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Acta Pharmaceutica Sinica. B Jan 2021This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4...
Design, synthesis, and biological evaluation of quinazolin-4(3)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy.
This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound showed its antitumor activity in breast cancer susceptibility gene 1/2 () wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.
PubMed: 33532187
DOI: 10.1016/j.apsb.2020.06.003 -
Physiological Research Dec 2020Obesity is characterized by chronic, low-grade systemic inflammation. Obesity may also be associated with chronic cough. The aim of this pilot study was to clarify...
Obesity is characterized by chronic, low-grade systemic inflammation. Obesity may also be associated with chronic cough. The aim of this pilot study was to clarify relation of cough reflex sensitivity and body mass index (BMI) in children with chronic cough. Altogether 41 children having symptoms of chronic cough were submitted to cough reflex sensitivity measurement. We assessed the relation of cough reflex sensitivity (CKR) due to BMI. Cough reflex sensitivity was defined as the lowest capsaicin concentration which evoked two (C2) or five (C5) coughs. Capsaicin aerosol in doubling concentrations (from 0.61 to 1250 micromol/l) was inhaled by a single breath method (KoKo DigiDoser; nSpire heath Inc, Louisville, CO, USA), modified by the addition of an inspiratory flow regulator valve (RIFR; nSpire heath Inc, Louisville, CO, USA). BMI was calculated. Pulmonary function was within normal range. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Children (22 boys and 19 girls, mean age 6.8 years) cough reflex sensitivity (median, with the Inter-Quartile Range) for C2 was 19.5 (73.4) micromol/l; for C5 it was 78.1 (605.5) micromol/l. We have noticed statistically significant relation of the cough reflex sensitivity (C5) and body mass index (P<0.0001); however, the effect size was small, R2=0.03. Increase of body mass index in one unit is associated with -34.959 micromol/l decrease of C5. We did not find a statistically significant relation between C2 and BMI (P=0.41). The median value of CKR (C2) in boys is not statistically significantly different than the median value of CKR (C2) in girls (P-value 0.5). The median value of CKR (C5) in boys is not statistically significantly different than the median value of CKR (C5) in girls (P-value 0.5). Increase of body mass index in children suffering from chronic cough relates to decrease of cough reflex sensitivity (C5 value).
Topics: Adolescent; Body Mass Index; Capsaicin; Child; Child, Preschool; Chronic Disease; Cough; Female; Humans; Hypersensitivity; Male; Pilot Projects; Reflex; Sensory System Agents
PubMed: 33471546
DOI: 10.33549/physiolres.934596 -
Physiological Research Dec 2020Individual studies have suggested the utility of fractional exhaled nitric oxide (FeNO) measurement in detecting cough-variant asthma and eosinophilic bronchitis in...
Individual studies have suggested the utility of fractional exhaled nitric oxide (FeNO) measurement in detecting cough-variant asthma and eosinophilic bronchitis in patients with chronic cough. The aim of this study was to clarify a correlation of cough reflex sensitivity and fractional exhaled nitric oxide in asthmatic children. 25 children with asthma and 15 controls were submitted to cough reflex sensitivity measurement - capsaicin aerosol in doubling concentrations (from 0.61 to 1250 micromol/l) was inhaled by a single breath method. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Fractional exhaled nitric oxide (FeNO) measurement was included. Asthmatic children' (11 boys and 14 girls, mean age 9+/-1 years) and control group (unconfirmed diagnosis of asthma) (6 boys and 9 girls, mean age 8+/-1 years) were included into the study. FeNO vs. C2 in asthma (Spearman´s rank correlation: -0.146, p=0.49); FENO vs. C5 in asthma (Spearman´s rank correlation: -0.777, p=0.71). We found that there is no correlation between cough reflex sensitivity and fractional exhaled nitric oxide either in children with asthma or in the control group.
Topics: Asthma; Child; Cough; Exhalation; Female; Humans; Hypersensitivity; Male; Nitric Oxide; ROC Curve; Reflex; Respiratory Function Tests
PubMed: 33471545
DOI: 10.33549/physiolres.934601 -
SLAS Discovery : Advancing Life... Jun 2021A key activity in small-molecule drug discovery is the characterization of compound-target interactions. Surface plasmon resonance (SPR) is a flexible technique for this...
A key activity in small-molecule drug discovery is the characterization of compound-target interactions. Surface plasmon resonance (SPR) is a flexible technique for this purpose, with a wide affinity range (micromoles to picomoles), low protein requirements, and the ability to characterize the kinetics of compound binding. However, a key requirement of SPR is the immobilization of the target protein to the surface of the sensor chip. The most commonly used immobilization techniques (covalent immobilization, streptavidin-biotin) are irreversible in nature, which can afford excellent baseline stability but impose limitations throughput for slowly dissociating compounds or unstable targets. Reversible immobilization (e.g., His-tag-Ni-NTA) is possible but typically precludes accurate quantification of slow dissociation kinetics due to baseline drift.Here we present our investigation of three immobilization strategies (dual-His-tagged target protein, His-tagged streptavidin, and switchavidin) that combine the robustness of irreversible immobilization with the flexibility of reversible immobilization. Each has its own advantages and limitations, and while a universal immobilization procedure remains to be found, these strategies add to the immobilization toolbox that enables previously out-of-scope applications. Such applications are highlighted in two examples that greatly increased throughput for the kinetic characterization of potent kinase inhibitors and kinetic profiling of covalent inhibitors.
Topics: Biosensing Techniques; Drug Discovery; Humans; Kinetics; Small Molecule Libraries; Surface Plasmon Resonance
PubMed: 33289457
DOI: 10.1177/2472555220975358 -
International Journal of Neonatal... Nov 2020Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase...
Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.
PubMed: 33202836
DOI: 10.3390/ijns6040089 -
Translational Andrology and Urology Aug 2020Renal cell carcinoma (RCC) is one of the most common malignant tumors in the world. Vitexin (apigenin-8-C-D-glucopyranoside), a bioactive compound isolated from a...
BACKGROUND
Renal cell carcinoma (RCC) is one of the most common malignant tumors in the world. Vitexin (apigenin-8-C-D-glucopyranoside), a bioactive compound isolated from a variety of plants, has multiple protective effects on human health. The purpose of this study was to investigate the role of vitexin in RC and the related molecular mechanism.
METHODS
Proliferation was tested with Cell Counting Kit-8 and Edu staining. Apoptosis was studied with flow cytometry. Immunofluorescent was applied to show LC3 spots. BALB/c nude mice bearing ACHN cells were established and immunohistochemical staining was applied to validate the in vivo effects of vitexin. All the effects and possible signaling pathways involved were validated with western blotting.
RESULTS
Seventy micromole of vitexin started to show significant effect on the growth of normal renal tubular epithelial cells (HK-2), so 0, 10, 20 and 40 µM of vitexin were used in later experiments. Vitexin inhibited growth and induced apoptosis of ACHN and OS-RC-2 cells in a dose-dependent manner, and promoted excessive autophagy by reducing p62 levels and increasing Beclin1 and LC3II levels. Western blotting revealed that vitexin significantly increased the phosphorylation levels of Adenosine Monophosphate Activated Protein Kinase (AMPK) and c-Jun N-terminal kinase (JNK) in ACHN and OS-RC-2 cells, while decreasing the phosphorylation levels of phosphatidylinositol 3-kinase/activates protein kinase/mammalian target of rapamycin (PI3K/AKT/mTOR). In BALB/c nude mice bearing ACHN cells, vitexin inhibited tumor growth, reduced Ki67 and increased caspase-3 levels in the tumor tissues.
CONCLUSIONS
The results indicated that the tumor suppressive role of vitexin in ACHN and OS-RC-2 cells involved AMPK/mTOR, PI3K/AKT/mTOR, and JNK pathways. Therefore, vitexin may be a promising drug for the treatment of RCC.
PubMed: 32944531
DOI: 10.21037/tau-20-1094 -
Kidney360 Nov 2020Hyperoxaluria is typically associated with excessive oxalate intake in the diet, decreased dietary calcium, hyperabsorption of oxalate, or increased endogenous... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hyperoxaluria is typically associated with excessive oxalate intake in the diet, decreased dietary calcium, hyperabsorption of oxalate, or increased endogenous production of oxalate. The disorder spectrum extends from recurrent kidney stones to ESKD. This clinical trial sought to evaluate the effectiveness of an acid stable oxalate decarboxylase (OxDC) to reduce urinary oxalate in healthy subjects on a high-oxalate diet.
METHODS
In this prospective, double-blind, randomized, placebo-controlled, crossover clinical trial, 33 healthy volunteers were randomized into two crossover sequences separated by a 2-day washout period. A controlled high-oxalate diet (750-800 mg oxalate, 500-550 mg calcium daily) was utilized, and six 24-hour urine collections were measured. Subjects were given approximately 1000 U (micromoles per minute per milligram) of OxDC or placebo with meals three times daily during the 4 days of treatment.
RESULTS
Urinary oxalate significantly decreased with OxDC treatment. The baseline corrected within-subject mean reduction in 24-hour urinary excretion (after OxDC dosing versus high-oxalate baseline preceding treatment) was 12.5 mg or 29% (<0.001). OxDC treatment was effective (>5% reduction) in 31 of 33 subjects (94%). Compared with placebo, OxDC produced a 24% reduction (<0.001) in 24-hour oxalate excretion. Other urinary parameters (creatinine, uric acid, citrate, magnesium, calcium) were not affected by OxDC. No serious adverse events and no product-related adverse events occurred.
CONCLUSIONS
An orally administered OxDC is capable of significantly reducing urinary oxalate levels in healthy volunteers on a high-oxalate diet without affecting creatinine clearance, urine creatinine, or other solutes related to supersaturation of calcium oxalate.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Evaluation of Nephure, and the Reduction of Dietary Oxalate, in Healthy Volunteers, NCT03661216.
Topics: Carboxy-Lyases; Cross-Over Studies; Humans; Kidney Calculi; Prospective Studies
PubMed: 35372879
DOI: 10.34067/KID.0001522020 -
Materials (Basel, Switzerland) Aug 2020This article explores the effect of the synthetic method of titanium dioxide (TiO)/C composites (physical mixture and the water-assisted/unassisted sol-gel method) on...
This article explores the effect of the synthetic method of titanium dioxide (TiO)/C composites (physical mixture and the water-assisted/unassisted sol-gel method) on their photocatalytic activity for hydrogen production through glycerol photoreforming. The article demonstrates that, apart from a high surface area of carbon and the previous activation of its surface to favor titania incorporation, the appropriate control of titania formation is crucial. In this sense, even though the amount of incorporated titania was limited by the saturation of carbon surface groups (in our case, ca. 10 wt.% TiO), the sol-gel process without water addition seemed to be the best method, ensuring the formation of small homogeneously-distributed anatase crystals on mesoporous carbon. In this way, a ca. 110-fold increase in catalyst activity compared to Evonik P25 (expressed as hydrogen micromole per grams of titania) was achieved.
PubMed: 32872129
DOI: 10.3390/ma13173800 -
PloS One 2020Solid phase peptide synthesis (SPPS) has enabled widespread use of synthetic peptides in applications ranging from pharmaceuticals to materials science. The demand for...
Solid phase peptide synthesis (SPPS) has enabled widespread use of synthetic peptides in applications ranging from pharmaceuticals to materials science. The demand for synthetic peptides has driven recent efforts to produce automated SPPS synthesizers which utilize fluid-handling components common to chemistry laboratories to drive costs down to several thousand dollars. Herein, we describe the design and validation of a more 'frugal' SPPS synthesizer that uses inexpensive, consumer-grade fluid-handling components to achieve a prototype price point between US$300 and $600. We demonstrated functionality by preparing and characterizing peptides with a variety of distinct properties including binding functionality, nanoscale self-assembly, and oxidation-induced fluorescence. This system yielded micromoles of peptide at a cost of approximately $1/residue, a cost which may be further reduced by optimization and bulk purchasing.
Topics: Amino Acid Sequence; Automation; Cell-Penetrating Peptides; Equipment Design; Fluorometry; Nanostructures; Oxidation-Reduction; Peptides; Solid-Phase Synthesis Techniques
PubMed: 32813720
DOI: 10.1371/journal.pone.0237473 -
Pakistan Journal of Medical Sciences 2020To analyse the frequency, co morbidities and outcome ofAcute Kidney Injury (AKI) in elderly patients.
OBJECTIVES
To analyse the frequency, co morbidities and outcome ofAcute Kidney Injury (AKI) in elderly patients.
METHODS
This is an observational retrospective study performed in a secondary care Hospital located in Abu Dhabi. Study include adult patients admitted during 01 January 2018 till 31 December 2018. We uses KDIGO criteria of more than 26.5 micromol/L increase in serum creatinine within 48 hours or 1.5 times increase from baseline within seven days to define AKI. Patients were followed from admission till discharge from hospital either to Home, to other facility or death. Analysis was done on SPSS version 20.
RESULTS
Total admissions for age 60 and above were 880. AKI was observed in 71 patients (8.0%). Most common co-morbidity found was hypertension being observed in 85.9%. Renal recovery was observed in 70.4% out of whom complete recovery was seen in only 32.4% and rest shows partial recovery. Hemodialysis was required in 16.90% and death results in 22.5% of our study patients.
CONCLUSION
AKI is frequent among elderly admitted patients, commonest co- morbidity in these patients is hypertension. Outcome of AKI in elderly patients is poor with death in 22% of our patients.
PubMed: 32704264
DOI: 10.12669/pjms.36.5.2429