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Oxidative stress is a pivotal stimulating factor in neurocyte apoptosis and has been involved in the pathogenesis of Parkinson’s disease (PD). In this study, we have demonstrated that the improvement in the motor disorder of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/Pro-induced mice caused by b-Ecdysterone (b-Ecd) treatment is due to its antioxidant properties. Using open field, rotarod, and pole climbing tests, we have found that b-Ecd alleviates motor disorder in MPTP/Pro-induced mice and ultimately reduces the impairment of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra (SN). Notably, these effects of b-Ecd were not observed in Nrf2-KO mice. In addition, b-Ecd significantly reduced the formation of ROS and the level of MDA, blocked the increase of LPO, and partially reversed the GSH/GSSG ratio in MPTP/Pro-induced WT mice; however, these results were also not observed in MPTP/Pro-induced Nrf2-KO mice. Mechanistically, b-Ecd enhanced the expression levels of heme oxygenase 1 (HO-1) and GCLc, but not NQO1 (NAD(P)H quinone dehydrogenase 1) and GCLm expression. Interestingly, b-Ecd failed to increase the protein and mRNA levels of HO-1 and GCLc in Nrf2-KO mice, suggesting that b-Ecd attenuates oxidative stress through an Nrf2-dependent mechanism. Furthermore, b-Ecd promoted the expressions of PI3K/Akt phosphorylation (activity) and GSK-3b phosphorylation (inactivity). Conversely, administration of b-Ecd markedly decreased Fyn phosphorylation levels. Collectively, our findings suggest that b-Ecd focuses on Nrf2 in reducing MPTP/Pro-induced oxidative stress and subsequent motor deficits by inhibiting its nuclear export through PI3K/Akt/GSK-3b/Fyn pathway regulation. These further indicate that b-Ecd may be an absorbing therapeutic agent for PD.

Acute lung injury (ALI) is a clinically prevalent inflammatory disorder that still needs to be developed with more accurate diagnostic biomarkers and more satisfactory therapies. This study intended to explore the therapeutic material basis and molecular mechanisms of a classical traditional Chinese medicinal prescription, Sang Ju Yin (SJY), against ALI, focusing on the chemical components of formula composition, the disturbance of host genes/metabolites and the dysbiosis of intestinal flora. First, based on liquid chromatography-mass spectrometry (LC-MS) component analysis, 212 in vitro and 44 in vivo compounds were identified respectively in SJY. Then, network pharmacology was adopted to calculate potential anti-ALI compounds in SJY and predict that CXCR2, PI3K-Akt signaling and arachidonic acid (AA) metabolism could be potential targets. Subsequently, integrative multi-omics techniques were employed to elaborate deeper systematic molecular mechanisms. Metabolomic data combining both 1H NMR and LC-MS techniques illustrated that 146 pulmonary and 75 fecal biomarkers, associated with AA and other metabolisms, were recuperated by SJY’s intervention. Transcriptomic analyses suggested that SJY could significantly regulate genes and signaling pathways involved with inflammation and apoptosis, such as PI3K-Akt. Further the obtained key targets (IL-10, LCAT, CXCR2 and C5) were verified by qRT-PCR and their relative compound-target interaction were validated by molecular docking. Notably, the disturbance of intestinal microbial community (such as the abundance of Lactobacillus, etc.) was detected through 16S rRNA gene sequencing, that could be effectively reshaped by SJY. Collectively, our integrated work showed SJY could regulate the crosstalk of metabolite-target-pathway-microflora along the gut-microbiota-lung axis on the whole. Noteworthy, our study provided fundamental and new insights into how molecular networks connected different types of components, genes, metabolites, microbes and potential pathways to map an endogenous functional landscape for clinical ALI diagnosis and SJY application.

Ulcerative colitis (UC) is a recurrent inflammatory disease related to gut microbiota disorder. Metabolites and their sensors play an important role in the communication between gut microbes and their host. Our previous study revealed that G protein‐coupled receptor 35 (GPR35) is a key guardian of kynurenic acid (KA) and a core element of the defense responses against gut damage. However, the mechanism remains unknown. In this study, a DSS‐induced rat colitis model was established and 16S rRNA sequencing was applied to explore the influence of GPR35‐mediated KA sensing on gut microbiota homeostasis. Our results demonstrated that GPR35‐mediated KA sensing is a necessary component in maintaining gut barrier integrity against DSS‐induced damage. Furthermore, we provide compelling evidence suggesting that GPR35‐mediated KA sensing plays a crucial role in maintaining gut microbiota homeostasis, which contributes to alleviation of DSS‐induced colitis. In addition, five classes (Actinobacteria, Beta‐/Gamma‐proteobacteria, Erysipelotrichi, and Coriobacteriia) and six genera (Corynebacterium, Allobaculum, Parabacteroides, Sutterella, Shigella, and Xenorhabdus) were identified as the marked bacterial taxa that characterized the progression and outcome of colitis and are regulated by GPR35‐mediated KA sensing. Our findings highlight that GPR35‐mediated KA sensing is an essential defense mechanism against disorder of gut microbiota in UC. The results provide insights into the key role of specific metabolites and their monitor in maintaining gut homeostasis.

To discover new lead compounds with anti-tumour activities, in the present study, natural diosgenin was hybridised with the reported benzoic acid mustard pharmacophore. The in vitro cytotoxicity of the resulting newly synthesised hybrids (8–10, 14a–14f, and 15a–15f) was then evaluated in three tumour cells (HepG2, MCF-7, and HeLa) as well as normal GES-1 cells. Among them, 14f possessed the most potential anti-proliferative activity against HepG2 cells, with an IC50 value of 2.26 µM, which was 14.4-fold higher than that of diosgenin (IC50 = 32.63 µM). Furthermore, it showed weak cytotoxicity against GES-1 cells (IC50 > 100 µM), thus exhibiting good antiproliferative selectivity between normal and tumour cells. Moreover, 14f could induce G0/G1 arrest and apoptosis of HepG2 cells. From a mechanistic perspective, 14f regulated cell cycle-related proteins (CDK2, CDK4, CDK6, cyclin D1 and cyclin E1) as well mitochondrial apoptosis pathway-related proteins (Bax, Bcl-2, caspase 9, and caspase 3). These findings suggested that hybrid 14f serves as a promising anti-hepatoma lead compound that deserves further research.

Currently, the obvious side effects of anti-tumor drugs, premature drug release, and low tumor penetration of nanoparticles have largely reduced the therapeutic effects of chemotherapy. A drug delivery vehicle (MCN-SS-GQDs) was designed innovatively. For this, the mesoporous carbon nanoparticles (MCN) with the capabilities of superior photothermal conversion efficiency and high loading efficiency were used as the skeleton structure, and graphene quantum dots (GQDs) were gated on the mesopores via disulfide bonds. The doxorubicin (DOX) was used to evaluate the pH-, GSH-, and NIR-responsive release performances of DOX/MCN-SS-GQDs. The disulfide bonds of MCN-SS-GQDs can be ruptured under high glutathione concentration in the tumor microenvironment, inducing the responsive release of DOX and the detachment of GQDs. The local temperature of a tumor increases significantly through the photothermal conversion of double carbon materials (MCN and GQDs) under near-infrared light irradiation. Local hyperthermia can promote tumor cell apoptosis, accelerate the release of drugs, and increase the sensitivity of tumor cells to chemotherapy, thus increasing treatment effect. At the same time, the detached GQDs can take advantage of their extremely small size (5–10 nm) to penetrate deeply into tumor tissues, solving the problem of low permeability of traditional nanoparticles. By utilizing the photothermal properties of GQDs, synergistic photothermal conversion between GQDs and MCN was realized for the purpose of synergistic photothermal treatment of superficial and deep tumor tissues.

As a vital ecological barrier in China, Yellow River Basin (YRB) is strategically significant for China’s national development and modernization. However, YRB has fragile ecosystems, and is sensitive to climatic change. Extreme climate events (e.g., heavy precipitation, heatwaves, and extreme hot and cold) occur frequently in this basin, but the implications (positive and negative effects) of these events on vegetation dynamics remains insufficiently understood. Combing with net primary productivity (NPP), the normalized difference vegetation index (NDVI) and extreme climate indexes, we explored the spatio–temporal characteristics of plants’ growth and extreme climate, together with the reaction of plants’ growth to extreme climate in the Yellow River Basin. This study demonstrated that annual NPP and NDVI of cropland, forest, and grassland in the study region all revealed a climbing tendency. The multi-year monthly averaged NPP and NDVI were characterized by a typical unimodal distribution, with the maximum values of NPP (66.18 gC·m−2) and NDVI (0.54) occurring in July and August, respectively. Spatially, multi–year averaged of vegetation indicators decreased from southeast to northwest. During the study period, carbon flux (NPP) and vegetation index (NDVI) both exhibited improvement in most of the YRB. The extreme precipitation indexes and extreme high temperature indexes indicated an increasing tendency; however, the extreme low temperature indexes reduced over time. NPP and NDVI were negatively associated with extreme low temperature indexes and positively correlated with extreme high temperature indexes, and extreme precipitation indicators other than consecutive dry days. Time lag cross–correlation analysis displayed that the influences of extreme temperature indexes on vegetation indexes (NPP and NDVI) were delayed by approximately six months, while the effects of extreme precipitation indexes were immediate. The study outcomes contribute to our comprehension of plants’ growth, and also their reaction to extreme climates, and offer essential support for evidence–based ecological management practices in the Yellow River Basin.

Abstract In this paper, double PWM converter AC excitation system of the variable speed constant frequency doubly fed induction generator (DFIG) for wind power generation is taken as the research object. At present, most vector control systems of rotor‐side PWM converter adopt feedforward compensation to realize the purpose of power decoupling control. The decoupling effect is greatly affected by the power changes. A power decoupling control strategy based on auto‐disturbance rejection control (ADRC) is proposed. The decoupling control between active power and reactive power is realized by observing the coupling term and the total disturbance of the d‐axis and q‐axis components of the stator current and the stator voltage with the extended state observer and compensating. Simulation analysis and experimental test show that, on the basis of vector transformation, the rotor‐side PWM converter power decoupling control based on ADRC has a small overshoot and fast dynamic response when tracking the change of wind turbine input power, which can achieve the decoupling control between active power and reactive power well. The system has strong robustness and adaptability.

Background: The extract of Euphorbia fischeriana Steud. and Ziziphus jujuba Mill. (ESZM) is a formula composed of Euphorbia fischeriana Steud. (E. fischeriana) and Ziziphus jujuba Mill. (Z. jujuba). Previous studies have shown that the ESZM extract has good anti-breast cancer effects in vitro. However, its in vivo therapeutic efficacy and underlying mechanism are still unclear, particularly for different subtypes of breast cancer. Our study aimed to investigate the pharmacological effects and the underlying molecular mechanism of the ESZM extract on growth inhibition and apoptosis in breast cancer nude mice of MCF-7 (ER+) cells or MDA-MB-453 (ER-) cells Methodology: In this paper, growth inhibition, cell cycle arrest and apoptosis of tumour tissues treated with the ESZM extract in ER(+) or ER(-) breast cancer xenografts were determined based on the tumour inhibition rates, using a cycle analysis kit, Annexin V-FITC/PI and Hoechst 33,342/PI staining and TEM observations, and a TUNEL test. The related gene and protein expression levels were measured using a qRT-PCR assay, Western blotting, immunohistochemistry and immunofluorescence. Serum biochemistry tests and H&E staining were performed to evaluate the toxicity of the ESZM extract. Results: The results showed that the ESZM extract could inhibit the cell growth, block the cell cycle at the G2/M phase, and induce the apoptosis of subcutaneously transplanted tumours, especially of ER(-) breast cancer transplanted tumours. Furthermore, we demonstrated that the polyjuice could down-regulate or up-regulate the expression of the Bcl-2 family factors and of PI3k/Akt pathway-related signalling molecules in vivo. The ESZM extract increased the levels of ALT, AST, Cr and BUN, and increased the hepatic and renal toxicity in cancer-bearing mice. Conclusions: these experimental results indicate that the ESZM extract has significant anti-breast cancer effects, particularly in ER(-) breast cancer xenografts, which might be implemented through the mitochondrion-dependant and the PI3k/Akt signalling pathways. The toxicity tests showed that the ESZM extract may have hepatorenal toxicity. Finally, we believe that the ESZM extract can be developed as a novel therapeutic option for the treatment of breast carcinoma.

The outbreak of COVID-19 at the beginning of 2020 had a significant impact on China’s economy, society, and citizens; it also had a negative impact on the development of the construction industry. In particular, small and medium-sized construction enterprises with low ability to withstand risk have been strongly impacted, aggravating a crisis of survival among these firms. The focus of this study is to analyze the impact of COVID-19 on the growth of small and medium-sized construction companies. Based on the characteristics of small and medium-sized construction enterprises, this paper establishes a growth evaluation index and builds a growth evaluation model based on factor analysis. Twenty-three construction enterprises listed on small and medium-sized enterprises board are selected as samples, and the quarterly data of 2019 and 2020 are used for empirical analysis. The results show that the epidemic has had a high short-term impact on construction enterprises, and the total output value of the construction industry in the first quarter of 2020 was 16% lower than that in the same period of last year. In the long run, the impact of the epidemic on the growth of small and medium-sized construction enterprises has been limited. In the first quarter of 2020, the growth score of enterprises decreased by only 1.95% year-over-year, and it was essentially flat in the second and third quarters. The epidemic has had little influence on solvency, tangible resources or intangible resources but a high short term influence on profitability, capital expansion and market expectations. The long-term impact is small; It is conducive to the improvement of enterprise operation ability. Finally, to both address the influence of the COVID-19 on small and medium-sized construction enterprises and to realize their transformation and upgrading, targeted suggestions are offered at the policy and enterprise levels. The results will help to understand the impact of the epidemic on the growth of construction enterprises, and provide decision support for the healthy and orderly development of the follow-up construction industry.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects human health, and current treatment strategies are far from meeting clinical needs. Inspired by multi-target drug design strategies, a series of novel natural products-based melatonin-hydroxyquinoline hybrids were designed and synthesized, targeting anti-oxidation and metal-chelating at the same time. Most of the compounds showed significant oxygen radical absorbance capacity and Aβ1-42 aggregation inhibition. Moreover, the compounds possess good blood-brain barrier permeability. 6b and 6c have a good ability to alleviate oxidative stress induced by hydrogen peroxide. 6b and 6c possess metal-chelating properties with the chelation ratio being 2:1. Furthermore, 6b can significantly mitigate metal-induced Aβ aggregation. This work may provide a new multi-target treatment strategy for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Oxidative stress is a pivotal stimulating factor in neurocyte apoptosis and has been involved in the pathogenesis of Parkinson's disease (PD). In this study, we have demonstrated that the improvement in the motor disorder of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/Pro-induced mice caused by β-Ecdysterone (β-Ecd) treatment is due to its antioxidant properties. Using open field, rotarod, and pole climbing tests, we have found that β-Ecd alleviates motor disorder in MPTP/Pro-induced mice and ultimately reduces the impairment of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra (SN). Notably, these effects of β-Ecd were not observed in Nrf2-KO mice. In addition, β-Ecd significantly reduced the formation of ROS and the level of MDA, blocked the increase of LPO, and partially reversed the GSH/GSSG ratio in MPTP/Pro-induced WT mice; however, these results were also not observed in MPTP/Pro-induced Nrf2-KO mice. Mechanistically, β-Ecd enhanced the expression levels of heme oxygenase 1 (HO-1) and GCLc, but not NQO1 (NAD(P)H quinone dehydrogenase 1) and GCLm expression. Interestingly, β-Ecd failed to increase the protein and mRNA levels of HO-1 and GCLc in Nrf2-KO mice, suggesting that β-Ecd attenuates oxidative stress through an Nrf2-dependent mechanism. Furthermore, β-Ecd promoted the expressions of PI3K/Akt phosphorylation (activity) and GSK-3β phosphorylation (inactivity). Conversely, administration of β-Ecd markedly decreased Fyn phosphorylation levels. Collectively, our findings suggest that β-Ecd focuses on Nrf2 in reducing MPTP/Pro-induced oxidative stress and subsequent motor deficits by inhibiting its nuclear export through PI3K/Akt/GSK-3β/Fyn pathway regulation. These further indicate that β-Ecd may be an absorbing therapeutic agent for PD. [ABSTRACT FROM AUTHOR]

It is a key issue to assure that the experimental results of scaled-down models of long-span spatial grid structure under inner blasting loads can truly reflect the characteristics of their prototype structure. The existing method to deal with the dynamic scaling laws of structures is not suitable for long-span spatial grid structures subjected to inner explosion. This paper derives and modifies the dynamic scaling laws among scaled-down models and full-size structure under inner explosion on the basis of dimensional analysis, taking long-span cylindrical grid shell structure as research case and considering the strain-rate effect, yield stress and dimension distortions. In this article, the improved scaling laws were verified and proved by comparing the simulation results with the test results of long-span cylindrical grid shell structure and its scaled-down models. The research results revealed that the maximum errors of the peak values of displacement responses and strain responses between the scaled-down model and the prototype were unacceptable without considering material and geometric distortions. Moreover, the empirical formulae to calculate the mass of explosive based on specific impulse were proposed and the corrected method to predict the inner explosion responses of full-size structure according to the results of scaled-down model tests was presented. [ABSTRACT FROM AUTHOR]