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Shea Irwin posted an update 6 months ago
Platelets, lacking nuclei, still contain entirely functional mitochondria, and the current understanding is that several processes carried out by platelets necessitate mitochondrial function. Although the literature is rich with mitochondrial-targeting compounds for cancer, their interaction with platelet mitochondria and consequent effect on platelet activity has been investigated in a very limited number of studies. In melanoma and oral cancer cells, recent studies have shown that magnolia extract hinders mitochondrial respiration, and mitochondria-targeted magnolol diminishes cell proliferation. These mechanisms also result in ROS induction and mitophagy. The impact of alkyl chain length variations in triphenylphosphonium cations on the interaction of magnolol with human-washed platelets was examined in this study. Magnolol (MGN4)’s antiplatelet efficacy was substantially enhanced—a three-fold decrease in IC50 was observed—when triphenylphosphonium was appended via a four-carbon linker. Furthermore, platelets subjected to MGN4 at a concentration of 5 µM exhibited several distinctions from the control group, including heightened basal respiration, enhanced collagen-stimulated respiration, increased ATP-independent respiration, and decreased ATP-dependent respiration, as well as diminished non-mitochondrial respiration.
Twenty-one analogs, based on benzimidazole and incorporating a substituted benzaldehyde moiety, were synthesized (1-21). These samples were then evaluated for their ability to inhibit acetylcholinesterase and butyrylcholinesterase. Apart from derivatives 13, 14, and 20, the remaining compounds demonstrated a spectrum of inhibitory potential against acetylcholinesterase, with IC50 values ranging from 0.0001 M to 0.0050 M, and against butyrylcholinesterase, with IC50 values ranging from 0.0001 M to 0.0080 M, when contrasted with the standard drug donepezil, having IC50 values of 0.016-0.12 M and 0.0010-0.030 M, for acetylcholinesterase and butyrylcholinesterase, respectively. In both experimental scenarios, Compound 3 exhibited the highest potency, a result of the chloro groups situated at the 3rd and 4th positions of the phenyl ring structure. A structure-activity relationship examination was carried out on all analogs excluding 13, 14, and 20. The subsequent step involved molecular dynamics simulations on the top two compounds, alongside the reference compound, in their respective complexes with acetylcholinesterase and butyrylcholinesterase. Through molecular dynamics simulations, it was determined that compound 3 created the most stable complex with both acetylcholinesterase and butyrylcholinesterase, followed in stability by compound 10. The standard inhibitor donepezil was outperformed by both compounds, which exhibited higher stability and binding affinities for both acetylcholinesterase and butyrylcholinesterase.
The efficacy of treatments for various types of tumors has been enhanced through the transformative use of targeted anti-tumor therapies. Highlighting phosphatidylinositol-3 kinase (PI3K) among the validated targets is warranted. PI3K inhibitors, such as gedatolisib (4), have been developed to treat cancer. Given its selection as a prototype, this inhibitor initiated plans for molecular modifications, which will create a fresh series of simplified gedatolisib analogues (5a-f). In phenotypic models using solid and non-adherent tumour cell lines, the comparative cytotoxic activity profile of the synthesized analogues was determined. sphk signal LASSBio-2252, or compound 5f, demonstrated exceptional promise within the series, featuring robust aqueous solubility (4238 M at pH 7.4; 3933 M at pH 5.8), a favorable partition coefficient (cLogP = 2.96), potent cytotoxicity against human leukemia cell lines (CCRF-CEM, K562, and MOLT-4), and an exemplary metabolic stability profile in rat liver microsomes (t1/2 = 462 minutes; Clapp = 0.058 mL/min/g). Flow cytometry, comparing to gedatolisib, demonstrated 5f’s cytotoxic effect’s dependence on modulating the PI3K pathway.
The current study’s purpose is the development of Doxorubicin-Erlotinib nanoparticles (Dox-Erlo NPs) and folate-bound Dox-Erlo-NP constructs to specifically target glioma cancer. Brain glial cells serve as the point of origin for glioma, a frequently encountered cancerous growth that progresses. In spite of its semi-permeable character, the blood-brain barrier (BBB) demonstrates high selectivity for compounds; consequently, the development of pharmaceutical agents that penetrate this barrier represents a significant challenge. The NP conjugates examined in this article are shown to potentially enhance BBB permeability and concentrate the drug within the target region, sidestepping the BBB. Folic acid-functionalized NPs were prepared via a double-emulsion solvent evaporation process utilizing a biopolymer for site-specific targeting. Characterizing Dox-Erlo NPs and Dox-Erlo-NP conjugates in vitro involved a multifaceted assessment of numerous parameters. The z-average size of Dox-Erlo nanoparticles was 9535 ± 1025 nm, and that of the Dox-Erlo-NP conjugates was 11012 ± 92 nm. In terms of zeta potential, Dox-Erlo NPs exhibited a value of -181 mV, while Dox-Erlo-NP conjugates displayed a potential of -251 mV. A TEM imaging technique indicated that the NPs exhibited a consistent, uniform, and de-aggregated distribution. A hemolytic assay validated the hemocompatibility of the developed formulation, enabling safe administration procedures. Dox-Erlo-NP conjugates yielded a substantial reduction in the number of viable U87 cells, decreasing to 2466, representing 208% fewer cells, and in C6 cells, to 3233, representing 251% fewer cells. After 24 hours, IC50 values of 3064 μM and 3350 μM were observed for U87 and C6 cells, respectively. A significant concentration of Dox and Erlo was found in the brain, as a biodistribution study demonstrated, in comparison to the drug suspension. For three months, Dox-Erlo-NP conjugates demonstrated exceptional stability. In glioma therapy, the findings suggest the possibility of Dox-Erlo-NP conjugates as a highly promising agent for administration.
Personal distress and psychological well-being are often directly correlated with the condition of one’s hair. Despite hair loss (alopecia) having no effect on human biological health, it nonetheless has a detrimental effect on an individual’s social well-being. Consequently, the solutions to hair problems and the upkeep of a healthy hair condition are mandatory. Several pharmaceutical and cosmetic treatments are available to address the issue of hair loss and stimulate hair regrowth. A multitude of elements impacting hair health encompass inherited traits, medical conditions, pharmaceutical agents, daily routines, environmental toxins, and detrimental practices such as smoking, poor dietary habits, and mental strain. Hair problems are prompting a trend towards natural compound-based remedies, as synthetic and chemical formulations are now recognized for their potential side effects. The use of phytochemicals to support healthy hair has a history that is documented in ancient writings. Despite this, hair loss research has undergone a notable acceleration in the past several decades. This review investigates alopecia types, the factors that affect hair health, therapeutic strategies for alopecia, the contributions of phytochemicals in managing hair loss, and the mechanisms by which phytochemicals stimulate hair follicle growth. Phytochemicals, as per the literature review, are promising agents in the development of treatments for a range of hair issues. To bring scientific findings to the market, further rigorous study is essential.
Elevated drug efflux, primarily facilitated by P-glycoprotein (P-gp) of ATP-binding cassette transporters, is a key mechanism in multidrug resistance (MDR). The present study investigated the mechanisms by which pinostrobin and tectochrysin inhibit P-gp activity in multidrug-resistant cancer cells. Investigations into fluorescence substrate efflux, multidrug resistance 1 (MDR1) shift assays, P-gp ATPase activity, Western blotting, and docking simulations were undertaken. Investigations into the test compounds’ ability to reverse MDR, and their underlying molecular mechanisms, were conducted using cell viability assays, cell cycle analyses, apoptosis assays, and the calculation of combination indices. As revealed by the results, pinostrobin and tectochrysin were not substrates for P-gp, and they had no effect on the expression of this transporter. Through noncompetitive mechanisms, both compounds prevented the expulsion of rhodamine 123 and doxorubicin by P-gp. In addition, chemotherapeutic drugs, specifically vincristine, paclitaxel, and docetaxel, caused a resensitization of MDR cancer cells, leading to a significant reversal of multidrug resistance. Our findings confirm the effectiveness of pinostrobin and tectochrysin as P-gp inhibitors, positioning them as viable options for enhancing the sensitivity of multidrug-resistant cancer cells.
Through this study, a unique acridine derivative was synthesized, a compound unprecedented in the literature, and subjected to thorough chemical characterization employing NMR, MS, and IR techniques, followed by an assessment of its antileishmanial efficacy. In vitro assays, employing MTT, annexin V-FITC/PI, and CBA, were conducted to determine the compound’s antileishmanial activity against L. amazonensis strains, cytotoxicity against macrophages, and immunomodulatory properties. In vitro and in silico analyses were employed to examine DNA interaction as a means of discovering potential molecular targets. The compound exhibited potent antileishmanial activity, with IC50 values of 657 µg/mL against amastigotes and 9497 µg/mL against promastigotes, and displayed no cytotoxicity against macrophages, with a CC50 exceeding 25600 µg/mL. Upon flow cytometric assessment, the viability of macrophages was found to be 99.8%. The compound’s influence on infected macrophages resulted in an antileishmanial effect, along with modifications to the expression levels of TNF-, IL-10, and IL-6, indicative of a subtle immunomodulatory response.
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