Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Background: Urogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology have not been well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology. Methods: Purified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry. Results: We demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection. Conclusion: S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control.

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Lancemaside A fromCodonopsis lanceolataModulates the Inflammatory Responses Mediated by Monocytes and Macrophages

Mediators of Inflammation ◽

10.1155/2014/405158 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Eunji Kim ◽

Woo Seok Yang ◽

Ji Hye Kim ◽

Jae Gwang Park ◽

Han Gyung Kim ◽

...

Keyword(s):

Intracellular Signaling ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Morphological Changes ◽

Costimulatory Molecule ◽

Raw264.7 Cells ◽

U937 Cells ◽

Neutralizing Capacity ◽

Lancemaside A ◽

Monocytes And Macrophages

In this study, we aimed to examine the cellular and molecular mechanisms of lancemaside A fromCodonopsis lanceolata(Campanulaceae) in the inflammatory responses of monocytes (U937 cells) and macrophages (RAW264.7 cells). Lancemaside A significantly suppressed the inflammatory functions of lipopolysaccharide- (LPS-) treated RAW264.7 cells by suppressing the production of nitric oxide (NO), the expression of the NO-producing enzyme inducible NO synthase (iNOS), the upregulation of the costimulatory molecule CD80, and the morphological changes induced by LPS exposure. In addition, lancemaside A diminished the phagocytic activity of RAW264.7 cells and boosted the neutralizing capacity of these cells when treated with the radical generator sodium nitroprusside (SNP). Interestingly, lancemaside A strongly blocked the adhesion activity of RAW264.7 cells to plastic culture plates, inhibited the cell-cell and cell-fibronectin (FN) adhesion of U937 cells that was triggered by treatment with an anti-β1-integrin (CD29) antibody and immobilized FN, respectively. By evaluating the activation of various intracellular signaling pathways and the levels of related nuclear transcription factors, lancemaside A was found to block the activation of inhibitor ofκB kinase (IKK) and p65/nuclear factor- (NF-)κB. Taken together, our findings strongly suggest that the anti-inflammatory function of lancemaside A is the result of its strong antioxidative and IKK/NF-κB inhibitory activities.

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Elongation of stigmatic papillae induced by heat stress is associated with disturbance of pollen attachment in Arabidopsis thaliana

10.1101/2019.12.21.885640 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kazuma Katano ◽

Takao Oi ◽

Nobuhiro Suzuki

Keyword(s):

Arabidopsis Thaliana ◽

Heat Stress ◽

Stress Responses ◽

Molecular Mechanisms ◽

Morphological Changes ◽

Reproductive Organs ◽

Histochemical Staining ◽

Morphological Alteration ◽

Yield Production ◽

Stigmatic Papillae

ABSTRUCTHeat stress can seriously impact on yield production and quality of crops. Many studies uncovered the molecular mechanisms that regulate heat stress responses in plants. Nevertheless, effects of heat stress on the morphology of plants were still not extensively studied. In this study, we observed the detailed morphological changes of reproductive organs in Arabidopsis thaliana caused by heat stress. Larger area of stigma, and shorter length of anthers, filaments and petals were observed in plants subjected to heat stress compared to those under controlled conditions. Scanning electron microscopy (SEM) observation showed that length of stigmatic papillae without pollens seemed to be longer than that with pollens. In addition, classification of stigmas based on pollen attachment patterns together with artificial pollination assay revealed that pollen attachment onto stigma was clearly decreased by heat stress, and indicated that heat induced elongation of stigmatic papillae might be associated with disturbance of pollen attachment onto stigma. Furthermore, histochemical staining experiments revealed that crosstalk between Ca2+ and NO derived from pollens and O2− derived from stigma might be associated with morphological alteration of stigma.

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Arid1a protects against hepatic steatosis and insulin resistance via PPARα-mediated fatty acid oxidation

10.1101/507517 ◽

2019 ◽

Author(s):

Yu-Lan Qu ◽

Chuan-Huai Deng ◽

Qing Luo ◽

Xue-Ying Shang ◽

Jiao-Xiang Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Hepatic Steatosis ◽

Fatty Acid Oxidation ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Lifestyle Changes ◽

Health Concern ◽

Acid Oxidation ◽

Alcoholic Fatty Liver

AbstractNon-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become a worldwide health concern because of lifestyle changes, but it is still lack of specific therapeutic strategies as the underlying molecular mechanisms remain poorly understood. Our previous study indicated that deficiency of Arid1a, a key component of SWI/SNF chromatin remodeling complex, initiated mouse steatohepatitis, implying that Arid1a might be essentially required for the integrity of hepatic lipid metabolism. However, the exact mechanisms of the pathological process due to Arid1a loss are unclear. In the present work, we show that hepatocyte-specific deletion of Arid1a significantly increases susceptibility to develop hepatic steatosis and insulin resistance in mice fed with high-fat diet (HFD), along with the aggravated inflammatory responses marked by increment of serum alanine amino transferase (AST), aspartate amino transferase (AST) and TNFα. Mechanistically, Arid1a deficiency leads to the reduction of chromatin modification characteristic of transcriptional activation on multiple metabolic genes, especially Cpt1a and Acox1, two rate-limiting enzyme genes for fatty acid oxidation. Furthermore, our data indicated that Arid1a loss promotes hepatic steatosis by downregulating PPARα, thereby impairing fatty acid oxidation which leads to lipid accumulation and insulin resistance. These findings reveal that targeting ARID1a might be a promising therapeutic strategy for NAFLD, NASH and insulin resistance.

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Specialized pro-resolving mediator network: an update on production and actions

Essays in Biochemistry ◽

10.1042/ebc20200018 ◽

2020 ◽

Vol 64 (3) ◽

pp. 443-462 ◽

Cited By ~ 2

Author(s):

Nan Chiang ◽

Charles N. Serhan

Keyword(s):

Tissue Regeneration ◽

Animal Studies ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Docosapentaenoic Acid ◽

Health Concern ◽

Public Health Concern ◽

Protective Actions ◽

Chemical Mediators ◽

The Ideal

Abstract Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2–3 years from human and preclinical animal studies, together with the structural–functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.

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Resolution-Associated Molecular Patterns (RAMPs) as Endogenous Regulators of Glia Functions in Neuroinflammatory Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200702143719 ◽

2020 ◽

Vol 19 (7) ◽

pp. 483-494

Author(s):

Tyler J. Wenzel ◽

Evan Kwong ◽

Ekta Bajwa ◽

Andis Klegeris

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Bioactive Lipids ◽

Prothymosin Α ◽

Neuroinflammatory Disease ◽

Cellular Debris ◽

Αb Crystallin ◽

Endogenous Regulators ◽

The Central Nervous System ◽

Molecular Patterns

: Glial cells, including microglia and astrocytes, facilitate the survival and health of all cells within the Central Nervous System (CNS) by secreting a range of growth factors and contributing to tissue and synaptic remodeling. Microglia and astrocytes can also secrete cytotoxins in response to specific stimuli, such as exogenous Pathogen-Associated Molecular Patterns (PAMPs), or endogenous Damage-Associated Molecular Patterns (DAMPs). Excessive cytotoxic secretions can induce the death of neurons and contribute to the progression of neurodegenerative disorders, such as Alzheimer’s disease (AD). The transition between various activation states of glia, which include beneficial and detrimental modes, is regulated by endogenous molecules that include DAMPs, cytokines, neurotransmitters, and bioactive lipids, as well as a diverse group of mediators sometimes collectively referred to as Resolution-Associated Molecular Patterns (RAMPs). RAMPs are released by damaged or dying CNS cells into the extracellular space where they can induce signals in autocrine and paracrine fashions by interacting with glial cell receptors. While the complete range of their effects on glia has not been described yet, it is believed that their overall function is to inhibit adverse CNS inflammatory responses, facilitate tissue remodeling and cellular debris removal. This article summarizes the available evidence implicating the following RAMPs in CNS physiological processes and neurodegenerative diseases: cardiolipin (CL), prothymosin α (ProTα), binding immunoglobulin protein (BiP), heat shock protein (HSP) 10, HSP 27, and αB-crystallin. Studies on the molecular mechanisms engaged by RAMPs could identify novel glial targets for development of therapeutic agents that effectively slow down neuroinflammatory disorders including AD.

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Effect of RIP Overexpression on Abiotic Stress Tolerance and Development of Rice

International Journal of Molecular Sciences ◽

10.3390/ijms22031434 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1434

Author(s):

Pieter Wytynck ◽

Jeroen Lambin ◽

Simin Chen ◽

Sinem Demirel Asci ◽

Isabel Verbeke ◽

...

Keyword(s):

Methyl Jasmonate ◽

Stress Responses ◽

Abiotic Stress Tolerance ◽

Protein Translation ◽

Ribosome Inactivating Proteins ◽

Close Proximity ◽

Inhibit Protein Translation ◽

Plant Ribosomes ◽

A Cell ◽

Type 3

Ribosome-inactivating proteins (RIPs) are a class of cytotoxic enzymes that can inhibit protein translation by depurinating rRNA. Most plant RIPs are synthesized with a leader sequence that sequesters the proteins to a cell compartment away from the host ribosomes. However, several rice RIPs lack these signal peptides suggesting they reside in the cytosol in close proximity to the plant ribosomes. This paper aims to elucidate the physiological function of two nucleocytoplasmic RIPs from rice, in particular, the type 1 RIP referred to as OsRIP1 and a presumed type 3 RIP called nuRIP. Transgenic rice lines overexpressing these RIPs were constructed and studied for developmental effects resulting from this overexpression under greenhouse conditions. In addition, the performance of transgenic seedlings in response to drought, salt, abscisic acid and methyl jasmonate treatment was investigated. Results suggest that both RIPs can affect methyl jasmonate mediated stress responses.

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Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis

Oncogene ◽

10.1038/s41388-021-01956-6 ◽

2021 ◽

Author(s):

Satoshi Takagi ◽

Yuki Sasaki ◽

Sumie Koike ◽

Ai Takemoto ◽

Yosuke Seto ◽

...

Keyword(s):

Platelet Activation ◽

Pulmonary Metastasis ◽

Lysophosphatidic Acid ◽

Therapeutic Intervention ◽

Molecular Mechanisms ◽

Morphological Changes ◽

Osteosarcoma Cells ◽

Invasion And Metastasis ◽

Platelet Releasate

AbstractOsteosarcoma is the most common primary malignant bone cancer, with high rates of pulmonary metastasis. Osteosarcoma patients with pulmonary metastasis have worse prognosis than those with localized disease, leading to dramatically reduced survival rates. Therefore, understanding the biological characteristics of metastatic osteosarcoma and the molecular mechanisms of invasion and metastasis of osteosarcoma cells will lead to the development of innovative therapeutic intervention for advanced osteosarcoma. Here, we identified that osteosarcoma cells commonly exhibit high platelet activation-inducing characteristics, and molecules released from activated platelets promote the invasiveness of osteosarcoma cells. Given that heat-denatured platelet releasate maintained the ability to promote osteosarcoma invasion, we focused on heat-tolerant molecules, such as lipid mediators in the platelet releasate. Osteosarcoma-induced platelet activation leads to abundant lysophosphatidic acid (LPA) release. Exposure to LPA or platelet releasate induced morphological changes and increased invasiveness of osteosarcoma cells. By analyzing publicly available transcriptome datasets and our in-house osteosarcoma patient-derived xenograft tumors, we found that LPA receptor 1 (LPAR1) is notably upregulated in osteosarcoma. LPAR1 gene KO in osteosarcoma cells abolished the platelet-mediated osteosarcoma invasion in vitro and the formation of early pulmonary metastatic foci in experimental pulmonary metastasis models. Of note, the pharmacological inhibition of LPAR1 by the orally available LPAR1 antagonist, ONO-7300243, prevented pulmonary metastasis of osteosarcoma in the mouse models. These results indicate that the LPA–LPAR1 axis is essential for the osteosarcoma invasion and metastasis, and targeting LPAR1 would be a promising therapeutic intervention for advanced osteosarcoma.

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Deficiency of Lipin2 Results in Enhanced NF-κB Signaling and Osteoclast Formation in RAW-D Murine Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms22062893 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2893

Author(s):

Asami Watahiki ◽

Seira Hoshikawa ◽

Mitsuki Chiba ◽

Hiroshi Egusa ◽

Satoshi Fukumoto ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Osteoclast Formation ◽

Fine Tuning ◽

Nuclear Accumulation ◽

Innate Immune Responses ◽

Osteoclastic Resorption ◽

Bone Disorder ◽

Proinflammatory Responses ◽

Potential Therapeutic Intervention

Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.

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Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms22020751 ◽

2021 ◽

Vol 22 (2) ◽

pp. 751

Author(s):

Min Young Park ◽

Bala Murali Krishna Vasamsetti ◽

Wan Seop Kim ◽

Hee Jung Kang ◽

Do-Young Kim ◽

...

Keyword(s):

Graft Rejection ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Cardiac Tissue ◽

Inflammatory Responses ◽

Blood Parameters ◽

Quantitative Real Time Pcr ◽

Porcine Heart ◽

End Stage Heart Failure ◽

End Stage

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey’s blood parameters were analyzed on days −7, −3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.

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Histatin-1 Attenuates LPS-Induced Inflammatory Signaling in RAW264.7 Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms22157856 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7856

Author(s):

Sang Min Lee ◽

Kyung-No Son ◽

Dhara Shah ◽

Marwan Ali ◽

Arun Balasubramaniam ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cytokine Production ◽

Inflammatory Responses ◽

Critical Role ◽

Mapk Signaling ◽

Response To Treatment ◽

No Production ◽

Inflammatory Signaling ◽

Raw264.7 Macrophages ◽

Inflammatory Mediator Production

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.

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