Lyophilized Symbiotic Mitigates Mucositis Induced by 5-Fluorouracil

Mucositis is an adverse effect of cancer chemotherapies using 5-Fluorouracil (5-FU). It is characterized by mucosal inflammation, pain, diarrhea, and weight loss. Some studies reported promising healing effects of probiotic strains, when associated with prebiotics, as adjuvant treatment of mucositis. We developed a lyophilized symbiotic product, containing skimmed milk, supplemented with whey protein isolate (WPI) and with fructooligosaccharides (FOS), and fermented by Lactobacillus casei BL23, Lactiplantibacillus plantarum B7, and Lacticaseibacillus rhamnosus B1. In a mice 5-FU mucositis model, this symbiotic lyophilized formulation was able to reduce weight loss and intestinal permeability. This last was determined in vivo by quantifying blood radioactivity after oral administration of 99mTc-DTPA. Finally, histological damages caused by 5-FU-induced mucositis were monitored. Consumption of the symbiotic formulation caused a reduced score of inflammation in the duodenum, ileum, and colon. In addition, it decreased levels of pro-inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α in the mice ileum. The symbiotic product developed in this work thus represents a promising adjuvant treatment of mucositis.

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Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway

Molecules ◽

10.3390/molecules26092529 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2529

Author(s):

Haeyeop Kim ◽

Woo Seok Yang ◽

Khin Myo Htwe ◽

Mi-Nam Lee ◽

Young-Dong Kim ◽

...

Keyword(s):

Ethanol Extract ◽

Serum Levels ◽

Hepatoprotective Activity ◽

Tnf Α ◽

Anti Inflammatory ◽

Related Proteins ◽

Pro Inflammatory Cytokines ◽

Inflammatory Effect

Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.

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Steroid Sulfates from Ophiuroids (Brittle Stars): Action on Some Factors of Innate and Adaptive Immunity

Natural Product Communications ◽

10.1177/1934578x1601100613 ◽

2016 ◽

Vol 11 (6) ◽

pp. 1934578X1601100

Author(s):

Anna K Gazha ◽

Lyudmila A. Ivanushko ◽

Eleonora V. Levina ◽

Sergey N. Fedorov ◽

Tatyana S. Zaporozets ◽

...

Keyword(s):

Adaptive Immunity ◽

Inflammatory Cytokines ◽

Brittle Stars ◽

Innate And Adaptive Immunity ◽

Functional Activities ◽

In Vivo Experiments ◽

Tnf Α ◽

Pro Inflammatory Cytokines

The action of seven polyhydroxylated sterol mono- and disulfates (1-7), isolated from ophiuroids, on innate and adaptive immunity was examined in in vitro and in vivo experiments. At least, three of them (1, 2 and 4) increased the functional activities of neutrophils, including levels of oxygen-dependent metabolism, adhesive and phagocytic properties, and induced the expression of pro-inflammatory cytokines TNF-α and IL-8. Compound 4 was the most active for enhancing the production of antibody forming cells in the mouse spleen.

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IKK-2 inhibitor TPCA-1 represses nasal epithelial inflammation in vitro

Rhinology Journal ◽

10.4193/rhino10.099 ◽

2011 ◽

Vol 49 (2) ◽

pp. 168-173

Author(s):

F. Sachse ◽

K. Becker ◽

T.J. Basel ◽

D. Weiss ◽

C. Rudack

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Disease ◽

Inflammatory Process ◽

Nasal Polyposis ◽

Paraffin Sections ◽

Tnf Α ◽

Epithelial Inflammation ◽

Pro Inflammatory Cytokines

BACKGROUND: Nasal polyposis (NP) is considered a subgroup within chronic rhinosinusitis. NP can be further subdivided into aspirin sensitive- and aspirin tolerant types (ASNP/ ATNP). Although the true etiology of NP has not been identified so far, it is agreed that NP represents an inflammatory disease of the nasal mucosa. Alterations of cellular kinase activities including that of IKK-2 might play a role in this inflammatory process. METHODS: Paraffin sections of ASNP, ATNP and controls were immunostained with Phospho-IkB-α antibody that detects the direct IKK-2 product (IkB-α. Intensity of epithelial staining was analysed semi-quantitatively by two independent observers. In cultured nasal polyp epithelial cells (NPECs) epithelial derived cytokines IL-8 and GRO α were induced by TNF-α or Staphylococcal supernatants and subsequently repressed by IKK-2 inhibitor TPCA-1. RESULTS: Significant Phospho-IkB-α staining was observed in the nasal epithelium of ASNP compared to ATNP and controls suggesting strong IKK-2 activation in patients with ASNP in vivo. In vitro, pro-inflammatory cytokines IL-8 and GRO-α in NPECs were significantly repressed by TPCA-1. CONCLUSION: IKK-2 activity is increased in the subgroup of ASNP. IL-8 and GRO-α responses were repressed by IKK-2 inhibitor TPCA-1 in vitro. IKK-2 inhibitors might represent a potential target for anti-inflammatory intervention in ASNP.

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Intestinal Epithelium-Derived Luminally Released Extracellular Vesicles in Sepsis Exhibit the Ability to Suppress TNF-α and IL-17A Expression in Mucosal Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21228445 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8445

Author(s):

Michael G. Appiah ◽

Eun Jeong Park ◽

Samuel Darkwah ◽

Eiji Kawamoto ◽

Yuichi Akama ◽

...

Keyword(s):

Epithelial Cell ◽

Extracellular Vesicles ◽

Inflammatory Responses ◽

Quantitative Polymerase Chain Reaction ◽

Mucosal Inflammation ◽

Inflammatory Disorder ◽

Intestinal Epithelial ◽

Tnf Α ◽

Polymerase Chain ◽

Pro Inflammatory Cytokines

Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-α and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target TNF-α and IL-17A. These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.

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Over-expression of PTEN attenuates the inflammation of fibroblast-like synoviocytes in rheumatoid arthritis

10.21203/rs.2.22411/v1 ◽

2020 ◽

Author(s):

Xiao-Feng Li ◽

Qing-Qing Xu ◽

Man-Wen Yang ◽

He Chen ◽

Su-Qin Yin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Dna Methylation ◽

Inflammatory Cytokines ◽

Pten Expression ◽

Over Expression ◽

Tnf Α ◽

And Migration ◽

Fibroblast Like Synoviocytes ◽

Pro Inflammatory Cytokines

Abstract Background: Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the survival of fibroblast-like synoviocytes (FLS) and the production of pro-inflammatory cytokines in RA.Methods : The expression was determined in RA and adjuvant-induced arthritis (AIA) synovial tissues by immunohistochemistry. FLSs were treatment with bpv, PTEN-RNAi or over-expression plasmid in RA and AIA. FLSs migration was assessed. The ad-PTEN was also injected into the knee of AIA in vivo. Chromatin Immunoprecipitation (ChIP) and Methylation-special PCR (MSP) assay were used to study the expression of PTEN mRNA in DNA methylation.Results : Down-regulated level of PTEN expression was observed in RA and AIA. Inhibition PTEN expression by bpv or PTEN-RNAi could promote the expression of pro-inflammatory cytokines, chemokines and migration of FLS with TNF-α in RA and AIA. Consistently, over-expression of PTEN reduced their low-expression of pro-inflammatory cytokines, chemokines and migration. Intra-articular injection of ad-PTEN in AIA knees dramatically reduced inflammatory and paw swelling in vivo. The ChIP and MSP assay has clearly detected the DNA methylation of PTEN was increased in FLS with TNF-α. Moreover, intraperitoneally injected 5-Aza in AIA also suppressed the inflammatory and paws swelling in vivo.Conclusions: Our findings suggest that over-expression PTEN attenuates the formation of pro-inflammatory cytokines, chemokines and migration of FLS, and it may be regulated by DNA methylation in the pathogenesis of RA.

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Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00110.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. E527-E533 ◽

Cited By ~ 438

Author(s):

Jens M. Bruun ◽

Aina S. Lihn ◽

Camilla Verdich ◽

Steen B. Pedersen ◽

Søren Toubro ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Mrna Levels ◽

Plasma Adiponectin ◽

Tnf Α ◽

Adiponectin Mrna ◽

Before And After

Adiponectin is an adipose tissue-specific protein that is abundantly present in the circulation and suggested to be involved in insulin sensitivity and development of atherosclerosis. Because cytokines are suggested to regulate adiponectin, the aim of the present study was to investigate the interaction between adiponectin and three adipose tissue-derived cytokines (IL-6, IL-8, and TNF-α). The study was divided into three substudies as follows: 1) plasma adiponectin and mRNA levels in adipose tissue biopsies from obese subjects [mean body mass index (BMI): 39.7 kg/m2, n = 6] before and after weight loss; 2) plasma adiponectin in obese men (mean BMI: 38.7 kg/m2, n = 19) compared with lean men (mean BMI: 23.4 kg/m2, n = 10) before and after weight loss; and 3) in vitro direct effects of IL-6, IL-8, and TNF-α on adiponectin mRNA levels in adipose tissue cultures. The results were that 1) weight loss resulted in a 51% ( P < 0.05) increase in plasma adiponectin and a 45% ( P < 0.05) increase in adipose tissue mRNA levels; 2) plasma adiponectin was 53% ( P < 0.01) higher in lean compared with obese men, and plasma adiponectin was inversely correlated with adiposity, insulin sensitivity, and IL-6; and 3) TNF-α ( P < 0.01) and IL-6 plus its soluble receptor ( P < 0.05) decreased adiponectin mRNA levels in vitro. The inverse relationship between plasma adiponectin and cytokines in vivo and the cytokine-induced reduction in adiponectin mRNA in vitro suggests that endogenous cytokines may inhibit adiponectin. This could be of importance for the association between cytokines (e.g., IL-6) and insulin resistance and atherosclerosis.

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IRAK-4 in macrophages contributes to inflammatory osteolysis of wear particles around loosened hip implants

Innate Immunity ◽

10.1177/17534259211018740 ◽

2021 ◽

pp. 175342592110187

Author(s):

Yang-chun Zhang ◽

Jian-hong Xiao ◽

Shao-jie Deng ◽

Guo-liang Yi

Keyword(s):

Endotoxin Tolerance ◽

Wear Particles ◽

Hip Implants ◽

Prosthesis Loosening ◽

Specific Mechanism ◽

Local Immunity ◽

Tnf Α ◽

Local Inflammatory Reaction ◽

Pro Inflammatory Cytokines

TLRs recognizing PAMPS play a role in local immunity and participate in implant-associated loosening. TLR-mediated signaling is primarily regulated by IL-1 receptor associated kinase-M (IRAK-M) negatively and IRAK-4 positively. Our previous studies have proved that wear particles promote endotoxin tolerance in macrophages by inducing IRAK-M. However, whether IRAK-4 is involved in inflammatory osteolysis of wear particles basically, and the specific mechanism of IRAK-4 around loosened hip implants, is still unclear. IRAK-4 was studied in the interface membranes from patients in vivo and in particle-stimulated macrophages to clarify its role. Also, IL-1β and TNF-α levels were measured after particle and LPS stimulation in macrophages with or without IRAK-4 silenced by siRNA. Our results showed that the interface membranes around aseptic and septic loosened prosthesis expressed more IRAK-4 compared with membranes from osteoarthritic patients. IRAK-4 in macrophages increased upon particle and LPS stimulation. In the former, IL-1β and TNF-α levels were lower compared with those of LPS stimulation, and IRAK-4 siRNA could suppress production of pro-inflammatory cytokines. These findings suggest that besides IRAK-M, IRAK-4 also plays an important role in the local inflammatory reaction and contributes to prosthesis loosening.

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Target-Based Small Molecule Drug Discovery Towards Novel Therapeutics for Inflammatory Bowel Diseases

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab190 ◽

2021 ◽

Vol 27 (Supplement_2) ◽

pp. S38-S62 ◽

Cited By ~ 1

Author(s):

Yi Li ◽

Jianping Chen ◽

Andrew A Bolinger ◽

Haiying Chen ◽

Zhiqing Liu ◽

...

Keyword(s):

Drug Discovery ◽

Therapeutic Potential ◽

Biological Response ◽

Mucosal Inflammation ◽

Interacting Protein ◽

Iκb Kinase ◽

Tnf Α ◽

Inflammatory Bowel

Abstract Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a class of severe and chronic diseases of the gastrointestinal (GI) tract with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is a major contributing factor to neoplastic transformation and the development of colitis-associated colorectal cancer. Conversely, persistence of transmural inflammation in CD is associated with formation of fibrosing strictures, resulting in substantial morbidity. The recent introduction of biological response modifiers as IBD therapies, such as antibodies neutralizing tumor necrosis factor (TNF)-α, have replaced nonselective anti-inflammatory corticosteroids in disease management. However, a large proportion (~40%) of patients with the treatment of anti-TNF-α antibodies are discontinued or withdrawn from therapy because of (1) primary nonresponse, (2) secondary loss of response, (3) opportunistic infection, or (4) onset of cancer. Therefore, the development of novel and effective therapeutics targeting specific signaling pathways in the pathogenesis of IBD is urgently needed. In this comprehensive review, we summarize the recent advances in drug discovery of new small molecules in preclinical or clinical development for treating IBD that target biologically relevant pathways in mucosal inflammation. These include intracellular enzymes (Janus kinases, receptor interacting protein, phosphodiesterase 4, IκB kinase), integrins, G protein-coupled receptors (S1P, CCR9, CXCR4, CB2) and inflammasome mediators (NLRP3), etc. We will also discuss emerging evidence of a distinct mechanism of action, bromodomain-containing protein 4, an epigenetic regulator of pathways involved in the activation, communication, and trafficking of immune cells. We highlight their chemotypes, mode of actions, structure-activity relationships, characterizations, and their in vitro/in vivo activities and therapeutic potential. The perspectives on the relevant challenges, new opportunities, and future directions in this field are also discussed.

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Bone Resorption Induced by Titanium Implantation Through Activation of Osteoclast Formation via C3a

10.21203/rs.3.rs-66781/v1 ◽

2020 ◽

Author(s):

Xiaohan Liu ◽

Siwen Li ◽

Yuan Meng ◽

Yu Fan ◽

Ce Shi ◽

...

Keyword(s):

Bone Resorption ◽

Inflammatory Responses ◽

Titanium Implant ◽

Osteoclast Formation ◽

Alternative Pathways ◽

Tnf Α ◽

Differentiation And Proliferation ◽

Pro Inflammatory Cytokines

Abstract Titanium implantation is widely used for dental replacement with advantages of excellent mechanical strength, corrosion resistance, chemical stability and biocompatibility. Some patients, however, are subject to the failure of implantation due to bone resorption, which closely related to the inflammatory responses without clear mechanisms. In this study, first we found that there were inflammatory responses and increases of osteoclasts in the surrounding tissues near by the titanium implant. Further, data revealed that the C3 was increased in the serum and surrounding tissues near by the titanium implant, and activated by classical and alternative pathways. Next, we recognized that the C3a/C3aR, no C3b played an important role in stimulating secretions of pro-inflammatory cytokines of TNF-α and MMP9 via transcription factors NF-kB and NFATc1. This cascade of responses to titanium implant leaded the differentiation and proliferation of osteoclasts in vivo and in vitro, bone resorption of surrounding tissues of Ti implant. These suggest that the cleaved C3a fragment plays predominant roles in the activation of osteoclast. Therefore, the blocking C3a activation should provide potential to prevent bone resorption and prolong the survival of biomaterial implants.

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The therapeutic promises of Lianhuaqingke in the mice model of coronavirus pneumonia (HCoV-229E and SARS-CoV-2)

Chinese Medicine ◽

10.1186/s13020-021-00513-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Mingye Wang ◽

Wenyan Li ◽

Wenwen Cui ◽

Yuanyuan Hao ◽

Yao Mi ◽

...

Keyword(s):

Weight Loss ◽

Inflammatory Cytokines ◽

Peripheral Blood ◽

Morphological Changes ◽

Antiviral Effect ◽

Positive Staining ◽

Therapeutic Effects ◽

Reduce Weight Loss ◽

Pro Inflammatory Cytokines

Abstract Background Lianhuaqingke (LHQK) has been approved for the treatment of acute tracheobronchitis and exerts a broad-spectrum antiviral effect in our previous study. Methods Acute pneumonia caused by HCoV-229E was modeled in BALB/c mice. The anti-viral effect of LHQK was assessed by measuring the lung index and virus titer of lung tissues. The expression levels of pro-inflammatory cytokines in lung tissues and peripheral blood were measured by ELISA. The morphological changes of lung tissues were observed by H&E staining. The subsets of Th cells were assayed by the flow cytometry, including Th0, Th1, Th2, Treg, and Th17. The expression level of MUC5AC in 16HBE cells treated with TNFα was measured by ELISA. Immunofluorescence staining for β-IV tubulin was used to identify the airway epithelial ciliary in the condition-cultured RTE cells treated with TNFα. The direct antiviral effect of LHQK was assessed in vitro in Vero E6 infected by SARS-CoV-2, validated in vivo in the COVID-19 model of hACE2 transgenic mouse by detecting the lung index, the SARS-CoV-2 virus load, and the morphological changes of lung tissues. Results LHQK reduced the weight loss and the lung index by inhibiting the HCoV-229E replication and reducing the expression of pro-inflammatory cytokines in lung tissues. An assay for the Th cell subsets in peripheral blood revealed that LHQK could reduce the ratio of Th1/Th2 and increase the Treg/Th17 ratio in a dose-dependent way, which indicated that LHQK could coordinate the Th-mediated immune responses against the virus. In in vitro injury by TNFα, LHQK inhibited MUC5AC expression in 16HBE cells and increased the number of β-IV tubulin positive staining cells in the condition-cultured RTE cells. In the SARS-CoV-2-infected mice, LHQK could reduce weight loss, inhibit viral replication, and alleviate lung tissue damage. Conclusions Our results demonstrate that LHQK exerts therapeutic effects on pneumonia caused by HCoVs (HCoV-229E and SARS-CoV-2) in mice, and that the anti-HCoV effects might depend on its immunomodulatory capacities. All these results suggest that LHQK serves as a potential adjuvant for anti-HCoV therapies.

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