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Organic & Biomolecular Chemistry Jun 2024Sialyl Lewis (sLe), also known as cancer antigen 19-9, is a tumor-associated carbohydrate antigen. In this article, chemical and chemoenzymatic syntheses of a...
Sialyl Lewis (sLe), also known as cancer antigen 19-9, is a tumor-associated carbohydrate antigen. In this article, chemical and chemoenzymatic syntheses of a tetrasaccharide glycan 1 structurally derived from sLe are reported. Challenges involved in the chemical synthesis include the highly stereoselective construction of 1,2--α-L-fucoside and α-D-sialoside, as well as the assembly of the 3,4-disubstituted -acetylglucosamine subunit. Perbenzylated thiofucoside and -acetyl-5-,4--oxazolidinone protected sialic acid thioglycoside were employed as glycosyl donors, respectively, for the efficient preparation of the desired α-fucoside and α-sialoside. The 3,4-branched glucosamine backbone was established through a 3- and then 4- glycosylation sequence in which the 3-hydroxyl group of the glucosamine moiety was glycosylated first and then the 4-hydroxyl. A facile chemoenzymatic approach was also exploited to synthesize the target molecule. The chemically obtained free disaccharide 30 was sequentially sialylated and fucosylated in an enzyme-catalyzed regio- and stereospecific manner to form 1 in high yields. The linker appended 1 can be covalently attached to a carrier protein for further immunological studies.
PubMed: 38934561
DOI: 10.1039/d4ob00809j -
Neural Regeneration Research Jun 2024TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon. TAU is missorted and aggregated in an array of diseases known as...
TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon. TAU is missorted and aggregated in an array of diseases known as tauopathies. Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications (PTMs), changes of which affect microtubule stability and dynamics, microtubule interaction with other proteins and cellular structures, and mediate recruitment of microtubule-severing enzymes. As impairment of microtubule dynamics causes neuronal dysfunction, we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics. We therefore aimed to study the effects of a disease-causing mutation of TAU (P301L) on the levels and localization of microtubule PTMs indicative of microtubule stability and dynamics, to assess whether P301L-TAU causes stability-changing modifications to microtubules. To investigate TAU localization, phosphorylation, and effects on tubulin PTMs, we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons (iNeurons) and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU (pR5 mice). Human neurons expressing the longest TAU isoform (2N4R) with the P301L mutation showed increased TAU phosphorylation at the AT8, but not the p-Ser-262 epitope, and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons. P301L-TAU showed pronounced somatodendritic presence, but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU. P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation, but reduced acetylation, of microtubules compared with non-transgenic littermates. In sum, P301L-TAU results in changes in microtubule PTMs, suggestive of impairment of microtubule stability. This is accompanied by missorting and aggregation of TAU in mice but not in iNeurons. Microtubule PTMs/impairment may be of key importance in tauopathies.
PubMed: 38934386
DOI: 10.4103/NRR.NRR-D-23-01742 -
The New Phytologist Jun 2024Climate warming poses a significant threat to global crop production and food security. However, our understanding of the molecular mechanisms governing thermoresponsive...
Climate warming poses a significant threat to global crop production and food security. However, our understanding of the molecular mechanisms governing thermoresponsive development in crops remains limited. Here we report that the auxiliary subunit of N-terminal acetyltransferase A (NatA) in rice OsNAA15 is a prerequisite for rice thermoresponsive growth. OsNAA15 produces two isoforms OsNAA15.1 and OsNAA15.2, via temperature-dependent alternative splicing. Among the two, OsNAA15.1 is more likely to form a stable and functional NatA complex with the potential catalytic subunit OsNAA10, leading to a thermoresponsive N-terminal acetylome. Intriguingly, while OsNAA15.1 promotes plant growth under elevated temperatures, OsNAA15.2 exhibits an inhibitory effect. We identified two glycolate oxidases (GLO1/5) as major substrates from the thermoresponsive acetylome. These enzymes are involved in hydrogen peroxide (HO) biosynthesis via glycolate oxidation. N-terminally acetylated GLO1/5 undergo their degradation through the ubiquitin-proteasome system. This leads to reduced reactive oxygen species (ROS) production, thereby promoting plant growth, particularly under high ambient temperatures. Conclusively, our findings highlight the pivotal role of N-terminal acetylation in orchestrating the glycolate-mediated ROS homeostasis to facilitate thermoresponsive growth in rice.
PubMed: 38934055
DOI: 10.1111/nph.19928 -
Kidney Research and Clinical Practice Jun 2024Traditional acute kidney injury (AKI) classifications, which are centered around semi-anatomical lines, can no longer capture the complexity of AKI. By employing...
Traditional acute kidney injury (AKI) classifications, which are centered around semi-anatomical lines, can no longer capture the complexity of AKI. By employing strategies to identify predictive and prognostic enrichment targets, experts could gain a deeper comprehension of AKI's pathophysiology, allowing for the development of treatment-specific targets and enhancing individualized care. Subphenotyping, which is enriched with AKI biomarkers, holds insights into distinct risk profiles and tailored treatment strategies that redefine AKI and contribute to improved clinical management. The utilization of biomarkers such as N-acetyl-β-D-glucosaminidase, tissue inhibitor of metalloprotease-2•insulin-like growth factor-binding protein 7, kidney injury molecule-1, and liver fatty acid-binding protein garnered significant attention as a means to predict subclinical AKI. Novel biomarkers offer promise in predicting persistent AKI, with urinary motif chemokine ligand 14 displaying significant sensitivity and specificity. Furthermore, they serve as predictive markers for weaning patients from acute dialysis and offer valuable insights into distinct AKI subgroups. The proposed management of AKI, which is encapsulated in a structured flowchart, bridges the gap between research and clinical practice. It streamlines the utilization of biomarkers and subphenotyping, promising a future in which AKI is swiftly identified and managed with unprecedented precision. Incorporating kidney biomarkers into strategies for early AKI detection and the initiation of AKI care bundles has proven to be more effective than using care bundles without these novel biomarkers. This comprehensive approach represents a significant stride toward precision medicine, enabling the identification of high-risk subphenotypes in patients with AKI.
PubMed: 38934040
DOI: 10.23876/j.krcp.23.284 -
Frontiers in Molecular Neuroscience 2024Rho guanine nucleotide exchange factors (Rho GEFs) activate Rho GTPases, which act as molecular switches regulating various essential cellular functions. This study...
Rho guanine nucleotide exchange factors (Rho GEFs) activate Rho GTPases, which act as molecular switches regulating various essential cellular functions. This study investigated the role of ARHGEF5, a Rho GEF known for its involvement in cell migration and invasion processes, in the context of brain development. We found that ARHGEF5 is essential for dendrite development during the early stages of neuronal growth. We also discovered that ARHGEF5 binds to Drebrin E, which is vital for coordinating actin and microtubule dynamics, and facilitates the interaction between Drebrin E and Cyclin-dependent kinase 5, which phosphorylates Drebrin E. Notably, ARHGEF5 deficiency resulted in a decrease in acetylated α-tubulin levels, and the expression of an α-tubulin acetylation mimetic mutant (K40Q) rescued the defects in dendrite development and neuronal migration, suggesting ARHGEF5's role in modulating microtubule stability. Additionally, ARHGEF5 was shown to influence Golgi positioning in the leading processes of migrating cortical neurons during brain development. Our study suggests that ARHGEF5 plays a crucial role in integrating cytoskeletal dynamics with neuronal morphogenesis and migration processes during brain development.
PubMed: 38932934
DOI: 10.3389/fnmol.2024.1421932 -
Nutrients Jun 2024High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and...
BACKGROUND
High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD).
RESULTS
C57BL/6 mice (5-6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. , and were highly abundant in C-HFD group, while the , (TM7), , and were more abundant in F-HFD group. Other taxa in C-HFD group included the (AF12), and An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (), Fatty acid synthase (), Stearoyl-CoA desaturase-1 (), Elongation of long-chain fatty acids family member 6 (), Peroxisome proliferator-activated receptor-gamma () and cholesterol synthesis (β-(hydroxy β-methylglutaryl-CoA reductase (). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (), Fatty acid binding protein-1 () and efflux (ATP-binding cassette G1 (), Microsomal TG transfer protein () in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (), C-C motif chemokine ligand 2 (), and Interleukin-12 (), as well as a tendency for liver fibrosis.
CONCLUSION
These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance.
Topics: Animals; Dysbiosis; Gastrointestinal Microbiome; Insulin Resistance; Diet, High-Fat; Mice, Inbred C57BL; Male; Mice; Fatty Liver; Liver; Dietary Fats; Sucrose
PubMed: 38931284
DOI: 10.3390/nu16121929 -
Plants (Basel, Switzerland) Jun 2024, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present...
, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present investigation was to search for alternative sources of cytotoxic compounds in . prepared as leaves and in vitro callus cultures. The friable callus of was established using a combination of plant growth regulators: 4 mgL of 2,4-dichlorophenoxyacetic acid (2,4-D), 1 mgL Naphthaleneacetic Acid (NAA) and 1 mgL Zeatin. The maximum cell growth was at day 28 with a specific growth rate of μ = 0.059 days and duplication time td = 11.8 days. HPLC quantification of the dichloromethane callus biomass extract showed that Scopoletin, with a concentration of 10.7 µg g dry weight, was the main compound inducible as a phytoalexin by the addition of high concentrations of 2,4-D, as well as by the absence of nutrients in the culture medium. In this same extract, the compounds γ-sitosterol and stigmasterol were also identified by GC-MS analysis. Open column chromatography was used to separate and identify yatein, acetyl podophyllotoxin and 7',8'-dehydropodophyllotoxin in the leaves of the wild plant. Cytotoxic activity on four cancer cell lines was tested, with PC-3 prostate carcinoma (IC of 12.6 ± 4.6 µgmL) being the most sensitive to the wild-type plant extract and HeLa cervical carcinoma (IC of 72 ± 5 µgmL) being the most sensitive to the callus culture extract.
PubMed: 38931054
DOI: 10.3390/plants13121622 -
Molecules (Basel, Switzerland) Jun 20241,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported....
1,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported. Recently, we reported a facile synthesis of trisubstituted allenamides via -acetylation followed by DBU-promoted isomerization, where various substituted allenamides were conveniently synthesized from readily available propargylamines with high efficiency. In light of this research background, we focused on the utility of this methodology for the synthesis of substituted 1,2-dihydroisoquinolines. In this study, a palladium-catalyzed cascade cyclization-coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids is described. When -acetyl diphenyl-substituted trisubstituted allenamide and phenylboronic acid were treated with 10 mol% of Pd(OAc), 20 mol% of P(-tolyl), and 5 equivalents of NaOH in dioxane/HO (4/1) at 80 °C, the reaction proceeded to afford a substituted 1,2-dihydroisoquinoline. The reaction proceeded via intramolecular cyclization, followed by transmetallation with the arylboronic acid of the resulting allylpalladium intermediate. A variety of highly substituted 1,2-dihydroisoquinolines were concisely obtained using this methodology because the allenamides, as reaction substrates, were prepared from readily available propargylamines in one step.
PubMed: 38930982
DOI: 10.3390/molecules29122917 -
Molecules (Basel, Switzerland) Jun 2024Organic arsenic compounds such as -aminophenylarsine oxide (-APAO) are easier for structural optimization to improve drug-like properties such as pharmacokinetic...
Organic arsenic compounds such as -aminophenylarsine oxide (-APAO) are easier for structural optimization to improve drug-like properties such as pharmacokinetic properties, therapeutic efficacy, and target selectivity. In order to strengthen the selectivity of 4-(1,3,2-dithiarsinan-2-yl) aniline 7 to tumor cell, a thiourea moiety was used to strengthen the anticancer activity. To avoid forming a mixture of α/β anomers, the strategy of 2-acetyl's neighboring group participation was used to lock the configuration of 2,3,4,6-tetra--acetyl-β-d-glucopyranosyl isothiocyanate from 2,3,4,6-tetra--acetyl-α-d-glucopyranosyl bromide. 1-(4-(1,3,2-dithiarsinan-2-yl) aniline)-2-N-(2,3,4,6-tetra--acetyl-β-d-glucopyranos-1-yl)-thiourea 2 can increase the selectivity of human colon cancer cells HCT-116 (0.82 ± 0.06 μM vs. 1.82 ± 0.07 μM) to human embryonic kidney 293T cells (1.38 ± 0.01 μM vs. 1.22 ± 0.06 μM) from 0.67 to 1.68, suggesting a feasible approach to improve the therapeutic index of arsenic-containing compounds as chemotherapeutic agents.
Topics: Humans; Thiourea; Antineoplastic Agents; Drug Design; Glucose; Cell Line, Tumor; Cell Proliferation; HCT116 Cells; Molecular Structure; Arsenicals; Structure-Activity Relationship
PubMed: 38930915
DOI: 10.3390/molecules29122850 -
Molecules (Basel, Switzerland) Jun 2024A new series of chiral 4,5-dihydro-1-[1,2,4]-triazoline molecules, featuring a β-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition...
Stereoselective Asymmetric Syntheses of Molecules with a 4,5-Dihydro-1-[1,2,4]-Triazoline Core Possessing an Acetylated Carbohydrate Appendage: Crystal Structure, Spectroscopy, and Pharmacology.
A new series of chiral 4,5-dihydro-1-[1,2,4]-triazoline molecules, featuring a β-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition reaction between various hydrazonyl chlorides and carbohydrate Schiff bases. The isolated enantiopure triazolines (-) were identified through high-resolution mass spectrometry (HRMS) and vibrational spectroscopy. Subsequently, their solution structures were elucidated through NMR spectroscopic techniques. Single-crystal X-ray analysis of derivative provided definitive evidence for the 3-D structure of this compound and revealed important intermolecular forces in the crystal lattice. Moreover, it confirmed the ()-configuration at the newly generated stereo-center. Selected target compounds were investigated for anti-tumor activity in 60 cancer cell lines, with derivative showing the highest potency, particularly against leukemia. Additionally, substituent-dependent anti-fungal and anti-bacterial behavior was observed.
Topics: Humans; Crystallography, X-Ray; Triazoles; Cell Line, Tumor; Antineoplastic Agents; Carbohydrates; Molecular Structure; Stereoisomerism; Acetylation; Structure-Activity Relationship; Magnetic Resonance Spectroscopy
PubMed: 38930904
DOI: 10.3390/molecules29122839