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International Journal of Molecular... May 2024Podophyllotoxin (PPT) is an active pharmaceutical ingredient (API) with established antitumor potential. However, due to its systemic toxicity, its use is restricted to...
Cellular Distribution and Ultrastructural Changes in HaCaT Cells, Induced by Podophyllotoxin and Its Novel Fluorescent Derivative, Supported by the Molecular Docking Studies.
Podophyllotoxin (PPT) is an active pharmaceutical ingredient (API) with established antitumor potential. However, due to its systemic toxicity, its use is restricted to topical treatment of anogenital warts. Less toxic PPT derivatives (e.g., etoposide and teniposide) are used intravenously as anticancer agents. PPT has been exploited as a scaffold of new potential therapeutic agents; however, fewer studies have been conducted on the parent molecule than on its derivatives. We have undertaken a study of ultrastructural changes induced by PPT on HaCaT keratinocytes. We have also tracked the intracellular localization of PPT using its fluorescent derivative (PPT-FL). Moreover, we performed molecular docking of both PPT and PPT-FL to compare their affinity to various binding sites of tubulin. Using the Presto blue viability assay, we established working concentrations of PPT in HaCaT cells. Subsequently, we have used selected concentrations to determine PPT effects at the ultrastructural level. Dynamics of PPT distribution by confocal microscopy was performed using PPT-FL. Molecular docking calculations were conducted using Glide. PPT induces a time-dependent cytotoxic effect on HaCaT cells. Within 24 h, we observed the elongation of cytoplasmic processes, formation of cytoplasmic vacuoles, progressive ER stress, and shortening of the mitochondrial long axis. After 48 h, we noticed disintegration of the cell membrane, progressive vacuolization, apoptotic/necrotic vesicles, and a change in the cell nucleus's appearance. PPT-FL was detected within HaCaT cells after ~10 min of incubation and remained within cells in the following measurements. Molecular docking confirmed the formation of a stable complex between tubulin and both PPT and PPT-FL. However, it was formed at different binding sites. PPT is highly toxic to normal human keratinocytes, even at low concentrations. It promptly enters the cells, probably via endocytosis. At lower concentrations, PPT causes disruptions in both ER and mitochondria, while at higher concentrations, it leads to massive vacuolization with subsequent cell death. The novel derivative of PPT, PPT-FL, forms a stable complex with tubulin, and therefore, it is a useful tracker of intracellular PPT binding and trafficking.
Topics: Humans; Molecular Docking Simulation; Podophyllotoxin; HaCaT Cells; Tubulin; Keratinocytes; Cell Survival; Mitochondria; Fluorescent Dyes; Binding Sites; Endoplasmic Reticulum Stress
PubMed: 38892135
DOI: 10.3390/ijms25115948 -
Heliyon Jun 2024is a functional fruit with tonic effect and was widely used by traditional Chinese medicine for treatment and health care. The quality of fruit may vary by different...
is a functional fruit with tonic effect and was widely used by traditional Chinese medicine for treatment and health care. The quality of fruit may vary by different storage condition. In this study, the influence of ambient temperature, humidity, packaging materials and period of storage on the quality of fruits were investigated. The contents of main active components lignans and organic acids were simultaneously determined by ultra-performance liquid chromatography coupled to quadrupole electrostatic field orbitrap high resolution mass spectrometry (UPLC Orbitrap HRMS). The antioxidant activity was determined using DPPH radical scavenging capacity, ABTS inhibition rate and FRAP value. The correlation of multicomponent and antioxidant activity was analyzed by grey relevance analysis. Taking the changes of multicomponent and antioxidant activity as investigation index, fruits under different storage conditions was comprehensively evaluated. Schisandrol A, malic acid, sorbic acid, schizandrin A, schizandrin B, and schisandrol B were the main effective components of antioxidant activity. Ambient temperature at 5 °C and humidity at 40 % were more suitable for fruits and kraft paper bag was better packaging material. Do not exceed 1 year was the effective storage period. For the safety evaluation, no aflatoxin was detected within the storage period of 2 years, demonstrated the storage was satisfactory. This study provided a reference for the high-quality storage and standardized operating procedures for storage of fruits.
PubMed: 38882346
DOI: 10.1016/j.heliyon.2024.e32194 -
Biomedicine & Pharmacotherapy =... Jul 2024Enterovirus 71 (EV71), a prominent pathogen associated with hand, foot, and mouth disease (HFMD), has been reported worldwide. To date, the advancement of effective...
Enterovirus 71 (EV71), a prominent pathogen associated with hand, foot, and mouth disease (HFMD), has been reported worldwide. To date, the advancement of effective drugs targeting EV71 remains in the preliminary experimental stage. In this study, magnolol demonstrated a significant dose-dependent inhibition of EV71 replication in vitro. It upregulated the overall expression level of nuclear factor erythroid 2 - related factor 2 (Nrf2) and facilitated its nucleus translocation, resulting in the increased expression of various ferroptosis inhibitory genes. This process led to a reduction in reactive oxygen species (ROS) accumulation induced by viral infection. Additionally, magnolol exhibited a broad-spectrum antiviral effect against enteroviruses. Notably, treatment with magnolol substantially enhanced the survival rate of EV71-infected mice, attenuated viral load in heart, liver, brain, and limb tissues, and mitigated tissue inflammation. Taken together, magnolol emerges as a promising candidate for the development of anti-EV71 drugs.
Topics: Animals; Biphenyl Compounds; NF-E2-Related Factor 2; Lignans; Enterovirus A, Human; Antiviral Agents; Mice; Humans; Glutathione; Virus Replication; Reactive Oxygen Species; Enterovirus Infections; Signal Transduction; Chlorocebus aethiops; Vero Cells; Ferroptosis
PubMed: 38876045
DOI: 10.1016/j.biopha.2024.116866 -
European Journal of Medicinal Chemistry May 2024Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of...
Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of cancer, obesity, and viral infection. A target of diphyllin and naturally occurring derivatives is the vacuolar ATPase (V-ATPase) complex. Although diphyllin-related natural products are active with in vitro models for viral entry, the potencies and unknown pharmacokinetic properties limit well-designed in vivo evaluations. Previous studies demonstrated that diphyllin derivatives have the utility of blocking the Ebola virus cell entry pathway. However, diphyllin shows limited potency and poor oral bioavailability in mice. An avenue to improve the potency was used in a new library of synthetic derivatives of diphyllin. Diphyllin derivatives exploiting ether linkages at the 4-position with one-to-three carbon spacers to an oxygen or nitrogen atom provided compounds with EC values ranging from 7 to 600 nM potency and selectivity up to >500 against Ebola virus in infection assays. These relative potencies are reflected in the Ebola virus infection of primary macrophages, a cell type involved in early pathogenesis. A target engagement study reveals that reducing the ATPV0a2 protein expression enhanced the potency of diphyllin derivatives to block EBOV entry, consistent with effects on the endosomal V-ATPase function. Despite the substantial enhancement of antiviral potencies, limitations were identified, including rapid clearance predicted by in vitro microsome stability assays. However, compounds with similar or improved half-lives relative to diphyllin demonstrated improved pharmacokinetic profiles in vivo. Importantly, these derivatives displayed suitable plasma levels using oral administration, establishing the feasibility of in vivo antiviral testing.
PubMed: 38875806
DOI: 10.1016/j.ejmech.2024.116537 -
CNS Neuroscience & Therapeutics Jun 2024Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized...
Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1 transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1β/NF-κB pathways.
AIM
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.
METHODS
A-1 at 33.3 mg/kg was administrated in SOD1 transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.
RESULTS
A-1 administration in SOD1 mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1β, pIκBα/IκBα, and pNF-κB/NF-κB.
CONCLUSIONS
A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1β/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.
Topics: Animals; Mice, Transgenic; Sirtuin 1; Mice; NF-kappa B; AMP-Activated Protein Kinases; Furans; Amyotrophic Lateral Sclerosis; Interleukin-1beta; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Lignans; Signal Transduction; Superoxide Dismutase-1; Male; Motor Neurons; Spinal Cord
PubMed: 38872258
DOI: 10.1111/cns.14692 -
Redox Biology Aug 2024Silicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair...
BACKGROUND
Silicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair and structural integrity maintenance. Inhibiting ATII cell senescence has shown promise in silicosis treatment. However, the mechanism behind silica-induced senescence remains elusive.
METHODS
The study employed male C57BL/6 N mice and A549 human alveolar epithelial cells to investigate silicosis and its potential treatment. Silicosis was induced in mice via intratracheal instillation of crystalline silica particles, with honokiol administered intraperitoneally for 14 days. Silica-induced senescence in A549 cells was confirmed, and SIRT3 knockout and overexpression cell lines were generated. Various analyses were conducted, including immunoblotting, qRT-PCR, histology, and transmission electron microscopy. Statistical significance was determined using one-way ANOVA with Tukey's post-hoc test.
RESULTS
This study elucidates how silica induces ATII cell senescence, emphasizing mtDNA damage. Notably, honokiol (HKL) emerges as a promising anti-senescence and anti-fibrosis agent, acting through sirt3. honokiol effectively attenuated senescence in ATII cells, dependent on sirt3 expression, while mitigating mtDNA damage. Sirt3, a class III histone deacetylase, regulates senescence and mitochondrial stress. HKL activates sirt3, protecting against pulmonary fibrosis and mitochondrial damage. Additionally, HKL downregulated cGAS expression in senescent ATII cells induced by silica, suggesting sirt3's role as an upstream regulator of the cGAS/STING signaling pathway. Moreover, honokiol treatment inhibited the activation of the NF-κB signaling pathway, associated with reduced oxidative stress and mtDNA damage. Notably, HKL enhanced the activity of SOD2, crucial for mitochondrial function, through sirt3-mediated deacetylation. Additionally, HKL promoted the deacetylation activity of sirt3, further safeguarding mtDNA integrity.
CONCLUSIONS
This study uncovers a natural compound, HKL, with significant anti-fibrotic properties through activating sirt3, shedding light on silicosis pathogenesis and treatment avenues.
Topics: Animals; Silicosis; Sirtuin 3; Cellular Senescence; Mice; Alveolar Epithelial Cells; Biphenyl Compounds; Humans; Lignans; Signal Transduction; Male; A549 Cells; Nucleotidyltransferases; Disease Models, Animal; Membrane Proteins; Mice, Inbred C57BL; DNA Damage; Allyl Compounds; Phenols
PubMed: 38865904
DOI: 10.1016/j.redox.2024.103224 -
Ecotoxicology and Environmental Safety Jun 2024Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The...
Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.
PubMed: 38850705
DOI: 10.1016/j.ecoenv.2024.116548 -
Ultrasonics Sonochemistry Jul 2024The utilization of metallic nanoparticles in bio-nanofabrication holds significant potential in the field of applied research. The current study applied and compared...
UPLC-qTOF-MS phytochemical profile of Commiphora gileadensis leaf extract via integrated ultrasonic-microwave-assisted technique and synthesis of silver nanoparticles for enhanced antibacterial properties.
The utilization of metallic nanoparticles in bio-nanofabrication holds significant potential in the field of applied research. The current study applied and compared integrated ultrasonic-microwave-assisted extraction (US/MICE), ultrasonic extraction (USE), microwave-assisted extraction (MICE), and maceration (MAE) to extract total phenolic content (TPC). In addition, the study examined the antioxidant activity of Commiphora gileadensis (Cg) leaf. The results demonstrated that the TPC of US/MICE exhibited the maximum value at 59.34 ± 0.007 mg GAE/g DM. Furthermore, at a concentration of 10 μg/mL, TPC displayed a significant scavenging effect on DPPH (56.69 %), with an EC (6.48 μg/mL). Comprehensive metabolite profiling of the extract using UPLC-qTOF-MS/MS was performed to identify active agents. A total of 64 chromatographic peaks were found, out of which 60 were annotated. The most prevalent classes of metabolites found were polyphenols (including flavonoids and lignans), organic compounds and their derivatives, amides and amines, terpenes, and fatty acid derivatives. Transmission electron microscopy (TEM) revealed the aggregate size of the synthesized nanoparticles and the spherical shape of C. gileadensis-mediated silver nanoparticles (Cg-AgNPs). The nanoparticles had a particle size ranging from 7.7 to 42.9 nm. The Cg-AgNPs exhibited more inhibition zones against S. aureus and E. coli. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Cg-extract, AgNPs, and Cg-AgNPs were also tested. This study demonstrated the feasibility of using combined ultrasonic-microwave-assisted extraction to separate and extract chemicals from C. gileadensis on a large scale. These compounds have potential use in the pharmaceutical industry. Combining antibacterial and biocompatible properties in materials is vital for designing new materials for biomedical applications. Additionally, the results showed that the biocompatibility of the Ag-NPs using C. gileadensis extracts demonstrated outstanding antibacterial properties.
Topics: Anti-Bacterial Agents; Silver; Commiphora; Metal Nanoparticles; Plant Leaves; Plant Extracts; Ultrasonic Waves; Microwaves; Chromatography, High Pressure Liquid; Microbial Sensitivity Tests; Antioxidants; Staphylococcus aureus; Escherichia coli; Phytochemicals; Chemistry Techniques, Synthetic
PubMed: 38815489
DOI: 10.1016/j.ultsonch.2024.106923 -
Frontiers in Microbiology 2024In recent years, the world's attention has been drawn to antimicrobial resistance (AMR) because to the frightening prospect of growing death rates. Nanomaterials are...
INTRODUCTION
In recent years, the world's attention has been drawn to antimicrobial resistance (AMR) because to the frightening prospect of growing death rates. Nanomaterials are being investigated due to their potential in a wide range of technical and biological applications.
METHODS
The purpose of this study was to biosynthesis zinc oxide nanoparticles (ZnONPs) using sp. SA17 fungal extract, followed by characterization of the produced nanoparticles (NP) using electron microscopy (TEM and SEM), UV-analysis, X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR).
RESULTS AND DISCUSSION
The HR-TEM revealed spherical nanoparticles with an average size of 7.2 nm, and XRD validated the crystalline nature and crystal structure features of the generated ZnONPs, while the zeta potential was 18.16 mV, indicating that the particles' surfaces are positively charged. The FT-IR was also used to identify the biomolecules involved in the synthesis of ZnONPs. The antibacterial and anticancer properties of both the crude fungal extract and its nano-form against several microbial strains and cancer cell lines were also investigated. Inhibition zone diameters against pathogenic bacteria ranged from 3 to 13 mm, while IC values against cancer cell lines ranged from 17.65 to 84.55 M. Additionally, 33 compounds, including flavonoids, phenolic acids, coumarins, organic acids, anthraquinones, and lignans, were discovered through chemical profiling of the extract using UPLC-QTOF-MS/MS. Some molecules, such pomiferin and glabrol, may be useful for antibacterial purposes, according to study, while daidzein 4'-sulfate showed promise as an anti-cancer metabolite.
PubMed: 38803373
DOI: 10.3389/fmicb.2024.1366614 -
Nutrients May 2024Extra virgin olive oil (EVOO) is a symbol of the Mediterranean diet, constituting its primary source of fat. The beneficial effect of EVOO is strictly related to the... (Review)
Review
Extra virgin olive oil (EVOO) is a symbol of the Mediterranean diet, constituting its primary source of fat. The beneficial effect of EVOO is strictly related to the presence of fatty acids and polyphenols, bioactive compounds endowed with nutraceutical properties. Among EVOO polyphenols, lignans possess a steroid-like chemical structure and are part of the phytoestrogen family, which is renowned for its health properties. The natural lignans (+)-pinoresinol and 1-acetoxypinoresinol (1-AP) are commonly present in olives and in EVOO. Although (+)-pinoresinol is found in different edible plants, such as flaxseed, beans, whole-grain cereals, sesame seeds, and certain vegetables and fruit, 1-AP was exclusively identified in olives in 2000. So far, the scientific literature has extensively covered different aspects of (+)-pinoresinol, including its isolation and nutraceutical properties. In contrast, less is known about the olive lignan 1-AP. Therefore, this review aimed to comprehensively evaluate the more important aspects of 1-AP, collecting all the literature from 2016 to the present, exploring its distribution in different cultivars, analytical isolation and purification, and nutraceutical properties.
Topics: Lignans; Olea; Dietary Supplements; Humans; Olive Oil; Fruit; Furans
PubMed: 38794712
DOI: 10.3390/nu16101474