Pleiotropic Action of TGF-Beta in Physiological and Pathological Liver Conditions.

The aim of this study is to review and analyze the pleiotropic effects of TGF-ß in physiological and pathological conditions of the liver, with particular emphasis on its role in immune suppression, wound healing, regulation of cell growth and differentiation, and liver cell apoptosis. A literature review was conducted, including 52 studies, comprising review articles, in vitro and in vivo studies, and meta-analyses. Only studies published in peer-reviewed scientific journals were included in the analysis. TGF-ß is a pleiotropic growth factor that is crucial for the liver, both in physiology and pathophysiology. Although its functions are complex and diverse, TGF-ß plays a constant role in immune suppression, wound healing, and the regulation of cell growth and differentiation. In concentrations exceeding the norm, it can induce the apoptosis of liver cells. Increased TGF-ß levels are observed in many liver diseases, such as fibrosis, inflammation, and steatosis. TGF-ß has been shown to play a key role in many physiological and pathological processes of the liver, and its concentration may be a potential diagnostic and prognostic marker in liver diseases.

Autoimmune Encephalitis with Antibodies: Anti-NMDAR, Anti-AMPAR, Anti-GQ1b, Anti-DPPX, Anti-CASPR2, Anti-LGI1, Anti-RI, Anti-Yo, Anti-Hu, Anti-CV2 and Anti-GABAAR, in the Course of Psychoses, Neoplastic Diseases, and Paraneoplastic Syndromes.

Encephalitis is a condition with a variety of etiologies, clinical presentations, and degrees of severity. The causes of these disorders include both neuroinfections and autoimmune diseases in which host antibodies are pathologically directed against self-antigens. In autoimmune encephalitis, autoantibodies are expressed in the central nervous system. The incidence of this disease is approximately 4% of all reported cases of encephalitis. Autoimmune encephalitis can be induced by antibodies against neuronal surface antigens such as N-methyl-D-aspartate-activated glutamate receptors (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPAR) or gangliosides GQ1b, DPPX, CASPR2, LGI1, as well as by antibodies against neuronal intracellular antigens. The paper presents a number of both mental and neurological symptoms of autoimmune encephalitis. Moreover, the coexistence of psychoses, neoplastic diseases, and the methods of diagnosing autoimmune encephalitis are discussed. Attention was also drawn to the fact that early diagnosis, as well as early initiation of targeted treatment, increases the chance of a successful course of the therapeutic process. Strategy and Methodology: The articles on which the following paper was based were searched using search engines such as PubMed and Medline. Considering that anti-NMDAR antibodies were first described in 2007, the articles were from 2007 to 2023. The selection of papers was made by entering the phrases "autoimmune encephalitis and psychosis/paraneplastic syndromes or cancer". The total number of articles that could be searched was 747, of which 100 items were selected, the most recent reports illustrating the presented topic. Thirty-four of them were rejected in connection with case reports or papers that could not be accessed.

["Sickness behavior"--mechanisms of origin and significance]. / "Sickness Behavior"--mechanizmy powstania i znaczenie.

Psychoneuroimmunology, a combination of immunology and neurobiology, is a new field that has emerged over the past 20 years. There is now overwhelming evidence suggesting that the central nervous system is capable of regulating the immune response via two pathways--the autonomic and the neuroendocrine. It is also well documented that the immune system can influence the central nervous system by regulatory molecules or cytokines produced by activated immune cells. In this way, there is a bi-directional communication pathway between the two systems. Sickness behavior seems to present excellent evidence for the existence of immune-system-brain communication. Nonspecific symptoms of infection and inflammation include not only profound physiological but also behavioral changes. Behavioral changes can include anorexia, adipsia, increased sleepiness and depression in social, sexual exploration and general activity. These behavioral changes triggered by pro-inflammatory cytokines are thought to have evolved to conserve the energy necessary to fight infection. They may also minimize infection of conspecifics and reduce susceptibility to predation. Taken together, sickness behavior represents a behavioral reorganization highly motivated to promote survival and recovery. Knowing the mechanisms of neuroimmunomodulation allow us to better understand both the behavioral changes associated with immunotherapy and the changes in immune activation in major depression and other mental disorders.

[The pathogenesis and the adaptive value of fever]. / Mechanizmy powstania i znaczenie goraczki.

Fever is a part of the acute phase response to infection and inflammation. We now understand that fever is a complex physiological response that is aimed at facilitating survival of the host. The fever is induced by endogenous inflammatory mediators, such as prostaglandins and pyrogenic cytokines, that are released by immune cells activated by exogenous pyrogens. Although the pathways (humoral and/or neuronal) responsible for transfer of the pyretic signals from the blood to the brain are still under discussion, it is generally accepted that they act on the level of the anterior hypothalamus to raise the thermoregulatory set-point. Results of studies of the adaptive value of fever demonstrate an association between a rise in body temperature and a decrease in mortality and morbidity during infection. These data along with data from evolutionary studies provide a strong support for the concept that fever is a beneficial during infection in endotherms and ectotherms, vertebrates as well as in invertebrates. There are also evidence showing that fever may be used as a therapeutic tool, especially in cancer therapy. Based on the data reviewed in this article, it can be concluded that fever has evolved as a host defense mechanism which was preserved within the animal kingdom through hundreds of millions of years of evolution.

Inhibition of nitric oxide synthase delays the development of tolerance to LPS in rats.

The role of nitric oxide (NO) was investigated in endotoxin (lipopolysaccharide, LPS) tolerance in freely moving biotelemetered rats. We monitored changes in febrile response and feeding behavior (food intake, water intake) during the development of tolerance to repeated intraperitoneal injections of LPS (50 microg/kg) along with injections of N(omega)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg), an inhibitor of NO synthase. Rats were treated with LPS and L-NAME for three consecutive days. On the fourth day, all rats were injected with LPS alone. Control rats were injected with saline along with saline or with L-NAME for four consecutive days. Rats repeatedly injected with LPS became tolerant to pyrogenic and hypophagic/cachexic effects of LPS as early as on the second day of experiment. The treatment with L-NAME prevented the attenuation of febrile response following the second LPS injection. Moreover, the depressive effects of LPS on body weight as well as on water and food intake were prolonged in rats treated with a combination of L-NAME and LPS. Injection of LPS caused a 3.5-fold increase in plasma nitrite within 3 h and nitrite levels remained significantly elevated 6 and 24 h after LPS. Rats injected secondly with LPS did have still 2.5- to 3-fold increase in plasma nitrite levels 3 and 6 h, but not 24 h, after injection. Third injection of LPS did not elevate nitrite level in plasma. Taken together, presented data provide clear evidence that NO formation is involved in mechanisms responsible for development of early-stage tolerance to endotoxin.

IL-6 and IL-1 beta in fever. Studies using cytokine-deficient (knockout) mice.

Previous data support the hypothesis that during inflammation, interleukin (IL)-1 beta and IL-6 are involved in fever, in activation of the hypothalamic-pituitary-adrenal (HPA) axis, and in the induction of eicosanoids. Most of the pathophysiologic effects of IL-1 beta and Il-6 are mediated by prostaglandins (PGs), modulated by other cytokines, and antagonized by glucocorticoids (GC), a final product of the HPA axis. To further test these relationships, we measured changes in body temperature using biotelemetry in mice deficient in genes for IL-1 beta and/or IL-6 (IL-1 beta knockout [KO] and IL-6 KO) following injection with lipopolysaccharide (LPS) to induce systemic inflammation or turpentine to induce local abscess. Circulating IL-6, tumor necrosis factor alpha (TNF-alpha), GC, and PGE2 were measured in these mice after treatment. IL-1 beta KO mice responded with reduced fever and IL-6 KO mice with normal fever to a high dose of LPS. In contrast, neither type of KO mice produced fever to turpentine. PGE2 levels (measured in the circulation) were suppressed in both types of KO mice injected with turpentine. IL-1 beta KO mice showed deficiency in IL-6 following turpentine, but not LPS, injection. LPS-induced increases in TNF-alpha did not differ between IL-1 beta KO mice and their wild-type counterparts, whereas IL-6 KO mice showed exacerbated LPS-induced circulating TNF-alpha. No differences were noted in plasma elevations of GC between KO and wild-type mice following injection of LPS or turpentine, indicating that IL-1 beta and IL-6 are not required for activation of the HPA axis during inflammation. Our data demonstrate that in the mouse, IL-1 beta and IL-6 are critical for the induction of fever during local inflammation, whereas in systemic inflammation they appear only to contribute to fever.

Role of fever in disease.

Infection, trauma, and injury result in a stereotypical response that includes loss of food appetite, increased sleepiness, muscle aches, and fever. For thousands of years fever was considered a protective response, and fevers were induced by physicians to combat certain infections. But with the advent of antipyretic drugs, physicians started to reduce fevers, and fever therapy was virtually abandoned. As a result of (1) studies on the evolution of fever, (2) further understanding of just how tightly the process of fever is regulated, and (3) detailed studies on how fever affects host morbidity and mortality, the view of fever as a host defense response has reemerged. However, data indicate that not all fevers are protective and that high fevers are maladaptive. These issues are discussed in the context of the evolution of host defense responses versus modern medical technology. In short, we speculate that patients who would not have survived severe sepsis in the past are now being kept alive and that the occasionally high fevers seen in these patients may be maladaptive.