Accumulated LPS induced by colitis altered the activities of vitamin D-metabolizing hydroxylases and decreased the generation of 25-hydroxyvitamin D.

It is generally accepted that low vitamin D (VD) levels are associated with a high prevalence factor for Inflammatory bowel disease (IBD). IBD patients have observed higher levels of lipopolysaccharide (LPS), ALT, and AST than healthy people. Gut-derived LPS causes inflammatory injury in the liver and kidney. The VD-metabolizing mechanism is involved in the liver and kidney, which means IBD might impact VD metabolism. However, whether IBD affects VD metabolism has not been studied. In vitro LPS resulted in decreased CYP2R1 in liver cells as well as decreased CYP27B1 and increased CYP24A1 in kidney cells, revealing that LPS changed the activities of several hydroxylases. Mice with acute colitis had an increased LPS in serum and liver with mild hepatic injuries, while mice with chronic colitis had a significant elevation of LPS in serum, liver, and kidney with hepatorenal injuries. Thus, the liver hydroxylase for VD metabolism would be the first to be affected in IBD. Consequently, serum 25-hydroxyvitamin D declined dramatically with a significant elevation of 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D. Unchanged serum levels of 1,25-dihydroxyvitamin D might be the result of other factors in vivo. In acute colitis, a small dosage (4 IU/day) of cholecalciferol could protect the colon, decrease the serum level of LPS, and finally increase serum 25-hydroxyvitamin D. However, this improvement of cholecalciferol was fading in chronic colitis. These results suggested that VD supplementations for preventing and curing IBD in the clinic should consider hepatorenal hydroxylases and be employed as soon as possible for a better outcome.

Integrated metabolomics and network pharmacology to reveal the lipid-lowering mechanisms of Qizha Shuangye granules in hyperlipidemic rats.

BACKGROUND: Qizha Shuangye granules (QSG) comprise six traditional Chinese herbal medicines (TCHMs), which have a long history of treating hyperlipidemia (HLP) in China. This study aimed to evaluate the potential lipid-lowering effects of QSG in an HLP rat model and investigate possible mechanisms. The HLP rat model was induced by a high-fat diet. Lipid-related indicators in serum were detected. Serum and liver metabolites were investigated using a liquid chromatography-mass spectrometry-based metabolomics approach. A herb-compound-target-metabolite (H-C-T-M) network was further constructed to reveal the possible molecular mechanism of QSG to alleviate HLP. RESULTS: The administration of QSG inhibited the HLP-induced changes in total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and non-esterified fatty acid (NEFA) levels. Additionally, QSG significantly attenuated the liver histopathological changes induced by HLP. Metabolomic analysis showed the serum and liver metabolic disorders presented in HLP rats. QSG can reverse the abnormal metabolism caused by HLP. Through network pharmacology analysis, key proteins such as androgen receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and peroxisome proliferator-activated receptor-α were screened out, and they were speculated to be possible therapeutic targets for QSG to treat HLP. CONCLUSION: The present study integrated metabolomics and network pharmacology analysis to reveal the efficacy and possible mechanism of QSG in treating HLP, which provides a new reference for the research and development of QSG as a functional food. © 2023 Society of Chemical Industry.

Multi-omics analysis of lung tissue metabolome and proteome reveals the therapeutic effect of Shegan Mahuang Decoction against asthma in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Shegan Mahuang Decoction (SMD) is a classic traditional Chinese medicine (TCM) formula for asthma treatment, but the anti-asthma mechanism of SMD is still not fully studied. AIMS OF THE STUDY: In this study, we established an ovalbumin (OVA)-induced asthma rat model and treated it with SMD to observe its anti-asthma effect and explore the related mechanism. MATERIALS AND METHODS: We evaluated the anti-inflammatory effect of SMD via testing the levels of immunoglobulin E (IgE), C-reactive protein (CRP), interleukin-4 (IL-4), interleukin-6 (IL-6) in serum and performing the hematoxylin-eosin (H&E) staining of lung tissue slices. We analyzed the variations of metabolites and proteins in the lung tissue of different groups using liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics and TMT-based proteomics approaches. The metabolic biomarkers and differentially expressed proteins (DEPs) were picked, and the related signal transduction pathways were also investigated. In addition, the key proteins on the signaling pathway were validated through western blotting (WB) experiment to reveal the anti-asthma mechanism of SMD. RESULTS: The results showed that the SMD could significantly reduce the serum levels of IgE, CRP, IL-4, and IL-6 and attenuate the OVA-induced pathological changes in lung tissue. A total of 34 metabolic biomarkers and 84 DEPs were screened from rat lung tissue, which were mainly associated with lipid metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, the excessive production of reactive oxygen species (ROS), and lysosome pathway. Besides, SMD could inhibit the myeloid differentiation factor 88 (MyD88)/inhibitor of kappa B kinase (IKK)/nuclear factor-kappa B (NF-κB) signaling pathway to exhibit anti-inflammatory activities. CONCLUSIONS: SMD exhibited a therapeutic effect on asthma, which possibly be exerted by inhibiting the MyD88/IKK/NF-κB signaling pathway.

Exploring the in vitro anti-inflammatory activity of gross saponins of Tribulus terrestris L. fruit by using liquid chromatography-mass spectrometry-based cell metabolomics approach.

Our previous studies confirmed the efficacy of gross saponins of Tribulus terrestris L. fruit in treating cerebral ischemia. This study aimed to investigate the related mechanisms in vitro. The lipopolysaccharide-induced BV2 cells model was constructed and treated with gross saponins at different concentrations to explore its anti-inflammatory activity. The cell metabolite changes were tracked by liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and the metabolic biomarkers and related metabolic pathways were analyzed. Molecular biochemistry analysis was further used to verify the relevant inflammatory pathways. The results showed that the saponins reduced nitric oxide release and the secretion of tumor necrosis factor-alpha, interleukin-1ß, and interleukin-6 from lipopolysaccharide-induced BV2 cells. Metabolic perturbations occurred in lipopolysaccharide-treated BV2 cells, which could be reversed by drug treatment via mainly regulating glycerophospholipid metabolism, tryptophan metabolism, purine metabolism pathways, etc. The western blot analysis demonstrated that saponin could suppress the activation of the inflammatory-related signaling pathway. The present study explored the in vitro anti-inflammatory mechanism of gross saponins of Tribulus terrestris L. fruit using an LC-MS-based cell metabolomics approach, which confirms the great potential of LC-MS for drug efficacy evaluation and can be applied in other herbal medicine-related analyses.

Effects of guanidinoacetic acid supplementation on growth performance, hypothalamus-pituitary-adrenal axis, and immunity of broilers challenged with chronic heat stress.

Heat stress can cause systemic immune dysregulation and threaten the health of broilers. Guanidinoacetic acid (GAA) has been shown to be effective against heat stress, but whether it is beneficial for immunity is unclear. Therefore, the effects of dietary GAA supplementation on the immunity of chronic heat-stressed broilers were evaluated. A total of 192 Arbor Acres male broilers (28-day old) were randomly allocated to 4 treatments: the normal control group (NC, 22°C, ad libitum feeding), the heat stress group (HS, 32°C, ad libitum feeding), the pair-fed group (PF, kept at 22°C and received food equivalent to that consumed by the HS group on the previous day), and the GAA group (HG, 32°C, ad libitum feeding; basal diet supplemented with 0.6 g/kg GAA). Samples were collected on d 7 and 14 after treatment. Results showed that broilers exposed to heat stress exhibited a decrease (P < 0.05) in ADG, ADFI, thymus and bursa of Fabricius indexes, and an increase (P < 0.05) in feed conversion ratio and panting frequency, compared to the NC group. Levels of corticotropin-releasing factor, corticosterone (CORT), heat shock protein 70 (HSP70), IL-6, and TNF-α were elevated (P < 0.05) while lysozyme and IgG concentration was decreased (P < 0.05) in the HS group compared with the NC group after 7 d of heat exposure. The concentrations of IgG and IL-2 were decreased (P < 0.05) and CORT was increased (P < 0.05) in the HS group compared with the NC group after 14 d of heat exposure. Noticeably, GAA supplementation decreased the levels of CORT (P < 0.05) and increased the IL-2, IgG, and IgM concentrations (P < 0.05) compared with the HS group. In conclusion, chronic heat stress increased CORT release, damaged immune organs, and impaired the immunity of broilers. Dietary supplementation of 0.6 g/kg GAA can reduce the CORT level and improve the immune function of broilers under heat stress conditions.

Effect of chronic heat stress on the carbonylation of glycolytic enzymes in breast muscle and its correlation with the growth performance of broilers.

Chronic heat stress has detrimental effects on the growth performance of broilers, and the potential mechanism is under exploration. In this study, the protein carbonyl modification was introduced to glycolytic enzymes to evaluate its relationship with the growth performance of heat-stressed (HS) broilers. A total of 144 male 28-day-old broilers were assigned to 3 treatments: the normal control group (NC, raised at 22°C with free access to feed and water), the HS group (raised at 32°C with free access to feed and water), and the pair-fed group (PF, raised at 22°C with an amount of feed equal to that consumed by the HS group on a previous day). Results showed that heat stress decreased the average daily growth, increased the feed-to-gain ratio (F/G), decreased breast muscle rate, and increased abdominal fat rate compared with the NC and PF groups (P < 0.05). Higher cloacal temperature and serum creatine kinase activity were found in the HS group than those of the NC and PF groups (P < 0.05). Heat stress increased the contents of carbonyl, advanced glycation end-products, malonaldehyde, and the activities of catalase, glutathione peroxidase, and total antioxidant capacity compared with the NC and PF groups (P < 0.05). Heat stress increased the contents of glucose and lactate, declined the glycogen content, and lowered the relative protein expressions of pyruvate kinase muscle type, lactate dehydrogenase A type (LDHA), and citrate synthase compared to those of the NC group (P < 0.05). In contrast to the NC and PF groups, heat stress intensified the carbonylation levels of phosphoglucomutase 1, triosephosphate isomerase 1, ß-enolase, and LDHA, which were positively correlated with the F/G (P < 0.05). These findings demonstrate that heat stress depresses growth performance on account of oxidative stress and glycolysis disorders. It further increases the carbonylation of glycolytic enzymes, which potentially correlates with the F/G by disturbing the mode of energy supply of broilers.

Near-Infrared II Hemicyanine Dye with Large Stokes Shift Designed by TICT Regulation for Boosting Imaging-Guided Photothermal Therapy.

The serious threat that cancer poses to human health highlights the significance of early detection and effective treatment. The integration of fluorescence diagnosis and photothermal therapy in NIR-II has gained attention due to its high sensitivity, fast response, and noninvasiveness. Fluorescence, produced by the radiative relaxation process of electrons in a molecule, and photothermal, generated by the nonradiative relaxation process of electrons in a molecule, are competing photophysical processes. Hence, it is a challenge for the molecule to balance between the properties of fluorescence and photothermal. In this study, a NIR-II hemicyanine with TICT character is designed to obtain molecules with both better fluorescence and photothermal properties, utilizing positively charged pyridine salt and triphenylamine as electron acceptor and donor, respectively, and oxole as the conjugated π-bridge. HCY-995, one of the synthesized compounds, has a quantum yield of 0.09%, photothermal conversion efficiency of 54.90%, and a significant Stoke shift of 232 nm, which makes it appropriate for the integration of photothermal therapy and high-resolution imaging. This study provides new insights into the development of NIR-II molecules with fluorescent and photothermal integrated properties.

Gemcitabine enhances pharmacokinetic exposure of the major components of Danggui Buxue Decoction in rat via the promotion of intestinal permeability and down-regulation of CYP3A for combination treatment of non-small cell lung cancer.

CONTEXT: Danggui Buxue Decoction (DBD), a traditional Chinese medicine formula, has the potential to enhance the antitumor effect of gemcitabine in non-small cell lung cancer (NSCLC) treatment by increasing gemcitabine's active metabolites. However, whether gemcitabine affects the pharmacokinetics of DBD's major components remains unclear. OBJECTIVE: This study evaluates the herb-drug interaction between DBD's major components and gemcitabine and validates the underlying pharmacokinetic mechanism. MATERIALS AND METHODS: The pharmacokinetics of 3.6 g/kg DBD with and without a single-dose administration of 50 mg/kg gemcitabine was investigated in Sprague-Dawley rats. The effects of gemcitabine on intestinal permeability, hepatic microsomal enzymes in rat tissues, and CYP3A overexpressing HepG2 cells were determined using western blot analysis. RESULTS: The combination of gemcitabine significantly altered the pharmacokinetic profiles of DBD's major components in rats. The Cmax and AUC of calycosin-7-O-ß-d-glucoside notably increased through sodium-glucose transporter 1 (SGLT-1) expression promotion. The AUC of ligustilide and ferulic acid was also significantly elevated with the elimination half-life (t1/2) prolonged by 2.4-fold and 7.8-fold, respectively, by down-regulating hepatic CYP3A, tight junction proteins zonula occludens-1 (ZO-1) and occludin expression. DISCUSSION AND CONCLUSIONS: Gemcitabine could modulate the pharmacokinetics of DBD's major components by increasing intestinal permeability, enhancing transporter expression, and down-regulating CYP3A. These findings provide critical information for clinical research on DBD as an adjuvant for NSCLC with gemcitabine and help make potential dosage adjustments more scientifically and rationally.

Composition, functional properties, health benefits and applications of oilseed proteins: A systematic review.

Common oilseeds, such as soybean, peanut, rapeseed, sunflower seed, sesame seed and chia seed, are key sources of edible vegetable oils. Their defatted meals are excellent natural sources of plant proteins that can meet consumers' demand for health and sustainable substitutes for animal proteins. Oilseed proteins and their derived peptides are also associated with many health benefits, including weight loss and reduced risks of diabetes, hypertension, metabolic syndrome and cardiovascular events. This review summarizes the current status of knowledge on the protein and amino acid composition of common oilseeds as well as the functional properties, nutrition, health benefits and food applications of oilseed protein. Currently, oilseeds are widely applied in the food industry regarding for their health benefits and good functional properties. However, most oilseed proteins are incomplete proteins and their functional properties are not promising compared to animal proteins. They are also limited in the food industry due to their off-flavor, allergenic and antinutritional factors. These properties can be improved by protein modification. Therefore, in order to make better use of oilseed proteins, methods for improving their nutrition value, bioactive activity, functional and sensory characteristics, as well as the strategies for reducing their allergenicity were also discussed in this paper. Finally, examples for the application of oilseed proteins in the food industry are presented. Limitations and future perspectives for developing oilseed proteins as food ingredients are also pointed out. This review aims to foster thinking and generate novel ideas for future research. It will also provide novel ideas and broad prospects for the application of oilseeds in the food industry.

Mechanisms of Qingyi Decoction in Severe Acute Pancreatitis-Associated Acute Lung Injury via Gut Microbiota: Targeting the Short-Chain Fatty Acids-Mediated AMPK/NF-κB/NLRP3 Pathway.

The pivotal roles of gut microbiota in severe acute pancreatitis-associated acute lung injury (SAP-ALI) are increasingly revealed, and recent discoveries in the gut-lung axis have provided potential approaches for treating SAP-ALI. Qingyi decoction (QYD), a traditional Chinese medicine (TCM), is commonly used in clinical to treat SAP-ALI. However, the underlying mechanisms remain to be fully elucidated. Herein, by using a caerulein plus lipopolysaccharide (LPS)-induced SAP-ALI mice model and antibiotics (Abx) cocktail-induced pseudogermfree mice model, we tried to uncover the roles of the gut microbiota by administration of QYD and explored its possible mechanisms. Immunohistochemical results showed that the severity of SAP-ALI and intestinal barrier functions could be affected by the relative depletion of intestinal bacteria. The composition of gut microbiota was partially recovered after QYD treatment with decreased Firmicutes/Bacteroidetes ratio and increased relative abundance in short-chain fatty acids (SCFAs)-producing bacteria. Correspondingly increased levels of SCFAs (especially propionate and butyrate) in feces, gut, serum, and lungs were observed, generally consistent with changes in microbes. Western-blot analysis and RT-qPCR results indicated that the AMPK/NF-κB/NLRP3 signaling pathway was activated after oral administration of QYD, which was found to be possibly related to the regulatory effects on SCFAs in the intestine and lungs. In conclusion, our study provides new insights into treating SAP-ALI through modulating the gut microbiota and has prospective practical value for clinical use in the future. IMPORTANCE Gut microbiota affects the severity of SAP-ALI and intestinal barrier function. During SAP, a significant increase in the relative abundance of gut pathogens (Escherichia, Enterococcus, Enterobacter, Peptostreptococcus, Helicobacter) was observed. At the same time, QYD treatment decreased pathogenic bacteria and increased the relative abundance of SCFAs-producing bacteria (Bacteroides, Roseburia, Parabacteroides, Prevotella, Akkermansia). In addition, The AMPK/NF-κB/NLRP3 pathway mediated by SCFAs along the gut-lung axis may play an essential role in preventing the pathogenesis of SAP-ALI, which allows for reduced systemic inflammation and restoration of the intestinal barrier.

The facilitating role of phycospheric heterotrophic bacteria in cyanobacterial phosphonate availability and Microcystis bloom maintenance.

BACKGROUND: Phosphonates are the main components in the global phosphorus redox cycle. Little is known about phosphonate metabolism in freshwater ecosystems, although rapid consumption of phosphonates has been observed frequently. Cyanobacteria are often the dominant primary producers in freshwaters; yet, only a few strains of cyanobacteria encode phosphonate-degrading (C-P lyase) gene clusters. The phycosphere is defined as the microenvironment in which extensive phytoplankton and heterotrophic bacteria interactions occur. It has been demonstrated that phytoplankton may recruit phycospheric bacteria based on their own needs. Therefore, the establishment of a phycospheric community rich in phosphonate-degrading-bacteria likely facilitates cyanobacterial proliferation, especially in waters with scarce phosphorus. We characterized the distribution of heterotrophic phosphonate-degrading bacteria in field Microcystis bloom samples and in laboratory cyanobacteria "phycospheres" by qPCR and metagenomic analyses. The role of phosphonate-degrading phycospheric bacteria in cyanobacterial proliferation was determined through coculturing of heterotrophic bacteria with an axenic Microcystis aeruginosa strain and by metatranscriptomic analysis using field Microcystis aggregate samples. RESULTS: Abundant bacteria that carry C-P lyase clusters were identified in plankton samples from freshwater Lakes Dianchi and Taihu during Microcystis bloom periods. Metagenomic analysis of 162 non-axenic laboratory strains of cyanobacteria (consortia cultures containing heterotrophic bacteria) showed that 20% (128/647) of high-quality bins from eighty of these consortia encode intact C-P lyase clusters, with an abundance ranging up to nearly 13%. Phycospheric bacterial phosphonate catabolism genes were expressed continually across bloom seasons, as demonstrated through metatranscriptomic analysis using sixteen field Microcystis aggregate samples. Coculturing experiments revealed that although Microcystis cultures did not catabolize methylphosphonate when axenic, they demonstrated sustained growth when cocultured with phosphonate-utilizing phycospheric bacteria in medium containing methylphosphonate as the sole source of phosphorus. CONCLUSIONS: The recruitment of heterotrophic phosphonate-degrading phycospheric bacteria by cyanobacteria is a hedge against phosphorus scarcity by facilitating phosphonate availability. Cyanobacterial consortia are likely primary contributors to aquatic phosphonate mineralization, thereby facilitating sustained cyanobacterial growth, and even bloom maintenance, in phosphate-deficient waters. Video Abstract.

Qingyi granules ameliorate severe acute pancreatitis in rats by modulating the gut microbiota and serum metabolic aberrations.

CONTEXT: Qingyi granules can be used to effectively treat patients with severe acute pancreatitis (SAP). OBJECTIVE: To elucidate the role of gut microbiota-mediated metabolism in the therapeutic effects of Qingyi granules. MATERIALS AND METHODS: Sprague-Dawley rats were grouped into the sham operation, SAP model, Qingyi granule intervention (Q, 1.8 g/kg) and emodin intervention (E, 50 mg/kg) groups and observed for 24 h. H&E staining and ELISA were used for histopathological analysis and serum enzyme and cytokine assays. 16S rDNA sequencing and UHPLC-HRMS were used for gut microbiota analysis and untargeted metabolomics. RESULTS: In SAP rats, Qingyi granules decreased the pancreatic pathological score (Q, 7.4 ± 1.14; SAP, 11.6 ± 1.14, p < 0.01); serum amylase (Q, 121.2 ± 6.7; SAP, 144.3 ± 8.86, p < 0.05), lipase (Q, 566 ± 20.34; SAP, 656.7 ± 29.32, p < 0.01), and diamineoxidase (Q, 492.8 ± 26.08; SAP, 566.1 ± 26.83, p < 0.05) activities; and IL-1ß (Q, 29.48 ± 0.88; SAP, 36.17 ± 1.88, p < 0.01), IL-6 (Q, 112.2 ± 3.57; SAP, 128.9 ± 9.09, p < 0.05) and TNF-α (Q, 215.3 ± 8.67; SAP, 266.4 ± 28.03, p < 0.05) levels. SAP induced Helicobacter and Lactobacillus overgrowth and suppressed Romboutsia and Allobaculum growth and caused aberrations in bacterial metabolites, which were partly reversed by Qingyi granules. DISCUSSION AND CONCLUSIONS: Qingyi granules can modulate the gut microbiota and metabolic abnormalities to ameliorate SAP. Multi-omics approaches allow systematic study of the pharmacological mechanisms of compound prescriptions for critical illnesses.

Investigating the in vivo effect of Tribulus terrestris extract in middle cerebral artery occlusion rats using LC-MS-based metabolomics combined with molecular docking.

Tribulus terrestris L. fruit (TT) is a traditional Chinese herbal medicine used to treat ischemic stroke (IS). This study aimed to investigate the protective effect of TT extract, named TT15, on middle cerebral artery occlusion (MCAO) rats using metabolomics and molecular docking and find the targets of action and the material basis of TT15 against IS. The results of the infarct volume and neurological defect scores confirmed the efficacy of TT15. Serum metabolomics analysis using LC-MS revealed that model group animals experienced a variety of metabolic disturbances when compared to the sham group. TT15 can restore the MCAO-induced serum metabolite changes by modulating multiple metabolic pathways. Six enzymes were highlighted by the metabolite-reaction-enzyme-gene (M-R-E-G) network analysis, which might be the possible targets for the TT15 against IS. Molecular docking analysis was applied to show the binding affinities between active compounds and these enzymes. The representative docking mode with the lowest binding energy between three compounds and phospholipase A 2 (PLA2) and peroxidase (POD) was displayed by the ribbon binding map. This study profiles the metabolic changes in MCAO-induced IS and investigates the efficacy and the corresponding mechanism of TT15 in the treatment of IS.

Methodological, reporting, and evidence quality of systematic reviews of traditional Chinese medicine for ischemic stroke.

Objective: The aim of this study is to critically appraise whether published systematic reviews/meta-analyses of traditional Chinese medicine for adults with ischemic stroke are of sufficient quality and to rate the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Method: A literature search was performed in the Cochrane Library, PubMed, Chinese National Knowledge Infrastructure, and SinoMed databases by March 2022. The inclusion criteria were systematic reviews/meta-analyses of traditional Chinese medicine in adults who suffered from ischemic stroke. A Measurement Tool to Access Systematic Reviews 2 (AMSTAR-2) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Abstract (PRISMA-A) statements were used to assess the methodological and reporting quality of the included reviews. The Grading of Recommendations, Assessment, Development, and Evaluation system was utilized to assess each report's evidence level. Results: Of the 1,908 titles and abstracts, 83 reviews met the inclusion criteria. These studies were published between 2005 and 2022. The results of AMSTAR-2 showed that 51.4% of the items were reported, but the registration, reasons for the inclusion of study design, the list of excluded studies, and funding information were ignored in the majority of the reviews. The results of PRISMA-A showed that 33.9% of items were reported, and the information on registration, limitation, and funding was not available in many publications. The assessment of the evidence with the Grading of Recommendations, Assessment, Development, and Evaluation showed that more than half (52/83) of the included studies had either low or very low levels of evidence. Conclusion: The reporting quality in the abstract of systematic reviews/meta-analyses on traditional Chinese medicine for ischemic stroke is poor and does not facilitate timely access to valid information for clinical practitioners. Although the methodological quality is of a medium level, this evidence lacks certainty, especially with a high risk of bias in individual studies.

Yishen Tongluo formula alleviates diabetic kidney disease through regulating Sirt6/TGF-ß1/Smad2/3 pathway and promoting degradation of TGF-ß1.

ETHNOPHARMACOLOGICAL RELEVANCE: Yishen Tongluo formula (YSTLF) is formulated based on traditional Chinese medicine theory for the treatment of Diabetic kidney disease (DKD) and has been shown to be effective in improving the symptoms of DKD according to the clinical observation. AIM OF THE STUDY: To explore the effect of YSTLF on DKD and figure out whether its effects were due to the regulation Sirt6/TGF-ß1/Smad2/3 pathway and promoting degradation of TGF-ß1. MATERIALS AND METHODS: The extract of YSTLF at 1, 2.5 and 5 g/kg was orally administered to C57BLKS/J (db/db) mice for 8 weeks and db/db mice were given valsartan as a positive control. The littermate db/m and db/db mice were given vehicle as the control and model group, respectively. Blood urea nitrogen and serum creatinine were detected and the urinary albumin excretion, urea albumin creatinine ratio was calculated. The histopathological change of renal tissues in each group was determined. Simultaneously, the levels of fibrosis-related proteins and messenger RNA (mRNA) in kidney and high glucose (HG)-induced SV40-MES-13 cells were detected. The roles of YSTLF in regulating of Sirt6/TGF-ß1/Smad2/3 signaling pathway were investigated in HG-stimulated SV40-MES-13 cells and validated in db/db mice. Furthermore, the effect of YSTLF on TGF-ß1 degradation was investigated in HG-stimulated SV40-MES-13 cells. RESULTS: YSTLF significantly improved the renal function in DKD mice. YSTLF dose-dependently attenuated pathological changes and suppressed the expression of type I collagen, alpha smooth muscle actin, type IV collagen, and fibronectin in vitro and in vivo, resulting in ameliorating of renal fibrosis. YSTLF positively regulated Sirt6 expression, while inhibited the activating of TGF-ß1/Smad2/3 signaling pathway. TGF-ß1 was steady expressed in HG-stimulated SV40-MES-13 cells, whereas was continuously degraded under YSTLF treatment. CONCLUSIONS: YSTLF significantly ameliorates renal damages and fibrosis may via regulating Sirt6/TGF-ß1/Smad2/3 signaling pathway as well as promoting the degradation of TGF-ß1.

Ferulic acid supplementation alleviates hyperuricemia in high-fructose/fat diet-fed rats via promoting uric acid excretion and mediating the gut microbiota.

The prevalence of hyperuricemia (HUA) has been rising, and it is typically accompanied by renal injury and intestinal flora disorder, leading to a non-negligible health crisis. Ferulic acid (FA), as a familiar polyphenol, has been proven to exert anti-hyperuricemic properties via inhibiting uric acid (UA) synthesis; however, the detailed underlying mechanisms remain unclear. The aim of this study was to explore the regulatory effect of FA on UA excretion as a potential strategy for reducing UA levels, and the comorbidities of HUA. FA treatment downregulated the expression of urate absorption transporter genes and repressed the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway in UA-stimulated HK-2 cells. To examine these effects in vivo, FA or allopurinol (positive control) was given to rats with HUA induced by a high-fructose/fat diet (HFFD) for 20 weeks. FA markedly decreased the serum UA, blood urea nitrogen, and creatinine levels. The expression of urate absorption transporters was downregulated, whereas the expression of secretion transporters was upregulated in the kidneys and intestines of FA-treated HUA rats. Additionally, FA mitigated renal oxidative stress, and suppressed the activation of the TLR4/NF-κB pathway and the downstream inflammatory response-related markers in the kidneys. Moreover, FA remodeled the composition of the gut microbiota, characterized by an increase in beneficial bacteria (e.g., Lactobacillus and Ruminococcus) and a decrease in pathogenic bacteria (e.g., Bacteroides). In conclusion, our study validated FA as an effective nutrient to ameliorate HFFD-induced HUA, suggesting its potential to mitigate the HUA-associated renal impairment and intestinal microbiota disturbance.

Ebracteolatain A exerts anti-proliferation of breast cancer by inhibiting Protein kinase D 1 in MEK/ERK and PI3K/AKT signaling pathways.

BACKGROUND: Ebracteolatain A (EA) is an acetyl-phloroglucinol compound extracted from Euphorbiae Ebracteolatae Radix, which has been shown to have antitumor activity. PURPOSE: Current research addressed the antitumor activity of EA in breast cancer and further clarified its mechanism. STUDY DESIGN: Based on the pharmacodynamic evaluation in breast cancer cells and animal models, the antitumor effects of EA will be validated in vitro and in vivo. METHODS: Breast cancer cells were processed with increasing concentrations of EA. CCK-8 and colony formation assays were employed to examine the effects of EA on proliferation and survival. Flow cytometry detected the blocking function of EA on the cell cycle. The specific mechanism of EA in breast cancer was studied by transfection experiments and Western Blot analysis. Finally, a nude mice xenograft tumor model was constructed to assess the therapeutic and potential mechanism of EA. RESULTS: We proved that EA caused a dose-dependent inhibition on MCF-7 and MDA-MB-415 cells with IC50 of 6.164 and 6.623 µmol/l, respectively. While EA reduced cell proliferation and clone formation, and markedly arrested cells in the G0/G1 phase. In vivo, EA remarkably suppressed the tumor weight and volume in xenograft nude mice. Besides, PKD1 reversed the inhibition of EA on breast cancer cell proliferation, clone formation, and cycle arrest, and restored tumor growth in xenograft nude mice. Western Blot confirmed that EA regulates breast cancer by suppressing PKD1 in MEK/ERK and PI3K/AKT signaling pathways. CONCLUSION: Herein, we first confirmed EA exerts anti-proliferation by inhibiting PKD1 in MEK/ERK and PI3K/AKT signaling pathways, indicating that EA is a prodigious breast cancer drug candidate.

Design and experiments of an automatic depth-adjusting double screw trencher and fertiliserning.

In response to the problems of low fertilizer application efficiency, poor operation quality, and uneven application of fertilizer by domestic tea garden trenching and fertilizing machines, an automatic depth-adjusting double screw trenching and fertilizing machine was designed. The machine uses a double spiral furrowing and fertilizer application method, which can complete the integrated operation of furrowing, fertilizer application, and mulching at one time. The key components of the machine such as the screw-type fertilizer discharger, trenching, and fertilizer application mechanism are designed using theoretical analysis, and the trenching depth is automatically adjusted through the hydraulic control system to maintain a consistent depth. A single-factor test and a quadratic regression rotary orthogonal test were conducted to select the diameter of the spiral fertilizer discharger, the rotational speed of the spiral fertilizer discharger, and the rotational speed of the trenching and fertilizer application mechanisms. Based on these tests, the fertilizer application performance of the fertilizer machine was evaluated, and a mathematical model of the fertilizer application volume and coefficient of variation was established. The influence of the test factors on the coefficient of variation was also analyzed. In the study, 58.36 and 480.35 r/min were found to be the optimal rotational speeds for spiral fertilizer discharge and trenching and fertilizer application, respectively, while 88.90 mm was found to be the optimal diameter for spiral fertilizer discharge. The coefficient of variation for the spiral fertilizer discharge was 3.95%, which meets the tea plantation's fertilizer application requirements.

Study on Oil Recovery Mechanism of Polymer-Surfactant Flooding Using X-ray Microtomography and Integral Geometry.

Understanding pore-scale morphology and distribution of remaining oil in pore space are of great importance to carry out in-depth tapping of oil potential. Taking two water-wet cores from a typical clastic reservoir in China as an example, X-ray CT imaging is conducted at different experimental stages of water flooding and polymer-surfactant (P-S) flooding by using a high-resolution X-ray microtomography. Based on X-ray micro-CT image processing, 3D visualization of rock microstructure and fluid distribution at the pore scale is achieved. The integral geometry newly developed is further introduced to characterize pore-scale morphology and distribution of remaining oil in pore space. The underlying mechanism of oil recovery by P-S flooding is further explored. The results show that the average diameter of oil droplets gradually decreases, and the topological connectivity becomes worse after water flooding and P-S flooding. Due to the synergistic effect of "1 + 1 > 2" between the strong sweep efficiency of surfactant and the enlarged swept volume of the polymer, oil droplets with a diameter larger than 124.58 µm can be gradually stripped out by the polymer-surfactant system, causing a more scattered distribution of oil droplets in pore spaces of the cores. The network-like oil clusters are still dominant when water flooding is continued to 98% of water cut, but the dominant pore-scale oil morphology has evolved from network-like to porous-type and isolated-type after P-S flooding, which can provide strong support for further oil recovery in the later stage of chemical flooding.

Multitarget and Multipathway Regulation of Zhenqi Fuzheng Granule against Non-Small Cell Lung Cancer Based On Network Pharmacology and Molecular Docking.

Background and Objective. The morbidity and mortality rates of non-small cell lung cancer (NSCLC) remain high. Zhenqi Fuzheng (ZQFZ) granule, which consists of Astragali Radix and Ligustri Lucidi Fructus, is commonly used to improve the immunity of cancer patients. However, the mechanism of ZQFZ granule against NSCLC is still unclear. In this study, the network pharmacology and molecular docking approaches were used to investigate the potential mechanism of ZQFZ granule on NSCLC. Methods. The ingredients in the ZQFZ granule were considered in one study based on UPLC, and the potential targets were predicted in the SwissTargetPrediction database. NSCLC targets were gathered from GeneCards, OMIM, and TTD databases. The ingredient-target-NSCLC network was drawn by Cytoscape. The protein-protein interaction was obtained from the STRING database, and the gene function and biological pathways were analyzed by Metascape. AutoDock Vina was used to verify the molecular docking between the key compounds and core targets, and PyMol visualized the results. Results. 244 targets were related to 13 candidate compounds and 1904 targets were related to NSCLC, of which a total of 106 anti-NSCLC targets were predicted. The compound-target-NSCLC network indicated that sinapinic acid, ferulic acid, asiatic acid, pratensein, and glycitein might be the key components for treating NSCLC. The 41 vital targets (out of 106 targets) above the median calculated by PPI degree were selected for bioinformatics analysis. The top 10 targets out of 41 ranked by MCC were IL-6, SRC, CTNNB1, STAT3, CASP3, TNF, EGFR, MAPK8, HSP90AA1, and PTGS2. ZQFZ granule treatment for NSCLC involved many pathways through KEGG analyses, which included pathways in cancer (hsa05200), proteoglycans in cancer (hsa05205), endocrine resistance (hsa01522), microRNAs in cancer (hsa05206), PI3K-Akt signaling pathway (hsa04151), and IL-17 signaling pathway (hsa04657). Molecular docking studies revealed that sinapinic acid, ferulic acid, asiatic acid, pratensein, and glycitein had good infinity with most core targets. Conclusions. This study indicated that ZQFZ granule with multicompounds could treat NSCLC through multitargets and multipathways.