Intravenously Injected Amyloid-β Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice Model of Alzheimer’s Disease

Cerebral β-amyloidosis, an accumulation in the patient’s brain of aggregated amyloid-β (Aβ) peptides abnormally saturated by divalent biometal ions, is one of the hallmarks of Alzheimer’s disease (AD). Earlier, we found that exogenously administrated synthetic Aβ with isomerized Asp7 (isoD7-Aβ) induces Aβ fibrillar aggregation in the transgenic mice model of AD. IsoD7-Aβ molecules have been implied to act as seeds enforcing endogenous Aβ to undergo pathological aggregation through zinc-mediated interactions. On the basis of our findings on zinc-induced oligomerization of the metal-binding domain of various Aβ species, we hypothesize that upon phosphorylation of Ser8, isoD7-Aβ loses its ability to form zinc-bound oligomeric seeds. In this work, we found that (i) in vitro isoD7-Aβ with phosphorylated Ser8 (isoD7-pS8-Aβ) is less prone to spontaneous and zinc-induced aggregation in comparison with isoD7-Aβ and intact Aβ as shown by thioflavin T fluorimetry and dynamic light scattering data, and (ii) intravenous injections of isoD7-pS8-Aβ significantly slow down the progression of institutional β-amyloidosis in AβPP/PS1 transgenic mice as shown by the reduction of the congophilic amyloid plaques’ number in the hippocampus. The results support the role of the zinc-mediated oligomerization of Aβ species in the modulation of cerebral β-amyloidosis and demonstrate that isoD7-pS8-Aβ can serve as a potential molecular tool to block the aggregation of endogenous Aβ in AD

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition

The triggers of late-onset sporadic Alzheimer’s disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a potential seeding mechanism for the formation of neurotoxic Aβ oligomers and aggregates. Phosphorylation of Aβ by Ser8 (pS8-Aβ), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of Aβ, and moreover pS8-Aβ suppresses zinc-driven aggregation of non-modified Aβ in an equimolar mixture. We have further analyzed the effect of pS8-Aβ on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified Aβ that has no influence on the amyloidosis progression in murine models of AD, pS8-Aβ injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by Aβ, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of Aβ are neutralized by its phosphorylation

Blockade of MMP14 Activity in Murine Breast Carcinomas: Implications for Macrophages, Vessels, and Radiotherapy

Background: Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects. Methods: Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5-10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor β (TGFβ) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided. Results: DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFβ and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4%-38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm3: control, 12 days, IQR = 9-13 days; DX-2400 plus radiation, 29 days, IQR = 26-30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors. Conclusion: MMP14 blockade decreased immunosuppressive TGFβ, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumor

Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors—inexpensive drugs with decades of safe use—could be rapidly repurposed as cancer therapeutics.National Cancer Institute (U.S.) (Grant P01-CA080124)National Cancer Institute (U.S.) (Grant R01-CA126642)National Cancer Institute (U.S.) (Grant R01-CA085140)National Cancer Institute (U.S.) (Grant R01-CA115767)National Cancer Institute (U.S.) (Grant R01-CA098706)United States. Dept. of Defense. Breast Cancer Research Program (Innovator Award W81XWH-10-1-0016)Lustgarten Foundation (Dana-Farber Cancer Institute/David H. Koch Institute for Integrative Cancer Research at MIT Bridge Project Grant

LINEAR ANTIGENIC DETERMINANTS OF CYTOCHROMES R450 101 AND R450 2V4

The aim of the work is to perform the total antigenic mapping of cytochromes R450 101 and R450 2V4. The data about antigenic determinants of the cytochromes R450 101 and R450 2V4 have been obtained firstly. A possibility to obtain the antipeptide antibodies with functional activity has been shown. Application field: biochemistryAvailable from VNTIC / VNTIC - Scientific & Technical Information Centre of RussiaSIGLERURussian Federatio

[Rev.] From precarious employment to precarization of life. Ed. by Zh.T. Toshchenko. Moscow: Ves’ Mir publ., 2022

This article is a review of the recently published collective monograph edited by corresponding member of the Russian Academy of Sciences, Doctor of Philosophy, Professor Zh. Toshchenko, titled “From precarious employment to precarization of life” (2022). The publication of the reviewed book was made possible thanks to financial assistance from “ARB-Forum M”. It is based on an extensive database of representative all-Russian sociological research conducted between 2014 and 2021. The two main goals of the book were: (a) to substantiate that “precarization of labor” has a pronounced tendency to project instability onto other areas of life; (b) to identify a creative and applied concept of “precarization of life” in relation to the emerging proto-class — the precariat. According to the reviewers, the author’s team managed, as usual, to give the reader a good understanding of the origins of how the precariat came about and its further development in society. At the same time, the authors of the work note that precarization is a complex phenomenon that should not be viewed through the prism of a single scientific discipline or sphere, as it was clearly illustrated to us in the book that precarization has already found its way into such spheres as healthcare, culture, education, politics, economics, household needs, i.e. into the public and private life of Russian people. But perhaps the most significant question is whether precarization can cease? The authors do not give the reader their own unambiguous answer to this question, but recognize that it is on the rise all around the world. In the reviewers’ opinion, this collective monograph makes a worthy contribution to the study of the precarization of life (and the precariat in general). At the end of the article, its authors summarize the main propositions of the book, briefly mentioning them, and also point out the weak and rather contradictory (controversial) sides of the reviewed monograph that require much more thorough study in the future.</p

Interplay of histidine residues of the Alzheimer's disease Aβ peptide governs its Zn-induced oligomerization

Conformational changes of Aβ peptide result in its transformation from native monomeric state to the toxic soluble dimers, oligomers and insoluble aggregates that are hallmarks of Alzheimer’s disease (AD). Interactions of zinc ions with Aβ are mediated by the N-terminal Aβ(1–16) domain and appear to play a key role in AD progression. There is a range of results indicating that these interactions trigger the Aβ plaque formation. We have determined structure and functional characteristics of the metal binding domains derived from several Aβ variants and found that their zinc-induced oligomerization is governed by conformational changes in the minimal zinc binding site (6)HDSGYEVHH(14). The residue H6 and segment (11)EVHH(14), which are part of this site are crucial for formation of the two zinc-mediated interaction interfaces in Aβ. These structural determinants can be considered as promising targets for rational design of the AD-modifying drugs aimed at blocking pathological Aβ aggregation