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Journal of Medicinal Chemistry Dec 2023The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[,'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III)...
Design, Synthesis, Electrochemical, and Biological Evaluation of Fluorescent Chlorido[,'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) Complexes as Anticancer Agents.
The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[,'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes (-) inhibited proliferation, migration, and metabolic activity in a concentration-dependent manner following the rank order: > > . In particular, was highly cytotoxic with an IC of 4.2 μM which was 6.6-fold lower than that of cisplatin (IC of 27.9 μM). In contrast, hydroxylated complexes - were almost inactive up to the highest concentration tested due to lack of cellular uptake. caused a dual mode of cell death, ferroptosis, and necroptosis, whereby at higher concentrations, ferroptosis was the preferred form. Ferroptotic morphology and the presence of ferrous iron and lipid reactive oxygen species proved the involvement of ferroptosis. was identified as a promising lead compound for the design of drug candidates inducing ferroptosis.
Topics: Humans; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Ethylenediamines; Iron; Coordination Complexes
PubMed: 38013413
DOI: 10.1021/acs.jmedchem.3c01359 -
American Journal of Physiology. Cell... Mar 2024Ion channels in the blood-brain barrier (BBB) play a main role in controlling the interstitial fluid composition and cerebral blood flow, and their dysfunction...
Ion channels in the blood-brain barrier (BBB) play a main role in controlling the interstitial fluid composition and cerebral blood flow, and their dysfunction contributes to the disruption of the BBB occurring in many neurological diseases such as epilepsy. In this study, using morphological and functional approaches, we evaluated the expression and role in the BBB of Kv7 channels, a family of voltage-gated potassium channels including five members (Kv7.1-5) that play a major role in the regulation of cell excitability and transmembrane flux of potassium ions. Immunofluorescence experiments showed that Kv7.1, Kv7.4, and Kv7.5 were expressed in rat brain microvessels (BMVs), as well as brain primary- and clonal (BEND-3) endothelial cells (ECs). Kv7.5 localized at the cell-to-cell junction sites, whereas Kv7.4 was also found in pericytes. The Kv7 activator retigabine increased transendothelial electrical resistance (TEER) in both primary ECs and BEND-3 cells; moreover, retigabine reduced paracellular dextran flux in BEND-3 cells. These effects were prevented by the selective Kv7 blocker XE-991. Exposure to retigabine also hyperpolarized cell membrane and increased tight junctions (TJs) integrity in BEND-3 cells. BMVs from rats treated with kainic acid (KA) showed a disruption of TJs and a selective reduction of Kv7.5 expression. In BEND-3 cells, retigabine prevented the increase of cell permeability and the reduction of TJs integrity induced by KA. Overall, these findings demonstrate that Kv7 channels are expressed in the BBB, where they modulate barrier properties both in physiological and pathological conditions. This study describes for the first time the expression and the functional role of Kv7 potassium channels in the blood-brain barrier. We show that the opening of Kv7 channels reduces endothelial cell permeability both in physiological and pathological conditions via the hyperpolarization of cell membrane and the sealing of tight junctions. Therefore, activation of endothelial Kv7 channels might be a useful strategy to treat epilepsy and other neurological disorders characterized by blood-brain barrier dysfunction.
Topics: Animals; Rats; Blood-Brain Barrier; Endothelial Cells; Kainic Acid; Brain; Epilepsy; Carbamates; Phenylenediamines
PubMed: 38284124
DOI: 10.1152/ajpcell.00709.2023 -
European Journal of Nuclear Medicine... Feb 2024To compare the diagnostic accuracy and detection rates of PET/MRI with [Ga]Ga-PSMA-11 and [Ga]Ga-M2 in patients with biochemical recurrence of prostate cancer (PCa).
Diagnostic accuracy of fully hybrid [Ga]Ga-PSMA-11 PET/MRI and [Ga]Ga-RM2 PET/MRI in patients with biochemically recurrent prostate cancer: a prospective single-center phase II clinical trial.
PURPOSE
To compare the diagnostic accuracy and detection rates of PET/MRI with [Ga]Ga-PSMA-11 and [Ga]Ga-M2 in patients with biochemical recurrence of prostate cancer (PCa).
METHODS
Sixty patients were enrolled in this prospective single-center phase II clinical trial from June 2020 to October 2022. Forty-four/60 completed all study examinations and were available at follow-up (median: 22.8 months, range: 6-31.5 months). Two nuclear medicine physicians analyzed PET images and two radiologists interpreted MRI; images were then re-examined to produce an integrated PET/MRI report for both [Ga]Ga-PSMA-11 and [Ga]Ga-RM2 examinations. A composite reference standard including histological specimens, response to treatment, and conventional imaging gathered during follow-up was used to validate imaging findings. Detection rates, accuracy, sensitivity, specificity, positive, and negative predictive value were assessed. McNemar's test was used to compare sensitivity and specificity on a per-patient base and detection rate on a per-region base. Prostate bed, locoregional lymph nodes, non-skeletal distant metastases, and bone metastases were considered. p-value significance was defined below the 0.05 level after correction for multiple testing.
RESULTS
Patients' median age was 69.8 years (interquartile range (IQR): 61.8-75.1) and median PSA level at time of imaging was 0.53 ng/mL (IQR: 0.33-2.04). During follow-up, evidence of recurrence was observed in 31/44 patients. Combining MRI with [Ga]Ga-PSMA-11 PET and [Ga]Ga-RM2 PET resulted in sensitivity = 100% and 93.5% and specificity of 69.2% and 69.2%, respectively. When considering the individual imaging modalities, [Ga]Ga-RM2 PET showed lower sensitivity compared to [Ga]Ga-PSMA-11 PET and MRI (61.3% vs 83.9% and 87.1%, p = 0.046 and 0.043, respectively), while specificity was comparable among the imaging modalities (100% vs 84.6% and 69.2%, p = 0.479 and 0.134, respectively).
CONCLUSION
This study brings further evidence on the utility of fully hybrid PET/MRI for disease characterization in patients with biochemically recurrent PCa. Imaging with [Ga]Ga-PSMA-11 PET showed high sensitivity, while the utility of [Ga]Ga-RM2 PET in absence of a simultaneous whole-body/multiparametric MRI remains to be determined.
Topics: Male; Humans; Aged; Gallium Radioisotopes; Prospective Studies; Prostatic Neoplasms; Magnetic Resonance Imaging; Positron Emission Tomography Computed Tomography; Edetic Acid; Gallium Isotopes
PubMed: 37897615
DOI: 10.1007/s00259-023-06483-y -
Clinical Nuclear Medicine Feb 2024We describe hitherto unreported physiological low-grade 68Ga-PSMA-11 uptake in dural sinuses of patients who underwent 68Ga-PSMA-11 PET/CT for evaluation of prostate...
We describe hitherto unreported physiological low-grade 68Ga-PSMA-11 uptake in dural sinuses of patients who underwent 68Ga-PSMA-11 PET/CT for evaluation of prostate carcinoma. A strong positive correlation was found between SUVmax of tracer uptake in dural sinuses and SUVmax of blood pool activity in superior vena cava. Low-grade 68Ga-PSMA-11 uptake seen in dural sinuses is physiological and is most likely result of venous blood pool activity. Such uptake should not be interpreted as pathological. Knowledge of such physiological uptake is essential for optimal interpretation of PSMA PET/CT images and differentiating physiological versus pathological uptake.
Topics: Male; Humans; Positron Emission Tomography Computed Tomography; Vena Cava, Superior; Edetic Acid; Oligopeptides; Retrospective Studies; Gallium Radioisotopes; Prostatic Neoplasms
PubMed: 38178373
DOI: 10.1097/RLU.0000000000004997 -
Poultry Science Aug 2023White Roman goose (12-wk-old male, N = 30) carcasses were obtained from a local government-inspected slaughter plant at approximately ∼10-min postmortem. Each...
White Roman goose (12-wk-old male, N = 30) carcasses were obtained from a local government-inspected slaughter plant at approximately ∼10-min postmortem. Each carcass was individually sealed in a zip-lock bag and chilled immediately in a water bath at 15°C for 1 h. Both sides of Pectoralis major muscles were excised from each carcass and incubated in 30 mM CaCl or 30 mM EDTA at 15°C for 5 h. After incubation, calcium-incubated and EDTA-incubated breast muscles were vacuum-packaged individually and stored at 5°C for 72 h. Control samples (without CaCl or EDTA incubation) were directly vacuum-packaged and chilled in a water bath at 15°C for 5 h and stored at 5°C for 72 h. Muscle specimens were taken from the left side of breast muscles at 1 h of chilling (∼1-h postmortem) and at 5 h of incubation at 15°C (∼6-h postmortem), as well as 24, 48, and 72 h of aging at 5°C for measuring the activities of calpain-1 and calpain-11 as well as the contents of 80 kDa calpain-1 subunit and desmin. The samples of shear force value and myofibril fragmentation index (MFI) were taken from the right side of breast muscle at 24 h and 72 h of 5°C storage. Our results showed that the decrease of the activities of calpain-1 and calpain-11 and the contents of 80 kDa calpain-1 subunit and desmin was more rapid (P < 0.05) in calcium-incubated samples than in control and EDTA-incubated samples. The shear force was lower, but the MFI was higher in calcium-incubated samples than in control and EDTA-incubated samples (P < 0.05). Therefore, our results suggest that the calpain-mediated proteolysis and tenderization in postmortem goose muscle could be greatly enhanced by combine effects of stepwise chilling with calcium incubation at 15°C and thereafter aging at 5°C. With applying this procedure, commercial slaughter plants may have an alternative way to improve the tenderness of goose meat.
Topics: Animals; Proteolysis; Calpain; Geese; Calcium; Muscle, Skeletal; Edetic Acid; Calcium Chloride; Desmin; Postmortem Changes; Chickens; Calcium, Dietary; Meat; Water
PubMed: 37300909
DOI: 10.1016/j.psj.2023.102811 -
Food Chemistry Mar 2024Biogenic amines (BA) are molecules with biological functions, which can accumulate at toxic concentrations in foods. Several microorganisms have been identified as... (Review)
Review
Biogenic amines (BA) are molecules with biological functions, which can accumulate at toxic concentrations in foods. Several microorganisms have been identified as responsible for their accumulation at elevated concentrations. Histamine, tyramine and putrescine are the BA most commonly found at highest concentrations. The ingestion of food containing high BA concentrations leads to intoxication with symptoms depending on the BA and the amount consumed. Moreover, there is evidence of synergy between different BA, something of toxicological importance given that some foods accumulate different BA. This work reviews the BA toxic effects and examines recent discoveries regarding their synergy, cytotoxicity and genotoxicity. These advances in the toxicological consequences of ingesting BA contaminated foods support the need to regulate their presence in foods to preserve the consumer's health. However, more research efforts -focused on the establishment of risk assessments- are needed to reach a consensus in their limits in different food matrices.
Topics: Biogenic Amines; Histamine; Food Microbiology; Putrescine; DNA Damage
PubMed: 37783126
DOI: 10.1016/j.foodchem.2023.137558 -
The Journal of Biological Chemistry Aug 2023Polyamines are positively charged alkylamines ubiquitous among eukaryotes, prokaryotes, and archaea. Humans obtain polyamines through dietary intake, metabolic...
Polyamines are positively charged alkylamines ubiquitous among eukaryotes, prokaryotes, and archaea. Humans obtain polyamines through dietary intake, metabolic production, or uptake of polyamines made by gut microbes. The polyamine biosynthetic pathway used by most gut microbes differs from that used by human cells. This alternative pathway employs carboxyspermidine dehydrogenase (CASDH), an enzyme with limited characterization. Here, we solved a 1.94 Å X-ray crystal structure of Bacteroides fragilis CASDH by molecular replacement. BfCASDH is composed of three domains with a fold similar to saccharopine dehydrogenase but with a distinct active site arrangement. Using steady-state methods, we determined k and k/K for BfCASDH and Clostridium leptum CASDH using putrescine, diaminopropane, aspartate semi-aldehyde, NADH, and NADPH as substrates. These data revealed evidence of cooperativity in BfCASDH. Putrescine is the likely polyamine substrate and NADPH is the coenzyme used to complete the reaction, forming carboxyspermidine as a product. These data provide the first kinetic characterization of CASDH-a key enzyme in the production of microbial polyamines.
Topics: Humans; NADP; Oxidoreductases; Polyamines; Putrescine; Spermidine; Bacteroides fragilis
PubMed: 37437886
DOI: 10.1016/j.jbc.2023.105033 -
European Journal of Nuclear Medicine... Feb 2024This study aimed to quantitatively assess [Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs in prostate cancer using the total-body [Ga]Ga-PSMA-11 PET/CT...
Assessing dynamic metabolic heterogeneity in prostate cancer patients via total-body [Ga]Ga-PSMA-11 PET/CT imaging: quantitative analysis of [Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs.
PURPOSE
This study aimed to quantitatively assess [Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs in prostate cancer using the total-body [Ga]Ga-PSMA-11 PET/CT and to characterize the dynamic metabolic heterogeneity of prostate cancer.
METHODS
Dynamic total-body [Ga]Ga-PSMA-11 PET/CT scans were performed on ten prostate cancer patients. Manual delineation of volume-of-interests (VOIs) was performed on multiple normal organs displaying high [Ga]Ga-PSMA-11 uptake, as well as pathological lesions. Time-to-activity curves (TACs) were generated, and the four compartment models including one-tissue compartmental model (1T1k), reversible one-tissue compartmental model (1T2k), irreversible two-tissue compartment model (2T3k) and reversible two-tissue compartmental model (2T4k) were fitted to each tissue TAC. Various rate constants, including K (forward transport rate from plasma to the reversible compartment), k (reverse transport rate from the reversible compartment to plasma), k (tracer binding on the PSMA-receptor and its internalization), k (the externalization rate of the tracer) and K (net influx rate), were obtained. The selection of the optimal model for describing the uptake of both lesions and normal organs was determined using the Akaike information criteria (AIC). Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for differentiating physiological and pathological [Ga]Ga-PSMA-11 uptake.
RESULTS
Both 1T1k and 1T2k models showed relatively high AIC values compared to the 2T3k and 2T4k models in both pathological lesions and normal organs. The kinetic behavior of pathological lesions was better described by the 2T3k model compared to the 2T4k model, while the normal organs were better described by the 2T4k model. Significant variations in kinetic metrics, such as K, k, and k, and K, were observed among normal organs with high [Ga]Ga-PSMA-11 uptake and pathological lesions. The high K value in normal organs was primarily determined by elevated K and low k, rather than k. Conversely, the high K value in pathological lesions, ranking second to the kidney and similar to salivary glands and spleen, was predominantly determined by the highest k value. Notably, k exhibited the highest performance in distinguishing between physiological and pathological [Ga]Ga-PSMA-11 uptake, with an area under the curve (AUC) of 0.844 (95% CI, 0.773-0.915), sensitivity of 82.9%, and specificity of 74.1%. The k values showed better performance than SUVmean (AUC, 0.659), SUVmax (AUC, 0.637), and other kinetic parameter including K (AUC, 0.604), k (AUC, 0.634), and K (AUC, 0.651).
CONCLUSIONS
Significant discrepancies in kinetic metrics were detected between pathological lesions and normal organs, despite their shared high uptake of [Ga]Ga-PSMA-11. Notably, the k value exhibits a noteworthy capability to distinguish between pathological lesions and normal organs with elevated [Ga]Ga-PSMA-11 uptake. This discovery implies that k holds promise as a prospective imaging biomarker for distinguishing between pathologic and non-specific [Ga]Ga-PSMA-11 uptake in patients with prostate cancer.
Topics: Male; Humans; Gallium Radioisotopes; Positron Emission Tomography Computed Tomography; Prospective Studies; Prostatic Neoplasms; Edetic Acid
PubMed: 37889299
DOI: 10.1007/s00259-023-06475-y -
Food Chemistry Mar 2024Meat freshness is related to food safety and human health. Developing a simple and effective method for on-site detection of meat freshness is essential to ensure food...
Meat freshness is related to food safety and human health. Developing a simple and effective method for on-site detection of meat freshness is essential to ensure food safety. This study aimed to explore a ratiometric fluorescence platform for on-site screening of meat freshness. We synthesized a series of benzothiazole-based fluorescent compounds (BM, BHM and BTH), each with different recognition groups for detecting meat freshness biomarkers cadaverine (Cad) and putrescine (Pte). The optimized 2-(2'-hydroxyphenyl-3-aldehyde-5-1,3-indanedione) benzothiazole (BTH) demonstrated a noticeable color and fluorescence change, a fast response (<15 min), and high selectivity and sensitivity (LOD = 70 nM) to Cad. Portable test strips based on BTH were prepared for rapid visual detection of meat freshness, which exhibited visible color and fluorescen color changes to Cad and Pte. Furthermore, a portable smartphone-based fluorescence device integrated with a self-programmed Python program was fabricated and used on-site to monitor Cad and Pte within 5 min. The BTH-loaded portable test strips were successfully employed as low-cost, high-contrast, fast-response, and smartphone-adaptable fluorescent labels for detecting Cad and Pte in meat samples under different temperatures (25 °C, 4 °C, and -20 °C). This enabled consumers and food supply chain stakeholders to quickly and visually monitor the meat freshness in real beef, chicken, and pork products.
Topics: Animals; Cattle; Humans; Fluorescence; Meat; Food Safety; Cadaverine; Putrescine; Coloring Agents; Benzothiazoles
PubMed: 37862987
DOI: 10.1016/j.foodchem.2023.137769 -
Microscopy Research and Technique Apr 2024The aim of the study was to evaluate the structural and chemical changes in intracanal dentin after root canal irrigation with sodium hypochlorite (NaOCl) and...
Effect of sodium hypochlorite and ethylenediaminotetraacetic acid activated by laser and ultrasonic energy on surface morphology and chemical composition of intracanal dentin.
The aim of the study was to evaluate the structural and chemical changes in intracanal dentin after root canal irrigation with sodium hypochlorite (NaOCl) and ethylenediaminetetraacetic acid (EDTA) using additional activation with a novel Er:YAG Shock Wave-Enhanced Emission Photoacoustic Streaming (SWEEPS), ultrasonic irrigation (UI), and Nd:YAG irradiation. Root canals of extracted human premolars were instrumented with distilled water and distributed into groups according to the irrigation protocol used: Group 1: conventional needle irrigation (CI) with 3% NaOCl; group 2: CI with 15% EDTA; and group 3: CI with NaOCl+EDTA. In group 4, root canals were irrigated with NaOCl+EDTA+NaOCl using the following techniques: CI (group 4A), SWEEPS (group 4B), UI (group 4C). In group 4D, root canals were finally irradiated with Nd:YAG laser. After the irrigation, the intracanal dentin sample was collected and analyzed using spectroscope with a Fourier transformation of infrared spectrum in Attenuated total reflection technique (FTIR-ATR) to calculate apatite/collagen ratio. Scanning electron microscopy (SEM) and energy dispersive x-ray spectrometry (EDS) were used to determine its chemical composition. FTIR-ATR showed no significant difference in the phosphate/amid I ratio between the control and the experimental groups (p > 0.05). SWEEPS and UI of NaOCl+EDTA+NaOCl caused the most pronounced decrease of Ca and P (p < 0.05) value compared to CI and control group, and canal wall erosion. SWEEPS and UI of NaOCl+EDTA+NaOCl caused the most pronounced decrease of Ca and P value and significant canal wall erosion. However, no difference in phosphate/amide ratio was reported among groups. RESEARCH HIGHLIGHTS: SWEEPS and UI of NaOCl+EDTA+NaOCl caused the most pronounced decrease of Ca and P values and significant canal wall erosion. There was no difference in phosphate/amide ratio among the irrigation protocols.
Topics: Humans; Sodium Hypochlorite; Ultrasonics; Edetic Acid; Lasers; Amides; Phosphates; Dentin
PubMed: 38100184
DOI: 10.1002/jemt.24474