ABSTRACT
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is currently the only viable method of curing patients with acute myeloid leukaemia. In 30% to 50% of patients, donors and recipients have some level of ABO blood group incompatibility. ABO blood group incompatibility can cause antibodies against the donor's red blood cells to persist in the recipient's body, resulting in a delay of several months in the recovery of red blood cells. A number of different treatments have been reported for post-transplant pure red cell aplastic anaemia (PRCA), such as plasmapheresis, donor lymphocyte infusions, anti-thymocyte globulin, rituximab and steroids. CASE SUMMARY: A 41-year-old female diagnosed with acute myeloid leukaemia underwent peripheral blood allogeneic haematopoietic stem cell transplantation in November 2013 from an HLA matched unrelated donor. The donor was AB-positive and the recipient was O-positive. The patient was diagnosed with PRCA three months after receiving the donor stem cell transplant. After failing multiple lines of therapy, the patient applied for daratumumab. After receiving three doses of daratumumab, the patient developed a reticulocyte response and no longer required blood transfusions. CONCLUSION: The use of daratumumab anti-CD38 for the remove of plasma cells is safe and effective and may be tried for refractory patients with PRCA after undergoing allo-HSCT for ABO incompatibility.
ABSTRACT
Novel magnetic covalent organic frameworks (COFs) were prepared by one-pot synthetic strategy and employed as an efficient adsorbent for magnetic solid-phase extraction (MSPE) of naphthaleneacetic acid (NAA) in food samples. Depending on the predesigned the hydrogen bonding, π-π and hydrophobic interactions of magnetic COFs, the efficient and selective extraction process for NAA was achieved within 15 min. The magnetic COFs adsorbent combined with HPLC-UV was devoted to develop a novel quantitative method for NAA in complex food. The method afforded good coefficient in range of 0.002-10.0 µg mL-1 and low limit of detection was 0.0006 µg mL-1. And the newly established method afforded less adsorbent consumption, wider linearity and lower LODs than the reported analytical methods. Ultimately, the method was successfully applied to determine NAA in fresh pear, tomato and peach juice. The magnetic COFs based MSPE coupled with HPLC-UV method provided a simple, efficient and dependable alternative to monitor trace NAA in food samples.
Subject(s)
Limit of Detection , Metal-Organic Frameworks , Naphthaleneacetic Acids , Solid Phase Extraction , Solid Phase Extraction/methods , Chromatography, High Pressure Liquid/methods , Naphthaleneacetic Acids/analysis , Naphthaleneacetic Acids/chemistry , Metal-Organic Frameworks/chemistry , Adsorption , Food Contamination/analysis , Solanum lycopersicum/chemistry , Fruit and Vegetable Juices/analysisABSTRACT
Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.
ABSTRACT
Chronic kidney disease (CKD) poses a significant global health dilemma, emerging from complex causes. Although our prior research has indicated that a deficiency in Reticulon-3 (RTN3) accelerates renal disease progression, a thorough examination of RTN3 on kidney function and pathology remains underexplored. To address this critical need, we generated Rtn3-null mice to study the consequences of RTN3 protein deficiency on CKD. Single-cell transcriptomic analyses were performed on 47,885 cells from the renal cortex of both healthy and Rtn3-null mice, enabling us to compare spatial architectures and expression profiles across 14 distinct cell types. Our analysis revealed that RTN3 deficiency leads to significant alterations in the spatial organization and gene expression profiles of renal cells, reflecting CKD pathology. Specifically, RTN3 deficiency was associated with Lars2 overexpression, which in turn caused mitochondrial dysfunction and increased reactive oxygen species levels. This shift induced a transition in renal epithelial cells from a functional state to a fibrogenic state, thus promoting renal fibrosis. Additionally, RTN3 deficiency was found to drive the endothelial-to-mesenchymal transition process and disrupt cell-cell communication, further exacerbating renal fibrosis. Immunohistochemistry and Western-Blot techniques were used to validate these observations, reinforcing the critical role of RTN3 in CKD pathogenesis. The deficiency of RTN3 protein in CKD leads to profound changes in cellular architecture and molecular profiles. Our work seeks to elevate the understanding of RTN3's role in CKD's narrative and position it as a promising therapeutic contender.
Subject(s)
Disease Progression , Fibrosis , Gene Expression Profiling , Renal Insufficiency, Chronic , Single-Cell Analysis , Animals , Mice , Fibrosis/pathology , Fibrosis/metabolism , Fibrosis/genetics , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/metabolism , Mice, Knockout , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Kidney/pathology , Kidney/metabolism , Transcriptome , Reactive Oxygen Species/metabolism , Epithelial-Mesenchymal Transition/genetics , Disease Models, Animal , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/geneticsABSTRACT
Paclitaxel (trade name Taxol) is a rare diterpenoid with anticancer activity isolated from Taxus. At present, paclitaxel is mainly produced by the semi-synthetic method using extract of Taxus tissues as raw materials. The studies of regulatory mechanisms in paclitaxel biosynthesis would promote the production of paclitaxel through tissue/cell culture approaches. Here, we systematically identified 990 transcription factors (TFs), 460 microRNAs (miRNAs), and 160 phased small interfering RNAs (phasiRNAs) in Taxus chinensis to explore their interactions and potential roles in regulation of paclitaxel synthesis. The expression levels of enzyme genes in cone and root were higher than those in leaf and bark. Nearly all enzyme genes in the paclitaxel synthesis pathway were significantly up-regulated after jasmonate treatment, except for GGPPS and CoA Ligase. The expression level of enzyme genes located in the latter steps of the synthesis pathway was significantly higher in female barks than in male. Regulatory TFs were inferred through co-expression network analysis, resulting in the identification of TFs from diverse families including MYB and AP2. Genes with ADP binding and copper ion binding functions were overrepresented in targets of miRNA genes. The miRNA targets were mainly enriched with genes in plant hormone signal transduction, mRNA surveillance pathway, cell cycle and DNA replication. Genes in oxidoreductase activity, protein-disulfide reductase activity were enriched in targets of phasiRNAs. Regulatory networks were further constructed including components of enzyme genes, TFs, miRNAs, and phasiRNAs. The hierarchical regulation of paclitaxel production by miRNAs and phasiRNAs indicates a robust regulation at post-transcriptional level. Our study on transcriptional and posttranscriptional regulation of paclitaxel synthesis provides clues for enhancing paclitaxel production using synthetic biology technology.
ABSTRACT
This systematic review examines the role of dosimetric parameters in predicting temporal lobe necrosis (TLN) risk in nasopharyngeal carcinoma (NPC) patients treated with three-dimensional conformal RT (3D-CRT), intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). TLN is a serious late complication that can adversely affect the quality of life of NPC patients. Understanding the relationship between dosimetric parameters and TLN can guide treatment planning and minimize radiation-related complications. A comprehensive search identified relevant studies published up to July 2023. Studies reporting on dosimetric parameters and TLN in NPC patients undergoing 3D-CRT, IMRT, and VMAT were included. TLN incidence, follow-up duration, and correlation with dosimetric parameters of the temporal lobe were analyzed. The review included 30 studies with median follow-up durations ranging from 28 to 110 months. The crude incidence of TLN varied from 2.3 % to 47.3 % and the average crude incidence of TLN is approximately 14 %. Dmax and D1cc emerged as potential predictors of TLN in 3D-CRT and IMRT-treated NPC patients. Threshold values of >72 Gy for Dmax and >62 Gy for D1cc were associated with increased TLN risk. However, other factors should also be considered, including host characteristics, tumor-specific features and therapeutic factors. In conclusion, this systematic review highlights the significance of dosimetric parameters, particularly Dmax and D1cc, in predicting TLN risk in NPC patients undergoing 3D-CRT, IMRT, and VMAT. The findings provide valuable insights that can help in developing optimal treatment planning strategies and contribute to the development of clinical guidelines in this field.
Subject(s)
Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Necrosis , Radiation Injuries , Radiotherapy, Intensity-Modulated , Temporal Lobe , Humans , Nasopharyngeal Carcinoma/radiotherapy , Nasopharyngeal Carcinoma/pathology , Temporal Lobe/radiation effects , Temporal Lobe/pathology , Necrosis/etiology , Radiation Injuries/etiology , Radiation Injuries/pathology , Nasopharyngeal Neoplasms/radiotherapy , Nasopharyngeal Neoplasms/pathology , Radiotherapy, Intensity-Modulated/adverse effects , Radiotherapy, Intensity-Modulated/methods , Radiotherapy Dosage , Radiotherapy, Conformal/adverse effects , Radiotherapy, Conformal/methodsABSTRACT
Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.
Subject(s)
Histones , Neoplasms, Squamous Cell , United States , Humans , Protein Processing, Post-Translational , Proteolysis , Epigenesis, Genetic , LysosomesABSTRACT
The discovery of the endothelium as a major regulator of vascular tone triggered intense research among basic and clinical investigators to unravel the physiologic and pathophysiologic significance of this phenomenon. Sphingosine-l-phosphate (S1P), derived from the vascular endothelium, is a significant regulator of blood pressure. However, the mechanisms underlying the regulation of S1P biosynthetic pathways in arteries remain to be further clarified. Here, we reported that Reticulon 3 (RTN3) regulated endothelial sphingolipid biosynthesis and blood pressure. We employed public datasets, patients, and mouse models to explore the pathophysiological roles of RTN3 in blood pressure control. The underlying mechanisms were studied in human umbilical vein endothelial cells (HUVECs). We reported that increased RTN3 was found in patients and that RTN3-null mice presented hypotension. In HUVECs, RTN3 can regulate migration and tube formation via the S1P signaling pathway. Mechanistically, RTN3 can interact with CERS2 to promote the selective autophagy of CERS2 and further influence S1P signals to control blood pressure. We also identified an RTN3 variant (c.116C>T, p.T39M) in a family with hypertension. Our data provided the first evidence of the association between RTN3 level changes and blood pressure anomalies and preliminarily elucidated the importance of RTN3 in S1P metabolism and blood pressure regulation.
ABSTRACT
Reticulum 3 (RTN3) is an endoplasmic reticulum (ER) protein that has been reported to act in neurodegenerative diseases and lipid metabolism. However, the role of RTN3 in acute kidney injury (AKI) has not been explored. Here, we employed public datasets, patient data, and animal models to explore the role of RTN3 in AKI. The underlying mechanisms were studied in primary renal tubular epithelial cells and in the HK2 cell line. We found reduced expression of RTN3 in AKI patients, cisplatin-induced mice, and cisplatin-treated HK2 cells. RTN3-null mice exhibit more severe AKI symptoms and kidney fibrosis after cisplatin treatment. Mitochondrial dysfunction was also found in cells with RTN3 knockdown or knockout. A mechanistic study revealed that RTN3 can interact with HSPA9 in kidney cells. RTN3 deficiency may disrupt the RTN3-HSPA9-VDAC2 complex and affect MAMs during ER-mitochondrion contact, which further leads to mitochondrial dysfunction and exacerbates cisplatin-induced AKI. Our study indicated that RTN3 was important in the kidney and that a decrease in RTN3 in the kidney might be a risk factor for the aggravation of AKI.
Subject(s)
Acute Kidney Injury , Mitochondrial Diseases , Humans , Mice , Animals , Cisplatin/adverse effects , Apoptosis , Acute Kidney Injury/chemically induced , Kidney/metabolism , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Carrier Proteins , Membrane Proteins/genetics , Membrane Proteins/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolismABSTRACT
Cephalosporins (CEFs) are a class of widely used toxic antibiotics. Development of a rapid and sensitive method for detecting trace CEF residues in food samples is still challenging. Herein, we report preparation of an amide and carboxyl groups dual-functionalized core-shelled magnetic microporous organic network MMON-COOH-2CONH for efficient magnetic solid-phase extraction (MSPE) of CEFs from milk powder samples. Under optimal conditions, the established MMON-COOH-2CONH-MSPE-HPLC-UV method owns wide linear range (3-10000 µg kg-1), low limits of detection (1-3 µg kg-1), large enrichment factors (93.9-99.4), low adsorbent consumption (3 mg), and short extraction time (6 min). Synergistic extraction mechanisms of ionic bonding, hydrogen bonding, π-π, and hydrophobic interactions were elucidated by both theoretical density functional theory calculations and experimental data. This study confirms that preparation of dual-functionalized MMONs and introduction of ionic groups are feasible to promote MMONs application in sample pretreatment.
Subject(s)
Amides , Cephalosporins , Magnetics , Physical Phenomena , Solid Phase Extraction/methods , Chromatography, High Pressure Liquid , Magnetic Phenomena , Limit of DetectionABSTRACT
Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histone Demethylases/metabolismABSTRACT
Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.
Subject(s)
Lysine , Neoplasms , Humans , Lysine/therapeutic use , Histone Demethylases/metabolism , Histone Demethylases/therapeutic use , Monoamine Oxidase Inhibitors/therapeutic use , Histones , Neoplasms/drug therapy , Drug Discovery , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic useABSTRACT
OBJECTIVES: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. METHODS: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. RESULTS: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. CONCLUSION: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis.
Subject(s)
Colitis , Saponins , Rats , Mice , Animals , Pyruvate Carboxylase/metabolism , NF-kappa B/metabolism , Lipopolysaccharides/pharmacology , Molecular Docking Simulation , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Inflammation/metabolism , Saponins/pharmacology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Macrophages/metabolism , Dextran Sulfate/adverse effects , Dextran Sulfate/metabolism , Mice, Inbred C57BL , Disease Models, AnimalABSTRACT
Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC50 = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer.
Subject(s)
Antineoplastic Agents , Stomach Neoplasms , Animals , Mice , Antineoplastic Agents/chemistry , Structure-Activity Relationship , Stomach Neoplasms/drug therapy , Molecular Docking Simulation , Acridines/pharmacology , Cell Line, Tumor , Immunity , Histone Demethylases , Enzyme Inhibitors/pharmacology , Cell ProliferationABSTRACT
Chinese milk vetch (Astragalus sinicus L.) is an important organic nutrient resource in the southern Henan rice-growing area. Thus, the effects of Chinese milk vetch (MV) returning incorporated with reduced chemical fertilizer on the physicochemical properties and bacterial community characteristics in paddy soil were studied. These results can provide a certain theoretical basis for the improvement of soil fertility and reduction of chemical fertilizer in this area. A field experiment was conducted for 12 consecutive years, involving six fertilization treatments (blank control, CK; 100% chemical fertilizer, F100; 80% chemical fertilizer+22.5 t·hm-2 MV, MV1F80; 80% chemical fertilizer+45 t·hm-2 MV, MV2F80; 60% chemical fertilizer+22.5 t·hm-2 MV, MV1F60; and 60% chemical fertilizer+45 t·hm-2 MV, MV2F60). The high-throughput sequencing method was used to compare the effects of different fertilization treatments on soil bacterial community diversity, composition, and structural characteristics. The FAPROTAX function prediction method was used to analyze the abundance differences of functional groups between different fertilization treatments. Additionally, combined with soil physicochemical properties and bacterial community characteristics, we explored the key soil environmental factors that changed the structure and functional characteristics of the soil bacterial community. Compared with that under CK, the soil bulk density (BD) under the MV returning incorporated with reduced chemical fertilizer treatment was decreased, whereas soil organic carbon (SOC), total nitrogen (TN), total phosphorus (TP), and total potassium (TK) were increased by 12.7%-35.5%, 38.2%-65.7%, 66.7%-95.2%, and 20.3%-31.6%, respectively. Compared with that under the F100 treatment, the Sobs index and Shannon diversity index of the bacterial community under the MV returning incorporated with reduced chemical fertilizer were decreased, and the Sobs index and Shannon diversity index were significantly positively correlated with BD (P<0.05) but significantly negatively correlated with SOC and TN (P<0.05). Compared with that under the F100 treatment, the relative abundances of Firmicutes under the MV1F80 and MV2F60 treatments were significantly increased by 82.2% and 67.4% (P<0.05), but the relative abundances of Acidobacteria were significantly reduced by 32.6% and 40.5% (P<0.05), respectively. The relative abundance of Actinobacteria under the MV2F60 treatment was significantly increased by 30.0% (P<0.05) compared with that under the F100 treatment. According to RDA analysis, soil SOC, TN, and TK were the main soil environmental factors that significantly affected bacterial community (P<0.05). Compared with that under CK and the F100 treatment, the abundance of functional groups of chemoheterotrophy, nitrogen fixation, fermentation, and ureolysis under the MV returning incorporated with reduced chemical fertilizer treatment were improved, whereas the abundance of functional groups of animal parasites or symbionts, all human pathogens, and human pathogen pneumonia were reduced, particularly under MV1F80 and MV2F60. To summarize, the long-term MV returning to the field incorporated with reduced chemical fertilizer improved the soil physical and chemical properties, thus changing the structure and functional characteristics of the soil bacterial communities, contributing to the improvement in the soil fertility, stability, and health of micro-ecosystems in paddy fields, thus ensuring the green and sustainable development of regional agriculture.
Subject(s)
Oryza , Soil , Animals , Humans , Soil/chemistry , Fertilizers/analysis , Ecosystem , Carbon , Soil Microbiology , Agriculture/methods , Bacteria , Nitrogen/analysis , Oryza/microbiologyABSTRACT
Chemodynamic immunotherapy that utilizes catalysts to produce reactive oxygen species (ROS) for killing tumor cells and arousing antitumor immunity has received considerable attention. However, it is still restricted by low ROS production efficiency and insufficient immune activation, due to intricate redox homeostasis in the tumor microenvironment (TME). Herein, a metalloprotein-like hybrid nanozyme (FeS@GOx) is designed by in situ growth of nanozyme (ferrous sulfide, FeS) in a natural enzyme (glucose oxidase, GOx) to amplify ROS cascade for boosting chemodynamic immunotherapy. In FeS@GOx, GOx allows the conversion of endogenous glucose to gluconic acid and hydrogen peroxide, which provides favorable increasing hydrogen peroxide for subsequent Fenton reaction of FeS nanozymes, thus reinforcing ROS production. Notably, hydrogen sulfide (H2 S) release is activated by the gluconic acid generation-related pH decrease, which can suppress the activity of endogenous thioredoxin reductase and catalase to further inhibit ROS elimination. Thus, FeS@GOx can sustainably amplify ROS accumulation and perturb intracellular redox homeostasis to improve chemodynamic therapy and trigger robust immunogenic cell death for effective immunotherapy combined with immune checkpoint blockade. This work proposes a feasible H2 S amplified ROS cascade strategy employing a bioinspired hybrid nanozyme, providing a novel pathway to multi-enzyme-mediated TME modulation for precise and efficient chemodynamic immunotherapy.
Subject(s)
Hydrogen Peroxide , Hydrogen Sulfide , Hydrogen Sulfide/pharmacology , Reactive Oxygen Species , Immunotherapy , Tumor MicroenvironmentABSTRACT
Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC50 = 5.135 µM), and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s (IC50 = 0.247 µM) was the most potent one. More importantly, compound 3s inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response. An in vivo study confirmed that compound 3s can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor 3s tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.
Subject(s)
Enzyme Inhibitors , Stomach Neoplasms , Animals , Mice , Enzyme Inhibitors/pharmacology , Stomach Neoplasms/drug therapy , Cell Line, Tumor , Chlorpromazine/therapeutic use , T-Lymphocytes/metabolism , Cell Proliferation , Histone Demethylases/metabolism , Cell Death , Structure-Activity RelationshipABSTRACT
LSD1 is overexpressed in various cancers and promotes tumor cell proliferation, tumor expansion, and suppresses immune cells infiltration and is closely associated with immune checkpoint inhibitors therapy. Therefore, the inhibition of LSD1 has been recognized as a promising strategy for cancer therapy. In this study, we screened an in-house small-molecule library targeting LSD1, an FDA-approved drug amsacrine for acute leukemia and malignant lymphomas was found to exhibit moderate anti-LSD1 inhibitory activity (IC50 = 0.88 µM). Through further medicinal chemistry efforts, the most active compound 6x increased anti-LSD1 activity significantly (IC50 = 0.073 µM). Further mechanistic studies demonstrated that compound 6x inhibited the stemness and migration of gastric cancer cell, and decreased the expression of PD-L1 (programmed cell death-ligand 1) in BGC-823 and MFC cells. More importantly, BGC-823 cells are more susceptible to T-cell killing when treated with compound 6x. Moreover, tumor growth was also suppressed by compound 6x in mice. Altogether, our findings demonstrated that acridine-based novel LSD1 inhibitor 6x may be a lead compound for the development of activating T cell immune response in gastric cancer cells.
Subject(s)
Antineoplastic Agents , Stomach Neoplasms , Animals , Mice , Antineoplastic Agents/chemistry , Enzyme Inhibitors/pharmacology , Stomach Neoplasms/drug therapy , Acridines/pharmacology , Acridines/therapeutic use , Cell Line, Tumor , Histone Demethylases , Cell ProliferationABSTRACT
In recent decades, the development of targeted drugs has featured prominently in the treatment of cancer, which is among the major causes of mortality globally. Triazole-fused pyrimidines, a widely-used class of heterocycles in medicinal chemistry, have attracted considerable interest as potential anticancer agents that target various cancer-associated targets in recent years, demonstrating them as valuable templates for discovering novel anticancer candidates. The current review concentrates on the latest advancements of triazole-pyrimidines as target-based anticancer agents, including works published between 2007 and the present (2007-2022). The structure-activity relationships (SARs) and multiple pathways are also reviewed to shed light on the development of more effective and biotargeted anticancer candidates.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Triazoles/pharmacology , Triazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To explore the expression pattern and clinical significance of Integral membrane protein 2Aï¼ITM2Aï¼ in drug resistant patients with chronic myeloid leukemia (CML). METHODS: The expression of ITM2A in CML was evaluated by qRT-PCR, Western blot and immunocytochemistry. In order to understand the possible biological effects of ITM2A, apoptosis, cell cycle and myeloid differentiation antigen expression of CML cells were detected by flow cytometry after over-expression of ITM2A. The nuderlying molecular mechanism of its biological effect was explored. RESULTS: The expression of ITM2A in bone marrow of CML resistant patients was significantly lower than that of sensitive patients and healthy donorsï¼P<0.05ï¼. The CML resistant strain cell K562R was successfully constructed in vitro. The expression of ITM2A in the resistant strain was significantly lower than that in the sensitive strain(P<0.05). Overexpression of ITM2A in K562R cells increased the sensitivity of K562R cells to imatinib and blocked the cell cycle in G2 phase(P<0.05), but did not affect myeloid differentiation. Mechanistically, up-regulation of ITM2A reduced phosphorylation in ERK signaling (P<0.05). CONCLUSION: The expression of ITM2A was low in patients with drug resistance of CML, and the low expression of ITM2A may be the key factor of imatinib resistance in CML.