Feroptoza: regulirana stanična smrt

Ferroptosis is a recently identified form of regulated cell death that differs from other known forms of cell death morphologically, biochemically, and genetically. The main properties of ferroptosis are free redox-active iron and consequent iron-dependent peroxidation of polyunsaturated fatty acids in cell membrane phospholipids, which results in the accumulation of lipid-based reactive oxygen species due to loss of glutathione peroxidase 4 activity. Ferroptosis has increasingly been associated with neurodegenerative diseases, carcinogenesis, stroke, intracerebral haemorrhage, traumatic brain injury, and ischemia-reperfusion injury. It has also shown a significant therapeutic potential in the treatment of cancer and other diseases. This review summarises current knowledge about and the mechanisms that regulate ferroptosis.Feroptoza je nedavno identificirani oblik regulirane stanične smrti koji se od ostalih poznatih oblika stanične smrti razlikuje morfološki, biokemijski i genetski. Glavna svojstva feroptoze uključuju slobodno redoks aktivno željezo i posljedičnu, o željezu ovisnu, peroksidaciju polinezasićenih masnih kiselina u fosfolipidima staničnih membrana te gubitak aktivnosti glutation peroksidaze 4, što rezultira akumulacijom lipidnih, reaktivnih kisikovih spojeva. Feroptoza se sve više povezuje s raznim bolestima kao što su neurodegenerativne bolesti, karcinom, moždani udar, intracerebralna krvarenja, traumatične ozljede mozga i ishemijsko-reperfuzijska ozljeda. Također je pokazan značajan terapijski potencijal u liječenju raka i drugih bolesti. Ovaj pregled sažima trenutačne spoznaje i mehanizme koji reguliraju feroptozu

Istine i kontroverze o selenu

Selenium is a trace element, essential in small amounts, but can be toxic in larger amounts. Levels in the body are mainly dependent on the amount of selenium in the diet, which is a function of the selenium content of the soil. Humans and animals require selenium for normal function of more than about 30 known selenoproteins, of which approximately 15 have been purified to allow characterisation of their biological functions. The selenoproteins are comprised of four glutathione peroxidases, three iodothyronine deiodinases, three thioredoxin reductases, selenoprotein P, selenoprotein W and selenophosphate synthetase. Selenium is essential for normal functioning of the immune system and thyroid gland, making selenium an essential element for normal development, growth, metabolism, and defense of the body. Supportive function of selenium in health and disease (male infertility, viral infections, including HIV, cancer, cardiovascular and autoimmune diseases) is documented in great number of clinical examinations. A great number of studies confirm that selenium supplementation play a preventive and therapeutical role in different diseases. Definitive evidence regarding the preventive and therapeutical role of selenium as well as the exact mechanism of its action should be investigated in further studies. Investigations in Croatia indicate a possibility of inadequate selenium status of people in the area.Selen je mikroelement neophodan organizmu u malim količinama, a toksičan u većim količinama. Količina selena u hrani ovisi o količini selena u tlu. Ljudi i životinje trebaju ga za normalno funkcioniranje brojnih procesa. Selen je sastavni dio više od tridesetak poznatih selenoproteina, od kojih su za petnaestak dobro poznata biološka svojstva, primjerice četiri glutation peroksidaze, tri jodtironin dejodinaze, tri tioredoksin reduktaze, selenoprotein P, selenoprotein W i selenofosfat sintetaza. Selen je nužan za normalno funkcioniranje obrambenog sustava i za funkcioniranje tireoidne žlijezde, što znači da je selen esencijalan za normalan razvoj, rast, metabolizam i obranu organizma. Brojna su klinička ispitivanja potvrdila da selen potpomaže u zdravlju i bolesti (muška neplodnost, virusne infekcije, uključujući HIV, karcinom, kardiovaskularne bolesti, autoimune bolesti). Brojne su studije pokazale da suplementacija selena može imati i preventivnu i terapijsku ulogu kod različitih bolesti, ali za konačnu potvrdu kao i točan mehanizam njegova djelovanja nužna su daljnja istraživanja. Istraživanja u Hrvatskoj ukazuju na smanjenu količinu selena u tlu i moguć nedostatan unos selena u ljudski ogranizam

Istine i kontroverze o selenu

Selenium is a trace element, essential in small amounts, but can be toxic in larger amounts. Levels in the body are mainly dependent on the amount of selenium in the diet, which is a function of the selenium content of the soil. Humans and animals require selenium for normal function of more than about 30 known selenoproteins, of which approximately 15 have been purified to allow characterisation of their biological functions. The selenoproteins are comprised of four glutathione peroxidases, three iodothyronine deiodinases, three thioredoxin reductases, selenoprotein P, selenoprotein W and selenophosphate synthetase. Selenium is essential for normal functioning of the immune system and thyroid gland, making selenium an essential element for normal development, growth, metabolism, and defense of the body. Supportive function of selenium in health and disease (male infertility, viral infections, including HIV, cancer, cardiovascular and autoimmune diseases) is documented in great number of clinical examinations. A great number of studies confirm that selenium supplementation play a preventive and therapeutical role in different diseases. Definitive evidence regarding the preventive and therapeutical role of selenium as well as the exact mechanism of its action should be investigated in further studies. Investigations in Croatia indicate a possibility of inadequate selenium status of people in the area.Selen je mikroelement neophodan organizmu u malim količinama, a toksičan u većim količinama. Količina selena u hrani ovisi o količini selena u tlu. Ljudi i životinje trebaju ga za normalno funkcioniranje brojnih procesa. Selen je sastavni dio više od tridesetak poznatih selenoproteina, od kojih su za petnaestak dobro poznata biološka svojstva, primjerice četiri glutation peroksidaze, tri jodtironin dejodinaze, tri tioredoksin reduktaze, selenoprotein P, selenoprotein W i selenofosfat sintetaza. Selen je nužan za normalno funkcioniranje obrambenog sustava i za funkcioniranje tireoidne žlijezde, što znači da je selen esencijalan za normalan razvoj, rast, metabolizam i obranu organizma. Brojna su klinička ispitivanja potvrdila da selen potpomaže u zdravlju i bolesti (muška neplodnost, virusne infekcije, uključujući HIV, karcinom, kardiovaskularne bolesti, autoimune bolesti). Brojne su studije pokazale da suplementacija selena može imati i preventivnu i terapijsku ulogu kod različitih bolesti, ali za konačnu potvrdu kao i točan mehanizam njegova djelovanja nužna su daljnja istraživanja. Istraživanja u Hrvatskoj ukazuju na smanjenu količinu selena u tlu i moguć nedostatan unos selena u ljudski ogranizam

Ferroptosis - a link between iron biology, aging and COVID-19?

Severe form of COVID-19 is more common in the elderly and although it may include a variety of extrapulmonary manifestations, respiratory dysfunction is primarily present, which includes iron dy- shomeostasis. The aging process is characterized by a chronic pro-inflammatory condition of a milder type, and COVID-19 by strong acute inflammation, both resulting in changes in iron metabolism. A new, iron-dependent form of programmed cell death, ferroptosis, is associated with iron dyshomeosta- sis. The main features of ferroptosis include intracellular iron overload, inhibition of the cellular GSH / GPX4 system, and accumulation of lipid reactive compounds. Clinical manifestations of COVID-19 and changes during aging include GSH depletion, GPX4 inactivation, changes in iron metabolism markers as well as markers of enhanced lipid peroxidation. There is therefore a possibility that SARS- CoV-2 may cause feroptotic death of lung cells but also cells of other organs. This review considers the molecular mechanisms of ferroptosis, their relationship to the aging process and the pathogenesis of COVID-19, and the consideration of ferroptosis as a factor linking aging and the pathogenesis of COVID-19

Ferroptosis - a link between iron biology, aging and COVID-19?

Severe form of COVID-19 is more common in the elderly and although it may include a variety of extrapulmonary manifestations, respiratory dysfunction is primarily present, which includes iron dy- shomeostasis. The aging process is characterized by a chronic pro-inflammatory condition of a milder type, and COVID-19 by strong acute inflammation, both resulting in changes in iron metabolism. A new, iron-dependent form of programmed cell death, ferroptosis, is associated with iron dyshomeosta- sis. The main features of ferroptosis include intracellular iron overload, inhibition of the cellular GSH / GPX4 system, and accumulation of lipid reactive compounds. Clinical manifestations of COVID-19 and changes during aging include GSH depletion, GPX4 inactivation, changes in iron metabolism markers as well as markers of enhanced lipid peroxidation. There is therefore a possibility that SARS- CoV-2 may cause feroptotic death of lung cells but also cells of other organs. This review considers the molecular mechanisms of ferroptosis, their relationship to the aging process and the pathogenesis of COVID-19, and the consideration of ferroptosis as a factor linking aging and the pathogenesis of COVID-19

SARS-CoV-2 – a new challenge for laboratory medicine

The new corona virus SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus 2) causes a disease called COVID-19 (coronavirus disease 2019), that develops mostly in subjects with already impaired immune system function, primarily in the elderly and in individuals with some chronic disease or condition. The reasons for this should be sought in the processes of aging and chronic latent inflammation, i.e. immunosenescence and inflammaging. Laboratory medicine specialists are currently focused on proving the presence of the virus and defining biomarkers that would enable the prediction of disease progression. For now, it has been shown that useful biomarkers can include general biomarkers of inflammation (parameters of complete blood count, C-reactive protein, interleukin-6, procalcitonin), biomarkers of myocardial damage (high sensitivity troponin I/T, B-type natriuretic peptide, and N-terminal B type natriuretic peptide), and vascular biomarkers (D-dimer, prothrombin time, fibrinogen). Their actual diagnostic specificity, sensitivity and predictive value need to be tested on a larger number of subjects. In addition, it is important to find and evaluate specific biomarkers of immunosenescence

Scanning of reverse translation via de novo peptide sequencig by tandem mass spectrometry

Sekvenciranje peptida i proteina de novo korišteno je kao alat za reverzno iščitavanje translacije. Pri tome je nedvojbeno sekvenciranje de novo omoguceno selektivnim obilježavanjem N-kraja peptida 5-formil-1,3-benzen-di-sulfonicnom kiselinom prije analize tandemnom spektrometrijom masa. Opisana kemijska modifikacija usmjerava fragmentaciju peptidnih iona ka disocijaciji peptidne veze prilikom kolizijom inducirane disocijacije u spektrometru masa. Nastali fragmentni ioni b-serije detektiraju se u negativnom načinu rada spektrometra masa, a fragmentni ioni y-serije detektiraju se u pozitivnom načinu spektrometra masa. Stoga je, za isti peptid, aminokiselinski slijed iščitan iz spektra snimljenog u pozitivnom načinu rada spektrometra masa moguće dodatno provjeriti iščitavanjem iz spektra snimljenog pri negativnom načinu rada spektrometra masa (tzv. nedvojbeno sekvenciranje peptida de novo). Jedna od primjena ovakvog načina sekvenciranja de novo je i identifikacija proteina, koja se provodi pretragom, iz spektra iščitane sekvence peptida, u bazi podataka, odnosno iščitavanjem reverzne translacije. Disertacija prikazuje primjenjivost, pouzdanost i točnost kao i komparativnu prednost novorazvijene de novo tehnike nad klasičnim tehnikama identifikacije proteina.De novo peptide and protein sequencing was used as a tool for reverse translation scanning. Unambiguous de novo sequencing is achived by selective derivatization of peptide N-terminus by 5-formyl-1,3-benzendisulfonic acid before tandem mass spectrometry analysis. Described chemical modification of peptide directs fragmentation pathway to the peptide bound dissociation during collision-induced dissociation in the mass spectrometer. The resulting b-series of fragmentation ions is detected in the negative ion mode of the mass spectrometer, and y-series of fragmentation ions is detected in the positive ione mode of the mass spectrometer. Therefore, for the same peptide, amino acid sequence read out from the spectrum recorded in the positive ione mode can be additionally verified by reading out from the spectrum obtained in the negative ion mode of mass spectrometer (the so-called unambiguous de novo sequencing). One application of the described de novo sequencing technique is protein identification, which is performed by searching for previously spectral obtained peptide sequence, in the protein database ie. by scanning of reverse translation. This thesis presents applicability, reliability and accuracy as well as the comparative advantage of the newly developed de novo sequencing technique over the conventional protein identification techniques

Scanning of reverse translation via de novo peptide sequencig by tandem mass spectrometry

Sekvenciranje peptida i proteina de novo korišteno je kao alat za reverzno iščitavanje translacije. Pri tome je nedvojbeno sekvenciranje de novo omoguceno selektivnim obilježavanjem N-kraja peptida 5-formil-1,3-benzen-di-sulfonicnom kiselinom prije analize tandemnom spektrometrijom masa. Opisana kemijska modifikacija usmjerava fragmentaciju peptidnih iona ka disocijaciji peptidne veze prilikom kolizijom inducirane disocijacije u spektrometru masa. Nastali fragmentni ioni b-serije detektiraju se u negativnom načinu rada spektrometra masa, a fragmentni ioni y-serije detektiraju se u pozitivnom načinu spektrometra masa. Stoga je, za isti peptid, aminokiselinski slijed iščitan iz spektra snimljenog u pozitivnom načinu rada spektrometra masa moguće dodatno provjeriti iščitavanjem iz spektra snimljenog pri negativnom načinu rada spektrometra masa (tzv. nedvojbeno sekvenciranje peptida de novo). Jedna od primjena ovakvog načina sekvenciranja de novo je i identifikacija proteina, koja se provodi pretragom, iz spektra iščitane sekvence peptida, u bazi podataka, odnosno iščitavanjem reverzne translacije. Disertacija prikazuje primjenjivost, pouzdanost i točnost kao i komparativnu prednost novorazvijene de novo tehnike nad klasičnim tehnikama identifikacije proteina.De novo peptide and protein sequencing was used as a tool for reverse translation scanning. Unambiguous de novo sequencing is achived by selective derivatization of peptide N-terminus by 5-formyl-1,3-benzendisulfonic acid before tandem mass spectrometry analysis. Described chemical modification of peptide directs fragmentation pathway to the peptide bound dissociation during collision-induced dissociation in the mass spectrometer. The resulting b-series of fragmentation ions is detected in the negative ion mode of the mass spectrometer, and y-series of fragmentation ions is detected in the positive ione mode of the mass spectrometer. Therefore, for the same peptide, amino acid sequence read out from the spectrum recorded in the positive ione mode can be additionally verified by reading out from the spectrum obtained in the negative ion mode of mass spectrometer (the so-called unambiguous de novo sequencing). One application of the described de novo sequencing technique is protein identification, which is performed by searching for previously spectral obtained peptide sequence, in the protein database ie. by scanning of reverse translation. This thesis presents applicability, reliability and accuracy as well as the comparative advantage of the newly developed de novo sequencing technique over the conventional protein identification techniques

DOB I INFEKCIJA VIRUSOM SARS-COV-2

SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus 2), a novel virus of the beta coronavirus group RNA viruses, is responsible for a zoonotic disease named COVID-19 (coronavirus disease from 2019). The main receptor through which the virus enters the host cell is angiotensin-converting enzyme 2 (ACE2), known as a multifunctional protein. ACE2 expression has been found in oral and nasal mucosa, lungs, adipose tissue, heart, brain, kidneys, vascular tissue, stomach, liver. Upon entry of the virus into the target host cells, two processes are initiated, the host’s immune response and the infl ammatory cascade. As immune (innate and adaptive) and infl ammatory responses change throughout life both qualitatively and quantitatively, both processes are responsible for varying degrees of disease severity depending on the patient’s age. Short-time experience with SARS-CoV-2 infection has shown that: (i) children and adolescents develop the disease with mild symptoms, mainly on upper respiratory airways; (ii) the disease has a more severe course in adult patients with associated chronic diseases such as cardiovascular and renal diseases, chronic respiratory diseases, diabetes, etc.; and (iii) the most severe, often fatal disease occurs in the elderly, due to more pronounced processes of immunosenescence and infl amm-aging.RSARS-CoV-2 (engl. Severe Acute Respiratory Syndrome Coronavirus 2), novi virus iz skupine RNA betakoronavirusa, odgovoran je za zoonotsku bolest nazvanu COVID-19 (bolest uzrokovana koronavirusom iz 2019.). Glavni receptor pomoću kojega virus ulazi u stanicu domaćina je angiotenzin konvertirajući enzim 2 (ACE2), poznat kao multifunkcionalni protein. Receptor ACE2 prisutan je u oralnoj i nosnoj sluznici, plućima, masnom tkivu, srcu, mozgu, bubrezima, vaskularnom tkivu, želucu, jetri. Nakon ulaska virusa u ciljne stanice domaćina pokreću se dva procesa, imunosni odgovor domaćina i upalna kaskada. Budući da se imunosni (urođeni i stečeni) i upalni odgovori tijekom života mijenjaju u kvalitativnom i kvantitativnom smislu, oba procesa su odgovorna za različit stupanj ozbiljnosti bolesti, ovisno o pacijentovoj dobi. Kratkotrajno iskustvo s infekcijom uzrokovanom virusom SARS-CoV-2 pokazalo je da: (i) djeca i adolescenti razvijaju bolest s blagim simptomima, uglavnom na gornjim dišnim putevima; (ii) bolest ima teži tijek u odraslih bolesnika s pridruženim kroničnim bolestima kao što su kardiovaskularne i bubrežne bolesti, kronične respiratorne bolesti, dijabetes i sl.; (iii) najteži, često fatalni oblik pojavljuje se u starijih osoba zbog izraženijih procesa imunosenescencije i upale pri starenju

DOB I INFEKCIJA VIRUSOM SARS-COV-2

SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus 2), a novel virus of the beta coronavirus group RNA viruses, is responsible for a zoonotic disease named COVID-19 (coronavirus disease from 2019). The main receptor through which the virus enters the host cell is angiotensin-converting enzyme 2 (ACE2), known as a multifunctional protein. ACE2 expression has been found in oral and nasal mucosa, lungs, adipose tissue, heart, brain, kidneys, vascular tissue, stomach, liver. Upon entry of the virus into the target host cells, two processes are initiated, the host’s immune response and the infl ammatory cascade. As immune (innate and adaptive) and infl ammatory responses change throughout life both qualitatively and quantitatively, both processes are responsible for varying degrees of disease severity depending on the patient’s age. Short-time experience with SARS-CoV-2 infection has shown that: (i) children and adolescents develop the disease with mild symptoms, mainly on upper respiratory airways; (ii) the disease has a more severe course in adult patients with associated chronic diseases such as cardiovascular and renal diseases, chronic respiratory diseases, diabetes, etc.; and (iii) the most severe, often fatal disease occurs in the elderly, due to more pronounced processes of immunosenescence and infl amm-aging.RSARS-CoV-2 (engl. Severe Acute Respiratory Syndrome Coronavirus 2), novi virus iz skupine RNA betakoronavirusa, odgovoran je za zoonotsku bolest nazvanu COVID-19 (bolest uzrokovana koronavirusom iz 2019.). Glavni receptor pomoću kojega virus ulazi u stanicu domaćina je angiotenzin konvertirajući enzim 2 (ACE2), poznat kao multifunkcionalni protein. Receptor ACE2 prisutan je u oralnoj i nosnoj sluznici, plućima, masnom tkivu, srcu, mozgu, bubrezima, vaskularnom tkivu, želucu, jetri. Nakon ulaska virusa u ciljne stanice domaćina pokreću se dva procesa, imunosni odgovor domaćina i upalna kaskada. Budući da se imunosni (urođeni i stečeni) i upalni odgovori tijekom života mijenjaju u kvalitativnom i kvantitativnom smislu, oba procesa su odgovorna za različit stupanj ozbiljnosti bolesti, ovisno o pacijentovoj dobi. Kratkotrajno iskustvo s infekcijom uzrokovanom virusom SARS-CoV-2 pokazalo je da: (i) djeca i adolescenti razvijaju bolest s blagim simptomima, uglavnom na gornjim dišnim putevima; (ii) bolest ima teži tijek u odraslih bolesnika s pridruženim kroničnim bolestima kao što su kardiovaskularne i bubrežne bolesti, kronične respiratorne bolesti, dijabetes i sl.; (iii) najteži, često fatalni oblik pojavljuje se u starijih osoba zbog izraženijih procesa imunosenescencije i upale pri starenju