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ChemPlusChem Jul 2024Angucyclines and angucyclinones represent a class of natural compounds that belong to the group of aromatic polyketides. They exhibit a wide array of biological...
Angucyclines and angucyclinones represent a class of natural compounds that belong to the group of aromatic polyketides. They exhibit a wide array of biological properties, such as antimicrobial, antiviral, and cytotoxic. Their considerable therapeutic potential and diverse scaffolds have attracted many synthetic chemists to devise novel strategies to construct their intricate molecular architecture. Over 300 class members have been isolated from natural sources, mainly from bacterial strains of Streptomyces species. This review highlights recent advancements in their synthesis, such as oxidative cyclization, photooxidation, and metal-catalyzed [4+2]-cycloaddition, which has facilitated the efficient and practical total syntheses of various angucyclines natural products.
PubMed: 38958029
DOI: 10.1002/cplu.202400307 -
Angewandte Chemie (International Ed. in... Jul 2024All-benzenoid polycyclic aromatic hydrocarbons or macrocycles usually display localized aromaticity. On the other hand, incorporation of quinoidal units into the...
All-benzenoid polycyclic aromatic hydrocarbons or macrocycles usually display localized aromaticity. On the other hand, incorporation of quinoidal units into the skeleton could lead to effective electron delocalization and global (anti)aromaticity. In this work, fully π-conjugated macrocycle 1 and bismacrocycle 2 containing both para-quinodimethane and triphenylamine units are efficiently synthesized mainly through intermolecular Friedel-Crafts alkylation reaction. They can be considered as a tetraazasuperbenzene and a hexaazasupernaphthalene, respectively, due to their similar geometry and electronic structures to the benzene and naphthalene. X-ray crystallographic analyses reveal a largely planar geometry for both 1 and 2 and variable-temperature NMR measurements disclose slow dynamic processes owing to restricted ring flipping of the phenyl rings. 1 and 2 can be easily oxidized into higher-oxidation-state species. NMR and theoretical calculations indicate that 12+ and 14+ show global anti-aromaticity and aromaticity, respectively, with a dominant 32π and 30π conjugation pathway, while for the bismacrocycle 2, its dication 22+, tetracation 24+ and hexacation 26+exhibit global aromaticity, antiaromaticity, and aromaticity with a 54π, 52π and 50π conjugation pathway along the outermost backbone, respectively.
PubMed: 38958027
DOI: 10.1002/anie.202407990 -
Circulation Research Jul 2024PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial...
BACKGROUND
PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated.
METHOD
We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1).
RESULTS
PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45), particularly neutrophils (CD11b, Ly6g), to the myocardium.
CONCLUSIONS
Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.
PubMed: 38957990
DOI: 10.1161/CIRCRESAHA.124.324650 -
Physiological Research Jul 2024Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous...
Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous ligands and a synthetic ligand that does not interact with the wild-type receptors. Many different types of these receptors and their respective ligands for inhibiting or excitating neuronal subpopulations were designed in the past few decades. It has been mainly the G-protein coupled receptors (GPCRs) selectively responding to clozapine-N-oxide (CNO), namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that have been employed in research. Chemogenetics offers great possibilities since the activity of the receptors is reversible, inducible on demand by the ligand, and non-invasive. Also, specific groups or types of neurons can be selectively manipulated thanks to the delivery by viral vectors. The effect of the chemogenetic receptors on neurons lasts longer, and even chronic activation can be achieved. That can be useful for behavioral testing. The great advantage of chemogenetic tools is especially apparent in research on brain diseases since they can manipulate whole neuronal circuits and connections between different brain areas. Many psychiatric or other brain diseases revolve around the dysfunction of specific brain networks. Therefore, chemogenetics presents a powerful tool for investigating the underlying mechanisms causing the disease and revealing the link between the circuit dysfunction and the behavioral or cognitive symptoms observed in patients. It could also contribute to the development of more effective treatments.
PubMed: 38957949
DOI: No ID Found -
Journal of the Indian Society of... Apr 2024Many practitioners have questioned whether the construction method of pediatric zirconia crowns impacts the periodontal health and clinical performance of severely... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Many practitioners have questioned whether the construction method of pediatric zirconia crowns impacts the periodontal health and clinical performance of severely decayed primary molars. The objective of this study was to compare the periodontal health and clinical performance of primary molars restored with custom-made zirconia crowns (CZCs) and prefabricated zirconia crowns.
METHODS
Twenty primary molars indicated for crown restorations were selected from ten patients (5-9 years old) randomly. Each patient received two pediatric zirconia crowns constructed by two different methods: one custom-made and one prefabricated. The primary molars were divided into two groups: Group 1: primary molars received CZCs and Group 2: primary molars received prefabricated zirconia crowns (PZCs).
RESULTS
After a 12-month follow-up, there was no statistically significant difference between the periodontal health of primary molars restored with custom-made and prefabricated zirconia crowns. The clinical performance of primary molars restored with CZCs was statistically significantly higher than those restored with PZCs in terms of retention and fracture resistance (P ≤ 0.05).
CONCLUSIONS
The construction method of pediatric zirconia crowns does not significantly affect the periodontal health of primary molars; however, clinical performance is significantly affected in terms of retention and fracture resistance.
CLINICAL SIGNIFICANCE
A CZC is an excellent alternative option, especially for primary molars whose permanent successors still have a long time to erupt. The PZC is a quick and easy restoration, but the technique is sensitive.
Topics: Humans; Zirconium; Crowns; Molar; Tooth, Deciduous; Follow-Up Studies; Child, Preschool; Child; Dental Prosthesis Design; Male; Female; Dental Caries
PubMed: 38957914
DOI: 10.4103/jisppd.jisppd_39_24 -
Journal of the Indian Society of... Apr 2024Pharmacological methods, specifically sedatives, have gained popularity in managing the behavior of children during dental appointments. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Comparative evaluation of intranasal dexmedetomidine, intranasal midazolam, and nitrous oxide for conscious sedation of anxious children undergoing dental treatment: A randomized cross-over trial.
BACKGROUND
Pharmacological methods, specifically sedatives, have gained popularity in managing the behavior of children during dental appointments.
AIM
The aim of this study was to compare 1 m/kg intranasal dexmedetomidine, 0.3 mg/kg intranasal midazolam, and nitrous oxide in evaluating the level of sedation, behavior of the child, onset of sedation, physiologic signs, and adverse effects.
MATERIALS AND METHODS
In this cross-over trial, 15 children aged 6-8 years were randomized to receive intranasal atomized dexmedetomidine, intranasal atomized midazolam, and inhalation nitrous oxide at three separate visits. After administering the sedative agent, a single pulpectomy was performed during each appointment, and the outcomes were recorded. The washout period between each visit was 1 week.
RESULTS
All three sedative agents were equally effective in controlling overall behavior. Dexmedetomidine showed lower sedation level scores (agitated; score 9) than the other groups. There was a statistically significant difference in the onset of sedation, with dexmedetomidine having the longest onset of 36.2 ± 9.47 min. Coughing and sneezing were predominantly observed after administration of intranasal midazolam. Oxygen saturation levels were statistically lower in the intranasal midazolam group during local anesthesia administration and post-treatment.
CONCLUSION
0.3 mg/kg intranasal midazolam is as effective as nitrous oxide sedation for controlling behavior and providing adequate sedation in pediatric dental patients. However, 1 m/kg dexmedetomidine did not provide the same level of sedation and had a significantly longer onset. 0.3 mg/kg intranasal midazolam is an effective alternative to nitrous oxide sedation in anxious children.
Topics: Humans; Nitrous Oxide; Midazolam; Child; Administration, Intranasal; Cross-Over Studies; Hypnotics and Sedatives; Dexmedetomidine; Conscious Sedation; Male; Female; Dental Anxiety; Anesthesia, Dental; Anesthetics, Inhalation; Dental Care for Children; Child Behavior; Pulpectomy
PubMed: 38957912
DOI: 10.4103/jisppd.jisppd_104_24 -
Physical Chemistry Chemical Physics :... Jul 2024The nature of the Ni-O bond is relevant to catalytic and environmental applications. The vibrational frequency and electronic structure of NiO were calculated using...
The nature of the Ni-O bond is relevant to catalytic and environmental applications. The vibrational frequency and electronic structure of NiO were calculated using CASSCF, icMRCI+Q, CCSD(T), and DFT. CASSCF predicted a quintet state (Σ) ground state for the equilibrium bond distance with a state crossing at 1.65 Å, where the triplet (Σ) state becomes of lower energy. These states arise from the 3d(F)4s (F) and 3d(D)4s (D) configurations of Ni. The icMRCI+Q method predicts a triplet (Σ) ground state and does not predict a state crossing with the quintet. This state has significant ionic character with the 2p of O bonding with the 4s/3d of the Ni to form a σ bond. The NiO frequency at the icMRCI+Q level of 835.0 cm is in excellent agreement with experiment; the value of is 1.5992 Å at this computational level. CCSD(T) predicts = 888.80 cm when extrapolated to the complete basis set limit. Frequencies predicted using CCSD(T) deviate from experiment consistent with the calculations showing large multireference character. A wide array of density functionals were benchmarked. Of the 43 functionals tested, the ones that gave the best prediction of the frequency are ωB97XD, CAM-B3LYP, and τ-HCTH with respective values of 831.8, 838.3, and 837.4 cm respectively. The bond dissociation energy (BDE) of NiO is predicted to be 352.4 kJ mol at the Feller-Peterson-Dixon (FPD) level in good agreement with one of the experimental values. The calculated BDEs at the DFT level are sensitive to the choice of functional and atomic asymptote. Sixteen functionals predicted the BDE within 20 kJ mol of the FPD value.
PubMed: 38957895
DOI: 10.1039/d4cp01796j -
Oxygen (Basel, Switzerland) Jun 2024Uterine fibroids are the most common tumors in females affecting up to 70% of women world-wide, yet targeted therapeutic options are limited. Oxidative stress has...
Uterine fibroids are the most common tumors in females affecting up to 70% of women world-wide, yet targeted therapeutic options are limited. Oxidative stress has recently surfaced as a key driver of fibroid pathogenesis and provides insights into hypoxia-induced cell transformation, extracellular matrix pathophysiology, hypoxic cell signaling cascades, and uterine biology. Hypoxia drives fibroid tumorigenesis through (1) promoting myometrial stem cell proliferation, (2) causing DNA damage propelling transformation of stem cells to tumor initiating cells, and (3) driving excess extracellular matrix (ECM) production. Common fibroid-associated DNA mutations include MED12 mutations, HMGA2 overexpression, and Fumarate hydratase loss of function. Evidence suggests an interaction between hypoxia signaling and these mutations. Fibroid development and growth are promoted by hypoxia-triggered cell signaling via various pathways including HIF-1, TGFβ, and Wnt/β-catenin. Fibroid-associated hypoxia persists due to antioxidant imbalance, ECM accumulation, and growth beyond adequate vascular supply. Current clinically available fibroid treatments do not take advantage of hypoxia-targeting therapies. Growing pre-clinical and clinical studies identify ROS inhibitors, anti-HIF-1 agents, Wnt/β-catenin inhibition, and TGFβ cascade inhibitors as agents that may reduce fibroid development and growth through targeting hypoxia.
PubMed: 38957794
DOI: 10.3390/oxygen4020013 -
Toxicology Research Aug 2024Alzheimer's disease (AD) presents as a widespread neurodegenerative condition impacting over 55 million individuals globally, with an annual rise of 10 million new...
BACKGROUND
Alzheimer's disease (AD) presents as a widespread neurodegenerative condition impacting over 55 million individuals globally, with an annual rise of 10 million new cases. Despite its staggering prevalence, the absence of a definitive cure establishes the need for a revisit.
METHODS
We explore the alternative strategies, focusing on the potential therapeutic efficacy of ethanolic extracts derived from the fruit and leaf of Linn.
RESULTS
The investigation comprehensively explores pharmacognostic, phytochemical, toxicological, and pharmacological characteristics. In addition to pharmacognostic and physicochemical analyses, toxicological evaluations conducted on experimental animals demonstrated the innocuous nature of the ethanolic extracts (from both fruit and leaf) of , as evidenced by assessments of hemocompatibility, oxidative parameters, and vital organ histology. Phytochemical profiling via GC-MS identified 48 and 80 phytoconstituents in the fruit and leaf extracts, respectively. These constituents were screened for bioactive potential using the "Lipinski Rule of Five," resulting in the selection of 25 and 33 constituents from fruit and leaf extracts, respectively. Subsequent molecular docking studies against the AChE enzyme revealed promising interactions of the selected phytoconstituents. Furthermore, the top-scoring phytoconstituents were subjected to in silico screening to assess their interactions with β- and γ-secretase enzymes, in addition to the AChE enzyme. The cumulative findings substantiate the therapeutic utility of the plant extracts, particularly in the context of AD.
CONCLUSION
In conclusion, our investigation highlights the promising therapeutic potential of selected phytoconstituents derived from ethanolic extracts of in mitigating AD pathology by targeting key enzyme sites such as AChE, β-, and γ-secretase.
PubMed: 38957785
DOI: 10.1093/toxres/tfae098 -
Toxicology Research Aug 2024Allergic rhinitis (AR) a common and complicated upper airway disease mediated by specific IgE antibodies. Our study aims to explore the pharmacological effects of...
BACKGROUND
Allergic rhinitis (AR) a common and complicated upper airway disease mediated by specific IgE antibodies. Our study aims to explore the pharmacological effects of astragalus polysaccharide (APS) on AR and elucidate the mechanisms involved.
METHODS
RT-qPCR and Western blotting were used to analyze mRNA and protein expression. Interleukin (IL)-13-treated human nasal epithelial cells (hNECs) was employed as the AR cell model. Cell apoptosis and viability were evaluated by TUNEL staining and MTT assay, respectively. ROS level was examined by the DCFH-DA probe. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) levels were measured by the corresponding kits. FBXW7 mA modification level was assessed by MeRIP assay.
METHODS
Our results showed that APS treatment reduced cell apoptosis, ROS, and MDA levels while increasing SOD, CAT, and GSH-Px levels in IL-13-treated hNECs by activating the Nrf2/HO-1 pathway. Moreover, APS alleviated IL-13-induced oxidative stress injury in hNECs by downregulating WTAP. In addition, WTAP knockdown increased FBXW7 mRNA stability by regulating FBXW7 mRNA mA modification. It also turned out that APS alleviated IL-13-induced oxidative stress injury in hNECs through the WTAP/FBXW7 axis.
CONCLUSIONS
Taken together, APS inhibited WTAP-mediated FBXW7 mA modification to alleviate IL-13-induced oxidative stress injury in hNECs.
PubMed: 38957784
DOI: 10.1093/toxres/tfae099