Osthole alleviates pulmonary vascular remodeling by modulating microRNA-22-3p mediated lipid metabolic reprogramming.

BACKGROUND: Pulmonary vascular remodeling is the key pathological feature of pulmonary arterial hypertension (PAH) characterized by a pattern of lipid-related insulin resistance(IR), hormonal derangements and metabolic reprogramming. Our previous studies have demonstrated osthole as natural coumarin compound derived from traditional Chinese medicine is a promising agent for the treatment of pulmonary vascular remodeling in PAH. PURPOSE: The present study sought to delineate lipid metabolic modulatory mechanism of osthole against pulmonary vascular remodeling by employing an interdisciplinary strategy. METHODS: Rat model with PAH induced with MCT and PASMCs proliferation model induced with PDGF-BB were established in this study. Serum and lung tissues were used to lipid-related IR, hormone related indexes, pulmonary vascular remodeling analysis. Then, lipid metabolic gene, key enzymes, metabolites and cell proliferation indexes were examined to investigate metabolic regulatory mechanism in vivo and vitro model of PAH. RESULTS: Osthole significantly showed improvement of lipid-related IR and hormone dysregulation in rats with PAH evidenced by elevating testosterone, androgen receptor and cyclic guanosine monophosphate (cGMP), inhibiting phosphodiesterase-5(PDE-5), modulating lipid-related IR indexes total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG)/HDL-C ratio. Additionally, osthole limited key metabolic gene and enzymes to inhibit accumulation of decadienyl-l-carnitine in lipid metabolism, thus to promote oxidative phosphorylation and ATP production through inhibition of miRNA-22-3p, fatty acid translocase (CD36), fatty acid synthase (FAS), phospholipase A2 (PLA2), carnitine palmitoyltransferase 1A (CPT1A), hexokinase 2 (HK2), activation of metabolic switch isocitrate dehydrogenase 3α (IDH3α), NADH dehydrogenase 1 (ND1). We found for the first time miRNA-22-3p modulated PASMCs proliferation and vascular remodeling by regulating lipid metabolism reprogramming. Those modifications uncovered therapeutic mechanism of osthole against pulmonary vascular remodeling. CONCLUSION: Our findings revealed the function of miRNA-22-3p in PASMCs and demonstrated a novel mechanism that miRNA-22-3p as a regulator can be targeted by osthole to greatly restore dysregulated lipid metabolism thus to alleviate pulmonary vascular remodeling in PAH, which provides novel insight into the potential therapeutic target for PAH, further highlights the development potential of osthole derived new drug against PAH.

Rhodiola crenulata extract decreases fatty acid oxidation and autophagy to ameliorate pulmonary arterial hypertension by targeting inhibiton of acylcarnitine in rats.

Pulmonary arterial hypertension (PAH) is a devastating pulmonary circulation disease lacking high-efficiency therapeutics. The present study aims to decipher the therapeutic mechanism of Rhodiola crenulata, a well-known traditional chinese medicine with cardiopulmonary protection capacity, on PAH by exploiting functional lipidomics. The rat model with PAH was successfully established for first, following Rhodiola crenulata water extract (RCE) treatment, then analysis of chemical constituents of RCE was performed, additional morphologic, hemodynamic, echocardiographic measurements were examined, further targeted lipidomics assay was performed to identify differential lipidomes, at last accordingly mechanism assay was done by combining qRT-PCR, Western blot and ELISA. Differential lipidomes were identified and characterized to differentiate the rats with PAH from healthy controls, mostly assigned to acylcarnitines, phosphatidylcholines, sphingomyelin associated with the PAH development. Excitingly, RCE administration reversed high level of decadienyl-L-carnitine by the modulation of metabolic enzyme CPT1A in mRNA and protein level in serum and lung in the rats with PAH. Furthermore, RCE was observed to reduce autophagy, confirmed by significantly inhibited PPARγ, LC3B, ATG7 and upregulated p62, and inactivated LKB1-AMPK signal pathway. Notably, we accurately identified the constituents in RCE, and delineated the therapeutic mechansim that RCE ameliorated PAH through inhibition of fatty acid oxidation and autophagy. Altogether, RCE might be a potential therapeutic medicine with multi-targets characteristics to prevent the progression of PAH. This novel findings pave a critical foundation for the use of RCE in the treatment of PAH.

Osthole attenuates pulmonary arterial hypertension by the regulation of sphingosine 1-phosphate in rats.

Osthole is observed to have the capacity to treat pulmonary arterial hypertension (PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro. These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1P via microRNA-21-PI3K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.

The Reparative Effect of Dendrobium officinale Protocorms against Photodamage Caused by UV-Irradiation in Hairless Mice.

Dendrobium officinale protocorms (DOPs) are a specific developmental stage of Dendrobium officinale KIMURA et MIGO, which is used in folk medicine to ease skin issues, such as wrinkles and erythema. The purpose of the current study was to evaluate the effect of DOPs on UV irradiation-induced skin damage in bc_nu hairless mice, using matrixyl as a positive control. Hairless mice were randomly separated into 6 groups (8 mice per group). The normal control group received solvent and was not exposed to UV irradiation, while the model control group received solvent and was exposed to UV irradiation. The positive control group was subjected to UV irradiation and then received a 10 mg/mL formulation of matrixyl. The DOPs-treated groups received a transdermal application of a DOPs formulation after 4 weeks of UV irradiation. Relevant indicators, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), thiobarbituric acid reactive substances (TBARS) and matrix metalloproteinases (MMPs), were then used to evaluate the ability of DOPs to repair photodamage. The results indicated that DOPs significantly reduced erythema and protected the skin from dryness and therefore exhibits a significant anti-photoaging effect. In addition, the expression of CAT, SOD, and GSH-Px increased while TBARS and MMPs levels decreased in DOPs-treated mice. This demonstrated that DOPs can inhibit photodamage in the skin of hairless mice. DOPs could be used as a potential therapeutic agent to protect the skin against UV-induced photoaging.

[Research on HPLC fingerprint of Rheum palmatum from Gansu Province called "quan-shui-da-huang"].

OBJECTIVE: To establish an analysis method for HPLC fingerprint of Rheum palmatum collected from Gansu province (called "Quan-shui-da-huang"), and provide basis for quality control of Quan-shui-da-huang. METHODS: The Cosmosil 5C18-PAQ column (250 mm x 4.6 mm, 5 microm) was used with the mixture of 0.1% acetic acid and acetonitrile as mobile phase in a gradient elution mode. The flow rate was 1 mL/min, column temperature was 30 degrees C and detection wavelength was set at 280 nm. The similarity evaluation, principal component analysis (PCA) and cluster analysis of crude drugs collected from different habitats were carried out. RESULTS: The analysis method of HPLC fingerprint was set up. The characteristic fingerprint was obtained by chemometrics methods. CONCLUSION: Under the selected chromatographic conditions, constituents in Rheum palmatum can be separated well. This method can be used for the quality control of Quan-shui-da-huang.

Geostatistical analysis and risk assessment on soil total nitrogen and total soil phosphorus in the Dongting Lake plain area, China.

Nonpoint-source pollution and water body eutrophication have become increasing concerns for scientists and policymakers. Nitrogen and phosphorus affect environmental pollution, especially lake eutrophication. To assess the environmental risk of soil total nitrogen (TN) and total phosphorus (TP) pollution, a typical ecological unit of Dongting Lake plain was selected as the experimental site. To verify the stationary of the data, a moving windows technique was adopted. Our results showed that Box-Cox transformation achieved normality in the data set and dampened the effect of outliers. The best theoretical model for semivariogram of TN and TP was a spherical model. The ordinary kriging estimates of TN and TP concentrations were mapped. The integrative comparisons of semivariogram parameters with different trends to the kriging prediction errors of TN and TP indicated that the two-order trend is preferable. Kriging SDs provided valuable information that will increase the accuracy of TN and TP mapping. The probability kriging method is useful to assess the risk of N and P pollution by providing the conditional probability of N and P concentrations exceeding the threshold concentrations of 3.2 and 1.05 g/kg, respectively. The probability distribution of TN and TP at different levels will be helpful to conduct risk assessment, optimize fertilization, and control the pollution of N and P.