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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 -
Astrobiology Mar 2020The molecules feeding life's emergence are thought to have been provided through the hydrothermal interactions of convecting carbonic ocean waters with minerals...
The molecules feeding life's emergence are thought to have been provided through the hydrothermal interactions of convecting carbonic ocean waters with minerals comprising the early Hadean oceanic crust. Few laboratory experiments have simulated ancient hydrothermal conditions to test this conjecture. We used the JPL hydrothermal flow reactor to investigate CO reduction in simulated ancient alkaline convective systems over 3 days (T = 120°C, = 100 bar, pH = 11). H-rich hydrothermal simulant and CO-rich ocean simulant solutions were periodically driven in 4-h cycles through synthetic mafic and ultramafic substrates and Fe>Ni sulfides. The resulting reductants included micromoles of HS and formate accompanied possibly by micromoles of acetate and intermittent minor bursts of methane as ascertained by isotopic labeling. The formate concentrations directly correlated with the CO input as well as with millimoles of Mg ions, whereas the acetate did not. Also, tens of micromoles of methane were drawn continuously from the reactor materials during what appeared to be the onset of serpentinization. These results support the hypothesis that formate may have been delivered directly to a branch of an emerging acetyl coenzyme-A pathway, thus obviating the need for the very first hydrogenation of CO to be made in a hydrothermal mound. Another feed to early metabolism could have been methane, likely mostly leached from primary CH present in the original Hadean crust or emanating from the mantle. That a small volume of methane was produced sporadically from the CO-feed, perhaps from transient occlusions, echoes the mixed results and interpretations from other laboratories. As serpentinization and hydrothermal leaching can occur wherever an ocean convects within anhydrous olivine- and sulfide-rich crust, these results may be generalized to other wet rocky planets and moons in our solar system and beyond.
Topics: Acetyl Coenzyme A; Carbon Dioxide; Earth, Planet; Hydrogen; Hydrothermal Vents; Iron Compounds; Magnesium Compounds; Methane; Oceans and Seas; Origin of Life; Seawater; Silicates
PubMed: 32125196
DOI: 10.1089/ast.2018.1949 -
Radiology May 2022Background Data on the long-term pulmonary sequelae in COVID-19 are lacking. Purpose To assess symptoms, functional impairment, and residual pulmonary abnormalities on... (Observational Study)
Observational Study
Background Data on the long-term pulmonary sequelae in COVID-19 are lacking. Purpose To assess symptoms, functional impairment, and residual pulmonary abnormalities on serial chest CT scans in COVID-19 survivors discharged from hospital at up to 1-year follow-up. Materials and Methods Adult patients with COVID-19 discharged between March 2020 and June 2020 were prospectively evaluated at 3 months and 1 year through systematic assessment of symptoms, functional impairment, and thoracic CT scans as part of the PHENOTYPE study, an observational cohort study in COVID-19 survivors. Lung function testing was limited to participants with CT abnormalities and/or persistent breathlessness. Bonferroni correction was used. Results Eighty participants (mean age, 59 years ± 13 [SD]; 53 men) were assessed. At outpatient review, persistent breathlessness was reported in 37 of the 80 participants (46%) and cough was reported in 17 (21%). CT scans in 73 participants after discharge (median, 105 days; IQR, 95-141 days) revealed persistent abnormalities in 41 participants (56%), with ground-glass opacification (35 of 73 participants [48%]) and bands (27 of 73 participants [37%]) predominating. Unequivocal signs indicative of established fibrosis (ie, volume loss and/or traction bronchiectasis) were present in nine of 73 participants (12%). Higher admission serum C-reactive protein (in milligrams per liter), fibrinogen (in grams per deciliter), urea (millimoles per liter), and creatinine (micromoles per liter) levels; longer hospital stay (in days); older age (in years); and requirement for invasive ventilation were associated with CT abnormalities at 3-month follow-up. Thirty-two of 41 participants (78%) with abnormal findings at 3-month follow-up CT underwent repeat imaging at a median of 364 days (range, 360-366 days), with 26 (81%) showing further radiologic improvement (median, 18%; IQR, 10%-40%). Conclusion CT abnormalities were common at 3 months after COVID-19 but with signs of fibrosis in a minority. More severe acute disease was linked with CT abnormalities at 3 months. However, radiologic improvement was seen in the majority at 1-year follow-up. ClinicalTrials.gov identifier: NCT04459351. © RSNA, 2022
Topics: COVID-19; Dyspnea; Fibrosis; Hospitals; Humans; Lung; Patient Discharge; Tomography, X-Ray Computed
PubMed: 34609195
DOI: 10.1148/radiol.2021211746 -
Veterinary Medicine and Science Mar 2022The condition of footpad is an important aspect of poultry welfare. This is a problem that plagues the poultry industry because it occurs whether birds are reared in the...
BACKGROUND/AIM
The condition of footpad is an important aspect of poultry welfare. This is a problem that plagues the poultry industry because it occurs whether birds are reared in the cage or on the floor. It is reported that feeding phytase to floor-reared broiler chicks could ameliorate footpad lesions, which is related to the reduction of litter moisture. However, some studies reported that phytase supplementation could ameliorate footpad lesions, but did not affect litter quality. Therefore, phytase supplementation may have other potential mechanisms to improve the footpad lesions. Cage-reared broiler chicks were used in this study because they had no access to litter.
MATERIAL AND METHODS
A total of 234 1-day-old broiler chicks were randomly assigned to three groups based on the initial body weight (42.22 ± 0.18 g) with six replicate cages and 13 birds (mixed sex) per cage. The experimental period was 45 days. Dietary treatments were based on a corn-soybean meal-basal diet and supplemented with 500 and 750 FTU/kg Saccharomyces pombe expressed phytase. The unit of phytase (FTU) was defined as the amount of enzyme that catalyzes the release of one micromole phosphate from phytate per minute at 37°C and pH 5.5.
RESULT AND CONCLUSION
We found that dietary supplementation of S. pombe expressed phytase could improve calcium and phosphorus digestibility and subsequent improvement in toe ash, thus ameliorating footpad lesions in broiler chicks with no access to litter.
Topics: 6-Phytase; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Chickens; Saccharomyces
PubMed: 35218318
DOI: 10.1002/vms3.745 -
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 -
ACS Medicinal Chemistry Letters Aug 2021SARS-CoV-2 entry into host cells relies on the spike (S) protein binding to the human ACE2 receptor. In this study, we investigated the structural dynamics of the viral...
SARS-CoV-2 entry into host cells relies on the spike (S) protein binding to the human ACE2 receptor. In this study, we investigated the structural dynamics of the viral S protein at the fusion peptide (FP) domain and small molecule binding for therapeutics development. Following comparative modeling analysis and docking studies of our previously identified fusion inhibitor chlorcyclizine, we performed a pharmacophore-based virtual screen and identified two novel chemotypes of entry inhibitors targeting the FP. The compounds were evaluated in the pseudoparticle viral entry assay and SARS-CoV-2 cytopathic effect assay and showed single-digital micromole inhibition against SARS-CoV-2 as well as SARS-CoV-1 and MERS. The characterization of the FP binding site of SARS-CoV-2 S protein provides a promising target for the structure-based development of small molecule entry inhibitors as drug candidates for the treatment of COVID-19.
PubMed: 34394844
DOI: 10.1021/acsmedchemlett.1c00263 -
RSC Advances Mar 2023Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1'-spiro-pyridine...
Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1'-spiro-pyridine derivatives were designed and synthesized based on an -(ethyl benzoate) moiety. The structure of the designed derivatives was confirmed by different spectroscopic techniques (FT-IR and NMR) and elemental analysis and then evaluated as antiproliferative against HepG-2 and Caco-2 cell lines compared with Doxorubicin. The spiro-pyridine derivatives 5, 7, and 8 exhibited a remarkably higher activity against Caco-2 cell lines than that of other derivatives. Additionally, these derivatives exhibited activation in the Bax and suppressed Bcl-2 expression with variable degrees. Interestingly, compound 7 showed the lowest cytotoxicity value on Caco-2 cells (IC = 7.83 ± 0.50 μM) compared with Doxorubicin (IC = 12.49 ± 1.10 μM). Additionally, this compound showed activation of the Bax gene (7.508-fold) and suppressed Bcl-2 (0.194-fold) compared to untreated Caco-2 cells, as revealed by the qRT-PCR technique. Moreover, compound 7 could inhibit EGFR and VEGFR-2 with sub-micromole values of 0.124 μM and 0.221 μM compared with Erlotinib (IC = 0.033 μM) and Sorafenib (IC = 0.043 μM), respectively. Further, cell cycle and apoptosis analysis demonstrated that compound 7 promoted apoptosis by increasing the apoptosis rate from 1.92 to 42.35% and the S cell accumulation ratio from 31.18 to 42.07% compared to untreated Caco-2 cells. Finally, the most active compound 7 showed good drug-likeness and toxicity profiles. Besides, molecular docking studies were performed to determine the binding mode, which is in agreement with the results.
PubMed: 37020892
DOI: 10.1039/d3ra00887h -
Pakistan Journal of Biological Sciences... Jan 2024<b>Background and Objective:</b> Diabetic foot ulcer (DFU) is a well-recognized vascular complication of uncontrolled diabetes mellitus. Unless immediate...
<b>Background and Objective:</b> Diabetic foot ulcer (DFU) is a well-recognized vascular complication of uncontrolled diabetes mellitus. Unless immediate measures are taken some patients end up with amputation. The hallmarks of DFU are hyperglycemia, neuropathy, ischemia and infection (Andrew). Recent studies confirmed the role of low serum arginine in the development of foot ulcer in diabetic patients. The current study aimed to investigate the relationship between low serum magnesium and diabetic foot ulcer and to identify the incidence of low plasma arginine levels in diabetic patients with DFU in Sudan. <b>Materials and Methods:</b> A total of 120 subjects were recruited in this study and were divided into three groups, namely, diabetic with foot ulcer (group-I), diabetic without foot ulcer (group-II) and non-diabetic healthy subjects (group-III). These subjects were investigated for FBS, HbA1c and serum arginine. Data were analysed using SPSS (28th release). <b>Results:</b> Analysis of the results obtained showed significantly marked reduced plasma arginine levels in group I than the other two groups where mean plasma arginine level was 12.08, 49.25 and 94.1 micromole/L, respectively. There was no statistical difference between the duration of diabetes and DFU in diabetic patients with DFU and diabetic patients without DFU, as well as levels of HbA1c (p-value 0.457, 0.89) respectively. <b>Conclusion:</b> The low serum arginine levels were significantly associated with foot ulcers in diabetic patients and play an important role in the development of diabetic foot ulcers.
Topics: Humans; Diabetic Foot; Glycated Hemoglobin; Hyperglycemia; Amputation, Surgical; Incidence; Risk Factors; Diabetes Mellitus
PubMed: 38413397
DOI: 10.3923/pjbs.2024.46.51 -
Obstetrics and Gynecology Dec 2020To evaluate differences between fasting and nonfasting bile acid levels in asymptomatic and symptomatic pregnant women. (Comparative Study)
Comparative Study
OBJECTIVE
To evaluate differences between fasting and nonfasting bile acid levels in asymptomatic and symptomatic pregnant women.
METHODS
This is a report of two prospective cohort studies describing bile acid levels in the fasting and nonfasting state in pregnancy. The first cohort included asymptomatic women with singleton pregnancies. Women with a diagnosis of cholestasis, symptoms of cholestasis, or intolerance to components of a standardized meal were excluded. Bile acid levels were measured during the second and third trimesters after fasting and again 2 hours after a standardized meal. The second cohort included symptomatic women with singleton pregnancies in whom fasting and nonfasting bile acid levels were measured at the time of symptom evaluation. A cutoff of 10 micromoles/L was used for diagnosis.
RESULTS
A total of 27 women were included in the asymptomatic cohort. Median [interquartile range] fasting bile acid levels were significantly lower than nonfasting levels in both the second trimester (4.65 micromoles/L [1.02-29.57] vs 13.62 micromoles/L [2.03-40.26]; P<.001) and third trimester (8.31 micromoles/L [1.14-51.26] vs 17.35 micromoles/L [1.77-62.93]; P<.001). Bile acid levels exceeded 10 micromoles/L in 21% of the fasting samples and in 58% of the nonfasting samples in the third trimester. A total of 26 women were included in the symptomatic cohort. Median [interquartile range] fasting bile acid levels were significantly lower than nonfasting values (11.5 micromoles/L [7-56] vs 13.5 micromoles/L [9-142]; P<.001). Six patients in the symptomatic cohort (23%) had nonfasting bile acid levels greater than 10 micromoles/L that dropped below 10 micromoles/L when fasting.
CONCLUSION
Fasting bile acid levels are significantly lower when compared with nonfasting values in both asymptomatic and symptomatic pregnant women. In asymptomatic women, nonfasting bile acid levels often exceeded 10 micromoles/L whereas fasting values did not. In symptomatic women, fasting bile acid levels resulted in 23% fewer diagnoses of cholestasis when compared with nonfasting values. These findings suggest that fasting evaluation of bile acid levels or a higher threshold for diagnosis of cholestasis should be considered.
Topics: Adult; Bile Acids and Salts; Cholestasis, Intrahepatic; Fasting; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prospective Studies; Young Adult
PubMed: 33156200
DOI: 10.1097/AOG.0000000000004160 -
Aging Jul 2021Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical...
Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.
Topics: Animals; Antinematodal Agents; Antineoplastic Agents; Apoptosis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cisplatin; Drug Repositioning; Drug Resistance, Neoplasm; Female; Humans; Mebendazole; Mice; Mice, Nude; Ovarian Neoplasms; Signal Transduction; Tumor Stem Cell Assay; Wound Healing; Xenograft Model Antitumor Assays
PubMed: 34232919
DOI: 10.18632/aging.203232