Azeem Alam

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.

Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon.

Growing and consistent preclinical evidence, combined with early clinical epidemiological observations, suggest potentially neurotoxic effects of commonly used anesthetic agents in the developing brain. This has prompted the FDA to issue a safety warning for all sedatives and anesthetics approved for use in children under three years of age. Recent studies have identified dexmedetomidine, the potent α2-adrenoceptor agonist, and xenon, the noble gas, as effective anesthetic adjuvants that are both less neurotoxic to the developing brain, and also possess neuroprotective properties in neonatal and other settings of acute ongoing neurologic injury. Dexmedetomidine and xenon are effective anesthetic adjuvants that appear to be less neurotoxic than other existing agents and have the potential to be neuroprotective in the neonatal and pediatric settings. Although results from recent clinical trials and case reports have indicated the neuroprotective potential of xenon and dexmedetomidine, additional randomized clinical trials corroborating these studies are necessary. By reviewing both the existing preclinical and clinical evidence on the neuroprotective effects of dexmedetomidine and xenon, we hope to provide insight into the potential clinical efficacy of these agents in the management of pediatric surgical patients.

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, Alzheimers disease and Parkinsons 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 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 Ca2+ 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.

Acute-on-chronic liver failure: recent update

Acute on chronic liver failure (ACLF) was first described in 1995 as a clinical syndrome distinct to classic acute decompensation. Characterized by complications of decompensation, ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between 45% and 90%. Despite the clinical relevance of the condition, it still remains largely undefined with continued disagreement regarding its precise etiological factors, clinical course, prognostic criteria and management pathways. It is concerning that, despite our relative lack of understanding of the condition, the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%. This paper highlights our current understanding of ACLF, including its etiology, diagnostic and prognostic criteria and pathophysiology. It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates. The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters, while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.Acute on chronic liver failure (ACLF) was first described in 1995 as a clinical syndrome distinct to classic acute decompensation. Characterized by complications of decompensation, ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between 45% and 90%. Despite the clinical relevance of the condition, it still remains largely undefined with continued disagreement regarding its precise etiological factors, clinical course, prognostic criteria and management pathways. It is concerning that, despite our relative lack of understanding of the condition, the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%. This paper highlights our current understanding of ACLF, including its etiology, diagnostic and prognostic criteria and pathophysiology. It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates. The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters, while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.

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.

Surgery, neuroinflammation and cognitive impairment

Trauma experienced during surgery can contribute to the development of a systemic inflammatory response that can cause multi-organ dysfunction or even failure. Post-surgical neuroinflammation is a documented phenomenon that results in synaptic impairment, neuronal dysfunction and death, and impaired neurogenesis. Various pro-inflammatory cytokines, such as TNFα, maintain a state of chronic neuroinflammation, manifesting as post-operative cognitive dysfunction and post-operative delirium. Furthermore, elderly patients with post-operative cognitive dysfunction or delirium are three times more likely to experience permanent cognitive impairment or dementia. We conducted a narrative review, considering evidence extracted from various databases including Pubmed, MEDLINE and EMBASE, as well as journals and book reference lists. We found that further pre-clinical and well-powered clinical studies are required to delineate the precise pathogenesis of post-operative delirium and cognitive dysfunction. Despite the burden of post-operative neurological sequelae, clinical studies investigating therapeutic agents, such as dexmedetomidine, ibuprofen and statins, have yielded conflicting results. In addition, evidence supporting novel therapeutic avenues, such as nicotinic and HMGB-1 targeting and remote ischaemic pre-conditioning, is limited and necessitates further investigation.

Ischemia-Reperfusion Injury Reduces Long Term Renal Graft Survival: Mechanism and Beyond

Ischemia-reperfusion injury (IRI) during renal transplantation often initiates non-specific inflammatory responses that can result in the loss of kidney graft viability. However, the long-term consequence of IRI on renal grafts survival is uncertain. Here we review clinical evidence and laboratory studies, and elucidate the association between early IRI and later graft loss. Our critical analysis of previous publications indicates that early IRI does contribute to later graft loss through reduction of renal functional mass, graft vascular injury, and chronic hypoxia, as well as subsequent fibrosis. IRI is also known to induce kidney allograft dysfunction and acute rejection, reducing graft survival. Therefore, attempts have been made to substitute traditional preserving solutions with novel agents, yielding promising results.

VEGF mitigates histone-induced pyroptosis in the remote liver injury associated with renal allograft ischemia-reperfusion injury in rats

Clinical evidence has indicated a possible link between renal injury and remote liver injury. We investigated whether extracellular histone mediates remote hepatic damage after renal graft ischemia–reperfusion injury, while vascular endothelial growth factor (VEGF) is protective against remote hepatic injury. In vitro, hepatocyte HepG2 cultures were treated with histone. In vivo, the Brown‐Norway renal graft was stored in 4°C preservation solution for 24 hours and then transplanted into a Lewis rat recipient; blood samples and livers from recipients were harvested 24 hours after surgery. Prolonged cold ischemia in renal grafts enhanced liver injury 24 hours after engraftment. Caspase‐1, ASC, NLRP3, and AIM2 expressions in hepatocyte, CD68+‐infiltrating macrophages, tissue, and serum interleukin‐1β and ‐18 were greatly elevated, indicating that pyroptosis occurred in the liver and resulted in acute liver functional impairment. Blocking the caspase‐1 pathway decreased the number of necrotic hepatocytes. VEGF treatment suppressed the hepatocyte pyroptosis and liver function was partially restored. Our data suggested that renal allograft ischemia–reperfusion injury is likely associated with acute liver damage due to hepatocyte pyroptosis induced by histone and such injury may be protected by VEGF administration. VEGF, therefore, may serve as a new strategy against other remote organ injuries related to renal transplantation.