PMID: 

ACS Chem Neurosci. 2019 Nov 7. Epub 2019 Nov 7. PMID: 31697467

Abstract Title: 

The natural flavonoid Naringenin elicits analgesia through inhibition of NaV1.8 voltage-gated sodium channels.

Abstract: 

Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Since (2S)-Naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-Naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel – both key for pain signaling. Here we set out to identify the possible mechanism of action of Naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP- and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of Naringenin. Instead, Naringenin inhibited NaV1.8-dependent, tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where Naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of Naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of post-surgical and neuropathic pain. Here, driven by a call by the NCCIH's strategic plan to advance fundamental research into basic biological mechanisms of action of natural products, we advance the antinociceptive potential of the flavonoid Naringenin.

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PMID: 

Evid Based Complement Alternat Med. 2018 ;2018:3624094. Epub 2018 Dec 2. PMID: 30622597

Abstract Title: 

Clinical Pharmacology ofandfor the Treatment of Anxiety.

Abstract: 

Objective: The aim of this review is to analyze preclinical and clinical studies investigating the anxiety effects oforessential oils (EOs).Design: The bibliographic research was made on the major scientific databases. Analysis included only articles written in English and published on peer-reviewed scientific journals describing preclinical experiments and clinical trials carried out to investigate the antianxiety effects ofEOs on anxiety disorders. Clinical studies reporting the antianxiety effects of products containingorEOs in combination with other active substances, including medicinal plants, were excluded. Nine clinical studies fulfilled the criteria adopted for analysis.Results: Data show thatorEOs produce anxiolytic effects both in preclinical experiments and in different clinical conditions.EO aromatherapy reduced anxiety level in the great part of stress conditions studied (subjects affected by chronic myeloid leukemia and preoperative patients) except for a sample of patients subjected to colonoscopy. Exposition toEO in clinical studies shows to be positive in reducing anxiety level in patients waiting for dental treatment as well as in healthy volunteers submitted to an anxiogenic situation.Conclusions: Overview of clinical trials conducted withoron people with anxiety showed that inhalation or oral administration ofand inhalation ofcan exert beneficial effects on anxiety; however, because of incomplete accuracy in the reporting of methodology, further more complete clinical studies are warranted.

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PMID: 

J Biol Chem. 2002 Nov 29 ;277(48):46408-14. Epub 2002 Sep 25. PMID: 12351627

Abstract Title: 

Fermented wheat germ extract inhibits glycolysis/pentose cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T-cell leukemia tumor cells.

Abstract: 

The fermented extract of wheat germ, trade name Avemar, is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of Avemar on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC(50) concentration of Avemar for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, Avemar inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G(1) peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodide- and annexin V-stained cells indicated that the growth-inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of Avemar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased (13)C incorporation and pentose cycle substrate flow into RNA ribose. This decrease in pentose cycle enzyme activities and carbon flow toward nucleic acid precursor synthesis provide the mechanistic understanding of the cell growth-controlling and apoptosis-inducing effects of fermented wheat germ. Avemar exhibits about a 50-fold higher IC(50) (10.02 mg/ml) for peripheral blood lymphocytes to induce a biological response, which provides the broad therapeutic window for this supplemental cancer treatment modality with no toxic effects.

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PMID: 

Ann N Y Acad Sci. 2007 Sep ;1110:348-61. PMID: 17911450

Abstract Title: 

Fermented wheat germ extract (avemar) inhibits adjuvant arthritis.

Abstract: 

Anti-inflammatory efficacy of the fermented wheat germ extract (FWGE, Avemar) in the rat adjuvant arthritis (AA) model was examined. To Wistar rats with AA, different doses of FWGE and anti-inflammatory drugs (indomethacin, dexamethasone) as monotherapies were administered and FWGE and either diclofenac or dexamethasone were also given in combination. Besides plethysmographies of the paws, histological investigations of synovial tissues were also performed along with detection of CD4+ and CD8+ T lymphocytes. Gene expressions of COX-1 and 2 were determined by real-time polymerase chain reaction (PCR). FWGE monotherapy significantly inhibited the development of the secondary (immune-mediated) response in AA, and dexamethasone and indomethacin exerted inhibitory effects in a degree comparable to that of FWGE. Histological analysis of the affected joints confirmed the results. FWGE inhibited COX-1 and -2, while indomethacin enhanced COX-2 gene expressions. FWGE had an additive interaction with diclofenac. It is concluded that FWGE has significant anti-inflammatory efficacy confirmed by plethysmography, histology, and real-time PCR.

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PMID: 

Nutr Cancer. 2009 ;61(6):891-9. PMID: 20155632

Abstract Title: 

Avemar (wheat germ extract) in cancer prevention and treatment.

Abstract: 

Many healthy foods are derived from wheat germ. The molecular composition of these products, however, greatly differs as shown by normal-phase HPLC-mass spectrometry analysis; thus, experimental data obtained by one of them is not necessarily true for the other. Avemar is a nontoxic wheat germ extract registered as a special nutriment for cancer patients in Hungary. It shows potent anticancer activity on cell lines by deeply interfering with glucose metabolism and affecting expressions of several kinases. In in vivo experimental models, Avemar is also effective by enhancing the activity of the immune system such as stimulating NK cell activity (by reducing MHC I molecule expression), enhancing TNF secretion of the macrophages, increasing ICAM 1 molecule expression on the vascular endothelial cells. All of these lead to apoptosis of tumor cells. The wide range of biological activity of Avemar probably cannot be explained by only one active ingredient. Since there are numerous experimental data and the clinical benefit repeatedly confirmed Avemar can be one of the most potent and best researched food supplements available for cancer patients.

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PMID: 

J Exp Clin Cancer Res. 2011 Apr 16 ;30:42. Epub 2011 Apr 16. PMID: 21496306

Abstract Title: 

Promising cytotoxic activity profile of fermented wheat germ extract (Avemar®) in human cancer cell lines.

Abstract: 

Fermented wheat germ extract (FWGE) is currently used as nutrition supplement for cancer patients. Limited recent data suggest antiproliferative, antimetastatic and immunological effects which were at least in part exerted by two quinones, 2-methoxy benzoquinone and 2,6-dimethoxybenzquinone as ingredients of FWGE. These activity data prompted us to further evaluate the in vitro antiproliferative activity of FWGE alone or in combination with the commonly used cytotoxic drugs 5-FU, oxaliplatin or irinotecan in a broad spectrum of human tumor cell lines. We used the sulforhodamine B assay to determine dose response relationships and IC50-values were calculated using the Hill equation. Drug interaction of simultaneous and sequential drug exposure was estimated using the model of Drewinko and potential clinical activity was assessed by the model of relative antitumor activity (RAA). Apoptosis was detected by DNA gel electrophoresis.FWGE induced apoptosis and exerted significant antitumor activity in a broad spectrum of 32 human cancer cell lines. The highest activity was found in neuroblastoma cell lines with an average IC50 of 0.042 mg/ml. Furthermore, IC50-range was very narrow ranging from 0.3 mg/ml to 0.54 mg/ml in 8 colon cancer cell lines. At combination experiments in colon cancer cell lines when FWGE was simultaneously applied with either 5-FU, oxaliplatin or irinotecan we observed additive to synergistic drug interaction, particularly for 5-FU. At sequential drug exposure with 5-FU and FWGE the observed synergism was abolished.Taken together, FWGE exerts significant antitumor activity in our tumor model. Simultaneous drug exposure with FWGE and 5-FU, oxaliplatin or irinotecan yielded in additive to synergistic drug interaction. However, sequential drug exposure of 5-FU and FWGE in colon cancer cell lines appeared to be schedule-dependent (5-FU may precede FWGE).Further evaluation of FWGE as a candidate for clinical combination drug regimens appeared to be warranted.

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PMID: 

Carcinogenesis. 2001 Oct ;22(10):1649-52. PMID: 11577004

Abstract Title: 

Wheat germ extract inhibits experimental colon carcinogenesis in F-344 rats.

Abstract: 

It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in laboratory animals. Four-week-old inbred male F-344 rats were used in the study. Colon carcinogenesis has been induced by azoxymethane (AOM). Ten rats served as untreated controls (group 1). For the treatment of the animals in group 2, AOM was dissolved in physiologic saline and the animals were given three subcutaneous injections 1 week apart, 15 mg/kg body weight (b/w) each. In two additional groups Avemar (MSC), a fermented wheat germ extract standardized to 2,6-dimethoxy-p-benzoquinone was administered as a tentative chemo-preventive agent. MSC was dissolved in water and was given by gavage at a dose of 3 g/kg b/w once a day. In group 3, animals started to receive MSC 2 weeks prior to the first injection of AOM daily and continuously thereafter until they were killed 32 weeks later. In group 4 the basal diet and MSC were administered only. At the end of the experiment all the rats were killed by exsanguination, the abdominal large vessels were cut under a light ether anesthesia and a complete autopsy was performed. Percentage of animals developing colon tumors and number of tumors per animals: group 1 – 0 and 0; group 2- 83.0 and 2.3; group 3 – 44.8 (P

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PMID: 

Pancreas. 2001 Aug ;23(2):141-7. PMID: 11484916

Abstract Title: 

Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells.

Abstract: 

The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption. uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation-related and cell differentiation-related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation-related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture.

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PMID: 

Wei Sheng Yan Jiu. 2001 Jul ;30(4):215-7. PMID: 12561518

Abstract Title: 

[Antioxidation of flavones of wheat germ on mammary tumor of rats].

Abstract: 

The effect of flavonoids of wheat germ on mammary tumor of rats induced by 7,12-dimethylben(a) anthracene (DMBA) was investigated. Sprague-Dawley female rats (50 day-old, weighted around 176 g) were randomly divided into 4 groups. The negative and positive control group were fed on stoke diet. The high and low dose test groups were fed on diets with wheat germ flavonoids 10 and 2 g/kg respectively. Except rats in the negative control group, each rat was given DMBA 15 mg dissolved in 1.5 ml vegetable oil by tube feeding. After the administration of DMBA for 24 weeks, the incidence of tumor in the high dose test group was lower than that in the positive control group. The activity of blood and liver glutathione peroxidase (GSH-Px) and peroxidase dismutase(SOD) in the test groups was significantly higher than those in the positive control group, while the MDA level was significantly lower. The results suggested that the effect of flavonoids on inducing peroxidase might be one of the chemical prevention mechanisms on mammary tumors.

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PMID: 

J Agric Food Chem. 2015 Mar 11 ;63(9):2449-57. Epub 2015 Mar 2. PMID: 25658135

Abstract Title: 

Effect of fermented wheat germ extract with lactobacillus plantarum dy-1 on HT-29 cell proliferation and apoptosis.

Abstract: 

This study aimed to evaluate the anticarcinogenic activities of aqueous extract of fermented wheat germ with Lactobacillus plantarum dy-1 (LFWGE). The anticarcinogenic activities, including antiproliferative effects and the induction of apoptosis, were studied in human HT-29 colon cancer cells. The 2,6-dimethoxybenzoquinone and total phenol contents in LFWGE were determined by HPLC and the Folin-Ciocalteu method. In addition, some functional proteins were separated and purified by gel filtration chromatography. There were 21 proteins identified by LC-MS/MS. The sugars isolated from LFWGE did not possess any anticarcinogenic activity. The results of an MTT assay showed high antiproliferative effects of LFWGE. In addition, LFWGE attenuated the progression from the G0-G1 to the G2-M phase of the cell cycle, and LFWGE-induced cell apoptosis was associated with the activation of caspase-3. LFWGE and its major bioactive ingredients inhibited the proliferation of HT-29 cells via apoptosis and thus may be a potential anticarcinogenic agent.

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