Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3ß (GSK-3ß), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.

Nrf2 and Ferroptosis: Exploring Translational Avenues for Therapeutic Approaches to Neurological Diseases.

Nrf2, a crucial protein involved in defense mechanisms, particularly oxidative stress, plays a significant role in neurological diseases (NDs) by reducing oxidative stress and inflammation. NDs, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, stroke, epilepsy, schizophrenia, depression, and autism, exhibit ferroptosis, iron-dependent regulated cell death resulting from lipid and iron-dependent reactive oxygen species (ROS) accumulation. Nrf2 has been shown to play a critical role in regulating ferroptosis in NDs. Age-related decline in Nrf2 expression and its target genes (HO-1, Nqo-1, and Trx) coincides with increased iron-mediated cell death, leading to ND onset. The modulation of iron-dependent cell death and ferroptosis by Nrf2 through various cellular and molecular mechanisms offers a potential therapeutic pathway for understanding the pathological processes underlying these NDs. This review emphasizes the mechanistic role of Nrf2 and ferroptosis in multiple NDs, providing valuable insights for future research and therapeutic approaches.

Aquaporin proteins: A promising frontier for therapeutic intervention in cerebral ischemic injury.

Cerebral ischemic injury is characterized by reduced blood flow to the brain, remains a significant cause of morbidity and mortality worldwide. Despite improvements in therapeutic approaches, there is an urgent need to identify new targets to lessen the effects of ischemic stroke. Aquaporins, a family of water channel proteins, have recently come to light as promising candidates for therapeutic intervention in cerebral ischemic injury. There are 13 aquaporins identified, and AQP4 has been thoroughly involved with cerebral ischemia as it has been reported that modulation of AQP4 activity can offers a possible pathway for therapeutic intervention along with their role in pH, osmosis, ions, and the blood-brain barrier (BBB) as possible therapeutic targets for cerebral ischemia injury. The molecular pathways which can interacts with particular cellular pathways, participation in neuroinflammation, and possible interaction with additional proteins thought to be involved in the etiology of a stroke. Understanding these pathways offers crucial information on the diverse role of AQPs in cerebral ischemia, paving the door for the development of focused/targeted therapeutics.

Sirtuin dysregulation in Parkinson's disease: Implications of acetylation and deacetylation processes.

Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor function and is caused by a gradual decline of dopaminergic neurons in the brain's substantia pars compacta (Snpc) region. Multiple molecular pathways are involved in the pathogenesis, which results in impaired cellular functions and neuronal degeneration. However, the role of sirtuins, a type of NAD+-dependent deacetylase, in the pathogenesis of Parkinson's disease has recently been investigated. Sirtuins are essential for preserving cellular homeostasis because they control a number of biological processes, such as metabolism, apoptosis, and DNA repair. This review shed lights on the dysregulation of sirtuin activity in PD, highlighting the role that acetylation and deacetylation processes play in the development of the disease. Key regulators of protein acetylation, sirtuins have been found to be involved in the aberrant acetylation of vital substrates linked to PD pathology when their balance is out of balance. The hallmark characteristics of PD such as neuroinflammation, oxidative stress, and mitochondrial dysfunction have all been linked to the dysregulation of sirtuin expression and activity. Furthermore, we have also explored how the modulators of sirtuins can be a promising therapeutic intervention in the treatment of PD.

Therapeutic implication of Sonic Hedgehog as a potential modulator in ischemic injury.

Sonic Hedgehog (SHh) is a homology protein that is involved in the modeling and development of embryonic tissues. As SHh plays both protective and harmful roles in ischemia, any disruption in the transduction and regulation of the SHh signaling pathway causes ischemia to worsen. The SHh signal activation occurs when SHh binds to the receptor complex of Ptc-mediated Smoothened (Smo) (Ptc-smo), which initiates the downstream signaling cascade. This article will shed light on how pharmacological modifications to the SHh signaling pathway transduction mechanism alter ischemic conditions via canonical and non-canonical pathways by activating certain downstream signaling cascades with respect to protein kinase pathways, angiogenic cytokines, inflammatory mediators, oxidative parameters, and apoptotic pathways. The canonical pathway includes direct activation of interleukins (ILs), angiogenic cytokines like hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and hypoxia-inducible factor alpha (HIF-), which modulate ischemia. The non-canonical pathway includes indirect activation of certain pathways like mTOR, PI3K/Akt, MAPK, RhoA/ROCK, Wnt/-catenin, NOTCH, Forkhead box protein (FOXF), Toll-like receptors (TLR), oxidative parameters such as GSH, SOD, and CAT, and some apoptotic parameters such as Bcl2. This review provides comprehensive insights that contribute to our knowledge of how SHh impacts the progression and outcomes of ischemic injuries.

Modified chitosan-hyaluronic acid based hydrogel for the pH-responsive Co-delivery of cisplatin and doxorubicin.

Combination chemotherapy has attracted more attention in the field of anticancer treatment due to the synergetic effects achieved in the targeted delivery of anticancer drugs. In the present work a hydrogel-based drug delivery system (CS-NSA/A-HA) was successfully developed from chitosan modified by nitrosalicylaldehyde and aldehyde hyaluronic acid. Anticancer drugs, Cisplatin (CDDP) and Doxorubicin (DOX) were incorporated into this hydrogel separately and a dual drug loaded system was synthesized and the potential of the single and dual drug loaded materials for lung cancer therapy was compared. The obtained hydrogel was characterized by various spectroscopic techniques. Morphological studies conducted by FE-SEM analysis. The loading and encapsulation efficiencies and percentage of drug release were determined by UV-Vis spectroscopy at different pHs. Cytotoxicity studies performed in A549 lung cancer cells confirmed the enhanced activity of the material as a dual drug carrier compared with the single loaded system. All the findings strongly suggest the applicability of the material for lung cancer therapy.

Repair of nasal complex fractures and the need for secondary septo-rhinoplasty.

PURPOSE: This study was undertaken to evaluate the efficacy of closed reduction of nasal fractures and determine the incidence of the need for post-traumatic septo-rhinoplasty in the management of residual nasal deformities. PATIENTS AND METHODS: Medical records of all patients with nasal fractures evaluated and treated by the Division of Oral and Maxillofacial Surgery at the University of Florida Health Science Center, Jacksonville, FL between January 2001 and October 2004 were retrospectively evaluated. Out of a total of 344 patients, 50 patients met the inclusion criteria. Forty-four patients (group A) underwent closed reduction of nasal bones and septum along with a septoplasty if needed within 2 weeks of initial injury. Six patients (group B) could not tolerate any surgical intervention because of multisystem injury or comorbidities. All 50 patients were then followed up in the Division of Oral and Maxillofacial Surgery to determine overall efficacy of the initial treatment modality, as well as the need for secondary post-traumatic septo-rhinoplasty. Group A was then further subdivided into groups A1 and A2. Group A1 consisted of patients who underwent a closed reduction of their nasal complex fracture without a residual deformity or the need for a secondary post-traumatic septo-rhinoplasty. Group A2 consisted of patients who underwent a closed reduction of their nasal complex fracture and developed a secondary nasal deformity significant enough to require a septo-rhinoplasty. RESULTS: The follow-up period ranged from 1 week to 12 months. Nine patients in group A were lost to follow-up. Patients in group A1 (31 patients) were pleased with their results and did not require a secondary surgery. Four patients developed a post-traumatic nasal deformity requiring a post-traumatic septo-rhinoplasty (group A2). All patients in group B required post-traumatic septo-rhinoplasty. CONCLUSION: Closed reduction of nasal fractures appears to be an effective method of treatment as long as careful attention is paid to the key regions in the nasal complex, including the septum at the initial time of treatment. Ideal results are obtained when surgery is performed within 2 weeks of initial injury. Factors such as timing of surgery, the status of the nasal septum, delay in treatment, and other associated injuries may influence the overall result.