Cardiac sarcoidosis completely mimicking biventricular arrhythmogenic cardiomyopathy.

Cardiac sarcoidosis (CS) is a chameleon of cardiology, and it can mimic different cardiac diseases; among them is arrhythmogenic cardiomyopathy (ACM). We admitted a 70-year-old female patient with heart failure symptoms in 2015, who fulfilled all major ECG and non-invasive imaging criteria of biventricular ACM. She was well with the recommended medications for 3 years, showing only isolated cardiac involvement, but in 2018, cervical and mediastinal lymphadenopathy appeared and cervical lymph node core biopsy histology, bronchoalveolar lavage flow cytometry strongly suggested extracardiac sarcoidosis. Therefore, our suspicion was that sarcoidosis is responsible for the cardiac involvement, which was not confirmed by PET-CT and gallium scintigraphy examinations. At the end of 2018, she died in septicaemia with multiorgan failure, and only autopsy verified her CS. A new ECG algorithm published in 2021 for the differential diagnosis of CS and biventricular ACM, when applied on her ECGs recorded in 2015, suggested the diagnosis of CS.

Cardiac Amyloidosis with Normal Wall Thickness: Prevalence, Clinical Characteristics and Outcome in a Retrospective Analysis.

Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this disease into the field of interest. Increased left ventricular wall thickness (IWT) detected by echocardiography is generally thought to be a necessary part of the diagnosis. We aimed to determine the proportion of CA patients without IWT, and to define the clinical characteristics of this cohort. Methods: In an academic tertiary center for CA, we identified patients diagnosed and treated for CA between January 2009 and February 2022. In a retrospective analysis we defined the proportion of patients with (≥12 mm) and without (<12 mm) IWT, and described their clinical features. Results: We identified 98 patients suitable for the analysis. In total, 70 had AL and 27 ATTR CA; 89 patients had CA with IWT and 9 patients (9%) had CA without IWT. All non-IWT patients had AL type CA. Both group of patients had clinically significant disease, which is supported by the relevant elevation in cardiac biomarker levels. There was no difference between the outcome of the two groups. Conclusion: Patients without IWT form a relevant subgroup among those with CA. Our results suggest that diagnostic algorithms and criteria should take these individuals into consideration, and, therefore, give them access to effective treatments.

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features.

BACKGROUND: Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited disease, where the mutation of the transthyretin gene (TTR) results in the deposition of pathogenic protein fibrils in various tissues. The mutation type influences the clinical course. Until now, no data were available on the genotype, phenotype, and prevalence of Hungarian ATTRv patients. The aim of our study was to assess the prevalence, regional distribution, genotypes, and phenotypes of Hungarian patients with ATTRv. METHODS: With the collaboration of Hungarian regional and university centers, we identified patients diagnosed with ATTRv. We also searched prior publications for case studies of Hungarian ATTRv patients. RESULTS: 40 individuals in 23 families with ATTRv were identified within the borders of Hungary. At the time of the diagnosis, 24 of them were symptomatic. The two most common mutations were ATTRHis88Arg (nine families) and ATTRIle107Val (8 families). ATTRVal30Met was demonstrated in 2 families, and ATTRVal122del, ATTRPhe33Leu, ATTRIle84Ser, and ATTRAsp18Gly in one family each. The median age of the symptomatic patients at the time of clinical diagnosis was 65 years. The most common clinically significant organ involvement was restrictive cardiomyopathy, found in 24 patients. Polyneuropathy was diagnosed in 20 patients. A total of 19 patients showed a mixed phenotype. The leading symptom was heart failure in 8 cases (3 of them had only cardiac symptoms), polyneuropathy in 11 cases (all of them also had cardiac symptoms), and equally severe cardiac and neuropathy symptoms were present in 3 cases. Out of 24 symptomatic patients, 10 received targeted pharmacological therapy. The follow-up period ranged from 1 to 195 months. At the time of the retrospective analysis, 12 patients had already died, and 1 patient underwent heart transplantation. CONCLUSIONS: As TTR genotype influences the phenotype and clinical course of ATTRv, it is important to know the regional data. In Hungary, ATTRHis88Arg and ATTRIle107Val are the most common mutations in ATTRv, both presenting with mixed phenotype, but the median age at the time of the diagnosis is 9 years lower in patients with ATTRHis88Arg than in patients with ATTRIle107Val.

Inhibition of microsomal cortisol production by (-)-epigallocatechin-3-gallate through a redox shift in the endoplasmic reticulum--a potential new target for treating obesity-related diseases.

Conversion of cortisone to cortisol by 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) in the endoplasmic reticulum (ER) of the target cells is a major determinant of glucocorticoid action, and plays an important role in the development of obesity-related diseases. Inhibition of 11ßHSD1 activity is, therefore, considered as a promising novel strategy for the treatment of metabolic syndrome and diabetes. Tea flavanols and their major representative, epigallocatechin gallate are known as antiobesity and antidiabetic agents. Their impacts on blood glucose level, hepatic glucose production, and insulin responsiveness resemble those observed on inhibition or depletion of 11ßHSD1. We aimed to study the effect of epigallocatechin gallate on 11ßHSD1 activity in ER-derived rat liver microsomes by measuring cortisone and cortisol with HPLC. Cortisol production was efficiently suppressed in a concentration dependent manner in intact microsomal vesicles. However, this effect was abolished by membrane permeabilization; and the three proteins involved in the overall process (11ßHSD1, hexose 6-phosphate dehydrogenase, and glucose 6-phosphate transporter) were not or only mildly affected. Further investigation revealed the oxidation of luminal NADPH to NADP⁺, which attenuates cortisone reduction and favors cortisol oxidation in this compartment. Such a redox shift in the ER lumen might contribute to the beneficial health effects of tea flavanols and should be regarded as a promising strategy for the development of novel selective 11ßHSD1 inhibitors to treat obesity-related diseases.

Luminal accumulation of newly synthesized morphine-3-glucuronide in rat liver microsomal vesicles.

Morphine is converted to morphine 3-ß-D-glucuronide (M3G) by the UDP-glucuronosyltransferase Ugt2b1 in the endoplasmic reticulum (ER) of rat liver. Because of its luminal localization, UGT activity requires UDP-glucuronate import and glucuronide export across the ER membrane. The former transport is generally considered to be rate limiting and to explain the latency of UGT activities in intact microsomal vesicles. However, some observations indicate that the release of bulky glucuronides, such as M3G, might also be rate limiting for glucuronidation. This assumption was tested by characterizing the transport of M3G and its distribution between the intra- and extravesicular spaces during synthesis in rat liver microsomes. The amount of vesicle-associated M3G was measured using rapid filtration and LC-MS measurement. Our results reveal a remarkable accumulation of newly synthesized M3G in the microsomal lumen above the equilibrium. The transport showed a linear concentration-dependence in a wide range (5-200 µM). Therefore, the build-up of high (about 20 µM) luminal M3G concentration could adjust the rate of release to that of synthesis (44.85 ± 4.08 pmol/min/mg protein) during the conjugation of 100 µM morphine. These data can explain earlier findings indicative of separate intracellular pools of M3G in rat liver. Accumulation of bulky glucuronides in the ER lumen might also play an important role in their targeting and in the control of biliary excretion.

Inhibition of glycoprotein synthesis in the endoplasmic reticulum as a novel anticancer mechanism of (-)-epigallocatechin-3-gallate.

(-)-Epigallocatechin-3-gallate (EGCG) has been found to trigger the unfolded protein response (UPR) likely due to the inhibition of glucosidase II, a key enzyme of glycoprotein processing and quality control in the endoplasmic reticulum (ER). These findings strongly suggest that EGCG interferes with glycoprotein maturation and sorting in the ER. This hypothesis was tested in SK-Mel28 human melanoma cells by assessing the effect of EGCG and deoxynojirimycin (DNJ) on the synthesis of two endogenous glycoproteins. Both tyrosinase and vascular endothelial growth factor (VEGF) protein levels were remarkably reduced despite unaltered mRNA expression in EGCG- or DNJ-treated cells compared to control. The hindrance of tyrosinase and VEGF protein synthesis could be prevented by proteasome inhibitor, lactacystine. Collectively, our results support that glucosidase II inhibitor EGCG interferes with protein processing and quality control in the ER, which diverts tyrosinase, VEGF, and likely other glycoproteins towards proteasomal degradation. This mechanism provides a novel therapeutic approach in dermatology and might play an important role in the antitumor effect or hepatotoxicity of EGCG.

Tea flavan-3-ols as modulating factors in endoplasmic reticulum function.

Regular green tea consumption has been shown to reduce the risk of cancer and diabetes mellitus. These effects are attributed to tea flavan-3-ols, especially to epigallocatechin gallate; however, the molecular targets and mechanisms of action are still subject of extensive research. The special roles of the endoplasmic reticulum (ER) in biotransformation, protein synthesis, calcium homeostasis, and glucose production make this organelle a potential target of the antitumor and antidiabetic effects of tea flavan-3-ols. The purpose of this review is to present evidence for the biologic actions of tea flavan-3-ols on specific ER targets associated with normal function and disease. Reactivation of chemical carcinogens can be reduced by tea flavan-3-ols through inhibition of glucuronide transport across the ER membrane. Catechins modulate Ca(2+) release from the ER lumen and interfere with glycoprotein maturation, which can lead to decreased viability and increased drug sensitivity of tumor cells. Epigallocatechin gallate inhibits glucose transport across the ER membrane, which can underlie the reduction of hepatic glucose production by tea flavan-3-ols. These mechanisms likely contribute to the chemopreventive and glucose-lowering effects of tea catechins. Investigating the effects of flavan-3-ols on ER functions is a promising field of medical and biochemical research to understand disease and improve health.

[Effect of green tea flavonols on the function of the endoplasmic reticulum]. / Zöldtea-flavanolok hatása az endoplazmás retikulum muködésére.

The various (e.g. anti-tumor and anti-diabetic) health effects of green tea attributed to its flavonols, primarily to epigallocatechin-gallate, got into the focus of interest. The endoplasmic reticulum, which plays key role in the metabolism of carcinogens, in the synthesis of secreted or cell surface proteins as well as in the glucose production, might be a potential target for anti-tumor and anti-diabetic agents. Therefore, it is an important question how the flavonols affect its functions. Experiments carried out in microsomes and hepatoma cells revealed that flavonols inhibit glucuronide transport in the endoplasmic reticulum, which may reduce the reactivation of carcinogens; they inhibit glucosidase II, which may cause endoplasmic reticulum stress and apoptosis in hepatoma cells; and they hinder glucose efflux, which may decrease hepatic glucose production and blood glucose level. These observations are useful for further investigation of the relevant transport processes and transporters and also contribute to the better understanding of the mechanisms of flavanol effects.

Glucuronide transport across the endoplasmic reticulum membrane is inhibited by epigallocatechin gallate and other green tea polyphenols.

Toxic endogenous or exogenous compounds can be inactivated by various conjugation reactions. Glucuronidation (i.e. conjugation with glucuronate) is especially important due to the large number of drugs and chemical carcinogens that are detoxified through this pathway. Stable and harmless glucuronides can be reactivated by enzymatic hydrolysis thus inhibitors of glucuronidase activity reduce the risk of chemical carcinogenesis. The aim of this study was to reveal whether this mechanism contributes to the anti-cancer effect of green tea flavanols, which has been shown in various animal models. Therefore, we investigated the effect of these polyphenols on deglucuronidation in rat liver microsomes and in Hepa 1c1c7 mouse hepatoma cells, using 4-methylumbelliferyl glucuronide as model substrate. Tea flavanols inhibited beta-glucuronidase in intact vesicles, where glucuronide transport across the microsomal membrane is rate-limiting, but were almost ineffective in permeabilized vesicles. Epigallocatechin gallate, the major green tea flavanol was shown to have a concentration-dependent inhibitory effect on both beta-glucuronidase activity and glucuronide transport in native vesicles. Epigallocatechin gallate also inhibited beta-glucuronidase activity in native Hepa 1c1c7 mouse hepatoma cells, while failed to affect the enzyme in alamethicin-permeabilized cells, where the endoplasmic membrane barrier was eliminated. Our findings indicate that tea flavanols inhibit deglucuronidation in the endoplasmic reticulum at the glucuronide transport stage. This phenomenon might potentially contribute to the cancer-preventing dietary or pharmacological effect attributed to these catechins.

[Anemia and iron metabolism in patients with type-2 diabetes mellitus]. / Anaemia es vasanyagcsere 2-es típusú diabetes mellitusban szenvedo betegekben.

INTRODUCTION: Nowadays the iron status in chronic illnesses can be judged by non-invasive methods, too. The soluble transferrin receptor, that is also measurable in most laboratories, means a leap forward among the new markers. AIMS: The authors examined the prevalence of anemia and the iron status of type-2 diabetic patients with markers of the iron metabolism. They studied the clinical applicability of these laboratory procedures. METHODS: Concentration of iron, transferrin, ferritin and soluble transferrin receptor levels of healthy and diabetic patients were compared with a Mann-Whitney U-test. They examined the incidence and the type of anemia, the cause of the elevation in soluble transferrin receptor levels, and the effect of inflammation and nephropathy on the iron status. Relationship of the transferrin saturation, the concentration of ferritin and soluble transferrin receptor levels were depicted by graphic representations. RESULTS: The authors have found difference between the transferrin levels of women and men in contrast to the literature (z = 3.56; p < 0.05). The reference intervals of the ferritin levels of the control and patient groups also showed a significant difference between women and men (z = 7.59; z = 5.69; p < 0.05). 7% of the patients have suffered from anemia. 23% of the patient group had nephropathy, 10% of this subgroup was anemic, and further 8% of this subgroup had iron distribution disorder. 6% of the patients had elevated soluble transferrin receptor levels. Anemia or iron metabolism alteration was found only in 14% of the cases with elevated C-reactive protein levels. CONCLUSIONS: According to these findings ferritin reference levels of healthy people can not be used in diabetes mellitus similarly to other chronic illnesses. It seems that anemia is not frequent in diabetes mellitus. There is no connection between nephropathy and anemia, and not all of the inflammatory conditions are accompanied with iron metabolism disturbance. The soluble transferrin receptor can be interpreted only together with the other markers. In the opinion of the authors, the iron status of an individual can be judged with the collective use of all markers in chronic diseases, too.