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Despite increasing awareness of the need to study both sexes, only two papers (one each in 2020 and 2021) discussed the limitations of using only one sex or implied that the findings might not generalise from one sex to the other. Also, when the use of a single sex was accepted by the editors, we asked that the manuscript should include a statement in the discussion, to acknowledge that the research findings might not generalise across both sexes and to consider what the findings might mean for the other sex. For instance, if only one sex were used, then they can ensure that (1) the justification has scientific merit; (2) the title and abstract specify the sex of the subjects that were used; and (3) the limitations of using only one sex are discussed fully. [Extracted from the article]

The article discusses the retraction of research articles in the British Journal of Pharmacology (BJP) between the years 2000-2023. The frequency of retracted papers has been steadily increasing, with more than 0.2% of articles being retracted in 2023. The reasons for retraction include errors in the published article, failure to conform to editorial policies, and research misconduct such as data fabrication or falsification. Of the 18 retractions in BJP, 11 were due to proven fraud or strong indications of such practices. In some cases, authors associated with fraud-related retractions have been linked to multiple retractions, suggesting serial cases of fraud. The article suggests several measures to address this issue, including sharing information among journals, flagging individuals involved in fraud cases, and producing clear retraction notes to protect innocent authors. The author emphasizes the importance of cleaning up the scientific record and preventing future fraudulent publications through various approaches. [Extracted from the article]

The article discusses the issue of predatory journals, which prioritize profit over quality scholarship and compromise the integrity of scientific discourse. It highlights a symposium held at Semmelweis University, where editors in chief from top journals discussed topics such as detecting publication fraud, combating paper mills, and the importance of robust submission and review processes. The participants emphasized the need for collaboration and community-building to uphold scientific integrity. They also discussed the role of AI and open science in improving publication standards. The article concludes by emphasizing the importance of non-predatory journals working together to combat unethical publications and maintain high standards in scientific research. [Extracted from the article]

In 2021, we reached the 50th anniversary of the publication of Sir John Vane's seminal paper in Nature New Biology describing the experiments supporting his mechanistic hypothesis that inhibition of prostaglandin synthesis might explain the main pharmacological effects of aspirin and aspirin‐like drugs, that is, reduction in pain, fever and inflammation. Bengt Samuelsson's subsequent discoveries elucidating the cyclooxygenase pathway of platelet arachidonic acid metabolism motivated my research interest towards measuring platelet thromboxane A2 biosynthesis as a tool to investigate the clinical pharmacology of cyclooxygenase inhibition by aspirin in health and disease. What followed was a long, winding road of clinical research leading to the characterization of low‐dose aspirin as a life‐saving antiplatelet drug that still represents the cornerstone of antithrombotic therapy. Having witnessed and participated in these 50 years of aspirin research, I thought of providing a personal testimony of how things developed and eventually led to a remarkable success story of independent research. [ABSTRACT FROM AUTHOR]

The chemopreventive and chemotherapeutic properties of soy and soy‐derived compounds, especially isoflavones, have been extensively studied in recent years. However, in contrast to their anticancer effects, such as cell growth inhibition, cell cycle arrest and apoptosis induction, isoflavones have also been found to promote the growth of cancer cells. Therefore, the aim of this comprehensive review article is to present the current state of knowledge regarding the molecular mechanisms by which soy‐derived isoflavones target multiple cellular signalling pathways in cancer cells. Our findings indicate that soy‐derived isoflavones act as, among other things, potent modulators of HOX transcript antisense RNA (HOTAIR)/SWI/SNF‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 (SMARCB1), vascular endothelial growth factor (VEGF)/C–X–C motif chemokine ligand 12 (CXCL12)/C–X–C motif chemokine receptor type 4 (CXCR4), 17‐β‐oestradiol (E2)/oestrogen receptor‐α (ERα)/neuroglobin (NGB) and sonic hedgehog signalling pathways, epigenetic modulatory agents (i.a. miR‐155, miR‐34a and miR‐10a‐5p) and cancer stem cells and epithelial‐to‐mesenchymal transition inhibitors. The paper also discusses the latest epidemiological studies and clinical trials and provides an insight into recent extensive research on the chemo‐preventive and therapeutic potential of soy‐derived isoflavones. [ABSTRACT FROM AUTHOR]

Liver disease constitutes a significant global health concern, particularly in China where it has distinctive characteristics. China grapples with a staggering 300 million cases, predominantly due to hepatitis B and metabolic non‐alcoholic fatty liver disease. Additionally, hepatocellular carcinoma has become a prevalent which is a lethal type of cancer. Despite the scarcity of innovative treatment options, Chinese hepatologists and researchers have achieved notable breakthroughs in the prevention, diagnosis, management and treatment of liver diseases. Traditional Chinese medicines have found widespread application in the treatment of various liver ailments owing to their commendable pharmacological efficacy and minimal side effects. Furthermore, there is a growing body of research in extracellular vesicles, cell therapy and gene therapy, offering new hope in the fight against liver diseases. This paper provides a comprehensive overview of the epidemiological characteristics of liver diseases and the diverse array of treatments that Chinese scholars and scientists have pursued in critical field. [ABSTRACT FROM AUTHOR]

LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc [ABSTRACT FROM AUTHOR]

This document is a correction to an article titled "RTP801 is a critical factor in the neurodegeneration process of A53T α-synuclein in a mouse model of Parkinson's disease under chronic restraint stress." The correction states that there were accidental mistakes during the preparation of the article, specifically in Figure 8e. The images of the A53T+ RTP801 shRNA+ CRS group in Figure 8e were incorrect, but the rest of the data in Figure 8e remain unchanged. The correction does not affect the interpretation of the results or the conclusions of the paper. The British Pharmacological Society apologizes for this error. [Extracted from the article]

Scientists who plan to publish in British Journal of Pharmacology (BJP) must read this article before undertaking a study. This editorial provides guidance for the design of experiments. We have published previously two guidance documents on experimental design and analysis (Curtis et al., 2015; Curtis et al., 2018). This update clarifies and simplifies the requirements on design and analysis for BJP manuscripts. This editorial also details updated requirements following an audit and discussion on best practice by the BJP editorial board. Explanations for the requirements are provided in the previous articles. Here, we address new issues that have arisen in the course of handling manuscripts and emphasise three aspects of design that continue to present the greatest challenge to authors: randomisation, blinded analysis and balance of group sizes. [ABSTRACT FROM AUTHOR]

This drug class, known as ditans, represent the first migraine therapy devoid of effects on the vasculature; and therefore open therapeutic options for migraine patients with co-morbid cardiovascular diseases. Furthermore, infusion of PACAP-38 evokes migraine-like headache in migraine patients, and to a lesser extent in healthy controls (Schytz et al., 2009). This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). PACAP38 induces migraine-like attacks in patients with migraine without aura. [Extracted from the article]

Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and 9 -tetrahydrocannabinol. Expression of Concern: Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and 9-tetrahydrocannabinol Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and 9 -tetrahydrocannabinol. [Extracted from the article]

Background and Purpose: Mitochondrial oxidative stress, inflammation and apoptosis primarily underlie gastric mucosal injury caused by the widely used non‐steroidal anti‐inflammatory drugs (NSAIDs). Alternative gastroprotective strategies are therefore needed. Sirtuin‐3 pivotally maintains mitochondrial structural integrity and metabolism while preventing oxidative stress; however, its relevance to gastric injury was never explored. Here, we have investigated whether and how sirtuin‐3 stimulation by the phytochemical, honokiol, could rescue NSAID‐induced gastric injury. Experimental Approach: Gastric injury in rats induced by indomethacin was used to assess the effects of honokiol. Next‐generation sequencing‐based transcriptomics followed by functional validation identified the gastroprotective function of sirtuin‐3. Flow cytometry, immunoblotting, qRT‐PCR and immunohistochemistry were used measure effects on oxidative stress, mitochondrial dynamics, electron transport chain function, and markers of inflammation and apoptosis. Sirtuin‐3 deacetylase activity was also estimated and gastric luminal pH was measured. Key Results: Indomethacin down‐regulated sirtuin‐3 to induce oxidative stress, mitochondrial hyperacetylation, 8‐oxoguanine DNA glycosylase 1 depletion, mitochondrial DNA damage, respiratory chain defect and mitochondrial fragmentation leading to severe mucosal injury. Indomethacin dose‐dependently inhibited sirtuin‐3 deacetylase activity. Honokiol prevented mitochondrial oxidative damage and inflammatory tissue injury by attenuating indomethacin‐induced depletion of both sirtuin‐3 and its transcriptional regulators PGC1α and ERRα. Honokiol also accelerated gastric wound healing but did not alter gastric acid secretion, unlike lansoprazole. Conclusions and Implications: Sirtuin‐3 stimulation by honokiol prevented and reversed NSAID‐induced gastric injury through maintaining mitochondrial integrity. Honokiol did not affect gastric acid secretion. Sirtuin‐3 stimulation by honokiol may be utilized as a mitochondria‐based, acid‐independent novel gastroprotective strategy against NSAIDs. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic pain is considered a key factor contributing to alcohol use disorder (AUD). The mechanisms responsible for chronic pain associated with chronic alcohol consumption are unknown. We evaluated the development of chronic pain in a mouse model of alcohol dependence and investigate the role of neuroinflammation. Experimental Approach: The chronic‐intermittent ethanol two‐bottle choice CIE‐2BC paradigm generates three groups: alcohol‐dependent with escalating alcohol intake, nondependent (moderate drinking) and alcohol‐naïve control male and female mice. We measured mechanical allodynia during withdrawal and after the last voluntary drinking. Immunoblotting was used to evaluate the protein levels of IBA‐1, CSFR, IL‐6, p38 and ERK2/1 in spinal cord tissue of dependent and non‐dependent animals. Key Results: We found significant escalation of drinking in the dependent group in male and female compared with the non‐dependent group. The dependent group developed mechanical allodynia during 72 h of withdrawal, which was completely reversed after voluntary drinking. We observed an increased pain hypersensitivity compared with the naïve in 50% of non‐dependent group. Increased IBA‐1 and CSFR expression was observed in spinal cord tissue of both hypersensitivity‐abstinence related and neuropathy‐alcohol mice, and increased IL‐6 expression and ERK1/2 activation in mice with hypersensitivity‐related to abstinence, but not in mice with alcohol‐evoked neuropathic pain. Conclusions and Implications: The CIE‐2BC model induces two distinct pain conditions specific to the type of ethanol exposure: abstinence‐related hypersensitivity in dependent mice and alcohol‐evoked neuropathic pain in about a half of the non‐dependent mice. [ABSTRACT FROM AUTHOR]

Background and Purpose: The illicit use of fentanyl‐like drugs (fentanyls), which are μ opioid receptor agonists, and the many overdose deaths that result, has become a major problem. Fentanyls are very potent in vivo, leading to respiratory depression and death. However, the efficacy and possible signalling bias of different fentanyls is not clearly known. Here, we compared the relative efficacy and bias of a series of fentanyls. Experimental Approach: For agonist signalling bias and efficacy measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken in HEK293T cells transiently transfected with μ opioid receptors, to assess Gi protein activation and β‐arrestin 2 recruitment. Agonist‐induced cell surface receptor loss was assessed using an enzyme‐linked immunosorbent assay, whilst agonist‐induced G protein‐coupled inwardly rectifying potassium channel current activation was measured electrophysiologically from rat locus coeruleus slices. Ligand poses in the μ opioid receptor were determined in silico using molecular dynamics simulations. Key Results: Relative to the reference ligand DAMGO, carfentanil was β‐arrestin‐biased, whereas fentanyl, sufentanil and alfentanil did not display bias. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein‐coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor. Molecular dynamics simulations suggested unique interactions of carfentanil with the orthosteric site of the receptor that could underlie the bias. Conclusions and Implications: Carfentanil is a β‐arrestin‐biased opioid drug at the μ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls. [ABSTRACT FROM AUTHOR]

Background and Purpose: Low‐grade inflammation, a common feature of both diabetes and periodontitis, partly accounts for the complexity and refractoriness of diabetes‐associated periodontitis. Adiponectin (APN), the most abundant adipokine in human blood, has been widely reported to have anti‐inflammatory functions. Herein, we investigated the ability of an APN receptor agonist, AdipoAI, to alleviate diabetes‐associated periodontitis. Furthermore, we revealed the possible mechanism underlying its anti‐inflammatory effects. Experimental Approach: The maxillary first molar of Zucker diabetic fatty (ZDF) rats was ligated to construct a diabetes‐associated periodontitis model, and rats were administered AdipoAI by gavage. We examined diabetes‐related indexes, pathological changes in insulin target organs, alveolar bone resorption and systemic and local inflammation. In vitro, transwell assays were used to evaluate monocyte/macrophage migration induced by human gingival fibroblasts (hGFs) with/without AdipoAI treatment. Additionally, we examined chemokine expression levels in hGFs and hGF‐induced monocyte/macrophage migration upon siRNA knockdown of Adiponectin receptor expression. Expression of Adipo1/Adipo2 receptors and inflammation‐related signalling pathways were examined by IHC and WB, followed by confirmation with an NF‐κB P65 inhibitor (BAY 11‐7082). Key Results: AdipoAI lowered fasting blood glucose and serum insulin in ZDF rats and alleviated inflammation in insulin target tissues. Locally, AdipoAI reduced alveolar bone absorption and gingival inflammation. Mechanistically, AdipoAI inhibited hGF‐induced monocyte/macrophage migration by reducing CCL2 secretion. In hGFs, AdipoAI attenuated LPS‐induced activation of NF‐κB P65 and CCL2 expression, which was dependent on the Adipo receptor 1. Conclusion and Implications: AdipoAI, with its ability to alleviate inflammatory damage in tissues, is a candidate for diabetes‐associated periodontitis treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Complement activation may drive hypertension through its effects on immunity and tissue integrity. Experimental Approach: We examined expression of C3, the central protein of the complement cascade, in hypertension. Key Results: Increased C3 expression was found in kidney biopsies and micro‐dissected glomeruli of patients with hypertensive nephropathy. Renal single cell RNA sequence data from normotensive and hypertensive patients confirmed expression of C3 in different cellular compartments of the kidney. In angiotensin II (Ang II) induced hypertension renal C3 expression was up‐regulated. C3−/− mice revealed a significant lower albuminuria in the early phase of hypertension. However, no difference was found for blood pressure, renal injury (histology, glomerular filtration rate, inflammation) and cardiac injury (fibrosis, weight, gene expression) between C3−/− and wildtype mice after Ang II infusion. Also, in deoxycorticosterone acetate (DOCA) salt hypertension, a significantly lower albuminuria was found in the first weeks of hypertension in C3 deficient mice but no significant difference in renal and cardiac injury. Down‐regulation of C3 by C3 targeting GalNAc (n‐acetylgalactosamine) small interfering RNA (siRNA) conjugate decreased C3 in the liver by 96% and lowered albuminuria in the early phase but showed no effect on blood pressure and end‐organ damage. Inhibition of complement C5 by siRNA showed no effect on albuminuria. Conclusion and Implications: Increased C3 expression is found in the kidneys of hypertensive mice and men. Genetic and therapeutic knockdown of C3 improved albuminuria in the early phase of hypertension but did not ameliorate arterial blood pressure nor renal and cardiac injury. [ABSTRACT FROM AUTHOR]

Background and Purpose: High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well known that the angiotensin II (Ang II)‐AT1 receptor and prostaglandin E2 (PGE2)‐EP1 receptor systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS‐mediated hypertension and emotional and cognitive impairments remains unclear. Experimental Approach: Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks, and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II‐AT1 and PGE2‐EP1 systems in HS‐induced hypertension and neuronal and behavioural impairments was examined by treatment with losartan, an AT1 receptor blocker (ARB), or EP1 gene knockout. Key Results: We demonstrate that hypertension and impaired social behaviour and object recognition memory following HS intake may be associated with tau hyperphosphorylation, decreased phosphorylation of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP1 receptor gene knockout. Conclusions and Implications: Our findings suggest that the interaction of Ang II‐AT1 receptor and PGE2‐EP1 receptor systems could be novel therapeutic targets for hypertension‐induced cognitive impairment. [ABSTRACT FROM AUTHOR]

Background and purpose: Alcohol abuse has been associated with erectile dysfunction (ED), but the implicated molecular mechanisms are unresolved. This study analyses the role of alterations in soluble guanylyl cyclase (sGC) in ED. Experimental approach: ED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm. Erectile function was assessed in anaesthetised mice in vivo by evaluating intracavernosal pressure (ICP) and in vitro in isolated mice corpora cavernosa (CC) mounted in a myograph. Protein expression and reactive oxygen species were analysed by western blot and dihydroethidium staining, respectively. Key results: In CIE mice, we observed a significant decrease in the relaxant response of the CC to stimulation of NO release from nitrergic nerves by electrical field stimulation, to NO release from endothelial cells by acetylcholine, to the PDE5 inhibitor sildenafil, and to the sGC stimulator riociguat. Conversely, the response to the sGC activator cinaciguat, whose action is independent of the oxidation state of sGC, was significantly enhanced in these CC. The responses to adenylyl cyclase stimulation with forskolin were unchanged. We found an increase in reactive oxygen species in the CC from CIE mice as well as an increase in CYP2E1 and NOX2 protein expression. In vivo pre‐treatment with tempol prevented alcohol‐induced erectile dysfunction. Conclusions and implications: Our results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration in the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism. [ABSTRACT FROM AUTHOR]

Background and Purpose: In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival. We have explored the role of the N/OFQ‐NOP system in freshly isolated volunteer human B‐ and T‐cells incubated with lipopolysaccharide (LPS) and peptidoglycan G (PepG) as a model of in vitro sepsis. Experimental Approach: B‐ and T‐cell NOP expression was measured using the NOP fluorescent probe N/OFQATTO594, N/OFQ content was measured using immunofluorescence, N/OFQ release was tracked using a CHOhNOPGαiq5 biosensor assay and NOP function was measured using transwell migration and cytokine/chemokine release using a 25‐plex assay format. Cells were challenged with LPS/PepG. Key Results: CD19‐positive B‐cells bound N/OFQATTO594; they also contain N/OFQ. Stimulation with CXCL13/IL‐4 increased N/OFQ release. N/OFQ trended to reduced migration to CXCL13/IL‐4. Surface NOP expression was unaffected by LPS/PepG, but this treatment increased GM‐CSF release in an N/OFQ sensitive manner. CD3‐positive T‐cells did not bind N/OFQATTO594; they did contain N/OFQ. Stimulation with CXCL12/IL‐6 increased N/OFQ release. When incubated with LPS/PepG, NOP surface expression was induced leading to N/OFQATTO594 binding. In LPS/PepG‐treated cells, N/OFQ reduced migration to CXCL12/IL‐6. LPS/PepG increased GM‐CSF release in an N/OFQ sensitive manner. Conclusions and Implications: We suggest both a constitutive and sepsis‐inducible N/OFQ‐NOP receptor autocrine regulation of B‐ and T‐cell function, respectively. These NOP receptors variably inhibit migration and reduce GM‐CSF release. These data provide mechanistic insights to the detrimental role for increased N/OFQ signalling in sepsis and suggest a potential role for NOP antagonists as treatments. [ABSTRACT FROM AUTHOR]

Background and Purpose: Mitochondrial dysfunction and inflammation contribute to a myriad of cardiovascular diseases. Deleterious crosstalk of mitochondria and persistent endoplasmic reticulum (ER) stress triggers oxidative stress, which is involved in the development of vascular diseases. This study determined if inhibition of mitochondrial stress reduces aneurysm development in angiotensin II (Ang II)‐infused apolipoprotein‐E‐deficient (ApoE−/−) mice and its effect on ER stress. Experimental Approach: The mitochondria‐targeted tetrapeptide, Szeto‐Schiller 31 (SS31), ameliorated mitochondrial dysfunction and the enhanced expression of ER stress markers triggered by Ang II in ApoE−/− mice, and limited plasmatic and vascular reactive oxygen species (ROS) levels. Interestingly, SS31 improved survival, reduced the incidence and severity of abdominal aortic aneurysm (AAA), and the Ang II‐induced increase in aortic diameter as evaluated by ultrasonography, resembling the response triggered by the classic ER stress inhibitors tauroursodeoxycholic acid (TUDCA) and 4‐phenylbutyrate (PBA). Key Results: Disorganization of the extracellular matrix, increased expression of metalloproteinases and pro‐inflammatory markers and infiltration of immune cells induced by Ang II in the abdominal aorta were effectively reduced by SS31 and ER inhibitors. Further, C/EBP homologous protein (CHOP) deficiency in ApoE−/− mice attenuated Ang II‐mediated increase in vascular diameter and incidence of AAA, suggesting its contribution to the favourable response induced by ER stress inhibition. Conclusions and Implications: Our data demonstrate that inhibition of mitochondrial stress by SS31 limits AAA formation and increases survival through a reduction of vascular remodelling, inflammation and ROS, and support that attenuation of ER stress contributes to the favourable response elicited by SS31. [ABSTRACT FROM AUTHOR]

Background and Purpose: Local blood flow regulation relies on the coordination between neurons and pericyte‐containing capillaries. Pericyte relaxation and contraction are influenced by vasoactive substances and regulated by neurotransmitters. α7 nicotinic acetylcholine receptors (α7‐nAChRs), involved in the regulation of vascular function and inhibitory γ‐aminobutyric acid (GABA) systems, have neuroprotective effects against CNS diseases. Although α7‐nAChRs are found throughout the retina, their contribution to the retinal capillary tone remains unknown. Here, we investigated the neurovascular coupling mechanism underlying α7‐nAChR‐mediated retinal capillary tone regulation. Experimental Approach: Changes in capillary diameter and pericyte transverse diameter during drug perfusion were observed using differential interference contrast (DIC) microscopy, to help elucidate signalling pathways underlying α7‐nAChR‐mediated regulation of capillary blood flow at the whole retinal level. Patch clamp technique was used to investigate α7‐nAChR‐mediated regulation of the GABA synaptic circuit. Immunofluorescence was used to explore the expression of α7‐nAChRs and GABA receptors. Key Results: Activating α7‐nAChRs on the endothelial cell membrane caused perinuclear accumulation of endothelial nitric oxide synthase (eNOS), resulting in dilated retinal capillaries and pericytes via the nitric oxide synthase (NOS)/nitric oxide (NO)/guanosine 3′,5′‐ monophosphate (cGMP) signalling pathway. Neuronal α7‐nAChR activation directly relaxed retinal capillaries and pericytes via a neurovascular coupling mechanism. α7‐nAChR also increased the vesicular release of GABA, possibly promoting the release of NO by binding to GABAA receptors in retinal ganglion cells (RGCs) and relaxing blood vessels via eNOS–NO, with GABA binding to GABAB receptors on retinal capillary endothelial cells. Conclusion and Implications: α7‐nAChR activation causes vasorelaxation of retinal capillaries. [ABSTRACT FROM AUTHOR]

Background and Purpose: Renal fibrosis is a common feature of chronic kidney disease. Myeloid fibroblasts and macrophages contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying myeloid fibroblast activation and macrophage polarization are not fully understood. In this study, we examined the role of Jumonji domain‐containing protein‐3 (JMJD3) in myeloid fibroblast activation, macrophage polarization, and renal fibrosis development in a preclinical model of obstructive nephropathy. Experimental Approach: To examine the role of JMJD3 in renal fibrosis, we generated mice with global or myeloid cell‐specific deletion of JMJD3, and we treated wild‐type mice with vehicle or GSK‐J4 (selective JMJD3 inhibitor). Mice were subjected to unilateral ureteral obstructive injury to induce renal fibrosis. Key Results: JMJD3 expression was significantly increased in the kidneys during the development of renal fibrosis, which was associated with an increase in H3K27 dimethylation. Mice with either global or myeloid JMJD3 deficiency exhibited significantly reduced total collagen deposition and extracellular matrix protein production, myeloid fibroblast activation and M2 macrophage polarization in the obstructed kidney. Moreover, IFN regulatory factor 4, a mediator of M2 macrophage polarization, was significantly induced in the obstructed kidneys, which was abolished by JMJD3 deficiency. Furthermore, pharmacological inhibition of JMJD3 with GSK‐J4 attenuated kidney fibrosis, reduced myeloid fibroblast activation and suppressed M2 macrophage polarization in the obstructed kidney. Conclusion and Implications: Our study identifies JMJD3 as a critical regulator of myeloid fibroblast activation, macrophage polarization, and renal fibrosis development. Therefore, JMJD3 may represent a promising therapeutic target for chronic kidney disease. [ABSTRACT FROM AUTHOR]

Background and Purpose: MicroRNA‐9 (miR‐9) has previously been described as a dual‐functional RNA during breast cancer progression and its roles need to be clarified thoroughly. Experimental Approach: A miR‐9 knockout mode of mouse breast cancer, the MMTV‐PyMT model (PyMT‐miR‐9−/−), combined with different human breast cancer cell lines were used to evaluate the effects of miR‐9 on breast cancer initiation, progression and metastasis. Lin‐NECs (Neoplastic mammary epithelial cells) and pNECs (Pre‐neoplastic mammary epithelial cells) were isolated and subjected to tumour‐initiation assay. Whole‐mount staining of mammary gland and histology was performed to determine mammary gland growth. Tumour‐initiating analysis combining a series of in vitro experiments were carried out to evaluate miR‐9 roles in tumour‐initiating ability. RNA‐sequencing of human breast cancer cells, and mammary glands at hyperplastic stages and established tumours in PyMT and PyMT‐miR‐9−/− mice, ChIP and luciferase report assays were conducted to reveal the underlying mechanisms. Key Results: MiR‐9 is ectopically expressed in breast cancer and its level is negatively correlated with the prognosis, especially in basal‐like breast cancer patients. Additionally, miR‐9 is essential for breast cancer progression by promoting the expansion and activity of tumour‐initiating cells (TICs) in preneoplastic glands, established tumours and xenograft modes. Mechanistically, the activity of TICs hinges on a positive TGF‐β/miR‐9 regulatory loop mediated by the STARD13/YAP axis. Conclusions and Implications: These findings demonstrate that miR‐9 is an oncogenic miRNA rather than a tumour‐suppressor in breast cancer, calling for rectification of the model for this conserved and highly abundant miRNA. [ABSTRACT FROM AUTHOR]

Background and Purpose: High‐fat diet (HFD) induces dysregulated pathways in coronary artery endothelial cells (CAECs), which leads to altered regulation of vascular tone, tissue perfusion and increases the risk of coronary artery diseases. Ca2+‐activated K+ (KCa) channels are known to be associated with transient receptor potential (TRP) channels, which are important for regulating endothelial function. But how TRPV4 channels interacts with KCa channels in regulating coronary vascular tone in HFD mice requires further exploration. Experimental Approach: TRPV4 channel activity was assessed by fluorescent Ca2+ imaging. Interactions between TRPV4 and KCa3.1 channels were verified by co‐immunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site‐directed mutagenesis. Endothelium‐specific TRPV4 knockout (TRPV4EC−/−) mice were used to study the effect of the interactions between TRPV4‐KCa3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device. Key Results: TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca2+‐sensitive K+ channel (KCa3.1) in CAECs, affecting vasodilation and coronary blood flow. In mice fed a HFD diet, the coupling was damaged by a high concentration of plasma 1‐heptadecanoyl‐2‐hydroxy‐sn‐glycero‐3‐phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4‐KCa3.1 channels and to improve coronary arterial function. Conclusion and Implications: Our data highlight the importance of coupling between TRPV4 and KCa3.1 channels in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events. [ABSTRACT FROM AUTHOR]

Background and Purpose: Itch is associated with several pathologies and is a common drug‐induced side effect. Chloroquine (CQ) is reported to induce itch by activating the Mas‐related G protein‐coupled receptor MrgprA3 and subsequently TRPA1. In this study, we demonstrate that CQ employs at least two MrgprA3‐independent mechanisms to activate or sensitize TRPA1 and TRPV1. Experimental Approach: Patch clamp and calcium imaging were utilized to examine effects of CQ on TRPA1 and TRPV1 expressed in HEK 293T cells. Key Results: In calcium imaging, CQ induces a concentration‐dependent but MrgprA3‐independent activation of TRPA1 and TRPV1. Although CQ itself inhibits TRPA1 and TRPV1 in patch clamp recordings, co‐application of CQ and ultraviolet A (UVA) light evokes membrane currents through both channels. This effect is inhibited by the reducing agent dithiothreitol (DTT) and is reduced on mutants lacking cysteine residues accounting for reactive oxygen species (ROS) sensitivity. The combination of CQ and UVA light triggers an accumulation of intracellular ROS, removes fast inactivation of voltage‐gated sodium currents and activates TRPV2. On the other hand, CQ is a weak base and induces intracellular alkalosis. Intracellular alkalosis can activate TRPA1 and TRPV1, and CQ applied at alkaline pH values indeed activates both channels. Conclusion and Implications: Our data reveal novel pharmacological properties of CQ, allowing activation of TRPA1 and TRPV1 via photosensitization as well as intracellular alkalosis. These findings add more complexity to the commonly accepted dogma that CQ‐induced itch is specifically mediated by MrgprA3 coupling to TRPA1. [ABSTRACT FROM AUTHOR]

Background and Purpose: Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil‐associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil‐associated psoriasiform dermatitis. Experimental Approach: The anti‐inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod‐induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms. Key Results: This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti‐inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3‐kinase (PI3K) but not CDK4/6 in human neutrophils. Palbociclib preferentially targeted the p110δ catalytic subunit of PI3K and thereby blocked signalling via the PI3K/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod‐induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up‐regulation. Conclusions and Implications: This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil‐associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: Vascular smooth muscle cells (SMCs) undergo phenotypic switching during sustained inflammation, contributing to an unfavourable atherosclerotic plaque phenotype. PPARδ plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we explored the pathological roles of PPARδ in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidated the underlying mechanisms. Experimental Approach: Plasma levels of PPARδ were measured in patients with acute coronary syndrome (ACS) and stable angina (SA). SMC contractile and synthetic phenotypic markers, endoplasmic reticulum (ER) stress, and features of atherosclerotic plaque vulnerability were analysed for the brachiocephalic artery of apolipoprotein E‐knockout (ApoE−/−) mice, fed a high‐cholesterol diet (HCD) and treated with or without the PPARδ agonist GW501516. In vitro, the role of PPARδ was elucidated using human aortic SMCs (HASMCs). Key Results: Patients with ACS had significantly lower plasma PPARδ levels than those with SA. GW501516 reduced atherosclerotic plaque vulnerability, a synthetic SMC phenotype, ER stress markers, and NLRP3 inflammasome expression in HCD‐fed ApoE−/− mice. ER stress suppressed PPARδ expression in HASMCs. PPARδ activation inhibited ER stress‐induced synthetic phenotype development, ER stress‐NLRP3 inflammasome axis activation and matrix metalloproteinase 2 (MMP2) expression in HASMCs. PPARδ inhibited NFκB signalling and alleviated ER stress‐induced SMC phenotypic switching. Conclusions and Implications: Low plasma PPARδ levels may be associated with atherosclerotic plaque vulnerability. Our findings provide new insights into the mechanisms underlying the protective effect of PPARδ on SMC phenotypic switching and improvement the features of atherosclerotic plaque vulnerability. [ABSTRACT FROM AUTHOR]

Background and Purpose: Acute respiratory distress syndrome (ARDS) is a catastrophic pulmonary inflammatory dysfunction with a high mortality rate. An overwhelming immune response by neutrophils is a key feature in infective or sterile ARDS. The formyl peptide receptor 1 (FPR1) is a crucial damage‐sensing receptor for inflammatory reactions in the initiation and progression of neutrophil‐mediated ARDS. However, effective targets for controlling dysregulated neutrophilic inflammatory injuries in ARDS are limited. Experimental Approach: Human neutrophils were used to explore the anti‐inflammatory effects of cyclic lipopeptide anteiso‐C13‐surfactin (IA‐1) from marine Bacillus amyloliquefaciens. The lipopolysaccharide‐induced model of ARDS in mice was used to determine the therapeutic potential of IA‐1 in ARDS. Lung tissues were harvested for histology analyses. Key Results: The lipopeptide IA‐1 inhibited immune responses of neutrophils, including respiratory burst, degranulation, and expression of adhesion molecules. IA‐1 inhibited the binding of N‐formyl peptides to FPR1 in human neutrophils and in hFPR1‐transfected HEK293 cells. We identified IA‐1 as a competitive FPR1 antagonist, thus diminishing the downstream signalling pathways involving calcium, mitogen‐activated protein kinases and Akt. Furthermore, IA‐1 ameliorated the inflammatory damage to lung tissue, by decreasing neutrophil infiltration, reducing elastase release and oxidative stress in endotoxemic mice. Conclusion and Implications: The lipopeptide IA‐1 could serve as a therapeutic option for ARDS by inhibiting FPR1‐mediated neutrophilic injury. [ABSTRACT FROM AUTHOR]

Background and Purpose: Drugs of abuse, including alcohol, increase dopamine in the mesocorticolimbic system via actions on dopamine neurons in the ventral tegmental area (VTA). Increased dopamine transmission can activate inhibitory G protein signalling pathways in VTA dopamine neurons, including those controlled by GABAB and D2 receptors. Members of the R7 subfamily of regulator of G protein signalling (RGS) proteins can regulate inhibitory G protein signalling, but their influence on VTA dopamine neurons is unclear. Here, we investigated the influence of RGS6, an R7 RGS family memberthat has been implicated in the regulation of alcohol consumption in mice, on inhibitory G protein signalling in VTA dopamine neurons. Experimental Approach: We used molecular, electrophysiological and genetic approaches to probe the impact of RGS6 on inhibitory G protein signalling in VTA dopamine neurons and on binge‐like alcohol consumption in mice. Key Results: RGS6 is expressed in adult mouse VTA dopamine neurons and it modulates inhibitory G protein signalling in a receptor‐dependent manner, tempering D2 receptor‐induced somatodendritic currents and accelerating deactivation of synaptically evoked GABAB receptor‐dependent responses. RGS6−/− mice exhibit diminished binge‐like alcohol consumption, a phenotype replicated in female (but not male) mice lacking RGS6 selectively in VTA dopamine neurons. Conclusions and Implications: RGS6 negatively regulates GABAB‐ and D2 receptor‐dependent inhibitory G protein signalling pathways in mouse VTA dopamine neurons and exerts a sex‐dependent positive influence on binge‐like alcohol consumption in adult mice. As such, RGS6 may represent a new diagnostic and/or therapeutic target for alcohol use disorder. [ABSTRACT FROM AUTHOR]

Background and Purpose: Respiratory diseases have become a global health problem and may lead to acute lung injury (ALI) in severe cases. ALI progression is associated with complex pathological changes; however, there are currently no effective therapeutic drugs. Excessive activation and recruitment of immunocytes in the lungs and the release of large amounts of cytokines are considered the primary causes of ALI, but the cellular mechanisms involved remain unknown. Therefore, new therapeutic strategies need to be developed to control the inflammatory response and prevent the further aggravation of ALI. Experimental Approach: Lipopolysaccharide was administered to mice via tail vein injection to establish an ALI model. Key genes regulating lung injury in mice were screened by RNA sequencing (RNA‐seq), and their regulatory effects on inflammation and lung injury were assessed in in vivo and in vitro experiments. Key Results: The key regulatory gene KAT2A up‐regulated the expression of inflammatory cytokines and induced lung epithelial injury. Chlorogenic acid, a small natural molecule and KAT2A inhibitor, inhibited the inflammatory response and significantly improved the decreased respiratory function caused by lipopolysaccharide administration in mice by inhibiting the expression of KAT2A. Conclusion and Implications: Targeted inhibition of KAT2A suppressed the release of inflammatory cytokines and improved respiratory function in this murine model of ALI. Chlorogenic acid, a specific KAT2A‐targeting inhibitor, was effective in treating ALI. In conclusion, our results provide a reference for the clinical treatment of ALI and contribute to the development of novel therapeutic drugs for lung injury. [ABSTRACT FROM AUTHOR]

Background and Purpose: The causal relationship between altered host microbiome composition, especially the respiratory tract microbiome, and the occurrence of pulmonary hypertension (PH) has not yet been studied. An increased abundance of airway streptococci is seen in patients with PH compared with healthy individuals. This study aimed to determine the causal link between elevated airway exposure to Streptococcus and PH. Experimental Approach: The dose‐, time‐ and bacterium‐specific effects of Streptococcus salivarius (S. salivarius), a selective streptococci, on PH pathogenesis were investigated in a rat model established by intratracheal instillation. Key Results: Exposure to S. salivarius successfully induced typical PH characteristics, such as elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy (Fulton's index) and pulmonary vascular remodelling, in a dose‐ and time‐dependent manner. Moreover, the S. salivarius‐induced characteristics were absent in either the inactivated S. salivarius (inactivated bacteria control) treatment group or the Bacillus subtilis (active bacteria control) treatment group. Notably, S. salivarius‐induced PH is characterized by elevated inflammatory infiltration in the lungs, in a pattern different from the classic hypoxia‐induced PH model. Moreover, in comparison with the SU5416/hypoxia‐induced PH model (SuHx‐PH), S. salivarius‐induced PH causes similar histological changes (pulmonary vascular remodelling) but less severe haemodynamic changes (RVSP, Fulton's index). S. salivarius‐induced PH is also associated with altered gut microbiome composition, suggesting potential communication of the lung‐gut axis. Conclusion and Implications: This study provides the first evidence that the delivery of S. salivarius in the respiratory tract could cause experimental PH in rats. [ABSTRACT FROM AUTHOR]

Background and Purpose: The protein PIEZO1 forms mechanically activated, calcium‐permeable, non‐selective cation channels in numerous cell types from several species. Options for pharmacological modulation are limited and so we modified a small‐molecule agonist at PIEZO1 channels (Yoda1) to increase the ability to modulate these channels. Experimental Approach: Medicinal chemistry generated Yoda1 analogues that were tested in intracellular calcium and patch‐clamp assays on cultured cells exogenously expressing human or mouse PIEZO1 or mouse PIEZO2. Physicochemical assays and wire myography assays on veins from mice with genetic disruption of PIEZO1. Key Results: A Yoda1 analogue (KC159) containing 4‐benzoic acid instead of the pyrazine of Yoda1 and its potassium salt (KC289) have equivalent or improved reliability, efficacy and potency, compared with Yoda1 in functional assays. Tested against overexpressed mouse PIEZO1 in calcium assays, the order of potency (as EC50 values, nM) was KC289, 150 > KC159 280 > Yoda1, 600). These compounds were selective for PIEZO1 over other membrane proteins, and the physicochemical properties were more suited to physiological conditions than those of Yoda1. The vasorelaxant effects were consistent with PIEZO1 agonism. In contrast, substitution with 2‐benzoic acid failed to generate a modulator. Conclusion and Implications: 4‐Benzoic acid modification of Yoda1 improves PIEZO1 agonist activity at PIEZO1 channels. We suggest naming this new modulator Yoda2. It should be a useful tool compound in physiological assays and facilitate efforts to identify a binding site. Such compounds may have therapeutic potential, for example, in diseases linked genetically to PIEZO1 such as lymphatic dysplasia. [ABSTRACT FROM AUTHOR]

Background and Purpose: Despite its contradictory clinical performance, remdesivir (Veklury®) has a pivotal role in COVID‐19 therapy. Possible contributions of the vehicle, sulfobutylether‐β‐cyclodextrin (SBECD) to Veklury® effects have been overlooked. The powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane‐coupled events of SARS‐CoV‐2 infection focusing on the cholesterol depletion‐mediated role of SBECD. Experimental Approach: Using time‐correlated flow cytometry and quantitative three‐dimensional confocal microscopy, we studied early molecular events of SARS‐CoV‐2–host cell membrane interactions. Key Results: Veklury® and different cholesterol‐depleting cyclodextrins (CDs) reduced binding of the spike receptor‐binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan‐Hu‐1, Delta and Omicron variants. Correlations of these effects with cholesterol‐dependent changes in membrane structure and decreased lipid raft‐dependent ACE2–TMPRSS2 interaction establish that SBECD is not simply a vehicle but also an effector along with remdesivir due to its cholesterol‐depleting potential. Veklury® solution inhibited RBD binding more efficiently due to its twice higher SBECD content. The CD‐induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression, indicating that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low. Conclusion and Implications: Our findings call for the differentiation of Veklury® formulations in meta‐analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant cyclodextrin (CD) therapy, even at higher doses, in COVID‐19. [ABSTRACT FROM AUTHOR]

Background and Purpose: Therapies based on apolipoprotein A‐I (ApoA‐I), classically tested for cardiovascular diseases, were recently proposed for Alzheimer's disease (AD). Based on a drug reprofiling approach, our objective was to explore the use of a natural variant of ApoA‐I form, ApoA‐I‐Milano (M), as a treatment for AD. ApoA‐I‐M contains the R173C mutation, and confers protection against atherosclerosis development, although ApoA‐I‐M carriers exhibit low HDL levels. Experimental Approach: Middle‐aged (12‐month‐old) and aged (21‐month‐old) APP23 mice were intraperitoneally treated for 10 weeks with human recombinant ApoA‐I‐M (hrApoA‐I‐M) protein or saline. Pathology progression through behavioural parameters and biochemical determinations was evaluated. Key Results: In middle‐aged group, hrApoA‐I‐M treatment reduced the anxiety behaviour associated with this AD model. In aged mice, hrApoA‐I‐M reversed T‐Maze performance alterations, a cognitive improvement accompanied by neuronal loss recovery in the dentate gyrus. Aged mice treated with hrApoA‐I‐M showed lower brain Aβ40 soluble levels and elevated Aβ40 levels in cerebrospinal fluid, without modifying insoluble brain Aβ burden. Interestingly, hrApoA‐I‐M sub‐chronic treatment induced a molecular effect on the cerebrovasculature, increasing occludin expression and ICAM‐1 presence, as well as promoting an elevation of plasma soluble RAGE in all hrApoA‐I‐M‐treated mice, drastically decreasing the AGEs/sRAGE ratio, a marker of endothelial damage. Conclusion and Implications: Peripheral hrApoA‐I‐M treatment shows a beneficial impact on working memory, involving mechanisms related with brain Aβ mobilization and modulation of the levels of cerebrovascular markers. Our study shows the potential therapeutic applicability of a safe and non‐invasive treatment based on peripheral administration of hrApoA‐I‐M in AD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Heart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). The microsomal prostaglandin E synthase‐1 (mPGES‐1)/PGE2 pathway has been shown to constrain reperfusion injury after acute myocardial ischaemia. However, it is unknown whether pharmacological inhibition of mPGES‐1, a target with lower risk of thrombosis compared with selective inhibition of cyclooxygenase‐2, affects chronic cardiac remodelling after MI. Experimental Approach: Mice were subjected to left anterior descending coronary artery ligation, followed by intraperitoneal treatment with the mPGES‐1 inhibitor compound III (CIII) or 118, celecoxib (cyclooxygenase‐2 inhibitor) or vehicle, once daily for 28 days. Urinary prostanoid metabolites were measured by liquid chromatography–tandem mass spectrometry. Key Results: Chronic administration of CIII improved cardiac function in mice after MI compared with vehicle or celecoxib. CIII did not affect thrombogenesis or blood pressure. In addition, CIII reduced infarct area, augmented scar thickness, decreased collagen I/III ratio, decreased the expression of fibrosis‐related genes and increased capillary density in the ischaemic area. Shunting to urinary metabolites of PGI2, not thromboxane B2 or PGD2, after inhibition of mPGES‐1 was positively correlated with cardiac function after MI. CIII administration significantly increased urinary PGI2/PGE2 metabolite ratio compared to vehicle or celecoxib. The PGI2/PGE2 metabolite ratio correlated positively with ejection fraction, fractional shortening and scar thickness. Treatment with 118 also improved cardiac function. Conclusion and Implications: Inhibition of mPGES‐1 prevented chronic adverse cardiac remodelling via an augmented PGI2/PGE2 metabolite ratio and therefore represents a potential therapeutic strategy for development of HFrEF after MI. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic inflammation is pathogenic and contributes to human diseases, causing a significant threat to public health. The NLR family pyrin domain‐containing protein 3 (NLRP3) is the best‐characterized factor regulating inflammation. Therefore, targeting NLRP3 has the potential to treat inflammatory diseases and improve human health. Experimental Approach: Lipopolysaccharide was used to induce inflammation in cell cultures. Lipopolysaccharide/d‐galactosamine and dextran sulfate sodium salt were used to induce acute liver inflammation and ulcerative colitis respectively in C57BL/6J mice. Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme‐linked immunosorbent assay (ELISA) were used to evaluate the activation of the inflammatory response in cell cultures and in mice. Key Results: JNUTS013, a novel sorbicillinoid compound recently synthesized by us, significantly inhibited inflammation both in cell cultures and in mouse models. Mechanistically, JNUTS013 induced proteasome‐dependent degradation of NLRP3. Hence, it suppressed the formation of the NLRP3 inflammasome and the production of downstream inflammatory cytokines and chemokines. The inhibitory effect of JNUTS013 on NLRP3 protein expression was confirmed in mice. Importantly, JNUTS013 failed to ameliorate bowel inflammation in Nlrp3‐/‐ knockout mice, supporting NLRP3 as the biological target by which JNUTS013 inhibits inflammation. Further studies revealed critical chemical moieties of JNUTS013 required for inducing NLRP3 degradation. Conclusion and Implications: This study identifies a novel compound JNUTS013 that inhibits inflammation through inducing NLRP3 protein degradation in vitro and in vivo, which not only supports the development of JNUTS013 as an anti‐inflammation agent but also creates a new way for the treatment of inflammation by chemically inducing NLRP3 degradation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cardiovascular disease affects up to half of the patients with chronic obstructive pulmonary disease (COPD), exerting deleterious impact on health outcomes and survivability. Vascular endothelial dysfunction marks the onset of cardiovascular disease. The present study examined the effect of a potent NADPH Oxidase (NOX) inhibitor and free‐radical scavenger, apocynin, on COPD‐related cardiovascular disease. Experimental Approach: Male BALB/c mice were exposed to either room air (Sham) or cigarette smoke (CS) generated from 9 cigarettes·day−1, 5 days a week for up to 24 weeks with or without apocynin treatment (5 mg·kg−1·day−1, intraperitoneal injection). Key Results: Eight‐weeks of apocynin treatment reduced airway neutrophil infiltration (by 42%) and completely preserved endothelial function and endothelial nitric oxide synthase (eNOS) availability against the oxidative insults of cigarette smoke exposure. These preservative effects were maintained up until the 24‐week time point. 24‐week of apocynin treatment markedly reduced airway inflammation (reduced infiltration of macrophage, neutrophil and lymphocyte), lung function decline (hyperinflation) and prevented airway collagen deposition by cigarette smoke exposure. Conclusion and Implications: Limiting NOX activity may slow COPD progression and lower cardiovascular disease risk, particularly when signs of oxidative stress become evident. [ABSTRACT FROM AUTHOR]

Background and Purpose: Traumatic brain injury (TBI) comprises a primary injury directly induced by impact, which progresses into a secondary injury leading to neuroinflammation, reactive astrogliosis, and cognitive and motor damage. To date, treatment of TBI consists solely of palliative therapies that do not prevent and/or limit the outcomes of secondary damage and only stabilize the deficits. The neurotrophin, nerve growth factor (NGF), delivered to the brain parenchyma following intranasal application, could be a useful means of limiting or improving the outcomes of the secondary injury, as suggested by pre‐clinical and clinical data. Experimental Approach: We evaluated the effect of acute intranasal treatment of young (20‐postnatal day) rats, with NGF in a TBI model (weight drop/close head), aggravated by hypoxic complications. Immediately after the trauma, rats were intranasally treated with human recombinant NGF (50 μg·kg−1), and motor behavioural test, morphometric and biochemical assays were carried out 24 h later. Key Results: Acute intranasal NGF prevented the onset of TBI‐induced motor disabilities, and decreased reactive astrogliosis, microglial activation and IL‐1β content, which after TBI develops to the same extent in the impact zone and the hypothalamus. Conclusion and Implications: Intranasal application of NGF was effective in decreasing the motor dysfunction and neuroinflammation in the brain of young rats in our model of TBI. This work forms an initial pre‐clinical evaluation of the potential of early intranasal NGF treatment in preventing and limiting the disabling outcomes of TBI, a clinical condition that remains one of the unsolved problems of paediatric neurology. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic heart failure, a progressive disease with limited treatment options currently available, especially in heart failure with preserved ejection fraction (HFpEF), represents an unmet medical need as well as an economic burden. The development of a novel therapeutic to slow or reverse disease progression would be highly impactful to patients and society. Relaxin‐2 (relaxin) is a human hormone regulating cardiovascular, renal, and pulmonary adaptations during pregnancy. A short‐acting recombinant relaxin, Serelaxin, demonstrated short‐term heart failure symptom relief and biomarker improvement in acute heart failure trials. Here, we present the development of a long‐acting relaxin analogue to be tested in the treatment of chronic heart failure. Experimental Approach: LY3540378 is a long‐acting protein therapeutic composed of a human relaxin analogue and a serum albumin‐binding VHH domain. Key Results: LY3540378 is a potent agonist of the relaxin family peptide receptor 1 (RXFP1) and maintains selectivity against RXFP2/3/4 comparable to native relaxin. The half‐life of LY3540378 in preclinical species is extended through high affinity binding of the albumin‐binding VHH domain to serum albumin. When tested in a single dose administration, LY3540378 elicited relaxin‐mediated pharmacodynamic responses, such as reduced serum osmolality and increased renal blood flow in rats. In an isoproterenol‐induced cardiac hypertrophy mouse model, treatment with LY3540378 significantly reduced cardiac hypertrophy and improved isovolumetric relaxation time. In a monkey cardiovascular safety study, there were no adverse observations from administration of LY3540378. Conclusion and Implications: LY3540378 demonstrated to be a suitable clinical development candidate, and is progressing in clinical trials. [ABSTRACT FROM AUTHOR]

Epigenetics studies the heritable modifications of genome expression that do not affect the nucleotide sequence. Epigenetic modifications can be divided into: DNA methylation, histone modifications, and modulation of genome expression by non‐coding RNAs. Alteration of these mechanisms can alter the phenotype, and can lead to disease onset. The endogenous gasotransmitter hydrogen sulfide (H2S) plays pleiotropic roles in many systems, including the cardiovascular (CV) system, and its mechanism of action mainly includes S‐persulfidation of cysteine residues. Recent evidence suggests that many H2S‐mediated biological activities are based on the epigenetic regulation of cellular function, with effects ranging from DNA methylation to modification of histones and regulation of non‐coding RNAs. This review describes the role of H2S‐regulating epigenetic mechanisms, providing a panorama of the current literature, and offers a novel scenario for the development of H2S‐releasing 'epidrugs' with a potential clinical use in the prevention and treatment of many CV and non‐CV disorders. [ABSTRACT FROM AUTHOR]

Background and Purpose: All previous rodent models lacking the peptide hormone angiotensin II (Ang II) were hypotensive. A mixed background strain with global deletion of the angiotensinogen gene was backcrossed to the FVB/N background (Agt‐KO), a strain preferred for transgenic generation. Surprisingly, the resulting line turned out to be normotensive. Therefore, this study aimed to understand the unique blood pressure regulation of FVB/N mice without angiotensin peptides. Experimental Approach: Acute and chronic recordings of blood pressure (BP) in freely‐moving adult mice were performed to establish baseline BP. The pressure responses to sympatholytic and sympathomimetic as well as a nitric oxide inhibitor and donor compounds were used to quantify the neurogenic tone and endothelial function. The role of the renal nerves on baseline BP maintenance was tested by renal denervation. Finally, further phenotyping was done by gene expression analysis, histology and measurement of metabolites in plasma, urine and tissues. Key Results: Baseline BP in adult FVB/N Agt‐KO was unexpectedly unaltered. As compensatory mechanisms Agt‐KO presented an increased sympathetic nerve activity and reduced endothelial nitric oxide production. However, FVB/N Agt‐KO exhibited the renal morphological and physiological alterations previously found in mice lacking the production of Ang II including polyuria and hydronephrosis. The hypotensive effect of bilateral renal denervation was blunted in Agt‐KO compared to wildtype FVB/N mice. Conclusion and Implications: We describe a germline Agt‐KO line that challenges all previous knowledge on BP regulation in mice with deletion of the classical RAS. This line may represent a model of drug‐resistant hypertension because it lacks hypotension. [ABSTRACT FROM AUTHOR]

Background and Purpose: Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug‐seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]–ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine. Experimental Approach: In a model of cocaine self‐administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anaesthetised rats during early and protracted abstinence and evaluated the involvement of the BLA–VP pathway using a pharmacological approach. Key Results: We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short‐term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity. Conclusion and Implications: Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA–VP pathway in cocaine‐induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence. [ABSTRACT FROM AUTHOR]

Background and Purpose: Repeated amino acid sequences in proteins are widely found, and the glycine–serine–alanine repeat is an element with a general propensity to form β‐sheet aggregates as found in key pathological factors, in several neurodegenerative diseases. Such properties of this repeat may guide development of disease‐modifying therapies for neurodegenerative disease. However, details of its role and underlying mechanism(s) remain largely unknown. Experimental Approach: Actions of specific glycine–serine–alanine repeat peptides (SNPs), especially SNP‐9, on Alzheimer's disease (AD)‐like abnormalities were evaluated in transgenic mice and Caenorhabditis elegans, and in rat and cell models. Entry of SNPs into the brain, SNP activity in neuronal cells and peptide entry into cells were analysed in vivo and in vitro. Cell‐free systems and the yeast two‐hybrid system were also used to explore possible targets of SNP‐9, and interactions of potential targets with SNP‐9 were confirmed in cell‐based systems. Key Results: We first identified SNP‐9 as a potent neuroprotective peptide with the activity to decrease oligomeric amyloid β (Aβ) via co‐assembling with the toxic Aβ oligomer to form hetero‐oligomers. Also, calcyclin‐binding protein was found to act as a SNP‐9‐binding protein, by screening of a human brain cDNA library. Such binding showed that SNP‐9 could regulate the abnormal hyperphosphorylation of tau via calcyclin‐binding protein. Conclusion and Implications: Our study provides a foundation for development of SNPs, especially SNP‐9, as potential therapeutic interventions for AD. We propose SNP‐9 as a potential therapeutic agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Optimal antibiotic prophylaxis is crucial to prevent postoperative infection in spinal surgery. Sufficient time above the minimal inhibitory concentration (fT > MIC) for relevant bacteria in target tissues is required for cefuroxime. We assessed cefuroxime concentrations and fT > MIC of 4 μg·ml−1 for Staphylococcus aureus in the intrathecal (spinal cord and cerebrospinal fluid, CSF) and extrathecal (epidural space) compartments of the lumbar spine. Experimental Approach: Eight female pigs were anaesthetized and laminectomized at L3–L4. Microdialysis catheters were placed for sampling in the spinal cord, CSF, and epidural space. A single dose of 1500 mg cefuroxime was administered intravenously over 10 min. Microdialysates and plasma were obtained continuously during 8 h. Cefuroxime concentrations were determined by ultra‐high‐performance liquid chromatography. Key Results: Mean fT > MIC (4 μg·ml−1) was 58 min in the spinal cord, 0 min in the CSF, 115 min in the epidural space, and 123 min in plasma. Tissue penetration was 32% in the spinal cord, 7% in the CSF, and 63% in the epidural space. Conclusion and Implications: fT > MIC (4 μg·ml−1) and tissue penetration for cefuroxime were lower in the intrathecal compartments (spinal cord and CSF) than in the extrathecal compartment (epidural space) and plasma, suggesting a significant effect of the blood–brain barrier. In terms of fT > MIC, a single dose of 1500 mg cefuroxime seems inadequate to prevent intrathecal infections related to spinal surgery for bacteria presenting with a MIC target of 4 μg· ml−1 or above. [ABSTRACT FROM AUTHOR]

Background and Purpose: Piezo1 channels are mechanosensitive cationic channels that are activated by mechanical stretch or shear stress. Endothelial Piezo1 activation by shear stress caused by blood flow induces ATP release from endothelial cells; however, the link between shear stress and endothelial ATP production is unclear. Experimental Approach: The mitochondrial respiratory function of cells was measured by using high‐resolution respirometry system Oxygraph‐2k. The intracellular Ca2+ concentration was evaluated by using Fluo‐4/AM and mitochondrial Ca2+ concentration by Rhod‐2/AM. Key Results: The specific Piezo1 channel activator Yoda1 or its analogue Dooku1 increased [Ca2+]i in human umbilical vein endothelial cells (HUVECs), and both Yoda1 and Dooku1 increased mitochondrial oxygen consumption rates (OCRs) and mitochondrial ATP production in HUVECs and primary cultured rat aortic endothelial cells (RAECs). Knockdown of Piezo1 inhibited Yoda1‐ and Dooku1‐induced increases of mitochondrial OCRs and mitochondrial ATP production in HUVECs. The shear stress mimetics, Yoda1 and Dooku1, and the Piezo1 knock‐down technique also demonstrated that Piezo1 activation increased glycolysis in HUVECs. Chelating extracellular Ca2+ with EGTA or chelating cytosolic Ca2+ with BAPTA‐AM did not affect Yoda1‐ and Dooku1‐induced increases of mitochondrial OCRs and ATP production, but chelating cytosolic Ca2+ inhibited Yoda1‐ and Dooku1‐induced increase of glycolysis. Confocal microscopy showed that Piezo1 channels are present in mitochondria of endothelial cells, and Yoda1 and Dooku1 increased mitochondrial Ca2+ in endothelial cells. Conclusion and Implications: Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells, suggesting a novel role of Piezo1 channel in endothelial ATP production. [ABSTRACT FROM AUTHOR]