Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.

Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.

Influential factors and transcriptome analyses of immature diploid embryo anthocyanin accumulation in maize.

BACKGROUND: Anthocyanins are widely applied as a marker for haploid identification after haploid induction in maize. However, the factors affecting anthocyanin biosynthesis in immature embryos and the genes regulating this process remain unclear. RESULTS: In this study, we analyzed the influence of genetic background of the male and female parents, embryo age and light exposure on anthocyanin accumulation in embryos. The results showed that light exposure was the most crucial factor enhancing the pigmentation of immature embryos. The identification accuracy of haploid embryos reached 96.4% after light exposure, but was only 11.0% following dark treatment. The total anthocyanin content was 7-fold higher in immature embryos cultured for 24 h under light conditions compared to embryos cultured in the dark. Transcriptome analysis revealed that the differentially expressed genes between immature embryos cultured for 24 h in dark and light chambers were significantly enriched in the pathways of flavonoid, flavone, flavonol and anthocyanin biosynthesis. Among the genes involved in anthocyanin biosynthesis, five up-regulated genes were identified: F3H, DFR, ANS, F3'H and the MYB transcription factor-encoding gene C1. The expression patterns of 14 selected genes were confirmed using quantitative reverse transcription-polymerase chain reaction. CONCLUSION: Light is the most important factor facilitating anthocyanin accumulation in immature embryos. After 24 h of exposure to light, the expression levels of the structural genes F3H, DFR, ANS, F3'H and transcription factor gene C1 were significantly up-regulated. This study provides new insight into the factors and key genes regulating anthocyanin biosynthesis in immature embryos, and supports improved efficiency of immature haploid embryo selection during doubled haploid breeding of maize.

Administration route governs the therapeutic efficacy, biodistribution and macrophage targeting of anti-inflammatory nanoparticles in the lung.

BACKGROUND: Uncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined. RESULTS: In this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not. CONCLUSION: The i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects.

Transcatheter closure of muscular ventricular septal defects using the Cardi-O-Fix plug.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of the Cardi-O-Fix plug used for the treatment of muscular ventricular septal defects. METHODS: We retrospectively reviewed the medical records of five patients with muscular ventricular septal defects who underwent transcatheter closure using the Cardi-O-Fix Plug, from November 2017 to August 2019. The median age was 5.1 years (range: 3.2-6.5). Their median body weight was 18.1 kg (range: 13.4-21.8). All the patients underwent detailed two-dimensional Doppler and colour flow imaging by transthoracic echocardiography. The left ventricular median defect size of the muscular ventricular septal defects was 5.6 mm (range: 5.3-7.0). The right ventricular median defect size of the muscular ventricular septal defects was 3.9 mm (range: 3.3-4.7). All the procedures were performed on beating hearts. RESULTS: All the patients underwent successful device implantation with no displacement or detachment, they have complete echocardiographic closure at the 1-year follow-up. There were no occluder-related arrhythmia, chordae tendineae rupture, tricuspid insufficiency, aortic regurgitation, haemolysis, or embolisation. CONCLUSIONS: Application of the Cardi-O-Fix plug appears to be a feasible, safe, and effective treatment option for patients with muscular ventricular septal defects. Longer follow-up periods are warranted to prove the conclusion for long-term outcomes.

Manipulation of macrophage polarization by peptide-coated gold nanoparticles and its protective effects on acute lung injury.

BACKGROUND: Macrophage polarization and reprogramming in the lung play a critical role in the initiation, development and progression of acute lung injury (ALI). Regulating the activation and differentiation of pulmonary macrophages may provide a potential therapeutic strategy to treat ALI. We previously developed a novel class of anti-inflammatory nanoparticles (P12) that can potently inhibit Toll-like receptor (TLR) signaling in macrophages. These bioactive nanodevices were made of gold nanoparticles (GNPs) coated with hexapeptides to not only ensure their physiological stability but also enable GNPs with TLR inhibitory activity. RESULTS: In this study, using a lipopolysaccharide (LPS) induced ALI mouse model, we showed that P12 was able to alleviate lung inflammation and damage through reducing the infiltration of inflammatory cells and increasing the anti-inflammatory cytokine (IL-10) in the lung. These results prompted us to investigate possible macrophage polarization by P12. We first confirmed that P12 primarily targeted macrophages in the lung to exert anti-inflammatory activity. We then showed that P12 could drive the polarization of mouse bone marrow-derived macrophages (BMDMs) toward anti-inflammatory M2 phenotype. Interestingly, in the ALI mouse model, P12 was able to increase the alveolar M2 macrophages and reduce both the alveolar and interstitial M1 macrophages in the bronchoalveolar lavage fluid (BALF) and lung tissues. CONCLUSION: This study demonstrated that peptide-coated GNPs could induce M2 macrophage polarization in vitro and in vivo to effectively regulate lung inflammation, protect lung from injuries and promote inflammation resolution. The ability of regulating macrophage polarization together with TLR inhibition made such a bioactive nanodevice a new generation of potent therapeutics to treat ALI.

Mapping of a major QTL for salt tolerance of mature field-grown maize plants based on SNP markers.

BACKGROUND: Salt stress significantly restricts plant growth and production. Maize is an important food and economic crop but is also a salt sensitive crop. Identification of the genetic architecture controlling salt tolerance facilitates breeders to select salt tolerant lines. However, the critical quantitative trait loci (QTLs) responsible for the salt tolerance of field-grown maize plants are still unknown. RESULTS: To map the main genetic factors contributing to salt tolerance in mature maize, a double haploid population (240 individuals) and 1317 single nucleotide polymorphism (SNP) markers were employed to produce a genetic linkage map covering 1462.05 cM. Plant height of mature maize cultivated in the saline field (SPH) and plant height-based salt tolerance index (ratio of plant height between saline and control fields, PHI) were used to evaluate salt tolerance of mature maize plants. A major QTL for SPH was detected on Chromosome 1 with the LOD score of 22.4, which explained 31.2% of the phenotypic variation. In addition, the major QTL conditioning PHI was also mapped at the same position on Chromosome 1, and two candidate genes involving in ion homeostasis were identified within the confidence interval of this QTL. CONCLUSIONS: The detection of the major QTL in adult maize plant establishes the basis for the map-based cloning of genes associated with salt tolerance and provides a potential target for marker assisted selection in developing maize varieties with salt tolerance.

Pentoxifylline Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats: Possibly via Inhibiting TLR 4/NF-κB Signaling Pathway.

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) generally causes significant and lasting damage. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, has shown anti-inflammatory and neuroprotective properties in several brain injury models, but the role of PTX with respect to EBI following SAH remains uncertain. The purpose of this study was to investigate the effects of PTX on EBI after SAH in rats. Adult male Sprauge-Dawley rats were randomly assigned to the sham and SAH groups. PTX (30 or 60 mg/kg) or an equal volume of the administration vehicle (normal saline) was administrated at 30 min intervals following SAH. Neurological scores, brain edema, and neural cell apoptosis were evaluated. In order to explore other mechanisms, changes in the toll-like receptor 4 (TLR4) and the nuclear factor-κB (NF-κB) signaling pathway, in terms of the levels of apoptosis-associated proteins, were also investigated. We found that administration of PTX (60 mg/kg) notably improved neurological function and decreased brain edema at both 24 and 72 h following SAH. Treatment with PTX (60 mg/kg) significantly inhibited the protein expressions of TLR4, NF-κB, MyD88 and the downstream pro-inflammatory cytokines, such as the tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). PTX also significantly reduced neural cell death and BBB permeability. Our observations may be the first time that PTX has been shown to play a neuroprotective role in EBI after SAH, potentially by suppressing the TLR4/NF-κB inflammation-related pathway in the rat brain.

Increased Expression of Caspase-12 After Experimental Subarachnoid Hemorrhage.

Convincing evidences have proved that apoptosis plays a vital role in the pathogenesis of early and delayed brain injury following subarachnoid hemorrhage (SAH). Recently, a novel caspase-12-mediated apoptotic pathway has been reported to be induced by excess endoplasmic reticulum (ER) stress. Extensive protein damage occurs after SAH, which may trigger ER stress-associated apoptotic pathway. Thus, we hypothesized that caspase-12, as the major molecular marker of this novel apoptotic pathway, may be activated and involved in the pathogenesis of apoptotic injury after SAH. This study sought to investigate the changes of caspase-12 expressions in both in vitro and in vivo SAH models. Western blot analysis found significantly increased protein expressions of both pro- and active forms of caspase-12 after SAH. Quantitative real-time PCR and immunohistochemistry assays confirmed elevated caspase-12 level after SAH in vivo. Further, double immunofluorescence staining revealed obvious caspase-12 over-expression in both cortical neurons and astrocytes. Moreover, immunofluorescent co-staining in vivo demonstrated that neural cells with high immunoreactivity of caspase-12 also expressed caspase-3, and dual-immunofluorescent staining for caspase-12 and TUNEL in vitro showed that TUNEL-positive cells were more likely to exhibit higher caspase-12 immunoreactivity, indicating a potential contribution of caspase-12 activation to apoptosis in SAH. Collectively, our results showed significant upregulation of caspase-12 expression after experimental SAH. These findings also offer important implications for further investigations of the therapeutic potential of caspase-12 associated apoptosis in SAH.

Reconstruction of Digital Skin Defects with the Free Wrist Crease Flap.

BACKGROUND: Soft-tissue digital defects frequently need to be covered by a flap rather than a skin graft. In hand surgery, functional preservation and aesthetic appearance are often as important as procedural efficacy. OBJECTIVE: We present our clinical experience with reconstruction of digital skin defects with the free wrist crease flap. METHODS: From January 2012 to September 2013, 14 digits of 14 patients (10 males, 4 females) were included for evaluation. The procedure was performed with brachial plexus block anesthesia. The superficial palmar branch of the radial artery, a subcutaneous superficial vein, and the palmar cutaneous branch of the median nerve were included in the free wrist crease flap. The flaps were used to reconstruct the skin defect of injured digits through microvascular anastomosis, and donor sites were closed primarily. RESULTS: Postoperative follow-up time ranged from 3 to 25 months. All digital deformities were corrected, all flaps survived completely without ischemia, and none were aesthetically bulky. The area of free wrist crease flaps ranged from 2.5 to 5.0 cm by 2.0 to 3.1 cm. Slight wound infections appeared in two cases. Venous crisis occurred in one case, but it was successfully addressed after vascular exploration and reanastomosis. Sensation determined by static two-point discrimination measured in these flaps 2 months postsurgery was "good" at a mean 9.7 ± 2.1 mm (range, 6-14 mm). The mean motion range of the distal interphalangeal joint and proximal interphalangeal joint was 23.4 ± 6.9 degrees (0-42 degrees) and 75.8 ± 22.1 degrees (0-98 degrees) preoperatively. The mean motion range of the distal interphalangeal joint recovered to 40.3 ± 5.7 degrees (36-42 degrees), and that of the proximal interphalangeal joint was 90.3 ± 15.3 degrees (85-98 degrees) postoperatively. Both joints reached normal motion angle and difference was statistically significant preoperatively and postoperatively (p < 0.05). The mean disabilities of arm and shoulder (DASH) score was 6.8 ± 3.4 (0-15), and there was statistically significant difference when compared with the preoperative score of 13.5 ± 4.3 (3-19) (p < 0.05). CONCLUSION: We found the free wrist crease flap to be an ideal solution for reconstruction of skin defects of digits.

T-shaped excision of the orbicularis oris muscle: an innovative technique for upper lip lift procedures.

BACKGROUND: The lips are a prominent part of the face and they age along with the face. Microsurgery for upper lip lifts is becoming popular because of its association with minimal trauma and rapid recovery. OBJECTIVES: The authors introduced an innovative method of lifting the upper lip. METHODS: From January 2009 to March 2013, a cohort of 30 women underwent an upper lip lift surgical procedure. Patients received local anesthesia for a regional block of the infraorbital nerve. A T-shaped orbicularis oris and a strip of skin were excised. The superior edge of the orbicularis oris muscle was sutured to the base of the nose, and the incision was closed with a continuous intradermal suture. Postoperative follow-up time ranged from 1 to 5 years. RESULTS: At the time of follow-up, the incisional scar was not visible on the patient. The nasolabial angle was 96.20° ± 1.86° before operation and 88.23° ± 2.58° after operation. The difference was statistically significant (P = 0.000 and P < 0.001). The upper lip angle was 65.56° ± 8.60° before operation and 51.90° ± 3.93° after operation. The difference was statistically significant (P = 0.000) and P < 0.001). After operation, the upper lip appeared to be clearly thickened. CONCLUSIONS: This innovative surgical technique is a simple and effective way to lift the upper lip.

A novel stability criterion and precise control for linear time delay systems based on regional configuration of the poles.

This paper presents the concept of region stability and provides criteria for region stability of linear time delay systems, which can reveal the dynamic and steady-state performance of the systems more precisely. Corresponding design schemes for stabilization and tracking control that can accurately control various performance of time delay systems have also been explored. First, in the light of the connection between the poles and the dynamic properties of the system, the concept of region stability is given to describe the finer dynamic behavior of time delay systems. The criteria for the region stability are also presented. Second, the region stabilization methods are investigated, which can ensure that the system satisfies a certain dynamic performance by setting the eigenvalues in a certain convex region. Third, a precise tracking control of the linear time delay systems is addressed as an application of region stabilization. It can control the steady state performance and transient response of the tracking signal more precisely. Finally, three instances are provided to display the superiority of the new method for the performance indexes of the linear time delay systems.

Applications of artificial intelligence for surgical extraction in stomatology: a systematic review.

OBJECTIVES: Artificial intelligence (AI) has been extensively used in the field of stomatology over the past several years. This study aimed to evaluate the effectiveness of AI-based models in the procedure, assessment, and treatment planning of surgical extraction. STUDY DESIGN: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a comprehensive search was conducted on the Web of Science, PubMed/MEDLINE, Embase, and Scopus databases, covering English publications up to September 2023. Two reviewers performed the study selection and data extraction independently. Only original research studies utilizing AI in surgical extraction of stomatology were included. The Cochrane risk of bias tool for randomized trials (RoB 2) was selected to perform the quality assessment of the selected literature. RESULTS: From 2,336 retrieved references, 35 studies were deemed eligible. Among them, 28 researchers reported the pioneering role of AI in segmentation, classification, and detection, aligning with clinical needs. In addition, another 7 studies suggested promising results in tooth extraction decision-making, but further model refinement and validation were required. CONCLUSIONS: Integration of AI in stomatology surgical extraction has significantly progressed, enhancing decision-making accuracy. Combining and comparing algorithmic outcomes across studies is essential for determining optimal clinical applications in the future.

LKB1 prevents ILC2 exhaustion to enhance antitumor immunity.

Group 2 innate lymphoid cells (ILC2s) play crucial roles in mediating allergic inflammation. Recent studies also indicate their involvement in regulating tumor immunity. The tumor suppressor liver kinase B1 (LKB1) inactivating mutations are associated with a variety of human cancers; however, the role of LKB1 in ILC2 function and ILC2-mediated tumor immunity remains unknown. Here, we show that ablation of LKB1 in ILC2s results in an exhausted-like phenotype, which promotes the development of lung melanoma metastasis. Mechanistically, LKB1 deficiency leads to a marked increase in the expression of programmed cell death protein-1 (PD-1) in ILC2s through the activation of the nuclear factor of activated T cell pathway. Blockade of PD-1 can restore the effector functions of LKB1-deficient ILC2s, leading to enhanced antitumor immune responses in vivo. Together, our results reveal that LKB1 acts to restrain the exhausted state of ILC2 to maintain immune homeostasis and antitumor immunity.

A comparison of skin expansion and contraction between one expander and two expanders: a preliminary study.

BACKGROUND: This study aimed to compare the difference between the skin expansion and contraction rates for an expanded flap with one versus two expanders. METHODS: The study cohort comprised 24 cases of two overlapping expanders and 15 cases of a single implanted expander involving 22 patients. The method of "wet-cloth sampling" was applied to measure the expanded flap area and the initial unexpanded area and to calculate the skin expansion rate. Two points 5 cm apart in the center of the expanded flap were selected before the second surgical stage. After removal of the expander, the distance between the two fixed points was measured and recorded. The contraction rate of the expanded flap then was calculated. RESULTS: During the same period of expansion in the two groups (p = 0.06, >0.01), the skin expansion rate was 3.5 ± 0.9 % in the group with two overlapping expanders and 2.6 ± 0.6 % in the control group. The difference between the two groups was statistically significant (p = 0.002, <0.05). The instantly expanded flap contraction rates were 30.3 ± 0.8 and 32.3 ± 0.9 %, respectively for the two groups, and the difference was not statistically significant (p = 0.47, >0.05). We fitted a linear regression model that was Y = 0.533 − 0.003X, where Y was the contraction rate of the expanded flap and X was the period of expansion. The contraction rate of the expanded flap was negatively correlated with the period of expansion. CONCLUSIONS: Compared with the traditional method of implanting a single expander, the new method of overlapping two expanders in a single cavity increased the skin expansion rate. The instantly expanded flap contraction rate did not differ significantly between the two groups, so the amount of expanded skin area absolutely increased. The clinical application of the new method is worth promoting. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Risk factors of postoperative cerebral hyperperfusion syndrome and its relationship with clinical prognosis in adult patients with moyamoya disease.

BACKGROUND: To investigate the incidence, risk factors, and clinical prognosis of cerebral hyperperfusion syndrome (CHS) after superficial temporal artery-middle cerebral artery anastomosis combined with encephalo-duro-arterio-synangiosis (STA-MCA/EDAS) in adult patients with moyamoya disease (MMD). METHODS: The clinical data of 160 adult patients with MMD treated by STA-MCA/EDAS from January 2016 to January 2017 were retrospectively analyzed. According to CHS diagnosis, MMD patients were divided into CHS and non-CHS group. Univariate and multivariate analysis of risk factors and Kaplan-Meier curve of stroke-free survival for CHS were performed. RESULTS: A total of 12 patients (7.5%) developed postoperative CHS, of which 4 patients (2.5%) presented with cerebral hemorrhage. Univariate and multivariate analysis showed moyamoya vessel on the surgical hemisphere (OR = 3.04, 95% CI = 1.02-9.03, P = 0.046) and left operated hemisphere (OR = 5.16, 95% CI = 1.09-21.34, P = 0.041) were independent risk factors for CHS. The other variables, such as age, gender, presentation, hypertension, diabetes, smoking, mean mRS score on admission, modified Suzuki stage and pre-infarction stage on surgical hemisphere, and bypass patency, had no association with postoperative CHS (P > 0.05). At final follow-up with average 38 months, there were 18 out of 133 patients (13.5%, 4.91% per person year) presented with newly developed complications. There was no significant difference between newly developed complications, mean mRS scores, and Kaplan-Meier curve of stroke-free survival in patients with and without CHS (P > 0.05). CONCLUSION: The concentration of moyamoya vessels and left operated hemisphere was independent risk factors for CHS, which could not affect the clinical prognosis if treated timely and properly. The current study offers a new perspective of moyamoya vessels and supporting data for choosing MMD candidates on cerebral revascularization.

Treatment outcomes of neuroendoscopic and microscopic trans-sphenoidal pituitary adenomectomies and the effects on hormone levels.

BACKGROUND: We aimed to compare the treatment outcomes of neuroendoscopic and microscopic trans-sphenoidal pituitary adenomectomies, as well as the effects on hormone levels and clinical symptoms. METHODS: A total of 82 patients with pituitary adenomas that were surgically resected from June 2018 to March 2021 were selected and divided into a group receiving neuroendoscopic trans-sphenoidal pituitary adenomectomy (group A, N.=40), and the other group receiving microscopic surgery (group B, N.=42). Surgery-related indices, hormone levels before discharge and alleviation of symptoms 24 weeks after surgery were compared. RESULTS: Both groups had significantly different degrees of tumor resection (P<0.05). The proportion of cases receiving total adenomectomy in group A significantly exceeded that of group B (P<0.05). The surgical time of group A was significantly longer than that of group B (P<0.05). Group A had significantly shorter mean hospitalization stay than that of group B (P<0.05). The postoperative hormone levels of both groups decreased significantly differently (P<0.05). Before discharge, the hormone recovery rate of group A significantly surpassed that of group B (P<0.05). The hormone levels of cases with prolactinoma, adrenocorticotropic hormone adenoma and growth hormone adenoma in group A dropped more significantly than those of group B did (P<0.05). CONCLUSIONS: Compared with microscopic surgery, neuroendoscopic trans-sphenoidal pituitary adenomectomy worked more effectively, induced fewer postoperative complications and better promoted the postoperative recovery of hormone levels.

Dihydromyricetin confers cerebroprotection against subarachnoid hemorrhage via the Nrf2-dependent Prx2 signaling cascade.

BACKGROUND: Several clinical and experimental studies have shown that therapeutic strategies targeting oxidative damage are beneficial for subarachnoid hemorrhage (SAH). A brain-permeable flavonoid, dihydromyricetin (DHM), can modulate redox/oxidative stress and has cerebroprotective effects in several neurological disorders. The effects of DHM on post-SAH early brain injury (EBI) and the underlying mechanism have yet to be clarified. PURPOSE: This work investigated a potential role for DHM in SAH, together with the underlying mechanisms. METHODS: Cerebroprotection by DHM was studied using a SAH rat model and primary cortical neurons. Atorvastatin (Ato) was a positive control drug in this investigation. The effects of DHM on behavior after SAH were evaluated by performing the neurological rotarod and Morris water maze tests, as well as by examining its effects on brain morphology and on the molecular and functional phenotypes of primary cortical neurons using dichlorodihydrofluorescein diacetate (DCFH-DA), immunofluorescent staining, biochemical analysis, and Western blot. RESULTS: DHM was found to significantly reduce the amount of reactive oxygen species (ROS), suppress mitochondrial disruption, and increase intrinsic antioxidant enzymatic activity following SAH. DHM also significantly reduced neuronal apoptosis in SAH rats and improved short- and long-term neurological functions. DHM induced significant increases in peroxiredoxin 2 (Prx2) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, while decreasing phosphorylation of p38 and apoptotic signal-regulated kinase 1 (ASK1). In contrast, reduction of Prx2 expression using small interfering ribonucleic acid or by inhibiting Nrf2 with ML385 attenuated the neuroprotective effect of DHM against SAH. Moreover, DHM dose-dependently inhibited oxidative damage, decreased neuronal apoptosis, and increased the viability of primary cultured neurons in vitro. These positive effects were associated with Nrf2 activation and stimulation of Prx2 signaling, whereas ML385 attenuated the beneficial effects. CONCLUSION: These results reveal that DHM protects against SAH primarily by modulating the Prx2 signaling cascade through the Nrf2-dependent pathway. Hence, DHM could be a valuable therapeutic candidate for SAH treatment.

PLZF restricts intestinal ILC3 function in gut defense.

Group 3 innate lymphoid cells (ILC3s) play important roles in maintaining intestinal homeostasis by protecting the host from pathogen infections and tissue inflammation. The transcription factor PLZF (promyelocytic leukemia zinc finger), encoded by zinc finger BTB domain containing 16 (Zbtb16), is highly and transiently expressed in ILC precursors (ILCPs). However, the role of PLZF in regulating ILC3 development and function remains unknown. Here, we show that PLZF was specifically expressed in mature intestinal ILC3s compared with other ILC subsets. PLZF was dispensable for ILC3 development. However, PLZF deficiency in ILC3s resulted in increased innate interleukin-22 (IL-22) secretion and protection against gut infection and inflammation. Mechanistically, PLZF negatively regulated IL-22 expression by ILC3s in a cell-intrinsic manner by binding to the IL-22 promoter region for transcriptional repression. Together, our data suggest that PLZF restricts intestinal ILC3 function to regulate gut immune homeostasis.

Peroxiredoxin 2 Is a Potential Objective Indicator for Severity and the Clinical Status of Subarachnoid Hemorrhage Patients.

Purpose: We have demonstrated that peroxiredoxin 2 (Prx2) released from lytic erythrocytes and damaged neurons into the subarachnoid space could activate microglia and then result in neuronal apoptosis. In this study, we tested the possibility of using Prx2 as an objective indicator for severity of the subarachnoid hemorrhage (SAH) and the clinical status of the patient. Materials and Methods: SAH patients were prospectively enrolled and followed up for 3 months. Cerebrospinal fluid (CSF) and blood samples were collected 0-3 and 5-7 days after SAH onset. The levels of Prx2 in the CSF and the blood were measured by an enzyme-linked immunosorbent assay (ELISA). We used Spearman's rank coefficient to assess the correlation between Prx2 and the clinical scores. Receiver operating characteristic (ROC) curves were used for Prx2 levels to predict the outcome of SAH by calculating the area under the curve (AUC). Unpaired Student's t-test was used to analyze the differences in continuous variables across cohorts. Results: Prx2 levels in the CSF increased after onset while those in the blood decreased. Existing data showed that Prx2 levels within 3 days in the CSF after SAH were positively correlated with the Hunt-Hess score (R = 0.761, P < 0.001). Patients with CVS had higher levels of Prx2 in their CSF within 5-7 days after onset. Prx2 levels in the CSF within 5-7 days can be used as a predictor of prognosis. The ratio of Prx2 in the CSF and the blood within 3 days of onset was positively correlated with the Hunt-Hess score and negatively correlated with Glasgow Outcome Scale (GOS; R = -0.605, P < 0.05). Conclusion: We found that the levels of Prx2 in the CSF and the ratio of Prx2 in the CSF and the blood within 3 days of onset can be used as a biomarker to detect the severity of the disease and the clinical status of the patient.

Elevated Level of Cerebrospinal Fluid Pyruvate Dehydrogenase Kinase 4 Is a Predictive Biomarker of Clinical Outcome after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a central nervous system disease with high mortality and morbidity. Some independent factors valuable for prognosis prediction in patients with SAH are still lacking. In our earlier study, we found that PDK4 exerts a protective effect after SAH, primarily by reducing oxidative stress and neuronal death via the ROS/ASK1/p38 signaling pathway. Therefore, we investigated the changes in the level of pyruvate dehydrogenase kinase 4 (PDK4) in patients after subarachnoid hemorrhage (SAH) and analyzed the value of the cerebrospinal fluid (CSF) PDK4 level in predicting the prognoses of patients with SAH after interventional embolization surgery. Some knee arthritis subjects who needed surgery were recruited as a control group. The results showed that PDK4 expression was elevated in the CSF of SAH patients compared with that of controls. PDK4 levels in CSF (OR = 4.525; 95% CI: 1.135-18.038; p = 0.032), time to surgery (OR = 0.795; 95% CI: 0.646-0.977; p = 0.029), and initial GCS scores (OR = 2.758; 95% CI: 0.177-43.106; p = 0.469) were independent prognostic risk factors for SAH patients after surgery. The receiver operating characteristic (ROC) curve showed PDK4 levels in CSF had a higher predictive value. Thus, PDK4 in CSF could be an independent prognostic risk factor for SAH patients after surgery. PDK4 has the potential to serve as a new therapeutic target and biomarker for use in the diagnosis of SAH severity and the prediction of recovery.