Abstract
Pyroptosis is a key inflammatory form of cell death participating in the progression of many inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and sepsis. ...Identification of small molecules to inhibit pyroptosis is emerging as an attractive strategy. In this study, we performed a screening based on in silico docking of compounds on the reported Gasdermin D (GSDMD) three-dimensional structure and found C202-2729 demonstrated strong anti-inflammatory effects in both endotoxin shock and EAE mouse models. Oral administration of C202-2729 was capable of attenuating EAE disease severity significantly and has the comparable effects to teriflunomide, the first-line clinical drug of multiple sclerosis. We found C202-2729 remarkably suppressed macrophage and T cell–associated immune inflammation. Mechanistically, C202-2729 neither impact GSDMD cleavage nor the upstream inflammasome activation in mouse immortalized bone marrow–derived macrophages. However, C202-2729 exposure significantly repressed the IL-1β secretion and cell pyroptosis. We found C202-2729 directly bonds to the N terminus of GSDMD and blocks the migration of the N-terminal GSDMD fragment to cell membrane, restraining the pore-forming and mature IL-1β release. Collectively, our findings provide a new molecule with the potential for translational application in GSDMD-associated inflammatory diseases.
•The anammox performance was greatly affected by realistic seasonal temperatures.•The reactor underwent a long process of recovery from psychrophilic stress.•The properties of the anammox granules ...changed with temperature fluctuation.•The links between anammox performance and sludge characteristics were revealed.
In this study, the effects of realistic seasonal temperatures on the nitrogen removal performance of anaerobic ammonium oxidation (anammox) and the properties of the anammox granules were comparatively investigated for 330days. The results demonstrated that the nitrogen removal efficiency (NRE), nitrogen loading rate (NLR) and nitrogen removal rate (NRR) were decreased dramatically, as the temperature decreased from 31.2 to 2.5°C. However, the nitrogen removal performance recovered andante as the temperature increased gradually. After low temperature exposure, the settleability tended to worsen, and granules appeared to be more irregular with a smaller average granule diameter, and the extracellular polymeric substances (EPS) content increased slightly, while the specific anammox activity (SAA) decreased obviously. This realistic seasonal temperatures based research was an illation of the actual operation, and could be potentially implemented to maintain stability for the application of anammox technology.
Background:
Stem cell transplantation is emerging as a potential therapeutic strategy in several autoimmune diseases. However, the safety and feasibility of long-term combined intravenous (IV) and ...intrathecal (IT) administration of hUC-MSCs in relapse remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO) is largely unknown.
Objectives:
In this study, we followed up the long-term safety and feasibility of combined IV and IT human umbilical cord mesenchymal stem cells (hUC-MSCs) transplantation in patients with RRMS and NMO.
Methods:
Five NMO patients and 5 RRMS patients were treated intravenously (4 times) and intrathecally (3 times) over a 21-day period with low-dose allogeneic umbilical cord blood–derived MSCs. All of the patients were monitored regularly by an investigator in a blinded manner to access the Expanded Disability Status Scale, MRI characteristics, and adverse events every 3 months within 12 months and once every year thereafter for 10 years after transplantation.
Results:
During the long-term follow-up, our data suggested that combined IV and IT administration of hUC-MSCs transplantation is safe and feasible. None of the intolerant adverse events, such as tumor formation and peripheral organ/tissue disorders, were observed throughout the 10-year follow-up.
Conclusions:
These data suggest that combined intravenous and intrathecal low-dose hUC-MSCs transplantation is safe and feasible in RRMS and NMO patients in the long term. The conclusion requires confirmation by future clinical trials in a larger cohort.
The feasibility of the anaerobic ammonium oxidation (anammox) process to treat synthetic swine wastewater containing antibiotics and heavy metals was studied in this work. Nitrogen removal ...performance and granule characteristics were tracked by continuous-flow monitoring to evaluate the long-term joint effects of Cu and Zn and of Cu and oxytetracycline (OTC). Cu and Zn with a joint loading rate (JLR) of 0.04 kg m⁻³ day⁻¹ did not affect the performance, while a JLR of 0.12 kg m⁻³ day⁻¹ caused a rapid collapse in performance. Cu and OTC addition with a JLR of 0.04 kg m⁻³ day⁻¹ for approximately 2 weeks induced significant nitrite accumulation. Granule characteristic analysis elucidated the disparate inhibition mechanisms of heavy metals and antibiotics: the internalization of heavy metals caused metabolic disorders, whereas OTC functioned as a growth retarder. However, anammox reactors could adapt to a JLR of 0.04 kg m⁻³ day⁻¹ via self-regulation during the acclimatization to subinhibitory concentrations, which had a stable nitrogen removal rate (>8.5 kg m⁻³ day⁻¹) and removal rate efficiency (>75 %) for reactors with Cu-OTC addition. Therefore, this study supports the great potential of using anammox granules to treat swine wastewater.
The stability and resilience of an anaerobic ammonium oxidation (anammox) system under transient nanoscale Zero-Valent Iron (nZVI) (50, 75 and 100 mg L−1), hydraulic shock (2-fold increase in flow ...rate) and their combination were studied in an up-flow anaerobic sludge blanket reactor. The response to the shock loads can be divided into three phases i.e. shock, inertial and recovery periods. The effects of the shock loads were directly proportional to the shock intensity. The effluent quality was gradually deteriorated after exposure to high nZVI level (100 mg L−1) for 2 h. The higher effluent sensitivity index and response caused by unit intensity of shock was observed under hydraulic and combined shocks. Notably, the specific anammox activity and the content of heme c were considerably reduced during the shock phase and the maximum loss rates were about 30.5% and 24.8%, respectively. Nevertheless, the extracellular polymeric substance amount in the shock phase was enhanced in varying degrees and variation tendency was disparate at all the tested shock loads. These results suggested that robustness of the anammox system was dependent on the magnitude shocks applied and the reactor resistance can be improved by reducing hydraulic retention time with the increase of nZVI concentration under these circumstances.
Display omitted
•The stability of the anammox process under nZVI shock was investigated.•The robustness of the process under combined nZVI and hydraulic shocks was evaluated.•The effects of shock tests on the anammox system were related to the shock intensity.•Variations in the physiological characteristics of the sludge are presented.
A novel low-volatile starlike aliphatic polyamine with extraordinarily high –NH
2 functionalities, N,N,N′,N′,N′′-penta(3-aminopropyl)-diethylenetriamine (PADT), is synthesized and its molecular ...structure is confirmed by the FTIR,
1H NMR and ESI-MS analysis. Then PADT is employed as the curing agent for the epoxy resin of diglycidyl ether of bisphenol A (DGEBA) and the isothermal reaction of DGEBA/PADT is systematically investigated with differential scanning calorimetry (DSC) according to the model-fitting approach and model-free advanced isoconversional method developed by Vyazovkin. The result shows that PADT possesses the high reactivity and the reaction is autocatalytic in nature. The further reaction kinetic analysis indicates that the Kamal model can well fit the reaction rate at the reaction-controlled stage, whereas the extended Kamal model with a diffusion term can provide an excellent match throughout the isothermal reaction. On the other hand, the model-free kinetic analysis reveals a strong dependence of effective activation energy,
E
α
, on fractional conversion,
α, which could mirror the drastic change of the reaction mechanisms, in particular, the rapid drop in
E
α
observed in the deep-conversion regime due to the diffusion-controlled reaction kinetics. Then, a dynamic mechanical analysis (DMA) of the cured DGEBA/PADT network discloses three relaxations from the low- to high-temperature range:
β (
T
β
=
−34.4
°C),
α′ (
T
α
′
=
68.0
°C) and
α (
T
g
=
144.3
°C). Moreover, compared to linear propanediamine, PADT can much increase the crosslink density and glass temperature of the cured epoxy resin. Finally, the thermogravimetric (TG) analysis reveals PADT, like propanediamine, can impart the cured epoxy resin with the excellent thermal stability with the initial decomposition temperature as high as ∼300
°C. On the basis of these experimental data, we can conclude that PADT exhibits a great potential to partially replace conventional high-volatile aliphatic-amine curing agents of low molecular weights.
CD8
+
T cells are recognized as key players in exacerbation of ischemic stroke; however, the underlying mechanism in modulating the function of CD8
+
T cells has not been completely elucidated. Here, ...we uncovered that FasL enhanced the cytotoxicity of CD8
+
T cells to neurons after ischemic stroke. Inactivation of FasL specific on CD8
+
T cells protected against brain damage and neuron loss. Proteomic analysis identified that PDPK1 functioned downstream of FasL signaling and inhibition of PDPK1 effectively reduced cytotoxicity of CD8
+
T cells and improved ischemic neurological deficits. Taken together, these results highlight an intrinsic FasL-PDPK1 pathway regulating the cytotoxicity of CD8
+
T cells in ischemic stroke.
Colorectal cancer (CRC) is recognized as a common type of human cancer, and KRAS mutations are correlated with poor CRC survival outcomes. The evaluation and prediction of CRC results remain ...challenging. In the present study, RNA sequencing and clinical data from The Cancer Genome Atlas were used to identify KRAS mutation-related prognostic long intergenic non-coding RNAs (lincRNAs) in CRC. Significantly dysregulated lincRNAs and independent prognostic lincRNAs with KRAS mutations in CRC were identified. Two lincRNAs with KRAS mutations, LINC00265 and AL390719.2, were selected as key prognostic lincRNAs for both 10- and 5-year survival rates. In addition, competing endogenous (ce)RNA models were constructed to comprehensively assess the oncogenic performance of the two key lincRNAs. The ceRNA models suggested that LINC00265 and AL390719.2 are critical for the cell cycle and cancer pathways. Finally, reverse transcription-quantitative PCR was used to validate the ceRNA models in 12 pairs of CRC tissue samples. These prognostic lincRNAs may provide novel biomarkers for the prognostic prediction of CRC. The ceRNA model may also demonstrate the underlying mechanism of these lincRNAs in CRC. Key words: colorectal cancer, long intergenic non-coding RNA, KRAS mutation, microRNAs
Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with ...COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.
IL-37 is a newly identified immune-suppressive factor; however, the function, cellular sources, and mechanism of IL-37 in humoral immunity and Myasthenia gravis (MG) are still unclear. In this study, ...we found IL-37 were substantially downregulated in the serum and PBMCs of MG patients compared with healthy controls. The lower IL-37 was associated with severer disease (quantitative MG score) and higher follicular Th (Tfh)/Tfh17 and B cell numbers. Flow cytometry analysis revealed that IL-37 was mainly produced by CD4
T cells without overlapping with Th1, Th17, and Tfh subsets in MG patients. Regulatory IL-37
T cell rarely expressed Foxp3 and CD25 but produced numerous IL-4. Tfh and B cell expressed high levels of SIGIRR, the receptor of IL-37, in MG patients. Mechanically, IL-37 directly bond to SIGIRR, repressed the proliferation, cytokine production of Tfh and B cells, and the secretion of autoantibody via inhibition of STAT3 signaling in Tfh and B cells.
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