Microglial NOX2 as a therapeutic target in traumatic brain injury: Mechanisms, consequences, and potential for neuroprotection.

Traumatic brain injury (TBI) is a leading cause of long-term disability worldwide, with secondary injury mechanisms, including neuroinflammation and oxidative stress, driving much of its chronic pathology. While NADPH oxidase 2 (NOX2)-mediated reactive oxygen species (ROS) production is a recognized factor in TBI, the specific role of microglial NOX2 in perpetuating oxidative and inflammatory damage remains underexplored. Addressing this gap is critical, as current therapeutic approaches primarily target acute symptoms and fail to interrupt the persistent neuroinflammation that contributes to progressive neurodegeneration.

The Huntington's disease drug pipeline: a review of small molecules and their therapeutic targets.

Huntington's disease (HD) is a progressive neurodegenerative condition resulting from a CAG repeat expansion in the huntingtin gene (HTT). Recent advancements in understanding HD's cellular and molecular pathways have paved the way for identifying various effective small-molecule candidates to treat the disorder. Two small molecules, Tetrabenazine and Deutetrabenazine, are approved for managing chorea associated with HD, and several others are under clinical trials.

Microglial Autophagic Dysregulation in Traumatic Brain Injury: Molecular Insights and Therapeutic Avenues.

Traumatic brain injury (TBI) is a complex and multifaceted condition that can result in cognitive and behavioral impairments. One aspect of TBI that has received increasing attention in recent years is the role of microglia, the brain-resident immune cells, in the pathophysiology of the injury. Specifically, increasing evidence suggests that dysfunction in microglial autophagy, the process by which cells degrade and recycle their own damaged components, may contribute to the development and progression of TBI-related impairments.

Targeting Wnt signaling pathway with small-molecule therapeutics for treating osteoporosis.

Small molecules are emerging as potential candidates for treating osteoporosis by activating canonical Wnt signaling. These candidates work either by inhibiting DKK-1, sclerostin, SFRP-1, NOTUM, and S1P lyase or by preventing β-catenin degradation through inhibition of GSK-3β, or by targeting Dvl-CXXC5 and axin/β-catenin interactions. While many of these anti-osteoporotic small molecules are in preclinical development, the paucity of FDA-approved small molecules, or promising candidates, that have progressed to clinical trials for treating bone disorders through this mechanism poses a challenge.

Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.

Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases.

Unraveling the Puzzle of Therapeutic Peptides: A Promising Frontier in Huntington's Disease Treatment.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by a mutation in the huntingtin (HTT) gene, resulting in the production of a mutant huntingtin protein (mHTT). The accumulation of mHTT leads to the development of toxic aggregates in neurons, causing cell dysfunction and, eventually, cell death. Peptide therapeutics target various aspects of HD pathology, including mHTT reduction and aggregation inhibition, extended CAG mRNA degradation, and modulation of dysregulated signaling pathways, such as BDNF/TrkB signaling.

Oxytosis/Ferroptosis in Neurodegeneration: the Underlying Role of Master Regulator Glutathione Peroxidase 4 (GPX4).

Oxytosis/ferroptosis is an iron-dependent oxidative form of cell death triggered by lethal accumulation of phospholipid hydroperoxides (PLOOHs) in membranes. Failure of the intricate PLOOH repair system is a principle cause of ferroptotic cell death. Glutathione peroxidase 4 (GPX4) is distinctly vital for converting PLOOHs in membranes to non-toxic alcohols.

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington's Disease.

Huntington's disease (HD) is a rare and fatal neurodegenerative disorder with no diseasemodifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief.

The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington's Disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). The new insights into HD's cellular and molecular pathways have led to the identification of numerous potent small-molecule therapeutics for HD therapy. The field of HD-targeting small-molecule therapeutics is accelerating, and the approval of these therapeutics to combat HD may be expected in the near future.

Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment.

The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD.

Proteinopathies: Deciphering Physiology and Mechanisms to Develop Effective Therapies for Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are a cluster of diseases marked by progressive neuronal loss, axonal transport blockage, mitochondrial dysfunction, oxidative stress, neuroinflammation, and aggregation of misfolded proteins. NDs are more prevalent beyond the age of 50, and their symptoms often include motor and cognitive impairment. Even though various proteins are involved in different NDs, the mechanisms of protein misfolding and aggregation are very similar.

The Protective Effects of AT2R Agonist, CGP42112A, Against Angiotensin II-Induced Oxidative Stress and Inflammatory Response in Astrocytes: Role of AT2R/PP2A/NFκB/ROS Signaling.

Angiotensin II receptor type 2 (AT2R) agonists have been known to promote neuroprotection by limiting ischemic insult, neuronal proliferation, and differentiation. Further, AT2R agonists have also been associated with the suppression of neuroinflammation and neurodegeneration. Of note, brain astrocytes play a critical role in these neuroinflammatory and neurodegenerative processes.

Biomediated synthesis, characterization, and biological applications of nickel oxide nanoparticles derived from Toona ciliata, Ficus carica and Pinus roxburghii.

Biomediated ecofriendly method for the synthesis of nickel oxide nanoparticles using plants extracts (Toona ciliata, Ficus carica and Pinus roxburghii) has been reported. The nanoparticles so obtained were characterized by various techniques such as ultraviolet-visible, powder X-ray diffraction, Fourier transform infrared spectroscopy, attenuated total reflectance spectroscopy, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, thermogravimetric analysis and fluorescence spectroscopy. Formation of nickel oxide nanoparticles was confirmed by Fourier transform infrared spectroscopy and X-ray diffraction where the former technique ascertains the formation of bond between nickel and oxygen.

Enhanced Akt/GSK-3β/CREB signaling mediates the anti-inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice.

We have previously shown that treatment with a mGluR5 positive allosteric modulator (PAM) is neuroprotective after experimental traumatic brain injury (TBI), limiting post-traumatic neuroinflammation by reducing pro-inflammatory microglial activation and promoting anti-inflammatory and neuroprotective responses. However, the specific molecular mechanisms governing this anti-inflammatory shift in microglia remain unknown. Here we show that the mGluR5 PAM, VU0360172 (VuPAM), regulates microglial inflammatory responses through activation of Akt, resulting in the inhibition of GSK-3β.

Copper Oxide Nanomaterials Derived from Zanthoxylum armatum DC. and Berberis lycium Royle Plant Species: Characterization, Assessment of Free Radical Scavenging and Antibacterial Activity.

Copper oxide nanomaterials were synthesized by a facile sustainable biological method using two plant species (Zanthoxylum armatum DC. and Berberis lycium Royle). The formation of materials was confirmed by FT-IR, ATR, UV-visible, XRD, TEM, SEM, EDX, TGA and PL.

Malus pumila and Juglen regia plant species mediated zinc oxide nanoparticles: Synthesis, spectral characterization, antioxidant and antibacterial studies.

Zinc oxide nanoparticles derived from Malus pumila (apple) and Juglen regia (walnut) plant is an attractive area of research because of their widespread use. The use of plant material to synthesize zinc oxide nanoparticles has been considered as one of the best environmentally friendly approach. This method appears to be low-cost as compare to other conventional method of synthesis.

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury.

Neuroinflammation is one of the key secondary injury mechanisms triggered by traumatic brain injury (TBI). Microglial activation, a hallmark of brain neuroinflammation, plays a critical role in regulating immune responses after TBI and contributes to progressive neurodegeneration and neurologic deficits following brain trauma. Here we evaluated the role of neutral sphingomyelinase (nSMase) in microglial activation by examining the effects of the nSMase inhibitors altenusin and GW4869 in vitro (using BV2 microglia cells and primary microglia), as well as in a controlled cortical injury (CCI) model in adult male C57BL/6 mice.