Introduction The stress response is different in various individuals, however, the mechanisms that could explain these distinct effects are not well known and the molecular correlates have been considered one at the time. Particular harmful conditions occur if the subject, instead to cope the stressful events, succumb to them, in this case, a cascade reaction happens that through different signaling causes a specific reaction named “sickness behaviour.” The aim of this article is to review the complex relations among important molecules belonging to Central nervous system (CNS), immune system (IS), and endocrine system (ES) during the chronic stress response. Methods After having verified the state of art concerning the function of cortisol, norepinephrine (NE), interleukin (IL)‐1β and melatonin, we describe as they work together. Results We propose a speculative hypothesis concerning the complex interplay of these signaling molecules during chronic stress, highlighting the role of IL‐1β as main biomarker of this effects, indeed, during chronic stress its increment transforms this inflammatory signal into a nervous signal (NE), in turn, this uses the ES (melatonin and cortisol) to counterbalance again IL‐1β. During cortisol resistance, a vicious loop occurs that increments all mediators, unbalancing IS, ES, and CNS networks. This IL‐1β increase would occur above all when the individual succumbs to stressful events, showing the Sickness Behaviour Symptoms. IL‐1β might, through melatonin and vice versa, determine sleep disorders too. Conclusion The molecular links here outlined could explain how stress plays a role in etiopathogenesis of several diseases through this complex interplay.
If occupational tumors are excluded, cancer causes are largely unknown. Therefore, it appeared useful to work out a theory explaining the complexity of this disease. More than fifty years ago the first demonstration that cells communicate with each other by exchanging ions or small molecules through the participation of connexins (Cxs) forming Gap Junctions (GJs) occurred. Then the involvement of GJ Intercellular Communication (GJIC) in numerous physiological cellular functions, especially in proliferation control, was proven and accounts for the growing attention elicited in the field of carcinogenesis. The aim of the present paper is to verify and discuss the role of Cxs, GJs, and GJIC in cancer hallmarks, pointing on the different involved mechanisms in the context of the multi-step theory of carcinogenesis. Functional GJIC acts both as a tumor suppressor and as a tumor enhancer in the metastatic stage. On the contrary, lost or non-functional GJs allow the uncontrolled proliferation of stem/progenitor initiated cells. Thus, GJIC plays a key role in many biological phenomena or epiphenomena related to cancer. Depending on this complexity, GJIC can be considered a tumor suppressor in controlling cell proliferation or a cancer ally, with possible preventive or therapeutic implications in both cases.
A number of observations indicate that heavy metals are able to alter cellular metabolic pathways through induction of a prooxidative state. Nevertheless, the outcome of heavy metal-mediated effects in the development of human diseases is debated and needs further insights. Cancer is a well-established DNA mutation-linked disease; however, epigenetic events are perhaps more important and harmful than genetic alterations. Unfortunately, we do not have reliable screening methods to assess/validate the epigenetic (promoter) effects of a physical or a chemical agent. We propose a mechanism of action whereby mercury acts as a possible promoter carcinogen. In the present contribution, we resume our previous studies on mercury tested at concentrations comparable with its occurrence as environmental pollutant. It is shown that Hg(II) elicits a prooxidative state in keratinocytes linked to inhibition of gap junction-mediated intercellular communication and proinflammatory cytokine production. These combined effects may on one hand isolate cells from tissue-specific homeostasis promoting their proliferation and on the other hand tamper the immune system defense/surveillance checkmating the whole organism. Since Hg(II) is not a mutagenic/genotoxic compound directly affecting gene expression, in a broader sense, mercury might be an example of an epigenetic tumor promoter or, further expanding this concept, a “metagenetic” effector.
Agricultural exposure to the organomanganese fungicide MANEB (manganese-ethylene-bis-dithiocarbamate) may induce an extrapyramidal syndrome resembling parkinsonism. To evaluate the relative role of manganese (Mn) and ethylene-bis-dithiocarbamate (EBDTC) in the hazard of organomanganese fungicides, we studied the effects of MANCOZEB (Mn-Zinc-EBDTC) and ZINEB (Zinc-EBDTC) on serumless dissociated mesencephalic-striatal primary coculture. High affinity 3H-dopamine (DA) and 14C GABA uptakes as well as immunocytochemical staining of tyrosine hydroxylase (TH)-containing cells were used as specific functional markers of DA and GABA neuron viability. Both MANCOZEB and ZINEB, at 10 and 50 microM concentrations, dose dependently reduced DA and GABA viability parameters. These data suggest that EBDTC rather than Mn may be primarily responsible for the cytotoxicity of organomanganese fungicides on neuronal systems relevant to the pathophysiology of parkinsonism.
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