Targeted delivery of the metastasis-specific tumour homing TMTP1 peptide to non-small-cell lung cancer (NSCLC) using inhalable hybrid nano-assemblies.

Lung cancer is one of the most fatal malignancies, with the highest death rate (∼19%), and the NSCLC type accounts for ∼85% of lung cancers. In the search for new treatments, antimicrobial peptides have received much attention due to their propensity for selective destruction of cancer cells. In the current study, we evaluated the efficacy of the metastasis-specific tumour-homing-TMTP1 peptide against lung cancer using inhalable hybrid nano-assemblies of the PEG-PLGA copolymer as a carrier for pulmonary delivery which was assessed for aerodynamic and physicochemical properties, along with the peptide-release profile, physical stability, cellular uptake and biocompatibility, generation of reactive oxygen species, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Optimization of inhaled dose, lung retention, and efficacy studies was conducted to evaluate the formulation in an NNK (nicotine-derived nitrosamine ketone) induced tumour-bearing lung cancer murine model. After inhalation, the formulation with nano-scale physiognomies showed good lung deposition, retention, and metabolic stability. The inhalable nano-assemblies have shown enhanced generation of reactive oxygen species with increased autophagy flux and apoptotic cell death. Pre-clinical animal trials show substantial tumour regression by inhalable TMTP1-based nano-formulation with limited side effects. Our results on metastasis targeting and tumour-homing peptide TMTP1 demonstrate its effective tumour targeting and tumour-killing efficacy and provide a reference for the development of new therapeutics for NSCLC.

Inhalable chitosan-coated nano-assemblies potentiate niclosamide for targeted abrogation of non-small-cell lung cancer through dual modulation of autophagy and apoptosis.

Lung carcinoma, particularly non-small-cell lung cancer (NSCLC), accounts for a significant portion of cancer-related deaths, with a fatality rate of approximately 19 %. Niclosamide (NIC), originally an anthelmintic drug, has attracted attention for its potential in disrupting cancer cells through various intracellular signaling pathways. However, its effectiveness is hampered by limited solubility, reducing its bioavailability. This study investigates the efficacy of NIC against lung cancer using inhalable hybrid nano-assemblies with chitosan-functionalized Poly (ε-caprolactone) (PCL) as a carrier for pulmonary delivery. The evaluation encompasses various aspects such as aerodynamic and physicochemical properties, drug release kinetics, cellular uptake, biocompatibility, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Increasing NIC dosage correlates with enhanced inhibition of cell proliferation, showing a dose-dependent profile (approximately 75 % inhibition efficiency at 20 µg/mL of NIC). Optimization of inhaled dosage and efficacy is conducted in a murine model of NNK-induced tumor-bearing lung cancer. Following inhalation, NIC-CS-PCL-NA demonstrates significant lung deposition, retention, and metabolic stability. Inhalable nano-assemblies promote autophagy flux and induce apoptotic cell death. Preclinical trials reveal substantial tumor regression with minimal adverse effects, underscoring the potential of inhalable NIC-based nano-formulation as a potent therapeutic approach for NSCLC, offering effective tumor targeting and killing capabilities.

'Comprehensive review of emerging drug targets in traumatic brain injury (TBI): challenges and future scope.

Traumatic brain injury (TBI) is a complex brain problem that causes significant morbidity and mortality among people of all age groups. The complex pathophysiology, varied symptoms, and inadequate treatment further precipitate the problem. Further, TBI produces several psychiatric problems and other related complications in post-TBI survival patients, which are often treated symptomatically or inadequately. Several approaches, including neuroprotective agents targeting several pathways of oxidative stress, neuroinflammation, cytokines, immune system GABA, glutamatergic, microglia, and astrocytes, are being tried by researchers to develop effective treatments or magic bullets to manage the condition effectively. The problem of TBI is therefore treated as a challenge among pharmaceutical scientists or researchers to develop drugs for the effective management of this problem. The goal of the present comprehensive review is to provide an overview of the several pharmacological targets, processes, and cellular pathways that researchers are focusing on, along with an update on their current state.

Neuroprotective mechanism of trans,trans-Farnesol in an ICV-STZ-induced rat model of Alzheimer's pathology.

BACKGROUND: Alzheimer's disease (AD) is a prominent cause of dementia, resulting in neurodegeneration and memory impairment. This condition imposes a considerable public health burden on both patients and their families due to the patients' functional impairments as well as the psychological and financial constraints. It has been well demonstrated that its aetiology involves proteinopathy, mitochondriopathies, and enhanced reactive oxygen species (ROS) generation, which are some of the key features of AD brains that further result in oxidative stress, excitotoxicity, autophagy, and mitochondrial dysfunction. OBJECTIVE: The current investigation was created with the aim of elucidating the neurological defence mechanism of trans,trans-Farnesol (TF) against intracerebroventricular-streptozotocin (ICV-STZ)-induced Alzheimer-like symptoms and related pathologies in rodents. MATERIALS AND METHODS: The current investigation involved male SD rats receiving TF (25-100 mg/kg, per oral) consecutively for 21 days in ICV-STZ-treated animals. An in silico study was carried out to explore the possible interaction between TF and NADH dehydrogenase and succinate dehydrogenase. Further, various behavioural (Morris water maze and novel object recognition test), biochemical (oxidants and anti-oxidant markers), activities of mitochondrial enzyme complexes and acetylcholinesterase (AChE), pro-inflammatory (tumor necrosis factor-alpha; TNF-α) levels, and histopathological studies were evaluated in specific brain regions. RESULTS: Rats administered ICV-STZ followed by treatment with TF (25, 50, and 100 mg/kg) for 21 days had significantly better mental performance (reduced escape latency to access platform, extended time spent in target quadrant, and improved differential index) in the Morris water maze test and new object recognition test models when compared to control (ICV-STZ)-treated groups. Further, TF treatment significantly restored redox proportion, anti-oxidant levels, regained mitochondrial capacities, attenuated altered AChE action, levels of TNF-α, and histopathological alterations in certain brain regions in comparison with control. In in silico analysis, TF caused greater interaction with NADH dehydrogenase and succinate dehydrogenase. CONCLUSION: The current work demonstrates the neuroprotective ability of TF in an experimental model with AD-like pathologies. The study further suggests that the neuroprotective impacts of TF may be related to its effects on TNF-α levels, oxidative stress pathways, and mitochondrial complex capabilities.

Therapeutic potential of Allium Sativum against the Aß(1-40)-induced oxidative stress and mitochondrial dysfunction in the Wistar rats.

From the early stages of any neurodegenerative-disease mitochondrial functionality has been mortally extricated, though the exact timeline of these events is still unclear, it is likely to represent a progressive neurons-decline and cognitive-functions. Hence strategies suggested by herbal extract to restore mitochondrial functions may be a remedial approach to chronic neurodegenerative disorder like Alzheimer's disease (AD). This research was designed to evaluate if Aß1-40 induced oxidative stress and mitochondrial dysfunction could be inhibited by Allium Sativum (AS) supplementation. AD was induced by a single intra-hippocampal injection of Aß1-40 (5 µg/4 µl), while herbal supplementation was given orally (100, 250, 500 mg/kg body weight, daily) for 3 weeks. Morris water maze was used to assess cognitive function shows deficits in Aß1-40 treated animals, there is no significant alteration in locomotor function as examined by actophotometer. This was accompanied by enhancement in oxidative stress indicating by accentuated ROS and protein carbonyl levels. Concomitantly, decrease in activity of antioxidant enzymes was observed in diseased animals; as expressed by reduced superoxide-dismutase and catalase activity, as well as reduction in GSH levels and impaired mitochondrial functions. Medium dose of AS has been found effective in restoring the memory impairment along with antioxidant levels but high dose is more efficient as observed in the Aß1-40 treated rats. High dose of AS, on the other hand significantly ameliorates the mitochondrial-dysfunction in comparison to medium dose. Taken together, the findings reveal that AS reverses Aß1-40 induced brain alteration, it could be an efficient clinical mitigation action against AD growth.