Search

Purpose : Peripheral neuropathy (PN) is common in multiple myeloma (MM) patients. More insight has been gained concerning the role of vitamin D in preventing PN. However, studies evaluating the effects of vitamin D3 supplementation on PN are lacking. The aims of this study are to (1) evaluate the effectiveness of a vitamin D3 regimen on achieving adequate vitamin D levels in deficient MM patients and to (2) exploratively evaluate the effect of vitamin D3 supplementation on PN. Methods: Thirty-nine MM patients with inadequate (< 75 nmol/L [= 30 ng/mL]) 25-hydroxyvitamin D (25(OH)D) levels were included in this multicenter, prospective, single-arm study, of whom 35 patients completed the study. They received oral vitamin D3 for 6 months according to a dose escalation regimen that consisted of one or two loading doses of 200,000 international units (IU), and maintenance doses of 800, 1600, or 3200 IU/day depending on the 25(OH)D level. A validated questionnaire was used to measure PN. Results: Median 25(OH)D increased from 38 (IQR 32–52) nmol/L at baseline to 77 (IQR 72–87) nmol/L after 6 months (P < 0.001). Adequate 25(OH)D levels were achieved by 66% of the subjects, and 34% were within the range of 50–75 nmol/L. Furthermore, in 37% of the participants, PN severity decreased (P = 0.007). Conclusion: The use of substantially higher vitamin D3 doses than recommended in current guidelines resulted in a significant increase in vitamin D levels in MM patients. Furthermore, evaluation of PN showed a significant decrease in PN grading. However, this exploratory evaluation needs further confirmatory research. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate the preclinical safety of Shenfu injection for the treatment of sepsis. Tests were designed and conducted to determine the acute and long-term toxicity of Shenfu injection in rats, based on the recommended indications and dosage for human use., Materials and Methods: Rats were administered 22.5 g of raw drug/kg/day via tail vein injection. Toxicity symptoms were monitored for 14 days following the intravenous injection of Shenfu injection, and target organs affected by toxicity were analyzed. To assess long-term toxicity, rats were given 12, 9, or 6 g of raw drug/kg/day by intraperitoneal injection, equivalent to 12, 9, and 6 times the daily clinical dose for adult sepsis patients (3.3 mL of stock solution per 1 g of raw drug/kg/day), for 30 consecutive days. This was followed by a 28-day recovery period after withdrawal of the drug. During the administration and recovery periods, signs of toxicity were observed and compared with those in the control (stromal fluid) group. The aim was to predict potential clinical adverse reactions, including the nature and severity of these reactions, dose-response and time-response relationships, and the reversibility of the effects. Additionally, the study sought to identify the target organs or tissues potentially affected by repeated administration and suggest clinical indicators that should be monitored during the product's use. Furthermore, the safety of co-administration with commonly used chemical medications for the treatment of sepsis was investigated., Results: In the acute toxicity test, administration of the maximum dose of Shenfu injection (75 mL of stock solution/22.5 g of raw drug/kg/day) via tail vein injection resulted in transient symptoms, including piloerection (vertical hair response), weight loss, and reduced food intake. In the long-term toxicity experiments, rats received intraperitoneal injections of 0.3 g/mL (stock solution), 0.225 g/mL, and 0.15 g/mL Shenfu injection per day, which corresponded to 12, 9, and 6 times the daily clinical dose for adults with sepsis. The injections were administered twice daily for 30 days, followed by a 28-day drug withdrawal period for recovery. After 28 days, no significant toxicological changes were observed, apart from a hemodilution effect caused by the excessive volume of the drug and a slight increase in alkaline phosphatase and total bilirubin levels. The effects were reversible upon drug discontinuation., Conclusions: A single intravenous injection of 22.5 g of raw drug/kg/day and long-term intraperitoneal administration of up to 12 g of raw drug/kg/day are considered safe doses for rats., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Tripterygii wilfordii Radix, (TW) as a toxic herbal medicine, is the root of Tripterygium wilfordii Hook. F. , which commonly used in China for the treatment of rheumatoid arthritis and autoimmune diseases, but its severe toxicity, particularly hepatotoxicity, significantly impacts its clinical application., Aim of the Study: The hepatotoxicity and its molecular mechanism of 70% TW ethanol extract (TWE) on male mice were demonstrated based on metabolomics, network pharmacological analysis and experimental validation., Materials and Methods: The toxic and bioactive ingredients in TWE were quantitative analyzed by Triple quadrupole (TQ) mass spectrometry method. The liver organ index, as well as the liver function indexes AST and ALT were evaluated after administering different doses of TWE for 24 h, and a pathological change was analyzed in liver tissue. Non-targeted metabolomics using UPLC-QTOF/MS was performed on both the plasma and liver tissue samples in combination with network toxicology to screen for key targets related to TWE toxicity in the liver. These key targets including caspase 3, NF-κB, TLR4, TNF-α, NQO1, and Bcl2 were subsequently verified through Western blotting experiments., Results: The six toxic and active ingredients of raphenolactone, ranolactone, triptolide tripterine, wilforlide A, demethylzeylasterain in TWE for the contents of 0.709, 1.408, 0.353, 0.354, 0.882, 0.227 mg g -1 , respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels increased and liver index decreased after administration of TWE for 24 h. Pathological analysis showed that TWE could produce toxicity to mouse liver, and its toxicity was dose-dependent. In the high-dose group, TW-D (11.23 g/kg) and TW-E (22.46 g/kg) caused a large amount of rupture in mouse liver nucleus and a large amount of inflammatory infiltration at the same time. Furthermore, 64 metabolites in plasma and 59 metabolites in the liver tissue were identified. The main metabolic pathways involved glycerol phospholipid metabolism, glycosylphosphatidylinositol-ether lipid metabolism, fatty acid metabolism, sphingomyelin metabolism, and ether lipid metabolism in plasma and liver tissue. Through analysis of the top 10 correlated targets, 6 out of the top 10 selected target proteins exhibited consistent expression patterns with liver injury. The levels of Bcl2 and NQO1 decreased with increasing exposure dose. The expression of Caspase 3, NF-κB, TLR4, and TNF-α increased with increasing dose. These findings suggest that protein expression has a regulatory effect at different doses groups compared to the control group.These findings suggest a regulatory effect of protein expression in different dose groups compared to the control group., Conclusion: The hepatotoxic effects of TWE can increase ALT and AST levels in plasma, leading to hepatic oxidative damage and inflammatory response. The toxic mechanisms that produce are closely related to the regulating of the abnormal metabolites in plasma and liver tissue. Furthermore, the regulating the expression levels of targeted proteins of TNF-α, NF-κB, Caspase 3, NQO1, and Bcl2 were confirmed by examining the liver tissue. These data clearly elucidate the toxicity mechanism of TW, laying the foundation for ensuring the quality and safety of drugs., Competing Interests: Declaration of competing interest We the undersigned declare that this manuscript entitled “Exploring the liver toxicity mechanism of Tripterygium wilfordii extract based on metabolomics, network pharmacological analysis and experimental validation” is original, has not been published before and is not currently being considered for publication elsewhere. We would like to draw the attention of the Editor to the following publications of one or more of us that refer to aspects of the manuscript presently being submitted. Where relevant copies of such publications are attached. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The Kai-Xin-San (KXS), as an ancient classic prescription, has been used for the treatment of amnesia for thousands of years. Modern clinical and non-clinical pharmacological studies have found that it has significant therapeutic effects on dementia and depression, but there are relatively few studies on its safety., Aim of the Study: Subacute and chronic toxicity studies were conducted to investigate the symptoms, severity, target organs, development and recovery of toxic reactions, as well as the toxic dose. These studies provide technical data for ensuring the safety of KXS., Materials and Methods: In the sub-acute toxicity study, rats were orally administered KXS at doses of 0.80, 1.61, 3.22, and 6.43 g/kg body weight for a duration of 4 weeks. In the chronic toxicity study, rats were orally administered KXS at doses of 0.27, 0.81, and 2.43 g/kg body weight for a duration of 26 weeks, and a withdrawal study was conducted for a period of 4 weeks after the treatment.The rats were observed daily for clinical signs and mortality. Changes in body weight, food consumption, and water consumption were periodically monitored. Additionally, urinalysis results, hematological and biochemical parameters, relative organ weights, and pathology were monitored at specific observation time points., Results: In the sub-acute toxicity study, necropsy of dead and moribund rats revealed evident distension and swelling of the gastrointestinal tract, as well as thinning of the intestinal wall. The main adverse reactions observed included flatulence, piloerection, abnormal breathing sounds, and emaciation. Doses of 1.61 g/kg and below did not cause animal death. The gastrointestinal system is the main target organ of toxicity. In the chronic toxicity study, the no-observed-adverse-effect-level (NOAEL) of KXS was 0.27 g/kg, and its toxic effects were primarily concentrated in the gastrointestinal system. This led to secondary pathological changes in the immune system, hematopoietic system, and heart, suggesting that relevant indicators should be monitored when large doses are used clinically for an extended period of time., Conclusions: During the rodent toxicity evaluation, severe gastrointestinal damage was observed when KXS, powdered with crude drugs, was administered. The NOAEL for rats was found to be 0.27 g/kg/day., 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.)

Ethnopharmacological Relevance: Neem (Azadirachta indica A. Juss.) is native to India and belongs to the Meliaceae family. It has been used for centuries in Eastern medicine, and more recently, as a natural pesticide. Although the use of bioinsecticides is supported by organic food production, further research is needed on each formulation, particularly on their effects on organisms., Aim of the Study: This study evaluated the reproductive toxicity of an aqueous extract of neem leaves in male Wistar rats of reproductive age after eight days of exposure., Materials and Methods: For this study, 20 rats were divided into four groups of five animals each and treated with different concentrations: Group 1 received 10,000 ppm, Group 2 received 7500 ppm, Group 3 received 5000 ppm, and Group 4 served as the control, received distilled water. The animals were observed for eight days for any clinical signs of toxicity. Semen quality, including sperm motility and viability, was analyzed., Results: No significant differences in physiological changes were observed between treatments. However, sperm motility and viability were affected in a concentration-dependent manner, with the group that received the highest dose exhibiting inviable spermatozoa., Conclusion: The data suggested that the administered doses had low toxicity. Nevertheless, concerns regarding reproductive toxicity remain because motility and sperm viability are negatively affected at the highest dose. Although bioinsecticides are widely used in organic food production, further research on each formulation, particularly regarding their long-term effects on organisms, is required., 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.)

Ethnopharmacological Relevance: Vaisvanara Churna used traditionally for the treatment of Amavata (Rheumatoid arthritis), Shotaprasamana (Anti-inflammatory) and as Saraka (Laxative)., Aim: Aim of the study is to evaluate anti arthritic activity and in vitro anti-inflammatory potential of Vaisvanara Churna in experimental animals., Materials and Methods: In-vitro anti-inflammatory activity of aqueous extract of Vaisvanara Churna (100-500 μg/ml) was evaluated by using membrane stabilization methods. Anti arthritic activity was evaluated by using 0.1 ml of Complete Freund's Adjuvant (CFA) injected into sub plantar surface of left hind paw of each wistar rat on day 1 followed by treatment with Vaisvanara Churna at various dose levels (450, 900, and 1800 mg/kg b.w) and standard drug Prednisolone (5 mg/kg) for 21 days. The following parameters namely change in the body weight of animals, paw volume, ankle joint thickness were measured at 0, 3, 8, 17 & 21 day intervals and radiographic changes were assessed. In addition to this, response to painful stimuli by application of forced pressure was measured by using Pressure Application Measurement (PAM) method., Results: In-vitro anti-inflammatory activity Vaisvanara Churna exhibited dose dependent membrane stabilizing activity. Treatment with Vaisvanara Churna showed significant (p < 0.05) inhibition of paw edema, reduction in ankle joint thickness and increase in the body weight of wistar albino rats was observed. There is a significant increase (p < 0.001) in the latency of limb withdrawal response, reduction in the organ indices (spleen and thymus) were noted., Conclusion: This study demonstrates that Vaisvanara Churna possesses in vitro anti inflammatory and anti-arthritic potential and supports its folklore use in the treatment of arthritis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Spermatogenic Pill (SP) is a commonly used clinical preparation in the Third Clinical Hospital of Changchun University of Traditional Chinese Medicine. Has accumulated a good reputation for more than a decade. However, because SP is a hospital clinical agent, it has received little extensive attention from researchers, which has led to a systematic lack of basic research on it. Therefore, it is impossible to determine whether there are safety hazards that may limit its widespread clinical application, and an in-depth toxicological evaluation of SP is essential and urgent., Aim of the Study: The aim of this study was to assess the safety of SP by conducting acute and subacute toxicity examinations., Materials and Methods: Identify active compounds contained in SP by LC-MS, and determination of inorganic elements in SP using ICP-MS. The in vivo acute toxicity of SP was assessed over a duration of 14 days following administration at doses of 7.5, 15, or 30 g/kg. To evaluate subacute toxicity, mice were administered daily doses of SP (7.5, 15, or 30 g/kg) for a period of 28 days. After the treatment period, the animals were euthanized, and standard blood tests, liver and kidney function tests, as well as tests related to glycolipid metabolism, were performed. The principal organs of the mice were collected to calculate organ coefficients and undergo hematoxylin-eosin (HE) staining., Results: LC-MS analysis showed that the active components of SP include Quercetin, Kaempferol, Beta-sitosterol, Stigmasterol, Diosbulbin B, Schizandrin, Naringenin, 2,3-hydroxycinnamic acid, L-proline, Histidine and Pluviatolide. The total amount of detected inorganic elements accounted for 3.0919% of SP. During the SP acute toxicity experiment, the groups that received the drug exhibited no signs of adverse reactions or poisoning symptoms. In subacute toxicity experiments, drug-treated mice showed overall favorable status, but the effects of continuous administration of the 30 g/kg group on body weight and food intake were reduced. An increase in the white marrow of spleen tissue after long-term administration of the drug treatment was also observed, suggesting that the drug can increase the maturation process and the number of mature lymphocytes in the spleen, and improve the lymphocyte immunity and humoral immunity function of the organism. Suggests that possibly this should be taken into account in clinical application. The routine blood examinations, as well as the assessments of liver and kidney functions, and the tests for glucose and lipid metabolism, did not reveal any notable toxic effects., Conclusion: SP contains more flavonoids, and terpenoid active ingredients, and is non-toxic in the body. This discovery not only strengthens the safety foundation of its clinical application, provides a solid scientific basis for the establishment of reasonable clinical dosage and the implementation of effective clinical toxicity monitoring, but also further lays a solid theoretical cornerstone for the subsequent clinical drug trials., 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.)

Background and Aims: Daily dosing frequency is an important factor influencing the plasma concentration of clozapine. This study investigated pharmacokinetic parameters in different daily dosing frequency regimens of clozapine in a naturalistic therapeutic drug monitoring sample to establish the necessary clozapine dosage to achieve plasma levels of 350-600 ng/mL in the Chinese population., Study Design: A single-center, retrospective, cross-sectional study was conducted at Xi'an Mental Health Center in China, where data on clozapine-treated patients between 2019 and 2022 were collected. The clozapine concentration-to-dose (C/D) ratios were compared between subgroups receiving different dosing regimens (once, twice, or three times per day) using Kruskal-Wallis H and Mann-Whitney U-tests., Study Results: The Kruskal-Wallis H test indicated significant variations in the C/D ratios among the three groups (p < 0.001). These findings were also consistent with the sex and age subgroup analyses. The receiver operating characteristic (ROC) analysis revealed that the twice-daily group required a daily clozapine dose of 125-225 mg to achieve the expected therapeutic reference concentration, with a corresponding clozapine C/D ratio of 1.6-2.8. The daily dose needed to reach therapeutic clozapine levels was higher in men than in women and in patients aged ≤ 44 years than in those aged ≥ 45 years., Conclusions: The daily clozapine dosing frequency is an important factor influencing the pharmacokinetic profile of clozapine. Large-scale, multicenter, prospective studies are needed to validate the clinically significant results of this study by administering the same total daily dose at different daily dosing frequencies., 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.)

The present study investigated the involvement of hippocampal nicotinic acetylcholine receptors (nAChRs) in the anti-allodynic effect of ketamine/morphine on neuropathic pain in adult male Wistar rats. Morphine or ketamine administration decreased the percentage of maximum possible effect (MPE%), indicating an analgesic effect. The most significant decrease occurred with a 5 mg/kg dose of morphine (average MPE% = 98), while a 0.5 mg/kg dose of ketamine resulted in a high response (average MPE% = 91), using decision trees as a machine learning tool. Combining morphine and ketamine improved neuropathic pain (average MPE% = 91). Intra-CA1 microinjection of mecamylamine (2 μg/rat) with morphine (3 mg/kg) reduced neuropathic pain (average MPE% = 94). Co-administration of lower doses of ketamine (0.1 mg/kg, i.p.) and mecamylamine (0.5 or 1 μg/rat) with morphine (3 mg/kg) led to a considerable reduction in pain (average MPE% = 91). Utilizing the generalized least squares (GLS) model enabled the establishment of a continuous relation between drug dose and MPE% as the outcome of interest. There was a 19.60 higher average MPE% for each mg/kg increase in morphine dose. In contrast, there was a 17.05 higher average MPE% for every 0.1 mg/kg increase in ketamine dose. Each 0.1 mg/kg increase in ketamine dose, when combined with morphine (3 mg/kg), led to a 30.85 higher average MPE%. A tenfold impact of increasing mecamylamine dosage on MPE% was observed when paired with morphine. Thus, hippocampal nAChRs play a significant role in mediating the anti-allodynic effect of ketamine and morphine in neuropathic pain., 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 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Increasing evidence indicates that neuropeptide FF (NPFF) produces analgesic effects and augments opioid-induced analgesia at the spinal level. However, our recent research demonstrated that NPFF exerted complex opioid-modulating effects in an inflammatory pain model after intrathecal (i.t.) injection. Consistent with previous findings, we found that i.t. NPFF dose-dependently attenuated complete Freund's adjuvant-induced pain hypersensitivity. Interestingly, pharmacological results illustrated that NPFF exhibited opposite opioid-modulating effects at the spinal level depending on its administration dosage, wherein i.t. NPFF potentiated morphine-induced anti-allodynia at the dose of 10 nmol, while attenuated morphine analgesia at an ultra-low-dose of 10 pmol. Behavioral results obtained from neuropeptide FF receptor 2 (NPFFR2) knockout animals suggested that both pro- and anti-opioid effects of NPFF were mediated by NPFFR2. Moreover, these modulating effects of spinal NPFFR2 were selectively targeting mu-opioid receptor, had no effect on delta- and kappa-opioid receptor agonist-induced analgesia. Finally, the opioid-modulating effects of NPFF were further verified using in vitro calcium imaging assay, demonstrating that pretreated with NPFF in primary-cultured spinal neurons significantly attenuated the inhibitory effects of morphine on high-K + -induced neuronal excitability. Taken together, our results suggested that NPFF exhibited dual modulating effects on morphine-induced analgesia after i.t. administration, which provides a possible mechanism to explain the complex opioid-modulating effects of endogenous NPFF systems., 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 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

It is common knowledge that the cerebellum is a structure of the central nervous system that influences the processes of balance and motor coordination. Recently its influence on social interactions has also been emphasized. The sigma receptor agonist: 3-di-o-tolylguanidine (DTG) is characterized by high affinity for sigma 1 and sigma 2 receptors, widely distributed in the cerebellum. In the experiment we assessed the effect of long term administration of DTG to adult male Sprague Dawley rats on social behavior and the concentration of neurotransmitters in the cerebellum. DTG was administered orally at a dose of 3 mg/kg body weight (bw) (DTG3), 10 mg/kg bw (DTG10) and 30 mg/kg bw (DTG30) for 9 weeks before the behavioral test. After the experiment, the concentration of catecholamines and amino acids in the cerebellum was assessed using high performance liquid chromatography (HPLC). Treatment groups showed reductions in social interactions such as grooming, sniffing and total time spent interacting. At the same time, it was shown that in the group receiving the lowest dose of the drug, a decrease in the concentration of dopamine and serotonin in the cerebellum was observed. Furthermore, changes in the concentration of taurine, alanine, glutamic acid and gamma-aminobutyric acid were observed in the treated groups. We found that long term administration of DTG disturbs animals' social interactions and the concentration of neurotransmitters in the cerebellum., 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 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Esketamine is commonly used for sedation or general anaesthesia in infants and young children. However, repeated esketamine administration during periods of rapid brain growth and development may result in various pathophysiological and cognitive changes. Therefore, this study aimed to investigate the influence of recurrent esketamine exposure on long-term behavioural and white matter consequences. Seven-day-old (P7) male rats were allocated to control, high-, and low-dose groups. Behavioural paradigm assessment was conducted at P25-29. Diffusion tensor imaging revealed long-term effects on water diffusivity in the splenium and cingulum white matter of the corpus callosum at P30. Subsequent two-dimensional structure-tensor analysis of brain tissue sections stained with Luxol fast blue (LFB) showed marked changes in the white matter microstructure in rats after multiple exposures to varying esketamine doses. High-dose esketamine significantly reduced activity time and total distance in the open-field experiment. High-dose esketamine exposure might lead to impaired short-term memory in rats. Additionally, the high-dose group showed prolonged immobility time during the forced swimming test. On the balance beam, the high-dose group displayed more right turns and right-foot slips and lower time spent on the rotating bar, indicating motor defects, than did the other groups. Diffusion tensor imaging demonstrated a decreased water molecule diffusion ability in the corpus callosum in the high-dose group. LFB staining indicated microstructural differences in the white matter of animals in the high-dose group. These findings suggest that behavioural deficits in high-dose esketamine-treated rats are at least partially attributed to changes in the white matter microstructure., 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.)

Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35. S35 exhibited excellent WRN helicase inhibitory activity (ADP-Glo kinase assay IC 50  = 16.1 nM, fluorometric helicase assay IC 50  = 23.5 nM). Additionally, S35 exhibited excellent cellular selectivity, with antiproliferative activity against multiple MSI cell lines (GI 50  = 36.4-306 nM), while the GI 50 values for multiple microsatellite stability (MSS) cell lines were greater than 20,000 nM. Furthermore, we observed that compound S35 induced DNA damage and caused G2/M cell cycle arrest in MSI cells, which did not occur in MSS cells. S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors., 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 Masson SAS.)

G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency., 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.)

The clinical development of PROTACs targeting the androgen receptor (AR) for degradation has made significant progress. However, effective treatments for metastatic prostate cancers containing the androgen receptor splice variant 7 (AR-V7), a constitutively active mutant without the ligand-binding domain (LBD), are still lacking. Here, we reported the identification of a highly potent, noncovalent PROTAC targeting the N-terminal domain (NTD) of AR, NP18, which is developed from the covalent AR-NTD antagonist EPI-002, and effectively degrades both AR-FL and AR-V7 in 22Rv1 cells (DC 50 : 18 and 26 nM respectively). Mechanistically, NP18 interacts with the N-terminal domain (NTD) of both full-length AR (AR-FL) and splice variant 7 (AR-V7), leading to their selective and proteasomal degradation. Importantly, NP18 exhibited remarkably superior antitumor activity in both 22Rv1 xenograft and patient-derived xenograft (PDX) models than EPI-002. Taken together, these findings highlight NP18 as a promising candidate to counteract AR splice variant-driven resistance., 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.)

Bisepoxylignans have been reported to possess a variety of biological functions, especially in anti-inflammatory aspects. However, the bis-tetrahydrofuran scaffold restricts the type and position of substituents, which further limits the further optimization of their biological activity and druggability. Here, a series of novel derivative s of bisepoxylignans bearing 7H-pyrrolo[2,3-d]pyrimidin-4-amine and 1H-pyrazolo[3,4-d]pyrimidin-4-amine scaffolds were designed and synthesized by a scaffold hopping strategy. Biological evaluation demonstrated that compound 7x exhibited the most potent anti-inflammatory activity, both in vitro and in vivo. Additionally, 7x displayed an excellent oral safety profile at a dose of 500 mg/kg. The anti-inflammatory effect of 7x is potentially mediated by the inhibition of the TLR4/NF-κB pathway and the promotion of M1 to M2 microglial phenotypic conversion. Taken together, 7x could be a promising lead compound for the development of novel therapeutic agents for the treatment of inflammatory diseases., 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.)

SHP2, a non-receptor protein tyrosine phosphatase involved in cancers, plays a pivotal role in numerous cellular signaling cascades, including the MAPK and PD-L1/PD-1 pathways. Although several SHP2 allosteric inhibitors have already entered clinical trials, none have been approved to date. Therefore, the development of new SHP2 allosteric inhibitors with improved efficacy is urgently required. Herein, we report the optimization of tail heterocycles in SHP2 allosteric inhibitors using a structure-based drug design strategy. Four series of compounds with different tail skeletons were synthesized, among which D13 showed notable inhibitory activity (IC 50  = 1.2 μM) against SHP2. Molecular docking and binding studies indicated that the newly synthesized compounds exerted enzymatic inhibitory effects by directly binding to SHP2 with relatively slow dissociation rates. At the cellular level, Huh7 cells demonstrated heightened sensitivity to the novel SHP2 inhibitors, and D13 exhibited superior antiproliferative activity (IC 50  = 38 μM) by arresting G0/G1 cell cycle, facilitating cell apoptosis and suppressing the MAPK signaling pathway. In the in vivo study, D13 displayed significant antitumor activity in a Huh7 xenograft model and possessed favorable druggability with acceptable oral bioavailability (F = 54 %) and half-life (t 1/2  = 10.57 h). Collectively, this study lays a robust foundation for further optimization of the tail heterocycle skeleton in SHP2 allosteric inhibitors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Zhiyi Yu reports financial support was provided by National Natural Science Foundation of China. Tao Zhang reports financial support was provided by National Natural Science Foundation of China. Zhiyi Yu reports financial support was provided by Natural Science Foundation of Shandong Province. Yuqian Cui reports financial support was provided by Natural Science Foundation of Shandong Province. Zhiyi Yu reports financial support was provided by Taishan Scholars Program Young Experts of Shandong Province. Tao Zhang reports financial support was provided by Taishan Scholars Program Young Experts of Shandong Province. If there are other authors, they 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.)

Particulate matter with diameter ≤2.5 μm particles (PM2.5) can trigger pulmonary inflammation and lung injury. However, there is still no specific and effective treatment. Lansiumamide B (LB) is a natural cis-enamide compound isolated from wampee seeds, and has potential anti-inflammatory effect. Herein, two series of pyrazole enamide analogues were designed and synthesized based on the scaffold hopping strategy. The inhibition rates of inflammatory cytokines on compound 11a were superior to other compounds and exhibited good dose-dependent manner and safety. Mechanism studies shown that 11a activated the Keap1/Nrf2/HO-1 signaling pathway and promoted Nrf2 entering into nucleus. Further, 11a alleviated pulmonary inflammation, collagen formation and mucus secretion in PM2.5 induced lung injury mice. Besides, 11a administration inhibited M1 macrophage polarization and neutrophil infiltration. Overall, 11a is an effective anti-inflammatory agent which might be a potent candidate to treat lung injury., 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.)

Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC 50 value of 1.061 ± 0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B., 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.)

Background: The number needed to treat (NNT) for efficacy and number needed to harm (NNH) for tolerability/safety were evaluated for adjunctive cariprazine in major depressive disorder (MDD)., Methods: Data were extracted from five randomized, double-blind, placebo-controlled trials of adjunctive cariprazine in MDD. NNTs (response, remission, severity shift) and NNHs (discontinuations due to adverse events [AEs], AEs, laboratory shifts) were determined in dose groupings; likelihood to be helped/harmed (LHH) was calculated., Results: NNTs (95 % CI) for adjunctive cariprazine versus placebo were statistically significant at week 6/early termination for response on the Montgomery-Åsberg Depression Rating Scale (MADRS), as defined by a decrease in total score ≥ 50 % (doses ≥ 1 mg/d = 12 [9-21]; 1-2 mg/d = 12 [8-25]; 2-4.5 mg/d = 14 [9-43]) and other response/remission outcomes. NNHs for cariprazine versus placebo were generally ≥ 10 for AEs that were statistically significant; an apparent dose-response was seen for akathisia (lower dose = 24 [17-43]; higher dose = 9 [7-11]). LHHs were ≥ 1 (acceptable benefit/harm ratio) for MADRS total score response versus most important cariprazine AEs in most dose groupings. For response versus discontinuation because of an AE, adjunctive cariprazine 1-2 mg/d had a more favorable response/tolerability profile in indirect comparison with other approved atypical antipsychotics., Limitations: Post hoc analysis; indirect comparisons., Conclusions: Patients receiving adjunctive cariprazine encountered benefits more often than harms; NNT values at week 6/early termination were statistically significant versus placebo on response/remission outcomes across dose groupings from the five pooled studies. Adjunctive cariprazine was well tolerated; NNH values versus placebo were generally > 10, with better akathisia tolerability in the lower-dose range., Competing Interests: Declaration of competing interest Leslie Citrome is a clinical professor in the Department of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York. He has served as consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, MapLight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies; owns stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago, stock options: Reviva; and receives royalties/publishing Income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer because of the difficulty in diagnosis and its resistance to chemotherapy. Focal adhesion kinase (FAK) is found overexpressed in PDAC, and targeting FAK has been proved to impede the progress of PDAC. However, most of FAK inhibitors were reported to bind with FAK in a DFG-in conformation, leading to a limited anti-tumor effect in clinical studies. Herein, to develop FAK inhibitors targeting the inactive DFG-out conformation, a series of large aromatic rings were selected to improve the interaction with Phe565 of the DFG motif. Compound 26 was designed to effectively inhibit FAK and the proliferation of PANC-1 cells with IC 50 of 50.94 nM and 0.15 μM, respectively. Besides, compound 26 was proved to strongly suppress the proliferation, colony formation, migration, and invasion in FAK-overexpressing PDAC cells. This inhibitor was confirmed to induce the apoptosis and G2/M arrest in PANC-1 cells through the suppression of FAK/PI3K/Akt signal pathway. Meanwhile, compound 26 was found to simultaneously inhibit FAK with DFG-out conformation and JAK3/Aurora B (IC 50 of 9.99 nM and 0.49 nM, respectively). In vivo, compound 26 effectively inhibited the tumorigenesis and metastasis of PDAC with desirable biosafety. Overall, these results suggested that compound 26 was a promising candidate for the treatment of PDAC., 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.)

The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Allemand F, Cotelle P, Gelin M, Guichou JF, Lebegue N, Melnyk P, Toulotte F, Zagiel B. has patent #Arylalkyloxyindole compounds and derivatives and their use. EP 23307402.0 pending to no. If there are other authors, they 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 Masson SAS.)

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation is a key target for acute myeloid leukemia (AML) treatment. The second-generation inhibitors such as Gilteritinib still present off-target effects and associated side effects. Therefore, identifying novel FLT3-ITD inhibitors has become a promising strategy for AML treatment. In this study, a 4D-QSAR model was developed based on Gilteritinib and its analogues, and it was found that introducing hydrophobic bulky groups at the piperazine or piperidine of Gilteritinib would enhance the binding affinity to FLT3-ITD. So, three series of targeted compounds (A1-A5, B1-B5 and C1-C5) were designed and synthesized. The antiproliferative activity against MOLM-13 cells was evaluated in vitro. Compound A1 (IC 50  = 25.65 nM), with a cubane group at the piperazine position; Compounds B2 (IC 50  = 63.38 nM) and C2 (IC 50  = 54.96 nM), with a norbornene group at the piperidine position, showed the strongest inhibition in their series. Their IC 50 values were comparable to that of the positive control Gilteritinib (IC 50  = 22.37 nM). FLT3-ITD was confirmed as the degradation target through a kinase inhibition assay, where the IC 50 values were 2.12 nM (Compound A1), 1.29 nM (Compound B2), and 3.06 nM (Compound C2), which were comparable to that of Gilteritinib (IC 50  = 0.43 nM). Additionally, molecular docking and molecular dynamics (MD) simulations showed that Compounds A1, B2, and C2 had similar binding modes to that of Gilteritinib with more stable affinities. Overall, these results demonstrated that Compounds A1, B2, and C2 were promising inhibitors for targeting AML with FLT3-ITD mutation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Juan Wang reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they 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.)

Small molecules that possess the ability to regulate the interactions between Son of Sevenless 1 (SOS1) and Kristen rat sarcoma (KRAS) offer immense potential in the realm of cancer therapy. In this study, we present a novel series of SOS1 inhibitors featuring a tricyclic quinazoline scaffold. Notably, we have identified compound 8d, which demonstrates the highest potency with an IC 50 value of 5.1 nM for disrupting the KRAS:SOS1 interaction. Compound 8d exhibits a promising pharmacokinetic profile and achieves a remarkable 70.5 % inhibition of tumor growth in pancreas tumor xenograft models. Furthermore, molecular dynamic simulations have unveiled that the tricyclic quinazoline derivatives exhibit extensive interaction with Tyr884, a crucial residue for the recognition between SOS1 and KRAS. Our findings provide fresh insights into the design of future SOS1 inhibitors, paving the way for innovative therapeutic strategies., 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.)

Chalcones have the characteristics of simple structure, easy synthesis and potent anti-tumor activity. Herein, a small library of fifty-five novel indole-chalcone derivatives were rationally designed and facilely synthesized. Consequently, their antiproliferative activity was systematically evaluated. Among which, compound 26 exhibited the most potent antiproliferative activity, with IC 50 value of 0.764 μM against MD-MBA-231 cells. Moreover, it displayed a 5-fold selectivity compared with normal human cells. Further investigation revealed that compound 26 bound at the colchicine binding site of tubulin, disrupted their fibrous structure, thereby blocking the progression of the cell cycle and inducing apoptosis. Molecular docking and cellular thermal shift assay (CETSA) experiments further demonstrated that compound 26 could specifically bind to hexokinase 2 (HK2) and inhibit its activity, leading to impaired mitochondrial function and hindered mitochondrial respiration. Based on the quantitative structure-activity relationship study, further structure modifications were performed. Employing biotin probe pull-down assays, we demonstrated that compound 26 exerted its antiproliferative activity through a dual targeting mechanism, which simultaneously disrupted microtubule function and inhibited HK2 activity. Taken together, these results highlighted that compound 26 might be a promising antiproliferative agent for human cancer therapy., 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.)

CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3-d]pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC 50 values in the nanomolar range. Compound 10b demonstrated the most balanced activity profile with a cell-free IC 50 value of 36.7 nM and a notable cellular activity with a GI 50 of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. 10b displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range., 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 Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant global health threat, necessitating the development of new therapeutic agents. Pleuromutilin derivatives offer a promising solution due to their potent antibacterial activity, particularly against Gram-positive bacteria such as MRSA. In this study, we synthesized a series of pleuromutilin derivatives with phenol linker containing C14 side chains and evaluated in vitro and in vivo antibacterial activities. Several compounds showed potent activity against MRSA and Staphylococcus aureus with minimal inhibitory concentrations (MICs) as low as 0.03125 μg/mL. In particular, compounds a4 and b4 showed rapid bactericidal activity, significantly reducing MRSA loads in time-kill kinetics and exhibiting slower resistance development compared to tiamulin. In vivo, compound a4 showed superior efficacy in reducing MRSA-induced lung damage in a mouse model at a lower effective dose (ED50 = 6.48 mg/kg) compared to tiamulin (ED50 = 11.38 mg/kg). Molecular docking and molecular dynamics studies also showed that compound a4 binds strongly to the ribosomal peptidyl transferase center (PTC), a key target for pleuromutilin derivatives. These results suggest that compound a4, with its enhanced antibacterial activity and low resistance potential, is a promising candidate for further development as an effective treatment for MRSA infections., 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.)

Six C-6 fluorinated d-swainsonine derivatives and their enantiomers have been designed based on initial docking calculations, and synthesized from enantiomeric ribose-derived aldehydes, respectively. Glycosidase inhibition assay of these derivatives with d-swainsonine (1) and l-swainsonine (ent-1) as contrasts found that the C-6 fluorinated d-swainsonine derivatives with C-8 configurations as R (α) showed specific and potent inhibitions of jack bean α-mannosidase (model enzyme of Golgi α-mannosidase II); whereas their enantiomers with C-8 configurations as S (β) were powerful and selective α-l-rhamnosidase inhibitors. Molecular docking calculations found the C-6 fluorinatedd-swainsonine derivatives 21, 24 and 25 with highly coincident binding conformations with d-swainsonine (1) in their interactions with the active site of α-mannosidase (PDB ID: 1HWW). Reliability of the docking results were confirmed by Molecular Dynamics (MD) simulation. Additionally, solid interactions with residues Gln-392 and Tyr-393 in the active site of α-l-rhamnosidase (PDB ID: 3W5N) were proved to be vital for potent α-l-rhamnosidase inhibitions of the l-swainsonine derivatives. The role of C-6 fluorines in swainsonine derivatives well demonstrated the "mimic effect" of fluorine to hydrogen by minimal influence on the binding conformations and effective compensation for any possible lost interactions. This work contributes to a comprehensive understanding of the structure-activity relationship (SAR) of the fluorinated swainsonines and ever reported branched swainsonines, and has laid good foundation for development of more potent α-mannosidase and α-l-rhamnosidase inhibitors., 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.)

Platinum-based drugs are a mainstay in chemotherapy, with traditional forms exerting their work directly on DNA. In recent years, it has been observed that platinum complexes had the potential to induce immunogenic cell death (ICD) and effectively trigger antitumor immune responses. Herein, to obtain novel platinum complexes with chemo-immunological properties, a series of Pt(ΙΙ)-N-heterocyclic carbene (Pt(ΙΙ)-NHC) complexes derived from 4,5-diarylimidazoles were synthesized. Among them, the dominant complex 3f was proved to exhibit better anti-liver cancer capacity compared to cisplatin and oxaliplatin. Complex 3f showed the ability to cause DNA damage by binding to DNA. In addition, it triggered intracellular reactive oxygen species (ROS) generation, affected the function of mitochondria, and blocked cells in G0/G1 phase, ultimately induced apoptosis in liver cancer cells. Furthermore, complex 3f activated endoplasmic reticulum stress (ERS) which promoted the release of damage-associated molecular patterns (DAMPs), induced ICD and dendritic cells (DCs) maturation. Interestingly, complex 3f also upregulated PD-L1, consequently converted "cold tumors" into "hot tumors". Overall, complex 3f had the potential to be regarded as a promising chemoimmunotherapy for the treatment of liver cancer., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Heme, abundant in the mitochondria of cancer cells, is a key target for the anticancer activity of artemisinin (ART). Current strategies to enhance the anticancer activity of ART focus solely on its delivery to heme-enriched subcellular localizations while overlooking the decisive effects of ART-heme interactions. Here, we propose an ingenious strategy that synergizes mitochondria-targeted drug delivery and linker-mediated drug conformation modulation, thereby significantly enhancing the anticancer activity of ART. By strategically conjugating artemisinin (ART) with the mitochondria-targeting rhein (R) using different linkers, we aimed to precisely adjust the conformation of the conjugates. Comprehensive computational analysis revealed that the conjugate with the optimal linker length (C 4 ) displayed a favorable conformation that facilitated cell permeability and exhibited the highest binding affinity to heme and Fe ions. Moreover, it exhibited superior tumor suppression capabilities both in vitro and in vivo, overcoming the uncertainty of in vivo application caused by the rapid clearance of the conventional mitochondria-targeted cation TPP + , and even inducing immunogenic cell death associated with immunotherapy. This novel strategy opens up a new avenue for the development of drug conjugate systems., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The emergence of multi-drug resistance (MDR) presents a significant impediment to the efficacy of cancer treatment. Aberrant expression of ABC (ATP-binding cassette) transporters is acknowledged as one of the underlying factors contributing to MDR. P-glycoprotein (P-gp, MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2), and MDR-associated protein 1 (MRP1, ABCC1) are members of the ABC transporter, and their over-expression usually occurs in drug-resistant tumor cells. In this work, the structure-activity relationships of the biaryl amide skeleton were systematically investigated via structural optimization step by step, which led to the identification of an exceptionally potent resistance reversal agent, D2. Compound D2 effectively reversed MDR to paclitaxel and cisplatin in A2780/T, A2780/CDDP and A549/T cell lines. It could directly bind to P-gp and downregulate the expression of both P-gp and MRP1. The treatment with D2 increased the intracellular accumulation of Rh123 and inhibited P-gp-mediated drug efflux of Rh123 in A2780/T cells. Therefore, compound D2 exhibits promising potential in overcoming multidrug resistance (MDR) induced by P-gp in cancer., 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.)

Peptidomimetics of Suppressors of cytokine signaling 1 (SOCS1) protein demonstrated valid therapeutic potentials as anti-inflammatory agents. Indeed, SOCS1 has a small kinase inhibitory region (KIR) primarily involved in the inhibition of the JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway Herein, on the basis of previous investigations on a potent mimetic of KIR-SOCS1, named PS5, we designed and evaluated the SAR (Structure Activity Relationship) features of two xylene-based macrocycles analogues of PS5. These novel compounds bear thiol-xylene linkages with mono- and bi-cyclic scaffolds: they were in vitro functionally investigated toward JAK2 catalytic domain, as ligands with microscale thermophoresis (MST) and as inhibitors through LC-MS analyses. To evaluate structural properties Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies were employed along with serum stability assays. Results indicated that a monocycle scaffold is well-tolerated by PS5 sequence enhancing the affinity toward the kinase with a K D in the low micromolar range and providing consistent inhibitory effects of the catalytic activity, which were evaluated for the first time in the case of SOCS1 mimetics. Conformationally, the presence of xylene scaffold affects the flexibility of the compounds and their stabilities to proteases degradation. This study contributes to the understanding of the factors necessary for accurately mimicking the inhibitory mechanism of SOCS1 protein towards JAK2 and to the translation of proteomimetics into drugs., 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 Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ferroptosis is an iron-dependent regulated cell death, which has been implicated in the onset and progression of numerous diseases. Ferroptosis inhibitors are thought as potential agents for treating these related diseases. However, the majority of currently available ferroptosis inhibitors are antioxidants or iron chelators (called classical ferroptosis inhibitors), which might have potential risks of side effects during clinical use. Herein, we report the discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors. Structure-activity relationship of these series compounds led to the discovery of the most active compound 13l with an EC 50 value of 0.0007 μM. Mechanistically, 13l could inhibit NCOA4-mediated ferritinophagy, hence protecting cells from ferroptosis. Notably, in the acetaminophen-induced acute liver injury model, 13l showed an excellent therapeutic effect. Overall, this compound reported here could be a promising lead compound for drug discovery targeting ferroptosis., 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.)

AlkB homolog 2 (ALKBH2) is a Fe (II) and 2-oxoglutarate (2OG)-dependent DNA demethylase. It has been reported to be highly expressed in many cancers including glioblastoma (GBM) and affected disease progression by regulating gene expression. Small molecule inhibitors of ALKBH2 might be used as disease intervention reagents or chemical tools for bio-functional studies of ALKBH2, but currently no potent and selective ALKBH2 inhibitors are reported. We herein disclose a new potent and selective ALKBH2 inhibitor (AH2-15c), which showed an IC 50 value of 0.031 ± 0.001 μM in a fluorescence polarization (FP) assay and exhibited more than 200-fold selectivity towards ALKBH2 versus other AlkB subfamily members. Since AH2-15c showed very low cellular activity due to its poor cell membrane permeability originating from the carboxyl group, we investigated the un-hydrolyzed counterpart AH2-14c. AH2-14c could directly bind to ALKBH2 and increase the abundance of DNA N 3 -methylcytosine (3meC) modifications in GBM U87 cells, with a superior effect to AH2-15c. In addition, AH2-14c exhibited much better activities of anti-viability, anti-proliferation and anti-migration against U87 cells. Collectively, we discovered the first potent and selective ALKBH2 inhibitor, which could be taken as a foundation for future drug development and mechanism of action studies., 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.)

A series of semisynthetic noscapine-urea congeners (7a-7h) as potential tubulin-binding agents are being developed by integrating a urea pharmacophore at the C-9 position of the noscapine scaffold. Their binding affinity to tubulin was predicted through molecular docking, molecular dynamics (MD) simulations, and the MM-PBSA approach. These molecules were subsequently chemically synthesized and assessed using breast cancer cell lines (MCF-7 and MDA-MB-231) and normal human embryonic kidney cells (HEK). Both the docking score and the predicted binding free energy (ΔG bind,pred ) revealed that urea congeners had a stronger affinity towards tubulin than noscapine and effectively inhibited the proliferation of all cancer cell types without affecting normal healthy cells. The results indicated that compound 7g exhibited the most promise and was chosen for further studies. Moreover, MDA-MB-231 cells treated with 7g at its IC 50 concentration showed morphological changes such as membrane blebbing, fragmented nuclei, and the presence of apoptotic bodies. Apoptosis induction was further confirmed by flow cytometry. Moreover, the tubulin binding assay revealed a greater binding affinity with an equilibrium dissociation constant (KD) of 42 ± 2.4 μM for compound 7g. The number of MCF-7 cells engrafted as breast tumors in nude mice was found to be reduced significantly without any adverse effects. Noscapine is already in clinical trials, but the urea noscapine congener offers an advantage because of its increased potency without impacting the nontoxic profile of noscapine., Competing Interests: Declaration of competing interest The authors declared that there is no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

In recent years salinomycin has emerged as a promising anticancer drug. Many literature reports have proved its remarkable antiproliferative activity. Moreover, chemical modifications of salinomycin lead to analogues with even higher cytotoxicity against cancer cell lines and a better selectivity index for malignant cells than those of the unmodified compound or a standard anticancer drug such as doxorubicin. In this paper we report the synthesis of a series of twelve novel salinomycin conjugates and their characterization by spectroscopic and spectrometric methods. Salinomycin was conjugated with different triphenylphosphonium cations in order to find out whether the conjugation with mitochondrial targeting vectors would have a beneficial impact on biological properties. Salinomycin and its novel conjugates were tested to determine their in vitro antiproliferative and antimicrobial activity. Taking into account the presence of triphenylphosphonium moiety, the impact of the obtained analogues on mitochondria activity was evaluated by MitoTrackers dyes, furthermore their apoptosis effect and cell cycle arrest were assessed. In addition, the changes in the mitochondrial membrane potential were measured and the ability to generate reactive oxygen species was assessed. Finally, we conducted biophysical studies to investigate the impact of the obtained salinomycin analogues on mitochondrial respiration rates and their electrophysiological properties. Results of this study have proved that conjugation of salinomycin with phosphonium cations leads to promising results in the search for promising anticancer agents., 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 Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Disrupting microtubule dynamics has emerged as a promising strategy for cancer therapy. Novel trimethoxyanilino-substituted pyrimidine and quinazoline derivatives were designed and synthesized to serve as potent microtubule-inhibiting agents with anti-proliferative activity. Compound 2k demonstrates high efficacy against B16-F10 cancer cells at low nanomolar concentrations, with an IC 50 of 0.098 ± 0.006 μM, which is comparable to colchicine. Mechanistic studies have revealed that 2k has the ability to inhibit microtubule protein polymerization in vitro, resulting in cell cycle arrest and apoptosis. Furthermore, 2k inhibits tumor cell migration and exhibits significant anti-tumor efficacy in a melanoma tumor model without causing obvious toxicity. In summary, the pyrimidine derivative 2k exhibits excellent anticancer activity and provides a new scaffold for the development of novel microtubule inhibitors, which deserves further in-depth research., 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.)

Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF. The epithelial sodium channel (ENaC), unlike CFTR which is secretory, is an absorptive pathway, and therefore its inhibition is an alternative and potentially complementary approach to aid hydration of the airways. Due to the adverse effect of ENaC inhibition in the kidney we, as have several others, focused on the design and synthesis of novel ENaC inhibitors for direct delivery to the airways via inhalation. A new series of ENaC inhibitors is described, wherein the well-established pyrazine core of first-generation inhibitors was replaced with a pyrrolopyrazine. Aiming for high retention at the surface of the lung following inhalation, optimisation of this template focused on significantly increasing polarity to minimize passive cellular permeability. The resulting optimized clinical candidate ETD001 demonstrates potent inhibition of ENaC (59 nM) prolonged retention in the airways of rats (13 % of the delivered dose retained after 6h) following intratracheal administration and a potent and long-acting effect in a sheep model of mucociliary clearance following inhalation (ED 100 (4-6h) = 9 μg/kg). ETD001 entered a phase II study in CF patients in July 2024., 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 Enterprise Therapeutics Limited. Published by Elsevier Masson SAS.. All rights reserved.)

Kinesin spindle protein (KSP) plays a crucial role during mitosis, making it an attractive target for cancer treatment. Herein, we report the design, synthesis, and evaluation of the first series of KSP degraders by using the utilization of the proteolysis-targeting chimera (PROTAC) technology. Compound 21 was identified as a potent KSP degrader with a DC 50 (concentration causing 50 % of protein degradation) value of 114.8 nM and a D max (maximum degradation) of 90 % in the HCT-116 cells. Compound 21 showed strong antiproliferative activity against HCT-116 cells with an IC 50 values of 10 nM. Mechanistic investigations revealed that 21 causes the cell arrest at the G2/M phase and subsequent cell apoptosis. In addition, 21 demonstrated more significant inhibition of tumor growth in an HCT-116 xenograft model compared to its parent compound 1. Our findings suggest that 21 may become the promising leads for further development., 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.)

Given the vulnerability of colorectal cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC 50 value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC., 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.)

Invariant natural killer T (iNKT) cells are a subset of innate T cells displaying powerful immunomodulatory functions. Despite extensive preclinical research on the use of iNKT agonist and antagonist for various diseases, translating these findings into successful clinical applications has proven challenging, leaving no approved treatments to date. Efforts to optimize therapeutic outcomes by developing alternative glycolipids to α-galactosylceramide (α-GalCer or KRN7000), the prototypical iNKT antigen, have shown improved preclinical results. However, significant obstacles remain, including the relatively laborious synthesis of α-glycosides and their vulnerability to degradation by α-glycosidases. To overcome these limitations, we explored the use of sp 2 -iminosugars, a class of glycomimetics, to replace the carbohydrate moiety in α-GalCer-like glycolipids. This substitution offers enhanced biostability and precise control over α-selectivity in glycosylation reactions. The resulting sp 2 -iminoglycolipids (sp 2 -IGLs) were tested for their immunomodulatory effects, demonstrating the ability to bind the α-GalCer binding site on the CD1d protein in antigen-presenting cells (APCs), and functioning as iNKT antagonists in α-GalCer-stimulated splenocytes. Notably, analogs featuring a 4-alkyl-1,2,3-aminotriazol-1-yl segment in place of the C 25 N-acyl tail in α-GalCer additionally exhibited mild agonistic activity in the absence of α-GalCer stimulation. Computational studies support the formation of stable CD1d- sp 2 -IGL and CD1d - sp 2 -IGL - T-cell receptor complexes, with significant differences in the dynamics depending on the glycone nature and lipid tail length. These findings provide a molecular rationale for the observed experimental data. Furthermore, in vivo studies using murine models of asthma and autoimmune hepatitis have identified promising sp 2 -IGL candidates for further development in immunotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carmen Ortiz Mellet reports financial support was provided by State Agency of Research. Jose M. Garcia Fernandez reports financial support was provided by State Agency of Research. Jesus Angulo reports financial support was provided by State Agency of Research. Carmen Ortiz Mellet reports financial support was provided by Spain Ministry of Science and Innovation. Jose M. Garcia Fernandez reports was provided by Spain Ministry of Science and Innovation. Jesus Angulo reports was provided by Spain Ministry of Science and Innovation. Carmen Ortiz Mellet reports financial support was provided by European Regional Development Fund. Jose M. Garcia Fernandez reports financial support was provided by European Regional Development Fund. Jesus Angulo reports financial support was provided by European Regional Development Fund. Ya-Jen Chang reports financial support was provided by National Science and Technology Council. Jose M. Garcia Fernandez reports financial support was provided by Government of Andalusia Department of University Research and Innovation. Reports a relationship with that includes:. Has patent pending to. If there are other authors, they 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 Masson SAS.)

The amphiphilic and asymmetric structure of porphyrins, when used as photosensitizers (PSs) for photodynamic therapy (PDT), has been shown through numerous previous studies to be a very important property that facilitates their entry into cells, which improves their efficiency in PDT. In this work, two groups of cationic AB 3 pyridiniumporphyrins, free-base and chelated with Zn(II), both substituted with alkyl chains of various lengths, were studied in PDT on melanoma cell lines. The aim was to investigate the impact of hydrophilic-lipophilic balance and Zn(II) chelation, and the importance of matching the irradiation wavelength to the optical properties of the PS on in vitro PDT efficiency. Therefore, spectroscopic studies, singlet oxygen production and lipophilicity as well as cellular uptake, localization and cytotoxicity studies of the two series of porphyrins were performed. In both series of porphyrins, the longest alkyl chain (17 C-atoms long) enables the greatest internalization of the PS. Chelation with Zn(II) resulted in better physicochemical properties, but slower cellular internalization. As expected, free-base porphyrins were more PDT efficient than their Zn(II) complexes after 30-min photoactivation by low-fluence (2 mW/cm 2 ) red light (643 nm). However the use of orange light (606 nm) with the same fluence rate was more suitable for Zn(II) porphyrins and resulted in similar overall toxicity to their free-base analogues with similar lipophilicity. Although the highest phototoxicity was achieved with the PSs carrying the longest alkyl chain, TMPyP3-C 13 H 27 and Zn(II)-TMPyP3-C 13 H 27 proved to be the most promising candidates for use in PDT as they exhibit high phototoxicity, but also greater selectivity towards melanoma cell lines (MeWo and A375) compared to fibroblasts (HDF)., 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.)

Factor XIa (FXIa) has emerged as a novel anticoagulant target with a reduced risk of bleeding. However, due to the nearly identical residues it shares with its closest homologue, plasma kallikrein (PKa), only a few selective FXIa inhibitors have been reported. Herein, we describe the discovery of novel triazole-based pyridone derivatives as potent and selective FXIa inhibitors. Structural optimization identified triazole-based benzoic acids as optimal P2' fragments. The representative compound (S)-10h (IC 50  = 0.38 nM for FXIa) was approximately 3-fold more potent than asundexian for FXIa, along with up to 150-fold selectivity over PKa (13-fold for asundexian) and up to 100,000-fold selectivity over FXa and thrombin (5000-fold for asundexian). Extensive molecular dynamics simulations and free energy calculations revealed that electrostatic interactions with varied residues near the binding site, particularly the loop at the bottom of the S2' pocket (IP-loop), are critical factors contributing to the improved selectivity over PKa. Calculations of electrostatic potential (ESP) surfaces illustrated that FXIa forms a more positive ESP than PKa, thrombin, and FXa, which attracts the carboxylic acid group of the designed compounds, enhancing both potency and selectivity. Moreover, compound (S)-10h demonstrated potent in vitro anticoagulant activity with an EC 1.5X value of 0.55 μM for aPTT, without interfering with PT up to 100 μM. Thus, compound (S)-10h represents a promising lead for further optimization as a novel anticoagulant agent., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Metabolic dysfunction-associated steatohepatitis (MASH) has become a serious threat to human health, which exhibited an increasing prevalence globally. Recently, the farnesoid X receptor (FXR) has been identified as a promising strategy for the treatment of MASH by regulating multiple pathogenesis. In this study, a new series of FXR agonists bearing piperidine scaffold was designed to reduce the high lipophilicity of the existing FXR agonists. After comprehensive multiparameter optimization, LZ-007 was discovered as a highly potent FXR agonist with suitable stability in liver microsomes of multiple species. LZ-007 exhibited highly oral bioavailability and targeted tissue exposure in the liver and ileum, while the plasma exposure is low, which might minimize the systemic side effects. Moreover, LZ-007 was significantly up-regulated the expressions of FXR and its downstream genes in the liver and ileum. In MASH model, LZ-007 exerted potent anti-MASH effects by regulating the multiple signal pathways related to lipid metabolism, oxidative stress, inflammation and fibrosis. In a 30-day toxicity study, no apparent adverse effects were observed in LZ-007 treated groups, even at the high doses of 250 and 500 mg/kg. With the positive pharmacodynamics and safety profiles, LZ-007 is worthy of further evaluation as a new anti-MASH agent., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Buprenorphine is an FDA approved drug for the treatment of opioid use disorder and is a long-lasting, low efficacy (partial) agonist of the μ opioid receptor. As a partial agonist, buprenorphine can act as either an agonist or an antagonist depending on the efficiency of the cellular signaling system. Here we investigated the antagonist properties of buprenorphine using a genetically-encoded biosensor to monitor cAMP levels in real time in HEK293 cells expressing a relatively low density of the human μ receptor. Pre-treatment of cells with buprenorphine decreased the maximal response (Emax) of the μ receptor agonists DAMGO and fentanyl, consistent with expectations of a long-lasting partial agonist in these cells. However, buprenorphine pretreatment also reduced the potency of these agonists. In a Schild analysis, the reduction in Emax saturated with increasing concentrations of buprenorphine, while the reduction in potency did not. This unexpected behavior of buprenorphine on potency was mediated through the orthosteric site, as pretreatment with the opioid receptor antagonist naloxone prevented buprenorphine antagonism. Computation simulations using a model of hemi-equilibrium indicated that buprenorphine's slow receptor dissociation could account for both effects of antagonism. In support of this kinetic explanation, buprenorphine antagonism became surmountable with additional agonist incubation time. In this system, buprenorphine appeared to behave both as a competitive and non-competitive (insurmountable) antagonist due to its slow dissociation resulting in partial re-equilibration (hemi-equilibrium). As fast-acting biosensors become more prevalent, it will be important to consider kinetically-mediated effects such as hemi-equilibrium when characterizing the pharmacological properties of antagonists., 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.)

The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC 50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells)., 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.)

Ethnopharmacological Relevance: Acute kidney injury (AKI), a global public health concern that increases the risk of death, end-stage renal disease, and prolonged hospital admissions. As of this point, supportive measures like fluid resuscitation and replacement therapy for renal failure are the only treatments available for treating AKI. Asparagus racemosus (AR) also known as Shatavari, belongs to family Liliaceae and is considered exceptional in Ayurvedic medicine due to its versatility in treating and preventing a variety of illnesses., Aim of the Study: The purpose of this study is to determine the effectiveness of chloroform fraction of Asparagus racemosus (CFAR) against cisplatin (CP) induced AKI., Materials and Methods: HPLC was used to analyze the presence of bioactive phytocompounds in CFAR using standard quercetin. Further LC-MS study indicated the existence of different bioactive compounds. Normal Rat Kidney (NRK-52E) cells were used to study the nephroprotective effect of CFAR. Cells were untreated, treated or cotreated with CP (20 μM) and CFAR (5, 25, 50, 100, 200 and 400μg/mL) for 24 h. After 24 h of treatment, cell viability assay and assay of apoptosis parameters were performed. The CFAR at the dose of 50 mg, 100 mg and 200 mg/kg/day was administered orally for 15 days and acute kidney injury was induced in rats by intraperitoneal injection of CP (10 mg/kg body weight) at the 10th day of experimentation. Biochemical studies were performed to evaluate kidney function; protein expression by Western blot and mRNA expression of related gene were studied from the kidney tissues to evaluate the effects of CFAR. Histopathological analysis was done to investigate the structural abnormalities and fibrosis of renal tissues., Result: Our result reported that CFAR contain many bioactive phytomolecules having many pharmacological properties. Cell viability assay and assay of apoptosis reported that different doses of CFAR could reduced CP-induced cell death and cell apoptosis. The levels of kidney injury markers (BUN, sCr and eGFR), inflammatory markers (Interleukin-18, KIM-1, Cys-C, NF-kB and NGAL), and antioxidant markers (SOD, GSH, CAT, Nrf2 and Bcl2) and lipid peroxidation (MDA) were settled to a normal level by the oral administration of high doses (100 and 200 mg/kg body weight) of CFAR after intraperitoneal injection of CP as suggested by biochemical, histopathological, protein and gene expression studies., Conclusion: In conclusion, CFAR at the high doses (100 and 200 mg/kg body weight) could able to protect the kidneys from CP induced oxidative stress and inflammation due to presence of bioactive phytomolecules that prevent the activation of oxidative stress induced signalling cascades leading to kidney damage., 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.)

Ethnopharmacological Relevance: Inula viscosa (L.) Aiton is a traditional medicinal plant widely distributed and used in Mediterranean countries, its leaves are prepared by maceration to treat, rheumatic pain, inflammatory diseases, diabetes, anemia and cancer., Aim of the Study: The present study purpose to investigate the anti-inflammatory efficacy of I. viscosa leaves methanol extract (IVME) at three different doses on formaldehyde-induced arthritis in NMRI albinos mice., Materials and Methods: Mice were divided into six groups (n = 6) as follows: normal control, disease control, Diclofenac group (10 mg/kg, p.o. daily) and three groups, daily treated with 50, 100 and 200 mg/kg IVME (p.o.); Formaldehyde models were obtained by a sub-plantar administration of 20 μl of formaldehyde (3.75% v/v) into the right hind paws of NMRI albino mice on 1st and 3rd days of the 10 experimental days. Joint diameter was measured, arthritis severity was evaluated by inhibition of paw edema, histological changes, synovial hyperplasia and immune cells infiltration was evaluated by histological and immunohistochemical analyses of CD3 + , CD20 + and CD68 + . Post-mitochondrial supernatants (PMS) from liver tissues homogenates were collected for the assessment of enzymatic and non-enzymatic antioxidants: Catalase (CAT) & Myeloperoxidase (MPO) activities, glutathione (GSH) and an oxidative stress biomarker (nitric-oxide (NO)) level., Results: Administration of I. visocsa (at low dose: 50 mg/kg) significantly (∗∗∗p < 0.001) ameliorated the induced arthritis severity, reduced hyperplasia of synovial membrane, bone erosion and immune cells infiltration (∗p < 0.05), resulted by restoration of paw diameter. It also decreased levels of NO (∗∗∗p < 0.001) and MPO activity (∗∗∗p < 0.001), and significantly restored GSH levels (∗p < 0.05) and CAT activity (∗∗∗p < 0.001) in liver tissues., Conclusion: These findings suggest that I. viscosa leaves have an anti-arthritic property. Which is due to the combination of antioxidant activity regulating oxidative stress and anti-inflammatory effect by probably cytokines regulation., 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.)

Ethnopharmacology Relevance: Palm buds are a natural green resource of the forest, which are not only rich in nutrients but contain a large number of phenolic acids and flavonoids, among other components. It has a variety of biological activities such as antioxidant and uterine smooth muscle stimulation., Aim of the Study: To evaluate the safety of palm buds for use as a nutraceutical product and food by evaluating the toxicity, subacute toxicity and genotoxicity of the young palm buds. Also studied for its immune-enhancing activity., Materials and Methods: Acute toxicity tests were performed in mice using the maximum tolerance method, and the manifestations of toxicity and deaths were recorded after administration of 10,000 mg/mL for 14 consecutive d (days) of observations. To assess subacute toxicity, mice were treated with palm buds (750, 1500, or 3000 mg/mL) daily for 28 days. The teratogenicity of palm buds was assessed by the Ames test, the mouse bone marrow cell micronucleus test, and the mouse spermatozoa malformation test. In addition, we evaluated the immune-enhancing ability of palm buds by the mouse carbon profile test, delayed-type metamorphosis reaction, and serum hemolysin assay., Results: In the acute toxicity study, the Median Lethal Dose (LD 50 ) was greater than 10,000 mg/kg bw in both male and female rats. There were also no deaths or serious toxicities in the subacute study. The no-observed-adverse-effect level (NOAEL) was 3000 mg/kg bw. However, the mice's food intake decreased after one week. The medium and high dose groups had a reducing effect on body weight in mice of both sexes. In addition, the changes in organ coefficients of the liver, kidney and stomach in male mice were significantly higher in the high-dose group (3.23 ± 0.35, 0.75 ± 0.05, 0.57 ± 0.05 g) than in the control group (2.94 ± 0.18, 0.58 ± 0.05, 0.50 ± 0.02 g). Hematological analyses showed that all the indices of the rats in each palm sprout dose group were within the normal range. The results of blood biochemical indicators showed that there was a significant reduction in TP in the blood of male mice in the high-dose group (44.6 ± 7.8 g/L) compared to the control group (58.3 ± 15.1 g/L). In histopathological analysis, none of the significant histopathological changes were observed. The results of the immunological experiment in mice showed that the liver coefficient and thymus coefficient of the high-dose group (8400 mg/kg) were significantly lower than the control group. There was no remarkable difference in auricle swelling between each dose palm bud group (1400, 2800, or 8400 mg/kg) and the control group. The anti-volume number of the high-dose group was significantly increased., Conclusion: Palm buds have non-toxic effects in vivo and have little effect on non-specific and cellular immunity in the test mice within the dose range of this experiment. The immunoenhancement in mice is mainly achieved through humoral immunity. In conclusion, our results suggest that palm buds are safe for use as healthcare products and food., 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.)

Ethnopharmacological Relevance: The popularity of herbal medicine is expanding globally due to the common belief that herbal products are natural and nontoxic. Thymelaea hirsuta leaves are traditionally used for the treatment of recurrent abortion in humans and animals. However, a lack of safety evaluation of the plant, particularly in pregnant women, raises serious concerns regarding its potential embryotoxic effects., Aim of the Study: Therefore, the present study investigated the safety of Thymelaea hirsuta leaves aqueous extract (THLE) during pregnancy and lactation following maternal rat treatment., Materials and Methods: THLE phytochemical compounds were identified using high-performance liquid chromatography (HPLC). THLE was orally administered to pregnant rats and lactating dams at dosages of 0, 250, 500, and 1000 mg/kg/day. At the end of the study, dam s' and pups' body weights, serum biochemical and hematological indices, and histopathological changes were investigated. For the fetal observation and histopathological changes were also evaluated., Results: Our findings revealed that THLE is rich in different phenolic and flavonoid compounds. However, biochemical and hormonal parameters such as ALT, AST, and prolactin were significantly increased in dams treated with a higher dosage of THLE when compared to the control dams (P ≤ 0.05). Additionally, external, visceral and skeletal examinations of fetuses revealed a marked increase of malformation rates in treated fetuses., Conclusions: The results revealed that higher oral dosing of THLE during pregnancy could affect embryonic development in rats, while lower doses are safe and can be used during pregnancy and lactation to attain its beneficial effects., 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.)