The roles of calcium and ATP in the physiology and pathology of the exocrine pancreas

Physiological Reviews, Journal Year: 2021, Volume and Issue: 101(4), P. 1691 - 1744

Published: May 5, 2021

This review deals with the roles of calcium ions and ATP in control normal functions different cell types exocrine pancreas as well these molecules pathophysiology acute pancreatitis. Repetitive rises local cytosolic ion concentration apical part acinar cells not only activate exocytosis but also, via an increase intramitochondrial concentration, stimulate formation that is needed to fuel energy-requiring secretion process. However, intracellular overload, resulting a global sustained elevation has opposite effect decreasing mitochondrial production, this initiates processes lead necrosis. In last few years it become possible image signaling events simultaneously acinar, stellate, immune intact lobules pancreas. disclosed by which interact each other, particularly relation initiation development By unraveling molecular mechanisms underlying disease, several promising therapeutic intervention sites have been identified. provides hope we may soon be able effectively treat often fatal disease.

Language: Английский

---

Management of chronic pancreatitis

BMJ, Journal Year: 2024, Volume and Issue: unknown, P. e070920 - e070920

Published: Feb. 26, 2024

ABSTRACT Chronic pancreatitis results from repeated episodes of pancreatic inflammation and associated fibrosis leading to the loss functional exocrine endocrine function. The disease is manifested by abdominal pain, deterioration in quality life, food maldigestion malabsorption, diabetes, an increased risk for adenocarcinoma. This review summarizes latest evidence on diagnosis management chronic its manifestations. In particular, this discusses advances understanding role genetic disorders mechanisms surgical options patients refractory medical therapy. Furthermore, clinical trials are under way develop therapeutics.

Language: Английский

---

Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis

Gut, Journal Year: 2020, Volume and Issue: 70(1), P. 194 - 203

Published: Sept. 24, 2020

Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed cornerstone endeavours to decipher pathophysiology AP, because limitations such study human beings. While this provided us substantial understanding, we cannot answer several pressing questions. These are: (a) Why it that only a minority individuals gallstones, or who drink alcohol excessively, are exposed other causative factors develop AP? (b) do some more severe manifestations AP necrosis and/or organ failure? (c) have been unable find effective therapeutic for This manuscript provides state-of-the-art review our current understanding providing insights into unanswered clinical We describe multiple protective operating people, and stressors induce independently together, via amplification loops. present testable hypotheses aimed at halting progression severity development treatments unpredictable disease.

Language: Английский

---

Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial

Critical Care, Journal Year: 2020, Volume and Issue: 24(1)

Published: Aug. 14, 2020

Abstract Background Calcium release-activated calcium (CRAC) channel inhibitors stabilize the pulmonary endothelium and block proinflammatory cytokine release, potentially mitigating respiratory complications observed in patients with COVID-19. This study aimed to investigate safety efficacy of Auxora, a novel, intravenously administered CRAC inhibitor, adults severe or critical COVID-19 pneumonia. Methods A randomized, controlled, open-label Auxora was conducted Patients were randomized 2:1 receive three doses once-daily versus standard care (SOC) alone. The primary objective assess tolerability Auxora. Following FDA guidance, enrollment halted early allow for transition blinded, placebo-controlled study. Results In total, 17 pneumonia nine one SOC. Similar proportions receiving SOC experienced ≥ 1 adverse event (75% 80%, respectively). Fewer serious events (30% 50%, Two (10%) two (20%) died during 30 days after randomization. Among pneumonia, median time recovery 5 12 SOC; rate ratio 1.87 (95% CI, 0.72, 4.89). Invasive mechanical ventilation needed 18% 50% (absolute risk reduction = 32%; 95% − 0.07, 0.71). Outcomes measured by an 8-point ordinal scale significantly improved especially baseline PaO 2 /FiO 101–200. Conclusions demonstrated favorable profile outcomes These results, however, are limited design small patient population resulting from cessation response regulatory guidance. impact on will be further assessed planned Trial registration ClinicalTrials.gov, NCT04345614 . Submitted 7 April 2020. Graphical abstract

Language: Английский

---

Tackling SARS-CoV-2: Proposed Targets and Repurposed Drugs

Future Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 12(17), P. 1579 - 1601

Published: June 22, 2020

The SARS-CoV-2 pandemic, declared as a global health emergency by the WHO in February 2020, has currently infected more than 6 million people with fatalities near 371,000 and increasing exponentially, absence of vaccines drugs. pathogenesis is still being elucidated. Identifying potential targets repurposing drugs therapeutic options need hour. In this review, we focus on druggable suitable therapeutics, explored clinical trials, to treat infection. A brief understanding complex interactions both viral well host targets, possible repurposed drug candidates are described an emphasis mechanisms at molecular level.

Language: Английский

---

A Patent Review on the Current Developments of Benzoxazoles in Drug Discovery

ChemMedChem, Journal Year: 2021, Volume and Issue: 16(21), P. 3237 - 3262

Published: July 21, 2021

The benzoxazole moiety is widely found in various natural compounds, which are often to be biologically active. Due its versatile biological properties, has been incorporated as an essential pharmacophore and substructure many medicinal compounds. In the past years, numerous derivatives have synthesised evaluated for their potential. wide range therapeutic potential of related favourable interactions with different protein targets. Herein we review activities patented within six years. Using Lens database, granted patents issued from 2015 2020 were retrieved. demonstrated excellent activity against targets diseases, some reaching clinical trial stage. Pharmacological aspects discussed. recent development drawbacks also reviewed.

Language: Английский

---

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

Cells, Journal Year: 2022, Volume and Issue: 11(2), P. 253 - 253

Published: Jan. 12, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that causes disease 2019 (COVID-19). This illness was declared pandemic by the world health organization (WHO) in March 2020, just few weeks after being described for first time. Since then, global research effort has considerably increased humanity’s knowledge about both viruses and disease. It also spawned several vaccines have proven to be key tools attenuating spread of severity COVID-19. However, with vaccine-related skepticism on rise, as well breakthrough infections vaccinated population threat complete immune escape variant, alternative strategies fight against SARS-CoV-2 are urgently required. Calcium signals long been known play an essential role infection diverse thus constitute promising avenue further therapeutic strategies. In this review, we introduce pivotal calcium signaling viral cascades. Based this, discuss prospective calcium-related treatment targets cure COVID-19 exploit dependence signals.

Language: Английский

---

Regulation of neuropathic pain by microglial Orai1 channels

Science Advances, Journal Year: 2023, Volume and Issue: 9(4)

Published: Jan. 27, 2023

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity not well-understood. Here, we investigated role Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion in microglia attenuates Ca 2+ signaling production inflammatory cytokines by proalgesic agonists. Conditional attenuated proliferation dorsal horn, spinal cytokine levels, potentiation excitatory neurotransmission peripheral injury. These cellular effects were accompanied mitigation pain hyperalgesia knockout mice. A small-molecule inhibitor, CM4620, similarly mitigated allodynia male Unexpectedly, these protective seen female mice, revealing sexual dimorphism regulation hyperalgesia. Together, findings indicate key regulators sexually dimorphic

Language: Английский

---

Calcium signaling and regulation of neutrophil functions: Still a long way to go

Journal of Leukocyte Biology, Journal Year: 2019, Volume and Issue: 107(2), P. 285 - 297

Published: Dec. 16, 2019

Abstract Neutrophils are the most abundant leukocytes in blood and disruption their functions often results an increased risk of serious infections inflammatory autoimmune diseases. Following recent discoveries influence over disease progression, a resurgence interest for neutrophil biology has taken place. The multitude signaling pathways activated by engagement numerous types receptors, with which neutrophils endowed, reflects functional complexity these cells. It is therefore not surprising that there remains huge lack understanding molecular mechanisms underlining functions. Moreover, studies on undoubtedly limited difficulty to efficiently edit cell's genome. Over past 30 years, compelling evidence clearly highlighted Ca2+-signaling governing key processes associated confirmation role elevation intracellular Ca2+ concentration come from NADPH oxidase activation phagocytosis. In this review, we give overview update our current knowledge mobilization regulation pro-inflammatory neutrophils. particular, stress importance formation NETs cytokine secretion light newest findings. This will allow us embrace how much further have go understand complex dynamics Ca2+-dependent order gain more insights into pathogenesis potential therapeutics regulate functions, such as influx inhibitors prevent chronic diseases, been discussed last part review.

Language: Английский

---

Intracellular Ca2+ Signalling in the Pathogenesis of Acute Pancreatitis: Recent Advances and Translational Perspectives

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(11), P. 4005 - 4005

Published: June 3, 2020

Intracellular Ca2+ signalling is a major signal transductional pathway in non-excitable cells, responsible for the regulation of variety physiological functions. In secretory epithelial cells exocrine pancreas, such as acinar and ductal intracellular elevation regulates digestive enzyme secretion acini or fluid ion cells. Although uniquely versatile orchestrator physiology, unregulated global concentration an early trigger development acute pancreatitis (AP). Regardless aetiology, different forms AP all exhibit sustained common hallmark. The release endoplasmic reticulum (ER) stores by toxins (such bile acids fatty acid ethyl esters (FAEEs)) increased intrapancreatic pressure activates influx extracellular via Orai1 channel, process known store-operated entry (SOCE). overload can lead to premature activation trypsinogen pancreatic impaired HCO3- Increased unbalanced reactive oxygen species (ROS) production caused further contributes cell dysfunction, leading mitochondrial damage death. Translational studies identified several potential target molecules that be modified prevent overload. One most promising drugs, selective inhibitor channel has been shown inhibit protect from injury, currently being tested clinical trials. this review, we will summarise recent advances field, with special focus on translational aspects basic findings.

Language: Английский

---