Background and Purpose: The activation of the defense reaction inhibits the baroreflex response through the B3 and nucleus tractus solitarius (NTS) regions. Our aim was to determine whether and how baroreflex inhibition induced by the disinhibition of the rostral cuneiform nucleus, part of the defense pathway, involves serotonin cells in B3 and 5-HT3 receptors in the NTS. Experimental Approach: We performed immunohistochemistry and anatomical experiments to determine whether raphe serotonin cells expressing Fos were directly targeted by the rostral cuneiform nucleus. The effect of blocking raphe serotonin transmission and NTS 5-HT3 receptors, on cuneiform-induced inhibition of the baroreflex cardiac response, were also analyzed. Key Results: Bicuculline microinjected into the rostral cuneiform nucleus induced an increase of double labeled Fos-5-HT IR cells in both the LPGi and Raphe Magnus. The anterograde tracer Phaseolus vulgaris leucoaggutinin into the rostral cuneiform nucleus revealed a dense projection to the LPGi but not Raphe Magnus. Cuneiform-induced baroreflex inhibition was prevented by B3 injection of 8-OH-DPAT, a specific agonist for 5-HT1A receptors. Cuneiform disinhibition also failed to inhibit the baroreflex bradycardia after microinjection of a 5-HT3 receptor antagonist (granisetron) into the NTS or in 5-HT3 receptor knock-out mice. Conclusion and Implications: In conclusion, the rostral cuneiform nucleus participates in the defense inhibition of the baroreflex bradycardia via direct activation of the LPGi and a relay to the Raphe Magnus, to activate NTS 5-HT3 receptors and inhibit second-order baroreflex neurons. These data bring new insights in primary and secondary mechanisms involved in vital baroreflex prevention during stress.
Background and Purpose: Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal prostaglandin E2 synthase (mPGES) and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression are modulated by a variety of inflammatory factors and stimuli Considering that very little is known about the biological effects promoted by IL-17 in the context of mPGES-1/PPAR-γ modulation, we sought to investigate the contribution of this unique cytokine on these integrated pathways during the onset of inflammation. Experimental Approach: We evaluated PF 9184 (mPGES-1 antagonist) and Troglitazone (PPAR-γ agonist) activity utilising integrated in vitro and in vivo approaches. The dorsal air pouch model was employed, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto-chemokines and prostaglandins were assessed using ELISA assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways. Key Results: PF 9184 and Troglitazone, in a time and dose-dependent manner, were shown to significantly modulate leukocyte infiltration, myeloperoxidase activity, and the expression of COX-2/mPGES-1, NF-кB/IкB-α and mPGDS-1/PPAR-γ induced by IL-17. Moreover, both compounds were found to modulate prostaglandins (PGE2, PGD2, and PGJ2) production, the expression of different pro-inflammatory cyto-chemokines and the recruitment of inflammatory monocytes in response to IL-17. Conclusions and Implications: Collectively, the data presented suggests that IL-17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. Therefore, the results of this study show, for the first time, that IL-17/mPGES-1/PPAR-γ “axis” could represent a potential therapeutic target for inflammatory-based and immune-mediated diseases.
Background and Purpose Glutamate receptor mediated enhanced excitatory neurotransmission is typically associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Kynurenic acid (KYNA) and quinolinic acid (QUIN) are two important tryptophan-kynurenine pathway (KP) metabolites that modulate glutamate receptor activity. This study was designed to test the hypothesis that alteration in metabolism of KP metabolites in the hippocampus of patients with MTLE-HS contributes to abnormal glutamatergic transmission. Experimental Approach TKP metabolites level were determined using HPLC and LC-MS/MS in the hippocampal samples of patients with MTLE-HS compared to autopsy and non-seizure control samples. mRNA and protein expression of TKP enzymes were determined by qPCR and western blot. Spontaneous glutamatergic activities were recorded from pyramidal neurons in presence of kynurenine (KYN) and KYNA using whole cell patch clamp. Key Results We observed significantly reduced KYNA and elevated QUIN levels in the hippocampal samples, while KYN level remains unaltered. Spontaneous glutamatergic activity in the hippocampal samples was higher compared to that in non-seizure controls. Treatment with kynurenine inhibited the glutamatergic activity in non-seizure control samples but not in case of the hippocampal samples. However, exogenously applied KYNA inhibited glutamatergic activity in both non-seizure control and hippocampal samples. We also observed reduced levels of enzyme kynurenine aminotransferase II and its co-factor pyridoxal phosphate in the hippocampal samples. Conclusion Our findings indicate that altered metabolism of TKP metabolites in hippocampus could contribute to hyperglutamatergic tone in patients with MTLE-HS.
Since cell penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell penetrating peptides and suggest a clinically relevant way of boosting this process.
The Popeye Domain Containing Protein 1 (POPDC1), a tight junction-associated transmembrane protein with a unique binding site for cAMP, has been shown to act as a tumour suppressor in cancer cells. Through interaction with many downstream effectors and signalling pathways, POPDC1 promotes cell adhesion and inhibits uncontrolled cell proliferation, epithelial-to-mesenchymal transition, and metastasis. However, POPDC1 expression is downregulated in many types of cancer, thereby reducing its tumour-suppressive actions. This review discusses the role of POPDC1 in the progression of the malignant phenotype and highlights the broad range of benefits POPDC1 stabilisation may achieve therapeutically. Cancer stem cells (CSC) are a key hallmark of malignancies and commonly promote treatment resistance. This article provides a comprehensive overview of CSC signalling mechanisms, many of which have been shown to be regulated by POPDC1 in other cell types, thus suggesting an additional therapeutic benefit for POPDC1-stabilising anticancer drugs.
Background and Purpose: Diabetic nephropathy is one of the most common complications that is related to high morbidity and mortality in type 2 diabetic patients. We investigated ability of a novel dual modulator, PTUPB that concurrently acts as a soluble epoxide hydrolase inhibitor and as a cyclooxygenase-2 inhibitor against diabetic nephropathy. Experimental Approach: Sixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were orally treated with vehicle, PTUPB, or enalapril for 8 weeks. Key Results: PTUPB alleviated diabetic nephropathy in obese ZSF1 rats by reducing albuminuria by 50%, renal tubular cast formation by 60-70%, renal fibrosis by 40-50%, glomerular injury by 55% and preserved glomerular nephrin expression. Enalapril demonstrated comparable effects and alleviated diabetic nephropathy in obese ZSF1 rats by reducing all kidney injury parameters by 30 to 50%. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with 6-7-fold higher urinary MCP-1 level and renal infiltration of CD-68 positive cells. PTUPB and enalapril reduced renal inflammation but PTUPB demonstrated superior anti-inflammatory actions than enalapril. Obese ZSF1 rats were also hypertensive, hyperlipidemic, and exhibited liver injury. Interestingly, PTUPB but not enalapril decreased hyperlipidemia and liver injury in Obese ZSF1 rats. Conclusion and Implication: Overall, we demonstrate that a dual modulator PTUPB does not treat hyperglycemia, but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidemia, and liver injury in type 2 diabetic rats. Therefore, we suggest that PTUPB has promising potential to be developed as a novel therapy for type 2 diabetic nephropathy and other complications.
Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has been an increased interest in determining how these lipid mediators orchestrate tumor development and metastasis through promoting a pro-tumoral microenvironment. Upregulation of CysLTs receptors and CysLTs production is found in a number of cancers and has been associated with increased tumorigenesis. Understanding the molecular mechanisms underlying the role of CysLTs and their receptors in cancer progression will help investigate the potential of targeting CysLTs signaling for anti-cancer therapy. This review gives an overview of the biological effects of CysLTs and their receptors, along with current knowledge of their regulation and expression. It also provides a recent update on the molecular mechanisms that have been postulated to explain their role in tumorigenesis and on the potential of anti-CysLTs in the treatment of cancer.
Background and purpose: Increasing evidence has shown that human cholestasis is closely related to hepatic macrophage accumulation and activation. Research has indicated that peroxisome proliferator-activated receptor-g (PPARg) activation exerts liver protection in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARg agonists, such as troglitazone and rosiglitazone, have significant side effects that impede their clinical application in the treatment of CLD. In this study, we found that tectorigenin (TEC) can alleviate intrahepatic cholestasis in mice by activating PPARg. Experimental approach: Wild-type mice received intragastric administration of a-naphthylisothiocyanate (ANIT) or were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to establish an experimental intrahepatic cholestasis model and TEC intervention simultaneously, followed by determination of intrahepatic cholestasis and the involved mechanisms. In addition, PPARg deficient mice were administered ANIT and/or TEC to determine whether TEC exerts its liver protection effect by activating PPARg. Key results: Our results demonstrated that TEC intervention alleviated intrahepatic cholestasis by inhibiting hepatic macrophage recruitment and activation as well as promoting the expression of bile transporters through activating PPARg. Furthermore, our results show that TEC increased bile salt export pump (Bsep) expression through enhanced PPARg binding to the Bsep promoter. We also demonstrated that PPARg deficiency blocked the hepatocyte protective effect of TEC during cholestasis. Conclusions and implications: In conclusion, TEC reduced hepatic macrophage recruitment and activation, and enhanced bile acid export by activating PPARg. Taken together, our results suggest that TEC is a potential drug for the prevention of CLD.
BACKGROUND AND PURPOSE: The α7 and α4β2* (* denotes possibly assembly with another subunit) nicotinic acetylcholine receptors (nAChR) are the most abundant nAChR in the mammalian brain. These subtypes are also the most commonly targeted nAChR in drug discovery programs for brain disorders. However, the development of subtype-specific agonists remains challenging, mainly due to the high degree of sequence homology coupled to the conservation of function in the nAChR family. Here, we determined the structural underpinning of the selectivity of 10-methylcytisine, a compound with high-affinity for α4β2* nAChR but negligible selectivity for the α7 subtype. EXPERIMENTAL APPROACH: The structural underpinning of the receptor selectivity of 10-methylcytisine was investigated using molecular dynamics simulations combined with mutagenesis and whole-cell and single-channel current recordings. KEY RESULTS: We identify a conserved arginine residue in the β3-strand that exhibits a non-conserved salt-bridge in the nAChR family. In α4β2 nAChR, the arginine forms an inter-subunit salt-bridge with an aspartate residue in loop B that is necessary for functional expression, whereas in the α7 subtype, this residue is not stabilised by electrostatic interactions, making its side chain highly mobile. This produces steric clashes with agonists and affects the dynamics of residues involved in agonist binding or the coupling network. CONCLUSIONS AND IMPLICATIONS: We conclude that the high mobility of the arginine residue in the α7 nAChR subtype affects agonist function by influencing agonist binding and the pathway communicating agonist binding to the ion channel. The findings have implications for the rational design of subtype-selective cholinergic agents.
Background and Purpose: It is well established that both smokers and patients with COPD are at a significantly heightened risk of cardiovascular disease (CVD), although the mechanisms underpinning the onset and progression of comorbid CVD are largely unknown. Here, we explored whether cigarette smoke (CS) exposure impairs vascular function in mice and given the well-known pathological role for oxidative stress in COPD, whether the antioxidant compound ebselen prevents CS-induced vascular dysfunction in mice. Experimental Approach: Male BALB/c mice were exposed to either room air (sham) or CS generated from 9 cigarettes per day, 5 days a week for 8 weeks. Mice were treated with ebselen (10mg/kg, oral gavage once daily) or vehicle (5% w/v CM cellulose in water) 1 h prior to the first CS exposure of the day. Upon sacrifice, bronchoalveolar lavage fluid (BALF) was collected to assess pulmonary inflammation and the thoracic aorta was excised to investigate vascular endothelial and smooth muscle dilator responses ex-vivo. Key Results: CS exposure caused a significant increase in lung inflammation which was reduced by ebselen. CS also caused significant endothelial dysfunction in the thoracic aorta which was attributed to a downregulation of eNOS expression and increased vascular oxidative stress. Ebselen abolished the aortic endothelial dysfunction seen in CS-exposed mice by reducing the oxidative burden and preserving eNOS expression. Conclusion and Implications: Targeting CS-induced oxidative stress with ebselen may provide a novel means for treating the life-threatening pulmonary and cardiovascular manifestations associated with cigarette smoking and COPD.
Background and Purpose: Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in NSCLC primary tumor tissues and the association between prognosis of NSCLC patients remain largely unknown. Experimental Approach: Clinical pathological analysis was performed to determine the relationship between thrombin and tumor progression. Effect of r-hirudin and DTIP on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r-hirudin and DTIP. Therapeutic effect of combination of DTIP and chemotherapy was determined. Key Results: We illustrated thrombin expression in NSCLC tissues is closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumor progression. The novel thrombin inhibitors, r-hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumor growth and metastasis in orthotopic lung cancer model; inhibited cells invasion and prolonged survival after injection tumor cells via tail vein; they also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumors. The promotional activity of thrombin in invasion and metastasis was abolished in PAR-1 deficient-NSCLC cells. r-hirudin and DTIP inhibit tumor progression through the thrombin-PAR-1-mediated RhoA and NF-κB signaling cascades via inhibiting the MMP9 and IL6 expression. DTIP potentiated chemotherapy-induced growth and metastatic inhibition and inhibited chemotherapy-induced resistance in mice. Conclusions and Implications: Thrombin makes a substantial contribution, together with PAR-1, to NSCLC malignancy. We concluded the anticoagulants, r-hirudin and DTIP, could be expanded for anti-tumor therap. Combination therapy of DTIP and chemotherapy might achieve a better therapeutic effect.
Background and Purpose Inactivation of Cys674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) by causing the accumulation of intracellular Ca2+ to activate calcineurin-mediated nuclear factor of activated T-lymphocytes (NFAT)/NF-κB pathways, resulted in the phenotypic modulation of smooth muscle cells (SMCs) to accelerate angiotensin II-induced aortic aneurysm. Our goal was to investigate the mechanism involved. Experimental Approach We used heterozygous SERCA2 C674S knock-in (SKI) mice, where half of C674 was substituted by serine, to represent partial irreversible oxidation of C674. The aortas of SKI mice and their littermate wild-type mice were collected for RNA sequencing, cell culture, protein expression, luciferase activity and aortic aneurysm analysis. KEY RESULTS Inactivation of C674 inhibited the promoter activity and protein expression of PPARγ, which could be reversed by inhibitors of calcineurin or NF-κB. Overexpression of PPARγ2 inhibited the phenotypic modulation of SKI SMCs. Pioglitazone, the activator of PPARγ, blocked the activation of NFAT/NF-κB, inhibited SMC phenotypic modulation, and ameliorated angiotensin II-induced aortic aneurysms in SKI mice. CONCLUSIONS AND IMPLICATIONS The inactivation of SERCA2 C674 promotes the development of aortic aneurysm by disrupting the balance between PPARγ and NFAT/NF-κB. Our study highlights the importance of C674 redox status in regulating PPARγ to maintain aortic homeostasis.
Background: Vascular Endothelial Growth Factor A (VEGF-A) is a key mediator of angiogenesis, primarily signalling via VEGF Receptor 2 (VEGFR2). Endothelial cells also express the co-receptor Neuropilin-1 (NRP1) that potentiates VEGF-A/VEGFR2 signalling. VEGFR2 and NRP1 had distinct real-time ligand binding kinetics when monitored using Bioluminescence Resonance Energy Transfer (BRET). We previously characterised fluorescent VEGF-A isoforms tagged at a single site with tetramethylrhodamine (TMR). Here, we explore differences between VEGF-A isoforms in living cells that co-expressed both receptors. Experimental Approach: Receptor localisation was monitored in HEK293T cells expressing both VEGFR2 and NRP1 using a membrane-impermeant HaloTag and SnapTag technologies. To isolate ligand binding pharmacology at a defined VEGFR2/NRP1 complex, we developed an assay using NanoBiT complementation technology whereby heteromerization is required for luminescence emissions. Binding affinities and kinetics of VEGFR2-selective VEGF165b-TMR and non-selective VEGF165a-TMR were monitored using BRET from this defined complex. Key Results: Cell surface VEGFR2 and NRP1 were co-localised and formed a constitutive heteromeric complex. Despite being selective for VEGFR2, VEGF165b-TMR had a distinct kinetic ligand binding profile at the complex that largely remained elevated in cells over 90 minutes. VEGF165a-TMR bound to the VEGFR2/NRP1 complex with kinetics comparable to those of VEGFR2 alone. Using a binding-dead mutant of NRP1 had no impact on the binding kinetics or affinity of VEGF165a-TMR. Conclusions and Implications: This NanoBiT approach enabled real-time ligand binding to be quantified in living cells at 37°C from a specified complex between a receptor tyrosine kinase and its co-receptor for the first time.
Background: Glucagon-like peptide-2 (GLP-2) is a 33 amino acid pro-glucagon-derived hormone produced in the intestinal enteroendocrine L-cells with trophic actions on both the gut and bones. GLP-2(1-33) is cleaved by the ubiquitous protease dipeptidyl peptidase-4 (DPP-4), resulting in GLP-2(3-33) with competitive antagonistic properties on the GLP-2 receptor (GLP-2R). Here we present two new hGLP-2 radioligands with different pharmacodynamic profiles. Experimental Approach: The methionine in position 10 of GLP-2(1-33) was substituted with tyrosine to enable oxidative iodination with incorporation of the iodine isotope [125I]. Similar substitution was done in GLP-2(3-33), thereby creating two new radioligands; an agonist -hGLP-2(1-33,M10Y) and an antagonist -hGLP-2(3-33,M10Y). Both were characterized regarding competition binding, binding kinetics and target tissue autoradiography. Key results: High and similar binding affinities for the human GLP-2R were observed for [125I]-hGLP-2(1-33,M10Y) and [125I]-hGLP-2(3-33,M10Y) with KD values of 59.3 nM and 40.6 nM, respectively. The M10Y substitution did not change the functional properties of GLP-2(1-33) or GLP-2(3-33). The antagonist [125I]-hGLP-2(3-33,M10Y) had higher Bmax and faster on-rate for the hGLP-2R compared to the agonist [125I]-hGLP-2(1-33,M10Y). Using autoradiography in mice strong labeling was observed in subepithelial myofibroblasts (SEMF) and pancreas islet cells. Both radioligands were selective for the GLP-2R, except for a low affinity binding to the GLP-1R (IC50 of 130 and 330 nM, respectively) Conclusion and implications: We successfully developed two new high affinity radioligands for GLP-2R studies and identified SEMF and pancreatic islets as target for GLP-2. It is uncertain whether binding in the pancreas islets results from GLP-2R or GLP-1R binding.
Background and Purpose: Hypertensive vascular remodeling (VR) is responsible for end-organ damage and is the result of increased extracellular matrix accumulation and excessive vascular smooth muscle cell (VSMC) proliferation. MicroRNA-26a (miR-26a), a non-coding small RNA, is involved in multiple cardiovascular diseases. We aimed to validate the effect and mechanisms of miR-26a in hypertensive VR. Experimental Approach: Spontaneously hypertensive rats (SHRs) were injected intravenously with recombinant adeno-associated virus-miR-26a. In vitro experiments, angiotensin II (AngII)-induced VSMCs were transfected with miR-26a mimic or inhibitor. Key Results: We found miR-26a downregulated in the thoracic aorta and plasma of SHRs. Overexpression of miR-26a inhibited extracellular matrix deposition by targeting connective tissue growth factor (CTGF) and mitigated VSMC proliferation by regulating the enhancer of zeste homolog 2 (EZH2)/p21 pathway both in vitro and in vivo. AngII-mediated Smad3 activation suppressed miR-26a expression, which in turn promoted Smad3 activation via targeted regulation of Smad4, leading to further downregulation of miR-26a. Conclusion and Implications: Our study reveals that AngII stimulates a Smads/miR-26a positive feedback loop, which further reduces miR-26a expression, leading to collagen production and VSMC proliferation and consequently, VR. MiR-26a has an antagonistic effect on hypertensive VR and can be a strategy for treating hypertensive VR.
Hyperexcitability-related diseases include epilepsies, pain syndromes, neuromuscular disorders, and cardiac arrhythmias. Sodium channel inhibitors can be used to treat these conditions, however, their applicability is limited by their nonspecific effect on physiological function. They act by channel block (obstructing ion conduction, since the binding site is within the channel pore), and by modulation (delaying recovery from the non-conducting inactivated state). Channel block inhibits healthy and pathological tissue equally, while modulation can preferentially inhibit pathological activity. Therefore, an ideal sodium channel inhibitor drug would act by modulation alone. Unfortunately, thus far no such drug has been known to exist. Here we present evidence that riluzole acts by this “ideal” mechanism, “non-blocking modulation” (NBM). We propose that, being a relatively small molecule, riluzole is able to stay bound to the binding site, but nonetheless stay off the conduction pathway, by residing in one of the “fenestrations” (cavities connecting the central cavity to the membrane phase). Using precisely timed UV pulses to photolabel specific conformations of the channel, we show that association to the local anesthetic binding site requires prior inactivation. We discuss why kinetics of binding is crucial for selective inhibition of pathological activity, and how the NBM mechanism can be recognized using a special voltage- and drug application-protocol. Our results identify riluzole as the prototype of this new class of sodium channel inhibitors. Drugs of this class are expected to selectively prevent hyperexcitability, while having minimal effect on cells firing at a normal rate from a normal resting potential.
Background and purpose: Alpha 7 nicotinic acetylcholine receptors (CHRNA7) suppress inflammation through diverse pathways in immune cells, so is potentially involved in a number of inflammatory diseases. However, the detailed mechanisms underlying CHRNA7’s anti-inflammatory effects remain elusive. Experimental approach: The anti-inflammatory effects of CHRNA7 agonists in both murine macrophages (RAW 264.7) and bone marrow-derived macrophages (BMDM) stimulated with LPS were examined. The role of adenylyl cyclase 6 (AC6) in Toll-like Receptor 4 (TLR4) degradation was explored via overexpression and knockdown. A mouse model of chronic obstructive pulmonary disease was used to confirm key findings. Key results: Anti-inflammatory effects of CHRNA7 were largely dependent on AC6 activation, as knockdown of AC6 considerably abnegated the effects of CHRNA7 agonists while AC6 overexpression promoted them. We found that CHRNA7 and AC6 are co-localized in lipid rafts of macrophages and directly interact. Activation of AC6 led to the promotion of TLR4 degradation. Administration of CHRNA7 agonist PNU282987 attenuated pathological and inflammatory end points in a mouse model of chronic obstructive pulmonary disease (COPD). Conclusion and implications: CHRNA7 inhibit inflammation through activating AC6 and promoting degradation of TLR4. The use of CHRNA7 agonists might represent a novel therapeutic approach for treating COPD and likely other inflammatory diseases.
Prostate cancer (PCa) is the second most common malignancy in men, and androgen deprivation therapy (ADT) is the first-line therapy. However, most cases will eventually develop into castration-resistant prostate cancer (CRPC) after ADT treatment. Enzalutamide (Enz) is a second-generation androgen receptor inhibitor approved by the Food and Drug Administration to treat patients with CRPC. Unfortunately, patients receiving Enz treatment will ultimately develop resistance via various complicated mechanisms. In this review, we introduce the emerging information on resistance mechanisms, including androgen receptor-related signalling pathways, glucocorticoid receptor-related pathways, and metabolic mechanisms. Notably, lineage plasticity and phenotype switching, gene polymorphisms, and the relationship between microRNAs and drug resistance are addressed. Furthermore, potential therapeutic strategies for Enz-resistant CRPC treatment are suggested, which can help in the discovery of more effective and specific regimens to overcome Enz resistance.