Amyloid-induced neurodegeneration: A comprehensive review through aggregomics perception of proteins in health and pathology.

Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders. Prognostic amyloidosis is prominent in numerous degenerative infections such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS), etc. However, the molecular basis determining the intracellular or extracellular evidence of aggregates, playing a significant role as a causative factor in neurodegeneration is still unclear. Structural conversions and protein self-assembly resulting in the formation of amyloid oligomers and fibrils are important events in the pathophysiology of the disease. This comprehensive review sheds light on the evolving landscape of potential treatment modalities, highlighting the ongoing clinical trials and the potential socio-economic impact of novel therapeutic interventions in the realm of neurodegenerative diseases. Furthermore, many drugs are undergoing different levels of clinical trials that would certainly help in treating these disorders and will surely improve the socio-impact of human life.

Probing protein aggregation through spectroscopic insights and multimodal approaches: A comprehensive review for counteracting neurodegenerative disorders.

Aberrant accumulation of protein misfolding can cause aggregation and fibrillation and is one of the primary characteristic features of neurodegenerative diseases. Because they are disordered, misfolded, and aggregated proteins pose a significant setback in drug designing. The structural study of intermediate steps in these kinds of aggregated proteins will allow us to determine the conformational changes as well as the probable pathways encompassing various neurodegenerative disorders. The analysis of protein aggregates involved in neurodegenerative diseases relies on a diverse toolkit of biophysical techniques, encompassing both morphological and non-morphological methods. Additionally, Thioflavin T (ThT) assays and Circular Dichroism (CD) spectroscopy facilitate investigations into aggregation kinetics and secondary structure alterations. The collective application of these biophysical techniques empowers researchers to comprehensively unravel the intricate nature of protein aggregates associated with neurodegeneration. Furthermore, the topics covered in this review have summed up a handful of well-established techniques used for the structural analysis of protein aggregation. This multifaceted approach advances our fundamental understanding of the underlying mechanisms driving neurodegenerative diseases and informs potential therapeutic strategies.

Rationalizing the Role of Monosodium Glutamate in the Protein Aggregation Through Biophysical Approaches: Potential Impact on Neurodegeneration.

Monosodium glutamate (MSG) is the world's most extensively used food additive and is generally recognized as safe according to the FDA. However, it is well reported that MSG is associated with a number of neurological diseases, and in turn, neurological diseases are associated with protein aggregation. This study rationalized the role of MSG in protein aggregation using different biophysical techniques such as absorption, far-UV CD, DLS, and ITC. Kinetic measurements revealed that MSG causes significant enhancement of aggregation of BSA through a nucleation-dependent polymerization mechanism. Also, CTAB-BSA aggregation is enhanced by MSG significantly. MSG-induced BSA aggregation also exhibits the formation of irreversible aggregates, temperature dependence, non-Arrhenius behavior, and enhancement of hydrodynamic diameter. From the isothermal titration calorimetry measurement, the significant endothermic heat of the interaction of BSA-MSG indicates that protein aggregation may be due to the coupling of MSG with the protein. The determined enthalpy change (ΔH) is largely positive, also suggesting an endothermic nature, whereas entropy change (ΔS) is positive and Gibbs free energy change (ΔG) is largely negative, suggesting the spontaneous nature of the interaction. Furthermore, even a low concentration of MSG is involved in the unfolding of the secondary structure of protein with the disappearance of original peaks and the formation of a unique peak in the far-UV CD, which is an attention-grabbing observation. This is the first investigation which links the dietary MSG with protein aggregation and thus will be very instrumental in understanding the mechanism of various MSG-related human physiological as well as neurological diseases.

Trehalose Restrains the Fibril Load towards α-Lactalbumin Aggregation and Halts Fibrillation in a Concentration-Dependent Manner.

Protein aggregation and misfolding are some of the most challenging obstacles, customarily studied for their association with amyloid pathologies. The mechanism of amyloid fibrillation development is a dynamic phenomenon involving various factors such as the intrinsic properties of protein and the physical and chemical environmental conditions. The purpose of this study was to see the thermal aggregation profile of alpha-lactalbumin (α-LA) and to delineate the effect of trehalose on its aggregation profile. α-LA was subjected to thermal aggregation at high concentrations. UV-Vis spectroscopy, a turbidity assay, intrinsic fluorescence, Rayleigh scattering and a thioflavin T (ThT) assay explained the steady outcomes that 1 M trehalose repressed α-LA aggregation in the most effective way followed by 0.75 M and 0.5 M and to a significantly lesser degree by 0.25 M. Multi spectroscopic obser Sania Bashir ations were further entrenched by microscopy. Transmission electron microscopy confirmed that in the presence of its higher concentration, trehalose hinders fibril development in α-LA. In vitro studies were further validated by in silico studies. Molecular docking analysis indicated that trehalose occupied the binding pocket cavity of α-LA and offered several significant interactions, including H-bonds with important residues. This study provides a platform for trehalose in the therapeutic management of protein aggregation-related diseases.

Biophysical Elucidation of Fibrillation Inhibition by Sugar Osmolytes in α-Lactalbumin: Multispectroscopic and Molecular Docking Approaches.

Protein aggregation is among the most challenging new frontiers in protein chemistry as well as in molecular medicine and has direct implications in protein misfolding. This study investigated the role of sugar molecules (glucose, fructose, sucrose, and the mixture of glucose and fructose) in protecting the structural integrity of α-lactalbumin (α-LA) against aggregation. The research focused here is the inhibitory capabilities of sugars against α-LA fibril formation investigated employing diverse multispectroscopic and microscopic techniques. The aggregation was induced in α-LA thermally with a change in concentration. UV-vis spectroscopy, ThT binding assay, Trp fluorescence, Rayleigh scattering, and turbidity assay depicted synchronized results. Further, transmission electron microscopy (TEM) complemented that a mixture of glucose and fructose was the best inhibitor of α-LA fibril formation. Inhibition of α-LA aggregation by sugar osmolytes is attributed to the formation of hydrogen bonds between these osmolytes, as evidenced by the molecular docking results. This hydrogen bonding is a key player that prevents aggregation in α-LA in the presence of sugar osmolytes. This study provides an insight into the ability of naturally occurring sugar osmolytes to inhibit fibril formation and can serve as a platform to treat protein misfolding and aggregation-oriented disorders.

Molecular mechanisms and mode of tamoxifen resistance in breast cancer.

Breast cancer is one of the most common cancers in women around the globe Tamoxifen is used for the last 40 years as an endocrine therapy for breast cancer. This resulted in the reduction of mortality rate by 30% and it still remains one of the most effective therapies against breast cancer. However, resistance against tamoxifen is still one of the major hurdles in the effective management of breast cancer. Intense research has been conducted in the past decade to further explore its resistance mechanism, but still a lot of research will be needed to effectively alleviate this problem. Several biochemical factors and molecular pathways, such as the modulation of ER signaling, upregulation of growth factors had been observed as key factors for tamoxifen resistance (TR). After, initial therapy of five to ten years, breast cancer patients develops resistance towards this drug. The resistance leads to the development of other cancers like uterine cancer. Here, we briefly explore all the molecular events related to tamoxifen resistance and focus on its mechanism of action as well as other pharmacological approaches to better its beneficial effects in the treatment of breast carcinoma.