The utilization of neutral receptors for the molecular recognition of anions based on chalcogen bonding (ChB) is an undeveloped area of host‐guest chemistry. In this manuscript, the synthesis of two ...new families of sulfur, selenium, and tellurium‐based ChB binding motifs are reported. The stability of the thiophene, selenophene, and tellurophene binding motifs has enabled the determination of the association constants for ChB halide anion binding in the polar aprotic solvent THF by 1H, 77Se, and 125Te NMR experiments. Two different aromatic cores are used and one or two Ch‐binding motifs are incorporated with the purpose of encapsulating the anion, offering up to two concurrent chalcogen bonds. Theoretical calculations and NMR experiments reveal that, for S and Se receptors, hydrogen‐bonding interactions involving the acidic H atom adjacent to the chalcogen atom are energetically favored over the ChB interaction. However, for the tellurophene binding motif, the σ‐hole interaction is competitive and more favored than the hydrogen bond.
Chalcogen binding motifs: The synthesis of three new families of sulfur, selenium, and tellurium‐based chalcogen binding (ChB) motifs is reported. The stability of the chalcophene binding motifs has enabled the determination of the association constants for ChB halide anion binding in the polar aprotic solvent THF by 1H, 77Se, and 125Te NMR experiments.
Astrocytes are important for information processing in the brain and they achieve this by fine‐tuning neuronal communication via continuous uptake and release of biochemical modulators of ...neurotransmission and synaptic plasticity. Often overlooked are their important functions in mechanosensation. Indeed, astrocytes can detect pathophysiological changes in the mechanical properties of injured, ageing, or degenerating brain tissue. We have recently shown that astrocytes surrounding mechanically‐stiff amyloid plaques upregulate the mechanosensitive ion channel, Piezo1. Moreover, ageing transgenic Alzheimer's rats harboring a chronic peripheral bacterial infection displayed enhanced Piezo1 expression in amyloid plaque‐reactive astrocytes of the hippocampus and cerebral cortex. Here, we have shown that the bacterial endotoxin, lipopolysaccharide (LPS), also upregulates Piezo1 in primary mouse cortical astrocyte cultures in vitro. Activation of Piezo1, via the small molecule agonist Yoda1, enhanced Ca2+ influx in both control and LPS‐stimulated astrocytes. Moreover, Yoda1 augmented intracellular Ca2+ oscillations but decreased subsequent Ca2+ influx in response to adenosine triphosphate (ATP) stimulation. Neither blocking nor activating Piezo1 affected cell viability. However, LPS‐stimulated astrocyte cultures exposed to the Piezo1 activator, Yoda1, migrated significantly slower than reactive astrocytes treated with the mechanosensitive channel‐blocking peptide, GsMTx4. Furthermore, our data show that activating Piezo1 channels inhibits the release of cytokines and chemokines, such as IL‐1β, TNFα, and fractalkine (CX3CL1), from LPS‐stimulated astrocyte cultures. Taken together, our results suggest that astrocytic Piezo1 upregulation may act to dampen neuroinflammation and could be a useful drug target for neuroinflammatory disorders of the brain.
Main Points
Activation of Piezo1 channels in LPS‐stimulated astrocytes induces calcium influx and augments intracellular calcium oscillations.
Piezo1 activation inhibits the release of pro‐inflammatory cytokines, IL‐1β and TNFα, from LPS‐stimulated astrocytes.
The synthesis of glycerol carbonate from glycerol and dimethyl carbonate by transesterification is reported. Basic catalysts work much better than acidic ones. Catalytic activity is strongly ...dependent on base strength. After a catalyst screening study, CaO was selected as catalyst. Following an optimization study a ∼100% conversion and a 95% yield were achieved in 90
min at 95
°C, 0.06 catalyst:glycerol molar ratio and 3.5 dimethyl carbonate:glycerol molar ratio.
The synthesis of glycerol carbonate from glycerol and dimethyl carbonate by transesterification is reported. Firstly, a catalyst screening has been performed by studying the influence of different basic and acid homogeneous and heterogeneous catalysts on reaction results. Catalytic activity is extremely low for acidic catalysts indicating that reaction rate is very slow. On the contrary, high conversions and yields are obtained for basic catalysts. Catalytic activity increases with catalyst basic strength. The best heterogeneous catalyst is CaO. Calcination of CaO increases dramatically its activity due to calcium hydroxide removal from its surface. A reaction optimization study has been carried out with CaO as catalyst by using a factorial design of experiments leading to operation conditions for achieving a 100% conversion and a >95% yield at 1.5
h reaction time: 95
°C, catalyst/glycerol molar ratio
=
0.06 and dimethyl carbonate/glycerol molar ratio
=
3.5. Carbonate glycerol can be easily isolated by filtering the catalyst out and evaporating the filtrate at vacuum. Leaching of catalyst in reaction medium was lower than 0.34%. Catalyst recycling leads to a quick decrease in both conversions and yields probably due to a combination of catalyst deactivation by CaO exposure to air between catalytic runs, and a decrease in the catalyst surface area available for reaction due to particle agglomeration.
Piezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through a process termed, mechanotransduction. ...In the central nervous system (CNS), mechanically gated ion channels are important regulators of neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination of axons by oligodendrocytes. Here, we present evidence that pharmacologically mediated overactivation of Piezo1 channels negatively regulates CNS myelination. Moreover, we found that the peptide GsMTx4, an antagonist of mechanosensitive cation channels such as Piezo1, is neuroprotective and prevents chemically induced demyelination. In contrast, the positive modulator of Piezo1 channel opening, Yoda‐1, induces demyelination and neuronal damage. Using an ex vivo murine‐derived organotypic cerebellar slice culture model, we demonstrate that GsMTx4 attenuates demyelination induced by the cytotoxic lipid, psychosine. Importantly, we confirmed the potential therapeutic effects of GsMTx4 peptide in vivo by co‐administering it with lysophosphatidylcholine (LPC), via stereotactic injection, into the cerebral cortex of adult mice. GsMTx4 prevented both demyelination and neuronal damage usually caused by the intracortical injection of LPC in vivo; a well‐characterized model of focal demyelination. GsMTx4 also attenuated both LPC‐induced astrocyte toxicity and microglial reactivity within the lesion core. Overall, our data suggest that pharmacological activation of Piezo1 channels induces demyelination and that inhibition of mechanosensitive channels, using GsMTx4, may alleviate the secondary progressive neurodegeneration often present in the latter stages of demyelinating diseases.
Main points
Piezo1 negatively regulates central nervous system myelination.
Piezo1 antagonist, GsMTx4, enhances myelination and attenuates demyelination.
GsMTx4 is neuroprotective and inhibits lysophosphatidylcholine‐induced astrocyte toxicity.
Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is ...characterized by a decrease in cardiac macrophage content.
This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis.
Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI.
Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI.
The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.
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Enzyme-linked immunosorbent assays (ELISAs) are widely used in biology and clinical diagnosis. Relying on antigen–antibody interaction through diffusion, the standard ELISA protocol can be ...time-consuming, preventing its use in rapid diagnostics. We present a time-saving and more sensitive ELISA without changing the standard setup and protocol, using surface acoustic waves (SAWs) to enhance performance. Each step of the assay, from the initial antibody binding onto the walls of the well plate to the target analyte molecules’ binding for detectionexcept, notably, for the blocking stepis improved principally via acoustic streaming-driven advection. Using SAWs, the time required for one step of an example ELISA is reduced from 60 to 15 min to achieve the same binding amount. By extending the duration of SAW exposure to 20 min, the sensitivity can be significantly improved over the 60 min, 35 °C ELISA without SAWs. It is also possible to confer beneficial improvements to bead-based ELISA by combining it with SAWs to further reduce the time required for binding to 2 min. By significantly increasing the speed of ELISA, its utility may be improved for a wide range of point-of-care diagnostics applications.
Chimeric antigen receptor–based therapies beyond cancer Velasco‐de Andrés, María; Muñoz‐Sánchez, Guillermo; Carrillo‐Serradell, Laura ...
European Journal of Immunology,
March 2023, 2023-03-00, 20230301, Letnik:
53, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Adoptive cell transfer (ACT) therapies have gained renewed interest in the field of immunotherapy following the advent of chimeric antigen receptor (CAR) technology. This immunological breakthrough ...requires immune cell engineering with an artificial surface protein receptor for antigen‐specific recognition coupled to an intracellular protein domain for cell activating functions. CAR‐based ACT has successfully solved some hematological malignancies, and it is expected that other tumors may soon benefit from this approach. However, the potential of CAR technology is such that other immune‐mediated disorders are beginning to profit from it. This review will focus on CAR‐based ACT therapeutic areas other than oncology such as infection, allergy, autoimmunity, transplantation, and fibrotic repair. Herein, we discuss the results and limitations of preclinical and clinical studies in that regard.
Engineering immune cells with chimeric antigen receptors (CARs) for adoptive cell immunotherapy has captivated the interest of oncologists to combat hematological cancer. Novel applications of CAR‐based technology are beginning to be implemented in a myriad of medical conditions as diverse as autoimmunity, infection, asthma, transplantation, hemophilia, or cardiac fibrosis.
Multicentre studies focussing on specific long-term post-COVID-19 symptoms are scarce.
The aim of this study was to determine the levels of fatigue and dyspnoea, repercussions on daily life ...activities, and risk factors associated with fatigue or dyspnoea in COVID-19 survivors at long term after hospital discharge.
Age, gender, height, weight, symptoms at hospitalization, pre-existing medical comorbidity, intensive care unit admission, and the presence of cardio-respiratory symptoms developed after severe acute respiratory syndrome coronavirus 2 infection were collected from patients who recovered from COVID-19 at 4 hospitals in Madrid (Spain) from March 1 to May 31, 2020 (first COVID-19 wave). The Functional Impairment Checklist was used for evaluating fatigue/dyspnoea levels and functional limitations.
A total of 1,142 patients (48% women, age: 61, standard deviation SD: 17 years) were assessed 7.0 months (SD 0.6) after hospitalization. Fatigue was present in 61% patients, dyspnoea with activity in 55%, and dyspnoea at rest in 23.5%. Only 355 (31.1%) patients did not exhibit fatigue and/or dyspnoea 7 months after hospitalization. Forty-five per cent reported functional limitations with daily living activities. Risk factors associated with fatigue and dyspnoea included female gender, number of pre-existing comorbidities, and number of symptoms at hospitalization. The number of days at hospital was a risk factor just for dyspnoea.
Fatigue and/or dyspnoea were present in 70% of hospitalized COVID-19 survivors 7 months after discharge. In addition, 45% patients exhibited limitations on daily living activities. Being female, higher number of pre-existing medical comorbidities and number of symptoms at hospitalization were risk factors associated to fatigue/dyspnoea in COVID-19 survivors 7 months after hospitalization.
Background and Purpose
The synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of ...paricalcitol associated with the VDR pathway, less information is available about the structural and functional cardiac effects of paricalcitol on established heart failure (HF) and particularly its effects on associated electrophysiological or Ca2+ handling remodelling.
Experimental Approach
We used a murine model of transverse aortic constriction (TAC) to study the effect of paricalcitol on established HF. Treatment was initiated 4 weeks after surgery over five consecutive weeks, and mice were sacrificed 9 weeks after surgery. Cardiac MRI (CMRI) was performed 4 and 9 weeks after surgery. Hearts were used for biochemical and histological studies and to isolate ventricular myocytes for electrophysiological and calcium imaging studies.
Key Results
CMRI analysis revealed that, compared with vehicle, paricalcitol treatment prevented the progression of ventricular dilation and hypertrophy after TAC and halted the corresponding decline in ejection fraction. These beneficial effects were related to the attenuation of intracellular Ca2+ mishandling remodelling, antifibrotic and antihypertrophic effects and potentially antiarrhythmic effects by preventing the reduction of K+ current density and the long QT, JT and TpTe intervals observed in HF animals.
Conclusion and Implications
The results suggest that paricalcitol treatment in established HF hampers disease progression and improves adverse electrophysiological and Ca2+ handling remodelling, attenuating the vulnerability to HF‐associated ventricular arrhythmias. Paricalcitol may emerge as a potential therapeutic option in the treatment of HF.
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