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? >D>D�%�������							&	9998N9j<�&	{��
=��B"�B�B�B�C��F4�G���������������$q�hِPІe	0Z�C�C0Z0ZІ		�B�B�5��i�i�i0Z	�B	�B\|N
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|LK�0{�oR)�lh)�`o`o�)�	0p��H*�M��i�Q��T�sHD�H�HІІ�id�H�H�H{�0Z0Z0Z0Z&	$J	$n	!r*�&	J	n	r*&	&	&							����Safety and efficacy study of Hoodia Parviflora in treating liver damage in rodents and humans
 
Meir Mizrahi1, Ami Ben Ya'acov1, Yehudit Shabat1, Yoav Lichtenstein1, Gadi Lalazar1&, Tomer Adar1, Miriam Levy Sklair2, Svetlana Gaska 3, Refael Aharon4, Yaron Ilan1
1Liver Unit, Department of Medicine, 2Department of Radiology, and 3Goldyne Savad Institute of Gene Therapy, Hebrew University-Hadassah Medical Center, Jerusalem, Israel 4Planylight, Israel
& Current Address: Marion Bessin Liver Research Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461.


Short title: Hoodia Parviflora alleviates fatty liver 
Key words: Hoodia, Parviflora, diabetes, NASH, insulin resistance

Disclosure: Yaron Ilan is the medical director of Plantylight 
This work was supported in part by Hoodia Arava Growers and by the Roaman-Epstein Liver Research Foundation (to Y.I.).


Abbreviations:
HP: Hoodia parviflora; ALT: alanine aminotransferase; AST: aspartate aminotransferase; MRI: magnetic resonance imaging; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; GLP-1: Glucagon-like peptide-1; OGTT: oral glucose tolerance test.




Address all communications to
  
Ami Ben Ya'acov,�Ph.D
Liver Unit
Hebrew University-Hadassah Medical Center
Ein-Karem, Jerusalem, Israel
POB 1200 
Tel: 972-2-6777559
Email:  HYPERLINK "mailto:amib@hadassah.org.il" amib@hadassah.org.il

Abstract

Background and aims: Metabolic syndrome is recognized as a pro-inflammatory condition that leads to hepatic steatosis and NASH. The aim of this study was to determine the safety and efficacy of the oral administration of Hoodia parviflora extracts in animal models and in patients with NASH. Methods: We first tested the effects of a succulent of the Hoodia family, Hoodia parviflora (HP), in animal models of NASH and insulin resistance. We analyzed liver enzyme levels, glucose levels, hepatic histology, triglycerides and total fat and serum insulin levels. Subsequently, in an open-label trial, HP was orally administered to ten subjects for 30 days. The subjects were monitored for safety, glucose tolerance test, liver enzyme and lipid profile assessments. We also monitored GLP-1 levels and circulating CD4+CD25+ cells. Results: In an animal model of NASH, the oral administration of HP-derived extracts resulted in the alleviation of insulin resistance and decreases in both intra-hepatic triglyceride levels and total hepatic fat, as well as improved hepatic histology. In patients with NASH, the oral administration of HP was demonstrated to be safe and well-tolerated; no adverse events were observed. In treated subjects, GLP-1 serum levels were increased, insulin resistance was alleviated, and there was a decrease in both serum triglyceride and liver enzyme levels. These effects were associated with changes in the phenotypic profile of CD4+CD25+ cells. Conclusions: The oral administration of HP was demonstrated to be safe and to alleviating insulin resistance and the associated liver injury. 
  
  Introduction

Plants have played a significant role in both maintaining human health and in improving the quality of human life for thousands of years. Indeed, the plant kingdom includes a wide range of plants that possess biologically active molecules of medicinal value. Recently, certain natural products have been used as alternatives to pharmaceutical drugs in Western countries. Many of these plant-derived molecules have been identified, isolated, and successfully introduced into international markets. Herbal remedies are believed to have a range of biomedical efficacies, including the treatment of arteriosclerosis, hyperlipidemia, osteoporosis, inflammation, cardiovascular diseases, immune deficiency, central nervous system disorders and cancer  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_1" \o "Craig, 1999 #224" 1-4). 
Obesity is a serious health problem that has become one of the most common health concerns of modern times. It is therefore unsurprising that many targets for anti-obesity agents have been explored and that numerous herbal formulations are currently commercially available.
Obesity leads to many pathological conditions, including nonalcoholic fatty liver disease (NAFLD). NAFLD represents a continuum of hepatic injuries, which range in severity from simple fatty liver to steatohepatitis (NASH). The increasing prevalence of obesity and insulin resistance, as well as the metabolic syndrome epidemic, have significant implications for the future of the treatment of chronic liver disease  ADDIN EN.CITE <EndNote><Cite><Author>Almeda-Valdes</Author><Year>2009</Year><RecNum>78</RecNum><DisplayText>(5)</DisplayText><record><rec-number>78</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">78</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Almeda-Valdes, P.</author><author>Cuevas-Ramos, D.</author><author>Aguilar-Salinas, C. A.</author></authors></contributors><auth-address>Departamento de Endocrinologia y Metabolismo del Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City.</auth-address><titles><title>Metabolic syndrome and non-alcoholic fatty liver disease</title><secondary-title>Ann Hepatol</secondary-title></titles><pages>S18-24</pages><volume>8 Suppl 1</volume><keywords><keyword>Disease Progression</keyword><keyword>Fatty Acids/biosynthesis</keyword><keyword>Fatty Liver/*etiology/metabolism</keyword><keyword>Humans</keyword><keyword>Insulin Resistance</keyword><keyword>Liver/metabolism</keyword><keyword>Metabolic Syndrome X/*complications/metabolism</keyword><keyword>Triglycerides/metabolism</keyword></keywords><dates><year>2009</year></dates><isbn>1665-2681 (Print)</isbn><accession-num>19381120</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=19381120 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_5" \o "Almeda-Valdes, 2009 #78" 5). There is currently no medical treatment for NASH. Clinical and epidemiological evidence suggests that NASH, being the hepatic manifestation of metabolic syndrome, is associated with insulin resistance  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_6" \o "Edmison, 2007 #225" 6,  HYPERLINK  \l "_ENREF_7" \o "Polyzos, 2009 #94" 7). Insulin resistance, oxidative stress, mitochondrial dysfunction, immune deregulation and adipokines appear to be crucial to NAFLD pathogenesis  ADDIN EN.CITE <EndNote><Cite><Author>Machado</Author><Year>2006</Year><RecNum>226</RecNum><DisplayText>(8)</DisplayText><record><rec-number>226</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">226</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Machado, M.</author><author>Cortez-Pinto, H.</author></authors></contributors><auth-address>Unidade de Nutricao e Metabolismo, Departamento de Gastrenterologia, Instituto de Medicina Molecular, Hospital de Santa Maria, Lisbon, Portugal.</auth-address><titles><title>Non-alcoholic steatohepatitis and metabolic syndrome</title><secondary-title>Curr Opin Clin Nutr Metab Care</secondary-title><alt-title>Current opinion in clinical nutrition and metabolic care</alt-title></titles><periodical><full-title>Curr Opin Clin Nutr Metab Care</full-title><abbr-1>Current opinion in clinical nutrition and metabolic care</abbr-1></periodical><alt-periodical><full-title>Curr Opin Clin Nutr Metab Care</full-title><abbr-1>Current opinion in clinical nutrition and metabolic care</abbr-1></alt-periodical><pages>637-42</pages><volume>9</volume><number>5</number><keywords><keyword>Fatty Liver/*etiology/metabolism/*physiopathology</keyword><keyword>Humans</keyword><keyword>*Insulin Resistance</keyword><keyword>Liver/*metabolism</keyword><keyword>Liver Cirrhosis/etiology</keyword><keyword>Metabolic Syndrome X/metabolism/*physiopathology</keyword><keyword>Oxidative Stress/physiology</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1363-1950 (Print)</isbn><accession-num>16912563</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16912563 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_8" \o "Machado, 2006 #226" 8). Cytokines (particularly chemokines) are important in driving the inflammatory infiltrate in cases of steatohepatitis  ADDIN EN.CITE <EndNote><Cite><Author>Lalor</Author><Year>2007</Year><RecNum>227</RecNum><DisplayText>(9)</DisplayText><record><rec-number>227</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">227</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lalor, P. F.</author><author>Faint, J.</author><author>Aarbodem, Y.</author><author>Hubscher, S. G.</author><author>Adams, D. H.</author></authors></contributors><auth-address>Liver Research Group, MRC Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom.</auth-address><titles><title>The role of cytokines and chemokines in the development of steatohepatitis</title><secondary-title>Semin Liver Dis</secondary-title><alt-title>Seminars in liver disease</alt-title></titles><periodical><full-title>Semin Liver Dis</full-title><abbr-1>Seminars in liver disease</abbr-1></periodical><alt-periodical><full-title>Semin Liver Dis</full-title><abbr-1>Seminars in liver disease</abbr-1></alt-periodical><pages>173-93</pages><volume>27</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>CD4-Positive T-Lymphocytes/metabolism</keyword><keyword>CD8-Positive T-Lymphocytes/metabolism</keyword><keyword>Chemokines/*metabolism</keyword><keyword>Ethanol/adverse effects</keyword><keyword>Fatty Liver/chemically induced/*immunology/*physiopathology</keyword><keyword>Fatty Liver, Alcoholic/immunology/physiopathology</keyword><keyword>Fibrosis/physiopathology</keyword><keyword>Humans</keyword><keyword>Oxidative Stress</keyword></keywords><dates><year>2007</year><pub-dates><date>May</date></pub-dates></dates><isbn>0272-8087 (Print)</isbn><accession-num>17520517</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17520517 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_9" \o "Lalor, 2007 #227" 9). 
Hoodia is a genus of succulent plants that is originally from the arid regions of South Africa and Namibia. Hoodia plants are multi-stemmed succulents with thick, erect, cylindrical, glabrous, fleshy and fairly hard stems that are gray-green to gray-brown in color. These plants bear large, cup-shaped corollas that can reach 100 mm in diameter  ADDIN EN.CITE <EndNote><Cite><Author>van Heerden</Author><Year>2007</Year><RecNum>111</RecNum><DisplayText>(10)</DisplayText><record><rec-number>111</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">111</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Heerden, F. R.</author><author>Marthinus Horak, R.</author><author>Maharaj, V. J.</author><author>Vleggaar, R.</author><author>Senabe, J. V.</author><author>Gunning, P. J.</author></authors></contributors><auth-address>School of Chemistry, University of KwaZulu-Natal, Private Bag X01, Scottsville 3209, South Africa.</auth-address><titles><title>An appetite suppressant from Hoodia species</title><secondary-title>Phytochemistry</secondary-title><alt-title>Phytochemistry</alt-title></titles><pages>2545-53</pages><volume>68</volume><number>20</number><keywords><keyword>Administration, Oral</keyword><keyword>Animals</keyword><keyword>Apocynaceae/*chemistry</keyword><keyword>Appetite/*drug effects</keyword><keyword>*Appetite Depressants/chemistry/isolation &amp; purification/pharmacology</keyword><keyword>Body Weight/drug effects</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Feeding Behavior/drug effects</keyword><keyword>Female</keyword><keyword>*Glycosides/chemistry/isolation &amp; purification/pharmacology</keyword><keyword>Molecular Structure</keyword><keyword>Plant Extracts/chemistry</keyword><keyword>Plant Stems/chemistry</keyword><keyword>*Pregnanes/chemistry/isolation &amp; purification/pharmacology</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword></keywords><dates><year>2007</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0031-9422 (Print)</isbn><accession-num>17603088</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17603088 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_10" \o "van Heerden, 2007 #111" 10). 
 Historically, the San people of the Kalahari Desert ate fresh Hoodia plants during their hunting trips to suppress hunger. Within the past decade, Hoodia has grown from a nearly forgotten spiny, desert plant to one of the most widely consumed anti-obesity products of natural origin  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_11" \o "Vermaak, 2011 #216" 11-13). However, scientific publications regarding the key properties of this plant, such as its in vivo biopharmaceutical characteristics, the biological activity of its chemical constituents, its clinical efficacy, and especially its safety, are insufficient or absent altogether. This lack of data is of great concern.
The genus Hoodia is classified as one of the Stapeliads, a group of stem succulents that belong to the family Apocynaceae. The Hoodia genus includes 13 reported species: H. alstonii, H. currorii, H. dregei, H. flava, H. gordonii, H. juttae, H. mossamedensis, H. officinalis, H. parviflora, H. pedicellata, H. pilifera, H. ruschii and H. triebner  ADDIN EN.CITE <EndNote><Cite><Author>Avula</Author><Year>2008</Year><RecNum>115</RecNum><DisplayText>(14)</DisplayText><record><rec-number>115</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">115</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Avula, B.</author><author>Wang, Y. H.</author><author>Pawar, R. S.</author><author>Shukla, Y. J.</author><author>Smillie, T. J.</author><author>Khan, I. A.</author></authors></contributors><auth-address>National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, University, MS 38677, USA.</auth-address><titles><title>A rapid method for chemical fingerprint analysis of Hoodia species, related genera, and dietary supplements using UPLC-UV-MS</title><secondary-title>J Pharm Biomed Anal</secondary-title><alt-title>Journal of pharmaceutical and biomedical analysis</alt-title></titles><dates><year>2008</year><pub-dates><date>Jul 15</date></pub-dates></dates><isbn>0731-7085 (Print)</isbn><accession-num>18718731</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18718731 </url></related-urls></urls><language>Eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_14" \o "Avula, 2008 #115" 14). The appetite-suppressing properties of this genus have been attributed primarily to two pregnane glycosides. In comparing the chemical fingerprints of four Hoodia species, namely, H. gordonii, H. currorii, H. ruschii and H. parviflora, chemical differences were identified between the different Hoodia species. For instance, a novel compound was identified that was more prevalent in H. parviflora than in the other Hoodia species  ADDIN EN.CITE <EndNote><Cite><Author>Rumalla</Author><Year>2008</Year><RecNum>119</RecNum><DisplayText>(15)</DisplayText><record><rec-number>119</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">119</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rumalla, C. S.</author><author>Avula, B.</author><author>Shukla, Y. J.</author><author>Wang, Y. H.</author><author>Pawar, R. S.</author><author>Smillie, T. J.</author><author>Khan, I. A.</author></authors></contributors><auth-address>National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, University, MS 38677, USA.</auth-address><titles><title>Chemical fingerprint of Hoodia species, dietary supplements, and related genera by using HPTLC</title><secondary-title>J Sep Sci</secondary-title></titles><pages>3959-64</pages><volume>31</volume><number>22</number><edition>2008/12/10</edition><keywords><keyword>Apocynaceae/*chemistry</keyword><keyword>Carbohydrate Conformation</keyword><keyword>Carbohydrate Sequence</keyword><keyword>Chromatography, Thin Layer/*methods</keyword><keyword>*Dietary Supplements</keyword><keyword>Glycosides/chemistry</keyword><keyword>Magnetic Resonance Spectroscopy</keyword><keyword>Molecular Sequence Data</keyword><keyword>Species Specificity</keyword><keyword>Spectrometry, Mass, Electrospray Ionization</keyword></keywords><dates><year>2008</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1615-9314 (Electronic)&#xD;1615-9306 (Linking)</isbn><accession-num>19065611</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19065611</url></related-urls></urls><electronic-resource-num>10.1002/jssc.200800441</electronic-resource-num><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_15" \o "Rumalla, 2008 #119" 15). It is assumed that the different chemical profiles of the various Hoodia species confer distinct hunger-suppressing effects upon these species. 
Clinical studies regarding the beneficial effects of Hoodia species in obesity-related liver disease have not been performed. The aim of our study was to determine the medicinal value of H. parviflora (HP) in the treatment of NASH and type II diabetes, which is a related condition. Several animal models were investigated in this study. Our aim was achieved through a preliminary screening effort in the hepatitis-induced liver injury model. In that model we characterized certain anti-inflammatory effects of HP. Next, we demonstrate the beneficial effects of HP in two animal models of NASH: the ob/ob mouse and the sand rat (Psammomys obesus), which also develop type II diabetes.  Lastly, we report the results of a human trial in which ten NASH patients were orally treated for 30 days with HP extracts.
This study demonstrates that HP extract is safe for human use and has the potential both to reduce liver damage and to alleviate the insulin resistance that is associated with NASH.











Methods

Pre-clinical study

Sample preparation for LC/MS.
Twenty grams of frozen cactus were freeze-dried for 16 hours, which yielded 2 grams of dried material (10% dry weight). For the extraction of the dried cactus, both water and methanol extraction methods were used. Fifty milliliters of LCMS-quality water was added to 2 grams of freeze-dried material. The same procedure was performed using 50 ml of LCMS-quality methanol to another 2 grams of freeze-dried material. Both samples were sonicated for 20 minutes followed by centrifugation for 10 min at 3500 rpm. Prior to injection, an adequate volume (1.5 ml) was passed through a 0.45-m�m membrane filter. Next, 5 m�l of the methanol or water extract was injected simultaneously into the UV and MS detector. 

Identification of P57 in Hoodia species.  
The identification of the active ingredient, P57, was achieved via liquid chromatography coupled to mass spectrometry (LC/MS). Because no analytical standard was available, the identification of the analyte was based on data from the literature  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_14" \o "Avula, 2008 #115" 14,  HYPERLINK  \l "_ENREF_16" \o "Avula, 2006 #114" 16). The analyses were performed by Laboratorium ECCA NV- Ambachtsweg 3 � 9820 Merelbeke, Belgium. In the present study, P2 refers to Hoodia Parviflora (HP).

Preparation of the HP extracts. The HP mother plants were grown in separate greenhouses (temperature range of 25-30�C and relative humidity range of 30-35%) at Kibbutz Yotvata (southern Arava Valley, Israel), which is an area that is characterized by its desert climate. The mother plants were propagated by tissue culture, and the resulting daughter plants were grown in separated net-houses for four years prior to harvesting.  Following harvesting, the upper portion of the HP plant was cut, washed and frozen at        -20�C. Subsequently, the thawed, cut plant tissue was re-suspended in 5-20% (v/v) water. Next, solid particles were blended and filtered through a filter with a filter opening of less than 100 m�m. Following the first screening through a 400-m�m filter, solids were removed, and an initial basic extract of 100% pure blended plant tissue was obtained. From 1 kg of plant tissue, 800 ml of the initial basic extract was obtained. Next, 30% (v/v) water was added to the initial basic extract and blended under cold conditions (refrigerated tank, 40�C). All of the solids were removed from mixture using a mechanical filter press (filter opening size of 300 �m). The purification of the squeezed liquid was performed using a SWECO vibration screener (200 and 100 m�m) followed by flash freezing of the liquid in 3-ml containers. The samples were subsequently divided into individual doses and stored at -20�C. The concentration of the final clear extract was 0.8 g of plant tissue per ml.  The dose of the oral administration was based on the dose that is currently used in medicinal foods that contain Hoodia in Western countries.

Effect of HP on ConA-induced liver injury

Animals. 20 male wild-type C57BL/6 (B6) mice aged 11�12 weeks were purchased from Harlan Laboratories (Jerusalem, Israel) and divided into two groups: The HP group which was treated with 0.043 ml/kg of HP and was compared to vehicle (control) group, with 10 mice in each group. To induce autoimmune hepatitis all mice were injected intravenously with concanavalin A (ConA) of 20 mg/kg. The Con A was purchased from MP Biomedicals (Ohio, US) and was dissolved in 200 m�l of 50 mM Tris (pH 7), 150 mM NaCl and 4 mM CaCl2. Both doses of HP and vehicle were administered orally to the mice 2h before the injection of ConA. The mice were sacrificed the next morning. 
Hepatocellular damage. The effect of the HP extracts on liver injury was determined by measuring the enzymatic activity levels of AST and ALT activities. These activities were measured using a Reflovet Plus clinical chemistry analyzer (Roche Diagnostics, GmbH, Mannheim, Germany).
Cytokine level determination. Serum IFN-g� levels were determined by  sandwich  ELISA using commercial kits (Quantikine, R&D Systems, MN, US) according to the manufacturer s instructions.

Effect of HP on nonalcoholic fatty liver disease (NAFLD) models

For the NASH model, we used 12 male 6-7-week-old leptin-deficient ob/ob mice that were purchased from Harlan Laboratories (Indianapolis, USA) and orally administered with 0.043 ml/kg of HP or vehicle daily for 4 weeks.
For the nutrition-induced type II diabetes model (which is also a NASH model), we used 12 male sand rat (Psammomys obesus), 8-10-week old that were purchased from Harlan laboratories (Jerusalem, Israel) and were fed a high-energy (HE; 2.93 kcal/g) artificial diet.   P. obesus were orally administered with 0.043 ml/kg of HP or vehicle daily for 4 weeks.  The rats were housed in solid-bottomed polypropylene cages that were equipped with water bottles and Aspen woodchip bedding. 
All of the animal experiments were performed in accordance with the guidelines of the Hebrew University-Hadassah Institutional Committee for Care and Use of Laboratory Animals and with the committee�s approval.
Measurement of plasma lipid levels. Plasma triglyceride and total cholesterol levels were determined using a Reflovet Plus clinical chemistry analyzer (Roche Diagnostics, GmbH, Mannheim, Germany). 
Hepatic fat content measured by MRI. P. obesus rats underwent an MRI on day 21 of the study. The hepatic fat content was measured using a double-echo chemical shift gradient-echo sequence technique. This technique provides in- and out-of-phase images in a single acquisition for fat assessment and quantification. T1-weighted out-of-phase MRI can sensitively detect relatively small proportions of tissue fat. The MRIs were acquired using a 1.5-T system (Sigma LX; General Electric, Milwaukee, WI, US). A double-echo MRI protocol was performed using a repetition time (TR) of 125 msec, double echo times (TEs) of 4 and 6.5 msec and a flip angle of 80�. The imaging parameters included a section thickness of 3 mm, a 13-cm field of view and a 256 x 160 matrix. Axial and coronal images were obtained. The signal intensity (SI) changes between in-phase and out-of-phase images were computed. The SI index was calculated as follows: SI index=(SIip"Siop)/SIip, where SIip=in-phase SI and SIop=out-of-phase SI. Low SI index values indicate a smaller amount of tissue fat. 
Body fat distribution as measured by MRI. To determine the effect of the treatment on body fat distribution, cervical and intraperitoneal fat contents were evaluated in terms of peripheral and central fat levels.
Insulin level determination. The serum insulin levels were determined using a commercially available ELISA kit (Mercodia AB; Uppsala, Sweden), according to the manufacturer�s instructions. The serum was collected from euthanized ob/ob mice or from P. obesus rats on the day of sacrifice.
Glucose Tolerance Test. The mice or P. obesus rats from all of the groups underwent a glucose tolerance test (GTT) following overnight fasting on day 28. The glucose was administered orally (1.25 g per kg). The serum glucose measurements were performed on tail-vein blood every 15 min for 3 h and were measured using a standard glucometer.
Assessment of intrahepatic lipid accumulation. The accumulation of heaptic triglycerides (TGs) was quantified using a modification of the Folch method. TGs were extracted from aliquots of snap-frozen livers and were spectrophotometrically assayed using a GPO-Trinder kit (Sigma, Rehovot, Israel). The TGs levels were normalized to the protein contents in the homogenate. For the Oil Red O staining, the livers were removed immediately after sacrifice (P. obesus). The livers were subsequently cut into small square sections, were mounted on stubs with Tissue-Tek OCT (Reichert Jung, Buffalo, NY, US) and were rapidly frozen in liquid nitrogen. The cut sections (6 �m thick) were mounted on gelatin-coated slides for the Oil Red O staining.
Statistical analyses. The comparisons of two independent groups were performed using the student s t-test and the expressed as means � standard deviation (SD). All tests applied were two-tailed and a P-value of 0.05 or less was considered to be statistically significant. 


Clinical study
Study population and treatment.  The patients were initially screened during an out-patient clinic visit during which a brief medical history was taken, outside medical records were reviewed and routine blood tests were conducted. Based on this screening, 10 adult patients (6 men and 4 women) with liver biopsy findings (within the previous 3 years) that were diagnostic for NASH were enrolled in this trial. HP was prepared as described above and stored at -20oC. Each vial contained clear extract of�0.8gr plant tissue in daily doses of 0.043ml/kg, based on the dose currently used in medical foods containing Hoodia in western world countries. During the treatment period, subjects daily ingested HP in the morning before breakfast for 30 days.  The study was performed in accordance with the guidelines of the Hebrew University-Hadassah Institutional Committee for Human Clinical Trials and with the approval of the Israel Ministry of Health Committee for Human Trials. 
The study was registered in the NIH: ClinicalTrials.govIdentifier: NCT00816465
 Informed consent for the study was obtained from all of the subjects before any protocol-specific procedures were performed. 
Inclusion criteria. Subjects between the ages of 18 and 60 years were initially screened through a medical history evaluation and a physical examination. A liver biopsy was performed according to the standard protocol.  The NASH diagnosis was based on (i) a liver biopsy score of 4 or above and altered glucose metabolism, including type 2 diabetes (untreated or treated with as many as two drugs, not including insulin, without any change in medication two months prior to enrollment); (ii) impaired fasting glucose or impaired glucose tolerance; and (iii) HbA1c levels between 5.5 and 14%. Impaired fasting glucose was defined as >100 mg/dl.  Impaired glucose tolerance was defined as a blood sugar level >140 mg/dl two hours post-glucose load and an HbA1c level between 5.5 and 8%. No evidence of other viral or immune-mediated liver disease was detected.
Exclusion criteria. The subjects who met any of the following criteria were excluded from the study: active co-infection with hepatitis A, B, or C viruses; the presence of a human immunodeficiency virus (HIV) infection, hepatocellular carcinoma, fulminant liver failure, severe deteriorating synthetic liver functions or a clinically significant infectious, immune-mediated or malignant disease; any history of treatment with immunomodulatory drugs, including steroids and NSAIDs at any time within the previous four weeks; a history of coagulopathy; women with childbearing potential unless surgically sterile or using adequate contraception (i.e., IUD, oral or Depo-Provera contraceptive or barrier plus spermicide); anemia (Hb <10.5 gm/dl), thrombocytopenia (platelets <100 k/�l), lymphopenia (absolute lymphocyte count <0.7) or previous exposure to HP.
Preoperative assessment. The subjects were followed for 30 days through regular weekly scheduled visits. The preoperative assessment included a medical history and a physical examination; BP determination; anthropometric investigations (weight, height, and waist circumference); and psychiatric and nutritional evaluations. Blood samples were also obtained following an overnight fasting for the determination of glucose, insulin, C-peptide, glycosylated hemoglobin (HbA1c), lipid levels (i.e., HDL cholesterol, LDL cholesterol and triglyceride levels), complete blood counts, sedimentation rate (ESR) and INR. The patients were also assessed for plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and g� glutamyl transferase (g�GT). Insulin sensitivity was assessed using the Matsuda index based on oral glucose tolerance values. All of the subjects performed a repeat i.v. glucose tolerance test and a HOMA score evaluation at the end of the study. 
Serum adiponectin levels were determined using a commercial ELISA kit from Linco Research (Missouri, USA). The circulating levels of GLP-1 (glucagon-like peptide) were measured using a commercial ELISA kit from Millipore (MA, USA), according to the manufacturer�s instructions.

Preparation of the HP extracts for the human trial. As described above. 
Flow cytometry. Blood samples were obtained on days 0 and 30 of the trial, and PBMCs were isolated using a Ficoll-Hypaque gradient. The cells were re-suspended in PBS containing 1% BSA. For the surface staining, the PBMCs were incubated for 30 minutes at 4�C with either fluorochrome-conjugated antibodies against the indicated cell surface markers (eBioscience, San Diego, CA, USA) at the recommended dilution or with isotype control antibodies. The following cell surface antibodies were used: CD4-FITC, CD25-PE, CD8-FITC, CD56-FITC, CD69-PE, CD3-APC, CD62-PE and HLA-DR-APC. The cells were later washed in PBS containing 1% BSA and fixed with fixation buffer (eBiosciences) for a further 50 minutes. For the intracellular staining of Foxp3, the cells were permeabilized with Foxp3 staining buffer (eBioscience) following fixation and stained with APC-conjugated antibodies against Foxp3 (eBioscience). The stained cells were subsequently washed twice and resuspended in 250 �l of PBS containing 1% BSA. The cells were maintained at 4�C. A total of 106 stained cells in 250 �l of PBS containing 1% BSA were subsequently analyzed using a FACS LSR II instrument (Becton Dickinson, San Jose, CA) with the FCS express V.3 software (DeNovo software, CA, USA). Only live cells were counted, and the background fluorescence from non-antibody-treated lymphocytes was subtracted.

Assessment of the treatment�s effect on satiety. Standard questionnaires were used to assess the effect of oral administration of HP on the degree of satiety of the subjects. The subjects answered the following items on the questionnaire using a scale of 1-10: "How hungry do you feel?" "How much do you feel you need to eat?" and "What is your degree of satiety?"  
Sample size and power. This study was not designed to detect rarely occurring treatment-associated adverse events. The summary statistics of all of the clinical and the laboratory variables were calculated by time point. The statistical significance of changes from baseline was assessed using Student�s ttest. All of the tests that were applied were two-tailed, and a p value of 0.05 or less was considered to be statistically significant.

�
�
Pre-clinical Results

P57 identification

P57 is an oxypregnane steroidal glycoside and is the only reported active constituent from the plant Hoodia gordonii, which is known to be an appetite suppressant. However, H. gordonii is native to the Kalahari Desert, and its growth outside of its natural environment is notably difficult. H. gordonii is now listed as an endangered species, and its export from South Africa is strictly controlled.  Because no analytical standard was available, the identification of the analyte was based on data from the literature. Liquid chromatography coupled to mass spectrometry (LC/MS) was tested to confirm the absence or presence of P57 in various Hoodia samples. Figure 1 illustrates a chromatogram of a MS full-scan spectrum of P57 in the plant extract. The major peaks are circled. Table 1 shows the presence or absence of these peaks (ratio 457, ratio 761 and ratio 901) in several Hoodia species. Sample X4 (H. gordonii) exhibited the largest peak for P57, whereas the samples of H. Paviflora (P1, P2,) exhibited the lowest peak. These results correspond with the spectrum that was described by Avula et al.  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_14" \o "Avula, 2008 #115" 14,  HYPERLINK  \l "_ENREF_17" \o "Avula, 2008 #116" 17).

HP alleviates liver injury in Concanavalin A immune-mediated hepatitis
The ConA immune-mediated hepatitis model provides a useful tool to rapidly determine basic anti-inflammatory effects of potential treatments for liver damage. As shown in Figure 2A, the mice that were treated with HP extract prior to ConA injection exhibited a significant decrease in serum levels of ALT and AST relative to control mice. Con A-induced hepatitis is associated with the release of high amounts of IFN-g�. We determined whether the beneficial effect of HP extracts on liver enzymes was associated with serum IFN-g� levels. Figure 2B shows that the decrease in liver enzyme levels that was induced by administration of the HP extract was paralleled by a fourfold decrease in serum IFN-� levels in the treated animals. Taken together, the data imply that the HP extract has a potent anti-inflammatory effect.

HP alleviates NASH and insulin resistance in P. obesus rats
Conditions that are commonly associated with NAFLD are chronic over-nutrition with consequent obesity and, often, insulin resistance  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_18" \o "Sanyal, 2001 #97" 18,  HYPERLINK  \l "_ENREF_19" \o "Marchesini, 2007 #163" 19). We therefore investigated the effect of HP extracts in a high fat model (HFD).  The gerbil P. obesus is a useful model to address questions that are related to the medicinal value of HP extracts in nutritionally induced diabetes and fatty liver. Upon changing from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops obesity-related liver disease that is associated with hyperglycemia  ADDIN EN.CITE <EndNote><Cite><Author>Kaiser</Author><Year>2005</Year><RecNum>229</RecNum><DisplayText>(20)</DisplayText><record><rec-number>229</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">229</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaiser, N.</author><author>Nesher, R.</author><author>Donath, M. Y.</author><author>Fraenkel, M.</author><author>Behar, V.</author><author>Magnan, C.</author><author>Ktorza, A.</author><author>Cerasi, E.</author><author>Leibowitz, G.</author></authors></contributors><auth-address>Endocrinology and Metabolism Service, Department of Internal Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel. kaiser@md.huji.ac.il</auth-address><titles><title>Psammomys obesus, a model for environment-gene interactions in type 2 diabetes</title><secondary-title>Diabetes</secondary-title><alt-title>Diabetes</alt-title></titles><periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></periodical><alt-periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></alt-periodical><pages>S137-44</pages><volume>54 Suppl 2</volume><keywords><keyword>Animal Feed</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 2/*epidemiology/*genetics</keyword><keyword>Diet</keyword><keyword>Disease Models, Animal</keyword><keyword>Environment</keyword><keyword>Gerbillinae</keyword><keyword>Insulin/secretion</keyword><keyword>Islets of Langerhans/secretion</keyword></keywords><dates><year>2005</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0012-1797 (Print)</isbn><accession-num>16306331</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16306331 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_20" \o "Kaiser, 2005 #229" 20).  Figure 3A shows that the oral administration of HP extract for four weeks improved liver function, as indicated by the animals exhibiting decreased liver enzyme levels after 28 days of treatment. Figure 3B shows the beneficial effect of the HP extract on liver steatosis. We further examined the accumulation of hepatic triglycerides. Figure 3C shows Oil Red O staining of livers from treated P. obesus rats, demonstrating a clear reduction in hepatic fat content, relative to untreated controls. This effect was also noted in H&E staining of liver tissue (Figure 3D), in which a lower fat content was observed in HP-treated animals compared to control-treated animals. Weight changes were not statistically  significant (data not shown) To assess further the quantitative decrease in liver steatosis in treated animals, a whole-body MR was performed to allow for a quantitative assessment of the amount of fat per 2 cm segment of the liver. Figure 3E shows representative MR sections, indicating a decrease in the amount of fat accumulation in the livers of the treated animals. A computerized assessment of the total liver fat revealed a reduction in this metric in the experimental group compared to the control group (0.2 vs. 0.4, respectively, p<0.05). Figure 3F shows the beneficial effect of HP extracts on insulin resistance. The oral glucose tolerance test (OGTT) was performed on P. obesus rats that had received HP orally. For each of the time points, an improvement in glucose levels was observed in the rats that were treated with the HP extract. The most profound effect was noted after 120 min for rats that were treated with HP (p<0.05). Figure 3G shows the effect of HP extracts on serum insulin levels. An increase in serum insulin levels was noted in HP-treated animals after fasting.

 HP alleviates NASH in ob/ob mice
To evaluate the effect of HP extract in a second model of NASH, we explored the effect of this herb on leptin-deficient ob/ob mice. Figure 4A shows the effect of the HP extract on liver injury in ob/ob mice. A significant decrease in ALT levels was observed 28 days post-treatment in HP-treated mice compared to control mice. Figure 4B shows a beneficial effect of HP extract on hepatic triglyceride (TGs) level, as was observed in the P. obesus rat model. Figure 4C shows a slight increase in serum insulin levels that was noted in HP-treated animals after fasting, which was similar to the effect that was observed in P. obesus.  A further evaluation of the effect of HP extracts on insulin resistance was performed using OGTT tests. Figures 4D-I demonstrates the improved OGTT results in HP-treated animals. A significant result was obtained after 60 min. Fasting glucose levels were significantly decreased in HP-treated animals after 21 and 28 days of treatment compared with those of the vehicle-treated mice, as shown in Figures 4D-II.
 




Results of the clinical trial

Safety and clinical parameters	
	             All of the ten subjects completed the study according to the protocol. No treatment-related adverse events were recorded with respect to any of the clinical and laboratory parameters that were tested during the treatment or follow-up. Safety was the primary endpoint of the study. Due to the low number of subjects that were enrolled in this clinical trial, most of the parameters did not reach statistical significance.
The clinical characteristics of all of the patients are summarized in Table 2.  ALT, AST and g�-GTP levels were reduced after 30 days of treatment with the HP extract, as were serum triglycerides levels. An improvement in the oral glucose tolerance test (OGTT) result, as indicated by the area under the curve, was noted in NASH patients after 30 days of treatment. Furthermore, certain improvements in insulin levels were also recorded (data not shown). However, HbA1c levels did not change during the treatment. 
The oral administration of HP led to a certain degree of weight loss, but this effect was deemed not to be clinically significant.  Taking together, these results suggest that HP extracts are able to alleviate liver damage and insulin resistance. 

The effect of oral administration of HP on degree of fullness and hunger
Standard questionnaires were used to assess the effect of oral HP on the degree of fullness and hunger. For seven of the ten treated subjects, a decrease in the score in response to the question, "How hungry do you feel?" was noted (3 vs. 2.3 %). In five subjects, a significant decrease in the score in response to the question, "How much do you feel you must eat?" was noted (7.12 vs. 3.7 % p<0.04). Six subjects noted an increase in their degree of satiety (5.92 vs. 7.95). These data are consistent with previous published studies regarding the appetite suppressant properties of various Hoodia species, including H. parviflora  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_14" \o "Avula, 2008 #115" 14,  HYPERLINK  \l "_ENREF_15" \o "Rumalla, 2008 #119" 15).

The effect of oral administration of HP on serum GLP-1 levels 
GLP-1 plays an important role glucose homeostasis  ADDIN EN.CITE <EndNote><Cite><Author>Salvatore</Author><Year>2009</Year><RecNum>123</RecNum><DisplayText>(21)</DisplayText><record><rec-number>123</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">123</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salvatore, T.</author><author>Carbonara, O.</author><author>Cozzolino, D.</author><author>Torella, R.</author><author>Sasso, F. C.</author></authors></contributors><auth-address>Unit of Internal Medicine, Department of Clinical and Experimental Medicine Lanzara-Magrassi, Second University of Naples, Naples, Italy. teresa.salvatore@unina2.it</auth-address><titles><title>Progress in the oral treatment of type 2 diabetes: update on DPP-IV inhibitors</title><secondary-title>Curr Diabetes Rev</secondary-title></titles><pages>92-101</pages><volume>5</volume><number>2</number><edition>2009/05/16</edition><keywords><keyword>Administration, Oral</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Diabetes Mellitus, Type 2/*drug therapy/enzymology</keyword><keyword>*Dipeptidyl-Peptidase IV Inhibitors/*administration &amp; dosage</keyword><keyword>Glucagon-Like Peptide 1/*metabolism</keyword><keyword>Glucose/*metabolism</keyword><keyword>Humans</keyword><keyword>Incretins/metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><isbn>1875-6417 (Electronic)&#xD;1573-3998 (Linking)</isbn><accession-num>19442094</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19442094</url></related-urls></urls><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_21" \o "Salvatore, 2009 #123" 21).  GLP-1 is produced in the intestines from a pro-glucagon precursor, and the secretion of GLP-1 is greatly reduced in patients with type 2 diabetes. We compared the serum GLP-1 levels prior to and following the oral glucose tolerance test (OGTT) at the beginning (day 0) and at the end (day 30) of the study. Figure 5 shows that treatment with oral HP for 30 days induced a significant (p<0.03) increase in serum GLP-1 levels post-OGTT in all of the treated subjects, as reflected by the net increase in the ratio between the pre- and post-OGTT values. 

The effect of oral administration of HP on Tregs
The involvement of the unique population of regulatory T lymphocytes in obesity and in associated liver diseases was supported in recently published animal studies  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_22" \o "Winer, 2009 #121" 22,  HYPERLINK  \l "_ENREF_23" \o "Ilan, 2010 #103" 23). Furthermore, preliminary implications for the equivalent human abnormalities were also suggested  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_24" \o "Feuerer, 2009 #126" 24). We characterized two subsets of Treg cells that were isolated from PBMCs using flow cytometry. Figure 6A shows that the number of CD4+CD25+ cells was significantly increased in PBMCs following 30 days of oral treatment with HP (p<0.04). An increase was also noted in the percentage of CD4+CD25+Foxp3+ cells. However, these results did not reach statistical significance. Representative dot blots of the FACS results that were obtained for both the CD4+CD25+ and CD4+CD25+Foxp3+ staining are presented in figures 6B and 6C, respectively.  An interesting increase the percentage of CD4+CD62+ cells was also observed in seven of the treated subjects (data not shown). Taken together, the presented results suggest that oral administration of HP is associated with marked changes in the phenotypic profile of T regulatory lymphocytes, potentially contributing to its anti-inflammatory effects.


Discussion

Various Hoodia species have become some of the most widely consumed anti-obesity products of natural origin in many developed countries  ADDIN EN.CITE <EndNote><Cite><Author>Vermaak</Author><Year>2011</Year><RecNum>214</RecNum><DisplayText>(25)</DisplayText><record><rec-number>214</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">214</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vermaak, I.</author><author>Viljoen, A. M.</author><author>Hamman, J. H.</author></authors></contributors><auth-address>Department of Pharmaceutical Sciences, Faculty of Science, Tshwane University of Technology, Private Bag X680, Pretoria 0001, South Africa.</auth-address><titles><title>Natural products in anti-obesity therapy</title><secondary-title>Nat Prod Rep</secondary-title></titles><periodical><full-title>Nat Prod Rep</full-title></periodical><pages>1493-533</pages><volume>28</volume><number>9</number><edition>2011/07/09</edition><keywords><keyword>Adipocytes/drug effects</keyword><keyword>Animals</keyword><keyword>Anti-Obesity Agents/*therapeutic use</keyword><keyword>Appetite Depressants/therapeutic use</keyword><keyword>Energy Metabolism/drug effects</keyword><keyword>Humans</keyword><keyword>Lipase/antagonists &amp; inhibitors</keyword><keyword>Lipid Metabolism/drug effects</keyword><keyword>Mice</keyword><keyword>Obesity/*drug therapy</keyword><keyword>*Plant Extracts/chemistry/pharmacology/therapeutic use</keyword><keyword>Plants, Medicinal/chemistry</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1460-4752 (Electronic)&#xD;0265-0568 (Linking)</isbn><accession-num>21738930</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21738930</url></related-urls></urls><electronic-resource-num>10.1039/c1np00035g</electronic-resource-num><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_25" \o "Vermaak, 2011 #214" 25). However, clinical trials to develop an anti-obesity drug from this species have not been proceeded. Studies have identified the Hoodia Gordonii compound P57 as possessing appetite-suppressing properties  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_10" \o "van Heerden, 2007 #111" 10,  HYPERLINK  \l "_ENREF_14" \o "Avula, 2008 #115" 14). However, the effects of compounds that are derived from these succulents for the treatment of NASH have not been investigated.  
In the present study, we demonstrate the safety and efficacy of HP extracts in treating NASH and associated insulin resistance in both animal models and human subjects. It is important to note that LC/MS techniques have demonstrated the low level of P57 in HP extracts. 
Many plant extracts are known to poses various inflammatory activities  ADDIN EN.CITE <EndNote><Cite><Author>Talhouk</Author><Year>2007</Year><RecNum>233</RecNum><DisplayText>(26)</DisplayText><record><rec-number>233</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">233</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Talhouk, R. S.</author><author>Karam, C.</author><author>Fostok, S.</author><author>El-Jouni, W.</author><author>Barbour, E. K.</author></authors></contributors><auth-address>Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon. rtalhouk@aub.edu.lb</auth-address><titles><title>Anti-inflammatory bioactivities in plant extracts</title><secondary-title>J Med Food</secondary-title></titles><periodical><full-title>J Med Food</full-title></periodical><pages>1-10</pages><volume>10</volume><number>1</number><edition>2007/05/03</edition><keywords><keyword>Animals</keyword><keyword>Anthemis/chemistry</keyword><keyword>Anti-Inflammatory Agents/*analysis/therapeutic use</keyword><keyword>Calendula/chemistry</keyword><keyword>Centaurea/chemistry</keyword><keyword>Echinops Plant/chemistry</keyword><keyword>Flavonoids/therapeutic use</keyword><keyword>Lebanon</keyword><keyword>Medicine, Traditional</keyword><keyword>Mediterranean Region</keyword><keyword>Phytotherapy</keyword><keyword>Plant Extracts/*chemistry/therapeutic use</keyword><keyword>Salvia/chemistry</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1096-620X (Print)&#xD;1096-620X (Linking)</isbn><accession-num>17472460</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17472460</url></related-urls></urls><electronic-resource-num>10.1089/jmf.2005.055</electronic-resource-num><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_26" \o "Talhouk, 2007 #233" 26). In the present study, we demonstrate that HP extracts exhibit anti-inflammatory effects on ConA-induced immune-mediated liver damage, as reflected by a significant decrease in liver enzyme and serum IFN-� levels. 
Nutritional changes trigger inflammation, and metabolic inflammation affects the signaling and functions of metabolic tissues and cells  ADDIN EN.CITE <EndNote><Cite><Author>Day</Author><Year>2006</Year><RecNum>80</RecNum><DisplayText>(27)</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">80</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Day, C. P.</author></authors></contributors><auth-address>The Medical School, University of Newcastle upon Tyne, England. c.p.day@ncl.ac.uk</auth-address><titles><title>From fat to inflammation</title><secondary-title>Gastroenterology</secondary-title></titles><pages>207-10</pages><volume>130</volume><number>1</number><edition>2006/01/13</edition><keywords><keyword>Fatty Liver/*immunology/*physiopathology</keyword><keyword>Humans</keyword><keyword>*Inflammation</keyword><keyword>Insulin Resistance</keyword><keyword>NF-kappa B/physiology</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>16401483</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16401483</url></related-urls></urls><electronic-resource-num>S0016-5085(05)02297-3 [pii]&#xD;10.1053/j.gastro.2005.11.017</electronic-resource-num><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_27" \o "Day, 2006 #80" 27). The condition that is most commonly associated with NASH is chronic over-nutrition with consequent obesity and insulin resistance. Many studies support the concept that end-organ damage in NASH is an inflammatory state, and the consequences of this systemic inflammation include type 2 diabetes and NAFLD  ADDIN EN.CITE <EndNote><Cite><Author>Hotamisligil</Author><Year>2006</Year><RecNum>83</RecNum><DisplayText>(28)</DisplayText><record><rec-number>83</rec-number><foreign-keys><key app="EN" db-id="vf0sdaf5w9xve1evwd6p0xpvrptrt2wp2azp">83</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hotamisligil, G. S.</author></authors></contributors><auth-address>Department of Genetics &amp; Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA. ghotamis@hsph.harvard.edu</auth-address><titles><title>Inflammation and metabolic disorders</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><pages>860-7</pages><volume>444</volume><number>7121</number><keywords><keyword>Adipose Tissue/immunology/pathology</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 2/complications/*metabolism/pathology</keyword><keyword>Humans</keyword><keyword>Inflammation/complications/drug therapy/*metabolism/*pathology</keyword><keyword>Insulin Resistance</keyword><keyword>Metabolic Syndrome X/complications/*metabolism</keyword><keyword>Obesity/complications/*metabolism/pathology</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec 14</date></pub-dates></dates><isbn>1476-4687 (Electronic)</isbn><accession-num>17167474</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17167474 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>( HYPERLINK  \l "_ENREF_28" \o "Hotamisligil, 2006 #83" 28). 
The observed liver injury in subjects with NASH is mediated by insulin resistance and the secondary inflammatory insult  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_19" \o "Marchesini, 2007 #163" 19,  HYPERLINK  \l "_ENREF_29" \o "London, 2007 #162" 29). P. obesus is a member of the gerbil subfamily and serves as a model of nutritionally induced type 2 diabetes, which is characterized by primary insulin resistance  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_20" \o "Kaiser, 2005 #229" 20,  HYPERLINK  \l "_ENREF_30" \o "Kalman, 1996 #230" 30-32). These rats, when fed high-energy diets, also develop NASH. In the present study, insulin resistance was alleviated in HP-treated animals, as reflected by improved OGTT test results in both P. obesus rats and ob/ob mice. The alleviated glucose intolerance led to an effect on liver steatosis in both P. obesus rats and ob/ob mice. These results included a significant decrease in liver triglyceride levels and improved liver biopsy scores. Similar effects were observed in human subjects with NASH. Sspecifically, the oral administration of HP led to an alleviation of insulin resistance, which was characterized by improved OGTT results and by decreased serum triglyceride and liver enzyme levels.  Glycated hemoglobin levels did not change in HP-treated patients by the end of the study. This result may be attributed to the short period of HP treatment.  Although the treatment period was relatively short, alcohol consumption was not addressed and a second liver biopsy was not performed, the data suggest that the oral administration of HP may be associated with the observed alleviation of liver injury in these subjects. Our data indicate that the HP treatment was safe and well-tolerated; no adverse events were observed. 
Improved insulin resistance in humans is also associated with the emerging role of gut peptides, particularly GLP-1  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_33" \o "D'Alessio, 1994 #171" 33,  HYPERLINK  \l "_ENREF_34" \o "Valverde, 1994 #167" 34), in the regulation of energy balance and food intake. Such peptides also exhibit beneficial effects on glucose homeostasis  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_35" \o "Drucker, 2006 #166" 35). In the present study, we observed that circulating GLP-1 levels were significantly reduced in subjects with NASH. 
Regulatory T cells (Tregs) play a central role in the maintenance of immunological self-tolerance and have been demonstrated to inhibit the development of autoimmune diseases  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_36" \o "Weiner, 2011 #234" 36,  HYPERLINK  \l "_ENREF_37" \o "Roncarolo, 2007 #95" 37). However, Tregs also play important roles in liver damage pathogenesis in immune-mediated hepatitis, metabolic syndrome, insulin resistance and NASH  ADDIN EN.CITE  ADDIN EN.CITE.DATA ( HYPERLINK  \l "_ENREF_22" \o "Winer, 2009 #121" 22-24,  HYPERLINK  \l "_ENREF_38" \o "Hotamisligil, 2003 #832" 38). In our small clinical study, the oral administration of HP induced an increase of the number of Tregs in PBMCs that were taken from NASH subjects. 
In the present study, the oral administration of HP was associated with a non-significant decrease in body weight in nine of the ten treated subjects. The weight loss was partially related to an increase in satiety and a decrease in the degree of hunger, as indicated by the results of the standard questionnaire. These effects may be attributed to different oxypregnane glycosides, including P57. The present clinical study has several limitations, including a small cohort and a short treatment period, both of which were factors that limited the power of the statistical analyses. To examine the manifestations of liver disease at later times, the performance of a second liver biopsy may have been more informative. 
In summary, the oral administration of HP is safe and exerts an immunomodulatory effect in subjects with NASH and type 2 diabetes. This anti-inflammatory effect and the induction of Tregs were observed to be associated with the alleviation of insulin resistance, hyperlipidemia and liver damage. Further placebo-controlled trials will aim to study larger cohorts, thereby strengthening these results.

 













Figure legends

Figure 1
MS full-scan spectrum of P57.  The key P57 fragments based on analysis with liquid chromatography coupled to mass spectrometry (LC/MS) are illustrated.  

Table 1:
Summary of the freeze-dried residues of the different samples of Hoodia species.
P1, P2, P3 are various HP samples. Sample X4 produced the largest peak for P57. Twenty milliliters of the different water extracts were freeze-dried and methanol-extracted. 
The freeze-dried residues are summarized in the table. The results are expressed as the amount (gram) of freeze dried material. The relation towards the largest area in the batch of samples is also given for the MS full scan ions 457.4, 761.4 and 901.5 and also the SRM transition of the precursor ion 901.5. A ratio of 1.00 is the largest peak area that was observed for this sample.


Figure 2
HP alleviated liver injury in the ConA model. The mice were treated with vehicle (controls) or with 0.043ml/kg of HP two hours before ConA injection. (A) Liver damage was assessed by the increase of liver enzymes as determined 20 h following ConA injection. (B) The effect of HP extract on serum INF-� levels as  measured 20 h following the ConA injection. 
HP, Hoodia parviflora.  The values are presented as the mean �SD.


Figure 3
The effects of HP extract in P. obesus. (A) Serum levels of ALT and AST as measured 28 days post-treatment. (B) The hepatic triglyceride (TGs) levels 28 days post-treatment. (C) Representative images of Oil Red O staining in livers that were harvested after 28 days of HP or pure sap treatment. (D) Representative images of liver sections that were stained with H and E after 30 days of treatment with HP. (E) Representative MR images that indicate a decrease in the amount of fat accumulation in the livers of the treated animals. Double-echo MRI was performed using a repetition time (TR) of 125 msec, double echo times (TEs) of 4 and 6.5 msec and a flip angle of 80�. The imaging parameters included a section thickness of 3 mm, a 13-cm field of view and a 256 x 160 matrix. Axial and coronal images were obtained. The signal intensity (SI) changes between in-phase and out-of-phase images were computed. The SI index was calculated as follows: SI index=(SIip"Siop)/SIip, where SIip=in-phase SI and SIop=out-of-phase SI. Low SI index values indicate a smaller amount of tissue fat. (F) The effect on the oral glucose tolerance test (OGTT) following overnight fasting, as measured on day 28 post-treatment. The glucose was administered orally (1.25 g/kg). The serum glucose measurements were performed on tail-vein blood every 15 min for 3 h. The glucose levels were measured using a standard glucometer.  (G). The effect on serum insulin levels as measured 28 days following the treatment.
The values are presented as the mean �SD.

Figure 4
The effect of HP extract administration in leptin-deficient mice. (A) The effect on liver enzyme levels 28 days post-treatment. (B) The effect on hepatic TGs content 28 days post-treatment. The effect on insulin resistance as measured by fasting insulin levels. (C) The effect on the serum insulin levels as measured 28 days following the treatment. (D) I. The effect on the oral glucose tolerance test (OGTT) following overnight fasting, measured on day 30 post-treatment. The glucose was administered orally (1.25 g/kg). The serum glucose measurements were performed on tail-vein blood every 15 min for 3 h. The glucose levels were measured using a standard glucometer. II. The fasting glucose levels that were measured on days 1, 7, 14, 21 and 28.  
The values are presented as the mean �SD.

Table 2
Demographic and laboratory data. The data are the means of the following parameters; BMI, body mass index; HbA1c, Glycated hemoglobin; GTT- Glucose Tolerance Test given in area under the curve (AUC) units.
 

Figure 5 
HP induces decreased GLP-1 secretion levels in NASH subjects. 
Circulating GLP-1 levels were measured by ELISA using sera samples that were taken from all ten of the treated subjects prior to and following the OGTT. The ratio of the GLP-1 levels prior to following the OGTT was later calculated. This ratio was calculated on day 0 and on day 30 of the trial. Ten subjects were tested. The data are presented as means � SD, p<0.03, t-test.


Figure 6 
HP increases the induction of Tregs in subjects with NASH.
PBMCs were isolated from all of the treated subjects on days 0 and 30 of the trial. The cells were then stained and analyzed using flow cytometry. (A) The mean percentage of CD4+CD25+ and CD4+CD25+Foxp3+ cells in the PBMCs that were isolated form treated subjects on days 0 and 30 of the trial (seven subjects, p=0.006, t-test). (B) Representative FACS plots that were obtained from the analysis of PMBCs from two subjects (008, 009) indicating changes in the percentage of CD4+CD25+ cells (circled) between days 0 and 30. The numbers in the top right quadrant indicate the percentage of CD4+ CD25+ cells in the PBMCs. (C) Representative FACS plots that were obtained from the analysis of PMBCs from two subjects (006, 010). The plots indicate changes in the percentage of CD4+CD25+Foxp3+ cells (circled) between days 0 and 30. The numbers in the top right quadrant indicate the percentage of CD25+ Foxp3+ T cells (CD4-gated) in the PBMCs.




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