In the last two decades, a school of thought emerged that perceives male reproductive health, testicular function, and sperm output as a sentry for general, somatic health. Large-scale epidemiologic studies have already linked the reduced sperm count to increased risk of chronic somatic disease (e.g., cancer, cardiovascular, neurological and bone diseases), yet most of these studies have not taken full advantage of advanced andrological analysis. Altered proteostasis, i.e., the disbalance between protein synthesis and turnover, is a common denominator of many diseases, including but not limited to cancer and neurodegenerative diseases. This chapter introduces the concept of cellular proteostasis as a measure of sperm structural and functional integrity and an endpoint of varied impacts on spermiogenesis and sperm maturation, including heritability, general health, lifestyle, and occupational and environmental reprotoxic exposure. Special consideration is given to small molecule protein modifiers, sperm-binding seminal plasma proteins, zinc-interacting proteins, and redox proteins responsible for the maintenance of protein structure and the protection of spermatozoa from oxidative damage. While the main focus is on human male infertility, serious consideration is given to relevant animal models, and in particular to male food animals with extensive records of fertility from artificial insemination services. Altogether, the proteostatic biomarker discovery and validation studies set the stage for the integration of proteomics of sperm proteostasis with genomic and high throughput phenomic approaches to benefit both human and animal reproductive medicine.

• MeSH
• fertilita * fyziologie   MeSH
• homeostáze proteinů * fyziologie   MeSH
• lidé MeSH
• mužská infertilita * metabolismus   genetika   patologie   patofyziologie   MeSH
• spermatogeneze * MeSH
• spermie * metabolismus   patologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Genomic alterations and enormous monoclonal immunoglobulin production cause multiple myeloma to heavily depend on proteostasis mechanisms, including protein folding and degradation. These findings support the use of proteasome inhibitors for treating multiple myeloma and mantle cell lymphoma. Myeloma treatment has evolved, especially with the availability of new drugs, such as proteasome inhibitors, into therapeutic strategies for both frontline and relapsed/refractory disease settings. However, proteasome inhibitors are generally not effective enough to cure most patients. Natural resistance and eventual acquired resistance led to relapsed/refractory disease and poor prognosis. Advances in the understanding of cellular proteostasis and the development of innovative drugs that also target other proteostasis network components offer opportunities to exploit the intrinsic vulnerability of myeloma cells. This review outlines recent findings on the molecular mechanisms regulating cellular proteostasis pathways, as well as resistance, sensitivity, and escape strategies developed against proteasome inhibitors and provides a rationale and examples for novel combinations of proteasome inhibitors with FDA-approved drugs and investigational drugs targeting the NRF1 (NFE2L1)-mediated proteasome bounce-back response, redox homeostasis, heat shock response, unfolding protein response, autophagy, and VCP/p97 to increase proteotoxic stress, which can improve the efficacy of antimyeloma therapy based on proteasome inhibitors.

• MeSH
• chemorezistence MeSH
• homeostáze proteinů * účinky léků   MeSH
• inhibitory proteasomu * terapeutické užití   farmakologie   MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   metabolismus   MeSH
• protinádorové látky * terapeutické užití   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Accumulating evidence suggests that manganese oxide nanoparticles (NPs) show multiple enzyme-mimicking antioxidant activities, which supports their potential in redox-targeting therapeutic strategies for diseases with impaired redox signaling. However, the systemic administration of any NP requires thorough hemocompatibility testing. In this study, we assessed the hemocompatibility of synthesized Mn3O4 NPs, identifying their ability to induce spontaneous hemolysis and eryptosis or impair osmotic fragility. Concentrations of up to 20 mg/L were found to be safe for erythrocytes. Eryptosis assays were shown to be more sensitive than hemolysis and osmotic fragility as markers of hemocompatibility for Mn3O4 NP testing. Flow cytometry- and confocal microscopy-based studies revealed that eryptosis induced by Mn3O4 NPs was accompanied by Ca2+ overload, altered redox homeostasis verified by enhanced intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS), and a decrease in the lipid order of cell membranes. Furthermore, Mn3O4 NP-induced eryptosis was calpain- and caspase-dependent.

• MeSH
• buněčná membrána * metabolismus   účinky léků   MeSH
• eryptóza * účinky léků   MeSH
• erytrocyty účinky léků   metabolismus   MeSH
• hemolýza účinky léků   MeSH
• kalpain * metabolismus   MeSH
• kaspasy * metabolismus   MeSH
• lidé MeSH
• nanočástice * chemie   MeSH
• oxidy * farmakologie   chemie   MeSH
• reaktivní formy dusíku * metabolismus   MeSH
• reaktivní formy kyslíku * metabolismus   MeSH
• sloučeniny manganu * farmakologie   chemie   MeSH
• vápník * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Úvod: V důsledku metabolických dějů dochází v živých strukturách k endogenní produkci chemiluminiscence, kterou také označujeme jako biologickou autochemiluminiscenci (BAL). Generování BAL je úzce spojeno s oxidačními procesy, tvorbou volných radikálů a obecně oxidačně-redukční homeostázou zkoumaného biologického materiálu. BAL byla již dříve studována v savčích buněčných modelech a tkáních. Doposud ovšem nebyl tento jev popsán v případě struktur zubní tkáně. Kromě endogenně generované BAL lze BAL indukovat i exogenně, a to jak fyzikálními (UV záření, mechanické poškození, teplo), tak i chemickými (oxidační činidla, např. H2O2) a biotickými (patogeny) faktory. Metodika: V předložené práci byla zkoumána endogenně produkovaná i exogenně indukovaná BAL v povrchových a vnitřních strukturách semiretinovaných a retinovaných třetích molárů, které byly indikovány k extrakci zubním lékařem pro jejich nevhodné uložení v čelisti u dvou pacientů (žena, 21 let, muž, 22 let). Detekce BAL byla provedena po mechanickém odstranění zubního plaku rotačním kartáčkem. Pomocí piezoelektrické pily byly připraveny podélné řezy vedené tak, aby došlo k odhalení všech vnitřních částí zubu. Takto připravené vzorky – celého vnitřního řezu a vnější části celého zubu – byly podrobeny detekci BAL ve světlotěsné komoře za použití fotonásobičového modulu. Následně byly vzorky ošetřeny roztokem oxidačního činidla 3% H2O2 a redukčního činidla 10 mM TCEP (tris(karboxyethyl)fosfin). Výsledky: U obou vzorků zubu bylo prokázáno, že produkují BAL. Produkce endogenní chemiluminiscence byla pozorována ve vnitřních strukturách zubu (18 600 pulzů/600 s), která byla přibližně 2,7krát vyšší než BAL detekovaná na povrchových strukturách zubu (6 900 pulzů/600 s). Po ošetření H2O2 došlo k významnému (až 14násobnému) nárůstu BAL pro vnitřní struktury zubu ve srovnání s bazální intenzitou endogenně produkované BAL. Aplikace TCEP (negativní kontrola) vedla k mírnému potlačení produkce BAL. Závěr: Výsledky této pilotní studie ukazují, že BAL může být produkována nejenom měkkými tkáněmi, ale i tvrdou zubní tkání. Získané výsledky by mohly být využity k výzkumu metabolické aktivity a reaktivity vnitřních i vnějších částí zubu, a to především v kontextu výzkumu oxidačněredukční homeostázy. Detekce BAL by také mohla být aplikována pro vývoj nových zobrazovacích technik.

Introduction: As a result of metabolic processes, the endogenous production of chemiluminescence occurs in living biological structures, which we also refer to as biological autochemiluminescence (BAL). The generation of BAL is closely connected with oxidation processes, the formation of free radicals, and in general the redox homeostasis of the investigated biological material. BAL has previously been studied in mammalian cells and tissues. So far, however, this phenomenon has not been described in dental tissue structures. In addition to endogenously generated BAL, BAL can be exogenously induced by physical (UV radiation, mechanical damage, heat), chemical (oxidizing agents, e.g. H2O2) or biotic (pathogens) factors. Methods: Endogenously and exogenously induced BAL were investigated on the surface and internal structures of semi-impacted and impacted third molars, which were indicated for extraction by a dentist due to their inappropriate placement in the jaw in two patients (a 21-year-old woman and a 22-year-old man). BAL detection was performed with samples after dental plaque was mechanically removed with a rotating brush. Using a piezosurgery unit with a saw headpiece, longitudinal sections were made to reveal all internal parts of the tooth. The samples prepared in this way – the entire internal section and the external part of the entire tooth – were subjected to BAL detection in a dark chamber using H7360-01 PMT photomultiplier. Subsequently, the samples were treated with a solution of the oxidizing agent 3% H2O2 or the reducing agent 10 mM TCEP (tris(carboxyethyl)phosphine). Results: Both tooth samples were shown to produce BAL. Endogenous chemiluminescence production was observed in the internal structures of the tooth (18,600 counts/600 s), which was 2.7-fold higher than the BAL detected on the tooth outer surfaces (6,900 counts/600 s). After H2O2 treatment, there was a significant (up to 14-fold) increase in BAL for internal tooth structures compared to the basal intensity of endogenously produced BAL. The application of TCEP (negative control) resulted in a residual suppression of BAL production. Conclusion: The results of this pilot study show that BAL can be produced not only by soft tissues but also by hard dental tissue. The obtained results could be used for further research of the metabolic activity and reactivity of the inner and outer parts of the tooth, especially in the context of redox biology research. BAL detection could also be applied in the development of new imaging techniques.

• MeSH
• lidé MeSH
• luminiscence * MeSH
• luminiscenční měření MeSH
• moláry MeSH
• oxidační stres MeSH
• peroxid vodíku chemie   MeSH
• pilotní projekty MeSH
• struktury zubu MeSH
• Check Tag
• lidé MeSH

Imbalanced redox homeostasis, involving either oxidative stress or reductive stress, can profoundly impact cellular functions, contributing to various diseases. While the implications of oxidative stress in the adverse effects of nanoparticles have been extensively studied, our comprehension of reductive stress within the context of nano-redox system interactions remains limited. Here we illuminate a domino effect initiated by the dehydrogenase-like activity of transition metal borides. Specifically, seven transition metal borides were identified to emulate the enzymatic activity of natural dehydrogenases, resulting in heightened levels of reductive constituents within critical biological redox pairs in cells. Mass cytometry analysis provides compelling evidence that reductive stress initiates an immunosuppressive environment within lung tissues, promoting the metastasis of breast cancer cells to the lungs. In summary, our study unveils the chemical basis of nano-induced reductive stress and establishes a mechanistic axis that interlinks dehydrogenase-like activity, reductive stress, immunosuppression and tumour metastasis.

• MeSH
• katalýza MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory plic sekundární   imunologie   MeSH
• nádory prsu patologie   imunologie   MeSH
• oxidace-redukce MeSH
• oxidační stres * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis.

• MeSH
• chondrocyty * metabolismus   MeSH
• ferroptóza * fyziologie   MeSH
• glukosa-6-fosfátdehydrogenasa metabolismus   MeSH
• glukosa metabolismus   MeSH
• myši MeSH
• oxidace-redukce MeSH
• oxidační stres * MeSH
• pentózofosfátový cyklus * MeSH
• reaktivní formy kyslíku * metabolismus   MeSH
• sbalování proteinů * MeSH
• signální dráha UPR MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) plays a crucial role in regulation of metabolic homeostasis. To understand the role of the catalytic α2 subunit of AMPK in skeletal muscle energy metabolism, myotube cultures were established from AMPKα2+/+ and AMPKα2-/- mice. Myotubes from AMPKα2-/- mice had lower basal oleic acid and glucose oxidation compared to myotubes from AMPKα2+/+ mice. However, the relative response to mitochondrial uncoupling was increased for oleic acid oxidation. Incorporation of acetate into lipids was also lower in myotubes from AMPKα2-/- mice. Proteomics analysis revealed that AMPKα2-/- myotubes had upregulated pathways related to mitochondrial function and fatty acid oxidation, and decreased pathways related to fatty acid biosynthesis. In conclusion, ablation of AMPKα2 catalytic subunit in skeletal muscle cells resulted in reduced basal oxidation of glucose and fatty acids, however upregulated pathways related to mitochondrial function and fatty acid oxidation and reduced lipid formation.

• MeSH
• energetický metabolismus MeSH
• glukosa * metabolismus   MeSH
• kosterní svalová vlákna * metabolismus   cytologie   MeSH
• kosterní svaly metabolismus   MeSH
• kultivované buňky MeSH
• mastné kyseliny metabolismus   MeSH
• metabolismus lipidů * MeSH
• mitochondrie metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• oxidace-redukce MeSH
• proteinkinasy aktivované AMP * genetika   metabolismus   nedostatek   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Hypoxic pulmonary vasoconstriction (HPV) rapidly and reversibly matches lung ventilation (V) and perfusion (Q), optimizing oxygen uptake and systemic oxygen delivery. HPV occurs in small pulmonary arteries (PA), which uniquely constrict to hypoxia. Although HPV is modulated by the endothelium the core mechanism of HPV resides in PA smooth muscle cells (PASMC). The PASMC's mitochondrial oxygen sensor lies within the electron transport chain (ETC) and includes NDUFS2 in ETC Complex-I. PASMC mitochondria respond to hypoxia by varying production of reactive oxygen species (ROS) and hydrogen peroxide in proportion to alveolar oxygen tension. Hypoxic ROS inhibition results in a state of reduction which triggers a redox-mediated inhibition of oxygen-sensitive, voltage-gated, potassium channels, including Kv1.5 and Kv2.1. Kv channel inhibition depolarizes the PASMC, opening of large-conductance calcium channels (CaL), elevating cytosolic calcium and activating the contractile apparatus. HPV is strongest in small PAs where sensors (hypoxia-responsive mitochondria) and effectors (oxygen-sensitive K+ channels) are enriched. Oxygenation at birth reverses fetal HPV, contributing to the rapid neonatal drop in pulmonary vascular resistance (PVR). A similar mitochon-drial-K+ channel sensor-effector mechanism exists in the ductus arteriosus (DA), however in DASMC it is oxygen-induced increases in mitochondrial ROS that inhibit DASMC K+ channels, causing DA constriction. Atelectasis and pneumonia elicit HPV, which optimises V/Q matching, increasing systemic oxygenation. Whilst HPV in response to localized hypoxia in a single lung lobe does not increase PA pressure; global airway hypoxia, as occurs with altitude or sleep apnea, causes pulmonary hypertension. HPV can be inhibited by drugs, including calcium channel blockers, or used to maintain a dry operative field during single lung anesthesia for lung surgery. HPV does not normally cause lung edema but excessive, heterogenous HPV contributes to high altitude pulmonary edema. HPV is suppressed in COVID-19 pneumonia by a SARS-CoV-2 mitochondriopathy. HPV is a component of the body's homeostatic oxygen sensing system. Keywords: Ductus arteriosus, Redox, NDUFS2, Oxygen sensitive potassium, Channels, High altitude pulmonary edema (HAPE), Mitochondrial electron transport chain, COVID-19 pneumonia, Atelectasis.

• MeSH
• arteria pulmonalis metabolismus   MeSH
• COVID-19 metabolismus   komplikace   MeSH
• homeostáza * fyziologie   MeSH
• hypoxie * metabolismus   patofyziologie   MeSH
• kyslík * metabolismus   MeSH
• lidé MeSH
• vazokonstrikce * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Úvod: Dutina ústní představuje komplexní systém, kde probíhá vzájemná chemická komunikace mezi tkáněmi, mikrobiotou a složkami sliny a potravy. Tento článek je zaměřen na hormetické efekty a elektrofilní sloučeniny, které mohou hrát roli v obranných mechanismech proti oxidačnímu stresu a zánětlivým procesům. Hormetické efekty, vyvolané subletálními nebo subtoxickými stresory, mohou aktivovat reparační mechanismy a posílit odolnost tkání proti poškození. Metodika: Analýza byla provedena prostřednictvím vyhledávání ve třech elektronických databázích: Web of Science, PubMed a Scopus. V rámci rešerše jsme se soustředili na studie publikované mezi lety 2000 a 2023, které se zabývaly oxidačně-redukčními procesy, zánětlivými stavy a aktivací Nrf2 dráhy v ústní dutině. Vyloučeny byly studie zaměřené na nádorová onemocnění. Závěr: Elektrofilní sloučeniny působí jako jeden z činitelů zasahujících do homeostázy dutiny ústní a mohou tak představovat terapeutický potenciál v zubním lékařství, konkrétně v parodontologii. Zjištění založená na in vitro a preklinických studiích však vyžadují další ověření v klinických podmínkách, přičemž je třeba zvážit i interakce s orální mikrobiotou.

Introduction: The oral cavity is a complex system in which mutual chemical communication occurs between tissues, microbiota, and components of saliva and food. This paper focuses on hormetic effects and electrophilic compounds, which can play a role in defense mechanisms against oxidative stress and inflammatory processes. Hormetic effects, induced by sublethal or subtoxic stressors, can activate repair mechanisms and enhance tissue resistance to damage. Methods: The analysis was conducted through searches in three electronic databases: Web of Science, PubMed, and Scopus. Our research focused on studies published between 2000 and 2023 that dealt with redox processes, inflammatory conditions, and activation of the Nrf2 pathway in the oral cavity. Studies focused on cancerous diseases were excluded. Conclusion: Electrophilic compounds act as one of the agents that interfere with the homeostasis of the oral cavity, and can thus find therapeutic potential in dentistry, specifically in periodontology. However, findings based on in vitro and preclinical studies require further verification under clinical conditions, and also considering interactions with oral microbiota.

• MeSH
• antioxidační responzivní elementy * fyziologie   MeSH
• fyziologický stres MeSH
• homeostáza fyziologie   MeSH
• hormeze fyziologie   MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• oxidace-redukce MeSH
• ústa * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• systematický přehled MeSH

Viral infection may represent a stress condition to the host cell. Cells react to it by triggering the defence programme to restore homeostasis and these events may in turn impact the viral replication. The knowledge about tick-borne encephalitis virus (TBEV) infection-associated stress is limited. Here we investigated the interplay between TBEV infection and stress pathways in PMJ2-R mouse macrophage cell line, as macrophages are the target cells in early phases of TBEV infection. First, to determine how stress influences TBEV replication, the effect of stress inducers H2O2 and tunicamycin (TM) was tested. Viral multiplication was decreased in the presence of both stress inducers suggesting that the stress and cellular stress responses restrict the virus replication. Second, we investigated the induction of oxidative stress and endoplasmic reticulum (ER) stress upon TBEV infection. The level of oxidative stress was interrogated by measuring the reactive oxygen species (ROS). ROS were intermittently increased in infected cells at 12 hpi and at 72 hpi. As mitochondrial dysfunction may result in increased ROS level, we evaluated the mitochondrial homeostasis by measuring the mitochondrial membrane potential (MMP) and found that TBEV infection induced the hyperpolarization of MMP. Moreover, a transient increase of gene expression of stress-induced antioxidative enzymes, like p62, Gclm and Hmox1, was detected. Next, we evaluated the ER stress upon TBEV infection by analysing unfolded protein responses (UPR). We found that infection induced gene expression of two general sensors BiP and CHOP and activated the IRE1 pathway of UPR. Finally, since the natural transmission route of TBEV from its tick vector to the host is mediated via tick saliva, the impact of tick saliva from Ixodes ricinus on stress pathways in TBEV-infected cells was tested. We observed only marginal potentiation of UPR pathway. In conclusion, we found that TBEV infection of PMJ2-R cells elicits the changes in redox balance and triggers cellular stress defences, including antioxidant responses and the IRE1 pathway of UPR. Importantly, our results revealed the negative effect of stress-evoked events on TBEV replication and only marginal impact of tick saliva on stress cellular pathways.

• MeSH
• buněčné linie MeSH
• klíšťová encefalitida * MeSH
• myši MeSH
• peroxid vodíku metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• replikace viru MeSH
• viry klíšťové encefalitidy * genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH