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Search Results: 1 - 10 of 23474 matches for " Mark JS Miller "
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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
BMC Complementary and Alternative Medicine , 2011, DOI: 10.1186/1472-6882-11-66
Abstract: Primary 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.HLM 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.Our 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.Osteoarthritis (OA) is the most common form of joint disease that evolves from local inflammatory disease to a chronic process with variable degree of inflammation and degeneration of articular cartilage that ultimately results in exposure of underlying bone, pain and disability [1]. The aggregating cartilage proteoglycan, aggrecan (ACAN), along with the type II collagen (COL2A1) provide the robust mechanical properties to the cartilage in a healthy joint. The progressive degeneration of articular cartilage involves depletion of ACAN and the deregulation of matrix components, such a
Therapeutic utility of aspirin in the ApcMin/+ murine model of colon carcinogenesis
Brian K Reuter, Xiao-Jing Zhang, Mark JS Miller
BMC Cancer , 2002, DOI: 10.1186/1471-2407-2-19
Abstract: Min/+ 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.Administration 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.Aspirin 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, aspirin's ability to significantly promote apoptosis may render it suitable for use in combinatorial chemotherapy.Despite continuing decreases in incidence and mortality rates, cancers of the colon and rectum remain the third leading cause of cancer deaths in the North America [1,2]. The decline in incidence, and hence mortality, from colorectal cancers is most likely attributable to an increase in recommendations to perform routine screening on average risk individuals and to improved screening techniques [2]. In addition, there is ever advancing knowledge into the pathogenic mechanism of cancer and resulting strides in the development of more efficacious therapies.In recent years it has become evident that nonsteroidal anti-inflammatory drugs (NSAIDs) represent a potential class of cancer chemotherapeutic agents. The utility of NSAIDs, in particular aspirin, in the treatment of colon cancer has stemmed from studies conducted both in animals [3-11] and humans [12-15]. Evidence f
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
BMC Complementary and Alternative Medicine , 2006, DOI: 10.1186/1472-6882-6-13
Abstract: Human 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.RNI 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.The 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.Osteoarthritis is a painful and debilitating joint condition that affects hundreds of millions worldwide [1,2]. Despite the prevalence of the disease the current therapeutic options have significant limitations. The popular non-steroidal
Dietary antioxidants protect gut epithelial cells from oxidant-induced apoptosis
Mark JS Miller, Fausto M Angeles, Brian K Reuter, Paul Bobrowski, Manuel Sandoval
BMC Complementary and Alternative Medicine , 2001, DOI: 10.1186/1472-6882-1-11
Abstract: Cultured 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.The 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 cat's claw were equally protective against peroxynitrite and H2O2, but green tea was more effective than cat's 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 cat's claw and green tea (P < 0.01). In IEC-18 cells, all antioxidants were equally effective as anti-apoptotic agents.These results indicate that dietary antioxidants can limit epithelial cell death in response to oxidant stress. In the case of green tea and cat's claw, the cytoprotective response exceed their inherent ability to interact with the injurious oxidant, suggestive of actions on intracellular pathways regulating cell death.Epithelial apoptosis in the gastro-intestinal tract is normally restricted to superficial cells but in pathological states of inflammation or infection, apoptotic cell death can be far more expansive. Under these conditions apoptosis may result from the production of cytokines [1], cell activation [2-4], infective agents [5] and adverse responses to pharmaceuticals [6,7]. Depending on the agonist or eliciting milieu, apoptotic cell death is accompanied by the activation of various cell
Chondroprotective effects of a proanthocyanidin rich Amazonian genonutrient reflects direct inhibition of matrix metalloproteinases and upregulation of IGF-1 production by human chondrocytes
Mark JS Miller, Paul Bobrowski, Meenakshi Shukla, Kalpana Gupta, Tariq M Haqqi
Journal of Inflammation , 2007, DOI: 10.1186/1476-9255-4-16
Abstract: Acute oral safety and toxicity was tested in rats according under OECD protocol number 420. The profile of proanthocyanidin oligomers was determined by HPLC and progrado's antioxidant activity quantified by the ORAC, NORAC and HORAC assays. Human cartilage explants, obtained from surgical specimens, were used to assess chondroproteciton with activity related to direct inhibitory effects on human matrix metalloproteinase (MMP, gelatinolytic) activity using synovial fluid and chondrocytes activated with IL-1β (10 ng/ml). Additionally, progrado (2–10 μg/ml) was tested for its ability to maintain optimal IGF-1 transcription and translation in cartilage explants and cultured chondrocytes.Both progrado and zangrado at doses up to 2000 mg/kg (po) displayed no evidence of toxicity. Oligomeric proanthocyanidin content was high for both progrado (158 mg/kg) and zangrado (124 mg/kg), with zangrado almost entirely composed of short oligomers (<6 mer), whereas the majority of oligomers in progrado exceeded 10 mers. Progrado was a remarkably potent antioxidant in the standardized tests ORAC, NORAC and HORAC. Progrado was exceptionally effective in reducing both basal and IL-1β induced glycosaminoglycan release from human cartilage explants at concentrations that also directly blocked the gelatinolytic activity of MMP-2 and MMP-9. Progrado prevented IL-1β induced suppression of IGF-1 production from human cartilage explants as well as stimulating basal IGF-1 production (P < 0.05). Comparable changes in IGF-1 gene expression were noted in cultured human chondrocytes.Progrado has a promising safety profile, significant chondroprotective and antioxidant actions, directly inhibits MMP activity and promotes the production of the cartilage repair factor, IGF-1. This suggests that progrado may offer therapeutic benefits in joint health, wound healing and inflammation.There is growing interest in natural products as agents to manage health, particularly from a preventative perspective. On
A unique therapeutic approach to emesis and itch with a proanthocyanidin-rich genonutrient
Mark JS Miller, Brian K Reuter, John L Wallace, Keith A Sharkey
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-3
Abstract: Emesis was induced in ferrets with morphine-6-glucuronide (0.05 mg/kg sc) in the presence of Zangrado (3 mg/kg, ip) and the cannabinoid receptor 1 antagonist, AM 251 (5 mg/kg, ip). Topical Zangrado (1%) was assessed for anti-pruretic actions in the 5-HT-induced scratching model in rats and evaluated in capsaicin-induced gastric hyperemia as measured by laser doppler flow. In the ApcMinmouse model of precancerous adenomatosis polyposis, mice received Zangrado (100 μg/ml in drinking water) from the age of 6 – 16 weeks for effects on polyp number. In RAW 264.7 cells Zangrado was examined for effects on lipopolysaccharide-induced nitrite production.Zangrado was a highly effective anti-emetic, reducing morphine-induced vomiting and retching by 77%. These benefits were not associated with sedation or hypothermia and were not reversed by cannabinoid receptor antagonism. Itch responses were blocked in both the morphine and 5-HT models. Zangrado did not exacerbate the ApcMincondition rather health was improved. Capsaicin-induced hyperemia was blocked by Zangrado, which also attenuated the production of nitric oxide by activated macrophages.Zangrado is an effective anti-emetic and anti-itch therapy that is devoid of common side-effects, cannabinoid-independent and broadly suppresses sensory afferent nerve activation. This complementary medicine represents a promising new approach to the management of nausea, itch and irritable bowel syndrome.The latex of the Amazonian traditional medicine Croton palanostigma and related Croton species is traditionally used in the treatment of inflammation, pain, itch, and a number of gastrointestinal afflictions that are common in the rainforest [1]. This traditional medicine is derived from a fast growing tree that is known by different names in various countries: in Peru it is called sangre de grado and in Ecuador, sangre de drago. We have found substantial scientific support for a number of these ethnomedical applications [2-4]. A central
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
BMC Complementary and Alternative Medicine , 2007, DOI: 10.1186/1472-6882-7-34
Abstract: Subjects (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.Subject 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.Both 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.Current Controlled Trials ISRCTN2543
Early relief of osteoarthritis symptoms with a natural mineral supplement and a herbomineral combination: A randomized controlled trial [ISRCTN38432711]
Mark JS Miller, Komal Mehta, Sameer Kunte, Vidyanand Raut, Jayesh Gala, Ramesh Dhumale, Anil Shukla, Hemant Tupalli, Himanshu Parikh, Paul Bobrowski, Jayesh Chaudhary
Journal of Inflammation , 2005, DOI: 10.1186/1476-9255-2-11
Abstract: Patients (n = 107) with mild to moderate osteoarthritis of the knee were randomly assigned to one of 4 groups; high dose sierrasil (3 g/day), low dose sierrasil (2 g/day), low dose sierrasil (2 g/day) + cat's claw extract (100 mg/day) or placebo, administered for 8 weeks. Treatment was double blinded. Primary efficacy variables were WOMAC scores (A, B, C and total). Visual analog score (VAS) for pain, consumption of rescue medication (paracetamol), and tolerability were secondary variables. Safety measures included vital signs and laboratory-based assays.Ninety-one of the 107 patients successfully completed the protocol. All four groups showed improvement in WOMAC and VAS scores after 8 weeks (p < 0.001), in all 3 groups receiving sierrasil the magnitude of benefits were greater vs. placebo (WOMAC Total 38–43% vs. 27%) but this was not statistically significant. In reference to baseline values sierrasil treated groups had a considerably faster onset of benefits. Placebo-treated individuals failed to show significant benefits at 4 weeks (11% reduction in total WOMAC). In contrast, after 1 or 2 weeks of therapy all the sierrasil groups displayed significant reductions in WOMAC scores (p < 0.05) and at week 4 displayed a 38–43% improvement. VAS was significantly improved at 4 weeks in all groups (p < 0.001) but was significantly greater in all sierrasil groups compared to placebo (p < 0.05). Rescue medication use was 28-23% lower in the herbomineral combination and high dose sierrasil groups although not statistically different from placebo (P = 0.101 and P = 0.193, respectively). Tolerability was good for all groups, no serious adverse events were noted and safety parameters remained unchanged.The natural mineral supplement, sierrasil alone and in combination with a cat's claw extract, improved joint health and function within 1–2 weeks of treatment but significant benefits over placebo were not sustained, possibly due to rescue medication masking. Sierrasil may offer
General Relativistic Decompression of Binary Neutron Stars During Dynamic Inspiral
Mark Miller
Physics , 2005, DOI: 10.1103/PhysRevD.75.024001
Abstract: We investigate the dynamic stability of inspiraling neutron stars by performing multiple-orbit numerical relativity simulations of the binary neutron star inspiral process. By introducing eccentricities in the orbits of the neutron stars, significant changes in orbital separation are obtained within orbital timescales. We find that as the binary system evolves from apastron to periastron (as the binary separation decreases), the central rest mass density of each star decreases, thus stabilizing the stars against individual prompt collapse. As the binary system evolves from periastron to apastron, the central rest mass density increases; the neutron stars re-compress as the binary separation increases.
General Relativistic Initial Data for the Binary Black Hole / Neutron Star System in Quasicircular Orbit
Mark Miller
Physics , 2001,
Abstract: We present an algorithm for solving the general relativistic initial value equations for a corotating polytropic star in quasicircular orbit with a nonspinning black hole. The algorithm is used to obtain initial data for cases where the black hole mass is 1, 3, and 10 times larger than the mass of the star. By analyzing sequences of constant baryon mass, constant black hole mass initial data sets and carefully monitoring the numerical error, we find innermost stable circular orbit (ISCO) configuration for these cases. While these quasiequilibrium, conformally flat sequences of initial data sets are not true solutions of the Einstein equations (each set, however, solves the full initial value problem), and thus, we do not expect the ISCO configurations found here to be completely consistent with the Einstein equations, they will be used as convenient starting points for future numerical evolutions of the full 3+1 Einstein equations.
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