Carbon Monoxide Attenuates Dextran Sulfate Sodium-Induced Colitis via Inhibition of GSK-3βSignaling

Endogenous carbon monoxide (CO) is produced by heme oxygenase-1 (HO)-1 which mediates the degradation of heme into CO, iron, and biliverdin. Also, CO ameliorates the human inflammatory bowel diseases and ulcerative colitis. However, the mechanism for the effect of CO on the inflammatory bowel disease has not yet been known. In this study, we showed that CO significantly increases survival percentage, body weight, colon length as well as histologic parameters in DSS-treated mice. In addition, CO inhalation significantly decreased DSS induced pro-inflammatory cytokines by inhibition of GSK-3βin mice model. To support the in vivo observation, TNF-α, iNOS and IL-10 after CO and LiCl treatment were measured in mesenteric lymph node cells (MLNs) and bone marrow-derived macrophages (BMMs) from DSS treated mice. In addition, we determined that CO potentially inhibited GSK-3βactivation and decreased TNF-αand iNOS expression by inhibition of NF-κB activation in LPS-stimulated U937 and MLN cells pretreated with CO. Together, our findings indicate that CO attenuates DSS-induced colitis via inhibition of GSK-3βsignaling in vitro and in vivo. Importantly, this is the first report that investigated the molecular mechanisms mediated the novel effects of CO via inhibition GSK-3βin DSS-induced colitis model.

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HO-1/CO Maintains Intestinal Barrier Integrity through NF-κB/MLCK Pathway in Intestinal HO-1-/- Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6620873 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Zhenling Zhang ◽

Lijing Zhang ◽

Qiuping Zhang ◽

Bojia Liu ◽

Fang Li ◽

...

Keyword(s):

Molecular Mechanisms ◽

Intestinal Barrier ◽

Heme Oxygenase 1 ◽

Zinc Protoporphyrin ◽

Barrier Integrity ◽

Tnf Α ◽

Intestinal Barrier Integrity ◽

Deficient Mice

Background. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO-1/CO in barrier loss. Materials and Methods. We induced gut leakiness by injecting carbon tetrachloride (CCl4) to wildtype or intestinal HO-1-deficient mice. In addition, we administrated tumor necrosis factor-α (TNF-α) to cells with gain- or loss-of-HO-1 function. The effects of HO-1/CO maintaining intestinal barrier integrity were investigated in vivo and in vitro. Results. Cobalt protoporphyrin and CO-releasing molecule-2 alleviated colonic mucosal injury and TNF-α levels; upregulated tight junction (TJ) expression; and inhibited epithelial IκB-α degradation and phosphorylation, NF-κB p65 phosphorylation, long MLCK expression, and MLC-2 phosphorylation after administration of CCl4. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed in vitro, using Caco-2 cells with gain- or loss-of-HO-1-function after TNF-α. Pretreated with JSH-23 (NF-κB inhibitor) or ML-7 (long MLCK inhibitor), HO-1 overexpression prevented TNF-α-induced TJ disruption, while HO-1 shRNA promoted TJ damage even in the presence of JSH-23 or ML-7, thus suggesting that HO-1 dependently protected intestinal barrier via the NF-κB p65/MLCK/p-MLC-2 pathway. Intestinal HO-1-deficient mice further demonstrated the effects of HO-1 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO-1/CO repairing barrier loss in liver injury. Conclusion. HO-1/CO maintains intestinal barrier integrity through the NF-κB/MLCK pathway. Therefore, the intestinal HO-1/CO-NF-κB/MLCK system is a potential therapeutic target for diseases with a leaky gut.

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Stiffness Regulates Intestinal Stem Cell Fate

10.1101/2021.03.15.435410 ◽

2021 ◽

Author(s):

Shijie He ◽

Peng Lei ◽

Wenying Kang ◽

Priscilla Cheung ◽

Tao Xu ◽

...

Keyword(s):

Cell Fate ◽

Nuclear Translocation ◽

Goblet Cells ◽

Metabolic Phenotype ◽

Hydrogel Matrix ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

The Impact

SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate of intestinal stem cells (ISCs)? To address this question we first developed a novel long-term culture of quasi-3D gut organoids plated on hydrogel matrix of varying stiffness. Stiffening from 0.6kPa to 9.6kPa significantly reduces Lgr5high ISCs and Ki67+ progenitor cells while promoting their differentiation towards goblet cells. These stiffness-driven events are attributable to YAP nuclear translocation. Matrix stiffening also extends the expression of the stemness marker Olfactomedin 4 (Olfm4) into villus-like regions, mediated by cytoplasmic YAP. We next used single-cell RNA sequencing to generate for the first time the stiffness-regulated transcriptional signatures of ISCs and their differentiated counterparts. These signatures confirm the impact of stiffening on ISC fate and additionally suggest a stiffening-induced switch in metabolic phenotype, from oxidative phosphorylation to glycolysis. Finally, we used colon samples from IBD patients as well as chronic colitis murine models to confirm the in vivo stiffening-induced epithelial deterioration similar to that observed in vitro. Together, these results demonstrate stiffness-dependent ISC reprograming wherein YAP nuclear translocation diminishes ISCs and Ki67+ progenitors and drives their differentiation towards goblet cells, suggesting stiffening as potential target to mitigate gut epithelial deterioration during IBD.

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Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

Blood ◽

10.1182/blood-2003-08-2781 ◽

2004 ◽

Vol 103 (9) ◽

pp. 3465-3473 ◽

Cited By ~ 63

Author(s):

Shane C. McAllister ◽

Scott G. Hansen ◽

Rebecca A. Ruhl ◽

Camilo M. Raggo ◽

Victor R. DeFilippis ◽

...

Keyword(s):

Endothelial Cells ◽

Heme Oxygenase ◽

Cell Biology ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Kaposi Sarcoma ◽

Heme Oxygenase 1 ◽

Spindle Cell Proliferation

Abstract Kaposi sarcoma (KS) is the most common AIDS-associated malignancy and is characterized by angiogenesis and the presence of spindle cells. Kaposi sarcoma-associated herpesvirus (KSHV) is consistently associated with all clinical forms of KS, and in vitro infection of dermal microvascular endothelial cells (DMVECs) with KSHV recapitulates many of the features of KS, including transformation, spindle cell proliferation, and angiogenesis. To study the molecular mechanisms of KSHV pathogenesis, we compared the protein expression profiles of KSHV-infected and uninfected DMVECs. This comparison revealed that heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in heme catabolism, was up-regulated in infected endothelial cells. Recent evidence suggests that the products of heme catabolism have important roles in endothelial cell biology, including apoptosis and angiogenesis. Here we show that HO-1 mRNA and protein are up-regulated in KSHV-infected cultures. Comparison of oral and cutaneous AIDS-KS tissues with normal tissues revealed that HO-1 mRNA and protein were also up-regulated in vivo. Increased HO-1 enzymatic activity in vitro enhanced proliferation of KSHV-infected DMVECs in the presence of free heme. Treatment with the HO-1 inhibitor chromium mesoporphyrin IX abolished heme-induced proliferation. These data suggest that HO-1 is a potential therapeutic target for KS that warrants further study. (Blood. 2004;103: 3465-3473)

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Oral colon targeted delivery systems for treatment of inflammatory bowel diseases: Synthesis, in vitro and in vivo assessment

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2008.04.021 ◽

2008 ◽

Vol 358 (1-2) ◽

pp. 248-255 ◽

Cited By ~ 30

Author(s):

Amal H. El-Kamel ◽

Alaa A.-M. Abdel-Aziz ◽

Amal J. Fatani ◽

Hussein I. El-Subbagh

Keyword(s):

Inflammatory Bowel Diseases ◽

Targeted Delivery ◽

Delivery Systems ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

In Vivo Assessment ◽

Targeted Delivery Systems

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Protective effects of a novel probiotic strain, Lactococcus lactis ML2018, in colitis: in vivo and in vitro evidence

Food & Function ◽

10.1039/c8fo02301h ◽

2019 ◽

Vol 10 (2) ◽

pp. 1132-1145 ◽

Cited By ~ 12

Author(s):

Meiling Liu ◽

Xiuxia Zhang ◽

Yunpeng Hao ◽

Jinhua Ding ◽

Jing Shen ◽

...

Keyword(s):

Immune Responses ◽

Lactococcus Lactis ◽

Intestinal Microbiota ◽

Inflammatory Bowel Diseases ◽

Probiotic Strain ◽

Protective Effects ◽

Bowel Diseases ◽

Inflammatory Bowel

Multiple articles have confirmed that an imbalance of the intestinal microbiota is closely related to aberrant immune responses of the intestines and to the pathogenesis of inflammatory bowel diseases (IBDs).

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Polygonatum sibiricum Polysaccharides Protect against MPP-Induced Neurotoxicity via the Akt/mTOR and Nrf2 Pathways

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8843899 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Si Huang ◽

Haiyan Yuan ◽

Wenqun Li ◽

Xinyi Liu ◽

Xiaojie Zhang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Neuronal Loss ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Dependent Manner ◽

Quinone Oxidoreductase ◽

Glutamate Cysteine Ligase ◽

Dopaminergic Neuronal Loss

Polygonatum sibiricum, a well-known life-prolonging tonic in Chinese medicine, has been widely used for nourishing nerves in the orient, but the underlying molecular mechanisms remain unclear. In this study, we found that P. sibiricum polysaccharides (PSP) ameliorated 1-methyl-4-phenyl-1,2.3,6-tetrahydropyridine- (MPTP-) induced locomotor activity deficiency and dopaminergic neuronal loss in an in vivo Parkinson’s disease (PD) mouse model. Additionally, PSP pretreatment inhibited N-methyl-4-phenylpyridine (MPP+) induced the production of reactive oxygen species, increasing the ratio of reduced glutathione/oxidized glutathione. In vitro experiments showed that PSP promoted the proliferation of N2a cells in a dose-dependent manner, while exhibiting effects against oxidative stress and neuronal apoptosis elicited by MPP+. These effects were found to be associated with the activation of Akt/mTOR-mediated p70S6K and 4E-BP1 signaling pathways, as well as nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (Gclc), and glutamate-cysteine ligase modulatory subunit (Gclm), resulting in antiapoptotic and antioxidative effects. Meanwhile, PSP exhibited no chronic toxicity in C57BJ/6 mice. Together, our results suggest that PSP can serve as a promising therapeutic candidate with neuroprotective properties in preventing PD.

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Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

Molecules ◽

10.3390/molecules27010167 ◽

2021 ◽

Vol 27 (1) ◽

pp. 167

Author(s):

Seyed Hossein Shahcheraghi ◽

Fateme Salemi ◽

Niloufar Peirovi ◽

Jamshid Ayatollahi ◽

Waqas Alam ◽

...

Keyword(s):

Molecular Mechanisms ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Glutamate Cysteine Ligase ◽

Response Elements ◽

Nrf2 Signaling Pathway ◽

Anti Inflammatory ◽

Molecular Aspects

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc–curcumin Zn (II)–curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc–curcumin Zn (II)–curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.

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Health-Improving and Disease-Preventing Potential of Camel Milk Against Chronic Diseases and Autism

Handbook of Research on Health and Environmental Benefits of Camel Products - Practice, Progress, and Proficiency in Sustainability ◽

10.4018/978-1-7998-1604-1.ch008 ◽

2020 ◽

pp. 155-184

Author(s):

Mo'ez Al-Islam Ezzat Faris ◽

Hadeel Ghazzawi

Keyword(s):

Chronic Diseases ◽

Molecular Mechanisms ◽

Experimental Studies ◽

Nutritional Composition ◽

Camel Milk ◽

Bowel Diseases ◽

Liver And Kidney ◽

Health Promoting

Camel milk has been used as part of the human diet since ancient times. This chapter tries to elaborate the different aspects of nutraceutical functional properties of camel milk, focusing on the nutritional composition, presence of bioactive zoochemicals and peptides, antioxidant nutrients (vitamin C), and health rendering properties of this unique milk. Recent research has identified camel milk as a prophylactic and therapeutic functional food due to its noticeable content of essential macronutrients, namely bioactive functional proteins and peptides, along with its considerable content of essential micronutrients. Indeed, the presence of this unique mixture has shown to be promising contributors to the management and prevention of chronic diseases, such as cancer, diabetes, liver and kidney, metabolic syndrome, inflammatory bowel diseases in adults, and autism. In vivo, in vitro, and epidemiological and experimental studies were reviewed, and molecular mechanisms were highlighted for better understanding of the health-promoting, disease-preventing potential of camel milk.

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The Promising Effects of Astaxanthin on Lung Diseases

Advances in Nutrition ◽

10.1093/advances/nmaa143 ◽

2020 ◽

Author(s):

Junrui Cheng ◽

Abdulkerim Eroglu

Keyword(s):

Lung Cancer ◽

Lung Diseases ◽

Molecular Mechanisms ◽

Janus Kinase ◽

In Vivo Studies ◽

Chronic Obstructive ◽

Heme Oxygenase 1 ◽

Related Factor

ABSTRACT Astaxanthin (ASX) is a naturally occurring xanthophyll carotenoid. Both in vitro and in vivo studies have shown that it is a potent antioxidant with anti-inflammatory properties. Lung cancer is the leading cause of cancer death worldwide, whereas other lung diseases such as chronic obstructive pulmonary disease, emphysema, and asthma are of high prevalence. In the past decade, mounting evidence has suggested a protective role for ASX against lung diseases. This article reviews the potential role of ASX in protecting against lung diseases, including lung cancer. It also summarizes the underlying molecular mechanisms by which ASX protects against pulmonary diseases, including regulating the nuclear factor erythroid 2–related factor/heme oxygenase-1 pathway, NF-κB signaling, mitogen-activated protein kinase signaling, Janus kinase–signal transducers and activators of transcription-3 signaling, the phosphoinositide 3-kinase/Akt pathway, and modulating immune response. Several future directions are proposed in this review. However, most in vitro and in vivo studies have used ASX at concentrations that are not achievable by humans. Also, no clinical trials have been conducted and/or reported. Thus, preclinical studies with ASX treatment within physiological concentrations as well as human studies are required to examine the health benefits of ASX with respect to lung diseases.

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