Otofaji ve sinyal yolakları (Autophagy and signaling pathways)

Programlı hücre ölümü fizyolojik ve evrimsel olarak korunmuş bir süreç olup, özellikle çok hücreli organizmalarda embryolojik gelişim, doku sağlığı ve patojenlere karşı savunma gibi birçok yaşamsal olayda önemlidir. 1972 de yayınladıkları makalede, Kerr, Wyllie ve Currie, iki hücre ölümü türünden bahsederler; apoptoz, genetik olarak kontrol edilen programlı hücre ölümü ve nekroz, programlanmamış ve kazara olan hücre ölümü (Kerr et al. 1972). Takip eden 30 yılda, “apoptoz” terimi programlı hücre ölümünü tanımlamak için genel terim olarak kullanılıp, oluşumunun ardındaki moleküler mekanizma konusunda çok miktarda bilgi toplanmıştır. Apoptoz ve nekroz kavramlarının biyoloji camiasında yarattığı heyecan nedeniyle öne çıkması, apoptotik olmayan alternatif hücre ölüm mekanizmalarının varlığının bilim dünyasının büyük bölümü tarafından göz ardı edilmesine neden olmuştur. Son yıllarda, moleküler biyoloji alanında bilgi dağarcığının giderek genişlemesi ve apoptoz araştırmalarının artık bir doygunluğa ulaşması nedeniyle, alternatif programlı hücre ölüm yollarına olan ilgi artmıştır. Alternatif programlı hücre ölüm mekanizmalarından biri olan otofajik hücre ölümüne ilgi, maya otofaji genlerinin memeli karşılıklarının bulunması ve çalışmaların morfolojik tanımlardan moleküler düzeye inmeye başlaması sayesinde artmış, sonuç olarak, otofaji, apoptoza ek veya alternatif olarak düşünülen temel yollardan birisi haline gelmiştir. Bu makalede, otofaji ve otofajik hücre ölümünün morfolojik ve moleküler temelleri ve, apoptotik yolaklarla ilişkisi tanımlanacaktır. Bu konudaki temel problemlerden biri otofajinin katabolik ve yaşamsal rolleri ile hücre ölümündeki özelliklerini bir araya getirmektir. Bu yazıda bu konu son gelişmeler ışığında anlatılacaktır

Otofaji analiz yöntemleri ve uygulama aşamaları (Autophagy analysis techniques and applications)

Hücresel anlamda stres, hücrelerin işleyişini etkilemekte, doğal dengelerini bozmakta ve hatta ölümlerine neden olabilmektedir. Hücre düzeyinde maruz kalınan stres, doku ve organların işlevlerini aksatmalarına neden olabilmekte ve organizma genelinde kendisini hastalık olarak göstermektedir. Stres iç ve dış faktörlere bağlı olarak gelişebilir. Kronik hastalıkların metabolizma üzerinde etkileri, hormonal değişiklikler, biyokimyasal değişiklikler ya da uzun süreli enflamasyon iç faktörlere bağlı stresin nedenleri arasındadır. Besin, büyüme faktörü ya da oksijen eksikliği (iskemi), toksik maddeler, bazı ilaç ve kimyasallara maruz kalma, ultraviyole ışınları, radyasyon gibi ışımalar hücresel strese yol açabilen dış faktörler olarak sayılabilir. Ayrıca bazı kalıtsal hastalıklar (örneğin, kistik fibroz, alfa1-antitiripsin eksikliği vb) ya da kalıtsal komponenti olan hastalıklar (örneğin, Alzheimer ya da Parkinson hastalığı), hücre içinde ve dışında toksik etkiler gösteren anormal proteinlerin birikimine neden olarak hücresel strese yol açabilirler. Stresin nedenine göre farklı hücresel yolakların aktive olabilmesine karşın, yukarıda bahsedilenler dahil pek çok stres faktörüne karşı hücrelerin verdiği en temel iki yanıt otofaji ve stresin dozuna göre programlı hücre ölümüdür. Otofajik hücre ölümüne stres dışında, doku ve organ gelişimi sırasında da rastlamak mümkündür. Klasik olarak hücre ölümü apoptoz (programlı) ve nekroz (programsız) olarak iki sınıfa ayrılmıştı. Fakat son yıllarda yapılan çalışmalar, apoptoz dışı programlı hücre ölüm yolakları da bulunduğunu ortaya çıkarmıştır. Hatta “programlı nekroz” adı verilen hücre ölüm tiplerinin de bulunduğu önerilmiştir. Çoğunlukla bir stres yanıtı ve hayatta kalma mekanizması olarak işleyen otofajinin bile, özellikle apoptozun mümkün olmadığı durumlarda “otofajik hücre ölümü” adı verilen bir programlı hücre ölüm mekanizmasına dönüştüğü gözlenmiştir (Gozuacik D, 2007, Öz-Arslan D, 2011). Bu makalede otofajik hücre ölümü analiz yöntemleri tartışılacaktır

Crosstalk between mammalian autophagy and the ubiquitin-proteasome system

Autophagy and the ubiquitin-proteasome system (UPS) are the two major intracellular quality control and recycling mechanisms that are responsible for cellular homeostasis in eukaryotes. Ubiquitylation is utilized as a degradation signal by both systems, yet, different mechanisms are in play. The UPS is responsible for the degradation of short-lived proteins and soluble misfolded proteins whereas autophagy eliminates long-lived proteins, insoluble protein aggregates and even whole organelles (e.g., mitochondria, peroxisomes) and intracellular parasites (e.g., bacteria). Both the UPS and selective autophagy recognize their targets through their ubiquitin tags. In addition to an indirect connection between the two systems through ubiquitylated proteins, recent data indicate the presence of connections and reciprocal regulation mechanisms between these degradation pathways. In this review, we summarize these direct and indirect interactions and crosstalks between autophagy and the UPS, and their implications for cellular stress responses and homeostasis

Role of autophagy in cancer-associated fibroblast activation, signaling and metabolic reprograming

Tumors not only consist of cancerous cells, but they also harbor several normal-like cell types and non-cellular components. cancer-associated fibroblasts (CAFs) are one of these cellular components that are found predominantly in the tumor stroma. Autophagy is an intracellular degradation and quality control mechanism, and recent studies provided evidence that autophagy played a critical role in CAF formation, metabolic reprograming and tumor-stroma crosstalk. Therefore, shedding light on the autophagy and its role in CAF biology might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the exploitation of more efficient cancer diagnosis and treatment. Here, we provide an overview about the involvement of autophagy in CAF-related pathways, including transdifferentiation and activation of CAFs, and further discuss the implications of targeting tumor stroma as a treatment option

Bubbly cavitating flow generation and investigation of its erosional nature for biomedical applications

This paper was presented at the 2nd Micro and Nano Flows Conference (MNF2009), which was held at Brunel University, West London, UK. The conference was organised by Brunel University and supported by the Institution of Mechanical Engineers, IPEM, the Italian Union of Thermofluid dynamics, the Process Intensification Network, HEXAG - the Heat Exchange Action Group and the Institute of Mathematics and its Applications.The paper presents a study of the generation of hydrodynamic bubbly cavitation in microchannels to investigate the destructive energy output resulting from this phenomenon and its potential use in biomedical applications. The research performed in this study includes the experimental results from bubbly cavitation experiments and the findings showing the destructive effects of bubbly cavitating flow on selected specimens and cells. The bubbles caused by hydrodynamic cavitation are highly destructive at the surfaces of the target medium on which they are carefully focused. The resulting destructive energy output could be effectively used for good means such as destroying kidney stones or killing infected cancer cells. Motivated by this potential, the cavitation damage (material removal) to cancerous cells and chalk pieces having similar material properties as calcium phosphate in human bones was investigated. Also the potential of hydrodynamic bubbly cavitation generated at the microscale for biomedical treatments was revealed using the microchannel configuration of a microorifice (with an inner diameter of 0.147 mm and a length of 1.52cm).This work was supported by Sabancı University Internal Grant for Research Program under Grant FRG-C47004

Novel parameter estimation schemes in microsystems

This paper presents two novel estimation methods that are designed to enhance our ability of observing, positioning, and physically transforming the objects and/or biological structures in micromanipulation tasks. In order to effectively monitor and position the microobjects, an online calibration method with submicron precision via a recursive least square solution is presented. To provide the adequate information to manipulate the biological structures without damaging the cell or tissue during an injection, a nonlinear spring-mass-damper model is introduced and mechanical properties of a zebrafish embryo are obtained. These two methods are validated on a microassembly workstation and the results are evaluated quantitatively

Techniques to Study Autophagy in Plants

Autophagy (or self eating), a cellular recycling mechanism, became the center of interest and subject of intensive research in recent years. Development of new molecular techniques allowed the study of this biological phenomenon in various model organisms ranging from yeast to plants and mammals. Accumulating data provide evidence that autophagy is involved in a spectrum of biological mechanisms including plant growth, development, response to stress, and defense against pathogens. In this review, we briefly summarize general and plant-related autophagy studies, and explain techniques commonly used to study autophagy. We also try to extrapolate how autophagy techniques used in other organisms may be adapted to plant studies

Autophagy and cancer

Autophagy is an evolutionary conserved intracellular degradation and stress response mechanism that is mainly responsible for the breakdown and recycling of cytoplasmic materials, including long-lived proteins, protein aggregates, and damaged organelles. In this way, autophagy provides the cell with building blocks and allows the maintenance of homeostasis under stress conditions such as growth factor deficiency, nutrient deprivation, hypoxia, and toxins. Consequently, abnormalities of autophagy contribute to a number of pathologies ranging from neurodegenerative diseases to cancer. Autophagy was reported to have a dual role in cancer. Depending on cancer stage, autophagy seems to act as tumor suppressor or as a mechanism supporting tumor growth and spread. In this review, we provide a summary of the relevant literature and discuss the role of autophagy in cancer formation and chemotherapy responses

Hydroxychloroquine for chronic myeloid leukemia: complete cure on the horizon?

No abstract available

Autophagy: a cellular stres and a cell death mechanism (Otofaji: bir hücresel stres yanıtı ve ölüm mekanizması)

Autophagy is a physiological phenomenon responsible for the degradation of long-lived proteins, organelles and cytoplasmic fragments. It allows cellular recycling following lysosomal degradation and helps the cell to survive various stress conditions including starvation, growth factor and oxidative stress. Paradoxically, under certain conditions autophagy may kill the cell through a caspase-independent, non-apoptotic type of cell death (Type II cell death or autophagic cell death). Several lines of evidence point out to a direct connection between classical apoptosis and autophagy. Molecular mechanisms of apoptosis-autophagy connection start to be unraveled. The cross-talk between autophagy and apoptosis seems quite complex but certainly is critical for the development of novel diagnosis, follow-up and treatment modalities in health problems such as cancer, infections and neurodegenerative diseases