Circularly polarised luminescence from intramolecular excimer emission of bis-1,8-naphthalimide derivatives.

Chiral excimers exhibit unique photophysical behaviour. However, further molecular design is required along with systematic studies on the effect of spacer groups and solvent polarity. In this study, we prepared four circularly polarised luminescence (CPL)-active molecules that exhibit intramolecular excimer emission. Bis-1,8-naphthalimide (bNI) derivatives D-LybNI, L-LybNI, D-LyMebNI, and L-LyMebNI were prepared with chiral backbones and alkyl linkages between the NI rings with chain lengths of five carbon atoms, suitable for excimer fluorescence. The fluorescence properties were investigated experimentally and theoretically using density functional theory. The molecules exhibited intramolecular excimer fluorescence in polar organic solvents. Mirror-image circular dichroism and CPL spectra were obtained for the D and L forms. D- and L-LyMebNI exhibited relatively large luminescence dissymmetry factors (|glum|) in acetonitrile of 1.9 × 10-3 and 1.6 × 10-3, respectively. Thus, this study demonstrates chiral bNI derivatives with simple synthesis procedures that emit intramolecular excimer fluorescence and have effective CPL properties. These molecules are promising for developing organic molecular systems with bright, highly polarised emission.

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.

Case report: HLA-haploidentical hematopoietic cell transplant with posttransplant cyclophosphamide in a patient with leukocyte adhesion deficiency type I.

Leukocyte adhesion deficiency type I (LAD-I) is a rare autosomal recessive inborn error of immunity (IEI) caused by the defects in CD18, encoded by the ITGB2 gene. LAD-I is characterized by defective leukocyte adhesion to the vascular endothelium and impaired migration of leukocytes. Allogeneic hematopoietic cell transplant (HCT) is the only curative treatment for LAD-I. In an absence of ideal donor for HCT, human leukocyte antigen (HLA)-haploidentical HCT is performed. Posttransplant cyclophosphamide (PT-CY) is a relatively new graft-versus-host disease (GVHD) prophylactic measure and has been increasingly used in HLA-haploidentical HCT for malignant and nonmalignant diseases. However, experience in using PT-CY for rare IEIs, such as LAD-I, is very limited. We report a case of LAD-I successfully treated with HLA-haploidentical HCT with PT-CY. Complete chimerism was achieved, and the patient was cured. Her transplant course was complicated by mild GVHD, cytomegalovirus reactivation and veno-occlusive disease/sinusoidal obstruction syndrome, which were successfully treated. HLA-haploidentical HCT with PT-CY is a safe and effective option for patients with LAD-I when HLA-matched donors are unavailable.

The Role of Neutrophil NETosis in Organ Injury: Novel Inflammatory Cell Death Mechanisms.

NETosis is a type of regulated cell death dependent on the formation of neutrophil extracellular traps (NET), where net-like structures of decondensed chromatin and proteases are produced by polymorphonuclear (PMN) granulocytes. These structures immobilise pathogens and restrict them with antimicrobial molecules, thus preventing their spread. Whilst NETs possess a fundamental anti-microbial function within the innate immune system under physiological circumstances, increasing evidence also indicates that NETosis occurs in the pathogenic process of other disease type, including but not limited to atherosclerosis, airway inflammation, Alzheimer's and stroke. Here, we reviewed the role of NETosis in the development of organ injury, including injury to the brain, lung, heart, kidney, musculoskeletal system, gut and reproductive system, whilst therapeutic agents in blocking injuries induced by NETosis in its primitive stages were also discussed. This review provides novel insights into the involvement of NETosis in different organ injuries, and whilst potential therapeutic measures targeting NETosis remain a largely unexplored area, these warrant further investigation.

Postoperative remote lung injury and its impact on surgical outcome.

Postoperative remote lung injury is a complication following various surgeries and is associated with short and long-term mortality and morbidity. The release of proinflammatory cytokines, damage-associated molecular patterns such as high-mobility group box-1, nucleotide-biding oligomerization domain (NOD)-like receptor protein 3 and heat shock protein, and cell death signalling activation, trigger a systemic inflammatory response, which ultimately results in organ injury including lung injury. Except high financial burden, the outcome of patients developing postoperative remote lung injury is often not optimistic. Several risk factors had been classified to predict the occurrence of postoperative remote lung injury, while lung protective ventilation and other strategies may confer protective effect against it. Understanding the pathophysiology of this process will facilitate the design of novel therapeutic strategies and promote better outcomes of surgical patients. This review discusses the cause and pathology underlying postoperative remote lung injury. Risk factors, surgical outcomes and potential preventative/treatment strategies against postoperative remote lung injury are also addressed.

The role of osteopontin in the progression of solid organ tumour.

Osteopontin (OPN) is a bone sialoprotein involved in osteoclast attachment to mineralised bone matrix, as well as being a bone matrix protein, OPN is also a versatile protein that acts on various receptors which are associated with different signalling pathways implicated in cancer. OPN mediates various biological events involving the immune system and the vascular system; the protein plays a role in processes such as immune response, cell adhesion and migration, and tumorigenesis. This review discusses the potential role of OPN in tumour cell proliferation, angiogenesis and metastasis, as well as the molecular mechanisms involved in these processes in different cancers, including brain, lung, kidney, liver, bladder, breast, oesophageal, gastric, colon, pancreatic, prostate and ovarian cancers. The understanding of OPN's role in tumour development and progression could potentially influence cancer therapy and contribute to the development of novel anti-tumour treatments.

Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments.

Neuronal cell injury, as a consequence of acute or chronic neurological trauma, is a significant cause of mortality around the world. On a molecular level, the condition is characterized by widespread cell death and poor regeneration, which can result in severe morbidity in survivors. Potential therapeutics are of major interest, with a promising candidate being brain-derived neurotrophic factor (BDNF), a ubiquitous agent in the brain which has been associated with neural development and may facilitate protective and regenerative effects following injury. This review summarizes the available information on the potential benefits of BDNF and the molecular mechanisms involved in several pathological conditions, including hypoxic brain injury, stroke, Alzheimer's disease and Parkinson's disease. It further explores the methods in which BDNF can be applied in clinical and therapeutic settings, and the potential challenges to overcome.

The role of nuclear factor-erythroid 2 related factor 2 (Nrf-2) in the protection against lung injury.

Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a ubiquitous master transcription factor that upregulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. Activation of Nrf2 has been shown to be protective against lung injury. In the lung, diverse stimuli including environmental oxidants, medicinal agents, and pathogens can activate Nrf2. Nrf2 translocates to the nucleus and binds to an ARE. Through transcriptional induction of ARE-bearing genes encoding antioxidant-detoxifying proteins, Nrf2 induces cellular rescue pathways against oxidative pulmonary injury, abnormal inflammatory and immune responses, and apoptosis. The Nrf2-antioxidant pathway has been shown to be important in the protection against various lung injuries including acute lung injury/acute respiratory distress syndrome and bronchopulmonary dysplasia, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, and allergy and was widely examined for new therapeutic targets. The present review explores the protective role of Nrf-2 against lung injury and the therapeutic potential in targeting Nrf-2.

The Role of Extracellular Adenosine Triphosphate in Ischemic Organ Injury.

OBJECTIVES: Ischemic tissue injury contributes to significant morbidity and mortality and is implicated in a range of pathologic conditions, including but not limited to myocardial infarction, ischemic stroke, and acute kidney injury. The associated reperfusion phase is responsible for the activation of the innate and adaptive immune system, further accentuating inflammation. Adenosine triphosphate molecule has been implicated in various ischemic conditions, including stroke and myocardial infarction. STUDY SELECTION: Adenosine triphosphate is a well-defined intracellular energy transfer and is commonly referred to as the body's "energy currency." However, Laboratory studies have demonstrated that extracellular adenosine triphosphate has the ability to initiate inflammation and is therefore referred to as a damage-associated molecular pattern. Purinergic receptors-dependent signaling, proinflammatory cytokine release, increased Ca influx into cells, and subsequent apoptosis have been shown to form a common underlying extracellular adenosine triphosphate molecular mechanism in ischemic organ injury. CONCLUSIONS: In this review, we aim to discuss the molecular mechanisms behind adenosine triphosphate-mediated ischemic tissue injury and evaluate the role of extracellular adenosine triphosphate in ischemic injury in specific organs, in order to provide a greater understanding of the pathophysiology of this complex process. We also appraise potential future therapeutic strategies to limit damage in various organs, including the heart, brain, kidneys, and lungs.