ER stress and unfolded protein response (UPR) signaling modulate GLP-1 receptor signaling in the pancreatic islets.

Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by ß-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment.

Purification, characterization, and in vitro digestion of novel antioxidant peptides from chicken blood hemoglobin.

The study aimed to purify and characterize antioxidant peptides from chicken blood hemoglobin hydrolysate. The fraction M2  (< 3 KDa) with the strongest antioxidant activity was isolated by ultrafiltration, and its DPPH (1,1-diphenyl-2-picryl-hydrazyl radical) free radical scavenging rate, ABTS [2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate)] free radical scavenging rate, and iron ion chelation activity were 82.91%, 77.49%, and 80.99%, respectively. After in vitro digestion, the antioxidant capacity of chicken blood hydrolysate was significantly higher than that before digestion (p < 0.05). M2 exhibited the strongest antioxidant activity after stomach digestion, with a DPPH radical scavenging rate and iron ion chelating power of 82.91% and 79.61%, respectively. Component A was purified from M2 by Sephadex G-25 gel chromatography. The peptide sequences were identified by LC-MS/MS from fraction A, and four peptides, AEDKKLIQ (944.54 Da), APAPAAK (625.36 Da), LSDLHAHKL (1033.57 Da), and LSNLHAYNL (1044.54 Da) were synthesized using the solid-phase peptide method, among which APAPAAK was a novel antioxidant peptide. Molecular docking was used to simulate the binding of these four peptides to the key active site of Keap1 via hydrogen bonding. This study suggests that chicken blood may provide a new natural source of antioxidant peptides.

Coupled sorptive and oxidative antimony(III) removal by iron-modified biochar: Mechanisms of electron-donating capacity and reactive Fe species.

Sorption and oxidation are two potential pathways for the decontamination of trivalent antimony (Sb(III))-bearing water, using iron (Fe)-modified biochar (FeBC). Here we investigated the sorption and oxidation behavior of FeBC for Sb(III) in aqueous solutions. Results revealed that Sb(III) removal by FeBC was significantly improved showing the maximum Sb(III) sorption (64.0 mg g-1). Density functional theory (DFT) calculations indicated that magnetite (Fe3O4) in FeBC offered a sorption energy of -0.22 eV, which is 5 times that of non-modified biochar. With the addition of peroxymonosulfate (PMS), the sorption of Sb(III) on FeBC was 7 times higher than that on BC, indicating the sorption capacity of FeBC for Sb(III) could be substantially increased by adding oxidizing agents. Electrochemical analysis showed that Fe modification imparted FeBC higher electron-donating capacity than that of BC (0.045 v. s. 0.023 mmol e- (g biochar)-1), which might be the reason for the strong Sb(III) oxidation (63.6%) on the surface of FeBC. This study provides new information that is key for the development of effective biochar-based composite materials for the removal of Sb(III) from drinking water and wastewater. The findings from this study have important implications for protecting human health and agriculture.

Connexin 43 mediated the angiogenesis of buyang huanwu decoction via vascular endothelial growth factor and angiopoietin-1 after ischemic stroke.

Buyang Huanwu decoction (BYHWD), a classical prescription for ischemic stroke, has been reported to promote angiogenesis after focal ischemia. However, the mechanisms of the contribution of BYHWD on angiogenesis are still unclear. Connexin 43 (Cx43) played important roles in the functions of neurogliovascular unit. Therefore, the aim of this study was to explore the potential role of Cx43 in angiogenesis of the ischemic brain after BYHWD treatment. Middle cerebral artery occlusion (MCAO) was used to establish the model of focal ischemia. BYHWD was administrated intragastrically twice a day after MCAO with or without Gap26 (a specific Cx43 inhibitor). Western blot, neurological deficits, immunofluorescent staining, and Evans blue dye were used to confirm the role of Cx43 in angiogenesis after BYHWD treatment. The expression levels of total Cx43 and phosphorylated Cx43 were upregulated by BYHWD and peaked at 7 days post MCAO. Inhibition of Cx43 with Gap26 significantly attenuated the protective role of BYHWD in neurological behavior. BYHWD treatment promoted angiogenesis demonstrated by increased microvascular density, upregulated vascular endothelial growth factor (VEGF), and angiopoietin-1 (Ang-1), while inhibition of Cx43 with Gap26 attenuated these effects of BYHWD. In addition, Gap26 inhibited the beneficial effect of BYHWD on blood-brain barrier (BBB) integrity. These results suggested that Cx43 mediated the angiogenesis of BYHWD via VEGF and Ang-1 after focal ischemic stroke.

Cellular Stress-Modulating Drugs Can Potentially Be Identified by in Silico Screening with Connectivity Map (CMap).

Accompanied by increased life span, aging-associated diseases, such as metabolic diseases and cancers, have become serious health threats. Recent studies have documented that aging-associated diseases are caused by prolonged cellular stresses such as endoplasmic reticulum (ER) stress, mitochondrial stress, and oxidative stress. Thus, ameliorating cellular stresses could be an effective approach to treat aging-associated diseases and, more importantly, to prevent such diseases from happening. However, cellular stresses and their molecular responses within the cell are typically mediated by a variety of factors encompassing different signaling pathways. Therefore, a target-based drug discovery method currently being used widely (reverse pharmacology) may not be adequate to uncover novel drugs targeting cellular stresses and related diseases. The connectivity map (CMap) is an online pharmacogenomic database cataloging gene expression data from cultured cells treated individually with various chemicals, including a variety of phytochemicals. Moreover, by querying through CMap, researchers may screen registered chemicals in silico and obtain the likelihood of drugs showing a similar gene expression profile with desired and chemopreventive conditions. Thus, CMap is an effective genome-based tool to discover novel chemopreventive drugs.

Supramolecular assembly of poly(ß-cyclodextrin) block copolymer and benzimidazole-poly(ε-caprolactone) based on host-guest recognition for drug delivery.

A well-defined double hydrophilic poly(ß-cyclodextrin)-containing diblock copolymer PEG-b-PCD was synthesized by atom transfer radical polymerization (ATRP). Complex micelles with defined core-shell structure were formed based on the host-guest interactions between poly(ß-cyclodextrin) block copolymer and benzimidazole modified poly(ε-caprolactone) (BM-PCL). The hydrophobic PCD/BM-PCL resided in the core of micelles, while the hydrophilic poly(ethylene glycol) (PEG) chains acted as the micelles shell. The micelles exhibited regular spheres with diameter of about 255nm. The drug loading efficiency of micelles for doxorubicin (DOX) was high due to the hydrophobic core containing poly(ß-CD) and PCL. The in vitro release demonstrated that DOX-loaded polymer micelles exhibited an enhanced sustained manner after an initial burst release. The release of drugs was accelerated as the pH reduced from 7.0 to 2.0 and the temperature increased from 25 to 37°C. These results indicate that the complex micelles have potential applications in controlled drug delivery.

Sensitive complex micelles based on host-guest recognition from chitosan-graft-ß-cyclodextrin for drug release.

In this paper, pH-sensitive complex micelles were developed based on the host-guest recognition from chitosan-graft-ß-cyclodextrin (CS-g-CD) and benzimidazole-terminated poly(ε-caprolactone) (BM-PCL) for controlled drug release. The formation and characterization of complex micelles were confirmed by fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM) and laser particle analyzer. The size of complex micelles was about 200nm with the core formed by BM-PCL/ß-CD and the shell composed of chitosan. Doxorubicin (DOX), a model anticancer drug, was effectively loaded into the complex micelles via hydrophobic interactions. The encapsulation efficiency of DOX was up to 75%. The release of DOX from complex micelles was suppressed at neutral pH solutions due to the stability of micelles but accelerated at acidic solutions and high temperatures. These sensitive complex micelles might possess potential applications as intelligent nanocarriers for anticancer drug delivery.

Stimuli-sensitive hollow spheres from chitosan-graft-ß-cyclodextrin for controlled drug release.

In this paper, sensitive polymeric hollow spheres self-assembled from chitosan-grafted-ß-cyclodextrin (CS-g-CD) and sodium tripolyphosphate (TPP) were prepared for controlled release of doxorubicin (DOX). The assemblies were formed by electrostatic interactions between positively charged amino group in CS-g-CD and negatively charged phosphate in TPP. The hollow spheres with diameters about 100nm were confirmed by transmission electron microscopy (TEM) and laser particle analyzer. The microspheres with hollow cavity were beneficial to improve the drug loading capacity for DOX with entrapment efficiency above 60%. The cumulative release of DOX from CS-g-CD/TPP hollow microspheres increased with the decrease of pH and the increase of temperature or ionic strength. At 37 °C and pH 5.2, the maximum drug release was above 90% with a continuous release rate. In-vitro cytotoxicity tests indicate that drug loaded hollow spheres exhibited evidently inhibition against cancer cells. These sensitive polymeric hollow spheres are expected to be used in biomedical field as potential carrier.