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Cellular and Molecular Biology... Jun 2024Colorectal cancer (CRC) poses a significant global health challenge with high morbidity and mortality rates. This study investigates the role of LY6G6D, a member of the...
Colorectal cancer (CRC) poses a significant global health challenge with high morbidity and mortality rates. This study investigates the role of LY6G6D, a member of the LY6/uPAR superfamily, in CRC. Employing a bioinformatic approach, we analyzed LY6G6D expression across different cancer types, compared it with known oncogenes in CRC, explored the involved genomic alterations, and assessed associated clinicopathological characteristics. LY6G6D exhibited aberrant expression, particularly elevated in CRC adenocarcinoma and highly specific to tumor tissues when compared with other oncogenes, despite its comparatively low frequency of genomic alteration. Subsequently, tumor immune infiltration analysis revealed distinct associations, primarily indicating a negative correlation, suggesting immune down-regulation. Survival analysis in context of LY6G6D was conducted with Kaplan-Meier (KM) curves, indicating a 10% risk of disease recurrence in the case of elevated expression. Additionally, we constructed a 3D protein model of LY6G6D through ab-inito approach. The protein model was validated, followed by conservation analysis and active site identification. Active site identification of LY6G6D's final predicted model revealed some similar sites that were estimated to be conserved. Target-guided drug molecules were collected and molecular docking was executed, proposing Cardigin (Digitoxin) and Manzamine A as potential therapeutic candidates. In conclusion, LY6G6D emerges as a significant biomarker for diagnostic and therapeutic applications in CRC, highlighting its multifaceted role in tumorigenesis. The proposed drugs present avenues for further investigations.
Topics: Colorectal Neoplasms; Humans; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Molecular Docking Simulation; Antigens, Ly; GPI-Linked Proteins
PubMed: 38836687
DOI: 10.14715/cmb/2024.70.6.3 -
Journal of Fluorescence Sep 2023The interaction of orphenadrine hydrochloride (ORD) with the model protein, bovine serum albumin (BSA), was investigated using a variety of spectroscopic techniques such...
The interaction of orphenadrine hydrochloride (ORD) with the model protein, bovine serum albumin (BSA), was investigated using a variety of spectroscopic techniques such as steady-state fluorescence, ultraviolet-visible, Fourier transform infrared, 3-D spectroscopy, and electrochemical methods under physiological conditions. Stern-Volmer plots were used to calculate fluorescence quenching at various temperatures. The findings point to a static quenching mechanism between ORD and BSA. At various reaction times, the binding sites (n) and binding constants (K) of ORD to BSA were recorded. Thermodynamic parameters ∆H, ∆S and ∆G between ORD and BSA were calculated and reported. The average binding distance (r) between the donor (BSA) and acceptor (ORD) molecules was predicted using Förster's theory. Three-dimensional fluorescence spectra, Fourier transform infrared spectra, and synchronous fluorescence studies all supported the alternations in protein structure following the interaction with ORD. A displacement study using site probes such as warfarin, ibuprofen, and digitoxin confirmed ORD binding at Sudlow's site I of BSA. The effect of common metal ions such as Cu, Ni, Ca, Co, and Zn on binding constant values was investigated and reported.
Topics: Serum Albumin, Bovine; Orphenadrine; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Binding Sites; Thermodynamics; Protein Binding; Circular Dichroism
PubMed: 36976401
DOI: 10.1007/s10895-023-03199-y -
Journal of Chromatography. B,... Apr 2024Human serum albumin (HSA) is known to undergo modifications by glucose during diabetes. This process produces glycated HSA that can have altered binding to some drugs....
Human serum albumin (HSA) is known to undergo modifications by glucose during diabetes. This process produces glycated HSA that can have altered binding to some drugs. In this study, high-performance affinity microcolumns and competition studies were used to see how glycation affects the binding by two thiazolidinedione-class drugs (i.e., pioglitazone and rosiglitazone) at specific regions of HSA. These regions included Sudlow sites I and II, the tamoxifen and digitoxin sites, and a drug-binding site located in subdomain IB. At Sudlow site II, the association equilibrium constants (or binding constants) for pioglitazone and rosiglitazone with normal HSA were 1.7 × 10 M and 2.0 × 10 M at pH 7.4 and 37 °C, with values that changed by up to 5.7-fold for glycated HSA. Sudlow site I of normal HSA had binding constants for pioglitazone and rosiglitazone of 3.4 × 10 M and 4.6 × 10 M, with these values changing by up to 1.5-fold for glycated HSA. Rosiglitazone was found to also bind a second region that had a positive allosteric effect on Sudlow site I for all the tested preparations of HSA (binding affinity, 1.1-3.2 × 10 M; coupling constant for Sudlow site I, 1.20-1.34). Both drugs had a strong positive allosteric effect on the tamoxifen site of HSA (coupling constants, 13.7-19.9 for pioglitazone and 3.7-11.5 for rosiglitazone). Rosiglitazone also had weak interactions at a site in subdomain IB, with a binding constant of 1.4 × 10 M for normal HSA and a value that was altered by up to 6.8-fold with glycated HSA. Neither of the tested drugs had any significant binding at the digitoxin site. The results were used to produce affinity maps that described binding by these thiazolidinediones with HSA and the effects of glycation on these interactions during diabetes.
Topics: Humans; Serum Albumin, Human; Hypoglycemic Agents; Maillard Reaction; Rosiglitazone; Pioglitazone; Protein Binding; Serum Albumin; Diabetes Mellitus; Tamoxifen; Digitoxin; Chromatography, Affinity; Binding Sites
PubMed: 38460447
DOI: 10.1016/j.jchromb.2024.124070 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Jan 2024Digitoxin, an important secondary metabolite of Digitalis purpurea, is a commonly used cardiotonic in clinical practice. 3β-Hydroxysteroid dehydrogenase(3βHSD) is a...
Digitoxin, an important secondary metabolite of Digitalis purpurea, is a commonly used cardiotonic in clinical practice. 3β-Hydroxysteroid dehydrogenase(3βHSD) is a key enzyme involved in the biosynthesis of digitoxin. It belongs to the short-chain dehydrogenase/reductase(SDR) family, playing a role in the biosynthesis of cardiac glycosides by oxidizing and isomerizing the precursor sterol. In this study, two 3βHSD genes were cloned from D. purpurea. The results showed that the open reading frame(ORF) of Dp3βHSD1 was 780 bp, encoding 259 amino acid residues. The ORF of Dp3βHSD2 was 774 bp and encoded 257 residues. Dp3βHSD1/2 had the cofactor binding site TGxxxA/GxG and the catalytic site YxxxK. In vitro experiments confirmed that Dp3βHSD1/2 catalyzed the generation of progesterone from pregnenolone, and Dp3βHSD1 had stronger catalytic capacity than Dp3βHSD2. The expression level of Dp3βHSD1 was much higher than that of Dp3βHSD2 in leaves, and digitoxin was only accumulated in leaves. The results implied that Dp3βHSD1 played a role in the dehydrogenation of pregnenolone to produce progesterone in the biosynthesis of digitoxin. This study provides a reference for further exploring the biosynthetic pathway of cardiac glycosides in D. purpurea.
Topics: Digitoxin; Progesterone; Cloning, Molecular; Pregnenolone; Hydroxysteroid Dehydrogenases
PubMed: 38403313
DOI: 10.19540/j.cnki.cjcmm.20230905.101 -
Journal of Cardiology Cases Aug 2023We present the case series of two women aged 35 and 60 years who presented to our emergency department with severe vomiting, nausea, and malaise. Their symptoms...
UNLABELLED
We present the case series of two women aged 35 and 60 years who presented to our emergency department with severe vomiting, nausea, and malaise. Their symptoms started approximately 2 h after the ingestion of home-made mixed vegetables with freshly picked vegetables and leaves from the patients' garden, of which one was supposed to be borage. An electrocardiogram revealed diffuse ST-segment depression with down-up sloping in both patients. We supposed an accidental confusion of wild borage () with foxglove (). Both patients were subsequently admitted to the intermediate-care-unit for close monitoring and continuous activated charcoal administration. Digitoxin serum concentrations were elevated in both patients (40.9 and >50 ng/ml, respectively - reference therapeutic range 8-18 ng/ml). The younger woman, despite the relatively lower serum digitoxin concentrations, presented a single episode of advanced atrioventricular block and long-lasting sinus bradycardia. Both showed a complete recovery. Although not uncommon, our case series reiterates the fact that such plant misclassifications are potentially life-threating and warrant the treating physicians' full attention.
LEARNING OBJECTIVE
Plant poisoning is a frequent reason for consultation of poison information centers and may result in life-threatening cardiac arrhythmias. Confusion of foxglove leaves () with borage leaves (), which is a popular food ingredient for mixed salads, is not uncommon. Without a dedicated medical history, such cases are difficult to diagnose and warrant the treating physicians' full attention and the involvement of a local poison information center.
PubMed: 37521578
DOI: 10.1016/j.jccase.2023.04.007 -
Chemistry & Biodiversity Jan 2024Streptocaulon juventas (Lour.) Merr. (SJ) is a herbal medicine can promote wound healing. Cardiac glycosides, especially periplogenin, digitoxigenin, and their...
Streptocaulon juventas (Lour.) Merr. (SJ) is a herbal medicine can promote wound healing. Cardiac glycosides, especially periplogenin, digitoxigenin, and their glycosides were the main constituents of SJ. We aim to establish a method for the simultaneous determination of periplogenin and digitoxigenin in SJ and evaluate the wound healing activities of these two components. UPLC-QqQ-MS/MS was used for the determination of periplogenin and digitoxigenin. Meanwhile, rats were subjected to full-thickness skin resection on the back to investigate the wound healing effects of periplogenin and digitoxigenin. The content of periplogenin and digitoxigenin in 13 batches of SJ extracts ranged from 43.26 to 97.15 μg/g and 18.04 to 55.55 μg/g, respectively. Periplogenin and digitoxigenin significantly increased the rate of wound healing in rats, increased the content of hydroxyproline in wound tissue, and improved the pathological state of wound skin tissue.
Topics: Rats; Animals; Digitoxigenin; Tandem Mass Spectrometry; Apocynaceae; Wound Healing
PubMed: 38061998
DOI: 10.1002/cbdv.202301585 -
Journal of Cardiovascular Development... Jun 2024(1) Introduction: Digitalis use in patients with severe heart failure is controversial. We assessed the effects of digitalis therapy on mortality in a large,...
(1) Introduction: Digitalis use in patients with severe heart failure is controversial. We assessed the effects of digitalis therapy on mortality in a large, observational study in recipients of cardiac resynchronization therapy (CRT). (2) Methods: Consecutive patients receiving a CRT-defibrillator in three European tertiary referral centers were enrolled and followed-up for a mean 37 months ± 28 months. Digitalis use was assessed at the time of CRT implantation. A multivariate Cox-regression model and propensity score matching were used to determine all-cause mortality as the primary endpoint. CRT-response (defined as improvement of ≥1 NYHA class), echocardiographic improvement (defined as improvement of LVEF of ≥ 5%) and incidence of ICD shocks and rehospitalization were assessed as secondary endpoints in a subgroup of patients. (3) Results: The study comprised 552 CRT-recipients with standard indications, including 219 patients (40%) treated with digitalis. Compared to patients without digitalis, they had more often atrial fibrillation, poorer LVEF and a higher NYHA class (all ≤ 0.002). Crude analysis of all-cause mortality demonstrated a similar relative risk of death for patients with and without digitalis (HR = 1.14; 95% CI 0.88-1.5; = 0.40). After adjustment for independent predictors of mortality, digitalis therapy did not alter the risk for death (adjusted HR = 1.04; 95% CI 0.75-1.45; = 0.82). Furthermore, in comparison to 286 propensity-score-matched patients, mortality was not affected by digitalis intake (propensity-adjusted HR = 1.11; 95% CI 0.72-1.70; = 0.64). A CRT-response was predominant in digitalis non-users, concerning both improvement of HF symptoms and LVEF (NYHA < 0.01; LVEF < 0.01), while patients on digitalis had more often ventricular tachyarrhythmias requiring ICD shock ( = 0.01); although, rehospitalization for cardiac reasons was significantly lower among digitalis users compared to digitalis non-users (HR = 0.58; 95% C. I. 0.40-0.85; = 0.01). (4) Conclusions: Digitalis therapy had no effect on mortality, but was associated with a reduced response to CRT and increased susceptibility to ventricular arrhythmias requiring ICD shock treatment. Although, digitalis administration positively altered the likelihood for cardiac rehospitalization during follow-up.
PubMed: 38921673
DOI: 10.3390/jcdd11060173 -
ACS Omega Apr 2024Sortilin (SORT1) is a multifunctional protein intricately involved in atherogenesis, coronary artery disease (CAD), and various neurological disorders. It has...
Sortilin (SORT1) is a multifunctional protein intricately involved in atherogenesis, coronary artery disease (CAD), and various neurological disorders. It has materialized as a potential pharmacological target for therapeutic development due to its diverse biological roles in pathological processes. Despite its central role under these conditions, effective therapeutic strategies targeting SORT1 remain challenging. In this study, we introduce a drug repurposing strategy guided by structural insights to identify potent SORT1 inhibitors with broad therapeutic potential. Our approach combines molecular docking, virtual screening, and molecular dynamics (MD) simulations, enabling the systematic evaluation of 3648 FDA-approved drugs for their potential to modulate SORT1. The investigation reveals a subset of repurposed drugs exhibiting highly favorable binding profiles and stable interactions within the binding site of SORT1. Notably, two hits, ergotamine and digitoxin, were carefully chosen based on their drug profiles and subjected to analyze their interactions with SORT1 and stability assessment via all-atom MD simulations spanning 300 ns (ns). The structural analyses uncover the complex binding interactions between these identified compounds and SORT1, offering essential mechanistic insights. Additionally, we explore the clinical implications of repurposing these compounds as potential therapeutic agents, emphasizing their significance in addressing atherogenesis, CAD, and neurological disorders. Overall, this study highlights the efficacy of structure-guided drug repurposing and provides a solid foundation for future research endeavors aimed at the development of effective therapies targeting SORT1 under diverse pathological conditions.
PubMed: 38680294
DOI: 10.1021/acsomega.4c00470 -
Pharmaceuticals (Basel, Switzerland) Mar 2024SARS-CoV-2 infections, commonly referred to as COVID-19, remain a critical risk to both human life and global economies. Particularly, COVID-19 patients with weak...
SARS-CoV-2 infections, commonly referred to as COVID-19, remain a critical risk to both human life and global economies. Particularly, COVID-19 patients with weak immunity may suffer from different complications due to the bacterial co-infections/super-infections/secondary infections. Therefore, different variants of alternative antibacterial therapeutic agents are required to inhibit those infection-causing drug-resistant pathogenic bacteria. This study attempted to explore these bacterial pathogens and their inhibitors by using integrated statistical and bioinformatics approaches. By analyzing bacterial 16S rRNA sequence profiles, at first, we detected five bacterial genera and taxa (, , , and based on differentially abundant bacteria between SARS-CoV-2 infection and control samples that are significantly enriched in 23 metabolic pathways. A total of 183 bacterial genes were found in the enriched pathways. Then, the top-ranked 10 bacterial genes (, , , , , , , , , and ) were selected as the pathogenic bacterial key genes (bKGs) by their protein-protein interaction (PPI) network analysis. Then, we detected bKG-guided top-ranked eight drug molecules (Bemcentinib, Ledipasvir, Velpatasvir, Tirilazad, Acetyldigitoxin, Entreatinib, Digitoxin, and Elbasvir) by molecular docking. Finally, the binding stability of the top-ranked three drug molecules (Bemcentinib, Ledipasvir, and Velpatasvir) against three receptors (, and ) was investigated by computing their binding free energies with molecular dynamic (MD) simulation-based MM-PBSA techniques, respectively, and was found to be stable. Therefore, the findings of this study could be useful resources for developing a proper treatment plan against bacterial co-/super-/secondary-infection in SARS-CoV-2 infections.
PubMed: 38675393
DOI: 10.3390/ph17040432