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Chemical Reviews Jun 2024Within the canonical repertoire of the amino acid involved in protein biogenesis, proline plays a unique role as an amino acid presenting a modified backbone rather than... (Review)
Review
Within the canonical repertoire of the amino acid involved in protein biogenesis, proline plays a unique role as an amino acid presenting a modified backbone rather than a side-chain. Chemical structures that mimic proline but introduce changes into its specific molecular features are defined as proline analogues. This review article summarizes the existing chemical, physicochemical, and biochemical knowledge about this peculiar family of structures. We group proline analogues from the following compounds: substituted prolines, unsaturated and fused structures, ring size homologues, heterocyclic, e.g., pseudoproline, and bridged proline-resembling structures. We overview (1) the occurrence of proline analogues in nature and their chemical synthesis, (2) physicochemical properties including ring conformation and / amide isomerization, (3) use in commercial drugs such as nirmatrelvir recently approved against COVID-19, (4) peptide and protein synthesis involving proline analogues, (5) specific opportunities created in peptide engineering, and (6) cases of protein engineering with the analogues. The review aims to provide a summary to anyone interested in using proline analogues in systems ranging from specific biochemical setups to complex biological systems.
PubMed: 38941181
DOI: 10.1021/acs.chemrev.4c00007 -
Frontiers in Bioscience (Landmark... Jun 2024Rheumatic heart disease (RHD) is caused by inflammatory cells mistakenly attacking the heart valve due to Group A Streptococcus (GAS) infection, but it is still unclear...
BACKGROUND
Rheumatic heart disease (RHD) is caused by inflammatory cells mistakenly attacking the heart valve due to Group A Streptococcus (GAS) infection, but it is still unclear which cells or genes are involved in the process of inflammatory cells infiltrating the valve. Inflammatory infiltration into the target tissue requires an increase in the expression of phosphorylated vascular endothelial-cadherin (p-VE-cad), p-VE-cad can increase the endothelial permeability and promote the migration of inflammatory cells across the endothelium. P-VE-cad is potentially regulated by RAS-related C3 botulinum substrate 1 (RAC1), together with phosphorylated proline-rich tyrosine kinase 2 (p-PYK2). While RAC1/p-PYK2/p-VE-cad is triggered by the activation of vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is related to M1 macrophages adhering to the endothelium via very late antigen 4 (VLA4). Inflammatory infiltration into the valve is extremely important in the early pathogenesis of RHD. However, there is no relevant research on whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved in RHD; therefore, what we explored in this study was whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved.
METHODS
We established a rat model of RHD and a cell model of M1 macrophage and endothelial cell cocultivation. Subsequently, we measured the degree of inflammatory cell infiltration, the levels of IL-6/IL-17, the degree of fibrosis (COL3/1), and the expression levels of fibrosis markers (FSP1, COL1A1 and COL3A1) in the heart valves of RHD rats. Additionally, we detected the expression of M1/M2 macrophage biomarkers in rat model and cell model, as well as the expression of M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad. We also tested the changes in endothelial permeability after coculturing M1 macrophages and endothelial cells.
RESULTS
Compared to those in the control group, the levels of inflammatory cell infiltration and fibrotic factors in the heart valves of RHD rats were significantly higher; the expression of M1 macrophage biomarkers (iNOS, CD86 and TNF-α) in RHD rats was significantly higher; and significantly higher than the expression of M2 macrophage biomarkers (Arg1 and TGF-β). And the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad in the hearts of RHD rats were significantly higher. At the cellular level, after coculturing M1 macrophages with endothelial cells, the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad were significantly higher, and the permeability of the endothelium was significantly greater due to cocultivation with M1 macrophages.
CONCLUSIONS
All the results suggested that M1 macrophages and the VLA4/VCAM-1 pathway are potentially involved in the process of inflammatory infiltration in RHD.
Topics: Animals; Rheumatic Heart Disease; Vascular Cell Adhesion Molecule-1; Macrophages; Rats; Integrin alpha4beta1; Male; Heart Valves; Signal Transduction; Rats, Sprague-Dawley; rac1 GTP-Binding Protein; Disease Models, Animal; Humans
PubMed: 38940032
DOI: 10.31083/j.fbl2906219 -
Plant Physiology and Biochemistry : PPB Jun 2024The emergence of microplastics (MPs) as pollutants in agricultural soils is increasingly alarming, presenting significant threats to soil ecosystems. Given the...
Elucidating the role of rice straw biochar in modulating Helianthus annuus L. antioxidants, secondary metabolites and soil post-harvest characteristics in different types of microplastics.
The emergence of microplastics (MPs) as pollutants in agricultural soils is increasingly alarming, presenting significant threats to soil ecosystems. Given the widespread contamination of ecosystems by various types of MPs, including polystyrene (PS), polyvinyl chloride (PVC), and polyethylene (PE), it is crucial to understand their effects on agricultural productivity. The present study was conducted to investigate the effects of different types of MPs (PS, PVC, and PE) on various aspects of sunflower (Helianthus annuus L.) growth with the addition of rice straw biochar (RSB). This study aimed to examine plant growth and biomass, photosynthetic pigments and gas exchange characteristics, oxidative stress indicators, and the response of various antioxidants (enzymatic and non-enzymatic) and their specific gene expression, proline metabolism, the AsA-GSH cycle, cellular fractionation in the plants and post-harvest soil properties. The research outcomes indicated that elevated levels of different types of MPs in the soil notably reduced plant growth and biomass, photosynthetic pigments, and gas exchange attributes. Different types of MPs also induced oxidative stress, which caused an increase in various enzymatic and non-enzymatic antioxidant compounds, gene expression and sugar content; notably, a significant increase in proline metabolism, AsA-GSH cycle, and pigmentation of cellular components was also observed. Favorably, the addition of RSB significantly increased plant growth and biomass, gas exchange characteristics, enzymatic and non-enzymatic compounds, and relevant gene expression while decreasing oxidative stress. In addition, RSB amendment decreased proline metabolism and AsA-GSH cycle in H. annuus plants, thereby enhancing cellular fractionation and improving post-harvest soil properties. These results open new avenues for sustainable agriculture practices and show great potential for resolving the urgent issues caused by microplastic contamination in agricultural soils.
PubMed: 38936071
DOI: 10.1016/j.plaphy.2024.108865 -
Journal of Occupational and... Jun 2024To investigate the mediating role of the activation degree of arginine-proline metabolism in the association of coal dust and decreased lung function.
OBJECTIVES
To investigate the mediating role of the activation degree of arginine-proline metabolism in the association of coal dust and decreased lung function.
METHODS
CDE represented coal dust exposure, while the Hyp/Arg in BALF gauged arginine-proline metabolism activation. Pulmonary function indicators, including FVC%pred, FEV1/FVC%, and FEV1%pred, DLCO%pred, P(A-a) O2 and 6MWT, were assessed.
RESULTS
Findings revealed a significant association between elevated CDE and increased Hyp/Arg, increased P(A-a) O2, decreased 6MWT, DLCO%pred, and decreased FVC%pred. However, no statistically significant association was found between CDE and FEV1%pred or FEV1/FVC%. The mediating effect of Hyp/Arg was significant for CDE's impact on P(A-a) O2 and DLCO%pred but not on 6MWT and FVC%pred.
CONCLUSIONS
These results highlight the role of Hyp/Arg in mediating the association between CDE and lung function parameters, shedding light on potential therapeutic avenues for mitigating coal dust-induced lung function impairment.
PubMed: 38935365
DOI: 10.1097/JOM.0000000000003171 -
Frontiers in Genetics 2024The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: ), specifying the variant proline (P64) to histidine (H64), is known to...
INTRODUCTION
The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: ), specifying the variant proline (P64) to histidine (H64), is known to affect the protein's functions and has been associated with the risk of several types of cancer, including differentiated thyroid carcinoma (DTC).
MATERIALS AND METHODS
To deepen our understanding of the biological effects of this SNP, we analyzed the proteome of two isogenic cell lines (NC-P64 vs. NA-H64) derived from the immortalized non-malignant thyrocyte cell line Nthy-Ori, generated through the CRISPR-Cas9 technique to differ by rs4644 genotype. We compared the proteome of these cells to detect differentially expressed proteins and studied their proteome in relation to their transcriptome.
RESULTS
Firstly, we found, consistently with previous studies, that gal-3-H64 could be detected as a monomer, homodimer, and heterodimer composed of one cleaved and one uncleaved monomer, whereas gal-3-P64 could be found only as a monomer or uncleaved homodimer. Moreover, results indicate that rs4644 influences the expression of several proteins, predominantly upregulated in NA-H64 cells. Overall, the differential protein expression could be attributed to the altered mRNA expression, suggesting that rs4644 shapes the function of gal-3 as a transcriptional co-regulator. However, this SNP also appeared to affect post-transcriptional regulatory mechanisms for proteins whose expression was oppositely regulated compared to mRNA expression. It is conceivable that the rs4644-dependent activities of gal-3 could be ascribed to the different modalities of self-dimerization.
CONCLUSION
Our study provided further evidence that rs4644 could affect the gal-3 functions through several routes, which could be at the base of differential susceptibility to diseases, as reported in case-control association studies.
PubMed: 38933925
DOI: 10.3389/fgene.2024.1380495 -
Pharmaceutics May 2024We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence...
We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence (Q/D)-(R/K)-X-X-A-(Gln/Asp)-(Arg/Lys)-AA-AA-Ala-based on a motif called "shared epitope (SE)", specifically present in specific alleles of the gene. This SE binds to a particular site within the proline reach domain (P-domain) of the cell surface-calreticulin (CS-CRT). CS-CRT is a multifunctional endoplasmic reticulum (ER) calcium-binding protein that is located on the cell surface of T cells and triggers innate immune signaling, leading to the development of inflammatory autoimmune diseases. The development of Clarstatin was based on the parent peptide W-G-D-K-S-G-A- derived from the active region of the SE. Following the design based on the cycloscan method, the synthesis of Clarstatin was performed by the Fmoc solid phase peptide synthesis (SPPS) method, purified by HPLC to 96% homogeneity, and its structure was confirmed by LC-MS. Clarstatin reduced calcium levels in Jurkat lymphocyte cultures, ameliorated uveitis in vivo in the experimental autoimmune uveitis (EAU) mice model, and was safe upon acute toxicity evaluation. These findings identify Clarstatin as a promising lead compound for future drug development as a novel class of therapeutic agents in the therapy of uveitis.
PubMed: 38931845
DOI: 10.3390/pharmaceutics16060723 -
Plants (Basel, Switzerland) Jun 2024Alkaline stress with high pH levels could significantly influence plant growth and survival. The enzyme 9-cis-epoxycarotenoid dioxygenase (NCED) serves as a critical...
Alkaline stress with high pH levels could significantly influence plant growth and survival. The enzyme 9-cis-epoxycarotenoid dioxygenase (NCED) serves as a critical bottleneck in the biosynthesis of abscisic acid (ABA), making it essential for regulating stress tolerance. Here, we show that -overexpressing rice lines have increased ABA content by up to 50.90% and improved transcription levels of numerous genes involved in stress responses that significantly enhance seedling survival rates. Overexpression of increased the dry weight contents of the total chlorophyll, proline, soluble sugar, starch, and the activities of antioxidant enzymes of rice seedlings, while reducing the contents of O·, HO, and malondialdehyde under hydroponic alkaline stress conditions simulated by 10, 15, and 20 mmol L of NaCO. Additionally, the -overexpressing rice lines exhibited a notable increase in the expression of ; ABA response-related genes and ; ion homeostasis-related genes , , , and ; and ROS scavenging-related genes , , , , , and in rice seedling leaves. The results of these findings suggest that overexpression of upregulates endogenous ABA levels and the expression of stress response genes, which represents an innovative molecular approach for enhancing the alkaline tolerance of rice seedlings.
PubMed: 38931145
DOI: 10.3390/plants13121713 -
Plants (Basel, Switzerland) Jun 2024In this study, processing tomato ( L.) 'Ligeer 87-5' was hydroponically cultivated under 100 mM NaCl to simulate salt stress. To investigate the impacts on ion...
In this study, processing tomato ( L.) 'Ligeer 87-5' was hydroponically cultivated under 100 mM NaCl to simulate salt stress. To investigate the impacts on ion homeostasis, osmotic regulation, and redox status in tomato seedlings, different endogenous levels of ascorbic acid (AsA) were established through the foliar application of 0.5 mM AsA (NA treatment), 0.25 mM lycorine (LYC, an inhibitor of AsA synthesis; NL treatment), and a combination of LYC and AsA (NLA treatment). The results demonstrated that exogenous AsA significantly increased the activities and gene expressions of key enzymes (L-galactono-1,4-lactone dehydrogenase (GalLDH) and L-galactose dehydrogenase (GalDH)) involved in AsA synthesis in tomato seedling leaves under NaCl stress and NL treatment, thereby increasing cellular AsA content to maintain its redox status in a reduced state. Additionally, exogenous AsA regulated multiple ion transporters via the SOS pathway and increased the selective absorption of K, Ca, and Mg in the aerial parts, reconstructing ion homeostasis in cells, thereby alleviating ion imbalance caused by salt stress. Exogenous AsA also increased proline dehydrogenase (ProDH) activity and gene expression, while inhibiting the activity and transcription levels of Δ1-pyrroline-5-carboxylate synthetase (P5CS) and ornithine-δ-aminotransferase (OAT), thereby reducing excessive proline content in the leaves and alleviating osmotic stress. LYC exacerbated ion imbalance and osmotic stress caused by salt stress, which could be significantly reversed by AsA application. Therefore, exogenous AsA application increased endogenous AsA levels, reestablished ion homeostasis, maintained osmotic balance, effectively alleviated the inhibitory effect of salt stress on tomato seedling growth, and enhanced their salt tolerance.
PubMed: 38931104
DOI: 10.3390/plants13121672 -
Plants (Basel, Switzerland) Jun 2024Abiotic stress significantly affects plant growth and has devastating effects on crop production. Drought stress is one of the main abiotic stressors. Actin is a major...
Abiotic stress significantly affects plant growth and has devastating effects on crop production. Drought stress is one of the main abiotic stressors. Actin is a major component of the cytoskeleton, and actin-depolymerizing factors (ADFs) are conserved actin-binding proteins in eukaryotes that play critical roles in plant responses to various stresses. In this study, we found that , an gene from the soybean , showed drastic upregulation under drought stress. Subcellular localization experiments in tobacco epidermal cells and tobacco protoplasts showed that GmADF13 was localized in the nucleus and cytoplasm. We characterized its biological function in transgenic and hairy root composite soybean plants. plants transformed with displayed a more robust drought tolerance than wild-type plants, including having a higher seed germination rate, longer roots, and healthy leaves under drought conditions. Similarly, -overexpressing (OE) soybean plants generated via the -mediated transformation of the hairy roots showed an improved drought tolerance. Leaves from OE plants showed higher relative water, chlorophyll, and proline contents, had a higher antioxidant enzyme activity, and had decreased malondialdehyde, hydrogen peroxide, and superoxide anion levels compared to those of control plants. Furthermore, under drought stress, OE activated the transcription of several drought-stress-related genes, such as , , , , and . Thus, is a positive regulator of the drought stress response, and it may play an essential role in plant growth under drought stress conditions. These results provide new insights into the functional elucidation of soybean . They may be helpful for breeding new soybean cultivars with a strong drought tolerance and further understanding how help plants adapt to abiotic stress.
PubMed: 38931083
DOI: 10.3390/plants13121651 -
Plants (Basel, Switzerland) Jun 2024Aluminum (Al) toxicity in acidic soils can significantly reduce peanut yield. The physiological response of peanut leaves to Al poisoning stress still has not been fully...
Aluminum (Al) toxicity in acidic soils can significantly reduce peanut yield. The physiological response of peanut leaves to Al poisoning stress still has not been fully explored. This research examined the influences of Al toxicity on peanut leaves by observing the leaf phenotype, scanning the leaf area and perimeter, and by measuring photosynthetic pigment content, physiological response indices, leaf hormone levels, and mineral element accumulation. Fluorescence quantitative RT-PCR (qPCR) was utilized to determine the relative transcript level of specific genes. The results indicated that Al toxicity hindered peanut leaf development, reducing their biomass, surface area, and perimeter, although the decrease in photosynthetic pigment content was minimal. Al toxicity notably affected the activity of antioxidative enzymes, proline content, and MDA (malondialdehyde) levels in the leaves. Additionally, Al poisoning resulted in the increased accumulation of iron (Fe), potassium (K), and Al in peanut leaves but reduced the levels of calcium (Ca), manganese (Mn), copper (Cu), zinc (Zn), and magnesium (Mg). There were significant changes in the content of hormones and the expression level of genes connected with hormones in peanut leaves. High Al concentrations may activate cellular defense mechanisms, enhancing antioxidative activity to mitigate excess reactive oxygen species (ROS) and affecting hormone-related gene expression, which may impede leaf biomass and development. This research aimed to elucidate the physiological response mechanisms of peanut leaves to Al poisoning stress, providing insights for breeding new varieties resistant to Al poisoning.
PubMed: 38931038
DOI: 10.3390/plants13121606