A rapid, sensitive and accurate UPLC‐MS/MS method was developed for the simultaneous quantification of components of Huangqi decoction (HQD), such as calycosin‐7‐O‐β‐d‐glucoside, ...calycosin‐glucuronide, liquiritin, formononetin‐glucuronide, isoliquiritin, liquiritigenin, ononin, calycosin, isoliquiritigenin, formononetin, glycyrrhizic acid, astragaloside IV, cycloastragenol, and glycyrrhetinic acid, in rat plasma. After plasma samples were extracted by protein precipitation, chromatographic separation was performed with a C18 column, using a gradient of methanol and 0.05% acetic acid containing 4mm ammonium acetate as the mobile phase. Multiple reaction monitoring scanning was performed to quantify the analytes, and the electrospray ion source polarity was switched between positive and negative modes in a single run of 10 min. Method validation showed that specificity, linearity, accuracy, precision, extraction recovery, matrix effect and stability for 14 components met the requirements for their quantitation in biological samples. The established method was successfully applied to the pharmacokinetic study of multiple components in rats after intragastric administration of HQD. The results clarified the pharmacokinetic characteristics of multiple components found in HQD. This research provides useful information for understanding the relation between the chemical components of HQD and their therapeutic effects.
The present work describes the in vitro antibacterial evaluation of some new pyrimidine derivatives. Twenty-two target compounds were designed, synthesized and preliminarily explored for their ...antimicrobial activities. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungal including drug-resistant pathogens. Compound
7c
presented the most potent inhibitory activities against Gram-positive bacteria (e.g.,
Staphylococcus aureus
4220), Gram-negative bacteria (e.g.,
Escherichia coli
1924) and the fungus
Candida albicans
7535, with an MIC of 2.4 μmol/L. Compound
7c
was also the most potent, with MICs of 2.4 or 4.8 μmol/L against four multidrug-resistant, Gram-positive bacterial strains. The toxicity evaluation of the compounds
7c
,
10a
,
19d
and
26b
was assessed in human normal liver cells (L02 cells). Molecular docking simulation and analysis suggested that compound
7c
has a good interaction with the active cavities of dihydrofolate reductase (DHFR). In vitro enzyme study implied that compound
7c
also displayed DHFR inhibition.
Graphic abstract
The vertebral body’s Hounsfield unit (HU) value can credibly reflect patients’ bone mineral density (BMD). Given that poor bone-screw integration initially triggers screw loosening and regional ...differences in BMD and strength in the vertebral body exist, HU in screw holding planes should better predict screw loosening. According to the stress shielding effect, the stress distribution changes in the fixation segment with BMD reduction should be related to screw loosening, but this has not been identified. We retrospectively collected the radiographic and demographic data of 56 patients treated by single-level oblique lumbar interbody fusion (OLIF) with anterior lateral single rod (ALSR) screw fixation. BMD was identified by measuring HU values in vertebral bodies and screw holding planes. Regression analyses identified independent risk factors for cranial and caudal screw loosening separately. Meanwhile, OLIF with ALSR fixation was numerically simulated; the elastic modulus of bony structures was adjusted to simulate different grades of BMD reduction. Stress distribution changes were judged by computing stress distribution in screws, bone-screw interfaces, and cancellous bones in the fixation segment. The results showed that HU reduction in vertebral bodies and screw holding planes were independent risk factors for screw loosening. The predictive performance of screw holding plane HU is better than the mean HU of vertebral bodies. Cranial screws suffer a higher risk of screw loosening, but HU was not significantly different between cranial and caudal sides. The poor BMD led to stress concentrations on both the screw and bone-screw interfaces. Biomechanical deterioration was more severe in the cranial screws than in the caudal screws. Additionally, lower stress can also be observed in fixation segments’ cancellous bone. Therefore, a higher proportion of ALSR load transmission triggers stress concentration on the screw and bone-screw interfaces in patients with poor BMD. This, together with decreased bony strength in the screw holding position, contributes to screw loosening in osteoporotic patients biomechanically. The trajectory optimization of ALSR screws based on preoperative HU measurement and regular anti-osteoporosis therapy may effectively reduce the risk of screw loosening.
•The duration of the main magmatism is limited by the Monte Carlo simulation.•It is the first case to use the “Magma Chamber Simulator (MCS_PhaseEQ_2019AC)” to discuss the heat source of UHT ...metamorphism.•The interrelationship between the formation of UHT metamorphism and mantle-derived magmatism is established from the perspective of geochronology and EC-AFC.
The Paleoproterozoic Khondalite Belt from the northwestern North China Craton (NCC) is characterized by a wide distribution of high-temperature/ultrahigh-temperature (UHT) metamorphism and extensive magmatic events in its eastern segment, the Jining terrane. Although it has been proven that UHT metamorphism is related to large-scale thermal perturbation at the crustal level, the ultimate heat source has been kept unclear and the reliable interrelationship between the formation of UHT metamorphism and mantle-derived magmatism has not been established yet. We report data of two-layered complexes emplaced in duration over 100 Ma, as the candidates of the heat source of the UHT metamorphism. The samples include 1929 ± 23 Ma Sanchakou amphibole-gabbro (ZK0-3) and 1824 ± 2 Ma Hulu norite-gabbro(HL1517). Based on the published geochronological data of basic intrusive rocks in the Jining terrane, it is found that the Late Paleoproterozoic magmatism appears as two stages of ∼1.95 Ga (M1) and ∼1.85 Ga (M2). We calculated that the duration of M1-magmatism can reach ∼71 Myr through Monte Carlo simulation. The sample ZK0-3 is formed in M1-magmatism, coupled with the peak period of metamorphism and the slow cooling process of UHT pelitic granulite/gneiss. We used the “Magma Chamber Simulator (MCS_PhaseEQ_2019AC)” to simulate the genesis of these basic intrusive rocks. It is found that they have experienced the magmatic process of assimilationand fractional crystallizationunder energy constraints(EC-AFC). The augite, pargasite, and zircon record the crystallization temperatures during the slow cooling process of magma. Therefore, mantle-derived magmatism might have supplied heat to generate the UHT metamorphism in the Jining terrane.
Estimating the impact of pesticide residue bioaccessibility in fruits on dietary exposure is a complex task in human health risk assessment. This research investigated the bioaccessibility of ten ...commonly used and detected pesticides in bananas and mangoes, as well as the factors influencing it, using an in vitro model. The highest bioaccessibility was observed at pH levels of 2.5 and 6.5 in the gastric and intestinal stages, respectively. Bioaccessibility decreased significantly with increasing solid/liquid ratios for most pesticides. The consumption of protein and four dietary components (carbohydrates, protein, lipids, and dietary fiber) could significantly reduce pesticide bioaccessibility by 9.89–48.32% (p < 0.05). Bioaccessibility in oral and gastric stages among four populations followed the order of adults/the elderly > children > infants, due to decreasing concentrations of α-amylase and pepsin. Pesticides in bananas generally exhibited a higher bioaccessibility (18.65–82.97%) compared to that in mangoes (11.68–87.57%). Bioaccessibility showed a negative correlation with the Log P values of the target pesticide, while no clear relationship was found between bioaccessibility and initial pesticide concentrations. Incorporating bioaccessible pesticide concentrations into risk assessments could lower dietary risk estimates by 11.85–79.57%. Assessing human exposure to pesticides based on bioaccessibility would greatly improve the accuracy of the risk assessment.
Although the benefits of electroacupuncture (EA) for peripheral nerve injury (PNI) are well accepted in clinical practice, the underlying mechanism remains incompletely elucidated. In our study, we ...observed that EA intervention led to a reduction in the expression of the long non-coding RNA growth-arrest-specific transcript 5 (GAS5) and an increased in miR-21 levels within the injured nerve, effectively promoting functional recovery and nerve regeneration following sciatic nerve injury (SNI). In contrast, administration of adeno-associated virus expressing GAS5 (AAV-GAS5) weakened the therapeutic effect of EA. On the other hand, both silencing GAS5 and introducing a miR-21 mimic prominently enhanced the proliferation activity and migration ability of Schwann cells (SCs), while also inhibiting SCs apoptosis. On the contrary, inhibition of SCs apoptosis was found to be mediated by miR-21. Additionally, overexpression of GAS5 counteracted the effects of the miR-21 mimic on SCs. Moreover, SCs that transfected with the miR-21 mimic promoted neurite growth in hypoxia/reoxygenation-induced neurons, which might be prevented by overexpressing GAS5. Furthermore, GAS5 was found to be widely distributed in the cytoplasm and was negatively regulated by miR-21. Consequently, the targeting of GAS5 by miR-21 represents a potential mechanism through which EA enhances reinnervation and functional restoration following SNI. Mechanistically, the GAS5/miR-21 axis can modulate the proliferation, migration, and apoptosis of SCs while potentially influencing the neurite growth of neurons.
The rhizome of Atractylodes lancea (AL, Compositae, Chinese name: Cangzhu; Japanese name: Sou-ju-tsu) has been used traditionally for the treatment of various diseases such as digestive disorders, ...rheumatic diseases, and influenza in China, Korea and Japan. The crude AL and AL bran-processed are both listed in the Chinese Pharmacopoeia. However, the differences between the effects of the crude and AL bran-processed on gastric ulcer were poorly understood, and the mechanisms for the treatment of gastric ulcer were not clear. This study aimed at comparing the anti-ulcer effects between the crude AL and AL processed in acetic acid induced model in rats and evaluating the mechanisms of action involved in the anti-ulcer properties of AL.
The model of gastric ulcer was imitated by acetic acid in rats, and AL was gavaged. The serum and gastric tissues were collected. The levels of epidermal growth factor (EGF), trefoil factor2 (TFF2), tumor necrosis factor-α (TNF-α), interleukin 6, 8 (IL-6, 8) and prostaglandin E2 (PGE2) in serum and gastric tissues were determined by the double-antibody sandwich enzyme-linked immunosorbent assay (ELISA), and the mRNA expressions of EGF, TFF2, TNF-α, and IL-8 in stomach were analyzed by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Meanwhile, histopathological changes were evaluated by hematoxylin and eosin (HE) stain. The protein expressions of EGF, TFF2, TNF-α, and IL-8 were examined by immunohistochemistry in stomach.
The results demonstrated that the damage of gastric tissue was obviously alleviated and the productions of TNF-α, IL-8, IL-6, and PGE2 and the mRNA expressions of TNF-α, and IL-8 were notably inhibited. Furthermore, the productions of EGF and TFF2 and the mRNA expressions of EGF and TFF2 were significantly stimulated by both crude AL and AL processed in a dose-dependent manner. Compared with the crude AL, the processed AL was more effective.
The AL processed had more satisfactory effects in treatment of gastric-ulcer than the crude AL. The anti-ulcer effects of AL could be attributed to the anti-inflammatory properties via down-regulating TNF-α, IL-8, IL-6 and PGE2 and to the gastroprotective effects via up-regulating EGF and TFF2.
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This study investigated the mechanism of drug resistance in non-small cell lung cancer (NSCLC) patients. We specifically studied whether long noncoding RNAs influence drug resistance in NSCLC to ...discover new therapeutic targets to increase the survival rate of drug-resistant NSCLC patients.
Tissue samples were collected from NSCLC patients, and total RNA was isolated for assessment of HOTAIR expression and drug resistance status. MTT assays, tumor sphere formation assays, and western blot were performed to cytologically determine the relationship between HOTAIR expression and cisplatin resistance, as well as to elucidate the potential molecular mechanism involved.
HOTAIR expression in tissues of drug-resistant NSCLC patients was higher than that of non-drug-resistant patients. HOTAIR expression was elevated in cisplatin-resistant cell strains (A549/CDDP), and reducing HOTAIR expression increased the sensitivity of A549/CDDP cells to cisplatin. In addition, overexpression of HOTAIR in A549 cells increased resistance to cisplatin. Tumor sphere formation assays showed that the volume of spheres formed by cell strains expressing elevated levels of HOTAIR was greater than that of cell strains with low expression. Western blot experiments showed that elevated expression of HOTAIR upregulated tumor stem cell-related biomarkers and HOTAIR expression was directly related to Klf4 expression.
Elevated HOTAIR expression is associated with drug resistance in NSCLC patients and is related to Klf4 upregulation, providing a new therapeutic target for drug-resistant NSCLC patients.
Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as a promising therapeutic target for the treatment of malignant tumors characterized by dysregulated tryptophan metabolism. However, the antitumor ...efficacy of existing small-molecule IDO1 inhibitors is still unsatisfactory, and the underlying mechanism remains largely undefined. To identify novel IDO1 inhibitors, an in-house natural product library of 2000 natural products was screened for inhibitory activity against recombinant human IDO1. High-throughput fluorescence-based screening identified 79 compounds with inhibitory activity > 30% at 20 μM. Nine natural products were further confirmed to inhibit IDO1 activity by > 30% using Ehrlich's reagent reaction. Compounds 2, 7, and 8 were demonstrated to inhibit IDO1 activity in a cellular context. Compounds 2 and 7 were more potent against IDO1 than TDO2 in the enzymatic assay. The kinetic studies showed that compound 2 exhibited noncompetitive inhibition, whereas compounds 7 and 8 were graphically well matched with uncompetitive inhibition. Compounds 7 and 8 were found to bind to the ferric-IDO1 enzyme. Docking stimulations showed that the naphthalene ring of compound 8 formed "T-shaped" π-π interactions with Phe-163 and that the 6-methyl-naphthalene group formed additional hydrophobic interactions with IDO1. Compound 8 was identified as a derivative of tanshinone, and preliminary SAR analysis indicated that tanshinone derivatives may be promising hits for the development of IDO1 inhibitors. This study provides new clues for the discovery of IDO1/TDO2 inhibitors with novel scaffolds.
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