Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

• Klíčová slova
• Autophagy, BNIP3L, PINK1, TFEB, mild cognitive impairment, mitophagy,
• MeSH
• Alzheimerova nemoc * mozkomíšní mok   krev   diagnóza   MeSH
• biologické markery * mozkomíšní mok   krev   metabolismus   MeSH
• kognitivní dysfunkce mozkomíšní mok   krev   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny mozkomíšní mok   metabolismus   krev   MeSH
• mitofagie * MeSH
• mozek metabolismus   patologie   MeSH
• nádorové supresorové proteiny MeSH
• proteinkinasy metabolismus   MeSH
• proteiny tau mozkomíšní mok   metabolismus   MeSH
• protoonkogenní proteiny mozkomíšní mok   krev   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory BHLH-Zip metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery * MeSH
• BNIP3L protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• nádorové supresorové proteiny MeSH
• proteinkinasy MeSH
• proteiny tau MeSH
• protoonkogenní proteiny MeSH
• PTEN-induced putative kinase MeSH Prohlížeč
• TFEB protein, human MeSH Prohlížeč
• transkripční faktory BHLH-Zip MeSH

Human fetal membranes (amniochorion) that line the intrauterine cavity consist of two distinct cell layers; single-layer amnion epithelial cells (AEC) and multilayer chorion trophoblast cells (CTC). These layers are connected through a collagen-rich extracellular matrix. Cellular remodeling helps support membrane growth and integrity during gestation and helps to maintain pregnancy. Preterm prelabor rupture of the human amniochorionic (fetal) membrane (pPROM) is antecedent to 40% of all spontaneous preterm birth. Oxidative stress (OS) induced activation of the p38 MAPK due to various maternal risk exposures and the amniochorion cells' senescence are reported pathological features of pPROM. Our transcriptomics analysis implicated dysregulated autophagy and epithelial-mesenchymal transition (EMT) in fetal membranes from pPROM. The molecular interplay between OS-induced p38 MAPK activation, autophagy, and EMT was investigated in AECs and CTCs to better understand the involvement of autophagy and EMT. We report the differential impact of OS on the autophagic machinery in AECs and CTCs, resulting in distinct cell fates. In AECs, OS-induced p38 MAPK activation causes autophagosome accumulation and reduced autophagic flux mediated by decreased ULK1 activity and kinase activity, leading to senescence. In CTCs, induction of autophagy has a limited effect; however, inhibition of autophagy led to SQSTM1-mediated EMT of trophoblast cells. Autophagy, EMT, and senescence were associated with proinflammatory changes. Thus, AECs and CTCs respond differently to OS via differential autophagy response, partly mediated via p38 MAPK. Besides senescence, OS-induced autophagy dysregulation in amniochorion cells may play a mechanistic role in pPROM pathophysiology.

• Klíčová slova
• Membrane rupture, Oxidative stress, amnion, autophagy, chorion, epithelial-mesenchymal transition, p38 MAPK, preterm birth, preterm premature rupture of membranes, senescence, trophoblast,
• Publikační typ
• časopisecké články MeSH

Multi-drug resistance (MDR) is a leading cause of cancer-related death, and it continues to be a major barrier to cancer treatment. The tumour microenvironment (TME) has proven to play an essential role in not only cancer progression and metastasis, but also the development of resistance to chemotherapy. Despite the significant advances in the efficacy of anti-cancer therapies, the development of drug resistance remains a major impediment to therapeutic success. This review highlights the interplay between various factors within the TME that collectively initiate or propagate MDR. The key TME-mediated mechanisms of MDR regulation that will be discussed herein include (1) altered metabolic processing and the reactive oxygen species (ROS)-hypoxia inducible factor (HIF) axis; (2) changes in stromal cells; (3) increased cancer cell survival via autophagy and failure of apoptosis; (4) altered drug delivery, uptake, or efflux and (5) the induction of a cancer stem cell (CSC) phenotype. The review also discusses thought-provoking ideas that may assist in overcoming the TME-induced MDR. We conclude that stressors from the TME and exposure to chemotherapeutic agents are strongly linked to the development of MDR in cancer cells. Therefore, there remains a vast area for potential research to further elicit the interplay between factors existing both within and outside the TME. Elucidating the mechanisms within this network is essential for developing new therapeutic strategies that are less prone to failure due to the development of resistance in cancer cells.

• Klíčová slova
• cancer stem cells, drug resistance, reactive oxygen species, tumour microenvironmental stress,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Autophagy is best known for its role in organelle and protein turnover, cell quality control, and metabolism. The autophagic machinery has, however, also adapted to enable protein trafficking and unconventional secretory pathways so that organelles (such as autophagosomes and multivesicular bodies) delivering cargo to lysosomes for degradation can change their mission from fusion with lysosomes to fusion with the plasma membrane, followed by secretion of the cargo from the cell. Some factors with key signalling functions do not enter the conventional secretory pathway but can be secreted in an autophagy-mediated manner.Positive clinical results of some autophagy inhibitors are encouraging. Nevertheless, it is becoming clear that autophagy inhibition, even within the same cancer type, can affect cancer progression differently. Even next-generation inhibitors of autophagy can have significant non-specific effects, such as impacts on endosome-related secretory pathways and secretion of extracellular vesicles (EVs). Many studies suggest that cancer cells release higher amounts of EVs compared to non-malignant cells, which makes the effect of autophagy inhibitors on EVs secretion highly important and attractive for anticancer therapy. In this review article, we discuss how different inhibitors of autophagy may influence the secretion of EVs and summarize the non-specific effects of autophagy inhibitors with a focus on endosome-related secretory pathways. Modulation of autophagy significantly impacts not only the quantity of EVs but also their content, which can have a deep impact on the resulting pro-tumourigenic or anticancer effect of autophagy inhibitors used in the antineoplastic treatment of solid cancers.

• Klíčová slova
• Amphisomes, Autophagy, Autophagy inhibitors, Cancer, Endosomes, Exosomes, Extracellular vesicles, Multivesicular bodies, Non-conventional secretory pathways,
• MeSH
• autofagie účinky léků   MeSH
• autofagozomy metabolismus   MeSH
• cílená molekulární terapie * MeSH
• endocytóza účinky léků   MeSH
• endozomy metabolismus   MeSH
• exozómy metabolismus   MeSH
• lidé MeSH
• nádory farmakoterapie   etiologie   metabolismus   MeSH
• progrese nemoci MeSH
• proteolýza MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• sekreční dráha účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové látky MeSH