The GPR40 novel agonist SZZ15-11 improves non-alcoholic fatty liver disease by activating the AMPK pathway and restores metabolic homeostasis in diet-induced obese mice.

AIM: Non-alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15-11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15-11 in fatty liver treatment. METHODS: In vivo, diet-induced obese (DIO) mice received SZZ15-11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40-knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15-11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells. RESULTS: SZZ15-11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15-11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15-11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibited acetyl-CoA carboxylase activity. Furthermore, SZZ15-11 promotes AMPK activity via [cAMP]i accumulation. CONCLUSION: This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.

Chlorophyl-Passivated Ytterbium-Doped Perovskite Quantum-Cutting Film for High-Performance Solar Energy Conversion and Near-Infrared Light-Emitting Diode Applications.

The quantum cutting ytterbium (Yb3+)-doped CsPbX3 (X = Cl, Cl, or Br) nanocrystals, exhibiting photoluminescence quantum yields (PLQYs) exceeding 100%, hold significant promise for applications in solar energy conversion technologies and near-infrared (NIR) light-emitting diodes (LEDs). This work investigates the usage of chlorophyll (CHL), a naturally existing organic pigment, as an efficient molecular passivator to improve the performance of quantum cutting films. With the assistance of CHL, the resultant perovskite film displays an increased PLQY of 176%. The commercial silicon solar cells (SSCs) with CHL-treated perovskite films demonstrate a remarkable photon-to-current conversion efficiency improvement of 1.83% for a 330.15 cm2 area SSC device. Additionally, a CHL-modified Yb3+:CsPbCl3 film was used to create 988 nm NIR LEDs with an external quantum efficiency of 3.2%. This work provides a new, eco-friendly approach for producing high-quality, large-area Yb3+-doped perovskite film for deployment in photoelectric and night vision applications.

A Molecular Cage Accessed by Threefold Click Reaction of a C3v-Symmetric Triazido-Functionalized Tribenzotriquinacene.

The hitherto unknown hexakis(halomethyl)-functionalized tribenzotriquinacenes (TBTQs) 9 and 10 were synthesized from the key 4b,8b,12b-tribromo-TBTQ derivative 6 by an improved route in 67% overall yield. Extension of the bowl-shaped framework of 9 or 10 by threefold condensation with propargylamine or 2-azidoethylamine afforded the corresponding TBTQ-trialkyne 11 and TBTQ-triazide 12, respectively. While attempts to construct bis-TBTQ cages, including homodimerization of 11 and heterocoupling of 11 with 12, were unsuccessful, triazide 12 was found to undergo threefold [3 + 2]-cycloaddition with 3-ethynylaniline and phloroglucinol tripropargyl ether under click chemistry conditions. The latter reaction enabled facile capping of the TBTQ bowl to give the novel cage compound 5 in 22% yield.

Physics-informed kernel function neural networks for solving partial differential equations.

This paper proposes an improved version of physics-informed neural networks (PINNs), the physics-informed kernel function neural networks (PIKFNNs), to solve various linear and some specific nonlinear partial differential equations (PDEs). It can also be considered as a novel radial basis function neural network (RBFNN). In the proposed PIKFNNs, it employs one-hidden-layer shallow neural network with the physics-informed kernel functions (PIKFs) as the customized activation functions. The PIKFs fully or partially contain PDE information, which can be chosen as fundamental solutions, green's functions, T-complete functions, harmonic functions, radial Trefftz functions, probability density functions and even the solutions of some linear simplified PDEs and so on. The main difference between the PINNs and the proposed PIKFNNs is that the PINNs add PDE constraints to the loss function, and the proposed PIKFNNs embed PDE information into the activation functions of the neural network. The feasibility and accuracy of the proposed PIKFNNs are validated by some benchmark examples.

Solar-blind ultraviolet photodetector based on Nb2C/ß-Ga2O3heterojunction.

ß-Ga2O3has been widely investigated for its stability and thermochemical properties. However, the preparation ofß-Ga2O3thin films requires complex growth techniques and high growth temperatures, and this has hindered the application ofß-Ga2O3thin films. In this study,ß-Ga2O3thin films with good crystalline quality were prepared using a green method, and an ultraviolet (UV) detector based onß-Ga2O3with a photocurrent of 2.54 × 10-6A and a dark current of 1.19 × 10-8A has been developed. Two-dimensional materials have become premium materials for applications in optoelectronic devices due to their high conductivity. Here, we use the suitable energy band structure between Nb2C and Ga2O3to create a high carrier migration barrier, which reduces the dark current of the device by an order of magnitude. In addition, the device exhibits solar-blind detection, high responsiveness (28 A W-1) and good stability. Thus, the Nb2C/ß-Ga2O3heterojunction is expected to be one of the promising devices in the field of UV photoelectric detection.

Trivalent Europium-Doped CsCl Quantum Dots for MA-Free Perovskite Solar Cells with Inherent Bandgap through Lattice Strain Compensation.

Cesium-formamidinium (Cs-FA) perovskites have garnered widespread interest owing to their excellent thermal- and photostability in achieving stable perovskite solar cells (PSCs). However, Cs-FA perovskite typically suffers from Cs+ and FA+ mismatches, affecting the Cs-FA morphology and lattice distortion, resulting in an enlarged bandgap (Eg ). In this work, "upgraded" CsCl, Eu3+ -doped CsCl quantum dots, are developed to solve the key issues in Cs-FA PSCs and also exploit the advantage of Cs-FA PSCs on stability. The introduction of Eu3+ promotes the formation of high-quality Cs-FA films by adjusting the Pb-I cluster. CsCl:Eu3+ also offsets the local strain and lattice contraction induced by Cs+ , which maintains the inherent Eg of FAPbI3 and decreases the trap density. Finally, a power conversion efficiency (PCE) of 24.13% is obtained with an excellent short-circuit current density of 26.10 mA cm-2 . The unencapsulated devices show excellent humidity stability and storage stability, and an initial PCE of 92.2% within 500 h under continuous light illumination, and bias voltage conditions is achieved. This study provides a universal strategy to address the inherent issues of Cs-FA devices and maintain the stability of MA-free PSCs to satisfy future commercial criteria.

New anti-diabetic drug Morus alba L. (Sangzhi) alkaloids (SZ-A) improves diabetic nephropathy through ameliorating inflammation and fibrosis in diabetic rats.

Background: Morus alba L. (Sangzhi) alkaloid (SZ-A) is a new antidiabetic drug approved by the China National Medical Products Administration in 2020. Diabetic nephropathy (DN) is a common diabetic complication and an important cause of morbidity and mortality in patients with diabetes. The effects of SZ-A on DN remain unknown. Purpose: This study evaluated the effects of SZ-A on DN in Zucker diabetic fatty (ZDF) rats and explored the underlying mechanisms based on nitrosative stress, inflammation, and fibrosis. Methods: Diabetic ZDF rats were orally administered 100 and 200 mg/kg of SZ-A once daily for 9 weeks. The glucose metabolism and kidney function were assayed. The pathological injury and fibrosis of the kidneys were separately evaluated using hematoxylin and eosin staining and Masson's staining. The oxidative and nitrosative stress and inflammation were assayed by determining the levels of related indices in the blood and kidneys and quantifying the related gene and protein expression. The expression of transforming growth factor ß1 (TGFß1) gene and protein were assayed by quantitative real-time PCR and immunohistochemistry, respectively. The renal transcriptomics was analyzed using RNA sequencing. Results: Repeated treatment with SZ-A significantly improved glucose metabolism, dose-dependently decreased the levels of blood urea nitrogen, urinary albumin, and ß2-microglobulin, and evidently relieved the renal injury in diabetic ZDF rats. As for the mechanisms, SZ-A remarkably ameliorated systemic nitrosative stress through lowering the levels of blood inducible nitric oxide synthase and nitric oxide, and significantly relieved systemic and renal inflammation by reducing the levels of blood interleukin-1ß and monocyte chemoattractant protein-1 (MCP-1) and decreasing the levels of renal C-reactive protein content and expression of tumor necrosis factor-α in the kidneys. SZ-A also improved renal fibrosis by lowering the expression of TGFß1 in the kidneys. Additionally, SZ-A significantly lowered the expression of stimulator of chondrogenesis 1 in the kidneys. Conclusion: Repeated treatments with SZ-A significantly ameliorates DN by regulating systemic nitrosative stress, renal inflammation, and renal fibrosis partially through inhibition of the cytokine-NO and TGF-ß1 signaling in ZDF rats, providing evidence for the additional application of SZ-A in clinical use for the treatment of DN.

Interfacial Engineering of Au@Nb2CTx-MXene Modulates the Growth Strain, Suppresses the Auger Recombination, and Enables an Open-Circuit Voltage of over 1.2 V in Perovskite Solar Cells.

Defects at the interface of charge transport layers can cause severe charge accumulation and poor charge transferability, which greatly affect the efficiency and stability of stannic oxide (SnO2)-based perovskite solar cells (PSCs). Herein, a new type of MXene (Nb2CTx-MXene) is applied to the interface of SnO2 layers to passivate the interfacial defects and promote charge transport. Nb2CTx-MXene in PSCs realizes the role of boosting the conductivity, reducing the tin vacancies in the interstitial void of the SnO2 layer, decreasing the defect density, and aligning the bandgap. Afterward, Nb2CTx-MXene is decorated with gold nanospheres, which has the ability to modulate the tensile strain of perovskites and suppress the Auger recombination. Eventually, the Au@Nb2CTx-MXene-modified device yields an excellent power conversion efficiency (PCE) of 23.78% with a relatively high open-circuit voltage of 1.215 V (Eg ∼ 1.60 eV). The unencapsulated devices maintain 90% of their initial PCE values after storage in the air with a relative humidity of 40% for 1000 h and remain above 80% of their initial efficiency after operation at the maximum power point for 500 h under 1 sun illumination. Our work provides an avenue to fabricate high-efficiency and stable PSCs with MXene adapting to commercial development.

Efficient single-component white light emitting diodes enabled by lanthanide ions doped lead halide perovskites via controlling Förster energy transfer and specific defect clearance.

Currently, a major challenge for metal-halide perovskite light emitting diodes (LEDs) is to achieve stable and efficient white light emission due to halide ion segregation. Herein, we report a promising method to fabricate white perovskite LEDs using lanthanide (Ln3+) ions doped CsPbCl3 perovskite nanocrystals (PeNCs). First, K+ ions are doped into the lattice to tune the perovskite bandgap by partially substituting Cs+ ions, which are well matched to the transition energy of some Ln3+ ions from the ground state to the excited state, thereby greatly improving the Förster energy transfer efficiency from excitons to Ln3+ ions. Then, creatine phosphate (CP), a phospholipid widely found in organisms, serves as a tightly binding surface-capping multi-functional ligand which regulates the film formation and enhances the optical and electrical properties of PeNC film. Consequently, the Eu3+ doped PeNCs based-white LEDs show a peak luminance of 1678 cd m-2 and a maximum external quantum efficiency (EQE) of 5.4%, demonstrating excellent performance among existing white PeNC LEDs from a single chip. Furthermore, the method of bandgap modulation and the defect passivation were generalized to other Ln3+ ions doped perovskite LEDs and successfully obtained improved electroluminescence (EL). This work demonstrates the comprehensive and universal strategies in the realization of highly efficient and stable white LEDs via single-component Ln3+ ions doped PeNCs, which provides an optimal solution for the development of low-cost and simple white perovskite LEDs.

Voglibose Regulates the Secretion of GLP-1 Accompanied by Amelioration of Ileal Inflammatory Damage and Endoplasmic Reticulum Stress in Diabetic KKAy Mice.

Voglibose is an α-glycosidase inhibitor that improves postprandial hyperglycemia and increases glucagon-like peptide-1 (GLP-1) secretion in patients with type 2 diabetes. Recently, there has been increasing interest in the anti-inflammatory effects of voglibose on the intestine, but the underlying mechanism is not clear. This study evaluated the effects and mechanisms of voglibose on glycemic control and intestinal inflammation. Type 2 diabetic KKAy mice were treated with voglibose (1 mg/kg) by oral gavage once daily. After 8 weeks, glucose metabolism, levels of short-chain fatty acids (SCFAs), systematic inflammatory factors, intestinal integrity and inflammation were evaluated using hematoxylin and eosin staining, immunohistochemistry, immunofluorescence and Western blot analysis. Voglibose ameliorated glucose metabolism by enhancing basal- and glucose-dependent GLP-1 secretion. Several beneficial SCFAs, such as acetic acid and propionic acid, were increased by voglibose in the fecal sample. Additionally, voglibose notably decreased the proportion of pro-inflammatory macrophages and the expression of nuclear factor kappa B but increased the expression of tight junction proteins in the ileum, thus markedly improving intestinal inflammatory damage and reducing the systematic inflammatory factors. Ileal genomics and protein validation suggested that voglibose attenuated inositol-requiring protein 1α-X-box binding protein 1-mediated endoplasmic reticulum stress (ERS). Together, these results showed that voglibose enhanced the secretion of GLP-1, which contributed to the glycemic control in KKAy mice at least in part by regulating intestinal inflammation and the expression of ERS factors.

Diphenyl Diselenide Alleviates Tert-Butyl Hydrogen Peroxide-Induced Oxidative Stress and Lipopolysaccharide-Induced Inflammation in Rat Glomerular Mesangial Cells.

Hyperglycemia, oxidative stress, and inflammation play key roles in the onset and development of diabetic complications such as diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple organic selenium compound with anti-hyperglycemic, anti-inflammatory, and anti-oxidative activities. Nevertheless, in vitro, the role and molecular mechanism of DPDS on DN remains unknown. Therefore, we investigated the effects of DPDS on tert-butyl hydrogen peroxide (t-BHP)-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation in rat glomerular mesangial (HBZY-1) cells and explored the underlying mechanisms. DPDS attenuated t-BHP-induced cytotoxicity, concurrent with decreased intracellular ROS and MDA contents and increased SOD activity and GSH content. Moreover, DPDS augmented the protein and mRNA expression of Nrf2, HO-1, NQO1, and GCLC in t-BHP-stimulated HBZY-1 cells. In addition, DPDS suppressed LPS-induced elevations of intracellular content and mRNA expression of interleukin (IL)-6, IL-1ß and TNF-α. Furthermore, LPS-induced NFκB activation and high phosphorylation of JNK and ERK1/2 were markedly suppressed by DPDS in HBZY-1 cells. In summary, these data demonstrated that DPDS improves t-BHP-induced oxidative stress by activating the Nrf2/Keap1 pathway, and also improves LPS-induced inflammation via inhibition of the NFκB/MAPK pathways in HBZY-1 cells, suggesting that DPDS has the potential to be developed as a candidate for the prevention and treatment of DN.

Halide anions engineered ionic liquids passivation layer for highly stable inverted perovskite solar cells.

Long-term stability remains a great challenge for metal halide perovskite solar cells (PSCs). The utilization of ionic liquids (ILs) is a promising strategy to solve the stability problem. However, few studies have focused on controlling the halide anions of ILs, in which different organic cations can modulate the melting point of ILs and film crystal growth. Here, ILs with a 1-ethyl-3-methylimidazolium (EMIM+) cation and different halide anions (X = Cl, Br, and I) are employed in inverted PSCs. The results show that EMIMX can form a 1D passivation layer by the in situ growth technique and influence the surface morphology of the perovskite film. These EMIMX-treated layers simultaneously suppress the surface defects and nonradiative energy losses and improve the hydrophobic properties. As a result, a power conversion efficiency (PCE) of 20.0% is obtained for the EMIMBr-modified PSCs compared to 18.06% for the control device. Moreover, the unencapsulated devices maintain more than 90% of their initial PCE over 3000 h under ambient air, which is among the best long-term stabilities reported for NiOx-based inverted PSCs. It also retains 74.2% and 49.5% of the initial PCE value after aging under harsher conditions, such as an 85 ± 5% relative humidity (RH) environment and at 85 °C for 48 h, respectively.

Ramulus Mori (Sangzhi) Alkaloids Alleviate High-Fat Diet-Induced Obesity and Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes mellitus (T2DM) have highly related mechanisms. Ramulus Mori (Sangzhi) alkaloids (SZ-A) from Morus alba L. were approved in 2020 for the treatment of T2DM. In this study, we examined the therapeutic effects and mechanism of SZ-A on obesity and NAFLD in mice. Mice (C57BL/6J) fed a high-fat diet (HFD) for 14 weeks were treated with SZ-A for another 6 weeks. HFD-induced weight gain was reduced by SZ-A in a dose-dependent manner. SZ-A treatment significantly stimulated adiponectin expression and secretion in adipose tissue and 3T3-L1 adipocytes. Additionally, SZ-A markedly reduced hepatic steatosis (triglyceride, total cholesterol) and expression of pro-inflammatory and pro-fibrotic genes. SZ-A regulated lipid metabolism and oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH)) in the liver. Palmitic acid-induced insulin resistance and lipid accumulation in HepG2 cells were also repressed by SZ-A. Collectively, SZ-A protected mice from HFD-induced NAFLD through an indirect effect of improved systemic metabolism reducing bodyweight, and a direct effect by enhancing the lipid metabolism of HepG2 cells. The weight-loss effect of SZ-A in mice was partly due to improved fatty oxidation instead of influencing food consumption.

Morus alba L. (Sangzhi) Alkaloids Promote Insulin Secretion, Restore Diabetic ß-Cell Function by Preventing Dedifferentiation and Apoptosis.

Background: Morus alba L. (Sangzhi) alkaloids (SZ-A), extracted from the Chinese herb Morus alba L. (mulberry twig), have been shown to ameliorate hyperglycemia in type 2 diabetes and have been approved for diabetes treatment in the clinic. However, their versatile pharmacologic effects and regulatory mechanisms are not yet completely understood. Purpose: This study explored the protective effects of SZ-A on islet ß cells and the underlying mechanism. Methods: Type 2 diabetic KKAy mice were orally administered SZ-A (100 or 200 mg/kg, once daily) for 11 weeks, and oral glucose tolerance, insulin tolerance, intraperitoneal glucose tolerance and hyperglycemia clamp tests were carried out to evaluate the potency of SZ-A in vivo. The morphology and ß-cell dedifferentiation marker of KKAy mouse islets were detected via immunofluorescence. The effect of SZ-A on glucose-stimulated insulin secretion was investigated in both the islet ß-cell line MIN6 and mouse primary islets. Potential regulatory signals and pathways in insulin secretion were explored, and cell proliferation assays and apoptosis TUNEL staining were performed on SZ-A-treated MIN6 cells. Results: SZ-A alleviated hyperglycemia and glucose intolerance in type 2 diabetic KKAy mice and improved the function and morphology of diabetic islets. In both MIN6 cells and primary islets, SZ-A promoted insulin secretion. At a normal glucose level, SZ-A decreased AMPKα phosphorylation, and at high glucose, SZ-A augmented the cytosolic calcium concentration. Additionally, SZ-A downregulated the ß-cell dedifferentiation marker ALDH1A3 and upregulated ß-cell identifying genes, such as Ins1, Ins2, Nkx2.2 and Pax4 in KKAy mice islets. At the same time, SZ-A attenuated glucolipotoxicity-induced apoptosis in MIN6 cells, and inhibited Erk1/2 phosphorylation and caspase 3 activity. The major active fractions of SZ-A, namely DNJ, FAG and DAB, participated in the above regulatory effects. Conclusion: Our findings suggest that SZ-A promotes insulin secretion in islet ß cells and ameliorates ß-cell dysfunction and mass reduction under diabetic conditions both in vivo and in vitro, providing additional supportive evidence for the clinical application of SZ-A.

Discovery of Novel Indole Derivatives as Fructose-1,6-bisphosphatase Inhibitors and X-ray Cocrystal Structures Analysis.

Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis, and its inhibitors are expected to be novel antidiabetic agents. Herein, a series of new indole and benzofuran analogues were designed and synthesized to evaluate the inhibitory activity against FBPase. As a result, the novel FBPase inhibitors bearing N-acylsulfonamide moiety on the 3-position of the indole-2-carboxylic acid scaffold (compounds 22f and 22g) were identified with IC50s at the submicromolar levels. Three X-ray crystal structures of the complexes were solved and revealed the structural basis for the inhibitory activity. The chemoinformatics analysis further disclosed the distinct binding features of this class of inhibitors, providing an insight for further modifications to create structurally distinct FBPase inhibitors with high potency and drug-like properties.

Berberine combined with stachyose improves glycometabolism and gut microbiota through regulating colonic microRNA and gene expression in diabetic rats.

AIMS: Berberine is effective for type 2 diabetes mellitus (T2DM), but has limited use in clinic. This study aims to evaluate the effect of berberine combined with stachyose on glycolipid metabolism and gut microbiota and to explore the underlying mechanisms in diabetic rats. MAIN METHODS: Zucker diabetic fatty (ZDF) rats were orally administered berberine, stachyose and berberine combined with stachyose once daily for 69 days. The oral glucose tolerance and levels of blood glucose, insulin, triglyceride and total cholesterol were determined. The gut microbial profile, colonic miRNA and gene expression were assayed using Illumina sequencing. The quantitative polymerase chain reaction was used to verify the expression of differentially expressed miRNAs and genes. KEY FINDINGS: Repeated treatments with berberine alone and combined with stachyose significantly reduced the blood glucose, improved the impaired glucose tolerance, and increased the abundance of beneficial Akkermansiaceae, decreased that of pathogenic Enterobacteriaceae in ZDF rats. Furthermore, combined treatment remarkably decreased the abundances of Desulfovibrionaceae and Proteobacteria in comparison to berberine. Combined treatment evidently decreased the expression of intestinal early growth response protein 1 (Egr1) and heparin-binding EGF-like growth factor (Hbegf), and significantly increased the expression of miR-10a-5p, but berberine alone not. SIGNIFICANCE: Berberine combined with stachyose significantly improved glucose metabolism and reshaped gut microbiota in ZDF rats, especially decreased the abundance of pathogenic Desulfovibrionaceae and Proteobacteria compared to berberine alone, providing a novel strategy for treating T2DM. The underlying mechanisms may be associated with regulating the expression of intestinal Egr1, Hbegf and miR-10a-5p, but remains further elucidation.

Morus alba L. (Sangzhi) alkaloids (SZ-A) exert anti-inflammatory effects via regulation of MAPK signaling in macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Morus alba L. (Sangzhi) alkaloids (SZ-A) tablets have been approved by the China National Medical Products Administration for T2DM treatment. Our previous study (Liu et al., 2021) revealed that SZ-A protected against diabetes and inflammation in KKAy mice. However, the mechanism and components in SZ-A exerting anti-inflammatory effects are unclear. AIM OF THE STUDY: Investigate the effects and molecular mechanisms of SZ-A on inflammation, and identify anti-inflammatory active components in SZ-A. MATERIALS AND METHODS: The major ingredients in SZ-A were analyzed by HPLC and sulfuric acid - anthrone spectrophotometry. The inhibitory activities of SZ-A on lipopolysaccharide (LPS)-stimulated inflammation were determined in bone marrow-derived macrophage (BMDM) and RAW264.7 cells. The cytokine levels of IL-6 and TNF-α in cell culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gene expression levels of IL-6 and TNF-α were detected by qRT-PCR. The levels of protein phosphorylation of p38 MAPK, ERK, and JNK were analyzed by Western blot. RESULTS: The main components in SZ-A were found to be 1-deoxynojirimycin (DNJ), 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), fagomine (FAG), polysaccharide (APS), and arginine (ARG). SZ-A reduced the levels of IL-6 and TNF-α secreted by LPS-induced RAW264.7 and BMDM cells. Simultaneously, the mRNA expression levels of IL-6 and TNF-α were all significantly suppressed by SZ-A in a concentration-dependent manner. Furthermore, SZ-A inhibited the phosphorylation of p38 MAPK, ERK, and JNK in BMDM and the activation of ERK and JNK signaling in RAW264.7 cells. We also observed that DNJ, DAB, FAG, and ARG markedly downregulated IL-6 and TNF-α cytokine levels, while APS did not have an obvious effect. CONCLUSIONS: SZ-A attenuates inflammation at least partly by blocking the activation of p38 MAPK, ERK, and JNK signaling pathways. DNJ, FAG, DAB, and ARG are the main constituents in SZ-A that exert anti-inflammatory effects.

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice.

The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.

Quantitative determination of Cpd118, A novel FBPase inhibitor, in dog plasma by HPLC-MS/MS.

Aim: A HPLC-MS/MS method was first developed and validated for the quantification of Cpd118, a novel fructose-1, 6-bisphosphatase inhibitor for controlling gluconeogenesis in Type 2 diabetes mellitus. Materials & methods: Cpd118 was extracted from dog plasma following acetonitrile protein precipitation, separated by HPLC on a CAPCELL PAK ADME column (3.5 µm, 2.1 mm × 100 mm) and quantified using negative heated electrospray ion source-MS/MS. Results: Cpd118 was quantified from plasma using the method described above over a linear range of 10-20,000 ng/ml, with interday and intraday assay accuracy from -11.78 to 4.01% and the precision was ≤11.15%. Conclusion: The method was sensitive and selective for the quantification of Cpd118 and was successfully used to the pharmacokinetic and bioavailability study of Cpd118 in dogs.

Diphenyl diselenide ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats via suppressing oxidative stress and inflammation.

Oxidative stress and inflammation are implicated in the occurrence and progression of diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple diaryl diselenide with anti-hyperglycemic, anti-inflammatory, and antioxidant activities. However, the effects of DPDS on DN are still unclear to date. Herein, we aimed to explore whether DPDS could improve renal dysfunction in streptozotocin (STZ)-induced diabetic rats and its underlying mechanisms. STZ-induced DN rats were administered with DPDS (5 or 15 mg/kg) or metformin (200 mg/kg) once daily by intragastric gavage for 12 weeks. DPDS supplementation significantly improved hyperglycemia, glucose intolerance, dyslipidemia, and the renal pathological abnormalities, concurrent with significantly reduced serum levels of creatinine, urea nitrogen, urine volume, and urinary levels of micro-albumin, ß2-microglobulin and N-acetyl-glucosaminidase activities. Moreover, DPDS effectively promoted the activities of antioxidant enzymes, and reduced the levels of MDA and pro-inflammatory factors in serum and the kidney. Furthermore, DPDS supplementation activated the renal Nrf2/Keap1 signaling pathway, but attenuated the high phosphorylation levels of NFκB, JNK, p38 and ERK1/2. Altogether, the current study indicated for the first time that DPDS ameliorated STZ-induced renal dysfunction in rats, and its mechanism of action may be attributable to suppressing oxidative stress via activating the renal Nrf2/Keap1 signaling pathway and mitigating inflammation by suppressing the renal NFκB/MAPK signaling pathways, suggesting a potential therapeutic approach for DN.