Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

Central nervous system (CNS) disorders encompass a vast spectrum of pathological conditions and represent a growing concern worldwide. Despite the high social and clinical interest in trying to solve these pathologies, there are many challenges to bridge in order to achieve an effective therapy. One of the main obstacles to advancements in this field that has hampered many of the therapeutic strategies proposed to date is the presence of the CNS barriers that restrict the access to the brain. However, adequate brain biodistribution and neuronal cells specific accumulation in the targeted site also represent major hurdles to the attainment of a successful CNS treatment. Over the last few years, nanotechnology has taken a step forward towards the development of therapeutics in neurologic diseases and different approaches have been developed to surpass these obstacles. The versatility of the designed nanocarriers in terms of physical and chemical properties, and the possibility to functionalize them with specific moieties, have resulted in improved neurotargeted delivery profiles. With the concomitant progress in biology research, many of these strategies have been inspired by nature and have taken advantage of physiological processes to achieve brain delivery. Here, the different nanosystems and targeting moieties used to achieve a neuronal delivery reported in the open literature are comprehensively reviewed and critically discussed, with emphasis on the most recent bioinspired advances in the field. Finally, we express our view on the paramount challenges in targeted neuronal delivery that need to be overcome for these promising therapeutics to move from the bench to the bedside.This work was financially supported by the project PTDC/CTM-NAN/3547/2014 (POCI-01-0145-FEDER-016639) funded by FEDER funds through the Programa Operacional Competitividade e Internacionalização-COMPETE 2020 and Portuguese funds through FCT–Fundação para a Ciência e a Tecnologia. A.P.S., B.C. and S.D.S. acknowledge FCT for the Ph.D. scholarships (SFRH/BD/137073/2018 and SFRH/BD/145652/2019) and the contract under the Norma Transitória–DL57/2016/CP/CP1360/CT0013, respectively. V.L. acknowledges her contract in the framework of the project NORTE-01-0247-FEDER-033399, funded by FEDER funds through the Sistema de Incentivos à Investigação e Desenvolvimento Tecnológico (SI I&DT), Aviso nº 03/SI/2017, Projetos em Co-promoção do Programa Interfac

Synthetic matrix enhances transplanted satellite cell engraftment in dystrophic and aged skeletal muscle with comorbid trauma

Muscle satellite cells (MuSCs) play a central role in muscle regeneration, but their quantity and function decline with comorbidity of trauma, aging, and muscle diseases. Although transplantation of MuSCs in traumatically injured muscle in the comorbid context of aging or pathology is a strategy to boost muscle regeneration, an effective cell delivery strategy in these contexts has not been developed. We engineered a synthetic hydrogel-based matrix with optimal mechanical, cell-adhesive, and protease-degradable properties that promotes MuSC survival, proliferation, and differentiation. Furthermore, we establish a biomaterial-mediated cell delivery strategy for treating muscle trauma, where intramuscular injections may not be applicable. Delivery of MuSCs in the engineered matrix significantly improved in vivo cell survival, proliferation, and engraftment in nonirradiated and immunocompetent muscles of aged and dystrophic mice compared to collagen gels and cell-only controls. This platform may be suitable for treating craniofacial and limb muscle trauma, as well as postoperative wounds of elderly and dystrophic patients.Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH under award numbers R21AR072287 (to Y.C.J.) and R01AR062368 (to A.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also funded by the Parker H. Petit Institute for Bioengineering and Bioscience Seed Grant Program (to A.J.G. and Y.C.J.)

Synthetic matrix enhances transplanted satellite cell engraftment in dystrophic and aged skeletal muscle with comorbid trauma

Muscle satellite cells (MuSCs) play a central role in muscle regeneration, but their quantity and function decline with comorbidity of trauma, aging, and muscle diseases. Although transplantation of MuSCs in traumatically injured muscle in the comorbid context of aging or pathology is a strategy to boost muscle regeneration, an effective cell delivery strategy in these contexts has not been developed. We engineered a synthetic hydrogel-based matrix with optimal mechanical, cell-adhesive, and protease-degradable properties that promotes MuSC survival, proliferation, and differentiation. Furthermore, we establish a biomaterial-mediated cell delivery strategy for treating muscle trauma, where intramuscular injections may not be applicable. Delivery of MuSCs in the engineered matrix significantly improved in vivo cell survival, proliferation, and engraftment in nonirradiated and immunocompetent muscles of aged and dystrophic mice compared to collagen gels and cell-only controls. This platform may be suitable for treating craniofacial and limb muscle trauma, as well as postoperative wounds of elderly and dystrophic patients.Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH under award numbers R21AR072287 (to Y.C.J.) and R01AR062368 (to A.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also funded by the Parker H. Petit Institute for Bioengineering and Bioscience Seed Grant Program (to A.J.G. and Y.C.J.)

An Overview

Funding Information: Funding: This work was supported by FCT–Fundação para a Ciência e a Tecnologia (grants UIDB/04567/2020 and UIDP/04567/2020 to CBIOS, PTDC/BIA-MOL/31104/2017, and PhD grants 2020.07813.BD to Í.G. and 2020.04630.BD to D.C.). C.F.-P. and R.M. are funded by FCT Scientific Employment Stimulus contract with the reference numbers CEEC/CBIOS/NUT/2018 and CEEC/04567/CBIOS/2020, respectively. Authors also acknowledge COFAC/ILIND–Cooperativa De Formação E Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021). Authors also acknowledge the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 804229. iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is co-funded by FCT/Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement.Kidney diseases constitute a worldwide public health problem, contributing to morbidity and mortality. The present study aimed to provide an overview of the published data regarding the potential beneficial effects of polyphenols on major kidney diseases, namely acute kidney injury, chronic kidney disease, diabetic nephropathy, renal cancer, and drug-induced nephrotoxicity. This study consists of a bibliographical review including in vitro and in vivo studies dealing with the effects of individual compounds. An analysis of the polyphenol metabolome in human urine was also conducted to estimate those compounds that are most likely to be responsible for the kidney protective effects of polyphenols. The biological effects of polyphenols can be highly attributed to the modulation of specific signaling cascades including those involved in oxidative stress responses, anti-inflammation processes, and apoptosis. There is increasing evidence that polyphenols afford great potential in renal disease protection. However, this evidence (especially when in vitro studies are involved) should be considered with caution before its clinical translation, particularly due to the unfavorable pharmacokinetics and extensive metabolization that polyphenols undergo in the human body. Future research should consider polyphenols and their metabolites that indeed reach kidney tissues.publishersversionpublishe

A Target for Protective Interventions against Parkinson’s Disease

Funding Information: This research was funded by FWO and F.R.S.-FNRS under the Excellence of Science Program (EOS), MODEL-IDI Ref. number 30826052, and CD-INFLADIS Ref. number 40007512. A.C.P. is funded by FCT SFRH/BD/14611/2019. I.S.L was funded by FCT SFRH/BD/114552/2016 and is funded by MODEL-IDI Ref. number 30826052; A.C.M. was funded by FCT SFRH/BD/104599/2014; R.G. was funded by FCT IF 01495/2015. Publisher Copyright: © 2023 by the authors.Sub-chronic inflammation, caused by age-related dysbiosis, primes the brain to neuroinflammation and neurodegenerative diseases. Evidence revealed that Parkinson’s disease (PD) might originate in the gut, demonstrating gastro-intestinal disturbances, as reported by PD patients long before developing motor symptoms. In this study, we conducted comparative analyses in relatively young and old mice maintained in conventional or gnotobiotic conditions. We aimed to confirm that the effects induced by age-related dysbiosis, rather than aging itself, sensitize to PD onset. This hypothesis was confirmed in germ-free (GF) mice, which proved resistant to the pharmacological induction of PD, regardless of their age. Contrary to conventional animals, old GF mice did not develop an inflammatory phenotype or an accumulation of iron in the brain, two catalysts sensitizing to disease onset. The resistance of GF mice to PD is reverted when colonized with stool collected from conventional old animals, but not if receiving bacterial content from young mice. Hence, changes in gut microbiota composition are a risk factor for PD development and can be targeted preventively by iron chelators, shown to protect the brain from pro-inflammatory intestinal priming that sensitizes to neuroinflammation and the development of severe PD.publishersversionpublishe

Congenital ocular motor apraxia

PURPOSE: Congenital ocular motor apraxia is a rare disease characterized by defective or absent voluntary and optically induced horizontal saccadic movements. Jerky head movements or thrusts on attempted lateral gaze are a compensatory sign. Most affected children have delayed motor and speech development. Cases associated with systemic diseases, neurologic maldevelopment, metabolic deficits, and chromosomal abnormalities have been described. METHODS: Case report and review of the scientific literature. RESULTS: The authors describe the ophthalmologic, pediatric, and neurologic evaluations and follow up of a child with impaired horizontal saccades, jerky head movements, and delayed motor and speech development. CONCLUSIONS: Congenital ocular motor apraxia is an uncommon disorder of ocular motility. Even so, ophthalmologists should be aware of the developmental delay and the other associated conditions, in order to grant the patients the multidisciplinary assistance they often require

Clear-water scour at comparatively large cylindrical piers

New long-duration clear-water scour data were collected at single cylindrical piers with the objective of investigating the effect of sediment coarseness, Dp=D50 (Dp = pier diameter; D50 = median grain size) on the equilibrium scour depth and improving the scour depth time evolution modeling by making use of the exponential function suggested in the literature. Experiments were carried out for the flow intensity close to the threshold condition of initiation of sediment motion, imposing wide changes of sediment coarseness and flow shallowness, d=Dp (d = approach flow depth). The effect of sediment coarseness on the equilibrium scour depth was identified; existing predictors were modified to incorporate this effect for U=Uc ≈ 1.0; Dp=D50 > ≈60 and d=Dp ≥ 0.5; the complete characterization of a known scour depth time evolution model was achieved for U=Uc ≈ 1.0, 60 < Dp=D50 < 500 and 0.5 ≤ d=Dp ≤ 5.0

Exercise-induced pulmonary hypertension in scleroderma patients: a common finding but with elusive pathophysiology

BACKGROUND: The etiology of exercise-induced pulmonary hypertension (exPH) in systemic sclerosis (SSc) remains a complex task, as both left ventricle (LV) diastolic dysfunction and pulmonary vascular disease can contribute to its development. We determined the incidence of exPH in SSc and examined the association between pulmonary artery systolic pressure (PASP) and tissue Doppler-derived indexes of pulmonary capillary wedge pressure (PCWP). METHODS: Thirty-eight patients with SSc were studied, using a cycloergometer protocol; 10 were excluded due to resting PH or absence of tricuspid regurgitation (TR); TR and mitral E-wave velocities, LV outflow tract time-velocity integral and LV septal E'-wave were measured before and in peak exercise to calculate cardiac output (CO), PCWP and pulmonary vascular resistance (PVR). RESULTS: Mean age of diagnosis was 57.9 ± 8.9 years. At a mean workload of 64 ± 29 Watts, 48% of patients increased PASP ≥ 50 mmHg. PCWP, assessed by the E/e' ratio, did not change significantly during exercise (10.2 ± 3.1-10.0 ± 5.1; P = NS). Only 3 patients had elevations of the E/e' ratio ≥ 13 during exercise; 2 of them had an exercise PASP ≥ 50 mmHg, yielding a proportion of exPH due to elevated LV filling pressures of 2/11 (18%). Patients with exPH had lower DLCO and had more frequently the diffuse SSc. CONCLUSION: The elevation of PASP during exercise in most patients of this cohort seems to be related to a reduced pulmonary vascular reserve, and not to an increase in PCWP. Further studies are warranted to determine the therapeutic, as well as prognostic implications of these findings.info:eu-repo/semantics/publishedVersio

Exercise echocardiography for the assessment of pulmonary hypertension in systemic sclerosis: a systematic review

BACKGROUND: Pulmonary arterial hypertension (PAH) complicates the course of systemic sclerosis (SSc) and is associated with poor prognosis. The elevation of systolic pulmonary arterial pressure (sPAP) during exercise in patients with SSc with normal resting haemodynamics may anticipate the development of PAH. Exercise echocardiography (ExEcho) has been proposed as a useful technique to identify exercise-induced increases in sPAP, but it is unclear how to clinically interpret these findings. In this systematic review, we summarize the available evidence on the role of exercise echocardiography to estimate exercise-induced elevations in pulmonary and left heart filling pressures in patients with systemic sclerosis. METHODS: We conducted a systematic review of the literature using MEDLINE, Cochrane Library and Web of Knowledge, using the vocabulary terms: ('systemic sclerosis' OR 'scleroderma') AND ('exercise echocardiography') AND ('pulmonary hypertension'). Studies including patients with SSc without a prior diagnosis of PAH, and subjected to exercise echocardiography were included. All searches were limited to English and were augmented by review of bibliographic references from the included studies. The quality of evidence was assessed by the Effective Public Health Practice Project system. RESULTS: We identified 15 studies enrolling 1242 patients, who were mostly middle-aged and female. Several exercise methods were used (cycloergometer, treadmill and Master's two step), with different protocols and positions (supine, semi-supine, upright); definition of a positive test also varied widely. Resting estimated sPAP levels varied from 18 to 35 mm Hg, all in the normal range. The weighted means for estimated sPAP were 22.2 ± 2.9 mmHg at rest and 43.0 ± 4.3 mmHg on exercise; more than half of the studies reported mean exercise sPAP ≥40 mmHg. The assessment of left ventricular diastolic function on peak exercise was reported in a minority of studies; however, when assessed, surrogate variables of left ventricular (LV) diastolic dysfunction were associated with higher sPAP on exercise. CONCLUSIONS: We found very high heterogeneity in the methods, the protocols and the estimated sPAP response to exercise. LV diastolic dysfunction was common and was associated with greater elevation of sPAP on exercise.info:eu-repo/semantics/publishedVersio