ASC-expressing pyroptotic extracellular vesicles alleviate sepsis by protecting B cells.

Pyroptosis is an inflammatory programmed cell death process characterized by membrane rupture. Interestingly, pyroptotic cells can generate plenty of nanosized vesicles. Non-inflammatory apoptotic cell death-derived apoptotic vesicles (apoVs) were systemically characterized and displayed multiple physiological functions and therapeutic potentials. However, the characteristics of pyroptotic cell-generated extracellular vesicles (EVs) are largely unknown. Here, we identified a group of pyroptotic EVs (pyroEVs) from in vitro cultured pyroptotic mesenchymal stem cells (MSCs), as well as from septic mouse blood. Compared with apoVs, pyroEVs express similar levels of annexin V, calreticulin, and common EV markers, but express a decreased level of apoptotic marker cleave caspase-3. PyroEVs, but not apoVs and exosomes, specifically express pyroptotic maker apoptosis-associated speck-like protein containing CARD (ASC). More importantly, MSC-derived pyroEVs protect B cells in the spleen and bone marrow to relieve inflammatory responses and enhance the survival rate of the septic mice. Mechanistically, pyroEV membrane-expressed ASC binds to B cells to repress cell death by repressing Toll-like receptor 4. This study uncovered the characteristics of pyroEVs and their therapeutic role in sepsis and B cell-mediated immune response.

Multiple cell death modalities and immune response in pulpitis.

AIM: To investigate the level and distribution of apoptosis, pyroptosis, necroptosis, and NETosis in pulpitis with or without necrosis on a basis of histological classification. Additionally, to examine the effect of pulpitis with necrosis (PWN) on the number and activation of peripheral and bone marrow (BM) neutrophils, as well as spleen lymphocytes, in a mouse model of pulpitis. METHODOLOGY: The material comprised 20 permanent teeth, with or without caries, which were classified into three histological categories based on the distribution of inflammatory cells and the presence or absence of necrosis: (i) healthy pulp (HP), (ii) pulpitis without necrosis (PWON), and (iii) PWN. The levels of the four regulated cell death (RCD) pathways were detected by immunohistochemical and immunofluorescent staining with specific markers: apoptosis (caspase-8, cleaved caspase-3), pyroptosis (cleaved caspase-1, membrane-binding gasdermin D), necroptosis (receptor-interacting kinase 3, phosphorylated MLKL), and NETosis (myeloperoxidase, citrullinated histone H3). Acute pulpitis was induced in C57BL/6J mice via pulp exposure, and the mice were divided into four groups: (i) control (no tooth preparation, n = 6), (ii) Day 1 (sacrificed at 1 day after pulp exposure, n = 3), (iii) Day 3 (n = 3), and (iv) Day 5 (n = 7). The control and Day 5 groups were used for further immunofluorescent analysis to assess the levels of RCD and flow cytometry to monitor the changes in peripheral and BM neutrophils, as well as spleen lymphocytes. Human dental pulp stem cells (hDPSCs) were isolated and cultured from extracted healthy third molars. Apoptosis and necroptosis in hDPSCs were induced by staurosporine, whilst pyroptosis was induced by lipopolysaccharide and nigericin. One-way analysis of variance (ANOVA) with Tukey's test, Welch's ANOVA with Tamhane's test, and Student's t-tests were used to compare immunohistochemical labelling and flow cytometric data amongst groups (p < .05). RESULTS: The pulpal tissue of PWN can be divided into the abscess core (PWN-AC) and fibrous tissue (PWN-FT). The ratio of total necrotic cells (TUNEL-positive) in PWN-AC was significantly higher than in PWN-FT and PWON (both p < .01). Compared with HP, the expression levels of markers for apoptosis and pyroptosis were increased in PWON, whilst the expression levels of markers for apoptosis, pyroptosis, and NETosis were elevated in PWN, primarily detected in PWN-AC. Interestingly, myeloperoxidase (MPO) was exclusively observed in PWN-AC, with minimal detection in PWN-FT and PWON. Additionally, the frequency of MPO+ cells was significantly higher than that of MB-GSDMD+ cells and Cl-cas3+ cells in PWN-AC (both p < .01). Histological observation and TUNEL staining showed abundant necrotic cells in mouse pulpal tissue after pulp exposure, indicating a simulation of human PWN. In mouse pulpitis tissue, markers of apoptosis, pyroptosis, and NETosis were detected. In vitro, various cell deaths including apoptosis, pyroptosis, and necroptosis were also triggered in hDPSCs under various cell death treatments. Furthermore, in terms of systemic changes, pulp exposure-induced pulpitis could increase the number (p < .05) and cellular activity (p < .01) of neutrophils from BM in a mouse model. No significant changes in peripheral blood neutrophils, spleen T cells, B cells, or the CD4/CD8 ratio were detected between the control and pulpitis mice. CONCLUSIONS: Our findings uncover distinct patterns of mixed cell death at different histological stages of human pulpitis and the impact of pulpitis on the number and activity of BM neutrophils. Notably, NETosis occurs specifically and predominates in the abscess area of pulpitis, suggesting a potential effect of neutrophil extracellular traps (NETs) on pulpitis progression and NETs-targeted diagnostic strategy may play a role in decision making for vital pulp therapy.

Characteristics of glucolipid metabolism and oxidative stress in breeding pigeons (Columba livia) during lactation.

Breeding pigeons is a fundamental source of profit in various enterprises but little is known on the metabolic laws governing their lactation. In this study, we analysed the metabolic profile of different sex of breeding pigeons (Columba livia, European pigeons, Mimas) during lactation. We found that male pigeons exhibited catabolism during lactation. Extension of lactation resulted in increased weight loss, then slow recovery of body weight. Conversely, the weight loss in female pigeons peaked on the seventh day of lactation. They then gradually recovered their body weight. Male pigeons showed more duration of combing, while female pigeons showed more duration of resting. In male pigeons, except for triglyceride (TG), which increased, blood lipid indexes barely changed during lactation. Conversely, in females, both TG and total cholesterol increased in middle and late lactation. The level of oxidative stress in female pigeons during lactation was higher than in males, lipid peroxide malondialdehyde, hydrogen peroxide (H2 O2 ), plasma calcium (Ca) and phosphorus (P) levels increased in late lactation. Levels of estradiol and progesterone in female pigeons increased during lactation, whereas those of luteotropic hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL) and testosterone gradually decreased. As per LC-MS spectra analysis, the differential metabolites in the plasma on the day of hatching and before laying in female pigeons in lactation were enriched in retrograde endocannabinoid signalling, α-linolenic acid, arachidonic acid, choline, glycerophospholipid metabolisms, and valine, leucine, and isoleucine degradations. Levels of fatty acids, amino acids, sphingomyelin and phosphatidylinositol related to the secretion of pigeon milk had reduced, whereas the levels of phosphatidylcholine, phosphatidylethanolamine, and TG, which are all related to egg production, had increased. In conclusion, our study systematically revealed the different metabolic characteristics of male and female breeding pigeons during lactation. This is useful for precision feeding of pigeons and applicable in nutritional interventions for improved production.

Electrostatic Charge-Mediated Apoptotic Vesicle Biodistribution Attenuates Sepsis by Switching Neutrophil NETosis to Apoptosis.

Mesenchymal stem cell (MSC) therapy can attenuate organ damage and reduce mortality in sepsis; however, the detailed mechanism is not fully elucidated. In this study, it is shown that MSC-derived apoptotic vesicles (apoVs) can ameliorate multiple organ dysfunction and improve survival in septic mice. Mechanistically, it is found that tail vein-infused apoVs mainly accumulate in the bone marrow of septic mice via electrostatic charge interactions with positively charged neutrophil extracellular traps (NETs). Moreover, apoVs switch neutrophils NETosis to apoptosis via the apoV-Fas ligand (FasL)-activated Fas pathway. In summary, these findings uncover a previously unknown role of apoVs in sepsis treatment and an electrostatic charge-directed target therapeutic mechanism, suggesting that cell death is associated with disease development and therapy.

Cladding Mode Fitting-Assisted Automatic Refractive Index Demodulation Optical Fiber Sensor Probe Based on Tilted Fiber Bragg Grating and SPR.

In the paper based on surface plasmon resonance (SPR) in a tilted fiber Bragg grating (TFBG), a novel algorithm is proposed, which facilitates demodulation of surrounding refractive index (SRI) via cladding mode interrogation and accelerates calibration and measurement of SRI. Refractive indices with a tiny index step of 2.2 × 10-5 are prepared by the dilution of glucose aqueous solution for the test and the calibration of this fiber sensor probe. To accelerate the calibration process, automatic selection of the most sensitive cladding mode is demonstrated. First, peaks of transmitted spectrum are identified and numbered. Then, sensitivities of several potentially sensitive cladding modes in amplitude adjacent to the left of the SPR area are calculated and compared. After that, we focus on the amplitudes of the cladding modes as a function of a SRI, and the highest sensitivity of -6887 dB/RIU (refractive index unit) is obtained with a scanning time of 15.77 s in the range from 1520 nm to 1620 nm. To accelerate the scanning speed of the optical spectrum analyzer (OSA), the wavelength resolution is reduced from 0.028 nm to 0.07 nm, 0.14 nm, and 0.28 nm, and consequently the scanning time is shortened to 6.31 s, 3.15 s, and 1.58 s, respectively. However, compared to 0.028 nm, the SRI sensitivity for 0.07 nm, 0.14 nm, and 0.28 nm is reduced to -5685 dB/RIU (17.5% less), -5415 dB/RIU (21.4% less), and -4359 dB/RIU (36.7% less), respectively. Thanks to the calculation of parabolic equation and weighted Gauss fitting based on the original data, the sensitivity is improved to -6332 dB/RIU and -6721 dB/RIU, respectively, for 0.07 nm, and the sensitivity is increased to -5850 dB/RIU and -6228 dB/RIU, respectively, for 0.14 nm.

Effectiveness of antiplatelet drugs for the prevention of diabetic nephropathy: A meta-analysis of randomized controlled trials
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AIMS: To evaluate the effects of antiplatelet drugs on proteinuria, renal function, and blood pressure (BP) in patients with diabetic nephropathy (DN). MATERIALS AND METHODS: A meta-analysis of randomized controlled trials (RCTs) was performed. Relevant RCTs were identified by a systematic search of the PubMed, Cochrane Library, and Embase databases. A random-effects model was applied to pool the results. RESULTS: Antiplatelet drugs significantly reduced urinary albumin excretion (weighted mean difference (WMD) = -69.25 mg/24, p = 0.005) and the urinary albumin/creatinine ratio (standardized mean difference (SMD) = -0.33, p = 0.009). However, renal function as reflected by the estimated glomerular filtration rate (WMD = -1.15 mL/min/1.73m2, p = 0.46) and BP (systolic BP: WMD = 1.53 mmHg, p = 0.35; diastolic BP: WMD = 0.40 mmHg, p = 0.70) were not significantly affected by antiplatelet drugs within 12 months of use (p > 0.05). CONCLUSION: Antiplatelet drugs may benefit patients with DN by reducing proteinuria. The long-term effects of antiplatelet drugs on the progression of DN warrant further evaluation.
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Compact Reconfigurable Antenna with an Omnidirectional Pattern and Four Directional Patterns for Wireless Sensor Systems.

A compact reconfigurable antenna with an omnidirectional mode and four directional modes is proposed. The antenna has a main radiator and four parasitic elements printed on a dielectric substrate. By changing the status of diodes soldered on the parasitic elements, the proposed antenna can generate four directional radiation patterns and one omnidirectional radiation pattern. The main beam directions of the four directional modes are almost orthogonal and the four directional beams can jointly cover a 360° range in the horizontal plane, i.e., the main radiation plane of omnidirectional mode. The whole volume of the antenna and the control network is approximately 0.70 λ × 0.53 λ × 0.02 λ, where λ is the wavelength corresponding to the center frequency. The proposed antenna has a simple structure and small dimensions under the requirement that the directional radiation patterns can jointly cover the main radiation plane of the omnidirectional mode, therefore, it can be used in smart wireless sensor systems for different application scenarios.

Strategically reducing carbapenem-resistant Acinetobacter baumannii through PDCA cycle-driven antibiotic management.

PURPOSE: With the escalating global challenge of antibiotic resistance, particularly the resistance rate of Acinetobacter baumannii, the need to rationalize carbapenem antibiotic use in clinical settings has become paramount. Our study tapped into a fishbone diagram to uncover the irrationalities in applying these antibiotics and highlight potential influencing factors. METHODS: Based on these analyses, we initiated targeted intervention strategies. A PDCA cycle-based scientific management approach was implemented through the combined efforts of our antimicrobial stewardship team and relevant departments. RESULTS: Our study showed a significant post-intervention increase in the rational use of carbapenem antibiotics (P < 0.01) and a concurrent decrease in the detection of carbapenem-resistant Acinetobacter baumannii. CONCLUSION: Our findings underscore that carbapenem usage can be effectively minimized with the continuous refinements offered by the PDCA cycle, leading to a reduction in multidrug-resistant bacteria, thus fostering rational drug use in healthcare.

Astragaloside IV attenuates renal tubule injury in DKD rats via suppression of CD36-mediated NLRP3 inflammasome activation.

Background: In recent years, diabetic kidney disease (DKD) has emerged as a prominent factor contributing to end-stage renal disease. Tubulointerstitial inflammation and lipid accumulation have been identified as key factors in the development of DKD. Earlier research indicated that Astragaloside IV (AS-IV) reduces inflammation and oxidative stress, controls lipid accumulation, and provides protection to the kidneys. Nevertheless, the mechanisms responsible for its protective effects against DKD have not yet been completely elucidated. Purpose: The primary objective of this research was to examine the protective properties of AS-IV against DKD and investigate the underlying mechanism, which involves CD36, reactive oxygen species (ROS), NLR family pyrin domain containing 3 (NLRP3), and interleukin-1ß (IL-1ß). Methods: The DKD rat model was created by administering streptozotocin along with a high-fat diet. Subsequently, the DKD rats and palmitic acid (PA)-induced HK-2 cells were treated with AS-IV. Atorvastatin was used as the positive control. To assess the therapeutic effects of AS-IV on DKD, various tests including blood sugar levels, the lipid profile, renal function, and histopathological examinations were conducted. The levels of CD36, ROS, NLRP3, Caspase-1, and IL-1ß were detected using western blot analysis, PCR, and flow cytometry. Furthermore, adenovirus-mediated CD36 overexpression was applied to explore the underlying mechanisms through in vitro experiments. Results: In vivo experiments demonstrated that AS-IV significantly reduced hyperglycemia, dyslipidemia, urinary albumin excretion, and serum creatinine levels in DKD rats. Additionally, it improved renal structural abnormalities and suppressed the expression of CD36, NLRP3, IL-1ß, TNF-α, and MCP-1. In vitro experiments showed that AS-IV decreased CD36 expression, lipid accumulation, and lipid ROS production while inhibiting NLRP3 activation and IL-1ß secretion in PA-induced HK-2 cells. Conclusion: AS-IV alleviated renal tubule interstitial inflammation and tubule epithelial cell apoptosis in DKD rats by inhibiting CD36-mediated lipid accumulation and NLRP3 inflammasome activation.

Carbon Dot-Loaded Apoptotic Vesicles Improve the Liver Kupffer Cell-Mediated Antibacterial Effect to Synergistically Alleviate Sepsis.

Sepsis is a lethal systemic inflammatory disease against infection that lacks effective therapeutic approaches. Liver resident macrophage Kupffer cell (KC)-initiated bacterial clearance is crucial for the host to defend against infection. However, it remains unclear whether this process also governs the antibacterial therapy of sepsis that would be used to improve therapeutic outcomes. Here, we found that copper-doped carbon dots (Cu-CDs) exhibited superior antibacterial capabilities in vitro but displayed limited therapeutic effects in septic mice due to their limited ability to target the liver and restore KC antimicrobial capacity. Thus, we developed a composite nanodrug of copper-doped carbon dot-loaded apoVs (CC-apoVs) that combined the antibacterial ability of Cu-CDs and liver KC targeting features of apoV. Moreover, intravenous injection of CC-apoVs markedly alleviated the systemic infection and decreased the mortality of septic mice compared to Cu-CD and apoV infusion alone. Mechanistically, CC-apoV injection rescued impaired liver KCs during sepsis and enhanced their ability to capture and kill bloodborne bacteria. In addition, apoV-promoted macrophage killing of bacteria could be blocked by the inhibition of small GTPase Rab5. This study reveals a liver KC-targeted therapeutic strategy for sepsis and provides a nanodrug CC-apoV to improve the host antibacterial defense and amplify the therapeutic effect of the nanodrug.