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PubMed2002

Sensory neurone responses to mucosal noxae in the upper gut: relevance to mucosal integrity and gastrointestinal pain.

The digestive tract is supplied by extrinsic and intrinsic sensory neurones that, together with endocrine and immune cells, form a surveillance network that is essential to gut function. This article focuses on the responses of extrinsic afferent neurones to chemical insults of the gastrointestinal mucosa and their pathophysiological relevance to mucosal integrity and abdominal pain. Within the gastroduodenal region, spinal afferents subserve an emergency function because, in case of alarm by influxing acid, they stimulate mechanisms of mucosal protection via an efferent-like release of transmitters. Other sensory neurones signal chemical noxae to the brain, a task that is not confined to spinal afferents because vagal afferents communicate gastric acid and peripheral immune challenges to the brainstem and in this way elicit autonomic, endocrine, affective and behavioural reactions. Emerging evidence indicates that hypersensitivity of extrinsic afferent pathways to mechanical and chemical stimuli makes an important contribution to the abdominal hyperalgesia seen in functional dyspepsia and irritable bowel syndrome. Sensitization may be brought about by inflammatory processes that lead to up-regulation and functional alterations of receptors and ion channels on sensory neurones. Such sensory neurone-specific molecules, which include vanilloid (capsaicin) receptors, may represent important targets for novel drugs to treat abdominal pain.

Animals↗

PubMed2004

BOK and NOXA are essential mediators of p53-dependent apoptosis.

Cellular stress leads to DNA damage and activation of the intrinsic apoptotic pathway in which translocation of mitochondrial cytochrome c to the cytosol plays a critical role. Previous studies have suggested alternative mechanisms responsible for this process. We examined initiation mechanisms of the intrinsic apoptotic pathway using human neuroblastoma and breast cancer cells. Results indicated that translocation of cytochrome c does not require prior activation of caspases but rather depends on activation of specific BCL-2 family members, depending upon the type of death signal. Thus, DNA damage-induced apoptosis requires new protein synthesis, accumulation of p53 tumor suppressor protein, and p53-dependent induction of BOK and NOXA genes, while a role for BAX in this pathway is not essential. In contrast, apoptosis induced by staurosporine does not require protein synthesis but is characterized by translocation of BAX. Based on these findings, we propose a model of the intrinsic apoptotic cascade induced by DNA damage where proapoptotic BOK substitutes for a function of BAX.

Apoptosis↗

PubMed2007

The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to conventional chemotherapy. The Bcl-2 pathway is deregulated in these tumors and may represent an interesting target for new therapeutic strategies. The new small-molecule pan-Bcl-2 inhibitor GX15-070 mimics BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members. Here we show that GX15-070 induced apoptosis in vitro in MCL cell lines and primary cells from patients with MCL by releasing Bak from Mcl-1 and Bcl-X(L) at short incubation times and low micromolar doses. GX15-070 was effective in cells bearing defective DNA damage-sensor genes or cell-cycle regulators, inducing Bax and Bak conformational changes, mitochondrial depolarization, phosphatidylserine exposure, and caspase-3 activation. Furthermore, GX15-070 synergized with bortezomib, sensitizing MCL cells to low doses of this proteasome inhibitor, by neutralizing bortezomib-induced Mcl-1 accumulation and cooperating with Noxa to induce Bak displacement from this protein. These events led to an increased activation of the mitochondrial apoptotic pathway. Importantly, GX15-070 alone or in combination with bortezomib showed no significant cytotoxic effect in peripheral blood mononuclear cells from healthy donors. All these findings suggest that GX15-070 alone or in combination with bortezomib represents a new attractive therapeutic approach for MCL treatment.

Antineoplastic Agents↗

PubMed1992

[The effect of occupational noxae in the tobacco industry on pulmonary function in exposed workers].

A study was carried out to determine respiratory hazards to workers in tobacco manufacture. The investigations at the workplace included analysis of the work technology and measurements of chemical pollutants and dust concentrations in the work rooms. Ventilatory lung function tests were performed in 95 workers exposed to tobacco dust and in 129 control workers. Results of workplace analysis showed the presence of tobacco dust levels exceeding the maximum permissible concentrations. The values of some lung function tests for exposed workers non-smokers were significantly lower than for control workers non-smokers. They could be attributed to the effect of occupational noxae on the respiratory system.

Adult↗

PubMed2003

Carcinogenesis and chemotherapy viewed from the perspective of stoichiometric network analysis (SNA): what can the biological system of the elements contribute to an understanding of tumour induction by elemental chemical noxae (e.g., Ni2+ , Cd2+ ) and to an understanding of chemotherapy?

The biological application of stoichiometric network analysis (SNA) permits an understanding of tumour induction, carcinogenesis, and chemotherapy. Starting from the Biological System of the Elements, which provides a comprehensive treatment of the functions and distributions of chemical (trace) elements in biology, an attempt is made to interrelate the essential feature of biology and--regrettably--of tumour genesis by superimposing SNA reasoning on common features of all crucial biological processes. For this purpose, aspects, effects and drawbacks of autocatalysis (identical reproduction which can occur either under control or without control [in tumours]) are linked with the known facts about element distributions in living beings and about interference of metals with tumours (in terms of both chemotherapy and carcinogenesis). The essential role of autocatalysis in biology and the drawbacks of either controlled or spontaneous cell division can be used to understand crucial aspects of carcinogenesis and chemotherapy because SNA describes and predicts effects of autocatalysis, including phase effects that may be due to some kind of intervention. The SNA-based classifications of autocatalytic networks in cell biology are outlined here to identify new approaches to chemotherapy.

Cadmium↗

PubMed1955