Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases.

Currently, one of the most significant and rapidly growing unmet medical challenges is the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This challenge encompasses the imperative development of efficacious therapeutic agents and overcoming the intricacies of the blood-brain barrier for successful drug delivery. Here we focus on the delivery aspect with particular emphasis on cell-penetrating peptides (CPPs), widely used in basic and translational research as they enhance drug delivery to challenging targets such as tissue and cellular compartments and thus increase therapeutic efficacy. The combination of CPPs with nanomaterials such as nanoparticles (NPs) improves the performance, accuracy, and stability of drug delivery and enables higher drug loads. Our review presents and discusses research that utilizes CPPs, either alone or in conjugation with NPs, to mitigate the pathogenic effects of neurodegenerative diseases with particular reference to AD and PD.

Exploring the significance of potassium homeostasis in copper ion binding to human αB-Crystallin.

αB-Crystallin (αB-Cry) is a small heat shock protein known for its protective role, with an adaptable structure that responds to environmental changes through oligomeric dynamics. Cu(II) ions are crucial for cellular processes but excessive amounts are linked to diseases like cataracts and neurodegeneration. This study investigated how optimal and detrimental Cu(II) concentrations affect αB-Cry oligomers and their chaperone activity, within the potassium-regulated ionic-strength environment. Techniques including isothermal titration calorimetry, differential scanning calorimetry, fluorescence spectroscopy, inductively coupled plasma atomic emission spectroscopy, cyclic voltammetry, dynamic light scattering, circular dichroism, and MTT assay were employed and complemented by computational methods. Results showed that potassium ions affected αB-Cry's structure, promoting Cu(II) binding at multiple sites and scavenging ability, and inhibiting ion redox reactions. Low concentrations of Cu(II), through modifications of oligomeric interfaces, induce regulation of surface charge and hydrophobicity, resulting in an increase in chaperone activity. Subunit dynamics were regulated, maintaining stable interfaces, thereby inhibiting further aggregation and allowing the functional reversion to oligomers after stress. High Cu(II) disrupted charge/hydrophobicity balance, sewing sizable oligomers together through subunit-subunit interactions, suppressing oligomer dissociation, and reducing chaperone efficiency. This study offers insights into how Cu(II) and potassium ions influence αB-Cry, advancing our understanding of Cu(II)-related diseases.

Amyloid management by chaperones: The mystery underlying protein oligomers' dual functions.

Protein oligomerization has two notable aspects: it is crucial for the performing cellular and molecular processes accurately, and it produces amyloid fibril precursors. Although a clear explanation for amyloidosis as a whole is lacking, most studies have emphasized the importance of protein misfolding followed by formation of cytotoxic oligomer structures, which are responsible for disorders as diverse as neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and metabolic disorders, such as type 2 diabetes. Constant surveillance by oligomeric protein structures known as molecular chaperones enables cells to overcome the challenge of misfolded proteins and their harmful assemblies. These molecular chaperones encounter proteins in cells, and benefit cell survival as long as they perform correctly. Thus, this review highlights the roles of structural aspects of chaperone protein oligomers in determining cell fate-either succumbing to amyloid oligomers or survival-as well as experimental approaches used to investigate these entities.

Inhibiting mTTR Aggregation/Fibrillation by a Chaperone-like Hydrophobic Amino Acid-Conjugated SPION.

Transthyretin (TTR) aggregation via misfolding of a mutant or wild-type protein leads to systemic or partial amyloidosis (ATTR). Here, we utilized variable biophysical assays to characterize two distinct aggregation pathways for mTTR (a synthesized monomer TTR incapable of association into a tetramer) at pH 4.3 and also pH 7.4 with agitation, referred to as mTTR aggregation and fibrillation, respectively. The findings suggest that early-stage conformational changes termed monomer activation here determine the aggregation pathway, resulting in developing either amorphous aggregates or well-organized fibrils. Less packed partially unfolded monomers consisting of more non-regular secondary structures that were rapidly produced via a mildly acidic condition form amorphous aggregates. Meanwhile, more hydrophobic and packed monomers consisting of rearranged ß sheets and increased helical content developed well-organized fibrils. Conjugating superparamagnetic iron oxide nanoparticles (SPIONs) with leucine and glutamine (L-SPIONs and G-SPIONs in order) via a trimethoxysilane linker provided the chance to study the effect of hydrophobic/hydrophilic surfaces on mTTR aggregation. The results indicated a powerful inhibitory effect of hydrophobic L-SPIONs on both mTTR aggregation and fibrillation. Monomer depletion was introduced as the governing mechanism for inhibiting mTTR aggregation, while a chaperone-like property of L-SPIONs by maintaining an mTTR native structure and adsorbing oligomers suppressed the progression of further fibril formation.

Enhancement of Shikalkin Production in Arnebia euchroma Callus by a Fungal Elicitor, Rhizoctonia solani.

BACKGROUND: There is a growing demand for mass production of shikalkin (a natural pigment consisted of shikonin and alkannin) due to its increasing applications in cosmetics, pharmaceutical and nutrition industries. The root of Iranian Arnebia euchroma produces shikalkin. The promising capability of this plant for shikalkin production has already been demonstrated in cell culture studies. OBJECTIVES: Elicitation effect of Rhizoctonia solani (R. solani) in comparison with the effects of Cu2+, methyl jasmonate (MJ), and salicylic acid (SA) on the shikalkin production was investigated in A. euchroma callus. MATERIALS AND METHODS: The calli from different origins (leaf, collar and root) were proliferated on a modified Linsmaier-Skoog (mLS) medium and were subsequently transferred onto the pigment production medium containing various amounts of the desirable elicitor. Observations were quantified and the pigment production was precisely measured spectrophotometrically. RESULTS: Pigment biosynthesis was induced on White medium containing IAA (1 µM) and kinetin (10 µM) in dark at 25°C. Use of R. solani increased the pigment production by 7 fold greater than normal White medium. Cu2+ only doubled the shikalkin production. MJ and SA showed enhancing effects comparable to that of Cu2+. DISCUSSIONS: It is assumed that upon binding of the polysaccharides of the fungal cells to the plant cell surface, a cascade of signaling is initiated that led to expression of genes involving in the biosynthesis of shikalkin.