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Bladder cancer poses a significant challenge to chemotherapy due to its resistance to cisplatin, especially at advanced stages. Understanding the mechanisms behind cisplatin resistance is crucial for improving cancer therapy. The enzyme glutathione S‐transferase omega class 1 (GSTO1) is known to be involved in cisplatin resistance in colon cancer. This study focused on its role in cisplatin resistance in bladder cancer. Our analysis of protein expression in bladder cancer cells stimulated by secretions from tumor‐associated macrophages (TAMs) showed a significant increase in GSTO1. This prompted further investigation into the role of GSTO1 in bladder cancer. We found a strong correlation between GSTO1 expression and cisplatin resistance. Mechanistically, GSTO1 triggered the release of large extracellular vesicles (EVs) that promoted cisplatin efflux, thereby reducing cisplatin–DNA adduct formation and enhancing cisplatin resistance. Inhibition of EV release effectively counteracted the cisplatin resistance associated with GSTO1. In conclusion, GSTO1‐mediated EV release may contribute to cisplatin resistance caused by TAMs in bladder cancer. Strategies to target GSTO1 could potentially improve the efficacy of cisplatin in treating bladder cancer. [ABSTRACT FROM AUTHOR]

Osteoporosis is a common bone disease in aging populations, particularly in postmenopausal women. Anti‐resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are linked with a variety of adverse effects. Antrodia cinnamomea extracts (ACE) are highly renowned for their anticancer, antioxidative, and anti‐inflammatory properties. However, whether ACE‐enriched anti‐osteoporosis functions are largely unknown. In a preclinical animal model, we found that ovariectomy significantly decreased bone volume in the ovariectomized (OVX) rats. Administration of ACE antagonized OVX‐induced bone loss. In addition, ACE reversed OVX‐reduced biomechanical properties. The serum osteoclast marker also showed improvement in the ACE‐treated group. In the cellular model, it was indicated that ACE inhibits RANKL‐induced osteoclast formation. Taken together, ACE seems to be a hopeful candidate for the development of novel anti‐osteoporosis treatment. [ABSTRACT FROM AUTHOR]

A one‐pot strategy for the synthesis of substituted isocoumarin, flavone, and isoquinolinedione derivatives through a switchable C‐arylation/lactonization or SNAr reaction from a wide range of soft nucleophiles and o‐quinol acetates has been developed. This base‐mediated protocol proceeds under transition‐metal‐free conditions and selectively affords various heteroarenes in 13–98% yields from readily prepared or commercially available 1,3‐dicarbonyl and α‐EWG‐substituted carbonyl compounds. The synthetic utility is further demonstrated in the synthesis of potential anti‐HIV and anti‐coronavirus derivatives and COX‐2 inhibitors. In addition, detailed experimental and computational studies are performed to provide an intensive understanding and strong support of the reaction mechanism. [ABSTRACT FROM AUTHOR]

In this study, we attempted to explain why the substitution of a cyano group onto the 1‐azadiene moiety promotes N‐(2,3‐diphenylallylidene)pent‐4‐en‐1‐amine to undergo an intramolecular aza‐Diels–Alder reaction. Our M06‐2X study found that the intramolecular aza‐Diels–Alder reaction of N‐(2,3‐diphenylallylidene)pent‐4‐en‐1‐amine has an inverse electron demand. Therefore, the attachment of a cyano group to the diene moiety (1‐azadiene) makes the intramolecular aza‐Diels–Alder reaction feasible. Moreover, the intramolecular aza‐Diels–Alder reaction of N‐(2,3‐diphenylallylidene)pent‐4‐en‐1‐amine was found to be a kinetically controlled reaction. [ABSTRACT FROM AUTHOR]

Introduction: Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti‐GCa effects in experimental models, are currently being investigated. Method: The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5‐fluracil were applied onto AGS, SC‐M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web‐based GCa cohort for Ar expression association with prognosis was performed. Result: The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5‐FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer‐suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor‐suppressing index (TSI) score of 90% over a 6‐week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements. [ABSTRACT FROM AUTHOR]

Aurora kinase A (AURKA) carries out an essential role in proliferation and involves in cisplatin resistance in various cancer cells. Overexpression of AURKA is associated with the poor prognosis of cancer patients. Thus, AURKA has been considered as a target for cancer therapy. Developing AURKA inhibitors became an important issue in cancer therapy. A natural compound emodin mainly extracted from rhubarbs possesses anti‐cancer properties. However, the effect of emodin on AURKA has never been investigated. In the present study, molecular docking analysis indicated that emodin interacts with AURKA protein active site. We also found nine emodin analogues from Key Organic database by using ChemBioFinder software. Among that, one analogue 8L‐902 showed a similar anti‐cancer effect as emodin. The bindings of emodin and 8L‐902 on AURKA protein were confirmed by cellular thermal shift assay. Furthermore, emodin inhibited the AURKA kinase activity in vitro and enhanced the cisplatin‐DNA adduct level in a resistant ovarian cancer cell line. It seems that emodin may have the potential to inhibit cancer cell growth and enhance cisplatin therapy in cancer with resistance. Collectively, our finding reveals a novel AURKA inhibitor, emodin, which may be vulnerable to ovarian cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL‐X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine‐rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor‐bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment. [ABSTRACT FROM AUTHOR]

The structures, names, bioactivities, and references of 75 marine diterpenoids from octocorals possessing a hydroperoxy group, including 46 cembranes, 8 eunicellins, 5 briaranes, 5 dolabellanes, 4 germacranes, 3 xenicins, 2 caryophyllanes, 1 decalin, and 1 pseudopterosin, are summarized in this review article. All the hydroperoxyditerpenoids mentioned in this review were isolated from octocorals from Alcyonacea (Briareum excavatum, Briareum polyanthes, Briareum violaceum, Briareum sp., Cespitularia sp., Cladiella tuberculosa, Cladiella sp., Clavularia inflata, Klyxum simplex, Lemnalia sp., Lobophytum crassum, Lobophytum sp., Nephthea pacifica, Sarcophyton cherbonnieri, Sarcophyton crassocaule, Sarcophyton glaucum, Sarcophyton mililatensis, Sarcophyton trocheliophorum, Sarcophyton sp., Sinularia arborea, Sinularia erecta, Sinilaria flexibilis, Sinularia gibberosa, Sinularia manaarensis, Xenia umbellata) and Gorgonacea (Astrogorgia sp., Eunicea calyculata, Eunicea pinta, Eunicea succinea, Eunicea sp., Pseudopterogorgia sp.). Among these isolates, 41 compounds exhibited potential biomedical activities, including cytotoxicity, antimalarial activity, anti‐inflammatory activity, and antibacterial activity. [ABSTRACT FROM AUTHOR]

Pursuing epigenetic manipulation approach in fungi led to the isolation of an unusual coumarin metabolite from fungi. An addition of the histone deacetylase inhibitor, suberohydroxamic acid (SBHA), to the culture medium of Arthrobotrys foliicola induced production of the coumarin‐type secondary metabolite represented by a single intensive peak in the HPLC profile of the ethyl acetate extract. The compound which was identified as 4‐ethyl‐7‐hydroxy‐8‐methyl‐2H‐chromen‐2‐one (1) was isolated from nature for the first time. Moreover, the investigation on the remaining part of the HPLC profile led to the separation of 6‐ethyl‐2,4‐dihydroxy‐3‐methylbenzaldehyde (2) and ten 2,5‐diketopiperazine compounds (3–12). The structures of isolates were deduced by their mass and NMR spectroscopic data. The coumarin‐type secondary metabolite (1) with peculiar smell induced by epigenetic stimulation is found for the first time in the Arthrobotrys species and the family Orbiliaceae. We evaluated 1 for the cytotoxic, anti‐inflammatory, anti‐allergic and nematocidal activities, however, it was found inactive. [ABSTRACT FROM AUTHOR]

A new indoleglycerol, designated as arecine (1), and twenty‐three known diketopiperazines 2–24 were isolated from the endophytic fungus Diaporthe arecae associated with mangrove Kandelia obovate. Structures of all secondary metabolites 1–24 were identified on the basis of their spectrometric data, especially the nuclear magnetic resonance, optical rotation, and mass data. The absolute stereochemistry of compound 1 was determined by comparing its experimental electronic circular dichroism spectrum to those of in silico generated. Moreover, the 1H and 13C NMR spectroscopic data of isolated diketopiperazines 3–24 were measured in dimethyl sulfoxide‐d6 and presented in Table 2 for a convenient comparison. Pharmacological study showed cordysinin A (2) possessed mild anti‐angiogenic activity, which suppressed tube formation with an IC50 value of 15.1±0.2 μg/mL. [ABSTRACT FROM AUTHOR]

Chemoselectivity, Regioselectivity, Quinones, Computational chemistry, Inflammation Front Cover Picture: Chemo- and Regioselective Construction of Functionalized Isocoumarin, Flavone, and Isoquinolinedione via a One-pot Reaction of o-Quinol Acetate and Soft Nucleophiles (Adv. Keywords: Chemoselectivity; Regioselectivity; Quinones; Computational chemistry; Inflammation EN Chemoselectivity Regioselectivity Quinones Computational chemistry Inflammation 2763 2763 1 09/07/23 20230905 NES 230905 The front cover picture illustrates the synthetic strategy for the regioselective installation of various soft nucleophiles at the C6 position of the highly reactive I o i -quinol acetate by 1,6-addition. [Extracted from the article]

Abstract: Sphingosine‐1‐phosphate (S1P) is a bioactive lipid that exerts various pathophysiological functions through binding to its receptor family (S1PRs). Since first report of the breast cancer (BCA) promoting function by S1P production (through the function of sphingosine kinases) and S1P/S1PR signaling, their antagonists have never been successfully progress to clinics after three decades. Taking advantage of bioinformatics linking to gene expression to disease prognosis, we examined the impact of associated genes in BCA patients. We found high gene expressions involved in S1P anabolism suppressed disease progression of patients who are basal cell type BCA or receiving adjuvant therapy. In addition, S1PRs expression also suppressed disease progress of multiple categories of BCA patient progression. This result is contradictory to tumor promoter role of S1P/S1PRs which revealed in the literature. Further examination by directly adding S1P in BCA cells found a cell growth suppression function, which act via the expression of S1PR1. In conclusion, our study is the first evidence claiming a survival benefit function of S1P/S1PR signaling in BCA patients, which might explain the obstacle of relative antagonist apply in clinics. [ABSTRACT FROM AUTHOR]

Abstract: Reactive oxygen species (ROS) induction had been previously reported in 4β‐hydroxywithanolide (4βHWE)‐induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8‐oxo‐2′deoxyguanosine [8‐oxodG]) were detected in 4βHWE‐treated oral cancer (Ca9‐22) and/or normal (HGF‐1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N‐acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE‐treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine‐DNA glycolyase (Fpg)‐based comet assay and 8‐oxodG‐based flow cytometry, the 8‐oxodG expressions were higher in 4βHWE‐treated oral cancer cells than in oral normal cells. All the 4βHWE‐induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS‐mediated selective killing of oral cancer cells. [ABSTRACT FROM AUTHOR]

The selective synthesis of various dideuterochalcones as potentially bioactive deuterium-labeled products is presented, by means of the highly controlled partial deuteration of antidiabetic chalcone derivatives. The benefits of continuous-flow processing in combination with on-demand electrolytic D2 gas generation has been exploited to avoid over-reaction to undesired side products and to achieve selective deuterium addition to the carbon-carbon double bond of the starting enones without the need for unconventional catalysts or expensive special reagents. The roles of pressure, temperature, and residence time proved crucial for the fine-tuning of the sensitive balance between the product selectivity and the reaction rate. The presented flow-chemistry-based deuteration technique lacks most of the drawbacks of the classical batch methods, and is convenient, time- and cost-efficient, and safe. [ABSTRACT FROM AUTHOR]

A phytochemical investigation of MeOH extract of Desmos cochinchinensis var. fulvescens Ban afforded two new compounds, 1 β,7 α-dihydroxyeudesman-4-one ( 1) and 5 αH-megastigm-7-ene-3 α,4 α,6 β,9-tetrol ( 2), together with nine known terpenoids. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopic analysis. Their relative configurations were assigned by NOESY experiments. [ABSTRACT FROM AUTHOR]

Flavonoids have been intensively explored for their anticancer activity. In this study, a total synthetic flavonoid protoapigenone, known as WYC02, was analysed for its potential anticancer activity on human cervical cancer cells as well as the underlying mechanisms for these effects. The site-moiety maps are used to explore the binding site similarity, pharmacophore and docking pose similarity. The effect of WYC02 on cell viability, migration, invasion and apoptosis as well as the underlying mechanisms was analysed in vitro using human cervical cancer cells. The effect of WYC02 on in vivo tumour growth was assessed in a tumour xenograft study. WYC02 inhibited cell proliferation, MMPs activity, migration and invasion in cervical cancer cells. We speculated that WYC02 might inhibit the activities of PIK3 family proteins, including PIK3 CA, PIK3 CB, PIK3 CD and PIK3 CG. Indeed, WYC02 decreased the expression of PIK3 family proteins, especially PIK3 CG, through ubiquitination and inhibited the activities of PIK3 CG and PIK3 downstream molecules AKT1 and MTOR in cervical cancer cells. Furthermore, PIK3 signalling pathway was involved in the inhibitory effect of WYC02 on cervical cancer cell proliferation and tumour growth in vitro and in vivo. WYC02 inhibits cervical cancer cell proliferation and tumourigenesis via PIK3 signalling pathway and has the potential to be developed as a chemotherapeutic agent in cervical cancer. [ABSTRACT FROM AUTHOR]

Copper catalysed oxidative coupling reaction of formamides with β-keto esters and 2-carbonyl-substituted phenols successfully proceeded through direct C-H bond activation of formamides. The corresponding carbamates were formed with high stereoselectivity under mild reaction conditions. This protocol was successfully applied to the synthesis of three novel halogenated carbamates and a carbaryl insecticide derivative. Our results suggest the use of 6.0 equiv. TBHP is crucial for this type of reaction. [ABSTRACT FROM AUTHOR]

An efficient method for the synthesis of flavones and γ-benzopyranones has been developed utilizing a mild Sonogashira coupling and 18-crown-6 ether mediated 6- endo cyclization of o-alkynoylphenyl acetates. By using this strategy, flavones and γ-benzopyranones bearing electron-donating groups, halogens, and simple alkyl substituents were synthesized in satisfactory yields. [ABSTRACT FROM AUTHOR]

Background and Purpose: Activation of human platelets by thrombin is mediated predominately through two proteinase-activated receptors (PARs), PAR1 and PAR4. Phosphatidylinositol 3-kinase (PI3K) inhibition leads to reversible PAR1-mediated platelet aggregation, but has no effect on the stability of platelet aggregation induced by thrombin. In the present study, the molecular mechanisms underlying this difference were investigated.Experimental Approach: The functions of PI3K and PAR4 were assessed using specific inhibitors and aggregometry. The duration of platelet glycoprotein (GP) IIb/IIIa exposure was determined by flow cytometry with the antibody PAC-1. Western blotting and fluo-3 was used to evaluate the activation of Akt and protein kinase C (PKC) and intracellular Ca(2+) mobilization respectively.Key Results: When PAR4 function was inhibited either by the PAR4 antagonist YD-3 [1-benzyl-3-(ethoxycarbonylphenyl)-indazole] or by receptor desensitization, the PI3K inhibitor wortmannin turned thrombin-elicited platelet aggregation from an irreversible event to a reversible event. Moreover, wortmannin plus YD-3 markedly accelerated the inactivation of GPIIb/IIIa in thrombin-stimulated platelets. The aggregation-reversing activity mainly resulted from inhibition of both PI3K-dependent PKC activation and PAR4-mediated sustained intracellular Ca(2+) rises. Blockade of ADP P2Y(12) receptor with 2-methylthioadenosine 5'-monophosphate triethylammonium salt mimicked the inhibitory effect of wortmannin on PI3K-dependent PKC activation and its ability to reverse PAR1-activating peptide-induced platelet aggregation. Co-administration of 2-methylthioadenosine 5'-monophosphate triethylammonium salt with YD-3 also decreased the stability of thrombin-induced platelet aggregation.Conclusions and Implications: These results suggest that PAR4 acts in parallel with the P2Y(12)/PI3K pathway to stabilize platelet aggregates, and provide new insights into the mechanisms of thrombus stabilization and potential applications for antithrombotic therapy. [ABSTRACT FROM AUTHOR]

Abstract: Calotropin is one of cardenolides isolated from milkweed used for medicinal purposes in many Asian countries. Whereas calotropin possesses cytotoxicity against several cancer cells, the mechanisms of action remain unclear. We set out to evaluate the cytotoxic mechanism of calotropin on human chronic myeloid leukemia K562 cells. Calotropin inhibited the growth of K562 cells in a time- and dose-dependent manner by G2/M phase arrest. It upregulated the expression of p27 leading to this arrest by downregulating the G2/M regulatory proteins, cyclins A and B, and by upregulating the cdk inhibitor, p27. Furthermore, it downregulated anti-apoptotic signaling (XIAP and survivin) and survival pathways (p-Akt and NFκB), leading to caspase-3 activation which resulted in the induction of apoptosis. In all, calotropin exerted its anticancer activity on K562 cells by modulating the pro-survival signaling that leads to induction of apoptosis. [Copyright &y& Elsevier]

A simple and reliable high-performance liquid chromatographic method with ultraviolet detection (280 nm) has been developed for the simultaneous analysis of 12 bioactive components in San-huang-xie-xin-tang (SHXXT), a traditional Chinese medicine containing Rhei rhizome, Coptidis rhizome and Scutellariae radix. A relatively simple extraction procedure was employed and optimised, and separation of the components was obtained within 1 h using a reversed-phase column under gradient elution with acetonitrile and a buffer containing 0.01 m sodium 1-pentanesulphonate (pH 3). The lower limit of detection for the analytes ranged from 25 to 75 ng/mL. The correlation coefficients associated with each calibration curve were greater than 0.99. The precision and accuracy of the method ranged from 1.0 to 10.5% at low concentration levels, 0.8 to 8.7% at medium levels and 1.2 to 5.8% at high levels. In commercial products of SHXXT, baicalin and berberine were present in the highest amounts with levels up to 4.0 and 3.3%, respectively, in one sample. The HPLC method was able rapidly and efficiently to analyse constituents in crude herb and traditional Chinese medicinal preparations containing Rhei rhizome, Coptidis rhizome and Scutellariae radix. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

An abstract of the article "Copper-Catalyzed Selective C-O Bond Formation by Oxidative α-C(sp3)-H/O-H Coupling Between Ethers and Salicylaldehydes" by Balaji D. Barve and colleagues is presented.

Chemical equations for the article "Copper-Catalyzed Oxidative Coupling of Formamides with Salicylaldehydes: Synthesis of Carbamates in the Presence of a Sensitive Aldehyde Group" by B. D. Barve and colleagues that was published in "Journal of Organic Chemistry" in 2014 are presented.

A simple iron carbonyl catalyzed method for the α-selective aryloxylation of cyclic ethers is developed using a variety of salicylic aldehydes as phenol derivative and tBuOOH as the oxidant. [ABSTRACT FROM AUTHOR]