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP3/DAG/Ca++ and/or kinases such as MAPK, JNK.

Depending on the different combinations of WNT ligands and the receptors, WNT signaling activates several different intracellular pathways  (i.e. canonical versus noncanonical)

 

In addition different Wnt ligands are expressed at different times (temporally) and different cell types in development and in the process of oncogenesis. 

The following paper on Wnt signaling in ovarian oncogenesis shows how certain Wnt ligands are expressed in normal epithelial cells but the Wnt expression pattern changes upon transformation and ovarian oncogenesis. In addition, differential expression of canonical versus noncanonical WNT ligands occur during the process of oncogenesis (for example below the authors describe the noncanonical WNT5a is expressed in normal ovarian  epithelia yet WNT5a expression in ovarian cancer is lower than the underlying normal epithelium. However the canonical WNT10a, overexpressed in ovarian cancer cells, serves as an oncogene, promoting oncogenesis and tumor growth.

Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence

Benjamin G. Bitler,1 Jasmine P. Nicodemus,1 Hua Li,1 Qi Cai,2 Hong Wu,3 Xiang Hua,4 Tianyu Li,5 Michael J. Birrer,6Andrew K. Godwin,7 Paul Cairns,8 and Rugang Zhang1,*

A.           Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the US. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a non-canonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We demonstrate that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; p = 0.039) or fallopian tube epithelium (n = 28; p < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (p = 0.003) and predicts shorter overall survival in EOC patients (p = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A (HIRA)/promyelocytic leukemia (PML) senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.

Oncol Lett. 2017 Dec;14(6):6611-6617. doi: 10.3892/ol.2017.7062. Epub 2017 Sep 26.

Clinical significance and biological role of Wnt10a in ovarian cancer. 

Li P1Liu W1Xu Q1Wang C1.

Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of β-catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK-974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/β-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/β-catenin signaling pathway.

Targeting the Wnt Pathway includes curations of articles related to the clinical development of Wnt signaling inhibitors as a therapeutic target in various cancers including hepatocellular carcinoma, colon, breast and potentially ovarian cancer.

 

2.         Question: Given that different Wnt ligands and receptors activate different signaling pathways, AND  WNT ligands  can be deferentially and temporally expressed  in various tumor types and the process of oncogenesis, how would you approach a personalized therapy targeting the WNT signaling pathway?

3.         Question: What are the potential mechanisms of either intrinsic or acquired resistance to Wnt ligand antagonists being developed?

 

Other related articles published in this Open Access Online Scientific Journal include the following:

Targeting the Wnt Pathway [7.11]

Wnt/β-catenin Signaling [7.10]

Cancer Signaling Pathways and Tumor Progression: Images of Biological Processes in the Voice of a Pathologist Cancer Expert

e-Scientific Publishing: The Competitive Advantage of a Powerhouse for Curation of Scientific Findings and Methodology Development for e-Scientific Publishing – LPBI Group, A Case in Point 

Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

 

Read Full Post »


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Scientists at the Stanford University School of Medicine have completed the first-ever characterization of the meticulously timed immune system changes in women that occur during pregnancy. The findings were published in Science Immunology revealed that there is an immune clock of pregnancy and suggest it may help doctors predict preterm birth.

 

The timing of immune system changes follows a precise and predictable pattern in normal pregnancy. Although physicians have long known that the expectant mother’s immune system adjusts to prevent her body from rejecting the fetus, no one had investigated the full scope of these changes, nor asked if their timing was tightly controlled.

 

Nearly 10 percent of U.S. infants are born prematurely, arriving three or more weeks early, but physicians lack a reliable way to predict premature deliveries. Previous research at Stanford and other places suggested that inflammatory immune responses may help in triggering early labor. It suggested that if scientists identify an immune signature of impending preterm birth, they should be able to design a blood test to detect it.

 

The researchers used mass cytometry, a technique developed at Stanford, to simultaneously measure up to 50 properties of each immune cell in the blood samples. They counted the types of immune cells, assessed what signaling pathways were most active in each cell, and determined how the cells reacted to being stimulated with compounds that mimic infection with viruses and bacteria.

 

The researchers developed an algorithm that captures the immunological timeline during pregnancy that both validates previous findings and sheds new light on immune cell interaction during gestation. By defining this immunological chronology during normal term pregnancy, they can now begin to determine which alterations associate with pregnancy-related pathologies.

 

With an advanced statistical modeling technique, introduced for the first time in this study, the scientists then described in detail how the immune system changes throughout pregnancy. Instead of grouping the women’s blood samples by trimester for analysis, the model treated gestational age as a continuous variable, allowing the researchers to account for the exact time during pregnancy at which each sample was taken. The mathematical model also incorporated knowledge from the existing scientific literature of how immune cells behave in nonpregnant individuals to help determine which findings were most likely to be important.

 

The study confirmed immune features of pregnancy that were already known. Such as the scientists saw that natural killer cells and neutrophils have enhanced action during pregnancy. The researchers also uncovered several previously unappreciated features of how the immune system changes, such as the finding that activity of the STAT5 signaling pathway in CD4+T cells progressively increases throughout pregnancy on a precise schedule, ultimately reaching levels much higher than in nonpregnant individuals. The STAT5 pathway is involved in helping another group of immune cells, regulatory T cells, to differentiate. Interestingly, prior research in animals has indicated that regulatory T cells are important for maintaining pregnancy.

 

The next step will be to conduct similar research using blood samples from women who deliver their babies prematurely to see where their trajectories of immune function differ from normal.

 

This study revealed a precisely timed chronology of immune adaptations in peripheral blood over the course of a term pregnancy. This finding was enabled by high-content, single-cell mass cytometry coupled with a csEN algorithm accounting for the modular structure of the immune system and previous knowledge. The study provided the conceptual backbone and the analytical framework to examine whether disruption of this chronology is a diagnostically useful characteristic of preterm birth and other pregnancy-related pathologies.

 

References:

 

http://immunology.sciencemag.org/content/2/15/eaan2946.full

 

http://med.stanford.edu/news/all-news/2017/09/immune-system-changes-during-pregnancy-are-precisely-timed.html

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078586/

 

http://www.nature.com/nm/journal/v19/n5/full/nm.3160.html?foxtrotcallback=true

 

https://www.ncbi.nlm.nih.gov/pubmed/14758358

Read Full Post »


Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours

Curator: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

 

The role of melatonin is important in regulating natural sleep and wake cycles. Typically, melatonin levels decline with age, significantly decreasing after age 40. An estimated 50 to 70 million Americans are affected by sleep difficulties – a process regulated by melatonin — and long-term sleep deprivation has been associated with negative health consequences, including an increased risk of diabetes, hypertension, heart attack, stroke, obesity, and depression.

Clinical data from a new pharmacokinetic study suggests that REMfresh®, the first and only continuous release and absorption melatonin (CRA-melatonin), helps maintain sleep for up to 7 hours. REMfresh® contains 99 percent ultra-pure melatonin and is sourced in Western Europe, a factor that is significant and important to many sleep specialists.

Three research abstracts on the REMfresh® data were published in an online supplement in the journal, Sleep, and were presented recently at the 31st Annual Meeting of the Associated Professional Sleep Societies LLC (APSS).

REMfresh Photo

Image SOURCE: Photograph courtesy of Physician’s Seal®

How REMfresh® Works

REMfresh® (CRA-melatonin) mimics the body’s own 7-hour Mesa Wave™, a natural pattern of melatonin blood levels during a normal night’s sleep cycle.

The study demonstrated the continuous release and absorption of 99 percent ultra-pure melatonin in REMfresh® (CRA-melatonin) was designed to induce sleep onset and provide continuous, lasting restorative sleep over 7 hours.

The scientifically advanced, patented formulation, called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products.

Since REMfresh® (CRA-melatonin) is not a drug, there is no drug hangover.

REMfresh MesaCurveNew-1

Image SOURCE: Diagram courtesy of Physician’s Seal®

 

Data Based on Scientifically Advanced Delivery Technology

According to the primary study author, David C. Brodner, M.D., “These study results represent an unparalleled breakthrough in drug-free, sleep maintenance that physicians and patients have been waiting for in a sleep product.” Dr. Brodner is a sleep specialist who is double board-certified in Otolaryngology – Head and Neck Surgery and Sleep Medicine and is the founder and principle physician at the Center for Sinus, Allergy, and Sleep Wellness in Palm Beach County, Florida.

Dr. Brodner said, “Melatonin products have been used primarily as a chronobiotic to address sleep disorders, such as jet lag and shift work. The patented delivery system in REMfresh mimics the body’s own natural sleep pattern, so individuals may experience consistent, restorative sleep and have an improved quality of life with this drug-free product.”

Study Findings With REMAKT

The study findings are based on REMAKT™ (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin).

The study found that melatonin levels with REMfresh® exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

Additional analysis presented showed that REMfresh® (CRA-melatonin) builds upon the body of evidence from prolonged-release melatonin (PR-M), which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency and quality of life in patients aged 55 years and older compared with placebo.

REMfresh® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave™, a flat-topped hill with steep sides). There was a faster time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave™ may help to improve sleep maintenance and morning alertness.

REFERENCE/SOURCE

Physician’s Seal® and REMfresh® (www.remfresh.com)

REMfresh® press release, June 5, 2017 (http://www.prnewswire.com/news-releases/scientifically-advanced-delivery-technology-in-sleep-management-debuts-at-sleep-2017-with-clinical-data-showing-remfresh-the-first-and-only-continuous-release-and-absorption-melatonin-helps-maintain-sleep-for-up-to-7-hours-300468218.html)

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness  (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:

2017

Sleep Research Society announces 2017 award recipients including Thomas S. Kilduff, PhD, Director, Center for Neuroscience at SRI International in Menlo Park, California

https://pharmaceuticalintelligence.com/2017/04/28/sleep-research-society-announces-2017-award-recipients-including-thomas-s-kilduff-phd-director-center-for-neuroscience-at-sri-international-in-menlo-park-california/

2016

Sleep Science

Genetic link to sleep and mood disorders

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

2015

Sleep quality, amyloid and cognitive decline

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

2013

Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

Read Full Post »


Results of New Clinical Data Presented at Digestive Week (DDW), Symptom Reduction and Rapid Pain Relief of Functional Dyspepsia with FDgard®

Reporter: Gail S. Thornton, MA

 

RESULTS OF NEW CLINICAL DATA PRESENTED AT DIGESTIVE DISEASE WEEK (DDW), A PREMIER GASTROENTEROLOGY MEETING, SHOW UNPRECEDENTED SYMPTOM REDUCTION AND RAPID RELIEF OF FUNCTIONAL DYSPEPSIA (FD – PERSISTENT OR RECURRING INDIGESTION) WITH FDgard®, A NEW PRODUCT FOR THIS CONDITION

 First-ever clinical study highlights an advance in the management of Functional Dyspepsia (FD) with FDgard®, a new, non-prescription medical food specially formulated for the dietary management of FD

  • In FD patients, FDgard® significantly reduced symptoms of FD in as early as 24 hours
  • Data showed FDgard®, as an add-on product, improved FD symptoms in patients already using commonly used, off-label medications prescribed for FD
  • Functional Dyspepsia, known for its symptoms of persistent or recurring indigestion, impacts an estimated 1 in 6 adults in the U.S.
  • This medical advance is important because there are no approved products for FD

 CHICAGO – (May 8, 2017) – Landmark clinical data highlight an advance in the management of Functional Dyspepsia (FD) with FDgard®, the only product available for the dietary management of FD. FDgard® demonstrated unprecedented symptom reduction and rapid relief of FD symptoms in patients in only 24 hours. This data was presented during Digestive Disease Week (DDW), a premier gastroenterology meeting.

FDgard® showed effective symptom reduction and rapid relief of FD symptoms in a sub-group of FD patients with Epigastric Pain Syndrome (EPS, which is epigastric pain or burning) and Postprandial Distress Syndrome (PDS, which is early fullness, pressure and heaviness). Additionally, the study findings showed that FDgard® as an add-on product improved FD symptoms in patients already using commonly used, off-label medications prescribed for FD, such as proton pump inhibitors (PPIs) and histamine receptor 2 antagonists (H2RAs), anticonvulsants, antibiotics, antihistamines, antidepressants, and antacids as rescue medications (permitted no more than three doses per week).

FD is often characterized as persistent or recurring indigestion with no known organic cause and is an area of high unmet medical need. Currently, off-label medications are used to treat FD as there is no U.S. Food and Drug Administration (FDA)-approved pharmaceutical product for the condition.

Data from the landmark, multi-centered, post-marketing, parallel group, U.S-based study, entitled FDREST™ (Functional Dyspepsia Reduction and Evaluation Safety Trial), showed that patients with FD who received FDgard® versus a control arm of placebo plus commonly used, off-label FD medications experienced a statistically significant reduction in Postprandial Distress Syndrome (PDS) symptoms and near statistical significance in Epigastric Pain Syndrome (EPS) symptoms at 24 hours. In spite of the polypharmacy and use of rescue medications after 48 hours of first dose, FDgard® helped further improve symptoms at 4 weeks.

Specifically, the FDREST™ study showed that at 24 hours, FDgard® improved FD symptoms in patients and provided rapid and significant reduction in EPS and PDS symptoms in the PDS sub-group as well as a statistically significant reduction in EPS and PDS symptoms in the EPS sub-group. At 4 weeks, approximately 75 percent of the EPS and PDS patients in the FDgard® arm reported substantial symptom improvement vs. approximately half in the control arm.

An estimated 62 percent of FD patients suffer from EPS, while an estimated 73 percent of FD patients suffer from PDS. The overlap of EPS and PDS, which are those FD patients who suffer from both syndromes, is estimated to be 35 percent.[1]

FDgard® is specially formulated for the dietary management of FD, which is persistent or recurring indigestion. It is the first product using a patented, breakthrough technology called Site Specific Targeting (SST®) to deliver individually triple-coated, solid-state microspheres of caraway oil and l-Menthol, the primary component in peppermint oil, quickly and reliably where they are needed most in FD — the upper belly.

The three posters with data from the FDREST™ study were selected for presentation at DDW on Saturday, May 6, 2017.

“These study results are uniquely important and represent an advance in the management of Functional Dyspepsia,” said Michael S. Epstein, M.D., F.A.C.G., A.G.A.F., a leading gastroenterologist and Chief Medical Advisor for IM HealthScience®. “We believe that FDgard® possesses anti-inflammatory, analgesic, and gastro-protective properties, which likely are responsible for the rapid relief and steady improvement of FD symptoms in patients even when used as an add-on therapy to commonly used, off-label medications to treat FD, as demonstrated in the FDREST™ study. In particular, many FD symptoms flare within 2 hours after a meal, so the fast action seen in this FDgard® study is an important advance.”

 

FDREST Results

“Functional dyspepsia can have a significant impact on a patient’s quality of life,” said

William D. Chey, M.D., F.A.C.G., the lead study author and Director in the Division of Gastroenterology, Michigan Medicine Gastroenterology Clinic, Ann Arbor, Michigan. “These study results suggest that FDgard® can provide rapid relief to a subset of patients with functional dyspepsia – a condition for which there are few effective treatments.”

Analysis of FDREST™ data showed that treatment with FDgard® resulted in:

Change in Epigastric Pain Syndrome (EPS) and Postprandial Distress Syndrome (PDS) Symptoms In Overall Participants at 24 hours:

  • 14% improvement of EPS symptoms from baseline at 24 hours. Close to statistical significance compared to the control group (P=0.0737).
  • 9.9% reduction of PDS symptoms from baseline at 24 hours. Statistically significant compared to the control group (P=0.0393).

 

Change in Epigastric Pain Syndrome (EPS) and Postprandial Distress Syndrome (PDS) Symptoms In PDS Group at 24 hours:

  • 19.5% reduction of EPS symptoms from baseline at 24 hours. Statistically significant compared to the control group (P=0.0121).
  • 15.8% reduction of PDS symptoms from baseline at 24 hours. Statistically significant compared to the control group (P=0.0225).

 

Change in Epigastric Pain Syndrome (EPS) and Postprandial Distress Syndrome (PDS) Symptoms In EPS Group at 24 hours:

  • 20.7% reduction of EPS symptoms from baseline at 24 hours. Statistically significant compared to the control group (P=0.0028).
  • 13.2% reduction of PDS symptoms from baseline at 24 hours. Statistically significant compared to the control (P=0.0186).

 

Change in the Clinical Global Impressions Scale (CGI, a measure of symptom severity, treatment response and treatment efficacy):

  • At the end of treatment, 77.7% of PDS patients and 72.2% of EPS patients reported either a “much” or “very much” improved assessment of the Clinical Global Impressions (CGI) scale, compared to 50% (P=0.09) and 40% (P=0.046) in the control groups, respectively.
  • EPS patients had a statistically significant reduction in epigastric pain or discomfort symptoms at 24 hours and were objectively better, although measures did not reach statistical significance, compared to the control group, in all measures at 2-14 days and 15-28 days.
  • PDS patients had a statistically significant reduction in sensations of pressure, heaviness, or fullness compared with the control group at 24 hours and were objectively better, although measures did not reach statistical significance, compared to the control group, in all measures at 2-14 days and 15-28 days.

 

Study Design

FDREST™ (Functional Dyspepsia Reduction and Evaluation Safety Trial) was a multi-centered, post-marketing, parallel group, U.S-based study conducted at eight university-based or gastroenterology research-based centers in the U.S. (study period July 1, 2015, to September 14, 2016). The study was designed to compare the efficacy and safety of FDgard®, plus commonly used FD medications vs a control group of placebo plus commonly used, off-label medications prescribed for FD.

  • There were 100 study participants (76% female; 24% male), aged 18-60 (mean age 43.4 years), with symptoms of FD, all of whom met Rome III criteria for FD.
  • They were selected if they met one or both of the following criteria, based on symptoms:
    • Postprandial Distress Syndrome (PDS, early fullness, pressure and heaviness) – Bothersome postprandial fullness or early satiation at least 3 days per week
    • Epigastric Distress Syndrome (EPS, epigastric pain or burning) – Bothersome epigastric pain or burning at least 1 day per week.
  • They had to have at least moderate symptoms (≥4 points on either question of the 7-point Global Overall Symptoms (GOS) scale on at least 4 days during a 14-day screening period. The GOS scale is a self-reported 7-point scale, adapted from a previously validated 5-point scale. With this scale, patients are asked to grade the overall severity of their dyspepsia symptoms, as defined as upper abdominal symptoms over a certain period of time.
  • The study also showed an improvement at 4 weeks in the Clinical Global Impressions (CGI) Scale, a physician-administered measure of symptom severity, treatment response and treatment efficacy.
  • In the trial, study participants took two capsules of FDgard® or matching placebo in the morning and at dinner time 30 to 60 minutes before a meal. FDgard® or placebo was added to each patients existing FD medication regimen, which included proton pump inhibitors (PPIs), histamine receptor 2 antagonists (H2RAs), anticonvulsants, beta blockers, antihistamines, antidepressants/tricyclic antidepressants (TCAs), pain modulators, antacids, and/or antibiotics. In addition, rescue medications (including prokinetics, antiemetics, anticholinergics, laxatives, antidiarrheals, misoprostol, oral antibiotics, probiotics, calcium channel antagonists, NSAIDs, aspirin (>81 mg per day), antispasmodics, narcotic analgesics, sedative hypnotic agents and other medications that may affect the study) were allowed 48 hours after the first dose, if approved by the medical monitor.
  • Over the course of the study, no serious treatment-emergent adverse events were reported.

 

About Functional Dyspepsia (FD)

Approximately 30 percent of adults suffer from dyspepsia, and about half are estimated to have FD, or non-ulcer dyspepsia.[2] This condition can have a negative effect on workplace attendance and productivity, with associated costs estimated in excess of $18 billion annually.[3]

In FD, which is persistent or recurring indigestion, the normal digestive processes are disrupted along with the digestion and absorption of food nutrients. FD is accompanied by symptoms, such as epigastric pain or discomfort, epigastric burning, postprandial fullness, early satiation, bloating in the upper abdomen, nausea and belching. When doctors diagnose FD, they often identify patients as follows: patients should have these symptoms for at least three months with symptom onset six months previously.

 About FDgard® 

FDgard® is medical food designed to address an unmet medical need for products to help in managing FD, which is persistent or recurring indigestion and its accompanying symptoms.  FDgard® capsules contain caraway oil and l-Menthol, the primary component in peppermint oil, for the dietary management of Functional Dyspepsia (FD). With its patented Site Specific Targeting (SST®) technology, pioneered by IM HealthScience®, FDgard® capsules release individually triple-coated, solid-state microspheres of caraway oil and l-Menthol quickly and reliably where they are needed most in FD — the upper belly. The l-Menthol helps with smooth muscle relaxation and caraway oil helps mitigate the effect of gastric acid on the stomach wall and also helps to normalize gallbladder function as well as deliver promotility and analgesic action in the small intestine (the duodenum) and the stomach.[4] [5] [6] In addition to caraway oil and l-Menthol, FDgard® also provides fiber and amino acids (from gelatin protein). These ingredients have additional positive effects on the gut wall and, thus, help toward normalizing digestion and absorption.

Caraway oil and peppermint oil have a history of working in FD. In multiple clinical studies, the combination of caraway oil and peppermint oil has been shown to manage FD and its accompanying symptoms, such as reducing the intensity of epigastric pain, pain frequency, dyspeptic discomfort and reducing the intensity of sensations of pressure, abdominal heaviness and fullness…significantly better than placebo. A randomized, placebo-controlled multicenter study in Europe[7], previously conducted with the same endpoints and measurements as used in FDREST™, had shown the effectiveness of caraway oil and peppermint oil (l-Menthol) in managing FD symptoms. This study was rated as the highest-quality study on the Jadad scale with a rating of 5, which independently assesses the methodological quality of a clinical trial, and is the most widely used assessment in the world.  The study had used the older single-unit, oil-filled capsule technology, which has challenges in rapid and targeted delivery. Targeted delivery to the upper belly is desirable as recent studies have identified this as the area of disturbance in FD. With SST®, it has now become possible to deliver the combination of caraway oil and peppermint oil (l-Menthol) to this site.

The usual adult dose of FDgard® is 2 capsules, as needed, up to two times a day, not to exceed six capsules per day. While FDgard® does not require a prescription, it must be used under medical supervision, since it is a medical food. FDgard® is available to patients in the digestive aisle at most Rite Aid, CVS/pharmacy and Walgreens stores nationwide.

 

About IM HealthScience®

IM HealthScience® (IMH) is the innovator of IBgard® and FDgard® for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. It is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address gastrointestinal issues where there is a high unmet need. The IM HealthScience® advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting (SST®). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com or www.FDgard.com.

 

Data Presented at DDW Poster Session on Functional Dyspepsia, Nausea and Vomiting

Saturday, May 6, 2017

  • (Poster Session #Sa1618) Randomized Controlled Trial to Assess the Efficacy & Safety of Caraway Oil/L-Menthol plus Usual Care Polypharmacy vs. Placebo plus Usual Care Polypharmacy for Functional Dyspepsia 
    • Dr. William Chey, Dr. Brian Lacy, Dr. Brooks Cash, Dr. Michael Epstein and Dr. Syed Shah
  •  (Poster Session #Sa1620) A caraway oil/menthol combination improves functional dyspepsia (FD) symptoms within the first 24 hours: Results of a randomized controlled trial, which allowed usual FD treatments
    • Dr. Brian Lacy, Dr. William Chey, Dr. Brooks Cash, Dr. Michael Epstein and Dr. Syed Shah
  •  (Poster Session #Sa1619) Efficacy of caraway oil/L-menthol plus usual care vs placebo plus usual care, in functional dyspepsia patients with post-prandial distress (PDS) or epigastric pain (EPS) syndromes: Results from a US RCT
    • Dr. William Chey, Dr. Brian Lacy, Dr. Brooks Cash, Dr. Michael Epstein and Dr. Syed Shah

For more information about featured studies, as well as a schedule of availability for featured researchers, please visit www.ddw.org/press.

About Digestive Disease Week® (DDW)

Digestive Disease Week® (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 6-9, 2017, at McCormick Place, Chicago, IL. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology. More information can be found at www.ddw.org.

Regulation of Medical Foods

FDgard® is a medical food product and not a drug or dietary supplement.  A medical food is defined by section 5(b)(3) of the Orphan Drug Act (21 U.S.C, 360ee (b)(3) as a “food which is formulated to be consumed or administered internally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinct nutritional requirements, based on scientific principles, are established by medical evaluation.” Medical foods do not require prior approval by the FDA and are in a unique category separate from drugs or dietary supplements. Medical foods must contain ingredients that are “Generally Recognized As Safe” (GRAS), or are approved food additives, as defined under sections 201(s) and 409 of the Federal Food, Drug and Cosmetic Act.

###

REFERENCE/SOURCE

[1] Talley, N.J. & Ford, A.C. (2015). Functional Dyspepsia. The New England Journal of Medicine, 373, 1853-63. doi: 10.1056/NEJMra1501505.

[2] Copyright © 1997 International Foundation for Functional Gastrointestinal Disorders (IFFGD). All rights reserved. Functional Dyspepsia and IBS: Incidence and Characteristics.

[3] Lacy, B.E., Weiser, K.T., Kennedy, A.T., Crowell, M.D., & Talley, N.J. (2013). Functional dyspepsia: the economic impact to patients. Alimentary Pharmacology & Therapeutics, 38:170-177. doi: 10.111/apt.12355.

[4] Shams, R., Oldfield, E.C., Copare, J., & Johnson, D.A. (2015). Peppermint Oil: Clinical Uses in the Treatment of Gastrointestinal Diseases. JSM Gastroenterology and Hepatology, 3 (1): 1035-1046.

[5] Sun, J. (2007). D-Limonene: Safety & Clinical Applications. Alternative Medicine Review, 12 (3): 259-264.

[6] Goncalves, J.C.R., Alves, A. de Miranda H., de Araujo, A.E.V., Cruz, J.S., & Araujo, D.A.M. (2010). Distinct effects of carvone analogues on the isolated nerve of rats. European Journal of Pharmacology, 645:108-112. doi: 10.1016/j.ejphar.2010.07.027.

[7] May, B., Köhler, S., & Schneider, B. (2000). Efficacy and tolerability of a fixed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. Alimentary Pharmacology and Therapeutics, 14 (12), 1671–1677. doi: 10.1046/j.1365-2036.2000.00873.x.

SOURCE

http://www.prnewswire.com/news-releases/results-of-new-clinical-data-presented-at-digestive-disease-week-ddw-a-premier-gastroenterology-meeting-show-unprecedented-symptom-reduction-and-rapid-relief-of-functional-dyspepsia-fd—persistent-or-recurring-indigestion-w-300452368.html

Read Full Post »


New Studies toward Understanding Alzheimer Disease

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

There is no unifying concept of Alzheimer Disease beyond the Tau and beta amyloid roles.  Recently, Ingenbleek and Bernstein (journal AD) made the connection between the age related decline of liver synthesis of plasma transthyretin and the more dramatic decline of transthyretin at the blood brain barrier, and the relationship to inability to transfer vitamin A via retinol binding protein to the brain.  Related metabolic events are reported by several groups.

 

What else is New?

 

Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease.

Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD.

Sci Transl Med. 2016 May 25;8(340):340ra72.  http://dx.doi.org:/10.1126/scitranslmed.aaf1059

They show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes….Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria.

This is quite interesting in that infection drives the production of acute phase reactants resulting in decreased production of transthyretin.  Whether this also has ties to chronic disease in the elderly and risk of AD is not known.

Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease.

Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE, Malinow R.

Sci Signal. 2016 May 10;9(427):ra47.  http://dx.doi.org:/10.1126/scisignal.aaf6209.

Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), they identified three highly penetrant variants in PRKCA, the gene that encodes protein kinase Cα (PKCα), in five of the families. All three variants linked with LOAD displayed increased catalytic activity relative to wild-type PKCα as assessed in live-cell imaging experiments using a genetically encoded PKC activity reporter. Deleting PRKCA in mice or adding PKC antagonists to mouse hippocampal slices infected with a virus expressing the Aβ precursor CT100 revealed that PKCα was required for the reduced synaptic activity caused by Aβ. In PRKCA(-/-) neurons expressing CT100, introduction of PKCα, but not PKCα lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKCα to the synapse is required for its mediation of the effects of Aβ. Thus, enhanced PKCα activity may contribute to AD, possibly by mediating the actions of Aβ on synapses.

 

Science Signaling Podcast for 10 May 2016: PKCα in Alzheimer’s disease.

Newton AC, Tanzi RE, VanHook AM.

Sci Signal. 2016 May 10;9(427):pc11. doi: 10.1126/scisignal.aaf9436.

Relevance of the COPI complex for Alzheimer’s disease progression in vivo.

Bettayeb K, Hooli BV, Parrado AR, Randolph L, Varotsis D, Aryal S, Gresack J,Tanzi RE, Greengard P, Flajolet M.

Proc Natl Acad Sci U S A. 2016 May 10;113(19):5418-23. http://dx.doi.org:/10.1073/pnas.1604176113

Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.

Kim BM, You MH, Chen CH, Suh J, Tanzi RE, Ho Lee T.

Hum Mol Genet. 2016 Apr 19. pii: ddw114.

Extracellular deposition of amyloid-beta (Aβ) peptide, a metabolite of sequential cleavage of amyloid precursor protein (APP), is a critical step in the pathogenesis of Alzheimer’s disease (AD). While death-associated protein kinase 1 (DAPK1) is highly expressed in AD brains and its genetic variants are linked to AD risk, little is known about the impact of DAPK1 on APP metabolism and Aβ generation. This study demonstrated a novel effect of DAPK1 in the regulation of APP processing using cell culture and mouse models. DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ. In Tg2576 APPswe-overexpressing mice, knockout of DAPK1 shifted APP processing toward non-amyloidogenic pathway and decreased Aβ generation. Finally, in AD brains, elevated DAPK1 levels showed co-relation with the increase of APP phosphorylation. Combined together, these results suggest that DAPK1 promotes the phosphorylation and amyloidogenic processing of APP, and that may serve a potential therapeutic target for AD.

Recapitulating amyloid β and tau pathology in human neural cell culture models: clinical implications.

Choi SH, Kim YH, D’Avanzo C, Aronson J, Tanzi RE, Kim DY.

US Neurol. 2015 Fall;11(2):102-105.    Free PMC Article

The “amyloid β hypothesis” of Alzheimer’s disease (AD) has been the reigning hypothesis explaining pathogenic mechanisms of AD over the last two decades. However, this hypothesis has not been fully validated in animal models, and several major unresolved issues remain. Our 3D human neural cell culture model system provides a premise for a new generation of cellular AD models that can serve as a novel platform for studying pathogenic mechanisms and for high-throughput drug screening in a human brain-like environment.

The two key pathological hallmarks of AD are senile plaques (amyloid plaques) and neurofibrillary tangles (NFTs), which develop in brain regions responsible for memory and cognitive functions (i.e. cerebral cortex and limbic system) 3. Senile plaques are extracellular deposits of amyloid-β (Aβ) peptides, while NFTs are intracellular, filamentous aggregates of hyperphosphorylated tau protein 4.

The identification of Aβ as the main component of senile plaques by Drs. Glenner and Wong in 1984 5 resulted in the original formation of the “amyloid hypothesis.” According to this hypothesis, which was later renamed the “amyloid-β cascade hypothesis” by Drs. Hardy and Higgins 6, the accumulation of Aβ is the initial pathological trigger in the disease, subsequently leading to hyperphosphorylation of tau, causing NFTs, and ultimately, neuronal death and dementia 4,710. Although the details have been modified to reflect new findings, the core elements of this hypothesis remain unchanged: excess accumulation of the pathogenic forms of Aβ, by altered Aβ production and/or clearance, triggers the vicious pathogenic cascades that eventually lead to NFTs and neuronal death.

Over the last two decades, the Aβ hypothesis of AD has reigned, providing the foundation for numerous basic studies and clinical trials 4,7,10,11. According to this hypothesis, the accumulation of Aβ, either by altered Aβ production and/or clearance, is the initial pathological trigger in the disease. The excess accumulation of Aβ then elicits a pathogenic cascade including synaptic deficits, altered neuronal activity, inflammation, oxidative stress, neuronal injury, hyperphosphorylation of tau causing NFTs and ultimately, neuronal death and dementia 4,710.

One of the major unresolved issues of the Aβ hypothesis is to show a direct causal link between Aβ and NFTs 1214. Studies have demonstrated that treatments with various forms of soluble Aβ oligomers induced synaptic deficits and neuronal injury, as well as hyperphosphorylation of tau proteins, in mouse and rat neurons, which could lead to NFTs and neurodegeneration in vivo 1821. However, transgenic AD mouse models carrying single or multiple human familial AD (FAD) mutations in amyloid precursor protein (APP) and/or presenilin 1 (PS1) do not develop NFTs or robust neurodegeneration as observed in human patients, despite robust Aβ deposition 13,22,23. Double and triple transgenic mouse models, harboring both FAD and tau mutations linked with frontotemporal dementia (FTD), are the only rodent models to date displaying both amyloid plaques and NFTs. However, the NFT pathology in these models stems mainly from the overexpression of human tau as a result of the FTD, rather than the FAD mutations24,25.

Human neurons carrying FAD mutations are an optimal model to test whether elevated levels of pathogenic Aβ trigger pathogenic cascades including NFTs, since those cells truly share the same genetic background that induces FAD in humans. Indeed, Israel et al., observed elevated tau phosphorylation in neurons with an APP duplication FAD mutation 33. Blocking Aβ generation by β-secretase inhibitors significantly decreased tau phosphorylation in the same model, but γ-secretase inhibitor, another Aβ blocker, did not affect tau phosphorylation 33. Neurons with the APP V717I FAD mutation also showed an increase in levels of phospho tau and total tau levels 28. More importantly, Muratore and colleagues showed that treatments with Aβ-neutralizing antibodies in those cells significantly reduced the elevated total and phospho tau levels at the early stages of differentiation, suggesting that blocking pathogenic Aβ can reverse the abnormal tau accumulation in APP V717I neurons 28.

Recently, Moore et al. also reported that neurons harboring the APP V717I or the APP duplication FAD mutation showed increases in both total and phospho tau levels 27. Interestingly, altered tau levels were not detected in human neurons carrying PS1 FAD mutations, which significantly increased pathogenic Aβ42 species in the same cells 27. These data suggest that elevated tau levels in these models were not due to extracellular Aβ accumulation but may possibly represent a very early stage of tauopathy. It may also be due to developmental alterations induced by the APP FAD mutations.

As summarized, most human FAD neurons showed significant increases in pathogenic Aβ species, while only APP FAD neurons showed altered tau metabolism that may represent very early stages of tauopathy. However, all of these human FAD neurons failed to recapitulate robust extracellular amyloid plaques, NFTs, or any signs of neuronal death, as predicted in the amyloid hypothesis.

In our recent study, we moved one step closer to proving the amyloid hypothesis. By generating human neural stem cell lines carrying multiple mutations in APP together with PS1, we achieved high levels of pathogenic Aβ42 comparable to those in brains of AD patients 4446.

An external file that holds a picture, illustration, etc. Object name is nihms740236f1.jpg

 

Platform for AD drug screening in human neural progenitor cells with FAD mutations in a 3D culture system, which successfully reproduce human AD pathogenesis (amyloid plaques-driven tauopathy).

In addition to the impact on toxic Aβ species, our 3D culture model can test if these antibodies can block tau pathologies in 3D human neural cell culture systems 4446. Human cellular AD models can also be used to determine optimal doses of candidate AD drugs to block Aβ and/or tau pathology without affecting neuronal survival (Fig. 1).

While much progress has been made, many challenges still lie on the path to creating human neural cell culture models that comprehensively recapitulate pathogenic cascades of AD. A major difficulty lies in reconstituting the brain regions most affected in AD: the hippocampus and specific cortical layers. Recent progress in 3D culture technology, such as “cerebral organoids,” may also be helpful in rebuilding the brain structures that are affected by AD in a dish 52,53. These “cerebral organoids” were able to model various discrete brain regions including human cortical areas 52, which enabled them to reproduce microcephaly, a brain developmental disorder. Similarly, pathogenic cascades of AD may be recapitulated in cortex-like structures using this model. Adding neuroinflammatory components, such as microglial cells, which are critical in AD pathogenesis, will illuminate the validity of the amyloid β hypothesis. Reconstitution of robust neuronal death stemming from Aβ and tau pathologies will be the next major step in comprehensively recapitulating AD in a cellular model.

 

Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer’s disease with OSBPL6, PTPRG, and PDCL3.

Herold C, Hooli BV, Mullin K, Liu T, Roehr JT, Mattheisen M, Parrado AR, Bertram L, Lange C, Tanzi RE.

Mol Psychiatry. 2016 Feb 2. http://dx.doi.org:/10.1038/mp.2015.218.

Relationship between ubiquilin-1 and BACE1 in human Alzheimer’s disease and APdE9 transgenic mouse brain and cell-based models.

Natunen T, Takalo M, Kemppainen S, Leskelä S, Marttinen M, Kurkinen KM, Pursiheimo JP, Sarajärvi T, Viswanathan J, Gabbouj S, Solje E, Tahvanainen E, Pirttimäki T, Kurki M, Paananen J, Rauramaa T, Miettinen P, Mäkinen P, Leinonen V, Soininen H, Airenne K, Tanzi RE, Tanila H, Haapasalo A, Hiltunen M.

Neurobiol Dis. 2016 Jan;85:187-205. http://dx.doi.org:/10.1016/j.nbd.2015.11.005.

Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimer’s disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation. Here, we have investigated ubiquilin-1 expression in human brain in relation to AD-related neurofibrillary pathology and the effects of ubiquilin-1 overexpression on BACE1, tau, neuroinflammation, and neuronal viability in vitro in co-cultures of mouse embryonic primary cortical neurons and microglial cells under acute neuroinflammation as well as neuronal cell lines, and in vivo in the brain of APdE9 transgenic mice at the early phase of the development of Aβ pathology. Ubiquilin-1 expression was decreased in human temporal cortex in relation to the early stages of AD-related neurofibrillary pathology (Braak stages 0-II vs. III-IV). There was a trend towards a positive correlation between ubiquilin-1 and BACE1 protein levels. Consistent with this, ubiquilin-1 overexpression in the neuron-microglia co-cultures with or without the induction of neuroinflammation resulted in a significant increase in endogenously expressed BACE1 levels. Sustained ubiquilin-1 overexpression in the brain of APdE9 mice resulted in a moderate, but insignificant increase in endogenous BACE1 levels and activity, coinciding with increased levels of soluble Aβ40 and Aβ42. BACE1 levels were also significantly increased in neuronal cells co-overexpressing ubiquilin-1 and BACE1. Ubiquilin-1 overexpression led to the stabilization of BACE1 protein levels, potentially through a mechanism involving decreased degradation in the lysosomal compartment. Ubiquilin-1 overexpression did not significantly affect the neuroinflammation response, but decreased neuronal viability in the neuron-microglia co-cultures under neuroinflammation. Taken together, these results suggest that ubiquilin-1 may mechanistically participate in AD molecular pathogenesis by affecting BACE1 and thereby APP processing and Aβ accumulation.

Correction to Cathepsin L Mediates the Degradation of Novel APP C-Terminal Fragments.

Wang H, Sang N, Zhang C, Raghupathi R, Tanzi RE, Saunders A.

Biochemistry. 2015 Sep 22;54(37):5781.  http://dx.doi.org:/10.1021/acs.biochem.5b00968. Epub 2015 Sep 8. No abstract available.

Massachusetts Alzheimer’s Disease Research Center: progress and challenges.

Hyman BT, Growdon JH, Albers MW, Buckner RL, Chhatwal J, Gomez-Isla MT, Haass C, Hudry E, Jack CR Jr, Johnson KA, Khachaturian ZS, Kim DY, Martin JB, Nitsch RM, Rosen BR, Selkoe DJ, Sperling RA, St George-Hyslop P, Tanzi RE, Yap L, Young AB, Phelps CH, McCaffrey PG.

Alzheimers Dement. 2015 Oct;11(10):1241-5. http://dx.doi.org:/10.1016/j.jalz.2015.06.1887. Epub 2015 Aug 19. No abstract available.

Alzheimer’s in 3D culture: challenges and perspectives.

D’Avanzo C, Aronson J, Kim YH, Choi SH, Tanzi RE, Kim DY.

Bioessays. 2015 Oct;37(10):1139-48. doi: 10.1002/bies.201500063. Epub 2015 Aug 7. Review.

Synaptotagmins interact with APP and promote Aβ generation.

Gautam V, D’Avanzo C, Berezovska O, Tanzi RE, Kovacs DM.

Mol Neurodegener. 2015 Jul 23;10:31. doi: 10.1186/s13024-015-0028-5.

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease.

Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, Ran C.

Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9734-9. doi: 10.1073/pnas.1505420112. Epub 2015 Jul 21.

A 3D human neural cell culture system for modeling Alzheimer’s disease.

Kim YH, Choi SH, D’Avanzo C, Hebisch M, Sliwinski C, Bylykbashi E, Washicosky KJ, Klee JB, Brüstle O, Tanzi RE, Kim DY.

Nat Protoc. 2015 Jul;10(7):985-1006. doi: 10.1038/nprot.2015.065. Epub 2015 Jun 11.

Cathepsin L Mediates the Degradation of Novel APP C-Terminal Fragments.

Wang H, Sang N, Zhang C, Raghupathi R, Tanzi RE, Saunders A.

Biochemistry. 2015 May 12;54(18):2806-16. doi: 10.1021/acs.biochem.5b00329. Epub 2015 Apr 28. Erratum in: Biochemistry. 2015 Sep 22;54(37):5781.

γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation.

D’Avanzo C, Sliwinski C, Wagner SL, Tanzi RE, Kim DY, Kovacs DM.

FASEB J. 2015 Aug;29(8):3335-41. doi: 10.1096/fj.15-271015. Epub 2015 Apr 22.

PLD3 gene variants and Alzheimer’s disease.

Hooli BV, Lill CM, Mullin K, Qiao D, Lange C, Bertram L, Tanzi RE.

Nature. 2015 Apr 2;520(7545):E7-8. doi: 10.1038/nature14040. No abstract available.

Read Full Post »


Targeted Therapy for Triple Negative Breast Cancer

Curator: Larry H. Bernstein, MD, FCAP

LPBI

 

Triple-Negative Breast Cancer Target Is Found

May 17, 2016   Researchers at UC Berkeley discover a target that drives cancer metabolism in triple-negative breast cancer.
http://www.technologynetworks.com/Genotyping/news.aspx?ID=191502

UC Berkeley researchers have found a long-elusive Achilles’ heel within “triple-negative” breast tumors, a common type of breast cancer that is difficult to treat. The scientists then used a drug-like molecule to successfully target this vulnerability, killing cancer cells in the lab and shrinking tumors in mice.

“We were looking for targets that drive cancer metabolism in triple-negative breast cancer, and we found one that was very specific to this type of cancer,” said Daniel K. Nomura, an associate professor of chemistry and of nutritional sciences and toxicology at UC Berkeley and senior author for the study, which is published online ahead of print in Cell Chemical Biology.

Triple-negative breast cancers account for about one in five breast cancers, and they are deadlier than other forms of breast cancer, in part because no drugs have been developed to specifically target these tumors.

Triple-negative breast cancers do not rely on the hormones estrogen and progesterone for growth, nor on human epidermal growth factor receptor 2 (HER2). Because they do not depend on these three targets, they are not vulnerable to modern hormonal therapies or to the HER2-targeted drug Herceptin (trastuzumab).

Instead, oncologists treat triple-negative breast cancer with older chemotherapies that target all dividing cells. If triple-negative breast cancer spreads beyond the breast to distant sites within the body, an event called metastasis, there are few treatment options.

Tumor cells develop abnormal metabolism, which they rely on to get the energy boost they need to fuel their rapid growth. In their new study, the research team used an innovative approach to search for active enzymes that triple-negative breast cancers use differently for metabolism in comparison to other cells and even other tumors.

Inhibiting cancer metabolism

They discovered that cells from triple-negative breast cancer cells rely on vigorous activity by an enzyme called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells, GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving them of energy, nutrients and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

Co-author Eranthie Weerapana, an associate professor of chemistry at Boston College, developed a molecule named LAS17 that tightly and irreversibly attaches to the target site on the GSTP1 molecule. By binding tightly to GSTP1, LAS17 inhibits activity of the enzyme. The researchers found that LAS17 was highly specific for GSTP1, and did not attach to other proteins in cells.

According to Nomura, LAS17 did not appear to have toxic side effects in mice, where it shrank tumors grown to an invasive stage from surgically transplanted, human, triple-negative breast cancer cells that had long been maintained in lab cultures.

The research team intends to continue studying LAS17, Nomura said, with the next step being to study tumor tissue resected from human triple-negative breast cancers and transplanted directly into mice.

“Inhibiting GSTP1 impairs glycolytic metabolism,” Nomura said. “More broadly, this inhibition starves triple-negative breast cancer cells, preventing them from making the macromolecules they need, including the lipids they need to make membranes and the nucleic acids they need to make DNA. It also prevents these cells from making enough ATP, the molecule that is the basic energy fuel for cells.”

Beyond the metabolic role they first sought to track down, GSTP1 also appears to aid signaling within triple-negative breast cancer cells, helping to spur tumor growth, the researchers found.

Technique identifies Achilles’ heels

Nomura said it was surprising that a single, unique target emerged from the research team’s search.

The method used by the researchers, called “reactivity-based chemoproteomics,” can quickly lead to specific targetable sites — the Achilles’ heels — on proteins of interest, and eventually to drug development strategies, Nomura said.

The approach is to search for protein targets that are actively functioning within cells, instead of first using the well-trod path of surveying all genes to identify the specific genes that have taken the first step toward protein production. With that more conventional strategy, the switching on, or “expression,” of genes is evidenced by the easily quantified molecule called messenger RNA, made by the cell from a gene’s DNA template.

Nomura’s team instead first used chemical probes that can react with certain configurations of two of the amino acid building blocks of protein — cysteine and lysine — known to be involved in several kinds of important structural and functional transitions that active proteins can undergo.

“A lot can happen after the first step in protein production, and we believe our method for identifying fully formed, active proteins is more useful for tracking down relevant differences in cellular physiology,” Nomura said.

The researchers analyzed and compared cells from five distinct triple-negative breast cancers that had been grown in cell cultures for generations, along with cells from four distinct breast cancers that were not triple negative.

The scientists used a chemical identification technique known as mass spectrometry to narrow down the set of proteins that had active lysines and cysteines to just those that were metabolic enzymes. Only then did they use the more conventional approach of measuring gene expression in the different cancer cell types.

GSTP1 was the only metabolically active enzyme that was specifically expressed only in triple-negative breast cancer cells compared to other breast cancer cell types, the researchers found. Separate analysis of databases of human breast cancer by UC San Francisco co-authors confirmed that GSTP1 is overexpressed in patients with triple-negative breast cancers in comparison to patients with other breast cancers.

In addition to Nomura and Weerapana, study authors included Sharon Louie, Elizabeth Grossman, Lucky Ding, Tucker Huffman and David Miyamoto, from UC Berkeley; Roman Camarda and Andrei Goga, from UC San Francisco, and Lisa Crawford, from Boston College. Study funders included the National Institutes of Health, the American Cancer Society, the U.S. Department of Defense, and the Searle Scholar Foundation.

 

Triple-negative breast cancer target is found

UC Berkeley researchers have found a long-elusive Achilles’ heel within “triple-negative” breast tumors, a common type of breast cancer that is difficult to treat. The scientists then used a drug-like molecule to successfully target this vulnerability, killing cancer cells in the lab and shrinking tumors in mice.

“We were looking for targets that drive cancer metabolism in triple-negative breast cancer, and we found one that was very specific to this type of cancer,” said Daniel K. Nomura, an associate professor of chemistry and of nutritional sciences and toxicology at UC Berkeley and senior author for the study, which is published online ahead of print on May 12 in Cell Chemical Biology.

Triple-negative breast cancers account for about one in five breast cancers, and they are deadlier than other forms of breast cancer, in part because no drugs have been developed to specifically target these tumors.

Triple-negative breast cancers do not rely on the hormones estrogen and progesterone for growth, nor on human epidermal growth factor receptor 2 (HER2). Because they do not depend on these three targets, they are not vulnerable to modern hormonal therapies or to the HER2-targeted drug Herceptin (trastuzumab).

Instead, oncologists treat triple-negative breast cancer with older chemotherapies that target all dividing cells. If triple-negative breast cancer spreads beyond the breast to distant sites within the body, an event called metastasis, there are few treatment options.

Tumor cells develop abnormal metabolism, which they rely on to get the energy boost they need to fuel their rapid growth. In their new study, the research team used an innovative approach to search for active enzymes that triple-negative breast cancers use differently for metabolism in comparison to other cells and even other tumors.

Inhibiting cancer metabolism

They discovered that cells from triple-negative breast cancer cells rely on vigorous activity by an enzyme called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells, GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving them of energy, nutrients and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

for mor see.. http://news.berkeley.edu/2016/05/12/triple-negative-breast-cancer-target-is-found/

 

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

Sharon M. Louie, Elizabeth A. Grossman, Lisa A. Crawford….., Eranthie Weerapana, Daniel K. Nomura
Figure thumbnail fx1
  • We used chemoproteomics to profile metabolic drivers of breast cancer
  • GSTP1 is a novel triple-negative breast cancer-specific target
  • GSTP1 inhibition impairs triple-negative breast cancer pathogenicity
  • GSTP1 inhibition impairs GAPDH activity to affect metabolism and signaling

Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways.

Read Full Post »

Older Posts »