-
ACS Synthetic Biology May 2024spp. are "nature's antibiotic factories" that produce valuable bioactive metabolites, such as the cytotoxic anthracycline polyketides. While the anthracyclines have...
spp. are "nature's antibiotic factories" that produce valuable bioactive metabolites, such as the cytotoxic anthracycline polyketides. While the anthracyclines have hundreds of natural and chemically synthesized analogues, much of the chemical diversity stems from enzymatic modifications to the saccharide chains and, to a lesser extent, from alterations to the core scaffold. Previous work has resulted in the generation of a BioBricks synthetic biology toolbox in M1152Δ that could produce aklavinone, 9--aklavinone, auramycinone, and nogalamycinone. In this work, we extended the platform to generate oxidatively modified analogues two crucial strategies. (i) We swapped the ketoreductase and first-ring cyclase enzymes for the aromatase cyclase from the mithramycin biosynthetic pathway in our polyketide synthase (PKS) cassettes to generate 2-hydroxylated analogues. (ii) Next, we engineered several multioxygenase cassettes to catalyze 11-hydroxylation, 1-hydroxylation, 10-hydroxylation, 10-decarboxylation, and 4-hydroxyl regioisomerization. We also developed improved plasmid vectors and M1152Δ expression hosts to produce anthracyclinones. This work sets the stage for the combinatorial biosynthesis of bespoke anthracyclines using recombinant hosts.
Topics: Polyketide Synthases; Anthracyclines; Streptomyces coelicolor; Streptomyces; Biosynthetic Pathways; Hydroxylation; Anti-Bacterial Agents
PubMed: 38662967
DOI: 10.1021/acssynbio.4c00043 -
PloS One 2024With aging, men develop testosterone-deficiency syndrome (TDS). The development is closely associated with age-related mitochondrial dysfunction of Leydig cell and...
Ameliorative effects of elderberry (Sambucus nigra L.) extract and extract-derived monosaccharide-amino acid on H2O2-induced decrease in testosterone-deficiency syndrome in a TM3 Leydig cell.
With aging, men develop testosterone-deficiency syndrome (TDS). The development is closely associated with age-related mitochondrial dysfunction of Leydig cell and oxidative stress-induced reactive oxygen species (ROS). Testosterone-replacement therapy (TRT) is used to improve the symptoms of TDS. However, due to its various side effects, research on functional ingredients derived from natural products that do not have side effects is urgently needed. In this study, using the mitochondrial dysfunction TM3 (mouse Leydig) cells, in which testosterone biosynthesis is reduced by H2O2, we evaluated the effects of elderberry extract and monosaccharide-amino acid (fructose-leucine; FL) on mRNA and protein levels related to steroidogenesis-related enzymes steroidogenic acute regulatory protein (StAR), cytochrome P450 11A1(CYP11A1, cytochrome P450 17A1(CYP17A1), cytochrome P450 19A1(CYP19A1, aromatase), 3β-hydroxysteroid dehydrogenase (3β-HSD), and 17β-hydroxysteroid dehydrogenase(17β-HSD). We analyzed elderberry extract and extract-derived FL for changes in ROS scavenging activity and testosterone secretion. Elderberry extract and FL significantly reduced H2O2-induced intracellular ROS levels, improved testosterone secretion, and increased the mRNA and protein expression levels of steroidogenesis-related enzymes (StAR, 3b-HSD, 17b-HSD, CYP11A1, CYp17A1). However, the conversion of testosterone to estradiol was inhibited by elderberry extract and extract-derived FL, which reduced the mRNA and protein expression of CYP19A1. In conclusion, elderberry extract and FL are predicted to have value as novel functional ingredients that may contribute to the prevention of TDS by ameliorating reduced steroidogenesis.
Topics: Animals; Leydig Cells; Mice; Hydrogen Peroxide; Plant Extracts; Testosterone; Male; Cell Line; Amino Acids; Monosaccharides; Sambucus; Reactive Oxygen Species; Oxidative Stress; Phosphoproteins
PubMed: 38662754
DOI: 10.1371/journal.pone.0302403 -
Surgical Case Reports Apr 2024Letrozole, an aromatase inhibitor, is used to treat breast cancer in postmenopausal women. Tumor lysis syndrome (TLS) is a complication that can trigger multiple organ...
BACKGROUND
Letrozole, an aromatase inhibitor, is used to treat breast cancer in postmenopausal women. Tumor lysis syndrome (TLS) is a complication that can trigger multiple organ failure caused by the release of intracellular nucleic acids, phosphate, and potassium into the blood due to rapid tumor cell disintegration induced by drug therapy. TLS is uncommon in solid tumors and occurs primarily in patients receiving chemotherapy. Herein, we report a rare occurrence of TLS that developed in a patient with locally advanced breast cancer following treatment with letrozole.
CASE PRESENTATION
An 80-year-old woman with increased bleeding from a fist-sized left-sided breast mass presented to our hospital. Histological examination led to a diagnosis of invasive ductal carcinoma of the luminal type. The patient refused chemotherapy and was administered hormonal therapy with letrozole. Seven days after letrozole initiation, she complained of anorexia and diarrhea. Blood test results revealed elevated blood urea nitrogen (BUN) and creatinine (Cr) levels, and she was admitted to our hospital for intravenous infusions. On the second day after admission, marked elevations of LDH, BUN, Cr, potassium, calcium, and uric acid levels were observed. Furthermore, metabolic acidosis and prolonged coagulation capacity were observed. We suspected TLS and discontinued letrozole, and the patient was treated with hydration, febuxostat, and maintenance hemodialysis. On the third day after admission, her respiratory status worsened because of acute respiratory distress syndrome associated with hypercytokinemia, and she was intubated. On the fourth day after admission, her general condition did not improve, and she died.
CONCLUSIONS
Although TLS typically occurs after chemotherapy initiation, the findings from the present case confirm that this syndrome can also occur after hormonal therapy initiation and should be treated with caution.
PubMed: 38656713
DOI: 10.1186/s40792-024-01901-1 -
Marine Biotechnology (New York, N.Y.) Jun 2024This study is the first investigation for using sex-related gene expression in tail fin tissues of seabass as early sex determination without killing the fish. The...
A Novel Investigation for Early Sex Determination in Alive Adult European Seabass (Dicentrarchus labrax) Using cyp19a1a, dmrt1a, and dmrt1b Genes Expression in Tail Fin tissues.
This study is the first investigation for using sex-related gene expression in tail fin tissues of seabass as early sex determination without killing the fish. The European seabass (Dicentrarchus labrax) is gonochoristic and lacks distinguishable sex chromosomes, so, sex determination is referred to molecular actions for some sex-related genes on autosomal chromosomes which are well known such as cyp19a1a, dmrt1a, and dmrt1b genes which play crucial role in gonads development and sex differentiation. cyp19a1a is expressed highly in females for ovarian development and dmrt1a and dmrt1b are for testis development in males. In this study, we evaluated the difference in the gene expression levels of studied genes by qPCR in tail fins and gonads. We then performed discriminant analysis (DA) using morphometric traits and studied gene expression parameters as predictor tools for fish sex. The results revealed that cyp19a1a gene expression was significantly higher in future females' gonads and tail fins (p ≥ 0.05). Statistically, cyp19a1a gene expression was the best parameter to discriminate sex even the hit rate of any other variable by itself could not correctly classify 100% of the fish sex except when it was used in combination with cyp19a1a. In contrast, Dmrt1a gene expression was higher in males than females but there were difficulties in analyzing dmrt1a and dmrt1b expressions in the tail because levels were low. So, it could be used in future research to differentiate and determine the sex of adult fish using the cyp19a1a gene expression marker without killing or sacrificing fish.
Topics: Animals; Bass; Male; Female; Animal Fins; Aromatase; Transcription Factors; Sex Determination Processes; Fish Proteins; Ovary; Gonads; Gene Expression Regulation, Developmental; Sex Differentiation
PubMed: 38649627
DOI: 10.1007/s10126-024-10313-z -
Breast Cancer Research and Treatment Jul 2024The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking.
METHODS
Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC-MS/MS method established in our laboratory.
RESULTS
Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women.
CONCLUSION
To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane.
Topics: Humans; Letrozole; Female; Androstadienes; Breast Neoplasms; Nitriles; Middle Aged; Neoadjuvant Therapy; Aged; Triazoles; Aromatase Inhibitors; Estrogens; Cross-Over Studies; Estradiol; Postmenopause; Adult; Treatment Outcome; Antineoplastic Agents; Aged, 80 and over
PubMed: 38649619
DOI: 10.1007/s10549-024-07313-x -
The Journal of Reproduction and... Jun 2024Metabolic stress and subsequent hepatic dysfunction in high-producing dairy cows are associated with inflammatory diseases and declining fertility. Lipopolysaccharide...
Metabolic stress and subsequent hepatic dysfunction in high-producing dairy cows are associated with inflammatory diseases and declining fertility. Lipopolysaccharide (LPS)-binding protein (LBP) is produced by hepatocytes and controls the immune response, suggesting that it is involved in the pathophysiology of inflammation-related attenuation of reproductive functions during metabolic stress. This study investigated the effect of LBP on the inflammatory status, oocyte quality, and steroidogenesis in the follicular microenvironment of dairy cows. Using bovine ovaries obtained from a slaughterhouse, follicular fluid and granulosa cells were collected from large follicles to evaluate the follicular status of metabolism, inflammation, and steroidogenesis. Cumulus-oocyte complexes were aspirated from small follicles and subjected to in vitro embryo production. The results showed that follicular fluid LBP concentrations were significantly higher in cows with fatty livers and hepatitis than in those with healthy livers. Follicular fluid LBP and LPS concentrations were negatively correlated, whereas LPS concentration showed a positive correlation with the concentrations of non-esterified fatty acids (NEFA) and β-hydroxybutyric acid in follicular fluid. The blastulation rate of oocytes after in vitro fertilization was impaired in cows in which coexisting large follicles had high NEFA levels. Follicular fluid NEFA concentration was negatively correlated with granulosa cell expression of the estradiol (E) synthesis-related gene (CYP19A1). Follicular fluid LBP concentration was positively correlated with follicular fluid E concentration and granulosa cell CYP19A1 expression. In conclusion, follicular fluid LBP may be associated with favorable conditions in the follicular microenvironment, including low LPS levels and high E production by granulosa cells.
Topics: Animals; Female; Follicular Fluid; Cattle; Granulosa Cells; Acute-Phase Proteins; Carrier Proteins; Ovarian Follicle; Membrane Glycoproteins; Inflammation; Lipopolysaccharides; Oocytes; Estradiol; Fertilization in Vitro; Fatty Acids, Nonesterified; Cattle Diseases; Aromatase
PubMed: 38644218
DOI: 10.1262/jrd.2023-104 -
Breast Cancer (Tokyo, Japan) Jul 2024A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer... (Observational Study)
Observational Study
Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study.
BACKGROUND
A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2- ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice.
METHODS
Real-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2- ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival.
RESULTS
Of the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9-29.4) for first-line and 14.5 months (10.2-19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1-87.7), 82.0% (70.7-89.3), and 66.0% (57.9-72.9), respectively.
CONCLUSION
The addition of palbociclib to ET was effective for treating HR+/HER2- ABC in Japanese routine clinical practice.
Topics: Humans; Female; Piperazines; Breast Neoplasms; Pyridines; Receptor, ErbB-2; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Receptors, Progesterone; Progression-Free Survival; Japan; Receptors, Estrogen; Adult; Aromatase Inhibitors; Aged, 80 and over; East Asian People
PubMed: 38642245
DOI: 10.1007/s12282-024-01575-5 -
Medicine Apr 2024Several studies have revealed the risk factors for carpal tunnel syndrome (CTS). However, no studies have evaluated the influence of these risk factors on the selection...
Association of carpal tunnel syndrome risk factors with treatment modality selection focusing on corticosteroid injection and surgery: A nationwide population-based study.
Several studies have revealed the risk factors for carpal tunnel syndrome (CTS). However, no studies have evaluated the influence of these risk factors on the selection of treatment modalities for CTS. This study aimed to determine the influence of CTS risk factors on the selection of CTS treatment modalities with a focus on corticosteroid injection (CI) and surgery. We conducted a retrospective cohort study of patients aged ≥20 years with newly diagnosed CTS in the Korean health insurance review and assessment service between 2010 and 2019. We evaluated the demographic information, the existence of CTS risk factors, and the applied treatment modalities for CTS, including CI and operation. The CTS risk factors include age, sex, diabetes mellitus, osteoarthritis of the hand or wrist, rheumatoid arthritis, hypothyroidism, gout, chronic kidney disease (CKD) on dialysis, antiestrogen or aromatase inhibitor medication, and a history of distal radius fracture (DRF). Multivariable logistic regression analyses were conducted. Age over 80 years was the most significantly associated factor for the selection of CI in CTS (odd ratio [OR], 2.149; 95% confidence interval [CI], 2.092 to 2.209; P < .001). Among underlying diseases or medications, CKD on dialysis (OR, 4.001; 95% CI, 3.819-4.193; P < .001) was the most significant associated factor for the selection of operation for CTS, followed by a history of DRF (OR, 1.803; 95% CI, 1.749-1.860; P < .001). Old age was the most significantly related factor for selecting CI. Among underlying diseases or medications, CKD on dialysis and the history of DRF were the most significantly related factors for selecting operative treatment. For these patients, clinicians should proactively consider an operation to reduce the long-term discomfort and economic burdens.
Topics: Humans; Carpal Tunnel Syndrome; Retrospective Studies; Renal Dialysis; Risk Factors; Adrenal Cortex Hormones; Renal Insufficiency, Chronic
PubMed: 38640326
DOI: 10.1097/MD.0000000000037781 -
Journal of Chromatography. B,... May 2024A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase...
A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase inhibitor, and its main carbinol metabolite (CM) in support of murine pharmacokinetic studies. Using polarity switching, simultaneous ESI-MS measurement of letrozole and CM was achieved in positive and negative mode, respectively. The assay procedure involved a one-step protein precipitation and extraction of all analytes from mouse plasma requiring only 5 μL of sample. Separation was optimized on an Accucore aQ column with gradient elution at a flow rate of 0.4 mL/min in 5 min. Two calibration curves per day over four consecutive measurement days showed satisfactory linear responses (r > 0.99) over concentration ranges of 5-1000 ng/mL and 20-2000 ng/mL for letrozole and CM, respectively. No matrix effect was found, and the mean extraction recoveries were 103-108 % for letrozole and 99.8-107 % for CM. Precision and accuracy within a single run and over four consecutive measurement days were verified to be within acceptable limits. Application of the developed method to preclinical pharmacokinetic studies in mice receiving oral letrozole at a dose 1 or 10 mg/kg revealed that the systemic exposure to letrozole was dose-, formulation-, and strain-dependent. These findings may inform the future design of preclinical studies aimed at refining the pharmacological profile of this clinically important drug.
Topics: Animals; Letrozole; Mice; Tandem Mass Spectrometry; Aromatase Inhibitors; Chromatography, High Pressure Liquid; Nitriles; Triazoles; Reproducibility of Results; Linear Models; Limit of Detection; Female; Male
PubMed: 38636136
DOI: 10.1016/j.jchromb.2024.124106 -
PloS One 2024Aromatase inhibitors have positive impacts on the disease-free life of patients with breast cancer. However, their side effects, especially arthralgia, may be... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Aromatase inhibitors have positive impacts on the disease-free life of patients with breast cancer. However, their side effects, especially arthralgia, may be experienced by many patients. This study sought to assess the efficacy of Progressive Relaxation Exercises on the prevalent side effects of Aromatase Inhibitors in patients with breast cancer.
MATERIALS AND METHODS
This clinical trial was conducted with single-blind randomization at a physiotherapy department in a local hospital. Patients who received Aromatase Inhibitor were assigned at random to either the study or control group. The study group (n = 22) performed a Progressive Relaxation Exercises program four days a week for six weeks, while the control group (n = 22) received advice on relaxation for daily life. Data was collected before the intervention and after six weeks. The study's primary endpoint was the Brief Pain Inventory, which was used to measure pain severity. Secondary endpoints included assessments of quality of life and emotional status, which were measured using the Functional Assessment of Chronic Illness Therapy and Hospital Anxiety and Depression scales, respectively.
RESULTS
The study group exhibited a significant reduction in Pain Severity (p = 0.001) and Pain Interference (p = 0.012) sub-scores. Reduction in Pain Severity (p<0.001) and Patient Pain Experience (p = 0.003) sub-scores was also noted between the groups. Quality of Life and Emotional Status showed no significant variation both within and between the groups (p>0.05).
CONCLUSION
The study demonstrated that Progressive Relaxation Exercises caused a significant reduction in pain scores among Breast Cancer patients receiving Aromatase Inhibitors. While a decrease in pain during the 6-week period is valuable data, it is necessary to monitor the long-term effects of relaxation techniques.
Topics: Humans; Female; Aromatase Inhibitors; Breast Neoplasms; Relaxation Therapy; Autogenic Training; Quality of Life; Single-Blind Method; Treatment Outcome; Pain
PubMed: 38635763
DOI: 10.1371/journal.pone.0301020