Osage Orange (Maclura pomifera) is a tree/shrub of unending uniqueness and use. Growing up on a Midwestern farm, it is my sacred tree. I say tree, because if left to its natural instincts this once propagated livestock hedge will grow into 30' trees. This tree has always fascinated me as no other tree could. The wood can easily last 50 years without any appreciable decay. A log will sink if thrown into a pond. It will burn the hottest of any wood in the Midwest and in addition, burn green. The hardness and durability of the Osage wood is unparalleled. Before barb-wire, this tree was sold throughout the Midwest as a livestock hedge fence which in four years was said to grow to be, horse-high, bull-strong, and hog-tight.

     I have always been interested in natural anti-microbials found in nature. I have been much impressed with the Olive tree leaf as a very effective anti-microbial and often wished that a similar tree grew in my area. The Olive tree is very disease resistant, few insects seem to bother it, and it can live for an eternity. I was also equally impressed with the South American tree, Pau d'Arco. The Pau d'Arco is widely coveted as a superb anti-fungal medicinal and it is a specific for leukemia. In fact, it may have been instrumental in saving my brother who succumbed to leukemia over 5 years ago. I placed him on Pau d'Arco and I think it might have helped him survive! It eventually occurred to me that the physical descriptions of the Olive and Pau d'Arco trees also described our locally growing American Osage Orange tree. The Maclura pomifera never seems to die. Its leaves are as bright green and perfect from insect or microbe damage from Spring to Fall's end. Its wood, dead or alive, seems almost impervious to all fungi that will attack it. Few dead woods have that property unprotected out in the open! The Osage Orange is a vibrant life force. But best of all, the Osage Orange leaves are non-toxic. I have seen livestock routinely take mouthfuls from the lower branches without ill effect. Perhaps they were even doctoring themselves?

Description:    Osage Orange is a deciduous tree which can grow beyond 30 feet. It has a rounded silhouette with the main trunk generally rather short. The roundness is due to many radiating large branches. The twigs tend to zigzag with leaves that alternate. Leaves are simple, oval affairs with a long stem and sharp, long point. They are smooth edged, a glossy dark-green on top, a dull light green on the bottom, and have a characteristic milky sap excreted from torn petioles. Leaves tend to be from 3 to 5 inches in length. Some varieties produce thorns, others don't. The famous fruit, hedge apples, are only produced by female trees. The fruit resembles oranges with brain-like outer skin. The fruit of female trees must be pollinated in order for the fruit to contain seeds.

Location:     Osage Orange was originally native to a very limited belt starting in Southwestern Arkansas and neighboring Southeastern Oklahoma southward into Eastern Texas and Northwestern Louisiana. Now through manual commerce and introduction, this tree can be found in almost all sections of the USA. It is a very drought tolerant tree, easily transplanted, and tolerates poor soils, extreme heat, and occasional subzero cold spells well.

Parts Used: Roots, inner bark, and leaves.

Medicinal Properties:    It is said that the Indians utilized a root/water infusion for eye conditions, but not much more seemed to have been done medicinally with this tree from an ethnobotanical point of view. If the truth be known, I would bet this tree had far more native American applications medicinally than the white man will ever be aware of. The leaves and inner bark will probably offer the most promise for future medicinal compound extractions—not so much the roots or the fruit. Modern researchers are scrutinizing many of the compounds in the Osage Orange. One of the active compounds is Tetrahydroxystilbene (THS) which shows significant antifungal activity and probably the one we are most interested in. It is also known as an analog of Resveratrol. That name should ring a bell with most of you! Resveratrol (3,5,4'-trihydroxy-trans-stibene), a phytoalexin present in grapes, peanuts and pines has antioxidant and anti-inflammatory activities. The TV show, 60 Minutes did a piece on this exciting new compound as featured in wines a few years ago and set off the craze. However, it should be noted that no one herb or tree is simply one isolated compound! An herb is a sum of its many parts and the Osage Orange tree should be considered in that light. You can take out of it tetrahydroxystilbene but there are far too many other synergistic compounds to only relegate this tree to just a tetrahydroxystilbene source. It was found in a study below that tetrahydroxystilbene was not very effective against combating the common fungus, Candida albicans. I guarantee one thing! The Osage Orange is very resistant to Candida infections! So there is much more to this tree than just tetrahydroxystilbene! The Osage Orange is a soup of many anti-microbial chemicals working together to protect this tree in a way that few trees have ever been protected. It is just not about tetrahydroxystilbene, but because so much research has been done on this one compound, we will concentrate on it below.

      There are a number of herbalists and alternative health researchers that will tell you that fungi in its many forms is the true general cause of cancer and other chronic diseases. It may or may not be, but I am sure of one thing, fungi is absolutely underestimated by the medical community in the havoc it can cause in both human and animal pathology. There are few really good, nontoxic antifungals out there for one to use. Osage Orange is one plant that can bring you a very effective non-toxic, antifungal component. There isn't much out there on the Internet on the value of Osage Orange for medicinal purposes. You will run across some people using the hedge apple fruit as the main part of the tree to fight cancer, etc. I doubt seriously they are doing themselves justice by concentrating on just the fruit. As with most medicinal trees, the value is not in the fruit, but found in the leaf or the inner bark of trees. Osage Orange is no different! Almost without exception in the herbal literature, the inner bark (cambium layer and phloem) contains the most powerful concentration of a plant's chemicals. Compare the Osage to the Olive tree. The olive fruit is unpalatable in its natural state just like the Osage orange ball and both are not the part of the tree generally used in herbal medicine as a remedy. If you want to experiment with Osage Orange, I urge you to forego the fruit in favor of the leaf or inner bark. If some people are getting that much benefit from just eating the raw fruit, think what the potent leaf or inner bark will do medicinally! I would suggest either the ethanol extract for oral use or the DMSO extract for topical application in your animals.




There has been quite a bit of research done on Tetrahydroxystilbene as a tumor inhibitor. Here we find this wonderful analog in the Osage Orange!

     Other promising antibiotic compounds have been isolated as a non-toxic food preservative from the osage orange. The subfraction with the greatest inhibitory effect on wood decay fungi as characterized by spectroscopic methods, seems to be a mixture of tetra- & pentahydroxystilbenes. Research is continuing in the laboratory and there is no reason why we can not do our own veterinary experimenting. Tetrahydroxystilbene may not be the only healing component to this unique tree! Osage Orange extracts should offer a very interesting non-toxic alternative to combating various infections of a fungal and bacterial nature.

     Resveratrol, a trihydroxystilbene found in grapes and other plants, has been shown to be active in inhibiting multistage carcinogenesis. Using resveratrol as a prototype, we have synthesized a number of polyhydroxy- and polymethoxy-stilbenes and tested their anti-proliferative effect in normal and transformed human cells. Here we show that one of the resveratrol analogs, 3,4,5,4'-tetrahydroxystilbene (R-4), specifically inhibited the growth of SV40 virally transformed WI38 cells (WI38VA) at 10 ¥M, but had no effect on normal WI38 cells at even higher concentrations. R-4 also prominently induced apoptosis in WI38VA cells, but not in WI38 cells. RNase protection assay showed that R-4 significantly induced the expression of p53, GADD45 and Bax genes and concomitantly suppressed the expression of bcl-2 gene in WI38VA, but not in WI38 cells. A large increase in p53 DNA binding activity and the presence of p53 in the Bax promoter binding complex suggested that p53 was responsible for the Bax gene expression induced by R-4 in transformed cells. Within 4 h of treatment with R-4, the Bax to bcl-2 protein ratio in WI38 and WI38VA cells was, respectively, 0.1 and 105, a difference of three orders of magnitude. While R-4 prominently induced the p53/Bax pro-apoptotic genes, it also concomitantly suppressed the expression of Cox-2 in WI38VA cells. Taken together, our study suggests that the induction of p53 gene by R-4 in transformed cells may play a key role in the differential growth inhibition and apoptosis of transformed cells.

     Piceatannol (3,4,3',5'-tetrahydroxystilbene) is a naturally occurring polyphenol and analog of the cancer chemopreventive agent resveratrol (3,5,4'-trihydroxystilbene). Piceatannol is present in the skins of grapes, rhubarb, and sugar cane and is known to have anti-inflammatory and anti-carcinogenic activity. In the present study, we examined piceatannol-mediated regulation of cell cycle progression in androgen-insensitive DU145 human prostate cancer cells. Cells were treated with 0-10 µM piceatannol. The percentage of cells in G1 phase was increased in cells treated with piceatannol for 24 h. Piceatannol decreased incorporation of [3H]thymidine into DNA. Piceatannol decreased the protein levels of cyclin A, and cyclin D1. In addition, cyclin-dependent kinase (CDK)2 and CDK4 protein levels decreased in cell treated with piceatannol. But piceatannol did not affect the expression of the CDK inhibitor p21 or p27. The activity of CDK2 and CDK4 decreased following piceatannol treatment in a concentration-dependent manner. The present results indicate that piceatannol inhibits the growth of DU145 cell growth by delaying G1 cell cycle progression, which may be mediated via inhibition of CDK activities

Xeno factors are nartural compounds found in plants that possess medicinal properties for animals. Many of them may be classified as polyphenols. Polyphenol compounds are antioxidants. Many fruits and vegitables contain polyphenols and the Osage Orange has some unique types and higher levels than most . Polyphenols stimulate and protect the well being of plants and when plants are stressed, they tend to produce more polyphenols. This is why stressed plants (from drought, infections, etc) contain more polyphenols than unstressed plants. Animals eating these compounds will also benefit. Resveratrol and all of its analogs are polyphenols.

   "Isoflavones from both soy and Osage orange recently have been demonstrated by other laboratories to protect brain cells, or neurons, from the toxic effect of amyloid beta peptide. Amyloid beta peptide is believed to be responsible for the degeneration of neurons in Alzheimer's patients. However, the precise mechanisms by which isoflavones block the toxicity of amyloid beta peptide are unknown. Soybeans contain less than one-tenth of one percent isoflavone compounds, Whaley said. By comparison, between 5 percent and 10 percent of the dry mass of a bois d'arc apple is composed of isoflavone compounds. This plant has somehow developed the ability to produce extraordinary high levels of isoflavone compounds," Whaley said. "There is no known dietary plant that contains this high level of isoflavones.Whaley's research is focused on determining the molecular structure of the unique kind of isoflavones found in the Osage orange and on identifying the enzymes, and the genes that encode them, that are responsible for producing these compounds. Once the genes are identified and cloned, it may be possible to insert these genes into other, more palatable dietary plants, or forage plants eaten by livestock, he said.There are different kinds of isoflavones, each with their own unique structure," Whaley said. "The ones in the Osage orange have a peculiar structure that makes them very water insoluble. But they could be used as precursors in the chemical synthesis of other ingestible isoflavones.Whaley is particularly interested in how isoflavones protect brain cells from the toxic effects of the amyloid beta protein, which travels through the blood stream by hitching a ride within low-density lipoprotein, or LDL, particles. Whaley's recent research has focused on how isoflavones get inside, or partition into, lipid structures called micelles. These micelles are simple lipid structures that are chemically similar to LDL particles. To study the mechanisms for how isoflavones get inside the LDL particles in the body, Whaley has used micelles as a simple model. He adds a special detergent to water that forms micelles, and by adding isoflavones to the mix, he can then observe how the isoflavones position and orient themselves within the micelle structure. The position and orientation of isoflavones is a key consideration in understanding how they protect lipid structures from reactive oxygen species, which are also called free radicals. It is the reactivity of free radicals that ultimately is responsible for the aging process. "The next step is to take the techniques we've developed for studying detergent micelles and translate those techniques into more complex models and eventually into cells," he said. "The mechanism by which isoflavones block neurotoxicity could be related to their ability to lodge into lipid membranes, because that is where the precursor to amyloid beta peptide is usually located. Understanding the basic structure of the isoflavones and their interaction with lipid structures hopefully will give us insight into how natural chemicals in fruits and vegetables may lower the risk for developing diseases such as Alzheimer's disease or atherosclerosis. "Coming up with a magic bullet to treat Alzheimer's disease is a long way off, but I think there's a chance of learning something through natural products such as the isoflavones produced by Osage orange. They probably will not provide an immediate drug, but understanding their biological activities may indicate an avenue of research for developing a new pharmaceutical."

 
Abstract:   The fruit of the osage orange tree (Maclua pomifera [Raf.] Schneider) was shown to contain at least four pigments with antioxidant activity. Pomiferin was present as 3 to 4% of the dry fruit and, as a primary antioxidant, was responsible for 20-25% of the activity exhibited by methanol extracts. An unidentified substance was also present which reacted synergistically with pomiferin, increasing its contribution to the overall activity to approximately 75%. The three new pigments, totalling 0.5% to .75% of the dry fruit, all showed antioxidant activity exceeding that of pomiferin when tested at equal concentrations. A chromatographic procedure, employing anhydrous magnesium sulfate, was developed and applied successfully in separating mixtures of several iso-flavone pigments.


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     In Osage orange, osajin and pomiferin account for between 5 and 10 percent of the dry mass of the fruit tissue. This is an extraordinary amount of isoflavone and is much higher than the isoflavone content of soybean (approximately 0.1% by mass). Osajin and pomiferin were first isolated and characterized by researchers at The Ohio State University in the late 1930s. It appears from this study that a 90/10, v/v, methanol/water solvent was used to extract these isoflavones. O sajin and pomiferin have low solubility in solvent mixtures containing small amounts of water.


Abstract:    The objective of the present 15-day study was to evaluate the cardioprotective potential of flavonoid pomiferin isolated from the infructences of Maclura pomifera , Moraceae, against ischemia-reperfusion induced injury in rat hearts as a model of antioxidant-based composite therapy. Studies were performed with isolated, modifi ed Langendorff-perfused rat hearts and ischemia of heart was initiated by stopping the coronary flow for 30 min, followed by 60 min of reperfusion (14 ml min-1 ). Wistar rats were divided into three groups. The treated group received pomiferin (5 mg/kg/day in 0.5% Avicel); the placebo group received only 0.5% Avicel; the intact group was left without any applications. Biochemical indicators of oxidative damage, lipid peroxidation product malondialdehyde, antioxidant enzymes (superoxide dismutase, glutathione peroxidase, total antioxidant activity in serum and myocardium has been evaluated. We also examined the effect of pomiferin on cardiac function (left ventricular end-diastolic pressure, left ventricular pressure, peak positive +dP/dt (rate of pressure development) after ischemia and reperfusion. Our results demonstrate that pomiferin attenuates the myocardial dysfunction provoked by ischemiareperfusion. This was confirmed by the increase in both the antioxidant enzyme values and the total antioxidant activity. The cardio-protection provided by pomiferin treatment results from the suppression of oxidative stress and correlates with the improved ventricular function.


Abstract:    Recent findings that many human chronic diseases are associated with oxidative stresses have instigated the search for dietary antioxidants. Many phytochemicals, particularly phenolic compounds, have been found to possess strong antioxidant activity and reduce the risks of those diseases. Isoflavones, a special phenolic group found in soybean, have been found to act as antioxidants in some model systems. This study investigated the isoflavone content in a unique nonedible tree fruit, Osage orange [Maclura pomifera (Raf.) Schneid], and methods for the extraction, identification, and quantification of the two major isoflavones, osajin and pomiferin, were developed. The ethyl acetate extract contained 25.7% osajin and 36.2% pomiferin, and the two isoflavones were at 9.5 g kg(-1) of fresh Osage orange. Two model systems, FRAP and beta-CLAMS, were used to measure the antioxidant activity of these two isoflavones. Pomiferin was found to be a strong antioxidant in both systems, comparable to the antioxidant vitamins C and E and the synthetic antioxidant BHT. Osajin and the two soybean isoflavones (genistein and daidzein) showed no antioxidant activity. Although the Osage orange fruit is not a food source, it is considered to be safe and, therefore, a potentially good source of an antioxidant nutraceutical and functional food ingredient.

The fruits of Maclura pomifera extracts inhibits glioma stem-like cell growth and invasion.
Zhao D1, Yao C, Chen X, Xia H, Zhang L, Liu H, Jiang X, Dai Y, Liu J.

Abstract
Glioma is the most common primary intracranial tumour. Recently, growing evidence showed that glioma possesses stem-like cells, which are thought to be chemo- and radio-resistant and believed to contribute to the poor clinical outcomes of these tumours. In this study, we found that stem-like glioma cells (CD133+) were significantly increased in neurosphere cells, which are highly invasive and resistant to multiple chemotherapeutic agents. From our natural products library, we screened 48 natural products and found one compound, Pomiferin, which was of particular interest. Our results showed that Pomiferin could inhibit cell viability, CD133+ cell population, sphere formation, and invasion ability of glioma neurosphere cells. We also found that multiple stemness-associated genes (BIM1, Nestin, and Nanog) were down-regulated by Pomiferin treatment of glioma neurosphere cells. Taken together, our results suggest that Pomiferin could kill the cancer stem-like cells in glioma and may serve as a potential therapeutic agent in the future.

Air is being pumped out of a mason jar containing Osage Orange heartwood.in a 80% ethanol/water menstruum. This process aids in the efficiency of producing a herbal tincture by removing the air bubbles in the marc resulting in the menstruum being drawn more intimately into contact of the plant material.

The osage orange heartwood macerate in vacuumed jar is next placed in an ultrasonic bath to sonicate the tincture. This avoids the high heats of many other traditional extraction processes in favor of this ultrasonic low heat, high energy method. It produces a far superior quality of tincture. I allow this tincture to macerate for 30 days, routinely sonicating the jar every few days in 20 minute cycles.