Reactant-Product Decoupling Technique Using the Intermediate Coordinate Method.

Although the reactant-product decoupling (RPD) technique was proposed over two decades ago, it remains an efficient approach for calculating product state-resolved information on some simple direct reactions using the quantum wave packet method. In the past, usually the RPD technique employed the collocation method to transform the wave function between reactant and product arrangements, which requires quite large computational efforts. In this work, the intermediate coordinate (IC) method is employed to realize the RPD technique. Numerical examples demonstrate that this new IC RPD (IRPD) technique has superior computational efficiency compared with the original method employing the collocation method. Especially, the new IRPD technique significantly saves disk space and computer memory. To illustrate the features of our new method, the total reaction probabilities of the H + H2, H + Br2, and F + H2 reactions with J = 0 and the differential cross sections of the H + H2 and F + H2 reactions at a series of collision energy are calculated and presented. With this efficient and effective new RPD technique, the Li + HF reaction, which involves sharp resonances with long-range wave functions in the van der Waals wells in both the reactant and product arrangements, is also calculated with several J at the product state-resolved level to reveal the ability of the RPD technique for describing resonance wave functions. With these numerical examples, it is found that, for the reaction with resonances, the RPD approach should be applied carefully. Otherwise, it is very possible that the resonances could disappear with the application of the RPD technique.

Dexmedetomidine attenuates lipopolysaccharide-induced renal cell fibrotic phenotypic changes by inhibiting necroinflammation via activating α2-adrenoceptor: A combined randomised animal and in vitro study.

BACKGROUND: Acute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α2-adrenoreceptor (AR) agonist, has cytoprotective and "anti-" inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models. METHODS: C57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10 mg/kg) alone, LPS with Dex (25 µg/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500 µg/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1 µg/ml) alone, LPS and Dex (1 µM), transforming growth factor-beta 1 (TGF-ß1) (5 ng/ml) alone, TGF-ß1 and Dex, with or without Atip (100 µM) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined. RESULTS: Dex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-ß1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation. CONCLUSIONS: Dex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α2-AR activation in the renal tubular cells. The "anti-fibrotic" and cytoprotective properties and its clinical use of Dex need to be further studied.

Single-cell sequencing reveals the immune landscape of breast cancer patients with brain metastasis.

BACKGROUND: Breast cancer has the highest incidence rate of cancer worldwide, and brain metastases (BrM) are among the most malignant cases. While some patients have benefited from immune checkpoint inhibitors (ICIs), the complex anatomical structure of the brain and the heterogeneity of metastatic tumors have made it difficult to characterize the tumor immune microenvironment (TME) of metastatic tumors. METHODS: To address this, we used single-cell RNA sequencing (scRNA-seq) to analyze immune cells in the cerebrospinal fluid (CSF) of BrM patients with breast cancer, thereby providing a comprehensive view of the immune microenvironment landscape of BrM. RESULTS: Based on canonical marker genes, we identified nine cell types, and further identified their subtypes through differential expression gene (DEG) analysis. We compared the changes in cells and functions in the immune microenvironment of patients with different prognoses. Our analysis revealed a series of genes that promote tumor immune function (CCR5, LYZ, IGKC, MS4A1, etc.) and inhibit tumor immune function (SCGB2A2, CD24, etc.). CONCLUSIONS: The scRNA-seq in CSF provides a noninvasive method to describe the TME of breast cancer patients and guide immunotherapy.

Theoretical Development of the Interaction-Asymptotic Region Decomposition Method for Tetratomic Reactive Scattering.

An accurate and efficient time-dependent wave packet method is proposed for solving the product state-resolved reaction probabilities of the tetratomic reactive system. In this method, the entire scattering process is divided into the interaction region and multiple asymptotic regions, sharing the same spirit as the interaction-asymptotic region decomposition (IARD) approach in a triatomic reactive scattering process. The hyperspherical coordinate is adopted in the interaction region, while the corresponding Jacobi coordinate is employed in each asymptotic region. Therefore, in this IARD method, the "coordinate problem", the difficulty of expressing the wave function in the entire region using a single coordinate system, can be effectively avoided, and only a very small number of the grid points (or the basis functions) are required. For the numerical illustration, the typical tetratomic reaction H2 + OH with zero total angular momentum is calculated, and compared with other quantum wave packet methods. Our proposed IARD method for the tetratomic reactive system is much more efficient and accurate.

Regulated cell death and inflammasome activation in gut injury following traumatic surgery in vitro and in vivo: implication for postoperative death due to multiorgan dysfunction.

Postoperative multi-organ dysfunction (MOD) is associated with significant mortality and morbidity. Necroptosis has been implicated in different types of solid organ injury; however, the mechanisms linking necroptosis to inflammation require further elucidation. The present study examines the involvement of necroptosis and NLR family pyrin domain containing 3 (NLRP3) inflammasome in small intestine injury following traumatic surgery. Kidney transplantation in rats and renal ischaemia-reperfusion (I/R) in mice were used as traumatic and laparotomic surgery models to study necroptosis and inflammasome activation in the small intestinal post-surgery; additional groups also received receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin-1s (Nec-1s). To investigate whether necroptosis regulates inflammasome activity in vitro, necroptosis was induced in human colonic epithelial cancer cells (Caco-2) by a combination of tumour necrosis factor-alpha (TNFα), SMAC mimetic LCL-161 and pan-caspase inhibitor Q-VD-Oph (together, TLQ), and necroptosis was blocked by Nec-1s or mixed lineage kinase-domain like (MLKL) inhibitor necrosulfonamide (NSA). Renal transplantation and renal ischaemia-reperfusion (I/R) upregulated the expression of necroptosis mediators (RIPK1; RIPK3; phosphorylated-MLKL) and inflammasome components (P2X purinoceptor subfamily 7, P2X7R; NLRP3; caspase-1) in the small intestines at 24 h, and Nec-1s suppressed the expression of inflammasome components. TLQ treatment induced NLRP3 inflammasome, promoted cleavage of caspase-1 and interleukin-1 beta (IL-1ß), and stimulated extracellular ATP release from Caco-2 cells, and MLKL inhibitor NSA prevented TLQ-induced inflammasome activity and ATP release from Caco-2 cells. Our work suggested that necroptosis and inflammasome interactively promote remote postoperative small intestinal injury, at least in part, through ATP purinergic signalling. Necroptosis-inflammasome axis may be considered as novel therapeutic target for tackling postoperative MOD in the critical care settings.

Tackling regulated cell death yields enhanced protection in lung grafts.

Background: Effective preservation strategies to ameliorate lung graft ischaemia injury are needed to rescue 'extended criteria' or 'marginal' lung grafts, and to improve recipient outcomes after transplantation. Methods: Lung grafts from male Lewis rats were extracted after 40 min of cardiocirculatory death, and healthy human lung tissues were collected from patients undergoing a lobectomy. Lung samples were then preserved in a 4°C preservation solution supplemented with 0.1 nM Dexmedetomidine (Dex, α2-adrenoceptor agonist) for 16 h. In vitro, human lung epithelial A549 cells were preserved in the 4°C preservation solution with 0.1 nM Dex for 24 h, then re-cultured in the cell culture medium at 37°C to mimic the clinical scenario of cold ischaemia and warm reperfusion. Lung tissues and cells were then analysed with various techniques including western blot, immunostaining and electron microscope, to determine injuries and the protection of Dex. Results: Prolonged warm ischaemia after cardiocirculatory death initiated Rip kinase-mediated necroptosis, which was exacerbated by cold storage insult and enhanced lung graft injury. Dex supplementation significantly reduced necroptosis through upregulating Nrf2 activation and reducing oxidative stress, thereby significantly improving lung graft morphology. Dex treatment also attenuated endoplasmic reticulum stress, stabilised lysosomes and promoted cell membrane resealing function, consequently reducing cell death and inflammatory activation after hypothermic hypoxia-reoxygenation in A549 cells. Conclusions: Inhibition of regulated cell death through Dex supplementation to the graft preservation solution improves allograft quality which may aid to expand the donor lung pool and enhance lung transplant outcomes per se.

General anesthetic action profile on the human prefrontal cortex cells through comprehensive single-cell RNA-seq analysis.

The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2 h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.

Bv8 mediates myeloid cell migration and enhances malignancy of colorectal cancer.

Colorectal cancer (CRC) is the third most predominant malignancy in the world. Although the importance of immune system in cancer development has been well established, the underlying mechanisms remain to be investigated further. Here we studied a novel protein prokineticin 2 (Prok2, also known as Bv8) as a key pro-tumoral factor in CRC progression in in vitro and ex vivo settings. Human colorectal tumor tissues, myeloid cell lines (U937 cells and HL60 cells) and colorectal cancer cell line (Caco-2 cells) were used for various studies. Myeloid cell infiltration (especially neutrophils) and Bv8 accumulation were detected in human colorectal tumor tissue with immunostaining. The chemotactic effects of Bv8 on myeloid cells were presented in the transwell assay and chemotaxis assy. Cultured CRC cells treated with myeloid cells or Bv8 produced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF). Furthermore, ROS and VEGF acted as pro-angiogenesis buffer in myeloid cell-infiltrated CRC microenvironment. Moreover, myeloid cells or Bv8 enhanced energy consumption of glycolysis ATP and mitochondria ATP of CRC cells. Interestingly, myeloid cells increased CRC cell viability, but CRC cells decreased the viability of myeloid cells. ERK signalling pathway in CRC cells was activated in the presence of Bv8 or co-cultured myeloid cells. In conclusion, our data indicated the vital roles of Bv8 in myeloid cell infiltration and CRC development, suggesting that Bv8 may be a potential therapeutic target for colorectal cancer-related immunotherapy.

The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence.

Anaesthetics may modify colorectal cancer cell biology which potentially affects long-term survival. This study aims to compare propofol and sevoflurane regarding with the direct anaesthetic effects on cancer malignancy and the indirect effects on host immunity in a cancer xenograft mode of mice. Cultured colon cancer cell (Caco-2) was injected subcutaneously to nude mice (day 1). Mice were exposed to either 1.5% sevoflurane for 1.5 h or propofol (20 µg g-1; ip injection) with or without 4 µg g-1 lipopolysaccharide (LPS; ip) from days 15 to 17, compared with those without anaesthetic exposure as controls. The clinical endpoints including tumour volumes over 70 mm3 were closely monitored up to day 28. Tumour samples from the other cohorts were collected on day 18 for PCR array, qRT-PCR, western blotting and immunofluorescent assessment. Propofol treatment reduced tumour size (mean ± SD; 23.0 ± 6.2mm3) when compared to sevoflurane (36.0 ± 0.3mm3) (p = 0.008) or control (23.6 ± 4.7mm3). Propofol decreased hypoxia inducible factor 1α (HIF1α), interleukin 1ß (IL1ß), and hepatocyte growth factor (HGF) gene expressions and increased tissue inhibitor of metalloproteinases 2 (TIMP-2) gene and protein expression in comparison to sevoflurane in the tumour tissue. LPS suppressed tumour growth in any conditions whilst increased TIMP-2 and anti-cancer neutrophil marker expressions and decreased macrophage marker expressions compared to those in the LPS-untreated groups. Our data indicated that sevoflurane increased cancer development when compared with propofol in vivo under non-surgical condition. Anaesthetics tested in this study did not alter the effects of LPS as an immune modulator in changing immunocyte phenotype and suppressing cancer development.

Syringic Acid Suppressed Proliferation, Invasion, and Migration via Inhibition of Matrix Metalloproteinases Expression on Glioblastoma Cells by Promoting Apoptosis.

BACKGROUND: Human brain tumor glioblastoma (GBM) is the most hostile malignancy, currently lacking a successful cure and good prognosis. OBJECTIVE: To examine the anticancer effects of syringic acid (SA) on human cancer GBM cells. METHODOLOGY: The different doses of SA were added to GBM cells to study its effect on viability, invasion, relocation, apoptosis, and mRNA and protein levels. Hence, we explored the antiproliferative, anti-invasive, and apoptotic activity of SA on GBM human U-251 cells. RESULTS: MTT assay and live/dead assay revealed the anti-proliferative activity of SA on U-251 glioma cells. Apoptotic activity of SA was shown by DAPI staining, caspase-3, Bax, and Bcl-2 mRNA expressions. The cell cycle regulation was also confirmed by reducing the mRNA expression of cyclinD1, CDK4, and CDK6. Treatment of SA with U-251 cells suppressed MMPs expressions and enhanced TIMPs protein levels. CONCLUSION: Our findings put forward that SA could prevent GBM cells' invasion and relocation. SA is an ideal neuroprotective agent for controlling brain malignancy.

Strategies Australian junior doctors use to maintain their mental, physical and social well-being: a qualitative study.

OBJECTIVES: This study aimed to uncover the strategies that junior doctors implement to maintain their mental, physical and social well-being, and the barriers they experience in practising these strategies. PARTICIPANTS: Fifteen junior doctors in their postgraduate year 1 or 2 currently practising in Australia were recruited. OUTCOME MEASURES: Semistructured interviews were conducted, and the transcripts underwent thematic analysis. RESULTS: Three key themes emerged from thematic analysis, namely: well-being strategies, barriers to well-being and and future interventions. Exercise, a healthy and balanced diet, quality sleep, and workplace organisations were frequently reported well-being strategies. High workload, unpredictable routines, lack of familiarity with the healthcare system and ongoing stigma surrounding mental health were seen as barriers to well-being. Suggested interventions included increased control over rosters, subsidised access to facilities such as gyms and increased internship preparedness programmes organised by the medical schools. CONCLUSIONS: The findings from this study may assist in developing more personalised and targeted methods to help junior doctors maintain their mental, physical and social well-being. Future studies may address the structural and systemic changes required to develop a workforce that fosters the well-being of junior doctors and reduces the institutional barriers to practising well-being strategies.

Noble gas and neuroprotection: From bench to bedside.

In recent years, inert gases such as helium, argon, and xenon have gained considerable attention for their medical value. Noble gases present an intriguing scientific paradox: although extremely chemically inert, they display a remarkable spectrum of clinically useful biological properties. Despite a relative paucity of knowledge about their mechanisms of action, some noble gases have been used successfully in clinical practice. The neuroprotection elicited by these noble gases has been investigated in experimental animal models of various types of brain injuries, such as traumatic brain injury, stroke, subarachnoid hemorrhage, cerebral ischemic/reperfusion injury, and neurodegenerative diseases. Collectively, these central nervous system injuries are a leading cause of morbidity and mortality every year worldwide. Treatment options are presently limited to thrombolytic drugs and clot removal for ischemic stroke, or therapeutic cooling for other brain injuries before the application of noble gas. Currently, there is increasing interest in noble gases as novel treatments for various brain injuries. In recent years, neuroprotection elicited by particular noble gases, xenon, for example, has been reported under different conditions. In this article, we have reviewed the latest in vitro and in vivo experimental and clinical studies of the actions of xenon, argon, and helium, and discuss their potential use as neuroprotective agents.

Xenon attenuated neonatal lipopolysaccharide exposure induced neuronal necroptosis and subsequently improved cognition in juvenile rats.

Background: Neonatal sepsis is known to cause neurodevelopment impairment and has been reported to increase risks for neurological/psychiatric disorders. In this study, we investigated the effect of xenon, a well-known potent neuroprotective gas, on neonatal sepsis-induced neurodevelopment impairment in rats together with underlying mechanism by focusing on receptor-interacting protein kinase (RIP) mediated neuronal necroptosis. Methods: 3-day-old Sprague-Dawley rat pups were exposed to either 70% xenon or N2 balanced with O2 for 6 h, during which lipopolysaccharide (LPS) was injected intraperitoneally for 3 times (500 µg/kg for the 1st and 250 µg/kg for the second and third dose; n = 6-10/group). In another cohort of 3-day-old rat pups, intracerebroventricular injection of necrostatin-1 (4 µg in 4 µl saline, a RIP-1-targeted inhibitor of necroptosis) was performed 20 min after the third dose of LPS. The learning ability and memory were assessed 25 days after LPS injection. Then, their hippocampus was collected for neuronal necroptosis with RIP and MIKL assessments using western blot and in situ immunostaining. Systemic and neuro-inflammation was also assessed. Results: LPS insult resulted in elevation of pro-inflammatory cytokine TNF-𝝰 and IL-6, caused neuronal necroptosis and damaged synaptic integrity at the brain developing stage, which finally led to the long-term cognitive impairment. Xenon inhibited necroptosis associated mediator RIP-1, RIP-3, and MLKL activation, protected neurons and attenuated cognitive dysfunction induced by LPS. Like xenon, the similar pattern changes induced by a RIP-1 inhibitor Necrostatin-1 were also found. Conclusion: This study indicates that necroptosis is involved in neonatal sepsis-induced neurofunctional impairments and xenon may be a novel therapeutic strategy to prevent/treat cognitive impairment in neonatal septic patients.

Circular RNAs in organ injury: recent development.

Circular ribonucleic acids (circRNAs) are a class of long non-coding RNA that were once regarded as non-functional transcription byproducts. However, recent studies suggested that circRNAs may exhibit important regulatory roles in many critical biological pathways and disease pathologies. These studies have identified significantly differential expression profiles of circRNAs upon changes in physiological and pathological conditions of eukaryotic cells. Importantly, a substantial number of studies have suggested that circRNAs may play critical roles in organ injuries. This review aims to provide a summary of recent studies on circRNAs in organ injuries with respect to (1) changes in circRNAs expression patterns, (2) main mechanism axi(e)s, (3) therapeutic implications and (4) future study prospective. With the increasing attention to this research area and the advancement in high-throughput nucleic acid sequencing techniques, our knowledge of circRNAs may bring fruitful outcomes from basic and clinical research.

Long Chain Non Coding RNA Targeting miR Signal Axis Regulates the Mechanism of Apoptosis and Invasion and Migration of Glioma U251 Cells.

The occurrence of glioma is gradually promoted by various factors, and it has gone through multiple stages of development, involving abnormal expression of multiple genes. One of the important reasons for the development of gliomas is the interaction of genetic factors and the environment. Non-coding transcripts can also form this high-level structure, and the formation of binding sites for interactions between lncRNA and proteins, DNA, and other RNA molecules may be related to their structural diversity. Due to the importance of glioma-related research and the potential effectiveness of lncRNA, this paper focuses on the mechanism of long-chain non-coding RNA targeting the Mir signal axis to regulate apoptosis, invasion and migration of glioma U251 cells. In this paper, human glioma cell line U251 was used as experimental material for simulation analysis. The results showed that after miR simulation, the pass rate of U251 stem cells through the filter was 17.3%, which was significantly less than 85.4% of group C; compared with 77.6% of the negative control group, the cell penetration rate of the miR inhibitor group was significantly improved. 92.5%. The miR expression level can affect the invasion ability of U251 stem cells, and can negatively regulate the expression of fzd4 to inhibit the invasion and metastasis of glioma U251 cells.

Dexmedetomidine Activates Akt, STAT6 and IRF4 Modulating Cytoprotection and Macrophage Anti-Inflammatory Phenotype Against Acute Lung Injury in vivo and in vitro.

Purpose: This study aims to investigate the cytoprotective and anti-inflammatory effects of an α2-adrenoreceptor (α2-AR) agonist, dexmedetomidine (Dex), on lipopolysaccharides (LPS)-induced acute lung injury and underlying mechanisms with focus on alveolar macrophage polarization modulation. Methods: C57BL/6 mice were intraperitoneally injected LPS (10 mg/kg) with or without Dex (25 µg/kg) and/or α2-AR antagonist atipamezole (Atip, 500 µg/kg). Lung tissues were then analysed to determine injuries. In vitro, human pulmonary epithelial cells (A549) and mice alveolar macrophages (MH-S) were exposed to LPS (10 ng/mL) with or without different concentrations of Dex (0.1-100 nM). Alveolar macrophage polarization, NLRP3 inflammasome activation and inflammatory responses were determined. PTEN/Akt signaling and its downstream transcriptional factors as targets for macrophage polarization were assessed. Results: Dex treatment significantly reduced pro-inflammatory M1 macrophage polarization and NLRP3 inflammasome activation in the lungs relative to the mice treated with LPS. The similar pattern reduction of NLRP3 inflammasome activation by Dex was also found in A549 cells. Atip partly reversed the anti-inflammatory effects of Dex. In cultured alveolar macrophages, Dex reduced LPS-mediated expression of IL-1, -6 and TNF-α receptors while promoting alveolar macrophages differentiation towards a M2 anti-inflammatory phenotype. Additionally, LPS increased Akt signaling activation in a time-dependent manner, which was further activated by Dex via inhibiting phosphatase and tensin homolog (PTEN). The action of Dex on Akt signaling shifted alveolar macrophages from M1 to M2 phenotype through increasing STAT6 and IRF4 transcriptional factors. Conclusion: Dex protected against LPS-induced lung injury and suppressed LPS-induced pulmonary inflammatory responses by attenuating the NLRP3 inflammasome activation and promoting anti-inflammatory M2 macrophage polarization.

Epithelial-mesenchymal transition in organ fibrosis development: current understanding and treatment strategies.

Organ fibrosis is a process in which cellular homeostasis is disrupted and extracellular matrix is excessively deposited. Fibrosis can lead to vital organ failure and there are no effective treatments yet. Although epithelial-mesenchymal transition (EMT) may be one of the key cellular mechanisms, the underlying mechanisms of fibrosis remain largely unknown. EMT is a cell phenotypic process in which epithelial cells lose their cell-to-cell adhesion and polarization, after which they acquire mesenchymal features such as infiltration and migration ability. Upon injurious stimulation in different organs, EMT can be triggered by multiple signaling pathways and is also regulated by epigenetic mechanisms. This narrative review summarizes the current understanding of the underlying mechanisms of EMT in fibrogenesis and discusses potential strategies for attenuating EMT to prevent and/or inhibit fibrosis. Despite better understanding the role of EMT in fibrosis development, targeting EMT and beyond in developing therapeutics to tackle fibrosis is challenging but likely feasible.

Methionine Restriction Prevents Lipopolysaccharide-Induced Acute Lung Injury via Modulating CSE/H2S Pathway.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result in high mortality, whereas effective treatments are limited. Methionine restriction (MR) has been reported to offer various benefits against multiple pathological processes of organ injuries. However, it remains unknown whether MR has any potential therapeutic value for ALI/ARDS. The current study was set to investigate the therapeutic potential of MR on lipopolysaccharide (LPS)-induced ALI and its underlying mechanisms. We found that MR attenuated LPS-induced pulmonary edema, hemorrhage, atelectasis, and alveolar epithelial cell injuries in mice. MR upregulated cystathionine-gamma-lyase (CSE) expression and enhanced the production of hydrogen sulfide (H2S). MR also inhibited the activation of Toll-like receptors 4 (TLR4)/NF-κB/NOD-like receptor protein 3 (NLRP3), then reduced IL-1ß, IL-6, and TNF-α release and immune cell infiltration. Moreover, the protective effects of MR on LPS-induced ALI were abrogated by inhibiting CSE, whereas exogenous H2S treatment alone mimicked the protective effects of MR in Cse-/- mice after LPS administration. In conclusion, our findings showed that MR attenuated LPS-induced lung injury through CSE and H2S modulation. This work suggests that developing MR towards clinical use for ALI/ARDS patients may be a valuable strategy.

Triiodothyronine attenuates neurocognitive dysfunction induced by sevoflurane in the developing brain of neonatal rats.

BACKGROUND: Whilst concerns have been raised about the detrimental effects of general anaesthetics on the brain's development and function in the young, reports have indicated that thyroid hormones are able to promote neurogenesis in the developing brain. This present study aimed to investigate the effects of triiodothyronine (T3) on the neonatal rat brain, following sevoflurane exposure. METHODS: Postnatal day 7 (P7) ratpups were treated with Triiodothyronine (T3) (1 µg/100 g body weight, i.p. injection, once/day for 3 days) after 2% sevoflurane exposure for 6 h. They were sacrificed at either P7 (immediately), P15 or P30 and their brains were harvested to assess cell death, proliferation in the hippocampus, N-methyl-D-aspartate (NMDA) receptor subunit A and B, and a post-synaptic protein (PSD-95 in the hippocampus,). Neuro-behavioral changes in other cohorts between P27 and P30 were evaluated with Morris water maze and open field tests. RESULTS: Sevoflurane exposure caused cell death and suppressed the proliferation of astrocytes and neurons, as well as the dendritic growth of neurons in the hippocampus which were all reversed by the administration of T3. Moreover, cognitive function, including learning, memory, and adaptability to a new environment, were impaired by sevoflurane exposure, which was also negated by T3 treatment. Furthermore, sevoflurane decreased the expression of NMDA receptor subunits NR2A and NR2B, as well as PSD-95 in the hippocampus at P15 and those effects of sevoflurane were abolished by T3 administration. CONCLUSIONS: A potential therapeutic role of T3 in protecting general anesthetic induced neuronal injury in the developing brain is likely to occur through enhancing expression of PSD-95 and the NMDA NR2A and NR2B expression.