An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells.

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility.

Histamine H- and H-receptor expression in human colon-derived cell lines.

In previous studies, we demonstrated the involvement of HR in inflammatory bowel disease (IBD) and IBD-associated colon cancer in mice and could ascribe HR-mediated histamine function to colon epithelial cells. The transferability of obtained data to humans is however lacking. Functional expression of HR on colon epithelial cells is a prerequisite to pursue the hypothesis of involvement of HR in carcinogenesis.

Report of the 24th Meeting on Signal Transduction 2021.

The annual meeting "Signal Transduction-Receptors, Mediators and Genes" of the Signal Transduction Society (STS) is an interdisciplinary conference which is open to all scientists sharing a common interest in the elucidation of the signaling pathways mediating physiological or pathological processes in the health and disease of humans, animals, plants, fungi, prokaryotes, and protists. The 24th meeting on signal transduction was held from 15 to 17 November 2021 in Weimar, Germany. As usual, keynote presentations by invited scientists introduced the respective workshops, and were followed by speakers chosen from the submitted abstracts.

cCMP and cUMP come into the spotlight, finally.

cCMP and cUMP have been identified in numerous biological systems and proposed to serve as second messengers. However, this proposal remained controversial because of the base-promiscuity of generators, effectors, phosphodiesterases, and bacterial toxins. With the identification of specific cytidylyl and uridylyl cyclases, cCMP and cUMP research enters a new era.

Problems associated with the use of the term "antibiotics".

The term "antibiotics" is a broadly used misnomer to designate antibacterial drugs. In a recent article, we have proposed to replace, e.g.

The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut.

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (HR) antagonists, which are used to control allergic inflammation, antagonists at HR, which therapeutically decrease gastric acid release, and an antagonist at HR, which is indicated to treat narcolepsy.

A case to stop the use of the term 'antibiotics'.

The word 'antibiotics' is an historical, but imprecise, term. Today, 'antibiotics' are also used for other indications and 'non-antibiotics' are repurposed for infectious diseases. This situation calls for a revision of antipathogenic drug terminology.

A simple mechanistic terminology of psychoactive drugs: a proposal.

Antidepressants, antiepileptics, mood stabilizers, and antipsychotics are extremely broadly used psychoactive drugs. These drug terms are universally used in the literature. However, the indications of these drugs have broadened substantially and overlap.

Report of the 23rd Meeting on Signal Transduction 2019-Trends in Cancer and Infection.

The annual meeting "Signal Transduction-Receptors, Mediators and Genes" of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating the signalling pathways underlying the physiological or pathological processes in health and disease of humans, animals, plants, fungi, prokaryotes and protists. The 23rd meeting on signal transduction was held from 4-6 November 2019 in Weimar, Germany, and focused on "Trends in Cancer and Infection". As usual, keynote presentations by invited scientists introduced the respective workshops and were followed by speakers chosen from the submitted abstracts.

Genetic Deficiency of the Histamine H-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice.

Colorectal cancer (CRC), a severe complication of inflammatory bowel diseases, is a common type of cancer and accounts for high mortality. CRC can be modeled in mice by application of the tumor promoter, azoxymethane (AOM), in combination with dextran sodium sulfate (DSS), which are able to induce colitis-like manifestations. Active colitis correlates with high mucosal concentrations of histamine, which, together with the histamine receptor subtype 4 (HR), provide a pro-inflammatory function in a mouse colitis model.

Mouse Colonic Epithelial Cells Functionally Express the Histamine H Receptor.

We hypothesized that, in mice, histamine via the histamine receptor subtype 4 (HR) on colon epithelial cells affects epithelial barrier integrity, perturbing physiologic function of the colonic mucosa and thus aggravating the severity of colitis. To test this hypothesis, bone marrow-chimeric mice were generated from HR knockout (HR) and wild-type (WT) BALB/cJ mice and subjected to the dextrane sodium sulfate (DSS)-induced acute colitis model. Clinical symptoms and pathohistological derangements were scored.

Report of the Signal Transduction Society Meeting 2018-Signaling: From Past to Future.

The annual meeting "Signal Transduction-Receptors, Mediators, and Genes" of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating signaling pathways in physiological or pathological processes in humans, animals, plants, fungi, prokaryotes, and protists. On the occasion of the 20th anniversary of the STS, the 22nd joint meeting took place in Weimar from 5⁻7 November 2018. With the focus topic "Signaling: From Past to Future" the evolution of the multifaceted research concerning signal transduction since foundation of the society was highlighted.

Evidence for Partial Activation of Eosinophils via the Histamine H-Receptor: Adoptive Transfer Experiments Using Eosinophils From HR and HR Mice.

Our previous studies revealed that histamine via histamine the H-receptors (HR), as compared to other stimuli, such as eotaxin or formylpeptides, rather partially activates eosinophilic granulocytes (eosinophils). In order to evaluate the HR-mediated activation of eosinophils , we employed dextran sodium sulfate (DSS)-induced colitis in mice, closely resembling human ulcerative colitis (UC), which is largely characterized by a local eosinophilic infiltration of the colon. IL-5-deficient BALB/c mice served as a model with reduced endogenous numbers of eosinophils, in which wild-type (HR) or HR-deficient (HR) eosinophils were adoptively transferred during the course of DSS-induced colitis.

The Role of ExoY in an Acute Mouse Lung Infection Model.

The effector protein Exotoxin Y (ExoY) produced by is injected via the type III secretion system (T3SS) into host cells. ExoY acts as nucleotidyl cyclase promoting the intracellular accumulation of cyclic nucleotides. To what extent nucleotidyl cyclase activity contributes to the pathogenicity of ExoY and which mechanisms participate in the manifestation of lung infection is still unclear.

Report of the Signal Transduction Society Meeting 2017-Metabolism in Health and Disease.

The annual "Joint Meeting Signal Transduction-Receptors, Mediators and Genes" of the Signal Transduction Society (STS) aims to be an interdisciplinary forum for researchers who share a common interest in deciphering signal transduction pathways in normal or transformed cells, in health and disease, in humans and animal models, or in plants or bacteria. The special focus of the 21st annual Joint Meeting, which took place from 8-10 November 2017 in Weimar, was the topic "Metabolism in Health and Disease" and covered multiple aspects of this highly exciting and fast developing research field. Invited keynote speakers introduced the impact of metabolism on tumor immunology, immune cell signaling, and posttranslational modifications in three specific workshops to the audience.

The ExoY phenotype of high-copy-number recombinants is not detectable in natural isolates.

The nucleotidyl cyclase ExoY is an effector protein of the type III secretion system of We compared the cyclic nucleotide production and lung disease phenotypes caused by the ExoY-overexpressing strain PA103Δ pUCP, its vector control strain PA103Δ pUCP18, its loss-of-function control PA103Δ pUCP K81M and natural ExoY-positive and ExoY-negative isolates in a murine acute airway infection model. Only the carrier of the plasmid produced high levels of cUMP and caused the most severe course of infection. The pathology ascribed to ExoY from studies using the high-copy-number plasmid on mammalian cells and was not observed with natural isolates.

Lack of Histamine H-Receptor Expression Aggravates TNBS-Induced Acute Colitis Symptoms in Mice.

Inflammatory bowel diseases (IBD) are a growing health problem worldwide, severely affecting patients' life qualities and life expectancies. Therapeutic options, which are rare and focus on symptoms associated with the disease, suffer from increasing numbers of patients refractory to the established strategies. Thus, in order to generate new therapeutic regimens, the detailed understanding of the pathogenic mechanisms causing IBD is necessary.

Deletion of IL-18 Expression Ameliorates Spontaneous Kidney Failure in MRLlpr Mice.

The role of IL-18 in the pathogenesis of systemic lupus erythematosus is still not definitively solved. In this study, we generated MRLlpr mice, which develop a disease resembling systemic lupus erythematosus, genetically devoid of IL-18 expression. These mice in comparison to IL-18-competent MRLlpr mice show reduced signs of renal pathogenesis, while other parameters such as mean survival time, lymphadenopathy, constitutive interferon-γ production, and frequency of CD3+B220+ abnormal T cells were without differences.

Proinflammatory role of the histamine H4 receptor in dextrane sodium sulfate-induced acute colitis.

Millions of people worldwide are suffering from inflammatory bowel disease (IBD), which severely affects patients' life qualities and even life expectancies. The cause of the ailment is unknown and a profound understanding of the underlying pathogenetic mechanisms is still lacking. The biogenic amine histamine is one of several inflammatory mediators, to which a pathogenetic role in IBD has been attributed.

cCMP and cUMP occur in vivo.

Mammalian cells contain the cyclic pyrimidine nucleotides cCMP and cUMP. It is unknown whether these tentative new second messenger molecules occur in vivo. We used high performance liquid chromatography quadrupole tandem mass spectrometry to quantitate nucleoside 3',5'-cyclic monophosphates.

Protective effects of finasteride on the pulmonary immune response in a combined model of trauma-hemorrhage and polymicrobial sepsis in mice.

Unlabelled: Literature supports findings about a gender specific outcome following multiple trauma. Male sex hormones such as dihydrotestosterone (DHT) exert deleterious effects on the posttraumatic immune response whereas increased estradiol concentrations are correlated with improved outcome. Pretreatment with the 5α-reductase inhibitor finasteride resulted in an improved outcome following trauma-hemorrhage (TH) in mice.