Life Extension Magazine®

Issue: May 2018

Allergy Symptoms, Nicotinamide Riboside, Joint Health, Astaxanthin, and Lycopene

Allergy Symptoms, Nicotinamide Riboside, Joint Health, Astaxanthin, and Lycopene

Allergy symptoms

Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study.

IMPORTANCE: Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia. OBJECTIVE: To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia. DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3,434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses. EXPOSURES: Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time. MAIN OUTCOMES AND MEASURES: Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities. RESULTS: The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1,095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses. CONCLUSIONS AND RELEVANCE: Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.

JAMA Inter Med. 2015 Mar;175(3):401-7.

Effect of milk fermented with Lactobacillus acidophilus strain L-92 on symptoms of Japanese cedar pollen allergy: a randomized placebo-controlled trial.

A placebo-controlled, single-blind study was conducted to evaluate the effects of Lactobacillus acidophilus strain L-92 (L-92) on the symptoms of Japanese cedar-pollen allergy. This study was carried out during the 2002 and 2003 seasons of Japanese cedar pollination. Twenty-three in-house volunteers were asked to drink 100 ml of heat-treated milk fermented with L-92 containing 5 x 10(10) of the bacteria, twice a day, for 6 consecutive weeks. A similar study was carried out during the 2003 season for 10 weeks, but the daily dose of bacteria was 2 x 10(10). A significant improvement of the ocular symptom-medication score (SMS) was observed in 2002 and of the score of distress of life in 2003. These data show that a daily oral intake of not less than 2 x 10(10) heat-treated L-92 cells improved the symptoms of Japanese cedar pollinosis, thereby contributing to reduce the dose of concomitant medications. However, no blood parameter was significantly affected in these trials.

Biosci Biotechnol Biochem. 2005 Sep;69(9):1652-60.

Clinical effects of Lactobacillus acidophilus strain L-92 on perennial allergic rhinitis: a double-blind, placebo-controlled study.

Studies in animals have suggested that lactic acid bacteria alleviate allergic diseases, however, little information is available on their clinical effect on allergy in humans. Thus, we examined the efficacy of orally administered Lactobacillus acidophilus strain L-92 (L-92) on perennial allergic rhinitis. In a randomized, double-blind, placebo-controlled clinical trial, 49 patients with perennial allergic rhinitis were randomized to receive either 100 mL of heat-treated fermented milk containing L-92 (n = 25) or acidified milk without lactic acid bacteria (placebo; n = 24) for 8 wk. The severity of symptoms was evaluated based on the changes in the scores of clinical symptoms. Oral administration of milk fermented with L-92 resulted in a statistically significant improvement of nasal symptom-medication scores. Ocular symptom-medication scores of patients in the L-92 intervention group tended to improve compared with those in the placebo group. In addition, clear decreases of the scores of swelling and color of the nasal mucosa were observed in the L-92 intervention group at 6 and 8 wk after the start of ingestion of fermented milk. There were no significant differences in serum antihouse dust mite immunoglobulin E levels nor in T helper type 1/T helper type 2 ratio between the 2 groups. These results suggest that oral administration of L-92 can alleviate the symptoms of perennial allergic rhinitis, however, statistically significant changes were not shown in blood parameters.

J Dairy Sci. 2005 Feb;88(2):527-33.

Decrease in ovalbumin specific IgE of mice serum after oral uptake of lactic acid bacteria.

Different kinds of lactobacilli and Bifidobacteria fermented milk were fed to ovalbumin-specific IgE-elevated mice for 3 days, and after the final administration, changes in the ovalbumin-specific IgE values for each sample were compared to the value for non-fermented milk. Seven of the Lactobacillus-fermented milks caused a significant decrease in the serum ovalbumin-specific IgE levels. Above all, Lactobacillus acidophilus L92, Lactobacillus acidophilus CP1613, and Lactobacillus fermentum CP34 fermented milk had the most significant effects of decreasing the serum ovalbumin-specific IgE levels compared to a control group. The L. acidophilus L92 and L. fermentum CP34 cells also showed significant ovalbumin-specific IgE lowering activities. From these results, an active component seems to exist in the cells of L. acidophilus L92 and L. fermentum CP34 strains. Recovery of the radiolabeled L. acidophilus L92 and L. fermentum CP34 cells from the small intestine and the large intestine of the mouse 13 h after oral administration were higher than the recovery of any other strain.

Biosci Biotechnol Biochem. 2003 May;67(5):951-7.

Lactobacillus Acidophilus strain L-92 regulates the production of Th1 cytokine as well as Th2 cytokines.

BACKGROUND: There is growing interest in probiotics such as lactic acid bacteria (LAB), not only for treatment of T helper type (Th) 1-mediated diseases but also for Th2-mediated diseases, including allergic diseases, since lactic acid bacteria may be able to modulate the Th1/Th2 balance, in addition to having an immunomodulative effect through induction of Th1 bias. METHODS: The effect of oral administration of heat-killed Lactobacillus acidophilus Strain L-92 (L-92) on ovalbumin (OVA)-specific immunoglobulin (Ig)E production was investigated in BALB/c mice. L-92 was orally administered to mice for 8 weeks from 2 weeks after initiation of OVA-immunization. Patterns of cytokine and Ig production in splenocytes and cells from Peyer’s patches (PPs) from these mice were examined after restimulation with OVA in vitro. RESULTS: L-92 significantly suppressed serum OVA-specific IgE levels for a long period. Cytokines such as interferon (IFN)-gamma, interleukin (IL)-4 and IL-10 and Igs such as total IgE and OVA-specific IgE were produced at significantly lower levels by splenocytes of L-92-treated mice, compared with those of control mice. In contrast, transforming growth factor (TGF)-beta and IgA levels produced by PPs from L-92-treated mice were significantly higher than in those from control mice. CONCLUSIONS: Oral L-92 administration regulated both Th1 and Th2 cytokine responses, suppressed serum OVA-specific IgE, and induced TGF-beta production in PPs. TGF-beta is known to be associated with activation of regulatory T (Treg) cells. These data suggest that LAB may have immunomodulative effect by Treg cells via TGF-beta activity.

Allergol Int. 2007 Sep;56(3):293-301.

Effects of oral administration of Lactobacillus acidophilus L-92 on the symptoms and serum markers of atopic dermatitis in children.

BACKGROUND: Few studies have investigated the complementary effects of long-term oral administration of Lactobacillus acidophilus on traditional medical therapy in the treatment of patients with atopic dermatitis (AD). METHODS: The Atopic Dermatitis Area and Severity Index was used to evaluate AD severity. Symptom severity was assessed using the symptom score. The effect of medical therapy was evaluated by adding the medication score, calculated as the sum of each product of the amount of steroid ointment used for therapy and its designated strength graded on a 4-point scale, to the symptom score. The complementary effect of long-term oral administration of L. acidophilus strain L-92 (L-92) as a probiotic or biogenic strain in patients with AD was evaluated using the symptom-medication score, which was calculated as the sum of the symptom score and medication score. Both a preliminary casuistic study and a double-blinded, placebo-controlled study were performed to evaluate the effects of L-92 on the symptoms of AD in children. RESULTS: Orally administered L-92 significantly ameliorated the symptoms of AD in Japanese children. L-92 also affected the serum concentrations of thymus and activation-regulated chemokine in a time-dependent manner. CONCLUSIONS: The results of the preliminary trial and the double-blinded, placebo-controlled study revealed a complementary effect of oral L-92 on the standard medical therapy (topical application of a steroid ointment) in patients with AD that was mediated, at least in part, by alterations in the Th1/Th2 balance.

Int Arch Allergy Immunol. 2011;154(3):236-45.

Efficacy of prolonged ingestion of Lactobacillus acidophilus L-92 in adult patients with atopic dermatitis.

To evaluate the safety and efficacy of prolonged ingestion of Lactobacillus acidophilus L-92 (L-92) on skin symptoms in adult atopic dermatitis (AD) patients, a placebo-controlled double-blinded parallel-group comparison study was performed. This included daily administration of heat-killed and dried L-92 or placebo for 24wk in 50 AD patients who were 16yr old or older. The severity of skin symptoms was evaluated at baseline and at 4, 8, 12, 16, 20, and 24wk during the intervention using the investigator global assessment, eczema area and severity index, and scoring atopic dermatitis. Serum cytokine and blood marker levels were also measured at baseline and at 4, 8, 16, and 24wk during the intervention. No adverse events were reported during the study period. Compared with the placebo group, the L-92 group showed significant decreases in investigator global assessment, eczema area and severity index, and scoring atopic dermatitis. Subjective symptoms in adult AD patients were reduced by intake of L-92. Furthermore, it was suggested that sustained ingestion of L-92 resulted in suppression of scratching behavior and maintenance of remission status of skin symptoms. Sixteen weeks after the study commenced, a significant decrease in lactate dehydrogenase and a significant increase in transforming growth factor-b were observed in the L-92 group compared with the placebo group. In the L-92 group, a significant elevation of IL-12 (p70) level at the end of treatment period compared with before the treatment was observed. This study suggested that L-92 suppresses type-2-helper-T-cell-dominant inflammation by activating regulatory T cells and type 1 helper T cells.

J Dairy Sci. 2016 Jul;99(7):5039-5046.

Nicotinamide riboside

NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency.

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polb+/- mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polb+/- mice have a reduced cerebral NAD+/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polb+/- mice but had no impact on amyloid b peptide (Ab) accumulation. NR-treated 3xTgAD/Polb+/- mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polb+/- mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polb+/- mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have therapeutic potential for AD.

Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1876-E1885.

Molecular and Cellular Basis of Neurodegeneration in Alzheimer’s Disease.

The most common form of senile dementia is Alzheimer’s disease (AD), which is characterized by the extracellular deposition of amyloid b-peptide (Ab) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson’s disease, and Pick’s disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than Ab plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD. A growing amount of evidence suggests that soluble Ab oligomers in concert with hyperphosphorylated tau (pTau) serve as the major pathogenic drivers of neurodegeneration in AD. Increased Ab oligomers trigger neuronal dysfunction and network alternations in learning and memory circuitry prior to clinical onset of AD, leading to cognitive decline. Furthermore, accumulated damage to mitochondria in the course of aging, which is the best-known nongenetic risk factor for AD, may collaborate with soluble Ab and pTau to induce synapse loss and cognitive impairment in AD. In this review, I summarize and discuss the current knowledge of the molecular and cellular biology of AD and also the mechanisms that underlie Ab-mediated neurodegeneration.

Mol Cells. 2017 Sep 30;40(9):613-620.

Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments.

The microtubule-associated protein tau is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in the form of paired helical filaments (PHF) in the brains of patients with Alzheimer’s disease (AD) and patients with several other tauopathies. Here, we show that the abnormally hyperphosphorylated tau from AD brain cytosol (AD P-tau) self-aggregates into PHF-like structures on incubation at pH 6.9 under reducing conditions at 35 degrees C during 90 min. In vitro dephosphorylation, but not deglycosylation, of AD P-tau inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six tau isoforms into tangles of PHF and straight filaments, and the microtubule binding domains/repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that tau self-assembles by association of the microtubule binding domains/repeats and that the abnormal hyperphosphorylation promotes the self-assembly of tau into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.

Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8

Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds.

The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.

Nat Rev Mol Cell Biol. 2016 Nov;17(11):679-690.

Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms.

Neurons affected in Alzheimer’s disease (AD) experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and promotes the disease-defining amyloid beta peptide (Ab) and Tau pathologies. Emerging findings suggest that the autophagy/lysosome pathway that removes damaged mitochondria (mitophagy) is also compromised in AD, resulting in the accumulation of dysfunctional mitochondria. Results in animal and cellular models of AD and in patients with sporadic late-onset AD suggest that impaired mitophagy contributes to synaptic dysfunction and cognitive deficits by triggering Ab and Tau accumulation through increases in oxidative damage and cellular energy deficits; these, in turn, impair mitophagy. Interventions that bolster mitochondrial health and/or stimulate mitophagy may therefore forestall the neurodegenerative process in AD.

Trends Neurosci. 2017 Mar;40(3):151-166.

Brain plasticity and functional losses in the aged: scientific bases for a novel intervention.

Aging is associated with progressive losses in function across multiple systems, including sensation, cognition, memory, motor control, and affect. The traditional view has been that functional decline in aging is unavoidable because it is a direct consequence of brain machinery wearing down over time. In recent years, an alternative perspective has emerged, which elaborates on this traditional view of age-related functional decline. This new viewpoint--based upon decades of research in neuroscience, experimental psychology, and other related fields--argues that as people age, brain plasticity processes with negative consequences begin to dominate brain functioning. Four core factors--reduced schedules of brain activity, noisy processing, weakened neuromodulatory control, and negative learning—interact to create a self-reinforcing downward spiral of degraded brain function in older adults. This downward spiral might begin from reduced brain activity due to behavioral change, from a loss in brain function driven by aging brain machinery, or more likely from both. In aggregate, these interrelated factors promote plastic changes in the brain that result in age-related functional decline. This new viewpoint on the root causes of functional decline immediately suggests a remedial approach. Studies of adult brain plasticity have shown that substantial improvement in function and/or recovery from losses in sensation, cognition, memory, motor control, and affect should be possible, using appropriately designed behavioral training paradigms. Driving brain plasticity with positive outcomes requires engaging older adults in demanding sensory, cognitive, and motor activities on an intensive basis, in a behavioral context designed to re-engage and strengthen the neuromodulatory systems that control learning in adults, with the goal of increasing the fidelity, reliability, and power of cortical representations. Such a training program would serve a substantial unmet need in aging adults. Current treatments directed at age-related functional losses are limited in important ways. Pharmacological therapies can target only a limited number of the many changes believed to underlie functional decline. Behavioral approaches focus on teaching specific strategies to aid higher order cognitive functions, and do not usually aspire to fundamentally change brain function. A brain-plasticity-based training program would potentially be applicable to all aging adults with the promise of improving their operational capabilities. We have constructed such a brain-plasticity-based training program and conducted an initial randomized controlled pilot study to evaluate the feasibility of its use by older adults. A main objective of this initial study was to estimate the effect size on standardized neuropsychological measures of memory. We found that older adults could learn the training program quickly, and could use it entirely unsupervised for the majority of the time required. Pre- and posttesting documented a significant improvement in memory within the training group (effect size 0.41, p<0.0005), with no significant within-group changes in a time-matched computer using active control group, or in a no-contact control group. Thus, a brain-plasticity-based intervention targeting normal age-related cognitive decline may potentially offer benefit to a broad population of older adults.

Prog Brain Res. 2006;157:81-109.

Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection.

PURPOSE OF REVIEW: This review focuses upon the biology and metabolism of a trace component in foods called nicotinamide riboside. Nicotinamide riboside is a precursor of nicotinamide adenine dinucleotide (NAD), and is a source of Vitamin B3. Evidence indicates that nicotinamide riboside has unique properties as a Vitamin B3. We review knowledge of the metabolism of this substance, as well as recent work suggesting novel health benefits that might be associated with nicotinamide riboside taken in larger quantities than is found naturally in foods. RECENT FINDINGS: Recent work investigating the effects of nicotinamide riboside in yeast and mammals established that it is metabolized by at least two types of metabolic pathways. The first of these is degradative and produces nicotinamide. The second pathway involves kinases called nicotinamide riboside kinases (Nrk1 and Nrk2, in humans). The likely involvement of the kinase pathway is implicated in the unique effects of nicotinamide riboside in raising tissue NAD concentrations in rodents and for potent effects in eliciting insulin sensitivity, mitochondrial biogenesis, and enhancement of sirtuin functions. Additional studies with nicotinamide riboside in models of Alzheimer’s disease indicate bioavailability to brain and protective effects, likely by stimulation of brain NAD synthesis. SUMMARY: Initial studies have clarified the potential for a lesser-known Vitamin B3 called nicotinamide riboside that is available in selected foods, and possibly available to humans by supplements. It has properties that are insulin sensitizing, enhancing to exercise, resisting to negative effects of high-fat diet, and neuroprotecting.

Curr Opin Clin Nutr Metab Care. 2013 Nov;16(6):657-61.

Joint health

A Botanical Composition Mitigates Cartilage Degradations and Pain Sensitivity in Osteoarthritis Disease Model.

Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive articular cartilage degradation manifested with significant functional impairment in consort with signs and symptoms of inflammation, stiffness, and loss of mobility. Current OA management is inadequate due to the lack of nominal therapies proven to be effective in hampering disease progression where symptomatic therapy focused intervention masks the primary etiology leading to irreversible structural damage. In this study, we describe the effect of UP1306, a composition containing a proprietary blend of two standardized extracts from the heartwood of Acacia catechu and the root bark of Morus alba, in maintaining joint structural integrity and alleviating OA associated symptoms in monosodium-iodoacetate (MIA)-induced rat OA disease model. Data from pain sensitivity, histopathology, and glycosaminoglycan (GAG) level were analyzed. Diclofenac at 10 mg/kg was used as a reference compound. Ex vivo proteoglycan protection model demonstrated 31.5%, 50.0%, and 54.8% inhibitions of proteoglycan degradations from UP1306 at concentrations of 50, 100, and 200 µg/mL, respectively. The merit of combining two bioflavonoid standardized extracts from A. catechu and M. alba was demonstrated in their Ex vivo synergistic proteoglycan protection activity. In the MIA in vivo OA model, administered orally at 500 mg/kg, UP1306 resulted in reductions of 17.5%, 29.0%, 34.4%, 33.5%, and 40.9% through week 1-5 in pain sensitivity, statistically significant improvements in articular cartilage matrix integrity, and minimal subchondral bone damage. Therefore, UP1306 could potentially be considered as an alternative remedy from natural sources for the management of OA and/or its associated symptoms.

J Med Food. 2017 Jun;20(6):568-576.

UP446, analgesic and anti-inflammatory botanical composition.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease. Long-term use of currently available therapies for RA produces adverse effects that limit dosage and duration; hence there is a need for safe and effective alternatives suitable for long term chronic use. UP446, a composition consisting primarily of baicalin from Scutellaria baicalensis Georgi (Family: Lamiaceae) and (+)-catechin from the heartwoods of Acacia catechu (Family: Mimosaceae), has been previously shown to reduce production of eicosanoids and leukotrienes through dual inhibition of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes and to decreased mRNA and protein levels of the proinflammatory cytokines, interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a. AIM: To evaluate the likelihood of UP446 in moderating arthritis and its associated symptoms in an experimental animal model of RA. MATERIALS AND METHODS: A RA rat model was induced by injecting Freund’s complete adjuvant into left and right hind paw and base of the tail. Animals were administered UP446 (50 mg/kg), ibuprofen (150 mg/kg mg/kg) or vehicle by oral gavage 30 min prior to arthritis induction and each day thereafter for 14 days. RESULT: Animals treated with UP446 showed 23.7, 31.9, 33.4, 29.3, and 33.1% reduction in pain sensitivity; 46.0, 36.7, 33.7, 34.8, and 33.4% reduction in ankle diameter on days 3, 5, 7, 9, and 13; respectively; compared to vehicle. Similarly paw edema was significantly reduced with an average of 30% for the first inflammatory reaction period (day 1-8) followed by 37.1 and 33.6% reduction on day 9 and 13. CONCLUSION: These data indicate potential benefit of UP446 in alleviating symptoms of RA and support human clinical evaluation of this botanical composition in patients with RA.

Pharmacognosy Res. 2013 Jul;5(3):139-45.

UP1304, a Botanical Composition Containing Two Standardized Extracts of Curcuma longa and Morus alba, Mitigates Pain and Inflammation in Adjuvant-induced Arthritic Rats.

BACKGROUND: Though, the initial etiologies of arthritis are multifactorial, clinically, patients share pain as the prime complaints. Present day pain relief therapeutics heavily relies on the use of prescription and over the counter nonsteroidal anti-inflammatory drugs as the first line of defense where their long-term usage causes gastrointestinal and cardiovascular-related side effects. Hence, the need for evidence-based safer and efficacious alternatives from natural sources to overcome the most prominent and disabling symptoms of arthritis is an overdue. Here, we evaluated the anti-inflammatory and analgesic effect of UP1304, a composition that contains a standardized blend of two extracts from the rhizome of Curcuma longa and the root bark of Morus alba in adjuvant-induced arthritis models in rats. MATERIALS AND METHODS: The anti-inflammatory and analgesic effects of the botanical composition were demonstrated in adjuvant-induced arthritis models in rats with oral dose ranges of 50-200 mg/kg. Ibuprofen at a dose of 100 mg/kg was used as a reference compound. Ex vivo sulfated glycosaminoglycan inhibition assays were performed. RESULTS: Statistically significant improvements in pain resistance, suppression of paw edema and ankle thickness were observed in animals treated with UP1304 compared to vehicle-treated diseased rats. These results were similar to those achieved by ibuprofen treatment. Inhibitions of proteoglycan degradation were observed in a range of 37.5-61.7% for concentration of UP1304 at 50-200 µg/mL when compared to interleukin-1a-exposed untreated explants. CONCLUSIONS: These data suggest that UP1304, for its analgesic and anti-inflammatory effects, could potentially be considered agent of botanical origin for the improvement of arthritis associated symptoms. SUMMARY: Pain is one of the cardinal signs of arthritis.Long term applications of commonly used non-steroidal anti-inflammatory drugs for pain relief are associated with cardiovascular and gastrointestinal side effects.Cartilage degradation evidenced as glycosaminoglycan loss from articular cartilage into the synovial fluid has been reported in arthritis patients.Adjuvant-induced arthritis model in rats are among the widely used models for efficacy evaluation of nutraceuticals.Efficacy of UP1304, a composition containing a blend of two standardized extracts from the rhizome of Curcuma longa and root bark of Morus alba, was evaluated in adjuvant-induced arthritis model in rats and in glycosaminoglycan releasing inhibition assays.UP1304 demonstrated its enhanced significance by improving the major cardinal signs of arthritis in vivo and ex vivo.UP1304 could potentially be considered as a dietary supplement product for the management of arthritis.

Pharmacognosy Res. 2016 Apr-Jun;8(2):112-7.

UP1306, a Botanical Composition with Analgesic and Anti-inflammatory Effect.

BACKGROUND: Pain, one of the cardinal signs of inflammation, is the most common clinical manifestations of arthritis. Conventional pain relief therapy heavily relies on the use of prescription and over the counter nonsteroidal anti-inflammatory drugs as the first line of defense where their long-term usage causes deleterious gastrointestinal and cardiovascular-related side-effects. Hence, there is an equivocal need for evidence-based safer and efficacious alternatives from natural sources to overcome the most prominent and disabling symptoms of arthritis. MATERIALS AND METHODS: Carrageenan-induced rat paw edema and abdominal constriction (writhing’s) assays in mouse were used to evaluate the anti-inflammatory and analgesic effects of UP1306, a composition that contains a standardized blend of extracts from the heartwood of Acacia catechu and the root bark of Morus alba administered orally at dose ranges of 100-300 mg/kg. Cyclooxygenase (COX) and lipoxygenase (LOX) inhibition assays were carried out to determine the IC50 of Acacia and Morus extracts. The merit of combining these two extracts was also assessed. RESULTS: Statistically significant improvement in pain resistance and suppression of edema were observed in animals treated with UP1306, when compared to vehicle-treated diseased rats and mice. Results from the high dose of UP1306 (300 mg/kg) were similar to those achieved by ibuprofen treatment at a dose of 200 mg/kg in early hours of treatment. In vitro, UP1306 showed dose-dependent inhibition of the enzymatic activities of COX and LO with IC50 values of 20.9 µg/mL, 49.2 µg/mL, and 11.1 µg/mL in COX-1, COX-2, and 5’-LO, respectively. CONCLUSIONS: These data suggest that UP1306, analgesic, and anti-inflammatory agent of botanical origin with dual COX-LO inhibition activity, could potentially be used to alleviate symptom associated to osteoarthritis. SUMMARY: Pain is the most common clinical manifestations of arthritisCarrageenan-induced rat paw edema and abdominal constriction (writhing’s) assays in mouse are among the widely used models to evaluate the anti-inflammatory and analgesic effects of nutraceuticalsCyclooxygenase and lipoxygenase (LO) inhibition assays were carried out to determine the IC50 of Acacia and Morus extracts.Efficacy of UP1306, a composition containing a blend of two standardized extracts from the heartwood of Acacia catechu and root bark of Morus alba, was evaluated in the above models.UP1306 demonstrated its enhanced significance by improving the major cardinal signs of arthritis in vivo and inflammation markers in vitro.UP1306 could potentially be considered as a dietary supplement product for the management of arthritis.

Pharmacognosy Res. 2016 Jul-Sep;8(3):186-92.

Astaxanthin

The Inhibitory Effects of Anti-Oxidants on Ultraviolet-Induced Up-Regulation of the Wrinkling-Inducing Enzyme Neutral Endopeptidase in Human Fibroblasts.

We recently reported that the over-expression of skin fibroblast-derived neutral endopeptidase (NEP) plays a pivotal role in impairing the three-dimensional architecture of dermal elastic fibers during the biological mechanism of ultraviolet (UV)-induced skin wrinkling. In that process, a UVB-associated epithelial-mesenchymal cytokine interaction as well as a direct UVA-induced cellular stimulation are associated with the up-regulation of NEP in human fibroblasts. In this study, we characterized the mode of action of ubiquinol10 which may abrogate the up-regulation of NEP by dermal fibroblasts, resulting in a reported in vivo anti-wrinkling action, and compared that with 3 other anti-oxidants, astaxanthin (AX), riboflavin (RF) and flavin mononucleotide (FMN). Post-irradiation treatment with all 4 of those anti-oxidants elicited an interrupting effect on the UVB-associated epithelial-mesenchymal cytokine interaction leading to the up-regulation of NEP in human fibroblasts but with different modes of action. While AX mainly served as an inhibitor of the secretion of wrinkle-inducing cytokines, such as interleukin-1a (IL-1a) and granulocyte macrophage colony stimulatory factor (GM-CSF) in UVB-exposed epidermal keratinocytes, ubiquinol10, RF and FMN predominantly interrupted the IL-1a and GM-CSF-stimulated expression of NEP in dermal fibroblasts. On the other hand, as for the UVA-associated mechanism, similar to the abrogating effects reported for AX and FMN, ubiquinol10 but not RF had the potential to abrogate the increased expression of NEP and matrix-metalloproteinase-1 in UVA-exposed human fibroblasts. Our findings strongly support the in vivo anti-wrinkling effects of ubiquinol10 and AX on human and animal skin and provide convincing proof of the UV-induced wrinkling mechanism that essentially focuses on the over-expression of NEP by dermal fibroblasts as an intrinsic causative factor.

PLoS One. 2016 Sep 20;11(9):e0161580.

Abrogating effect of a xanthophyll carotenoid astaxanthin on the stem cell factor-induced stimulation of human epidermal pigmentation.

We established a model for the stem cell factor (SCF)-associated stimulation of human epidermal equivalent (HEE) pigmentation. The addition of SCF (at 5 nM) gradually stimulated the visible pigmentation of HEEs over 14 days of treatment. A time course study using real-time RT-PCR and western blotting analysis demonstrated that the expression of all melanocyte-specific genes and proteins examined was gradually up-regulated over 7-10 days of treatment with SCF. The addition of astaxanthin (Ax) at concentrations of 1, 4, or 8 µM markedly abolished the SCF- but not the endothelin (EDN)1-elicited increase in visible pigmentation over 14 days in a dose-dependent manner, with almost complete inhibition at 8 µM. While no degeneration of the epidermal tissue was visible at day 14 by HE staining, melanin deposition throughout the epidermis was markedly reduced in the Ax-treated HEEs at day 14 compared to untreated controls. Ax significantly reduced the eumelanin content of HEEs to the non-SCF-stimulated level at concentrations of 4 or 8 µM compared with untreated controls. Real-time RT-PCR and western blotting of Ax-treated HEEs revealed that the SCF-stimulated expression of tyrosinase (TYR), TYR-related protein-1 (TYRP1), and Pmel17, as well as microphthalmia-associated transcription factor (MITF), is significantly suppressed by Ax at the transcriptional and translational levels. Studies using cultured normal human melanocytes revealed that pre-treatment with Ax interrupts the SCF- but not the EDN1-induced stimulation of TYR activity, and there was no direct inhibitory effect of Ax on TYR activity in vitro. These findings indicate that Ax attenuates SCF-stimulated pigmentation by directly interrupting SCF-associated intracellular signaling linkages through increased expression of MITF, which leads to the stimulated expression of melanogenic genes and proteins in a reactive oxygen species depletion-independent mechanism.

Arch Dermatol Res. 2012 Dec;304(10):803-16.

Astaxanthin attenuates the UVA-induced up-regulation of matrix-metalloproteinase-1 and skin fibroblast elastase in human dermal fibroblasts.

BACKGROUND: Repetitive exposure of the skin to UVA radiation elicits sagging more frequently than wrinkling, which is mainly attributed to its biochemical mechanism to up-regulate the expression of matrix-metalloproteinase (MMP)-1 and skin fibroblast elastase (SFE)/neutral endopeptidase (NEP), respectively. OBJECTIVE: In this study, we examined the effects of a potent antioxidant, astaxanthin (AX), on the induction of MMP-1 and SFE by UVA treatment of cultured human dermal fibroblasts.METHODS: Those effects were assessed by real-time RT-PCR, Western blotting and enzymic activity assays. RESULTS: UVA radiation elicited a significant increase in the gene expression of MMP-1 as well as SFE/NEP (to a lesser extent) which was followed by distinct increases in their protein and enzymatic activity levels. The addition of AX at concentrations of 4-8 microM immediately after UVA exposure significantly attenuated the induction of MMP-1 and SFE/NEP expression elicited by UVA at the gene, protein and activity levels although both the UVA stimulation and the subsequent AX inhibition were greater for MMP-1 than for SFE/NEP. Analysis of the UVA-induced release of cytokines revealed that UVA significantly stimulated only the secretion of IL-6 among the cytokines tested and that AX significantly diminished only the IL-6 secretion. CONCLUSION: These findings indicate that, based on different effective concentrations of AX, a major mode of action leading to the inhibition elicited by AX depends on inhibition of UVA effects of the reactive oxygen species-directed signaling cascade, but not on interruption of the IL-6-mediated signaling cascade. We hypothesize that AX would have a significant benefit on protecting against UVA-induced skin photo-aging such as sagging and wrinkles.

J Dermatol Sci. 2010 May;58(2):136-42.

Biological mechanisms underlying the ultraviolet radiation-induced formation of skin wrinkling and sagging II: over-expression of neprilysin plays an essential role.

Our previous studies strongly indicated that the up-regulated activity of skin fibroblast-derived elastase plays a pivotal role in wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. Fortunately, we succeeded in identifying human skin fibroblast-derived elastase as a previously known enzyme, neprilysin or neutral endopeptidase (NEP). We have also characterized epithelial-mesenchymal paracrine cytokine interactions between UVB-exposed-keratinocytes and dermal fibroblasts and found that interleukin-1a and granulocyte macrophage colony stimulatory factor (GM-CSF) are intrinsic cytokines secreted by UVB-exposed keratinocytes that stimulate the expression of neprilysin by fibroblasts. On the other hand, direct UVA exposure of human fibroblasts significantly stimulates the secretion of IL-6 and also elicits a significant increase in the gene expression of matrix metallo-protease(MMP)-1 as well as neprilysin (to a lesser extent), which is followed by distinct increases in their protein and enzymatic activity levels. Direct UVA exposure of human keratinocytes also stimulates the secretion of IL-6, IL-8 and GM-CSF but not of IL-1 and endothelin-1. These findings suggest that GM-CSF secreted by UVA-exposed keratinocytes as well as IL-6 secreted by UVA-exposed dermal fibroblasts play important and additional roles in UVA-induced sagging and wrinkling by up-regulation of neprilysin and MMP-1, respectively, in dermal fibroblasts.

Int J Mol Sci. 2015 Apr 8;16(4):7776-95.

Protecting skin photoaging by NF-kappaB inhibitor.

The skin photoaging is an inevitable process that occurs in daily life. It ischaracterized by acceralated keratinocyte proliferation and degradation of collagen fibers, causing skin wrinkling and laxity, and melanocyte proliferation that leads to pigmentation. Ultraviolet (UV) is considered to be a major cause of such skin changes. It is well established that nuclear factor kappa B (NF-kappaB) is activated upon UV irradiation and induces various genes including interleukin-1 (IL-1), tumor necrosis factor alpha (TNFalpha), and matrix metalloprotease-1 (MMP-1). It is also known that production of basic fibroblast growth factor (bFGF) is induced in skin tissues by UV irradiation and it promotes the proliferation of skin keratinocytes and melanocytes. We found that either UVB, IL-1 or TNFalpha could induce NF-kappaB by activating its signal transduction pathway. The activated NF-kappaB produces MMP-1 and bFGF in skin fibroblasts and human keratinocyte cell line HaCaT. In this experiment, we examined whether parthenolide and magnolol, NF-kappaB inhibitors, could block such UVB-mediated skin changes. We found that either parthenolide or magnolol could effectively inhibit the gene expression mediated by NF-kappaB and the production of bFGF and MMP-1 from cells overexpressing p65, a major subunit of NF-kappaB. We also found that these NF-kappaB inhibitors could inhibit the UVB-induced proliferation of keratinocytes and melanocytes in the mouse skin. These findings suggest that NF-kappaB inhibitors are useful in preventing the skin photoaging.

Curr Drug Metab. 2010 Jun 1;11(5):431-5.

Protective effects of astaxanthin on skin deterioration.

Astaxanthin is a carotenoid with potent antioxidant and anti-inflammatory activity. To evaluate the anti-inflammatory effect of astaxanthin on skin deterioration, we confirmed its role in epidermal-dermal interactions in vitro. Astaxanthin treatment suppressed ultraviolet B (UVB)-induced inflammatory cytokine secretion in keratinocytes, and matrix metalloproteinase-1 secretion by fibroblasts cultured in UVB-irradiated keratinocyte medium. To verify these findings, we conducted a 16-week clinical study with 65 healthy female participants. Participants were orally administered either a 6 mg or 12 mg dose of astaxanthin or a placebo. Wrinkle parameters and skin moisture content significantly worsened in the placebo group after 16 weeks. However, significant changes did not occur in the astaxanthin groups. Interleukin-1a levels in the stratum corneum significantly increased in the placebo and low-dose groups but not in the high-dose group between weeks 0 and 16. This study was performed in Japan from August to December, when changing environmental factors, such as UV and dryness, exacerbate skin deterioration. In conclusion, our study suggests that long-term prophylactic astaxanthin supplementation may inhibit age-related skin deterioration and maintain skin conditions associated with environmentally induced damage via its anti-inflammatory effect. (UMIN Clinical Trials Registry ID: UMIN000018550).

J Clin Biochem Nutr. 2017 Jul;61(1):33-39.

Preventive effect of dietary astaxanthin on UVA-induced skin photoaging in hairless mice.

Astaxanthin, a carotenoid found mainly in seafood, has potential clinical applications due to its antioxidant activity. In this study, we evaluated the effect of dietary astaxanthin derived from Haematococcus pluvialis on skin photoaging in UVA-irradiated hairless mice by assessing various parameters of photoaging. After chronic ultraviolet A (UVA) exposure, a significant increase in transepidermal water loss (TEWL) and wrinkle formation in the dorsal skin caused by UVA was observed, and dietary astaxanthin significantly suppressed these photoaging features. We found that the mRNA expression of lympho-epithelial Kazal-type-related inhibitor, steroid sulfatase, and aquaporin 3 in the epidermis was significantly increased by UVA irradiation for 70 days, and dietary astaxanthin significantly suppressed these increases in mRNA expression to be comparable to control levels. In the dermis, the mRNA expression of matrix metalloprotease 13 was increased by UVA irradiation and significantly suppressed by dietary astaxanthin. In addition, HPLC-PDA analysis confirmed that dietary astaxanthin reached not only the dermis but also the epidermis. Our results indicate that dietary astaxanthin accumulates in the skin and appears to prevent the effects of UVA irradiation on filaggrin metabolism and desquamation in the epidermis and the extracellular matrix in the dermis.

PLoS One. 2017 Feb 7;12(2):e0171178.

Lycopene

Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population.

In a prospective cohort study of 1,271 Massachusetts residents 66 years of age or older, we examined the association between consumption of carotene-containing vegetables and subsequent five year mortality. Dietary information was obtained by food frequency questionnaire in 1976. The relative risk of cancer mortality was examined within quintiles of green and yellow vegetable score (calculated from intake of carrots or squash, tomatoes, salads or leafy vegetables, dried fruits, fresh strawberries or fresh melon, and broccoli or brussel sprouts). After controlling for age and smoking behavior, those in the highest quintile of intake of these carotene-containing vegetables had a risk of cancer mortality which was 0.3 (95% confidence limits 0.10-0.96) that of those in the lowest quintile. The trend of decreased cancer risk with increasing intake of carotene containing vegetables was significant (p = .026). This relationship is consistent with the hypothesis that carotene may act as an inhibitor of carcinogenesis.

Am J Clin Nutr. 1985 Jan;41(1):32-6.

Vegetable consumption and lung cancer risk: a population-based case-control study in Hawaii.

We conducted a population-based study of diet and lung cancer among the multiethnic population of Hawaii in 1983-1985. We completed interviews for 230 men and 102 women with lung cancer and 597 men and 268 women controls, frequency-matched to the patients by age and sex. A quantitative dietary history assessed the usual intake of foods rich in vitamins A and C and carotenoids. A clear dose-dependent negative association was demonstrated between dietary beta-carotene and lung cancer risk in both sexes. After adjusting for smoking and other covariates, the men in the lowest quartile of beta-carotene intake had an odds ratio of 1.9 (95% confidence interval, 1.1-3.2) compared to those in the highest quartile of intake. The corresponding odds ratio for women was 2.7 (95% confidence interval, 1.2-6.1). No clear association was found for retinol, vitamin C, folic acid, iron, dietary fiber, or fruits. All vegetables, dark green vegetables, cruciferous vegetables, and tomatoes showed stronger inverse associations with risk than beta-carotene. This observation suggests that other constituents of vegetables, such as lutein, lycopene, and indoles, and others, may also protect against lung cancer in humans.

J Natl Cancer Inst. 1989 Aug 2;81(15):1158-64.

Serologic precursors of cancer: serum micronutrients and the subsequent risk of pancreatic cancer.

In a nested case-control study the stored, frozen sera from 22 cases of cancer of the pancreas and 44 matched control subjects were assayed for retinol, retinol-binding protein, total carotenoids, beta-carotene, lycopene, vitamin E (alpha-tocopherol), and selenium. Prediagnostic serum levels of lycopene and Se were lower among cases than among matched control subjects. These differences remained after adjustment was made for possible confounding by smoking, educational level, and the other measured serum levels. Low levels of serum vitamin E appeared to have a protective effect but a chance association between vitamin E and cancer of the pancreas could not reasonably be excluded. The association between cancer of the pancreas and serum Se was significant when the data were analyzed as a whole but its effect was seen principally in men.

Am J Clin Nutr. 1989 May;49(5):895-900.

Selenium, lycopene, alpha-tocopherol, beta-carotene, retinol, and subsequent bladder cancer.

To examine the association between serum nutrients and the development of bladder cancer we measured selenium, alpha-tocopherol, lycopene, beta-carotene, retinol, and retinol-binding protein in serum collected from 25,802 persons in Washington County, MD, in 1974. Serum samples were kept frozen at -70 degrees C. In the subsequent 12-year period, 35 cases of bladder cancer developed among participants. Comparisons of serum levels in 1974 among cases and two matched controls for each case showed that selenium was significantly lower among cases than controls (P = 0.03), lycopene was lower among cases at a borderline level of significance (P = 0.07), and alpha-tocopherol was nonsignificantly lower (P = 0.13). For selenium there was a nearly linear increase in risk with decreasing serum levels (P = 0.03). When examined by tertiles, the odds ratio associated with the lowest tertile of selenium compared to the highest tertile was 2.06. Serum levels of retinol, retinol-binding protein, and beta-carotene were similar among cases and controls. These results support a role for selenium in the prevention of bladder cancer.

Cancer Res. 1989 Nov 1;49(21):6144-8.

Lycopene Protects Keratinocytes Against UVB Radiation-Induced Carcinogenesis via Negative Regulation of FOXO3a Through the mTORC2/AKT Signaling Pathway.

Lycopene, one of the most potent anti-oxidants, has been reported to exhibit potent anti-proliferative properties in a wide range of cancer cells through modulation of the cell cycle and apoptosis. Forkhead box O3 (FOXO3a) plays a pivotal role in modulating the expression of genes involved in cell death. Herein, we investigated the role of FOXO3a signaling in the anti-cancer effects of lycopene. Results showed that lycopene pretreatment attenuated UVB-induced cell hyper-proliferation and promoted apoptosis, accompanied by decreased cyclin-dependent kinase 2 (CDK2) and CDK4 complex in both human keratinocytes and SKH-1 hairless mice. FOXO3a is phosphorylated in response to UVB irradiation and sequestered in the cytoplasm, while lycopene pretreatment rescued this sensitization. Gene ablation of FOXO3a attenuated lycopene-induced decrease in cell hyper-proliferation, CDK2, and CDK4 complex, indicating a critical role of FOXO3a in the lycopene-induced anti-proliferative effect of keratinocytes during UVB irradiation. Transfection with FOXO3a siRNA inhibited the lycopene-induced increase in cell apoptosis, BAX and cleaved PARP expression. Moreover, loss of AKT induced further accelerated lycopene-induced FOXO3a dephosphorylation, while loss of mechanistic target of rapamycin complex 2 (mTORC2) by transfection with RICTOR siRNA induced levels of AKT phosphorylation comparable to those obtained with lycopene. In contrast, overexpression of AKT or mTORC2 decreased the effects of lycopene on the expression of FOXO3a as well as AKT phosphorylation, suggesting that lycopene depends on the negative modulation of mTORC2/AKT signaling. Taken together, our findings demonstrate that the mTORC2/AKT/FOXO3a axis plays a critical role in the anti-proliferative and pro-apoptotic effects of lycopene in UVB-induced photocarcinogenesis. J. Cell. Biochem. 119: 366-377, 2018.

J Cell Biochem. 2018 Jan;119(1):366-377.

Colorectal cancer: an update on the effects of lycopene on tumor progression and cell proliferation.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Various factors, including oxidative stress, where excessive productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS) occur, contribute to its pathogenesis. Numerous studies have investigated the effect of antioxidant substances derived from food such as fruits and vegetables; however, data on Lycopene are still rare. Studies on HT-29 colorectal cancer cells and on animal models have shown that lycopene has effects on cell proliferation and on the progression of the CRC by interacting with various cellular signaling pathways. This analysis of the literature focused on the antioxidant effect of lycopene, a substance that is found in the tomato.

J Biol Regul Homeost Agents. 2017 Jul-Sep;31(3):769-774.