scholarly journals Simultaneous Inhibition of Three Major Cytokines and Its Therapeutic Effects: A Peptide-Based Novel Therapy against Endotoxemia in Mice

2021 ◽  
Vol 11 (5) ◽  
pp. 436
Author(s):  
Hung-Jen Shih ◽  
Chao-Yuan Chang ◽  
Milton Chiang ◽  
Van Long Le ◽  
Hao-Jen Hsu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Therapeutic Effects ◽  
The Novel ◽  
Tissue Water ◽  
Novel Therapy ◽  
Binding Domains ◽  
Tnf Α ◽  
Simultaneous Inhibition ◽  
Factor Α ◽  
Liver Tissues

Three major cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, mediate endotoxemia-induced liver injury. With the similar structures to the binding domains of the three cytokines to their cognate receptors, the novel peptide KCF18 can simultaneously inhibit TNF-α, IL-1β, and IL-6. We elucidated whether KCF18 can alleviate injury of liver in endotoxemic mice. Adult male mice (BALB/cJ) were intraperitoneally (i.p.) administered lipopolysaccharide (LPS, 15 mg/kg; LPS group) or LPS with KCF18 (LKCF group). Mice in the LKCF group received KCF18 (i.p.) at 2 h (0.6 mg/kg), 4 h (0.3 mg/kg), 6 h (0.3 mg/kg), and 8 h (0.3mg/kg) after LPS administration. Mice were sacrificed after receiving LPS for 24 h. Our results indicated that the binding levels of the three cytokines to their cognate receptors in liver tissues in the LKCF group were significantly lower than those in the LPS group (all p < 0.05). The liver injury level, as measured by performing functional and histological analyses and by determining the tissue water content and vascular permeability (all p < 0.05), was significantly lower in the LKCF group than in the LPS group. Similarly, the levels of inflammation (macrophage activation, cytokine upregulation, and leukocyte infiltration), oxidation, necroptosis, pyroptosis, and apoptosis (all p < 0.05) in liver tissues in the LKCF group were significantly lower than those in the LPS group. In conclusion, the KCF18 peptide–based simultaneous inhibition of TNF-α, IL-1β, and IL-6 can alleviate liver injury in mice with endotoxemia.

scholarly journals Let-7i-5p Mediates the Therapeutic Effects of Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells on Mitigating Endotoxin-Induced Mortality and Liver Injury in High-Fat Diet-Induced Obese Mice

2021 ◽  
Vol 15 (1) ◽  
pp. 36
Author(s):  
Chao-Yuan Chang ◽  
Kung-Yen Chen ◽  
Hung-Jen Shih ◽  
Milton Chiang ◽  
I-Tao Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Injury ◽  
Human Placenta ◽  
High Fat Diet ◽  
Therapeutic Effects ◽  
Obese Mice ◽  
High Fat ◽  
Tissue Water ◽  
Liver Tissues

Obesity complicates sepsis and increases the mortality of sepsis. We examined the effects of exosomes (from human placenta choriodecidual membrane-derived mesenchymal stem cells, pcMSCs) on preventing sepsis in obesity and the mitigating role of hsa-let-7i-5p microRNA. Obese mice (adult male C57BL/6J mice fed a high-fat diet for 12 weeks) received normal saline (HFD), endotoxin (10 mg/kg, intraperitoneal (ip); HFDLPS), endotoxin with exosomes (1 × 108 particles/mouse, ip; HLE), or endotoxin with let-7i-5p microRNA inhibitor-pretreated exosomes (1 × 108 particles/mouse, ip; HLEi). Our data demonstrated that the 48-h survival rate in the HLE (100%) group was significantly higher than in the HFDLPS (50%) and HLEi (58.3%) groups (both p < 0.05). In the surviving mice, by contrast, levels of liver injury (injury score, plasma aspartate transaminase and alanine transaminase concentrations, tissue water content, and leukocyte infiltration in liver tissues; all p < 0.05), inflammation (nuclear factor-κB activation, hypoxia-inducible factor-1α activation, macrophage activation, and concentrations of tumor necrosis factor-α, interleukin-6, and leptin in liver tissues; all p < 0.05), and oxidation (malondialdehyde in liver tissues, with p < 0.001) in the HLE group were significantly lower than in the HFDLPS group. Levels of mitochondrial injury/dysfunction and apoptosis in liver tissues in the HLE group were also significantly lower than in the HFDLPS group (all p < 0.05). Inhibition of let-7i-5p microRNA offset the effects of the exosomes, with most of the aforementioned measurements in the HLEi group being significantly higher than in the HLE group (all p < 0.05). In conclusion, exosomes mitigated endotoxin-induced mortality and liver injury in obese mice, and these effects were mediated by let-7i-5p microRNA.

Tumor Necrosis Factor-α Production-Enhancing Properties of Novel Adamantylalkylthio Derivatives of Some Heterocyclic Compounds

2005 ◽  
Vol 60 (4) ◽  
pp. 471-475 ◽  
Author(s):  
Barbara Orzeszko ◽  
Tomasz Świtaj ◽  
Anna B. Jakubowska-Mućka ◽  
Witold Lasek ◽  
Andrzej Orzeszko ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Heterocyclic Compounds ◽  
Tumor Necrosis ◽  
The Novel ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Factor Α ◽  
Derivatives Of ◽  
Necrosis Factor

Certain adamantylated heterocycles were previously shown to enhance the secretion of tumor necrosis factor alpha (TNF-α) by murine melanoma cells that have been transduced with the gene for human TNF-α and constitutively expressed this cytokine. The stimulatory potency of those compounds depended, among other factors, on the structure of the linker between the adamantyl residue and the heterocyclic core. In the present study, a series of (1-adamantyl)alkylsulfanyl derivatives of heterocyclic compounds was prepared by alkylation of the corresponding thioheterocyles. Of the novel adamantylalkylthio compounds tested in the aforementioned cell line, 2-(2-adamantan-1-ylethylsulfanyl)- 4-methyl-pyrimidine was found to be the most active

Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice

1999 ◽  
Vol 277 (3) ◽  
pp. G702-G708 ◽  
Author(s):  
Alix de la Coste ◽  
Monique Fabre ◽  
Nathalie McDonell ◽  
Arlette Porteu ◽  
Helène Gilgenkrantz ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transgenic Mice ◽  
Fas Ligand ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tnf Α ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Factor Α

Fas ligand (CD95L) and tumor necrosis factor-α (TNF-α) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-α-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing[Formula: see text]in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous[Formula: see text]or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-α caused massive apoptosis and death only when transcription was inhibited. Under these conditions,[Formula: see text]mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-α receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.

scholarly journals Autophagy Modulation in Lymphocytes From COVID-19 Patients: New Therapeutic Target in SARS-COV-2 Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Marta Vomero ◽  
Cristiana Barbati ◽  
Tania Colasanti ◽  
Alessandra Ida Celia ◽  
Mariangela Speziali ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Degradation Pathway ◽  
The Novel ◽  
Lysosomal Degradation ◽  
Tnf Α ◽  
Evolutionarily Conserved ◽  
Novel Coronavirus ◽  
Factor Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the novel coronavirus, causing coronavirus disease 2019 (COVID-19). During virus infection, several pro-inflammatory cytokines are produced, leading to the “cytokine storm.” Among these, interleukin (IL)-6, tumor necrosis factor‐α (TNF‐α), and IL-1β seem to have a central role in the progression and exacerbation of the disease, leading to the recruitment of immune cells to infection sites. Autophagy is an evolutionarily conserved lysosomal degradation pathway involved in different aspects of lymphocytes functionality. The involvement of IL-6, TNF‐α, and IL-1β in autophagy modulation has recently been demonstrated. Moreover, preliminary studies showed that SARS-CoV-2 could infect lymphocytes, playing a role in the modulation of autophagy. Several anti-rheumatic drugs, now proposed for the treatment of COVID-19, could modulate autophagy in lymphocytes, highlighting the therapeutic potential of targeting autophagy in SARS-CoV-2 infection.

scholarly journals Ocular Formulation Based on Palmitoylethanolamide-Loaded Nanostructured Lipid Carriers: Technological and Pharmacological Profile

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 287 ◽  
Author(s):  
Carmelo Puglia ◽  
Debora Santonocito ◽  
Carmine Ostacolo ◽  
Eduardo Maria Sommella ◽  
Pietro Campiglia ◽  
...  
Keyword(s):  
Physical Stability ◽  
Topical Administration ◽  
Diabetic Rats ◽  
Nanostructured Lipid Carrier ◽  
The Novel ◽  
Tnf Α ◽  
Mean Size ◽  
Retinal Distribution ◽  
Factor Α ◽  
Ophthalmic Formulation

The present work was aimed for the preparation of a stable nanostructured lipid carrier (NLC) system for the delivery of N-palmitoylethanolamide (PEA) to the back of the eye. PEA is an interesting natural compound showing anti-inflammatory and neuroprotective activities. The limits of PEA (poor solubility and high instability) justify its nanoencapsulation into drug delivery systems. Two different well-known techniques were compared to formulate NLC: the high shear homogenization technique (HSH) and the method based on a combination of HSH technique and ultrasonication (HSH/US). Nanoparticles were evaluated in relation to mean size, homogeneity, surface charge, and physical stability by Turbiscan technology. Retinal distribution of PEA was carried out in a rat eye after single instillation of PEA-NLC ophthalmic formulation. The novel formulation delivered remarkable levels of PEA to the retina. Lastly, topical administration of PEA-NLC ophthalmic formulation was able to significantly inhibits retinal tumor necrosis factor-α (TNF-α) levels in streptozotocin-induced diabetic rats. The present findings suggest that the novel ophthalmic formulation may be useful for the treatment of retinal diseases such as diabetic retinopathy. Clinical studies are in progress to evaluate this possibility.

Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1638-1645 ◽  
Author(s):  
Hirotaka Isobe ◽  
Kenji Okajima ◽  
Mitsuhiro Uchiba ◽  
Naoaki Harada ◽  
Hiroaki Okabe
Keyword(s):  
Nitric Oxide ◽  
Septic Shock ◽  
Nitric Oxide Synthase ◽  
Messenger Rna ◽  
Inos Mrna ◽  
Therapeutic Effects ◽  
Induced Hypotension ◽  
Tnf Α ◽  
Factor Α ◽  
Oxide Synthase

Antithrombin (AT) prevents Escherichia coli–induced hypotension in animal models of sepsis, and it further reduces the mortality of patients with septic shock. In the present study, we examined whether AT may prevent the endotoxin (ET)-induced hypotension by promoting the endothelial release of prostacyclin (PGI2) in rats. Intravenous administration of AT (250 U/kg) prevented both hypotension and the increases in plasma levels of NO2−/NO3− in rats given ET. Lung expression of messenger RNA (mRNA) for tumor necrosis factor-α (TNF-α) was transiently increased after ET administration, followed by the increases in lung tissue levels of TNF-α. Both the lung activity of the inducible form of nitric oxide synthase (iNOS) and the lung expression of iNOS mRNA in animals administered ET were gradually increased after the TNF-α mRNA expression had peaked. Administration of AT significantly inhibited these increases. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor Trp49-modified AT, which is not capable of promoting the endothelial release of PGI2, showed any effects on these changes induced by ET. Administration of antirat TNF-α antibody produced effects similar to those induced by AT. Indomethacin pretreatment abrogated the effects induced by AT. Iloprost, a stable derivative of PGI2, produced effects similar to those of AT. These findings suggested that AT prevents the ET-induced hypotension by inhibiting the induction of iNOS through inhibiting TNF-α production. These effects of AT could be mediated by the promotion of endothelial release of PGI2 and might at least partly explain the therapeutic effects for septic shock.

Natural limonoids protect mice from alcohol-induced liver injury

2020 ◽  
Vol 31 (5) ◽  
Author(s):  
Abacuc Valansa ◽  
Borris Rosnay Tietcheu Galani ◽  
Pascal Dieudonne Djamen Chuisseu ◽  
Armelle Tontsa Tsamo ◽  
Vincent Brice Ayissi Owona ◽  
...  
Keyword(s):  
Liver Injury ◽  
Positive Control ◽  
Negative Control ◽  
Protective Effects ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Different Doses ◽  
Better Than

AbstractBackgroundAlcoholic liver disease (ALD) is regarded as a global health problem with limited therapeutic options. Previous studies highlighted some anticancer, antiviral, and hepatoprotective activities of limonoids, but the effects of these compounds on ALD remain unknown. The present study aimed to evaluate the effect of some natural limonoids on ethanol-induced liver injury.MethodsThirty-five albino mice (Mus musculus) were administered with 40% ethanol in the presence or absence of the different limonoids [including three havanensin-type limonoids, TS1, TS3, Rubescin D isolated from an African medicinal plant, Trichilia rubescens Oliv. (Meliaceae), and one limonin], or silymarin at 50 mg/kg for 3 days. Thereafter, the effect of the most active compound was evaluated in a chronic model of ALD. For this purpose, 24 mice with each group consisting of six mice were administered orally with 40% ethanol and limonoid at different doses (50, 75, and 100 mg/kg) for 28 days. Finally, biochemical parameters such as alanine aminotransferase (ALT), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), triglyceride (TG), and tumor necrosis factor α (TNF-α) levels were quantified in liver homogenates.ResultsAll tested limonoids significantly (p < 0.01) reduced ALT levels relative to the negative control in the acute model. However, in comparison to other limonoids, limonin at 50 and 75 mg/kg significantly reduced TG, MDA, and TNF-α levels (1.8-fold); alleviated leukocyte infiltration in liver tissue; significantly increased the activity of SOD; and decreased those of CAT better than silymarin used as a positive control at 50 mg/kg.ConclusionsThese data suggest that limonin possesses protective effects on long-term alcohol poisoning partially due to antioxidant and anti-inflammatory mechanisms.

scholarly journals The Protective Effects of Water Extracts of Compound Turmeric Recipe on Acute Alcoholism: An Experimental Research Using a Mouse Model

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Xian-ting Liang ◽  
Yan-yan Wang ◽  
Xiao-yu Hu ◽  
Shao-bo Wang
Keyword(s):  
Liver Injury ◽  
Curcuma Longa ◽  
Protective Effects ◽  
Alcoholic Liver Injury ◽  
Therapeutic Drugs ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
Acute Alcoholism ◽  
Factor Α ◽  
The Brain

Acute alcoholism (AAI) is a common emergency. Currently, there is a lack of preventive and therapeutic drugs with superior safety and efficacy. Curcuma longa, Panax ginseng, Pueraria lobata, Pueraria flower, and Hovenia dulcis Thunb., which are the components of compound turmeric recipe (CTR), are, respectively, used in China as adjuvant therapeutic agents for AAI and alcoholic liver injury, respectively. The purpose of this research was to investigate the effect of traditional compound turmeric recipe in anti-inebriation treatment and to identify its underlying mechanisms. The mice were administered with CTR mixture, and ethanol was subsequently given to mice by gavage. The effects of CTR on the righting reflex, 24-hour survival, drunken behavior, blood ethanol concentration, and pathological changes of liver are depicted. The activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were detected. Besides, the activities of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P450 (P450), superoxide dismutase (SOD), and malondialdehyde (MDA) in the liver and the levels of β-endorphin (β-EP) and leucine enkephalin (LENK) in the brain were also measured. Our results demonstrated that CTR can increase the activities of ADH, ALDH, P450, and SOD and decrease the contents of TNF-α, IL-8, and MDA in the liver. In addition, it can decrease the activities of ALT, AST, and ALP in serum and β-EP and LENK activities in the brain. CTR showed effects on prevention of acute alcoholism, promoting wakefulness, and alleviating alcoholic liver injury, which were likely mediated by the above mechanisms.

Role of Microthrombus Formation in the Development of Ischemia/Reperfusion-induced Liver Injury in Rats

2002 ◽  
Vol 88 (09) ◽  
pp. 473-480 ◽  
Author(s):  
Naoaki Harada ◽  
Shigeki Kushimoto ◽  
Mitsuhiro Uchiba ◽  
Kenji Okajima
Keyword(s):  
Blood Flow ◽  
Liver Injury ◽  
Neutrophil Elastase ◽  
Ischemia Reperfusion ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Therapeutic Effects ◽  
Tnf Α ◽  
Hepatic Tissue Blood Flow

SummaryAlthough tumor necrosis factor-α (TNF-α) has been shown to play a critical role in the pathologic process leading to ischemia/reperfusion (I/R)-induced liver injury in rats by activating neutrophils, it is not clear whether or not microthrombus formation induced by TNF-α contributes to the liver injury. In the present study, we investigated the role of microthrombus formation in I/R-induced liver injury in rats. Hepatic tissue levels of TNF-α were significantly increased after reperfusion, and these were higher in animals subjected to 120 min-hepatic I/R than in those subjected to 60 min-hepatic I/R. Fibrin deposition was observed histologically in the hepatic sinusoidal space only in animals subjected to 120 min-hepatic I/R. Both the decrease in hepatic tissue blood flow and the extent of liver injury in animals subjected to 60 minand 120 min-hepatic I/R were significantly inhibited by pretreatment with anti-rat TNF-α antibody. Although neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 60 min-hepatic I/R, anticoagulants did not show any effects. Both anticoagulants and neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 120 min-hepatic I/R. Therapeutic effects of anti-rat TNF-α antibody on the120 min-I/R-induced liver injury were more marked than those of each anticoagulant or each neutrophil elastase inhibitor, and were comparable to those of combined use of anticoagulants and neutrophil elastase inhibitors. These observations strongly suggest that TNF-α induces I/R-induced liver injury primarily by activating neutrophils, and it exacerbates liver injury by inducing microthrombus formation when the production of TNF-α is further increased.

Response of hairy cells to IFN-α involves induction of apoptosis through autocrine TNF-α and protection by adhesion

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 647-653 ◽  
Author(s):  
Peter K. Baker ◽  
Andrew R. Pettitt ◽  
Joseph R. Slupsky ◽  
Hai J. Chen ◽  
Mark A. Glenn ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Interferon Α ◽  
The Novel ◽  
Tnf Α ◽  
Hairy Cells ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Blocking Antibodies ◽  
Biologic Basis ◽  
Necrosis Factor

Abstract Although hairy cell leukemia is uniquely sensitive to interferon-α (IFN-α), the biologic basis for this phenomenon remains unclear. Here we examine the effects of IFN-α on cultured hairy cells (HCs), taking into account the possible modifying influence of cell adhesion. We make the novel observation that therapeutic concentrations of IFN-α kill nonadherent HCs by inducing apoptosis. In keeping with the persistence of HCs in tissues during therapy, such killing was inhibited by integrin-mediated adhesion to vitronectin or fibronectin. Exposure of HCs to IFN-α resulted in a marked increase in tumor necrosis factor-α (TNF-α) secretion. Furthermore, blocking antibodies to TNF-RI or TNF-RII protected HCs from IFN-α–induced apoptosis, demonstrating that such killing was mediated by TNF-α. In the absence of IFN-α, exogenous TNF-α did not induce HC apoptosis, showing that IFN-α sensitized HCs to the proapoptotic effect of autocrine TNF-α. This sensitization to TNF-α–induced killing was attributable to suppression of IAP (inhibitors of apoptosis) production known to be regulated by the cytoprotective nuclear factor–κB–dependent arm of TNF-α signaling. Moreover, engagement of the receptors for fibronectin or vitronectin prevented this IFN-α–induced down-regulation of IAPs. Understanding of the signals involved in the combined effects of IFN-α and TNF-α and abrogation of those induced by integrin engagement offers the possibility of sensitizing other malignant cells to IFN-α–induced killing and thereby extending the therapeutic use of this cytokine.

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