| Effects
of restricted feeding, low-energy diet, and implantation of trenbolone
acetate plus estradiol on growth, carcass traits, and circulating concentrations
of insulin-like growth factor (IGF)-I and IGF-binding protein-3 in finishing
barrows.
Effects of restricted feeding (80% ad libitum), feeding a low-energy
diet containing 84% DE (2.95 Mcal/kg) of the control diet, and implantation
of Revalor H (140 mg trenbolone acetate plus 14 mg estradiol-17beta)
on growth, carcass traits, and serum concentrations of insulin-like
growth factor (IGF)-I and IGFbinding protein-3 (IGFBP-3) were studied
in crossbred finishing barrows beginning from 59 +/- 0.9 kg of body
weight. Blood samples were taken every three week and the animals were
slaughtered at approximately 105 kg body weight. Restricted feeding
caused a decrease (P < 0.01) in ADG; feeding the low-energy diet
was effective in reducing backfat thickness but decreased gain:feed;
the implantation caused a decrease in ADG, feed intake, and backfat
thickness and increased gain:feed. Overall pork quality based on pH,
drip loss, and the lightness in color of longissimus muscle was not
affected by any of the treatments. Serum IGF-I concentration increased
following the implantation but did not change (P > 0.05) due to other
treatments. Immunoreactive IGFBP-3 concentration was not changed by
any of the treatments. Overall ADG was positively correlated with early-stage
(d 21) IGF-I and IGFBP-3 concentrations only in unimplanted barrows,
whereas backfat thickness was negatively correlated with d-42 IGF-I
concentration in all but unimplanted barrows with ad libitum intake.
A strong positive correlation (P < 0.01) between IGF-I and IGFBP-3
concentrations was apparent with increasing age of the animals. Results
suggest that growth rate and backfat thickness are decreased by a moderate
restriction of feed or energy intake with no accompanying changes in
circulating IGF-I and IGFBP-3 concentrations and that the beneficial
effect of Revalor H implantation on feed efficiency may be mediated,
in part, by IGF-I. Moreover, both IGF-I and IGFBP-3 concentrations may
be useful as growth indices in pigs.
Anim Sci. 2002 Jan;80(1):84-93
Molecular targets for green tea in prostate
cancer prevention.
Prostate cancer (PCa) is the most frequently diagnosed malignancy and
the second leading cause of cancer-related deaths in American males.
For these reasons, it is necessary to intensify our efforts for better
understanding and development of novel treatment and chemopreventive
approaches for this disease. In recent years, green tea has gained considerable
attention as an agent that could reduce the risk of several cancer types.
The cancer-chemopreventive effects of green tea appear to be mediated
by the polyphenolic constituents present therein. Based on geographical
observations that suggest that the incidence of PCa is lower in Japanese
and Chinese populations that consume green tea on a regular basis, we
hypothesized that green tea and/or its constituents could be effective
for chemoprevention of PCa. To investigate this hypothesis, we initiated
a program for the chemoprevention of PCa by green tea. In cell-culture
systems that employ human PCa cells DU145 (androgen insensitive) and
LNCaP (androgen sensitive), we found that the major polyphenolic constituent
(-)-epigallocatechin-3-gallate (EGCG) of green tea induces 1) apoptosis,
2) cell-growth inhibition, and 3) cyclin kinase inhibitor WAF-1/p21-mediated
cell-cycle dysregulation. More recently, using a cDNA microarray, we
found that EGCG treatment of LNCaP cells results in 1) induction of
genes that functionally exhibit growth-inhibitory effects, and 2) repression
of genes that belong to the G-protein signaling network. In animal studies
that employ a transgenic adenocarcinoma of the mouse prostate (TRAMP),
which is a model that mimics progressive forms of human prostatic disease,
we observed that oral infusion of a polyphenolic fraction isolated from
green tea (GTP) at a human achievable dose (equivalent to 6 cups of
green tea/d) significantly inhibits PCa development and metastasis.
We extended these studies and more recently observed increased expression
of genes related to angiogenesis such as vascular endothelial growth
factor (VEGF) and those related to metastasis such as matrix metalloproteinases
(MMP)-2 and MMP-9 in prostate cancer of TRAMP mice. Oral feeding of
GTP as the sole source of drinking fluid to TRAMP mice results in significant
inhibition of VEGF, MMP-2 and MMP-9. These data suggest that there are
multiple targets for PCa chemoprevention by green tea and highlight
the need for further studies to identify novel pathways that may be
modulated by green tea or its polyphenolic constituents that could be
further exploited for prevention and/or treatment of PCa.
J Nutr. 2003 Jul;133(7 Suppl):2417S-2424S |
| Melatonin
as a chronobiotic/anticancer agent: cellular, biochemical, and molecular
mechanisms of action and their implications for circadian-based cancer
therapy.
Melatonin, as a new member of an expanding group of regulatory factors
that control cell proliferation and loss, is the only known chronobiotic,
hormonal regulator of neoplastic cell growth. At physiological circulating
concentrations, this indoleamine is cytostatic and inhibits cancer cell
proliferation in vitro via specific cell cycle effects. At pharmacological
concentrations, melatonin exhibits cytotoxic activity in cancer cells.
At both physiological and pharmacological concentrations, melatonin
acts as a differentiating agent in some cancer cells and lowers their
invasive and metastatic status through alterations in adhesion molecules
and maintenance of gap junctional intercellular communication. In other
cancer cell types, melatonin, either alone or in combination with other
agents, induces apoptotic cell death. Biochemical and molecular mechanisms
of melatonin's oncostatic action may include regulation of estrogen
receptor expression and transactivation, calcium/calmodulin activity,
protein kinase C activity, cytoskeletal architecture and function, intracellular
redox status, melatonin receptor-mediated signal transduction cascades,
and fatty acid transport and metabolism. A major mechanism mediating
melatonin's circadian stage-dependent tumor growth inhibitory action
is the suppression of epidermal growth factor receptor (EGFR)/mitogen-activated
protein kinase (MAPK) activity. This occurs via melatonin receptor-mediated
blockade of tumor linoleic acid uptake and its conversion to 13-hydroxyoctadecadienoic
acid (13-HODE) which normally activates EGFR/MAPK mitogenic signaling.
This represents a potentially unifying model for the chronobiological
inhibitory regulation of cancer growth by melatonin in the maintenance
of the host/cancer balance. It also provides the first biological explanation
of melatonin-induced enhancement of the efficacy and reduced toxicity
of chemo- and radiotherapy in cancer patients.
Curr Top Med Chem. 2002 Feb;2(2):113-32
Five years survival in metastatic non-small
cell lung cancer patients treated with chemotherapy alone or chemotherapy
and melatonin: a randomized trial.
Numerous experimental data have documented the oncostatic properties
of melatonin. In addition to its potential direct antitumor activity,
melatonin has proved to modulate the effects of cancer chemotherapy,
by enhancing its therapeutic efficacy and reducing its toxicity. The
increase in chemotherapeutic efficacy by melatonin may depend on two
main mechanisms, namely prevention of chemotherapy-induced lymphocyte
damage and its antioxidant effect, which has been proved to amplify
cytotoxic actions of the chemotherapeutic agents against cancer cells.
However, the clinical results available at present with melatonin and
chemotherapy in the treatment of human neoplasms are generally limited
to the evaluation of 1-year survival in patients with very advanced
disease. Thus, the present study was performed to assess the 5-year
survival results in metastatic non-small cell lung cancer patients obtained
with a chemotherapeutic regimen consisting of cisplatin and etoposide,
with or without the concomitant administration of melatonin (20 mg/day
orally in the evening). The study included 100 consecutive patients
who were randomized to receive chemotherapy alone or chemotherapy and
melatonin. Both the overall tumor regression rate and the 5-year survival
results were significantly higher in patients concomitantly treated
with melatonin. In particular, no patient treated with chemotherapy
alone was alive after 2 years, whereas a 5-year survival was achieved
in three of 49 (6%) patients treated with chemotherapy and melatonin.
Moreover, chemotherapy was better tolerated in patients treated with
melatonin. This study confirms, in a considerable number of patients
and for a long follow-up period, the possibility to improve the efficacy
of chemotherapy in terms of both survival and quality of life by a concomitant
administration of melatonin. This suggests a new biochemotherapeutic
strategy in the treatment of human neoplasms.
J Pineal Res. 2003 Aug;35(1):12-5
Role of melatonin in the regulation of human
circadian rhythms and sleep.
The circadian rhythm of pineal melatonin is the best marker of internal
time under low ambient light levels. The endogenous melatonin rhythm
exhibits a close association with the endogenous circadian component
of the sleep propensity rhythm. This has led to the idea that melatonin
is an internal sleep "facilitator" in humans, and therefore
useful in the treatment of insomnia and the readjustment of circadian
rhythms. There is evidence that administration of melatonin is able:
(i) to induce sleep when the homeostatic drive to sleep is insufficient;
(ii) to inhibit the drive for wakefulness emanating from the circadian
pacemaker; and (iii) induce phase shifts in the circadian clock such
that the circadian phase of increased sleep propensity occurs at a new,
desired time. Therefore, exogenous melatonin can act as soporific agent,
a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin
in the regulation of sleep, and the use of exogenous melatonin to treat
sleep or circadian rhythm disorders.
J Neuroendocrinol. 2003 Apr;15(4):432-7
Cancer anorexia-cachexia syndrome: current issues
in research and management.
Cachexia is among the most debilitating and life-threatening aspects
of cancer. Associated with anorexia, fat and muscle tissue wasting,
psychological distress, and a lower quality of life, cachexia arises
from a complex interaction between the cancer and the host. This process
includes cytokine production, release of lipid-mobilizing and proteolysis-inducing
factors, and alterations in intermediary metabolism. Cachexia should
be suspected in patients with cancer if an involuntary weight loss of
greater than five percent of premorbid weight occurs within a six-month
period. The two major options for pharmacological therapy have been
either progestational agents, such as megestrol acetate, or corticosteroids.
However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome
has led to, and continues to lead to, effective therapeutic interventions
for several aspects of the syndrome. These include antiserotonergic
drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic
acid, cannabinoids, melatonin, and thalidomide--all of which act on
the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived
catabolic factors to antagonize tissue wasting and/or host cytokine
release. Because weight loss shortens the survival time of cancer patients
and decreases performance status, effective therapy would extend patient
survival and improve quality of life.
CA Cancer J Clin. 2002 Mar-Apr;52(2):72-91
Extrapineal melatonin in pathology: new perspectives
for diagnosis, prognosis and treatment of illness.
During the last decade, attention was concentrated on melatonin -- one
of the hormones of the diffuse neuroendocrine system, which has been
considered only as a hormone of the pineal gland, for many years. Currently,
melatonin has been identified not only in the pineal gland, but also
in extrapineal tissues -- retina, harderian gland, gut mucosa, cerebellum,
airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas,
ovary, carotid body, placenta and endometrium as well as in non-neuroendocrine
cells like mast cells, natural killer cells, eosinophilic leukocytes,
platelets and endothelial cells. The above list of the cells storing
melatonin indicates that melatonin has a unique position among the hormones
of the diffuse neuroendocrine system, which is present in practically
all organ systems. Functionally, melatonin-producing cells are certain
to be part and parcel of the diffuse neuroendocrine system as a universal
system of response, control and organism protection. Taking into account
the large number of melatonin-producing cells in many organs, the wide
spectrum of biological activities of melatonin and especially its main
property as a universal regulator of biological rhythms, it should be
possible to consider extrapineal melatonin as a key paracrine signal
molecule for the local coordination of intercellular relationships.
Analysis of our long-term clinical investigations shows the direct participation
and active role of extrapineal melatonin in the pathogenesis of tumor
growth and many other non-tumor pathologies such as gastric ulcer, immune
diseases, neurodegenerative processes, radiation disorders, etc. The
modification of antitumor and other specific therapy by the activation
or inhibition of extrapineal melatonin activity could be useful for
the improvement of the treatment of illness.
Neuroendocrinol Lett. 2002 Apr;23 Suppl 1:92-6
Gastrointestinal melatonin: localization, function,
and clinical relevance.
The gastrointestinal tract of vertebrate species is a rich source of
extrapineal melatonin. The concentration of melatonin in the gastrointestinal
tissues surpasses blood levels by 10-100 times and there is at least
400x more melatonin in the gastrointestinal tract than in the pineal
gland. The gastrointestinal tract contributes significantly to circulating
concentrations of melatonin, especially during the daytime and melatonin
may serve as an endocrine, paracrine, or autocrine hormone influencing
the regeneration and function of epithelium, enhancing the immune system
of the gut, and reducing the tone of gastrointestinal muscles. As binding
sites for melatonin exhibit circadian variation in various species,
it has been hypothesized that some melatonin found in the gastrointestinal
tract might be of pineal origin. Unlike the photoperiodically regulated
production of melatonin in the pineal, the release of gastrointestinal
melatonin seems to be related to the periodicity of food intake. Phylogenetically,
melatonin and its binding sites were detected in the gastrointestinal
tract of lower vertebrates, birds, and mammals. Melatonin was found
also in large quantities in the embryonic tissue of the mammalian and
avian gastrointestinal tract. Food intake and, paradoxically, also longterm
food deprivation resulted in an increase of tissue and plasma concentrations
of melatonin. Melatonin release may have a direct effect on many gastrointestinal
tissues but may also well influence the digestive tract indirectly,
via the central nervous system and the sympathetic and parasympathetic
nerves. Melatonin prevents ulcerations of gastrointestinal mucosa by
an antioxidant action, reduction of secretion of hydrochloric acid,
stimulation of the immune system, fostering epithelial regeneration,
and increasing microcirculation. Because of its unique properties, melatonin
could be considered for prevention or treatment of colorectal cancer,
ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood
colic.
Dig Dis Sci. 2002 Oct;47(10):2336-48
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