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Featured researches published by Mark Js Miller.


Free Radical Biology and Medicine | 2000

Cat’s claw inhibits TNFα production and scavenges free radicals: role in cytoprotection

Manuel Sandoval; Randi M. Charbonnet; Nataly N. Okuhama; Jarod Roberts; Zdenka Krenova; Ann Marie Trentacosti; Mark Js Miller

Cats claw (Uncaria tomentosa) is a medicinal plant from the Amazon River basin that is widely used for inflammatory disorders and was previously described as an inhibitor of NF-kappaB. Cats claw was prepared as a decoction (water extraction) of micropulverized bark with and without concentration by freeze-drying. Murine macrophages (RAW 264.7 cells) were used in cytotoxicity assays (trypan blue exclusion) in response to the free radical 1, 1-diphenyl-2-picrilhydrazyl (DPPH, 0.3 microM) and ultraviolet light (UV) light. TNFalpha production was induced by lipopolysaccharide (LPS 0.5 microg/ml). Cats claw was an effective scavenger of DPPH; the EC(50) value for freeze-dried concentrates was significantly less than micropulverized (18 vs. 150 microg/ml, p <.05). Cats claw (10 microg/ml freeze-dried) was fully protective against DPPH and UV irradiation-induced cytotoxicity. LPS increased TNFalpha media levels from 3 to 97 ng/ml. Cats claw suppressed TNFalpha production by approximately 65-85% (p <.01) but at concentrations considerably lower than its antioxidant activity: freeze-dried EC(50) = 1.2 ng/ml, micropulverized EC(50) = 28 ng/ml. In conclusion, cats claw is an effective antioxidant, but perhaps more importantly a remarkably potent inhibitor of TNFalpha production. The primary mechanism for cats claw anti-inflammatory actions appears to be immunomodulation via suppression of TNFalpha synthesis.


Phytomedicine | 2002

Anti-inflammatory and antioxidant activities of cat's claw (Uncaria tomentosa and Uncaria guianensis) are independent of their alkaloid content

Manuel Sandoval; Nataly N. Okuhama; Xiao-Jing Zhang; L. A. Condezo; J. Lao; Fausto M. Angeles; R. A. Musah; P. Bobrowski; Mark Js Miller

Cats claw is an herbal medicine from the Amazon that is used widely to treat inflammatory disorders. The purpose of this study was to characterize the antioxidative and antiinflammatory properties of cats claw, Uncaria tomentosa (UT) and Uncaria guianensis (UG). Alkaloids and flavanols were determined using reversed-phase HPLC; scavenging of 1,1-diphenyl-2-picrilhydrazyl (DPPH), hydroxyl radicals, and lipid peroxidation by spectrophotometry; and TNFalpha production by ELISA. Anti-inflammatory activity was assessed in vitro by inhibition of TNFalpha and nitrite production from RAW 264.7 cells exposed to LPS (50 ng/ml) and in vivo using the indomethacin-induced gastritis model. Apoptosis was assessed using the TUNEL technique and TNFalpha mRNA by in situ RT-PCR. In each of the antioxidant assays tested, UG was more potent than UT (P < 0.01). The total oxindole and pentacyclic alkaloid content of UT was 35-fold > UG. The IC50 value for inhibition of TNFalpha production was significantly (P < 0.01) higher for UT (14.1 ng/ml) vs UG (9.5 ng/ml), yet at concentrations that were considerable lower than that required for antioxidant activity. Non-alkaloid HPLC fractions from UT decreased LPS-induced TNFalpha and nitrite production in RAW 264.7 cells (P < 0.01) at a concentration range comparable to the parent botanical. Oral pretreatment for 3 d with UT protected against indomethacin-induced gastritis, and prevented TNFalpha mRNA expression and apoptosis. These results indicate that while both species of cats claw provide effective antioxidant and anti-inflammatory activities, U. guianensis is more potent. In conclusion, the presence of oxindole or pentacyclic alkaloids did not influence the antioxidant and anti-inflammatory properties of cats claw.


Inflammation Research | 2001

Efficacy and safety of freeze-dried cat's claw in osteoarthritis of the knee: mechanisms of action of the species Uncaria guianensis

J. Piscoya; Z. Rodriguez; S.A. Bustamante; Nataly N. Okuhama; Mark Js Miller; Manuel Sandoval

Abstract. Aim: The purpose of this investigation was to evaluate the ability of cats claw, an Amazonian medicinal plant, to treat osteoarthritis of the knee, collect safety and tolerance information and compare the antioxidant, and anti-inflammatory actions of Uncaria guianensis and Uncaria tomentosa in vitro.¶Materials and methods: Forty-five patients with osteoarthritis of the knee were recruited, 30 were treated with freeze-dried U. guianensis, and 15 with placebo. Hematological parameters were assessed on entry and exit of the four-week trial. Pain, medical and subject assessment scores and adverse effects were collected at weeks 1, 2 and 4. The antioxidant and anti-inflammatory activity of the cats claw species was determined by the α,α-diphenyl-β-picrylhydrazyl (DPPH) free radical scavenging method. Inhibition of TNFα and prostaglandin E2 (PGE2) production was determined in RAW 264.7 cells by ELISA.¶Results: Cats claw had no deleterious effects on blood or liver function or other significant side-effects compared to placebo. Pain associated with activity, medical and patient assessment scores were all significantly reduced, with benefits occurring within the first week of therapy. Knee pain at rest or at night, and knee circumference were not significantly reduced by cats claw during this brief trial. In vitro tests indicated that U. guianensis and U. tomentosa were equivalent at quenching DPPH radicals (EC50, 13.6-21.7 μg/ml) as well as inhibiting TNFα production. However, the latter action was registered at much lower concentrations (EC50, 10.2-10.9 ng/ml). Cats claw (10 μg/ml) had no effect on basal PGE2 production, but reduced LPS-induced PGE2 release (P < 0.05), but at higher concentrations than that required for TNFα inhibition.¶Conclusion: Cats claw is an effective treatment for osteoarthritis. The species, U. guianensis and U. tomentosa are equiactive. They are effective antioxidants, but their anti-inflammatory properties may result from their ability to inhibit TNFα and to a lesser extent PGE2 production.


Food Chemistry | 2002

Antioxidant activity of the cruciferous vegetable Maca (Lepidium meyenii)

Manuel Sandoval; Nataly N. Okuhama; Fausto M. Angeles; Vanessa V. Melchor; Luis A. Condezo; Juan Lao; Mark Js Miller

Maca (Lepidium meyenii) is a plant from the Andes of Peru. Maca is used as a food for its nutritional value and ethnomedicinal properties linked to fertility and vitality. The purpose of this study was to evaluate the antioxidant activity of Maca. For all experiments an aqueous extract of Maca was used. The antioxidant activity of Maca was assessed by the inhibition of peroxynitrite, 1,1-diphenyl-2-picrylhydrazyl (DPPH), peroxyls and deoxyribose degradation. The cytoprotection capacity of Maca was assessed using macrophages (RAW 264.7) treated with peroxynitrite or hydrogen peroxide (H2O2). Catechins were quantified by reversedphase HPLC. Addition of Maca extract (0.3–1 mg/ml) to peroxynitrite (300 mM) decreased peroxynitrite concentration by 15 and 41%, respectively (P <0.01). The IC50 for scavenging DPPH and peroxyls was 0.61 and 0.43 mg/ml, respectively. Deoxyribose protection by Maca (1–3 mg/ml) against hydroxyl radicals was in the order of 57 and 74%. Maca (1 mg/ml) protected RAW 264.7 cells against peroxynitrite-induced apoptosis (P< 0.01), and increased ATP production in cells treated with H2O2 (1 mM). The concentration of catechins in Maca was lower than in green tea (2.5 mg/g vs 145 mg/g). Collectively, our results indicate that Maca has the capacity to scavenge free radicals and protect cells against oxidative stress. # 2002 Elsevier Science Ltd. All rights reserved.


BMC Complementary and Alternative Medicine | 2001

Dietary antioxidants protect gut epithelial cells from oxidant-induced apoptosis

Mark Js Miller; Fausto M. Angeles; Brian K Reuter; Paul Bobrowski; Manuel Sandoval

BackgroundThe potential of ascorbic acid and two botanical decoctions, green tea and cats claw, to limit cell death in response to oxidants were evaluated in vitro.MethodsCultured human gastric epithelial cells (AGS) or murine small intestinal epithelial cells (IEC-18) were exposed to oxidants – DPPH (3 μM), H2O2 (50 μM), peroxynitrite (300 μM) – followed by incubation for 24 hours, with antioxidants (10 μg/ml) administered as a 1 hour pretreatment. Cell number (MTT assay) and death via apoptosis or necrosis (ELISA, LDH release) was determined. The direct interactions between antioxidants and DPPH (100 μM) or H2O2 (50 μM) were evaluated by spectroscopy.ResultsThe decoctions did not interact with H2O2, but quenched DPPH although less effectively than vitamin C. In contrast, vitamin C was significantly less effective in protecting human gastric epithelial cells (AGS) from apoptosis induced by DPPH, peroxynitrite and H2O2 (P < 0.001). Green tea and cats claw were equally protective against peroxynitrite and H2O2, but green tea was more effective than cats claw in reducing DPPH-induced apoptosis (P < 0.01). Necrotic cell death was marginally evident at these low concentrations of peroxynitrite and H2O2, and was attenuated both by cats claw and green tea (P < 0.01). In IEC-18 cells, all antioxidants were equally effective as anti-apoptotic agents.ConclusionsThese results indicate that dietary antioxidants can limit epithelial cell death in response to oxidant stress. In the case of green tea and cats claw, the cytoprotective response exceed their inherent ability to interact with the injurious oxidant, suggestive of actions on intracellular pathways regulating cell death.


BMC Complementary and Alternative Medicine | 2006

The chrondoprotective actions of a natural product are associated with the activation of IGF-1 production by human chondrocytes despite the presence of IL-1β

Mark Js Miller; Salahuddin Ahmed; Paul Bobrowski; Tariq M. Haqqi

BackgroundCartilage loss is a hallmark of arthritis and follows activation of catabolic processes concomitant with a disruption of anabolic pathways like insulin-like growth factor 1 (IGF-1). We hypothesized that two natural products of South American origin, would limit cartilage degradation by respectively suppressing catabolism and activating local IGF-1 anabolic pathways. One extract, derived from cats claw (Uncaria guianensis, vincaria®), is a well-described inhibitor of NF-κB. The other extract, derived from the vegetable Lepidium meyenii (RNI 249), possessed an uncertain mechanism of action but with defined ethnomedical applications for fertility and vitality.MethodsHuman cartilage samples were procured from surgical specimens with consent, and were evaluated either as explants or as primary chondrocytes prepared after enzymatic digestion of cartilage matrix. Assessments included IGF-1 gene expression, IGF-1 production (ELISA), cartilage matrix degradation and nitric oxide (NO) production, under basal conditions and in the presence of IL-1β.ResultsRNI 249 enhanced basal IGF-1 mRNA levels in human chondrocytes by 2.7 fold, an effect that was further enhanced to 3.8 fold by co-administration with vincaria. Enhanced basal IGF-1 production by RNI 249 alone and together with vincaria, was confirmed in both explants and in primary chondrocytes (P <0.05). As expected, IL-1β exposure completely silenced IGF-1 production by chondrocytes. However, in the presence of IL-1β both RNI 249 and vincaria protected IGF-1 production in an additive manner (P <0.01) with the combination restoring chondrocyte IGF-1 production to normal levels. Cartilage NO production was dramatically enhanced by IL-1β. Both vincaria and RNI 249 partially attenuated NO production in an additive manner (p < 0.05). IL-1β – induced degradation of cartilage matrix was quantified as glycosaminoglycan release. Individually RNI 249 or vincaria, prevented this catabolic action of IL-1β.ConclusionThe identification of agents that activate the autocrine production of IGF-1 in cartilage, even in the face of suppressive pro-inflammatory, catabolic cytokines like IL-1β, represents a novel therapeutic approach to cartilage biology. Chondroprotection associated with prevention of the catabolic events and the potential for sustained anabolic activity with this natural product suggests that it holds significant promise in the treatment of debilitating joint diseases.


Journal of Ethnopharmacology | 2002

Sangre de grado Croton palanostigma induces apoptosis in human gastrointestinal cancer cells.

Manuel Sandoval; Nataly N. Okuhama; Melinda Clark; Fausto M. Angeles; Juan Lao; Sergio A. Bustamante; Mark Js Miller

Sangre de grado is an ethnomedicinal red tree sap obtained from Croton spp. that is used to treat gastrointestinal ulcers, cancer and to promote wound healing. To evaluate the potential role of sangre de grado (SdG) in cancer we examined its effects on human cancer cells, AGS (stomach), HT29 and T84 (colon). Viability of cells treated with SdG (10-200 microg/ml) decreased (P<0.01) in a dose dependent manner measured over a 24-h period. Cell proliferation at 48 h decreased (P<0.01) in all cells treated with SdG (>100 microg/ml). When cells in suspension were treated with SdG (100 microg/ml) cell adherence was severely compromised (>85%). Cells treated with SdG (100 microg/ml) underwent apoptosis as detected by nucleus condensation and DNA fragmentation determined by ELISA, and flow cytometry. Morphological changes as assessed by acridine orange. These effects were similar to that observed with Taxol (30 microM). A significant alteration of microtubular architecture was equally observed in both stomach and colon cancer cells exposed to SdG (100 microg/ml). The induction of apoptosis and microtubule damage in AGS, HT29 and T84 cells suggest that sangre de grado should be evaluated further as a potential source of anti-cancer agents.


BMC Complementary and Alternative Medicine | 2011

Effect of a Herbal-Leucine mix on the IL-1β-induced cartilage degradation and inflammatory gene expression in human chondrocytes

Nahid Akhtar; Mark Js Miller; Tariq M. Haqqi

BackgroundConventional treatments for the articular diseases are often effective for symptom relief, but can also cause significant side effects and do not slow the progression of the disease. Several natural substances have been shown to be effective at relieving the symptoms of osteoarthritis (OA), and preliminary evidence suggests that some of these compounds may exert a favorable influence on the course of the disease. The objective of this study was to investigate the anti-inflammatory/chondroprotective potential of a Herbal and amino acid mixture containing extract of the Uncaria tomentosa, Boswellia spp., Lepidium meyenii and L-Leucine on the IL-1β-induced production of nitric oxide (NO), glycosaminoglycan (GAG), matrix metalloproteinases (MMPs), aggrecan (ACAN) and type II collagen (COL2A1) in human OA chondrocytes and OA cartilage explants.MethodsPrimary OA chondrocytes or OA cartilage explants were pretreated with Herbal-Leucine mixture (HLM, 1-10 μg/ml) and then stimulated with IL-1β (5 ng/ml). Effect of HLM on IL-1β-induced gene expression of iNOS, MMP-9, MMP-13, ACAN and COL2A1 was verified by real time-PCR. Estimation of NO and GAG release in culture supernatant was done using commercially available kits.ResultsHLM tested in these in vitro studies was found to be an effective anti-inflammatory agent, as evidenced by strong inhibition of iNOS, MMP-9 and MMP-13 expression and NO production in IL-1β-stimulated OA chondrocytes (p < 0.05). Supporting these gene expression results, IL-1β-induced cartilage matrix breakdown, as evidenced by GAG release from cartilage explants, was also significantly blocked (p < 0.05). Moreover, in the presence of herbal-Leucine mixture (HLM) up-regulation of ACAN and COL2A1 expression in IL-1β-stimulated OA chondrocytes was also noted (p < 0.05). The inhibitory effects of HLM were mediated by inhibiting the activation of nuclear factor (NF)-kB in human OA chondrocytes in presence of IL-1β.ConclusionOur data suggests that HLM could be chondroprotective and anti-inflammatory agent in arthritis, switching chondrocyte gene expression from catabolic direction towards anabolic and regenerative, and consequently this approach may be potentially useful as a new adjunct therapeutic/preventive agent for OA or injury recovery.


BMC Complementary and Alternative Medicine | 2007

Comparison of glucosamine sulfate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomized controlled trial (ISRCTN25438351)

Komal Mehta; Jayesh Gala; Surendra Bhasale; Sattayasheel Naik; Millind Modak; Harshad Thakur; Nivedita Deo; Mark Js Miller

BackgroundThe efficacy and safety of a dietary supplement derived from South American botanicals was compared to glucosamine sulfate in osteoarthritis subjects in a Mumbai-based multi-center, randomized, double-blind study.MethodsSubjects (n = 95) were screened and randomized to receive glucosamine sulfate (n = 47, 1500 mg/day) or reparagen (n = 48, 1800 mg/day), a polyherbal consisting of 300 mg of vincaria (Uncaria guianensis) and 1500 mg of RNI 249 (Lepidium meyenii) administered orally, twice daily. Primary efficacy variable was response rate based on a 20% improvement in WOMAC pain scores. Additional outcomes were WOMAC scores for pain, stiffness and function, visual analog score (VAS) for pain, with assessments at 1, 2, 4, 6 and 8 weeks. Tolerability, investigator and subject global assessments and rescue medication consumption (paracetamol) were measured together with safety assessments including vital signs and laboratory based assays.ResultsSubject randomization was effective: age, gender and disease status distribution was similar in both groups. The response rates (20% reduction in WOMAC pain) were substantial for both glucosamine (89%) and reparagen (94%) and supported by investigator and subject assessments. Using related criteria response rates to reparagen were favorable when compared to glucosamine. Compared to baseline both treatments showed significant benefits in WOMAC and VAS outcomes within one week (P < 0.05), with a similar, progressive improvement over the course of the 8 week treatment protocol (45–62% reduction in WOMAC or VAS scores). Tolerability was excellent, no serious adverse events were noted and safety parameters were unchanged. Rescue medication use was significantly lower in the reparagen group (p < 0.01) at each assessment period. Serum IGF-1 levels were unaltered by treatments.ConclusionBoth reparagen and glucosamine sulfate produced substantial improvements in pain, stiffness and function in subjects with osteoarthritis. Response rates were high and the safety profile was excellent, with significantly less rescue medication use with reparagen. Reparagen represents a new natural productive alternative in the management of joint health.Trial registrationCurrent Controlled Trials ISRCTN25438351.


BMC Cancer | 2002

Therapeutic utility of aspirin in the ApcMin/+ murine model of colon carcinogenesis.

Brian K Reuter; Xiao-Jing Zhang; Mark Js Miller

BackgroundIn recent years it has become evident that nonsteroidal anti-inflammatory drugs, in particular aspirin represent a potential class of cancer chemotherapeutic agents. Despite the wealth of knowledge gained from epidemiological, clinical and animal studies, the effectiveness of aspirin to treat established gastrointestinal cancer has not been determined. The present study examines the ability of aspirin to treat established polyposis in Min/+ mice.MethodsMin/+ mice with established polyposis were treated orally once daily from 12–16 weeks of age with either drug vehicle or aspirin (25 mg/kg). Upon completion of treatment, the number, location and size of intestinal tumours was determined. Additional variables examined were the number of apoptotic cells within tumours and COX activity.ResultsAdministration of aspirin for 4 weeks to Min/+ mice produce no effect on tumour number compared to vehicle-treated Min/+ mice (65 ± 8 vs. 63 ± 9, respectively). In addition, aspirin had no effect on tumour size or location. However, aspirin treatment produced a greater than 2-fold (p < 0.05) increase in the number of apoptotic positive cells within tumours and significantly decreased hepatic PGE2 content.ConclusionsAspirin was found to have no effect on tumour number and size when administered to Min/+ mice with established polyposis. The findings in the present study call in to question the utility of aspirin as a stand-alone treatment for established GI cancer. However, aspirins ability to significantly promote apoptosis may render it suitable for use in combinatorial chemotherapy.

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Tariq M. Haqqi

Case Western Reserve University

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Salahuddin Ahmed

Case Western Reserve University

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