ABSTRACT
Till now, the diversity of entomopathogenic fungi in subtropical mountain forest was less studied. Here, the vertical distribution of forest soil fungi, entomopathogenic fungi, and their environmental influencing factors in a subtropical mountain in western China were investigated. Soil samples were collected from four elevations in a subtropical forest in Shaanxi. The results indicated a greater richness of soil fungi at middle elevations and soil fungi were more even at low elevation. Soil pH, available iron, available potassium, total potassium, and available zinc were the most important influencing factors affecting this vertical distribution of fungi. Interestingly, the Isaria genus was predominant while Metarhizium and Beauveria showed decreasing abundance. The presence of Isaria showed a significant positive correlation with both total phosphorus and available iron, while, available zinc was negatively correlated. Metarhizium was influenced by elevation, pH, available phosphorus, and available copper and Beauveria was influenced by soil organic carbon, total nitrogen, total potassium, available potassium, and available zinc. Overall, as environmental factors affecting soil fungi, elevation, and plant species diversity were less important than soil physical and chemical properties. The virulence of isolated entomopathogenic fungi were tested against larvae of Tenebrio molitor, with mortality ranging from 31.11% to 100%. The above findings provide valuable data to deepen our understanding of the diversity of entomopathogenic fungi in subtropical mountain forests.
Subject(s)
Biodiversity , Forests , Fungi , Soil Microbiology , Soil , China , Animals , Fungi/classification , Fungi/isolation & purification , Fungi/genetics , Soil/chemistry , Tenebrio/microbiology , Larva/microbiology , Potassium/analysis , Potassium/metabolism , Hydrogen-Ion ConcentrationABSTRACT
USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Pyrimidinones , Humans , Structure-Activity Relationship , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Animals , Pyrimidinones/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/chemical synthesis , Molecular Structure , Mice , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Ubiquitin-Specific Proteases/antagonists & inhibitors , Ubiquitin-Specific Proteases/metabolismABSTRACT
The colchicine binding site on tubulin has been widely acknowledged as an attractive target for anticancer drug exploitation. Here, we reported the structural optimization of the lead compound 4, which was proved in our previous work as a colchicine binding site inhibitor (CBSI). Based on docking researches for the active binding conformation of compound 4, a series of novel 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazole derivatives (9a-9x) were developed by replacing a CH group in the 1H-benzo[d]imidazole skeleton of compound 4 with a nitrogen atom as a hydrogen bond acceptor. Among them, compound 9a showed the strongest antiproliferative activity with IC50 values ranging from 14 to 45 nM against three human cancer cell lines (MCF-7, SGC-7901 and A549), lower than that of compound 4. Mechanistic studies indicated that compound 9a could inhibit tubulin polymerization, destroy the microtubule skeleton, block the cell cycle in G2/M phase, induce cancer cell apoptosis, prevent cancer cell migration and colony formation. Moreover, compound 9a significantly inhibited tumor growth in vivo without observable toxicity in the mice 4T1 xenograft tumor model. In conclusion, this report shows a successful case of the structure-based design approach of a potent tubulin polymerization inhibitor for cancer treatment.
Subject(s)
Antineoplastic Agents , Tubulin Modulators , Animals , Humans , Mice , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation , Colchicine/pharmacology , Drug Design , Drug Screening Assays, Antitumor , Polymerization , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistryABSTRACT
Monochamus alternatus is a serious trunk-boring pest. The isolation and utilization of entomopathogenic fungi to manage M. alternatus is important. Here, a new strain GQH6 of Metarhizium robertsii, isolated from the Loess Plateau, was identified morphologically and molecularly. The virulence of the strain GQH6 against the third-instar larvae of M. alternatus was studied. Then, the pathological process, including symptom observation and histopathological observation, was also researched. The corrected mortality was 100% at 109 and 108 conidia/mL, and 88.89 ± 5.88% at 107 conidia/mL. The LC50 was 1.93 × 106 conidia/mL and the LC90 was 1.35 × 107 conidia/mL. And the LT50 of the strain GQH6 was 3.96 days at 109 conidia/mL, and 4.99 days at 108 conidia/mL. These virulence indices showed high virulence against M. alternatus larvae. In addition, the symptoms of the infected M. alternatus larvae were obvious. After one day, dark spots appeared and increased in number. By four days, white mycelia appeared. Finally, the larvae body became green. Similarly, the histopathological changes after infection were obvious, mainly manifested in muscle tissue rupture, adipose tissue fracture and midgut disintegration. These results demonstrated that the M. robertsii strain GQH6 isolated from the Loess Plateau was highly virulent against M. alternatus larvae of the third instar.
ABSTRACT
BACKGROUND: Neurofibromatosis type 1 (NF 1) is an autosomal-dominant tumor predisposition genetic disease affecting approximately 1 in 3000 live births. The condition could present various manifestations ranging from skin abnormalities to neurological tumors. The musculoskeletal system could also be frequently affected, and scoliosis is the most common orthopedic manifestation. Characterized by the early-onset and rapid progression tendency, NF 1-related dystrophic scoliosis presented discrepancies from idiopathic scoliosis in terms of natural history, clinical features, and management outcomes and thus required special attention. In the current study, the authors conducted a systemic review to outline the body of evidence of the natural history, clinical characteristics, surgical outcomes, and surgical complications of NF 1-induced scoliosis, aiming to provide an elucidative insight into this condition. METHOD: Systemic review and meta-analysis were conducted according to the latest Preferred Reporting Items for Systematic Reviews Meta-Analyses (PRISMA) guidelines. The search was performed in Medline, Embase, and Web of Science Core Collection up to December 27, 2022, using related keywords. Clinical features such as frequencies, segmental involvement, and hereditary information were summarized and described qualitatively. Meta-analysis was conducted using R software and the 'meta' package to yield an overall outcome of efficacy and safety of surgical management, precisely, spinal fusion procedure and growing rods procedure. Corrective rate of Cobb angle, sagittal kyphosis angle, and T1-S1 length post-operative and at the last follow-up was used to evaluate the efficacy, and the occurrence of surgery-related complications was used to evaluate the safety. RESULT: A total of 37 articles involving 1023 patients were included. Approximately 26.6% of the NF 1 patients would present with scoliosis. Patients tend to develop scoliosis at an earlier age. The thoracic part turned out to be the most affected segment. No obvious correlation between scoliosis and genotype or hereditary type was observed. Both spinal fusion and growing rod surgery have shown acceptable treatment outcomes, with spinal fusion demonstrating better performance in terms of effectiveness and safety. The growing rods technique seemed to allow a better lengthening of the spine. The mainstay post-operative complications were implant-related complications but could be managed with limited revision surgery. Severe neurological deficits were rarely reported. CONCLUSION: Scoliosis, especially the subtype characterized by dystrophic bony changes, is a significant orthopedic manifestation of NF1. It has an early onset, a tendency to persistently and rapidly progress, and is challenging to deal with. The current review outlines the available evidence from the perspective of natural history, clinical features, and the treatment efficacy and safety of the mainstay surgical options. Patients with NF1 scoliosis will benefit from a better understanding of the disease and evidence based treatment strategies.
Subject(s)
Neurofibromatosis 1 , Scoliosis , Humans , Scoliosis/surgery , Scoliosis/etiology , Neurofibromatosis 1/surgery , Neurofibromatosis 1/complications , Spinal Fusion/methods , Treatment OutcomeABSTRACT
Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting intracellular hydrogen peroxide (H2O2) into cytotoxic oxidizing hydroxyl radicals (â OH). However, the therapeutic efficiency of CDT is compromised due to the insufficient endogenous H2O2 and metal catalysts in tumor cells. The use of multivalent polyphenols with multiple hydroxyl functions provides a facile yet robust means for efficient CDT augmentation. For this purpose, we reported herein the construction of polyphenol-metal nanoparticles (NPs) via a phenol-metal coordination strategy. The uniqueness of this study is the preparation of only one polymer construct with multivalency that can afford various supramolecular interactions for simultaneous "one-pot" loading of different therapeutic species, i.e., doxorubicin (DOX), glucose oxidases (GOD), and Fe3+ and further co-self-assembly into a stabilized nanomedicine for cascade amplified chemo-chemodynamic therapy. Specifically, the tumor intracellular acidic pH-triggered DOX release could serve for chemotherapy as well as enhance the intracellular H2O2 level. Together with the extra H2O2 and gluconic acid produced by the GOD-triggered glucose consumption, DOX@POAD-Fe@GOD NPs promoted Fe3+participation in the Fe-mediated Fenton reaction for cascade amplified chemo-chemodynamic therapy. Notably, this formulation displayed a greater anti-tumor effect with a tumor inhibition ratio 1.6-fold higher than that of free DOX in a BALB/c mice model bearing 4T1 tumors. Overall, the multivalent polyphenol-metal nanoplatform developed herein integrates chemotherapy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great potential for clinical translations. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insufficient endogenous H2O2 and metal catalysts in tumor cells. To develop a facile yet robust strategy for efficient CDT augmentation, we reported herein construction of a multivalent polyphenol-metal nanoplatform, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol-metal coordination strategy. This nanoplatform integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsulation of doxorubicin (DOX), Fe3+, and glucose oxidases (GOD), but also for cascade amplified chemo-chemodynamic therapy. Specifically, the intracellular acidic pH-triggered dissociation of DOX@POAD-Fe@GOD NPs promoted the release of Fe3+, DOX, and GOD for significantly increased ROS levels that can accelerate Fenton reactions for cascaded chemotherapy, starvation therapy, and CDT with amplified antitumor efficiency in vivo.
Subject(s)
Nanoparticles , Neoplasms , Animals , Mice , Polyphenols/pharmacology , Hydrogen Peroxide , Phenols , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Glucose Oxidase , Metals , Mice, Inbred BALB C , Glucose , Cell Line, Tumor , Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
The high thermodynamic instability and side reactions of Zn-metal anode (ZMA), especially at high current densities, greatly impede the commercialization of aqueous zinc-ion batteries (AZIBs). Herein, a fluorine-rich double protective layer strategy is proposed to obtain the high reversibility of AZIBs through the introduction of a versatile tetradecafluorononane-1,9-diol (TDFND) additive in aqueous electrolyte. TDFND molecule with large adsorption energy (-1.51â eV) preferentially absorbs on the Zn anode surface to form a Zn(OR)2 - (R=-CH2 -(CF2 )7 -CH2 -) cross-linking complex network, which balances space electric field and controls the Zn2+ ion flux, thus enabling the uniform and compact deposition of Zn (002) crystal planes. Meanwhile, TDFND with low Lowest unoccupied molecular orbital (LUMO, 0.10â eV) energy level is priorly decomposed to regulate the interfacial chemistry of ZMA by building a ZnF2 -rich solid electrode/electrolyte interface (SEI) layer. It is found that a 14â nm-thick SEI layer delivers excellent structural integrity to suppress parasitic reactions by blocking the direct contact of active water and ZMA. Consequently, the Zn electrode exhibits a superior cycling life over 430â h at 10â mA cm-2 and a high average Coulombic efficiency of 99.8 % at 5â mA cm-2 . Furthermore, a 68â mAh pouch cell delivers 80.3 % capacity retention for 1000 cycles.
ABSTRACT
The passivation effect of Fe3O4/mulberry pole biochar (Fe-MBC) prepared at different carbonization temperatures on soil available arsenic content was studied through soil culture experiments, and Fe-MBC-800 (prepared by carbonization at 800â) with good passivation effect was selected and characterized. The effects of 1%-7% (mass fraction of biochar to soil) Fe-MBC-800, MBC-800, and Fe3O4 on soil pH value, soil electrical conductivity, soil arsenic form, rice biomass, and total arsenic (As) content in rice were studied using a pot experiment. The results showed that:â Fe-MBC-800 successfully loaded Fe3O4, and its main functional groups were C=O double bond, O-H bond, C-O bond, and Fe-O bond. The specific surface areas of Fe-MBC-800, MBC-800, and Fe3O4 were 209.659 m2·g-1, 517.714 m2·g-1, and 68.025 m2·g-1, respectively. â¡The addition of Fe-MBC-800 could increase the soil pH value, decrease the soil EC value, increase the content of residual arsenic in soil, and reduce the content of water-soluble arsenic and available arsenic in the soil. Under the treatment using 7% Fe-MBC-800 (ω) amendments, the content of water-soluble arsenic and available arsenic in the soil decreased by 81.6% and 56.33%, respectively. â¢When the addition ratio of Fe-MBC-800 in the soil was 5%-7%, it could promote the growth of rice plants, increase rice biomass, and reduce the bioaccumulation of arsenic by between 62.5% and 68.75%.
Subject(s)
Arsenic , Charcoal , Ferric Compounds , Oryza , Soil , Morus , Oryza/chemistry , Arsenic/analysis , Plant Stems , Charcoal/chemistry , Ferric Compounds/chemistry , Soil/chemistryABSTRACT
Aflatoxins are potent carcinogenic compounds, mainly produced by fungi species of the genus Aspergillus in the soil. Because of their stability, they are difficult to remove completely, even under extreme conditions. Aflatoxin contamination is one of the main causes of safety in peanuts, maize, wheat and other agricultural products. Aflatoxin contamination originates from the soil. Through the investigation of soil properties and soil microbial distribution, the sources of aflatoxin are identified, aflatoxin contamination is classified and analysed, and post-harvest crop detoxification and corresponding contamination prevention measures are identified. This includes the team's recent development of the biofungicide ARC-BBBE (Aflatoxin Rhizobia Couple-B. amyloliquefaciens, B. laterosporu, B. mucilaginosus, E. ludwiggi) for field application and nanomaterials for post-production detoxification of cereals and oilseed crops, providing an effective and feasible approach for the prevention and control of aflatoxin contamination. Finally, it is hoped that effective preventive and control measures can be applied to a large number of cereal and oilseed crops.
Subject(s)
Aflatoxins , Soil , Aflatoxin B1 , Agriculture , Arachis , Crops, Agricultural , Edible GrainABSTRACT
Cyclic polymers with cleavable backbones triggered by either external or internal stimuli can realize simultaneous extracellular stability and intracellular destabilization of cyclic polymer-based nanocarriers but remain seldom reported. To this end, we prepared herein cyclic-ONB-P(OEGMA-st-DMAEMA) (c-ONB-P(OEGMA-st-DMAEMA)) with a light-cleavable junction in the polymer backbone based on oligo (ethylene glycol) monomethyl ether methacrylate (OEGMA) and N,N-dimethylaminoethyl methacrylate (DMAEMA) using a light-cleavable atom transfer radical polymerization (ATRP) initiator containing an o-nitrobenzyl (ONB) ester group. Together with the pH-sensitivity of DMAEMA, c-ONB-P(OEGMA-st-DMAEMA) shows a light-cleavable mainchain and pH-sensitive side chains. Notably, doxorubicin (DOX)-loaded c-ONB-P(OEGMA4-st-DMAEMA38) (C2) micelles mediated an IC50 value of 2.28 µg/mL in Bel-7402 cells, which is 1.7-fold lower than that acquired without UV irradiation. This study thus reported the synthesis of a cyclic copolymer with a UV-cleavable backbone and uncovered the effects of topological modulation on the in vitro controlled release properties of cyclic polymers.
Subject(s)
Drug Delivery Systems , Polymers , Methacrylates , Hydrogen-Ion ConcentrationABSTRACT
Congenital heart disease is the most frequent congenital disorder, affecting a significant number of live births. Gaining insights into its genetic etiology could lead to a deeper understanding of this condition. Although the Nf1 gene has been identified as a potential causative gene, its role in congenital heart disease has not been thoroughly clarified. We searched and summarized evidence from cohort-based and experimental studies on the issue of Nf1 and heart development in congenital heart diseases from various databases. Available evidence demonstrates a correlation between Nf1 and congenital heart diseases, mainly pulmonary valvar stenosis. The mechanism underlying this correlation may involve dysregulation of epithelial-mesenchymal transition (EMT). The Nf1 gene affects the EMT process via multiple pathways, including directly regulating the expression of EMT-related transcription factors and indirectly regulating the EMT process by regulating the MAPK pathway. This narrative review provides a comprehensive account of the Nf1 involvement in heart development and congenital cardiovascular diseases in terms of epidemiology and potential mechanisms. RAS signaling may contribute to congenital heart disease independently or in cooperation with other signaling pathways. Efficient management of both NF1 and cardiovascular disease patients would benefit from further research into these issues.
Subject(s)
Cardiovascular Diseases , Heart Defects, Congenital , Neurofibromatosis 1 , Humans , Neurofibromatosis 1/genetics , Neurofibromatosis 1/metabolism , Genes, Neurofibromatosis 1 , Neurofibromin 1/genetics , Neurofibromin 1/metabolism , Heart , Heart Defects, Congenital/genetics , Heart Defects, Congenital/epidemiology , Cardiovascular Diseases/geneticsABSTRACT
Historically, some edible insects have been processed into a complex of insect and fungus, such as Antherea pernyi and Samsoniella hepiali. Until now, the dynamics of the nutritional changes due to this infection were unclear. This study reveals the dynamic changes in nutritional components of Antherea pernyi pupa after infection with Samsoniella hepiali at post-infection time points of 0 d, 10 d, 20 d, and 30 d. The dynamic analysis of the components at different post-infection times showed that the content of polysaccharides and cordycepin increased with time while the content of fats and chitin decreased. The content of proteins showed a trend of decreasing at the beginning and then increasing. The essential amino acids (EAAs) decreased at the beginning and then increased, and non-essential amino acids (NEAA) changed similarly. The essential amino acid index showed a slight continuous decrease. Although the crude fat decreased dramatically due to the infection, from a value of 30.75% to 7.2%, the infection of S. hepiali produced five new fatty acids (14-methyl-pentadecanoic acid, docosanoic acid, succinic acid, arachidonic acid, and myristic acid) while the content of the seven fatty acids was greatly reduced after infection. Therefore, after being infected by S. hepiali and combined with it, the nutritional profile of A pernyi pupa was changed significantly and there were different characteristics at different infection stages. The above findings provide scientifically fundamental data to understand the nutritional value of the insect-fungus complex as human food and animal feed.
ABSTRACT
Nowadays, laser is the mainstay treatment for cafe-au-lait macules (CALMs), but no systematic review has been published to demonstrate the overall efficacy and it's still controversial which type of laser is optimal. Thus, we conduct the meta-analysis to evaluate the effectiveness and side effects of various types of lasers in treating CALMs. Original articles reporting the efficacy and side effects for CALMs in laser treatment were identified in PubMed, EMBASE, and Web of Science from 1983 to April 11, 2023. Using R software and the 'meta' package, meta-analysis was conducted for clearance and recurrence for evaluation of efficacy. And the occurrence of hypopigmentation and hyperpigmentation rate was pooled for safety evaluation. We used RoB2 and ROBINS-I tools to assess the risks of bias in RCT studies and non-RCT studies, respectively. The Grading of Recommendations, Assessment, Development and Evaluation system was used to assess the quality of the evidence. Nineteen studies involving 991 patients were included, which had a very low to moderate quality of evidence. The pooled 75% clearance rate was 43.3% (95% CI 31.8-54.7%, I2 = 96%), 50% clearance rate was 75% (95% CI 62.2-85.9%, I2 = 89%) and the recurrence rate was 13% (95% CI 3.2-26.5%, I2 = 88%). The pooled hypopigmentation and hyperpigmentation rates were 1.2% (95% CI 0.3-2.1%, I2 = 0%) and 1.2% (95% CI 0.3-2%, I2 = 0%), respectively. Subgroup analysis revealed that QS-1064-nm Nd:YAG laser treatment not only achieved more than 75% clearance rate in 50.9% of patients (95% CI 26.9-74.4%, I2 = 90%) but also resulted in the lowest hypopigmentation and hyperpigmentation rate of 0.5% (95% CI 0.0-2.5%, I2 = 26%) and 0.4% (95% CI 0.0-2.5%, I2 = 0%). To draw a conclusion, the laser treatment could reach an overall clearance rate of 50% for 75% of the patients with CALMs, for 43.3% of the patients, the clearance rate could reach 75%. When looking at different wavelength subgroups, QS-1064-nm Nd:YAG laser exhibited the best treatment capability. Laser of all the wavelength subgroups presented acceptable safety regarding of the low occurrence of side effects, namely, hypopigmentation and hyperpigmentation.
Subject(s)
Hyperpigmentation , Hypopigmentation , Lasers, Solid-State , Humans , Treatment Outcome , Lasers, Solid-State/adverse effects , Cafe-au-Lait Spots/radiotherapy , Cafe-au-Lait Spots/etiology , Hypopigmentation/etiology , Hypopigmentation/radiotherapy , Hyperpigmentation/etiologyABSTRACT
The symbiotic bacteria-insect interaction is considered to be associated with immunity and drug resistance. However, the wide variety of insect species and habitats is thought to have a significant impact on the symbiotic community, leading to disparate results. Here, we demonstrated that symbiotic bacteria regulated the immune response by changing the proportion of the Gram-positive and the Gram-negative bacterial community in Lymantria dispar (L. dispar) after infection with its viral pathogen, L. dispar Nucleopolyhedrovirus (LdMNPV). After oral infection, the immune deficiency pathway was activated immediately, and the expression of Relish was up-regulated to promote the secretion of antimicrobial peptides. Meanwhile, the abundance of the Gram-negative bacterial community increased at the same time. Moreover, the Toll pathway was not regulated in the same way as the Imd pathway was after infection. However, the change in the Toll pathway's expression remained positively correlated to the abundance of Gram-positive bacteria. This finding implied that the ratio of Gram-negative to Gram-positive bacteria in the LdMNPV infected larvae had an effect on the immune response. Our findings revealed that the immune regulation of L. dispar was regulated by the relative abundance of its symbiotic bacteria at different infection times with LdMNPV, which provides a new way to understand symbiotic bacteria-insect interactions.
Subject(s)
Moths , Animals , Larva , BacteriaABSTRACT
In this study, coconut shell biochar modified by KMnO4 (MCBC) was used as the adsorbent, and its removal performance and mechanism for Cd(â ¡) and Ni(â ¡) were discussed. When the initial pH and MCBC dosage were separately 5 and 3.0 g·L-1, respectively, the removal efficiencies of Cd(â ¡) and Ni(â ¡) were both higher than 99%. The removal of Cd(â ¡) and Ni(â ¡) was more in line with the pseudo-second-order kinetic model, indicating that their removal was dominated by chemisorption. The rate-controlling step for Cd(â ¡) and Ni(â ¡) removal was the fast removal stage, for which the rate depended on the liquid film diffusion and intraparticle diffusion (surface diffusion). Cd(â ¡) and Ni(â ¡) were mainly attached to the MCBC via surface adsorption and pore filling, in which the contribution of surface adsorption was greater. The maximum adsorption amounts of Cd(â ¡) and Ni(â ¡) by MCBC were individually 57.18 mg·g-1 and 23.29 mg·g-1, which were approximately 5.74 and 6.97 times that of the precursor (coconut shell biochar), respectively. The removal of Cd(â ¡) and Zn(â ¡) was spontaneous and endothermic and had obvious thermodynamic characteristics of chemisorption. Cd(â ¡) was attached to MCBC through ion exchange, co-precipitation, complexation reaction, and cation-π interaction, whereas Ni(â ¡) was removed by MCBC via ion exchange, co-precipitation, complexation reaction, and redox. Among them, co-precipitation and complexation were the main modes of surface adsorption of Cd(â ¡) and Ni(â ¡). Additionally, the proportion of amorphous Mn-O-Cd or Mn-O-Ni in the complex may have been higher. These research results will provide important technical support and theoretical basis for the practical application of commercial biochar in the treatment of heavy metal wastewater.
Subject(s)
Cocos , Potassium Permanganate , Cadmium , AdsorptionABSTRACT
HYPOTHESIS: Construction of dual gatekeepers-functionalized mesoporous organic silica nanoparticles (MONs) with both physical and chemical mechanisms for modulated drug delivery properties provides one solution to the extracellular stability vs. intracellular high therapeutic efficiency of MONs that hold great potential for clinical translations. EXPERIMENTS: We reported herein facile construction of diselenium-bridged MONs decorated with dual gatekeepers, i.e., azobenzene (Azo)/polydopamine (PDA) for both physical and chemical modulated drug delivery properties. Specifically, Azo can act as a physical barrier to block DOX in the mesoporous structure of MONs for extracellular safe encapsulation. The PDA outer corona serves not only as a chemical barrier with acidic pH-modulated permeability for double insurance of minimized DOX leakage in the extracellular blood circulation but also for inducing a PTT effect for synergistic PTT and chemotherapy of breast cancer. FINDINGS: An optimized formulation, DOX@(MONs-Azo3)@PDA resulted in approximately 1.5 and 2.4 fold lower IC50 values than DOX@(MONs-Azo3) and (MONs-Azo3)@PDA controls in MCF-7 cells, respectively, and further mediated complete tumor eradication in 4T1 tumor-bearing BALB/c mice with insignificant systematic toxicity due to the synergistic PTT and chemotherapy with enhanced therapeutic efficiency.
Subject(s)
Nanoparticles , Neoplasms , Mice , Animals , Silicon Dioxide/chemistry , Doxorubicin/chemistry , Nanoparticles/chemistry , Drug Delivery Systems , Neoplasms/drug therapy , Phototherapy , Drug LiberationABSTRACT
Fengycin possesses antifungal activity but has limited application due to its low yields. Amino acid precursors play a crucial role in fengycin synthesis. Herein, the overexpression of alanine, isoleucine, and threonine transporter-related genes in Bacillus subtilis increased fengycin production by 34.06%, 46.66%, and 7.83%, respectively. Particularly, fengycin production in B. subtilis reached 871.86 mg/L with the addition of 8.0 g/L exogenous proline after enhancing the expression of the proline transport-related gene opuE. To overcome the metabolic burden caused by excessive enhancement of gene expression for supplying precursors, B. subtilis and Corynebacterium glutamicum which produced proline, were co-cultured, which further improved fengycin production. Fengycin production in the co-culture of B. subtilis and C. glutamicum in shake flasks reached 1554.74 mg/L after optimizing the inoculation time and ratio. The fengycin level in the fed-batch co-culture was 2309.96 mg/L in a 5.0-L bioreactor. These findings provide a new strategy for improving fengycin production.
Subject(s)
Bacillus subtilis , Corynebacterium glutamicum , Bacillus subtilis/genetics , Bacillus subtilis/metabolism , Corynebacterium glutamicum/metabolism , Coculture Techniques , Proline/metabolism , Metabolic EngineeringABSTRACT
Scalable production of a clinically translatable formulation with enhanced therapeutic efficacy against cisplatin-resistant tumors without the use of any clinically unapproved reagents and additional manipulation remains a challenge. For this purpose, we report herein the construction of TPP-Pt-acetal-CA based on all commercially available, clinically approved reagents consisting of a cinnamaldehyde (CA) unit for reactive oxygen species generation, a mitochondrially targeted triphenylphosphonium (TPP)-modified Pt(IV) moiety for mitochondrial dysfunction, and an intracellular acidic pH-cleavable acetal link between these two moieties. The resulting self-assembled, stabilized TPP-Pt-acetal-CA nanoparticles mediated an IC50 value approximately 6-fold lower than that of cisplatin in A549/DDP cells and a tumor weight reduction 3.6-fold greater than that of cisplatin in A549/DDP tumor-bearing BALB/c mice with insignificant systematic toxicity due to the synergistic mitochondrial dysfunction and markedly amplified oxidative stress. Therefore, this study presents the first example of a clinically translatable Pt(IV) prodrug with enhanced efficiency for synergistically reversing drug resistance.
Subject(s)
Antineoplastic Agents , Prodrugs , Animals , Mice , Platinum/pharmacology , Cisplatin/pharmacology , Cisplatin/therapeutic use , Prodrugs/pharmacology , Prodrugs/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Acetals/pharmacology , Drug Resistance , Cell Line, Tumor , Drug Resistance, NeoplasmABSTRACT
BACKGROUND: Knee osteoarthritis (KOA) is a chronic musculoskeletal disease that can cause joint pain and dysfunction, affecting the quality of life of patients. Nonsurgical treatment is the conventional treatment of KOA, among which physical therapy is widely used because of its simplicity, convenience and effectiveness. The functional biomarker will add to the clinical fidelity and diagnostic accuracy. Therefore, our study chose a more objective evaluation indicator, functional near-infrared spectroscopy (fNIRS), to identify between healthy people and KOA patients, and to detect the pain change before and after treatment of KOA patients. METHODS: The study will be conducted in the Rehabilitation Medical Center of West China Hospital of Sichuan University and divided into 2 stages. In the first stage, we will compare and determine the differences in baseline data between healthy volunteers and KOA patients. In the second stage, 72 KOA patients will be randomly divided into two groups: the drug therapy group (DT) and the combination therapy group (CT) for 10 treatments. Outcome measures will be measured at baseline and on the 5th and 10th days after the intervention, including the numerical rating scale (NRS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain catastrophizing scale (PCS), the association of pain severity with task-state functional connectivity fNIRS and association of pain severity with task-activated fNIRS. DISCUSSION: By analyzing the fNIRS data of healthy volunteers and KOA patients, our study will be determined whether fNIRS can be used as a new indicator to reflect the severity of pain in KOA patients. Subsequently, the same fNIRS data for KOA patients before and after the intervention will be collected to provide an accurate evaluation criterion for the effect of physical therapy on KOA. TRIAL REGISTRATION: The study was registered on the Chinese Registry website (registered in ChiCTR.org with the identifiers ChiCTR2200064175 and 29/09/2022).
Subject(s)
Osteoarthritis, Knee , Humans , Osteoarthritis, Knee/complications , Osteoarthritis, Knee/diagnostic imaging , Osteoarthritis, Knee/therapy , Quality of Life , Physical Therapy Modalities , Pain , Arthralgia/diagnosis , Arthralgia/etiology , Arthralgia/therapy , Randomized Controlled Trials as TopicABSTRACT
Chemodynamic therapy (CDT) is an emerging tumor treatment; however, it is hindered by insufficient endogenous hydrogen peroxide (H2O2) and high glutathione (GSH) concentrations in the tumor microenvironment (TME). Furthermore, CDT has limited therapeutic efficacy as a monotherapy. To overcome these limitations, in this study, a nanoplatform is designed and constructed from Cu-doped mesoporous Prussian blue (CMPB)-encapsulated glucose oxidase (GOx) with a coating of hyaluronic acid (HA) modified with a nitric oxide donor (HN). In the proposed GOx@CMPB-HN nanoparticles, the dopant Cu2+ ions are crucial to combining and mutually promoting multiple therapeutic approaches, namely, CDT, photothermal therapy (PTT), and starvation therapy. The dopant Cu2+ ions in CMPB protect against reactive oxygen species to deplete the intracellular GSH in the TME. Additionally, the byproduct Cu+ ions act as a substrate for a Fenton-like reaction that activates CDT. Moreover, H2O2, which is another important substrate, is produced in large quantities through intracellular glucose depletion caused by the nanoparticle-loaded GOx, and the gluconic acid produced in this reaction further enhances the TME acidity and creates a better catalytic environment for CDT. In addition, Cu2+ doping greatly improves the mesoporous Prussian blue (MPB) photothermal conversion performance, and the resultant increase in temperature accelerates CDT catalysis. Finally, the HN coating enables the nanoparticles to actively target CD44 receptors in cancer cells and also enhances vascular permeability. Therefore, this coating has multiple effects, such as facilitating enhanced permeability and retention and deep laser penetration. In vitro and in vivo experiments demonstrate that the proposed GOx@CMPB-HN nanoplatform significantly inhibits tumor growth with the help of in situ enhanced synergistic therapies based on the properties of the TME. The developed nanoplatform has the potential to be applied to cancer treatment and introduces new avenues for tumor treatment research.