Anti-Diabetic Effect of a Shihunine-Rich Extract of Dendrobium loddigesii on 3T3-L1 Cells and db/db Mice by Up-Regulating AMPK-GLUT4-PPARα.

The stems of Dendrobium loddigesii, a Chinese herb, are often used to treat diabetes and its polar extract is rich in shihunine, a water-soluble Orchidaceae alkaloid, but little is known about the anti-diabetes effects and mechanism of shihunine. This study investigated the anti-diabetic effect of a shihunine-rich extract of D. loddigesii (DLS) based on 3T3-L1 cells and db/db mice. The underlying mechanisms were primarily explored using Western blot analysis and immunohistochemical staining. The 3T3-L1 cell experiments showed that DLS can reduce the intracellular accumulation of oil droplets as well as triglycerides (p < 0.001) and promote the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2deoxyglucose (2-NBDG) uptake of 3T3-L1 cells (p < 0.001). The animal experiments confirmed that after 8 weeks of DLS treatment, the body weight, fasting blood sugar, and serum lipid levels of mice were significantly lowered, and the oral glucose tolerance test and serum insulin level were significantly improved compared to the no-treatment diabetes mellitus group. Further histomorphology observation led to the conclusion that the quantities of islet cells were significantly increased and the increase in adipose cell size was significantly suppressed. The immunohistochemical test of pancreatic tissue revealed that DLS inhibited the expression of cleaved cysteine aspartic acid-specific protease 3 (cleaved caspase-3). Western blot experiments showed that DLS had agonistic effects on adenosine monophosphate (AMP)-activated protein kinase phosphorylation (p-AMPK) and increased the expression levels of peroxisome proliferator-activated receptor α (PPARα) and glucose transporter 4 (GLUT4) in liver or adipose tissues. These data suggest that the shihunine-rich extract of D. loddigesii is an anti-diabetic fraction of D. loddigesii. Under our experimental condition, DLS at a dose of 50 mg/kg has good anti-diabetic efficacy.

Effects of Rich-Polyphenols Extract of Dendrobium loddigesii on Anti-Diabetic, Anti-Inflammatory, Anti-Oxidant, and Gut Microbiota Modulation in db/db Mice.

Dendrobium is a traditional Chinese herb with anti-diabetic effects and has diverse bibenzyls as well as phenanthrenes. Little is known about Dendrobium polyphenols anti-diabetic activities, so, a rich-polyphenols extract of D. loddigesii (DJP) was used for treatment of diabetic db/db mice; the serum biochemical index and tissue appearance were evaluated. In order to gain an insight into the anti-diabetic mechanism, the oxidative stress index, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and gut microbiota modulation were determined by ELISA, immunohistochemistry or high throughput sequencing 16S rRNA gene. The results revealed that DJP had the effects to decrease the blood glucose, body weight, low density lipoprotein cholesterol (LDL-C) levels and increase insulin (INS) level in the mice. DJP improved the mice fatty liver and diabetic nephropathy. DJP showed the anti-oxidative abilities to reduce the malondialdehyde (MDA) level and increase the contents of superoxide dismutase (SOD), catalase (CAT) as well as glutathione (GSH). DJP exerted the anti-inflammatory effects of decreasing expression of IL-6 and TNF-α. After treatment of DJP, the intestinal flora balance of the mice was ameliorated, increasing Bacteroidetes to Firmicutes ratios as well as the relative abundance of Prevotella/Akkermansia and reducing the relative abundance of S24-7/Rikenella/Escherichia coli. The function's prediction of gut microbiota indicated that the microbial compositions involved carbohydrate metabolism or lipid metabolism were changed. This study revealed for the first time that DJP improves the mice symptoms of diabetes and complications, which might be due to the effects that DJP induced the decrease of inflammation as well as oxidative stress and improvement of intestinal flora balance.

Predicting dual-targeting anti-influenza agents using multi-models.

Influenza is an acute respiratory infectious disease caused by influenza viruses. Its subtype can be distinguished based on the antigenicity of two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). One of the main challenges in anti-influenza drug development is the quick evolution of drug resistance due to virus mutations. One solution to this problem is to develop dual-targeting anti-influenza agents. In this paper, a new rationally designed virtual screening protocol that combines structure-based approaches (molecular docking and molecular dynamic simulations) and ligand-based approaches (support vector machines and 3D shape & electrostatic similarity algorithms) is reported for the virtual screening of dual-targeting agents against HA and NA. The final hits came from the consensus of the ligand- and receptor-based knowledge of HA and NA and were tested using ADMET predictions. Evidence from the binding energy calculations and binding mode analyses suggested that several of the hits are promising as dual-targeting anti-influenza agents. The virtual screening protocol may also lead to the identification of innovative drugs in other fields.

Comprehensive measurement of carbonyls in Lhasa, Tibetan Plateau: Implications for strong atmospheric oxidation capacity.

Carbonyls are ubiquitous in the troposphere and play a crucial role in atmospheric oxidation capacity (AOC), particularly in photochemistry-active regions such as the Tibetan Plateau (TP). However, the composition and evolution of carbonyls over the TP is still poorly understood due to a lack of comprehensive observations and modelling. Here, we conducted an intensive field measurement of 37 carbonyls and their precursors at a suburban site in Lhasa during summer 2022. Markedly higher levels of carbonyls (7.24 ± 3.83 ppbv) were found during ozone pollution episodes, with 36 % higher than those during non-episodes. Formaldehyde was the most abundant carbonyl (38 %), which primarily originating from photochemical secondary formations. Simulations using the Rapid adaptive Optimization Model for Atmospheric Chemistry (ROMAC) indicated strong AOC in Lhasa, with the daytime maximum of ·OH and ·HO2 of 9.8 × 106 and 4.2 × 108 molecules cm-3, respectively, which were even higher than that in most of the megacities in China. Notably, AOC significantly enhanced with the increasing carbonyls during the episodes, with the concentrations of ·OH and ·HO2 were boosted 21 % and 67 % than those during non-episodes, respectively. Budget analysis revealed that the ·HO2 + NO (88 %) and ·OH + VOC (74 %) pathways dominated the generation and loss of ·OH, respectively. And for ·HO2, they were ·RO2 + NO (67 %) and ·HO2 + NO (83 %). This study provides valuable insights into the strong AOC in the ecologically-fragile and climate-sensitive TP region, and highlighted the crucial role of anthropogenic-biogenic interactions in the active photochemistry of TP.

Molecular dynamics-based virtual screening: accelerating the drug discovery process by high-performance computing.

High-performance computing (HPC) has become a state strategic technology in a number of countries. One hypothesis is that HPC can accelerate biopharmaceutical innovation. Our experimental data demonstrate that HPC can significantly accelerate biopharmaceutical innovation by employing molecular dynamics-based virtual screening (MDVS). Without using HPC, MDVS for a 10K compound library with tens of nanoseconds of MD simulations requires years of computer time. In contrast, a state of the art HPC can be 600 times faster than an eight-core PC server is in screening a typical drug target (which contains about 40K atoms). Also, careful design of the GPU/CPU architecture can reduce the HPC costs. However, the communication cost of parallel computing is a bottleneck that acts as the main limit of further virtual screening improvements for drug innovations.

Spill-over effect and efficiency of seven pilot carbon emissions trading exchanges in China.

With the negative impact of climate change on the environment becoming more and more obvious, countries all over the world have strengthened their attention to environmental protection, the establishment of carbon emission trading mechanism is widely regarded as the most effective way to reduce carbon emissions. The design of carbon emission trading markets (ETMs) operation mechanisms and operational efficiency directly affect whether carbon ETM can cope with climate change and achieve its environmental protection purpose. In this study, we use multiple model synthesis to comprehensively evaluate the operation of carbon ETM, determine unreasonable modes of carbon ETM operation and propose suggestions for improvement. First, we propose a methodological framework to comprehensively evaluate the operational efficiency of carbon ETMs, and use the DCC-GARCH model to analyse information exchange and interaction between domestic and international carbon ETMs. Then, from the four dimensions of trading processes, law and inspection systems, the internal operation of carbon ETMs, and the impact of carbon ETM operation on the regional economy, 13 input-output indicators are selected to establish a super-DEA model to evaluate the efficiency of seven carbon ETMs. The results show that the spillover effect among various carbon ETMs is unstable, exchange between carbon ETMs is low. The operational efficiency of China's carbon ETMs is increasing each year, but there are significant differences in the operation efficiency levels of carbon ETMs. The system in Hubei has the highest super-DEA score, followed by that in Shenzhen, and those in Chongqing and Tianjin have lower scores. From the perspective of pilot projects with good operation, strong legal system constraints and reasonable operation mechanisms are important means to ensure operational efficiency.

A Supramolecular Hydrogel of Puerarin.

Supramolecular hydrogels have drawn increased attention because of their advantages in facile synthesis, biocompatibility, easy degradation and fast responses to external stimuli. Until now, the example of hydrogelators of pure natural resources has rarely been reported. Here, we report on a novel hydrogelator of a natural resource, puerarin, which could self-assemble to hydrogels with excellent antioxidant properties and tremendous acid resistance. Our PG-4 could overcome exogenous ROS injury and promote the survival rate of H2O2 treated MSCs by down-regulating SOD activity and MDA level by 21.6% and 28.7% respectively. In addition, utilizing the good acid resistance of PG-4, we investigated its application as an oral formulation. The dissolution rate of puerarin in intestinal-fluid analogue (87.8% at 12 hr) was much faster than that in gastric-fluid analogue (35.6% at 12 hr), which demonstrated that the majority of puerarin was diffused from PG-4 in simulated intestinal fluid. The corresponding pharmacokinetics parameters indicated that PG-4 remarkably improved the absorption of puerarin by oral administration.

Bifunctional Supramolecular Hydrogel Alleviates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy and Apoptosis.

Generally, nitric oxide (NO) is an important multi-functional cardioprotective soluble gas molecule. However, it may be detrimental when in excessive levels or combined with O2- a kind of reactive oxygen species (ROS)-to form ONOO-. The latter will rapidly decompose to highly reactive oxidant components. ROS will be abundantly produced during the ischemia/reperfusion (I/R) procedure. Therefore, an NO donor coupled with another antioxidant would be a more promising strategy for I/R treatment. In this study, we report on a novel self-assembly supramolecular hydrogel capable of constantly releasing both NO and curcumin (Cur) simultaneously, and we found that the combinational treatment of Cur and NO from the gel could efficiently reduce I/R injuries. The underlining mechanism revealed that the hydrogel could reduce the ROS level and thus inhibit the expression of the ROS-associated p38 MAPK/NF-κB signaling pathway. Moreover, the hydrogel also significantly suppressed over-stimulated autophagy and apoptosis during I/R treatment which was responsible for mediating severe post-ischemia myocardial cell death. The results indicated that our supramolecular hydrogel was a promising biomaterial for the treatment of myocardial I/R injuries.

Nrf2 Is a Key Regulator on Puerarin Preventing Cardiac Fibrosis and Upregulating Metabolic Enzymes UGT1A1 in Rats.

Puerarin is an isoflavone isolated from Radix puerariae. Emerging evidence shown that puerarin possesses therapeutic benefits that aid in the prevention of cardiovascular diseases. In this study, we evaluated the effects of puerarin on oxidative stress and cardiac fibrosis induced by abdominal aortic banding (AB) and angiotensin II (AngII). We also investigated the mechanisms underlying this phenomenon. The results of histopathological analysis, as well as measurements of collagen expression and cardiac fibroblast proliferation indicated that puerarin administration significantly inhibited cardiac fibrosis induced by AB and AngII. These effects of puerarin may reflect activation of Nrf2/ROS pathway. This hypothesis is supported by observed decreases of reactive oxygen species (ROS), decreases Keap 1, increases Nrf2 expression and nuclear translocation, and decreases of collagen expressions in cardiac fibroblasts treated with a combination of puerarin and AngII. Inhibition of Nrf2 with specific Nrf2 siRNA or Nrf2 inhibitor brusatol attenuated anti-fibrotic and anti-oxidant effects of puerarin. The metabolic effects of puerarin were mediated by Nrf2 through upregulation of UDP-glucuronosyltransferase (UGT) 1A1. The Nrf2 agonist tBHQ upregulated protein expression of UGT1A1 over time in cardiac fibroblasts. Treatment with Nrf2 siRNA or brusatol dramatically decreased UGT1A1 expression in puerarin-treated fibroblasts. The results of chromatin immunoprecipitation-qPCR further confirmed that puerarin significantly increased binding of Nrf2 to the promoter region of Ugt1a1. Western blot analysis showed that puerarin significantly inhibited AngII-induced phosphorylation of p38-MAPK. A specific inhibitor of p38-MAPK, SB203580, decreased collagen expression, and ROS generation induced by AngII in cardiac fibroblast. Together, these results suggest that puerarin prevents cardiac fibrosis via activation of Nrf2 and inactivation of p38-MAPK. Nrf2 is the key regulator of anti-fibrotic effects and upregulates metabolic enzymes UGT1A1. Autoregulatory circuits between puerarin and Nrf2-regulated UGT1A1 attenuates side effects associated with treatment, but it does not weaken puerarin's pharmacological effects.

Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway.

BACKGROUND: Cyclosporin A (CsA) is an immunosuppressent which is used for preventing allograft rejection. Little is known, however, about the effect of CsA on the materno-fetal relationship. Our aim was to probe into the effect of CsA on the invasiveness of human first-trimester trophoblast cells and explore possible molecules involved, with a view to providing a new therapeutic approach for pregnancy complications with trophoblast disorder. METHODS: The effects of CsA on invasion of the first-trimester human trophoblasts were examined by matrigel invasion assay, and the transcription, translation and proteolytic activity of matrix metalloproteinase (MMP-9) and MMP-2 in these cells were estimated by RT-PCR, in-cell Western and zymography, respectively. The phosphorylation level of extracellular-signal related kinase (ERK) 1/2 in trophoblasts induced by CsA was also evaluated by in-cell Western. RESULTS: CsA increased the invasive index of first-trimester human trophoblasts (P < 0.01), as well as the messenger RNA, protein levels (both P < 0.01) and proteolytic activity (P < 0.05) of MMP-9 and MMP-U0126, a mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor, inhibited the enhanced invasiveness and activity of MMP-9 and MMP-in these cells induced by CsA. In addition, CsA activated the ERK1/2 in a time-dependent manner. CONCLUSIONS: CsA improves the invasiveness and activity of MMP 9 and MMP 2 in vitro of the first-trimester human trophoblast cells through activation of mitogen-activated protein kinase/extracellular-signal related kinase (ERK) 1/2 signaling pathway, which suggests this drug has a favorable modulation on the function of human first-trimester trophoblast cells.