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Role of Vitamin D and Antioxidants in the Prevention and Treatment of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Shilia Jacob Kurian, Ruby Benson, Sonal Sekhar Miraj, Mahadev Rao
In AD patients, the major mechanism that continually leads to neuronal toxicity is β-amyloid fibrils oligomerization. Evidence shows that vitamin A supplementation is effective in decreasing the aggregation and oligomerization of β-amyloid 40 and β-amyloid 42 fibrils (Iwatsubo et al. 1994). Vitamin A and β-carotene are traditionally considered antioxidants and play a role in maintaining higher CNS functions in older subjects and inversely influences the development of neurodegenerative disorders (Takasaki et al. 2011; Bourdel-Marchasson 2001). Because this vitamin inhibits the formation of both β-amyloid oligomers and fibrils, these compounds can be considered as key molecules and used as adjuvant therapy for AD.
Dengue Fever: A Viral Hemorrhagic Fever of Global Concern
Published in Jagriti Narang, Manika Khanuja, Small Bite, Big Threat, 2020
Bennet Angel, Neelam Yadav, Jagriti Narang, Annette Angel, Vinod Joshi
The NS4 protein of dengue comprises two forms: NS4a and NS4b having MWs of 16 and 27 KDa, respectively. This protein is hydrophobic in nature (Chambers et al., 1989; Speight et al., 1988; Speight and Westaway, 1989). Cell curvature is changed due to this protein, and it also triggers autophagy (Miller et al., 2007). This protein is mainly responsible for viral replication, and it leads to oligomerization (Lee et al., 2015). If mutation occurs in NS4A, then the viral replication gets inhibited because NS4B is not able to form association with NS4A. The interaction of NS4A with NS4B is must for viral replication (Zou et al., 2015) and is also required as a cofactor along with NS5 protein.
Colon cancer: pathology and natural history
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
The APC gene has an open reading frame of 8538 base pairs (bp)14 and comprises 15 coding exons, with exon 15 alone containing 6571 bp, making it the largest known human exon. The gene encodes a 2843–residue protein with a molecular weight of 310 kDa14 and wide tissue expression, including stomach, liver, esophagus, kidney, brain and eye. In Figure 4 the principal regions of the APC protein with their functions are schematically reported. This protein, which has a cytoplasmic localization, can be subdivided into two major regions: the carboxy terminal (75%) and the amino terminal (25%), the latter of which contains proline-free blocks with heptad repeats of hydrophobic residues. This pattern is characteristic of α-helical coils and implies protein-protein interactions. In fact, the amino terminus is critical for homo-oligomerization (Figure 4). Most APC gene mutations result in the production of a protein that is truncated at some point beyond residue 171. Thus, the potential for continued oligomerization should generally be preserved in truncated proteins, permitting the formation of inactivating complexes, explaining the dominant negative effect of the mutant protein.
High concentration formulation developability approaches and considerations
Published in mAbs, 2023
Jonathan Zarzar, Tarik Khan, Maniraj Bhagawati, Benjamin Weiche, Jasmin Sydow-Andersen, Alavattam Sreedhara
Regardless of the study design, detailed characterization of the observed impurities/degradation products (prominently high molecular weight species and/or particles) is required. This endeavor can be challenging and requires the use of a specialized toolkit of analytical methods. Apart from the low-resolution biophysical methods used for investigation of protein oligomerization and complex formation, such as DLS or more time-consuming experimental techniques like analytical ultracentrifugation, the most established and representative method for assessment of species of different molecular weights in the biopharmaceutical industry is size exclusion chromatography (SEC). While SEC alone does not provide an accurate size of the observed species, coupling it to a multi-angle light scattering (MALS) detector enables determination of the molar mass and concentration, which are proportional to the light scattered by the particles.52 Despite the wide and validated applicability of the SEC method for release and stability monitoring, further investigation of aggregation phenomena may require orthogonal techniques to SEC to gain additional or more precise data that is typically not necessary for release and stability monitoring.
Focusing on oligomeric tau as a therapeutic target in Alzheimer’s disease and other tauopathies
Published in Expert Opinion on Therapeutic Targets, 2023
The most obvious strategy is to target tau directly, although proteins with significant unstructured domains can be challenging to drug [107]. For example, a therapeutic antibody may bind tau and create steric constraints that inhibit tau oligomerization. Alternatively, a peptide therapeutic might compete for binding to an intermolecular interface that is critical for tau protein-protein interaction. As a general rule, disrupting protein-protein interaction is more feasible with larger molecules, such as peptides and antibodies in comparison to small molecules, because of topological considerations [108,109]. To overcome this limitation, small molecules may be designed to recognize ‘hot spots’ necessary for tau oligomerization [109]. Also, a small molecule might bind to an allosteric site and induce a conformational change that interferes with oligomerization. In any case, the design of potent therapeutics should be facilitated by high-resolution structural data for pathogenic tau conformations, with drug development efforts focusing on endogenous tau conformations rather than on recombinant preparations given their structural and functional differences [57,90,91].
Oxyresveratrol exerts ATF4- and Grp78-mediated neuroprotection against endoplasmic reticulum stress in experimental Parkinson’s disease
Published in Nutritional Neuroscience, 2021
Anuri Shah, Jianfei Chao, Cristina Legido-Quigley, Raymond Chuen-Chung Chang
OXY reduced the high molecular weight (>90 kDa) soluble oligomeric species of A30P α-syn, but not A53 T. This can be attributed to the slower aggregation rate of A30P compared to A53 T [57,58]. RES and PINO, however, did not show such effects. Oligomerization is a rate-limiting step in protein misfolding [59]. Therefore, halting the process at this stage is another strategy to protect neurons from a build-up of ER stress. Whether OXY modulates the oligomeric species via direct interactions remains to be investigated. The A30P mutant also had significantly higher Grp78 expression and overexpression of α-syn compared to the WT. Since Grp78 is a chaperone, it is likely that it was upregulated to stabilize the formation of oligomers. OXY prevented the expression of Grp78 in the A30P mutant, thereby mitigating ER stress. However, OXY had no effect on A30P-α-syn overexpression. The toxic effects of α-syn overexpression have been demonstrated in primate [60] and mouse [61] models. There are also reports elucidating the upregulation of CHOP by overexpression of α-syn [62]. Therefore, it is also worthwhile to investigate the activation of CHOP and its subsequent effects in the A30P mutation.