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Molecules (Basel, Switzerland) Jan 2022L., an indigenous plant in Egypt, is widely used in traditional medicine due to its various pharmacological properties. We aimed to evaluate the anticancer properties...
L., an indigenous plant in Egypt, is widely used in traditional medicine due to its various pharmacological properties. We aimed to evaluate the anticancer properties of fruit methanol extract (AME) against liver cancer and to elucidate the active compound(s) and their mechanisms of action. Three fractions from AME (Hexane, CHCl, and EtOAc) were tested for their anticancer activities against HepG2 cell line in vitro (cytotoxicity assay, cell cycle analysis, annexin V-FITC apoptosis assay, and autophagy efflux assay) and in silico (molecular docking). Among the AME fractions, CHCl fraction revealed the most potent cytotoxic activity. The structures of compounds isolated from the CHCl fraction were elucidated using H- and C-NMR and found that Compound (xanthotoxin) has the strongest cytotoxic activity against HepG2 cells (IC 6.9 ± 1.07 µg/mL). Treating HepG2 cells with 6.9 µg/mL of xanthotoxin induced significant changes in the DNA-cell cycle (increases in apoptotic pre-G1 and G2/M phases and a decrease in the S-phase). Xanthotoxin induced significant increase in Annexin-V-positive HepG2 cells both at the early and late stages of apoptosis, as well as a significant decrease in autophagic flux in cancer compared with control cells. In silico analysis of xanthotoxin against the DNA-relaxing enzyme topoisomease II (PDB code: 3QX3) revealed strong interaction with the key amino acid Asp479 in a similar fashion to that of the co-crystallized inhibitor (etoposide), implying that xanthotoxin has a potential of a broad-spectrum anticancer activity. Our results indicate that xanthotoxin exhibits anticancer effects with good biocompatibility toward normal human cells. Further studies are needed to optimize its antitumor efficacy, toxicity, solubility, and pharmacokinetics.
Topics: Ammi; Computer Simulation; Furocoumarins; In Vitro Techniques; Methoxsalen
PubMed: 35164207
DOI: 10.3390/molecules27030943 -
Transplantation and Cellular Therapy May 2022Therapy for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) involves intensive immunosuppression, which is associated with significant risk of infection....
Therapy for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) involves intensive immunosuppression, which is associated with significant risk of infection. Extracorporeal photopheresis (ECP) is used to treat SR-aGVHD and is considered more immunomodulatory than immunosuppressive. However, pediatric data are mostly retrospective and often involve multistep ECP that includes apheresis followed by separate photosensitizing/reinfusion on another device. This study aimed to prospectively evaluate the efficacy and safety of a single-device ECP system in children with SR-aGVHD. In this open-label multicenter phase 3 study of the Therakos CellEx Photopheresis System in children/young adults age 1 to 21 years with SR-aGVHD. Patients were treated 3 times per week for 4 weeks, then twice weekly through week 12 while maintaining standard aGVHD prophylaxis. The primary efficacy endpoint was the proportion of patients achieving an overall response (OR) at day +28 without the addition of next-line systemic treatment. Secondary endpoints included the proportion of patients achieving OR at weeks 8 and 12; the mean weekly steroid dose at weeks 4, 8, and 12; and treatment-emergent adverse events (TEAEs). Twenty-nine children (median age, 8 years) were enrolled. OR was 55% by day 28, 74% by week 8, and 79% by week 12. Progressive improvements were observed in the skin and the gastrointestinal tract. The mean steroid dose was decreased from 1.54 mg/kg/day at baseline to 0.90 mg/kg/day at week 4; 35% of patients achieved a >50% steroid dose reduction by week 4, and 75% achieved a >50% steroid dose reduction by week 12. Of the 168 TEAEs reported among 25 patients (86%), 28 events (17%) were infections and 14 events (8%) were considered likely treatment related (all nonserious). Of 627 ECP treatments administered in children and young adults, 68% required blood priming. TEAEs related to Uvadex or ECP were rare, hypocalcemia was the most common (3 events total). Three deaths occurred and were deemed unrelated to ECP by the investigators. Use of the Therakos CellEx Photopheresis System was effective in children with SR-aGVHD, with more than one-half experiencing improvement by day 28 and further responses observed over 12 weeks. Very few TEAEs were attributable to ECP, and no new safety signals were observed.
Topics: Adolescent; Adult; Child; Child, Preschool; Graft vs Host Disease; Humans; Infant; Photopheresis; Prospective Studies; Retrospective Studies; Steroids; Young Adult
PubMed: 35124293
DOI: 10.1016/j.jtct.2022.01.025 -
Frontiers in Chemistry 2021In this work, we synthesize the sulfonated Schiff bases of the chitosan derivatives 2a-2j without the use of a catalyst in two moderately straightforward steps with good...
In this work, we synthesize the sulfonated Schiff bases of the chitosan derivatives 2a-2j without the use of a catalyst in two moderately straightforward steps with good yield within a short reaction time. The morphology and chemical structure of chitosan derivatives were investigated using FT-IR, NMR (H-C), XRD, and SEM. Furthermore, our chitosan derivatives were tested for their anticancer activity against the MCF-7 cancer cell line, and doxorubicin was used as a standard. In addition, the normal cell lines of the breast cancer cell MCF-10A, and of the lung cell MRC-5 were tested. Compound 2 h, with a GI value of 0.02 µM for MCF-7, is highly active compared with the standard doxorubicin and other compounds. The synthesized compounds 2a-2j exhibit low cytotoxicity, with IC > 100 μg/ml, against normal cell lines MCF-10A, MRC-5. We also provide the results of an study involving the Methoxsalen protein (1Z11). Compound 2h exhibits a higher binding affinity for 1Z11 protein (-5.9 kcal/mol) and a lower binding affinity for Doxorubicin (-5.3 kcal/mol) than certain other compounds. As a result of the aforementioned findings, the use of compound 2h has an anticancer drug will be researched in the future.
PubMed: 35111729
DOI: 10.3389/fchem.2021.796599 -
International Journal of Pharmaceutics Feb 2022Vitiligo is a common autoimmune skin disorder that is characterized by patchy depigmentation of the skin due to melanocytes and melanin loss. Herein, photodynamic...
Vitiligo is a common autoimmune skin disorder that is characterized by patchy depigmentation of the skin due to melanocytes and melanin loss. Herein, photodynamic therapy mediated 8-methoxypsoralen (8-MOP), has been used fortified with topical oleyl alcohol-based transethosomes; to overcome the poor solubility and adverse effects associated with 8-MOP oral delivery. A 2 factorial design was used to study the formulation variables. In vitro and ex-vivo characterization besides a clinical study were conducted to assess therapeutic efficacy of the formulation. Results revealed that transethosomes were superior to transfersomes regarding drug protection from degradation. The optimized transethosomal formulation, composed of 50 mg oleyl alcohol, 10 mg Tween 80® and 20% v/v ethanol, exhibited high entrapment efficiency (83.87 ± 4.1%) and drug loading (105.0 ± 0.2%). Moreover, it showed small vesicular size (265.0 ± 2.9 nm) and PDI (0.19). The formulation depicted core and shell structure, high deformability index (12.45 ± 0.7 mL/s) and high ex-vivo skin permeation. The topical application of the developed 8-MOP transethosomal gel enhanced the effect of NB UVB radiation in the treatment of vitiligo patients and exhibited no side effects. Hence, it can be used as a future strategy for delivering 8-MOP without the need of systemic application.
Topics: Administration, Cutaneous; Drug Delivery Systems; Fatty Alcohols; Humans; Methoxsalen; Photochemotherapy; Skin; Vitiligo
PubMed: 35026313
DOI: 10.1016/j.ijpharm.2022.121459 -
International Journal of Molecular... Dec 2021Aqueous-ethanol extracts (70%) from the leaves of Regel. (Ranunculaceae Juss.)-collected from natural populations of Kyrgyzstan-were studied by liquid chromatography...
Aqueous-ethanol extracts (70%) from the leaves of Regel. (Ranunculaceae Juss.)-collected from natural populations of Kyrgyzstan-were studied by liquid chromatography with high-resolution mass spectrometry (LC-HRMS). There was no variation of the metabolic profiles among plants that were collected from different populations. More than 160 compounds were found in the leaves, of which 72 were identified to the class level and 58 to the individual-compound level. The class of flavonoids proved to be the most widely represented (19 compounds), including six aglycones [quercetin, kaempferol, aromadendrin, 6-methoxytaxifolin, phloretin, and (+)-catechin] and mono- and diglycosides (the other 13 compounds). In the analyzed samples of , 14 fatty acid-related compounds were identified, but coumarins and furochromones that were found in were the most interesting result; furochromones khelloside, khellin, visnagin, and cimifugin were found in for the first time. Coumarins 5,7-dihydroxy-4-methylcoumarin, scoparone, fraxetin, and luvangetin and furochromones methoxsalen, 5--methylvisammioside, and visamminol-3'-O-glucoside were detected for the first time in the genus Salisb. For all the above compounds, the structural formulas are given. Furthermore, detailed information (with structural formulas) is provided on the diversity of chromones and furochromones in other representatives of . The presence of chromones in plants of the genus confirms its closeness to the genus L. because chromones are synthesized by normal physiological processes only in these members of the Ranunculaceae family.
Topics: Chromatography, Liquid; Chromones; Coumarins; Mass Spectrometry; Phytochemicals; Ranunculaceae
PubMed: 35008829
DOI: 10.3390/ijms23010406 -
Biomedicine & Pharmacotherapy =... Feb 2022Acetylcholinesterase (AChE) inhibitor is the first choice for the treatment of Alzheimer's disease (AD), but it has some defects, such as dose limitation and... (Review)
Review
Acetylcholinesterase (AChE) inhibitor is the first choice for the treatment of Alzheimer's disease (AD), but it has some defects, such as dose limitation and unsatisfactory long-term treatment effect. Recent studies have shown that butyrylcholinesterase (BuChE) inhibitors or double acetyl and butyryl cholinesterase inhibitors have better curative effects on AD, and the side effects are lower than those of specific AChE inhibitors. Dual target cholinesterase inhibitors have become a new hotspot in the research of anti-AD drugs. Herein, the synthesis and bioactivities of BuChE inhibitors were reviewed.
Topics: Acridines; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Methoxsalen; Structure-Activity Relationship
PubMed: 34953393
DOI: 10.1016/j.biopha.2021.112556 -
Assay and Drug Development Technologies Jan 2022This study focuses on the development of topical formulation of methoxsalen using Babchi oil as formulation component that can be applied at body surfaces providing...
This study focuses on the development of topical formulation of methoxsalen using Babchi oil as formulation component that can be applied at body surfaces providing sustained delivery and enhanced penetration of methoxsalen leading to significant epidermal localization and better anti-psoriatic activity. The combination of psoralens, that is, methoxsalen (synthetic) and Babchi oil (natural) has been developed into nanoemulgel formulations. A total of four nanoemulsion formulations was developed using Babchi oil as oil phase and Tween 80 as surfactant by high-pressure homogenization method. The prepared nanoemulsions were characterized for entrapment efficiency, mean droplet size, and zeta potential. Based on characterization results, the optimized nanoemulsion formulation(s) were incorporated into the carbopol gel base to make a nanoemulgel. The prepared nanoemulgel formulations were analyzed for pH, drug content determination, spreadability, viscosity, skin permeation, and studies. The nanoemulsions showed droplet size between 51.3 and 146.7 nm, entrapment efficiency of 92.76%-98.10%, and zeta potential of -28.1 to -54.89 mev. The nanoemulsions showed varied in vitro drug release. In skin permeation, nanoemulgel (NG2) showed increased penetration and localized accumulation of methoxsalen across the skin compared with plain gel. results were substantiated by results showing significant amelioration of hyperproliferative skin symptoms. The promising results suggested that nanoemulgel system is a suitable carrier for the topical delivery of methoxsalen-Babchi oil.
Topics: Drug Liberation; Emulsions; Humans; Psoriasis; Skin; Skin Absorption
PubMed: 34883035
DOI: 10.1089/adt.2021.112 -
International Journal of Molecular... Nov 2021Cytochrome P450 2A13 is an omitted brother of CYP2A6 that has an important role in the drug metabolism of liver. Due to extrahepatic expression, it has gained less... (Review)
Review
Cytochrome P450 2A13 is an omitted brother of CYP2A6 that has an important role in the drug metabolism of liver. Due to extrahepatic expression, it has gained less attention than CYP2A6, despite the fact that it plays a significant role in toxicant-induced pulmonary lesions and, therefore, lung cancer. The purpose of this mini-review is to summarize the basic knowledge about this enzyme in relation to the substrates, inhibitors, genetic polymorphisms, and transcriptional regulation that are known so far (September 2021).
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Lung; Lung Neoplasms; Methoxsalen; Polymorphism, Genetic; Substrate Specificity
PubMed: 34830188
DOI: 10.3390/ijms222212306 -
Journal of Agricultural and Food... Nov 2021Adaptation to phytochemicals in herbivorous insects can influence tolerance to insecticides. However, it is unclear how insects use phytochemicals as cues to activate...
Adaptation to phytochemicals in herbivorous insects can influence tolerance to insecticides. However, it is unclear how insects use phytochemicals as cues to activate their metabolic detoxification systems. In this study, we found that dietary exposure to xanthotoxin enhanced tolerance of larvae to λ-cyhalothrin. Xanthotoxin ingestion significantly elevated the mRNA levels of 35 detoxification genes as well as the transcription factors Cap 'n' collar isoform-C () and its binding factor small muscle aponeurosis fibromatosis isoform-K (). Additionally, xanthotoxin exposure increased the levels of reactive oxygen species (ROS), while ROS inhibitor N-acetylcysteine (NAC) treatment blocked xanthotoxin-induced expression of , , and detoxification genes and also prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. The 20-hydroxyecdysone (20E) signaling pathway was effectively activated by xanthotoxin, while blocking of 20E signaling transduction prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. Application of 20E induced the expression of multiple xanthotoxin-induced detoxification genes and enhanced λ-cyhalothrin tolerance in . NAC treatment blocked xanthotoxin-induced 20E synthesis, while the CncC agonist curcumin activated the 20E signaling pathway. These results indicate that the ROS/CncC pathway controls the induction of metabolic detoxification upon exposure to xanthotoxin, at least in part, through its regulation of the 20E signaling pathway.
Topics: Animals; Ecdysterone; Insect Proteins; Insecticides; Larva; Methoxsalen; Nitriles; Pyrethrins; Reactive Oxygen Species; Signal Transduction; Spodoptera
PubMed: 34748318
DOI: 10.1021/acs.jafc.1c04519 -
Comparative Biochemistry and... Jan 2022Xanthotoxin (XAT) is widely present in many kinds of plants. Caenorhabditis elegans, a typical model organism, was used to study the effects of XAT on C. elegans...
Xanthotoxin (XAT) is widely present in many kinds of plants. Caenorhabditis elegans, a typical model organism, was used to study the effects of XAT on C. elegans developmental toxicity, neurotoxicity, reproductive toxicity induced under ultraviolet A (UVA), oxidative stress and apoptosis in C. elegans. The results showed that after XAT exposure treatment, the hatchability of C. elegans decreased significantly as the concentration increased; the body length and width increased markedly, the external morphology was swollen; the brood sizes had been decreased; and the frequencies of head thrashes and body bend decreased significantly. At 80 and 100 mg/L, XAT reduced the activities of mitochondrial complex enzymes I and III, resulting in the excessive production of ROS, and inhibited SOD and CAT so that the ROS could not be eliminated over time. ROS accumulation in the bodies further caused the contents of MDA, protein carbonyl and lipofuscin to increase significantly, the mitochondrial membrane potential to be severely damaged, apoptosis to occur, and the apoptosis genes ced-3 and ced-4 to be significantly upregulated. Thus, XAT showed photoactivated toxicity to C. elegans under UVA, which will help people to make full and rational use of plants containing XAT.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Methoxsalen; Oxidative Stress; Reactive Oxygen Species; Reproduction
PubMed: 34673249
DOI: 10.1016/j.cbpc.2021.109217