scholarly journals Kaempferol Alleviates Steatosis and Inflammation During Early Non-Alcoholic Steatohepatitis Associated With Liver X Receptor α-Lysophosphatidylcholine Acyltransferase 3 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongjiao Xiang ◽  
Mingmei Shao ◽  
Yifei Lu ◽  
Junmin Wang ◽  
Tao Wu ◽  
...  
Keyword(s):  
Cell Model ◽  
Biological Effects ◽  
Mice Model ◽  
Related Factors ◽  
Alcoholic Steatohepatitis ◽  
Liver X Receptor Α ◽  
Mrna And Protein Expression ◽  
Anti Oxidant

Background: Kaempferol (KP) has a variety of biological effects such as anti-inflammatory, anti-oxidant, anti-aging and cardiovascular protection. Whether KP has a therapeutic effect on non-alcoholic steatohepatitis (NASH), and the detailed mechanism is currently unclear. This study aims to explore the mechanism of KP in the treatment of NASH through in vivo and in vitro experiments.Methods: 1) In vivo experiment: In the C57BL/6 NASH mice model induced by high fat diet (HFD), KP was administered by gavage at a dose of 20 mg/kg/day. 2) In vitro experiment: Palmitic acid/Oleic acid (PA/OA, 0.375/0.75 mM) was used to intervene HepG2 and AML12 cells to establish a steatosis cell model. Three concentrations of KP, low (20 μmol/L), medium (40 μmol/L) and high (60 μmol/L) were used in vitro. The mRNA and protein expression of related molecules involved in LXRα-LPCAT3-ERS pathway were detected using RT-qPCR and Western blot.Results: In the NASH mouse model, KP can significantly reduce the expression of LXRα, LPCAT3 and ERS-related factors PERK, eIF2α, ATF6, ATF4, XBP1, CHOP, IRE1α and GRP78. In the PA/OA-induced cell model, KP could decrease the content of triglyceride and lipid droplets, and also decrease the expression of LXR α, LPCAT3 and ERS related factors PERK, eIF2α, ATF6, ATF4, XBP1, CHOP, IRE1α and GRP78.Conclusion: KP may decrease the expression level of LXRα and LPCAT3, thus improve ERS and reduce hepatic steatosis and inflammation.

scholarly journals Lipid-Lowering Effects of Inonotus obliquus Polysaccharide In Vivo and In Vitro

Foods ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3085
Author(s):  
Mo Yang ◽  
Dong Hu ◽  
Zhengying Cui ◽  
Hongxuan Li ◽  
Chaoxin Man ◽  
...  
Keyword(s):  
Oleic Acid ◽  
High Fat Diet ◽  
Cell Model ◽  
Lipid Lowering ◽  
Mice Model ◽  
High Fat ◽  
Inonotus Obliquus ◽  
Inonotus Obliquus Polysaccharide

Excessive lipid intake will cause hyperlipidemia, fatty liver metabolism disease, and endanger people’s health. Edible fungus polysaccharide is a natural active substance for lipid lowering. In this study, the HepG2 cell model induced by oleic acid and mice model induced by a high-fat diet was established. The lipid-lowering effects of Inonotus obliquus polysaccharide (IOP) was investigated in vivo and in vitro. Glucose (251.33 mg/g), rhamnose (11.53 mg/g), ribose (5.10 mg/g), glucuronic acid (6.30 mg/g), and galacturonic acid (2.95 mg/g) are present in IOP, at a ratio of 85.2:3.91:1.73:2.14:1. The molecular weight of IOP is 42.28 kDa. Treatment with 60 mg/L of IOP showed a significant lipid-lowering effect in HepG2 cells compared with the oleic acid-treated group. In the oil red O-stained images, the red fat droplets in the IOP-treated groups were significantly reduced. TC and TG levels of IOP-treated groups decreased. IOP can alleviate the lipid deposition in the mice liver due to high-fat diet, and significantly reduce their serum TC, TG, and LDL-C contents. IOP could activate AMPK but decrease the SREBP-1C, FAS, and ACC protein expression related to adipose synthesis in mice. IOP has a certain potential for lipid-lowering effects both in vivo and in vitro.

scholarly journals Exenatide Attenuates Non-Alcoholic Steatohepatitis by Inhibiting the Pyroptosis Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu Liu ◽  
Da-Wei Wang ◽  
Dan Wang ◽  
Bin-Hong Duan ◽  
Hong-Yu Kuang
Keyword(s):  
Type 2 Diabetes ◽  
Signaling Pathway ◽  
Leptin Receptor ◽  
Cell Model ◽  
Clinical Use ◽  
Male Mice ◽  
Alcoholic Steatohepatitis

Background/AimsExenatide is a glucagon-like polypeptide-1 analog, whose main clinical use is to treat type 2 diabetes. However, the mechanism of exenatide in mitigating non-alcoholic steatohepatitis (NASH) remains unclear. This study aimed to investigate the in vitro and in vivo effect of exenatide on NASH.MethodsLeptin receptor-deficient C57BL/KsJ- db/db male mice were fed with methionine-choline-deficient (MCD) diet for 4 weeks to induce NASH, while oleic acid/LPS-treated HepG2 cells were used as an in vitro cell model. Exenatide (20 µg/kg/day, subcutaneous) and specific exenatide inhibitors (20 µg/kg/day, intraperitoneal) were used to determine the effects of exenatide on NASH.ResultsExenatide treatment inhibited the pyroptosis signaling pathway to attenuate NASH.ConclusionTo the best of our knowledge, this report provides the first evidence showing that exenatide attenuated NASH by inhibiting the pyroptosis signaling pathway. Exenatide thus has important pathophysiological functions in NASH and may represent a useful new therapeutic target.

scholarly journals Anti-Hyperuricemic and Nephroprotective Effects of Dihydroberberine in Potassium Oxonate- and Hypoxanthine-Induced Hyperuricemic Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Lieqiang Xu ◽  
Guoshu Lin ◽  
Qiuxia Yu ◽  
Qiaoping Li ◽  
Liting Mai ◽  
...  
Keyword(s):  
Intragastric Administration ◽  
Inflammasome Activation ◽  
Mice Model ◽  
Protein Levels ◽  
Nlrp3 Inflammasome Activation ◽  
Mechanistic Investigation ◽  
Mrna And Protein Expression ◽  
Potassium Oxonate

Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation in vitro and in vivo. Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved in vivo efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. In vitro, DHB exhibited significant XOD inhibitory activity (IC50 value, 34.37 μM). The in vivo results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1β, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1β. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney.

scholarly journals Hei-Gu-Teng Zhuifenghuoluo Granule Modulates IL-12 Signal Pathway to Inhibit the Inflammatory Response in Rheumatoid Arthritis

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Kang Zheng ◽  
Zexu Chen ◽  
Wen Sun ◽  
Bin Liu ◽  
Danping Fan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Signaling Pathway ◽  
Bioinformatics Analysis ◽  
Cell Model ◽  
Mice Model ◽  
Sinomenium Acutum ◽  
Systemic Inflammatory Disease ◽  
Anti Inflammatory

Rheumatoid arthritis (RA) is a type of chronic systemic inflammatory disease; it has a very complicated pathogenesis, and multiple pathological changes are implicated. Traditional Chinese medicine (TCM) like Tripterygium wilfordii Hook. F. or Sinomenium acutum (Thunb.) Rehd et Wils. has been extensively used for centuries in the treatment of arthritic diseases and been reported effective for relieving the severity of RA. Hei-Gu-Teng Zhuifenghuoluo granule (HGT) which contains Periploca forrestii Schltr., Sinomenium acutum (Thunb.) Rehd et Wils., and Lysimachia paridiformis Franch. var. stenophylla Franch. was a representative natural rattan herb formula for the treatment of RA in China, but the mechanism has not been elucidated. This study aimed at exploring the mechanism of HGT on RA using the bioinformatics analysis with in vivo and in vitro experiment validation. The potential action mechanism was first investigated by bioinformatics analysis via Ingenuity Pathway Analysis (IPA) software. After that, we use experimental validation such as collagen-induced arthritis (CIA) mice model in vivo and U937 cell model in vitro. The bioinformatics results suggested that HGT may have anti-inflammatory characteristic on RA and IL-12 signaling pathway could be the potential key trigger. In vivo experiments demonstrated that HGT ameliorated the symptoms in CIA mice and decreased the production of inflammatory cytokines in both mice ankle joints and serum. Furthermore, HGT effectively inhibited the activation of IL-12R and STAT4 on IL-12 signaling pathway. In vitro experiments showed that HGT inhibited the production of IL-12R and STAT4 induced by IL-12 in lipopolysaccharide- (LPS-) stimulated U937 cells. Moreover, IL-12R knockdown was able to interfere with the inhibition effects of HGT on the production of these cytokines. Our results confirmed the anti-inflammatory property of HGT, which was attributed to its inhibition on IL-12 signaling pathway.

Borneol promotes apoptosis of human glioma cells by regulating mTORC1 / eIF4E / HIF-1a pathway

2020 ◽  
Author(s):  
zeng wang ◽  
Qinglin Li ◽  
Liang Xia ◽  
Xia Li ◽  
Caixing Sun ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Cell Model ◽  
Glioma Cells ◽  
Related Factors ◽  
Theoretical Support ◽  
Sd Rat ◽  
Key Factor ◽  
Primary Glioma

Abstract The main reason for the failure of malignant glioma treatment is local tumor recurrence. Tumor cells in hypoxic microenvironment activate HIF-1 α transcription, and thus promoting tumor invasion and metastasis is one of the important reasons. In our previous study, we clearly established that borneol opens the blood-brain tumor barrier and its related mechanism. However, the effects of borneol on glioma treatment have not yet been elucidated. Therefore, in this study, we evaluated the effects of borneol on cell proliferation and the expression of HIF-1a, mTORC1, eIF4E were by constructing in vivo SD rat brain glioma model and in vitro human primary cultured glioma cell model. Further, we measured the apoptosis effect and mechanism induced by borneol in human primary cultured glioma cells. We found that borneol could induce primary glioma cells apoptosis by suppressing the mTORC1 / eIF4E / HIF-1 α signaling pathway. Further, we also found that borneol could downregulate the expression of Bcl-2 and upregulation the expression of Bax and caspase-3,suggesting that borneol could further regulate the expression of apoptosis-related factors and induce the apoptosis of glioma cells. In conclusion, the findings of the present study suggest that HIF-1α may be a key factor in apoptosis of glioma cells, and mTORC1 / eIF4E / HIF-1a pathway is involved in the apoptosis induced by borneol in malignant glioma. Our results not only reveal the target and molecular mechanism and action of borneol leading to promote apoptosis in glioma cells, but also provide experimental basis and theoretical support for the clinical application of borneol.

Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation

2019 ◽  
Vol 133 (20) ◽  
pp. 2045-2059 ◽  
Author(s):  
Da Zhang ◽  
Xiuli Wang ◽  
Siyao Chen ◽  
Selena Chen ◽  
Wen Yu ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Endothelial Cell ◽  
Pulmonary Artery ◽  
Cell Model ◽  
Site Directed Mutagenesis ◽  
Critical Event ◽  
Hypertensive Rats ◽  
Pulmonary Artery Endothelial Cell

Abstract Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling. Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

The role of aromatic microbial metabolites

2018 ◽  
pp. 97-108
Author(s):  
Н.В. Белобородова ◽  
В.В. Мороз ◽  
А.Ю. Бедова
Keyword(s):  
Process Integration ◽  
Biological Effects ◽  
Clinical Findings ◽  
Multiple Organ ◽  
Critical Conditions ◽  
Clear Understanding ◽  
Microbial Metabolites ◽  
Blood Concentrations

Интеграция метаболизма макроорганизма и его микробиоты, обеспечивающая в норме симбиоз и саногенез, нарушается при заболеваниях, травме, критическом состоянии, и вектор взаимодействия может изменяться в пользу прокариотов по принципу «метаболиты бактерий - против хозяина». Анализ литературы показал, что, с одной стороны, имеется живой интерес к ароматическим микробным метаболитам, с другой - отсутствует четкое представление об их роли в организме человека. Публикации, касающиеся ряда ароматических микробных метаболитов (фенилкарбоновых кислот, ФКК), как правило, не связаны между собой по тематике и направлены на решение тех или иных прикладных задач в разных областях биологии и медицины. Цель обзора - анализ информации о происхождении, биологических эффектах ФКК в экспериментах in vitro и in vivo , и клинических наблюдениях. Обобщая результаты приведенных в обзоре исследований на клеточном, субклеточном и молекулярном уровнях, логично предположить участие ароматических микробных метаболитов в патогенезе полиорганной недостаточности при сепсисе. Наиболее перспективным для раскрытия роли ароматических микробных метаболитов представляется изучение механизмов вторичной почечной недостаточности и септической энцефалопатии. Важным направлением для будущих исследований является изучение влияния продуктов микробной биодеградации ароматических соединений на развитие диссеминированного внутрисосудистого свертывания крови, артериальной гипотензии и септического шока. Результаты дальнейших исследований будут иметь не только фундаментальное значение, но и обогатят практическую медицину новыми диагностическими и лечебными технологиями. Significant increases in blood concentrations of some aromatic metabolites (phenylcarboxylic acids, PhCAs) in patients with sepsis have been previously shown. Enhanced bacterial biodegradation of aromatic compounds has been demonstrated to considerably contribute to this process. Integration of macroorganism metabolism and its microbiota, which provides normal symbiosis and sanogenesis, is disturbed in diseases, trauma, and critical conditions. Direction of this interaction may change in favor of prokaryotes according to the principle, “bacterial metabolites are against the host”. Analysis of literature showed a particular interest of many investigators to aromatic microbial metabolites. However, there is no clear understanding of their role in the human body. Publications on PhCAs are generally not thematically interrelated and usually focus on solving applied tasks in different fields of biology and medicine. The aim of this work was to consolidate existing information about origin and biological effects of PhCAs in in vitro / in vivo experiments and some clinical findings. The presented summary of reported data from studies performed at cellular, sub-cellular, and molecular levels suggests participation of aromatic microbial metabolites in the pathogenesis of multiple organ failure in sepsis. Studying mechanisms of secondary renal failure and septic encephalopathy is most promising for discovering the function of aromatic microbial metabolites. Effects of microbial biodegradation products of aromatic substances on development of disseminated intravascular coagulation, hypotension, and septic shock are an important challenge for future studies. Results of further investigations will be not only fundamental, but will also enrich medical practice with new diagnostic and therapeutic technologies.

Antioxidant Activity, Phenolic Content and Hematoprotective Effects of Cleome arabica Polyphenolic Leaf Extract

2019 ◽  
Author(s):  
C. Tigrine ◽  
A. Kameli
Keyword(s):  
Antioxidant Activity ◽  
Biological Effects ◽  
Reducing Power ◽  
Hematological Toxicity ◽  
Protective Effects ◽  
Ferrous Ions ◽  
Polyphenolic Extract ◽  
Cleome Arabica

In this study a polyphenolic extract from Cleome arabica leaves (CALE) was investigated for its antioxidant activity in vitro using DPPH•, metal chelating and reducing power methods and for its protective effects against AraC-induced hematological toxicity in vivo using Balb C mice. Results indicated that CALE exhibited a strong and dose-dependent scavenging activity against the DPPH• free radical (IC50 = 4.88 μg/ml) and a high reducing power activity (EC50 = 4.85 μg/ml). Furthermore, it showed a good chelating effects against ferrous ions (IC50 = 377.75 μg/ml). The analysis of blood showed that subcutaneous injection of AraC (50 mg/kg) to mice during three consecutive days caused a significant myelosupression (P < 0.05). The combination of CALE and AraC protected blood cells from a veritable toxicity. Where, the number of the red cells, the amount of hemoglobin and the percentage of the hematocrite were significantly high. On the other hand, AraC cause an elevation of body temperature (39 °C) in mice. However, the temperature of the group treated with CALE and AraC remained normal and did not exceed 37.5 °C. The observed biological effects of CALE, in vitro as well as in vivo, could be due to the high polyphenol and flavonoid contents. In addition, the antioxidant activity of CALE suggested to be responsible for its hematoprotective effect.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

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