Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix ...components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling.
•In poxvirus infection, Gzmb−/− NK cell and CTL homing is impaired•In three inflammatory models, Gzmb−/− cytotoxic lymphocyte homing is impaired•Gzmb−/− CTLs extravasate inefficiently but show no defect in interstitial movement•GzmB facilitates chemokine-driven CTL migration in vitro and cleaves ECM proteins
Granzyme B (GzmB) is a secreted leukocyte protease that has a well-documented role in perforin-mediated killing of abnormal or compromised cells. Prakash and colleagues demonstrate that GzmB also expedites migration of leukocytes across the vascular endothelium by remodeling basement membrane.
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Methamphetamine (METH) is a powerful central nervous system stimulant which elevates mood, alertness, energy levels and concentration in the short-term. However, chronic use and/or at ...higher doses METH use often results in psychosis, depression, delusions and violent behavior. METH was formerly used to treat conditions such as obesity and attention deficit hyperactivity disorder, but now is primarily used recreationally. Its addictive nature has led to METH abuse becoming a global problem. At a cellular level, METH exerts a myriad of effects on the central and peripheral nervous systems, immune system and the gastrointestinal system. Here we present how these effects might be linked and their potential contribution to the pathogenesis of neuropsychiatric disorders. In the long term, this pathway could be targeted therapeutically to protect people from the ill effects of METH use. This model of METH use may also provide insight into how gut, nervous and immune systems might break down in other conditions that may also benefit from therapeutic intervention.
Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the ...microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.
Plant polyphenols have an array of health benefits primarily thought to be related to their high content of anti-oxidants. These are commonly undervalued and knowledge of their biological properties ...have grown exponentially in the last decade. Polyphenol-rich sugarcane extract (PRSE), a natural extract from sugar cane, is marketed as high in anti-oxidants and polyphenols, but its anti-cancer activity has not been reported previously. We show that, PRSE exerts anti-cancer properties on a range of cancer cells including human (LIM2045) and mouse (MC38, CT26) colon cancer cells lines; human lung cancer (A549), human ovarian cancer (SKOV-3), pro-monocytic human leukemia (U937) and to mouse melanoma (B16) cell lines; whereas no effects were noted on human breast (ZR-75-1) and human colon (HT29) cancer cell lines, as well as to human normal colon epithelial cell line (T4056). Anti-proliferative effects were shown to be mediated via alteration in cytokines, VEGF-1 and NF-κB expression.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic inflammation can lead to tumour initiation and progression. Vitamin B complex has the ability to regulate the immune response and, therefore, inflammation but many of the mechanistic and ...molecular processes involved in this regulation are still not fully understood. This study sought to determine some of these processes by studying the effects of vitamin B2 (riboflavin) B6 (pyridoxine) and B9 (folic acid) on un-differentiated pro-monocytic lymphoma cells in regard to their ability to alter the proliferation, migration, apoptosis, cytokines and expression levels of programmed death ligand 1. We show that vitamin B2, B6 and B9, on pro-monocytic lymphoma cells exerted an anti-tumorigenic effect. This data could form the basis for future studies in using vitamin B supplementation to reduce cancer cell growth in vivo.
There are well-characterized age-related differences in behavioral and neural responses to tasks of attentional control. However, there is also increasing recognition of individual variability in the ...process of neurocognitive aging. Using connectome-based predictive modeling, a method for predicting individual-level behaviors from whole-brain functional connectivity, a sustained attention connectome-based prediction model (saCPM) has been derived in young adults. The saCPM consists of two large-scale functional networks: a high-attention network whose strength predicts better attention and a low-attention network whose strength predicts worse attention. Here we examined the generalizability of the saCPM for predicting inhibitory control in an aging sample. Forty-two healthy young adults (n = 21, ages 18–30) and older adults (n = 21, ages 60–80) performed a modified Stroop task, on which older adults exhibited poorer performance, indexed by higher reaction time cost between incongruent and congruent trials. The saCPM generalized to predict reaction time cost across age groups, but did not account for age-related differences in performance. Exploratory analyses were conducted to characterize the effects of age on functional connectivity and behavior. We identified subnetworks of the saCPM that exhibited age-related differences in strength. The strength of two low-attention subnetworks, consisting of frontoparietal, medial frontal, default mode, and motor nodes that were more strongly connected in older adults, mediated the effect of age group on performance. These results support the saCPM's ability to capture attention-related patterns reflected in each individual's functional connectivity signature across both task context and age. However, older and younger adults exhibit functional connectivity differences within components of the saCPM networks, and it is these connections that better account for age-related deficits in attentional control.
Carnosine is a dipeptide molecule (β-alanyl-l-histidine) with anti-inflammatory, antioxidant, anti-glycation, and chelating properties. It is used in exercise physiology as a food supplement to ...increase performance; however, in vitro evidence suggests that carnosine may exhibit anti-cancer properties.
In this study, we investigated the effect of carnosine on breast, ovarian, colon, and leukemic cancer cell proliferation. We further examined U937 promonocytic, human myeloid leukemia cell phenotype, gene expression, and cytokine secretion to determine if these are linked to carnosine's anti-proliferative properties.
Carnosine (1) inhibits breast, ovarian, colon, and leukemic cancer cell proliferation; (2) upregulates expression of pro-inflammatory molecules; (3) modulates cytokine secretion; and (4) alters U937 differentiation and phenotype.
These effects may have implications for a role for carnosine in anti-cancer therapy.
Methamphetamine (METH) is a highly addictive drug abused by millions of users worldwide, thus becoming a global health concern with limited management options. The inefficiency of existing treatment ...methods has driven research into understanding the mechanisms underlying METH-induced disorders and finding effective treatments. This study aims to understand the complex interactions of the gastrointestinal–immune–nervous systems following an acute METH dose administration as one of the potential underlying molecular mechanisms concentrating on the impact of METH abuse on gut permeability. Findings showed a decreased expression of tight junction proteins ZO-1 and EpCAm in intestinal tissue and the presence of FABP-1 in sera of METH treated mice suggests intestinal wall disruption. The increased presence of CD45+ immune cells in the intestinal wall further confirms gut wall inflammation/disruption. In the brain, the expression of inflammatory markers Ccl2, Cxcl1, IL-1β, TMEM119, and the presence of albumin were higher in METH mice compared to shams, suggesting METH-induced blood–brain barrier disruption. In the spleen, cellular and gene changes are also noted. In addition, mice treated with an acute dose of METH showed anxious behavior in dark and light, open field, and elevated maze tests compared to sham controls. The findings on METH-induced inflammation and anxiety may provide opportunities to develop effective treatments for METH addiction in the future.
There is great interest in developing efficient therapeutic cancer vaccines, as this type of therapy allows targeted killing of tumor cells as well as long-lasting immune protection. High levels of ...tumor-infiltrating CD8
T cells are associated with better prognosis in many cancers, and it is expected that new generation vaccines will induce effective production of these cells. Epigenetic mechanisms can promote changes in host immune responses, as well as mediate immune evasion by cancer cells. Here, we focus on epigenetic modifications involved in both vaccine-adjuvant-generated T cell immunity and cancer immune escape mechanisms. We propose that vaccine-adjuvant systems may be utilized to induce beneficial epigenetic modifications and discuss how epigenetic interventions could improve vaccine-based therapies. Additionally, we speculate on how, given the unique nature of individual epigenetic landscapes, epigenetic mapping of cancer progression and specific subsequent immune responses, could be harnessed to tailor therapeutic vaccines to each patient.
Cancer development is often associated with chronic inflammation. To date, research into inflammation-induced cancer has largely focused on chemokines, cytokines, and their downstream targets. These ...inflammatory mediators may promote tumor growth, invasion, metastasis, and facilitate angiogenesis. However, the exact mechanisms by which inflammation promotes neoplasia remain unclear. Inflammatory bowel disease (IBD) is characterized by recurrent, idiopathic intestinal inflammation, the complications of which are potentially fatal. IBD incidence in Australia is 24.2 per 100,000 and its peak onset is in people aged 15 to 24 years. Symptoms include abdominal pain, cramps, bloody stool, and persistent diarrhoea or constipation and so seriously compromise quality of life. However, due to its unknown etiology, current treatment strategies combat the symptoms rather than the disease and are limited by inefficacy, toxicity, and adverse side-effects. IBD is also associated with an increased risk of colorectal cancer, for which treatment options are similarly limited. In recent years, there has been much interest in the therapeutic potential of mesenchymal stem cells (MSCs). However, whether MSCs suppress or promote tumor development is still contentious within the literature. Many studies indicate that MSCs exert anti-tumor effects and suppress tumor growth, whereas other studies report pro-tumor effects. Studies using MSCs as treatment for IBD have shown promising results in both animal models and human trials. However, as MSC treatment is still novel, the long-term risks remain unknown. This review aims to summarize the current literature on MSC treatment of inflammation-induced cancer, with a focus on colorectal cancer resulting from IBD.
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