On the origin of cysteamine-induced duodenal cytotoxicity and type II ferroptosis.

Cysteamine (CA) induces duodenal ulcers in rodents (Selye and Szabo, Nature 244:458-459, 1973). Cysteine (Cys), a precursor for the formation of CA (via catabolism of coenzyme A), does not cause lesions in the duodenum (Szabo et al., J Pharmacol Exp Ther 223:68-76, 1982). CA also has antimutagenic and anticancer pharmacology (Fujisawa et al., PLoS ONE 7, 2012; Lee, Adv Pharmacol Pharm Sci 2023:2419444, 2023). We propose a mechanism of CA-induced cell death dependent on oxygen and CA dioxygenase (ADO) that can explain the 50-year-old mystery as to why CA is, but Cys is not, ulcerogenic. Those cells expressing coenzyme A-catabolizing enzymes are subject to a unique type of oxygen- and enzyme-bound-Fe2+-dependent death, type II ferroptosis.

The post-COVID stress syndrome: from the three-stage stress response of Hans Selye to COVID-19.

Stress is the nonspecific response of the body to any demand made upon it, as defined by Hans Selye more than 80 years ago, based on his animal experiments at McGill University in Montreal, Canada. By emphasizing 'nonspecificity' he tried to underline that stress response is elicited my several factors, like nowadays in COVID-19, e.g., fear of infection, social isolation, death in family, loss of employment, etc. Thus, COVID-19 has been the largest new human stressor in the twenty-first century. Selye's studies in rats also revealed 3 stages of stress response: the short initial "alarm reaction" is followed by a longer "stage of resistance", associated with increased levels of corticosterone that is often terminated by a "stage of exhaustion", referring to an exhausted adrenal cortex when the secretion of glucocorticoids drops. Fast forward, that is exactly what has been documented in severe cases of infections caused by the SARS-CoV-2 virus: in hospitalized COVID-19 patients initially the blood levels of cortisol not only have been elevated, but only those with high concentration of this natural anti-inflammatory corticosteroid survived vs. those who had low levels of cortisol, suggesting diminished adrenocortical functions. Furthermore, patients with very severe cases of COVID-19 who ended up in intensive care units had significantly low cortisol blood levels, compared to patients with equal severity of diseases due to other causes. Thus, these 'natural phenomena' in clinical medicine, unfortunately confirmed Selye's studies in experimental animals several decades ago. Still, the good news is that astute clinicians empirically recognized this and started to give potent synthetic glucocorticoids such as dexamethasone to severe COVD-19 patients and this beneficial effect of exogenous corticoids has been extensively confirmed in the scientific literature.

What is really 'Long COVID'?

The previous acute respiratory diseases caused by viruses originating from China or the middle east (e.g., SARS, MERS) remained fast developing short diseases without major sequalae or any long-lasting complications. The new COVID-19, on the other hand, not only that it rapidly spread over the world, but some patients never fully recovered or even if they did, a few weeks later started to complain not only of shortness of breath, if any, but general weakness, muscle pains and 'brain fog', i.e., fuzzy memories. Thus, these signs and symptoms were eventually labelled 'long COVID', for which the most widely used definition is 'new signs and symptoms occurring 4-8 weeks after recovering from acute stage of COVID-19'. The other most frequent manifestations associated with long COVID include headache, loss of memory, smell and of hair, nausea, and vomiting. Thus, long COVID is not a simple disease, but complex disorder of several organ systems malfunctioning; hence, it is probably more appropriate to call this a syndrome. The pathogenesis of long COVID syndrome is poorly understood, but initial and persistent vascular endothelial injury that often triggers the formation of microthrombi that if dislodged as emboli, damage several organs, especially in the brain, heart and kidney, by creating microinfarcts. The other major contributory mechanistic factor is the persistent cytokine storm that may last longer in long COVID patients than in others, probably triggered by aggregates of SARS-Co-2 discovered recently in the adrenal cortex, kidney and brain. The prevalence of long COVID is relatively high, e.g., initially varied 3-30%, and recent data indicate that 2.5% of UK population suffers from this syndrome, while in the US 14.7% of acute COVID-19 patients continued to have symptoms longer than 2 months. Thus, the long COVID syndrome deserves to be further investigated, both from clinical and basic research perspectives.

A closer look at endothelial injury-induced platelet hyperactivity and the use of aspirin in the treatment of COVID infection.

In this commentary, we make a case that the mechanism of COVID pathogenesis is related to virus-induced endothelial injury resulting in platelet activation and the formation of microthrombi both systemically and in cardiac and pulmnonary circulation which result in major causes of COVID morbidity and mortality. Aspirin by virtue of its irreversible inhibition of platelet COX-1, should reverse these platelet-induced pathogenic changes associated with COVID infection for the 6-9 day lifetime of the platelet. We also cite recent findings of a retrospective analysis that supports the use of low-dose (81 mg) aspirin to treat the symptoms associated with the early stages of COVID infection.

Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target.

Acute gastritis is often untreatable by acid secretion-inhibiting drugs. Understanding the protective mechanisms including the role of Transient Receptor Potential Ankyrin1 (TRPA1) and Vanilloid1 (TRPV1) channels localized on capsaicin-sensitive afferents and non-neuronal structures might identify novel therapeutic approaches. Therefore, we characterized a translational gastritis model using iodoacetamide (IAA) and investigated TRPA1/V1 expressions. Wistar rats and CD1, C57Bl/6J mice were exposed to IAA-containing (0.05, 0.1, 0.2, 0.3, 0.5%) drinking water for 7 or 14 days. Body weight and water consumption were recorded daily. Macroscopic lesions were scored, qualitative histopathologic investigation was performed, TRPA1/V1 immunopositivity and mRNA expressions were measured. IAA induced a concentration-dependent weight loss and reduced water intake in both species. Hyperemia, submucosal edema, inflammatory infiltration and hemorrhagic erosions developed after 7 days, while ulcers after 14 days in rats. Trpa1 mRNA/protein expressions were upregulated at both timepoints. Meanwhile, TRPV1 immunopositivity was upregulated in the gastric corpus after 0.05% IAA ingestion, but downregulated after 0.2%, whereas Trpv1 mRNA did not change. Interestingly, no macroscopic/microscopic changes were observed in mice. These are the first data for the concentration- and duration-dependent changes in the IAA-induced gastritis in rats accompanied by TRPA1 upregulation, therefore, its therapeutic potential in gastritis should further be investigated.

[The early recognition of mental morbidities during psycho-oncologic treatment]. / A pszichés morbiditások korai felismerése a pszichoonkológiai ellátás során.

Unfortunately there have been no positive changes in the main indicators of cancer incidence in Hungarian population since the turn of the millennium. The main goal of psycho-oncologic treatment is to provide the highest possible quality of life to the patient. The prevalence of mental disorders in cancer patients is high and it is accompanied by a rather small number of qualified staff. Thus, the remedy might be the identification of high-risk patients, i.e. the systematic psycho-oncologic screening. Hungary is still lacking a unified screening method that involves all oncologic treatment-providing units. Compiling the Hungarian standards for the Distress Thermometer and the Problem List is the first step of a complex program for creating a general psycho-oncologic screening. Such a comprehensive program might improve oncologic patient-care and, eventually, the quality and prospect of the lives of patients.

Role of Dopamine and D2 Dopamine Receptor in the Pathogenesis of Inflammatory Bowel Disease.

BACKGROUND: VEGF-induced vascular permeability and blood vessels remodeling are key features of inflammatory bowel disease (IBD) pathogenesis. Dopamine through D2 receptor (D2R) inhibits VEGF/VPF-mediated vascular permeability and angiogenesis in tumor models. In this study, we tested the hypothesis that pathogenesis of IBD is characterized by the disturbance of dopaminergic system and D2R activity. METHODS: IL-10 knockout (KO) mice and rats with iodoacetamide-induced ulcerative colitis (UC) were treated intragastrically with D2R agonists quinpirole (1 mg/100 g) or cabergoline (1 or 5 µg/100 g). Macroscopic, histologic, and clinical features of IBD, colonic vascular permeability, and angiogenesis were examined. RESULTS: Although colonic D2R protein increased, levels of tyrosine hydroxylase and dopamine transporter DAT decreased in both models of IBD. Treatment with quinpirole decreased the size of colonic lesions in rats with iodoacetamide-induced UC (p < 0.01) and reduced colon wet weight in IL-10 KO mice (p < 0.05). Quinpirole decreased colonic vascular permeability (p < 0.001) via downregulation of c-Src and Akt phosphorylation. Cabergoline (5 µg/100 g) reduced vascular permeability but did not affect angiogenesis and improved signs of iodoacetamide-induced UC in rats (p < 0.05). CONCLUSIONS: Treatment with D2R agonists decreased the severity of UC in two animal models, in part, by attenuation of enhanced vascular permeability and prevention of excessive vascular leakage. Hence, the impairment dopaminergic system seems to be a feature of IBD pathogenesis.

[Naming and classification of steroids and human stress ulcers. Articles of historic significance published by Hans Selye 70 years ago]. / A szteroidok elnevezése, felosztása és az emberi stresszfekélyek. Selye János 70 éve megjelent történelmi jelentoségu cikkei.

The name of Hans Selye is mostly known worldwide as the discoverer of stress reaction. Yet, he made numerous other seminal and clinically relevant discoveries. Namely, since he had a focused research on steroid hormones originating from the adrenal cortex that play a crucial role in stress response, he was the first who introduced about 70 years ago the first classification of steroids that is still valid nowadays. This is based on three objective facts: (a) the names of steroid groups are identical with their organ of origin (e.g., corticoids from the adrenal cortex, testoids/androgens from the testis); (b) chemical structures of the steroids are identical within a group (e.g., all corticoids have pregnane nucleus with 21 carbon atoms); and (c) the biological effects are homogenous within a group (e.g., all glucocorticoids exert catabolic effect, while androgens are anabolic). It should be emphasized that Selye also discovered in animal models the pro-inflammmatory effect of mineralocorticoids and the anti-inflammatory properties of glucocorticoids, about 8-10 years before Nobel Prize was awarded to a physician for the first clinical use of adrenocorticotrop hormone and cortisone. Last, but not least, Selye was the first who recognized about 70 years ago the occurence of stress ulcers in humans, based on clinical reports on the huge increase in the number of perforated gastric anti-duodenal ulcers during bombings of London in World War II. The subsequent ulcer research by Selye`s former students and their contemporaries resulted in the recognition of anti-duodenal ulcer effect of dopamine, and the central gastroprotective actions of thyreotrop releasing hormone and endogenous opioids. Thus, Hans Selye made much more contributions to medical science and clinical practice than 'just' the discoverer of biologic stress response.

"Gastric cytoprotection" is still relevant.

Although Andre Robert's historic article on "gastric cytoprotection" in 1979 introduced this new name and concept, gastroprotective drugs (e.g. sofalcone, sucralfate), which prevent and/or accelerate healing of gastric ulcers without inhibiting acid secretion, were known in Japan before or around that time. But since Robert's studies were solely focused on prostaglandins (PG), they became the center of gastrointestinal research for more than 30 years. As endogenous products, PG were implicated in mediating the gastroprotective effect of other drugs such as sofalcone and sucralfate, despite that the cyclooxygenase inhibitor indomethacin diminished but never abolished gastroprotection by other drugs. Another group of endogenous substances, that is, sulfhydryls (SH), investigated in parallel with PG, also seem to play a mechanistic role in gastroprotection, especially since SH alkylators like N-ethylmaleimide counteract virtually any form of gastroprotection. In Robert's terms of "prevention of chemically induced acute mucosal lesions," so far no single mechanism could explain the beneficial effects of diverse protective agents, but I argue that these two endogenous substances (i.e. PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG and histamine, because as mediators of acute inflammation, they increase vascular permeability (VP), and SH scavenge free radicals. This is contrary to the search for a single mechanism of action, long focused on enhanced secretion of mucus and/or bicarbonate that may contribute but cannot explain all forms of gastroprotection. Nevertheless, based on research work of the last 30 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated: it's a complex but orderly and evolution-based physiologic response of the gastric mucosa under pathologic conditions. Namely, one of the first physiologic defense responses of any organ is inflammation that starts with rapid vascular changes (e.g. increased VP and blood flow), followed by cellular events (e.g. infiltration by acute and chronic inflammatory cells). Thus, PG and histamine, by increasing VP create a perivascular edema that dilutes and delays toxic agents reaching the subepithelial capillaries. Otherwise, damaging chemicals may induce severe early vascular injury resulting in blood flow stasis, hypoxia, and necrosis of surrounding epithelial and mesenchymal cells. In this complex response, increased mucus and/or bicarbonate secretion seem to cause luminal dilution of gastrotoxic chemicals that is further reinforced by a perivascular, histodilutional component. This mechanistic explanation would encompass the protective actions of diverse agents as PG, small doses of histamine, motility stimulants, and dilute irritants (i.e. "adaptive cytoprotection"). Thus, although markedly increased VP is pathologic, slight increase in VP seems to be protective, that is, a key element in the complex pathophysiologic response during acute gastroprotection. Over the years, "gastroprotection" was also applied to accelerated healing of chronic gastroduodenal ulcers without reduction of acid secretion. The likely main mechanism here is the binding of angiogenic growth factors (e.g. basic fibroblast growth factor, vascular endothelial growth factor) to the heparin-like structures of sucralfate and sofalcone. Thus, despite intensive research of the last 30 years, gastroprotection is incompletely understood, and we are still far away from effectively treating Helicobacter pylori-negative ulcers and preventing nonsteroidal anti-inflammatory drugs-caused erosions and ulcers in the upper and lower gastrointestinal tract; hence "gastric cytoprotection" research is still relevant.