Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis

Abstract Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting.

Download Full-text

Role of inflammation in the development of colorectal cancer

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200909092908 ◽

2020 ◽

Vol 20 ◽

Author(s):

Sridhar Muthusami ◽

R. Ileng Kumaran ◽

Kokelavani Nampalli Babu ◽

Sneha Krishnamoorthy ◽

Akash Guruswamy ◽

...

Keyword(s):

Colorectal Cancer ◽

Chronic Inflammation ◽

Interleukin 1 ◽

Cell Types ◽

Model Systems ◽

Cytokine Gene Expression ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Proinflammatory Molecules

: Chronic inflammation can lead to the development of many diseases including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation together with genetic and epigenetic changes has been shown to lead to the development and progression of CRC. Various cell types present in the colon such as enterocytes, Paneth cells, goblet cells and macrophages express receptors for inflammatory cytokines and respond to tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6 and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key proinflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of proinflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy), to alleviate the symptoms or treat inflammationassociated CRC by using monoclonal antibodies or aptamers to block proinflammatory molecules, inhibitors of tyrosine kinases in inflammatory signaling cascade, competitive inhibitors of proinflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/proinflammatory cytokine gene expression.

Download Full-text

Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

Communications Biology ◽

10.1038/s42003-021-02188-w ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Bastiaan van der Veen ◽

Sampath K. T. Kapanaiah ◽

Kasyoka Kilonzo ◽

Peter Steele-Perkins ◽

Martin M. Jendryka ◽

...

Keyword(s):

Gene Expression ◽

Anterior Cingulate Cortex ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Pyramidal Neurons ◽

Treatment Options ◽

Pyramidal Cells ◽

Cingulate Cortex ◽

Cell Types ◽

Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

Download Full-text

Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms22147536 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7536

Author(s):

Inez Wens ◽

Ibo Janssens ◽

Judith Derdelinckx ◽

Megha Meena ◽

Barbara Willekens ◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Diseases ◽

Stromal Cells ◽

Mononuclear Cells ◽

Treatment Options ◽

Cell Types ◽

Peripheral Blood Mononuclear ◽

Tailored Treatment ◽

Key Issues ◽

The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

Download Full-text

Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging

International Journal of Molecular Sciences ◽

10.3390/ijms22052238 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2238

Author(s):

Nao Nagai ◽

Yotaro Kudo ◽

Daisuke Aki ◽

Hayato Nakagawa ◽

Koji Taniguchi

Keyword(s):

Colorectal Cancer ◽

Chronic Inflammation ◽

Antitumor Immunity ◽

Suppressor Cells ◽

Treg Cells ◽

Cytotoxic T Cell ◽

Myeloid Derived Suppressor Cells ◽

Pro Inflammatory Cytokines

Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.

Download Full-text

Therapeutic strategy of central vein perforation accompanied by a mediastinal lesion after catheterization

Journal of International Medical Research ◽

10.1177/0300060519843686 ◽

2019 ◽

Vol 47 (6) ◽

pp. 2702-2708

Author(s):

Chi-Chang Li ◽

Wei Zhang ◽

Xing-Jie Wu ◽

Yang Bu ◽

Zhi-Peng Zheng

Keyword(s):

Therapeutic Strategy ◽

Rare Complication ◽

Treatment Options ◽

Central Vein ◽

Computed Tomographic ◽

Percutaneous Catheter ◽

Multidisciplinary Consultation ◽

Vein Injury ◽

Double Channel

Central vein perforation associated with a mediastinal lesion is a rare complication of catheterization. A 50-year-old woman was diagnosed with chronic kidney disease and required hemodialysis treatment. The patient developed central vein injury during attempted placement of a double-channel catheter. A computed tomographic scan and venography showed that the catheter had punctured the mediastinum from the central vein. After comprehensive assessment and multidisciplinary consultation, percutaneous catheter thrombin injection with follow-up balloon dilatation under fluoroscopy guidance successfully fixed the perforation. We summarize the therapeutic strategy of this complication and other treatment options, and discuss the related literature of central vein injury.

Download Full-text

Cellular and molecular mechanisms of statins: an update on pleiotropic effects

Clinical Science ◽

10.1042/cs20150027 ◽

2015 ◽

Vol 129 (2) ◽

pp. 93-105 ◽

Cited By ~ 54

Author(s):

Mamoru Satoh ◽

Yuji Takahashi ◽

Tsuyoshi Tabuchi ◽

Yoshitaka Minami ◽

Makiko Tamada ◽

...

Keyword(s):

Coronary Artery ◽

Chronic Inflammation ◽

Molecular Mechanism ◽

Coronary Atherosclerosis ◽

Molecular Mechanisms ◽

Cell Injury ◽

Plaque Instability ◽

Beneficial Effects ◽

Reductase Inhibitors ◽

Artery Disease

Coronary artery disease (CAD) is the leading cause of death worldwide. The efficacy and safety of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) in primary and secondary prevention of CAD are confirmed in several large studies. It is well known that statins have some pleiotropic, anti-atherosclerotic effects. We review the molecular mechanisms underlying the beneficial effects of statins revealed in recently published studies. Endothelial cell injury is regarded as the classic stimulus for the development of atherosclerotic lesions. In addition, the inflammatory process plays an important role in the aetiology of atherosclerosis. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Our previous reports and others have demonstrated beneficial effects of statins on endothelial dysfunction and chronic inflammation in CAD. A better understanding of the molecular mechanism underlying the effectiveness of statins against atherosclerosis may provide a novel therapeutic agent for the treatment of coronary atherosclerosis. The present review summarizes the cellular and molecular mechanism of statins against coronary atherosclerosis.

Download Full-text

Bromodomain protein inhibition: a novel therapeutic strategy in rheumatic diseases

RMD Open ◽

10.1136/rmdopen-2018-000744 ◽

2018 ◽

Vol 4 (2) ◽

pp. e000744 ◽

Cited By ~ 17

Author(s):

Kerstin Klein

Keyword(s):

Animal Models ◽

Rheumatic Diseases ◽

Transcriptional Activation ◽

Therapeutic Strategy ◽

Cell Types ◽

Protein Inhibition ◽

Different Cell Types ◽

Novel Therapeutic

The reading of acetylation marks on histones by bromodomain (BRD) proteins is a key event in transcriptional activation. Small molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins compete for binding to acetylated histones. They have strong anti-inflammatory properties and exhibit encouraging effects in different cell types in vitro and in animal models resembling rheumatic diseases in vivo. Furthermore, recent studies that focus on BRD proteins beyond BET family members are discussed.

Download Full-text

PERIOPERATIVE CHEMOTHERAPY IN LOCALLY ADVANCED GASTRIC CANCER

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032013000200042 ◽

2013 ◽

Vol 50 (3) ◽

pp. 236-242 ◽

Cited By ~ 5

Author(s):

Thales Paulo BATISTA ◽

Candice Amorim de Araujo Lima SANTOS ◽

Gustavo Fernandes Godoy ALMEIDA

Keyword(s):

Gastric Cancer ◽

Therapeutic Strategy ◽

Multimodal Therapy ◽

Standard Treatment ◽

Treatment Options ◽

Locally Advanced ◽

Special Focus ◽

Perioperative Chemotherapy ◽

Locally Advanced Gastric Cancer ◽

Advanced Stages

Gastric cancer is one of the most common cancers and a main cause of cancer-related death worldwide, since the majority of patients suffering of this malignancy are usually faced with a poor prognosis due to diagnosis at later stages. In order to improve treatment outcomes, the association of surgery with chemo and/or radiotherapy (multimodal therapy) has become the standard treatment for locally advanced stages. However, despite several treatment options currently available for management of these tumors, perioperative chemotherapy has been mainly accepted for the comprehensive therapeutic strategy including an appropriated D2-gastrectomy. This manuscript presents a (nonsystematic) critical review about the use of perioperative chemotherapy, with a special focus on the drugs delivery.

Download Full-text

Emerging Role of Immune Therapy in HCC

Digestive Disease Interventions ◽

10.1055/s-0041-1722932 ◽

2021 ◽

Author(s):

Stacey M. Stein

Keyword(s):

Kinase Inhibitors ◽

Immune Therapy ◽

Treatment Options ◽

Single Agent ◽

Small Subset ◽

Vascular Endothelial ◽

Number Of Patients ◽

Endothelial Growth Factor ◽

Expected Increase

AbstractHepatocellular carcinoma (HCC) remains a prevalent cancer diagnosis with an expected increase in incidence in the next decade. Treatment options for advanced disease have expanded significantly in the last decade since sorafenib was first approved in 2007. There have been approvals for multiple tyrosine kinase inhibitors (TKIs) with modest improvements in survival. Single-agent PD-1 inhibition has shown responses in ∼15% of patients, with a tail of the curve that is very beneficial to a small subset of patients. Most recently, studies of combination therapy with immune therapy drugs are showing more durable responses in a larger number of patients with unprecedented response rates over 30%. Different strategies have been pursued, including PD-1 and PD-L1 combinations with vascular endothelial growth factor inhibition, TKIs, and anti-CTLA-4 antibodies. This article provides a review of studies both completed and ongoing with immune therapy in advanced HCC.

Download Full-text

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

4open ◽

10.1051/fopen/2018009 ◽

2019 ◽

Vol 2 ◽

pp. 11 ◽

Cited By ~ 4

Author(s):

Björn L.D.M. Brücher ◽

Ijaz S. Jamall

Keyword(s):

Extracellular Matrix ◽

Chronic Inflammation ◽

Genetic Material ◽

Cell Communication ◽

Cell Types ◽

Complex Signaling ◽

Different Cell Types ◽

Multiple Signaling ◽

Extracellular Environment

Fibroblasts are actively involved in the creation of the stroma and the extracellular matrix which are important for cell adhesion, cell–cell communication, and tissue metabolism. The role of fibrosis in carcinogenesis can be examined by analogy to tissues of various cancers. The orchestration of letters in the interplay of manifold components with signaling and crosstalk is incompletely understood but available evidence suggests a hitherto underappreciated role for fibrosis in carcinogenesis. Complex signaling and crosstalk by pathogenic stimuli evoke persistent subclinical inflammation, which in turn, results in a cascade of different cell types, ubiquitous proteins and their corresponding enzymes, cytokine releases, and multiple signaling pathways promoting the onset of fibrosis. There is considerable evidence that the body's attempt to resolve such a modified extracellular environment leads to further disruption of homeostasis and the genesis of the precancerous niche as part of the six-step process that describes carcinogenesis. The precancerous niche is formed and can be understood to develop as a result of (1) pathogenic stimulus, (2) chronic inflammation, and (3) fibrosis with alterations of the extracellular matrix, stromal rigidity, and mechano-transduction. This is why carcinogenesis is not just a process of aberrant cell growth with damaged genetic material but the role of the PCN in its entirety reveals how carcinogenesis can occur without invoking the need for somatic mutations.

Download Full-text