Neural Tissue Research Articles

Controlled Elevation of Intraocular Pressure (CEI) Glaucoma Model in Rats.

Experimental elevation of intraocular pressure (IOP), a major glaucoma risk factor, has been a mainstay of research into mechanisms of glaucomatous optic nerve damage for decades. Methods that produce sustained IOP elevation can mimic the chronic nature of glaucoma and produce optic nerve damage. However, the pressure course for individual animals can be variable, unpredictably high at times, and difficult to monitor with current tonometry methods. All of this can complicate correlations of pressure history with axonal injury. An alternative is to control the extent and duration of IOP elevation over a period of several hour-long enough to produce axonal injury and gene expression changes within the optic nerve head that may indicate cellular mechanisms of glaucomatous optic nerve damage. The prolonged general anesthesia that this requires does have the potential to reduce systemic blood pressure, which may contribute to axonal injury in the face of elevated IOP. This chapter will describe our Controlled Elevation of IOP (CEI) model in laboratory rats. We will include methods for applying this to several animals at a time, as well as how to maintain blood pressure, oxygenation, and body temperature to ensure that the resulting injury and tissue events reflect the effects of elevated IOP on optic nerve tissues and not simply reduced ocular perfusion and ischemia.

Microglia-mediated neuroinflammation in traumatic brain injury: a review.

Traumatic brain injury (TBI) is a leading cause of disability worldwide, characterized by a complex interplay of primary and secondary injury mechanisms. Microglia, the resident immune cells of the central nervous system, play a crucial role in the inflammatory response following TBI. To review the current understanding of microglia-mediated neuroinflammation in TBI, exploring its dual nature as a protective and detrimental process. A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Google Scholar. Relevant studies investigating the role of microglia in TBI were included. In the early stages of TBI, microglia exhibit a protective response, releasing cytokines and chemokines to promote neuronal survival and tissue repair. However, prolonged or excessive microglial activation can lead to neurotoxicity and exacerbate secondary injury. Microglia-mediated neuroinflammation involves complex signaling pathways, including Toll-like receptors, purinergic receptors, and the complement system. Microglia-mediated neuroinflammation in TBI is a double-edged sword. While acute microglial activation can promote repair, chronic or excessive inflammation contributes to neuronal damage and functional deficits. Understanding the temporal and molecular dynamics of microglial responses is crucial for developing therapeutic strategies to modulate neuroinflammation and improve outcomes after TBI.

Natural polymeric biomaterials for managing peripheral nerve injuries : a novel approach for tissue repair and reconstruction.

Peripheral nerve injury serves as a major challenge to clinicians and researchers due to the complexity and functions of peripheral nerves that play the crucial role of transmitting signals between spinal cord and other human body tissues. Biomaterials offer promising solutions for regeneration of nerve tissues owing to their biodegradability, and biocompatibility. They can be fabricated as hydrogels, scaffolds, nanofibrous matrices, and nanoparticles that can facilitate the release of therapeutic molecules to reduce inflammation and promote neuronal growth. Managing peripheral nerve injuries through natural polymeric based biomaterials represents as a novel approach for tissue repair and reconstruction in the field of regenerative medicine. This correspondence will give an insight into the different types of natural polymeric biomaterials that can be efficiently used in managing peripheral nerve injuries.

Trans regulation of an odorant binding protein by a proto-Y chromosome affects male courtship in house fly.

The male-limited inheritance of Y chromosomes favors alleles that increase male fitness, often at the expense of female fitness. Determining the mechanisms underlying these sexually antagonistic effects is challenging because it can require studying Y-linked alleles while they still segregate as polymorphisms. We used a Y chromosome polymorphism in the house fly, Musca domestica, to address this challenge. Two male determining Y chromosomes (YM and IIIM) segregate as stable polymorphisms in natural populations, and they differentially affect multiple traits, including male courtship performance. We identified differentially expressed genes encoding odorant binding proteins (in the Obp56h family) as candidate agents for the courtship differences. Through network analysis and allele-specific expression measurements, we identified multiple genes on the house fly IIIM chromosome that could serve as trans regulators of Obp56h gene expression. One of those genes is homologous to Drosophila melanogaster CG2120, which encodes a transcription factor that binds near Obp56h. Upregulation of CG2120 in D. melanogaster nervous tissues reduces copulation latency, consistent with this transcription factor acting as a negative regulator of Obp56h expression. The transcription factor gene, which we name speed date, demonstrates a molecular mechanism by which a Y-linked gene can evolve male-beneficial effects.

Piezoelectric silk fibroin nanofibers: Structural optimization to enhance piezoelectricity and biostability for neural tissue engineering

Silk fibroin (SF) has garnered significant interest in tissue engineering due to its excellent biocompatibility and bioactivity. Notably, SF exhibits piezoelectric properties that can be harnessed to electrically stimulate cells, enhancing tissue morphogenesis. However, a systematic approach to control SF's piezoelectricity and biodegradation, and its application in neural morphogenesis, has not been fully explored. In this study, SF was electrospun into nanofibers of various sizes and subjected to a post-electrospinning chemical treatment to examine the effects of phase composition, especially the β-sheet formation, on the piezoelectricity and biostability of SF. The optimized SF scaffolds having a nanofiber diameter of 750 nm and a scaffold thickness of 250 µm allowed for the maintenance of nanofibrous structure for at least 6 weeks in aqueous environments while maintaining piezoelectric potential outputs of at least 200 mVp-p. This enabled cell membrane depolarization over an extended cell culture duration, facilitating the functional maturation of human neural stem cells (hNSCs). Specifically, acoustic piezo-activation of the SF scaffolds, resulting in mechano-electrical stimulation (MES) of the cells, accelerated their differentiation into neurons, astrocytes, and especially oligodendrocytes, leading to robust axon myelination within two weeks. Furthermore, MES enhanced neural connectivity and functional maturity, as evidenced by significant increases in excitatory and inhibitory synapse formation (46 % and 58 %, respectively), action potential amplitude (252 %), and velocity (210 %) compared to static control conditions. These findings demonstrate the potential of biodegradable electrospun SF nanofibers with balanced piezoelectricity and biostability for advancing neural tissue engineering.

Comparative assessment of neurotrophic proteins in vibration disease

Introduction. The problem of health impairment due to the impact of physical factors, including vibration disease (VD), retains medical and social relevance due to the significant specific gravity in the structure of occupational morbidity and high prevalence. Under vibration exposure, the acid-base equilibrium, immune status are disturbed, rheological properties and properties of the neurohumoral system, as well as functional indices of the central and peripheral nervous system change. Neurotrophins are known to play an important role in regulating the development and functioning of the central and peripheral nervous systems. In this regard, research is needed to determine in VD patients the levels of neurospecific proteins, which may serve as one of the markers for tracing changes in the nervous system in workers. The aim of the study was to identify the peculiarities of changes in neurospecific proteins (BDNF, S100β, and MBP) in the serum of patients with VD of different genesis. Materials and methods. Serum concentrations of neurotrophic proteins: brain neurotrophic factor – BDNF, S100β protein and myelin basic protein (MBP) were studied by solid-phase enzyme-linked immunoassay. Results. There was an increase in serum BDNF, S100β protein, and MBP concentrations in persons with VD due to combined exposure to local and general vibration, and an increase in MBP was observed in patients with VD due to exposure to local vibration. Limitations. The limitations of this work are small groups of employees. Conclusion. As a result of studies, it can be assumed that in VD due to exposure to combined vibration, changes are observed in the peripheral and central parts of the nervous system, and in VD due to local vibration, disorders seem to be mainly associated with the peripheral nervous system. The general pattern of the revealed disorders in the content of MBP lies in the neurodestructive processes occurring in the nerve fibers in patients with VD, regardless of genesis. Summarizing the above mentioned, the validity of studying the concentration of neurospecific proteins in vibration disease occurring with damaging processes in the nervous tissue should be recognized.

Corticosteroids and glaucoma: How do treatments trigger ocular nerve damage? - A systematic literature review

Corticosteroids are steroid hormone derivatives produced by the adrenal glands. Corticosteroids in the health sector have been widely utilized as anti-inflammatory agents because of their strong and rapid effects. This study aimed to identify the impact of long-term corticosteroid use on eye damage. This study uses a systematic literature review, which is guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to the article screening process. The data of this study, in the form of demographic variables, route of administration, steroid type, comorbidities, and patient risk factors, were descriptively analyzed. As a result, 15 of the 22 articles were selected for analysis. Chronic corticosteroid administration may precipitate optic neuropathy, manifesting as glaucoma, which is characterized by progressive structural degeneration of retinal ganglion cells (RGCs) and concomitant visual function deterioration. The locus of primary pathological insult in glaucomatous conditions is the optic nerve head, specifically at the optic disc. This anatomical site is notable for the abrupt 90-degree angular deviation of RGC axons as they transition from the retinal nerve fiber layer to their trajectory within the optic nerve proper. The use of corticosteroids can damage ocular nerve tissue through an increase in intraocular pressure (IOP) beyond 21 mmHg. This increase in IOP is due to changes in the microstructure of the trabeculum webbing, resulting in increased obstruction to the outflow of aqueous humor.

Phytochemical Profiling and Nutraceutical Benefits of Methanol Leaf Extracts from Datura alba ness

Introduction: Species of the Datura plant have demonstrated significant pharmacological benefits in combating various diseases over the past decade. However, little information is available on Datura alba ness (DAN), and no studies have yet reported its proximate composition or characterized its phytochemical components. This study aims to investigate the nutritional, phytochemical and bioactive properties of Datura alba ness. Materials and Methods: Fresh leaves of Datura alba ness were collected from Abua Odua local government area of Rivers State, Nigeria and properly identified and authenticated. The fresh leaves were subjected to proximate analysis using standard protocols while the dried leaves were extracted using methanol by the method of cold maceration to obtain methanolic extract of Datura alba ness (MEDAN). The MEDAN was further subjected to phytochemical screening to obtain the various phytochemicals and Gas chromatography and mass spectrometry (GC-MS) analysis for detailed identification and characterization of the various bioactive compounds. Results: Proximate analysis of fresh leaves of DAN showed the presence of moisture (60.4%), crude protein (21.9%), carbohydrate (7.6%), crude fibre (4.77%), ash (4.17%) and fat (1.19%) while the phytochemical screening revealed the presence of flavonoids (49.14%), alkaloids (19.16%), tannins 1(12.19%), saponins (11.72%), phenols (5.33%), cardiac glycosides (1.91%), oxalates (0.43%) and phytates (0.43%). Also, the GC-MS analysis of MEDAN identified twenty-nine (29) active compounds with four (4) observed as the most abundant (with area concentration >10%). They include Bis (2-ethylhexyl) phthalate (15.97%), 13-hexyloxacyclotridec-10-en-2-one (14.26%), n-hexadecanoic acid (12.87%) and Gamma.-Sitosterol (10.77). Conclusion: The identification of various nutrients, compounds, and bioactive substances through proximate, phytochemical, and GC-MS analysis of fresh leaves and methanol extract of Datura alba ness highlights its potential as a supplement and therapeutic agent. These findings suggest that Datura alba ness contains numerous bioactive compounds that may offer effective treatments for conditions related to oxidative stress, nervous system disorders, tissue damage, inflammation, and bacterial infections.

Inflammation of the temporalis muscle and adjacent nerve tissue in giant cell arteritis: expanding the spectrum of inflammatory lesions.

To investigate the histopathological features of the temporalis muscle (TM) and adjacent nerve tissue in active cranial giant cell arteritis (C-GCA). Temporal artery biopsy (TAB) specimens containing fragments of the TM from patients with active C-GCA fulfilling the 2022 ACR/EULAR classification criteria (n = 11) were assessed by conventional histology and immunohistochemistry in comparison with non-GCA controls (n = 3). Clinical, laboratory and imaging features based on patient charts at time of biopsy were retrospectively recorded. The majority of the studied TAB specimens showed inflammation of the TM (10/11) and adjacent nerve fascicles (7/11) that was characterized by prominent endomysial lymphomonocytic infiltrates, whereas controls showed no inflammatory lesions and no disruption of the local architecture. Association of active C-GCA with sarcolemmal MHC class I (8/8) and MHC class II (6/11) upregulation suggests primary inflammation of the TM in a subset of patients. αB-Crystallin positivity (10/11) highlights areas of pre-necrotic myofibres within the TM. The presence of endomysial fibrosis, signs of atrophy and variations of muscle fibre size suggest a rather longstanding and potentially subclinical process of myoinflammation. Our results expand the spectrum of inflammatory lesions known to be associated with active C-GCA. Specifically, inflammatory infiltration of the TM and adjacent nerve structures could contribute to localized symptoms of the temporomandibular region and may be included in future concepts of pathophysiology.

Glucosylceramide synthase inhibitor ameliorates chronic inflammatory pain

Gangliosides play pivotal roles in neuronal tissue processes, such as axonal elongation, synaptic transmission, and neuronal degeneration. Several studies have shown that mice injected with gangliosides synthesized from glucosylceramide exhibit mechanical allodynia. Thus, we hypothesized that glucosylceramide synthase inhibitors affect nociceptive behavior. We investigated the analgesic effect of intrathecal glucosylceramide inhibition on bilateral allodynia caused by prolonged unilateral hind paw inflammation in mice. Repeated administration of a glucosylceramide inhibitor reduced mechanical allodynia in both inflamed and non-inflamed hind paws. These results suggested that ganglioside reduction is critical for analgesia during inflammatory pain.

Fabrication and characterization of bioresorbable, electroactive and highly regular nanomodulated cell interfaces

Biomaterial-based implantable scaffolds capable of promoting physical and functional reconnection of injured spinal cord and nerves represent the latest frontier in neural tissue engineering. Here, we report the fabrication and characterization of self-standing, biocompatible and bioresorbable substrates endowed with both controlled nanotopography and electroactivity, intended for the design of transient implantable scaffolds for neural tissue engineering. In particular, we obtain conductive and nano-modulated poly(D,L-lactic acid) (PLA) and poly(lactic-co-glycolic acid) free-standing films by simply iterating a replica moulding process and coating the polymer with a thin layer of poly(3,4-ethylendioxythiophene) polystyrene sulfonate. The capability of the substrates to retain both surface patterning and electrical properties when exposed to a liquid environment has been evaluated by atomic force microscopy, electrochemical impedance spectroscopy and thermal characterizations. In particular, we show that PLA-based films maintain their surface nano-modulation for up to three weeks of exposure to a liquid environment, a time sufficient for promoting axonal anisotropic sprouting and growth during neuronal cell differentiation. In conclusion, the developed substrates represent a novel and easily-tunable platform to design bioresorbable implantable devices featuring both topographic and electrical cues.

Comparisons of MR and EM inferred tissue microstructure properties using a human autopsy corpus callosum sample

Degeneration of white matter (WM) microstructure in the central nervous system is characteristic of many neurodegenerative conditions. Previous research indicates that axonal degeneration visible in ex vivo electron microscopy (EM) photomicrographs precede the onset of clinical symptoms. Measuring WM microstructural features, such as axon diameter and packing fraction, currently require these highly invasive methods of analysis and it is therefore of great importance to develop methods for in vivo measurements. Diffusion weighted Magnetic Resonance Imaging (MRI) is a non-invasive method which can be used in conjunction with temporal diffusion spectroscopy (TDS) and an oscillating gradient spin echo (OGSE) pulse sequence to probe micron-scale structures within neural tissue. The current experiment aims to compare axon diameter measurements, mean effective axon diameter (AxD¯), and packing fractions calculated from EM histopathological analysis and inferred values from MR images. Mathematical models of axon diameters used for analysis include the ActiveAx Frequency-Dependent Extra-Axonal Diffusion (AAD) model and the AxCaliber Frequency-Dependent Extra-Axonal Diffusion (ACD) model using ROI (Region of Interest) based analysis (RBA) and voxel-based analysis (VBA), respectively. Overall, it was observed that MRI inferred WM microstructural parameters overestimate those calculated from EM. This may be attributable to tissue shrinkage during EM dehydration, the sensitivity of MR pulse sequences to larger diameter axons, and/or inaccurate model assumptions. The results of the current study provide a means to characterize the precision and accuracy of RBA-ACD and VBA-AAD OGSE-TDS and highlight the need for further research investigating the relationship between ex vivo MRI and EM, with the goal of reaching in vivo MRI.

Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson’s Disease

Individuals diagnosed with Parkinson’s disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches.

Dipeptide <i>L</i>-сarnosine (β-alanyl-<i>L</i>-histidine) — nervous tissue cryoprotector non-hybernate animals

In this work, the cryoprotective properties of dipeptide L-carnosine (β-alanyl-L-histidine) were studied on slices of the olfactory cortex of the brain of rats. Changes in the activity of N-methyl-D-aspartate receptors were analyzed as the most vulnerable to the effect of cryopreservation (CP), for this purpose, extracellular NMDA potentials were recorded. Slices were incubated with L-carnosine (20 mM) in the medium and frozen at a slow rate (0.1°C/min) down to –10°C and after CS (30 days) they were heated at the same rate (0.1°C/min) to +37°C. The effectiveness of cryoprotection of L-carnosine was determined by changes in the amplitudes of NMDA potentials after CP compared to before CP. The dipeptide restored the pH of the freezing medium 6.9 (without L-carnosine) to the optimum pH 7.3—7.4, promoted dehydration of free water from slices after CP, inhibited the development of glutamate excitotoxicity in slices. The data obtained prove that L-carnosine exhibits the properties of a non-toxic effective cryoprotector in the nervous tissue of warm-blooded non-hibernating animals.

An Algorithm for Creating a Synaptic Cleft Digital Phantom Suitable for Further Numerical Modeling

One of the most significant applications of mathematical numerical methods in biology is the theoretical description of the convectional reaction–diffusion of chemical compounds. Initial biological objects must be appropriately mimicked by digital domains that are suitable for further use in computational modeling. In the present study, an algorithm for the creation of a digital phantom describing a local part of nervous tissue—namely, a synaptic contact—is established. All essential elements of the synapse are determined using a set of consistent Boolean operations within the COMSOL Multiphysics software 6.1. The formalization of the algorithm involves a sequence of procedures and logical operations applied to a combination of 3D Voronoi diagrams, an experimentally defined inner synapse area, and a simple ellipsoid under different sets of biological parameters. The obtained digital phantom is universal and may be applied to different types of neuronal synapses. The clear separation of the designed domains reveals that the boundary’s conditions and internal flux dysconnectivity functions can be set up explicitly. Digital domains corresponding to the parts of a synapse are appropriate for further application of the derived numeric meshes, with various capacities of the included elements. Thus, the obtained digital phantom can be effectively used for further modeling of the convectional reaction–diffusion of chemical compounds in nervous tissue.

Optimizing Tubulin Yield from Porcine Brain Tissue.

Neural tissue from any source is an excellent material for tubulin isolation, as the dendrites and axons of neurons are rich in microtubules. Here, we present a procedure for extracting tubulin that can be employed, with minor modifications, for neural tissue from multiple sources. In the presented protocol, a new clarification step of the crude lysate has been introduced, which led to a significant reduction in the initial amount of insoluble debris before the first polymerization step occurred. This additional step allowed the processing of additional tissue while using the same instrumentation and, thus, increasing the relative volume of the processed homogenate. The newly introduced step has no significant effect on the quality of purified tubulin, as confirmed by in vitro activity assays and transmission electron microscopy. The described procedure contains all crucial steps, including tissue collection, transport, tissue homogenization, tubulin isolation cycles, and final polishing by ion exchange chromatography using FPLC and subsequent activity measurement assays. The homogeneity of purified tubulin was more than 97%, as confirmed by MS/MS analysis utilizing electrospray ionization and MALDI-TOF.

Drp1 acetylation mediated by CDK5-AMPK-GCN5L1 axis promotes cerebral ischemic injury via facilitating mitochondrial fission

The aberrant acetylation of mitochondrial proteins is involved in the pathogenesis of multiple diseases including neurodegenerative diseases and cerebral ischemic injury. Previous studies have shown that depletion of mitochondrial NAD+, which is necessary for mitochondrial deacetylase activity, leads to decreased activity of mitochondrial deacetylase and thus causes hyperacetylation of mitochondrial proteins in ischemic brain tissues, which results in altered mitochondrial dynamics. However, it remains largely unknown about how mitochondrial dynamics-related protein Drp1 is acetylated in ischemic neuronal cells and brain tissues. Here, we showed that Drp1 and GCN5L1 expression was up-regulated in OGD-treated neuronal cells and ischemic brain tissues induced by dMCAO, accompanied by the increased mitochondrial fission, mtROS accumulation, and cell apoptosis. Further, we confirmed that ischemia/hypoxia promoted Drp1 interaction with GCN5L1 in neuronal cells and brain tissues. GCN5L1 knockdown attenuated, while its overexpression enhanced Drp1 acetylation and mitochondrial fission, indicating that GCN5L1 plays a crucial role in ischemia/hypoxia-induced mitochondrial fission by acetylating Drp1. Mechanistically, ischemia/hypoxia induced Drp1 phosphorylation by CDK5 upregulation-mediated activation of AMPK in neuronal cells, which in turn facilitated the interaction of GCN5L1 with Drp1, thus enhancing Drp1 acetylation and mitochondrial fission. Accordingly, inhibition of AMPK alleviated ischemia/hypoxia- induced Drp1 acetylation and mitochondrial fission and protected brain tissues from ischemic damage. These findings provide a novel insight into the functional roles of GCN5L1 in regulating Drp1 acetylation and identify a previously unrecognized CDK5-AMPK-GCN5L1 pathway that mediates the acetylation of Drp1 in ischemic brain tissues.

Determination of Plasmalogen Molecular Species in Hen Eggs

(1) Background: Plasmalogens are vinyl ether-type glycerophospholipids that are characteristically distributed in neural tissues and are significantly reduced in the brains of individuals with dementia compared to those in healthy subjects, suggesting a link between plasmalogen deficiency and cognitive decline. Hen eggs are expected to be a potential source of dietary plasmalogens, but the details remain unclear. (2) Methods: We evaluated the fresh weight, dry weight, total lipid, neutral lipids, glycolipids, and phospholipids in the egg yolk and egg white of hen egg. Then, the molecular species of plasmalogens were quantified using HPLC-ESI-MS/MS. (3) Results: In egg yolk, the total plasmalogen content was 1292.1 µg/100 g fresh weight and predominantly ethanolamine plasmalogens (PE-Pls), specifically 18:0/22:6-PE-Pls, which made up 75.6 wt% of the total plasmalogen. In egg white, the plasmalogen content was 31.4 µg/100 g fresh weight and predominantly PE-Pls, specifically 18:0/20:4-PE-Pls, which made up 49.6 wt% of the total plasmalogen. (4) Conclusions: Plasmalogens were found to be more enriched in egg yolk than in egg white. It was found that humans are likely to ingest almost 0.3 mg of total plasmalogens from one hen egg. These findings highlight the importance of plasmalogens in the daily diet, and it is recommended to explore the impact of long-term dietary plasmalogen intake to assess its effect on human health. This provides a viewpoint for the development of new food products.

Destabilisation of Alzheimer's amyloid-β protofibrils by Baicalein: mechanistic insights from all-atom molecular dynamics simulations.

Alzheimer's disease (AD) is the most common form of dementia and the fifth leading cause of death globally. Aggregation and deposition of neurotoxic Aβ fibrils in the neural tissues of the brain is a key hallmark in AD pathogenesis. Destabilisation studies of the amyloid-peptide by various natural molecules are highly relevant due to their neuroprotective and therapeutic potential for AD. We performed molecular dynamics (MD) simulation to investigate the destabilisation mechanism of amyloidogenic protofilament intermediate by Baicalein (BCL), a naturally occurring flavonoid. We found that the BCL molecule formed strong hydrophobic contacts with non-polar residues, specifically F19, A21, V24, and I32 of Chain A and B of the pentameric protofibril. Upon binding, it competed with the native hydrophobic contacts of the Aβ protein. BCL loosened the tight packing of the hydrophobic core by disrupting the hydrogen bonds and the prominent D23-K28 inter-chain salt bridges of the protofibril. The decrease in the structural stability of Aβ protofibrils was confirmed by the increased RMSD, radius of gyration, solvent accessible surface area (SASA), and reduced β-sheet content. PCA indicated that the presence of the BCL molecule intensified protofibril motions, particularly affecting residues in Chain A and B regions. Our findings propose that BCL would be a potent destabiliser of Aβ protofilament, and may be considered as a therapeutic agent in treating AD.

Exploring protein-protein interactions for the development of new analgesics.

The development of new analgesics has been challenging. Candidate drugs often have limited clinical utility due to side effects that arise because many drug targets are involved in signaling pathways other than pain transduction. Here, we explored the potential of targeting protein-protein interactions (PPIs) that mediate pain signaling as an approach to developing drugs to treat chronic pain. We reviewed the approaches used to identify small molecules and peptide modulators of PPIs and their ability to decrease pain-like behaviors in rodent animal models. We analyzed data from rodent and human sensory nerve tissues to build associated signaling networks and assessed both validated and potential interactions and the structures of the interacting domains that could inform the design of synthetic peptides and small molecules. This resource identifies PPIs that could be explored for the development of new analgesics, particularly between scaffolding proteins and receptors for various growth factors and neurotransmitters, as well as ion channels and other enzymes. Targeting the adaptor function of CBL by blocking interactions between its proline-rich carboxyl-terminal domain and its SH3-domain-containing protein partners, such as GRB2, could disrupt endosomal signaling induced by pain-associated growth factors. This approach would leave intact its E3-ligase functions, which are mediated by other domains and are critical for other cellular functions. This potential of PPI modulators to be more selective may mitigate side effects and improve the clinical management of pain.