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Targeted cancer therapy using nanocarriers has emerged as a promising solution to the majority of drawbacks associated with conventional chemotherapy. The present research work describes the development of folic acid (FA)-targeted redox responsive [S-(PLA- b -PEG-CONH)] 2 polymeric nanoparticles for the co-delivery of pirarubicin (Pira) and salinomycin (Sal). The nanoparticles' redox responsiveness arises from embedded disulfide bonds within the polymer, which gradually break in response to high GSH levels in tumors, enabling sustained drug release. The nanoparticles exhibited a hydrodynamic size of ∼104 nm and a surface charge density of -15.5 mV with low PDI values. Blank nanoparticles (w/o drug) showed negligible toxicity towards both non-malignant human and murine cells and exhibited excellent stability under different environmental conditions for up to 3 weeks. A cellular internalization study conducted using Rho B/C6 dual-dye-encapsulated nanoparticles showed efficient uptake of the nanoparticles after just 1 hour of incubation with SUM-149 2D adherent cells and 3D spheroids. The release of Pira and Sal from Pira/Sal dual-loaded nanoparticles increased significantly in a reducing environment. The % cumulative release of Pira increased from 20.5% ± 1.0 in PBS (pH 7.4) to 40.1% ± 0.4 in dithiothreitol (DTT) after 20 days; similarly, the % cumulative release of Sal increased from 36.2% ± 1.7 in PBS (pH 7.4) to 51.5% ± 1.7 in DTT. The cytotoxicity studies of FA-targeted Pira/Sal dual-loaded nanoparticles with varying Pira : Sal ratios (1 : 1, 3 : 1 and 1 : 3) revealed that the nanoparticles displayed 8-10 fold lower IC 50 values than the respective free drug formulations across multiple breast cancer cell lines including SUM-149, MDA-MB-231 and EAC as well as in 3D mammospheres. Balb/c syngeneic mice bearing EAC tumors experienced ∼100% tumor regression upon treatment with FA-targeted Pira/Sal (3 : 1) dual-loaded nanoparticles, indicating synergistic anti-tumor potency. In vivo survival and histopathological studies indicated no significant toxicity in vital organs of the body as compared to free drugs. Based on the performance, the currently investigated FA-targeted Pira/Sal dual-loaded nano-formulation is recommended to be further explored in other cancer types as well as in higher animals for cancer therapy.

Candida albicans (C. albicans) biofilm infections are quite difficult to manage due to their resistance against conventional antifungal drugs. To address this issue, there is a desperate need for new therapeutic drugs. In the present study, a green and efficient protocol has been developed for the synthesis of 2-amino-4H-pyran-3-carbonitrile scaffolds 4a-i, 6a-j, and 8a-g by Knoevenagel-Michael-cyclocondensation reaction between aldehydes, malononitrile, and diverse enolizable C-H activated acidic compounds using guanidinium carbonate as a catalyst either under grinding conditions or by stirring at room temperature. This protocol is operationally simple, rapid, inexpensive, has easy workup and column-free purification. A further investigation of the synthesized compounds was conducted to examine their antifungal potential and their ability to inhibit the growth and development of biofilm-forming yeasts like fungus C. albicans. According to our findings, 4b, 4d, 4e, 6e, 6f, 6g, 6i, 8c, 8d, and 8g were found to be active and potential inhibitors for biofilm infection causing C. albicans. The inhibition of biofilm by active compounds were observed using field emission scanning electron microscopy (FESEM). Biofilm inhibiting compounds were also tested for in vitro toxicity by using 3T3-L1 cell line, and 4b, 6e, 6f, 6g, 6i, 8c, and 8d were found to be biocompatible. Furthermore, the in silico ADME descriptors revealed drug-like properties with no violation of Lipinski's rule of five. Hence, the result suggested that synthesized derivatives could serve as a useful aid in the development of novel antifungal compounds for the treatment of fungal infections and virulence in C. albicans., 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 Ltd.)

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p-NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic., 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.)

A series of new hybrid compounds was prepared combining tetrahydropyran rings with different aromatic systems by means of a 1,2,3-triazole, using a building block strategy. The design of these structures was guided by Lead-Likeness and Molecular Analysis (LLAMA) software, adding modifications to our most potent scaffold (the tetrahydropyran ring) to generate promising "lead-like" candidates, which were subsequently compared against reported anticancer compounds. Our synthesized compounds demonstrated significant antiproliferative activity when compared with the standards cisplatin and 5-fluorouracil, across a panel of six different tumor cell lines. Moreover, compared with our group's previous hybrid compounds, these new structures exhibit similar activity while offering simpler synthesis and greater potential for structural diversification, a fact that was previously an issue. Further investigations on the most active compounds included assessments of reproductive cell survival, inhibition of cell migration, and effects on nuclear morphology, indicating potential diverse mechanisms of action for these compounds. Pharmacokinetic properties were also calculated for the whole series of compounds using the pkCSM online software., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Salinomycin (Sal) has attracted considerable attention in the field of tumor treatment, especially for its inhibitory effect on cancer stem cells (CSCs) and drug-resistant tumor cells. However, its solubility and targeting specificity pose significant challenges to its pharmaceutical development. Sal-A6, a novel peptide-drug conjugate (PDC), was formed by linking the peptide A6 targeting the CSC marker CD44 with Sal using a specific linker. This conjugation markedly enhances the physicochemical properties of Sal and compared to Sal, Sal-A6 demonstrated a significantly increased activity against ovarian cancer. Furthermore, Sal-A6, employing a disulfide bond as a linker, exhibited bystander killing effect. Moreover, it induces substantial cytotoxic effect on both cancer stem cells and drug-resistant cells in addition to enhance chemosensitivity of resistant ovarian cancer cells. In summary, the results indicated that Sal-A6, a novel PDC derived from Sal, has potential therapeutic applications in the treatment of ovarian cancer and drug-resistant patients. Additionally, this discovery offers insights for developing PDC-type drugs using Sal as a foundation., 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.)

Carboxylic ionophores are polyether antibiotics used in production animals as feed additives, with a wide range of benefits. However, ionophore toxicosis often occurs as a result of food mixing errors or extra-label use and primarily targets the cardiac and skeletal muscles of livestock. The ultrastructural changes induced by 48 hours of exposure to 0.1 μM monensin, salinomycin, and lasalocid in cardiac (H9c2) and skeletal (L6) myoblasts in vitro were investigated using transmission electron microscopy and scanning electron microscopy. Ionophore exposure resulted in condensed mitochondria, dilated Golgi apparatus, and cytoplasmic vacuolization which appeared as indentations on the myoblast surface. Ultrastructurally, it appears that both apoptotic and necrotic myoblasts were present after exposure to the ionophores. Apoptotic myoblasts contained condensed chromatin and apoptotic bodies budding from their surface. Necrotic myoblasts had disrupted plasma membranes and damaged cytoplasmic organelles. Of the three ionophores, monensin induced the most alterations in myoblasts of both cell lines., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Henn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pirarubicin attracted considerable attention in clinical studies because of its high therapeutic efficacy and reduced toxicity in comparison with other anthracyclines. Nevertheless, ~ 30% patients undergoing PIRA treatment still experience relapse and metastasis. Clinical advancements unveiled that cancer stem cells (CSCs) residing in the tumor constitutes a major factor for such limitations and subsequently are the reason for treatment failure. Consequently, eradicating CSCs alongside bulk tumor is a crucial undertaking to attain utmost therapeutic efficacy of the treatment. Nevertheless, majority of the CSCs inhibitors currently under examination lack specificity, show unsynchronized bioavailability with other primary treatments and exhibit notable toxicity in their therapeutic applications, which is primarily attributable to their inadequate tumor-targeting capabilities. Therefore, we have developed a biodegradable polylactic acid based blend block copolymeric NPs for concomitant delivery of CSCs inhibitor Salinomycin (SAL) & chemotherapeutic drug Pirarubicin (PIRA) with an aim to improve the efficacy of treatment and prevent cancer relapse. Prepared NPs showed < 100 nm size and excellent loading with sustained release for both the drugs. Also, PIRA:SAL co-loaded NPs exhibits synergistically enhanced cytotoxicity against cancer cell as well as CSCs. Most importantly, NPs mediated co-delivery of the drugs showed complete tumor eradication, without any reoccurrence throughout the surveillance period. Additionally, NPs treatment didn't show any histopathological alteration in vital organs confirming their non-toxic nature. Altogether, present study concludes that the developed PIRA:SAL NPs have excellent efficacy for tumor regression as well as prevention of cancer relapse, hence can be used as a potential combination therapy for cancer treatment., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

To address lymphatic metastasis in lung cancer, we developed the Au@Gd-SiO 2 -HA-LyP-1 nanoprobe, assessing its diagnostic and therapeutic capabilities. This nanoprobe integrates a Au core with a Gd-SiO 2 shell and dual-targeting HA-LyP-1 molecules. We evaluated its size, shape, and functional properties using various characterization techniques, alongside in vivo and in vitro toxicity tests. The spherical nanoprobes have a 50 nm diameter and contain 1.37% Gd. They specifically target lymphatic metastasis sites and tumor cells, showing enhanced MRI contrast and effective, targeted DOX delivery with reduced normal tissue toxicity. The Au@Gd-SiO 2 -HA-LyP-1 nanoprobe is a promising tool for diagnosing and treating lung cancer lymphatic metastasis, featuring dual-targeting and superior imaging capabilities.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Parkinson's disease (PD) is a neurodegenerative condition characterized by both motor and non-motor symptoms. Although PD is commonly associated with a decline of dopaminergic neurons in the substantia nigra, other diagnostic criteria and biomarkers also exist. In the search for novel therapeutic agents, chromene and pyran derivatives have shown potential due to their diverse pharmacological activities. This study utilizes a comprehensive computational approach to investigate the viability of chromene/pyran compounds as potential treatments for PD. The drug-likeness characteristics of these molecules were analyzed using ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies. Molecular docking was performed against PDB ID: 2V5Z. The best three molecules chosen were compound 7, compound 24, and compound 67 have a binding energy of -6.7, -8.6, and -10.9 kcal/mol. Molecules demonstrating positive blood-brain barrier permeability, good solubility, and favorable binding affinity were further evaluated using Density Functional Theory (DFT) calculations and Molecular Dynamics (MD) simulations to assess their electronic structure and stability. DFT calculations indicated that molecule 82 has a dipole moment of 15.70 D. RMSD and RMSF results confirmed the stability of the complexes over a 100 ns simulation, with a maximum of 3 hydrogen bonds formed., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Cyclophosphamide is an anti-neoplastic drug that has shown competence in the management of a broad range of malignant tumors. In addition, it represents a keystone agent for management of immunological conditions. Despite these unique properties, induction of lung toxicity may limit its clinical use. Omarigliptin is one of the dipeptidyl peptidase-4 inhibitors that has proven efficacy in management of diabetes mellitus. Rosinidin is an anthocyanidin flavonoid that exhibited promising results in management of diseases characterized by oxidative stress, inflammation, and apoptosis. The present work investigated the possible effects of omarigliptin with or without rosinidin on cyclophosphamide-induced lung toxicity with an exploration of the molecular mechanisms that contribute to these effects. In a rodent model of cyclophosphamide elicited lung toxicity, the potential efficacy of omarigliptin with or without rosinidin was investigated at both the biochemical and the histopathological levels. Both omarigliptin and rosinidin exhibited a synergistic ability to augment the tissue antioxidant defenses, mitigate the inflammatory pathways, restore glucagon-like peptide-1 levels, modulate high mobility group box 1 (HMGB1)/receptors of advanced glycation end products (RAGE)/nuclear factor kappa B (NF-κB) axis, downregulate the fibrogenic mediators, and create a balance between the pathways involved in apoptosis and the autophagy signals in the pulmonary tissues. In conclusion, omarigliptin/rosinidin combination may be introduced as a novel therapeutic modality that attenuates the different forms of lung toxicities induced by cyclophosphamide., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin., Methods: This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24-72 h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR., Results: CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL., Conclusion: Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1β in the kidney. Harp was a promising anti-HUA agent., 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 Inc. All rights reserved.)

Karrikins and strigolactones govern plant development and environmental responses through closely related signaling pathways. The transcriptional repressor proteins SUPPRESSOR OF MAX2 1 (SMAX1), SMAX1-like2 (SMXL2), and D53-like SMXLs mediate karrikin and strigolactone signaling by directly binding downstream genes or by inhibiting the activities of transcription factors. In this study, we characterized the non-transcriptional regulatory activities of SMXL proteins in Arabidopsis. We discovered that SMAX1 and SMXL2 with mutations in their ethylene-response factor-associated amphiphilic repression (EAR) motif had undetectable or weak transcriptional repression activities but still partially rescued the hypocotyl elongation defects and fully reversed the cotyledon epinasty defects of the smax1 smxl2 mutant. SMAX1 and SMXL2 directly interact with PHYTOCHROME INTERACTION FACTOR 4 (PIF4) and PIF5 to enhance their protein stability by interacting with phytochrome B (phyB) and suppressing the association of phyB with PIF4 and PIF5. The karrikin-responsive genes were then identified by treatment with GR24 ent-5DS , a GR24 analog showing karrikin activity. Interestingly, INDOLE-3-ACETIC ACID INDUCIBLE 29 (IAA29) expression was repressed by GR24 ent-5DS treatment in a PIF4- and PIF5-dependent and EAR-independent manner, whereas KARRIKIN UPREGULATED F-BOX 1 (KUF1) expression was induced in a PIF4- and PIF5-independent and EAR-dependent manner. Furthermore, the non-transcriptional regulatory activity of SMAX1, which is independent of the EAR motif, had a global effect on gene expression. Taken together, these results indicate that non-transcriptional regulatory activities of SMAX1 and SMXL2 mediate karrikin-regulated seedling response to red light., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

The effect of salinomycin sodium alone and in combination with functional oils on performance and microbiota of broiler infected Eimeria were evaluated. 512 broilers were randomly assigned to 4 treatments (8 replicates, 16 birds/pen): a Control group (any additives); Ionophore group: salinomycin supplementation at 66 ppm (SS66); Ionophore +0.075% Functional oil (FO) group (SS66 + FO supplementation at 750 ppm); and Ionophore +0.10% FO group (SS66 + FO supplementation at 1000 ppm). At 14 days of age, birds were gavaged with 1 mL of a saline solution containing sporulated oocysts of E. tenella, E. acervulina and E. maxima. Performance indices were measured weekly. At 28 days, intestinal content was collected for microbiota analysis. Broilers of Control group presented the worst performance indices. Broilers of Ionophore + FO (0.075% and 0.10%) groups exhibited a higher BW at 28 days of age. The supplementation of Ionophore +0.075% FO resulted in a higher relative proportion of Firmicutes and a lower proportion of Actinobacteria in the ileum-jejunum. Lactobacillaceae was the dominant family in the jejunal, and ileal microbiotas of broilers fed diets supplemented with Ionophore, Ionophore +0.075% FO and Ionophore +0.10% FO. The supplementation of ionophore yielded higher numbers of Lactobacillaceae, Enterobactereaceae and Cloritridiaceae in the cecal. Ionophore associated with FO controlled the Lactobacillaceae, Enterobactereaceae and Cloritridiaceae families present in the cecum. Therefore, the combination of salinomycin with functional oil showed synergistic effect on performance and modulation of intestinal microbiota of broilers challenged with Eimeria., 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 Ltd. All rights reserved.)

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: John C. Schmitz reports financial support was provided by UPMC Hillman Cancer Center NCI Cancer Center Support Grant Developmental Funds. 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 Ltd. All rights reserved.)

Salinomycin (Sal) has been recently discovered as a novel chemotherapeutic agent against various cancers including prostate cancer which is one of the most commonly diagnosed cancers affecting male populations worldwide. Herein we designed salinomycin nanocarrier (Sal-NPs) to extend its systemic circulation and to increase its anticancer potential. Prepared nanoform showed high encapsulation and sustained release profile for salinomycin. The present study elucidated the cytotoxicity and mechanism of apoptotic cell death of Sal-NPs against prostate cancer both in vitro and in vivo. At all measured concentrations, Sal-NPs showed more significant cytotoxicity to DU145 and PC3 cells than Sal alone. This effect was mediated by apoptosis, as confirmed by ROS generation, loss of MMP and cell cycle arrest at the G1 phase in both cells. Sal-NPs efficiently inhibited migration of PC3 and DU145 cells via effectively downregulating the epithelial mesenchymal transition. Also, the results confirmed that Sal-NPs can effectively inhibit the induction of Prostate adenocarcinoma in male Wistar rats. Sal-NPs treatment exhibited a decrease in tumour sizes, a reduction in prostate weight, and an increase in body weight, which suggests that Sal-NPs is more effective than salinomycin alone. Our results suggest that the molecular mechanism underlying the Sal-NPs anticancer effect may lead to the development of a potential therapeutic strategy for treating prostate adenocarcinoma., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Hispidin was initially discovered in basidiomycete Inonotus hispidus (Bull.) P. Karst and this extraordinary compound possesses immense potency and can be extracted from the wild mushroom through specialized bioreactor cultivation techniques. In our study, we isolated it from Inonotus hispidus (Bull.) P. Karst., with a yield of 3.6 %. We identified and characterized hispidin through the implementation of spectroscopic techniques such as FTIR, NMR, and MS. Additionally, we utilized Thermogravimetric Analysis for thermal characterization of the compound. Computational studies based on DFT were performed to investigate the molecular structure, electronic properties, and chemical reactivity of hispidin. PASS analysis for hispidin demonstrated that 19 of them are anti-neoplastic activities. The Pharmacology prediction of hispidin confirm that it is not toxic, non-carcinogenesis with a good human intestinal absorption. The effect of hispidin on the viability of bone cancer cells was evaluated by MTT assay. The results showed that hispidin significantly reduced SaoS2 cell viability in a dose-dependent manner. Molecular docking was carried out using five targets related to bone cancer to determine the interactions between hispidin and the studied proteins. The results demonstrate that hispidin is a good inhibitor for the five targets. Dynamic simulation shows a good stability of the complex hispidin-protein., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Coordinated morphogenic adaptation of growing plants is critical for their survival and propagation under fluctuating environments. Plant morphogenic responses to light and warm temperatures, termed photomorphogenesis and thermomorphogenesis, respectively, have been extensively studied in recent decades. During photomorphogenesis, plants actively reshape their growth and developmental patterns to cope with changes in light regimes. Accordingly, photomorphogenesis is closely associated with diverse growth hormonal cues. Notably, accumulating evidence indicates that light-directed morphogenesis is profoundly affected by two recently identified phytochemicals, karrikins (KARs) and strigolactones (SLs). KARs and SLs are structurally related butenolides acting as signaling molecules during a variety of developmental steps, including seed germination. Their receptors and signaling mediators have been identified, and associated working mechanisms have been explored using gene-deficient mutants in various plant species. Of particular interest is that the KAR and SL signaling pathways play important roles in environmental responses, among which their linkages with photomorphogenesis are most comprehensively studied during seedling establishment. In this review, we focus on how the phytochemical and light signals converge on the optimization of morphogenic fitness. We also discuss molecular mechanisms underlying the signaling crosstalks with an aim of developing potential ways to improve crop productivity under climate changes., (© 2023 Institute of Botany, Chinese Academy of Sciences.)

Dehydroacetic acid (DHA) was utilized as a fundamental precursor in the synthesis of novel pyrano [4,3-b] pyran and pyrano [2,3-b] pyridine systems. Whereas, a new series of fused polyheteronuclear systems was achieved through the reaction of DHA with active methylene compounds such as malononitrile and pyrazolone. Whereas, the treatment of DHA 1 with cyclic ketones involving cyclohexanone and cyclododecanone afforded annulated tricyclic system 6 and spiro hybrid molecule 7. Also, the reaction of DHA 1 with cyanoacetamide derivatives 8 and 11 yielded their corresponding novel pyrano [2,3-b] pyridine-6-carbonitrile frameworks 9 and 12, respectively. Also, in silico predictive theoretical molecular docking studies for bioactive synthesized scaffolds against both HER2 and 6BBP displayed an optimistic result for compounds 2 b, 5, 9, and 12 highlighting their expediency as up-and-coming candidates for future preclinical trials. Additionally, all compounds were assessed as antibacterial agents against various types of four candidates of bacteria in the presence of ampicillin as a reference. Notably, compounds 6, 7, and 12 showed promising antibacterial potential against Bacillus subtilis with activity indexes (69.6, 91.3, and 82.6 %), respectively., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The process of creating a series of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-q) involved reacting 6-methoxynaphthalen-2-ol (1), the appropriate aromatic aldehydes (2a-q), and malononitrile (3) in an absolute ethanol/piperidine solution under Ultrasonic irradiation. However, the attempt to create 3-amino-1-aryl-1H-benzo[f]chromene-2,8-dicarbonitrile (6a, d, e) was unsuccessful when 6-cyanonaphthalen-2-ol (5) was stirred at room temperature, reflux, Microwave irradiation, or Ultrasonic irradiation. In addition, the target molecules were screened against Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Escherichia coli and Klebsiella pneumonia, as well as a panel of three human cancer cells lines such as MCF-7, HCT-116, HepG-2 and two normal cell lines HFL-1 and WI-38. The obtained results confirmed that the pyran derivatives (4 m, i, k) which have a double chlorine at 3,4/2,3/2,5-positions, a single halogen atom 3-Cl/4-Br (4c, e) and a double bromine at 3,5-positions with a single methoxy group at 2-position (4n), of phenyl ring, and, to a lesser extent, other pyran derivatives with monoihalogenated (4a, b, d, f), dihalogenated (4 g, h, j, l) or trisubstituent phenyl ring (4o, p, q). Furthermore, compounds 4b-e, g, i, j, m, and n showed negligible activity against the two normal cell lines, HFL-1 and WI-38. Moreover, compound 4 g exhibited the strongest antimicrobial activity among the other pyran derivatives (4a-f, g-q) when compared to Ciprofloxacin. The MIC was assessed and screened for compound 4 g, revealing bactericidal effects. Lastly, SAR and molecular docking were studied., (© 2024. The Author(s).)

In this study, new indol-fused pyrano[2,3-d]pyrimidines were designed and synthesized. These products were obtained in moderate to good yields and their structures were assigned by NMR, MS, and IR analysis. Afterwards, the biological important of the products was highlighted by evaluating in vitro for α-glucosidase inhibitory activity as well as acetylcholinesterase (AChE) inhibitory activity. Eleven products revealed substantial inhibitory activity against α-glucosidase enzyme, among which, two most potent products 11d,e were approximately 93-fold more potent than acarbose as a standard antidiabetic drug. Besides that, product 11k exhibited good AChE inhibition. The substituents on the 5-phenyl ring, attached to the pyran ring, played a critical role in inhibitory activities. The biological potencies have provided an opportunity to further investigations of indol-fused pyrano[2,3-d]pyrimidines as potential anti-diabetic 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 © 2023 Elsevier Ltd. All rights reserved.)

Background: Influenza virus is a kind of RNA virus. Nowadays, the high incidence of influenza and the morbidity and mortality of epidemic influenza are substantial. It has been reported that one hundred million people in the world are infected with influenza viruses, and two hundred and fifty thousand to five hundred thousand people die from the flu per year. In 2021, the number of infected persons in China was reported to be 654,700, and 0.07% of the infected persons died. The flu has caused a serious threat to human survival. Although several drugs, such as Zanamivir, Oseltamivir, Peramivir, and Laninamivir, have been used in clinics for the treatment of the influenza virus, there are some shortcomings of these drugs. The strain of influenza H5N1 (avian influenza) has been found to resist the effective drug Oseltamivir. Thus, there is an urgent demand to discover new influenza virus inhibitors to overcome the emergence of influenza antigens., Aims: This study aimed to develop new influenza virus inhibitors based on the rupestonic acid parent core., Objective: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized in this work for the development of influenza virus inhibitors., Methods: The target compounds were synthesized using rupestonic acid and L-ephedrine as starting materials. Their structures were characterized by 1 H NMR and 13 C NMR, and the purity was determined by HPLC. Then, their preliminary in vitro influenza activity was evaluated using Oseltamivir as a reference drug., Results: The results showed that the synthesized rupestonic acid L-ephedrine derivatives A and B were more potent influenza virus inhibitors against the strains of A/PR/8/34 (H 1 N 1 ) and A/FM/1/47 (H 1 N 1 ) with the IC 50 values of 51.0, 51.0 μM and 441.0, 441.0 μM, respectively, than that of rupestonic acid. By comparing the IC 50 of compounds A and B, compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors., Conclusion: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized and characterized using 1 H NMR and 13 C NMR. Moreover, their purity was determined by HPLC. Both compounds A and B exhibited more potent activities against the strains of A/PR/8/34 (H 1 N 1 ) and A/FM/1/47 (H 1 N 1 ) than rupestonic acid. Compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. Based on these results, more rupestonic acid derivatives will be designed and synthesized in the future for the development of influenza virus inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The development of analgesic and anti-inflammatory drugs plays a crucial role in modern medicine, aiming to alleviate pain and reduce inflammation in patients. Opioids and nonsteroidal anti-inflammatory drugs are groups of drugs conventionally used to treat pain and inflammation, but a wide range of adverse effects and ineffectiveness in some pathological conditions leads us to search for new drugs with analgesic and anti-inflammatory properties., Objectives: In this regard, the authors intend to investigate the ((2s,6s)-6-ethyl-tetrahydro-2h-pyran- 2-yl) methanol compound (LS20) on pain and acute inflammation., Methods: Male Swiss mice were evaluated using acetic acid-induced abdominal writhing, formalin, and tail-flick as models of nociceptive evaluation and edema paw, air pouch and cell culture as models of inflammatory evaluation besides the rotarod test for assessment of motor impairment., Results: The compound showed an effect on the acetic acid-induced abdominal writhing, formalin and tail-flick tests. Studying the mechanism of action, reversion of the antinociceptive effect of the compound was observed from previous intraperitoneal administration of selective and non-selective opioid antagonists on the tail flick test. In addition, the compound induced an antiedematogenic effect and reduced leukocyte migration and the production of pro-inflammatory cytokines in the air pouch model. LS20 was able to maintain cell viability, in addition to reducing cell production of TNF-α and IL-6., Conclusion: In summary, the LS20 compound presented an antinociceptive effect, demonstrating the participation of the opioid system and an anti-inflammatory effect related to the inhibition of pro-inflammatory cytokine production. The compound also demonstrated safety at the cellular level., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Four new phomalones A-D (1-4), together with five known analogues (5-9) were isolated from the deep-sea-derived fungus Trichobotrys effuse FS522. Their structures of the new compounds established by analysis of their NMR and HR-ESI-MS spectroscopic data, and the absolute configurations of 2 was determined by electronic circular dichroism (ECD) calculations. compounds 4, 6 and 8 substantially inhibited the production of nitric oxide (NO) with IC 50 values of 4.64, 13.90, and 34.07 μM., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Chelidonic acid is a phytoconstituent found in rhizomes of the perennial plant celandine. The current study aims to evaluate the acute and repeated dose oral toxicity study of chelidonic acid as per the OECD guidelines 425 and 407. The pharmacokinetic and toxicity profile of chelidonic acid was predicted using online servers and tools. A single dose of chelidonic acid (2000 mg/kg) was administered to female Wistar rats in an acute toxicity study, and the animals were monitored for 14 days. We studied the toxicity profile of chelidonic acid at 10, 20, and 40 mg/kg doses in Wistar rats for repeated dose toxicity (28 days). Clinical biochemistry, haematological, and urine parameters were estimated. A gross necropsy and histopathology were performed. A single oral dose of chelidonic acid (2000 mg/kg) showed no signs of toxicity or mortality. The Administration of chelidonic acid showed no significant alterations in haematological, biochemical, and urine parameters. The histopathology showed normal structure and architecture in all the vital organs. A gross necropsy of vital organs showed no signs of toxicity. The chelidonic acid was found to be safe at all selected dose levels in the acute and repeated dose toxicity study in rats., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

FR901464 is a cytotoxic natural product that binds splicing factor 3B subunit 1 (SF3B1) and PHD finger protein 5A (PHF5A), the components of the human spliceosome. The amide-containing tetrahydropyran ring binds SF3B1, and it remains unclear how the substituents on the ring contribute to the binding. Here, we synthesized meayamycin D, an analogue of FR901464, and three additional analogues to probe the conformation through methyl scanning. We discovered that the amide-containing tetrahydropyran ring assumes only one of the two possible chair conformations and that methylation of the nitrogen distorts the chair form, dramatically reducing cytotoxicity. Meayamycin D induced alternative splicing of MCL-1 , showed strong synergism with venetoclax in drug-resistant lung cancer cells, and was cancer-specific over normal cells. Meayamycin D incorporates an alkyl ether and shows a long half-life in mouse plasma. The characteristics of meayamycin D may provide an approach to designing other bioactive L-shaped molecules.

The extensive use of agricultural pesticides to improve crop quality and yield significantly increased the risk to the public of exposure to small but repeated doses of pesticides over time through various routes, including skin, by increasing the risk of disease outbreaks. Although much work was conducted to reduce the use of pesticides in agriculture, little attention was paid to prevention, which could reduce the toxicity of pesticide exposure by reducing its impact on human health. Extra virgin olive oil (EVOO), a major component of the Mediterranean diet, exerts numerous health-promoting properties, many of which are attributed to oleuropein aglycone (OleA), the deglycosylated form of oleuropein, which is the main polyphenolic component of EVOO. In this work, three pesticides with different physicochemical and biological properties, namely oxadiazon (OXA), imidacloprid (IMID), and glyphosate (GLYPHO), were compared in terms of metabolic activity, mitochondrial function and epigenetic modulation in an in vitro cellular model of human HaCaT keratinocytes to mimic the pathway of dermal exposure. The potential protective effect of OleA against pesticide-induced cellular toxicity was then evaluated in a cell pre-treatment condition. This study showed that sub-lethal doses of OXA and IMID reduced the metabolic activity and mitochondrial functionality of HaCaT cells by inducing oxidative stress and altering intracellular calcium flux and caused epigenetic modification by reducing histone acetylation H3 and H4. GLYPHO, on the other hand, showed no evidence of cellular toxicity at the doses tested. Pretreatment of cells with OleA was able to protect cells from the damaging effects of the pesticides OXA and IMID by maintaining metabolic activity and mitochondrial function at a controlled level and preventing acetylation reduction, particularly of histone H3. In conclusion, the bioactive properties of OleA reported here could be of great pharmaceutical and health interest, as they could be further studied to design new formulations for the prevention of toxicity from exposure to pesticide use.

Epithelial-to-mesenchymal transition (EMT) gives rise to cells with properties similar to cancer stem cells (CSCs). Targeting the EMT program to selectively eliminate CSCs is a promising way to improve cancer therapy. Salinomycin (Sal), a K+/H+ ionophore, was identified as highly selective towards CSC-like cells, but its mechanism of action and selectivity remains elusive. Here, we show that Sal, similar to monensin and nigericin, disturbs the function of the Golgi. Sal alters the expression of Golgi-related genes and leads to marked changes in Golgi morphology, particularly in cells that have undergone EMT. Moreover, Golgi-disturbing agents severely affect post-translational modifications of proteins, including protein processing, glycosylation and secretion. We discover that the alterations induced by Golgi-disturbing agents specifically affect the viability of EMT cells. Collectively, our work reveals a novel vulnerability related to the EMT, suggesting an important role for the Golgi in the EMT and that targeting the Golgi could represent a novel therapeutic approach against CSCs., Competing Interests: Competing interests G.L. is the owner of GENOS. All other authors declare no other competing interests., (© 2023. Published by The Company of Biologists Ltd.)

Salinomycin (Sal) is a potent veterinary antibiotic known to offer significant toxicity to the variety of neoplastic cells. Its therapeutic utility is limited due to its higher lipophilicity (logP 7.5) and poor hydrophilicity. Liquid crystalline nanoparticles (LCNPs) known to offer a suitable delivery platform for these kinds of drugs. The overexpressed nucleolin receptor on the cell surface and cytoplasm, could be selected as a target in cancer therapy. The present study involves the development and characterization of the F3 peptide functionalized LCNPs for delivering Sal (F3-Sal-NPs) for selectively targeting to the nucleolin receptor. The optimized LCNPs were characterized for particle size, zeta potential, surface morphology, drug release kinetics and stability. The LCNPs have a structure similar to nematic phases. In vitro drug release studies revealed sustained drug release characteristics (89.5 ± 1.5% at 120 h) with F3-Sal-NPs. The cytotoxicity results demonstrated that F3-Sal-NPs were 4.8, 2.6 and 5.5 folds more effective than naïve drug in MDA-MB-468, MDA-MB-231 and MCF-7 cells, respectively and the cell cycle was arrested in the S and G2/M phases. The expression of the gene responsible for the stemness (CD44 gene), apoptosis (BAX/Bcl-2 ration) and angiogenesis (LCN-2) was reduced by F3-Sal-NPs treatment. Ex vivo hemolytic toxicity was reduced (6.5 ± 1.5%) and the pharmacokinetics and bioavailability of Sal was improved with F3-Sal-NPs. The in vivo antitumor efficacy was tested in EAC bearing mice, where F3-Sal-NPs significantly reduced the tumor growth by 2.8-fold compared to pure Sal and induced necrosis of tumor cells. The results clearly demonstrate the outstanding performance of F3 peptide functionalized LCNPs for delivering Sal against breast 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 © 2023 Elsevier B.V. All rights reserved.)

Lead (Pb) is a highly toxic heavy metal that has deleterious effects on the central nervous system. This study aimed to investigate the effects of salinomycin (Sal) and deferiprone (DFP) on brain morphology and on the content of some essential elements in Pb-exposed mice. Adult male Institute of Cancer Research (ICR) mice were exposed to a daily dose of 80 mg/kg body weight ( b.w.) Pb(II) nitrate for 14 days and subsequently treated with Sal (16 mg/kg b.w.) or DFP (19 mg/kg b.w.) for another 14 days. At the end of the experimental protocol, the brains were processed for histological and inductively coupled plasma mass spectrometry (ICP-MS) analyses. Pb exposure resulted in a 50-fold increase in Pb concentration, compared with controls. Magnesium (Mg) and phosphorus (P) were also significantly increased by 22.22% and 17.92%, respectively. The histological analysis of Pb-exposed mice revealed brain pathological changes with features of neuronal necrosis. Brain Pb level remained significantly elevated in Sal- and DFP-administered groups (37-fold and 50-fold, respectively), compared with untreated controls. Treatment with Sal significantly reduced Mg and P concentrations by 22.56% and 18.38%, respectively, compared with the Pb-exposed group. Administration of Sal and DFP ameliorated brain injury in Pb-exposed mice and improved histological features. The results suggest the potential application of Sal and DFP for treatment of Pb-induced neurotoxicity.

Adiponectin and leptin are major adipocytokines that control crosstalk between adipose tissue and other organ systems. Hypoadiponectinemia and hypoleptinemia are associated with human metabolic diseases. Compounds with adipocytokine biosynthesis-stimulating activities could be developed as therapeutics against diverse metabolic conditions. In phenotypic screening with human bone marrow mesenchymal stem cells (hBM-MSCs), (E)-4-hydroxy-3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-6-methyl-2H-pyran-2-one (1) was identified to increase adiponectin biosynthesis during adipogenesis and simultaneously to stimulate leptin production. Using the compound 1 structure, the structure-activity relationship study was performed to discover more potent compounds stimulating both adiponectin and leptin production. (E)-3-(3-(2-fluoropyridin-4-yl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one (11) exhibited the most potent adiponectin (EC 50 , 2.87 μM) and leptin (EC 50 , 2.82 μM) biosynthesis-stimulating activities in hBM-MSCs. In a target identification study, compound 11 was characterized as a dual modulator binding to both peroxisome proliferator-activated receptor (PPAR) γ and glucocorticoid receptor (GR). This study provides a novel pharmacophore for PPARγ/GR dual modulators with therapeutic potential against human metabolic 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 © 2022 Elsevier Masson SAS. All rights reserved.)

The work aimed to synthesize and characterize two iridium(III) complexes [Ir(ppy) 2 (IPPH)](PF 6 ) (Ir1, IPPH = (2S,3R,5S,6R)-2-(2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, ppy = 2-phenylpyridine), [Ir(piq) 2 (IPPH)](PF 6 ) (Ir2, piq = 1-phenylisoquinoline). The cytotoxicity of the complexes against BEL-7402, A549, HCT-116, B16 cancer cells and normal LO2 was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The complexes show no cytotoxic activity (IC 50  > 100 μM) against these cancer cells, while their cytotoxicity can significantly be elevated upon illumination. The IC 50 values range from 0.2 ± 0.05 to 35.5 ± 3.5 μM. The cellular uptake, endoplasmic reticulum and mitochondria localization, reactive oxygen species, the change of mitochondrial membrane potential, γ-H2AX levels, cycle arrest, apoptosis and the expression of B-cell lymphoma-2 were investigated. The calreticulin (CRT), heat shock protein 70 (HSP70), high mobility group box 1 (HMGB1) were explored. This study demonstrates that photoactivatable complexes induce cell death in A549 through ROS-mediated endoplasmic reticulum stress-mitochondrial pathway, DNA damage pathways, immunogenic cell death (ICD), activation of PI3K/AKT signaling pathway and inhibit the cell growth at S phase., Competing Interests: Declaration of Competing Interest Authors declare no competing interest exists., (Copyright © 2022. Published by Elsevier Inc.)

Parquetina nigrescens has been used for decades in ethnomedicine for its antioxidant, antimicrobial, anti-inflammatory, analgesic, and aphrodisiac properties. In this study, the cytotoxic and genotoxic effect of aqueous crude leaf extracts of P. nigrescens on the root meristematic cells of Allium cepa was examined. Volatile organic compounds (VOCs) present in the plant extract were also identified using gas chromatography-mass spectrometry (GC-MS). The extract was prepared with tap water as is locally practised by many Nigerians. Onion bulbs were exposed to 1, 5, 10, 20, and 50% concentrations of the extract for the analysis of root growth inhibition and chromosomal aberration. Lead nitrate (10 ppm) and tap water were used as the positive and negative controls, respectively. The result showed cytotoxicity which was observed as statistically significant (p 

Objective: To explore the role and underlying mechanism of GW842166X on osteoarthritis and osteoarthritis-associated abnormal catabolism., Methods: The extracted mouse chondrocytes were treated with GW842166X followed by lipopolysaccharide (LPS). The chondrocytes were divided into the control group, LPS group, LPS+50 nmol/L GW842166X group, and LPS+100 nmol/L GW842166X group. The cytotoxicity of GW842166X was tested using the CCK-8 assay. Western blot, RT-qPCR, and ELISA were applied to evaluate the expression of the inflammatory biomarkers in mouse chondrocytes. The expression of extracellular matrix molecules was detected by the Western blot, RT-qPCR, and immunofluorescence. Additionally, the activity of NF-κB was checked by the Western blot and immunofluorescence. The mouse Hulth models were generated to examine the in vivo effects of GW842166X on osteoarthritis. Hematoxylin and eosin staining, safranin O/fast green staining, and immunohistochemistry were applied to detect the histological changes., Results: GW842166X below 200 µmol/L had no cytotoxicity on the mouse chondrocytes. LPS-induced high expression of TGF-β1, IL-10, TNF-α, and IL-6 was significantly reduced by GW842166X. In addition, GW842166X upregulated the expression of aggrecan and collagen type III, which was downregulated after the LPS stimulation. The upregulated expression of ADAMTS-5 and MMP-13 by LPS stimulation was dropped in response to the GW842166X treatment. Furthermore, LPS decreased the IκBα expression in the cytoplasm and increased the nuclear p65 expression. However, these changes were reversed by the GW842166X pretreatment. Moreover, the damages in the knees caused by the Hulth surgery in mice were restored by GW842166X., Conclusion: GW842166X impeded the LPS-mediated catabolism in mouse chondrocytes, thereby inhibiting the progression of osteoarthritis., (© 2022. Huazhong University of Science and Technology.)

2-Amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) was prepared from the reaction of cyclohexane-1,4-dione with elemental sulfur and malononitrile in 1,4-dioxane and triethylamine as catalyst. The latter compound reacted with triethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce 4H-thieno[2,3-f]chromene derivatives 10a,b. In addition, fused pyran and pyridine derivatives were synthesized starting from compound 3. The cytotoxicity of the synthesized compounds was studied on six cancer cell lines together with c-Met kinase and PC-3 cell line. The most active compounds were tested against five tyrosine kinases and Pim-1 kinase, most of which showed strong inhibition, encouraging further work.

Prenatal stress (PNS) impairs the circadian rhythm of the sleep/wake cycle. The melatonin (MT) analogue Piromelatine (Pir) was designed for the treatment of insomnia. The present study aimed to explore effects of Pir on circadian rhythmicity, motor activity, and sleep structure in male and female rats with a history of prenatal stress (PNS). In addition, we elucidated the role of MT receptors and brain-derived neurotrophic factor (BDNF) to ascertain the underlying mechanism of the drug. Pregnant rats were exposed to different stressors from day seven until birth. Piromelatine (20 mg/kg/day/14 days) was administered to young adult offspring. Home-cage locomotion, electroencephalographic (EEG) and electromyographic (EMG) recordings were conducted for 24 h. Offspring treated with vehicle showed sex-and phase-dependent disturbed circadian rhythm of motor activity and sleep/wake cycle accompanied by elevated rapid eye movement (REM) pattern and theta power and diminished non-rapid eye movement (NREM) sleep and delta power. While Pir corrected the PNS-induced impaired sleep patterns, the MT receptor antagonist luzindol suppressed its effects in male and female offspring. In addition, Pir increased the BDNF expression in the hippocampus in male and female offspring with PNS. Our findings suggest that the beneficial effect of Pir on PNS-induced impairment of sleep/wake cycle circadian rhythm and sleep structure is exerted via activation of MT receptors and enhanced BDNF expression in the hippocampus in male and female offspring.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes local bone erosion and systemic osteoporosis. Harpagoside (HAR), an iridoid glycoside, has various pharmacological effects on pain, arthritis, and inflammation. Our previous study suggests that HAR is more deeply involved in the mechanism of bone loss caused by inflammatory stimuli than hormonal changes. Here, we identified the local and systemic bone loss inhibitory effects of HAR on RA and its intracellular mechanisms using a type 2 collagen-induced arthritis (CIA) mouse model., Methods: The anti-osteoporosis and anti-arthritic effects of HAR were evaluated on bone marrow macrophage in vitro and CIA in mice in vivo by obtaining clinical scores, measuring hind paw thickness and inflammatory cytokine levels, micro-CT and histopathological assessments, and cell-based assay., Results: HAR markedly reduced the clinical score and incidence rate of CIA in both the prevention and therapy groups. Histological analysis demonstrated that HAR locally ameliorated the destruction of bone and cartilage and the formation of pannus. In this process, HAR decreased the expression of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in the serum of CIA mice. Additionally, HAR downregulated the expression of receptor activator of nuclear factor-κB ligand and upregulated that of osteoprotegerin. HAR suppressed systemic bone loss by inhibiting osteoclast differentiation and osteoclast marker gene expression in a CIA mouse model., Conclusions: Taken together, these findings show the beneficial effect of HAR on local symptoms and systemic bone erosion triggered by inflammatory arthritis., (© 2022. The Author(s).)

Natural polyether ionophore salinomycin (Sal) has been widely used in veterinary medicine as an antibiotic effective in the treatment of coccidian protozoa and Gram-positive bacteria. Moreover, chemical modification of the Sal structure has been found to be a promising strategy to generate semisynthetic analogs with biological activity profiles improved relative to those of the native compound. In this context, we synthesized and thoroughly evaluated the antibacterial potential of a library of C1/C20 singly and doubly modified derivatives of C20-epi-salinomycin, that is, analogs of Sal with inversed stereochemistry at the C20 position. Among the synthesized analog structures, the most promising antibacterial active agents were those obtained via regioselective O-acylation of C20-epi-hydroxyl, particularly esters 7, 9, and 11. Such C20 singly modified compounds showed excellent inhibitory activity against planktonic staphylococci, both standard and clinical strains, and revealed potential in preventing the formation of bacterial biofilms. In combination with their non-genotoxic properties, these Sal derivatives represent attractive candidates for further antimicrobial drug development., (© 2022. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Introduction: Splice modulators have been assessed clinically in treating haematologic malignancies exhibiting splice factor mutations and acute myeloid leukaemia. However, the mechanisms by which such modulators repress leukaemia remain to be elucidated., Objectives: The primary goal of this assessment was to assess the molecular mechanism by which the natural splice modulator GEX1A kills leukaemic cells in vitro and within in vivo mouse models., Methods: Using human leukaemic cell lines, we assessed the overall sensitivity these cells have to GEX1A via EC 50 analysis. We subsequently analysed its effects using in vivo xenograft mouse models and examined whether cell sensitivities were correlated to genetic characteristics or protein expression levels. We also utilised RT-PCR and RNAseq analyses to determine splice change and RNA expression level differences between sensitive and resistant leukaemic cell lines., Results: We found that, in vitro, GEX1A induced an MCL-1 isoform shift to pro-apoptotic MCL-1S in all leukaemic cell types, though sensitivity to GEX1A-induced apoptosis was negatively associated with BCL-xL expression. In BCL-2-expressing leukaemic cells, GEX1A induced BCL-2-dependent apoptosis by converting pro-survival BCL-2 into a cell killer. Thus, GEX1A + selective BCL-xL inhibition induced synergism in killing leukaemic cells, while GEX1A + BCL-2 inhibition showed antagonism in BCL-2-expressing leukaemic cells. In addition, GEX1A sensitised FLT3-ITD + leukaemic cells to apoptosis by inducing aberrant splicing and repressing the expression of FLT3-ITD. Consistently, in in vivo xenografts, GEX1A killed the bulk of leukaemic cells via apoptosis when combined with BCL-xL inhibition. Furthermore, GEX1A repressed leukaemia development by targeting leukaemia stem cells through inhibiting FASTK mitochondrial isoform expression across sensitive and non-sensitive leukaemia types., Conclusion: Our study suggests that GEX1A is a potent anti-leukaemic agent in combination with BCL-xL inhibitors, which targets leukaemic blasts and leukaemia stem cells through distinct mechanisms., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Pre-mRNA splicing is one of the most important mechanisms in gene expression in eukaryotes, and therefore splicing inhibition affects various cellular functions. We previously reported that the potent splicing inhibitor spliceostatin A (SSA) causes cell cycle arrest at G1 and G2/M phases. Upregulation of the p27 cyclin dependent kinase inhibitor, encoded by the CDKN1B gene, is one of the reasons for G1 phase arrest caused by SSA treatment. However, the molecular mechanism of p27 upregulation by SSA remains unknown. In this study, we found that SSA treatment caused stabilization of the p27 protein and increase of CDKN1B mRNA. SSA did not affect transcription of CDKN1B gene, but stabilized CDKN1B mRNA. Finally, we revealed that the 3' untranslated region of CDKN1B mRNA was involved in the stabilization. These results suggest that stabilization of CDKN1B mRNA is one of the reasons of upregulation of the p27 protein by SSA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daisuke Kaida reports financial support was provided by Japan Society for the Promotion of Science. Daisuke kaida reports financial support was provided by Takeda Science Foundation. Daisuke Kaida reports financial support was provided by Tamura Science & Technology Foundation. Daisuke Kaida reports a relationship with Japan Society for the Promotion of Science that includes: funding grants., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Salinomycin (SAL), a polyether antibiotic exerting K + /H + -exchange on cellular membranes, effectively kills cancer stem cells. A series of cationic triphenylphosphonium (TPP + )-linked SAL derivatives were synthesized aiming to render them mitochondria-targeted. Remarkably, attaching a TPP + moiety via a triazole linker at the C-20 position of SAL (compound 5) preserved the ion carrier potency of the antibiotic, while analogs with TPP + linked at the C-1 position of SAL (6, 8) were ineffective. On planar bilayer lipid membranes (BLM), the SAL analogs 6 and 8 exhibited slow electrical current relaxation upon a voltage jump, similar to previously studied alkyl-TPP compounds. However, 5 demonstrated much faster current relaxation, which suggested its high permeability through BLM resulting in its pronounced potency to transport potassium and hydrogen ions across both artificial (liposomal) and mitochondrial membranes. SAL and 5 did not induce a steady-state electrical current through the planar lipid bilayer, thereby confirming that the transport mechanism is the electrically silent K + /H + exchange. The ion exchange mediated by 5 in energized mitochondria was more active than that caused by SAL, which was apparently due to accumulation of 5 in mitochondria. Thus, compound 5 can be regarded as a promising lead compound for testing anticancer and antimicrobial activity., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cancer stem cells (CSCs) are a small subpopulation of cells within a tumor that can both self-renew and differentiate into other cell types forming the heterogeneous tumor bulk. Since CSCs are involved in all aspects of cancer development, including tumor initiation, cell proliferation, metastatic dissemination, therapy resistance, and recurrence, they have emerged as attractive targets for cancer treatment and management. Salinomycin, a widely used antibiotic in poultry farming, was identified by the Weinberg group as a potent anti-CSC agent in 2009. As a polyether ionophore, salinomycin exerts broad-spectrum activities, including the important anti-CSC function. Studies on the mechanism of action of salinomycin against cancer have been continuously and rapidly published since then. Thus, it is imperative for us to update its literature of recent research findings in this area. We here summarize the notable work reported on salinomycin's anticancer activities, intracellular binding target(s), effects on tumor microenvironment, safety, derivatives, and tumor-specific drug delivery; after that we also discuss the translational potential of salinomycin toward clinical application based on current multifaceted understandings., (© 2021 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)

Aims: The objectives of this work were to assess the possibility of administration of omarigliptin and/or galangin to combat lipopolysaccharide (LPS)-induced neuroinflammation in rats and to explore the possible mechanisms that might contribute to their actions., Materials and Methods: In a rat model of LPS-induced neuroinflammation, the changes in the behavioral tests, biochemical parameters, and the histopathological picture were assessed., Key Findings: Administration of either omarigliptin or galangin to LPS-injected rats was able to significantly improve the behavioral changes with restoration of the oxidant/antioxidant balance, decrement of toll-like receptor-4 levels, and amelioration of the neuroinflammation associated with inhibition of apoptosis and restoration of glucagon-like peptide-1 levels in the cerebral tissues. In addition, omarigliptin and/or galangin significantly reduced the levels of phospho-Akt and glycogen synthase kinase 3 beta (GSK-3β) and significantly increased the expression of beclin-1 in the cerebral tissues compared versus the group treated with LPS alone. As a result, these changes were positively reflected on the histopathological and the electron microscopic picture of the cerebral tissues. These beneficial effects were maximally evidenced in rats treated with omarigliptin/galangin combination relative to the use of either omarigliptin or galangin alone., Significance: Omarigliptin/galangin combination might be proposed as a promising therapeutic line for mitigation of the pathophysiologic events of LPS-induced neuroinflammation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: The growth factor receptor-bound protein 2 (Grb2)-Sos1 interaction, mediated by modular domains, plays an essential role in the oncogenic MAPK signaling pathway in osteosarcoma (OS). Recently, a dual-targeting peptide that targets the epidermal growth factor receptor and Grb2-Src homology 3 domain in OS cells was designed and synthesized., Aims: We investigated the synergistic effects of the peptide and salinomycin (Sal), a chemotherapeutic drug with effective anti-OS properties in clinical therapy., Subjects and Methods: Flow cytometry was used to measure the targeting efficacy of the peptide. Migration and CCK-8 assays were used to explore whether Sal and the peptide could synergistically inhibit OS cell behavior. Western blotting was used to detect apoptosis., Statistical Analysis Used: Data were analyzed using the GraphPad Prism 5.01. Statistical analysis was performed using the Student's t-test for the direct comparisons and one-way analysis of variance for the comparisons among the multiple groups. Statistical significance was set at P < 0.05., Results: The peptide was shown to target OS cells. When applied together, Sal and the peptide synergistically inhibited OS cell migration, invasion, and proliferation through the inhibition of Grb2-Sos1. This synergistic treatment also promoted the apoptosis of OS cells and inhibited tumor volume in vivo., Conclusions: These data provide valuable insights into the molecular mechanisms of OS and may be beneficial in clinical therapy., Competing Interests: None

SignificanceKarrikins are chemicals in smoke that stimulate regrowth of many plants after fire. However, karrikin responses are not limited to species from fire-prone environments and can affect growth after germination. Putatively, this is because karrikins mimic an unknown signal in plants, KAI2 ligand (KL). Karrikins likely require modification in plants to become bioactive. We identify a gene, KUF1 , that appears to negatively regulate biosynthesis of KL and metabolism of a specific karrikin. KUF1 expression increases in response to karrikin or KL signaling, thus forming a negative feedback loop that limits further activation of the signaling pathway. This discovery will advance understanding of how karrikins are perceived and how smoke-activated germination evolved. It will also aid identification of the elusive KL.

Background: Fibroblast growth factor receptor 4 (FGFR4) plays a key role in cancer progression, including tumour proliferation, invasion, and metastasis. Recent studies have shown that the FGFR4 selective inhibitor BLU-554 has clinical benefits on tumour regression in hepatocellular carcinoma patients. However, the effect of BLU-554 on gastric cancer remains unknown., Methods: Changes in cell proliferation, apoptosis and cell cycle, migration, and invasion capabilities of MKN-45 cells treated with FGFR4 selective inhibitors were detected by CCK-8 assay, flow cytometry, transwell assay, and wound healing assay, respectively. Western blotting was used to detect the effect of BLU-554 on the expression of FGFR4, FRS2α, and p-ERK1/2., Results: As the concentration of the inhibitor increased, the survival rate of gastric cancer cells decreased, and the trend of BLU-554 was more obvious; a high dose of BLU-554 caused significant cell apoptosis and cell cycle arrest as well as reduced cell invasion ability. The expression levels of FGFR4, FRS2α, and p-ERK1/2 were also significantly reduced when cells were treated with medium and high doses of BLU-554., Conclusion: BLU-554 inhibited the mitogen-activated protein kinase (RAS-RAF-MEK-ERK) pathway by inhibiting FGFR4, ultimately impeding the proliferation and invasion of gastric cancer cells and promoting cell apoptosis and cell cycle arrest., 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 © 2022 Elsevier Inc. All rights reserved.)

Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non-steroidal anti-inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyse the action of the hybrid compound cis- (±) -acetate of 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2h-pyran -2-yl) methyl2- (2- [2,6-dichlorophenylamine] phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male Swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail flick, capsaicin- and glutamate-induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid-induced abdominal writhing, formalin (both phases), tail flick, thermal stimulation in animals injected with capsaicin and capsaicin-induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor-binaltorphimine, naltrindole, methylnaltrexone, 7-nitroindazole, L-NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF-α, IL-1β and PGE 2 in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice., (© 2021 John Wiley & Sons Australia, Ltd.)

Chemical splicing modulators that bind to the spliceosome have provided an attractive avenue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. However, the biological effect of proteins containing translated intron sequences remains unclear. Here, we identify a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) via genome-wide ribosome profiling and bio-orthogonal noncanonical amino acid tagging (BONCAT) mass spectrometry. A subset of these truncated proteins has intrinsically disordered regions, forms insoluble cellular condensates, and triggers the proteotoxic stress response through c-Jun N-terminal kinase (JNK) phosphorylation, thereby inhibiting the mTORC1 pathway. In turn, this reduces global translation. These findings indicate that creating an overburden of condensate-prone proteins derived from introns represses translation and prevents further production of harmful truncated proteins. This mechanism appears to contribute to the antiproliferative and proapoptotic activity of splicing modulators., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

High mobility group box 1 (HMGB1) is acknowledged to have critical functions; therefore, targeting this protein may have therapeutic effects. One example is potential antiseptic activity obtained by suppressing HMGB1 secretion, leading to the recovery of vascular barrier integrity. Cornuside (CN), which is a product extracted from the fruit of Cornus officinalis Seib, is a natural bis-iridoid glycoside with the therapeutic effects of suppressing inflammation and regulating immune responses. However, the mechanism of action of CN and impact on sepsis is still unclear. We examined if CN could suppress HMGB1-induced excessive permeability and if the reduction of HMGB1 in response to LPS treatment increased the survival rate in a mouse model of sepsis. In human endothelial cells stimulated by LPS and mice with septic symptoms of cecal ligation and puncture (CLP), we examined levels of proinflammatory proteins and biomarkers as an index of tissue damage, along with decreased vascular permeability. In both LPS-treated human umbilical vein endothelial cells (HUVECs) and the CLP-treated mouse model of sepsis, we applied CN after the induction processes were over. CN suppressed excessive permeability and inhibited HMGB1 release, leading to the amelioration of vascular instability, reduced mortality, and improved histological conditions in the CLP-induced septic mouse model. Overall, we conclude that the suppressed release of HMGB1 and the increased survival rate of mice with CLP-induced sepsis caused by CN may be an effective pharmaceutical treatment for sepsis.