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Journal articles on the topic 'Membranes, physiopathology'
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1
Coraboeuf, E., and D. Escande. "Ionic Currents in the Human Myocardium." Physiology 5, no. 1 (February 1, 1990): 28–31. http://dx.doi.org/10.1152/physiologyonline.1990.5.1.28.
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Recent measurements by patch-clamp techniques of membrane currents from enzymatically isolated human cardiac cells have shown the existence in human atrial membranes of seven different types of ionic channels. Such studies open new perspectives for human cardiac pharmacology and physiopathology.
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Arsenijevic, Tatjana, Jason Perret, Jean-Luc Van Laethem, and Christine Delporte. "Aquaporins Involvement in Pancreas Physiology and in Pancreatic Diseases." International Journal of Molecular Sciences 20, no. 20 (October 11, 2019): 5052. http://dx.doi.org/10.3390/ijms20205052.
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Aquaporins are a family of transmembrane proteins permeable to water. In mammals, they are subdivided into classical aquaporins that are permeable to water; aquaglyceroporins that are permeable to water, glycerol and urea; peroxiporins that facilitate the diffusion of H2O2 through cell membranes; and so called unorthodox aquaporins. Aquaporins ensure important physiological functions in both exocrine and endocrine pancreas. Indeed, they are involved in pancreatic fluid secretion and insulin secretion. Modification of aquaporin expression and/or subcellular localization may be involved in the pathogenesis of pancreatic insufficiencies, diabetes and pancreatic cancer. Aquaporins may represent useful drug targets for the treatment of pathophysiological conditions affecting pancreatic function, and/or diagnostic/predictive biomarker for pancreatic cancer. This review summarizes the current knowledge related to the involvement of aquaporins in the pancreas physiology and physiopathology.
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Simó, Rafael, Marta Villarroel, Lídia Corraliza, Cristina Hernández, and Marta Garcia-Ramírez. "The Retinal Pigment Epithelium: Something More than a Constituent of the Blood-Retinal Barrier—Implications for the Pathogenesis of Diabetic Retinopathy." Journal of Biomedicine and Biotechnology 2010 (2010): 1–15. http://dx.doi.org/10.1155/2010/190724.
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The retinal pigment epithelium (RPE) is an specialized epithelium lying in the interface between the neural retina and the choriocapillaris where it forms the outer blood-retinal barrier (BRB). The main functions of the RPE are the following: (1) transport of nutrients, ions, and water, (2) absorption of light and protection against photooxidation, (3) reisomerization of all-trans-retinal into 11-cis-retinal, which is crucial for the visual cycle, (4) phagocytosis of shed photoreceptor membranes, and (5) secretion of essential factors for the structural integrity of the retina. An overview of these functions will be given. Most of the research on the physiopathology of diabetic retinopathy has been focused on the impairment of the neuroretina and the breakdown of the inner BRB. By contrast, the effects of diabetes on the RPE and in particular on its secretory activity have received less attention. In this regard, new therapeutic strategies addressed to modulating RPE impairment are warranted.
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LACABARATZ-PORRET, Christine, Elisabeth CORVAZIER, Tünde KOVÀCS, Régis BOBE, Raymonde BREDOUX, Sophie LAUNAY, Béla PAPP, and Jocelyne ENOUF. "Platelet sarco/endoplasmic reticulum Ca2+ATPase isoform 3b and Rap 1b: interrelation and regulation in physiopathology." Biochemical Journal 332, no. 1 (May 15, 1998): 173–81. http://dx.doi.org/10.1042/bj3320173.
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Platelet Ca2+ signalling involves intracellular Ca2+ pools, whose content is controlled by sarco/endoplasmic reticulum Ca2+ATPases (SERCAs). Among these, a key role is played by the inositol trisphosphate-sensitive Ca2+ pool, associated with the SERCA 3b isoform. We have investigated the control of this Ca2+ pool through the cAMP-dependent phosphorylation of the GTP-binding protein, Rap (Ras-proximate) 1b. We first looked for this Ca2+ pool target of regulation by studying the expression of the different SERCA and Rap 1 proteins in human platelets and various cell lines, by Western blotting and reverse transcription-PCR. Since co-expression of Rap 1b and SERCA 3b was obtained, we looked for their protein–protein interaction as a function of the cAMP-dependent phosphorylation of Rap 1b. Co-immunoprecipitations of SERCA 3b and Rap 1b proteins were found in the absence of phosphorylation, induced by the catalytic subunit of the cAMP-dependent protein kinase (csPKA). In contrast, upon pre-treatment of platelet membranes with csPKA, the SERCA 3b dissociated from the Rap 1b protein, in agreement with a role of its phosphorylated state in their interaction. Finally, we looked for adaptation of this complex in a platelet pathological model of hypertension. We investigated the expression of both proteins, as well as the cAMP-dependent phosphorylation of Rap 1b and SERCA 3b activity in platelets from control normotensive Wistar-Kyoto rats and from spontaneously hypertensive rats (SHRs). A decrease in SERCA 3b activity was associated with a decrease in Rap 1b endogenous phosphorylation in SHR platelets, consistent with a functional role in the regulation of the SERCA 3b-associated Ca2+ pool.
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Adrien, Vladimir, Hugo Fumat, Cédric Tessier, Philippe Nuss, and David Tareste. "T202. THE EFFECT OF ANTIPSYCHOTIC DRUGS ON MEMBRANE FUSION: AN IN VITRO STUDY." Schizophrenia Bulletin 46, Supplement_1 (April 2020): S308—S309. http://dx.doi.org/10.1093/schbul/sbaa029.762.
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Abstract Background Common clinical use of antipsychotics (AP) drugs shows that their therapeutic mode of action still needs further clarification although it is admitted that the Dopamine receptor D2 (D2R) antagonism plays a significant role. For instance, clozapine (CLOZ) - which is known to be the most effective AP in treating schizophrenic symptoms - has strikingly the lowest D2R antagonism. Non direct receptor-related effects might thus be involved in the activity of AP at the synapse level. AP, as well as neurotransmitters, are mostly lipophilic and insert within membranes. This characteristic is of interest as a significant proportion of schizophrenic patients has specific and abnormal membrane lipid composition. This possible proxy of the disease biotype can participate in the disease’s physiopathology but also be critical for the effect of AP drugs. We hypothesize that AP insertion into lipid membranes also contribute to their therapeutic effect. AP-induced modifications of synaptic membranes biophysics are likely to influence neurotransmission. In this study, we focus on the effect of AP on membrane fusion, a crucial step for the exocytosis of neurotransmitters. Methods Liposomes modelling synaptic vesicles were reconstituted in saline buffer. Two standard ternary and quaternary lipid mixtures have been studied: phosphatidylcholine:phosphatidylethanolamine:phosphatidylserine (PC:PE:PS) [65:25:10] and the synaptic-like PC:PE:PS:sphingomyelin:cholesterol (PC:PE:PS:SM:CHOL) [25:25:10:10:30]. Some liposomes were protein-free and others were functionalized with Soluble N-ethylmaleimide-sensitive-factor Attachment protein Receptor (SNARE) proteins, which trigger in vivo the fusion of synaptic vesicles with the pre-synaptic plasma membrane. The liposome size was checked by Dynamic Light Scattering. Insertion of AP within the membrane was checked by second derivative spectroscopy. Fusion was measured by Fluorescence Resonance Energy Transfer in the absence or presence of CLOZ or chlorpromazine (CPZ) at various lipid:AP ratios (10:1 to 100000:1). Protein-free liposomes were fused with Polyethylene glycol (PEG) and SNARE liposomes through the action of cognate SNARE proteins residing in their membrane. Results Liposomes of the same lipid composition were of the same size, with no effect of the addition of AP drugs at various concentrations. Molar partition coefficient of AP drugs within the membrane of protein-free liposomes was approximately 70–85%. CPZ or CLOZ inhibited the fusion of PC:PE:PS liposomes by about 20–40%. When liposomes were synaptic-like (PC:PE:PS:SM:CHOL), the inhibition of fusion by AP drugs reached 50%. CLOZ also inhibited SNARE-mediated fusion of PC:PE:PS liposomes by about 30%. This effect on SNARE-mediated fusion was not observed with CPZ. Discussion Altogether, these results, despite preliminary, could help to understand partially a non direct receptor-related effect of antipsychotics. Indeed, these drugs also seem to modify membrane dynamics at the synapse level. This seems to be particularly the case of CLOZ on SNARE-mediated fusion and could explain its specific therapeutic efficiency.
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Fernandes, Tânia, Rosa Resende, Diana F. Silva, Ana P. Marques, Armanda E. Santos, Sandra M. Cardoso, M. Rosário Domingues, Paula I. Moreira, and Cláudia F. Pereira. "Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer’s Disease." Biomedicines 9, no. 8 (July 24, 2021): 881. http://dx.doi.org/10.3390/biomedicines9080881.
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Alzheimer’s disease (AD) is characterized by the accumulation of extracellular plaques composed by amyloid-β (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau. AD-related neurodegenerative mechanisms involve early changes of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and impairment of cellular events modulated by these subcellular domains. In this study, we characterized the structural and functional alterations at MAM, mitochondria, and ER/microsomes in a mouse neuroblastoma cell line (N2A) overexpressing the human amyloid precursor protein (APP) with the familial Swedish mutation (APPswe). Proteins levels were determined by Western blot, ER-mitochondria contacts were quantified by transmission electron microscopy, and Ca2+ homeostasis and mitochondria function were analyzed using fluorescent probes and Seahorse assays. In this in vitro AD model, we found APP accumulated in MAM and mitochondria, and altered levels of proteins implicated in ER-mitochondria tethering, Ca2+ signaling, mitochondrial dynamics, biogenesis and protein import, as well as in the stress response. Moreover, we observed a decreased number of close ER-mitochondria contacts, activation of the ER unfolded protein response, reduced Ca2+ transfer from ER to mitochondria, and impaired mitochondrial function. Together, these results demonstrate that several subcellular alterations occur in AD-like neuronal cells, which supports that the defective ER-mitochondria crosstalk is an important player in AD physiopathology.
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Joël, Ngoumen Ngassa Dany, Ngondi Judith Laure, and Oben Julius Enyong. "Effect of Autranellacongolensis on Lipid Profile of Rats’ Brain with Experimentally Induced Alzheimer’s Disease." Journal of Food Research 9, no. 4 (July 15, 2020): 60. http://dx.doi.org/10.5539/jfr.v9n4p60.
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Lipids are essentials components of the brain. Changes in brain lipid composition affect the physical and functional properties of the neuronal cell membrane and have been implicated in the physiopathology of Alzheimer disease (AD). We evaluated in this study the effect of hydroethanolicbark extract of A. Congolensis on lipid profile of rats’ brain with experimentally induced AD. The experimental model consisted of female rats, which received orally for 8 consecutive weeks a single dose of 50 mg/Kg b.w./day of aluminum trichloride (AlCl3) (except control group) followed by distilled water (disease control group) or doses of the extract (150 or 300 mg/Kg b.w./day) or vitamin E (100 mg/Kg b.w./day) or galanthamine (2 mg/Kg b.w. /day). Brain cholesterol, phospholipids and plasmalogenlevels and fluidity were evaluated. Brain membranes ATPase activities, Ca2+, Mg2+and glucose levels were also assayed. Significant modifications of brain lipid composition and fluidity were observed in disease control group compared with control. In addition, Na+, K+-ATPase and Mg2+-ATPase activities significantly decreased, the level of intracellular Ca2+ increased, Mg2+ content decreased and brain glucose level was significantly higher. Standard drugs (vitamin E,galanthamine) showed a negative effect on brain lipid profile. The extract of 150 mg showed significant improvements of brain lipid profile and fluidity. It also indicated improved brain ATPase activities, ions and glucose brain homeostasis. The extract (150 mg/Kg b.w. dose) by maintaining the brain lipid composition may protect neuronal cell membraneand probably preventing the progression of AD.
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Moulis, Manon, Elisa Grousset, Julien Faccini, Kevin Richetin, Gary Thomas, and Cecile Vindis. "The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites." Cells 8, no. 6 (June 25, 2019): 638. http://dx.doi.org/10.3390/cells8060638.
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Mitochondria-associated ER membranes (MAMs) are crucial for lipid transport and synthesis, calcium exchange, and mitochondrial functions, and they also act as signaling platforms. These contact sites also play a critical role in the decision between autophagy and apoptosis with far reaching implications for cell fate. Vascular smooth muscle cell (VSMC) apoptosis accelerates atherogenesis and the progression of advanced lesions, leading to atherosclerotic plaque vulnerability and medial degeneration. Though the successful autophagy of damaged mitochondria promotes VSMC survival against pro-apoptotic atherogenic stressors, it is unknown whether MAMs are involved in VSMC mitophagy processes. Here, we investigated the role of the multifunctional MAM protein phosphofurin acidic cluster sorting protein 2 (PACS-2) in regulating VSMC survival following a challenge by atherogenic lipids. Using high-resolution confocal microscopy and proximity ligation assays, we found an increase in MAM contacts as in PACS-2-associated MAMs upon stimulation with atherogenic lipids. Correspondingly, the disruption of MAM contacts by PACS-2 knockdown impaired mitophagosome formation and mitophagy, thus potentiating VSMC apoptosis. In conclusion, our data shed new light on the significance of the MAM modulatory protein PACS-2 in vascular cell physiopathology and suggest MAMs may be a new target to modulate VSMC fate and favor atherosclerotic plaque stability.
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Baud, O., R. H. Fontaine, P. Olivier, L. Maury, F. El Moussawi, I. Bauvin, M. Arsac, S. Hovhannisyan, C. Farnoux, and Y. Aujard. "Rupture très prématurée des membranes: physiopathologie des conséquences neurologiques." Archives de Pédiatrie 14 (January 2007): S49—S53. http://dx.doi.org/10.1016/s0929-693x(07)80011-x.
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Blanchon, L., M. Accoceberry, C. Belville, A. Delabaere, C. Prat, D. Lemery, V. Sapin, and D. Gallot. "Rupture des membranes : physiopathologie, diagnostic, conséquences et prise en charge." Journal de Gynécologie Obstétrique et Biologie de la Reproduction 42, no. 2 (April 2013): 105–16. http://dx.doi.org/10.1016/j.jgyn.2012.12.012.
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Bonora, Massimo, Simone Patergnani, Daniela Ramaccini, Giampaolo Morciano, Gaia Pedriali, Asrat Endrias Kahsay, Esmaa Bouhamida, Carlotta Giorgi, Mariusz R. Wieckowski, and Paolo Pinton. "Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology." Biomolecules 10, no. 7 (July 4, 2020): 998. http://dx.doi.org/10.3390/biom10070998.
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Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.
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Papa, S., S. Scacco, A. M. Sardanelli, V. Petruzzella, R. Vergari, A. Signorile, and Z. Technikova-Dobrova. "Complex I and the cAMP Cascade in Human Physiopathology." Bioscience Reports 22, no. 1 (February 1, 2002): 3–16. http://dx.doi.org/10.1023/a:1016004921277.
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A cAMP-dependent protein kinase (PKA) is localized in mammalian mitochondria with the catalytic site at the matrix side of the membrane where it phosphorylates a number of proteins. One of these is the 18 kDa(IP) subunit of the mammalian complex I of the respiratory chain, encoded by the nuclear NDUFS4 gene. Mitochondria have a Ca2+-inhibited phosphatase, which dephosphorylates the 18 kDa phosphoprotein of complex I. In fibroblast and myoblast cultures cAMP-dependent phosphorylation of the 18 kDa protein is associated with stimulation of complex I and overall respiratory activity with NAD-linked substrates. Mutations in the human NDUFS4 gene have been found, which in the homozygous state are associated with deficiency of complex I and fatal neurological syndrome.
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Varlet, Alice-Anaïs, Emmanuèle Helfer, and Catherine Badens. "Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2." Cells 9, no. 9 (August 23, 2020): 1947. http://dx.doi.org/10.3390/cells9091947.
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Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the LMNA gene, with at least 20 mutations that are considered pathogenic. LMNA encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.
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Sechi, Stefano, Anna Frappaolo, Angela Karimpour-Ghahnavieh, Roberto Piergentili, and Maria Grazia Giansanti. "Oncogenic Roles of GOLPH3 in the Physiopathology of Cancer." International Journal of Molecular Sciences 21, no. 3 (January 31, 2020): 933. http://dx.doi.org/10.3390/ijms21030933.
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Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation.
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Muzi-Filho, Humberto, Larissa B. Jannuzzi, Ana C. S. Bouzan, Sarana Alves-Barros, Danilo S. Alves-Bezerra, Amaury Pereira-Acácio, Bruna S. N. Ferreira, Debora Silva-Pereira, Gloria Costa-Sarmento, and Adalberto Vieyra. "Histone Deacetylase Activity and the Renin-Angiotensin-Aldosterone System: Key Elements in Cardiorenal Alterations Provoked by Chronic Malnutrition in Male Adult Rats." Cellular Physiology and Biochemistry 54, no. 6 (November 18, 2020): 1143–62. http://dx.doi.org/10.33594/000000306.
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BACKGROUND/AIMS: Chronic malnutrition (M) affects >1 billion people worldwide. Epidemiological data point to long-term renal and cardiovascular outcomes (e.g. arterial hypertension, cardiorenal syndromes). The renin-angiotensin-aldosterone system (RAAS) has been implicated in the physiopathology of these disturbances, but M-induced alterations in RAAS-modulated renal Na+ handling and their cardiovascular repercussions are not known. Moreover, altered tissue-specific histone deacetylases (HDAC) results in arterial hypertension and the use of sodium Valproate (Val; a HDAC inhibitor) reduces blood pressure. However, there are no reports regarding the renal and cardiovascular effects of HDAC inhibition in M, or on the signaling pathways involved. The central aim of our study has been to investigate whether alterations in the HDAC/RAAS axis underpin alterations in active Na+ transport in the kidney and heart, and affects blood pressure. METHODS: Male rats aged 28 days were given either a control (C) or a multideficient diet (Regional Basic Diet, RBD), which mimics alimentary habits from developing countries. Subgroups received Losartan (Los), a blocker of type 1 Angiotensin II receptors. When the rats reached 70 days, new subgroups received Val until they were 90 days of age. Homogenates and enriched plasma membrane fractions from renal cortex corticis and cardiomyocytes were obtained by differential centrifugation of the tissues. The activity of renal and cardiac deacetylases was assayed by measuring - after incubation with the membranes - the amount of deacetylated lysines in a substrate containing an acetylated lysine side chain. Protein kinases activities were measured following the incorporation of the γ-phosphoryl group of [γ-32P]ATP into Ser/Thr residues of histone type III-S. The activity of Na+-transporting ATPases (kidney and heart) was quantified by measuring the release of Pi from ATP that was sensitive to ouabain ((Na++K+)ATPase), or sensitive to furosemide (Na+-ATPase). Tail-cuff plethysmography was used to measure systolic blood pressure and heart rate. RESULTS: M provoked HDAC downregulation, which was reversed by Los and Val, either alone or in combination, with selective upregulation of protein kinases C and A (PKC, PKA) in renal cortex corticis, but not in left ventricle cardiomyocytes. The 2 kinases were strongly inhibited by Los and Val in both organs. Malnourished rats developed elevated systolic arterial pressure (SAP) and heart rate (HR) at 70 days of age; Los and Val restored the control SAP, but not HR. Functional and the above biochemical alterations were associated with the deregulation of renal and cardiac Na+-transporting ATPases. (Na++K+)ATPase activities were downregulated in M rats in both organs, and were further inhibited by the pharmacological treatments in the renal cortex corticis (C and M groups) and the left ventricle (only in C rats). No additional effect was found in cardiac (Na++K+)ATPase from M rats. Ouabain-resistant Na+-ATPase was upregulated in renal cortex corticis and downregulated in cardiomyocytes, returning to C values after administration of Los and Val. CONCLUSION: The HDAC/RAAS axis appears to be a key regulator of Na+-transporting ATPases in renal cortex corticis and cardiomyocytes via an appropriate balance of PKC and PKA activities. Modifications within the HDAC/RAAS axis provoked by chronic M - with repercussions in renal and cardiac Na+ transport - underpin alterations in bodily Na+ homeostasis that culminate with the onset of arterial hypertension and potential cardiorenal syndrome.
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Palmieri, Beniamino, Thierry Conrozier, Maria Vadalà, and Carmen Laurino. "Synoviology: a new chapter entitled to joints care." Asian Journal of Medical Sciences 8, no. 3 (May 2, 2017): 1–10. http://dx.doi.org/10.3126/ajms.v8i3.16188.
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In order to extensively investigate on the synovial membrane – related diseases, we outlined a specific medical branch named “Synoviology”, targeted to the physiopathology and therapy of synovial membrane dysfunction. We searched Pubmed/Medline using the terms “synovial disease”, “therapy”, “synovial membrane”, “joints” and “drugs”, alone and combined. Selected papers from 1960 to 2015 were chosen based on their content (evidence-based quality and reliability). Clinical and experimental articles were included. Viscosupplementation with structurally different hyaluronic acid compounds, for restoration of the synovial membrane, and cartilage. The impact of other old and new medical treatments either locally or systemically administered was also included. Synoviology integrates biological, clinical and biochemical info for the progress of new therapeutic options in osteo-articular pathology.Asian Journal of Medical Sciences Vol.8(3) 2017 1-10
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Guieu, Régis, Michele Brignole, Jean Claude Deharo, Pierre Deharo, Giovanna Mottola, Antonella Groppelli, Franck Paganelli, and Jean Ruf. "Adenosine Receptor Reserve and Long-Term Potentiation: Unconventional Adaptive Mechanisms in Cardiovascular Diseases?" International Journal of Molecular Sciences 22, no. 14 (July 15, 2021): 7584. http://dx.doi.org/10.3390/ijms22147584.
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While the concept of a receptor reserve (spare receptors) is old, their presence on human cells as an adaptive mechanism in cardiovascular disease is a new suggestion. The presence of spare receptors is suspected when the activation of a weak fraction of receptors leads to maximal biological effects, in other words, when the half-maximal effective concentration (EC50) for a biological effect (cAMP production, for example) is lower than the affinity (KD) of the ligand for a receptor. Adenosine is an ATP derivative that strongly impacts the cardiovascular system via its four membrane receptors, named A1R, A2AR, A2BR, and A3R, with the A1R being more particularly involved in heart rhythm, while the A2AR controls vasodilation. After a general description of the tools necessary to explore the presence of spare receptors, this review focuses on the consequences of the presence of spare adenosine receptors in cardiovascular physiopathology. Finally, the role of the adenosinergic system in the long-term potentiation and its possible consequences on the physiopathology are also mentioned.
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Soudier, Guillaume, Alain Gaudric, Vincent Gualino, Mathieu Nardin, Claude Speeg-Schatz, and David Gaucher. "Epiretinal Membrane in Dome-Shaped Macula Complicated with Serous Retinal Detachment: Transient Efficacy of Surgery." Case Reports in Ophthalmology 8, no. 3 (November 16, 2017): 515–20. http://dx.doi.org/10.1159/000481703.
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Dome-shaped macula (DSM) is an entity recently described as a convex anterior protrusion of the macular area within a posterior myopic staphyloma. Specific complications were associated with DSM, like serous retinal detachment (SRD). We describe a woman presenting with a decreased vision at 20/50. SD-OCT scans were performed, showing a macular bulge. SRD was present and an epiretinal membrane could also be observed. Fluorescein angiography and indocyanin green angiography did not show any leakage nor choroidal neovascularization. Epiretinal membrane peeling was performed, and 3 months after surgery, SRD completely disappeared. However, SRD reappeared 1 year after surgery and enlarged within 2 years following surgery. In conclusion, two mechanisms could be considered for physiopathology of SRD: first, the epiretinal membrane may have exerted traction on the macular retina, second, vitreous body might constitute a tank for cytokines and/or other factors, triggering subretinal fluid accumulation, leading to SRD.
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Froelich, Sebastien C., Khaled M. Abdel Aziz, Paul D. Cohen, Harry R. van Loveren, and Jeffrey T. Keller. "Microsurgical and Endoscopic Anatomy of Liliequist's Membrane: A Complex and Variable Structure of the Basal Cisterns." Operative Neurosurgery 63, suppl_1 (July 1, 2008): ONS1—ONS9. http://dx.doi.org/10.1227/01.neu.0000316419.49633.04.
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Abstract Objective: Descriptions of Liliequist's membrane, as reported in the literature, vary considerably. In our cadaveric study of Liliequist's membrane, we attempted to clarify and define its anatomic features and boundaries, as well as its relationship with surrounding neurovascular structures. We describe the embryology of this membrane as a remnant of the primary tentorium. The clinical significance of our findings is discussed with respect to third ventriculostomy and surgical approaches to basilar tip aneurysms, suprasellar arachnoid cysts, and perimesencephalic hemorrhage. Methods: Thirteen formalin-fixed adult cadaveric heads were injected with colored silicone. After endoscopic exploration of Liliequist's membrane, a bilateral frontal craniotomy was performed, and the frontal lobes were removed to fully expose Liliequist's membrane. Results: Liliequist's membrane is a complex and highly variable structure that is composed of either a single membrane or two leaves. The membrane was absent in two specimens without any clear demarcation between the interpeduncular, prepontine, and chiasmatic cisterns. Conclusion: Understanding the variable anatomy of Liliequist's membrane is important, particularly to improve current and forthcoming microsurgical and endoscopic neurosurgical procedures. It is important as a surgical landmark in various neurosurgical operations and in the physiopathology of several pathological processes (suprasellar arachnoid cysts and perimesencephalic hemorrhage).
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Pasquier, J. C., and M. Doret. "Les membranes fœtales : développement embryologique, structure et physiopathologie de la rupture prématurée avant terme." Journal de Gynécologie Obstétrique et Biologie de la Reproduction 37, no. 6 (October 2008): 579–88. http://dx.doi.org/10.1016/j.jgyn.2007.12.001.
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Galeone, Antonella, Domenico Paparella, Silvia Colucci, Maria Grano, and Giacomina Brunetti. "The Role of TNF-αand TNF Superfamily Members in the Pathogenesis of Calcific Aortic Valvular Disease." Scientific World Journal 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/875363.
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Calcific aortic valve disease (CAVD) represents a slowly progressive pathologic process associated with major morbidity and mortality. The process is characterized by multiple steps: inflammation, fibrosis, and calcification. Numerous studies focalized on its physiopathology highlighting different “actors” for the multiple “acts.” This paper focuses on the role of the tumor necrosis factor superfamily (TNFSF) members in the pathogenesis of CAVD. In particular, we discuss the clinical and experimental studies providing evidence of the involvement of tumor necrosis factor-alpha (TNF-α), receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL), its membrane receptor RANK and its decoy receptor osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) in valvular calcification.
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Navarro-Tableros, Victor, Tatiana Fiordelisio, Arturo Hernández-Cruz, and Marcia Hiriart. "Physiological development of insulin secretion, calcium channels, and GLUT2 expression of pancreatic rat β-cells." American Journal of Physiology-Endocrinology and Metabolism 292, no. 4 (April 2007): E1018—E1029. http://dx.doi.org/10.1152/ajpendo.00457.2006.
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Insulin secretion in mature β-cells increases vigorously when extracellular glucose concentration rises. Glucose-stimulated insulin secretion depends on Ca2+ influx through voltage-gated Ca2+ channels. During fetal development, this structured response is not well established, and it is after birth that β-cells acquire glucose sensitivity and a robust secretion. We compared some elements of glucose-induced insulin secretion coupling in β-cells obtained from neonatal and adult rats and found that neonatal cells are functionally immature compared with adult cells. We observed that neonatal cells secrete less insulin and cannot sense changes in extracellular glucose concentrations. This could be partially explained because in neonates Ca2+ current density and synthesis of mRNA α1 subunit Ca2+ channel are lower than in adult cells. Interestingly, immunostaining for α1B, α1C, and α1D subunits in neonatal cells is similar in cytoplasm and plasma membrane, whereas it occurs predominantly in the plasma membrane in adult cells. We also observed that GLUT2 expression in adult β-cells is mostly located in the membrane, whereas in neonatal cells glucose transporters are predominantly in the cytoplasm. This could explain, in part, the insensitivity to extracellular glucose in neonatal β-cells. Understanding neonatal β-cell physiology and maturation contributes toward a better comprehension of type 2 diabetes physiopathology, where alterations in β-cells include diminished L-type Ca2+ channels and GLUT2 expression that results in an insufficient insulin secretion.
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Kammoun, R., A. Sayhi, I. Ghannouchi, H. Ben Saad, R. Bechikh, and S. Rouatbi. "Physiopathologie de l’atteinte de la membrane alvéolocapillaire dans le syndrome apnée–hypopnées obstructive du sommeil (SAHOS)." Revue des Maladies Respiratoires 35 (January 2018): A134. http://dx.doi.org/10.1016/j.rmr.2017.10.297.
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Haga, Sanae, Takeaki Ozawa, Naoki Morita, Mami Asano, Shigeki Jin, Yimin, and Michitaka Ozaki. "Photo-Activatable Akt Probe: A New Tool to Study the Akt-Dependent Physiopathology of Cancer Cells." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 26, no. 3 (April 10, 2018): 467–72. http://dx.doi.org/10.3727/096504017x15040166233313.
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Akt is commonly overexpressed and activated in cancer cells and plays a pivotal role in cell survival, protection, and chemoresistance. Therefore, Akt is one of the target molecules in understanding characters of cancer cells and developing anticancer drugs. Here we examined whether a newly developed photo-activatable Akt (PA-Akt) probe, based on a light-inducible protein interaction module of plant cryptochrome2 (CRY2) and cryptochrome-interacting basic helix‐loop‐helix (CIB1), can regulate Akt-associated cell functions. By illuminating blue light to the cells stably transfected with PA-Akt probe, CRY2-Akt (a fusion protein of CRY2 and Akt) underwent a structural change and interacted with Myr-CIBN (myristoylated N-terminal portion of CIB1), anchoring it at the cell membrane. Western blot analysis revealed that S473 and T308 of the Akt of probe-Akt were sequentially phosphorylated by intermittent and continuous light illumination. Endogenous Akt and GSK-3β, one of the main downstream signals of Akt, were also phosphorylated, depending on light intensity. These facts indicate that photo-activation of probe-Akt can activate endogenous Akt and its downstream signals. The photo-activated Akt conferred protection against nutritional deprivation and H2O2 stresses to the cells significantly. Using the newly developed PA-Akt probe, endogenous Akt was activated easily, transiently, and repeatedly. This probe will be a unique tool in studying Akt-associated specific cellular functions in cancer cells and developing anticancer drugs.
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Pérez-García, Selene, Mar Carrión, Irene Gutiérrez-Cañas, Raúl Villanueva-Romero, David Castro, Carmen Martínez, Isidoro González-Álvaro, Francisco J. Blanco, Yasmina Juarranz, and Rosa P. Gomariz. "Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin." Cells 9, no. 1 (December 22, 2019): 40. http://dx.doi.org/10.3390/cells9010040.
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The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of many diseases, including osteoarthritis (OA). OA is a chronic degenerative rheumatic disease characterized by a progressive loss of synovial joint function as a consequence of the degradation of articular cartilage, also associated with alterations in the synovial membrane and subchondral bone. During OA, ECM-degrading enzymes, including urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), cleave ECM components, such as fibronectin (Fn), generating fibronectin fragments (Fn-fs) with catabolic properties. In turn, Fn-fs promote activation of these proteinases, establishing a degradative and inflammatory feedback loop. Thus, the aim of this review is to update the contribution of ECM-degrading proteinases to the physiopathology of OA as well as their modulation by Fn-fs.
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Storme, L., T. Rakza, V. Houfflin-Debarge, P. Dufour, A. Bouissou, D. Subtil, and P. Deruelle. "Physiopathologie des conséquences respiratoires néonatales de la rupture prématurée des membranes : application à la prise en charge néonatale." Archives de Pédiatrie 14 (January 2007): S42—S48. http://dx.doi.org/10.1016/s0929-693x(07)80010-8.
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SARRADIN, P., P. BERTHON, and F. LANTIER. "Le point sur l’épidémiologie et la physiopathologie des encéphalopathies spongiformes des ruminants." INRAE Productions Animales 10, no. 2 (April 7, 1997): 123–32. http://dx.doi.org/10.20870/productions-animales.1997.10.2.3988.
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L’épidémie d’encéphalopathie spongiforme bovine (ESB) résulte de la consommation par les bovins de farines de viandes et d’os contaminées. En recyclant l’agent infectieux, ces farines ont permis d’amplifier la dissémination d’une maladie dont l’origine et l’agent responsable demeurent inconnus. Les hypothèses sur la nature protéique ou/et virale de l’agent sont évoquées, ainsi que l’éventualité d’une transmission à l’homme. Une grande partie de nos connaissances des encéphalopathies spongiformes résulte des études réalisées de longue date sur la tremblante des ovins. En particulier, l’idée que l’on peut se faire de la physiopathologie de l’infection des bovins est en grande partie extrapolée à partir du résultat d’infections expérimentales réalisées chez le mouton. Toutefois, la contamination des tissus lymphoïdes périphériques, qui est la règle au cours de la phase de dissémination dans l’organisme de l’agent de la tremblante, semble absente dans le cas de la maladie bovine. Il est donc possible que ce type de tissus, considéré comme infectieux en matière de tremblante, le soit peu au cours de la phase préclinique dans le cas de l’ESB. L’atteinte du système nerveux central des bovins pourrait alors résulter d’une dissémination empruntant les voies nerveuses.
Les mécanismes conduisant à la mort neuronale responsable des symptômes observés restent mal connus. La protéine PrP, protéine normale de la membrane de nombreux types cellulaires, et qui s’accumule sous sa forme pathologique PrPSC au niveau des lésions est indispensable au processus pathologique. Son polymorphisme influence considérablement le devenir de l’infection, mais elle ne peut être tenue pour seule responsable de la transmission de la maladie.
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Laszlo, Gabriel. "Respiratory measurements of cardiac output: from elegant idea to useful test." Journal of Applied Physiology 96, no. 2 (February 2004): 428–37. http://dx.doi.org/10.1152/japplphysiol.01074.2001.
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The measurement of cardiac output was first proposed by Fick, who published his equation in 1870. Fick's calculation called for the measurement of the contents of oxygen or CO2 in pulmonary arterial and systemic arterial blood. These values could not be determined directly in human subjects until the acceptance of cardiac catheterization as a clinical procedure in 1940. In the meanwhile, several attempts were made to perfect respiratory methods for the indirect determination of blood-gas contents by respiratory techniques that yielded estimates of the mixed venous and pulmonary capillary gas pressures. The immediate uptake of nonresident gases can be used in a similar way to calculate cardiac output, with the added advantage that they are absent from the mixed venous blood. The fact that these procedures are safe and relatively nonintrusive makes them attractive to physiologists, pharmacologists, and sports scientists as well as to clinicians concerned with the physiopathology of the heart and lung. This paper outlines the development of these techniques, with a discussion of some of the ways in which they stimulated research into the transport of gases in the body through the alveolar membrane.
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Lionello, Valentina M., Anne-Sophie Nicot, Maxime Sartori, Christine Kretz, Pascal Kessler, Suzie Buono, Sarah Djerroud, et al. "Amphiphysin 2 modulation rescues myotubular myopathy and prevents focal adhesion defects in mice." Science Translational Medicine 11, no. 484 (March 20, 2019): eaav1866. http://dx.doi.org/10.1126/scitranslmed.aav1866.
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Centronuclear myopathies (CNMs) are severe diseases characterized by muscle weakness and myofiber atrophy. Currently, there are no approved treatments for these disorders. Mutations in the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for X-linked CNM (XLCNM), also called myotubular myopathy, whereas mutations in the membrane remodeling Bin/amphiphysin/Rvs protein amphiphysin 2 [bridging integrator 1 (BIN1)] are responsible for an autosomal form of the disease. Here, we investigated the functional relationship between MTM1 and BIN1 in healthy skeletal muscle and in the physiopathology of CNM. Genetic overexpression of human BIN1 efficiently rescued the muscle weakness and life span in a mouse model of XLCNM. Exogenous human BIN1 expression with adeno-associated virus after birth also prevented the progression of the disease, suggesting that human BIN1 overexpression can compensate for the lack of MTM1 expression in this mouse model. Our results showed that MTM1 controls cell adhesion and integrin localization in mammalian muscle. Alterations in this pathway in Mtm1−/y mice were associated with defects in myofiber shape and size. BIN1 expression rescued integrin and laminin alterations and restored myofiber integrity, supporting the idea that MTM1 and BIN1 are functionally linked and necessary for focal adhesions in skeletal muscle. The results suggest that BIN1 modulation might be an effective strategy for treating XLCNM.
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Lacasse, C., S. Turcotte, D. Gingras, and M. Rola-Pleszczynski. "Adhesion-independent synergy of monocytes and endothelial cells in cytokine production: regulation of IL-6 and GM–CSF production by PAF." Mediators of Inflammation 5, no. 1 (1996): 56–61. http://dx.doi.org/10.1155/s0962935196000105.
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Co-Cultures of monocytes (MO) and endothelial cells (EC) were studied for their capacity to synergize in the production of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM–CSF), two cytokines potentially important in vascular physiopathology. Resting monocytes produced detectable amounts of IL-6 but no GM–CSF, whereas confluent EC produced significant quantities of GM–CSF, but minimal IL-6. In co-cultures without stimuli, additive synthesis of both cytokines was observed. When EC were pretreated, however, with either PAF, TNF or both stimuli, before addition of MO, synergistic production of IL-6 was observed. In contrast, GM–CSF production was not enhanced by coculture of monocytes with activated EC. When either cell population was fixed with paraformaldehyde or killed by freeze-thawing before addition to the co-culture, cytokine levels reverted to those produced by the unaffected population alone. On the other hand, separating the two cell populations by a cell-impermeable membrane in transwell cultures did not affect the synergistic production of the cytokines. Taken together, our data suggest that EC and MO can synergize in response to stimuli by producing IL-6 and that this synergy is dependent on the integrity of both cell populations, but independent of cell-cell contact.
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Koltai, Tomas. "Targeting the pH Paradigm at the Bedside: A Practical Approach." International Journal of Molecular Sciences 21, no. 23 (December 3, 2020): 9221. http://dx.doi.org/10.3390/ijms21239221.
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The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the “cancer problem”? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article’s goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.
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Zhang, Weilin, Qi Ma, Sami Siraj, Paul A. Ney, Junling Liu, Xudong Liao, Yefeng Yuan, Wei Li, Lei Liu, and Quan Chen. "Nix-mediated mitophagy regulates platelet activation and life span." Blood Advances 3, no. 15 (August 7, 2019): 2342–54. http://dx.doi.org/10.1182/bloodadvances.2019032334.
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Abstract Platelet activation requires fully functional mitochondria, which provide a vital energy source and control the life span of platelets. Previous reports have shown that both general autophagy and selective mitophagy are critical for platelet function. However, the underlying mechanisms remain incompletely understood. Here, we show that Nix, a previously characterized mitophagy receptor that plays a role in red blood cell maturation, also mediates mitophagy in platelets. Genetic ablation of Nix impairs mitochondrial quality, platelet activation, and FeCl3-induced carotid arterial thrombosis without affecting the expression of platelet glycoproteins (GPs) such as GPIb, GPVI, and αIIbβ3. Metabolic analysis revealed decreased mitochondrial membrane potential, enhanced mitochondrial reactive oxygen species level, diminished oxygen consumption rate, and compromised adenosine triphosphate production in Nix−/− platelets. Transplantation of wild-type (WT) bone marrow cells or transfusion of WT platelets into Nix-deficient mice rescued defects in platelet function and thrombosis, suggesting a platelet-autonomous role (acting on platelets, but not other cells) of Nix in platelet activation. Interestingly, loss of Nix increases the life span of platelets in vivo, likely through preventing autophagic degradation of the mitochondrial protein Bcl-xL. Collectively, our findings reveal a novel mechanistic link between Nix-mediated mitophagy, platelet life span, and platelet physiopathology. Our work suggests that targeting platelet mitophagy Nix might provide new antithrombotic strategies.
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Gallardo-Vara, Eunate, Luis Gamella-Pozuelo, Lucía Perez-Roque, José L. Bartha, Irene Garcia-Palmero, J. Ignacio Casal, José M. López-Novoa, Miguel Pericacho, and Carmelo Bernabeu. "Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4." Cells 9, no. 4 (April 16, 2020): 988. http://dx.doi.org/10.3390/cells9040988.
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Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators of hypertension, we analyzed the protein secretome of human endothelial cells in the presence of sEng. We found that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels, and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased transcript levels of BMP4 in lungs, stomach, and duodenum, and increased circulating levels of BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appeared 18 days after mating, coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 were positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the physiopathology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.
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Rettino, Alessandro, Francesca Rafanelli, Giannicola Genovese, Martina Goracci, Rosa Anna Cifarelli, Achille Cittadini, and Alessandro Sgambato. "Identification of Sp1 and GC-boxes as transcriptional regulators of mouse Dag1 gene promoter." American Journal of Physiology-Cell Physiology 297, no. 5 (November 2009): C1113—C1123. http://dx.doi.org/10.1152/ajpcell.00189.2009.
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Dystroglycan is a widely expressed adhesion complex that anchors cells to the basement membrane and is involved in embryonic development and differentiation. Dystroglycan expression is frequently reduced in human dystrophies and malignancies, and its molecular functions are not completely understood. Several posttranslational mechanisms have been identified that regulate dystroglycan expression and/or function, while little is known about how expression of the corresponding Dag1 gene is regulated. This study aimed to clone the Dag1 gene promoter and to characterize its regulatory elements. Analysis of the mouse Dag1 gene 5′-flanking region revealed a TATA and CAAT box-lacking promoter including a GC-rich region. Transfection studies with serially deleted promoter constructs allowed us to identify a minimal promoter region containing three Specificity protein 1 (Sp1) sites and an E-box. Sp1 binding was confirmed by chromatin immunoprecipitation assay, and Sp1 downregulation reduced dystroglycan expression in muscle cells. Treatment with 5-aza-2′-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A increased Dag1 mRNA expression levels in myoblasts, and methylation decreased promoter activity in vitro. Furthermore, Dag1 gene promoter methylation was reduced while its expression increased during differentiation of C2C12 myoblast cells in myotubes. In conclusion, for the first time we have characterized the activity of the mouse Dag1 gene promoter, confirming a complex regulation by Sp1 transcription factor, DNA methylation, and histone acetylation, which might be relevant for a better understanding of the physiopathology of the dystroglycan complex.
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Charrière, Sybil, Noël Peretti, Sophie Bernard, Mathilde Di Filippo, Agnès Sassolas, Micheline Merlin, Mireille Delay, et al. "GPIHBP1 C89F Neomutation and Hydrophobic C-Terminal Domain G175R Mutation in Two Pedigrees with Severe Hyperchylomicronemia." Journal of Clinical Endocrinology & Metabolism 96, no. 10 (October 1, 2011): E1675—E1679. http://dx.doi.org/10.1210/jc.2011-1444.
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Abstract Context: GPIHBP1 is a new endothelial binding site for lipoprotein lipase (LPL), the key enzyme for intravascular lipolysis of triglyceride-rich lipoproteins (TGRL). We have identified two new missense mutations of the GPIHBP1 gene, C89F and G175R, by systematic sequencing in a cohort of 376 hyperchylomicronemic patients without mutations on the LPL, APOC2, or APOA5 gene. Objective: Phenotypic expression and functional consequences of these two mutations were studied. Design: We performed clinical and genotypic studies of probands and their families. GPIHBP1 functional alterations were studied in CHO pgsA-745 transfected cells. Results: Probands are an adult with a homozygous G175R mutation and a child with a hemizygous C89F neomutation and a deletion of the second allele. C89F mutation was associated with a C14F signal peptide polymorphism on the same haplotype. Both patients had resistant hyperchylomicronemia, low LPL activity, and history of acute pancreatitis. In CHO pgsA-745 cells, both G175R and C14F variants reduce the expression of GPIHBP1 at the cell surface. C89F mutation is responsible for a drastic LPL-binding defect to GPIHBP1. C14F may further potentiate C89F effect. Conclusions: The emergence of hyperchylomicronemia in the generation after a neomutation further establishes a critical role for GPIHBP1 in TGRL physiopathology in humans. Our results highlight the crucial role of C65-C89 disulfide bond in LPL binding by GPIHBP1 Ly6 domain. Furthermore, we first report a mutation of the hydrophobic C-terminal domain that impairs GPIHBP1 membrane targeting.
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Saiz Garcia, H., L. Montes Reula, A. Portilla Fernandez, V. Pereira Sanchez, N. Olmo Lopez, E. Mancha Heredero, and A. S. Rosero Enriquez. "Neuroacanthocytosis syndromes and neuropsychiatry symptoms associated." European Psychiatry 41, S1 (April 2017): S702. http://dx.doi.org/10.1016/j.eurpsy.2017.01.1246.
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IntroductionNeuroacanthocytosis is an infrequent cause of both neurological and psychiatric manifestations, and acanthocytes, which are a special form of spiculated red blood cells. Clinically significant psychopathology, ranging from behavioural disturbance to frank psychiatric illness, has been reported to occur in up to 60% of ChAc patients.MethodsA review was conducted aiming to clarify the physiopathology of this illness and its clinical features in order to distinguish neuroacanthocytosis from other neurological or psychiatric diseases. The literature search was conducted in PubMed data reviewing articles dating between 2010 and 2016.Results– Neuroacanthocytosis autosomal recessive disorder associated with mutations or deletions in the VPS13A gene on chromosome 9q, which codes for the membrane protein chorein. Chorein is strongly expressed in the brain. Chorein loss particularly affects the basal ganglia, especially the caudate nucleus and putamen;– Dysexecutive syndromes, OCD, depression and possibly psychosis, which may precede the frank motor and cognitive impairment;– The most recently developed treatment for neuroacanthocytoses is the use of deep-brain stimulation (DBS), with stimulation of the globus pallidus internus.ConclusionsWhile conducting a neurological exam, secondary causes of psychosis have to be included in the differential diagnosis. It is important to notice the possible confusion between tardive dyskinesia and a primary movement disorder. It should be necessary to investigate all de novo movement disorders in psychotic patients in order to eliminate etiologies other than iatrogenic ones.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Fayezi, Shabnam, Jo L. M. R. Leroy, Marefat Ghaffari Novin, and Masoud Darabi. "Oleic acid in the modulation of oocyte and preimplantation embryo development." Zygote 26, no. 1 (December 15, 2017): 1–13. http://dx.doi.org/10.1017/s0967199417000582.
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SummaryPotential reproductive effects are considered as the major aspect of biomolecules functionality in an organism. The recent identification of differential patterns of fatty acids across ovarian follicles and their association with levels of sexual maturity highlights the importance of these biomolecules. It is well known that fatty acids are highly diverse in terms of their functional properties. Oleic acid is chemically classified as an unsaturated omega-9 fatty acid. Besides serving as an important energy source, oleic acid is involved in metabolic and structural roles. Free and esterified oleic acids are compartmentalized into discrete extracellular fluids, cell organelles and found within the cytosol. This review summarizes the current knowledge on the contribution of oleic acid in regulating female fertility, particularly its involvement in female germ cell growth and development. Oleic acid has been identified as a blastomeric and post-cryopreservation survival biomarker in bovine. Several related studies have shown the critical role of oleic acid in counteracting the detrimental effects of saturated fatty acids and in paracrine support of oocyte development. Although available data are not ideally detailed, most data suggest that oleic acid can contribute to normal oocyte and preimplantation embryo development via mechanisms involving metabolic partitioning of fatty acids, change in the membrane structural organization, attenuation of oxidative stress and regulation of intracellular signalling. Thus, oleic acid may play a significant role in oocyte and early embryo development, suggesting that future studies should explore in more detail its potential effects on the physiopathology of female reproduction.
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Castillo, Carlos Alberto, Inmaculada Ballesteros-Yáñez, David Agustín León-Navarro, José Luis Albasanz, and Mairena Martín. "Early Effects of the Soluble Amyloid β25-35 Peptide in Rat Cortical Neurons: Modulation of Signal Transduction Mediated by Adenosine and Group I Metabotropic Glutamate Receptors." International Journal of Molecular Sciences 22, no. 12 (June 19, 2021): 6577. http://dx.doi.org/10.3390/ijms22126577.
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The amyloid β peptide (Aβ) is a central player in the neuropathology of Alzheimer’s disease (AD). The alteration of Aβ homeostasis may impact the fine-tuning of cell signaling from the very beginning of the disease, when amyloid plaque is not deposited yet. For this reason, primary culture of rat cortical neurons was exposed to Aβ25-35, a non-oligomerizable form of Aβ. Cell viability, metabotropic glutamate receptors (mGluR) and adenosine receptors (AR) expression and signalling were assessed. Aβ25-35 increased mGluR density and affinity, mainly due to a higher gene expression and protein presence of Group I mGluR (mGluR1 and mGluR5) in the membrane of cortical neurons. Intriguingly, the main effector of group I mGluR, the phospholipase C β1 isoform, was less responsive. Also, the inhibitory action of group II and group III mGluR on adenylate cyclase (AC) activity was unaltered or increased, respectively. Interestingly, pre-treatment of cortical neurons with an antagonist of group I mGluR reduced the Aβ25-35-induced cell death. Besides, Aβ25-35 increased the density of A1R and A2AR, along with an increase in their gene expression. However, while A1R-mediated AC inhibition was increased, the A2AR-mediated stimulation of AC remained unchanged. Therefore, one of the early events that takes place after Aβ25-35 exposure is the up-regulation of adenosine A1R, A2AR, and group I mGluR, and the different impacts on their corresponding signaling pathways. These results emphasize the importance of deciphering the early events and the possible involvement of metabotropic glutamate and adenosine receptors in AD physiopathology.
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Rusnati, Marco, Maura Camozzi, Emanuela Moroni, Barbara Bottazzi, Giuseppe Peri, Stefano Indraccolo, Alberto Amadori, Alberto Mantovani, and Marco Presta. "Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis." Blood 104, no. 1 (July 1, 2004): 92–99. http://dx.doi.org/10.1182/blood-2003-10-3433.
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Abstract The long pentraxin PTX3 is a soluble pattern recognition receptor produced by monocytes and endothelial cells that plays a nonredundant role in inflammation. Several pathologic conditions are characterized by local production of both PTX3 and the angiogenic fibroblast growth factor-2 (FGF2). Here, solid-phase binding assays demonstrated that PTX3 binds with high affinity to FGF2 but not to a panel of cytokines and growth factors, including FGF1, FGF4, and FGF8. Accordingly, PTX3 prevented 125I-FGF2 binding to endothelial cell receptors, leading to specific inhibition of FGF2-induced proliferation. PTX3 hampered also the motogenic activity exerted by endogenous FGF2 on a wounded endothelial cell monolayer. Moreover, PTX3 cDNA transduction in FGF2-transformed endothelial cells inhibited their autocrine FGF2-dependent proliferation and morphogenesis in vitro and their capacity to generate vascular lesions when injected in nude mice. Finally, PTX3 suppressed neovascularization triggered by FGF2 in the chick embryo chorioallantoic membrane with no effect on physiologic angiogenesis. In contrast, the short pentraxin C-reactive protein was a poor FGF2 ligand/antagonist. These results establish the selective binding of a member of the pentraxin superfamily to a growth factor. PTX3/FGF2 interaction may modulate angiogenesis in various physiopathologic conditions driven by inflammation, innate immunity, and/or neoplastic transformation.
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Panepucci, Rodrigo Alexandre, Ana Cristina S. Pinto, Carolina Dias-Carlos, Felipe Saldanha-Araujo, Patricia VB Palma, Jacques Elion, Dimas T. Covas, and Marco A. Zago. "Hydroxyurea-Induced Changes of Components Involved In the Modulation of Adenosine Levels, In Blood Cells From Sickle Cell Disease Patients." Blood 116, no. 21 (November 19, 2010): 2674. http://dx.doi.org/10.1182/blood.v116.21.2674.2674.
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Abstract Abstract 2674 Introduction. Recent studies have demonstrated the role of high adenosine levels in priapism episodes in a mouse model of sickle cell disease (SCD). Interestingly, adenosine signaling is related to several physiopathological processes that may relate to clinical features observed in patients with SCD. Adenosine (ADO) is a purine nucleoside that plays diverse roles in distinct physiological contexts. Extracellular ADO production occurs sequentially by the ectonucleotidases CD39 (which converts ATP and ADP to 5′-AMP) and CD73 (which convert 5′-AMP to ADO). Moreover, ADO levels are controlled by its conversion to inosine by the enzyme Adenosine Deaminase (ADA). ADA can be anchored in the cell membrane by CD26, leading to an increased localized action and consequently, to reduced local concentrations of adenosine. Hydroxyurea (HU) is the only drug approved by FDA to reduce vaso-occlusive episodes in patients with SCD, partly by the induction of fetal hemoglobin (HbF) and reduction of polymerization of HbS. However, the clinical improvement of patients is not always associated with increased HbS levels, indicating the potential effect of HU on other processes. Given the known (or proposed) contribution of distinct blood cell types in the physiopathology of SCD, in this study, we aimed to evaluate the possible modulation in the expression of CD39, CD73 and CD26 on lymphocytes and monocytes from SCD patients, in HU treated patients. Methods. The expression of CD39, CD73 and CD26 was evaluated by flow cytometry on total lymphocytes (CD3+) and monocytes (CD14+) in the peripheral blood (PB) of 12 patients treated with HU, 21 untreated and seven control healthy individuals. Results. On average, while less than 0.3% and 1.7% of monocytes of controls and untreated patients express CD26, respectively; in patients treated with HU, more than 10% of the monocytes express CD26 (p=0.0171, unpaired T-test). Additionally, in treated patients, a significantly lower percentage of lymphocytes express CD39, as compared to untreated (p=0.0431, unpaired T-test). The CD73 protein was not expressed by monocytes, and there was no modulation of its levels in lymphocytes. Conclusions. During inflammation (a processes associated with the physiopathology of SCD), the extracellular concentration of adenosine is increased and distinct blood cell types localize to the affected tissue. The results indicate a potential mechanism of action of HU in SCD patients, mediated by the increased expression of CD26 on monocytes (with subsequent co-localization of the enzyme ADA) and by the decreased expression of CD39 on lymphocytes. As a result of the observed changes, a decrease in the local synthesis of adenosine, associated with its increased conversion to inosine, would be expected. Thus, HU may drive the reduction of adenosine levels, thereby reducing the aggravating effects of this molecule in different physiopathological processes affected in patients with SCD. Supported by: FAPESP, CNPQ, FINEP and INSERM. Disclosures: No relevant conflicts of interest to declare.
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Caramia, Martino, Luigi Sforna, Fabio Franciolini, and Luigi Catacuzzeno. "The Volume-Regulated Anion Channel in Glioblastoma." Cancers 11, no. 3 (March 5, 2019): 307. http://dx.doi.org/10.3390/cancers11030307.
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Malignancy of glioblastoma multiforme (GBM), the most common and aggressive form of human brain tumor, strongly depends on its enhanced cell invasion and death evasion which make surgery and accompanying therapies highly ineffective. Several ion channels that regulate membrane potential, cytosolic Ca2+ concentration and cell volume in GBM cells play significant roles in sustaining these processes. Among them, the volume-regulated anion channel (VRAC), which mediates the swelling-activated chloride current (IClswell) and is highly expressed in GBM cells, arguably plays a major role. VRAC is primarily involved in reestablishing the original cell volume that may be lost under several physiopathological conditions, but also in sustaining the shape and cell volume changes needed for cell migration and proliferation. While experimentally VRAC is activated by exposing cells to hypotonic solutions that cause the increase of cell volume, in vivo it is thought to be controlled by several different stimuli and modulators. In this review we focus on our recent work showing that two conditions normally occurring in pathological GBM tissues, namely high serum levels and severe hypoxia, were both able to activate VRAC, and their activation was found to promote cell migration and resistance to cell death, both features enhancing GBM malignancy. Also, the fact that the signal transduction pathway leading to VRAC activation appears to involve GBM specific intracellular components, such as diacylglicerol kinase and phosphatidic acid, reportedly not involved in the activation of VRAC in healthy tissues, is a relevant finding. Based on these observations and the impact of VRAC in the physiopathology of GBM, targeting this channel or its intracellular regulators may represent an effective strategy to contrast this lethal tumor.
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Borges Rezende, Carlos Eduardo, Stephanie Rissio, William José Gilioti, and Morgana Moreno Boschi. "Intra and extracranial complications of middle earths: literature review." Journal of Otolaryngology-ENT Research 11, no. 2 (2019): 145–51. http://dx.doi.org/10.15406/joentr.2019.11.00425.
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Otitis media (OM) has several forms and among the main are otitis media (AOM), OM with effusion and chronic otitis media (COM) (cholesteatomatous or not). For the most part, the OM progressed well, but there are risks of complications and sequelae. These are divided into extra and intracranial, the first being the most common, but less lethal. Among the extracranial are: labyrinthine fistula, subperiosteal abscess, mastoiditis, temporozigomatic abscess, Bezold's abscess, parapharyngeal abscess, facial palsy, petrositis and labyrinthitis. Among the intracranial are: meningitis, epidural abscess, subdural empyema, brain abscess, the sigmoid sinus thrombophlebitis and otological hydrocephalus. The aim of this study is to identify the main complications of otitis media, distinguishing them from the incidence, degree of morbidity and mortality and analyze the development, management and treatment required for each entity. Brain abscess is the most common entity and subperiosteal abscess is the most common extracranial complication. Labyrinthine fistula occurs most often related to OMC. This has the physiopathology erosion of the bone covering the semicircular canal, usually the lateral semicircular canal. Labyrinthitis results from the spread of infection from the cochlear window membrane and can be presented in two ways: serous or suppurative labyrinthitis. The most common intracranial complication is meningitis, rarely associated with cholesteatoma and most often associated with AOM, of higher incidence in children. CT with contrast is the gold standard when you suspect any complications in patients with otitis media after undergoing a thorough history and physical examination. When the physician knows the possible complications and their signs and symptoms, the diagnosis is early and the prognosis best. Treatment of complications in general is based on patient hospitalization, myringotomy with culture and sensitivity, intravenous antibiotic therapy as early as possible and mastoidectomy in all cases related to COM or recurrent complications.
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Méndez-López, Iago, Francisco J. Sancho-Bielsa, Tobias Engel, Antonio G. G. García, and Juan Fernando Padín. "Progressive Mitochondrial SOD1G93A Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 22, no. 15 (July 30, 2021): 8194. http://dx.doi.org/10.3390/ijms22158194.
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In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.
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Santos, Juliana Godoy, Andressa De Cássia Martini, Bianca Garay Monteiro, Deise Cristine Schroder, Gabrielle Dourado Franco, Lívia Caroline De Mascarenhas, and Roberto Lopes De Souza. "Urethral Prolapse in a Dog of the American Pit Bull Breed." Acta Scientiae Veterinariae 46 (January 7, 2018): 4. http://dx.doi.org/10.22456/1679-9216.85113.
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Background: The urethral prolapse in dogs is a rare condition known by the protrusion of the urethral mucous membrane and the external orifice of the urethra. It is more frequently seen in young males, especially of brachycephalic breeds, for instance the English bulldog. Despite the pathophysiology of this disorder being little elucidated, it is believed that the cause is related to factors such as genetic susceptibility, excessive sexual behavior, traumas, abnormalities and urinary and prostatic problems. Due to limited reports on the subject, this paper aims to describe the clinical and surgical aspects of a case of urethral prolapse in a dog, surgically corrected.Case: Admitted to the Veterinary Hospital of the Federal University of Mato Grosso (HOVET-UFMT) a dog, American Pit Bull, 7 months old, with previous history of bleeding in the penile region and pain while urinating. In the physical exam it presented: intermittent bleeding via external ostium of the urethra, increased volume and protrusion of the distal urethral mucous membrane and the external orifice of the urethra, which was presenting a round shape mass, edematous and little congested of red-purplish coloring, evidenced by the passing of urethral probe. The diagnosis of urethral prolapse was confirmed and, after conducting laboratory tests and obtaining normal results for the species, the animal was sent to surgery. It was opted for the technique of resection and anastomosis of the protruded portion of the mucous membrane. After the anesthetic protocol, it was performed the trichotomy and antisepsis of region, the fenestrated drapes were properly positioned and the urethral catheterization was done, afterwards 3 points of support were produced with nylon thread 3-0, involving the urethra and the external portion of the penis. Subsequently, it was incised 1/3 of the protruded mucous membrane (from a support point to the other) with a pair of iris scissors and the aid of a toothless Adson clamp. Promptly the anastomotic synthesis was manufactured with a simple interrupted suture pattern. By the end of the first one third theremaining ones with go under the same procedure and in the end of the resection and anastomosis of the urethral prolapse the animal was submitted to a bilateral orchiectomy. At the immediate post-surgery it was established antibiotic therapy and the use of anti-inflammatory and painkiller, after 48 h of observation the animal was discharged from the hospital. As a therapeutic measure it was opted to continue with the use of antibiotics and anti-inflammatory, and then recommended the use of Elizabethan collar 24 h a day until the removing of the stitches. It was also recommended that the animal returned for a new evaluation thirteen days after of the procedure.Discussion: That being said, even being an unusual pathology, which the physiopathology is not completely clear, the urethral prolapse is of simple diagnosis, which is based on direct observation of the protruded mucous membrane and by obtaining information of possible factors that cause its appearance, such as genetic susceptibility, in the case of the animalfrom the current report, since it had the English Bulldog as genetic predecessor. Even though there are techniques less traumatic for its diminishing the chosen technique is the resection and anastomose of the protruded portion of the urethral mucous membrane, due to being simple, quick, effective and with lower rates of relapses. Proven by the result of total recovering of the animal and excellent post-surgery healing, not having relapses.Keywords: dog, surgery, urethra.
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Baratti, Mariana O., Paulo R. M. Lima, Daniella C. Alberto, Luciene Borges, Kleber G. Franchini, Fernando F. Costa, and Sara T. O. Saad. "Re-Organization of Cardiac Band 3 (cAE1) in Neonatal Cardiomyocytes Submitted to Alkali Loading." Blood 108, no. 11 (November 16, 2006): 3744. http://dx.doi.org/10.1182/blood.v108.11.3744.3744.
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Abstract Band 3 was initially described as the first member of the anion exchanger family (AE1). It is an integral membrane protein, initially characterized in erythrocytes. The AE family is encoded by four genes, AE1, AE2, AE3 and AE4. Three AE1 isoforms have been described up to now: erythroid (eAE1), kidney (kAE1), and cardiac (cAE1). Increased expression and activity of AE1 and AE3, as well as of the Na+/H+ exchanger have been demonstrated in hypertrophic myocardium of rats. A physical association of band 3 with cardiac actin has been previously described by our group, using yeast two hybrid screening. It has also been suggested that this binding occurs in the intercalated disc, a site of cell-cell contact and attachment of the sarcomere to the plasma membrane. In the present study, immunolocalization analysis by confocal laser scanning microscopy was used to investigate the band 3 re-organization in neonatal cardiomyocytes (Wistar rats 1 to 2-day-old) submitted to different stimuli, such as pH changing or mechanical stretch (a model leading to cardiac hypertrophy). In the untreated cells, band 3 was dispersedly distributed in the cytoplasm, preferentially in the perinuclear region. On the other hand, when these cells were submitted to cyclic stretch (2 hours), band 3 appears between actin filaments, in the sarcomeric units. Similar distribution was showed in cardiac cells submitted to alkali loading (pH 8.9 for 2 hours). However, in experiments where the culture medium was pH 6.8, band 3 was dispersed in the cytoplasm, but was not concentrated in the perinuclear region. Intracellular pH (pHi) is a major regulator of diverse cellular processes including metabolic pathways, Ca2+ homeostasis, cell contractility, cell excitability and cell death; a rise in pHi activates Cl−/HCO3− exchanger. On the other hand, the mechanical stretch stimulates a rapid secretion of Angiotensin II, rise of pHi and activation of intracellular signaling molecules such as protein kinase C and tyrosine kinases. These processes induce cell proliferation, cardiac hypertrophy and reorganization of actin cytoskeleton. The demonstration of reorganization of band 3 and its localization in the sarcomeric units after these stimuli suggest that band 3 is involved in the cardiac hypertrophy physiopathology. Band 3 could function as an anchorage for the contractile apparatus, as well as in the transport of anions in the myocardium, which are well described processes in normal erythrocytes.
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Zennadi, Rahima, and Marilyn J. Telen. "Atypical Activation of Plasma Membrane-Bound ERK1/2 Is Associated with Regulation of Sickle Red Cell Adhesion to Endothelium." Blood 116, no. 21 (November 19, 2010): 266. http://dx.doi.org/10.1182/blood.v116.21.266.266.
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Abstract 266 Abnormal adhesion of erythrocytes homozygous for hemoglobin S (SS RBCs) and vaso-occlusion are hallmarks of sickle cell disease (SCD). SS RBC adhesion can be activated via stimulation of the cAMP/PKA pathway by the stress hormone epinephrine. We have found that the extracellular signal-regulated kinase-1 and 2 (ERK1/2) is abundantly expressed in mature RBCs and is bound to the isolated plasma membrane. Because aberrations in ERK1/2 signaling are associated with various pathologies, we predicted that this prototypical molecular regulator of cell division and differentiation remained functional in terminally differentiated SS RBCs and plays a role in regulating RBC adherence. Western blot analysis of RBC ghosts showed that ERK1/2 was phosphorylated to some degree in SS but not normal RBCs. Although this basal ERK1/2 phosphorylation was not detected in all SS RBC samples tested, ERK1/2 underwent increased phosphorylation (p<0.01) in all samples tested (n=8) in response to epinephrine stimulation. Incubation of SS RBCs with the MEK inhibitor (MEKI) U0126, which specifically inhibits MEK1/2, the upstream kinase of ERK activation, completely abolished epinephrine-induced ERK1/2 phosphorylation. In contrast, epinephrine completely failed to activate ERK1/2 in normal RBCs. We further confirmed that ERK1/2 preserved its activity in SS RBCs by determining that ERK1/2 immunoprecipitated from sham-treated SS RBCs was able to phosphorylate to some extent myelin basic protein (MBP), the ERK specific substrate. However, MBP phosphorylation by ERK1/2 isolated from epinephrine-treated SS RBCs increased by 62% compared to MPB phosphorylation by ERK1/2 isolated from sham-treated cells (n=4, p<0.03). This indicates that ERK1/2 is active in SS RBCs and that epinephrine amplifies its activity. Active ERK1/2 was also found to act downstream of cAMP/PKA, since treatment of SS RBCs with forskolin, which directly activates adenylyl cyclase to produce cAMP, increased ERK1/2 phosphorylation, and the PKA-specific inhibitor 14–22 amide completely blocked the effect of epinephrine on ERK phosphorylation (n=3, p<0.001). Importantly, we found that activation of ERK1/2 signaling was implicated in adhesion of SS RBC to endothelial cells (ECs). Epinephrine significantly up-regulated SS RBC adhesion at a shear stress of 2 dynes/cm2 (p < 0.001). However, SS RBC adhesion induced by epinephrine was completely inhibited by pre-treatment of SS RBCs with MEKI U0126 (p < 0.001). PhosphorImager analysis of immunoprecipitated 32P-radiolabeled ICAM-4, which mediates SS RBC adhesion to ECs, showed that the previously described phosphorylation of ICAM-4 in response to epinephrine was dependent on PKA and MEK1/2/ERK1/2. Furthermore, addition of recombinant ERK2 to RBC ghosts, followed by mass spectrometric analysis, showed that ERK phosphorylated its consensus motif on adducins α and β and dematin; band 4.1 also underwent phosphorylation but not at an ERK consensus motif. This suggests that phosphorylation of cytoskeletal proteins may induce membrane protein conformational changes that render ICAM-4 accessible to phosphorylation by an as yet unidentified kinase. Finally, SS RBC adhesion was closely related to the onset of ERK1/2 activation. Within 1 minute of stimulation, epinephrine induced a significant increase in both SS RBC adhesion to ECs and phosphorylation of ERK1/2 (p < 0.001). Both SS RBC adhesion and ERK phosphorylation decreased after longer exposure to epinephrine (30 min vs 1 min, p < 0.001 for each). Addition of recombinant ERK2 to SS RBC ghosts, followed by mass spectrometry, also showed that phosphorylation of the ERK consensus motif on adenylyl cyclase-associated protein 1 increased 5-fold (p < 0.0003). These data suggest that activation of adenylyl cyclase-associated protein 1, which is known to inhibit adenylyl cyclase activity, may negatively regulate activation of ERK in SS RBCs. In summary, our data indicate that ERK1/2 activity is atypically preserved in SS RBCs. These data also suggest that ICAM-4 adhesive function is regulated by ERK activation, and that ERK activity could probably be turned off by ERK-induced inactivation of adenylyl cyclase. Activation of ERK1/2 in SS RBCs is an extremely interesting phenomenon in SCD physiopathology, since its mode of action could become a potential therapeutic target, and MEK inhibitors are currently in development as therapeutic agents in cancer. Disclosures: Telen: GlycoMimetics: Consultancy.
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Rubio, Marie T., Marie A. Dragon-Durey, Sébastien Jacquelin, Jacques Blouin, Natacha Maillard, David Ghez, Felipe Suarez, et al. "Complement System Activation after Allogeneic Bone Marrow Transplantation May Early Predict the Development of Acute Gastrointestinal GVHD." Blood 110, no. 11 (November 16, 2007): 2186. http://dx.doi.org/10.1182/blood.v110.11.2186.2186.
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Abstract The Complement system consists of several serum proteins and receptors that belong to the innate immune response. It is activated by three possible pathways leading to the production of pro-inflammatory factors and the formation of the membrane attack complex. As it is known to be implicated in the physiopathology of several immune-mediated diseases, we investigated its role in GVHD in both humans and a mouse model. Thirty nine patients allografted for diverse haematological malignancies in our institution following myeloablative conditioning (n=22) or reduced intensity conditioning (RIC) (n=17) entered prospectively the study. Extensive exploration of the Complement system was carried out before and sequentially after allogeneic haematopoietic stem cell transplantation (HSCT). An activation of the classical pathway, as defined by a decrease of C3 and C4 proteins below normal values and of at least 50% of their pre-HSCT levels, was observed in 10/39 patients. Such activation was found in 9/22 (40%) patients who received myeloablative conditioning and in 1/17 (5.8%) patients allografted with RIC. This phenomenon occurred during the 4 first weeks after HSCT in 7 patients, at two months in one case and after withdrawal of immunosuppression in 2 patients. We observed a strong association between Complement activation and the development of acute gastrointestinal (GI) GVHD. Nine of the 10 patients who activated the Complement system (90%) developed GI GVHD within two weeks following the activation. By contrast only 4 of the 29 who did not activate the system, all of whom had received a RIC, developed GI GVHD (13.8%) (p<0.001). No correlation was found with the use of monoclonal antibodies, the degree of HLA and sex disparity between donor and recipient or the CMV status before the graft. We then analyzed Complement activation in a parent (C57BL/6, H–2b) to F1 [(C57BL/6×DBA2), H–bd] GVHD mouse model. Serum C3 Complement fraction and serum albumin protein (SAP) were measured sequentially after HSCT in lethally irradiated (9.75 Gy) mice reconstituted with either syngeneic or allogeneic bone marrow cells and splenocytes (107 and 13×106 cells/recipient, respectively). In comparison to naïve non HSCT recipient mice, the C3/SAP ratio was increased up to three times from Day 4 to 28 in syngeneic HSCT recipients (p=0.0002), reflecting the inflammatory response induced by the conditioning regimen without Complement activation in this conditioned non-GVHD control group. By contrast, the C3/SAP ratio was significantly decreased from Day 7 to 28 after HSCT in allogeneic recipients of HSCT in comparison to that of naïve (p=0.0005) and of syngeneic recipients (p=0.0002), indicating an activation of the Complement system in allografted mice that uniformly developed GI GVHD by Day 20 after HSCT. In conclusion, our results show that allogeneic HSCT induces Complement activation in both humans and mice, as a consequence of the immune alloresponse and not as a direct effect of the conditioning regimen. They also suggest that Complement C3 and C4 dosage might be useful in early prediction of acute gastrointestinal GVHD in humans. Ongoing studies are investigating the potential protective effect of pharmacological inhibitors of Complement activation on the development of GVHD in our mouse model.
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Kim-Anh, Nguyen-Peyre, Bodivit Gwellaouen, Foresti Roberta, Kiger Laurent, Gaetana Di Liberto, Philippe Chadebech, Alicia Jouard, et al. "Protective Effects of Carbon Monoxide Delivered By Corm-401 in Hyperhemolysis in Patients with Sickle Cell Disease." Blood 132, Supplement 1 (November 29, 2018): 2367. http://dx.doi.org/10.1182/blood-2018-99-112900.
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Abstract Introduction Hyperhemolysis has been well described in delayed hemolytic transfusion reaction (DHTR), which is one of the most serious complications of transfusion especially in patients with sickle cell disease (SCD). In the most severe cases, this life-threatening syndrome may reach 10% lysis of total red blood cells (RBCs) (Habibi A et. al. Am J Hematol 2016). DHTR is characterized by an acute anemia with increased plasma free Hb and free heme. Hyperhemolysis can also be found in other hemoglobinopathies and extracorporeal circulation procedures. Most in vitro studies on hyperhemolysis used only purified Hb or heme which did not allow to investigate all deleterious effects on the endothelium. We have developed a global and physiopathologic approach to assess the mechanism of hyperhemolysis-induced endothelial dysfunction. For this purpose, we created a microfluidic model reproducing hyperhemolysis observed in the most severe DHTR but it's also applicable for other pathogenesis of hyperhemolysis. Among the potential therapeutic approaches, carbon monoxide (CO) is beneficial on endothelial cells by its anti-inflammatory, antioxidant and vasodilator effect which reduce the toxicity of Hb and improve tissue perfusion (Motterlini R et.al. Nat. Rev. Drug Discov 2010). Here we investigated the therapeutic effects of a CO-releasing molecule, CORM-401, in hyperhemolysis-induced endothelial dysfunction. Materials and methods Flow culture Human Umbilical Vein Endothelial Cells (HUVECs) in fibronectin-coated µ-Slides were preconditioned for 4 hours under shear stress of 1dyn/cm² with sonicated RBCs of healthy donors (AA) reconstituted in serum of either AA or SCD patients (SS) at 7 g/L of free Hb. In negative control conditions, cells were pretreated similarly with either AA serum or culture medium. Cells were then collected for analyses of actin network, membrane markers and endothelial function. Treatment with CORM-401 or inactive CORM (iCORM) was performed at fixed concentration during the preconditioning and perfusion steps. ResultsHemolysis induces multiple endothelial damage and dysfunction After exposure to hemolysate, we noted a significant increase of subendothelial matrix exposition (fibronectin-coated surfaces) due to actin network reorganization and cells detachment. Immunofluorescence staining showed a moderate activation of HUVECs induced by hemolysate with membrane expression of adhesion molecules such as ICAM-1, E-Selectin and VCAM-1, but not VWF and P-Selectin. At a similar free Hb level, preconditioning with hemolysate without microparticles (MPs) had the lowest deleterious impact on HUVECs suggesting a role of MPs in hyperhemolysis. Perfusion of AA whole blood on HUVECs pretreated with hemolysate resulted in aggregation and activation of platelets in a GPIIbIIIa-dependent manner at injury sites. We also observed a significant increase of adhered RBCs (14-fold compared to control). Compared to whole blood RBC lysis, purified Hb induced similar subendothelial exposure and RBC adherence but did not lead to significant HUVECs activation. To study the DHTR in RBC transfusion of SCD patients, SS serum was used to perform hemolysis preconditioning of HUVECs. Adherence of RBCs was similar to condition using AA serum suggesting that endothelial damage in DHTR of SCD patients depend on hemolysate compositions and RBC MPs, rather than on patients' serum.Effects of CORM-401 on hemolysis-induced endothelial dysfunction Adding CORM-401 (50 to 100 µM) to the hemolysate produced 15% free COHb leading to a concentration-dependent decrease in hemolysis-induced HUVECs activation and RBC adherence (Figure 1 C, E). While no significant effects at the subendothelial exposure were observed, the aggregation of platelets at injury sites was decreased after CORM-401 treatment compared to controls (Figure 1 A, B, D), confirming the anti-platelet aggregation effect of this molecule (Chlopicki S et. al. Naunyn Schmiedebergs Arch Pharmacol 2012). Conclusion Our in vitro model enabled the reproduction of endothelial damage by hyperhemolysis and to determine the deleterious effects of each hemolysate component. The in vitro beneficial effects of CORM-401 were also demonstrated and an in vivo study on SCD mice is underway to explore the therapeutic effects of this molecule against hyperhemolysis-induced endothelial damage. Figure 1. Figure 1. Disclosures Bartolucci: Addmedica: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; Fondation Fabre: Research Funding; Novartis US: Membership on an entity's Board of Directors or advisory committees.
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Zappasodi, Roberta, Gaia C. Ghedini, Italia Bongarzone, Lorenzo Castagnoli, Maida de Bortoli, Piera Aiello, Alessandra Cavanè, et al. "Serological Identification of HSP105 as a Novel Non-Hodgkin Lymphoma Therapeutic Target." Blood 116, no. 21 (November 19, 2010): 463. http://dx.doi.org/10.1182/blood.v116.21.463.463.
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Abstract Abstract 463 We recently reported that vaccination with autologous monocyte-derived dendritic cells pulsed with dying autologous tumor cells elicited a clinical response strongly associated with multifaceted antitumor immune-activation in relapsed indolent non-Hodgkin lymphoma (NHL) patients. We have now set out to determine whether vaccine-induced humoral response is directed against common indolent NHL-restricted antigens (ags), which could thus be exploited as novel targets for therapy. Antibodies (Abs) were purified from pre- and post-vaccine patients' serum samples, biotin-conjugated, and initially tested by immunohistochemistry (IHC) and flow cytometry (FC) on allogeneic tumors biopsies or live tumor cells, both primary tumors and cell lines. We found that post-vaccine Abs from responders (R) reacted with allogeneic NHL at significantly higher levels than their matched pre-vaccine samples or non-R Abs. Furthermore, Rs' post-vaccine sera significantly impaired the growth of DOHH-2 and RL-19 follicular lymphoma (FL) cell lines, as revealed by standard 3-(4,5- dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. To identify the therapeutically targeted NHL ags, we then used biotin-conjugated patient Abs to immunoblot one-dimensional SDS-PAGE of DOHH-2 cell protein fractions obtained by isoelectrofocusing. Protein bands differentially revealed by post-vaccine Abs from R were analyzed by Mass Spectrometry (MS). One differential band migrating at about 100 kDa was revealed among the most acidic protein fractions only when post-vaccine samples from R were used. MS analysis identified heat shock protein (HSP) 105 in the differentially reacting bands. Immunoprecipitation with a commercial anti-HSP105 Ab followed by Western blot analysis with biotin-conjugated pre- and post-vaccine Abs from R confirmed the increased ability of the post-vaccine sample to recognize HSP105. FC disclosed HSP105 both on the cell membrane and in the cytoplasm of a panel of B-cell NHL cell lines and normal B cells. The extent of HSP105 surface expression increased in function of lymphoma istotype aggressiveness. The antitumor activity of anti-HSP105 Ab, measured by MTT assays, was thus higher against Burkitt's lymphoma (BL) cell lines than germinal centre-derived diffuse large B cell lymphoma and FL cell lines, which displayed an IC50 of 4.5, 7.5, 11.7 μg/ml, respectively. To confirm these finding in primary human tumors, we performed IHC analyses of HSP105 on 68 diagnostic NHL specimens (35 low-grade and 33 high-grade NHL) and 23 non-malignant lymph nodes obtained from our Institutional Tissue Bank. Low-grade NHL's cytoplasmic immunoreactivity was mainly restricted to actively proliferating cells (i.e. Ki67 positive germinal centre cells), whereas high-grade NHL displayed a significantly higher expression of HSP105, measured both as intensity and percentage of positive cells (p=0.0002). In addition, malignant cells in high-grade NHL more often displayed a specific cell-surface staining. Interestingly, the expression pattern and intensity of HSP105 was widely superimposable on that of the proliferation marker Ki67, as detected by the specific monoclonal Ab Mib-1. Lastly, the therapeutic effects of HSP105 functional inhibition was studied in Namalwa BL xenotransplanted SCID mice using a specific commercial Ab. Treated mice showed a significant delay in tumor growth compared to untreated control animals (p=0.0014). Taken as a whole, our results indicate that HSP105 could be a new potential biotarget for the treatment of NHL and a novel candidate biomarker for an improved management of B-cell lymphoma. Its location on the normal B cell surface, and its increasing expression with NHL aggressiveness open a new area in which to assess its role in B-cell biology and lymphoma physiopathology. Disclosures: No relevant conflicts of interest to declare.
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Chiu, Yi-Han, Shu-Chuan Amy Lin, Chen-Hsin Kuo, and Chia-Jung Li. "Molecular Machinery and Pathophysiology of Mitochondrial Dynamics." Frontiers in Cell and Developmental Biology 9 (September 17, 2021). http://dx.doi.org/10.3389/fcell.2021.743892.
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Mitochondria are double-membraned organelles that exhibit fluidity. They are the main site of cellular aerobic respiration, providing energy for cell proliferation, migration, and survival; hence, they are called “powerhouses.” Mitochondria play an important role in biological processes such as cell death, cell senescence, autophagy, lipid synthesis, calcium homeostasis, and iron balance. Fission and fusion are active processes that require many specialized proteins, including mechanical enzymes that physically alter mitochondrial membranes, and interface proteins that regulate the interaction of these mechanical proteins with organelles. This review discusses the molecular mechanisms of mitochondrial fusion, fission, and physiopathology, emphasizing the biological significance of mitochondrial morphology and dynamics. In particular, the regulatory mechanisms of mitochondria-related genes and proteins in animal cells are discussed, as well as research trends in mitochondrial dynamics, providing a theoretical reference for future mitochondrial research.