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Science Advances Jan 2024Photocatalytic water oxidation is a key half-reaction for various solar-to-fuel conversion systems but requires simultaneous water affinity and hole accumulation at the...
Photocatalytic water oxidation is a key half-reaction for various solar-to-fuel conversion systems but requires simultaneous water affinity and hole accumulation at the photocatalytic site. Here, we present the rational design and synthesis of an ionic-type covalent organic framework (COF) named tetraphenylporphyrin cobalt and cobalt bipyridine complex (CoTPP-CoBpy) COF, combining cobalt porphyrin and cobalt bipyridine building blocks as a photocatalyst for water oxidation. The good dispersibility of porous large-size (>2 micrometers) COF nanosheets (≈1.45 nanometers) facilitates local water collection; the ultrafast triplet-state charge transfer (1.8 picoseconds) and prolonged charge separation (1.2 nanoseconds) further contribute to the efficient accumulation of holes in the CoTPP moiety, leading to a photocatalytic dioxygen production rate of 7323 micromoles per gram per hour. Moreover, we have identified an end-on superoxide radical (O) intermediate at the active site of the CoTPP moiety and proposed an electron-intermediate cascade mechanism that elucidates the synergistic coupling of electron relay (S-T-T') and intermediate evolution during the photocatalytic process.
PubMed: 38232160
DOI: 10.1126/sciadv.adk8564 -
Cureus Apr 2023Background Placenta-mediated pregnancy complications (PMPCs) are a significant contributor to adverse maternal and fetal outcomes. Though the exact cause of the array of...
Background Placenta-mediated pregnancy complications (PMPCs) are a significant contributor to adverse maternal and fetal outcomes. Though the exact cause of the array of pregnancy-related vascular disorders is still unknown, increased maternal serum homocysteine (Hct) levels have been linked to the pathophysiology. Hyperhomocysteinemia (HHct) has been strongly linked with the risk of developing PMPCs such as preeclampsia (PE), fetal growth restriction (FGR), intrauterine fetal death (IUFD), preterm births and placental abruption. Methodology The present observational study was carried out on 810 low-risk antenatal women in their early second trimester (13-20 weeks gestation age) in the department of obstetrics and gynecology of a tertiary care rural hospital to identify the significance of abnormally raised maternal serum Hct level in developing PMPCs. Results Of the 810 participants studied, 224 (27.65%) had raised Hct levels whereas the rest of the 586 (72.35%) participants had normal Hct levels. The mean Hct level of raised homocysteine group (18.59 ± 2.46 micromol/L) was substantially raised than the normal Hct group (8.64 ± 3.1 micromol/L). It was observed that women with elevated serum Hct levels developed PMPCs significantly more than women with normal serum Hct levels (p-value <0.05). Among HHct subjects, 65.18% developed PE, 34.38% had FGR, 28.13% had a preterm delivery, 4.02% had abruptio placentae and 3.57% had IUFD. Conclusions The focus of the current study is on an easy and quick intervention such as assessing the often-ignored levels of Hct during pregnancy that can help predict and prevent PMPCs. It also highlights the necessity for well-thought-out large-scale studies and trials to further examine the phenomena, as pregnancy may be the only time when rural women will have the opportunity to receive advice and to be tested for HHct.
PubMed: 37187663
DOI: 10.7759/cureus.37461 -
European Journal of Medicinal Chemistry Nov 2021Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK...
Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK positive non-small cell lung cancer (NSCLC) naïve or resistant cells. In this work, we designed and synthesized a series of 2,4-pyrimidinediamine derivatives as dual ALK and HDAC inhibitors based on pharmacophore merged strategy. Among which, compound 10f displayed the most potent and balanced inhibitory activity against ALK (IC = 2.1 nM) and HDAC1 (IC = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALK (IC = 1.7 nM) as well as the Ceritinib-resistant ALK (IC = 0.4 nM) mutants. In antiproliferative activity assay, 10f exhibited impressive activity on ALK-addicted cancer cell lines at low micromole concentrations, which was comparable to that of Crizotinib and Ceritinib. Further flow cytometric analysis indicated that 10f could effectively induce cell death via cell apoptosis and cell cycle arrest. Taken together, these results suggested 10f would be a promising lead compound for the ALK-positive NSCLC treatment, especially the Ceritinib- or Crizotinib-resistant NSCLC.
Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diamines; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Molecular Dynamics Simulation; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship
PubMed: 34237620
DOI: 10.1016/j.ejmech.2021.113672 -
Biosensors & Bioelectronics Dec 2019A novel optical fiber glucose biosensor based on fluorescent carbon quantum dots (CQDs)-glucose oxidase (GOD)/cellulose acetate (CA) complex sensitive film was...
A novel optical fiber glucose biosensor based on fluorescent carbon quantum dots (CQDs)-glucose oxidase (GOD)/cellulose acetate (CA) complex sensitive film was fabricated, in which the dip-coating method was adopted to immobilize the CQDs-GOD/CA complex sensitive film onto the end face of the optical fiber. The surface morphology, microstructure and optical performances of the sensitive film were characterized by field emission scanning electron microscope (FESEM), atomic force microscope (AFM), Zeiss Axiovert 25 inverted microscope, Fourier transform infrared spectroscopy (FTIR), Ultraviolet-visible spectrophotometer and fluorescence spectrophotometer, respectively. The developed fiber-optic biosensor exhibits high sensitivity and repeatability for continuous online detection of low concentration glucose, allowing visualization of real-time glucose fluctuations over a period of time. The change ratios in fluorescence intensity of the biosensor are linear with glucose concentration in various ranges including micromole and nanomole levels, and the relationship between relative fluorescence intensity ratio and glucose concentration complies well with the modified Stern-Volmer equation in the range of 10-200 μmol/L with the detection limit of 6.43 μM, and in the range of 10-100 nmol/L with the detection limit of 25.79 nM, respectively.
Topics: Biosensing Techniques; Blood Glucose; Carbon; Cellulose; Equipment Design; Fiber Optic Technology; Fluorescence; Glucose Oxidase; Humans; Limit of Detection; Optical Fibers; Quantum Dots
PubMed: 31605987
DOI: 10.1016/j.bios.2019.111760 -
Cell Death & Disease Jul 2021An ultra-large structure-based virtual screening has discovered iKeap1 as a direct Keap1 inhibitor that can efficiently activate Nrf2 signaling. We here tested its...
An ultra-large structure-based virtual screening has discovered iKeap1 as a direct Keap1 inhibitor that can efficiently activate Nrf2 signaling. We here tested its potential effect against hydrogen peroxide (HO)-induced oxidative injury in osteoblasts. In primary murine and human osteoblasts, iKeap1 robustly activated Nrf2 signaling at micromole concentrations. iKeap1 disrupted Keap1-Nrf2 association, causing Nrf2 protein stabilization, cytosol accumulation and nuclear translocation in murine and human osteoblasts. The anti-oxidant response elements (ARE) activity and transcription of Nrf2-ARE-dependent genes (including HO1, NQO1 and GCLC) were increased as well. Significantly, iKeap1 pretreatment largely ameliorated HO-induced reactive oxygen species production, lipid peroxidation and DNA damage as well as cell apoptosis and programmed necrosis in osteoblasts. Moreover, dexamethasone- and nicotine-induced oxidative injury and apoptosis were alleviated by iKeap1. Importantly, Nrf2 shRNA or CRISPR/Cas9-induced Nrf2 knockout completely abolished iKeap1-induced osteoblast cytoprotection against HO. Conversely, CRISPR/Cas9-induced Keap1 knockout induced Nrf2 cascade activation and mimicked iKeap1-induced cytoprotective actions in murine osteoblasts. iKeap1 was ineffective against HO in the Keap1-knockout murine osteoblasts. Collectively, iKeap1 activated Nrf2 signaling cascade to inhibit HO-induced oxidative injury and death of osteoblasts.
Topics: Animals; Antioxidants; Apoptosis; Cells, Cultured; Humans; Hydrogen Peroxide; Kelch-Like ECH-Associated Protein 1; Lipid Peroxidation; NF-E2-Related Factor 2; Osteoblasts; Oxidative Stress; Signal Transduction
PubMed: 34226516
DOI: 10.1038/s41419-021-03962-8 -
Investigational New Drugs Oct 2021In order to fuel the uncontrolled cell proliferation and division, tumor cells reprogram the energy metabolism to Warburg effect, where glucose is preferably converted...
In order to fuel the uncontrolled cell proliferation and division, tumor cells reprogram the energy metabolism to Warburg effect, where glucose is preferably converted by glycolysis even in the presence of oxygen. However, the high energetic demand of tumor cells require upregulating the expression of glucose transporters, notably GLUT1, which substantially increases glucose uptake into cytoplasm. GLUT1 is overexpressed in a variety of tumor cells and is likely to be a potential drug target in the treatment of pan-cancers. Although many small molecules were reported to inhibit the glucose uptake function by various measurements, several shortcomings such as weak binding affinity, low specificity of the known inhibitors demand the identification of alternative inhibitors with novel scaffolds. In this study, we performed a virtual screening campaign by docking each compound from Chemdiv database to the glucose binding pocket based on the crystal structure of GLUT1 (PDB ID 4PYP) and four small molecules with novel scaffolds were identified to inhibit the glucose uptake of cancer cells at the sub-micromole level. The identified compounds may serve as starting points for the development of anti-cancer drugs via the manipulation of the energy metabolism.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Energy Metabolism; Glucose; Glucose Transporter Type 1; Humans; Lactic Acid; Molecular Docking Simulation
PubMed: 33900490
DOI: 10.1007/s10637-021-01109-2 -
Experimental Biology and Medicine... Aug 2021The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines,...
The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.
Topics: Adult; Blood Glucose; Carnitine; Cross-Sectional Studies; Glucose Intolerance; Humans; Insulin Resistance; Insulin Secretion; Insulins; Male; Middle Aged; Prediabetic State
PubMed: 33926260
DOI: 10.1177/15353702211009493 -
Chemical Biology & Drug Design Jan 2021P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and...
P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB Ch 8-5, SW480-VCR, and HCT-15). Both the analogs significantly increased the vincristine efficacy in MDR cancer cell lines at low micromole concentrations. Specifically, 3 caused complete reversal of vincristine resistance in KB Ch 8-5 cells and found to act as competitive inhibitor of P-gp as well as potentiated the vincristine-induced NF-KB-mediated apoptosis. Therefore, 3 ((2E,4E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dien-1-one) can serve as a potential P-gp inhibitor for in vivo investigations, to reverse multidrug resistance in cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Binding Sites; Cell Line, Tumor; Cell Survival; Cytochrome P-450 CYP3A; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Molecular Docking Simulation; Multidrug Resistance-Associated Proteins; NF-kappa B; Neoplasms; Piperidines; Polyunsaturated Alkamides; Vincristine
PubMed: 32633857
DOI: 10.1111/cbdd.13758 -
Circulation. Genomic and Precision... Oct 2022The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the -encoded Kv4.3 pore-forming α-subunit. gain-of-function mutations...
BACKGROUND
The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the -encoded Kv4.3 pore-forming α-subunit. gain-of-function mutations have been reported previously as a pathogenic substrate for J wave syndromes (JWS), including the Brugada syndrome and early repolarization syndrome, as well as autopsy-negative sudden unexplained death (SUD). Acacetin, a natural flavone, is a potent Ito current blocker. Acacetin may be a novel therapeutic for -mediated J wave syndrome.
METHODS
KCND3-V392I was identified in an 18-year-old male with J wave syndrome/early repolarization syndrome, and a history of cardiac arrest including ventricular tachycardia/ventricular fibrillation and atrial fibrillation/atrial flutter. Pathogenic mutation was engineered by site-directed mutagenesis and co-expressed with wild-type KChIP2 in TSA201 cells. Gene-edited/variant-corrected isogenic control and patient-specific pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from the p. Val392Ile-KCND3-positive patient were generated. I currents and action potentials were recorded before and after treatment with Acacetin using the whole cell patch-clamp and multielectrode array technique. Western blot and immunocytochemistry were performed to investigate KCND3 expression.
RESULTS
KCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak I current density by 92.2% (<0.05 versus KCND3-WT). KCND3 expression was significantly increased in KCND3-V392I-derived iPSC-CMs (<0.05 versus isogenic control). While KCND3-WT revealed an IC50 of 7.2±1.0 µmol/L for acacetin effect, 30 µmol/L acacetin dramatically inhibited KCND3-V392I peak Ito current density by 96.2% (<0.05 versus before Acacetin). Ito was also increased by 60.9% in Kv4.3-V392I iPSC-CM (<0.05 versus isogenic control iPSC-CM). Ten micromoles per liter acacetin, a concentration approaching its IC50 value, inhibited Ito by ≈50% in patient-derived iPSC-CMs and reduced the accentuated action potential notch displayed in KCND3-V392I-derived iPSC-CMs.
CONCLUSIONS
This preclinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated J wave syndrome by inhibiting I and abolishing the accentuated action potential notch in patient-derived iPSC-CMs.
Topics: Male; Humans; Shal Potassium Channels; Gain of Function Mutation; Brugada Syndrome; Flavones; Ventricular Fibrillation
PubMed: 35861988
DOI: 10.1161/CIRCGEN.120.003238 -
Biology Jun 2021Citrus production is facing an unprecedented problem because of huanglongbing (HLB) disease. Presently, no effective HLB-easing method is available when citrus becomes...
Citrus production is facing an unprecedented problem because of huanglongbing (HLB) disease. Presently, no effective HLB-easing method is available when citrus becomes infected. Guanosine 5'-monophosphate synthetase (GMPS) is a key protein in the de novo synthesis of guanine nucleotides. GMPS is used as an attractive target for developing agents that are effective against the patogen infection. In this research, homology modeling, structure-based virtual screening, and molecular docking were used to discover the new inhibitors against Las GMPS. Enzyme assay showed that folic acid and AZD1152 showed high inhibition at micromole concentrations, with AZD1152 being the most potent molecule. The inhibition constant (K) value of folic acid and AZD1152 was 51.98 µM and 4.05 µM, respectively. These results suggested that folic acid and AZD1152 could be considered as promising candidates for the development of Las agents.
PubMed: 34203217
DOI: 10.3390/biology10070594