LanGui tea, an herbal medicine formula, protects against binge alcohol-induced acute liver injury by activating AMPK-NLRP3 signaling.

BACKGROUND: LanGui tea, a traditional Chinese medicine formulation comprising of Gynostemma pentaphyllum (Thunb.) Makino, Cinnamomum cassia (L.) J. Presl, and Ampelopsis grossedentata (Hand-Mazz) W.T. Wang, has yet to have its potential contributions to alcoholic liver disease (ALD) fully elucidated. Consequently, the objective of this research is to investigate the protective properties of LanGui tea against binge alcohol-induced ALD and the mechanisms underlying its effects. METHODS: An experimental model of acute alcohol-induced liver disease was performed to assess the protective effects of extract of LanGui tea (ELG) at both 50 and 100 mg.kg-1 dosages on male C57BL/6 mice. Various parameters, including hepatic histological changes, inflammation, lipids content, as well as liver enzymes and interleukin 1ß (IL-1ß) in the serum were measured. The pharmacological mechanisms of ELG, specifically its effects on adenosine monophosphate-(AMP)-activated protein kinase (AMPK) and NLR family pyrin domain containing 3 (NLRP3) signaling, were investigated through Western blotting, qRT-PCR, ELISA, immunohistochemistry, immunofluorescence analyses, and by blocking the AMPK activity. RESULTS: ELG demonstrated a mitigating effect on fatty liver, inflammation, and hepatic dysfunction within the mouse model. This effect was achieved by activating AMPK signaling and inhibitingNLRP3 signaling in the liver, causing a reduction in IL-1ß generation. In vitro studies further confirmed that ELG inhibited cell damage and IL-1ß production in ethanol-induced hepatocytes by enhancing AMPK-NLRP3 signaling. Conversely, the pharmacological inhibition of AMPK activity nearly abrogated such alteration. CONCLUSIONS: Thus, LanGui tea emerges as a promising herbal therapy for ALD management involving AMPK-NLRP3 signaling.

Farmland protection and fertilization intensity: Empirical evidence from preservation policy of Heilongjiang's black soil.

The preservation of cultivated land quality stands as a vital prerequisite for ensuring food security and sustainability. In the black soil area of northeast China, a large amount of fertilizer was used to stabilize grain production in its early stages, which damaged soil structure and polluted the ecological environment. Based on the panel data of fertilization intensity of 48 districts and counties in Heilongjiang Province from 2010 to 2020, this study takes the implementation of the "Three-Year Action Plan for the Protection of Black Soil Farmland in Heilongjiang Province for the (2018-2020)" (TYAP) policy as a natural experiment, and uses the difference-in-differences (DiD) method to identify the causal effect of the policy on the local fertilization intensity. The results of the empirical study showed that the implementation of the TYAP policy significantly reduced the fertilization intensity of the black soil cultivated land implemented by the policy during the implementation period, which resulted in a decrease of 11.97% on average compared with the areas without the policy implementation. Several robustness tests provided additional confirmation of the aforementioned findings. This study further revealed that the policy mitigated fertilization intensity by fostering advancements in agricultural mechanization.

A Color-Changing Biomimetic Material Closely Resembling the Spectral Characteristics of Vegetation Foliage.

Multispectral/hyperspectral technologies can easily detect man-made objects in vegetation by subtle spectral differences between the object and vegetation, and powerful reconnaissance increases the demand for camouflage materials closely resembling vegetation spectra. However, previous biomimetic materials have only presented static colors that cannot change color, and camouflage in multiple bands is difficult to achieve. To address this challenge, inspiration is drawn from the color change of foliage, and a color-change model is proposed with active and static pigments embedded in a matrix medium. The color of a composite material is dominated by the colored active pigment, which conceals the color of the static pigments and the color is revealed when the active pigment fades. A color-changing biomimetic material (CCBM) is developed with a solution casting method by adopting microcapsuled thermochromic pigments and chrome titanate yellow pigments as fillers in a base film with polyvinyl alcohol and lithium chloride. A Kubelka-Munk four-flux model is constructed to optimize the component proportions of the CCBM. The material has a reversible color change, closely resembles the foliage spectrum in UV-vis-NIR ranges, and imitates the thermal behavior of natural foliage in the mid-infrared regime. These results provide a novel approach to multispectral and hyperspectral camouflage.

A novel benzothiazole-based mononuclear platinum(II) complex displaying potent antiproliferative activity in HepG-2 cells via mitochondrial-mediated apoptosis.

A novel mononuclear platinum(II) complex, [Pt(L-H)Cl] (1, where L= N-(4-(benzo[d]thiazol-2-yl)phenyl)-2-((2-pyridylmethyl)(2-hydroxyethyl)-amino)acetamide), was obtained by covalently tethering a benzothiazole derivative 2-(4-aminophenyl)benzothiazole to the 2-pyridylmethyl-2-hydroxyethylamine chelating PtII center. In vitro tests indicated that complex 1 displayed excellent antiproliferative activity against the tested cancer cell lines, especially liver cancer HepG-2 and SMMC-7221 cells. Importantly, the complex possessed 4.33-fold higher antiproliferative activity as compared with cisplatin against HepG-2 cells, but was less toxic to the normal cell line L02 with the selectivity index (SI = IC50(L02)/IC50(HepG-2)) value of 8.36 compared to cisplatin (SI, 1.40). The results suggested that 1 might have the potential to act as a candidate for the treatment of hepatocellular carcinoma (HCC). Cellular uptake and distribution studies showed that 1 could effectively pass through the membrane of cells, enter the nuclei and mitochondria, induce the platination of cellular DNA. The interaction of 1 with CT-DNA demonstrated that 1 could effectively bind to DNA in a dual binding mode, i.e., the intercalation of the 2-(4-aminophenyl)benzothiazole unit plus monofunctional platination of the platinum(II) moiety. In addition, Hoechst 33342 staining and flow cytometry analysis illustrated that 1 arrested the cell cycle in HepG-2 cancer cells at G2/M phases, induced mitochondrial membrane depolarization, increased ROS generation, and caused obvious cell apoptosis. Further cellular mechanism studies elucidated that 1 triggered HepG-2 cell apoptosis via the mitochondrial-mediated pathway by upregulating the gene and protein expression levels of Bax, downregulating the gene and protein expression levels of Bcl-2, and activating the caspase cascade.

International clinical practice guideline on the use of traditional Chinese medicine for ulcerative colitis by Board of Specialty Committee of Digestive System Disease of World Federation of Chinese Medicine Societies (2023).

Ulcerative colitis (UC), a chronic and nonspecific inflammatory disease of the intestine, has become a prevalent global health concern. This guideline aims to equip clinicians and caregivers with effective strategies for the treatment and management of adult UC patients using traditional Chinese medicine (TCM). The guideline systematically evaluated contemporary evidence through the Grading of Recommendations Assessment, Development, and Evaluation framework. Additionally, it incorporated insights from ancient Chinese medical sources, employing the evidence grading method found in traditional TCM literature. The development process involved collaboration with multidisciplinary experts and included input from patients with UC. The guideline, based on a comprehensive review of available evidence, present 40 recommendations. They offer a condensed overview of TCM's role in understanding the pathogenesis, diagnosis, and treatment of UC, along with an assessment of the efficacy of various TCM-based treatments. TCM exhibits promising outcomes in the treatment of UC. However, to establish its efficacy conclusively, further high-quality clinical studies on TCM for UC are essential.

Influences and mechanism of erythropoietin on the cognitive function of vascular dementia rats.

PURPOSE: To investigate the influences and mechanism of erythropoietin (EPO) on the cognitive function of vascular dementia (VD) rats. METHODS: 1) Spatial memory capacity was assessed by Morris water maze test; 2) Pathological conditions of brain tissues were detected by hematoxylin-eosin (HE) staining; 3) The effect of treatment on apoptosis was observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining; 4) Western blotting was used to examine the protein expression in hippocampal neurons. RESULTS: The escape latency and swimming distance in the EPO group were much shorter than those in the Model group on the fifth day. In the spatial exploration test, the time spent in the target quadrant was longer, the number of platform crossings was larger and the swimming speed was higher in the Sham group and EPO group than those in the Model group. The results of HE staining showed that the cells in the hippocampal CA1 region were arranged closely in the Sham group, loosely and disorderly in the Model group but significantly better in the EPO group. Compared with that in the Model group, the number of apoptotic cells in the EPO group was obviously smaller. The results of Western blotting revealed that the expressions of EPO, p-EPOR, p-SHP2, p-TrKB, p-PI3K, p-ERK1/2 and Bcl-2 rose, while the expressions of P22, P47, Caspase-3, Caspase-9 and Bax significantly declined in the EPO group. CONCLUSIONS: EPO can effectively ameliorate the cognitive dysfunction induced by chronic hypoperfusion in VD rats by mediating oxidative stress-related pathways.

Erythropoietin (EPO) and Hippocampal Neurons: Effects on Sports Performance, Fitness, and Football Players with Vascular Cognitive Impairment

Objective: This study delves into the impact of erythropoietin (EPO) on hippocampal neurons and its potential implications for sports performance, fitness, and the cognitive well-being of football players facing vascular cognitive impairment. Methodology: The study employs a comprehensive approach, utilizing a rat model of vascular dementia (VaD) induced by bilateral carotid artery ligation. Exogenous EPO is administered to the VaD rat model. Observations of EPO's influence on hippocampal neurons are made, and in vitro experiments are conducted to validate the specific mechanisms at play, particularly under oxygen/glucose-deprived conditions. Results: The results reveal several noteworthy findings. VaD rats treated with EPO demonstrate significantly shorter escape latency, increased neuronal populations, and enhanced preservation of Nissl bodies in hippocampal subfields, specifically cortical area 1 (CA1) and CA2. Moreover, these rats exhibit a lower count of TUNEL-positive cells compared to the model group, with higher doses of EPO demonstrating more notable improvements in escape latency. Molecular analysis shows that EPO up-regulates key protein expressions, including phosphorylated EPO receptor (p-EPOR), p-phosphatidylinositol 3-kinase (p-PI3K), p-protein kinase B (Akt), and p-cyclic AMP response element binding protein (p-CREB). Simultaneously, it down-regulates expressions of apoptosis- and autophagy-related proteins, such as B-cell lymphoma-2-associated X protein (Bax), cleaved-Caspase 3, cleaved-Caspase 9, light chain 3β (LC3β), Beclin, autophagy-related gene 5 (ATG5), and ATG7. Notably, in vitro experiments confirm the role of the PI3K/AKT pathway in EPO's mechanisms, with implications for cognitive health. (AU)

Assessing the structural connectivity of international trade networks along the "Belt and Road".

Assessing the trade network connectivity is essential for understanding the trade network structure, optimizing trade development patterns, and improving uneven trade development along the "Belt and Road" (BRI). From the perspective of connectivity, this paper integrates the frontier algorithms in network science and constructs an analytical framework to identify the mesoscale structures, including the community structure, core-periphery structure, and backbone structure embedded in the network, and further explore the structural connectivity of the BRI trade network. The results show that: (1) The BRI trade network represents a trade pattern of "one superpower, many great powers", with three major trade groups in Southeast Asia, the Middle East, and Northern Central and Eastern Europe in terms of geographical space. China is the super core of the BRI trade network, and the most considerable trade links are all centred in China. (2) Five distinctive trade blocs have formed in the BRI trade network. Nevertheless, the structure of the trade blocs shows significant geographical proximity, indicating that geographical distance still plays a vital role in the international trade system at the regional scale. (3) The BRI trade network demonstrates a significant core-periphery structure, with apparent trade clustering among the core countries within the trade network. Among them, nine countries led by China constitute the core structure, and the peripheral structure is large, reaching forty-four. (4) The trade links with China constitute the backbone structure of the whole trade network in the BRI region. In addition, the trade links related to energy trade and re-export trade are also crucial components of the BRI backbone structure. Methodologically, the analytical framework proposed for assessing the network structural connectivity has great potential to be widely applied to other disciplines and fields.

Serum Bile Acid Metabolites Predict the Therapeutic Effect of Mesalazine in Patients with Ulcerative Colitis.

Ulcerative colitis (UC) is a systematic chronic disease characterized by insufficient intestinal absorption, and mesalazine is a common medical treatment. In the present study, 20 normal healthy controls (NC group), 10 unmedicated UC patients (UC group), and 20 mesalazine-responsive and 20 mesalazine-nonresponsive UC patients were recruited. A total of 42 serum BA metabolites, including 8 primary bile acids and 34 secondary bile acids (SBAs), were quantitatively measured. Compared with the NC group, serum SBAs in the UC patients were significantly lower but increased after mesalazine therapy. Differences in the serum TDCA, DCA, GDCA-3S, 12-keto LCA, and GCDCA-3S metabolites were found between the UC and NC groups, with AUC values of 0.777, 0.800, 0.815, 0.775, and 0.740, respectively. Furthermore, we identified 12-keto LCA as a specific BA marker of UC and BA biomarkers of mesalazine responsiveness. It was concluded that serum SBAs were decreased in UC patients, and TDCA, DCA, GDCA-3S, 12-keto LCA, and GCDCA-3S might aid in the diagnosis of UC. The abundance of SBAs increased after the mesalazine therapy, and serum 12-keto LCA was identified as an alternative invasive biomarker associated with UC diagnosis and therapeutic response, thereby providing a new approach for the prediction of response to mesalazine therapy in UC patients.

Urbanization and vulnerable employment: Empirical evidence from 163 countries in 1991-2019.

Many urban residents have recently lost their jobs due to the COVID-19 pandemic, which has made employment vulnerability in cities attained attention. It is thus important to explore the relationship between urbanization and employment. This study quantitatively analyzes spatiotemporal evolution and data correlation of urbanization and vulnerable employment, and explores the role urbanization plays in vulnerable employment by using historical data on 163 countries in the period 1991-2019 to test the theoretical hypothesis. The results show: It's clearly observed that there is a high correlation between the rate of urbanization and that of vulnerable employment, and the examples of G7 and BRICs are for it. The estimated urbanization yields a negative and statistically significant regression coefficient (-0.168), indicating that urbanization has a negative effect on vulnerable employment. If the urbanization rate increased by 1 %, the rate of vulnerable employment decreased by 0.168 %. The rural-urban sector conversion and changes in employment relationship driven by urbanization account for this. Countries with different income groups or populations have reacted differently to the rise in urbanization. Vulnerable employment in higher-income countries has been more significantly affected by the rise in urbanization, and more populous countries are more sensitive to it as well. These findings provide evidence for how urbanization promotes employment and decent work.

A domain-agnostic approach for characterization of lifelong learning systems.

Despite the advancement of machine learning techniques in recent years, state-of-the-art systems lack robustness to "real world" events, where the input distributions and tasks encountered by the deployed systems will not be limited to the original training context, and systems will instead need to adapt to novel distributions and tasks while deployed. This critical gap may be addressed through the development of "Lifelong Learning" systems that are capable of (1) Continuous Learning, (2) Transfer and Adaptation, and (3) Scalability. Unfortunately, efforts to improve these capabilities are typically treated as distinct areas of research that are assessed independently, without regard to the impact of each separate capability on other aspects of the system. We instead propose a holistic approach, using a suite of metrics and an evaluation framework to assess Lifelong Learning in a principled way that is agnostic to specific domains or system techniques. Through five case studies, we show that this suite of metrics can inform the development of varied and complex Lifelong Learning systems. We highlight how the proposed suite of metrics quantifies performance trade-offs present during Lifelong Learning system development - both the widely discussed Stability-Plasticity dilemma and the newly proposed relationship between Sample Efficient and Robust Learning. Further, we make recommendations for the formulation and use of metrics to guide the continuing development of Lifelong Learning systems and assess their progress in the future.

Jianpi-Qingchang decoction alleviates ulcerative colitis by modulating endoplasmic reticulum stress-related autophagy in intestinal epithelial cells.

Endoplasmic reticulum stress (ERS)-related autophagy is involved in the occurrence and development of ulcerative colitis (UC). Therefore, regulating ERS-related autophagy is a potential therapeutic target for the treatment of UC. Jianpi-Qingchang (JPQC) decoction, consisting of nine Chinese herbal medicines, is used to treat patients with UC. However, its mechanism of action has not been completely elucidated. Here, we aimed to reveal the therapeutic effects and mechanisms of JPQC in UC. We established a colitis model using dextran sulfate sodium (DSS) and an ERS model using thapsigargin (Tg) and administered JPQC. We systematically examined ERS-related autophagy associated protein expression, inflammatory cytokines, apoptotic cells, and autophagic flux. Moreover, the cellular ultrastructure was observed via transmission electron microscopy (TEM). We found that JPQC reduced disease activity index (DAI) scores, counteracted colonic tissue damage, decreased the number of autophagosomes, inhibited proinflammatory cytokines, enhanced anti-inflammatory cytokines, and dampened ERS-related autophagy associated protein gene expression.

SALL4 activates PI3K/AKT signaling pathway through targeting PTEN, thus facilitating migration, invasion and proliferation of hepatocellular carcinoma cells.

This study aims to explore the specific mechanisms of SALL4 on the migration, invasion and proliferation of HCC. HepG2 and SMMC-7721 cells were transfected with SALL4 NC, mimics and inhibitors. The proliferation capability and cell cycle progression of HCC cells were detected through CCK8 assay and flow cytometry, and their migration and invasion capabilities were detected by wound healing assay and Transwell assay. In SALL4 inhibitor NC group and SALL4 inhibitor group, the PTEN inhibitor SF1670 was added, and the expression levels of PI3K/AKT, migration, invasion and proliferation-related proteins were detected by Western blotting. Results showed that after up-regulation of SALL4, the migration distance of HCC cells increased, the numbers of migrated cells and the number of colonies formed significantly rosed, and there were fewer cells in G1 phase but significantly more cells in S phase, thereby down-regulation of SALL4, the opposite results. The results of Western blotting revealed that after SF1670, the specific PTEN inhibitor was added in SALL4 inhibitor group and SALL4 inhibitor NC group, the protein expression of PTEN in HCC cells significantly declined, while the protein expressions of p-PI3K, p-AKT, MMP2, MMP9, CyclinD, CyclinA1, PCNA and P62 significantly rose. In conclusion, SALL4 activates the PI3K/AKT signaling pathway through targeting PTEN, thereby facilitating the migration, invasion and proliferation of HCC cells.

Analysis of the interprovincial embodied carbon flow network of China's exports.

We calculate the embodied carbon emissions of China's through the multiregional input-output (MRIO) method, then we construct the interprovincial embodied carbon flow networks of China's exports based on the mean threshold, and the application of complex network analysis to conduct a detailed examination of the overall characteristics, key nodes and edges, and community structure of China's interprovincial embodied carbon flow network. We extended the embodied carbon flow network analysis at the provincial level. The results demonstrated the following: (1) The interprovincial embodied carbon flow network of China's exports has small-world and scale-free characteristics. The node degree probability distribution curves for the networks obviously conformed to a decreasing power law distribution, indicating that a few industrial sectors carry a large amount of embodied carbon and suggesting that reducing the embodied carbon of China's exports could yield twice the results with half the effort as long as attention is paid to a few sectors. (2) The key nodes and edges in the networks show that industrial sectors and production chains such as the power and heat production and supply industry, the petroleum processing, coking, and nuclear fuel processing industry, and the metal smelting and calendering industry play the role of key "bridges" in the entire network, among which Guangdong, Hebei, Jiangsu, Inner Mongolia, and Shanxi are important node provinces and the main flow paths for the generation of embodied carbon in national exports. These industrial sectors and production chains should bolster their policies to encourage the innovation of carbon emission reduction technologies and decrease carbon emissions, so as to reduce the embodied carbon of national exports on a large scale. (3) The number of communities firstly increased then decreased from 2007 to 2017, while the aggregation coefficient of the node and correlation density within first community displayed firstly downward then upward trends, reflecting firstly decentralization then centralization of the interprovincial embodied carbon flow.

Thermoplastic starch based blends as a highly renewable filament for fused deposition modeling 3D printing.

3D printing technology is considered as a highly flexible method which can achieve a various customized end products. The employment of bio-based materials can significantly decrease the environmental footprint of the end 3D printing products. This study presents the preparation of thermoplastic starch (TPS)/poly(lactic acid) (PLA)/poly(butyleneadipate-co-terephthalate) (PBAT) composite that dedicated for the FDM 3D printing technology, the ratio of TPS:PLA:PBAT was fixed at 50:40:10 wt%. In addition, the chain extender ADR4468 (CE) was added to improve the brittleness of the blends to obtain better 3D printing filament. The mechanical properties of blends were improved by the addition of CE with 113 % increase in elongation at break and the 190 % raise in impact strength. Dynamic rheological analysis showed the maximum degree of complex viscosity and melt strength when the content of CE reached 1 wt%. The successful printability of TPS-based filament was demonstrated by accurate and complex printing samples. This paper provided a method to prepare highly renewable filaments for 3D printing.

Jianpi Qingchang Bushen decoction improves inflammatory response and metabolic bone disorder in inflammatory bowel disease-induced bone loss.

BACKGROUND: Bone loss and osteoporosis are commonly described as extra-intestinal manifestations of inflammatory bowel disease (IBD). Jianpi Qingchang Bushen decoction (JQBD) is a prescription used in clinical practice. However, further studies are needed to determine whether JQBD regulates the receptor activator of nuclear factor kappa B (NF-κB) (RANK)/receptor activator of NF-κB ligand (RANKL)/ osteoprotegerin (OPG) pathways and could play a role in treating IBD-induced bone loss. AIM: To evaluate the therapeutic effect of JQBD in IBD-induced bone loss and explore the underlying mechanisms. METHODS: An IBD-induced bone loss model was constructed by feeding 12 6-to-8-wk-old interleukin-10 (IL-10)-knockout mice with piroxicam for 10 d. The mice were randomly divided into model and JQBD groups. We used wild-type mice as a control. The JQBD group was administered the JQBD suspension for 2 wk by gavage, while the control and model groups were given normal saline at the corresponding time points. All mice were killed after the intervention. The effect of JQBD on body weight, disease activity index (DAI), and colon length was analyzed. Histopathological examination, colon ultrastructure observation, and micro-computed tomographic scanning of the lumbar vertebrae were performed. The gene expression of NF-κB, tumor necrosis factor-α (TNF-α), IL-1ß, IL-6, and IL-8 in the colon was evaluated by real-time polymerase chain reaction. Colon samples were assessed by Western blot for the expression of RANKL, OPG, RANK, and NF-κB proteins. RESULTS: The model group lost body weight, had a shorter colon, and showed a dramatic increase in DAI score, whereas JQBD had protective and therapeutic effects. Treatment with JQBD significantly improved inflammatory cell infiltration and reduced crypt abscess and ulcer formation. Three-dimensional imaging of the vertebral centrum in the model group revealed a lower bone mass, loose trabeculae, and "rod-shaped" changes in the structure compared to the control group and JQBD groups. The bone volume/total volume ratio and bone mineral density were significantly lower in the model group than in the control group. JQBD intervention downregulated the NF-κB, TNF-α, IL-1ß, IL-6, and IL-8 mRNA expression levels. The RANKL and OPG protein levels were also improved. CONCLUSION: JQBD reduces inflammation of the colonic mucosa and inhibits activation of the RANK/ RANKL/OPG signaling pathway, thereby reducing osteoclast activation and bone resorption and improving bone metabolism.

Identification of the effective α-amylase inhibitors from Dalbergia odorifera: Virtual screening, spectroscopy, molecular docking, and molecular dynamic simulation.

Inhibiting the activity of α-amylase has been considered as one efficient way to prevent and treat type 2 diabetes recently. Dalbergia odorifera, a kind of Leguminosae plant, has a positive therapeutic effect on type 2 diabetes, possibly contributing by some constituents that can inhibit the activity of α-amylase. In this study, we found that eriodictyol was one potential constituent through virtual screening. The interaction mode between eriodictyol and α-amylase was elucidated by molecular docking, multi-spectroscopic analysis, and molecular dynamic simulation. The results revealed that eriodictyol quenched the intrinsic fluorescence of α-amylase, and the quenching mode was static quenching. Eriodictyol could spontaneously interact with α-amylase, mostly stabilized and influenced by the hydrophobic interaction, while the binding sites (n) was 1.13 ± 0.07 and binding constant (Kb) was (1.43 ± 0.14) × 105 at 310 K, respectively. In addition, FT-IR and CD had been applied to identify that eriodictyol can trigger the conformational change of α-amylase. Taken together, the results provided some experimental data for developing new α-amylase inhibitors from Dalbergia odorifera, which may further prevent and treat diabetes and diabetes complications.

Jianpi Qingchang Decoction Ameliorates Chronic Colitis in Piroxicam-Induced IL-10 Knockout Mice by Inhibiting Endoplasmic Reticulum Stress.

BACKGROUND: Excessive endoplasmic reticulum (ER) stress in intestinal epithelial cells (IEC) may lead to impaired intestinal mucosal barrier function and then participate in the pathogenesis of ulcerative colitis (UC). Jianpi Qingchang decoction (JPQCD) has been shown to have protective effects on UC. However, further studies are needed to determine whether JPQCD regulates PERK/eIF2α/ATF4/CHOP pathways to play a role in treating UC. METHODS: IL-10 -/- mice were randomly assigned into five groups: control, model, low-dose JPQCD (JPQCD L), middle-dose JPQCD (JPQCD M), and high-dose JPQCD (JPQCD H). All groups except for the control group were given model feed containing 200 ppm piroxicam for 10 d to induce colitis. As a comparison, we used wild-type mice that were the progeny of IL-10 +/- matings, bred in the same facility. The control group and wild-type mice were fed with common feed. At the same time, mice in each group were given corresponding drugs by gavage for 14 d. The disease activity index of mice in each group was evaluated daily. Colon tissues of mice were collected, colon length was measured, and pathological changes and ultrastructure of colon epithelial cells were observed. The effects of JPQCD on the PERK/eIF2α/ATF4/CHOP pathways were evaluated by western blotting and reverse transcription-polymerase chain reaction (RT-PCR). The expression of CHOP in colon tissue was detected by tissue immunofluorescence assay. The expression of NF-κB, p-NF-κB p65 protein was analyzed by western blotting; the level of IL-17 in colon tissue was detected by enzyme-linked immunosorbent assay (ELISA) and verified by examining NF-κB and IL-17 mRNA levels by RT-PCR. RESULTS: Compared with the control group, the model group showed significant colitis symptoms and severe colonic tissue damage. The results showed that JPQCD significantly reduced body weight loss, ameliorated disease activity index, and restored colon length in IL-10 -/- mice with piroxicam-induced colitis. Western blotting and RT-PCR showed that the PERK/eIF2α/ATF4/CHOP pathway was activated in colon tissue of model mice, suggesting that the pathway is involved in the pathogenesis of ulcerative colitis (UC) and could become a potential therapeutic target. The JPQCD treatment inhibited the activation of the PERK/eIF2α/ATF4/CHOP pathway, alleviated the ER stress, and played a role in preventing and treating UC. In addition, JPQCD can also downregulate the protein of NF-κB, p-NF-κB p65, downregulate the mRNA expression of NF-κB, and reduce the content of IL-17 and its mRNA expression in colon tissues. CONCLUSION: JPQCD may play a protective role in UC by regulating the PERK/eIF2α/ATF4/CHOP signaling pathway and relieving endoplasmic reticulum stress.

Exploring the molecular mechanisms of the inhibition of acrolein-induced BEAS-2B cytotoxicity by luteolin using network pharmacology and cell biology technology.

Acrolein is a highly reactive unsaturated hazardous air pollutant, which is extremely irritating to the respiratory tract. Luteolin, an active flavonoid compound, possesses multiple biological activities. The purpose of this study was to evaluate the mechanism of the inhibition of acrolein-induced human bronchial epithelial (BEAS-2B) cells cytotoxicity by luteolin using network pharmacology and cell biology technology. Firstly, network pharmacology results indicated that oxidative stress processes might play an important role in luteolin inhibiting lung injury. Next, it was verified at the cellular level. Reactive oxygen species (ROS) generation increased, glutathione (GSH) level decreased after exposure to acrolein. MAPK signaling pathways were activated, which activated downstream IκBα/NF-κB signaling pathways. Meanwhile, acrolein caused oxidative DNA damage and double-strand breaks, induced DNA damage response (DDR) and apoptosis. These adverse effects were significantly reversed by luteolin, which inhibited the activation of MAPK/IκBα/NF-κB and DDR pathways, and reduced the ratio of Bax/Bcl-2. Moreover, luteolin also had a similar effect to antioxidant N-acetyl cysteine (NAC) in the regulation of signaling transduction mechanisms, which indicated that the regulation of oxidative stress played an important role in the process. These results provide an experimental basis for elucidating the molecular mechanisms of the inhibition of acrolein-induced BEAS-2B cytotoxicity with luteolin.

Toxicity mechanism of acrolein on DNA damage and apoptosis in BEAS-2B cells: Insights from cell biology and molecular docking analyses.

Acrolein is a hazardous air pollutant for humans and is responsible for many pulmonary diseases, but the underlying mechanisms have not been completely elucidated. This work is focused on the genotoxicity effects of human bronchial epithelial (BEAS-2B) cells induced by acrolein (20, 40, 80 µM). The molecular mechanism was investigated base on DNA damage and mitochondrial apoptosis pathways. The results showed that after exposure to acrolein, the cell viability, glutathione (GSH) of BEAS-2B cells were reduced. Reactive oxygen species (ROS) level significantly increased, accompanied by increased levels of DNA damage-related indicators 8-hydroxy-2 deoxyguanosine (8-OHdG), DNA content of comet tail (Tail DNA%), olive tail moment (OTM), and nucleus morphology. Cell arrested at the G2/M phase. Then, the DNA damage response (DDR) signaling pathway (Ataxia-telangiectasia-mutated (ATM) and Rad-3-related (ATR)/Chk1 and ATM/Chk2) and the consequent cell cycle checkpoints were activated. The expression of γ-H2AX was significantly increased, indicating that acrolein induced DNA double-strand breaks. Molecular docking assay showed that acrolein bound to DNA in a spontaneous process. Moreover, mitochondrial apoptosis pathway involved in apoptosis, mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) content of BEAS-2B cells were significantly reduced, and the apoptosis rate was significantly increased. The protein expression of Bax/Bcl-2 and Cleaved Caspase-3 were increased, and JNK signaling pathway was activated. All the results indicated that acrolein induced DNA damage, activated DDR and mitochondrial apoptosis pathways, which might be the pivotal factors to mediate cytotoxicity in BEAS-2B cells.