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Molecular Pharmaceutics Jul 2024Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously,...
Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [Ga]Ga-P16-093, containing a Ga(III) chelator, ,'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-,'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log = 22.18) or lutetium-177 (log = 21.85). The aim of this study is to evaluate AAZTA-Gly--(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, ) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, , was effectively accomplished. Labeling with either [Ga]GaCl or [Lu]LuCl in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [Ga]Ga- or [Lu]Lu- with high yields and excellent radiochemical purities. Results of binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [Ga]Ga-P16-093 and [Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 μM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [Ga]Ga- and [Lu]Lu- displayed excellent uptake and retention in the tumor. Results indicate that [Ga]Ga/[Lu]Lu- (Ga]Ga/[Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.
Topics: Male; Humans; Prostatic Neoplasms; Gallium Radioisotopes; Lutetium; Antigens, Surface; Radiopharmaceuticals; Glutamate Carboxypeptidase II; Cell Line, Tumor; Radioisotopes; Animals; Chelating Agents; Prostate-Specific Antigen; Tissue Distribution; Mice; Edetic Acid; Positron Emission Tomography Computed Tomography
PubMed: 38856975
DOI: 10.1021/acs.molpharmaceut.4c00020 -
Amino Acids Jun 2024Periodontitis is an inflammatory condition of supporting structures of teeth leading to attachment and bone loss. Cigarette smoking is the single most important and...
Periodontitis is an inflammatory condition of supporting structures of teeth leading to attachment and bone loss. Cigarette smoking is the single most important and modifiable risk factor with 5 to 20-fold susceptibility for periodontal diseases. Reverse smoking is a peculiar habit of smoking where the lit end is kept inside the mouth, which is predominant in the northern coastal districts of Andhra Pradesh. Polyamines are biologically active amines involved in tissue regeneration and modulation of inflammation. The study aimed to evaluate polyamines and check their utility as a marker in detection of periodontitis among different groups. Total polyamine levels showed significant increase in reverse smokers with periodontitis when compared to the other groups. Qualitative analysis by thin layer chromatography showed three polyamine bands with varying intensity among the different groups. Mass spectrometric and NMR analyses of the three bands identified them as N1, N8-diacetyl spermidine, N-acetyl cadaverine and lysine. Most significantly elevated levels of lysine was observed in the smoker and reverse smoker periodontitis groups when compared to healthy and non-smoker periodontitis groups. The significantly elevated levels of N-acetyl cadaverine could be responsible for the more destruction of periodontium in the reverse smoker group. Antioxidant potential decreased significantly in different smoker periodontitis groups. The present study suggests that the quantitative analysis of salivary polyamines, lysine and N-acetyl cadaverine can aid as an easy noninvasive diagnostic method for assessing the periodontal status, especially in smokers.
Topics: Humans; Periodontitis; Cadaverine; Biomarkers; Lysine; Adult; Male; Smokers; Female; Middle Aged; Smoking; Saliva
PubMed: 38851640
DOI: 10.1007/s00726-024-03396-4 -
Journal of Pharmaceutical and... Sep 2024Dingchuan Decoction (DCD) is a traditional Chinese medicine prescription commonly used in the treatment of asthma, but the mechanism of DCD in treating asthma has not...
Dingchuan Decoction (DCD) is a traditional Chinese medicine prescription commonly used in the treatment of asthma, but the mechanism of DCD in treating asthma has not yet been determined. In this study, we employed a combination of metabolomics and network pharmacology to investigate the mechanism of DCD in treating asthma. An allergic asthma rat model was induced by ovalbumin (OVA). Metabolomics based on H NMR and UHPLC-MS was used to identify differential metabolites and obtain the major metabolic pathways and potential targets. Network pharmacology was utilized to explore potential targets of DCD for asthma treatment. Finally, the results of metabolomics and network pharmacology were integrated to obtain the key targets and metabolic pathways of DCD for the therapy of asthma, and molecular docking was utilized to validate the key targets. A total of 76 important metabolites and 231 potential targets were identified through metabolomics. Using network pharmacology, 184 potential therapeutic targets were obtained. These 184 targets were overlaid with the 231 potential targets obtained through metabolomics and were analyzed in conjunction with metabolic pathways. Ultimately, the key targets were identified as aldehyde dehydrogenase 2 (ALDH2) and amine oxidase copper-containing 3 (AOC3), and the relevant metabolic pathways affected were glycolysis and gluconeogenesis as well as arginine and proline metabolism. Molecular docking showed that the key targets had high affinity with the relevant active ingredients in DCD, which further demonstrated that DCD may exert therapeutic effects by acting on the key targets. The present study demonstrated that DCD can alleviate OVA-induced allergic asthma and that DCD may have a therapeutic effect by regulating intestinal flora and polyamine metabolism through its effects on ALDH2 and AOC3.
Topics: Animals; Asthma; Metabolomics; Ovalbumin; Molecular Docking Simulation; Rats; Drugs, Chinese Herbal; Network Pharmacology; Rats, Sprague-Dawley; Male; Disease Models, Animal; Chromatography, High Pressure Liquid; Metabolic Networks and Pathways; Aldehyde Dehydrogenase, Mitochondrial; Medicine, Chinese Traditional
PubMed: 38850849
DOI: 10.1016/j.jpba.2024.116265 -
Cancer Medicine Jun 2024Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of...
OBJECTIVE
Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of mobilization failure and characterize the risk factors associated with poor mobilization (PM) of MM patients in novel therapies era.
METHODS
We conducted a retrospective study of 211 MM patients who received their first peripheral blood stem cells (PBSC) mobilization at our single center. The following data were collected: age, gender, clinical stage, disease status, complete blood cell count, induction regimen, CD34 cell count in peripheral blood (PB), and PBSC collections.
RESULTS
In addition to conventional drugs, 22 (10.4%) patients received daratumumab containing induction, and 33 (15.6%) patients used plerixafor for poor mobilization (pre-apheresis PB CD34 cells <20/μL). Failure of collection occurred in 24 (11.4%) patients and was correlated with low white blood cell (WBC), ≥3 cycles of lenalidomide treatment before mobilization, steady-state mobilization and nouse of plerixafor are associated with mobilization failure. Daratumumab-based induction treatment ≥2 courses, albumin >41 g/L before mobilization, and steady-state mobilization were risk factors for PM in subgroups of patients treated with lenalidomide for <3 courses. In addition, Hepatitis B virus infection at baseline, thalassemia and measurable residual disease positivity were recognized as predictive factors for PM in subset of chemo-mobilization patients.
CONCLUSION
In addition to some well-recognized risk factors, baseline WBC count and daratumumab exposure ≥2 courses before mobilization were revealed as the predictive factors of mobilization failure, providing consultation for preemptive use of plerixafor.
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Mobilization; Female; Male; Middle Aged; Retrospective Studies; Aged; Adult; Cyclams; Benzylamines; Peripheral Blood Stem Cells; Risk Factors; Antibodies, Monoclonal; Lenalidomide; Heterocyclic Compounds; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous
PubMed: 38850125
DOI: 10.1002/cam4.7356 -
Journal of the American Chemical Society Jun 2024Cancer immune therapies, particularly programmed cell death protein 1 (PD-1) blockade immunotherapy, falter in aged individuals due to compromised T-cell immunity....
Cancer immune therapies, particularly programmed cell death protein 1 (PD-1) blockade immunotherapy, falter in aged individuals due to compromised T-cell immunity. Spermidine, a biogenic polyamine that declines along with aging, shows promise in restoring antitumor immunity by enhancing mitochondrial fatty acid oxidation (FAO). Herein, we report a spermidine-based chemoproteomic probe (probe ) that enables profiling of spermidine-binding proteins and screening for small-molecule enhancers of mitochondrial FAO. Chemoproteomic profiling by the probe revealed 140 proteins engaged in cellular interaction with spermidine, with a significant majority being mitochondrial proteins. Hydroxyl coenzyme A (CoA) dehydrogenase subunits α (HADHA) and other lipid metabolism-linked proteins are among the mitochondrial proteins that have attracted considerable interest. Screening spermidine analogs with the probe led to the discovery of compound , which interacts with these lipid metabolism-linked proteins and activates HADHA. This simple and biostable synthetic compound we named "spermimic" mirrors spermidine's ability to enhance mitochondrial bioenergetics and displays similar effectiveness in augmenting PD-1 blockade therapy in mice. This study lays the foundation for developing small-molecule activators of antitumor immunity, offering potential in combination cancer immunotherapy.
PubMed: 38848460
DOI: 10.1021/jacs.3c14615 -
The Journal of Poultry Science 2024Cadaverine is a bioactive substance derived from lysine degradation by lysine decarboxylase and has gained attention for its physiological effects. Studies in rodents...
Cadaverine is a bioactive substance derived from lysine degradation by lysine decarboxylase and has gained attention for its physiological effects. Studies in rodents have revealed its role as a cell growth regulator, particularly intestinal bacterial-produced cadaverine. However, the nutritional and physiological roles of cadaverine during the embryonic period remain unclear, especially considering the immature state of the gut microbiota and digestive functions during this stage. This study explored the potential functions of cadaverine as a nutritional and metabolic signal during chicken embryonic development. Experiments were conducted using an administration method to evaluate the effects of nutritional bioactive substances on developing chicken embryos. Although there were no observable changes in body or organ weights of newly hatched chicks following cadaverine administration to day 18 chick embryos, plasma tryptophan, N-methylhistidine, and N-methylhistidine concentrations decreased and the gene expression of insulin/insulin-like growth factor 1 signaling in skeletal muscle was upregulated. These findings imply that cadaverine influences tryptophan metabolism and skeletal muscle catabolism during the embryonic period, suggesting its role as a bioactive factor contributing to energy metabolism signaling in skeletal muscle.
PubMed: 38846485
DOI: 10.2141/jpsa.2024017 -
Physiology and Molecular Biology of... May 2024Polyamines play an important role in growth and differentiation by regulating numerous physiological and biochemical processes at the cellular level. In addition to...
Polyamines play an important role in growth and differentiation by regulating numerous physiological and biochemical processes at the cellular level. In addition to their roborative effect, their essential role in plant stress responses has been also reported. However, the positive effect may depend on the fine-tuning of polyamine metabolism, which influences the production of free radicals and/or signalling molecules. In the present study, 0.3 mM hydroponic putrescine treatment was tested in wheat, maize, and rice in order to reveal differences in their answers and highlight the relation of these with polyamine metabolism. In the case of wheat, the chlorophyll content and the actual quantum yield increased after putrescine treatment, and no remarkable changes were detected in the stress markers, polyamine contents, or polyamine metabolism-related gene expression. Although, in maize, the actual quantum yield decreased, and the root hydrogen peroxide content increased, no other negative effect was observed after putrescine treatment due to activation of polyamine oxidases at enzyme and gene expression levels. The results also demonstrated that after putrescine treatment, rice with a higher initial polyamine content, the balance of polyamine metabolism was disrupted and a significant amount of putrescine was accumulated, accompanied by a detrimental decrease in the level of higher polyamines. These initial differences and the putrescine-induced shift in polyamine metabolism together with the terminal catabolism or back-conversion-induced release of a substantial quantity of hydrogen peroxide could contribute to oxidative stress observed in rice.
PubMed: 38846465
DOI: 10.1007/s12298-024-01462-5 -
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue May 2024To investigate the effect of nuclear factor E2-related factor 2 (Nrf2) protein on ferroptosis in mice with sepsis-associated liver injury (SALI).
OBJECTIVE
To investigate the effect of nuclear factor E2-related factor 2 (Nrf2) protein on ferroptosis in mice with sepsis-associated liver injury (SALI).
METHODS
he male Sprague-Dawley (SD) mice were divided into 6 groups according to the random number table method, with 6 mice in each group. The SALI model of mice was established by cecal ligation and puncture (CLP), and the Sham group was only treated with laparotomy. CLP+Fer-1 group, CLP+Erastin group, CLP+ML385 group and CLP+Curcumin group were intraperitoneally injected with iron death inhibitor Ferrostatin-1 (Fer-1) 10 mg×kg×d, iron death activator Erastin 20 mg×kg×d, Nrf2 inhibitor ML385 30 mg×kg×d and Nrf2 activator Curcumin 100 mg×kg×d after CLP, respectively; Sham group and CLP group were given normal saline 10 mg×kg×d, each group was administered continuously for 10 days. Ten days after operation, the serum and liver tissues of mice were collected to detect the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and the levels of malondialdehyde (MDA), glutathione (GSH) and Fe; in liver homogenate. The pathological changes of liver tissue were observed under light microscope after hematoxylin-eosin (HE) staining. The shape and length of mitochondria in liver cells were observed under transmission electron microscope. The protein expressions of Nrf2, glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) in liver tissue were detected by Western blotting.
RESULTS
Compared with Sham group, the serum levels of ALT and AST in the CLP group were significantly increased; histologically, the hepatic cord was disordered, the cells were swollen and necrotic, and the length of mitochondria was significantly shortened; the levels of MDA and Fe in liver tissue increased significantly, and the content of GSH decreased significantly; the protein expressions of Nrf2 and GPX4 in liver tissue decreased, and the protein expression of PTGS2 increased significantly. Compared with CLP group, the serum levels of ALT and AST in CLP+Fer-1 group and CLP+Curcumin group were significantly decreased [ALT (U/L): 80.65±19.44, 103.45±20.52 vs. 283.50±37.12, AST (U/L): 103.33±11.90, 127.33±15.79 vs. 288.67±36.82, all P < 0.05]; microscopically, the hepatic cord was irregular, the cells were slightly swollen, and the mitochondrial length was significantly increased (μm: 1.42±0.09, 1.43±0.21 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe; in liver tissue decreased significantly, and the content of GSH increased significantly [MDA (mol/g): 0.87±0.23, 1.85±0.43 vs. 4.47±0.95, Fe (μg/g): 63.80±7.15, 67.48±6.28 vs. 134.52±14.32, GSH (mol/g): 1.95±0.29, 1.95±0.45 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly increased, and the protein expression of PTGS2 was significantly decreased (Nrf2/GAPDH: 1.80±0.28, 2.10±0.43 vs. 0.70±0.24, GPX4/GAPDH: 0.80±0.06, 0.93±0.07 vs. 0.48±0.02, PTGS2/GAPDH: 0.76±0.05, 0.84±0.01 vs. 1.02±0.09, all P < 0.05). However, the results of the above indexes in the CLP+Erastin group and CLP+ML385 group were opposite, and the serum levels of ALT and AST were significantly increased [ALT (U/L): 344.52±40.79, 321.70±21.10 vs. 283.50±37.12, AST (U/L): 333.50±27.90, 333.00±16.67 vs. 288.67±36.82, all P < 0.05]; microscopically, the arrangement of hepatic cords was disordered, the cells were obviously swollen and necrotic, and the length of mitochondria was significantly shortened (μm: 0.78±0.13, 0.67±0.07 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe in liver tissue increased significantly, and the content of GSH decreased significantly [MDA (mol/g): 5.92±1.06, 5.62±0.56 vs. 4.47±0.95, Fe (μg/g): 151.40±8.03, 151.88±8.68 vs. 134.52±14.32, GSH (mol/g): 0.25±0.08, 0.23±0.11 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly decreased, and the protein expression of PTGS2 was significantly increased (Nrf2/GAPDH: 0.46±0.09, 0.46±0.11 vs. 0.70±0.24, GPX4/GAPDH: 0.34±0.05, 0.40±0.01 vs. 0.48±0.02, PTGS2/GAPDH: 1.24±0.13, 1.16±0.11 vs. 1.02±0.09, all P < 0.05).
CONCLUSIONS
CLP-induced SALI can lead to ferroptosis in mice hepatocytes, and Nrf2 protein in liver tissue can mediate SALI by regulating ferroptosis.
Topics: Animals; Ferroptosis; Male; Mice; NF-E2-Related Factor 2; Sepsis; Disease Models, Animal; Liver; Rats, Sprague-Dawley; Liver Diseases; Glutathione Peroxidase; Malondialdehyde; Curcumin; Phenylenediamines; Cyclohexylamines
PubMed: 38845495
DOI: 10.3760/cma.j.cn121430-20231105-00941 -
BMC Genomics Jun 2024Nitzschia closterium f. minutissima is a commonly available diatom that plays important roles in marine aquaculture. It was originally classified as Nitzschia...
BACKGROUND
Nitzschia closterium f. minutissima is a commonly available diatom that plays important roles in marine aquaculture. It was originally classified as Nitzschia (Bacillariaceae, Bacillariophyta) but is currently regarded as a heterotypic synonym of Phaeodactylum tricornutum. The aim of this study was to obtain the draft genome of the marine microalga N. closterium f. minutissima to understand its phylogenetic placement and evolutionary specialization. Given that the ornate hierarchical silicified cell walls (frustules) of diatoms have immense applications in nanotechnology for biomedical fields, biosensors and optoelectric devices, transcriptomic data were generated by using reference genome-based read mapping to identify significantly differentially expressed genes and elucidate the molecular processes involved in diatom biosilicification.
RESULTS
In this study, we generated 13.81 Gb of pass reads from the PromethION sequencer. The draft genome of N. closterium f. minutissima has a total length of 29.28 Mb, and contains 28 contigs with an N50 value of 1.23 Mb. The GC content was 48.55%, and approximately 18.36% of the genome assembly contained repeat sequences. Gene annotation revealed 9,132 protein-coding genes. The results of comparative genomic analysis showed that N. closterium f. minutissima was clustered as a sister lineage of Phaeodactylum tricornutum and the divergence time between them was estimated to be approximately 17.2 million years ago (Mya). CAFF analysis demonstrated that 220 gene families that significantly changed were unique to N. closterium f. minutissima and that 154 were specific to P. tricornutum, moreover, only 26 gene families overlapped between these two species. A total of 818 DEGs in response to silicon were identified in N. closterium f. minutissima through RNA sequencing, these genes are involved in various molecular processes such as transcription regulator activity. Several genes encoding proteins, including silicon transporters, heat shock factors, methyltransferases, ankyrin repeat domains, cGMP-mediated signaling pathways-related proteins, cytoskeleton-associated proteins, polyamines, glycoproteins and saturated fatty acids may contribute to the formation of frustules in N. closterium f. minutissima.
CONCLUSIONS
Here, we described a draft genome of N. closterium f. minutissima and compared it with those of eight other diatoms, which provided new insight into its evolutionary features. Transcriptome analysis to identify DEGs in response to silicon will help to elucidate the underlying molecular mechanism of diatom biosilicification in N. closterium f. minutissima.
Topics: Diatoms; Phylogeny; Gene Expression Profiling; Genome; Transcriptome; Molecular Sequence Annotation
PubMed: 38840265
DOI: 10.1186/s12864-024-10479-9 -
Scientific Reports Jun 2024Endophytes have been shown to promote plant growth and health. In the present study, a Bacillus velezensis CH1 (CH1) strain was isolated and identified from high-quality...
Endophytes have been shown to promote plant growth and health. In the present study, a Bacillus velezensis CH1 (CH1) strain was isolated and identified from high-quality oats, which was capable of producing indole-3-acetic acid (IAA) and strong biofilms, and capabilities in the nitrogen-fixing and iron carriers. CH1 has a 3920 kb chromosome with 47.3% GC content and 3776 code genes. Compared genome analysis showed that the largest proportion of the COG database was metabolism-related (44.79%), and 1135 out of 1508 genes were associated with the function "biosynthesis, transport, and catabolism of secondary metabolites." Furthermore, thirteen gene clusters had been identified in CH1, which were responsible for the synthesis of fifteen secondary metabolites that exhibit antifungal and antibacterial properties. Additionally, the strain harbors genes involved in plant growth promotion, such as seven putative genes for IAA production, spermidine and polyamine synthase genes, along with multiple membrane-associated genes. The enrichment of these functions was strong evidence of the antimicrobial properties of strain CH1, which has the potential to be a biofertilizer for promoting oat growth and disease resistance.
Topics: Bacillus; Avena; Indoleacetic Acids; Biofilms; Plant Diseases; Nitrogen Fixation; Phylogeny; Endophytes; Genome, Bacterial
PubMed: 38839805
DOI: 10.1038/s41598-024-63756-8