Background: T-type calcium channels are aberrantly expressed in different human cancers and regulate cell cycle progression, proliferation, migration, and survival. FAK-1 can promote tumor protein degradation (p53) through ubiquitination, leading to cancer cell growth and proliferation. Similar findings are obtained regarding protease inhibitors' effect on cytokine-induced neutrophil activation that suppresses Granulocyte-macrophage colony-stimulating-factor (GM-CSF) TNF-α-induced O2 release and adherence in human neutrophils without affecting phosphorylation of Extracellular signal-regulated kinase (ERK) and p38. Nanosuspensions are carrier-free, submicron colloidal dispersions which consist of pure drugs and stabilizers. Incorporating drug loaded in nanosuspensions possessed great advantages of passive drug targeting with improved solubility, stability, and bioavailability, as well as lower systemic toxicity. Objective: The present investigation objective was to establish a molecular association of Protease and Focal Adhesion Kinase 1 as cancer targets for isradipine a calcium channel blocker (CCB). Furthermore, the study also aimed to formulate its optimized nanosuspension and how the physical, morphological, and dissolution properties of isradipine impact nanosuspension stability. Material and Method: Five different molecular targets, namely Cysteine Proteases (Cathepsin B), Serine Proteases (Matriptase), Aspartate Proteases, Matrix Metalloproteases (MMP), and FAK-1 were obtained from RCSB-PDB, which has some leading associations with the inhibition in cancer pathogenesis. Molecular interactions of these targets with CCB isradipine were identified and established by the molecular simulation docking studies. Isradipine-loaded nanosuspension was prepared by precipitation technique by employing a 23 factorial design. PVP K-30, poloxamer 188, and sodium lauryl sulfate (SLS) were used as polymer, co-polymer, and surfactant. The nanosuspension particles are characterized for particle size, zeta potential, viscosity, polydispersity index (PDI), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), In-vitro drug release kinetics, and short-term stability study. Result: It was found to show considerable interaction with Cysteine, Serine, Aspartate, Threonine, and Matrix metalloproteases with the binding energy of -3.91, -6.7, -3.48, -8.42, respectively. Furthermore, the interaction of isradipine with FAK-1 was compared with 7 native ligands and was found to show significant interaction with a binding energy of -8.62, -7.27, -7.69, -5.67, -5.41, -7.44, -8.21. The optimized nanosuspension was evaluated and exhibited the particle size of 754.9 nm, zeta potential of 32.5 mV, the viscosity of 1.287 cp, and PDI of 1.000. The in-vitro dissolution of the optimized formulation (F8) was higher (96.57%). Conclusion: Isradipine could act as a potential inhibitor of different proteases and FAK-1 associated with tumor growth initiation, progression, and metastasis. Furthermore, isradipine-loaded nanosuspension with optimized release could be utilized to deliver the anticancer drug in a more targeted way as emerging cancer nanotechnology.
Aim: The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. Background: Alzheimer’s disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. Objective: The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer’s disease (AD) in the mouse model. Material and Method: The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. Result: Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. Conclusion: ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.
Post-menopausal osteoporosis is a chronic age-related illness marked by a decrease of bone density and quality, as well as a higher risk of fragility fractures. Fragility fractures are recognized to have a major impact on individuals and society both personal and financially. In recent years, it has been a hidden epidemic impacting over 200 million people globally. It is claimed that one osteoporosis fracture happens every three seconds throughout the world. The termination of ovarian hormone production, which causes rapid bone loss, puts postmenopausal women at greater risk of developing osteoporosis. The gradual changes in structure, quality and density of the bones lead to the fracture and a rise in morbidity and death among menopausal women. Interventions that enhance a woman’s well-being and quality of life by reducing the intensity and frequency of post-menopausal osteoporosis. Hormone therapy is helpful in managing menopausal symptoms; nevertheless, it has been linked to a number of potentially significant side effects, including the development of ovarian and breast cancer. As a result, there has been an increase in demand for alternative treatment options. Plant species with potential antiosteoporosis characteristics are highlighted and further discussed in order to aid future medication development for treating this illness. Many plants and there components have been demonstrated to have antiosteoporosis action based on a vast number of chemical and pharmacological studies. Plant-derived molecules have lately piqued the curiosity of researchers working on novel medicinal agents. As a result, therapeutic interventions that can delay reduce or prevent bone loss in ageing people, especially postmenopausal women, are essential to a person’s well-being and quality of life. The plants included in this review are those that have been frequently used in traditional medicine and have shown clinical efficacy in the management of post-menopausal osteoporosis. While numerous plants can prevent and treat osteoporosis, only a fraction of plants have been discussed, including their origin, active components, and pharmacological activity, we evaluated the challenges and methods utilized in the therapy of postmenopausal osteoporosis during the COVID-19 pandemic.
Background: Smoking causes cancer, breathing problems, heart attacks, and stroke and can lead to asthma and breathing problems. Nicotine replacement therapy (NRT) is considered one of the most widely accepted methods to quit smoking. However, it can lead to relapsed physical and psychological dependence. Aim: The present study aimed to explore propranolol, as a model drug to treat relapsed physical and psychological dependence due to NRT in smoking cessation. Furthermore, for its effective management, the transdermal drug delivery system has opted for effective and long-term release of propranolol. Material and Method: The molecular association of propranolol with eight different potential targets, namely, Acetylcholine Binding Protein (AChBP), Cannabinoid Receptor, CB1 and CB2, Monoamine oxidase (MAO), human dopamine D3 receptor, kainite, Leu- biogenic amine transporters (BAT) and α-type peroxisome proliferator-activated receptor were studied via molecular simulation models. Polymeric films containing propranolol HCI were prepared and evaluated to select a suitable formulation for developing transdermal drug delivery systems (TDDS). Films containing different ratios of HPMC K4M, HPMC 15M, and Sodium CMC were prepared by the solvent evaporation technique using PEG 4000 incorporated as a plasticizer, and SLS was used to act as a penetration enhancer. Manufactured transdermal films were physically evaluated for thickness, weight uniformity %, moisture content %, moisture uptake %, drug content %, and folding endurance. Result: Results indicated that propranolol can interact with all eight receptors at the active binding site. It was found to show considerable interaction with Acetylcholine Binding Protein (AChBP), MAO, human dopamine D3 receptor, kainite, and Leu- biogenic amine transporters (BAT) with the binding energy of -6.27, -6.74, -7.07, -6.84, and -6.63 kcal/mol respectively. The release rate of propranolol HCI decreased linearly with increasing polymer concentration in the film and depended on the film thickness. In contrast, the quantity of drug release was proportional to the square root of time. Kinetic data based on the release exponent, ‘n’ in the Peppas model showed that n values were between 0.95 and 1.08, indicating that drug release from polymer matrix was predominantly by diffusion with swelling. Conclusion: Transdermal drug delivery of propranolol could act as a potential regulator of all studied targets associated with physical and psychological dependence associated with NRT and smoking cessation. Furthermore, propranolol loaded transdermal patches with optimized release could be utilized to deliver the drug with optimum bioavailability for a considerable time.
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