In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

Background Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer’s disease (AD). We in vivo investigated if, when, and in which target regions [123I]FP-CIT-SPECT regional binding and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D), and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial correlation analysis. Results were deemed significant at p < 0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of [123I]FP-CIT binding in both AD-MCI and AD-D compared to controls. Binding reductions were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced [123I]FP-CIT binding, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient ≤ 0.25) and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local- and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

Design, Synthesis, and Utility of Defined Molecular Scaffolds

A growing theme in chemistry is the joining of multiple organic molecular building blocks to create functional molecules. Diverse derivatizable structures—here termed “scaffolds” comprised of “hubs”—provide the foundation for systematic covalent organization of a rich variety of building blocks. This review encompasses 30 tri- or tetra-armed molecular hubs (e.g., triazine, lysine, arenes, dyes) that are used directly or in combination to give linear, cyclic, or branched scaffolds. Each scaffold is categorized by graph theory into one of 31 trees to express the molecular connectivity and overall architecture. Rational chemistry with exacting numbers of derivatizable sites is emphasized. The incorporation of water-solubilization motifs, robust or self-immolative linkers, enzymatically cleavable groups and functional appendages affords immense (and often late-stage) diversification of the scaffolds. Altogether, 107 target molecules are reviewed along with 19 syntheses to illustrate the distinctive chemistries for creating and derivatizing scaffolds. The review covers the history of the field up through 2020, briefly touching on statistically derivatized carriers employed in immunology as counterpoints to the rationally assembled and derivatized scaffolds here, although most citations are from the past two decades. The scaffolds are used widely in fields ranging from pure chemistry to artificial photosynthesis and biomedical sciences.

In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

Background Preclinical and pathology evidence suggest an involvement of brain dopamine (DA) circuitry in Alzheimer’s Disease (AD). We in vivo investigated, if, when and in which target regions, DA signaling and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D) and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial-correlation analysis. Results were deemed significant at p<0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of dopamine transporter density in both AD-MCI and AD-D compared to controls. Dopaminergic deficits were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced dopaminergic transporter density, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient < 0.25), and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

Exploring the Protein Interactome Related to Hepatitis C Virus

Hepatitis C virus (HCV) stands as a health problem experienced across the globe leading to chronic or acute liver diseases such as cirrhosis, hepatocellular carcinoma and various others. It is a complex disease with extensive genetic heterogeneity with little known about the interactions of complex intra- and intercellular processes. The evolving tools in the application of network science to identify diseases have paved a way for the study of complex diseases at system level. This study focuses on identifying the significant proteins and the biological regulatory pathways involved in Hepatitis C virus and performing topological analysis of the PPIs derived by the proteins encoded by the susceptible genes in order to look for the molecular connectivity between these pathways.icant proteins and the biological regulatory pathways involved in Hepatitis C virus and performing topological analysis of the PPIs derived by the proteins encoded by the susceptible genes in order to look for the molecular connectivity between these pathways.

Addressing selectivity issues of aldose reductase 2 inhibitors for the management of diabetic complications

Aldose Reductase 2 (ALR2), the rate-limiting enzyme of the polyol pathway, plays an important role in detoxification of some toxic aldehydes. Under hyperglycemia, this enzyme overactivates and causes diabetic complications (DC). Therefore, ALR2 inhibition has been established as a potential approach to manage these complications. Several ALR2 inhibitors have been reported, but none of them could reach US FDA approval. One of the main reasons is their poor selectivity over ALR1, which leads to the toxicity. The current review underlines the molecular connectivity of ALR2 with DC and comparative analysis of the catalytic domains of ALR2 and ALR1, to better understand the selectivity issues. This report also discusses the key features required for ALR2 inhibition and to limit toxicity due to off-target activity.

Synthesis, Biological Evaluation, QSAR, Molecular Docking and ADMET Studies of N-aryl/N,N-dimethyl Substituted Sulphonamide Derivatives

<P>Background: Rapid evolution of drug resistance and side effects of currently used drugs develop more efficacious and newer antimicrobial agents. Further, for the management of Type II Diabetes, &#945;-gulcosidase and α-amylase inhibitors play a very important role by inhibiting the postprandial hyperglycemia. </P><P> Objectives: The objective of this study was to synthesize N-aryl/N,N-dimethyl sulphonamides, investigate their antihyperglycemic and antimicrobial potential, develop QSAR model for identifying molecular descriptors and predict their binding modes and in silico ADMET properties. </P><P> Methods: Synthesized derivatives were subjected to in vitro studies for their antidiabetic activity against &#945;-glucosidase and &#945;-amylase enzymes and antimicrobial activity. Molecular docking studies were carried out to find out molecular binding interactions of the ligand molecules with their respective targets. QSAR studies were carried out to identify structural determinants responsible for antimicrobial activity. </P><P> Results: Antidiabetic study demonstrated the potent activity of two compounds 2 and 6 as &#945;- glucosidase and &#945;-amylase inhibitors, as well as compound 1 and 2, exhibited potent antimicrobial activity against all the tested microbes. All the compounds have more antifungal potential against Candida albicans. QSAR studies confirmed the role of molecular connectivity indices (valence first order and second order) in controlling the antimicrobial activity. Molecular docking studies supported the observed in vitro biological activities of the synthesized compounds. </P><P> Conclusion: The compounds with 2,3-dimethyl substitution were found to be antidiabetic agents and molecules having bromo and 2,3-dimethyl substituents on phenyl ring have established themselves as potent antimicrobial agents. The role of valence first and 2nd order molecular connectivity indices as molecular properties were identified for antimicrobial activity and various electrostatic, hydrogen bonding and hydrophobic interactions were found to be prominent in the binding of molecules at the target site.</P>