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During the inflammatory storm of sepsis, a significant quantity of neutrophil extracellular traps (NETs) are generated, which act as a double-edged sword and not only impede the invasion of foreign microorganisms but also exacerbate organ damage. This study provides evidence that NETs can cause damage to alveolar epithelial cells in vitro. The sepsis model developed in this study showed a significant increase in NETs in the bronchoalveolar lavage fluid (BALF). The development of NETs has been shown to increase the lung inflammatory response and aggravate injury to alveolar epithelial cells. Bay-117082, a well-known NF-κB suppressor, is used to modulate inflammation. This analysis revealed that Bay-117082 efficiently reduced total protein concentration, myeloperoxidase activity, and inflammatory cytokines in BALF. Moreover, Bay-117082 inhibited the formation of NETs, which in turn prevented the activation of the pore-forming protein gasdermin D (GSDMD). In summary, these results indicated that excessive NET production during sepsis exacerbated the onset and progression of acute lung injury (ALI). Therefore, Bay-117082 could serve as a novel therapeutic approach for ameliorating sepsis-associated ALI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS), which leads to demyelination, axonal loss, and neurodegeneration. Increased oxidative stress and neurodegeneration have been implicated in all stages of MS, making neuroprotective therapeutics a promising strategy for its treatment. We previously have reported vinyl sulfones with antioxidative and anti-inflammatory properties that activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces the expression of cytoprotective genes against oxidative stress. In this study, we synthesized vinyl sulfoximine derivatives by modifying the core structure and determined therapeutic potential as Nrf2 activators. Among them, 10v effectively activated Nrf2 (EC 50 = 83.5 nM) and exhibited favorable drug-like properties. 10v successfully induced expression of Nrf2-dependent antioxidant enzymes and suppressed lipopolysaccharide (LPS)-induced inflammatory responses in BV-2 microglial cells. We also confirmed that 10v effectively reversed disease progression and attenuated demyelination in an experimental autoimmune encephalitis (EAE) mouse model of MS.

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The EXCITE-HT study aimed to evaluate the efficacy and safety of esaxerenone versus thiazide diuretics (trichlormethiazide) as second-line treatment for Japanese patients with uncontrolled essential hypertension. This was a 12-week, multicenter, randomized, open-label, parallel-group study. The non-inferiority of esaxerenone to trichlormethiazide was confirmed if the upper limit of the two-sided 95% confidence interval (CI) for the difference in systolic blood pressure (SBP)/diastolic blood pressure (DBP) change between groups was below 3.9/2.1 mmHg. A total of 295 and 290 patients were included in the esaxerenone and trichlormethiazide groups, respectively. The non-inferiority of esaxerenone to trichlormethiazide was demonstrated: least squares mean change differences in morning home SBP/DBP at end of treatment (EOT) were -2.2 (95% CI, -3.6, -0.8) mmHg for SBP/-0.6 (-1.4, 0.2) mmHg for DBP. Morning home, bedtime home, and office BP significantly decreased (all p < 0.001) from baseline to EOT in both groups. The urinary albumin-to-creatinine ratio and N-terminal pro-brain natriuretic peptide level decreased from baseline to Week 12 in both groups, with no notable intergroup difference. Serum potassium elevations occurred more frequently with esaxerenone, while serum potassium reductions occurred more with trichlormethiazide. Uric acid elevations were observed in both groups, but more frequently with trichlormethiazide than esaxerenone. No cases of gout occurred in this study. Reductions in estimated glomerular filtration rate were similarly observed in both groups. EXCITE-HT is the first randomized controlled study to demonstrate evidence that esaxerenone is non-inferior to trichlormethiazide as second-line treatment for Japanese patients with uncontrolled essential hypertension, with no new safety concerns. The EXCITE-HT study demonstrated the non-inferiority of esaxerenone to trichlormethiazide in its morning home blood pressure lowering effect and safety profile in Japanese patients with uncontrolled essential hypertension who were previously treated with an angiotensin II receptor blocker or calcium channel blocker., (© 2024. The Author(s).)

Anaplastic lymphoma kinase (ALK) fusion genes promote a variety of human malignancies. Although several ALK inhibitors have significantly improved disease prognosis in patients with ALK positive cancers, the persistent emergence of acquired drug-resistant mutations remain the major problem in clinic treatment. Adoption of new therapeutic strategies such as proteolysis targeting chimera (PROTAC) to overcome drug resistance in BTK/AR-related cancers have shown promising prospect. Herein, we reported the integrate ALK PROTACs through overall optimization of linker, revealed that subtle structural differences can lead to significant activity difference, indicating the key role of conformation of PROTACs in inducing the formation of E3-PROTAC-target protein ternary complexes. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. 4B effectively induced long lasting degradation of ALK fusion proteins and strong repression of downstream pathway in Karpas 299 cells (DC 50  = 119.33 nM, Dmax = 97.1 %) and showed comparable anti-proliferative activity to Ceritinib (IC 50  = 3.11 ± 0.08 nM vs IC 50  = 1.31 ± 0.43 nM). Furthermore, 4B significantly inhibited the growth of Karpas 299 xenografts in vivo with TGI of 49.5 % and showed superior anti-proliferative activity against G1202R mutation to Ceritinib (IC 50  = 52.82 nM vs IC 50  = 109.5 nM). Overall, 4B is expected to be a potential treatment for ALK-driven malignancies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Diabetic foot ulcers (DFUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Currently, there is a lack of effective therapeutic strategies. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has been reported to show strong anti-inflammation effects in many diseases. In this study, we unveiled the role of MCC950 in DFU mice model and its underlying molecular mechanisms. MCC950 could significantly accelerate diabetic wound healing, as shown by shortened healing time and better healing quality. Moreover, increased M2 phenotype macrophages and decreased pro-inflammatory genes were observed in MCC950-treated DFU mice. Additionally, myeloid-derived suppressor cells (MDSCs) were significantly increased in blood, spleen and wound tissues at different time courses. Specifically, MCC950 could recruit more MDSCs in an early phase in DFU mice, exerting an anti-inflammation effect. We identified the cell crosstalk between macrophages and MDSCs with MCC950 treatment process. Depleting MDSCs in vivo could eliminate the therapeutic effect of MCC950 on diabetic wound healing through inhibiting M2 macrophage polarization. Besides, MDSCs isolated from the wounds of MCC950 or saline treated mice were cocultured with bone marrow derived macrophage (BMDM) in a transwell system. Results confirmed that MDSCs sorted from MCC950 treated mice caused a significant increased percentage of M2 macrophages. Collectively, our findings suggest that the administration of MCC950 has the potential to accelerate diabetic wound healing by promoting M2 macrophage polarization in an MDSC-dependent manner. This study provides valuable insights into the utilization of pharmacological agents for DFU treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Obesity and type 2 diabetes mellitus (T2DM) are linked to osteoporosis development, with obesity being a significant risk factor for T2DM. T2DM patients with obesity exhibit a higher fracture rate and often have a poor prognosis post-fracture. To address the urgent need for understanding the mechanisms of diabetic osteoporosis (DOP), research is ongoing to explore how obesity and T2DM impact bone metabolism. The NLRP3 inflammasome has been implicated in the pathogenesis of osteoporosis, and MCC950, an NLRP3 inflammasome inhibitor, has shown promise in various diseases but its role in osteoporosis remains unexplored. In this study, BMMs and BMSCs were isolated and cultured to investigate the effects of MCC950 on bone metabolism, and DOP model was used to evaluate the efficacy of MCC950 in vivo. The study demonstrated that MCC950 treatment inhibited osteoclast differentiation, reduced bone resorption capacity in BMMs without suppression for osteoblast differentiation from BMSCs. Additionally, MCC950 suppressed the activation of the NF-κB signaling pathway and downregulated key factors associated with osteoclast differentiation. Additionally, MCC950 alleviated bone loss in DOP mouse. These findings suggest that MCC950, by targeting the NLRP3 inflammasome, may have a protective role in preventing osteoporosis induced by T2DM with obesity. The study highlights the potential therapeutic implications of MCC950 in managing diabetic osteoporosis and calls for further research to explore its clinical application in high-risk patient populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neurological disorder, characterized by cognitive deficits as one of its vital features. The nucleotide-binding oligomerization domain-like receptor (NLRP3) inflammasome is a key contributor to neuroinflammation and cognitive deficits in neurological diseases. However, the underlying mechanism of anti-NMDAR encephalitis remains unclear, and the biological function of the NLRP3 inflammasome in this condition has not been elucidated. In this study, a mouse model of anti-NMDAR encephalitis was induced by active immunization with the GluN1 356-385 peptide (NEA model). The NLRP3 inflammasome in the hippocampus and temporal cortex was investigated using real-time quantitative PCR (RT-qPCR), western blotting, and immunofluorescence staining. The impact of MCC950 on cognitive function and NLRP3 inflammation was assessed. Confocal immunofluorescence staining and Sholl analysis were employed to examine the function and morphology of microglia. In the current study, we discovered overactivation of the NLRP3 inflammasome and an enhanced inflammatory response in the NEA model, particularly in the hippocampus and temporal cortex. Furthermore, significant cognitive dysfunction was observed in the NEA model. While, MCC950, a selective inhibitor of the NLRP3 inflammasome, sharply attenuated the inflammatory response in mice, leading to mitigated cognitive deficits of mice and more regular arrangements of neurons and reduced number of hyperchromatic cells were also observed in the hippocampus area. In addition, we found that the excess elevation of NLRP3 inflammasome was mainly expressed in microglia accompanied with the overactivation of microglia, while MCC950 treatment significantly inhibited the increased number and activated morphological changes of microglia in the NEA model. Altogether, our study reveals the vital role of overactivated NLRP3 signaling pathway in aggravating the inflammatory response and cognitive deficits and the potential protective effect of MCC950 in anti-NMDAR encephalitis. Thus, MCC950 represents a promising strategy for anti-inflammation in anti-NMDAR encephalitis and our study lays a theoretical foundation for it to become a clinically targeted drug., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy., Methods: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling., Results: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042)., Conclusions: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs., (© 2024. The Author(s).)

Posttraumatic ankle osteoarthritis (PTAO) causes severe ankle and adjacent joint morbidity. We aimed to compare the treatment efficacy of previously tried and still applied intra-articular injections and oral methylsulfonylmethane (MSM) at functional and histopathological level in PTAO animal model. Thirty-two adult female Sprague-Dawley rats were divided into four groups (Group 1: Control, Group 2: 0.06 g/kg/day MSM, Group 3: 0.04 mg/µL methylprednisolone [MP], Group 4: 0.04 mg/µL hyaluronic acid [HA]). MSM was started orally between Day 0 to the end of 8 weeks. Intra-articular injections were applied to the right ankles of the subjects after surgery. All subjects were killed after radiological evaluation at the 8th week. Subsequently, functional (range of motion) and histopathological evaluation was performed. Radiological evaluation showed better results of the MP (p < 0.001) and MSM (p < 0.001) groups than the control group. Severity of osteoarthritis (OA) in the MP group was significantly less than in the HA group (p = 0.032). When the total Osteoarthritis Research Society International score was compared, the severity of OA was higher in the KS and HA groups than in the control group (p < 0.001). No significant statistical difference was found in the histopathological comparison of MSM and control group (p = 0.466). There was no difference between the groups in range of motion measurement according to the contralateral ankle joint. The radiological progression of OA was slowed in the MSM and MP groups, but significant histopathological worsening was found in the MP and HA applied groups. We suggest that the treatment methods used in daily practice need to be reviewed., (© 2024 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Current medical therapies for fibroids have major limitations due to their hypoestrogenic side effects. Based on our previous work showing the activation of NF-kB in fibroids, we hypothesized that inhibiting NF-kB in vivo would result in the shrinkage of tumors and reduced inflammation. Fibroid xenografts were implanted in SCID mice and treated daily with Bay 11-7082 (Bay) or vehicle for two months. Bay treatment led to a 50% reduction in tumor weight. RNAseq revealed decreased expression of genes related to cell proliferation, inflammation, extracellular matrix (ECM) composition, and growth factor expression. Validation through qRT-PCR, Western blotting, ELISA, and immunohistochemistry (IHC) confirmed these findings. Bay treatment reduced mRNA expression of cell cycle regulators ( CCND1 , E2F1 , and CKS2 ), inflammatory markers ( SPARC , TDO2 , MYD88 , TLR3 , TLR6 , IL6 , TNFα , TNFRSF11A , and IL1β ), ECM remodelers ( COL3A1 , FN1 , LOX , and TGFβ3 ), growth factors ( PRL , PDGFA , and VEGFC ), progesterone receptor, and miR-29c and miR-200c. Collagen levels were reduced in Bay-treated xenografts. Western blotting and IHC showed decreased protein abundance in certain ECM components and inflammatory markers, but not cleaved caspase three. Ki67, CCND1, and E2F1 expression decreased with Bay treatment. This preclinical study suggests NF-kB inhibition as an effective fibroid treatment, suppressing genes involved in proliferation, inflammation, and ECM remodeling.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALK G1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Exocrine pancreatic carcinomas are rarely reported in dogs. A ductal pancreatic adenocarcinoma in a 10-year-old intact beagle is described in this report. The diagnosis was made based on clinical signs, imaging (abdominal ultrasound and CT scan) and histopathology. Treatment consisted of partial right lobe pancreatectomy followed by adjuvant therapy with toceranib phosphate (Palladia®) and firocoxib (Previcox®) for six months. The treatment was well tolerated, and the survival time was 445 days. To our knowledge, this is the longest survival reported in the literature for a dog diagnosed with exocrine pancreatic adenocarcinoma. The results described here may contribute to provide a better understanding about this neoplasia and potential treatment options., (© 2024. The Author(s).)

Aims: To determine the concentration, in comparison with the maximum residue limit (MRL), of anthelmintic marker residues in the target tissues (liver and fat) of sheep treated concurrently with two oral drenches, one containing monepantel and abamectin and the other oxfendazole and levamisole., Methods: On day 0 of the study, 12 sheep (six male and six female; 8-9-months old) were dosed according to individual body weight determined the day prior. Zolvix Plus (dual-active oral drench containing 25 g/L monepantel and 2 g/L abamectin) was administered to all animals prior to administration of Scanda (dual-active oral drench containing 80 g/L levamisole hydrochloride and 45.3 g/L oxfendazole). Six sheep (three male and three female) were slaughtered 21 and 28 days after treatment and renal fat and liver samples were collected.Using validated methods, analyses for monepantel sulfone, abamectin, levamisole and oxfendazole (expressed as total fenbendazole sulfone following conversion of the combined concentrations of oxfendazole, fenbendazole and fenbendazole sulfone) were performed on liver samples while renal fat specimens were analysed for monepantel sulfone and abamectin residues only. Detected concentrations were compared to the established MRL in sheep for each analyte determined by the Ministry for Primary Industries., Results: All residues detected in samples of liver and fat collected 21 and 28 days after treatment were below the MRL for each analyte. All liver samples collected on day 21 had detectable monepantel sulfone (mean 232 (min 110, max 388) μg/kg) and oxfendazole (mean 98.7 (min 51.3, max 165) μg/kg) residues below the MRL (5,000 and 500 μg/kg, respectively). Monepantel sulfone (mean 644 (min 242, max 1,119) μg/kg; MRL 7,000 μg/kg) residues were detected in 6/6 renal fat samples. Levamisole residues were detected in 3/6 livers (mean 40.0 (min 14.3, max 78.3) μg/kg; MRL 100 μg/kg), and abamectin residues in 1/6 livers (0.795 μg/kg; MRL 25 μg/kg) and 2/6 fat samples, (mean 0.987 (min 0.514, max 1.46) μg/kg; MRL 50 μg/kg) 21 days after treatment., Conclusion and Clinical Relevance: These results suggest that concurrent administration of Zolvix Plus and Scanda to sheep is unlikely to result in an extended residue profile for any of the active ingredients, with all analytes measured being under the approved New Zealand MRL 21 days after treatment. This work was not completed in line with guidance for establishing official residue profiles, nor is it sufficient to propose a new withholding period.

This study aimed to assess the efficacy and safety of esaxerenone (CS-3150) in treating primary hypertension. PubMed (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched for articles published until April 18, 2023. The outcomes included were diastolic blood pressure (DBP), systolic blood pressure (SBP), 24 h DBP, 24 h SBP, and adverse events. The meta-analysis was conducted using RevMan 5.3. This study included three trials. CS-3150 5 mg had a greater effect on lowering the SBP, DBP, 24 h SBP, and 24 h DBP than either CS-3150 2.5 mg or eplerenone 50 mg. In contrast, CS-3150 2.5 mg and eplerenone 50 mg showed no significant difference in lowering DBP, SBP, 24 h DBP, and 24 h SBP. Moreover, adverse events occurred at comparable rates in the three groups. CS-3150 (especially CS-3150 5 mg) is an effective and safe treatment for primary hypertension; which can reduce blood pressure and alleviate hypertensive symptoms., (© 2024. The Author(s).)

Epilepsy is one of the most common serious chronic brain disorders, affecting up to 70 million people worldwide. Vascular disruption, including blood-brain barrier impairment and pathological angiogenesis, exacerbates its occurrence. However, its underlying mechanisms remain elusive. MCC950 is a specific small-molecule inhibitor that selectively blocks NLRP3 inflammatory vesicle activation across the blood-brain barrier, limits downstream IL-1β maturation and release, and exerts therapeutic effects across multiple diseases. In the present study, an epilepsy model was established by intraperitoneal administration of Kainic acid to adult male C57BL/6J wild-type mice. The results revealed that the epilepsy susceptibility of MCC950-treated mice was decreased, and neural damage following seizure episodes was reduced. In addition, immunofluorescence staining, RT-qPCR, and Western blot demonstrated that MCC950 inhibited the expression of the NLRP3 inflammasome and its related proteins in microglia, whereas microangiogenesis was found to be increased in the cerebral cortex and hippocampus of epileptic mice, and these effects could be reversed by MCC950. Furthermore, neurobehavioral impairment was observed in the epileptic mouse model, and MCC950 similarly alleviated the aforementioned pathological process. To the best of our knowledge, this is the first study to establish that pathological microangiogenesis is associated with NLRP3/IL-1β signaling pathway activation in a Kainic acid-induced epilepsy mouse model and that MCC950 administration attenuates the above-mentioned pathological changes and exerts neuroprotective effects. Therefore, MCC950 is a promising therapeutic agent for the treatment of epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Anaplastic lymphoma kinase (ALK) has been to be involved in the uptake and regulation of dopamine 2 receptor (D2R), a G protein-coupled receptor expressed in various brain regions. Therefore, it is crucial to understand the relationship between ALK inhibitors and seizures is an important issue. This study investigated the relationship between ALK inhibitors and seizures., Methods: This study investigated the relationship between ALK inhibitors and seizures through a disproportionality analysis using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The target drugs were the ALK inhibitors crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. The seizures covered were defined high-level group term (HLGT): "Seizures (incl. subtype)" including high-level term (HLT): "seizures and seizure disorders NEC." This study used the information component (IC), a signal score, as a Bayesian statistical method for disproportionality analysis. The signal detection criteria used in this study were the same as those reported previously: a lower limit of 95% credible interval (CrI) for IC >0., Results: The signal scores of '"seizures and seizure disorders not elsewhere classified (NEC)" "for each ALK inhibitor were crizotinib (IC: -0.00052, 95% CrI: -0.38-0.27), ceritinib (IC: 1.18, 95% CrI: 0.68-1.54), alectinib (IC: 0.68, 95% CrI: 0.19-1.02), brigatinib (IC: 1.04, 95% CrI: 0.32-1.54), and lorlatinib (IC: 0.82, 95% CrI: 0.11-1.32). On the other hand, "generalized tonic-clonic seizures," "partial simple seizures NEC," "absence seizures," and "partial complex seizures" had no or few reported cases, and no signal was detected., Conclusion: To our knowledge, this is the first report to evaluate the relationship between ALK inhibitors and seizures using post-marketing surveillance data. These results suggest that ceritinib, alectinib, brigatinib, and lorlatinib, which are highly brain-migrating drugs, are associated with seizures., (© 2024 S. Karger AG, Basel.)

Aims: The purpose of this study was to evaluate the role of the NLRP3-inflammasome in heart failure with preserved ejection fraction (HFpEF)., Main Methods: Serum inflammatory cytokines were detected in patients with heart failure. Correlation analysis was performed to investigate the relationship between serum inflammatory cytokines and left ventricular diastolic function. A 'two-hit' (metabolic stress and mechanical stress) mouse model of HFpEF was established. Furthermore, MCC950 was used to determine the role of NLRP3-inflammasome inhibition in cardiac and pulmonary artery remodelling in HFpEF mice., Key Findings: Compared with heart failure patients with reduced ejection fraction, patients with HFpEF have significantly elevated serum inflammatory cytokine levels. Serum NLRP3 and interleukin-1β levels were positively correlated with the diastolic function of HFpEF. In the HFpEF mouse model, the inhibition of the NLRP3-inflammasome by MCC950 improved exercise intolerance, glucose intolerance, and left ventricular diastolic function, but had no significant effect on systolic function. Meanwhile, MCC950 attenuated the release of inflammatory cytokines, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, the potential protective effects of MCC950 are achieved by inhibiting activation of the NLRP3-IL-1β pathway and cascade expansion of downstream inflammatory cytokines. Additionally, the inhibition of NLRP3-inflammasome by MCC950 reduced pulmonary artery pressure and improved pulmonary artery remodelling in HFpEF., Significance: The NLRP3-inflammasome plays a considerable role in inflammation and cardiac and pulmonary artery remodelling in HFpEF by activating the cascade reaction of inflammatory cytokines. This study is the first to comprehensively elucidate the role of the NLRP3-inflammasome in HFpEF, and will provide reference for future study., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Fasciola hepatica is a globally distributed trematode that causes significant economic losses. Triclabendazole is the primary pharmacological treatment for this parasite. However, the increasing resistance to triclabendazole limits its efficacy. Previous pharmacodynamics studies suggested that triclabendazole acts by interacting mainly with the β monomer of tubulin., Methods: We used a high-quality method to model the six isotypes of F. hepatica β-tubulin in the absence of three-dimensional structures. Molecular dockings were conducted to evaluate the destabilization regions in the molecule against the ligands triclabendazole, triclabendazole sulphoxide and triclabendazole sulphone., Results: The nucleotide binding site demonstrates higher affinity than the binding sites of colchicine, albendazole, the T7 loop and pβVII (p < 0.05). We suggest that the binding of the ligands to the polymerization site of β-tubulin can lead a microtubule disruption. Furthermore, we found that triclabendazole sulphone exhibited significantly higher binding affinity than other ligands (p < 0.05) across all isotypes of β-tubulin., Conclusions: Our investigation has yielded new insight on the mechanism of action of triclabendazole and its sulphometabolites on F. hepatica β-tubulin through computational tools. These findings have significant implications for ongoing scientific research ongoing towards the discovery of novel therapeutics to treat F. hepatica infections., (© 2023. The Author(s) under exclusive licence to Witold Stefański Institute of Parasitology, Polish Academy of Sciences.)

Background: Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available., Methods: This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1-24 months, hospitalized with RSV infection. In Part 1, patients ( n  = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients ( n  = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment., Results: No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A -4.0 (95% CI: -4.51, -2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with -2.0 (95% CI: -3.42, -1.82) in the placebo group., Conclusions: AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score., Clinical Trials Registration: NCT02654171., Competing Interests: JZW is a co‐inventor of patents (WO2013020993A, 2012; CN105726488B, 2014) covering a compound targeting RSV diseases and a preparation method of the formula. ST and JZW are co‐inventors of a patent (WO2021083290A1; 2020) covering RSV fusion protein inhibitor composition and its use for the treatment and prophylaxis of RSV. FG, ST, GZ, and JZW are or were employees of and are shareholders in Ark Biosciences. JPD served as a compensated scientific consultant for Ark Biosciences and is a shareholder in the company. All other authors declare no competing interests., (© 2023 Shanghai Ark Biopharmaceutical Ltd Co. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Minimally invasive interventions using drug-eluting stents or balloons are a first-line treatment for certain occlusive cardiovascular diseases, but the major long-term cause of failure is neointimal hyperplasia (NIH). The drugs eluted from these devices are non-specific anti-proliferative drugs, such as paclitaxel (PTX) or sirolimus (SMS), which do not address the underlying inflammation. MCC950 is a selective inhibitor of the NLRP3-inflammasome, which drives sterile inflammation commonly observed in NIH. Additionally, in contrast to broad-spectrum anti-inflammatory drugs, MCC950 does not compromise global immune function due this selective activity. In this study, MCC950 is found to not impact the viability, integrity, or function of human coronary endothelial cells, in contrast to the non-specific anti-proliferative effects of PTX and SMS. Using an in vitro model of NLRP3-mediated inflammation in murine macrophages, MCC950 reduced IL-1β expression, which is a key driver of NIH. In an in vivo mouse model of NIH in vascular grafts, MCC950 significantly enhanced re-endothelialization and reduced NIH compared to PTX or SMS. These findings show the effectiveness of a targeted anti-inflammatory drug-elution strategy with significant implications for cardiovascular device intervention., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Xanthine oxidase (XO), a key enzyme in purine catabolism, catalyzes the oxidation of xanthine to uric acid in the body, but overproduction of uric acid may lead to hyperuricemia. This study aims to investigate in vitro XO inhibitory and in vivo anti-hyperuricemic properties of sodium kaempferol-3'-sulfonate (KS). The kinetic analysis indicates that KS is a reversible competitive inhibitor and has significant inhibitory effects on XO activity with an IC 50 value of 0.338 μM. Fluorescence spectra suggested that KS could cause fluorescence quenching and conformational changes of XO due to the formation of a KS-XO complex. Molecular docking studies demonstrated that KS interacted with several amino acid residues of XO by the π-π stacking, hydrogen bonds, and hydrophobic interactions. The inhibitory mechanism of KS on XO activity might be the insertion of KS into the active site of XO to prevent the entrance of the substrate xanthine and induce conformational changes of XO. The results carried out in hyperuricemic mice showed that KS reduced serum XO activity, serum uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) levels, as well as alleviating renal histopathological injury. These findings suggest that KS may be a new potent XO inhibitor against hyperuricemia-related diseases., Competing Interests: Declaration of competing interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Esophageal motility disorders are a group of disorders associated with dysfunctional swallowing resulting from impaired neuromuscular coordination. Phosphodiesterase 5 (PDE-5) inhibitors induce smooth relaxation and are proposed as a treatment option for esophageal motility disorders such as achalasia., Methods: This study is conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We systematically searched MEDLINE/ PubMed, Scopus, EMBASE, and Web of Science databases for esophageal outcomes of individuals treated with PDE5 inhibitors. A random effect meta-analysis was conducted., Results: A total of 14 studies were included. They were conducted in different countries, with Korea and Italy having the highest number of articles. The main drug assessed was sildenafil. PDE-5 inhibitors resulted in a significant reduction in lower esophageal sphincter pressure (SMD - 1.69, 95% CI: -2.39 to -0.99) and the amplitude of contractions (SMD - 2.04, 95% CI: -2.97 to -1.11). Residual pressure was not significantly different between the placebo and sildenafil groups (SMD - 0.24, 95% CI: -1.20 to 0.72). Furthermore, a recent study reported contractile integral, stating that ingestion of sildenafil leads to a significant reduction in distal contractile integral and a significant increase in proximal contractile integral., Conclusion: PDE-5 inhibitors significantly reduce LES resting pressure and esophageal peristaltic vigor, decreasing esophageal body contractility and contraction reserve. Therefore, using these drugs in patients affected by esophageal motility disorders may potentially improve their condition regarding symptom relief and prevention of further associated complications. Future reports investigating larger sample size is necessary in order to establish definite evidence regarding the efficacy of these drugs., (© 2023. The Author(s).)

Background: Activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome contributes to heart failure (HF) pathogenesis. However, the effect of NLRP3 inhibition on β-adrenergic receptor agonist-induced HF remains unknown. Here, we evaluated the role of MCC950, a selective NLRP3 inhibitor, in isoproterenol (ISO)-induced cardiac dysfunction., Methods: Mice were administered ISO (30 mg/kg/day) for 14 days with or without MCC950 (10 mg/kg) injection every other day. Cardiac function and the extent of hypertrophy and fibrosis were measured by echocardiography, HE and Masson trichrome staining, respectively. Immunohistochemistry, quantitative real-time PCR and Western blotting were performed to investigate the impact of MCC950 on ISO-induced cardiac dysfunction. The levels of oxidative stress and cell senescence were detected in H9C2 cells to explore the mechanism of MCC950 on ISO-induced myocardial injury in vitro., Results: We found that the NLRP3 inflammasome was significantly activated in response to ISO treatment in mice. Selective inhibition of the NLRP3 inflammasome by MCC950 ameliorated cardiac fibrosis, hypertrophy and inflammation in ISO-treated mice, ultimately improving heart function. Furthermore, MCC950 significantly inhibited ISO-induced oxidative stress in the myocardium, accompanied by increased superoxide dismutase 2 (SOD2) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein. In addition, MCC950 attenuated cardiomyocyte death and senescence in ISO-treated H9C2 cells, which was attributed to the decreased oxidative stress., Conclusion: NLRP3 inhibition by MCC950 ameliorated ISO-induced cardiac dysfunction by inhibiting cardiomyocyte senescence and oxidative stress. Therefore, inhibition of the NLRP3 inflammasome may be a potential therapeutic strategy for preventing cardiac dysfunction, especially age-related HF., Competing Interests: Declarations of interest None., (Copyright © 2022. Published by Elsevier B.V.)

The objective of this review study is to evaluate the therapeutic role of PDE5 inhibitors (PDE5is) in the amelioration of oligoasthenospermia in infertile males. PDE5is have a beneficial influence on the secretory function of the Leydig and Sertoli cells, the biochemical environment within the seminiferous tubule, the contractility of the testicular tunica albuginea, and the prostatic secretory function. In several studies, the overall effect of sildenafil and vardenafil increased quantitative and qualitative sperm motility. Furthermore, some studies indicate that PDE5is influence positively the sperm capacity to undergo capacitation under biochemical conditions that are known to induce the sperm capacitation process. Additional research efforts are necessary in order to recommend unequivocally the usage of sildenafil, vardenafil, or avanafil for the alleviation of male infertility., (© 2022 The Japanese Urological Association.)

The metrological properties of two performance-based outcome measures of feline osteoarthritis (OA), namely Effort Path (Path) and Stairs Assay Compliance (Stairs), were tested. Cats naturally affected by OA (n = 32) were randomly distributed into four groups (A: 0.40, B: 0.25, C: 0.15, or D: 0.00 mg firocoxib/kg bodyweight) and assessed during baseline, treatment, and recovery periods. For Path, from an elevated walking platform, the cats landed on a pressure-sensitive mattress and jumped up onto a second elevated platform. Analysis included velocity, time to completion, peak vertical force (PVF), and vertical impulse. For Stairs, the number of steps and time to completion were recorded for 16 steps up and down in a 4 min period. Reliability was moderate to very good for Path and poor to good for Stairs. Different normalization methods are described in the manuscript. The placebo group remained stable within-time in Path, whereas treated cats trotted faster on the ramp (p < 0.0001), improved their PVF (p < 0.018) and completed the task quicker (p = 0.003). The percentage of cats completing the Stairs finish line was higher under treatment (p < 0.036), with huge effect size, the placebo group results being stable within-time. Both are promising performance-based outcome measures to better diagnose and manage feline OA pain.

Objective: To evaluate the effect of the cyclooxygenase-2-selective NSAID firocoxib, compared to the nonselective NSAID flunixin meglumine on viscoelastic coagulation parameters in healthy horses., Animals: 12 healthy adult mixed-breed horses., Procedures: Following a crossover protocol, horses were administered flunixin meglumine (1.1 mg/kg, IV, q 12 h for 5 days), allowed a 6-month washout period, and then administered firocoxib (0.3 mg/kg, PO, once, then 0.1 mg/kg, PO, q 24 h for 4 days). Omeprazole (1 mg/kg, PO, q 24 h) was administered concurrently with each NSAID. Viscoelastic coagulation profiles and traditional coagulation parameters (prothrombin time, partial thromboplastin time, and fibrinogen) were measured before and after each treatment., Results: Viscoelastic coagulation parameters were within reference intervals before and after both treatments. There was a statistically significant difference between treatments for amplitude at 10 minutes after clot time (P = .02) and maximum clot formation (P = .02); however, the magnitude of change was not clinically significant., Clinical Relevance: Short-term administration of flunixin meglumine and firocoxib did not result in significant alteration of viscoelastic coagulation profiles in healthy horses. However, clinicians should be aware of possible coagulopathy secondary to NSAID administration with long-term use or critical illness, and further study is indicated.

Background: Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and intravenous preparation - no study has been done in the past to compare the two forms. Each has its own benefits - but requires comparison in terms of efficacy and safety. This study was done to compare the efficacy of oral versus intravenous (IV) sildenafil in infants with mild to moderate pulmonary hypertension., Methods: An open labelled randomized trial was conducted in a neonatal intensive care unit of urban tertiary hospital in western India between February 2019 to December 2020. Infants born after 34 weeks of gestation with Pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth, were enrolled for the study. Participants were randomly assigned to receive sildenafil either orally or by intravenous route. Primary outcome was the time taken for PAP to decrease below 25 mm Hg. Secondary outcomes were time taken for oxygenation index to decrease by 25%, duration of invasive and non-invasive mechanical ventilation, nasal oxygen, hospital stay, time to achieve full feeds, mortality, and side effects., Results: Forty patients were enrolled. The baseline characteristics of neonates in both groups were similar except for APGAR scores at 1 min and 5 min, with oral group having lower score [MEDIAN (IQR) 5.00 (4.00- 7.00) and 7.00 (6.00- 8.00)] compared to IV group [MEDIAN (IQR) 7.00 (6.00-8.00) and 9.00 (8.00-9.00)] respectively. Time taken for PAP to decrease below 25 mm was not statistically different between the oral and intravenous groups. Systemic hypotension occurred in 4 neonates of the intravenous group but none in the oral group., Conclusion: Oral and intravenous sildenafil had equal efficacy at reducing PAP in neonatal pulmonary hypertension, albeit intravenous sildenafil use was associated with a greater complication rate., Trial Registration: Trial was registered in the clinical trials registry of India [ CTRI/2019/04/018781 ][25/04/2019]., (© 2022. The Author(s).)

Background: Erectile dysfunction (ED) is a major care problem worldwide. Tadalafil and sildenafil are the two most common phosphodiesterase-5 inhibitors (PDE5is) used to treat ED., Objective: This study aimed to evaluate patient data of a large online prescription platform (OPP), specifically analyzing preference for tadalafil over sildenafil., Design, Setting, and Participants: Data from a prospectively collected German OPP were retrospectively analyzed. This dataset included patients with a history of taking one or both substances (n = 26 821)., Outcome Measurements and Statistical Analysis: ED patient baseline characteristics were derived from medical questionnaires for PDE5i prescriptions between May 2019 and May 2020. Order behavior was analyzed in patients who ordered both substances over time. We applied Kruskal-Wallis tests, χ² tests, and fisher's exact tests for statistical analysis., Results and Limitations: Baseline characteristics were comparable for both PDE5is in patients with a median age of 49 yr (sildenafil [interquartile range {IQR} 38-57]; tadalafil [IQR 39-56]), a median body mass index (BMI) of 26 kg/m² (sildenafil [IQR 24.54-29.03]; tadalafil [IQR 24.49-28.69]), ED onset time of >12 mo (sildenafil [87%]; tadalafil [88%]), and the presence of morning erections (sildenafil [62%]; tadalafil [61%]). Tadalafil prescriptions increased significantly from 30% (first order) to 80% (last order) in patients who had already tested both drugs. Patients with age ≤40 yr, BMI ≤25 kg/m², and sustained morning erections preferred tadalafil to sildenafil., Conclusions: Using database information from an OPP, preference for tadalafil was shown for patients who had tested both PDE5is. This preference was particularly pronounced in patients with age ≤40 yr, BMI ≤25 kg/m², and sustained morning erections. A well-managed OPP can be used for research on more complex health services., Patient Summary: Analysis of large online prescription platforms provide the benefit of identifying young treatment-naïve patients with early-stage disease, which is highlighted by the fact that about two-thirds of our patients analyzed still maintained spontaneous morning erections. Patients who had tested tadalafil once developed preference for this drug., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. The VHL tumor suppressor protein marks hypoxia-inducible factor 1 (HIF1) and HIF2 for proteasomal degradation when oxygen is present. The inappropriate accumulation of HIF2 drives tumor formation by VHL tumor suppressor protein (pVHL)–defective ccRCC. Belzutifan, a first-in-class allosteric HIF2 inhibitor, has advanced to phase 3 testing for advanced ccRCC and is approved for ccRCCs arising in patients with VHL disease, which is caused by germline VHL mutations. HIF2 can suppress p53 function in some settings and preliminary data suggested that an intact p53 pathway, as measured by activation in response to DNA damage, was necessary for HIF2 dependence. Here, we correlated HIF2 dependence and p53 status across a broader collection of ccRCC cell lines. We also genetically manipulated p53 function in ccRCC lines that were or were not previously HIF2-dependent and then assessed their subsequent sensitivity to HIF2 ablation using CRISPR-Cas9 or the HIF2 inhibitor PT2399, which is closely related to belzutifan. From these studies, we conclude that p53 status does not dictate HIF2 dependence, at least in preclinical models, and thus is unlikely to be a useful biomarker for predicting which ccRCC patients will respond to HIF2 inhibitors.

Platelets play a critical role in arterial thrombosis. Rutaecarpine (RUT) was purified from Tetradium ruticarpum , a well-known Chinese medicine. This study examined the relative activity of RUT with NF-κB inhibitors in human platelets. BAY11-7082 (an inhibitor of IκB kinase [IKK]), Ro106-9920 (an inhibitor of proteasomes), and RUT concentration-dependently (1-6 μM) inhibited platelet aggregation and P-selectin expression. RUT was found to have a similar effect to that of BAY11-7082; however, it exhibits more effectiveness than Ro106-9920. RUT suppresses the NF-κB pathway as it inhibits IKK, IκBα, and p65 phosphorylation and reverses IκBα degradation in activated platelets. This study also investigated the role of p38 and NF-κB in cell signaling events and found that SB203580 (an inhibitor of p38) markedly reduced p38, IKK, and p65 phosphorylation and reversed IκBα degradation as well as p65 activation in a confocal microscope, whereas BAY11-7082 had no effects in p38 phosphorylation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay shows that RUT and BAY11-7082 did not exhibit free radical scavenging activity. In the in vivo study, compared with BAY11-7082, RUT more effectively reduced mortality in adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism without affecting the bleeding time. In conclusion, a distinctive pathway of p38-mediated NF-κB activation may involve RUT-mediated antiplatelet activation, and RUT could act as a strong prophylactic or therapeutic drug for cardiovascular diseases.

Background: Several paediatric malignancies, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbour activation of anaplastic lymphoma kinase (ALK) through different mechanisms. Here, we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies., Methods: This multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to <18 years) diagnosed with locally advanced or metastatic ALK-positive malignancies that had progressed despite standard therapy, or for which no effective standard therapy were available, were eligible. ALK-positive malignancies were defined as those with ALK rearrangement, amplification, point mutation, or in the case of rhabdomyosarcoma, expression in the absence of any genetic alteration. Eligible patients had evaluable or measurable disease as defined by either Response Evaluation Criteria in Solid Tumours, version 1.1 for patients with non-haematological malignancies, International Neuroblastoma Response Criteria scan for patients with neuroblastoma, or International Working Group criteria for patients with lymphoma. Other eligibility criteria were Karnofsky performance status score of at least 60% for patients older than 12 years or Lansky score of at least 50% for patients aged 12 years or younger. This study included a dose-escalation part, followed by a dose-expansion part, in which all patients received treatment at the recommended dose for expansion (RDE) established in the dose-escalation part. Both parts of the study were done in fasted and fed states. In the dose-escalation part, patients were treated with once-daily ceritinib orally, with dose adjusted for body-surface area, rounded to the nearest multiple of the 50 mg dose strength. The starting dose in the fasted state was 300 mg/m 2 daily and for the fed state was 320 mg/m 2 daily. The primary objective of this study was to establish the maximum tolerated dose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was established on the basis of the incidence of dose-limiting toxicities in patients who completed a minimum of 21 days of treatment with safety assessments and at least 75% drug exposure, or who discontinued treatment earlier because of dose-limiting toxicity. Overall response rate (defined as the proportion of patients with a best overall response of complete response or partial response) was a secondary endpoint. Activity and safety analyses were done in all patients who received at least one dose of ceritinib. This trial is registered with ClinicalTrials.gov (NCT01742286) and is completed., Findings: Between Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion (n=43) groups. The RDE of ceritinib was established as 510 mg/m 2 (fasted) and 500 mg/m 2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and seven with other tumour types) were treated with ceritinib at the RDE (13 patients at 510 mg/m 2 fasted and 42 patients at 500 mg/m 2 fed). The median follow-up was 33·3 months (IQR 24·8-39·3) for patients with neuroblastoma, 33·2 months (27·9-35·9) for those with IMT, 34·0 months (21·9-46·4) for those with ALCL, and 27·5 months (22·4-36·9) for patients with other tumour types. An overall response was recorded in six (20%; 95% CI 8-39) of 30 patients with neuroblastoma, seven (70%; 33-93) of ten patients with IMT, six (75%; 35-97) of eight patients with ALCL, and one (14%; <1-58) of seven patients with other tumours. The safety profile of ceritinib was consistent with that observed in adult patients. All patients had at least one adverse event. Grade 3 or 4 adverse events occurred in 67 (81%) of 83 patients and were mostly increases in aminotransferases (alanine aminotransferase increase in 38 [46%] patients and aspartate aminotransferase increase in 27 [33%] patients). At least one serious adverse event was reported in 40 (48%) of 83 patients and 31 (37%) of 83 patients had at least one grade 3 or 4 serious adverse event. 14 (17%) deaths occurred during the study, of which 12 were on-treatment deaths and two were after 30 days of the last dose. Of the 12 on-treatment deaths, ten were due to disease progression (neuroblastoma), one due to sepsis, and one due to intractable hypotension., Interpretation: Ceritinib 500 mg/m 2 once daily with food is the recommended dose for paediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumour activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for paediatric patients with malignancies with genetic ALK alterations., Funding: Novartis Pharmaceutical Corporation., Competing Interests: Declaration of interests MF has received personal fees for participation in scientific advisory boards from Novartis, Roche, Bayer, Bristol-Myers Squibb (BMS), and Janssen-Cilag; and grants from Bild hilft. LM reports consulting fees from Novartis and Shionogi; membership of the Executive Committee of SIOPEN (European neuroblastoma research cooperative group), which receives royalties for the sales of dinutuximab beta; and membership of data monitoring committees for clinical trials sponsored by Novartis, Actuate Therapeutics, Shionogi, Incyte, the University of Southampton, and the Royal Marsden NHS Foundation Trust. DSZ reports consulting fees from Day One Bio, Novartis, FivePhusion, Amgen, Bayer; support for attending meetings or travel from Bayer; and membership of advisory boards for Bayer and Day One. LVM has received advisory board fees from BMS, Day One, and Tesaro; and consulting fees and speaker's honorarium from Bayer; and is a member of data monitoring committees for clinical trials run by Merck and Eisai (which do not include ALK inhibitors). BW reports employment at F Hoffmann-La Roche. MS, LW, FKH, and FB report employment at Novartis. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To compare the effect of etoricoxib, a selective cyclooxygenase-2 inhibitor, with diclofenac, a non-selective nonsteroidal anti-inflammatory drug, on blood pressure in hypertensive patients., Methods: The prospective observational study was conducted at Al-Hussein Medical City, Karbala, Iraq, from July 2018 to March 2019, and comprised patients with hypertension already on antihypertensive treatment. The subjects were divided into 2 equal groups. Those in group 1 received etoricoxib, while patients in group 2 received diclofenac sodium. They were followed up for 2 weeks. Pulse rate, blood pressure and renal indices were noted and compared between the groups. Data was analysed using 2-tailed t-test for continuous variables, and chi-square test for categorial ones., Results: Of the 100 subjects, there were 50(50%) in group 1 with a mean age of 48.7±14.9 years including 15(30%) males, and the remaining 50(50%) were in group 2 with a mean age of 51.9 ± 13.4 years including 14(28%) males (p>0.05). The blood pressure was elevated above the normal upper limit in 16(32%) in group 1 patients compared to 6(12%) in group 2 (p=0.015). The mean rise in systolic blood pressure in group 1 was 16.2±15mmHg compared to 8.5±11 in group 2 (p=0.004), and the mean rise in diastolic blood pressure was 7.1±9 compared to 2.4±7 in the two groups, respectively (p=0.004). The mean increase in pulse rate was 8.1±16 in group 1 compared to 6.2±14 in group 2 (p=0.529). There was no significant change in renal indices between the two groups (p>0.05)., Conclusions: Etoricoxib was found to be significantly more effective than diclofenac on raising blood pressure of hypertensive patients. With respect to pulse rate and renal indices, the two drugs were not significantly different.

Esaxerenone, a mineralocorticoid receptor blocker (MRB), is a new antihypertensive agent. However, esaxerenone-related data with respect to hypertension with heart failure are limited. We investigated the safety and efficacy of esaxerenone in hypertensive patients with heart failure with reduced ejection fraction (HFrEF). Hypertensive patients with HFrEF treated with esaxerenone were retrospectively analyzed at two timepoints (short-term: 35±15 days; mid-term: 167±45 days). Adverse events including hyperkalemia (K+ >5.5 mEq/L), worsening renal function (WRF; estimated glomerular filtration rate (eGFR) reduction by ≥20%), and hypotension (systolic blood pressure <90 mmHg) were evaluated. eGFR and K+, serum creatinine, and brain natriuretic peptide (BNP) levels at baseline, short-term, and mid-term assessments were compared. Patients administered esaxerenone as their first MRB (first-MRB cohort) and those who converted from another MRB (conversion cohort) were separately analyzed. There were 50 (56±10 years old, 26% female) patients. At the short-term assessment, hyperkalemia or hypotension was not observed at a dose of 2.0±0.9 mg/day. Seven patients (14%) showed WRF. K+ was slightly elevated (4.12±0.41 to 4.25±0.39 mmol/L, p = 0.07) and eGFR was significantly reduced (66.9±19.6 mL/min/1.73 m2 to 62.4±19.7 mL/min/1.73 m2, p = 0.006). In the conversion cohort, significant changes in K+ and eGFR from baseline were not observed at the short-term assessment. BNP levels were consistently improved regardless of the cohorts (first-MRB cohort, 310 [110-370] pg/mL to 137 [47-152] pg/mL, p = 0.001; conversion cohort, 181 [30-203] pg/mL to 108 [26-146] pg/mL, p = 0.028). At the mid-term assessment, there were no significant changes in K+ and eGFR compared with the short-term assessment. In conclusion, esaxerenone was safe for hypertensive patients with HFrEF. Hyperkalemia and hypotension were rarely noted, while eGFR was marginally reduced. Moreover, esaxerenone might be beneficial for HFrEF in terms of BNP level reduction., Competing Interests: We declared that YK received lecture fees and research grant from Daiichi Sankyo Co., Ltd. YK does not have any other relation with this funder, including employment, consultancy, patents, products in development, or marketed products. This does not influence our adherence to PLOS ONE policies on sharing data and materials.

Cervical cancer is one of the leading female malignancy tumors worldwide. Structural maintenance of chromosomes 4 (SMC4), a member of the SMC family, is associated with cancer pathogenesis and progression. However, the role of SMC4 in cervical cancer is still unclear. In the study, SMC4 was increased in cervical cancer tissues compared with adjacent normal tissues. The SMC4 knockdown and overexpression were performed in cervical cancer cells. SMC4 knockdown inhibited cell proliferation, colony formation, cell migration and invasion, and suppressed epithelial-mesenchymal transition (EMT). Conversely, SMC4 overexpression exerted opposite effects. Moreover, SMC4 knockdown down-regulated stem cell markers, reduced the capacity of spheroid formation and inactivated NF-κB pathway. SMC4 overexpression contributed to stem cell markers, and stimulated spheroid formation and NF-κB pathway activation. Additionally, BAY11-7082 (an NF-κB inhibitor) alleviated the SMC4-mediated the effects in cervical cancer cells. In conclusion, these findings demonstrated that SMC4 overexpression facilitated the development of cervical cancer cells by activating NF-κBpathway, which provides a new therapeutic target for patients with cervical cancer., (© 2021. Japan Human Cell Society.)

Oral cancer is one of the most common human malignancies, and its incidence is increasing worldwide. In particular, oral squamous cell carcinoma (OSCC) is characterized by high rates of proliferation, invasiveness, and metastasis. Currently, standard treatment for OSCC includes surgical removal, chemotherapy, and radiotherapy; however, the survival rate of patients with OSCC remains low, thus new therapies are needed. It has been proven that excessive NLRP3 inflammasome activation and apoptosis alteration may contribute to oral cancer progression. This study aimed to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in an in vitro and in vivo xenograft model of oral cancer. In vitro results revealed that BAY-117082 at concentrations of 5, 10, and 30 µM was able to reduce OSCC cell viability. BAY-117082 at higher concentrations significantly reduced NLRP3, ASC, caspase-1, IL-1β, and IL-18 expression. Moreover, Bax, Bad, and p53 expression were increased, whereas Bcl-2 expression was reduced. Furthermore, the in vivo study demonstrated that BAY-117082 at doses of 2.5 and 5 mg/kg significantly decreased subcutaneous tumor mass, and also reduced NLRP3 inflammasome pathway activation. Therefore, based on these results, the use of BAY-117082 could be considered a promising strategy to counteract oral cancer progression, thanks its ability to modulate the NLRP3 inflammasome and apoptosis pathways.

Background: Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine)., Methods: We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m 2 and treated with a renin-angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K + ) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K + increase, and change in eGFR from baseline., Results: UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K + levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K + values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was - 8.3 mL/min/1.73 m 2 at week 24., Conclusions: Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine., Clinical Trial Registration: JapicCTI-173696., (© 2021. The Author(s).)

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear., Methods: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed., Results: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265&#95;C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%., Conclusions: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YTL has received speaking honoraria from ACT Genomics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Manudipharma, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and TTY Biopharm; and travel expense from Pfizer. CLC has received speaking honoraria from Chugai Pharmaceutical, Novartis, and Pfizer. SYW has received speaking honoraria from Boehringer Ingelheim, Merck Sharp & Dohme, Merck KGaA, Novartis, and Sanofi; and travel expense from Bristol-Myers Squibb and TTY Biopharm. HPC has received speaking honoraria from AstraZeneca, Chugai Pharmaceutical, Novartis, and Pfizer. CHC has received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda. JYS has been an advisory board member for AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Cstone Pharmaceuticals, Janssen Pharmaceutica, and Takeda. JYS has received speaking honoraria from AstraZeneca, Roche, Boehringer-Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb; and travel expense from Roche, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Chugai Pharmaceutical, and Bristol-Myers Squibb. The remaining authors declare no conflict of interest. Results from this study were presented, in part, at the 2020 Annual Congress of Taiwan Society of Pulmonary and Critical Care Medicine in Taipei, Taiwan, December 12, 2020., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

G protein-coupled receptor (GPR) 40 is a free fatty acid receptor mainly expressed in pancreatic β -cells activated by medium- and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca 2+ ] i ). Activation of GPR40 in pancreatic β -cells may improve glycemic control in type 2 diabetes through enhancement of glucose-stimulated insulin secretion. However, the most clinically advanced GPR40 agonist-TAK-875 (fasiglifam)-was withdrawn from phase III because of its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters. Here, we present a new, potent CPL207280 agonist and compare it with fasiglifam in numerous in vitro and in vivo studies. CPL207280 showed greater potency than fasiglifam in a Ca 2+ influx assay with a human GPR40 protein (EC 50 = 80 vs. 270 nM, respectively). At the 10 µM concentration, it showed 3.9 times greater enhancement of glucose-stimulated insulin secretion in mouse MIN6 pancreatic β -cells. In Wistar Han rats and C57BL6 mice challenged with glucose, CPL207280 stimulated 2.5 times greater insulin secretion without causing hypoglycemia at 10 mg/kg compared with fasiglifam. In three diabetic rat models, CPL207280 improved glucose tolerance and increased insulin area under the curve by 212%, 142%, and 347%, respectively. Evaluation of potential off-target activity (Safety47) and selectivity of CPL207280 (at 10 μM) did not show any significant off-target activity. We conclude that CPL207280 is a potent enhancer of glucose-stimulated insulin secretion in animal disease models with no risk of hypoglycemia at therapeutic doses. Therefore, we propose the CPL207280 compound as a compelling candidate for type 2 diabetes treatment. SIGNIFICANCE STATEMENT: GPR40 is a well-known and promising target for diabetes. This study is the first to show the safety and effects of CPL207280, a novel GPR40/free fatty acid receptor 1 agonist, on glucose homeostasis both in vitro and in vivo in different diabetic animal models. Therefore, we propose the CPL207280 compound as a novel, glucose-lowering agent, overcoming the unmet medical needs of patients with type 2 diabetes., (Copyright © 2021 by The Author(s).)

Sulfonium-ion-containing polymers exhibit significant potential benefits for various applications. An efficient strategy to synthesize a type of antibacterial sulfonium-ion-bearing polypeptoids via a combination of ring-opening polymerization and a post-polymerization functionalization with various functional epoxides is presented. A systematic investigation is further performed in order to explore the influence of the overall hydrophobic/hydrophilic balance on the antimicrobial activity and selectivity of the prepared polysulfoniums. Notably, those chlorepoxypropane-modified polysulfoniums with an optimized amphiphilic balance show higher selectivity toward both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, than to red blood cells. The polymers also show great efficiency in inhibiting S. aureus biofilm formations, as well as in further eradicating the mature biofilms. Remarkably, negligible antibacterial resistance and cross-resistance to commercial antibiotics is shown in these polymers. The polysulfoniums further show their potent in vivo antimicrobial efficacy in a multidrug-resistant S. aureus infection model that is developed on mouse skin. Similar to the antimicrobial peptides, the polysulfoniums are demonstrated to kill bacteria through membrane disruption. The obtained polypeptoid sulfoniums, with high selectivity and potent antibacterial property, are excellent candidates for antibacterial treatment and open up new possibilities for the preparation of a class of innovative antimicrobials., (© 2021 Wiley-VCH GmbH.)

Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2 . Extensive structure-activity relationship (SAR) studies resulted in AZD0284 ( 20 ), which combined potent inhibition of IL-17A secretion from primary human T H 17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.

Background: The purpose of this meta-analysis was to assess the clinical efficacy of etoricoxib in comparison with traditional NSAIDs for postoperative pain after third molar surgery., Methods: The quality of studies found in PubMed and Google Scholar was evaluated with Cochrane Collaboration's risk of bias tool. Data on total consumption of rescue analgesics, number of patients using rescue analgesics, global assessment of study treatments, and adverse effects were extracted exclusively from high-quality clinical trials. Each meta-analysis was performed with the Review Manager Software 5.3 for Windows., Results: The qualitative analysis showed that etoricoxib has better analgesic activity when compared with ibuprofen (2 clinical trials) and diclofenac (1 clinical trial). A similar analgesic efficacy between etoricoxib and nonselective Cox-2 NSAIDs was informed in 3/8 studies (2 compared to ibuprofen and 1 to naproxen sodium). Moreover, the number of patients requiring rescue analgesics in the postoperative period showed a statistical difference in favor of etoricoxib when compared to NSAIDs., Conclusion: Etoricoxib significantly reduces the number of patients needing rescue analgesics compared to NSAIDs after third molar surgery., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Lorenzo Franco-de la Torre et al.)

Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC<4), suggesting the possibility of a dose reduction in the in vivo T. cruzi infection. Next, the effect of combining suboptimal doses was assessed in an acute model of murine T. cruzi infection. Drug combinations led to a faster suppression of parasitemia than monotherapies. Also, the associations led to higher cure levels than those in the reference treatment BZ 100 mg day−1 (57.1%) (i.e. 83.3% with BZ/fex-SFN and 75% with NFX/fex-SFN). Importantly, toxic effects resulting from the associations were not observed, according to weight gain and hepatic enzyme levels in the serum of experimental animals. Taken together, this study is a starting point to explore the potential effects of nitro drugs combinations in preclinical models of kinetoplastid-related infections.

Pulmonary arterial hypertension (PAH) - a complex and progressive disease that carries significant morbidity and mortality despite optimal medical treatment. Combination therapy for PAH can be more effective than monotherapy. The present randomized trial compared the safety and efficacy of sildenafil ambrisentan combination therapy with sildenafil monotherapy. Twenty-two patients of Eisenmenger syndrome and five patients of idiopathic PAH were randomized to two arms. There was a significant improvement in NYHA functional class and mean pulmonary artery pressure, while an insignificant improving trend was observed for 6-min walk distance and oxygen saturation, following the 12 weeks of combination therapy. An upfront combination therapy was found to be safe and effective in the management of PAH patients., Competing Interests: Declaration of competing interest There is no conflict of interest on any of the authors about the present study., (Copyright © 2021 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na + /H + exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS)., Methods: Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR., Results: Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP + astrocytes and Iba1 + microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation., Conclusion: Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment., (© 2021. The Author(s).)

Pulmonary hypertension (PH) is a disease with a complex etiology and high mortality rate. Abnormal pulmonary vasoconstriction and pulmonary vascular remodeling lead to an increase in mean pulmonary arterial blood pressure for which, and there is currently no cure. Junctophilin-2 (JP2) is beneficial for the assembly of junctional membrane complexes, the structural basis for excitation-contraction coupling that tethers the plasma membrane to the sarcoplasmic reticulum/endoplasmic reticulum and is involved in maintaining intracellular calcium concentration homeostasis and normal muscle contraction function. Recent studies have shown that JP2 maintains normal contraction and relaxation of vascular smooth muscle. In some experimental studies of drug treatments for PH, JP2 expression was increased, which improved pulmonary vascular remodeling and right ventricular function. Based on JP2 research to date, this paper summarizes the current understanding of JP2 protein structure, function, and related heart diseases and mechanisms and analyzes the feasibility and possible therapeutic strategies for targeting JP2 in PH., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Rubin Tan et al.)

Background: In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed., Methods: We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385., Results: PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity., Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable., (© 2021. The Author(s).)

Rationale: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. G protein-coupled receptor 40 (GPR40) is expressed in brain in addition to periphery and is associated with cognitive function such as space orientation, memory, and learning. However, the effects and mechanisms of GPR40 agonist in improving the AD progression remain largely unknown., Objectives: The present study aimed to investigate the therapeutic effects and mechanisms of a potent and selective GPR40 agonist TAK-875 on the APPswe/PS1dE9 mice., Results: The results showed that intracerebroventricular administration of TAK-875 significantly rescued cognitive deficits in APPswe/PS1dE9 mice, and these effects may be mediated by the regulation of phospholipase C/protein kinase C signaling pathway, which enhanced α-secretase ADAM10 activity, promoted amyloid precursor protein non-amyloidogenic processing pathway, and reduced β-amyloid production., Conclusions: These results suggest that GPR40 may be a potential therapeutic target for AD, and GPR40 agonists may become promising AD drugs in the future., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)