Bletilla striata Polysaccharide Promotes Diabetic Wound Healing Through Inhibition of the NLRP3 Inflammasome.

The aim of this study was to evaluate the therapeutic effects of Bletilla striata polysaccharide (BSP) on wound healing in diabetes mellitus (DM) and to explore the underlying mechanisms. DM mouse models were induced by high fat-diet feeding combined with low-dose streptozocin injection. To establish diabetic foot ulcer (DFU) models, DM mice were wounded on the dorsal surface. Subsequently, mice were treated with vehicle or BSP for 12 days and wound healing was monitored. The effects of BSP on the production of interleukin-1ß (IL-1ß), tumor necrosis factor-α, macrophages infiltration, angiogenesis, the activation of nucleotide-binding and oligomerization (NACHT) domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome, and insulin sensitivity in wound tissues were subsequently evaluated. Separated- and cultured- bone marrow-derived macrophages (BMDMs) and cardiac microvascular endothelial cells (CMECs) were isolated from mice and used to investigate the effects of BSP on cell viability, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation and insulin sensitivity in vitro following exposure to high glucose (HG). BSP administration accelerated diabetic wound healing, suppressed macrophage infiltration, promoted angiogenesis, suppressed NLRP3 inflammasome activation, decreased IL-1ß secretion, and improved insulin sensitivity in wound tissues in DM mice. In vitro, co-treatment with BSP protected against HG-induced ROS generation, NLRP3 inflammasome activation, and IL-1ß secretion in BMDMs, and improved cell viability and decreased ROS levels in CMECs. Moreover, in HG exposed BMDMs-CMECs cultures, BSP treatment suppressed NLRP3 inflammasome activation and IL-1ß secretion in BMDMs, and improved cell viability and insulin sensitivity in CMECs. Furthermore, treatment with IL-1ß almost completely suppressed the beneficial effects of BSP on the NLRP3 inflammasome, IL-1ß secretion, and insulin sensitivity in HG-treated BMDMs-CMECs. BSP promotes DFU healing through inhibition of the HG-activated NLRP3 inflammasome.

The Pharmacokinetics and Tissue Distributions of Nine Steroidal Saponins from Paris polyphylla in Rats.

BACKGROUND AND OBJECTIVES: Paris polyphylla (P. polyphylla) is a herb widely used in traditional Chinese medicine to treat various diseases. This study used ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to study the pharmacokinetics and tissue distributions of nine steroidal saponins from P. polyphylla. METHODS: P. polyphylla extract was administered to rats intravenously (i.v.) and orally (p.o.). The concentrations of the nine main bioactive components of the extract were determined in plasma and tissue samples using UPLC-MS/MS. The nine saponin compounds were also incubated in an anaerobic environment with intestinal flora suspension solution to investigate hydrolysis by intestinal flora. RESULTS: After oral administration of the P. polyphylla extract, polyphyllin VII was found to have the highest maximum concentration (Cmax, 17.0 ± 2.24 µg/L) of all nine components, followed by the Cmax values of dioscin (16.17 ± 0.64 µg/L) and polyphyllin H (11.75 ± 1.28 µg/L), while the Cmax values of polyphyllin I, polyphyllin II, progenin III, polyphyllin IV, gracillin, and polyphyllin were less than 10 µg/L. The bioavailabilities of all nine components were less than 1%. All the compounds were hydrolyzed by intestinal flora and were predominantly distributed in the liver and lungs. CONCLUSIONS: The nine compounds presented different pharmacokinetic parameter values, and multiple administrations did not accumulate in the body. The bioavailabilities of the compounds were low, partly because of hydrolysis by intestinal flora. The nine compounds were mainly distributed in the liver and lungs, which may be target organs.

Pharmacokinetics, Bioavailability, and Tissue Distribution Study of Angoroside C and Its Metabolite Ferulic Acid in Rat Using UPLC-MS/MS.

Angoroside C is a phenylpropanoid glycoside compound isolated from the dried root of Scrophularia ningpoensis Hemsl., which possesses the effects of preventing ventricular remodeling, reducing pulmonary oedema, and reducing blood pressure, as well as having the properties of anti-platelet aggregation, hepatoprotection and anti-nephritis, etc. However, few investigations have been conducted on the absorption, distribution, metabolism, and excretion (ADME) study of angoroside C. Thus, a fast ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method was established for the determination of angoroside C and its metabolite ferulic acid in rat plasma and tissue homogenate. The two analytes were extracted from the biosamples using a simple protein precipitation with acetonitrile. The developed method was validated and successfully applied to the pharmacokinetics, bioavailability and tissue distribution study after the intragastric administration of angoroside C (100 mg/kg) or the intravenous administration of angoroside C (5 mg/kg), respectively. The results showed that angoroside C can be absorbed extremely quickly (T max = 15 min), can be eliminated very rapidly (t 1/2 = 1.26 h), and its oral bioavailability is only about 2.1%. Furthermore, angoroside C was extensively distributed in all main organs (liver, heart, spleen, lung, kidney, and brain), and the highest concentration was detected in the lung 15 min after oral administration. This paper also indicated that angoroside C could be converted to the active metabolite ferulic acid in vivo. The maximum concentrations of ferulic acid in the kidney occurred at 6 h after oral administration. In summary, this study explored some of the pharmacokinetic characteristics of angoroside C in vivo, and the data produced could provide a basis for the further investigation of angoroside C.

Ethyl 2-isopropyl-amino-5-methyl-4-oxo-3-phenyl-3,4-dihydro-thieno[2,3-d]pyrimidine-6-carboxyl-ate.

The title compound, C(19)H(21)N(3)O(3)S, was synthesized via an aza-Wittig reaction of a functionalized imino-phospho-rane with phenyl isocyanate under mild conditions. In the mol-ecule, the fused thienopyrimidine ring system makes a dihedral angle of 66.30 (11)° with the phenyl ring. An intra-molecular C-H⋯O hydrogen bond occurs. The terminal -OCH(2)CH(3) group is disordered over two sites with refined occupancies of 0.537 (13) and 0.463 (13). The crystal packing is stabilized by inter-molecular C-H⋯O and N-H⋯O hydrogen bonds.