Propolis with its active component CAPE (Caffeic Acid Phenethyl Ester) stops breast cancer cell growth. These results of CAPE are present in the naturopathic formulation
of propolis, a widely available natural substance with an extended safety record, making it a naturally-occurring and readily available epigenetic agent with great potential in breast cancer and oncology in general. The ability to link the biological effects of a naturopathic remedy to the pharmacologic effects seen with an exciting class of drugs in the treatment of cancer opens the door to a host of new therapeutic opportunities for patients.
ADAR2 editing activity in newly diagnosed versus relapsed pediatric high-grad...Enrique Moreno Gonzalez
High-grade (WHO grade III and IV) astrocytomas are aggressive malignant brain tumors affecting humans with a high risk of recurrence in both children and adults. To date, limited information is available on the genetic and molecular alterations important in the onset and progression of pediatric high-grade astrocytomas and, even less, on the prognostic factors that influence long-term outcome in children with recurrence. A-to-I RNA editing is an essential post-transcriptional mechanism that can alter the nucleotide sequence of several RNAs and is
mediated by the ADAR enzymes. ADAR2 editing activity is particularly important in mammalian brain and is impaired in both adult and pediatric high-grade astrocytomas.
Moreover, we have recently shown that the recovered ADAR2 activity in high-grade astrocytomas inhibits in vivo tumor growth. The aim of the present study is to investigate whether changes may occur in ADAR2-mediated RNA editing profiles of relapsed highgrade astrocytomas compared to their respective specimens collected at diagnosis, in four pediatric patients.
Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated ...Enrique Moreno Gonzalez
Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants,
vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August
Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
ADAR2 editing activity in newly diagnosed versus relapsed pediatric high-grad...Enrique Moreno Gonzalez
High-grade (WHO grade III and IV) astrocytomas are aggressive malignant brain tumors affecting humans with a high risk of recurrence in both children and adults. To date, limited information is available on the genetic and molecular alterations important in the onset and progression of pediatric high-grade astrocytomas and, even less, on the prognostic factors that influence long-term outcome in children with recurrence. A-to-I RNA editing is an essential post-transcriptional mechanism that can alter the nucleotide sequence of several RNAs and is
mediated by the ADAR enzymes. ADAR2 editing activity is particularly important in mammalian brain and is impaired in both adult and pediatric high-grade astrocytomas.
Moreover, we have recently shown that the recovered ADAR2 activity in high-grade astrocytomas inhibits in vivo tumor growth. The aim of the present study is to investigate whether changes may occur in ADAR2-mediated RNA editing profiles of relapsed highgrade astrocytomas compared to their respective specimens collected at diagnosis, in four pediatric patients.
Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated ...Enrique Moreno Gonzalez
Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants,
vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August
Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
As an uncommon malignant tumor, hypopharyngeal cancer accounts for 3–5% of head and neck tumors [1]. Most pathological types of hypopharyngeal cancer are squamous cell carcinoma. Due to the occult anatomical location of hypopharyngeal cancer and poor surgical effect, local recurrence or distant metastasis often occurs in patients with hypopharyngeal cancer following surgery.
Efficiency of cape gooseberry in attenuating some biochemical disorders and o...Professor-Dr Hanaa Hassan
In conclusion, the present data indicated the efficacy of CG juice supplementation as an
anti-hepatocellular carcinoma in addition to its ability as a chemosensitizer for ADR treatment. This is
mediated by intracellular pathways, involving improvement the alterations in liver functions as well as
other aspects of HCC, the suppression of oxidative stress and modulation of antioxidant defense
mechanism. Thus, supplementation with edible CG may help in safe application of cancer technology
in medicine as well as in many other aspects of nowadays life. Fractionation guided evaluation could
help in the development of ideal anticancer in the near future.
Search for atoxic cereals: a single blind, cross-over study on the safety of...Enrique Moreno Gonzalez
Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and exvivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD.
Inhibition of glutathione by buthionine sulfoximine enhanced the anti-cancer ...Ashujit
Multiple myeloma (MM) is an incurable blood cancer. Melphalan is an alkylating agent given prior to stem cell transplantation to MM patients. Increased glutathione confers resistance to melphalan. This study investigate the effect of inhibition of glutathione by BSO in preclinical models of MM. Pretreatment with BSO enhanced the anti-cancer effect of melphalan in cell lines and animal models. BSO and melphalan combination was well tolerated by animals and enhanced the survival as compared to controls, BSO and melphalan alone. BSO enhanced depth and duration of responses induced by melphalan. In the combination group, majority of treated animals achieved complete response (CR) and more than 20% had maintained CR. Also, the survival of animals was doubled after combination treatment as compared to BSO or melphalan alone. Mechanistic investigation demonstrated that BSO enhanced melphalan induced DNA damage, caspase cleavage and apoptosis. The combination also achieved multi-logs of cells kills in nine human multiple myeloma cell lines and primary MM cells isolated from blood and bone marrows. Interestingly, the effect of BSO and melphalan combination was abolished when cells were treated with N-acetyl cysteine and sodium thiosulfate but not with vitamin C and vitamin E. This observation suggests that effect of BSO is primarily driven by its ability to deplete glutathione and therefore preventing melphalan detoxification. Together, this study provides framework for testing the combination in a Phase I trial.
Variant G6PD levels promote tumor cell proliferation or apoptosis via the STA...Enrique Moreno Gonzalez
Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown.
Calcarea carbonica induces apoptosis in cancer cells in p53-dependent manner ...home
These observations delineate the significance of immuno-modulatory circuit during calcarea carbonicamediated
tumor apoptosis. The molecular mechanism identified may serve as a platform for involving calcarea
carbonica into immunotherapeutic strategies for effective tumor regression
Bee venom protects kidneys from cancer drug toxicityBee Healthy Farms
This study is good news for those receiving cancer treatment from a potent anticancer drug, Cisplatin, known to damage the kidneys. The results with mice found bee venom provided protection for the kidneys against the drug's negative side effects.
As an uncommon malignant tumor, hypopharyngeal cancer accounts for 3–5% of head and neck tumors [1]. Most pathological types of hypopharyngeal cancer are squamous cell carcinoma. Due to the occult anatomical location of hypopharyngeal cancer and poor surgical effect, local recurrence or distant metastasis often occurs in patients with hypopharyngeal cancer following surgery.
Efficiency of cape gooseberry in attenuating some biochemical disorders and o...Professor-Dr Hanaa Hassan
In conclusion, the present data indicated the efficacy of CG juice supplementation as an
anti-hepatocellular carcinoma in addition to its ability as a chemosensitizer for ADR treatment. This is
mediated by intracellular pathways, involving improvement the alterations in liver functions as well as
other aspects of HCC, the suppression of oxidative stress and modulation of antioxidant defense
mechanism. Thus, supplementation with edible CG may help in safe application of cancer technology
in medicine as well as in many other aspects of nowadays life. Fractionation guided evaluation could
help in the development of ideal anticancer in the near future.
Search for atoxic cereals: a single blind, cross-over study on the safety of...Enrique Moreno Gonzalez
Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and exvivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD.
Inhibition of glutathione by buthionine sulfoximine enhanced the anti-cancer ...Ashujit
Multiple myeloma (MM) is an incurable blood cancer. Melphalan is an alkylating agent given prior to stem cell transplantation to MM patients. Increased glutathione confers resistance to melphalan. This study investigate the effect of inhibition of glutathione by BSO in preclinical models of MM. Pretreatment with BSO enhanced the anti-cancer effect of melphalan in cell lines and animal models. BSO and melphalan combination was well tolerated by animals and enhanced the survival as compared to controls, BSO and melphalan alone. BSO enhanced depth and duration of responses induced by melphalan. In the combination group, majority of treated animals achieved complete response (CR) and more than 20% had maintained CR. Also, the survival of animals was doubled after combination treatment as compared to BSO or melphalan alone. Mechanistic investigation demonstrated that BSO enhanced melphalan induced DNA damage, caspase cleavage and apoptosis. The combination also achieved multi-logs of cells kills in nine human multiple myeloma cell lines and primary MM cells isolated from blood and bone marrows. Interestingly, the effect of BSO and melphalan combination was abolished when cells were treated with N-acetyl cysteine and sodium thiosulfate but not with vitamin C and vitamin E. This observation suggests that effect of BSO is primarily driven by its ability to deplete glutathione and therefore preventing melphalan detoxification. Together, this study provides framework for testing the combination in a Phase I trial.
Variant G6PD levels promote tumor cell proliferation or apoptosis via the STA...Enrique Moreno Gonzalez
Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown.
Calcarea carbonica induces apoptosis in cancer cells in p53-dependent manner ...home
These observations delineate the significance of immuno-modulatory circuit during calcarea carbonicamediated
tumor apoptosis. The molecular mechanism identified may serve as a platform for involving calcarea
carbonica into immunotherapeutic strategies for effective tumor regression
Bee venom protects kidneys from cancer drug toxicityBee Healthy Farms
This study is good news for those receiving cancer treatment from a potent anticancer drug, Cisplatin, known to damage the kidneys. The results with mice found bee venom provided protection for the kidneys against the drug's negative side effects.
This was a double blind randomized clinical trial, conducted on adult patients during a 6-year period from 2003 to 2009. Included in this study were 84 adult participants that had
experienced PPC (persistent post-infectious coughs) longer than 3 weeks. All of them had the history of several referrals to different physicians and despite treatment, their cough had persisted.
Comparing the effectiveness of all three treatment regimens, this study found "honey with coffee" as the most effective treatment modality for PPC (P<0.001). Combination of honey and coffee can successfully treat the PPC at a short time. Thus, it is recommended for the treatment of PPC.
Propolis Volatile Compounds - Review of its Chemical Diversity and Biological...Bee Healthy Farms
A thorough review of the chemical diversity and biological activity found in the volatile compounds in propolis. As a plant-derived product, the essential oils in propolis vary according to geography, plant origins and local biodiversity. Though antimicrobial properties of propolis are well-documented, this review confirmed effects on microorganisms including both Gram-positive and Gram-negative bacteria, as well as non-pathogenic fungi and fungal human pathogens. Regions covered include Europe, Asia, South American, Africa and tropical zones with stingless bees included.
Propolis as an adjuvant in the treatment of Chronic PeriodontitisBee Healthy Farms
Periodontitis has multifactorial causes with the primary being pathogenic bacteria that reside in the subgingival area and possess potent mechanisms of damaging host defences. Inflammatory responses triggered in response to periodontal pathogens are the major events responsible for periodontal destruction.
Propolis has been used for the treatment of aphthous ulcers, candidiasis, gingivitis, periodontitis, and pulpitis. Studies on propolis applications have increased because of its therapeutic and biological properties. A study evaluated the antibacterial action of propolis against certain anaerobic oral pathogens and found it to be very effective.
Cytotoxicity of Blended Versus Single Medicinal Mushroom Extracts on Human Ca...Jolene1981
ABSTRACT: The use of mushrooms contributes to human nutrition by providing low lipid content of lipids and high dietary fiber content, as well as significant content of other biologically active compounds such as polysaccharides, minerals, vitamins, and polyphenolic antioxidants. This study aimed to determine the content of polyphenols and polysaccharides, as well as the cytotoxic and antioxidative properties of several medicinal mushroom preparations. The content of total phenols and flavonoids of preparations of blended mushroom extracts (Lentifom, Super Polyporin, Agarikon, Agarikon Plus, Agarikon.1, and Mykoprotect.1) was evaluated quantitatively by using ultraviolet–visible spectroscopy spectrophotometric methods. The antioxidant capacity of the preparations was evaluated using the ABTS (2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) and ferric reducing/antioxidant power assays. The content of water-soluble polysaccharides was determined using a specific gravimetric method, based on ethanol precipitation. To determine cytotoxic effects of single and blended mushroom extracts, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and neutral red assays were conducted using human small cell lung cancer, lung adenocarcinoma, colon cancer, and brain astrocytoma cancer cells. The obtained results suggest that due to the significant content of beneficial polyphenolic antioxidants and soluble polysaccharides, use of these mushroom preparations is beneficial in maintaining good health, as well as in the prevention and adjuvant biotherapy of various human pathological aberrations. These results reveal that these extracts exhibit different cytotoxic effects on tumor cells originating from different tissues. In addition, the comparison of investigated blended mushroom extracts with three well-known commercial mushroom products derived from single mushroom species or single mushroom compounds shows that blended mushroom extracts exhibit significantly stronger cytotoxic effects on human tumor cell lines.
Disease can occur due to alterations in many physiological processes. A variety of factorsare known to be involved in the progression of cancer, a chronic diseasethat occurs due to permissible proliferative signaling, avoiding growth suppressors, resisting cell death, allowing replicative immortality, induction of angiogenesis, and inducing invasion and metastasis, along with reprogramming of metabolic pathways involved in energy production and avoiding the host immune response for cell destruction. Treatment of such a multifactorial disease has very less cure rate because of the singular agents tried in the past for targeting. Molecular level studies with deeper insight are urgently neededthat focus on the most promising herbal-derived bioactive substances for which thorough research was carried out in the literature in various data-bases such as PUB-MED, MEDLINE, SCOPUS indexed journals etc. to look for systematic reviews of the protocols or data interpretation, natural drug/immunological properties and validation. As immune system plays avery important role in the proliferation or suppression of cancer and other autoimmune diseases, It is the dire need to study the effect of such natural compound on the immune system so that a possible drug target or epitope can be identified for the treatment of such diseases. In nutshell there are many nonclinical in vitro and in vivo studies on herbal medicines which commonly supports the traditional therapeutic claims. It has been seen from the previos studies in literature that the yield and composition of bioactive compounds derived from plants are dependent upon the production source,culturing conditions and extraction protocols.Therefore appropriate optimization conditions would certainly assist the medical and scientific fraternity to accept herbal products as potential candidates for cancer treatment. In this article we explored the different natural products, their immunological effects concerning cancer with no or negligible side effects. However,one has to look for potential herb–drug or herb-epitope interactions and how immune system responds to such drugs.
BREAST CANCER DRUG DISCOVERY & RESEARCH FROM VARIOUS WELL KNOWN ETHNOMEDICINAL PLANTS. ESTABLISHED PHYTOMOLECULES WITH CHEMOPREVENTIVE, ANTICANCER ACTIVITIES WITH MINIMAL TOXICITY.
Curcumin for Cancer Prevention & Cure 09370322999Shibu Thankachan
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Cancer is a term used for a broad group of diseases involving unregulated cell growth. There are more than hundred types of cancerous growth of cells that can affect almost any part of the body including brain, lung, breast, skin, blood, colon or cervix.
Up to 40% of all cancer deaths can be prevented by eliminating tobacco use, improving diets and physical activity, lowering alcohol consumption, eliminating workplace carcinogens and immunizing against Hepatitis B virus and human papillomavirus. Also a large proportion of cancer can be cured if detected early.
Lot of Researches have shown that Curcumin the active ingredient in turmeric has emerged as a potent multimodal cancer-preventing agent. Daily intake of required amount of Curcumin can go a long way in preventing cancer
Voici une reference pour les plantes, les arbustes et les arbes qui donne le nectar et pollen necessaire pour les abeilles.
A listing of plants, bushes and trees that are rich in nectar and pollen for bees.
Naturopathic Air Purification - Holistic Healing with PropolisBee Healthy Farms
A naturopathic solution to breathing holistic air using the purifying properties of propolis. A review of scientific studies and testimonials from the use of Propolair diffusers to cleanse air of microbes, mold and pollutants. Presented at CMACC, Oct 26, 2018 in Providence RI.
Natural resin association with incense and propolis in zootechnologyBee Healthy Farms
Incense and propolis have common origins and composition. Though their content may differ - terpenes are prevalent in incense; flavanoids, aromatic acids and esters in propolis - their use for the treatment of human and animal diseases has been well-known since the earliest times.
On the basis of this preliminary data, we conclude that propolis and incense can be employed in zootechnology, to sanitise the closed environments of breeding farms.
Antiplaque efficacy of propolis based herbal toothpaste-a crossover clinical ...Bee Healthy Farms
This Dental School crossover clinical study found propolis toothpaste to be safe and effective in reducing plaque accumulation when compared to Miswak and Colgate total toothpaste.
Propolis in the field of dentistry is tough. It responds very well when in contact with mucous linings of the body. This super antioxidant also delivers antimicrobial, antifungal and antiseptic properties which make it very adaptable to numerous conditions found out of balance.
Brazilian Red Propolis Attenuates Hypertension and Renal DamageBee Healthy Farms
Incorporating Brazilian Red Propolis in the diet of rats with reduced kidney function experienced a reduction of hypertension and renal damage. This scenario simulated Chronic Kidney Disease.and found the anti-inflammatory and antioxidant effects of Brazilian Red Propolis effective but requires additional studies to determine which mechanisms were prominent.
Propolis - The Natural Antibiotic against MRSA, Candida, and MoreBee Healthy Farms
Propolis is made from the resins of trees and other plants, gathered by honey bees and instinctively chosen for the active components contained within. They then modify it by adding enzymes and beeswax for use within the hive. Extensive research worldwide has found that these rich components of flavonoids, polyphenols and vitamins provide antifungal, antibacterial and antiviral properties.
Diabetes mellitus is spreading around the world, penetrating populations not only in poor and developing countries, but also in developed ones. Propolis, a complex resinous material collected by honey bees from buds and exudates of certain plant sources, containing flavonoids pinocebrin, galangin, chrysin, and caffeic acid phenethyl ester.
The use of propolis as an alternative healing therapy for type-2 diabetes mellitus has been claimed to alleviate the disease. Previous studies state that propolis improves normal homeostasis by balancing the body’s condition through the enhancement of the immune system. The histological analysis of the liver shows that at a dose of 50–200 mg/kg BW propolis does not show a toxic effect so that the dose is categorized safe.
Therefore, the ethanolic soluble derivative of propolis (EEP) extract warrant further studies as an antidiabetic agent that is safe for humans.
Reduced toxicity achieved in liver, spleen and pancreas with ApitherapyBee Healthy Farms
The human body is exposed nowadays to increasing attacks by toxic compounds in air pollution, industrially processed foods, alcohol and drug consumption that increase liver toxicity, leading to more and more severe cases of hepatic disorders. This study evaluated the influence of an Apitherapy diet in Wistar rats with carbon
tetrachloride-induced hepatotoxicity, by analyzing the biochemical determinations (enzymatic, lipid and protein profiles, coagulation parameters, minerals, blood count parameters, bilirubin levels) and histopathological changes at the level of liver, spleen and pancreas.
The Department of Agriculture, Food and Marine advises Irish beekeepers of traces of lead found in Irish honey between 2010 through 2013.
Though an investigation is ongoing as to the cause(s) of the contamination, it provides beekeepers 4 points to follow in order to avoid contact with lead.
Indian Mustard Bee Pollen Exhibits High Antioxidant ContentBee Healthy Farms
This study was designed to investigate the nutraceutical potential of monofloral Indian mustard bee pollen. It was found to be a rich source of nutrients providing high caloric value, making it a candidate for a potential nutraceutical agent. The study also found it possesses a high antioxidant content, especially in the principle polyphenols and flavonoids, which suggests its potential role in the prevention of free radical-implicated diseases. The DPPH-scavenging effect of this Indian mustard bee pollen further confirmed its antioxidant potential.
A review of the history, research and clinical studies conducted with Propolair propolis vaporizers and diffusers. Manufactured by the Italian company, Kontak, it was invented by a beekeeper to aid those with respiratory ailments.
Clinical studies confirm its antibacterial effectiveness, as well as its capacity to clean the air of carcinogenic pollutants.
New research reveals it possesses the richest flavonoid content of important phenolic acids and compounds in this unique blend of Italian propolis. To date, these units are used in clinics, nurseries, hospitals, offices and homes around the world.
Ethiopian Propolis - Characteristics and Chemical CompositionBee Healthy Farms
Propolis is a sticky material mixed by honeybees to utilize it in protecting their hives from infection by bacteria and fungi. The therapeutic properties of propolis are due to its chemical composition with bio-active compounds. These propolis samples indicate that they are potential sources of natural bio-active compounds for biological and pharmacological applications. A unique compound was discovered which hasn't been found in other global studies of propolis.
The results of the study show a promising role of Acacia Honey, a natural product with proven therapeutic effects on skin wound healing. It accelerated the initial stage of corneal wound healing without the side effects found when using conventional treatments which contain preservatives. Corneal keratocytes cultured in media supplemented with 0.025% Acacia Honey showed an increase in proliferative capacity while retaining their morphology, gene and protein expressions with normal cell cycle.
Greek Honeys Exhibit Phenolic Acids with Antiatherogenic, Anticancer and Anti...Bee Healthy Farms
Greek honeys are rich in phenolic acids, in particular protocatechuic and p-hydroxybenzoic acid and exhibit significant antioxidant, anticancer and antiatherogenic activities which may be attributed, at least in part, to their phenolic acid content.
Honey Eye Drops Effective in Treating ConjunctivitisBee Healthy Farms
A double-blind study trial was designed to evaluate the efficacy and safety of topical honey eye drops in 60 patients with diagnosed Vernal Keratoconjunctivitis (VKC). This study aimed to determine the effect of honey drops on the symptoms of VKC and it was designed to find out a way to reduce the amount of corticosteroid usage. The results of this study showed that the use of honey drops in the treatment of VKC caused eye redness to improve, the limbal papillae to reduce, and allergic symptoms to improve.
This study investigated an anticancer effect of different honeys from Poland on tumor cell line - glioblastoma multiforme U87MG. Anti-proliferative activity of honeys and its interferences with temozolomide were determined by a cytotoxicity test and DNA binding by [H3]-thymidine incorporation. Results suggest that Polish honeys have an anti-proliferative and anti-metastatic effect on U87MG cell line. Therefore, natural bee honey can be considered as a promising adjuvant treatment for brain tumors
Neuroprotective responses of propolis and select flavonoidsBee Healthy Farms
The beneficial effects of propolis on human health and neurological diseases. Table describes the neuroprotective properties and biological activity of propolis and select flavonoids commonly found in propolis.
Antioxidant Activity and Biological Effects of Propolis ExplainedBee Healthy Farms
A thorough summary by Polish researchers of the magnificent properties of propolis. As stated below, "despite its variety, it is always highly biologically active". With over 300 compounds there are many applications in treating and preventing chronic diseases. Properties include: antibacterial, anti-inflammatory, anticarcinogenic, antiatherogenic, cardiovascular effects, estrogenic effects, anti-diabetic effects, anti-HIV activity and reparative-regenerative effects.
The high intake of refined sugars, mainly fructose has been implicated in the epidemiology of metabolic diseases in adults and children. With an aim to determine whether honey can substitute refined sugars without adverse effect, the long term efects of natural honey and cane syrup have been compared on visceral morphology in growing rats fed from neonatal age. Honey enhanced intestinal villi growth and did not cause pathology in the rodents' abdominal viscera, such as fatty degenerations in the liver.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
The prostate is an exocrine gland of the male mammalian reproductive system
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
2. Citation: Omene C, Kalac M, Wu J, Marchi E, Frenkel K, et al. (2013) Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE),
Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. J Cancer Sci Ther 5: 334-342.
doi:10.4172/1948-5956.1000224
(HDACi) like vorinostat, aliphatic acids and depsipeptide in models
of both epithelial and hematopoietic origin. Epigenetic mechanisms,
such as histone modification, regulate specific gene expression patterns
that are essential for normal development. This process can change
the accessibility of transcription factors to chromatin as well as recruit
co-activators or repressors to targeted genes, thereby modulating gene
expression [27,28]. HDAC inhibitors have been shown to have antitumor effects, especially in lymphoid malignancies where Vorinostat
and romidepsin have been approved for the treatment of patients with
relapsed or refractory cutaneous and peripheral T-cell lymphomas [2931].
In this study, we hypothesized that CAPE, which is structurally
similar to the hydroxamic acid class of HDAC inhibitors, may mediate
its effects on breast cancer through epigenetic modifications and
investigated its effects on histone proteins, as well as those therapeutic
targets shown to be modulated by other HDAC inhibitors in models
of breast cancer, including ER, PR, Her2 neu, and epidermal growth
factor receptor (EGFR).
Materials and Methods
Cell culture
MDA-MB-231, MCF-7, and SKBR3 were purchased from the
American Type Culture Collection (ATCC, Manassas, VA), and used
for in vitro experiments. Cells were cultured in DMEM (Cellgro,
Manassas, VA) supplemented with 10% heat-inactivated FBS (Cellgro,
Manassas, VA) at 37°C in a humidified 5% CO2 incubator. All cells
were passaged twice a week and maintained in exponential growth.
Cytotoxicity or cell viability
Cells were counted at 3×105 cells/mL in a 48 well plate (BD
Labware, Franklin Lakes, NJ). CAPE (Sigma, Aldrich) was used at
the concentrations of 0 to 80μM and propolis ethanolic extract (eBee
Honey, Ashland, OH) was diluted with ethanol to obtain concentrations
from 0% to 0.5%. Following incubation at 37°C in a 5% CO2 humidified
incubator, 100 μLfrom each well was transferred to a 96-well opaquewalled plate. Cell-Titer-Glo Reagent (Promega Corporation, Madison,
WI) was added in 1:1 ratio. Contents were mixed for 2 mins on an orbital
shaker to induce cell lysis then left to incubate at room temperature for
10 mins before recording luminescence with the Synergy HT MultiDetection Microplate Reader (Biotek Instruments, Inc., Winooski,
VT). Each experiment was performed in triplicate.
Western blotting
Cells were seeded and cultured for 12 h and then treated with CAPE
or propolis for 24 h. Alternatively, PBMC from a healthy volunteer was
collected after a 3 week oral ingestion of CAPE-containing propolis
Whole cell protein lysates were prepared according to standard protocol
using RIPA buffer (1 M Tris-HCl, pH 8, 2.5 M NaCl, 5% deoxycholic
acid, 100% NP-40, 20%SDS) with protease and phosphatase inhibitors
added. After protein quantification according to Bradford’s method,
electrophoresis was performed on 4-20% gradient SDS-PAGE gels.
Proteins were transferred to nitrocellulose membranes and the quality
of the proteins was checked with Ponceau. Membranes were blocked in
TBS-T (0.1% Tween 20) with 5% non-fat dry milk, incubated overnight
with the primary antibody (1:250), and then incubated with a secondary
peroxidase-linked antibody (1:5000). Detection was performed using
enhanced chemoluminescence system (Amersham Biosciences) and
the X-ray films were exposed to the membranes. Anti–β-actin antibody
was used to ensure equal loading of protein onto the gel. The following
primary antibodies were used: antibodies to EGFR, p-Her2, ER-α, and
PR were obtained from (Santa Cruz Biotechnology, Santa Cruz, CA)
and used at a ratio 1:250 dilution, acetyl-histone H3 (Lys9) antibody
(Catalog # 9671, Cell Signaling Technology, Boston, MA) and anti-βactin (Cell Signaling Technology, Boston, MA). Goat anti-rabbit (Santa
Cruz Biotechnology, Santa Cruz, CA) secondary antibody was used.
LBH 589 (HDACi control, Panobinostat) was obtained from Novartis
Pharmaceuticals, Inc. (Cambridge, Massachussets) and used at a
concentration of 100 nM as a positive control. Each experiment was
performed at least three times (Figure 1).
Immunofluorescence
3×104 cells were seeded and cultured for 12 h and then cultured
and treated with or without CAPE or propolis for 24 h or with LBH
Figure 1: Structural similarity between CAPE and established HDAC inhibitors.
J Cancer Sci Ther
ISSN: 1948-5956 JCST, an open access journal
Volume 5(10) 334-342 (2013) - 335
3. Citation: Omene C, Kalac M, Wu J, Marchi E, Frenkel K, et al. (2013) Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE),
Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. J Cancer Sci Ther 5: 334-342.
doi:10.4172/1948-5956.1000224
589 (HDACi control) in 96-well plates. Cells were washed with 1x
PBS and fixed in 4% formaldehyde at room temperature for 20 mins.
Permeabilization and blocking was carried out in 1X PBST containing
2%BSA/0.1% Triton X at room temperature for 20 mins. Cells were
then incubated with a primary antibody, i.e., anti-ER- α (1:50) and
incubated at 4C overnight. After 24 hours, cells were washed, incubated
with a secondary antibody (1:1000) and DAPI (1:1000) in the dark
for 1 h. Cells were washed 3 times prior to imaging. The images were
collected using Nikon Eclipse TE 2000-E inverted epifluorescent
microscope, a 40x/0.60 oil objective and a Nikon Photometrics
Coolsnap HQ2 camera. The images were analyzed using NIS-elements
AR 3.2 software and Volocity 5.5.1 software. Each experiment was
performed in triplicate.
RT PCR
3×105 cells were seeded, cultured in phenol red-free DMEM
containing charcoal stripped FBS (Cellgro, Manassas, VA)in six-well
tissue culture plates in 3 ml media in the absence or presence of CAPE
or propolis or with LBH 589 (200 nM) for 48 h. Total RNA from each
treated population was extracted by mini RNeasy kit (Qiagen). Reverse
transcription (RT) of total RNA to cDNA was carried out according
to the instructions provided (Invitrogen) using the following estrogen
receptor primer: ER sense (S): GCA CCC TGA AGT CTC TGG AA;
antisense (AS): TGG CTA AAG TGG TGC ATG AT. The resultant
cDNA was amplified by PCR to determine expression of the estrogen
receptor with β-actin used as a control. PCR was carried out in a
Thermal Cycler (Labnet International Inc.). After initial denaturation
at 95°C for 15 min, PCR was carried out as follows: denaturation at
94°C for 0.5 min, annealing at 58°C for 1 min, and extension at 72°C
for 10 min, for a total of 34 cycles. PCR products were separated on
1% agarose gel containing ethydium bromide and visualized under UV
light.
Results
Cytotoxicity of CAPE and propolis
The cytotoxic effects of various concentrations of CAPE and
propolis (normalized for CAPE content by High Performance Liquid
Chromatography [HPLC]) on breast cancer cells are shown in Figure 2.
The viability of MCF-7 (ER+), MDA-231 (ER-/PR-/Her2-, TNBC), and
SKBR3 (Her2+) breast cancer cells was decreased in a concentration
and time-dependent manner by CAPE at all time points tested (Figure
2A) with an IC50 of 20 μM (MCF-7, SKBR3) and 35 mM (MDA-231)
at 72 h. This decrease in viability was even more potent when using
propolis. Propolis exhibited enhanced cytotoxicity at all the time points
tested with an IC50 of about 10 μM for all the cell lines at 72 h (Figure
2B).
Acetylation of histone (H3)
Cells were treated with or without CAPE or propolis for 24
h and lysates immunoblotted for acetylated histones in Figure 3.
Concentration dependent acetylation of histone proteins was observed
for both CAPE and propolis in the MDA-231 and MCF-7 cell lines
(Figure 3A). The accumulation of acetylated histones as depicted by
Western blotting was observed at a much lower dose of CAPE when
propolis was used, up to 10-fold lower. A similar observation of
hyper-acetylated histone proteins was observed in peripheral blood
mononuclear cells (PBMC) from a healthy human volunteer after a
3-week oral ingestion of CAPE-containing propolis (Figure 3B).
Figure 2: A, B: Propolis/CAPE are cytotoxic to breast cancer cells: Cells were treated with CAPE or propolis for 24 h, 48h and 72 h. CAPE and propolis (normalized
for CAPE content by Human Plasma Liquid Chromatography (HPLC) exposure results in decreased viability of MDA-231 (ER-/PR-/Her2-, TNBC), MCF-7 (ER+) and
SKBR3 (Her2 +) breast cancercells in a time-dependent and concentration-dependent manner.
J Cancer Sci Ther
ISSN: 1948-5956 JCST, an open access journal
Volume 5(10) 334-342 (2013) - 336
4. Citation: Omene C, Kalac M, Wu J, Marchi E, Frenkel K, et al. (2013) Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE),
Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. J Cancer Sci Ther 5: 334-342.
doi:10.4172/1948-5956.1000224
Figure 3: Propolis/CAPE is an HDAC inhibitor and induces hyperacetylation of histone proteins: Protein lysates were obtained from cells were treated with CAPE or
propolis for 24 h, or from PBMC from a healthy volunteer after a 3 week oral ingestion of CAPE-containing propolis. Western Blotting was performed for acetylated
histone H3. Hyperacetylation of histone proteins is induced in a concentration-dependent manner by both CAPE and propolis (normalized for CAPE content) in
MCF-7 and MDA-231 cells (Figure 3A) and in peripheral blood mononuclear cells from a healthy human volunteer after oral ingestion of CAPE-containing propolis
(Figure 3B).
Figure 4: Propolis/CAPE decrease ER-α and PR expression in MCF-7 cells: MCF-7 cells were treated with CAPE or propolis for 24 h and Western blotting
performed. ER-α and PR expression decreases in a concentration-dependent manner after exposure with CAPE or propolis (normalized for CAPE content).
Epigenetic effects on ER-α and PR expression in MCF-7 cells
MCF-7 cells were treated with CAPE or propolis for 24 h and
lysates were immunoblotted to test for ER-α and PR. There was a
concentration dependent decrease in the expression of ER-α and PR
after treatment with CAPE or propolis (Figure 4). Similarly to the
previous observations shown in Figure 2 and 3, propolis, normalized
for CAPE content, was more potent than CAPE in reducing the amount
of the PR receptor to near undetectable levels at 0.4 μM. ER-α was also
decreased by CAPE and propolis, but again the inhibitory effect on
ER-α was more pronounced with propolis, when normalized for CAPE
content, where ER was undetectable at 4 μM.
Epigenetic effects on ER-α and EGFR expression in MDA-231
cells
MDA-231 cells were treated with or without CAPE as well as with a
control HDAC inhibitor, LBH 589 and then ER-α expression detected
by immunofluorescence (receptor protein) and RT-PCR (gene).
Immunofluorescence was performed and ER-α expression detected
using ER-α primary antibody and a DAPI nuclear stain. While MDA-
J Cancer Sci Ther
ISSN: 1948-5956 JCST, an open access journal
231 cells do not express ER-α at 40 μM CAPE, ER-α receptor protein
expression was markedly turned on, even to a level greater than that
seen in the control LBH 589 (Figure 5A, top panel). Treatment with
CAPE exposure resulted in the re-expression of a previously silenced
ER-α gene in MDA- 231 TNBC cells, which is comparable to the
established histone deacetylase inhibitor LBH 589 (Figure 5A, bottom
panel) as seen by PCR. EGFR is overexpressed in MDA -231 cells and
there is a known significant inverse association between expression
levels of estrogen receptor α and EGFR in human breast cancer [32].
CAPE and propolis treatment result in a decrease of EGFR expression
in MDA-231 cells, which was again more potent using propolis after
normalizing for CAPE content (Figure 5B).
Effects on p-Her2 expression in SKBR3 cells
Following treatment of SKBR3 cells with CAPE or propolis for 24
h, protein lysates were subjected to western blotting. Immunoblotting
with anti-phoshorylated Her2 (p-Her2) antibody demonstrated a
concentration dependent decrease in p-Her2 by both CAPE and
propolis and similar to previous results, propolis, when normalized
for CAPE content, effects this decline in p-Her2 at significantly lower
Volume 5(10) 334-342 (2013) - 337
5. Citation: Omene C, Kalac M, Wu J, Marchi E, Frenkel K, et al. (2013) Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE),
Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. J Cancer Sci Ther 5: 334-342.
doi:10.4172/1948-5956.1000224
A.
B.
Figure 5: Propolis/CAPE epigenetically modulates ER-α and EGFR in MDA-231 (TNBC) cells: MDA-231 cells were treated with and without CAPE or with control
LBH 589. ER-α is upregulated in the presence of CAPE as seen by immunofluorescence (top panel) and RT-PCR (bottom panel) (Figure 5A). CAPE and propolis
(normalized for CAPE content) decrease EGFR protein expression in a concentration-dependent manner in MDA-231 cells (Figure 5B).
A.
B.
Figure 6: Propolis/CAPE decreases p-Her2 in SKBR3 cells: SKBR3 cells were treated with CAPE or Propolis for 24 h and western blotting performed (Figure 6A).
There is a concentration-dependent decrease in p-Her2 protein expression by both CAPE and propolis (normalized for CAPE content). No hyperacetylation of
histone protein was observed in the SKBR3 cell line with the antibody used (Figure 6B).
J Cancer Sci Ther
ISSN: 1948-5956 JCST, an open access journal
Volume 5(10) 334-342 (2013) - 338
6. Citation: Omene C, Kalac M, Wu J, Marchi E, Frenkel K, et al. (2013) Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE),
Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. J Cancer Sci Ther 5: 334-342.
doi:10.4172/1948-5956.1000224
levels than CAPE alone (Figure 6A). No hyper-acetylation of histone
proteins was observed in the SKBR3 cell line with the antibodies used
(Figure 6B).
Discussion
There are different types of propolis based on its geographic origin,
including North America, Europe, New Zealand, Brazil and China.
While propolis from these different continents is made the same way,
differences in the botanicals indigenous to these areas leads to slight
differences in the relative concentrations of different chemicals in
propolis, including compounds such as flavonoids, phenolic acids, and
their esters, terpenoids, steroids and amino-acids [6].
We have previously described that CAPE, the major active
component of propolis, induces a diversity of anti-tumor effects in ER+
and ER- breast cancer [25,26]. Here, we compared propolis with CAPE
alone to determine whether CAPE’s effects were intact in the natural
product. We show that the cytotoxic effects of CAPE are intact in the
natural product, propolis in the different breast cancer cell lines and we
show for the first time the inhibitory effects on the Her2 over expressing
breast cancer cell line SKBR3. Moreover, the cytotoxic effects are more
potent with propolis when normalized for CAPE content by HPLC
(Figure 2). We previously demonstrated that CAPE inhibits growth
of breast cancer cells and breast cancer stem cells, induces cell cycle
arrest and apoptosis, and suppresses angiogenesis. Gene arrays showed
that CAPE causes extensive changes in gene expression in both ER+
and ER- types of breast cancer cells including the inhibition of NF-κB
[25,26].
These findings are reminiscent of the pleiotropic effects of histone
deacetylases inhibitors (HDACi) like vorinostat, aliphatic acids and
depsipeptide in models of both epithelial and hematopoietic origin.
Inhibitors of HDAC enzymes alter patterns of gene expression,
induce cellular differentiation, and promote cell cycle arrest and
apoptosis [33,34]. They include, the hydroxamic class of HDACi like
Panobinostat (LBH 589) an experimental drug in clinical trials,which
acts as a non-selective HDAC inhibitor [35,36], while Vorinostat
(SAHA, suberoylanilidehydroxamic acid) is a HDAC inhibitor that
binds directly to the catalytic site of the enzyme thereby blocking
substrate access, and it inhibits class I and class II HDACs at nanomolar
concentrations (IC50 <86 nM) [37,38]. We hypothesized that CAPE,
which is structurally similar to the hydroxamic acid class of HDAC
inhibitors (Figure 1), could mediate its effects on breast cancer through
epigenetic modifications and thus, could modulate breast cancer
therapeutic targets such as ER, PR, and Her2/neu.
We demonstrated exposure to CAPE and propolis (normalized
for CAPE content) leads to the accumulation of acetylated histone 3
proteins (Ac H3)in MCF-7 (ER+/PR+) and MDA-231 (triple negative
breast cancer (TNBC, ER-/PR-/Her2-) breast cancer cell lines (Figure
3). The international patent application on this finding was published
in January, 2013 by our group, Omene C, O’Connor OA and Frenkel K.
The ability to repress cyclin D1 and to increase the acetylation of histone
proteins is indicative of histone deacetylase inhibitor activity [39]. We
have previously shown that CAPE decreases cyclin D1 expression by
7 fold [25]. Together, this suggests that CAPE’s effects may lie in part
in its ability to inhibit histone deacetylases directly or indirectly, thus
making CAPE and propolis a naturally occurring epigenetic therapeutic
agent (Figure 3). We established that the epigenetic effects of CAPE are
recapitulated in the natural product, by determining the concentration
of CAPE in propolis by HPLC. The data provided show that when
normalized for the concentration of CAPE in propolis, the HDAC
J Cancer Sci Ther
ISSN: 1948-5956 JCST, an open access journal
inhibitory effects of the natural product, propolis, are in fact markedly
superior to that seen when CAPE is used as a single agent. Interestingly,
the aliphatic structure of CAPE is within the expected structural class
of chemicals known to possess this unusual activity. Alternatively, this
may also be due to the presence of caffeic acid, the hydrolyzed product
from CAPE metabolism, which is present alongside CAPE in propolis,
leading to enhanced HDAC inhibitory effects.
Two compounds, NBM-HD-1 and NBM-HD-3 have been
recently derived from the semi-synthesis of propolin G, isolated from
Taiwanese green propolis (TGP), and shown to act as an HDACi
[40,41]. Similarly, the flavonoid Chrysin, found in the Chinese propolis
has been demonstrated to be an HDAC inhibitor [42]. Here we show
for the first time that CAPE has HDAC inhibitory properties that are
even more potent when normalized by HPLC in its natural form in the
North American propolis. In an effort to interrogate this mechanism of
action, we explored the effect of CAPE and Propolis in different breast
cancer pathways. The results reveal that CAPE and propolis modulate
therapeutic determinants of breast cancer, including ER, PR, Her2 neu,
and EGFR (erbB1/Her1).
Estrogen plays a key role in normal breast development. In breast
cancer cells expressing estrogen receptors (ER), estrogen has potent
proliferative effects and also affects differentiation and survival [43].
Inhibition of ER and PR (an estrogen response gene) is a mainstay of
therapy in patients with ER and/or PR positive breast cancer using
selective estrogen receptor modulators, such as tamoxifen, aromatase
inhibitors and pure ER antagonists, like fulvestrant [44]. Blocking
estrogen activity represents an effective treatment for most ER+
metastatic breast cancer patients, however acquired drug resistance to
aromatase inhibitors leads to disease progression, ultimately requiring
less effective, more toxic chemotherapies [45]. Delaying resistance and
disease progression represents a significant unmet need that could
prolong survival while decreasing health care costs associated with
chemotherapy and hospitalization.
We demonstrate that ER+MCF7 cells treated with CAPE or
propolis downregulated both ER and PR, where the effects seen with
Propolis were more than that seen with CAPE alone. This consistent
pattern is probably attributed to the fact that propolis contains a variety
of other components which may complement the epigenetic effects of
CAPE alone (Figure 4). When combined with exemestane, entinostat,
an HDACi in Phase 2 clinical trials, provided survival benefit for postmenopausal women with estrogen-receptor positive metastatic breast
cancer [46,47]. With a median follow-up of 18 months, overall survival
was significantly longer with exemestane plus entinostat than with
exemestane plus placebo (26.94 versus 20.33 months, respectively). In
the subset of entinostat patients exhibiting histone hyperacetylation,
median progression free survival (PFS) increased to over six months
[47]. This provides support for future study of CAPE in ER+ breast
cancer and is particularly interesting given that we are able to show
hyperacetylation of histone proteins in a human volunteer after oral
ingestion with CAPE-containing propolis (Figure 3), thus this can
readily be used as a biomarker for efficacy in a clinical trial.
The reactivation of a functional estrogen receptor in ER negative
or triple negative breast cancer cells by an HDACi, including the
hydroxamic acid LBH 589 has been established in previous publications
[48,49]. Given the increased mortality rates and paucity of therapeutic
options for patients with ER negative breast cancers, novel agents that
could reactivate ER and allow for the use of endocrine therapy to target
the ER in these patients would be a valuable therapeutic approach.
We exhibit here that CAPE exposure epigenetically results in the re-
Volume 5(10) 334-342 (2013) - 339
7. Citation: Omene C, Kalac M, Wu J, Marchi E, Frenkel K, et al. (2013) Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE),
Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. J Cancer Sci Ther 5: 334-342.
doi:10.4172/1948-5956.1000224
expression of the previously silenced ER gene and protein in MDA231 TNBC cells comparable to more established HDAC inhibitors like
LBH 589 as shown by immunofluorescence (Figure 5A, top panel) and
RT-PCR (Figure 5A, bottom panel). A previous study showed CAPE
decreases ER expression rather than induction in MDA 231 cells which
is opposite to our findings [50]. This is an unexpected observation due
to the fact that MDA-231 cells, which are ER- should not express ER at
all. We show in Figure 5B using PCR that our MDA-231 cell line at the
gene expression level does not express ER. This is rather in agreement
with other published data including the pertinent paper by Zhou Q et al.
[48], which shows that their MDA-231 cell line clearly does not express
ER in any of the control (untreated) cell lanes. We can only speculate
that perhaps there may have been a contamination of their MDA231 cell line by MCF-7 (ER+) which they show as well in that paper
or perhaps subtle changes in culture conditions or variation in MDA231 cells accounts for the findings with the MDA-231 cells reported
in their paper. Several studies have suggested that over expression of
EGFR is a marker for poor prognosis in breast cancer patients that is
significantly correlated with the loss of endocrine sensitivity [51-53].
There is evidence that the re-expression of ER protein by a clinically
relevant HDAC inhibitor like SAHA, is coupled with loss of EGFR
in ER-negative human breast cancer cells [54]. We demonstrate that
treatment by CAPE, results in a decrease of EGFR in a concentrationdependent manner and that this inhibitory effect of CAPE is more
potent when using propolis (Figure 5B).
Approximately 25% of breast cancers exhibit amplification and
over-expression of her2/neu oncogene, which encodes for Her2, a
member of the family of epidermal growth factor receptor tyrosine
kinases [55,56]. Her2 over expression, similar to ER negative breast
cancer, has been associated with an inferior prognosis in breast cancer.
However, the existence of Her2 targeted therapy like the recombinant,
humanized, monoclonal anti-Her2 antibody, trastuzumab (Herceptin),
has exhibited significant clinical efficacy against breast cancer
[57,58], and has overcome some of the adverse prognostic features
of Her2 over-expression. Unfortunately, resistance to trastuzumab,
administered alone or in combination with chemotherapeutic agents
is common [59,60]. The HDAC Inhibitor entinostat induces apoptosis
in Her2 overexpressing breast cancer cells and causes a decrease in
phoshorylated Her2 [61]. Similarly, the HDAC inhibitor, SAHA
possesses activity against Her2 over-expressing human breast cancer
cells with associated decrease in Her2 [62]. We show that CAPE and
propolis are cytotoxic to Her2 over expressing breast cancer cells and
similarly to other HDACi causes a decrease in phoshorylated Her2 in
the Her2 over expressing cell line SKBR3 (Figure 6). We were not able
to show accumulation of acetylated histone proteins in the SKBR3 cell
line perhaps either due to the antibody used or that in this cell line, a
selective HDAC is being inhibited which does not acetylate the histone
3 protein tested.
Conclusion
In conclusion, we demonstrate here for the first time that CAPE
causes the accumulation of acetylated histone proteins suggesting that
it has HDAC inhibitory properties, and this mechanism is intact and
potent in the natural product propolis. This suggests that its anticancer
properties is in part due to its effects on HDACs and provides
support for the use of CAPE as a therapeutic agent in breast cancer.
Furthermore, the epigenetic effects result in a pharmacomodulation of
all the well known breast cancer therapeutic targets. More particularly,
the data presented herein show that in ER+ BC cell lines, CAPE, either
J Cancer Sci Ther
ISSN: 1948-5956 JCST, an open access journal
alone or present in ethanolic propolis extract, induces decreases in
hormone receptors, estrogen receptor (ER) and progesterone receptor
(PR), suggesting that this decrease in expression could lead to antihormonal effects in hormonal therapy refractory cells of estrogen
receptor positive patients.
The re-expression of ER-α receptor and gene in triple-negative
breast cancer cells following treatment with CAPE could render TNBC
patients susceptible to anti-estrogen therapy, when used in combination
with hormonal therapy, in either the adjuvant or metastatic setting
as well as for chemoprevention. The decreases in over-expression of
EGFR in TNBC and phosphorylated Her2 in Her2 overexpressing BC
following treatment with propolis or CAPE suggest that these could
be excellent candidates for targeted therapy against these proteins
in patients who have TNBC or in Her2 positive patients who have
progressed on anti-Her2 therapy.
Finally, our published work revealed that CAPE inhibits expression
of the mdr-1 [25] gene known to confer resistance to chemotherapeutic
drugs in cancer cells, which could account for the strong inhibition
of growth and cell cycle arrest by a concurrent treatment of CAPE
and Taxol in vitro and in vivo when each is used at suboptimal doses
(manuscript in preparation). This decrease in mdr genes/proteins
coupled with its inhibitory properties on HDACs, could allow CAPE to
be used in combination with standard chemotherapeutic drugs as well.
These results of CAPE are present in the naturopathic formulation
of propolis, a widely available natural substance with an extended safety
record, making it a naturally-occurring and readily available epigenetic
agent with great potential in breast cancer and oncology in general.
The ability to link the biological effects of a naturopathic remedy to
the pharmacologic effects seen with an exciting class of drugs in
the treatment of cancer opens the door to a host of new therapeutic
opportunities for patients with limited options like ER+ refractory
metastatic breast cancer or TNBC. Ongoing research should further
delineate the mechanism(s) of CAPE as an HDAC inhibitor, either
directly or indirectly, in the different subtypes of breast cancer.
Acknowledgements
We thank Dr. Mary Helen Barcellos-Hoff for her critical review of this
manuscript.
Financial Support
This work was supported in part by the following grants:
Dr. Coral Omene: K08CA172722 (NIH/NCI), the content is solely the
responsibility of the authors and does not necessarily represent the official views of
the National Institutes of Health.
Dr. KrystynaFrenkel: BCTR0600476 (Komen for the Cure) and ES00260
(NIEHS).
Dr. Owen A. O’Connor: Leukemia & Lymphoma Society grant LLS 7017-09.
Conflict of Interest
The authors do not have any conflicts of interest to disclose.
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Citation: Omene C, Kalac M, Wu J, Marchi E, Frenkel K, et al. (2013) Propolis
and its Active Component, Caffeic Acid Phenethyl Ester (CAPE), Modulate
Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism
of Action. J Cancer Sci Ther 5: 334-342. doi:10.4172/1948-5956.1000224
J Cancer Sci Ther
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