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| Immunotherapy |
A preliminary analysis of their immuno-mechanisms of action is
discussed. The preclinical murine models first tested with CaPterin and
dipterinyl calcium pentahydrate (DCP), a dimerized version of CaPterin, were
four murine breast tumor models. These four models included: C3H/HeN-MTV+
female mice with spontaneous mammary gland adenocarcinomas; Mammary EMT6
allografts implanted in nonimmune female Balb/c mice; MDA-MB-231 human breast
tumor xenographs in SCID mice; and MDA-MB-231 human breast tumor xenographs in
athymic nude mice. An analysis of the differing tumor responses in these breast
tumor models led to the determination that B-cell antibody-based antitumor
mechanisms were involved. A transgenic hepatitis B murine model and a
diabetes-induced obese (DIO) type 2 diabetes murine model were also tested with
DCP, giving positive results. Read more>>>>>>>
Easy
availability of herbal medicine has led to their increased use. This has
resulted to increased reports of their suspected toxicity and adverse events.
Such unwanted reactions can be due to side effects; reactions occurring as a result
of overdose, over duration, tolerance, dependence-addiction; hypersensitivity,
allergic and idiosyncratic reactions; mid-term and long-term toxic effects. It
is such reaction that necessitates toxicity evaluation.Mechanisms
of toxicity can present in several ways. One of them is on target whereby the
toxicant binds to a targeted receptor with unintended high affinity resulting
to untoward reaction. Off target is another mechanism whereby the toxicant
binds to unintended receptor resulting to unintended reaction.(Read More)
Cardiovascular
Disease (CVD) including stroke is one of the leading causes of death and
disability worldwide and an enormous economic burden to our societies. Based onthe latest statistics for heart and stroke disease released by the AmericanHeart Association in 2016, CVD is the leading global cause of death, accounting
for more than 17.3 million deaths per year, a number that is expected to grow
to more than 23.6 million by 2030. An estimated 83,600,000 adults in the United
State (US) (>30%) have one or more types CVD of whom more than 90% have
hypertension, 18% have Coronary Heart Disease (CHD), close to 10% have
Myocardial Infarction (MI) and 8% have stroke. The total direct and indirect
cost in the US alone for treatment of CVD (hospitalization, drugs, home
healthcare, etc.) and loss of productivity and morbidity totalled more than $315
billion US per year.
While there was a decline in cardiovascular mortality
reported in the American Heart Association 2014 update, the disease burden to
society remains high. Thus prevention by better diagnosis and treatment could
provide a huge saving for the health care cost worldwide. Despite advancement
in modern cardiovascular medicine, the prevalence of hypertension, Ischemic
Heart Disease (IHD) and stroke is still on the rise, particularly in
industrialized societies and in the elderly population, and finding an optimum
drug therapy to slow disease progression remains a therapeutic challenge.(Read more)
Serotonin
or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter which has broad
distribution in the brain. It was discovered by Erspamer and Asero in the 1950s.
5-HT is synthesized in two steps, with Tryptophan Hydroxylase (TPH) as therate-limiting enzyme. First, tryptophan is converted to 5-hydroxytryptophan
(5-HTP) by TPH. Second, the intermediate product, 5-HTP, is converted to 5-HT
by aromatic acid decarboxylase (AADC). 5-HT is primarily degraded by the
mitochondrial bound protein Monoamine Oxidase A (MAOA), leading to the
generation of the metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Importantly,
serotonin is also a substrate for melatonin synthesis. 5-HT is released from
the axonal terminals of serotoninergic neurons and acts on 14 distinct receptor
subtypes that are classified into 7 different families: 5-HT1 (1A, 1B, 1D, 1E,
1F), 5-HT2 (2A, 2B, and 2C), 5-HT3, 5-HT4, 5- HT5 (5A, 5B), 5-HT6, and 5-HT7.
Among all these receptors, only 5-HT3 receptor is a pentameric ligand-gated ion
channel composed of several subunits of which 5 different types have been
identified. All other 5-HT receptors are G-protein coupled receptors which
regulate the activity of the neurons expressing them. Released serotonin is
transported to the presynaptic neurons by serotonin transporter (SERT or
5-HTT), a type of monoamine transporter protein.
Serotonergic
neurons are located in the raphe nuclei. While the more caudal raphe nuclei
project to the Peripheral Nervous System (PNS), the neurons in the dorsal and
median raphe nuclei (DRN and MRN) primarily send their projections to forebrain
regions. 5-HT is critically involved in the development of many cortices, such
as somatosensory cortex and barrel cortex. In adult brain, 5-HT neurons project
to majority of cortical areas, including the entorhinal and cingulate cortices.
However, of all cortical regions, the frontal lobe contains the highest density
of serotonergic terminals and 5-HT receptors. These studies indicate that 5-HT
regulates cognitive and emotional functions that rely on frontal cortical
activity.(Read more)
Efonidipine hydrochloride ethanolate (NZ-105), (±)-2-
[Benzyl(phenyl)amino]ethyl-1,4-dihydro-2,6-dimethyl-5-(5,5-dimethy
-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitorophen-yl)-3- pyridine carboxylate
hydrochloride ethanol, is a dihydropyridine calcium antagonist with aphosphonate backbone and that was discovered at Nissan Chemical Industries, Ltd. This active drug
ingredient was initially studied for development as a hydrochloride salt
without ethanol, obtained through the addition of hydrochloric acid to
efonidipine acetone solution. It showed an excellent antihypertensive effect in
patients with various kinds of hypertension (essential, severe, renal).
Efonidipine has slow onset and long duration of action.
It is well known that many 1,4-dihydropyridine derivatives are subject
to the first-pass effect, and that the primary metabolismstep of most derivatives
involves oxidation of the dihydropyridine ring to the corresponding pyridine
analogue. However, it has been suggested that efonidipine is less likely to be
subject to the first-pass effect than other dihydropyridine derivatives and
that its dihydropyridine ring is oxidized mainly after metabolism of the side
chain. Additionally, efonidipine has distinct properties when compared with
other calcium channel blockers. The studies indicated that efonidipine therapy
simultaneously improves blood pressure, endothelial function, and metabolic
parameters without substantially altering insulin sensitivity in non-diabetic patients
with hypertension.(Read more)
Epigenetic alterations play
important roles in a wide variety of physiological and pathological events. As
one of the most important epigenetic regulators, Histone Deacetylases (HDACs)
are able to deacetylate lysine residues on histone and non-histone proteins,regulating chromatin structure, gene expression and protein function. Eighteen
human HDACs have been identified and grouped into 4 classes based on their
homology to respective yeast orthologous. The human sirtuins family, homologs of
the yeast silent information regulator 2(Sir2), belongs to class III HDACs.
They are NAD+-dependent deacetylases and contain seven members (SIRT1-7) with
varied functions, structures, and localizations. Among them, SIRT1 is the most
extensively studied, primarily because of its regulation of diverse cellular
targets and functions as well as its therapeutic potential.
Human SIRT1 comprises 747 amino
acids divided into three main regions: the central core, possessing the
deacetylase domain, which consists of a large NAD+-binding subdomain with a
Rossmann fold and a smaller subdomain composed of a helical module and a Zn2+-
binding module, and the N- and C-terminal domains, containing regulatory
elements and binding domains for SIRT1 co-activators or repressors.(Read more)
Iron, as the most abundant
transition metal in the human brain, occurs with uneven distribution. Highest concentration
of iron can be observed in areas associated with motor function (Globus
pallidus, putamen, Substantia nigra) than in other areas of the human
brain. Therefore, the actual role of iron accumulation in brain pathobiology isan active area of investigation nowadays.It is evident that amount of iron in
brain gradually grows with age. Accumulation of iron in basal ganglia is
probably associated with neuronal death leading to Alzheimer disease, Parkinson
disease, epilepsy, Huntington disease, dementia with Lewy bodies, and multiple
sclerosis. It was reported that iron participates in redox reactions, and
catalyzes the formation of reactive oxygen species responsible for oxidative
stress and damaging processes.
Iron in the human brain can be
found mostly in the form of ferritin, hemosiderin (a product of ferritin
breakdown) and other biomineralized oxidohydroxides and oxides such as hematite,
magnetite, and maghemite. Ferritin, as an iron storage nonheme-protein with
diameter up to 12 nm, consist of inorganic core (6 nm) formed of ferrihydrite and
minor portion of magnetite and hematite that is enclosed by two types of
polypeptides. The role of the heavy (Ft-H) form polypeptide coat of ferritin is
to catalyze Fe(II) to Fe(III) ions whereas the light (Ft-L) polypeptide coat
promotes the formation of ferritin iron core.The amount of Ft-H and Ft-L
polypeptide coats changes during ageing and the magnetic properties of ferritin
can also alter.(Read More)
