Fibrosis is a common process of tissue repair response to multiple injuries in all chronic progressive diseases, which featured with excessive deposition of extracellular matrix. Actually fibrosis can occur in all organs and tends to be nonreversible with the progresses of the diseases. Different cells types in different organs are involved in the occurrence and development of fibrosis, i.e. hepatic stellate cell, pancreatic stellate cell, fibroblasts, myofibroblasts. Present studies have shown that several programmed cell deaths including apoptosis, autophagy, ferroptosis, and necroptosis were closely related to organ fibrosis. Among these programmed cell deathes type, necroptosis, an emerging regulated cell death type were regard as a huge potential target to ameliorate organ fibrosis. In this review, we summarized the role of necroptosis signaling in organ fibrosis, and collected the present small molecule compounds targeting necroptosis. In addition, we have discussed the potential challenges, opportunities and open questions in using necroptosis signaling as a potential target for antifibrotic therapies.
Background and Purpose: Astrocytic nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a potential therapeutic target of ischemic preconditioning (IPC). Icariside Ⅱ (ICS Ⅱ) is a naturally occurring flavonoid derived from Herba Epimedii with Nrf2 induction potency. This study was designed to clarify whether ICS Ⅱ simulates IPC neuroprotection and to decipher if the astrocytic-Nrf2 is contributed to ICS Ⅱ preconditioning against ischemic stroke. Experimental Approach: Mice with transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia and oxygen-glucose deprivation (OGD)-injured primary astrocytes were used to explore the neuroprotective of ICS Ⅱ preconditioning. Additionally, Nrf2-deficient mice were pretreated with ICS Ⅱ to determine whether ICS Ⅱ exerts its neuroprotection by activating Nrf2. Key results: ICS Ⅱ pre-treatment dramatically mitigated the cerebral injury in ischemic stroke mice along with restoring long-term recovery. Furthermore, proteomics screening identified Nrf2 is a crucial gene evoked by ICS Ⅱ stimulation and is required for the anti-oxidative effect and anti-inflammatory effect of ICS Ⅱ. Most interestingly, ICS Ⅱ directly bound with Nrf2 and reinforced the transcriptional activity of Nrf2 after MCAO. Moreover, ICS Ⅱ pre-treatment exerted cytoprotective effect on astrocytes after lethal oxygen-glucose deprivation insult via promoting Nrf2 nuclear translocation and mediating OXPHOS/NF-κB/ferroptosis axis. While, abrogated neuroprotection in Nrf2-deficient mice and astrocyte potently supports Nrf2-dependent neuroprotection of ICS Ⅱ. Conclusions and implications: ICS Ⅱ preconditioning confers robust neuroprotection against ischemic stroke via astrocytic Nrf2-mediated OXPHOS/NF-κB/ferroptosis axis, it is concluded that ICS Ⅱ will be serve as a promising Nrf2 activator to rescue ischemic stroke.
Background and Purpose: Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest since iron deposition has been detected in the injured brain in the weeks to months post-TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity; and whether this is a cause or consequence of the long-term effects of TBI remains unknown. Experimental approach: We investigated the role of iron, and the effect of therapeutic intervention using a brain-permeable iron chelator, deferiprone, in a controlled cortical impact mouse model of TBI. An extensive assessment of cognitive, motor and anxiety/depressive outcome measures were examined, and neuropathological and biochemical changes, over a 3-month period post-TBI. Key Results: Lesion volume was significantly reduced at 3 months, which was preceded by a reduction in astrogliosis and a preservation of neurons in the injured brain at 2 weeks and/or 1-month post-TBI in mice receiving oral deferiprone. Deferiprone treatment showed significant improvements in neurological severity scores and locomotor/gait performance, and cognitive function, and attenuated anxiety-like symptoms post-TBI. Deferiprone reduced iron levels, oxidative stress and altered expression of neurotrophins in the injured brain over this period. Conclusion and Implications: Our findings support a detrimental role of iron in the injured brain and suggest that deferiprone (or similar iron chelators) may be promising therapeutic approaches to improve survival, functional outcomes and quality of life following TBI.
Background and Purpose: Traumatic hemorrhage (TH) is the leading cause of potentially preventable deaths that occur during the prehospital phase of care. No effective pharmacological therapeutics are available for critical TH patients yet. Here, we identify terminal complement activation (TCA) as a therapeutic target in combat casualties and evaluate the efficacy of TCA inhibitor (nomacopan) on organ damage and survival in vivo. Experimental Approach: Complement activation products and cytokines were analyzed in plasma from 54 combat casualties, and the correlations between activated complement pathway(s) and the clinical outcomes in trauma patients were assessed. Nomacopan was administrated to rats subjected to lethal TH (blast injury and hemorrhagic shock). Effects of nomacopan on TH were determined using survival rate, organ damage, physiologic parameters, and laboratory profiles. Key Results: Early TCA was found to be associated with systemic inflammatory responses and clinical outcomes in this trauma cohort. Lethal TH in the untreated rats induced early TCA that correlated with severity of tissue damage and mortality. The addition of nomacopan to a damage control resuscitation (DCR) protocol significantly inhibited TCA, decreased local and systemic inflammatory responses, improved hemodynamics and metabolism, attenuated tissue and organ damage, and increased survival. Conclusion and Implications: Our findings reveal that early TCA represents a rational therapeutic target for trauma patients; and nomacopan as a prosurvival and organ-protective drug, could emerge as a promising adjunct to DCR that may significantly reduce the morbidity and mortality in severe TH patients while awaiting transport to critical care facilities.
Background and Purpose: Improvement of cognitive deficits in schizophrenia remains an unmet need due to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia. Experimental Approach: Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated by immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis. Key Results: Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signalling pathway. Conclusion and Implications: To the best of our knowledge, this is the first preclinical study to assess the effects of fingolimod on cognitive function in schizophrenia models. Our results support the role of the immune system in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.
Background and Purpose: Pharmacological intervention to induce white adipose tissue browning provides a promising anti-obese therapy. The fruits of Garcinia cambogia (Clusiaceae) have been widely applied to manage body weight. The current study aims to uncover the chemical principles responsible for the anti-obese property of the fruits of G. cambogia and investigate the underlying mechanisms. Experimental Approach: The bioactivity-based molecular networking and Oil-red O staining on 3T3-L1 and C3H10T1/2 adipocytes were applied for guided isolation. High-fat diet-induced obese mice were recruited to evaluate the anti-obese activity. Key Results: Guided by the bioactivity-based molecular networking, several polycyclic polyprenylated acylphloroglucinols were targetedly isolated from the fruits of G. cambogia with lipid lowering effect on adipocytes, including guttiferone J (GOJ), garcinol and 14-deoxygarcinol. As the most potent one, GOJ (10 µM) reduced lipid accumulation by 70% and 76% in 3T3-L1 and C3H10T1/2 adipocytes, respectively. Furthermore, GOJ (2.5‒10 µM) activated the deacetylase Sirtuin 3 (SIRT3), which, in turn, reduced the acetylation level of PPARγ coactivator-1α to boost mitochondrial biogenesis, and promoted uncoupling protein 1 expression and function to enhance thermogenesis, resulting in browning of adipocytes. In high-fat diet-induced-obese mice, GOJ (10 and 20 mg∙Kg-1) protected against adiposity, hyperlipidemia, insulin resistance and liver lipotoxicity, through boosting SIRT3-mediated browning of inguinal white adipose tissue. Conclusions and Implications: The bioactivity-based molecular networking is a promising strategy for guided isolation of bioactive molecules, and GOJ represents a new scaffold of thermogenic inducer, which might be responsible for the anti-obese property of G. cambogia.
Sodium glucose co-transporter 2 inhibitors (SGLT-2i’s) significantly improve cardiovascular outcome in both diabetic and non-diabetic patients. Preclinical studies suggest that SGLT-2i’s directly affect endothelial function in a glucose-independent manner. The effects of SGLT-2i’s include reduction of oxidative stress and inflammatory reaction in endothelial cells. Furthermore, SGLT2i’s have been shown to restore endothelial-related vasodilation and to regulate angiogenesis. The favorable cardiovascular effects of SGLT-2i’s might be mediated via multiple pathways: 1) by inhibition of the overactive sodium-hydrogen exchanger; 2) by reduction of nicotinamide adenine dinucleotide phosphate oxidases expression; 3) by alleviation of mitochondrial injury; 4) by the suppression of inflammatory-related signaling pathways (e.g. by affecting nuclear factor kappa beta); 5) by modulation of glycolysis, as well as 6) by restoring impaired nitric oxide bioavailability. This review focuses on the most recent progress and existing gaps in preclinical investigations concerning the direct effects of SGLT-2i’s on endothelial dysfunction and their underlying mechanisms.
Background and Purpose Squalene epoxidase (SQLE) is a key enzyme involved in cholesterol biosynthesis, but increasing evidence reveals that SQLE is abnormally expressed in some types of malignant tumors, and the underlying mechanism remains poorly understood. Experimental Approach Bioinformatics analysis and RNA sequencing were applied to detect to differentially expressed genes in clinical HCC tumors. AnnexinV-FITC/PI, EdU assay, transwell, IHC staining, cytoskeleton F-actin filaments assay, RNA sequencing, dual-luciferase reporters and HE staining were evaluated to investigate the pharmacological effects and possible mechanisms of SQLE. Key Results We found that SQLE expression is specifically elevated in HCC tumors, correlating with poor clinical outcomes. SQLE promoted HCC growth, EMT, and metastasis both in vitro and in vivo. In contrast, silencing of SQLE expression prevented HCC development. Both RNA-seq and functional experiments revealed that the protumorigenic effect of SQLE on HCC is closely related to the activation of cellular TGF-β/SMAD signaling, but interestingly, the stimulatory effect of SQLE on TGF-β/SMAD signaling and HCC development is also critically dependent on STRAP, a serine and threonine kinase. SQLE expression is well correlated with STRAP in HCC, and further, to amplify TGF-β/SMAD signaling, SQLE even transcriptionally increased STRAP gene expression mediated by the trans-acting factor AP-2α. Finally, as a chemical inhibitor of SQLE, NB-598 markedly inhibited HCC cell growth and tumor development in mouse models. Conclusions and Implications Taken together, SQLE serves as an oncogene in HCC development by activating TGF-β/SMAD signaling, and targeting SQLE could be useful in drug development and therapy for HCC.
Targeting cancer metabolism has emerged as an attractive approach to improve therapeutic regimens in acute myeloid leukemia (AML). Mitochondrial proteases are closely related to cancer metabolism, but their biological functions have not been well characterized in AML. According to different catogory, we comprehensively reviewed the role of mitochondrial proteases in AML. This review highlights some ‘powerful’ mitochondrial protease targets, including their biological function, chemical modulators, and applicative prospect in AML.
Chronic liver diseases comprises a broad spectrum of burdensome diseases that still lack effective pharmacological therapies. Our research group focuses on Fibrosis which is a major precursor of liver cirrhosis. Fibrosis consists in a progressive disturbance of liver sinusoidal architecture characterised by connective tissue deposition as a reparative response to tissue injury. Multifactorial events and several types of cells, participate in fibrosis initiation and progression and the process still needs to be completely understood. The development of experimental models of liver fibrosis alongside the identification of critical factors progressing fibrosis to cirrhosis will facilitate the development of more effective therapeutic approaches for such condition. This review provides an overlook of the main process leading to hepatic fibrosis and therapeutic approaches that have emerged from a deep knowledge of the molecular regulation of fibrogenesis in the liver.
Background and Purpose T-type calcium channels, mainly the Cav3.2 subtype, are important contributors to the nociceptive signaling pathway. We investigated their involvement in inflammation and related pain-like symptoms. Experimental Approach The involvement of Cav3.2 and T-type channels was investigated using genetic and pharmacological inhibition to assess mechanical allodynia/hyperalgesia and edema development in two murine inflammatory pain models. The location of Cav3.2 involved in pain-like symptoms was studied in mice with Cav3.2 knocked out in C-low threshold mechanoreceptors (C-LTMR) and the use of ABT-639, a peripherally restricted T-type channel inhibitor. The anti-edematous effect of Cav3.2 inhibition was investigated in chimeric mice with immune cells deleted for Cav3.2. Lymphocytes and macrophages from either green fluorescent protein-targeted Cav3.2 or KO mice were used to determine the expression of Cav3.2 protein and the functional status of the cells. Key Results We showed the role of Cav3.2 channels in the development of pain-like symptoms and edema in the two murine inflammatory pain models. For the first time, we provide evidence of the involvement of Cav3.2 channels located on C-LTMRs in inflammatory pain at both peripheral and primary afferent terminals at the spinal level. We showed that Cav3.2 channels located in T cells and macrophages contribute to the inflammatory process. Conclusion and Implications This work highlights the crucial role of Cav3.2 channels in inflammation and related pain and suggests that targeting Cav3.2 channels with pharmacological agents could be an attractive and readily evaluable strategy in a clinical trial to relieve chronic inflammatory pain in affected patients.
Background and purpose: Increasing evidence suggests that ferroptosis plays a key role in the pathophysiology of acute kidney injury induced by cisplatin. The Nrf2 signaling pathway regulates oxidative stress and lipid peroxidation and positively regulates cisplatin-induced AKI (CI-AKI). However, Nrf2 and its activator leonurine on ferroptosis after CI-AKI remain unclear. Experimental Approach: The anti-ferroptotic effects of Nrf2 and its activator leonurine were assessed using a mouse model of cisplatin-induced AKI. In vitro, the potential effects of leonurine on erastin- and RSL3-induced HK-2 human PTEC ferroptosis were examined. Key Results: As expected, Nrf2 deletion induced ferroptosis-related protein expression and iron accumulation in vivo, further aggravating CI-AKI. The Nrf2 activator leonurine prevented iron accumulation and lipid peroxidation and inhibited ferroptosis in vitro, while these effects were abolished in siNrf2-treated cells. Moreover, leonurine potently ameliorated cisplatin-induced renal damage, as indicated by the assessment of SCr, BUN, KIM-1, and NGAL. Importantly, leonurine activated the Nrf2 antioxidative signaling pathway and prohibited changes in ferroptosis-related morphological and biochemical indicators, such as the MDA level, SOD and GSH depletion and GPX4 and xCT downregulation, in CI-AKI. Moreover, Nrf2 KO mice were more susceptible to ferroptosis after CI-AKI than control mice, and the protective effects of leonurine on AKI and ferroptosis were largely abolished in Nrf2 KO mice. Conclusion and Implications: These data suggest that the renal protective effects of Nrf2 and its activator leonurine on CI-AKI are achieved at least partially by inhibiting lipid peroxide-mediated ferroptosis and highlight the potential of leonurine as a CI-AKI treatment.
Brain mineralocorticoid receptors (MR) mediate effects of aldosterone in relation to salt homeostasis, and of glucocorticoid stress hormones corticosteroids in the context of stress adaptation. Brain stem MRs respond to aldosterone, while forebrain MRs mediate rapid and delayed MR-mediated glucocorticoids effects in conjunction with the glucocorticoid receptor. MR-mediated effects depend on gender, genetic variations and environmental influences. Disturbed MR activity by chronic stress or in certain (endocrine) diseases can cause deleterious effects on affective state, cognitive and behavioural function in susceptible individuals. High MR activation may have protective effects in healthy individuals, whereas dysregulated high MR activity during a stress response would require treatment with mineralocorticoid receptor antagonists (MRAs). Here, we discuss recent pharmacological and genetic developments, from the molecular underpinnings of MR signaling and function, to pharmacological interventions in the clinic. Improved understanding of MR dependent pathways will help to improve glucocorticoid therapy, unwanted side effects and psychiatric symptoms.
Vaccines have reduced the transmission and severity of COVID-19 but there remains a paucity of efficacious treatment for drug resistant strains and more susceptible individuals. Repurposing existing drugs is a timely, safe and scientifically robust method for treating pandemics such as COVID-19. Here, we review the pharmacology and scientific rationale for repurposing niclosamide, an anti-helminth already in human use as a treatment for COVID-19. In addition to potent antiviral activity, niclosamide has shown pleiotropic anti-inflammatory, antibacterial, bronchodilatory and anticancer effects in numerous pre-clinical and early clinical studies. The advantages and rationale for nebulised and intranasal formulations of niclosamide, which target the site of primary infection in COVID-19, are reviewed. Finally, we discuss the TACTIC-E clinical trial, an international COVID-19 therapeutic platform trial for the use of licensed and novel therapeutic agents, which is investigating niclosamide as a promising candidate against SARS-CoV-2.
The access of drugs into the central nervous system (CNS) is regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). A large body of evidence supports perturbation of these barriers in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Modifications to the BBB and BSCB are also reported in amyotrophic lateral sclerosis (ALS), albeit these modifications have received less attention relative to those in other neurodegenerative diseases. Such alterations to the BBB and BSCB have the potential to impact on CNS exposure of drugs in ALS, modulating the effectiveness of drugs intended to reach the brain and the toxicity of drugs that are not intended to reach the brain. Given the clinical importance of these phenomena, this review will summarise reported modifications to the BBB and BSCB in ALS, discuss their impact on CNS drug exposure and suggest further research directions so as to optimise medicine use in people with ALS.
Background and Purpose Refractory status epilepticus is a clinical emergency associated with high mortality and morbidity. Increasing evidence suggests neuroinflammatory pathways contribute to the development of drug-refractoriness during status epilepticus. The ATP-gated P2X7 receptor (P2X7R) has been described as potential link between inflammation and increased hyperexcitability. The aim of the present study was to determine the contribution of the P2X7R to drug-refractory status epilepticus and its therapeutic potential. Experimental Approach Status epilepticus was induced via a unilateral microinjection of kainic acid into the amygdala in adult mice. Severity of status epilepticus was compared in animals overexpressing or knock-out in the P2X7R, after inflammatory priming by the pre-injection of bacterial lipopolysaccharide (LPS) and in mice treated with P2X7R-targeting and anti-inflammatory drugs. Key Results P2X7R overexpressing mice were unresponsive to several anticonvulsants (lorazepam, midazolam, phenytoin and carbamazepine) during status epilepticus. P2X7R expression was increased in microglia during drug-refractory status epilepticus, P2X7R overexpression led to a pro-inflammatory phenotype in microglia during status epilepticus and the anti-inflammatory drug minocycline restored normal responsiveness to anticonvulsants in P2X7R overexpressing mice. Pre-treatment of wildtype mice with LPS increased P2X7R levels in the brain and promoted the development of pharmaco-resistant status epilepticus, which was overcome by either a genetic deletion of the P2X7R or the administration of the P2X7R antagonists AFC-5128 or ITH15004. Conclusion and Implications Our results demonstrate that P2X7R-induced pro-inflammatory effects contribute to resistance to pharmacotherapy during status epilepticus and suggest therapies targeting the P2X7R as novel adjunctive treatments for drug-refractory status epilepticus.
In the retina, mineralocorticoid receptor (MR), expressed in vessels, glial and neuronal cells, is mainly activated by glucocorticoids. Under pathological conditions, ocular MR expression and corticoids change, leading in most cases to MR overactivation. Experimental models using MR agonists or antagonists, administered systemically or intraocularly, acutely or chronically and transgenic models, allowed to identify the deleterious consequences of MR pathway overactivation. Among them, oxidative stress, inflammation, deregulation of hydro-ionic channels, alteration of choroidal vasculature, angiogenesis and cell death, are common to major retinal diseases. Specific MR antagonists showed efficacy in models of diabetic retinopathy, ischaemia, retinal and choroidal angiogenesis and in models of glaucoma. It is highly likely that MR antagonists will find a place in the therapeutic arsenal of age-related macular degeneration, diabetic retinopathy, glaucoma and in pachychoroid associated diseases. Their use in humans is still limited by the need of biomarkers of MR activation and specific ocular formulations.
G protein-coupled receptors modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Notably, depending on which ligand has activated a particular receptor, it can engage different intracellular transducers. This paradigm of ligand-dependent ‘biased signaling’ dictates a need to advance beyond the level of receptors to consider the combined ligand-receptor pair in order to understand physiological signaling. Bias signaling also has the potential to improve medicines by reducing adverse effects. However, this is challenged by inconsistent interpretation of results and lack of commonly agreed guidelines. Here, we present recommended terminology and guidelines to conduct, report and quantify bias in a comparable and reproducible fashion. We expect these recommendations will facilitate a common understanding of experiments and findings across basic receptor research and drug discovery, while the area and the analytical methods to measure bias are still evolving, especially in complex cellular, tissue and organismal systems.