A comprehensive review of biomarkers in psoriasis.

Psoriasis is a common, chronic skin disorder, the pathogenesis of which is incompletely understood. Results from various clinical and experimental studies indicate that psoriasis is a complex, multifactorial disease with a genetic predisposition. Factors such as climate, physical trauma, drug, stress and infections (Streptococcus, human immunodeficiency virus) are known to trigger psoriasis. The success of treatment of psoriasis with T-cell depletion and antitumour necrosis factor (TNF)-alpha treatment is explained by the involvement of T cells and TNF- alpha in the pathogenesis of psoriasis. The biochemical basis for the pathogenesis of psoriasis can be attributed to both overexpression and underexpression of certain proteins in psoriatic lesions. The anomalies in protein expression can be classified as abnormal keratinocyte differentiation, keratinocyte hyperproliferation and inflammation. Oxidative stress (OS) and increased free-radical generation have been linked to skin inflammation in psoriasis. The review presents evidence for various markers of psoriasis that can be targeted for effective treatment, including biomarkers of inflammation, keratinocyte hyperproliferation and abnormal differentiation, and stress.

Garlic extract exhibits antiamyloidogenic activity on amyloid-beta fibrillogenesis: relevance to Alzheimer's disease.

Alzheimer's disease is characterized pathologically by the deposition of amyloid plaques. Fibrillar Abeta is the principal component of amyloid plaques in the brain of AD patients. The prevention of Abeta aggregation or dissolution of fibrillar Abeta has clinical significance. The present communication examined in vitro the antiamyloidogenic properties of garlic extract. The effects of aqueous garlic extract (both fresh and boiled) on Abeta aggregation and defibrillation were studied by thioflavin-T based fluorescence assay, transmission electron microscopy and SDS-polyacrylamide gel electrophoresis. The aqueous fresh garlic extract not only inhibited Abeta fibril formation in a concentration and time dependent manner but was also able to defibrillate Abeta preformed fibrils. The maximum defibrillization was observed after 2-3 days of incubation. The boiled aqueous garlic extract also retained its antiamyloidogenic activity. This indicated that antiamyloidogenic activity of garlic extract is non-enzymatic, i.e. proteases present in garlic did not degrade Abeta in solution. However, the fibril degrading ability of boiled garlic extract was significantly lost. The findings suggest that consumption of garlic may lead to inhibition of Abeta aggregation in human brain.

Role of DNA dynamics in Alzheimer's disease.

DNA is a dynamic molecule, the conformation of which plays a major role in biological function. The non-B-form of DNA conformations are reported in the patho-physiology of diseases like Fragile X-syndrome, Huntington's chorea, Alzheimer's and others. Recently, our laboratory discovered the presence of Z-DNA in the hippocampal region of severely affected Alzheimer's disease (AD) brain samples. Alternate purine-pyrimidine bases, potential sequences adopting Z-DNA, are present in the promoter regions of AD specific genes like amyloid precursor protein (APP), Presenilin and ApoE. Thus, Z-DNA might be involved in the expression of these pathologically important genes. In the present review, we have focused on the possible mechanisms/hypothetical models of Z-DNA transition and its implications in AD. We propose that Z-DNA is formed in the promoter region of the APP, and Presenilin genes and Z-DNA may absorb the negative supercoils at that region. This decreases the supercoil density, altering the domain's native supercoiling state and facilitates the binding of effectors, which positively regulate gene expression of AD-related genes like APP and Presenilin. Further, it is presumed that Z-DNA may be involved in the down regulation of genes involved in Abeta clearance, anti-oxidant and defense mechanisms in AD. The proposed working model is novel and reveals possible triggering factors or precursors, which regulate the modulation of the supercoiling level of DNA involving putative Z-DNA forming sequences and regulatory proteins binding to DNA in AD.

Molecular understanding of copper and iron interaction with alpha-synuclein by fluorescence analysis.

Alpha-synuclein aggregation is a hallmark pathological feature in Parkinson's disease (PD). The conversion of alpha-synuclein from a soluble monomer to an insoluble fibril may underlie the neurodegeneration associated with PD. Redox-active metal ions such as iron (Fe) and copper (Cu) are known to enhance alpha-synuclein fibrillogenesis. In the present investigation, we analyzed the binding efficiency of Cu and Fe to alpha-synuclein by fluorescence studies. It is interesting to note that Cu and Fe showed differential binding pattern toward alpha-synuclein (wild type and A30P, A53T, and E46K mutant forms) as revealed by intrinsic tyrosine fluorescence, thioflavin-T fluorescence, 1-anilino-8-naphthalenesulfonate-binding studies, and scatchard plot analysis. The experimental data might prove useful in understanding the hierarchy of metals binding to alpha-synuclein and its role in neurodegeneration.

Studies on the role of amino acid stereospecificity in amyloid beta aggregation.

Amyloid beta (Abeta) deposition and neurodegeneration are the two related events in the pathogenesis of Alzheimer's disease. Several factors modulate the conformation and physical properties of Abeta, which in turn affects its biological functions. Among these, age-dependent changes in the stereospecificity of the amino acids comprising Abeta is one such factors. In the present study, we investigated the aggregation property of Abeta as a function of the stereospecificity of amino acids comprising the peptide. We carried out our study by comparing the physical properties of Abeta(1-40) all-L and Abeta(1-40) all-D enantiomers using various biophysical techniques. These results indicated that the aggregation and folding parameters of Abeta are stereospecific and the aggregation property strongly depends upon the amino acid sequence and their stereospecificity. This may possibly help to understand the stereospecific role of amino acids comprising Abeta in its aggregation and its relevance to neurodegeneration.

Assessment of serum macro and trace element homeostasis and the complexity of inter-element relations in bipolar mood disorders.

BACKGROUND: Bipolar disorders are complex neuropsychiatric in nature and are clinically classified as Type I, Type II, and Type V. The etiological factors include environmental-genetic inter-relations. Trace metals play a significant role in neurological disorders. There is very limited information on the role of macro and trace elements in bipolar disorders. METHODS: Trace elements namely Na, K, S, Ca, Mg, P, Cu, Fe, Zn, Mn and Al were analyzed in serum samples of 3 bipolar types: bipolar I, bipolar II and bipolar V with a control group using inductively coupled plasma-atomic emission spectrometry (ICP-AES). The patients were assessed as per the standard diagnostic criteria and classified into the bipolar type I, II hypomanic, II depressives and V. RESULTS: In bipolar I (mania), Na, K, P, Cu, Al and Mn were increased significantly (p<0.001). In bipolar II hypomania, Na, S, Al and Mn were increased significantly (p<0.02), while in bipolar II depression, Na, K, Cu and Al were increased (p<0.001). In bipolar V, Na, Mg, P, Cu, and Al were increased significantly (p<0.002), though S (p<0.00001), Fe (p<0.002) and Zn (p<0.004) were decreased in all 3 bipolar groups. CONCLUSIONS: There is a disturbance in the charge distribution and element-element interdependency in bipolar serum when compared to controls. These results suggest that there is a definite imbalance in macro and trace element homeostasis as evidenced by element inter-relationships in serum samples of bipolar groups when compared to controls.

Molecular toxicity of aluminium in relation to neurodegeneration.

Exposure to high levels of aluminium (Al) leads to neurofibrillary degeneration and that Al concentration is increased in degenerating neurons in Alzheimer's disease (AD). Nevertheless, the role of Al in AD remains controversial and there is little proof directly interlinking Al to AD. The major problem in understanding Al toxicity is the complex Al speciation chemistry in biological systems. A new dimension is provided to show that Al-maltolate treated aged rabbits can be used as a suitable animal model for understanding the pathology in AD. The intracisternal injection of Al-maltolate into aged New Zealand white rabbits results in pathology that mimics several of the neuropathological, biochemical and behavioural changes as observed in AD. The neurodegenerative effects include the formation of intraneuronal neurofilamentous aggregates that are tau positive, oxidative stress and apoptosis. The present review discusses the role of Al and use of Al-treated aged rabbit as a suitable animal model to understand AD pathogenesis.

Amyloid beta and neuromelanin--toxic or protective molecules? The cellular context makes the difference.

Alzheimer's disease (AD) and Parkinson's disease (PD) share several pathological mechanisms. The parallels between amyloid beta (Abeta) in AD and alpha-synuclein in PD have been discussed in several reports. However, studies of the last few years show that Abeta also shares several important characteristics with neuromelanin (NM), whose role in PD is emerging. First, both molecules accumulate with aging, the greatest risk factor for AD and PD. Second, in spite of their different structures, Abeta and NM have similar characteristics that could also lead to neuroprotection. Metals are required to catalyze their formation and they can bind large amounts of these metals, generating stable complexes and thus playing a protective role against metal toxicity. Moreover, they may be able to remove toxic species such as oligopeptides and excess cytosolic dopamine. Third, both Abeta and NM have been implicated in parallel aspects of the neuronal death that underlies AD and PD, respectively. For example, both molecules can activate microglia, inducing release of toxic factors such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO). A careful analysis of these parallel effects of Abeta and NM, including their seemingly paradoxical ability to participate in both cell death and protection, may lead to an improved understanding of the roles of these molecules in neurodegeneration and also provide insights into possible parallels in the pathological mechanisms underlying AD and PD.

Mathematical approach to understand the kinetics of alpha-synuclein aggregation: relevance to Parkinson's disease.

alpha-Synuclein aggregation is a hallmark pathological feature in Parkinson's disease (PD). The conversion of alpha-synuclein from soluble monomer to insoluble aggregates through the toxic oligomeric intermediates underlie the neurodegeneration associated with PD. Redox active metal ions such as iron (Fe) and copper (Cu) are known to enhance alpha-synuclein fibrillogenesis. In the present study, we have implemented mathematical approach to monitor the kinetics of aggregation of alpha-synuclein nucleation and elongation constants based on fluorescence studies. In this pretext, we have implemented mathematical simulations like self and absolute analysis. The mathematical model discussed in this paper is the first of its kind and might prove useful for predicting the drug intervention time to prevent alpha-synuclein aggregation and has future clinical application.

Copper- and iron-induced differential fibril formation in alpha-synuclein: TEM study.

alpha-Synuclein filaments are the central component of intracytoplasmic inclusion bodies characteristic of Parkinson's disease (PD) and related disorders. Metals are the significant etiological factors in PD, and their interaction with alpha-synuclein affect dramatically the kinetics of fibrillation. Currently, we have investigated the influence of Cu(II) and Fe(III) on alpha-synuclein fibril formation. Cu(II) and Fe(III) selectively and differentially induced the formation of discrete alpha-synuclein fibrillar species. Transmission electron microscopy was used to monitor the aggregation state of alpha-synuclein (wild-type, A30P, A53T, and E46K) after 60h with stirring at 37 degrees C in the presence and absence of metal ions. Cu(II) has induced thin long network-like fibrils with the wild-type of alpha-synuclein, while the mutant, showed amorphous aggregates with no fibrillar forms. Fe(III) induced short and thick fibrils with both wild and mutant forms and were similar to alpha-synuclein fibrils incubated without metal ion. The present study illustrates the metal-specific fibril morphology, and has relevance in understanding the role of metals in neurodegeneration.

Anti-amyloidogenic activity of S-allyl-L-cysteine and its activity to destabilize Alzheimer's beta-amyloid fibrils in vitro.

Alzheimer's disease involves Abeta accumulation, oxidative damage and inflammation and there is currently no clinically accepted treatment to stop its progression. Its risk is known to reduce with increased consumption of antioxidant and anti-inflammatory agents. Fibrillar aggregates of Abeta are major constituents of the senile plaques found in the brains of AD patients and have been related to AD neurotoxicity. It is reported that SAC (S-allyl-l-cysteine), a water-soluble organosulfur component present in garlic is known to prevent cognitive decline by protecting neurons from Abeta induced neuronal apoptosis. Hence, we investigated the effects of SAC on Abeta aggregation by employing Thioflavin-T, transmission electron microscopy, SDS-PAGE, size exclusion-HPLC. Under aggregating conditions in vitro, SAC dose-dependently inhibited Abeta fibrillation and also destabilized preformed Abeta fibrils. Further, Circular dichroism and fluorescence quenching studies supported the binding ability of SAC to Abeta and inducing a partially folded conformation in Abeta. The 3D structure of Abeta-SAC complex was also predicted employing automated docking studies.

A new insight on Al-maltolate-treated aged rabbit as Alzheimer's animal model.

Lack of an adequate animal model for Alzheimer's disease (AD) has limited an understanding of the pathogenesis of the disease and the development of therapeutic agents targeting key pathophysiological processes. There are undoubtedly few satisfactory animal models for exploring therapies targeting at amyloid beta (Abeta) secretion, deposition, aggregation, and probably the inflammatory response. However, an understanding of the complex events--tau, Abeta, oxidative stress, redox active iron, etc.--involved in the neuronal cell loss is still unclear due to the lack of a suitable animal model system. The use of neurotoxic agents particularly aluminum-organic complexes, especially Al-maltolate, expands the scope of AD research by providing new animal models exhibiting neurodegenerative processes relevant to AD neuropathology. Examination of different species of aged animals including the rapidly advancing transgenic mouse models revealed very limited AD-like pathology. Most other animal models have single event expression such as extracellular Abeta deposition, intraneuronal neurofilamentous aggregation of proteins akin to neurofibrillary tangles, oxidative stress or apoptosis. To date, there are no paradigms of any animal in which all the features of AD were evident. However, the intravenous injection of Al-maltolate into aged New zealand white rabbits results in conditions which mimics a number of neuropathological, biochemical and behavioral changes observed in AD. Such neurodegenerative effects include the formation of intraneuronal neurofilamentous aggregates that are tau positive, immunopositivity of Abeta, presence of redox active iron, oxidative stress and apoptosis, adds credence to the value of this animal model system. The use of this animal model should not be confused with the ongoing controversy regarding the possible role of Al in the neuropathogenesis, a debate which by no means has been concluded. Above all this animal model involving neuropathology induced by Al-maltolate provides a new information in understanding the mechanism of neurodegeneration.

Copper interactions with DNA of chromatin and its role in neurodegenerative disorders.

In this study, we have demonstrated the conformational changes to DNA induced by abnormal interactions of copper using circular dichroism, in combination with UV-absorbance and fluorescence spectroscopy. Results confirm that binding of copper to bases of DNA in chromatin is concentration dependent. Binding efficiency of Cu2+ ions to DNA is increased in proportion to the degree of unwinding of the double helix induced by denaturation. Altered B-DNA conformation will alter the integrity of DNA which may affect the normal process of DNA replication and transcription. Copper induced DNA damage in the brain may cause neurotoxicity and the neuronal cell death and is implicated in Alzheimer's disease and other neurological disorders.

Cognitive aging and early diagnosis challenges in Alzheimer's disease.

Despite the profound burden of Alzheimer's disease (AD) on public health, research to understand its underlying pathology has not yet produced new therapeutic approaches to improve symptoms or halt disease progression. AD is characterized by early cognitive deficits, particularly in short-term memory, followed by a gradual decline in other cognitive functions. Functional imaging studies indicate that hippocampal and medial temporal lobe cortices are the sites of early pathology underlying the initial memory impairments. Behaviors that rely on hippocampal integrity have been the focus of extensive research using animal models and represent useful functional endpoints in pre-clinical AD research. In this review, we argue that relevant information can be derived from studying normal, aging animals performing hippocampal-sensitive tasks. Because age is the greatest risk factor for developing clinical AD, the aspects of cognitive decline occurring in normal, aging animals that resemble those seen in aging humans are reliable endpoints that can be applied to improving human therapies. Ultimately, pre-clinical studies that employ tasks sensitive to hippocampal function can be applied toward novel hypotheses in AD intervention and could provide important insights for developing early detection devices for AD patients.

Aß(42) induced MRI changes in aged rabbit brain resembles AD brain.

Alzheimer's disease is the most common form of dementia and is structurally characterized by brain atrophy and loss of brain volume. Aß is one of the widely accepted causative factors of AD. Aß deposition is positively correlated with brain atrophy in AD. In the present study, structural brain imaging techniques such as Magnetic Resonance Imaging (MRI) were used to measure neuroanatomical alterations in Alzheimer's disease brain. MRI is a non-invasive method to study brain structure. The objective of the present study was to elucidate the role of Aß on brain structure in the aged rabbit brain. Among 20 aged rabbits, one batch (n=10) rabbits was injected chronically with Aß(1-42) and another batch (n=10) with saline. The MRI was conducted before Aß(1-42)/saline injection and after 45 days of Aß(1-42)/saline injection. All the aged rabbits underwent MRI analysis and were euthanized after 45 days. The MRI results showed a significant reduction in thickness of frontal lobe, hippocampus, midbrain, temporal lobe and increases in the lateral ventricle volume. We also conducted an MRI study on AD (n=10) and normal (n=10) cases and analyzed for the thicknesses of frontal lobe, hippocampus, midbrain, temporal lobe and lateral ventricle lobe. We found significant reductions in thickness of the frontal lobe and the hippocampus. However, no significant reduction in the thickness of midbrain, temporal lobe or increase in the lateral ventricle volume was observed compared to normal. Correlations in brain atrophy changes between rabbit brain and human AD brain were found for frontal lobe and hippocampal regions. In contrast, other regions such as midbrain, temporal lobe, and lateral ventricles were not correlated with rabbit brain atrophy changes in the corresponding regions. The relevance of these changes in AD is discussed.

Anti-amyloidogenic property of leaf aqueous extract of Caesalpinia crista.

Amyloid beta (Abeta) is the major etiological factor implicated in Alzheimer's disease (AD). Abeta(42) self-assembles to form oligomers and fibrils via multiple aggregation process. The recent studies aimed to decrease Abeta levels or prevention of Abeta aggregation which are the major targets for therapeutic intervention. Natural products as alternatives for AD drug discovery are a current trend. We evidenced that Caesalpinia crista leaf aqueous extract has anti-amyloidogenic potential. The studies on pharmacological properties of C. crista are very limited. Our study focused on ability of C. crista leaf aqueous extract on the prevention of (i) the formation of oligomers and aggregates from monomers (Phase I: Abeta(42)+extract co-incubation); (ii) the formation of fibrils from oligomers (Phase II: extract added after oligomers formation); and (iii) dis-aggregation of pre-formed fibrils (Phase III: aqueous extract added to matured fibrils and incubated for 9 days). The aggregation kinetics was monitored using thioflavin-T assay and transmission electron microscopy (TEM). The results showed that C. crista aqueous extract could able to inhibit the Abeta(42) aggregation from monomers and oligomers and also able to dis-aggregate the pre-formed fibrils. The study provides an insight on finding new natural products for AD therapeutics.

Molecular biology research in neuropsychiatry: India's contribution.

Neuropsychiatric disorders represent the second largest cause of morbidity worldwide. These disorders have complex etiology and patho-physiology. The major lacunae in the biology of the psychiatric disorders include genomics, biomarkers and drug discovery, for the early detection of the disease, and have great application in the clinical management of disease. Indian psychiatrists and scientists played a significant role in filling the gaps. The present annotation provides in depth information related to research contributions on the molecular biology research in neuropsychiatric disorders in India. There is a great need for further research in this direction as to understand the genetic association of the neuropsychiatric disorders; molecular biology has a tremendous role to play. The alterations in gene expression are implicated in the pathogenesis of several neuropsychiatric disorders, including drug addiction and depression. The development of transgenic neuropsychiatric animal models is of great thrust areas. No studies from India in this direction. Biomarkers in neuropsychiatric disorders are of great help to the clinicians for the early diagnosis of the disorders. The studies related to gene-environment interactions, DNA instability, oxidative stress are less studied in neuropsychiatric disorders and making efforts in this direction will lead to pioneers in these areas of research in India. In conclusion, we provided an insight for future research direction in molecular understanding of neuropsychiatry disorders.

Evidence of altered DNA integrity in the brain regions of suicidal victims of Bipolar Depression.

Deoxyribonucleic acid (DNA) integrity plays a significant role in cell function. There are limited studies with regard to the role of DNA damage in bipolar affective disorder (BP). In the present study, we have assessed DNA integrity, conformation, and stability in the brain region of bipolar depression (BD) patients (n=10) compared to age-matched controls (n=8). Genomic DNA was isolated from 10 postmortem BD patients' brain regions (frontal cortex, Pons, medulla, thalamus, cerebellum, hypothalamus, Parietal, temporal, occipital lobe, and hippocampus) and from the age-matched control subjects. DNA from the frontal cortex, pons, medulla, and thalamus showed significantly higher number of strand breaks in BD (P<0.01) compared to the age-matched controls. However, DNA from the hippocampus region was intact and did not show any strand breaks. The stability studies also indicated that the melting temperature and ethidium bromide binding pattern were altered in the DNA of BD patients' brain regions, except in the hippocampus. The conformation studies showed B-A or secondary B-DNA conformation (instead of the normal B-DNA) in BD patients' brain regions, with the exception of the hippocampus. The levels of redox metals such as Copper (Cu) and Iron (Fe) were significantly elevated in the brain regions of the sufferers of BD, while the Zinc (Zn) level was decreased. In the hippocampus, there was no change in the Fe or Cu levels, whereas, the Zn level was elevated. There was a clear correlation between Cu and Fe levels versus strand breaks in the brain regions of the BD. To date, as far as we are aware, this is a new comprehensive database on stability and conformations of DNA in different brain regions of patients affected with BD. The biological significance of these findings is discussed here.

Study on the levels of trace elements in mild and severe psoriasis.

BACKGROUND: Psoriasis is a chronic, recurrent skin disorder characterized histologically by cutaneous inflammation, increased epidermal proliferation, hyperkeratosis, angiogenesis, abnormal keratinization, shortened maturation time and parakeratosis. Data on the involvement of trace elements in the pathogenesis of psoriasis is limited. METHODS: The elements namely Na, K, Ca, P, S, Mg, Cu, Zn, and Fe were analyzed in the serum samples of mild and severe psoriasis patients with a control group using inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Patients were assessed as per standard clinical diagnostic criteria and classified into mild and severe psoriasis groups using Psoriasis Area Severity Index (PASI) score. RESULTS: In mild psoriasis, the levels of K, P, Cu, and Mg were increased significantly (p<0.001), while in severe psoriasis P, Mg, and Cu were increased significantly (p<0.001). The S and Fe concentrations were decreased significantly (p<0.001) in both mild and severe psoriasis types when compared to control. CONCLUSIONS: There is a disturbance in the under-study element contents and also element-element interdependency in psoriasis serum when compared to controls.

Thermodynamics imprinting reveals differential binding of metals to alpha-synuclein: relevance to Parkinson's disease.

The aggregation of alpha-synuclein is a hallmark feature of Parkinson's disease (PD) and other synucleinopathies. Metals are the significant etiological factors in PD, and their interaction with alpha-synuclein affect dramatically the kinetics of fibrillation in vitro and are proposed to play an important and potential neurodegenerative role in vivo. In the present study, we investigated the stoichiometry of binding of copper [Cu (II)] and iron [Fe (III)] with alpha-synuclein (wild recombinant type and A30P, A53T, E46K mutant forms) using isothermal titration calorimetry (ITC). alpha-Synuclein monomer (wild and mutant forms) titrated by Cu (II), showed two binding sites, with an apparent K(B) of 10(5)M and 10(4)M, respectively. But, alpha-synuclein (wild type and mutant forms) titrated with Fe (III) revealed a K(B) of 10(5)M with single binding site. The present investigation uncovers the detailed binding propensities between metals and alpha-synuclein and has biological implications in PD.