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1.
China Pharmacy ; (12): 2224-2229, 2022.
Article in Chinese | WPRIM | ID: wpr-943062

ABSTRACT

OBJECTIVE To study the protective effect and mechanism of Shiyifang medicinal wine (SYF) on knee osteoarthritis(KOA)of rabbit induced by papain . METHODS Thirty-five rabbits were randomly divided into blank group ,model group,positive group (Diclofenac diethylamine emulsion 200 mg/kg),SYF high -dose group (386 mg/kg)and SYF low -dose group(97 mg/kg),with 7 rabbits in each group (all had 4 males and 3 females). Except for the blank group ,the other groups ’ rabbits were injected 0.5 mL papain mixture (containing 2% papain and 0.03 mol/L L -cysteine)into the right knee cavity on day 1, 4 and 7,to replicate KOA model . Blank group was given constant volume of normal saline . From the 15th day ,drugs were applied to right hind knee joints of rabbits in each group ,twice a day for 20 days. At the same time ,the diameter of right knee joints of rabbits was measured by vernier calipers at day 0,8,14 and 35 to calculate swelling degree . After the experiment ,the levels of IL-1β,TNF-α and PGE 2 in synovial tissue were determined by enzyme -linked immunosorbent assay . Hematoxylin-eosin(HE) staining was used to prepare the sections of synovial tissue ,and the pathological changes were observed . The relative mRNA expressions of TLR 4,MyD88 and NF - кB p 65 in the TLR 4/MyD88/NF- кB signaling pathway were detected by real -time quantitative polymerase chain reaction . The relative protein expressions of TLR 4,MyD88,NF-кB p 65 and p -NF-кB p 65 were detect by Western blot . RESULTS Compared with blank group,the degree of knee swelling could be increased in model group ,the pathological damage of synovial tissue was more serious ,and the levels of IL -1β,TNF-α and PGE 2 were increased significantly in synovial tissue (P<0.05). The relative expression levels of TLR 4,MyD88,NF-кB p 65 mRNAs and TLR 4,MyD88,p-NF-кB p 65 proteins were significantly increased(P<0.05). Compared with model group ,swelling degree of right hind knee and the pathological injury degree of synovial tissue were significantly improved in each treatment group ,while the levels of IL -1β,TNF-α and PGE 2 in synovial tissue were significantly decreased (P<0.05). The relative mRNA expressions of TLR 4,MyD88 and NF -кB p 65 and relative protein expressions of TLR 4,MyD88(except for SYF low -dose group )and p -NF-кB p 65 were all significantly decreased (P<0.05). CONCLUSIONS SYF shows protective effect on KOA induced by papain ,the mechanism of which is associated with decreasing the levels of IL -1β,TNF-α and PGE 2 and down -regulating TLR 4/MyD88/NF-кB signaling pathway .

2.
Article in Chinese | WPRIM | ID: wpr-940759

ABSTRACT

ObjectiveTo investigate the effect of Chuanshanlong granule on Toll-like receptor 4 (TLR4)/myeloid differentiation protein 88 (MyD88)/nuclear transcription factor -κB (NF-κB) signaling pathway, and to explore the mechanism of its treatment of autoimmune thyroiditis (AIT) in rats. MethodForty AIT models were established following excess iodine and injection of porcine thyroglobulin and Freund's adjuvant into Lewis rats for six weeks. Then the rats were randomly divided into the model group, Chuanshanlong granule low-, medium- and high-dose group (0.52, 1.03, 2.06 g·kg-1·d-1), with ten in each group. Rats in the Chuanshanlong granule low-, medium- and high-dose groups were separately given 0.01 mL·g-1·d-1 Chuanshanlong granule, and those in the normal group and the model group were given the same volume of deionized water for eight weeks. Serum of rats was taken to measure thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) by enzyme-linked immunosorbent assay (ELISA), and the concentrations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were detected. The rat thyroid lobes were stained with hematoxylin and eosin (HE), and the pathological changes were observed under light microscope. In addition, the relative expression of TLR4, MyD88, NF-κB protein and mRNA was determined by immunohistochemistry and real-time polymerase chain reaction (Real-time PCR). ResultCompared with the conditions in the normal group, the serum concentrations of TPOAb and TgAb (P<0.01) and FT3 and FT4 (P<0.01) increased and TSH decreased (P<0.01) in the model group. Compared with the conditions in the model group, the concentrations of TPOAb and TgAb in the Chuanshanlong granule treatment groups reduced (P<0.01), and the concentrations of FT3 and FT4 were lowered (P<0.01) while TSH increased (P<0.01) in the Chuanshanlong granule high-dose group. HE staining showed that there was lymphocyte infiltration in the thyroid follicular space, a large number of destroyed or diminished follicular cavities, decreased colloid content, and thinned or destroyed follicular wall in the model group, while the thyroid lymphocyte infiltration in the Chuanshanlong granule treatment groups was significantly less and the structure of thyroid follicles was more complete than those in the model group. Compared with the normal group, the model group had up-regulated relative expression of TLR4, MyD88 and NF-κB protein (P<0.01) and mRNA (P<0.01). Compared with the model group, the Chuanshanlong granule high-dose group had down-regulated relative expression of TLR4 protein and mRNA (P<0.05), MyD88 protein (P<0.01) and mRNA (P<0.05), and NF-κB protein and mRNA (P<0.01). ConclusionChuanshanlong granule may play a therapeutic role in AIT by inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway.

3.
Article in Chinese | WPRIM | ID: wpr-940694

ABSTRACT

ObjectiveTo observe the effects of Scutellariae Radix (SR)-Paeoniae Radix Rubra (PRR) combination of different proportions on the expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor κB (NF-κB) and phosphatidylinositol kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in liver tissues of rats with hepatic fibrosis and explore the mechanism against hepatic fibrosis. MethodSixty male SD rats of SPF grade were randomly divided into a normal group, a model group, a positive control (silymarin) group, and SR-PRR 1∶1, SR-PRR 1∶2, and SR-PRR 1∶4 groups, with 10 rats in each group. The hepatic fibrosis model was induced in rats except for those in the normal group by intraperitoneal injection of 40% tetrachloromethane (CCl4)-olive oil solution at 3 mL·kg-1, 5 mL·kg-1 for the first time, for 8 weeks, twice per week. After 4 weeks, rats were treated correspondingly at 10 mL·kg-1 by intragastric administration, and the body weight of rats in each group was weighed for 8 weeks. After administration, histopathological changes in the liver were observed. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN), albumin (ALB), alkaline phosphatase (AKP), and superoxide dismutase (SOD) activities, malondialdehyde (MDA), and hydroxyproline (HYP) content in liver tissues were detected. The mRNA expression levels of TLR4, MyD88, NF-κB, PI3K, Akt, and mTOR in the liver of rats were detected by real-time fluorescence-based quantitative polymerase chain reaction (Real-time PCR). ResultCompared with the model group, SR-PRR combination of different proportions could recover the body weight and improve the pathological injury of the liver. As revealed by enzyme linked immunosorbent assay (ELISA) results, compared with the normal group, the model group showed increased ALT, AST, HA, LN, AKP, MDA, and HYP levels to different degrees (P<0.05). Compared with the model group, the groups with drug intervention showed decreased levels of ALT, AST, HA, LN, AKP, MDA, and HYP, potentiated SOD activity, and increased level of ALB (P<0.05). As revealed by Real-time PCR results, compared with the normal group, the model group showed increased mRNA expression of TLR4, MyD88, NF-κB, PI3K, Akt, and mTOR (P<0.05). Compared with the model group, the groups with drug intervention showed reduced mRNA expression of TLR4, MyD88, NF-κB, PI3K, Akt, and mTOR in the liver of rats (P<0.05). ConclusionSR-PRR combination of different proportions can improve the histopathological injury in liver tissues caused by CCl4, with the optimal effect observed in the SR-PRR 1∶4 group. SR-PRR may inhibit the development of liver fibrosis by inhibiting the expression of TLR4/MyD88/NF-κB and PI3K/Akt/mTOR signaling pathways, thereby alleviating chemical-induced liver injury.

4.
Article in Chinese | WPRIM | ID: wpr-940523

ABSTRACT

ObjectiveTo explore the therapeutic effect and mechanism of Qiling Tongluo prescription against idiopathic membranous nephropathy (IMN) in rats based on Toll-like receptor 4/myeloid differentiation factor 88/nuclear transcription factor-κB (TLR4/MyD88/NF-κB) signaling pathway. MethodSixty male SD rats were randomly divided into the normal group, model group, benazepril hydrochloride (10 mg·kg-1) group, and low-,medium-, and high-dose (6.48, 12.95, and 25.9 g·kg-1) Qiling Tongluo prescription groups. The IMN rat model was established by injection of cationized bovine serum albumin (C-BSA) into the tail vein. After the model was successfully prepared, the rats were gavaged with the corresponding drugs, once a day, for four consecutive weeks. After the treatment, the pathological changes in rat kidneys were observed by hematoxylin-eosin (HE) staining, Masson staining, and periodic acid-silver metheramine (PASM) staining, followed by the detection of 24 h urinary total protein (24 h UTP), plasma albumin (ALB), total serum protein (TP), serum creatinine (SCr), urea nitrogen (BUN), and uric acid (UA) levels. The levels of interleukin-1β (IL-1β) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA), and the mRNA and protein expression levels of TLR4, MyD88, and NF-κB in the kidney tissue were assayed by real-time fluorescent quantitative polymerase chain reaction (Real-time PCR), immunohistochemistry (IHC), and Western blot. ResultCompared with the normal group, the model group exhibited elevated 24 h UTP and serum SCr, BUN, UA, IL-1β, and IL-6 (P<0.05, P<0.01), decreased ALB and TP (P<0.01), up-regulated TLR4, MyD88, and NF-κB p65 mRNA and protein expression in kidney tissue (P<0.05, P<0.01), obvious inflammation, disordered glomerular structure with enlarged volume, irregularly thickened basement membrane, inflammatory cell infiltration in the renal interstitium, reduced renal tubular epithelial cells due to shedding and apoptosis, and some vacuolar degeneration. Compared with the model group, benazepril hydrochloride and Qiling Tongluo prescription at the high dose remarkably lowered the serum SCr and UA (P<0.05) and increased ALB and TP (P<0.05). Benazepril hydrochloride and Qiling Tongluo prescription at the low, medium, and high doses down-regulated the 24 h UTP, serum IL-1β and IL-6 levels, and renal TLR4, MyD88, and NF-κB p65 mRNA and protein expression to varying degrees (P<0.05, P<0.01), alleviated IMN inflammatory reaction, glomerular swelling, and volume increase, slightly dilated glomerular capillaries, proliferated mesangial matrix, and relieved pathological and morphological damages in rat kidney, with inflammatory cell infiltration occasionally observed. ConclusionQiling Tongluo prescription may reduce the release and expression of inflammatory factors by regulating the TLR4/MyD88/NF-κB signaling pathway to inhibit the inflammatory response in IMN rats, ameliorate proteinuria and kidney damage, and protect kidney function.

5.
Article in Chinese | WPRIM | ID: wpr-940446

ABSTRACT

ObjectiveTo observe the effect of classical prescription Gegen Qinliantang(GGQLT) on inflammatory factors and key targets in the inflammatory pathways mediated by lipopolysaccharide in KKAy mice and explore its mechanism in improving spontaneous type 2 diabetes mellitus (T2DM). MethodSixty-five SPF KKAy mice with spontaneous T2DM and 13 C57BL/6J mice (control) were selected in the barrier system and fed on a high-fat diet. The model was properly induced in 44 mice in the context of random blood glucose exceeding or equal to 13.9 mmol·L-1. Then the mice were assigned into a normal group (20 mL∙kg-1 normal saline), a model group (20 mL∙kg-1 normal saline), an acarbose group (3.9 mg∙kg-1), and high- and low-dose GGQLT groups (1.82 and 0.45 g∙kg-1), with 11 mice in each group. The mice in each group were treated correspondingly by gavage for eight weeks, once per day. Blood glucose and body weight were systematically evaluated. Twelve hours after the last administration, blood samples were collected from the eyes, and the serum and muscle and liver tissues were extracted. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and glucose transporter type 4 (GluT4) were detected by semi-quantitative enzyme-linked immunosorbent assay (ELISA). The protein expression of IκB kinase β (IKKβ) and nuclear factor-κB (NF-κB) in muscle tissues and Toll-like receptor 4 (TLR4) in liver tissues was detected by Western blot. ResultCompared with the normal group, the model group showed increased body weight and blood glucose (P<0.01). Compared with the model group, the acarbose group and the GGQLT groups showed reduced body weight and blood glucose (P<0.05, P<0.01). As revealed by ELISA results, compared with the normal group, the model group showed increased levels of TNF-α and IL-6 (P<0.01) and deceased GluT4 level (P<0.05). Compared with the model group, the groups with drug treatment showed reduced levels of TNF-α and IL-6 (P<0.05, P<0.01), and the acarbose group and the high-dose GGQLT group showed increased GluT4 level (P<0.05, P<0.01). As displayed by Western blot results, compared with the normal group, the model group showed increased protein expression of IKKβ, NF-κB, and TLR4 (P<0.01). Compared with the model group, the acarbose group and the GGQLT groups showed reduced protein expression of IKKβ, NF-κB, and TLR4 (P<0.05, P<0.01). ConclusionGGQLT can inhibit the inflammatory cascade effect and improve T2DM by down-regulating the levels of key inflammatory factors in the TLR4 pathway, inhibiting their activation, and increasing the translocation and activity of GluT4 on the basis of the regulation of intestinal flora.

6.
Article in Chinese | WPRIM | ID: wpr-940171

ABSTRACT

ObjectiveTo investigate the preventive and curative effect of Chaishao Liujunzi Tang (CSLJZT) on colonic mucosal injury induced by dextran sulfate sodium (DSS) in mice with ulcerative colitis (UC) and its mechanism. MethodFifty Balb/c male mice were randomly divided into normal group, model group, CSLJZT low-dose group, CSLJZT high-dose group, and sulfasalazine group. Except for the normal group, other groups were given 2.5% DSS freely for 7 d, and were given drug intervention after successful modeling for 7 d. Bodyweight, feces, and other general physiological statuses of mice were recorded every day, and disease activity index (DAI) scores were calculated.The colon length was measured, and stained by hematoxylin-eosin (HE) staining to observe the morphological changes of the colon.The enzyme-linked immunosorbent assay (ELISA) was used to determine the content of interleukin-1β (IL-1β), myeloperoxidase (MPO), and superoxide dismutase (SOD) in the serum. Western blot was used to determine the protein expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), inhibitor-kappa binding protein (IκB), Caspase-1, and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) in the colon tissues. ResultAs compared with the normal group, mice in the model group had significantly decreased body weight (P<0.01), severe diarrhea and hematochezia, and significantly increased DAI score (P<0.01). As compared with the model group, the decreasing trend of body weight was significantly alleviated in the CSLJZT groups (P<0.01), diarrhea and hematochezia were significantly improved, DAI score was significantly decreased (P<0.01), and colon length increased (P<0.05). HE staining showed that the pathological damage of colon tissue was significantly improved and the inflammatory cell infiltration was reduced in the CSLJZT groups as compared with the model group. As compared with the normal group, the serum levels of IL-1β and MPO were significantly higher (P<0.01) and SOD levels were significantly lower (P<0.01) of mice in the model group.Compared with the model group, the treated group reduced the serum IL-1β and MPO levels (P<0.01), and raised the SOD level (P<0.01). The results of Western blot showed that as compared with the normal group, the expression levels of TLR4, MyD88, NF-κB, Ccaspase-1, and NLRP3 proteins were significantly increased (P<0.01), whereas the expression level of IκB protein was significantly decreased (P<0.01) in the colonic tissue of mice in the model group. As compared with the model group, the expression levels of TLR4, MyD88, NF-κB, Caspase-1, and NLRP3 proteins were decreased (P<0.01), whereas the expression level of IκB protein was increased (P<0.01) in the colonic tissue of mice in the CSLJZT groups. ConclusionCSLJZT improves the inflammatory injury of the colon tissue in DSS-induced UC mice through TLR4/MyD88/NF-κB signaling pathway.

7.
Article in Chinese | WPRIM | ID: wpr-940139

ABSTRACT

ObjectiveTo investigate the preventive and curative effect of Chaishao Liujunzi Tang (CSLJZT) on colonic mucosal injury induced by dextran sulfate sodium (DSS) in mice with ulcerative colitis (UC) and its mechanism. MethodFifty Balb/c male mice were randomly divided into normal group, model group, CSLJZT low-dose group, CSLJZT high-dose group, and sulfasalazine group. Except for the normal group, other groups were given 2.5% DSS freely for 7 d, and were given drug intervention after successful modeling for 7 d. Bodyweight, feces, and other general physiological statuses of mice were recorded every day, and disease activity index (DAI) scores were calculated.The colon length was measured, and stained by hematoxylin-eosin (HE) staining to observe the morphological changes of the colon.The enzyme-linked immunosorbent assay (ELISA) was used to determine the content of interleukin-1β (IL-1β), myeloperoxidase (MPO), and superoxide dismutase (SOD) in the serum. Western blot was used to determine the protein expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), inhibitor-kappa binding protein (IκB), Caspase-1, and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) in the colon tissues. ResultAs compared with the normal group, mice in the model group had significantly decreased body weight (P<0.01), severe diarrhea and hematochezia, and significantly increased DAI score (P<0.01). As compared with the model group, the decreasing trend of body weight was significantly alleviated in the CSLJZT groups (P<0.01), diarrhea and hematochezia were significantly improved, DAI score was significantly decreased (P<0.01), and colon length increased (P<0.05). HE staining showed that the pathological damage of colon tissue was significantly improved and the inflammatory cell infiltration was reduced in the CSLJZT groups as compared with the model group. As compared with the normal group, the serum levels of IL-1β and MPO were significantly higher (P<0.01) and SOD levels were significantly lower (P<0.01) of mice in the model group.Compared with the model group, the treated group reduced the serum IL-1β and MPO levels (P<0.01), and raised the SOD level (P<0.01). The results of Western blot showed that as compared with the normal group, the expression levels of TLR4, MyD88, NF-κB, Ccaspase-1, and NLRP3 proteins were significantly increased (P<0.01), whereas the expression level of IκB protein was significantly decreased (P<0.01) in the colonic tissue of mice in the model group. As compared with the model group, the expression levels of TLR4, MyD88, NF-κB, Caspase-1, and NLRP3 proteins were decreased (P<0.01), whereas the expression level of IκB protein was increased (P<0.01) in the colonic tissue of mice in the CSLJZT groups. ConclusionCSLJZT improves the inflammatory injury of the colon tissue in DSS-induced UC mice through TLR4/MyD88/NF-κB signaling pathway.

8.
Article in Chinese | WPRIM | ID: wpr-928090

ABSTRACT

This study investigated the mechanism of baicalin on lipopolysaccharide(LPS)/interferon γ(IFN-γ)-induced inflammatory microglia based on the triggering receptor expressed on myeloid cells 2(TREM2)/Toll-like receptor 4(TLR4)/nuclear factor kappaB(NF-κB) pathway. Specifically, LPS and IFN-γ were used to induce inflammation in mouse microglia BV2 cells. Then the normal group, model group, low-dose(5 μmol·L~(-1)) baicalin group, medium-dose(10 μmol·L~(-1)) baicalin group, high-dose(20 μmol·L~(-1)) baicalin group, and minocycline(10 μmol·L~(-1)) group were designed. Cell viability was detected by CCK-8 assay and cell morphology was observed under bright field. The expression of interleukin-1β(IL-1β), interleukin-4(IL-4), inducible nitric oxide synthase(iNOS), interleukin-6(IL-6), interleukin-10(IL-10), and arginase-1(Arg-1) mRNA was detected by real-time quantitative PCR, the protein expression of tumor necrosis factor-α(TNF-α), IL-1β, TREM2, TLR4, inhibitor kappaB-alpha(IκBα), p-IκBα, NF-κB p65 and p-NF-κB p65 by Western blot, and transfer of NF-κB p65 from cytoplasm to nucleus by cellular immunofluorescence. Compared with the normal group, most of the BV2 cells in the model group tended to demonstrate the pro-inflammatory M1 amoeba morphology, and the model group showed significant increase in the mRNA levels of IL-1β, IL-6, and iNOS, decrease in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), rise of the protein expression of TNF-α, IL-1β, TLR4, p-IκBα, and p-NF-κB p65(P<0.01), reduction in TREM2 protein expression, and increase in the expression of NF-κB p65 in nucleus. Compared with the model group, baicalin groups and minocycline group showed the recovery of BV2 cell morphology, significant decrease in the mRNA levels of IL-1β, IL-6 and iNOS, increase in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), reduction in the protein expression of TNF-α, IL-1β, TLR4, p-IκBα, and p-NF-κB p65(P<0.05), rise of TREM2 protein expression, and decrease in the expression of NF-κB p65 in nucleus. In summary, these results suggest that baicalin can regulate the imbalance between TREM2 and TLR4 of microglia and inhibit the activation of downstream NF-κB, thus promoting the polarization of microglia from pro-inflammatory phenotype to anti-inflammatory phenotype.


Subject(s)
Animals , Flavonoids , Inflammation/genetics , Interferon-gamma , Lipopolysaccharides/adverse effects , Mice , NF-kappa B/metabolism , Toll-Like Receptor 4/metabolism
9.
Acta Pharmaceutica Sinica B ; (6): 1198-1212, 2022.
Article in English | WPRIM | ID: wpr-929355

ABSTRACT

Pulmonary endothelial barrier dysfunction is a hallmark of clinical pulmonary edema and contributes to the development of acute lung injury (ALI). Here we reported that ruscogenin (RUS), an effective steroidal sapogenin of Radix Ophiopogon japonicus, attenuated lipopolysaccharides (LPS)-induced pulmonary endothelial barrier disruption through mediating non-muscle myosin heavy chain IIA (NMMHC IIA)‒Toll-like receptor 4 (TLR4) interactions. By in vivo and in vitro experiments, we observed that RUS administration significantly ameliorated LPS-triggered pulmonary endothelial barrier dysfunction and ALI. Moreover, we identified that RUS directly targeted NMMHC IIA on its N-terminal and head domain by serial affinity chromatography, molecular docking, biolayer interferometry, and microscale thermophoresis analyses. Downregulation of endothelial NMMHC IIA expression in vivo and in vitro abolished the protective effect of RUS. It was also observed that NMMHC IIA was dissociated from TLR4 and then activating TLR4 downstream Src/vascular endothelial cadherin (VE-cadherin) signaling in pulmonary vascular endothelial cells after LPS treatment, which could be restored by RUS. Collectively, these findings provide pharmacological evidence showing that RUS attenuates LPS-induced pulmonary endothelial barrier dysfunction by inhibiting TLR4/Src/VE-cadherin pathway through targeting NMMHC IIA and mediating NMMHC IIA‒TLR4 interactions.

10.
Acta Pharmaceutica Sinica B ; (6): 801-820, 2022.
Article in English | WPRIM | ID: wpr-929328

ABSTRACT

Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.

11.
Acta Pharmaceutica Sinica B ; (6): 92-106, 2022.
Article in English | WPRIM | ID: wpr-929283

ABSTRACT

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.

12.
Article in English | WPRIM | ID: wpr-929264

ABSTRACT

Abelmoschus manihot (L.) Medik. (A. manihot) is a traditional Chinese herbal medicine with a variety of pharmacological properties. It was first recorded in Jiayou Materia Medica dating back to the Song dynasty to eliminate urinary tract irritation by clearing away heat and diuretic effect. However, its pharmacological action on urinary tract infections has not been investigated. The present study aims to evaluate the anti-inflammatory activity of A. manihot on a mouse model of lipopolysaccharide (LPS)-induced cystitis. The results showed that A. manihot decreased white blood cell (WBC) count in urine sediments of the cystitis mice, alleviated bladder congestion, edema, as well as histopathological damage, reduced the expression levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β simultaneously. Moreover, A. manihot administration significantly downregulated the expression levels of TLR4, MYD88, IκBα, p-IκBα, NF-κB p65, and p-NF-κB p65 in LPS-induced cystitis mice. These findings demonstrated the protective effect of A. manihot against LPS-induced cystitis, which is attributed to its anti-inflammatory profile by suppressing TLR4/MYD88/NF-κB pathways. Our results suggest that A. manihot could be a potential candidate for cystitis treatment.


Subject(s)
Abelmoschus/metabolism , Animals , Anti-Inflammatory Agents/therapeutic use , Cystitis , Female , Humans , Lipopolysaccharides/pharmacology , Male , Mice , Myeloid Differentiation Factor 88/metabolism , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Signal Transduction , Toll-Like Receptor 4/metabolism
13.
Braz. J. Pharm. Sci. (Online) ; 58: e181092, 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1374550

ABSTRACT

Abstract The present study was designed to examine the effects of atorvastatin on vascular inflammatory responses in human coronary artery endothelial cells(HCAECs), when challenged by lipopolysaccharide (LPS), a Toll-like receptor-4 (TLR4) ligand. HCAECs were pretreated with atorvastatin and induced by LPS. The expression of TLR4, interleukin -6(IL-6), monocyte chemoattractant protein 1(MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecular-1(ICAM-1), nuclear factor-κB (NF-κB) and p38 mitogen activated protein kinase(p38 MAPK) were evaluated using Real-time polymerase chain reaction, cytokine ELISA assay and Western blotting. The results showed that pretreatment with atorvastatin down-regulated the expression of TLR4 in LPS-activated HCAECs. Atorvastatin also attenuated the LPS-induced expression of interleukin IL-6 and MCP-1, at both the transcription and translation level in HCAECs. LPS-induced endothelial cell adhesion molecules, ICAM-1 and VCAM-1 expression were also reduced by pretreatment with atorvastatin. Furthermore, atorvastatin efficiently suppressed LPS-induced phosphorylation of NF-κB and p38 MAPK in HCAECs. These findings show that atorvastatin suppresses endothelial cell inflammation, suggesting that atorvastatin may be suitable for development as a therapeutic agent for inflammatory cardiovascular disease.

14.
Braz. j. med. biol. res ; 54(7): e10603, 2021. tab, graf
Article in English | LILACS | ID: biblio-1249320

ABSTRACT

Neonatal sepsis is an inflammatory system syndrome and a main cause of neonatal mortality. However, there is a lack of ideal biomarkers for early neonatal sepsis diagnosis. The aim of this study was to evaluate the clinical significance of miR-141 in sepsis in neonates, and explore the regulatory effects of miR-141 on inflammation in monocytes. This study used qRT-PCR to calculate the expression of miR-141 in the serum of septic neonates. The diagnostic values of procalcitonin (PCT) and serum miR-141 were evaluated by receiver operating characteristic (ROC) curves. The relationship between miR-141 and TLR4 was determined using luciferase reporter assay. An inflammation model was established using monocytes with lipopolysaccharide (LPS) treatment. ELISA assay was used to analyze the levels of pro-inflammatory cytokines. The expression of miR-141 in neonatal sepsis was significantly lower than healthy controls. ROC curves showed that miR-141 had diagnostic accuracy. LPS stimulation in monocytes led to a decrease in the expression of miR-141. A luciferase reporter assay proved that miR-141 targeted TLR4, and a negative correlation of miR-141 with TLR4 was found in septic neonates. ELISA results demonstrated that the overexpression of miR-141 inhibited LPS-induced inflammation in monocytes. In conclusion, serum decreased miR-141 expression served as a candidate diagnostic biomarker of neonatal sepsis. TLR4 is a target gene of miR-141, which may mediate the inhibitory effects of miR-141 overexpression on LPS-induced inflammation in monocytes. Therefore, miR-141 is expected to be a potential diagnostic biomarker and a therapeutic target in neonatal sepsis.


Subject(s)
Humans , Infant, Newborn , Sepsis , MicroRNAs , Neonatal Sepsis , Monocytes , Lipopolysaccharides , Toll-Like Receptor 4
15.
Journal of Chinese Physician ; (12): 848-852,858, 2021.
Article in Chinese | WPRIM | ID: wpr-909631

ABSTRACT

Objective:To investigate the effect of low molecular weight heparin (LMWH) on the inflammatory response of PC12 cells induced by oxygen glucose deprivation (OGD) and its related mechanism.Methods:The PC12 cells were cultured in vitro were randomly divided into sham(control) group, OGD group, LMWH group and blocking agent group. The latter group was divided into six groups: Eritoran+ OGD group, LMWH+ Eritoran+ OGD group, ST2825+ OGD group, LMWH+ ST2825+ OGD group, pyrrolidinedithiocarbamate (PDTC)+ OGD group and LMWH+ PDTC+ OGD group. OGD cell model was established. Cell counting kit-8 (CCK-8) assay was used to detect cell activity. The expressions of toll-like receptor 4 (TLR4), MyD88 and nuclear factor κB (NF-κB) mRNA and protein were detected by real time polymerase chain reaction (qRT-PCR) and Western blot. The concentration of interleukin (IL)-1β, IL-6, tumor necrosis factor-α(TNF-α) and S100β were determined by enzyme linked immunosorbent assay (ELISA). Results:The cell activity of OGD group was significantly lower than that of control group on the first, second, third day ( P<0.05). Compared with OGD group, the activity of LMWH group was increased on the second, third day ( P<0.05), but lower than that of control group ( P<0.01). The mRNA expression of TLR4, MyD88 and NF-κB was significantly increased in OGD group compared with the control group ( F=144.9, F=710.5, 79.51, P<0.01). Compared with OGD group, the mRNA expression of TLR4, MyD88 and NF-κB were significantly decreased after treatment with LMWH ( P<0.01), and the specific inhibitor of TLR4, MyD88 and NF-κB enhanced the anti-inflammatory effect of LMWH. The protein expression of this pathway was consistent with that of the gene. The concentration of IL-1β, IL-6, TNF-α and S100β in OGD group was significantly higher than control group ( P<0.05). After treatment with LMWH, the concentrations of inflammatory factors and S100β were significantly decreased compared with OGD group ( P<0.01). When hinder TLR4, MyD88 and NF-κB respectively by Eritoran, ST2825 and PDTC, the concentrations of inflammatory factors and S100β were significantly decreased, but it was still higher than control group ( P<0.05). Conclusions:OGD can cause pathological damage of PC12 cells, including high expression level of S100β and aggravation of inflammatory reaction. LMWH can improve cell activity, down-regulate inflammatory reaction degree and protect the cells. Using inhibitors of TLR4/MyD88/NF-κB pathway to inhibit the corresponding target, the up-regulation of inflammatory factors by OGD can be inhibited in varying degrees. These suggested that LMWH may regulate inflammatory reaction of PC12 cells induced by OGD through TLR4/MyD88/NF-κB pathway.

16.
Article in Chinese | WPRIM | ID: wpr-907737

ABSTRACT

Objective:To explore the mechanism of pioglitazone in reducing lung injury induced by acute pancreatitis.Methods:Thirty healthy male SD rats were randomly(random number) divided into the sham operation group, model group and pioglitazone group, with 10 rats in each group. After anesthesia, the rats in the sham operation group were injected with normal saline retrogradely through the pancreaticobiliary duct. In the model group, after anesthesia, the rats were retrogradely injected with sodium taurocholate into the pancreaticobiliary duct to construct the lung injury model of severe acute pancreatitis. In the pioglitazone group, the model was established after intraperitoneal injection of pioglitazone. Six rats in each group were randomly selected and killed 12 h after operation, and then lung tissue and venous blood were collected. The levels of serum amylase and TNF-α and NO in lung tissue homogenate were detected and compared among the three groups; the expression of TLR2 mRNA and TLR4 mRNA in lung tissue was detected by RT-PCR and compared among the three groups; the lung tissue pathological injury score and lung leakage index were calculated and compared among the three groups. The correlation of TLR2 and TLR4’s mRNA expression with lung tissue pathological injury score and lung leakage index was analyzed.Results:The levels of serum amylase and the levels of TNF-α and NO in lung tissue homogenate in the model group were significantly higher than those in the sham operation group, and the above indexes in the pioglitazone group were significantly lower than those in the model group ( P<0.05). The expression levels of TLR2 mRNA and TLR4 mRNA in lung tissue, the lung tissue pathological injury score and lung leakage index in the model group were significantly higher than those in the sham operation group, and the above indexes in the pioglitazone group were significantly lower than those in the model group ( P<0.05). Spearman correlation analysis showed that the expression levels of TLR2 mRNA and TLR4 mRNA in lung tissue were significantly positively correlated with the lung tissue pathological injury score ( rs=0.959, P<0.001; rs=0.924, P<0.001). Pearson correlation analysis showed that the expression levels of TLR2 mRNA and TLR4 mRNA in lung tissue were significantly positively correlated with the lung leakage index ( r=0.957, P<0.001; r=0.958, P<0.001). Conclusions:Pioglitazone may reduce the severity of severe acute pancreatitis induced lung injury by inhibiting the expression of TLR2 mRNA and TLR4 mRNA in lung tissue.

17.
Article in Chinese | WPRIM | ID: wpr-907719

ABSTRACT

Objective:To investigate the role of KLF4 in lipopolysaccharide induced cardiomyocyte injury.Methods:Primary rat cardiomyocytes were isolated and cultured, and randomly divided into 5 groups: control group, negative control (NC), LPS group, KLF4 overexpression group, KLF4 overexpression+LPS group. MTT method was used to detect cell activity, ROS, SOD 2, GPX and MDA were detected by kit, TNFa, IL-1 β and IL-6 were detected by ELISA. TUNEL staining was used to detect apoptosis. The protein levels of TLR4 and Nrf2 were detected by Western blot.Results:The expression of KLF4 in cardiomyocytes was significantly higher than that in the NC group ( P<0.001). The cell activity of LPS group was significantly lower than that of NC group ( P < 0.001), and that of KLF4 overexpression +LPS group was higher than that of LPS group ( P<0.001). The levels of TNFa, IL-1 β and IL-6 in LPS group were significantly higher than those in the NC group ( P<0.0001), and the levels of TNFa, IL-1 β and IL-6 in KLF4 overexpression +LPS group were lower than those in LPS group ( P<0.0001). The levels of ROS and MDA in LPS group were significantly higher than those in the control group, while the activities of SOD2 and GPX were lower than those in the NC group ( P<0.0001); the levels of ROS and MDA in KLF4 overexpression +LPS group were lower than those in LPS group, while the activities of SOD2 and GPX were higher than those in LPS group ( P<0.0001). The number of apoptosis in LPS group was significantly higher than that in the NC group, and that in KLF4 overexpression +LPS group was lower than that in LPS group ( P< 0.001). The level of TLR4 wan higher and Nrf2 protein in the nucleus of LPS group was lower than that of the NC group. The level of TLR4 was lower and Nrf2 protein in the nucleus of KLF4 overexpression+LPS group was significantly higher than that of LPS group ( P < 0.001). Conclusions:KLF4 can alleviate LPS induced cardiomyocyte injury by regulating TLR4 and NRF2 signals.

18.
Article in Chinese | WPRIM | ID: wpr-907681

ABSTRACT

Objective:To explore the protective effect of Shen’an decoction on cisplatin induced renal injury in rats by regulating TLR4/NF-κB signaling pathway. Methods:Sixty SD rats were randomly divided into blank group, model group, positive control group, high dose Shen’an Decoction group, medium dose Shen’an Decoction group and low dose Shen’an Decoction group, with 10 rats in each group. Except the blank group, the other groups were intraperitoneally injected with cisplatin 7.5 mg/kg to prepare the acute kidney injured rat model. After the modeling, the high, medium and low dose groups of Shen’an Decoction were gavaged with 0.698, 1.395 and 2.790 g/ml Shen’an Decoction respectively, and the positive control group was gavaged with benazepril hydrochloride suspension of 5 mg/kg, once a day for 14 days. The kidney histopathological changes of rats in each group were observed by HE staining. The content of BUN, creatinine(CR), Cystatin C (Cys-C), TNF-α, and IL-6 in serum were detected by ELISA. The expression of TLR-4, NF-κB p65, myeloid differentiation factor (MyD88), and tumor necrosis factor receptor related factor 6 (TRAF-6) in renal tissue were detected by Western blot. Results:Compared with the model group, the growth condition of rats in each dose group of Shen’an Decoction was significantly improved ( P<0.05), and the kidney coefficient was significantly decreased ( P<0.05). The serum levels of BUN, Cr, Cys-C, TNF-α, IL-6 of rats in each dose group of Shen’an Decoction were significantly decreased ( P<0.05). The expression of TLR-4 (0.54 ± 0.07, 0.52 ± 0.09, 0.41 ± 0.04 vs. 0.86 ± 0.06), NF-κB (0.74 ± 0.02, 0.72 ± 0.06, 0.67 ± 0.05 vs. 0.93 ± 0.03), MyD88 (0.86 ± 0.02, 0.82 ± 0.03, 0.61 ± 0.02 vs. 1.04 ± 0.03), and TRAF-6 (0.65 ± 0.04, 0.58 ± 0.08, 0.54 ± 0.07 vs. 0.90 ± 0.06) in kidney tissue of rats in each dose group of Shen’an Decoction was significantly decreased ( P<0.05). Conclusion:Shen’an Decoction can protect the renal function of rats by inhibiting TLR4/NF-κB signaling pathway and alleviating the pathological changes of renal injury induced by cisplatin.

19.
Article in Chinese | WPRIM | ID: wpr-906457

ABSTRACT

Objective:To explore the effect of Bushen Huatan prescription on serum lipopolysaccharide (LPS) and Toll-like receptor 4 (TLR4)/ myeloid cell differentiation protein 88 (MyD88)/nuclear transcription factor-<italic>κ</italic>B (NF-<italic>κ</italic>B) signaling pathway in rats with ovariectomy-induced osteoporosis. Method:Sixty SPF 6-month-old female rats were randomly divided into sham operation group, model group, estradiol valerate group and Bushen Huatan prescription low, medium and high dose groups.One week after modeling by bilateral ovariectomy, 8 rats in each group were selected to receive intragastric administration.The estradiol valerate group was given 0.184 mg·kg<sup>-1</sup> by gavage, and Bushen Huatan prescription low, middle and high dose groups were given 4.7, 9.4 and 18.8 g·kg<sup>-1</sup> by gavage, sham operation group and model group were given 0.9% saline 4 mL by gavage respectively.After 12 weeks of intervention, the rats were sacrificed for detection.Serum LPS was detected by enzyme linked immunosorbent assay (ELISA), while protein expressions of TLR4, MyD88 and phosphorylated (p)-NF-<italic>κ</italic>B p65 in bone tissue were detected by Western blot, and the mRNA expressions of TLR4, MyD88, NF-<italic>κ</italic>B p65, IL-1<italic>β</italic>, and IL-6 in bone tissue were detected by quantitative real-time polymerase chain reaction(PCR). Result:Compared with sham operation group, the serum LPS level as well as protein expression of TLR4, MyD88, p-NF-<italic>κ</italic>B p65 and mRNA expression of TLR4, MyD88, NF-<italic>κ</italic>B p65, IL-1<italic>β</italic>, and IL-6 significantly increased in model group(<italic>P</italic><0.05).Compared with the model group, serum LPS level, protein expression of TLR4, MyD88, and p-NF-<italic>κ</italic>B p65, mRNA levels of TLR4, MyD88, and NF-<italic>κ</italic>B p65 in bone tissues as well as downstream inflammatory factors IL-1<italic>β</italic>, IL-6 mRNA expression decreased to different degrees in estradiol valerate group and Bushen Huatan prescription high dose group(<italic>P</italic><0.05). Conclusion:Bushen Huatan prescription can reduce serum LPS content, regulate mRNA and protein expression of TLR4, MyD88, NF-<italic>κ</italic>B p65 and p-NF-<italic>κ</italic>B p65 in TLR4/MyD88/NF-<italic>κ</italic>B pathway, and down-regulate mRNA levels of IL-1<italic>β</italic> and IL-6 in bone tissues to improve bone microstructure and inhibit the development of postmenopausal osteoporosis (PMOP).

20.
Article in Chinese | WPRIM | ID: wpr-906455

ABSTRACT

Objective:To investigate the effects and mechanism of Gecko extract for treatment of depression in rats. Method:The depression rats were induced by intraperitoneal injection of reserpine (0.5 mg·kg<sup>-1</sup>). The successfully modeled rats were randomly divided into model group, fluoxetine group (1.8 mg·kg<sup>-1</sup>), high dose and low dose groups of Gecko extract (12, 6 g·kg<sup>-1</sup>). The rats were given corresponding dose of drugs once a day for 10 days. After administration, the levels of neurotransmitters and inflammatory factors in serum and prefrontal cortex of rats were detected by enzyme-linked immunosorbent assay (ELISA). The cell changes in hippocampal tissues were observed by hematoxylin-eosin (HE) staining. The mRNA levels of interleukin-6 (IL-6), nuclear factor-<italic>κ</italic>B (NF-<italic>κ</italic>B), and tumor necrosis factor (TNF-<italic>α</italic>) in the hippocampus of rats were detected by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR). The protein levels of Toll-like receptor 4 (TLR4) and NF-<italic>κ</italic>B in hippocampal tissues of rats were detected by Western blot. Result:Compared with the normal group, Gecko extract significantly shortened the immobility time of tail suspension and swimming in mice. Compared with model group, Gecko extract significantly reduced blepharoptosis and retention time in circles for the rats (<italic>P</italic><0.05), increased the levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in serum (<italic>P</italic><0.05), decreased the levels of Monoamine oxidase (MAO), IL-6, and TNF-<italic>α</italic> in serum (<italic>P</italic><0.05) and prefrontal cortex (<italic>P</italic><0.05), decreased the mRNA levels of inflammatory cytokines IL-6, NF-<italic>κ</italic>B and TNF-<italic>α</italic> and the protein expressions of TLR4 and NF-<italic>κ</italic>B in the hippocampus of rats (<italic>P</italic><0.05,<italic> P</italic><0.01), and improved the pathological symptoms of the hippocampus. Conclusion:Gecko extract can significantly alleviate the pathological damage of depression and improve the symptoms of depression, and its mechanism may be due to inhibiting TLR4/NF-<italic>κ</italic>B signaling pathway and reducing the expression of NF-<italic>κ</italic>B, IL-6 and other inflammatory factors in the hippocampus of rats.

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