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Frontiers in Immunology 2024Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells....
INTRODUCTION
Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Downregulation of MHC-I disengages inhibitory receptors on natural killer (NK) cells, resulting in activation and killing of the target cell if NK cell activating receptors such as NKG2D have engaged stress ligands upregulated on the target cells. Previous work has shown that HHV-6B downregulates three MHC-like stress ligands MICB, ULBP1, and ULBP3, which are recognized by NKG2D. The U20 glycoprotein of the related virus HHV-6A has been implicated in the downregulation of ULBP1, but the precise mechanism remains undetermined.
METHODS
We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches.
RESULTS
We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structural modeling of the U20 - ULBP1 complex indicates some similarities to the m152-RAE1γ complex.
Topics: Humans; Killer Cells, Natural; Herpesvirus 6, Human; GPI-Linked Proteins; NK Cell Lectin-Like Receptor Subfamily K; Lymphocyte Activation; Protein Binding; Viral Proteins; Glycoproteins; Intracellular Signaling Peptides and Proteins
PubMed: 38953028
DOI: 10.3389/fimmu.2024.1363156 -
RSC Advances Jun 2024Utilization of cell wall components of woody biomass has attracted attention as alternatives for fossil fuels towards a sustainable society. A semi-flow hydrothermal...
Fractionation of beech wood cell walls into digestible cellulose-rich residues and photoluminescent lignin-rich precipitates semi-flow hot-compressed water treatment with 2-naphthol.
Utilization of cell wall components of woody biomass has attracted attention as alternatives for fossil fuels towards a sustainable society. A semi-flow hydrothermal treatment was used to fractionate the beech () wood into cellulose-rich residues and lignin-rich precipitates. The enzymatic saccharification of the cellulose component in the residue was enhanced significantly because the preferential delignification from the secondary wall increased enzyme accessibility. Meanwhile, the precipitated lignin was soluble in organic solvent and exhibited clear photoluminescence (PL) according to the chromophore distances. Furthermore, the carbocation scavenger, 2-naphthol, was impregnated into the beech wood to inhibit the lignin re-condensation reaction. As a result, the digestibility of the cellulose component in the residue increased because unproductive enzymatic binding of lignin and lignin re-condensation were both suppressed. In addition, the PL intensity of the precipitates was significantly enhanced, indicating that 2-naphthol bound to the lignin molecules influenced the PL properties. Overall, fractionation using a semi-flow hydrothermal treatment efficiently uses both polysaccharides and lignin, especially the impregnation of 2-naphthol provided advantages for both saccharides and lignin. Monosaccharides can be converted into valuable products a sugar platform, and the lignin precipitates exhibit useful PL properties that give them significant potential as a feedstock for numerous valuable materials, such as fluorescence reagents and spectral conversion agents. The results presented herein provide insights that are crucial for the comprehensive utilization of cell wall components for sustainable biorefinery systems.
PubMed: 38952928
DOI: 10.1039/d4ra03094j -
Avicenna Journal of Phytomedicine 2024Periodontitis is a type of prevalent chronic inflammatory disorder resulting in a failure in the function of tissues supporting the tooth, like gingiva, alveolar bone,... (Review)
Review
OBJECTIVE
Periodontitis is a type of prevalent chronic inflammatory disorder resulting in a failure in the function of tissues supporting the tooth, like gingiva, alveolar bone, and periodontal ligament. Although antibiotic therapy is a common therapy for periodontitis cases, this approach can cause some adverse effects in these patients. Thus, finding an effective curative option with low side effects is still a puzzle.
MATERIALS AND METHODS
This narrative review was conducted on the effects of herbal and nano-based herbal medicine against periodontitis by searching different databases such as Google Scholar, PubMed, Scopus, Web of Science, Science Direct, and Scientific Information Databases.
RESULTS
According to published studies, some popular herbal formulations, such as Aloe vera, curcumin, Melaleuca alternifolia, and Scutellaria baicalensis Georgi, can be effective in periodontitis treatment. However, these herbal products may be accompanied by some pharmacological limitations, such as poor bioavailability, instability, and weak water solubility. On the other hand, harnessing nano-based herbal formulations can elevate the bioavailability, diminish toxicity, and omit repeated administration of drugs.
CONCLUSION
Herbal and nano-based herbal products can create a good chance to treat periodontitis efficiently.
PubMed: 38952769
DOI: 10.22038/AJP.2023.23261 -
Physical Chemistry Chemical Physics :... Jul 2024Single crystal X-ray diffraction analysis of needle shaped riboflavin (RF) crystals revealed π-stacking of RF's isoalloxazine units (distance: 3.643-3.313 Å) with...
Single crystal X-ray diffraction analysis of needle shaped riboflavin (RF) crystals revealed π-stacking of RF's isoalloxazine units (distance: 3.643-3.313 Å) with -orientated ribityl chains. In line with this, classical molecular dynamics (MD) (400 ns) using an isobaric-isothermal (NPT) ensemble of eight RF in a water box (〈〉 ∼ 508.62 nm, 〈〉 = 1.11 bar) revealed anti-aligned aggregation of RF in water (COM-distance: 4 Å). Comparing umbrella sampling for the separation of two RF molecules to the separation of two lumichrome molecules, the similar mean potential force for the separation of RF and lumichrome (22.8 kJ mol; 24.4 kJ mol) proved dispersive interactions as the origin of RF's aggregation. Though stacking of RF is the major water-solubility limiting factor, the conformation of RF's ribityl chain may alter the solubility in water. Both, MD (in water) and COSMO-RS (in water continuum) predicted that conformations of RF with an extended ribityl chain are thermodynamically preferred over any conformations with internal hydrogen bonds between hydroxyl groups and nitrogen/oxygen atoms of the pyrimidine moiety of the flavin ring. Interestingly, COSMO-RS predicted the solubility of the extended conformation to be significantly lower than the latter leading to the very low average solubility of RF. Nuclear Overhauser effect measurements (NOESY) of the structurally related sodium riboflavin 5'-monophosphate (RF-PO) in deuterium oxide confirmed π-stacking of the isoalloxazine rings. In conformity with the 350 times higher water-solubility of RF-PO, NOESY also indicated a contorted conformation of the ribityl phosphate chain, whereas, for RF, indications for a contorted chain were not observed.
PubMed: 38952212
DOI: 10.1039/d4cp02074j -
Drug Delivery Dec 2024Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to...
Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; drug release; viscosity; pH; anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.
Topics: Genistein; Melanoma; Skin Neoplasms; Humans; Particle Size; Drug Liberation; Hydrogels; Drug Delivery Systems; Cell Line, Tumor; Drug Stability; Antineoplastic Agents; Solubility; Drug Carriers; Chemistry, Pharmaceutical; Viscosity; Biological Availability; Administration, Cutaneous; Spheroids, Cellular
PubMed: 38952058
DOI: 10.1080/10717544.2024.2372277 -
Journal of Forensic Sciences Jul 2024Identification of vascular injuries is crucial for complete postmortem evaluation and understanding of trauma deaths by the Medical Examiner. Some vascular injuries are...
Identification of vascular injuries is crucial for complete postmortem evaluation and understanding of trauma deaths by the Medical Examiner. Some vascular injuries are difficult to evaluate due to challenging anatomic locations, especially in the head and neck. Documenting injuries of the facial and vertebral arteries is challenging and necessitates time-consuming dissections that can create artifacts and disfigurement. In busy medical examiner offices with a significant number of traumatic injuries, finding a creative solution to employ reliable postmortem angiography is desirable. At the Office of the Chief Medical Examiner for the State of Maryland (OCME), we created and effectively implemented a selective angiography procedure using traditional indwelling Foley catheters and water-soluble barium swallow contrast to evaluate arterial injuries using either digital radiography or computed tomography imaging modalities. This technique and imaging interpretation can be performed by a medical examiner or forensic pathology fellow after basic technical training and basic radiology training. This study outlines the technique, methods, and utilization of the procedure and describes the findings of six deaths due to vascular lesions from different injury mechanisms and disease processes and describes the ease of implementation on a broader scale in busy Medical Examiner's offices.
PubMed: 38951918
DOI: 10.1111/1556-4029.15568 -
Journal of Experimental & Clinical... Jun 2024During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or...
BACKGROUND
During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.
METHODS
aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).
RESULTS
As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).
CONCLUSIONS
HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.
TRIAL REGISTRATION
NCT05735392 retrospectively registered on January 31, 2023 https://www.
CLINICALTRIALS
gov/search?term=NCT05735392.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Liquid Biopsy; Middle Aged; Ado-Trastuzumab Emtansine; Aged; Trastuzumab; Adult; Biomarkers, Tumor
PubMed: 38951853
DOI: 10.1186/s13046-024-03105-9 -
Diabetology & Metabolic Syndrome Jun 2024This study sought to explore the clinical relevance of the associations of serum levels of advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), and...
BACKGROUND
This study sought to explore the clinical relevance of the associations of serum levels of advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), and thioredoxin-interacting protein (TXNIP) with the renal fat fraction (RFF) in individuals with type 2 diabetes mellitus (T2DM).
METHODS
A total of 133 patients with T2DM were enrolled in the study. RFF, which represents the renal fat level, was determined utilizing Dixon magnetic resonance imaging (MRI). Serum levels of AGEs, sRAGE, TXNIP, and other biochemical parameters were measured in patients who fasted.
RESULTS
RFF in T2DM patients was positively correlated with the fasting levels of C-peptide (CP), triglycerides (TG), AGEs, TXNIP, and sRAGE (P < 0.05) and negatively correlated with the high-density lipoprotein cholesterol (HDL-c) level (P < 0.05). Pearson's correlation analysis indicated that the serum levels of AGEs, sRAGE, and TXNIP were interrelated and positively correlated (P < 0.05). Then, all patients were assigned to four groups according to the RFF quartile. The HC, CP, TG, AGEs, sRAGE, TXNIP, and DKD percentages tended to increase as the RFF quartiles increased, while the HDL-c level tended to decrease (p for trend < 0.05). Next, multiple linear regression analysis was performed using RFF as the dependent variable. After controlling for covariates related to RFF, the results showed that the serum levels of AGEs and TXNIP were still significantly correlated with RFF.
CONCLUSION
These results suggest that circulating AGEs and TXNIP levels may be associated with ectopic fat accumulation in the kidneys of T2DM patients and may serve as indicators of the severity of renal fat deposition.
PubMed: 38951835
DOI: 10.1186/s13098-024-01361-5 -
Journal of Medicinal Chemistry Jul 2024Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One...
1,3,5-Triaza-7-phosphaadamantane and Cyclohexyl Groups Impart to Di-Iron(I) Complex Aqueous Solubility and Stability, and Prominent Anticancer Activity in Cellular and Animal Models.
Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series () emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with (8 mg kg dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.
PubMed: 38951717
DOI: 10.1021/acs.jmedchem.4c00641 -
Nature Cell Biology Jul 2024α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and...
α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)-a component of the SNARE complex that resides on SVs-directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn's function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn's function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson's disease.
PubMed: 38951706
DOI: 10.1038/s41556-024-01456-1