Abnormal Mitochondrial Dynamics—A Novel Therapeutic Target for Alzheimer's Disease?

Mitochondria are dynamic organelles that undergo continuous fission and fusion, which could affect all aspects of mitochondrial function. Mitochondrial dysfunction has been well documented in Alzheimer’s disease (AD). In the past few years, emerging evidence indicates that an imbalance of mitochondrial dynamics is involved in the pathogenesis of AD. In this review, we discuss in detail the abnormal mitochondrial dynamics in AD and how such abnormal dynamics may impact mitochondrial and neuronal function and contribute to the course of disease. Based on this discussion, we propose that mitochondrial dynamics could be a potential therapeutic target for AD.     

β-Arrestins as Potential Therapeutic Targets for Alzheimer’s Disease

β-arrestins represent a small family of G protein-coupled receptors (GPCRs) regulators, which provide modulating effects by facilitating desensitization and internalization of GPCRs as well as initiating their own signalings. Recent reports have demonstrated that β-arrestins levels were correlated with amyloid-β peptide (Aβ) pathology in brains of Alzheimer’s disease (AD) patients and animal models. β-arrestins could enhance the activity of γ-secretase via interacting with anterior pharynx defective 1 subunit, which increased Aβ production and contributed to the pathogenesis of AD. In addition, Aβ-induced internalization of β2-adrenergic receptor internalization and loss of dendritic spine in neurons were proven to be mediated by β-arrestins, further establishing their pathogenic role in AD. More importantly, deletion of β-arrestins markedly attenuated AD pathology, without causing any gross abnormality. Here, we review the evidence about the roles of β-arrestins in the progression of AD. In addition, the established and postulated mechanisms by which β-arrestins mediated in AD pathogenesis are also discussed. Based on the role of β-arrestins in AD pathogenesis, genetically or pharmacologically targeting β-arrestins might provide new opportunities for AD treatment.     

Synthesis of 1′-Deoxypsicofuranosyl-deoxynucleosides as Potential Anti-HIV Agents

Abstract

Various routes to the targets 1, 2, 3, 1-deoxy-psicofuranosyl nucleoside analogues related to anti-HIV agents, are reported. Two routes afforded their 6′-benzylated derivatives 9, 10 and 15. Only the epoxide 12 and deoxynucleosides 19 and 22 were able to be deprotected leading in the first case to 16 and its ring opening derivative 17 and in the second case to 20 and to the target 3.     

Orotidine Monophosphate Decarboxylase——A Fascinating Workhorse Enzyme with Therapeutic Potential

Orotidine 50-monophosphate decarboxylase(ODCase) is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 50-monophosphate(OMP) to uridine 50-monophosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved Dx Kxx Dx motif is present in all the groups,depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodouridine, a potential antimalarial agent.     

Synthesis of 3′-Trifluoromethyl Nucleosides as Potential Antiviral Agents

Abstract

1,2-Di-O-acetyl-3-deoxy-3-trifluoromethyl-5-O-benzoyl-β-D-riboruranose was synthesized from the precursor keto sugar by the use of Ruppert's reagent (CF₃SiMe₃) as the source of a nucleophilic trifluoromethyl group. Coupling of this trifluoromethyl sugar with nucleobases and elaboration gave novel deoxy and dideoxynucleosides. A single crystal X-ray analysis confirmed the structure and stereochemistry. The deoxynucleosides were converted through an elimination reaction to their dideoxydidehydro derivatives.     

Amyloid-β Peptide-specific DARPins as a Novel Class of Potential Therapeutics for Alzheimer Disease

Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Aβ-specific DARPins. We further showed their ability to delay Aβ aggregation and prevent Aβ-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Aβ-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble Aβ levels. These findings demonstrate the therapeutic potential of Aβ-specific DARPins for the treatment of Alzheimer disease.     

New Ionic Conjugates Based on α-Tocopheryl Succinate as Potential Cytotoxic Agents

Five new ionic conjugates based on α-tocopheryl succinate were synthesized, including amino- TEMPO, cytisine, convolvin, amantadine, and rimantadine as functional groups. Using bacterial test systems, the safety of the compounds obtained was shown, and antioxidant properties were studied. Investigation of the cytotoxic properties of synthesized conjugates with a chromane skeleton revealed their selectivity to the MCF7 breast cancer line, the effect was most pronounced for derivatives with amino-TEMPO and rimantadine fragments.     

Type I Interferon: Potential Therapeutic Target for Psoriasis?

Background

Psoriasis is an immune-mediated disease characterized by aberrant epidermal differentiation, surface scale formation, and marked cutaneous inflammation. To better understand the pathogenesis of this disease and identify potential mediators, we used whole genome array analysis to profile paired lesional and nonlesional psoriatic skin and skin from healthy donors.

Methodology/Principal Findings

We observed robust overexpression of type I interferon (IFN)–inducible genes and genomic signatures that indicate T cell and dendritic cell infiltration in lesional skin. Up-regulation of mRNAs for IFN-α subtypes was observed in lesional skin compared with nonlesional skin. Enrichment of mature dendritic cells and 2 type I IFN–inducible proteins, STAT1 and ISG15, were observed in the majority of lesional skin biopsies. Concordant overexpression of IFN-γ and TNF-α–inducible gene signatures occurred at the same disease sites.

Conclusions/Significance

Up-regulation of TNF-α and elevation of the TNF-α–inducible gene signature in lesional skin underscore the importance of this cytokine in psoriasis; these data describe a molecular basis for the therapeutic activity of anti–TNF-α agents. Furthermore, these findings implicate type I IFNs in the pathogenesis of psoriasis. Consistent and significant up-regulation of type I IFNs and their associated gene signatures in psoriatic skin suggest that type I IFNs may be potential therapeutic targets in psoriasis treatment.     

Phytoremediation—A Novel and Promising Approach for Environmental Clean-up

ABSTRACT

Phytoremediation is an eco friendly approach for remediation of contaminated soil and water using plants. Phytoremediation is comprised of two components, one by the root colonizing microbes and the other by plants themselves, which degrade the toxic compounds to further non-toxic metabolites. Various compounds, viz. organic compounds, xenobiotics, pesticides and heavy metals, are among the contaminants that can be effectively remediated by plants. Plant cell cultures, hairy roots and algae have been studied for their ability to degrade a number of contaminants. They exhibit various enzymatic activities for degradation of xenobiotics, viz. dehalogenation, denitrification leading to breakdown of complex compounds to simple and non-toxic products. Plants and algae also have the ability to hyper accumulate various heavy metals by the action of phytochelatins and metallothioneins forming complexes with heavy metals and translocate them into vacuoles. Molecular cloning and expression of heavy metal accumulator genes and xenobiotic degrading enzyme coding genes resulted in enhanced remediation rates, which will be helpful in making the process for large-scale application to remediate vast areas of contaminated soils. A few companies worldwide are also working on this aspect of bioremediation, mainly by transgenic plants to replace expensive physical or chemical remediation techniques. Selection and testing multiple hyperaccumulator plants, protein engineering of phytochelatin and membrane transporter genes and their expression would enhance the rate of phytoremediation, making this process a successful one for bioremediation of environmental contamination. Recent years have seen major investments in the R&D, which have also resulted in competition of filing patents by several companies for economic gains. The details of science & technology related to phytoremediation have been discussed with a focus on future trends and prospects of global relevance.     

Are Macrophages in Tumors Good Targets for Novel Therapeutic Approaches?

The development of cancer has been an extensively researched topic over the past few decades. Although great strides have been made in cancer prevention, diagnosis, and treatment, there is still much to be learned about cancer’s micro-environmental mechanisms that contribute to cancer formation and aggressiveness. Macrophages, lymphocytes which originate from monocytes, are involved in the inflammatory response and often dispersed to areas of infection to fight harmful antigens and mutated cells in tissues. Macrophages have a plethora of roles including tissue development and repair, immune system functions, and inflammation. We discuss various pathways by which macrophages get activated, various approaches that can regulate the function of macrophages, and how these approaches can be helpful in developing new cancer therapies.     

Synthesis of 3′-C-Substituted-2′,3′-Dideoxynucleosldes as Potential Antcaids Agents

Abstract

In this paper we report an efficient synthetic route to some novel 3′-C-substituted-2,3′-dideoxy-nucleosides. The critical 3′- C-C bond was constructed by an application of free radical methodology. This type of reaction was found to be stereoselective forming exclusively the 3′-“down” isomer. The stereo-chemical assignment at C-3′ was confirmed by both nmr nOe experiments and single crystal X-ray analysis.     

Synthesis and Biological Evaluation of Novel Steroidal 5α,8α-Endoperoxide Derivatives with Aromatic Hydrazone Side Chain as Potential Anticancer Agents

Russian Journal of Bioorganic Chemistry - Seven new steroidal 5α,8α-endoperoxide derivatives with C-17 aromatic hydrazone side chain were synthesized. Structures of the synthesized...     

Adducts of Mannose 6-Phosphate with 5-Iodo-2′-Deoxyuridine and 2-5A as Potential Antiviral Agents

Abstract

To examine the possibility that the mannose 6-phosphate receptor system might be capitalized upon to facilitate uptake of nucleotides or nucleotides into cell, adducts of mannose 6-phosphate with 5-iodo-2′-deoxyuridine 5′-monophosphate and with adenosine 5′-monophosphate, p5′A2′p5′A and p5′A2′p5′A2′p5′A were prepared and evaluated for their antiviral activities. The adducts with 2′,5′-oligoadenylates possessed no significant antiviral activity. The adduct with 5-iodo-2′-deoxyuridine 5′-monophosphate showed activity that could be fully explained by extracellular cleavage to free 5-iodo-2′-deoxyuridine.     

A Novel Class of 4′-Aza Analogues of 2′,3′-Dideoxynucleosides as Potential Anti-HIV Drugs

Abstract

The 1,3 dipolar cycloaddition approach represents the most valuable strategy for the preparation of isoxazolidine nucleosides. The latter posses more conformational degrees of freedom than the corresponding dideoxyribosides. Side reactions due to the presence of formaldehyde in the reaction media can be avoided by proper derivatization of the vinyl-nucleobase.     

Synthesis of 2′,3′-Dideoxy-2′-Fluoro-l-threo-Pentofuranosyl Nucleosides as Potential Antiviral Agents

Abstract

A series of 2′,3′-dideoxy-2′-fluoro-L-threo-pentofuranosyl nucleosides has been synthesized as potential antiviral agents. The synthesized compounds were evaluated against HIV-1, HBV, HSV-1, and HSV-2. Among the synthesized analogues, only the cytosine derivative showed moderate antiviral activity against HIV and HBV.