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Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo. Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients. JOSD2, a deubiquitinating enzyme, increases YAP/TAZ abundance and reinforces their signaling through the cleavage of polyubiquitin chains, observably contributing to cholangiocarcinoma progression. [Display omitted] [ABSTRACT FROM AUTHOR]

Misguided attack of immune systems on self-tissue or multifactorial uncontrolled inflammation is capable of causing inflammatory diseases. Neutrophils play a critical role in the initiation of inflammation and pathophysiological progression, and the pathological context can influence the biology of neutrophils. Moreover, they usually respond faster than other immune cells to pathological variation. Recently, due to their immunomodulation capability and intrinsic tropism to inflammatory sites, neutrophil-based therapeutic strategies, including neutrophil manipulation and development of neutrophil-based delivery systems, are emerging as a promising solution for the treatment of inflammation-related diseases. However, obstacles in neutrophil manipulation using small molecules or antibodies (e.g., lack of targeting ability to the inflammatory site, low bioavailability, and fast clearance) and the concerns about developing neutrophil-based delivery systems (e.g., stability of biopharmaceuticals, activity maintenance, and cargo loading efficiency) hindered the therapeutic outcomes of neutrophil-based therapeutic strategies. Nanotechnology, which has offered multiple resolutions for disease treatment, can be utilized to reinforce neutrophil-based therapeutic strategies. In order to afford a comprehensive overview of the state-of-the-art progress of this emerging field, the biology of neutrophils and their function in a certain inflammatory context is briefly introduced. Then the current research progresses about nanomaterials augmented efficient neutrophils manipulation and developing neutrophil-based carriers utilizing nanotechnology for inflammation-targeted treatment are illustrated with specific research examples. Finally, perspectives in light of the current challenges and future opportunities in this field are discussed. [Display omitted] • Progress of nanotechnology-reinforced neutrophil-based therapeutic strategies is summarized. • Nanotechnology assists neutrophil manipulation for inflammatory diseases therapy. • Nanotechnology augments neutrophil-based carriers for inflammation-targeted therapy. • The challenges and perspectives of neutrophil-based therapeutic strategies are discussed. [ABSTRACT FROM AUTHOR]

High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1 H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10. [Display omitted] • A series of quinolin-4(1 H)-one derivatives targeting USP10 was identified through protein structure prediction and virtual screening. • Compound D1 exhibited strong USP10 inhibition and promising selectivity against USP7. • Compound D1 could promote YAP degradation and inhibit the proliferation of HCC cells. [ABSTRACT FROM AUTHOR]

BRD9 is essential in regulating gene transcription and chromatin remodeling, and blocking BRD9 profoundly affects the survival of AML cells. However, the inhibitors of BRD9 suffer from various drawbacks, including poor phenotype and selectivity, and BRD9 PROTACs still face the challenge of druggability, which limits the development of blocking BRD9 in AML. This study described an oral activity BRD9 PROTAC C6 by recruiting the highly efficient E3 ligase. C6 demonstrated remarkable efficacy and selectivity in BRD9 degradation with a BRD9 degradation DC 50 value of 1.02 ± 0.52 nM and no degradation of BRD4 or BRD7. Moreover, our findings highlighted its therapeutic potential, as evidenced by profound in vitro activity against the AML cell line MV4-11. Furthermore, C6 exhibited superior oral activity, with a C max value of 3436.95 ng/mL. These findings demonstrated that C6 , as a novel BRD9 PROTAC with remarkable pharmacodynamic and pharmacokinetic properties, had the potential to be developed as a promising therapeutic agent for AML treatment. [Display omitted] • A new PROTAC C6 with potent and selective BRD9 degradation activity was identified. • Compound C6 showed potent MV4-11 inhibition activity based on rational design. • C6 exhibited significantly oral activity in ICR mice with the Cmax value of 3436.95 ng/mL. [ABSTRACT FROM AUTHOR]

Entecavir (ETV) is a first-line antiviral drug against the hepatitis B virus. This study was designed to investigate whether ETV pharmacokinetics changes during pregnancy and the underlying mechanism. The results showed that ETV exposure in plasma was higher in pregnant rats than in nonpregnant rats, whereas the exposure after delivery was recovered to that in nonpregnant rats. Because 70% of orally dosed ETV is eliminated by kidney, the effects of estradiol (E2) and progesterone (P4), 2 important hormones during pregnancy, on ETV-related renal transporters were investigated. Our results revealed that the activities of the ETV-related renal transporters hOAT1, hOAT3, hMATE1, and hMATE2-K were clearly inhibited by E2 and P4, resulting in reduced ETV accumulation in transporter-transfected cell models. However, the cumulative urinary excretion of ETV in pregnant rats exhibited no significant difference compared to nonpregnant rats, although the endogenous creatinine clearance in pregnant rats was 1.5-fold that of nonpregnant rats. In conclusion, ETV plasma exposure is increased during pregnancy, but ETV renal excretion displays no significant alteration. This may be because, during pregnancy, increased glomerular ETV filtration compensated for the decrease in renal tubular ETV secretion that occurs by E2- and P4-mediated inhibition of related transporters. [ABSTRACT FROM AUTHOR]

• The proportion of inappropriate use of nirmatrelvir-ritonavir is particularly high in China. • The main types of inappropriate use were delayed initiation of treatment, no dose adjustment for moderate renal impairment, use in severe-to-critical coronavirus disease 2019 (COVID-19), presence of contra-indicated drug‒drug interactions, and prescribing without a diagnosis of COVID-19. • Improvements in how nirmatrelvir-ritonavir is prescribed are needed urgently in the Chinese hospital setting. Nirmatrelvir-ritonavir (NMVr) is a recently developed antiviral agent for treating coronavirus disease 2019 (COVID-19); however, data describing its appropriate use are scarce. This study examined the prevalence of inappropriate use of NMVr in a Chinese hospital setting. A multi-centre retrospective chart review was performed for all hospitalized patients who received NMVr between 15 December 2022 and 15 February 2023 in four university-affiliated hospitals in Hangzhou, China. A multi-disciplinary team of experts developed the evaluation criteria. A group of senior clinical pharmacists examined and verified the suitability of NMVr prescriptions. In total, 247 patients received NMVr during the study period, of which 13.4% (n =31) met all the criteria for appropriate use of NMVr. The main types of inappropriate use of NMVr were delayed initiation of treatment (n =147, 59.5%), no dose adjustment for moderate renal impairment (n =46, 18.6%), use in patients with severe-to-critical COVID-19 (n =49, 19.8%), presence of contra-indicated drug‒drug interactions with other medications (n =36, 14.6%), and prescription for patients without a confirmed diagnosis of COVID-19 (n =36, 14.6%). The proportion of inappropriate use of NMVr was particularly high in the Chinese hospital setting, highlighting the urgent need to improve the appropriate use of NMVr. [ABSTRACT FROM AUTHOR]

Resveratrol, a common polyphenol, has extensive pharmacological activities. Resveratrol inhibits some steroid biosynthetic enzymes, indicating that it may block neurosteroid synthesis. The objective of the present study is to investigate the inhibition of resveratrol on neurosteroidogenic enzymes rat 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C9), and retinol dehydrogenase 2 (RDH2). The IC 50 values of resveratrol on SRD5A1, AKR1C9, and RDH2 were > 100 μM, 0.436 ± 0.070 μM, and 4.889 ± 0.062 μM, respectively. Resveratrol competitively inhibited rat AKR1C9 and RDH2 against steroid substrates. Docking showed that resveratrol bound to the steroid binding pocket of AKR1C9. It exerted a mixed mode on these AKR1C9 and RDH2 against cofactors. In conclusion, resveratrol potently inhibited rat AKR1C9 and RDH2 to regulate local neurosteroid levels. [ABSTRACT FROM AUTHOR]

• Tenofovir (TFV) concentrations in breast milk ranged from 1.4 to 11.7 ng/mL within 24 h after dosing in the third month postpartum. • The daily TFV dose in infants via breastfeeding was much lower than that in umbilical cord blood and amniotic fluid. • Breast cancer resistance protein did not mediate TFV pumped into breast milk. • One-year physical growth parameters of infants exposed to TFV via breastfeeding for three months were normal. • The findings contribute to improving compliance with breastfeeding recommendations. Tenofovir disoproxil fumarate (TDF) is recommended for the prevention of mother-to-infant transmission of the hepatitis B virus (HBV). This study investigated the safety of infants whose mothers continued to receive TDF while breastfeeding. Thirty women taking TDF daily from the second or third trimester of pregnancy to three months postpartum were enrolled. Tenofovir (TFV) concentrations in breast milk were determined and compared with those in umbilical cord (UC) blood and amniotic fluid. Infant growth parameters were assessed at birth, and at 3, 6, and 12 months. TFV uptake experiments were conducted in vitro to elucidate the mechanisms of TFV exposure via breast milk. TFV concentrations in breast milk ranged from 1.4 to 11.7 ng/mL within 24 h after dosing in the third month postpartum. The median trough concentration of TFV in breast milk was 3.7 (interquartile range, 2.6–6.2) ng/mL, which is lower than that in UC blood (median = 53.5 ng/mL) and amniotic fluid (median = 531.0 ng/mL). The low permeability of TFV in MCF-10A cells may explain the minimal exposure to TFV in breast milk. Body weights, body lengths, and head circumferences of the breastfed infants were comparable to the national standards for physical development. Infant exposure to TFV from breast milk is much lower than the exposure from placental transfer and swallowing from amniotic fluid. The physical growth parameters of all infants in this study were normal. The findings indicate that breastfeeding is safe for infants of HBV-infected mothers who continue to receive TDF through three months postpartum. [Display omitted] [ABSTRACT FROM AUTHOR]

Pharmacophore-probe reaction guided purification strategy can reduce the workload of natural product chemistry and raise the probability of obtaining undescribed and high-bioactive target compounds. In this study, a probe of N -acetyl cysteine (NAC) was used to confirm the pharmacophore of Tubocapsicum anomalum (Franch. et Sav.) Makino. Furthermore, a thiol probe named 4-bromothiophenol (BTP) guided the discovery of three undescribed (1–3) and nine known (4–12) electrophilic withanolides (EWs) featured potential anti-triple negative breast cancer (TNBC) pharmacophore. Notably, co-incubation with BTP made the single crystals of EW conjugates much more accessible, which facilitated the absolute configuration determination of EWs. Electrophilic natural products with the potential of thio-alkylation modification and covalent inhibition key proteins in tumor cell signal transduction pathways may display significant antitumor activity. The MTT results indicated that most EWs showed anti-TNBC activity and were expected to develop anti-TNBC candidate drugs with high selectivity and novel mechanism. [Display omitted] • Pharmacophore-probe reaction guided precision discovery strategy is reported. • Three undescribed withanolides were identified of which the structure of 1 is rare. • Four known withanolides exhibited significant anti-TNBC activity in vitro. • It may be a novel method to determine the absolute configuration of EWs using BTP. [ABSTRACT FROM AUTHOR]

• The P2X7R is mainly expressed in immune cells, particularly monocytes. • The P2X7R can be activated by physiological or non-physiological agonists. • The function of the P2X7R correlates with the duration and intensity of the stimulus. • The P2X7R is a switch for inflammation and immunity. • The P2X7R plays an important role in infection and metabolism. The P2X7 receptor (P2X7R) is a ligand-gated receptor belonging to the P2 receptor family. It is distributed in various tissues of the human body and is involved in regulating the physiological functions of tissues and cells to affect the occurrence and development of diseases. Unlike all other P2 receptors, the P2X7 receptor is mainly expressed in immune cells and can be activated not only by extracellular nucleotides but also by non-nucleotide substances which act as positive allosteric modulators. In this review, we comprehensively describe the role of the P2X7 receptor in infection and metabolism based on its role as an important regulator of inflammation and immunity, and briefly introduce the structure and general function of the P2X7 receptor. These provide a clear knowledge framework for the study of the P2X7 receptor in human health. Targeting the P2X7 receptor may be an effective method for the treatment of inflammatory and immune diseases. And its role in microbial infection and metabolism may be the main direction for in-depth research on the P2X7 receptor in the future. [ABSTRACT FROM AUTHOR]

Macrophages are immune cells with high heterogeneity and plasticity. M2 polarization is one extreme of the well-established phenotypes of macrophage polarization, and involves in diverse biological processes. The polarization process is initiated at the command of numerous components. Long non-coding RNAs (lncRNAs) are RNAs longer than 200 nucleotides with limited protein-coding capacity. Recent studies have revealed a newly found subset of lncRNAs engaged in the M2 polarization and their potent and multifunctional roles in developing diseases. By interfering with specific signaling pathways and altering the active mode, acting as the sponges of microRNAs or decoys of transcription factors, lncRNAs prompted macrophages to an M2 phenotype. Further, lncRNAs can bind to the genome to regulate the chromatin dynamics or work as a platform for protein complexes tether. Exosomal lncRNAs can also orchestrate the polarization in a paracrine way. To make it easier to interpret the roles of lncRNAs in the M2 polarization, we review the reported lncRNAs according to the underlying mechanisms. Moreover, we discuss the possibilities of targeting macrophages' M2 polarization using the oligonucleotides drugs or clustered regularly interspaced palindromic repeats (CRISPR) technologies to provoke wisdom on the therapeutic strategies. Unlabelled Image • LncRNAs are emerging as new regulators of the macrophage M2 polarization. • Antisense oligonucleotides and CRISPR-based interference make it possible to target lncRNAs as new approaches. • LncRNAs provide new druggable targets for the interference of macrophage engaged diseases. [ABSTRACT FROM AUTHOR]

Radiotherapy is an effective treatment for pancreatic cancer. However, radio-resistance often resulted in poor prognostic. Ibrutinib is an orally small molecule drug in B cell malignancies. Here, we investigated for the first time the effect of ibrutinib on radio-sensitivity of human pancreatic cancer cells in vitro and the potential mechanism involved in it. Human BXPC3 and Capan2 cell lines were treated with ibrutinib, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed after treated with ibrutinib and (or) radiation by clone formation assay. The cell cycle and cell apoptosis were measured by flow cytometry. Protein levels was analyzed by western blot. The results revealed that ibrutinib inhibited the proliferation of pancreatic cancer cells. Ibrutinib enhanced the effect of radiation with a sensitization enhancement ratio (SER) of 1.34, 1.68 in BXPC3 and Capan2 cells respectively. Ibrutinib combined with radiation induced G2/M arrest and cell apoptosis. Further investigations revealed that ibrutinib decreased the phosphorylation of EGFR, then reversed the upregulation of p-AKT and downstream genes by radiation. In conclusion, these results suggested that ibrutinib might be an excellent radiosensitizer in pancreatic cancer. [ABSTRACT FROM AUTHOR]

• Bruceine D inhibits the proliferation of NSCLC cell lines in vitro. • Bruceine D increases the apoptosis of A549 and H460 cells. • Bruceine D upregulates the expression of p-JNK, which contributes to the apoptosis of NSCLC cell lines. Bruceine D (BD) is the quassinoids isolated from the traditional Chinese herbal medicine Brucea javanica 's fruit, which exhibits anti-cancer activity. Here, we demonstrated that BD inhibited human non-small cell lung cancer (NSCLC) cell lines in vitro that were attributed to the induction of cell apoptosis. Human NSCLC H460 and A549 cell lines were treated with BD, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed by clone formation assay. Cell apoptosis was measured using DAPI staining and flow cytometry. Protein levels was analyzed by western blot. The results showed BD inhibited the cell viability of H460 and A549 cells in a dose-dependent manner with IC50 values of 0.5 and 0.6 μmol/L, respectively, at 48 h of treatment. Treatment with BD (0.125–1.0 μmol/L) dose-dependently promoted chromatin condensation, Annexin V-positive cell population and caspase-dependent apoptosis in H460 and A549 cells. Mechanistically, BD stimulated the phosphorylation of JNK. Furthermore, the anti-cancer effects of BD were alleviated effectively by a specific JNK inhibitor SP600125 in NSCLC cells. In conclusion, the results demonstrated that BD exerted anti-cancer activity against NSCLC cells through JNK activation, which suggests its potent usefulness for prevention and treatment of NSCLC. [ABSTRACT FROM AUTHOR]