A facile and metal-free visible-light-enabled three-component reaction of quinoxalin-2(1H)-ones, alkenes and CF3SO2Na has been developed under air at room temperature.
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A facile and ...metal-free visible-light-enabled three-component reaction of quinoxalin-2(1H)-ones, alkenes and CF3SO2Na has been developed under air at room temperature. This photocatalytic tandem reaction using 4CzIPN as the photocatalyst and air as the green oxidant, provides a mild and environmentally friendly approach to access a series of 3-trifluoroalkylated quinoxalin-2(1H)-ones.
A mild and efficient photochemical multi-component tandem reaction of quinoxalin-2(1H)-ones, alkenes and sulfinic acids is reported. This tandem reaction could be conveniently carried out at room ...temperature by employing 4CzIPN as the metal-free photocatalyst and dioxygen (air) as the environmentally benign oxidant. A number of sulfonated quinoxalin-2(1H)-ones were obtained in satisfactory yields with favorable functional group tolerance. Radical trapping experiment and fluorescence quenching experiments were performed to elucidate this visible-light mediated radical reaction process.
A mild and efficient photochemical multi-component reaction of quinoxalin-2(1H)-ones, alkenes and sulfinic acids was established for the synthesis of sulfonated quinoxalin-2(1H)-ones. This multi-component could be carried out at room temperature by employing 4CzIPN as the photocatalyst and dioxygen (air) as the environmentally benign oxidant. A number of sulfonated quinoxalin-2(1H)-ones were conveniently obtained in satisfactory yields. Display omitted
Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in ...luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)-dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR.
We used microperfusion, micropuncture, and renal clearance of FITC-inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa-specific NOS1 knockout mice.
Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response
and
and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa-specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR.
We identified a novel mechanism of acute hyperglycemia-induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1
SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.
An efficient and selective sulfonylation/cyclization of 1,6-enynes with arylazo sulfones has been developed under catalyst- and additive-free conditions.
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A convenient and ...regioselective sulfonylation/cyclization of 1,6-enynes with arylazo sulfones has been developed to access a series of sulfonylated γ-butyrolactams. The present reaction could be efficiently conducted under catalyst- and additive-free conditions, in which CS and CC bonds were selectively constructed in one-pot procedure.
Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease ...(CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg−1min−1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.
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•Orally administered TMAO aggravates Ang II-induced hypertension. Antibiotics alleviate Ang II-induced hypertension by reducing TMAO generation.•High concentrations of TMAO constrict afferent arterioles and mesenteric arteries and increase blood pressure.•Low concentrations of TMAO enhance Ang II-induced vasoconstriction and acute pressor response via activating PERK/ROS/CaMKII/PLCβ3/Ca2+ pathway.
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-glucose cotransporter (SGLT)1 mediates glucose reabsorption in late proximal tubules. SGLT1 also mediates macula densa (MD) sensing of an increase in luminal glucose, which increases nitric oxide ...(NO) synthase 1 (MD-NOS1)-mediated NO formation and potentially glomerular filtratrion rate (GFR). Here, the contribution of SGLT1 was tested by gene knockout (-/-) in type 1 diabetic Akita mice. A low-glucose diet was used to prevent intestinal malabsorption in
mice and minimize the contribution of intestinal SGLT1. Hyperglycemia was modestly reduced in
versus littermate wild-type Akita mice (480 vs. 550 mg/dl), associated with reduced diabetes-induced increases in GFR, kidney weight, glomerular size, and albuminuria. Blunted hyperfiltration was confirmed in streptozotocin-induced diabetic
mice, associated with similar hyperglycemia versus wild-type mice (350 vs. 385 mg/dl). Absence of SGLT1 attenuated upregulation of MD-NOS1 protein expression in diabetic Akita mice and in response to SGLT2 inhibition in nondiabetic mice. During SGLT2 inhibition in Akita mice,
mice had likewise reduced blood glucose (200 vs. 300 mg/dl), associated with lesser MD-NOS1 expression, GFR, kidney weight, glomerular size, and albuminuria. Absence of
in Akita mice increased systolic blood pressure, associated with suppressed renal renin mRNA expression. This may reflect fluid retention due to blunted hyperfiltration. SGLT2 inhibition prevented the blood pressure increase in
Akita mice, possibly due to additive glucosuric/diuretic effects. The data indicate that SGLT1 contributes to diabetic hyperfiltration and limits diabetic hypertension. Potential mechanisms include its role in glucose-driven upregulation of MD-NOS1 expression. This pathway may increase GFR to maintain volume balance when enhanced MD glucose delivery indicates upstream saturation of SGLTs and thus hyperreabsorption.
Sodium-glucose co-transporters (SGLTs) in the kidneys play a pivotal role in glucose reabsorption. Several clinical and population-based studies revealed the beneficial effects of SGLT2 inhibition on ...hypertension. Recent work from our lab provided significant new insight into the role of SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension, Dahl salt-sensitive (SS) rats. Dapagliflozin (Dapa) blunted the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in the Renin-Angiotensin-Aldosterone System. However, our initial study used male SS rats only, and the effect of SGLT2 inhibitors on hypertension in females has not been studied. Therefore, the goal of this study was to determine whether SGLT2 inhibition alters blood pressure and kidney function in female Dahl SS rats. The result showed that administration of Dapa for 3 weeks prevented the progression of salt-induced hypertension in female rats, similar to its effects in male SS rats. Diuresis and glucose excretion were significantly increased in Dapa-treated rats. SGLT2 inhibition also significantly attenuated kidney but not heart fibrosis. Despite significant effects on blood pressure, Dapa treatment caused minor changes to electrolyte balance and no effects on kidney and heart weights were observed. Our data suggest that SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension independent of sex.
A new series of 9-plex chemical isotope-labeling reagents, levofloxacin-based mass tags (LMTs) named as LMT359, 360, 361, 362, 363, 373, 375, 376, and 378, was firstly designed and synthesized for ...the high-throughput labeling of globotriaosylsphingosine (lyso-Gb3), a disease biomarker of Fabry disease. Creatively based on derivatization strategy—dummy template technique, dummy magnetic molecularly imprinted polymers (DMMIPs) were designed and prepared using LMT387-labeled lyso-Gb3 as a dummy template. The novel DMMIP material was used as sorbents for magnetic dispersive solid-phase extraction of 9-plexed LMT derivatives of lyso-Gb3 from equally mixed derivatization solutions. The enriched 8-plexed lyso-Gb3 derivatives from 8 real samples were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry in a single run using simultaneously extracted LMT359-labeled standard lyso-Gb3 as internal standards. DMMIPs were characterized by using the transmission electron microscope (TEM), Fourier transform infrared, X-ray photoelectron spectroscopy, and some other characterization techniques. TEM micrograph showed that the prepared DMMIPs had an apparent imprinting layer. Triple-recognition abilities of DMMIPs towards LMT-lyso-Gb3 mainly rely on the hydrogen bonding, electrostatic attraction, hydrophobic interaction, and boronate affinity. The imprinting factor of DMMIPs towards LMT-lyso-Gb3 was 5.1. This method shows the advantages of high selectivity (triple recognition), high sensitivity, high accuracy (recovery 93.5–108.8%), and high throughput (8 samples in a single run). The proposed method was successfully applied to the determination of lyso-Gb3 in plasma samples with spiked recoveries in the range of 95.0–102.4%. This indicates that the method is promising in bioanalysis and medical testing of lyso-Gb3 in the future.
Graphical abstract
Synthesis of multiplexed derivatization reagents and its correlative molecularly imprinted polymers for magnetic extraction of globotriaosylsphingosine
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