Carbon Ion Irradiation Activates Anti-Cancer Immunity.

Carbon ion beams have the unique property of higher linear energy transfer, which causes clustered damage of DNA, impacting the cell repair system. This sometimes triggers apoptosis and the release in the cytoplasm of damaged DNA, leading to type I interferon (IFN) secretion via the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Dendritic cells phagocytize dead cancer cells and damaged DNA derived from injured cancer cells, which together activate dendritic cells to present cancer-derived antigens to antigen-specific T cells in the lymph nodes.

Autophagy Inhibition Increased Sensitivity of Pancreatic Cancer Cells to Carbon Ion Radiotherapy.

Background/aims: Pancreatic cancer has the poorest survival rate among all cancer types. Therefore, it is essential to develop an effective treatment strategy for this cancer.

Methods: We performed carbon ion radiotherapy (CIRT) in human pancreatic cancer cell lines and analyzed their survival, apoptosis, necrosis, and autophagy.

Antithrombin Together with NETs Inhibitor Protected Against Postoperative Adhesion Formation in Mice.

Background/aims: Postoperative adhesions may induce adverse outcomes in patients. Adhesion formation is initiated by fibrin accumulation at the surgical site which is followed by local neutrophilia and the establishment of neutrophil extracellular traps (NET). Previous reports have suggested that the preventive efficacy of reagents designed to reduce postoperative adhesion is inversely correlated with neutrophilia and NET production.

Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle.

Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression.

Blockade of Tumor Necrosis Factor by Etanercept Prevents Postoperative Adhesion Formation in Mice.

Background/aims: Although adhesion formation is a frequent adverse event following intraperitoneal surgery, efficient prophylactic interventions have not yet been established. We recently reported that blockade of interleukin (IL)-6 prevented postoperative adhesion after cecum cauterization. Intriguingly, this intervention dampened tumor necrosis factor (TNF) induction in the injured serosa.

Anti-interleukin-6 receptor antibody treatment ameliorates postoperative adhesion formation.

Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer. Previously we demonstrated that interferon-γ-promoted fibrin deposition drove postoperative adhesion formation. However, its underlying cellular and molecular mechanisms remain poorly understood.

ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism.

It is widely accepted that inflammasomes protect the host from microbial pathogens by inducing inflammatory responses through caspase-1 activation. Here, we show that the inflammasome components ASC and NLRP3 are required for resistance to pneumococcal pneumonia, whereas caspase-1 and caspase-11 are dispensable. In the lung of S.

Interleukin-18 in Health and Disease.

Interleukin (IL)-18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells, especially in the presence of IL-12. Upon stimulation with Ag plus IL-12, naïve T cells develop into IL-18 receptor (IL-18R) expressing Th1 cells, which increase IFN-γ production in response to IL-18 stimulation. Therefore, IL-12 is a commitment factor that induces the development of Th1 cells.

The Effect of Daikenchuto, Japanese Herbal Medicine, on Adhesion Formation Induced by Cecum Cauterization and Cecum Abrasion in Mice.

Daikenchuto (DKT) has been widely used for the treatment of postsurgical ileus in Japan. However, its effect on postsurgical adhesion formation has been obscure. In this study, the effect of DKT on postsurgical adhesion formation induced by cecum cauterization or cecum abrasion in mice was investigated.

Caffeine-stimulated muscle IL-6 mediates alleviation of non-alcoholic fatty liver disease.

Caffeine intake is associated with a reduced risk developing non-alcoholic fatty liver disease (NAFLD), but the underlying molecular mechanisms remain to be fully elucidated. We report here that caffeine markedly improved high fat diet-induced NAFLD in mice resulting in a 10-fold increase in circulating IL-6 levels, leading to STAT3 activation in the liver. Interestingly, the expression of IL-6 mRNA was not increased in the liver, but increased substantially in the muscles of caffeine-treated mice.

Immunohistochemical characterization of cancer-associated fibroblasts at the primary sites and in the metastatic lymph nodes of human intrahepatic cholangiocarcinoma.

Cancer-associated fibroblasts (CAFs) are an important constituent of the cancer stroma. In intrahepatic cholangiocarcinoma (ICC), the features of CAFs at the primary site and in the metastatic lymph nodes (Met-LNs) and their origin have been unclear. In the present study, we characterized CAFs at the primary site (n = 42) and in the Met-LNs (n = 10) of human ICC by immunohistochemistry using potential molecular markers of CAFs, portal fibroblasts (PFs), hepatic stellate cells (HSCs), and bone marrow-derived fibrocytes (BMDFs).

Inflammasome and Fas-Mediated IL-1β Contributes to Th17/Th1 Cell Induction in Pathogenic Bacterial Infection In Vivo.

CD4 Th cells play crucial roles in orchestrating immune responses against pathogenic microbes, after differentiating into effector subsets. Recent research has revealed the importance of IFN-γ and IL-17 double-producing CD4 Th cells, termed Th17/Th1 cells, in the induction of autoimmune and inflammatory diseases. In addition, Th17/Th1 cells are involved in the regulation of infection caused by the intracellular bacterium in humans.

Effect of Helicobacter pylori infection on the link between GLP-1 expression and motility of the gastrointestinal tract.

Background: Although Helicobacter pylori (H. pylori) infection is closely associated with the development of peptic ulcer, its involvement in pathophysiology in the lower intestinal tract and gastrointestinal (GI) motility remains unclear. Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the lower intestinal tract and involved in GI motility.

Pu'erh tea extract-mediated protection against hepatosteatosis and insulin resistance in mice with diet-induced obesity is associated with the induction of de novo lipogenesis in visceral adipose tissue.

Background: White adipose tissue (WAT) is important for the maintenance of metabolic homeostasis, and metabolic syndrome is sometimes associated with WAT dysfunction in humans and animals. WAT reportedly plays a key, beneficial role in the maintenance of glucose and lipid homeostasis during de novo lipogenesis (DNL). Pu'erh tea extract (PTE) can inhibit harmful, ectopic DNL in the liver, thus protecting against hepatosteatosis, in mice with diet-induced obesity.

Caspase-1 deficiency promotes high-fat diet-induced adipose tissue inflammation and the development of obesity.

Caspase-1 is a cysteine protease responsible for the processing of the proinflammatory cytokine interleukin-1β and activated by the formation of inflammasome complexes. Although several investigations have found a link between diet-induced obesity and caspase-1, the relationship remains controversial. Here, we found that mice deficient in caspase-1 were susceptible to high-fat diet-induced obesity with increased adiposity as well as normal lipid and glucose metabolism.

Pu-erh tea extract ameliorates high-fat diet-induced nonalcoholic steatohepatitis and insulin resistance by modulating hepatic IL-6/STAT3 signaling in mice.

Background: Pu-erh tea, made from the leaves of Camellia sinensis, possesses activities beneficial for human health, including anti-inflammatory, anti-oxidant, and anti-obesity properties.

Objective: We investigated the effects of a pu-erh tea extract (PTE) on nonalcoholic steatohepatitis (NASH) and the molecular mechanisms underlying such effects.

Methods: Eight-week-old male C57BL/6J mice were fed a normal chow diet or high-fat diet (HFD) for 17 weeks, during which PTE was simultaneously administered in drinking water.

Interleukin-1 Family Cytokines in Liver Diseases.

The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases.

Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm.

Objective: Abdominal aortic aneurysm (AAA) is considered a chronic inflammatory disease; however, the molecular basis underlying the sterile inflammatory response involved in the process of AAA remains unclear. We previously showed that the inflammasome, which regulates the caspase-1-dependent interleukin-1β production, mediates the sterile cardiovascular inflammatory responses. Therefore, we hypothesized that the inflammasome is a key mediator of initial inflammation in AAA formation.

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages.

When nucleotide-binding oligomerization domain-like receptors (NLRs) sense cytosolic-invading bacteria, they induce the formation of inflammasomes and initiate an innate immune response. In quiescent cells, inflammasome activity is tightly regulated to prevent excess inflammation and cell death. Many bacterial pathogens provoke inflammasome activity and induce inflammatory responses, including cell death, by delivering type III secreted effectors, the rod component flagellin, and toxins.

Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin.

It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages.

Caspases as the key effectors of inflammatory responses against bacterial infection.

Caspase cysteine proteases are factors widely recognized for their role in the induction of apoptotic cell death. Caspases induce apoptosis during the inflammatory response to pathogen infection; in addition, caspases such as caspase-1 and caspase-11 are known to be involved in the production of inflammatory cytokines in response to bacterial infections. Caspase-1 is activated in the inflammasome, an intracellular protein complex that is formed by the recognition of intracellular ligands or cellular stresses by sensor molecules such as NOD-like receptors.

Pu-erh tea extract induces the degradation of FET family proteins involved in the pathogenesis of amyotrophic lateral sclerosis.

FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available.

Importance of Kupffer cells in the development of acute liver injuries in mice.

Kupffer cells reside within the liver sinusoid and serve as gatekeepers. They produce pro- and anti-inflammatory cytokines and other biologically important molecules upon the engagement of pattern recognition receptors such as Toll-like receptors. Kupffer cell-ablated mice established by in vivo treatment with clodronate liposomes have revealed many important features of Kupffer cells.

NLRP3 regulates neutrophil functions and contributes to hepatic ischemia-reperfusion injury independently of inflammasomes.

Inflammation plays a key role in the pathophysiology of hepatic ischemia-reperfusion (I/R) injury. However, the mechanism by which hepatic I/R induces inflammatory responses remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by I/R is mediated through a multiple-protein complex called the inflammasome.

Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective interferon-β.

The small intestine harbors a substantial number of commensal bacteria and is sporadically invaded by pathogens, but the response to these microorganisms is fundamentally different. We identified a discriminatory sensor by using Toll-like receptor 3 (TLR3). Double-stranded RNA (dsRNA) of one major commensal species, lactic acid bacteria (LAB), triggered interferon-β (IFN-β) production, which protected mice from experimental colitis.