Protective effects of biochanin A on articular cartilage: in vitro and in vivo studies

Interactions between the host and the microbiota are thought to significantly influence immunological tolerance mechanisms at mucosal sites. We recently described that the loss of an exopolysaccharide (EPS) from Bifidobacterium longum 35624™ eliminated its protective effects in colitis and respiratory allergy murine models. Our goal was to investigate the immune response to purified EPS from B. longum 35624, determine if it has protective effects within the lung and identify the protective mechanisms. Isolated EPS from B. longum 35624 cultures was used for in vitro, ex vivo and in vivo studies. Human monocyte-derived dendritic cells (MDDCs) were used to investigate in vitro immunological responses to EPS. Cytokine secretion, expression of surface markers and signalling pathways were examined. The ovalbumin (OVA) respiratory allergy murine model was used to evaluate the in vivo immunomodulatory potential of EPS. In addition, interleukin (IL)-10 knockout (KO) mice and anti-Toll-like receptor (TLR)-2 blocking antibody were used to examine the underlying protective mechanisms of intranasal EPS administration. Stimulation of human MDDCs with EPS resulted in IL-10 secretion, but not proinflammatory cytokines. IL-10 secretion was TLR-2-dependent. Eosinophil recruitment to the lungs was significantly decreased by EPS intranasal exposure, which was associated with decreased expression of the Th2-associated markers C-C motif chemokine 11 (CCL11), C-C chemokine receptor type 3 (CCR3), IL-4 and IL-13. TLR-2-mediated IL-10 secretion was shown to be required for the reduction in eosinophils and Th2 cytokines. EPS-treatment reduced eosinophil recruitment within the lung in a respiratory inflammation mouse model, which is both TLR-2 and IL-10 mediated. EPS can be considered as a novel molecule potentially reducing the severity of chronic eosinophil-related airway disorders.

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In Silico, in Vitro and in Vivo Investigation of a Newly Synthesized Ionic Compound As Anti-Alzheimer Multi-Target Dual AChE/BuChE Inhibitor Possessing Neuro-Protective Effects Against Aβ Induced Neurotoxicity in PC12 Cells and Alzheimer Rat Model

10.21203/rs.3.rs-230581/v1 ◽

2021 ◽

Author(s):

Hosna Karami ◽

somaieh soltani ◽

Gerhard Wolber ◽

Saeed Sadigh-Eteghad ◽

Roghaye Nikbakht ◽

...

Keyword(s):

Pc12 Cells ◽

Quaternary Ammonium ◽

Aqueous Solubility ◽

In Vivo Studies ◽

Protective Effects ◽

Rat Models ◽

Tnf Α ◽

Neuro Inflammation

Abstract Multi-target anti Alzheimer’s disease (AD) compounds are promising leads for the development of AD modifying agents. Ionic compounds containing quaternary ammonium moiety were synthesized and their multi-targeted anti-AD effects were examined in the current study. Compound 5g possessed suitable aqueous solubility and cell toxicity. It also showed non-competitive dual hAChE/hBuChE inhibition activity. Compound 5g reversed the Aβ-treated PC12 cells’ morphology alteration and reduced PC12 cells’ death. Compound 5g possessed anti-oxidative stress activity through anti-oxidant, anti-ROS production and anti-lipid peroxidation mechanisms. It also reduced the expression of IL-1β and TNF-α genes. Furthermore, compound 5g LDH inhibition, reduction of neuro-inflammation and prevention of autophagy-apoptosis were approved by the results of in vitro studies. Compound 5g delivery to brain was confirmed by in vivo studies. Administration of compound 5g to Aβ-induced AD rat models improved their cognition function and spatial memory learning behavior. TNF-α and NFkB down-regulated in compound 5g treated AD rats’ hippocamp. Besides, compound 5g reversed the up-regulation of AChE in Aβ treated rats’ hippocamp. Molecular modeling studies confirmed the interaction of compound 5g with both steric and catalytic sites of ChE enzymes. The newly synthesized quaternary ammonium containing derivative (compound 5g) possessed multi-target anti-AD efficacy based on in vitro and in vivo studies and its efficacy in AD rat models were approved by behavioral and molecular investigations.

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High Molecular Weight Hyaluronan Suppresses Macrophage M1 Polarization and Enhances IL-10 Production in PM2.5-Induced Lung Inflammation

Molecules ◽

10.3390/molecules24091766 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1766 ◽

Cited By ~ 8

Author(s):

Qiwen Shi ◽

Lan Zhao ◽

Chenming Xu ◽

Leifang Zhang ◽

Hang Zhao

Keyword(s):

Molecular Weight ◽

High Molecular Weight ◽

Lung Inflammation ◽

Macrophage Polarization ◽

Pulmonary Inflammation ◽

In Vivo Studies ◽

Protective Effects ◽

M1 Polarization

PM2.5 is particulate matter with a diameter of 2.5 μm or less. Airway macrophages are the key players regulating PM2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1β, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10.

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Targeting CCR1 for the Treatment of Osteolytic Bone Disease in Multiple Myeloma.

Blood ◽

10.1182/blood.v110.11.2503.2503 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2503-2503

Author(s):

Sonia Vallet ◽

Noopur Raje ◽

MariaTeresa Fulciniti ◽

Kenji Ishitsuka ◽

Teru Hideshima ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Clinical Trials ◽

Bone Disease ◽

Cell Number ◽

In Vivo Studies ◽

Protective Effects ◽

Osteolytic Bone Disease

Abstract Osteolytic bone disease (OBD) is a frequent complication of multiple myeloma (MM), affecting 70 to 80% of the patients. OBD is characterized by imbalanced bone remodeling, due to decreased osteoblast (OB) number and increased osteoclast (OC) formation and activity. MM cells secrete osteoclastogenic factors, such as receptor activator of nuclear factor kappa B ligand (RANKL) and CCL3. In turn, OC support MM cell proliferation and survival, thus promoting a positive feedback that exacerbates bone resorption. Chemokines modulate osteoclastogenesis and promote MM cell proliferation, in particular CCL3 and its receptor CCR1 play an important role in mediating OBD in MM. MLN3897 (Millennium Pharmaceuticals, Cambridge) is a novel small molecule specific antagonist of human CCR1 (IC50 0.8 nM). It has a favorable toxicity profile in healthy volunteers and is currently undergoing phase II clinical trials in rheumatoid arthritis and multiple sclerosis. Here we evaluate the effects of MLN3897 on OC function and activity, as well as OC-MM cell interactions. Our in vitro data demonstrates a dual mechanism of action for MLN3897: it inhibits osteoclastogenesis and also overcomes the protective effects conferred by OC on MM cells. Our data further shows inhibition of OC formation and function by 40 and 70%, respectively, following MLN3897 treatment. This is mediated via inhibition of the fusion process and is accompanied by downregulation of pERK and c-fos signaling. To analyze its effect on MM cells, we verified CCR1 and CCR5 expression levels on MM1.S (15% and 3.6%) and OPM1 (3.8 and 0.7%). Our data show that OC secrete high levels of CCL3 which triggers MM cell migration; and that MLN3897 abrogates these effects by inhibiting the PI3K/Akt pathway. Moreover, MLN3897 overcomes the proliferative advantage conferred by OC on MM cells, as demonstrated in INA6, MM1.S and MM patient derived primary cells. OC induced MM cell proliferation is mediated by adhesion and cytokine secretion, and MLN3897 abrogates both MM cell-to-OC adhesion and interleukin-6 (IL6) secretion by OC in a co-culture system, thereby resulting in decreased MM cell survival and proliferation. To confirm these in vitro results, in vivo studies in a SCID-hu mouse model are underway. Implanted SCID-Hu INA-6 bearing mice are treated with twice daily oral MLN3897 for 3 weeks. The evaluation of osteolytic lesions and OC, OB and endothelial cell number; and tumor burden will be presented. Our in vitro results therefore show novel biologic sequelae of CCL3 and its inhibition on both osteoclastogenesis and MM cell growth. Our in vivo experiments will further validate the role of CCR1 in a human BM microenvironment-MM model, providing the framework for clinical trials of MLN3897 for the treatment of OBD in MM.

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Onco-Preventive and Chemo-Protective Effects of Apple Bioactive Compounds

Nutrients ◽

10.3390/nu13114025 ◽

2021 ◽

Vol 13 (11) ◽

pp. 4025

Author(s):

Linda Nezbedova ◽

Tony McGhie ◽

Mark Christensen ◽

Julian Heyes ◽

Noha Ahmed Nasef ◽

...

Keyword(s):

Molecular Mechanisms ◽

Causes Of Death ◽

Epidemiological Studies ◽

In Vivo Studies ◽

Protective Effects ◽

Plant Metabolites ◽

Hallmarks Of Cancer ◽

Secondary Plant Metabolites

Cancer is one of the leading causes of death globally. Epidemiological studies have strongly linked a diet high in fruits to a lower incidence of cancer. Furthermore, extensive research shows that secondary plant metabolites known as phytochemicals, which are commonly found in fruits, have onco-preventive and chemo-protective effects. Apple is a commonly consumed fruit worldwide that is available all year round and is a rich source of phytochemicals. In this review, we summarize the association of apple consumption with cancer incidence based on findings from epidemiological and cohort studies. We further provide a comprehensive review of the main phytochemical patterns observed in apples and their bioavailability after consumption. Finally, we report on the latest findings from in vitro and in vivo studies highlighting some of the key molecular mechanisms targeted by apple phytochemicals in relation to inhibiting multiple ‘hallmarks of cancer’ that are important in the progression of cancer.

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Protective Effects of Chrysin against the Neurotoxicity Induced by Aluminium: In Vitro and In Vivo Studies

Toxicology ◽

10.1016/j.tox.2021.153033 ◽

2021 ◽

pp. 153033

Author(s):

Hericles Mesquita Campos ◽

Michael da Costa ◽

Lorrane Kelle da Silva Moreira ◽

Hiasmin Franciely da Silva Neri ◽

Cinthia Rio Branco da Silva ◽

...

Keyword(s):

In Vivo Studies ◽

Protective Effects

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Protective Effects of Processed Ginseng and Its Active Ginsenosides on Cisplatin-Induced Nephrotoxicity: In Vitro and in Vivo Studies

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.5b00782 ◽

2015 ◽

Vol 63 (25) ◽

pp. 5964-5969 ◽

Cited By ~ 40

Author(s):

Jun Yeon Park ◽

Pilju Choi ◽

Taejung Kim ◽

Hyeonseok Ko ◽

Ho-kyong Kim ◽

...

Keyword(s):

In Vivo Studies ◽

Protective Effects

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Medicinal Potential of Isoflavonoids: Polyphenols That May Cure Diabetes

Molecules ◽

10.3390/molecules25235491 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5491

Author(s):

Qamar Uddin Ahmed ◽

Abdul Hasib Mohd Ali ◽

Sayeed Mukhtar ◽

Meshari A. Alsharif ◽

Humaira Parveen ◽

...

Keyword(s):

Biological Effects ◽

Biochanin A ◽

In Vivo Studies ◽

Diabetic Patients ◽

Peroxisome Proliferator ◽

Inflammatory Mechanism ◽

Peroxisome Proliferator Activated Receptors

In recent years, there is emerging evidence that isoflavonoids, either dietary or obtained from traditional medicinal plants, could play an important role as a supplementary drug in the management of type 2 diabetes mellitus (T2DM) due to their reported pronounced biological effects in relation to multiple metabolic factors associated with diabetes. Hence, in this regard, we have comprehensively reviewed the potential biological effects of isoflavonoids, particularly biochanin A, genistein, daidzein, glycitein, and formononetin on metabolic disorders and long-term complications induced by T2DM in order to understand whether they can be future candidates as a safe antidiabetic agent. Based on in-depth in vitro and in vivo studies evaluations, isoflavonoids have been found to activate gene expression through the stimulation of peroxisome proliferator-activated receptors (PPARs) (α, γ), modulate carbohydrate metabolism, regulate hyperglycemia, induce dyslipidemia, lessen insulin resistance, and modify adipocyte differentiation and tissue metabolism. Moreover, these natural compounds have also been found to attenuate oxidative stress through the oxidative signaling process and inflammatory mechanism. Hence, isoflavonoids have been envisioned to be able to prevent and slow down the progression of long-term diabetes complications including cardiovascular disease, nephropathy, neuropathy, and retinopathy. Further thoroughgoing investigations in human clinical studies are strongly recommended to obtain the optimum and specific dose and regimen required for supplementation with isoflavonoids and derivatives in diabetic patients.

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Anticancer Activities of Citrus Peel Polymethoxyflavones Related to Angiogenesis and Others

BioMed Research International ◽

10.1155/2014/453972 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 41

Author(s):

Liwen Wang ◽

Jinhan Wang ◽

Lianying Fang ◽

Zuliang Zheng ◽

Dexian Zhi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Plant Secondary Metabolites ◽

In Vivo Studies ◽

Protective Effects ◽

Human Beings ◽

Anticancer Activities ◽

Citrus Peel ◽

Citrus Flavonoids

Citrus is a kind of common fruit and contains multiple beneficial nutrients for human beings. Flavonoids, as a class of plant secondary metabolites, exist in citrus fruits abundantly. Due to their broad range of pharmacological properties, citrus flavonoids have gained increased attention. Accumulative in vitro and in vivo studies indicate protective effects of polymethoxyflavones (PMFs) against the occurrence of cancer. PMFs inhibit carcinogenesis by mechanisms like blocking the metastasis cascade, inhibition of cancer cell mobility in circulatory systems, proapoptosis, and antiangiogenesis. This review systematically summarized anticarcinogenic effect of citrus flavonoids in cancer therapy, together with the underlying important molecular mechanisms, in purpose of further exploring more effective use of citrus peel flavonoids.

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