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Molecules (Basel, Switzerland) May 2024Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as...
Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as stress granules (SGs), which minimize stress-induced damage and promote stress adaptation and cell survival. SGs are hijacked by cancer cells to promote cell survival and are consequently involved in the development of anticancer drug resistance. However, the design and application of chemical compounds targeting SGs to improve anticancer drug efficacy have rarely been studied. Here, we developed two types of SG inhibitory peptides (SIPs) derived from SG core proteins Caprin1 and USP10 and fused with cell-penetrating peptides to generate TAT-SIP-C1/2 and SIP-U1-Antp, respectively. We obtained 11 SG-inducing anticancer compounds from cell-based screens and explored the potential application of SIPs in overcoming resistance to the SG-inducing anticancer drug sorafenib. We found that SIPs increased the sensitivity of HeLa cells to sorafenib via the disruption of SGs. Therefore, anticancer drugs which are competent to induce SGs could be combined with SIPs to sensitize cancer cells, which might provide a novel therapeutic strategy to alleviate anticancer drug resistance.
Topics: Humans; Sorafenib; Antineoplastic Agents; Stress Granules; HeLa Cells; Drug Resistance, Neoplasm; Peptides; Cell Survival; Ubiquitin Thiolesterase; Neoplasms; Cell Line, Tumor; Cell-Penetrating Peptides
PubMed: 38731625
DOI: 10.3390/molecules29092134 -
Briefings in Bioinformatics Mar 2024Protein acetylation is one of the extensively studied post-translational modifications (PTMs) due to its significant roles across a myriad of biological processes....
Protein acetylation is one of the extensively studied post-translational modifications (PTMs) due to its significant roles across a myriad of biological processes. Although many computational tools for acetylation site identification have been developed, there is a lack of benchmark dataset and bespoke predictors for non-histone acetylation site prediction. To address these problems, we have contributed to both dataset creation and predictor benchmark in this study. First, we construct a non-histone acetylation site benchmark dataset, namely NHAC, which includes 11 subsets according to the sequence length ranging from 11 to 61 amino acids. There are totally 886 positive samples and 4707 negative samples for each sequence length. Secondly, we propose TransPTM, a transformer-based neural network model for non-histone acetylation site predication. During the data representation phase, per-residue contextualized embeddings are extracted using ProtT5 (an existing pre-trained protein language model). This is followed by the implementation of a graph neural network framework, which consists of three TransformerConv layers for feature extraction and a multilayer perceptron module for classification. The benchmark results reflect that TransPTM has the competitive performance for non-histone acetylation site prediction over three state-of-the-art tools. It improves our comprehension on the PTM mechanism and provides a theoretical basis for developing drug targets for diseases. Moreover, the created PTM datasets fills the gap in non-histone acetylation site datasets and is beneficial to the related communities. The related source code and data utilized by TransPTM are accessible at https://www.github.com/TransPTM/TransPTM.
Topics: Acetylation; Protein Processing, Post-Translational; Neural Networks, Computer; Computational Biology; Databases, Protein; Software; Algorithms; Humans; Proteins
PubMed: 38725156
DOI: 10.1093/bib/bbae219 -
RSC Advances May 2024Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over...
Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over protein targets is one of the most interesting issues. The free energy difference of binding between a protein and a ligand was calculated the alchemical approach. The alchemical approach exhibits satisfactory accuracy over four targets, including AmpC beta-lactamase (AmpC); glutamate receptor, ionotropic kainate 1 (GluK1); heat shock protein 90 (Hsp90); and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). In particular, the correlation coefficients between calculated binding free energies and the respective experiments over four targets range from 0.56 to 0.86. The affinity computed free energy perturbation (FEP) simulations is overestimated over the experimental value. Particularly, the electrostatic interaction free energy rules the binding process of ligands to AmpC and GluK1. However, the van der Waals (vdW) interaction free energy plays an important role in the ligand-binding processes of HSP90 and SARS-CoV-2 Mpro. The obtained results associate with the hydrophilic or hydrophobic properties of the ligands. This observation may enhance computer-aided drug design.
PubMed: 38720975
DOI: 10.1039/d4ra00692e -
NeuroImmune Pharmacology and... Mar 2024HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the...
OBJECTIVES
HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the dopamine transporter (DAT) have been shown to reverse Tat-induced DAT dysfunction. We hypothesized that a novel DAT allosteric modulator, SRI-30827, would counteract Tat-induced potentiation of cocaine reward.
METHODS
Doxycycline (Dox)-inducible Tat transgenic (iTat-tg) mice and their G-tg (Tat-null) counterparts were tested in a cocaine conditioned place preference (CPP) paradigm. Mice were treated 14 days with saline, or Dox (100 mg/kg/day, i.p.) to induce Tat protein. Upon induction, mice were place conditioned two days with cocaine (10 mg/kg/day) after a 1-h daily intracerebroventricular (i.c.v.) pretreatment with SRI-30827 (1 nmol) or a vehicle control, and final place preference assessed as a measure of cocaine reward.
RESULTS
Dox-treatment significantly potentiated cocaine-CPP in iTat-tg mice over the response of saline-treated control littermates. SRI-30827 treatment eliminated Tat-induced potentiation without altering normal cocaine-CPP in saline-treated mice. Likewise, SRI-30827 did not alter cocaine-CPP in both saline- and Dox-treated G-tg mice incapable of expressing Tat protein.
CONCLUSIONS
These findings add to a growing body of evidence that allosteric modulation of DAT could provide a promising therapeutic intervention for patients with comorbid HIV-1 and cocaine use disorder (CUD).
PubMed: 38711842
DOI: 10.1515/nipt-2023-0022 -
Mitochondrial DNA. Part B, Resources 2024Lour. 1790 is a precious medicinal plant species, especially for treating chronic liver diseases. Genomic data on are limited. Therefore, this current study aimed to...
Lour. 1790 is a precious medicinal plant species, especially for treating chronic liver diseases. Genomic data on are limited. Therefore, this current study aimed to characterize the chloroplast genome of and reconstruct the phylogenetic relationship among Helicteroideae taxa. Consequently, the complete chloroplast genome of was 163,404 bp in length and contained 113 unique genes (79 protein-coding genes, 30 tRNA genes, and four rRNA genes). Notably, two introns of gene of were lost in comparison to that of other Helicteroideae species. The phylogenetic tree based on chloroplast genomes of eleven Helicteroideae species revealed that was closely related to species. In conclusion, our study described the first complete chloroplast genome of , which is essential for tracing evolutionary history in the Helicteroideae subfamily.
PubMed: 38707209
DOI: 10.1080/23802359.2024.2345794 -
Frontiers in Microbiology 2024Control of from farm to fork is challenging due to the frequent emergence of antimicrobial-resistant isolates. Furthermore, poultry production systems are known...
INTRODUCTION
Control of from farm to fork is challenging due to the frequent emergence of antimicrobial-resistant isolates. Furthermore, poultry production systems are known reservoirs of . The twin-arginine translocation (Tat) pathway is a crucial bacterial secretion system that allows to colonize the host intestinal tract by using formate as the main source of energy. However, Tat pathway is also a major contributing factor for resistance to copper sulfate (CuSO).
METHODS
Since mammals and chickens do not have proteins or receptors that are homologous to bacterial Tat proteins, identification of small molecule (SM) inhibitors targeting the Tat system would allow the development of safe and effective control methods to mitigate in infected or colonized hosts in both pre-harvest and post-harvest. In this study, we screened 11 commercial libraries ( = 50,917 SM) for increased susceptibility to CuSO (1 mM) in 81-176, a human isolate which is widely studied.
RESULTS
Furthermore, we evaluated 177 SM hits (2.5 μg/mL and above) that increased the susceptibility to CuSO for the inhibition of formate dehydrogenase (Fdh) activity, a Tat-dependent substrate. Eight Tat-dependent inhibitors (T1-T8) were selected for further studies. These selected eight Tat inhibitors cleared all tested strains ( = 12) at >10 ng/mL in the presence of 0.5 mM CuSO. These selected SMs were non-toxic to colon epithelial (Caco-2) cells when treated with 50 μg/mL for 24 h and completely cleared intracellular cells when treated with 0.63 μg/mL of SM for 24 h in the presence of 0.5 mM of CuSO. Furthermore, 3 and 5-week-old chicks treated with SM candidates for 5 days had significantly decreased cecal colonization (up to 1.2 log; < 0.01) with minimal disruption of microbiota. analyses predicted that T7 has better drug-like properties than T2 inhibitor and might target a key amino acid residue (glutamine 165), which is located in the hydrophobic core of TatC protein.
DISCUSSION
Thus, we have identified novel SM inhibitors of the Tat pathway, which represent a potential strategy to control spread on farms.
PubMed: 38694802
DOI: 10.3389/fmicb.2024.1342573 -
Biomedicine & Pharmacotherapy =... Jun 2024Alzheimer's disease (AD) is a global medical challenge. Studies have shown that neurotoxicity caused by pathological aggregation of β-amyloid (Aβ) is an important...
Alzheimer's disease (AD) is a global medical challenge. Studies have shown that neurotoxicity caused by pathological aggregation of β-amyloid (Aβ) is an important factor leading to AD. Therefore, inhibiting the pathological aggregation of Aβ is the key to treating AD. The recombinant human HspB5-ACD structural domain protein (AHspB5) prepared by our group in the previous period has been shown to have anti-amyloid aggregation effects, but its inability to penetrate biological membranes has limited its development. In this study, we prepared a recombinant fusion protein (T-AHspB5) of TAT and AHspB5. In vitro experiments showed that T-AHspB5 inhibited the formation of Aβ protofibrils and had the ability to penetrate the blood-brain barrier; in cellular experiments, T-AHspB5 prevented Aβ-induced oxidative stress damage, apoptosis, and inflammatory responses in neuronal cells, and its mechanism of action was related to microglia activation and mitochondria-dependent apoptotic pathway. In animal experiments, T-AHspB5 improved memory and cognitive dysfunction and inhibited pathological changes of AD in APP/PS1 mice. In conclusion, this paper is expected to reveal the intervention mechanism and biological effect of T-AHspB5 on pathological aggregation of Aβ, provide a new pathway for the treatment of AD, and lay the foundation for the future development and application of T-AHspB5.
Topics: Amyloid beta-Peptides; Animals; Humans; Alzheimer Disease; Mice; Apoptosis; Oxidative Stress; Peptide Fragments; Blood-Brain Barrier; Mice, Transgenic; alpha-Crystallin B Chain; Recombinant Fusion Proteins; Male; Recombinant Proteins; Protein Domains; Protein Aggregation, Pathological
PubMed: 38678965
DOI: 10.1016/j.biopha.2024.116661 -
Journal of Clinical Medicine Apr 2024: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial...
Usefulness of Combined Measurement of Surfactant Protein D, Thrombin-Antithrombin III Complex, D-Dimer, and Plasmin-α2 Plasmin Inhibitor Complex in Acute Exacerbation of Interstitial Lung Disease: A Retrospective Cohort Study.
: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial lung disease (AE-ILD). This study aimed to confirm coagulopathy in AE-ILD by evaluating the differences in the clinical characteristics of coagulation/fibrinolysis markers between stable ILD and AE-ILD. : Overall, 81 patients were enrolled in this retrospective study and categorized into the following two groups: a chronic ILD group comprising 63 outpatients and an acute ILD group comprising 18 inpatients diagnosed with AE-ILD. Serum markers, including thrombin-antithrombin III complex (TAT), D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), and surfactant protein D (SP-D), were compared between the groups. : Among the 18 patients with acute ILD, 17 did not meet the International Society of Thrombosis and Hemostasis scoring system for disseminated intravascular coagulation. In acute ILD, the SP-D levels were statistically significantly positively correlated with TAT, D-dimer, and PIC levels, while the Krebs von den Lungen 6 (KL-6) levels showed no correlation with any of these coagulation/fibrinolytic markers. A positive correlation was observed between SP-D levels and TAT, D-dimer, and PIC levels in acute ILD. Serum TAT, D-dimer, and PIC all showed good area under the receiver operating characteristic (ROC) curve (AUC) values in ROC analysis for the diagnosis of acute ILD. : In the clinical setting of AE-ILD, it may be important to focus not only on alveolar damage markers such as SP-D but also on coagulation/fibrinolytic markers including TAT, D-dimer, and PIC.
PubMed: 38673700
DOI: 10.3390/jcm13082427 -
Journal of Neuroinflammation Apr 2024NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier....
Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway.
BACKGROUND
NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat.
METHODS
Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2 mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study.
RESULTS
We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst.
CONCLUSIONS
Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.
Topics: Animals; NADPH Oxidase 2; Mice; Mice, Inbred C57BL; Blood-Retinal Barrier; Intraocular Pressure; Neuroinflammatory Diseases; Mice, Knockout; Cell Proliferation; MAP Kinase Signaling System; Neuroglia; Ocular Hypertension; Glaucoma; Oxidative Stress
PubMed: 38649885
DOI: 10.1186/s12974-024-03075-x -
Journal of Extracellular Vesicles Apr 2024Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a...
Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer's 's-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.
Topics: Extracellular Vesicles; Animals; Astrocytes; Mice; Rats; Hypoxia-Inducible Factor 1, alpha Subunit; HIV-1; Hippocampus; Neurons; tat Gene Products, Human Immunodeficiency Virus; Humans; Neurocognitive Disorders; HIV Infections; Male; AIDS Dementia Complex
PubMed: 38647111
DOI: 10.1002/jev2.12439