Pyroptosis is a form of programmed cell death mediated by gasdermin and is a product of continuous cell expansion until the cytomembrane ruptures, resulting in the release of cellular contents that ...can activate strong inflammatory and immune responses. Pyroptosis, an innate immune response, can be triggered by the activation of inflammasomes by various influencing factors. Activation of these inflammasomes can induce the maturation of caspase-1 or caspase-4/5/11, both of which cleave gasdermin D to release its N-terminal domain, which can bind membrane lipids and perforate the cell membrane. Here, we review the latest advancements in research on the mechanisms of pyroptosis, newly discovered influencing factors, antitumoral properties, and applications in various diseases. Moreover, this review also provides updates on potential targeted therapies for inflammation and cancers, methods for clinical prevention, and finally challenges and future directions in the field.
Aim
Novel long‐acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin‐4‐IgG4‐Fc (E4F4) is a long‐acting glucagon‐like peptide‐1 receptor agonist. ...This first‐in‐human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects.
Methods
This single‐centre, randomized, double‐blind, placebo‐controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level.
Results
E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose‐dependent relationship between frequency, severity or causality of treatment‐emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45‐14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose‐dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose‐response relationship in the 1.8‐10.35 mg dose range, with an increased response at the higher doses.
Conclusion
E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5‐10.35 mg once every 2 weeks.
•A Markov regenerative process model is developed to model the PMS under mixed random shocks.•A Monte Carlo simulation procedure is given to validate the proposed method.•The altitude and orbit ...control system is used to illustrate the proposed method.•The result analysis shows the influence of different shocks parameters.
Recently, phased mission systems (PMSs) have been widely studied due to their wide range of applications, such as man-made satellites or spacecraft. The lifetime of the PMSs can be separated into several phases, in which their tasks, system configurations, and failure criteria could be different. Meanwhile, the randomly occurred shocks, such as the space radiation from outer space, will cause additional wear and fatal damage on the electronic devices in these systems, which will obviously affect the system reliability. To consider these shocks’ effect in the reliability modeling of the PMSs, a Markov regenerative process (MRGP) based model is proposed in this paper. Firstly, shock models for components and the basic conceptions of MRGP are introduced. Then, a simple cold standby system is used to show the proposed MRGP model for systems under mixed shocks. And a Monte Carlo simulation procedure is applied to verify the results. At last, by integrating the proposed MRGP model and the modular method for PMSs, the reliability of an AOCS in a spacecraft is assessed to show the proposed method.
Chronic pain can cause both hyperalgesia and anxiety symptoms. However, how the two components are encoded in the brain remains unclear. The prelimbic cortex (PrL), a critical brain region for both ...nociceptive and emotional modulations, serves as an ideal medium for comparing how the two components are encoded. We report that PrL neurons projecting to the basolateral amygdala (PrLBLA) and those projecting to the ventrolateral periaqueductal gray (PrLl/vlPAG) were segregated and displayed elevated and reduced neuronal activity, respectively, during pain chronicity. Consistently, optogenetic suppression of the PrL-BLA circuit reversed anxiety-like behaviors, whereas activation of the PrL-l/vlPAG circuit attenuated hyperalgesia in mice with chronic pain. Moreover, mechanistic studies indicated that elevated TNF-α/TNFR1 signaling in the PrL caused increased insertion of GluA1 receptors into PrLBLA neurons and contributed to anxiety-like behaviors in mice with chronic pain. Together, these results provide insights into the circuit and molecular mechanisms in the PrL for controlling pain-related hyperalgesia and anxiety-like behaviors.
In this paper, two- and three-pole microstrip LC constant fractional bandwidth (CFBW) and constant absolute bandwidth (CABW) tunable bandpass filters are proposed. The equivalent-circuit models are ...presented to study the tunable mechanism. The filter can be reconfigured by changing the capacitance of the LC resonators. Based on electric coupling coefficient compensation, second- and third-order tunable equivalent-circuit models with CFBW/CABW are presented. For demonstration, a semiconductor varactor diode loaded microstrip LC resonator is adopted in our work to design the second- and third-order tunable filters. The S -parameters, group delays, and third-order intercept points for different center frequencies of the filters are presented. Each resonator requires only one varactor diode for both central frequency and resonator coupling coefficient control.
A specific bone capillary subtype, namely type H vessels, with high expression of CD31 and endomucin, was shown to couple angiogenesis and osteogenesis recently. The number of type H vessels in bone ...tissue declines with age, and the underlying mechanism for this reduction is unclear. Here, we report that microRNA-188-3p (miR-188-3p) involves this process. miRNA-188-3p expression is upregulated in skeletal endothelium and negatively regulates the formation of type H vessels during ageing. Mice with depletion of miR-188 showed an alleviated age-related decline in type H vessels. In contrast, endothelial-specific overexpression of miR-188-3p reduced the number of type H vessels, leading to decreased bone mass and delayed bone regeneration. Mechanistically, we found that miR-188 inhibits type H vessel formation by directly targeting integrin β3 in endothelial cells. Our findings indicate that miR-188-3p is a key regulator of type H vessel formation and may be a potential therapeutic target for preventing bone loss and accelerating bone regeneration.
High‐energy‐density lithium metal batteries (LMBs) are widely accepted as promising next‐generation energy storage systems. However, the safety features of practical LMBs are rarely explored ...quantitatively. Herein, the thermal runaway behaviors of a 3.26 Ah (343 Wh kg−1) Li | LiNi0.5Co0.2Mn0.3O2 pouch cell in the whole life cycle are quantitatively investigated by extended volume‐accelerating rate calorimetry and differential scanning calorimetry. By thermal failure analyses on pristine cell with fresh Li metal, activated cell with once plated dendrites, and 20‐cycled cell with large quantities of dendrites and dead Li, dendrite‐accelerated thermal runaway mechanisms including reaction sequence and heat release contribution are reached. Suppressing dendrite growth and reducing the reactivity between Li metal anode and electrolyte at high temperature are effective strategies to enhance the safety performance of LMBs. These findings can largely enhance the understanding on the thermal runaway behaviors of Li metal pouch cells in practical working conditions.
The thermal runaway features of Li | NCM523 pouch cells (343 Wh kg−1) over the whole life cycle are analyzed quantitatively. The formation of large amounts of dendritic Li and SEI is observed as cycling depth increasing, leading to strong exothermic reactions between SEI components and LiPF6, dendritic Li and electrolytes.
Neuroblastoma is one of the most devastating forms of childhood cancer. Despite large amounts of attempts in precise survival prediction in neuroblastoma, the prediction efficacy remains to be ...improved.
Here, we applied a deep-learning (DL) model with the attention mechanism to predict survivals in neuroblastoma. We utilized 2 groups of features separated from 172 genes, to train 2 deep neural networks and combined them by the attention mechanism.
This classifier could accurately predict survivals, with areas under the curve of receiver operating characteristic (ROC) curves and time-dependent ROC reaching 0.968 and 0.974 in the training set respectively. The accuracy of the model was further confirmed in a validation cohort. Importantly, the two feature groups were mapped to two groups of patients, which were prognostic in Kaplan-Meier curves. Biological analyses showed that they exhibited diverse molecular backgrounds which could be linked to the prognosis of the patients.
In this study, we applied artificial intelligence methods to improve the accuracy of neuroblastoma survival prediction based on gene expression and provide explanations for better understanding of the molecular mechanisms underlying neuroblastoma.
Treg are known to have a central role in orchestrating immune responses, but less is known about the destiny of Treg after being activated by specific Ags. This study aimed to investigate the role of ...superoxide dismutase, an active molecule in the regulation of oxidative stress in the body, in the prevention of Treg apoptosis induced by specific Ags. Ag‐specific Tregs were isolated from the DO11.10 mouse intestine. A food allergy mouse model was developed with ovalbumin as the specific Ag and here, we observed that exposure to specific Ag induced Treg apoptosis through converting the precursor of TGF‐β to its mature form inside the Tregs. Oxidative stress was induced in Tregs upon exposure to specific Ags, in which Smad3 bound the latency‐associated peptide to induce its degradation, converting the TGF‐β precursor to its mature form, TGF‐β. Suppressing oxidative stress in Tregs alleviated the specific Ag‐induced Treg apoptosis in in vitro experiments and suppressed experimental food allergy by preventing the specific Ag‐induced Treg apoptosis in the intestine. In conclusion, exposure to specific Ags induces Treg apoptosis and it can be prevented by upregulating superoxide dismutase or suppressing reactive oxidative species in Tregs.
Specific antigens contact Treg, antigen‐specific, generates ROS in Tregs that converts TGF‐β precursor (LTGFβ) to TGF‐β inside Tregs to induce Treg apoptosis, which can be abrogated by the presence of NAC (N‐acetylcystein), or Superoxide dismutase (SOD), or Maotai liquor (MTL).
leaves are used as a kind of phytomedicine and the main ingredient in some traditional Chinese medicine products for the relief of colitis. To understand the bioactive constituents of
L., we did a ...phytochemistry study and investigated anti-Inflammatory effects of compounds and explored the underlying mechanisms.
We isolated compounds from ethanol extract of
L. leaf and detected the most effective compound by NO inhibition assay. We investigated anti-Inflammatory effects on dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The disease activity index was determined by scores of body weight loss, diarrhea and rectal bleeding; histological damage was analyzed by H&E staining; macrophages change in the colon were analyzed by immunohistochemistry (IHC); myeloperoxidase activity was measured by myeloperoxidase assay kits; levels of proinflammatory cytokines were determined by qPCR and ELISA; protein production such as COX-2, iNOS, STAT3 and ERK1/2 were determined by western blotting.
We isolated uvaol from ethanol extract of
L. leaf and found uvaol has excellent potential of inhibiting NO production. We further found uvaol could attenuate disease activity index (DAI), colon shortening, colon injury, and colonic myeloperoxidase activity in DSS-induced colitis mice. Moreover, uvaol significantly reduces mRNA expression and production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1) and infiltration of macrophages in colonic tissues of colitis mice. Studies on LPS challenged murine macrophage RAW246.7 cells also revealed that uvaol reduces mRNA expression and production of pro-inflammatory cytokines and mediators. Mechanically, uvaol inhibits the pro-inflammatory ERK/STAT3 axis in both inflamed colonic tissues and macrophages.
leaf contains uvaol and uvaol has potent anti-inflammatory effects on DSS-induced experimental colitis and LPS-stimulated RAW264.7 macrophage cells. These results suggest uvaol is a prospective anti-inflammatory agent for colonic inflammation.
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