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1.
J Hazard Mater ; 474: 134573, 2024 May 31.
Article En | MEDLINE | ID: mdl-38824779

It has been demonstrated that microplastics (MPs) may be inadvertently ingested by aquatic animals, causing harm to their physiological functions and potentially entering the food chain, thereby posing risks to human food safety. To achieve an environmentally friendly and efficient reduction of MPs in freshwater environments, this experiment investigates the depuration effect of C. demersum on MPs using three common aquatic animals: Macrobrachium nipponense, Corbicula fluminea, and Bellamya aeruginosa as research subjects. The amounts of MPs, digestive enzyme activity, oxidative stress index, and energy metabolism enzyme activity in the digestive and non-digestive systems of three aquatic animals were measured on exposure days 1, 3, and 7 and on depuration days 1 and 3. The results indicated that the depuration effect of C. demersum and the species interaction were significant for the whole individual. Concerning digestive tissue, C. demersum was the most effective in purifying B. aeruginosa. When subjected to short-term exposure to MPs, C. demersum displayed a superior depuration effect. Among non-digestive tissues, C. demersum exhibited the earliest purifying effect on C. fluminea. Additionally, C. demersum alleviated physiological responses caused by MPs. In conclusion, this study underscores C. demersum as a promising new method for removing MPs from aquatic organisms.

2.
Melanoma Res ; 2024 Jun 05.
Article En | MEDLINE | ID: mdl-38842104

OBJECTIVE: This study aimed to elucidate the genetic aspects of the relationship between sex hormones and cutaneous melanoma risk, providing valuable insights into this complex association. METHODS: In this study, we used estradiol, bioavailable testosterone, sex hormone-binding globulin, and total testosterone as the exposure and melanoma as the outcome for two-sample Mendelian randomization analysis. In this study, a random-effects inverse-variance weighting (IVW) model was used as the main analysis model, and the corresponding weighted median, simple mode, weighted mode, and Mendelian randomization‒Egger methods were used as supplementary methods. We assessed both heterogeneity and horizontal pleiotropy in our study, scrutinizing whether the analysis results were affected by any individual single nucleotide polymorphism. RESULTS: The random-effects IVW method indicated that estradiol [odds ratio (OR), 1.000; 95% confidence interval (CI), 0.998-1.003; P = 0.658], bioavailable testosterone (OR = 1.001, 95% CI, 0.999-1.003; P = 0.294), sex hormone-binding globulin (IVW: OR, 1.000; 95% CI, 0.998-1.003; P = 0.658), and total testosterone (IVW: OR, 1.002; 95% CI, 0.999-1.005; P = 0.135) were not genetically linked to cutaneous melanoma. No analyses exhibited heterogeneity, horizontal pleiotropy, or deviations. CONCLUSION: We were unable to find genetic evidence for a causal relationship between sex hormones and the occurrence of cutaneous melanoma in this study. These results are limited by sample size and population, so the causal relationship between sex hormones and cutaneous melanoma needs to be further studied.

3.
Plant Cell Rep ; 43(7): 163, 2024 Jun 06.
Article En | MEDLINE | ID: mdl-38842544

KEY MESSAGE: Calcium polypeptide plays a key role during cadmium stress responses in rice, which is involved in increasing peroxidase activity, modulating pectin methylesterase activity, and regulating cell wall by reducing malondialdehyde content. Cadmium (Cd) contamination threatens agriculture and human health globally, emphasizing the need for sustainable methods to reduce cadmium toxicity in crops. Calcium polypeptide (CaP) is a highly water-soluble small molecular peptide acknowledged for its potential as an organic fertilizer in promoting plant growth. However, it is still unknown whether CaP has effects on mitigating Cd toxicity. Here, we investigated the effect of CaP application on the ability to tolerate toxic Cd in rice. We evaluated the impact of CaP on rice seedlings under varying Cd stress conditions and investigated the effect mechanism of CaP mitigating Cd toxicity by Fourier transform infrared spectroscopy (FTIR), fluorescent probe dye, immunofluorescent labeling, and biochemical analysis. We found a notable alleviation of Cd toxicity by reduced malondialdehyde content and increased peroxidase activity. In addition, our findings reveal that CaP induces structural alterations in the root cell wall by modulating pectin methylesterase activity. Altogether, our results confirm that CaP not only promoted biomass accumulation but also reduced Cd concentration in rice. This study contributes valuable insights to sustainable strategies for addressing Cd contamination in agricultural ecosystems.


Cadmium , Malondialdehyde , Oryza , Oxidative Stress , Pectins , Oryza/drug effects , Oryza/metabolism , Cadmium/toxicity , Oxidative Stress/drug effects , Pectins/metabolism , Malondialdehyde/metabolism , Plant Proteins/metabolism , Carboxylic Ester Hydrolases/metabolism , Cell Wall/metabolism , Cell Wall/drug effects , Seedlings/drug effects , Seedlings/metabolism , Seedlings/growth & development , Peptides/metabolism , Plant Roots/drug effects , Plant Roots/metabolism , Spectroscopy, Fourier Transform Infrared
4.
Front Nutr ; 11: 1402559, 2024.
Article En | MEDLINE | ID: mdl-38757132

Kashin-Beck disease (KBD) is an endochondral osteogenesis disorder characterised by epiphysis damage and secondary deformable arthropathy induced by multiple external factors, among which selenium (Se) and iodine deficiency are important influencing factors. Iodine deficiency is usually accompanied by a low Se content in the soil in the KBD areas of China. Se can reverse oxidative damage to chondrocytes. In addition, Se is related to the bone conversion rate and bone mineral density. Low Se will hinder growth and change bone metabolism, resulting in a decrease in the bone conversion rate and bone mineral density. Thyroid hormone imbalance caused by thyroid dysfunction caused by iodine deficiency can damage bone homeostasis. Compared with Se deficiency alone, Se combined with iodine deficiency can reduce the activity of glutathione peroxidase more effectively, which increases the vulnerability of chondrocytes and other target cells to oxidative stress, resulting in chondrocyte death. Clinical studies have shown that supplementation with Se and iodine is helpful for the prevention and treatment of KBD.

5.
Genomics ; 116(3): 110852, 2024 May.
Article En | MEDLINE | ID: mdl-38703969

Autophagy, a highly conserved process of protein and organelle degradation, has emerged as a critical regulator in various diseases, including cancer progression. In the context of liver cancer, the predictive value of autophagy-related genes remains ambiguous. Leveraging chip datasets from the TCGA and GTEx databases, we identified 23 differentially expressed autophagy-related genes in liver cancer. Notably, five key autophagy genes, PRKAA2, BIRC5, MAPT, IGF1, and SPNS1, were highlighted as potential prognostic markers, with MAPT showing significant overexpression in clinical samples. In vitro cellular assays further demonstrated that MAPT promotes liver cancer cell proliferation, migration, and invasion by inhibiting autophagy and suppressing apoptosis. Subsequent in vivo studies further corroborated the pro-tumorigenic role of MAPT by suppressing autophagy. Collectively, our model based on the five key genes provides a promising tool for predicting liver cancer prognosis, with MAPT emerging as a pivotal factor in tumor progression through autophagy modulation.


Autophagy , Liver Neoplasms , tau Proteins , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Autophagy/genetics , tau Proteins/genetics , tau Proteins/metabolism , Prognosis , Cell Line, Tumor , Survivin/genetics , Survivin/metabolism , Cell Proliferation , Animals , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Biomarkers, Tumor/genetics , Cell Movement , Mice , Apoptosis , Gene Expression Regulation, Neoplastic , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism
6.
Research (Wash D C) ; 7: 0340, 2024.
Article En | MEDLINE | ID: mdl-38665846

The methylation of adenosine base at the nitrogen-6 position is referred to as "N6-methyladenosine (m6A)" and is one of the most prevalent epigenetic modifications in eukaryotic mRNA and noncoding RNA (ncRNA). Various m6A complex components known as "writers," "erasers," and "readers" are involved in the function of m6A. Numerous studies have demonstrated that m6A plays a crucial role in facilitating communication between different cell types, hence influencing the progression of diverse physiological and pathological phenomena. In recent years, a multitude of functions and molecular pathways linked to m6A have been identified in the osteogenic, adipogenic, and chondrogenic differentiation of bone mesenchymal stem cells (BMSCs). Nevertheless, a comprehensive summary of these findings has yet to be provided. In this review, we primarily examined the m6A alteration of transcripts associated with transcription factors (TFs), as well as other crucial genes and pathways that are involved in the differentiation of BMSCs. Meanwhile, the mutual interactive network between m6A modification, miRNAs, and lncRNAs was intensively elucidated. In the last section, given the beneficial effect of m6A modification in osteogenesis and chondrogenesis of BMSCs, we expounded upon the potential utility of m6A-related therapeutic interventions in the identification and management of human musculoskeletal disorders manifesting bone and cartilage destruction, such as osteoporosis, osteomyelitis, osteoarthritis, and bone defect.

7.
ACS Biomater Sci Eng ; 10(5): 3355-3377, 2024 May 13.
Article En | MEDLINE | ID: mdl-38563817

An imbalance between M1 and M2 macrophage polarization is critical in osteoarthritis (OA) development. We investigated the effect of M2 macrophage-derived extracellular vesicles (M2-EVs) to reprogramme macrophages from the M1 to M2 phenotype for OA treatment. M1 macrophages and mouse OA models were treated with M2-EVs. Proteomic analysis was performed to evaluate macrophage polarization in vitro. The OA models were as follows: destabilization of the medial meniscus (DMM) surgery-induced OA and collagenase-induced OA (CIOA). Hyaluronic acid (HA) was used to deliver M2-EVs. M2-EVs decreased macrophage accumulation, repolarized macrophages from the M1 to M2 phenotype, mitigated synovitis, reduced cartilage degradation, alleviated subchondral bone damage, and improved gait abnormalities in the CIOA and DMM models. Moreover, HA increased the retention time of M2-EVs and enhanced the efficiency of M2-EVs in OA treatment. Furthermore, proteomic analysis demonstrated that M2-EVs exhibited a macrophage reprogramming ability similar to IL-4, and the pathways might be the NOD-like receptor (NLR), TNF, NF-κB, and Toll-like receptor (TLR) signaling pathways. M2-EVs reprogrammed macrophages from the M1 to M2 phenotype, which resulted in beneficial effects on cartilage and attenuation of OA severity. In summary, our study indicated that M2-EV-guided reprogramming of macrophages is a promising treatment strategy for OA.


Extracellular Vesicles , Hyaluronic Acid , Macrophages , Osteoarthritis , Hyaluronic Acid/pharmacology , Hyaluronic Acid/metabolism , Hyaluronic Acid/chemistry , Animals , Macrophages/drug effects , Macrophages/metabolism , Extracellular Vesicles/metabolism , Extracellular Vesicles/drug effects , Extracellular Vesicles/transplantation , Osteoarthritis/drug therapy , Osteoarthritis/pathology , Osteoarthritis/metabolism , Mice , Mice, Inbred C57BL , Male , Disease Models, Animal , RAW 264.7 Cells , Proteomics , Macrophage Activation/drug effects
8.
Bioorg Chem ; 147: 107328, 2024 Jun.
Article En | MEDLINE | ID: mdl-38583248

Discovering novel NDM-1 inhibitors is an urgent task for treatment of 'superbug' infectious diseases. In this study, we found that naturally occurring houttuynin and its sulfonate derivatives might be effective NDM-1 inhibitors with novel mechanism, i.e. the attribute of partially covalent inhibition of sulfonate derivatives of houttuynin against NDM-1. Primary structure-activity relationship study showed that both the long aliphatic side chain and the warhead of aldehyde group are vital for the efficiency against NDM-1. The homologs with longer chains (SNH-2 to SNH-5) displayed stronger inhibitory activities with IC50 range of 1.1-1.5 µM, while the shorter chain the weaker inhibition. Further synergistic experiments in cell level confirmed that all these 4 compounds (at 32 µg/mL) recovered the antibacterial activity of meropenem (MER) against E. coli BL21/pET15b-blaNDM-1.


Anti-Bacterial Agents , Dose-Response Relationship, Drug , Escherichia coli , Microbial Sensitivity Tests , Structure-Activity Relationship , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Escherichia coli/drug effects , Escherichia coli/enzymology , Molecular Structure , beta-Lactamases/metabolism , beta-Lactamase Inhibitors/pharmacology , beta-Lactamase Inhibitors/chemistry , beta-Lactamase Inhibitors/chemical synthesis , Biological Products/pharmacology , Biological Products/chemistry , Biological Products/chemical synthesis , Humans , Escherichia coli Proteins
9.
ACS Omega ; 9(13): 15259-15270, 2024 Apr 02.
Article En | MEDLINE | ID: mdl-38585050

Injection of carbon dioxide offers substantial social and economic advantages for reduction of carbon emission reduction. Utilizing CO2 in shale formations can significantly enhance the extraction of shale oil or gas. Conducting fundamental research on how CO2 affects shale rock's physical properties is crucial for enhancing its porosity and permeability. Particularly for deep shale layers, the effects of supercritical CO2 on shale physical properties should be investigated at a high temperature and pressure, differing from the standard conditions applied in shallower layers. A study examined the impact of supercritical CO2 under such conditions on the pore-throat structure and mineral composition of the shale. The experimental parameters included immersing shale rock in supercritical CO2 at pressures ranging from 10 to 70 MPa and temperatures between 55 and 95 °C. This study evaluated changes in mineral composition, pore-throat structure (using scanning electron microscopy and nitrogen adsorption tests), and the porosity and permeability of the shale rocks. Findings indicated that the dissolution of CO2 altered the relative content of certain minerals. The average quartz content rose and, potassium feldspar and the average contents of plagioclase declined conversely. When increasing the pressure, an increase in the relative content of I/S mixed layer and a decrease in illite content were observed and kaolinite content experienced minor changes. When increasing the temperature, kaolinite, I/S mixed layer, and chlorite all exhibited a decreasing trend with increasing temperature, while the relative contents of illite increased. Some of the pores become rounded in a high-magnification view under the impact of CO2 dissolution. Additionally, the Brunauer-Emmett-Teller specific surface area, pore volume, porosity, and permeability generally improved with increasing pressure and temperature. With the temperature and pressure of CO2 increased, the curves of nitrogen absorption had moved first upward and then downward. However, under specific CO2 conditions, the permeability enhancement effect could diminish or even negatively impact the shale's permeability. These findings underscore the need to optimize supercritical CO2 injection parameters under high-temperature and high-pressure conditions. This research aims to provide theoretical guidance for the efficient use of CO2 in deep shale applications to increase the shale gas output.

10.
Ann Med Surg (Lond) ; 86(4): 2058-2066, 2024 Apr.
Article En | MEDLINE | ID: mdl-38576958

Introduction: Perioperative neurocognitive disorder (PND) has attracted consistently increasing attention worldwide. However, there are few bibliometric studies that systematically evaluate this field. This study aimed to visualize the knowledge structure and research trends in PND through bibliometrics to help understand the future development of basic and clinical research. Methods: Literature related to PND in Web of Science and PubMed from 1990 to 2022 were collected through keywords retrospectively. Additionally, the source information, citation information, etc. of these publications were extracted. Finally, bibliometric analysis was performed by visualization software and statistical software. Results: There were 2837 articles and reviews in total. An exponential rise in PND-related publications was observed. China had the most publication, followed by the US and Germany. The institution with the most output and citations was Harvard University (149 papers, 8966 citations). The most prominent author was Marcantonio Edward R with 66 publications and 5721 citations. The journal with the highest productivity for PND research was Frontiers in Aging Neuroscience followed by Anesthesia and Analgesia. Keywords were identified as six topics, including postoperative delirium, postoperative neurocognitive disorder, cardiac surgery, anaesthesia, orthopedic surgery, and dementia. According to keyword analysis, the most recent popular keywords in PND research were prevention, older patients, emergence delirium, orthopedic surgery, and dexmedetomidine. Conclusions: Publications on PND are increasing at an alarming rate from 1990 to 2022. Current research and future trends will concentrate on the prevention and treatment of PND, as well as PND associated with orthopedic surgery in older adults.

11.
J Am Chem Soc ; 146(13): 8832-8838, 2024 Apr 03.
Article En | MEDLINE | ID: mdl-38507251

How mutations impact protein stability and structure dynamics is crucial for understanding the pathological process and rational drug design. Herein, we establish a time-resolved native mass spectrometry (TR-nMS) platform via a rapid-mixing capillary apparatus for monitoring the acid-initiated protein unfolding process. The molecular details in protein structure unfolding are further profiled by a 193 nm ultraviolet photodissociation (UVPD) analysis of the structure-informative photofragments. Compared with the wild-type dihydrofolate reductase (WT-DHFR), the M42T/H114R mutant (MT-DHFR) exhibits a significant stability decrease in TR-nMS characterization. UVPD comparisons of the unfolding intermediates and original DHFR forms indicate the special stabilization effect of cofactor NADPH on DHFR structure, and the M42T/H114R mutations lead to a significant decrease in NADPH-DHFR interactions, thus promoting the structure unfolding. Our study paves the way for probing the mutation-induced subtle changes in the stability and structure dynamics of drug targets.


Escherichia coli , Protein Unfolding , Escherichia coli/metabolism , NADP/metabolism , Protein Stability , Mutation , Mass Spectrometry , Tetrahydrofolate Dehydrogenase/metabolism
12.
Melanoma Res ; 34(3): 225-233, 2024 06 01.
Article En | MEDLINE | ID: mdl-38469881

Currently, numerous studies suggest a potential association between the gut microbiota and the progression of melanoma. Hence, our objective was to examine the genetic impact of the gut microbiota on melanoma through the utilization of the Mendelian randomization (MR) approach. This research employed Bacteroides, Streptococcus, Proteobacteria, and Lachnospiraceae as exposure variables and cutaneous melanoma (CM) as the outcome in a two-sample MR analysis. In this MR research, the primary analytical approach was the random-effects inverse-variance weighting (IVW) model. Complementary methods included weighted median, MR Egger, and basic and weighted models. We assessed both heterogeneity and horizontal pleiotropy in our study, scrutinizing whether the analysis results were affected by any individual SNP. The random-effects IVW outcomes indicated that Streptococcus, Bacteroides, Lachnospiraceae and Proteobacteria had no causal relationship with CM, with odds ratios of 1.001 [95% confidence interval (CI) = 0.998-1.004, P  = 0.444], 0.999 (95% CI = 0.996-1.002, P  = 0.692), 1.001 (95% CI = 0.998-1.003, P  = 0.306), and 0.999 (95% CI = 0.997-1.002, P  = 0.998), respectively. No analyses exhibited heterogeneity, horizontal pleiotropy, or deviations. Our research determined that Bacteroides, Streptococcus, Proteobacteria, and Lachnospiraceae do not induce CM at the genetic level. However, we cannot dismiss the possibility that these four gut microbiotas might influence CM through other mechanisms.


Gastrointestinal Microbiome , Melanoma , Mendelian Randomization Analysis , Skin Neoplasms , Humans , Melanoma/genetics , Melanoma/microbiology , Skin Neoplasms/genetics , Skin Neoplasms/microbiology , Melanoma, Cutaneous Malignant
13.
RSC Adv ; 14(12): 8075-8080, 2024 Mar 06.
Article En | MEDLINE | ID: mdl-38464689

The incorporation of deuterium into peptides and proteins holds broad applications across various fields, such as drug development and structural characterization. Nevertheless, current methods for peptide/protein deuteration often target exchangeable labile sites or require harsh conditions for stable modification. In this study, we present a late-stage approach utilizing an alkaline phosphate solution to achieve deuteration of non-exchangeable backbone sites of peptides and proteins. The specific deuteration regions are identified through ultraviolet photodissociation (UVPD) and mass spectrometry analysis. This deuteration strategy demonstrates site and structure selectivity, with a notable affinity for labeling the α-helix regions of myoglobin. The deuterium method is particularly suitable for peptides and proteins that remain stable under high pH conditions.

14.
Chem Sci ; 15(7): 2545-2557, 2024 Feb 14.
Article En | MEDLINE | ID: mdl-38362424

Due to the complex high-order structures and interactions of proteins within an aqueous solution, a majority of chemical functionalizations happen on the hydrophilic sites of protein external surfaces which are naturally exposed to the solution. However, the hydrophobic pockets inside proteins are crucial for ligand binding and function as catalytic centers and transporting tunnels. Herein, we describe a reagent pre-organization and in situ photochemical trifluoromethylation strategy to profile the functional sites inside the hydrophobic pockets of native proteins. Unbiased mass spectrometry profiling was applied for the characterization of trifluoromethylated sites with high sensitivity. Native proteins including myoglobin, trypsin, haloalkane dehalogenase, and human serum albumin have been engaged in this mild photochemical process and substantial hydrophobic site-specific and structure-selective trifluoromethylation substitutes are obtained without significant interference to their bioactivity and structures. Sodium triflinate is the only reagent required to functionalize the unprotected proteins with wide pH-range tolerance and high biocompatibility. This "in-pocket" activation model provides a general strategy to modify the potential binding pockets and gain essential structural insights into the functional hotspots inside protein hydrophobic pockets.

15.
Laryngoscope ; 2024 Feb 29.
Article En | MEDLINE | ID: mdl-38421050

HYPOTHESIS: Unilateral costal cartilage harvesting (UCCH) for auricle reconstruction in children tends to cause thoracic deformities. Therefore, our study aimed to develop a novel bilateral costal cartilage harvesting (BCCH) method to prevent and reduce thoracic deformities. METHODS: Patients with unilateral microtia who underwent either UCCH (n = 50) or BCCH (n = 46) were enrolled in this study. The grafts for the BCCH group were harvested from the 6th costal cartilage of the ipsilateral hemithorax and the 7th and 8th cartilage from the other hemithorax. Computed tomography and physical examination were performed to identify any physical deformities in the chest contours post-surgery. The cosmetic appearance of the thoracic scars post-surgery was evaluated using the Scar Cosmesis Assessment and Rating Scale (SCAR) and Visual Analogue Scales (VAS cosmetic). The numerical rating scale (NRS) was used to quantify the pain in donor sites. The reconstructed ears were assessed during the follow-up period. RESULT: None of the patients in the BCCH group developed thoracic deformities, while 16 patients within the UCCH group developed mild (n = 12) or severe (n = 4) thoracic deformities (p < 0.001). The SCAR (3.09 vs. 2.92, p = 0.580) and VAS scores (0.96 vs. 0.90, p = 0.813) did not differ significantly between the two groups. For both treatment arms, the NRS scores were highest on the first-day post-surgery and gradually dropped over the 10 days. No significant differences were found in the NRS scores and the aesthetic outcomes of the reconstructed ears between the two groups. CONCLUSION: The BCCH method effectively reduced the incidence of thoracic deformity at the donor site without increasing postoperative pain and cosmetic concerns for patients. It could be used clinically to improve patient outcomes of costal cartilage grafts. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

16.
Nat Prod Rep ; 41(5): 748-783, 2024 May 22.
Article En | MEDLINE | ID: mdl-38265076

Covering: up to August 2023Terpenoids, which are widely distributed in animals, plants, and microorganisms, are a large group of natural products with diverse structures and various biological activities. They have made great contributions to human health as therapeutic agents, such as the anti-cancer drug paclitaxel and anti-malarial agent artemisinin. Accordingly, the biosynthesis of this important class of natural products has been extensively studied, which generally involves two major steps: hydrocarbon skeleton construction by terpenoid cyclases and skeleton modification by tailoring enzymes. Additionally, fungi (Ascomycota and Basidiomycota) serve as an important source for the discovery of terpenoids. With the rapid development of sequencing technology and bioinformatics approaches, genome mining has emerged as one of the most effective strategies to discover novel terpenoids from fungi. To date, numerous terpenoid cyclases, including typical class I and class II terpenoid cyclases as well as emerging UbiA-type terpenoid cyclases, have been identified, together with a variety of tailoring enzymes, including cytochrome P450 enzymes, flavin-dependent monooxygenases, and acyltransferases. In this review, our aim is to comprehensively present all fungal terpenoid cyclases identified up to August 2023, with a focus on newly discovered terpenoid cyclases, especially the emerging UbiA-type terpenoid cyclases, and their related tailoring enzymes from 2015 to August 2023.


Fungi , Terpenes , Terpenes/metabolism , Terpenes/chemistry , Fungi/metabolism , Fungi/chemistry , Molecular Structure , Biological Products/metabolism , Biological Products/chemistry , Cytochrome P-450 Enzyme System/metabolism
17.
Microb Biotechnol ; 17(1): e14359, 2024 Jan.
Article En | MEDLINE | ID: mdl-37885073

Invasive fungal infections have increased remarkably, which have become unprecedented concern to human health. However, the effectiveness of current antifungal drugs is limited due to drug resistance and toxic side-effects. It is urgently required to establish the effective biosynthetic strategy for developing novel and safe antifungal molecules economically. Echinocandins become a promising option as a mainstay family of antifungals, due to specifically targeting the fungal specific cell wall. To date, three kinds of echinocandins for caspofungin, anidulafungin, and micafungin, which derived from pneumocandin B0 , echinocandin B, and FR901379, are commercially available in clinic and have shown potential in managing invasive fungal infections in a cost-effective manner. However, current echinocandins-derived precursors all are produced by environmental fungal isolates with long fermentation cycle and low yields, which challenge the production efficacy of these precursors in industry. Therefore, understanding their biosynthetic machinery is of great importance for improving antifungal titres and creating new echinocandins-derived products. With the development of genome-wide sequencing and establishment of gene-editing technology, there are a growing number of reports on echinocandins-derived products and their biosynthetic gene clusters. This review briefly summarizes the discovery and development history of echinocandins, compares their structural characteristics and biosynthetic processes, and sums up existed strategies for improving their production. Moreover, the genomic analysis of related biosynthetic gene clusters of echinocandins is discussed, highlighting the similarities and differences among the clusters. Last, the biosynthetic processes of echinocandins are compared, focusing on the activation and attachment of side-chains and the formation of the hexapeptide core. This review aims to provide insights into the development and production of new echinocandin drugs by modifying the structure of echinocandin-derived precursors and/or optimizing the fermentation processes; and achieve a new microbial chassis for efficient production of echinocandins in heterologous hosts.


Antifungal Agents , Invasive Fungal Infections , Humans , Antifungal Agents/chemistry , Echinocandins/chemistry , Fermentation , Invasive Fungal Infections/drug therapy , Microbial Sensitivity Tests , Lipopeptides
18.
Virulence ; 15(1): 2290757, 2024 12.
Article En | MEDLINE | ID: mdl-38085844

In pathogenic fungi, calcium-calmodulin-dependent serine-threonine-specific phosphatase calcineurin is involved in morphogenesis and virulence. Therefore, calcineurin and its tightly related protein complexes are attractive antifungal drug targets. However, there is limited knowledge available on the relationship between in vivo Ca2+-binding sites of calmodulin (CaM) and its functions in regulating stress responses, morphogenesis, and pathogenesis. In the current study, we demonstrated that calmodulin is required for hyphal growth, conidiation, and virulence in the human fungal pathogen, Aspergillus fumigatus. Site-directed mutations of calmodulin revealed that a single Ca2+-binding site mutation had no significant effect on A. fumigatus hyphal development, but multiple Ca2+-binding site mutations exhibited synergistic effects, especially when cultured at 42 °C, indicating that calmodulin function in response to temperature stress depends on its Ca2+-binding sites. Western blotting implied that mutations in Ca2+-binding sites caused highly degraded calmodulin fragments, suggesting that the loss of Ca2+-binding sites results in reduced protein stability. Moreover, normal intracellular calcium homeostasis and the nuclear translocation of the transcriptional factor CrzA are dependent on Ca2+-binding sites of AfCaM, demonstrating that Ca2+-binding sites of calmodulin are required for calcium signalling and its major transcription factor CrzA. Importantly, in situ mutations for four Ca2+-binding sites of calmodulin resulted in an almost complete loss of virulence in the Galleria mellonella wax moth model. This study shed more light on the functional characterization of putative calcium-binding sites of calmodulin in the morphogenesis and virulence of A. fumigatus, which enhances our understanding of calmodulin biological functions in cells of opportunistic fungal pathogens.


Aspergillus fumigatus , Calmodulin , Humans , Calmodulin/genetics , Calmodulin/metabolism , Calmodulin/pharmacology , Fungal Proteins/genetics , Fungal Proteins/metabolism , Calcium/metabolism , Calcineurin/genetics , Calcineurin/metabolism , Calcineurin/pharmacology , Virulence , Temperature , Transcription Factors/genetics , Binding Sites
19.
Talanta ; 270: 125547, 2024 Apr 01.
Article En | MEDLINE | ID: mdl-38101029

To realize the potential of ionic liquid functionalized silica to prepare mixed-mode and chiral stationary phases, two ionic liquid silane reagents with different anions were synthesized via a high-efficiency click reaction. Then they were decorated onto the surface of silica by a one-step bonding reaction. The functionalized silica was characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and elemental analysis (EA). Two stationary phases provided satisfactory performance when compared with a commercial mixed-mode column. Notably, Sil-C10Im-D-BCS with D-3-bromocamphor-8-sulfonate (D-BCS) as anion presented chiral separation capacity towards 1,2,3,4-Tetrahydro-1-naphthol. The separation mechanism was investigated through multiple pathways, and the results revealed that the prepared stationary phases can retain and separate solutes through multiple interactions, like hydrophobic effect, ion exchange, hydrogen-bond interaction, etc. Quantum chemical calculation (QC) was employed to obtain the optimized structures and the binding energy of anions to cations. The results provided some insights into the retention mechanism from a molecular perspective. This work demonstrated the superiority of ionic liquid functionalized silica as mixed-mode stationary phases and the potential of chiral ionic liquid as chiral selectors.

20.
Plants (Basel) ; 12(24)2023 Dec 08.
Article En | MEDLINE | ID: mdl-38140438

The precise control of free auxin (indole-3-acetic acid, IAA) gradient, which is orchestrated by biosynthesis, conjugation, degradation, hydrolyzation, and transport, is critical for all aspects of plant growth and development. Of these, the GRETCHEN HAGEN 3 (GH3) acyl acid amido synthetase family, pivotal in conjugating IAA with amino acids, has garnered significant interest. Recent advances in understanding GH3-dependent IAA conjugation have positioned GH3 functional elucidation as a hot topic of research. This review aims to consolidate and discuss recent findings on (i) the enzymatic mechanisms driving GH3 activity, (ii) the influence of chemical inhibitor on GH3 function, and (iii) the transcriptional regulation of GH3 and its impact on plant development and stress response. Additionally, we explore the distinct biological functions attributed to IAA-amino acid conjugates.

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