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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a monogenic disorder caused by mutations in the NOTCH3 gene. The main aim of our survey was to determine if there is an association between phenotypes and genotypes across the most common NOTCH3 mutations found in CADASIL patients. We systematically searched clinical studies and genomic databases from 1996 to 2023 to first identify the most common mutations responsible for CADASIL. We found the six most common NOTCH3 missense mutations globally were the p.R75P, p.R133C, p.R141C, p.R169C, p.R182C, and p.R544C, of which p.R133C was described to occur most often. Focusing on studies with comprehensive clinical records, our analysis further suggested that the p.R75P, p.R141C, p.R182C and p.R544C genotypes were highly congruent with the presence of white matter hyperintensities on magnetic resonance imaging (MRI), which was the most common phenotypic characteristic across all four mutations. We found the p.R141C mutation was associated with increased severity of disease. We also found the average age of onset in p.R544C carriers was more than a decade later compared to the p.R141C carriers. However, statistical analysis showed there were no overall differences between the phenotypic characteristics of the two common mutations, p.R141C and p.R544C. Geographically, China and Japan were the only two countries to report all the four common mutations vis a vis p.R75P, p.R141C, p.R182C and p.R544C. There is a possibility that this is due to a combination of a founder effect, but there also could be sampling biases.
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BACKGROUND AND OBJECTIVES: Mucopolysaccharidosis (MPS) is a group of lysosomal storage disorders that cause the deposition of polysaccharides in cells. This causes systemic and oral manifestations, which can be observed clinically and radiographically. The present study aimed to assess dental caries, the effect of salivary pH, and the change of microflora on teeth in patients diagnosed with MPS. MATERIALS AND METHODS: The study included children affected with mucopolysaccharidosis (n = 50) and healthy children (n = 50) in the control group between 3 and 15 years of age. The pH of saliva and decayed, missing, and filled teeth/decayed extracted and filled teeth index were noted and recorded. For the microbial analysis, saliva was inoculated into blood agar, MacConkey agar, Candida CHROMagar, and Mitis Salivarius agar, then inspected for colony-forming units, which were counted and recorded based on the colony characteristics and gram staining. STATISTICAL ANALYSIS: Intergroup comparison of the test parameters was done using the Mann-Whitney test. P < 0.05 was considered statistically significant. RESULTS: The results showed significantly higher total microbial load (P = 0.00008), streptococcus viridans species (P = 0.00001), and Candida species (P = 0.0038) in the study group. The caries incidence was also higher in the study group for both primary (P = 0.0096) and permanent dentition (P = 0.0251), and salivary pH was more acidic (P = 0.00001) in the patients diagnosed with MPS. INTERPRETATION AND CONCLUSION: Patients diagnosed with MPS have a higher microbial load, more acidic saliva, and subsequently, a higher caries incidence than normal healthy children. Hence, regular dental evaluation, prevention, and treatment must be integrated into their health-care regimen.
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Cárie Dentária , Mucopolissacaridoses , Saliva , Humanos , Saliva/microbiologia , Criança , Cárie Dentária/microbiologia , Cárie Dentária/diagnóstico , Adolescente , Mucopolissacaridoses/complicações , Mucopolissacaridoses/diagnóstico , Pré-Escolar , Feminino , Masculino , Concentração de Íons de Hidrogênio , Índice CPO , Candida/isolamento & purificação , Estudos de Casos e ControlesRESUMO
An intensive idea of bone tissue engineering is to design regenerative nanofibrous scaffolds that could afford a natural extracellular matrix (ECM) microenvironment with the ability to induce cell proliferation, biodegradation, sustained drug release, and bioactivity. Even the mechanical properties and orientation of the nanofibers may enhance the performance of the scaffolds. To address this issue, we designed novel sandwich-like hybrid silk fibroin (SF)/silica/poly(vinyl alcohol) (PVA) nanofibers scaffolds. The developed scaffold was further characterized using scanning electron microscopy (SEM), elemental mapping, X-ray diffraction (XRD), Fourier-transform infrared (FTIR), and water/blood contact angle measurements. Owing to the interfacial interaction between the layers of organic (chitosan/silk fibroin) and inorganic (silica) in the nanofibrous scaffold, a biocompatibility study has been made on an osteoblast-like (MG63) cell line, which has significant statistical differences; hemocompatibility and the mechanical profile were evaluated in detail to understand the suitability as a biomaterial. To endow the scaffold biodegradation rate, antibacterial activity, porosity profile, and cephalexin monohydrate (CEM), a drug-loading/drug release study was also performed for all of the nanofibers. This strategy explored superior mechanical strength with higher biomineralization on SF/silica/PVA nanofibers. Eventually, the proposed article compared the observation of monolayered scaffolds with designed sandwich-structured scaffolds for the enhancement of bone regeneration.
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Hexagonal boron nitride (h-BN) hosts pure single-photon emitters that have shown evidence of optically detected electronic spin dynamics. However, the electrical and chemical structures of these optically addressable spins are unknown, and the nature of their spin-optical interactions remains mysterious. Here, we use time-domain optical and microwave experiments to characterize a single emitter in h-BN exhibiting room temperature optically detected magnetic resonance. Using dynamical simulations, we constrain and quantify transition rates in the model, and we design optical control protocols that optimize the signal-to-noise ratio for spin readout. This constitutes a necessary step toward quantum control of spin states in h-BN.
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The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.
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Ligação Proteica , Proteínas Proto-Oncogênicas p21(ras) , Ubiquitinação , Humanos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Animais , Proteína p120 Ativadora de GTPase/metabolismo , Proteína p120 Ativadora de GTPase/genética , Camundongos , Linhagem Celular Tumoral , GTP Fosfo-Hidrolases/metabolismo , GTP Fosfo-Hidrolases/genética , Lisina/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas ras/metabolismo , Proteínas ras/genética , Neurofibromina 1RESUMO
Metal-organic complexes have shown astounding bioactive properties; however, they are rarely explored as biomaterials. Recent studies showed that carboxymethyl-chitosan (CMC) genipin-conjugated zinc biomimetic scaffolds have unique bioselective properties. The biomaterial was reported to be mammalian cell-friendly; at the same time, it was found to discourage microbial biofilm formation on its surface, which seemed to be a promising solution to addressing the problem of trauma-associated biofilm formation and development of antimicrobial resistance. However, the mechanically frail characteristics and zinc overload raise concerns and limit the potential of the said biomaterials. Hence, the present work is focused on improving the strength of the earlier scaffold formulations, testing its in vivo efficacy and reaffirming its action against biofilm-forming microbe Staphylococcus aureus. Scaling up of CMC proportion increased rigidity, and 8% CMC was found to be the ideal concentration for robust scaffold fabrication. Freeze-dried CMC scaffolds with or without genipin (GP) cross-linking were conjugated with zinc using 2 M zinc acetate solution. Characterization results indicated that the CMC-Zn scaffolds, without genipin, showed mechanical properties close to bone fillers, resist in vitro enzymatic degradation until 4 weeks, are porous in nature, and have radiopacity close to mandibular bones. Upon implantation in a subcutaneous pocket of Wistar rats, the scaffolds showed tissue in-growth with simultaneous degradation without any signs of toxicity past 28 days. Neither were there any signs of toxicity in any of the vital organs. Considering many superior properties among the other formulations, the CMC-Zn scaffolds were furthered for biofilm studies. CMC-Zn showed negligible S. aureus biofilm formation on its surface as revealed by an alamar blue-based study. RT-PCR analysis revealed that CMC-Zn downregulated the expression of pro-biofilm effector genes such as icaC and clfB. A protein docking study predicted the inhibitory mechanism of CMC-Zn. Although it binds strongly when alone, at high density, it may cause inactivation of the transmembrane upstream activators of the said genes, thereby preventing their dimerization and subsequent inactivation of the effector genes. In conclusion, zinc-conjugated carboxymethyl-chitosan scaffolds are mechanically robust, porous, yet biodegradable, harmless to the host in the long term, they are radiopaque and prevent biofilm gene expression in notorious microbes; hence, they could be a suitable candidate for bone filler applications.
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Materiais Biocompatíveis , Biofilmes , Teste de Materiais , Staphylococcus aureus , Zinco , Biofilmes/efeitos dos fármacos , Zinco/química , Zinco/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Animais , Porosidade , Ratos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Tamanho da Partícula , Quitosana/química , Quitosana/farmacologia , Testes de Sensibilidade Microbiana , Alicerces Teciduais/químicaRESUMO
OBJECTIVE: To report corneal epithelial and corneal endothelial cell (CEC) changes following Descemet stripping only (DSO) with and without topical ripasudil using in vivo confocal microscopy (IVCM). METHODS: Prospective interventional case series of patients who underwent DSO for Fuchs endothelial dystrophy with or without postoperative topical ripasudil (4%, 6 times per day). Patients underwent IVCM (ConfoScan 3; NIDEK Technologies, Padova, Italy) at baseline, monthly until corneal clearance, and then every 6 months. En face images were obtained of the epithelium, anterior and posterior corneal stroma, and endothelium of the central and superior cornea. The epithelial and endothelial layer images were evaluated qualitatively. RESULTS: IVCM imaging was obtained from 34 patients, 26 (76%) of whom were supplemented with ripasudil and 8 (24%) of whom were not. Two eyes (6%) did not clear and required a keratoplasty. IVCM confirmed epithelial and endothelial cell morphology changes and reestablishment of a CEC mosaic. Hyperreflective nuclei, pleomorphism, multinucleated cells, and pseudoguttae were identified within the descemetorhexis. In patients on ripasudil, epithelial cells demonstrated transition from stratified squamous to spindle cell shape in regions of ripasudil-induced honeycomb edema. Migrating cells adopted an amoeboid shape and cytoplasm elongation when crossing to central stroma. Transient epithelial cell morphology changes and endothelial cell amoeboid shape changes appear to be uniquely associated with ripasudil. Rarely, figures were noted in both ripasudil-treated and non-ripasudil-treated corneas that resembled mitotic bodies. CONCLUSIONS: CECs display a range of adaptive mechanisms during healing to re-form the endothelial mosaic following DSO. Ripasudil administration appears to induce unique epithelial and endothelial cell changes.
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Neurovascular unit mural cells called 'pericytes' maintain the blood-brain barrier and local cerebral blood flow. Pathological changes in the hippocampus predispose to cognitive impairment and dementia. The role of hippocampal pericytes in dementia is largely unknown. We investigated hippocampal pericytes in 90 post-mortem brains from post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer's disease (AD), and AD-VaD (Mixed) subjects, and post-stroke non-demented survivors as well as similar age controls. We used collagen IV immunohistochemistry to determine pericyte densities and a mouse model of VaD to validate the effects of chronic cerebral hypoperfusion. Despite increased trends in hippocampal microvascular densities across all dementias, mean pericyte densities were reduced by ~25-40% in PSD, VaD and AD subjects compared to those in controls, which calculated to 14.1 ± 0.7 per mm capillary length, specifically in the cornu ammonis (CA) 1 region (P = 0.01). In mice with chronic bilateral carotid artery occlusion, hippocampal pericyte loss was ~60% relative to controls (P < 0.001). Pericyte densities were correlated with CA1 volumes (r = 0.54, P = 0.006) but not in any other sub-region. However, mice subjected to the full-time environmental enrichment (EE) paradigm showed remarkable attenuation of hippocampal CA1 pericyte loss in tandem with CA1 atrophy. Our results suggest loss of hippocampal microvascular pericytes across common dementias is explained by a vascular aetiology, whilst the EE paradigm offers significant protection.
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Doença de Alzheimer , Isquemia Encefálica , Demência Vascular , Acidente Vascular Cerebral , Humanos , Camundongos , Animais , Doença de Alzheimer/patologia , Demência Vascular/patologia , Pericitos/patologia , Hipocampo/patologia , Encéfalo/patologia , Acidente Vascular Cerebral/patologia , Isquemia Encefálica/patologiaRESUMO
Chemical agents can cause cancer in animals by damaging their DNA, mutating their genes, and modifying their epigenetic signatures. Carcinogen-induced preclinical cancer models are useful for understanding carcinogen-induced human cancers, as they can reproduce the diversity and complexity of tumor types, as well as the interactions with the host environment. However, these models also have some drawbacks that limit their applicability and validity. For instance, some chemicals may be more effective or toxic in animals than in humans, and the tumors may differ in their genetics and phenotypes. Some chemicals may also affect normal cells and tissues, such as by causing oxidative stress, inflammation, and cell death, which may alter the tumor behavior and response to therapy. Furthermore, some chemicals may have variable effects depending on the exposure conditions, such as dose, route, and duration, as well as the animal characteristics, such as genetics and hormones. Therefore, these models should be carefully chosen, validated, and standardized, and the results should be cautiously interpreted and compared with other models. This review covers the main features of chemically induced cancer models, such as genetic and epigenetic changes, tumor environment, angiogenesis, invasion and metastasis, and immune response. We also address the pros and cons of these models and the current and future challenges for their improvement. This review offers a comprehensive overview of the state of the art of carcinogen-induced cancer models and provides new perspectives for cancer research.
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A palladium-catalyzed chelation-assisted direct aldehyde C-H bond amidation of quinoline-8-carbaldehydes with an amine was developed under mild reaction conditions. A wide range of amides were obtained in good to excellent yields from aldehyde with a variety of aniline derivatives and aliphatic amines. Our methodology was successfully applied to synthesize known DNA intercalating agents and can be easily scaled up to a gram scale.
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INTRODUCTION: The true global burden of vascular cognitive impairment (VCI) is unknown. Reducing risk factors for stroke and cardiovascular disease would inevitably curtail VCI. AREAS COVERED: The authors review current diagnosis, epidemiology, and risk factors for VCI. VCI increases in older age and by inheritance of known genetic traits. They emphasize modifiable risk factors identified by the 2020 Lancet Dementia Commission. The most profound risks for VCI also include lower education, cardiometabolic factors, and compromised cognitive reserve. Finally, they discuss pharmacological and non-pharmacological interventions. EXPERT OPINION: By virtue of the high frequencies of stroke and cardiovascular disease the global prevalence of VCI is expectedly higher than prevalent neurodegenerative disorders causing dementia. Since ~ 90% of the global burden of stroke can be attributed to modifiable risk factors, a formidable opportunity arises to reduce the burden of not only stroke but VCI outcomes including progression from mild to the major in form of vascular dementia. Strict control of vascular risk factors and secondary prevention of cerebrovascular disease via pharmacological interventions will impact on burden of VCI. Non-pharmacological measures by adopting healthy diets and encouraging physical and cognitive activities and urging multidomain approaches are important for prevention of VCI and preservation of vascular brain health.
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Doenças Cardiovasculares , Transtornos Cognitivos , Disfunção Cognitiva , Demência Vascular , Acidente Vascular Cerebral , Humanos , Transtornos Cognitivos/diagnóstico , Demência Vascular/prevenção & controle , Demência Vascular/diagnóstico , Demência Vascular/epidemiologia , Disfunção Cognitiva/prevenção & controle , Acidente Vascular Cerebral/complicações , EncéfaloRESUMO
White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.
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Transtornos Cerebrovasculares , Transtornos Cognitivos , Disfunção Cognitiva , Leucoencefalopatias , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Substância Branca , Animais , Camundongos , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Substância Branca/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismoRESUMO
Textile effluents containing toxic dyes must be treated effectively before discharge to prevent adverse environmental impacts. Traditional physical and chemical treatment methods are costly and generate secondary pollutants. In contrast, biological treatment is a more suitable, clean, versatile, eco-friendly, and cost-effective technique for treating textile effluent. It is well established that indigenous microbial populations present in effluents can effectively degrade toxic dyes. In this regard, Achromobacter xylosoxidans DDB6 was isolated from the effluent sample to decolorize crystal violet (CV), Coomassie brilliant blue (CBB), and alizarin red (AR) by 67.20%, 28.58%, and 20.41%, respectively. The growth parameters of A. xylosoxidans DDB6 in media supplemented with 100 ppm of various dyes were determined using the modified Gompertz growth model. The immobilized cells in calcium alginate beads showed apparent decolorization rate constant of 0.27, 0.18, and 0.13 h-1 for CV, CBB, and AR, respectively. The immobilized cells in a packed bed reactor with an optimum flow rate of 0.5 mL/min were used to treat 100 ppm of CV with a percentage decolorization of 79.47% after three cycles. Based on the findings, A. xylosoxidans DDB6 could be effectively used for decolorization of various dyes.
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Blood flow produces shear stress exerted on the endothelial layer of the vessels. Spatial characterization of the endothelial proteome is required to uncover the mechanisms of endothelial activation by shear stress, as blood flow varies in the vasculature. An integrative ubiquitinome and proteome analysis of shear-stressed endothelial cells demonstrated that the non-degradative ubiquitination of several GTPases is regulated by mechano-signaling. Spatial analysis reveals increased ubiquitination of the small GTPase RAP1 in the descending aorta, a region exposed to laminar shear stress. The ubiquitin ligase WWP2 is identified as a novel regulator of RAP1 ubiquitination during shear stress response. Non-degradative ubiquitination fine-tunes the function of GTPases by modifying their interacting network. Specifically, WWP2-mediated RAP1 ubiquitination at lysine 31 switches the balance from the RAP1/ Talin 1 (TLN1) toward RAP1/ Afadin (AFDN) or RAP1/ RAS Interacting Protein 1 (RASIP1) complex formation, which is essential to suppress shear stress-induced reactive oxygen species (ROS) production and maintain endothelial barrier integrity. Increased ROS production in endothelial cells in the descending aorta of endothelial-specific Wwp2-knockout mice leads to increased levels of oxidized lipids and inflammation. These results highlight the importance of the spatially regulated non-degradative ubiquitination of GTPases in endothelial mechano-activation.
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Células Endoteliais , GTP Fosfo-Hidrolases , Animais , Camundongos , Células Endoteliais/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteoma/metabolismo , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismo , Camundongos Knockout , UbiquitinaçãoRESUMO
Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in "gain-of-function" conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1-/- mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-/- and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1-/- mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders.
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Citocinas , Longevidade , Humanos , Animais , Camundongos , Idoso , Sequência de Aminoácidos , Ligação ProteicaRESUMO
Multi-omics is a cutting-edge approach that combines data from different biomolecular levels, such as DNA, RNA, proteins, metabolites, and epigenetic marks, to obtain a holistic view of how living systems work and interact. Multi-omics has been used for various purposes in biomedical research, such as identifying new diseases, discovering new drugs, personalizing treatments, and optimizing therapies. This review summarizes the latest progress and challenges of multi-omics for designing new treatments for human diseases, focusing on how to integrate and analyze multiple proteome data and examples of how to use multi-proteomics data to identify new drug targets. We also discussed the future directions and opportunities of multi-omics for developing innovative and effective therapies by deciphering proteome complexity.
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Despite centuries of developing strategies to prevent food-associated illnesses, food safety remains a significant concern, even with multiple technological advancements. Consumers increasingly seek less processed and naturally preserved food options. One promising approach is food biopreservation, which uses natural antimicrobials found in food with a long history of safe consumption and can help reduce the reliance on chemically synthesized food preservatives. The hurdle technology method that combines multiple antimicrobial strategies is often used to improve the effectiveness of food biopreservation. This review attempts to provide a research summary on the utilization of lactic acid bacteria, bacteriocins, endolysins, bacteriophages, and biopolymers helps in the improvement of the shelf-life of food and lower the risk of food-borne pathogens throughout the food supply chain. This review also aims to evaluate current technologies that successfully employ the aforementioned preservatives to address obstacles in food biopreservation.
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Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smooth muscle cells (VSMCs) are the key target in CADASIL, but the potential mechanisms involved in their degeneration are still unclear. Focusing on cerebral microvessels in the frontal and anterior temporal lobes and the basal ganglia, we used advanced proteomic and immunohistochemical methods to explore the extent of inflammatory and immune responses in CADASIL subjects compared to similar age normal and other disease controls. There was variable loss of VSMC in medial layers of arteries in white matter as well as the cortex, that could not be distinguished whether NOTCH3 mutations were in the epidermal growth factor (EGFr) domains 1-6 or EGFr7-34. Proteomics of isolated cerebral microvessels showed alterations in several proteins, many associated with endoplasmic reticulum (ER) stress including heat shock proteins. Cerebral vessels with sparsely populated VSMCs also attracted robust accrual of perivascular microglia/macrophages in order CD45+ > CD163+ > CD68+cells, with > 60% of vessel walls exhibiting intercellular adhesion molecule-1 (ICAM-1) immunoreactivity. Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation showed increased gene expression of the pro-inflammatory cytokine interleukin 6 and ICAM-1 by 16- and 50-fold, respectively. We further found evidence for activation of the alternative pathway of complement. Immunolocalisation of complement Factor B, C3d and C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral vessels. Increased complement expression was corroborated in > 70% of cultured VSMCs bearing the Arg133Cys mutation independent of N3ECD immunoreactivity. Our observations suggest that ER stress and other cellular features associated with arteriolar VSMC damage instigate robust localized inflammatory and immune responses in CADASIL. Our study has important implications for immunomodulation approaches to counter the characteristic arteriopathy of CADASIL.
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CADASIL , Humanos , CADASIL/genética , Molécula 1 de Adesão Intercelular , Proteômica , Proteínas do Sistema Complemento , Infarto CerebralRESUMO
The use of enteral nutrition (EN) continues to increase given benefits. However, with this increase in use, it is also becoming evident that enteral feeding intolerance (EFI) is also quite prevalent, leading to the inability to meet nutrition needs in many patients. Given the wide variability in the EN population as well as the number of formulas available, there is not a clear consensus regarding the best approach to EFI management. One approach that is emerging to improve EN tolerance is the use of peptide-based formulas (PBFs). PBFs refer to enteral formulas containing proteins that have been enzymatically hydrolyzed to dipeptides and tripeptides. These hydrolyzed proteins are often combined with higher medium-chain triglyceride content to generate an enteral formula that is essentially easier to absorb and utilize. Emerging data demonstrate that the use of PBF in patients with EFI may improve clinical outcomes along with a corresponding reduction in healthcare utilization and potentially the cost of care. This review aims to navigate through key clinical applications and benefits of PBF and to discuss relevant data shared in the literature.