Staining with Congo Red (CR) is a qualitative method used for the identification of amyloids
and in tissue sections. However, the drawbacks and artefacts obtained when using this dye can be found ...both
and
Analysis of scientific data from previous studies shows that CR staining alone is not sufficient for confirmation of the amyloid nature of protein aggregates
or for diagnosis of amyloidosis in tissue sections. In the present paper, we describe the characteristics and limitations of other methods used for amyloid studies. Our historical review on the use of CR staining for amyloid studies may provide insight into the pitfalls and caveats related to this technique for researchers considering using this dye.
Dietary intervention is widely used as a therapeutic approach ranging from the treatment of neurological disorders to attempts to extend lifespan. The most important effect of various diets is a ...change in energy metabolism. Since muscles constitute 40% of total body mass and are one of the major sites of glucose and energy uptake, various diets primarily affect their metabolism, causing both positive and negative changes in physiology and signaling pathways. In this review, we discuss changes in the energy metabolism of muscles under conditions of the low-carbohydrate, high-fat diet/ketogenic diet (KD), fasting, or administration of exogenous ketone bodies, which are all promising approaches to the treatment of various diseases. KD’s main influence on the muscle is expressed through energy metabolism changes, particularly decreased carbohydrate and increased fat oxidation. This affects mitochondrial quantity, oxidative metabolism, antioxidant capacity, and activity of enzymes. The benefits of KD for muscles stay controversial, which could be explained by its different effects on various fiber types, including on muscle fiber-type ratio. The impacts of KD or of its mimetics are largely beneficial but could sometimes induce adverse effects such as cardiac fibrosis.
Macrophages, the key cells of innate immunity, possess wide phenotypical and functional heterogeneity. In vitro studies showed that microenvironment signals could induce the so-called polarization of ...macrophages into two phenotypes: classically activated macrophages (M1) or alternatively activated macrophages (M2). Functionally, they are considered as proinflammatory and anti-inflammatory/pro-regenerative, respectively. However, in vivo studies into macrophage states revealed a continuum of phenotypes from M1 to M2 state instead of the clearly distinguished extreme phenotypes. An important role in determining the type of polarization of macrophages is played by energy metabolism, including the activity of oxidative phosphorylation. In this regard, hypoxia and ischemia that affect cellular energetics can modulate macrophage polarization. Here, we overview the data on macrophage polarization during metabolic shift–associated pathologies including ischemia and ischemia/reperfusion in various organs and discuss the role of energy metabolism potentially triggering the macrophage polarization.
Bioenergetics of the Fibrosis Yakupova, Elmira I.; Zorov, Dmitry B.; Plotnikov, Egor Y.
Biochemistry (Moscow),
12/2021, Letnik:
86, Številka:
12-13
Journal Article
Recenzirano
It is known that the development of fibrosis is associated with many diseases, being both a cause and effect of the damage to organs and tissues. Replacement of functional tissue with a scar can lead ...to organ dysfunction, which is often a life-threatening condition. The development of effective approaches for the prevention or treatment of fibrosis requires an in-depth understanding of all aspects of its pathogenesis, from epithelial-mesenchymal transformation to fibroblast proliferation. Fibrosis can be induced by trauma, ischemic injury, inflammation, and many other pathological states accompanied by repeated cycles of tissue damage and repair. Energy metabolism is the basis of functioning of all cells in an organism and its disruptions are associated with the development of different diseases, hence, it could be a target for the therapy of such pathological processes as ischemia/reperfusion, epilepsy, diabetes, cancer, and neurological disorders. The emergence of fibrosis is also associated with the changes in cell bioenergetics. In this work, we analyzed the changes in the energy metabolism that occur with the progression of fibrosis and evaluated the possibility of affecting energetics as target in the anti-fibrotic approach.
A giant multidomain protein of striated and smooth vertebrate muscles, titin, consists of tandems of immunoglobulin (Ig)- and fibronectin type III (FnIII)-like domains representing β-sandwiches, as ...well as of disordered segments. Chicken smooth muscles express several titin isoforms of ~500-1500 kDa. Using various structural-analysis methods, we investigated in vitro nonspecific amyloid aggregation of the high-molecular-weight isoform of chicken smooth-muscle titin (SMT
, ~1500 kDa). As confirmed by X-ray diffraction analysis, under near-physiological conditions, the protein formed amorphous amyloid aggregates with a quaternary cross-β structure within a relatively short time (~60 min). As shown by circular dichroism and Fourier-transform infrared spectroscopy, the quaternary cross-β structure-unlike other amyloidogenic proteins-formed without changes in the SMT
secondary structure. SMT
aggregates partially disaggregated upon increasing the ionic strength above the physiological level. Based on the data obtained, it is not the complete protein but its particular domains/segments that are likely involved in the formation of intermolecular interactions during SMT
amyloid aggregation. The discovered properties of titin position this protein as an object of interest for studying amyloid aggregation in vitro and expanding our views of the fundamentals of amyloidogenesis.
Chronic kidney disease can progress to the end-stage renal disease (ESRD) characterized by a high risk of morbidity and mortality. ESRD requires immediate therapy or even dialysis or kidney ...transplantation, therefore, its timely diagnostics is critical for many patients. ESRD is associated with pathological changes, such as inflammation, fibrosis, endocrine disorders, and epigenetic changes in various cells, which could serve as ESRD markers. The review summarizes information on conventional and new ESRD biomarkers that can be assessed in kidney tissue, blood, and urine. Some biomarkers are specific to a particular pathology, while others are more universal. Here, we suggest several universal inflammatory, fibrotic, hormonal, and epigenetic markers indicative of severe deterioration of renal function and ESRD progression for improvement of ESRD diagnostics.
Proteins can perform their specific function due to their molecular structure. Partial or complete unfolding of the polypeptide chain may lead to the misfolding and aggregation of proteins in turn, ...resulting in the formation of different structures such as amyloid aggregates. Amyloids are rigid protein aggregates with the cross-β structure, resistant to most solvents and proteases. Because of their resistance to proteolysis, amyloid aggregates formed in the organism accumulate in tissues, promoting the development of various diseases called amyloidosis, for instance Alzheimer’s diseases (AD). According to the main hypothesis, it is considered that the cause of AD is the formation and accumulation of amyloid plaques of Aβ. That is why Aβ-amyloid is the most studied representative of amyloids. Therefore, in this review, special attention is paid to the history of Aβ-amyloid toxicity. We note the main problems with anti-amyloid therapy and write about new views on amyloids that can play positive roles in the different organisms including humans.
Targeting Mitochondria for Cancer Treatment Zorova, Ljubava D; Abramicheva, Polina A; Andrianova, Nadezda V ...
Pharmaceutics,
04/2024, Letnik:
16, Številka:
4
Journal Article
Recenzirano
Odprti dostop
There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are ...both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines three specific features of adaptive mitochondrial changes in several malignant tumors. The first feature is characteristic of solid tumors, whose cells are forced to rebuild their energetics due to the absence of oxygen, namely, to activate the fumarate reductase pathway instead of the traditional succinate oxidase pathway that exists in aerobic conditions. For such a restructuring, the presence of a low-potential quinone is necessary, which cannot ensure the conventional conversion of succinate into fumarate but rather enables the reverse reaction, that is, the conversion of fumarate into succinate. In this scenario, complex I becomes the only generator of energy in mitochondria. The second feature is the increased proliferation in aggressive tumors of the so-called mitochondrial (peripheral) benzodiazepine receptor, also called translocator protein (TSPO) residing in the outer mitochondrial membrane, the function of which in oncogenic transformation stays mysterious. The third feature of tumor cells is the enhanced retention of certain molecules, in particular mitochondrially directed cations similar to rhodamine 123, which allows for the selective accumulation of anticancer drugs in mitochondria. These three features of mitochondria can be targets for the development of an anti-cancer strategy.
This work investigated in vitro aggregation and amyloid properties of skeletal myosin binding protein-C (sMyBP-C) interacting in vivo with proteins of thick and thin filaments in the sarcomeric ...A-disc. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) found a rapid (5-10 min) formation of large (>2 μm) aggregates. sMyBP-C oligomers formed both at the initial 5-10 min and after 16 h of aggregation. Small angle X-ray scattering (SAXS) and DLS revealed sMyBP-C oligomers to consist of 7-10 monomers. TEM and atomic force microscopy (AFM) showed sMyBP-C to form amorphous aggregates (and, to a lesser degree, fibrillar structures) exhibiting no toxicity on cell culture. X-ray diffraction of sMyBP-C aggregates registered reflections attributed to a cross-β quaternary structure. Circular dichroism (CD) showed the formation of the amyloid-like structure to occur without changes in the sMyBP-C secondary structure. The obtained results indicating a high in vitro aggregability of sMyBP-C are, apparently, a consequence of structural features of the domain organization of proteins of this family. Formation of pathological amyloid or amyloid-like sMyBP-C aggregates in vivo is little probable due to amino-acid sequence low identity (<26%), alternating ordered/disordered regions in the protein molecule, and S-S bonds providing for general stability.
Mitochondrial Network: Electric Cable and More Abramicheva, Polina A.; Andrianova, Nadezda V.; Babenko, Valentina A. ...
Biochemistry (Moscow),
10/2023, Letnik:
88, Številka:
10
Journal Article
Recenzirano
Mitochondria in a cell can unite and organize complex, extended structures that occupy the entire cellular volume, providing an equal supply with energy in the form of ATP synthesized in ...mitochondria. In accordance with the chemiosmotic concept, the oxidation energy of respiratory substrates is largely stored in the form of an electrical potential difference on the inner membrane of mitochondria. The theory of the functioning of extended mitochondrial structures as intracellular electrical wires suggests that mitochondria provide the fastest delivery of electrical energy through the cellular volume, followed by the use of this energy for the synthesis of ATP, thereby accelerating the process of ATP delivery compared to the rather slow diffusion of ATP in the cell. This analytical review gives the history of the cable theory, lists unsolved critical problems, describes the restructuring of the mitochondrial network and the role of oxidative stress in this process. In addition to the already proven functioning of extended mitochondrial structures as electrical cables, a number of additional functions are proposed, in particular, the hypothesis is put forth that mitochondrial networks maintain the redox potential in the cellular volume, which may vary depending on the physiological state, as a result of changes in the three-dimensional organization of the mitochondrial network (fragmentation/fission–fusion). A number of pathologies accompanied by a violation of the redox status and the participation of mitochondria in them are considered.
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