Highly oxidized guaiane 12(8),15(6)-dilactones with neuroprotective activities from the roots of Lindera aggregata (Sims) Kosterm.

In our search for neuroprotective agents, six previously undescribed highly oxidized guaiane sesquiterpenes, linderaggrols A-F (1-6), together with three known sesquiterpenes, were isolated from the roots of Lindera aggregata (Sims) Kosterm. Their structures including absolute configurations were established by a combination of NMR spectroscopic techniques and single crystal X-ray diffraction experiments. Compounds 1-6 represented the first instances of guaiane 12(8),15(6)-dilactones. Additionally, compound 6 possessed a rare 1,8-O-bridge. Neuroprotective effects against erastin-induced ferroptosis on HT-22 cells showed that some compounds demonstrated neuroprotective effects at 20.0 µM.

An enzyme-responsive hydrogel of ferrocene-grafted carboxymethyl chitosan as a soft electrochemical sensor for MMP-9 detection.

Matrix metalloproteinase 9 (MMP-9) plays an important role in wound healing. However, overexpression of MMP-9 leads to the degradation of the newly formed extracellular matrix, which delays wound healing, ultimately leading to chronic wounds. Therefore, timely monitoring of the MMP-9 activity using simple, cost-effective methods is important to prevent the formation of chronic wounds. In this work, ferrocene-modified MMP-9 cleavage peptide (Fc-MG) modified carboxymethyl chitosan hydrogels were prepared as electrochemical biosensors. In the presence of MMP-9, the peptide chain is sheared, and the electrochemically active ferrocene segment is released. Therefore, analyzing the electrochemical activity of hydrogels using differential pulse voltammetry (DPV) can be used to determine MMP-9 activity. The results showed that the DPV peaks were correlated with the MMP-9 concentration in phosphate-buffered saline (PBS, pH 7.4) and Dulbecco's modified Eagle's medium (DMEM). Specifically, the corresponding coefficient of determination (R2) were 0.918 and 0.993. The limit of detections were 73.08 ng/mL and 131.71 ng/mL, respectively. Compared with the enzyme-linked immunosorbent assay, the hydrogel biosensor determined the concentration of MMP-9 in solution with simpler steps. This study demonstrates a novel strategy based on Fc-MG-modified hydrogels to monitor MMP-9 activity in cell secretion samples and shows the potential application in chronic wounds.

Minimally invasive delivery of human umbilical cord-derived mesenchymal stem cells by an injectable hydrogel via Diels-Alder click reaction for the treatment of intrauterine adhesions.

Intrauterine adhesions (IUA) are the most common cause of uterine infertility, and conventional treatments have not consistently achieved satisfactory pregnancy rates. Stem cell therapy shows promising potential for the clinical treatment of IUA. Although various advanced biomaterials have been designed for delivering stem cells to the uterine cavity, there remain significant challenges, particularly in devising therapeutic strategies for clinical application that minimize surgical incisions and conform to the intricate structure of uterine cavity. Herein, an injectable hydrogel loaded with human umbilical cord-derived mesenchymal stem cells (UCMSCs) was synthesized via the Diels-Alder click reaction for endometrial regeneration and fertility restoration, exhibiting suitable mechanical properties, good biocompatibility, and desirable degradation properties. Notably, this hydrogel permitted minimally invasive administration and integrated seamlessly with surrounding tissue. Our study revealed that the UCMSCs-laden injectable hydrogel enhanced cell proliferation, migration, angiogenesis, and exhibited anti-fibrotic effects in vitro. The implantation of this hydrogel significantly facilitated endometrium regeneration and restored fertility in a rat endometrial damage model. Mechanistically, in vivo results indicated that the UCMSCs-laden injectable hydrogel effectively promoted macrophage recruitment and facilitated M2 phenotype polarization. Collectively, this hydrogel demonstrated efficacy in regenerating damaged endometrium, leading to the restoration of fertility. Consequently, it holds promise as a potential therapeutic strategy for endometrial damage and fertility decline arising from intrauterine adhesions. STATEMENT OF SIGNIFICANCE: Severe endometrial traumas frequently lead to intrauterine adhesions and subsequent infertility. Stem cell therapy shows promising potential for the clinical treatment of IUA; however, challenges remain, including low delivery efficiency and compromised stem cell activity during the delivery process. In this study, we fabricated an injectable hydrogel loaded with UCMSCs via the Diels-Alder click reaction, which exhibited unique bioorthogonality. The in situ-gelling hydrogels could be introduced through a minimally invasive procedure and adapt to the intricate anatomy of the uterus. The UCMSCs-laden injectable hydrogel promoted endometrial regeneration and fertility restoration in a rat endometrial damage model, efficaciously augmenting macrophage recruitment and promoting their polarization to the M2 phenotype. The administration of UCMSCs-laden injectable hydrogel presents a promising therapeutic strategy for patients with severe intrauterine adhesion.

A ferrocene-based hydrogel as flexible electrochemical biosensor for oxidative stress detection and antioxidation treatment.

Real-time sensing of reactive oxygen species (ROS) and timely scavenging of excessive ROS in physiological environments are critically important in the diagnosis and prevention of ROS-related diseases. To solve the mismatch problem between conventional rigid ROS biosensors and biological tissues in terms of both modulus and composition, here, we present a flexible ferrocene-based hydrogel biosensor designed for oxidative stress detection and antioxidation treatment. The hydrogel was fabricated through a supramolecular assembly of ferrocene-grafted polyethylenimine (PEI-Fc), sodium alginate (SA), and polyvinyl alcohol (PVA). Multiple non-covalent interactions, including electrostatic interactions between PEI-Fc and SA, hydrophobic interactions and π-π stacking among ferrocene groups, and the PVA crystalline domain, synergistically improve the mechanical properties of the PVA/SA/PEI-Fc hydrogel. The flexible PVA/SA/PEI-Fc hydrogel biosensor exhibited a broad detection range for hydrogen peroxide (H2O2), from 0 to 120 µM, using the differential pulse voltammetry method. Furthermore, the hydrogel demonstrated effective ROS scavenging and oxygen generation performance, desirable biocompatibility, and satisfactory antibacterial activity, making it suitable for biological interfaces. In vitro studies revealed that the PVA/SA/PEI-Fc hydrogel could monitor H2O2 concentration in the proximity of inflammatory cells, and effectively scavenge ROS to protect cells from oxidative stress damage. This all-in-one multifunctional hydrogel, integrating both sensing and treatment functions, holds great promise for clinical applications in the diagnosis and management of ROS-related diseases.

Natural product-derived ferroptosis mediators.

It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future.

Construction of a Soft Antifouling PAA/PSBMA Hydrogel Coating with High Toughness and Low Swelling through the Dynamic Coordination Bonding Provided by Al(OH)3 Nanoparticles.

Marine biofouling, resulting from the adhesion of marine organisms to ship surfaces, has long been a significant issue in the maritime industry. In this paper, we focused on utilizing soft and hydrophilic hydrogels as a potential approach for antifouling (AF) coatings. Acrylic acid (AA) with a polyelectrolyte effect and N-(3-sulfopropyl)-N-(methacryloxyethyl)-N,N-dimethylammonium betaine (SBMA) with an antipolyelectrolyte effect were selected as monomers. By adjusting the monomer ratio, we were able to create hydrogel coatings that exhibited low swelling ratio in both fresh water and seawater. The Al(OH)3 nanoparticle, as a physical cross-linker, provided better mechanical properties (higher tensile strength and larger elongation at break) than the chemical cross-linker through the dynamic coordination bonds and plentiful hydrogen bonds. Additionally, we incorporated trehalose into the hydrogel, enabling the repair of the hydrogel network through covalent-like hydrogen bonding. The zwitterion compound SBMA endowed the hydrogel with excellent AF performance. It was found that the highest SBMA content did not lead to the best antibacterial performance, as bacterial adhesion quantity was also influenced by the charge of the hydrogel. The hydrogel with appropriate SBMA content being close to electrical neutrality exhibits the strongest zwitterionic property of PSBMA chains, resulting in the best antibacterial adhesion performance. Furthermore, the pronounced hydrophilicity of SBMA enhanced the lubrication of the hydrogel surface, thereby reducing the friction resistance when applied to the hull surface during ship navigation.

Rare 7,9'-dinorlignans with neuroprotective activity from the roots of Lindera aggregata (Sims) Kosterm.

Linderagatins C-F (1-4), the first examples of naturally occurring diaryltetrahydrofuran-type 7,9'-dinorlignans, were characterized from the roots of Lindera aggregata (Sims) Kosterm. The structures of these dinorlignans were elucidated by extensive spectroscopic analysis. The absolute configurations were determined based on calculated and experimental ECD data. A biosynthetic pathway for these dinorlignans was hypothetically proposed. Compounds 2 and 3 showed significant neuroprotective effects on erastin-induced ferroptosis in HT-22 cells with EC50 values of 23.4 and 21.8 µM, respectively.

Noncoding RNAs: Versatile regulators of endothelial dysfunction.

Noncoding RNAs have recently emerged as versatile regulators of endothelial dysfunction in atherosclerosis, a chronic inflammatory disease characterized by the formation of plaques within the arterial walls. Through their ability to modulate gene expression, noncoding RNAs, including microRNAs, long noncoding RNAs, and circular RNAs, play crucial roles in various cellular processes involved in endothelial dysfunction (ECD), such as inflammation, pyroptosis, migration, proliferation, apoptosis, oxidative stress, and angiogenesis. This review provides an overview of the current understanding of the regulatory roles of noncoding RNAs in endothelial dysfunction during atherosclerosis. It highlights the specific noncoding RNAs that have been implicated in the pathogenesis of ECD, their target genes, and the mechanisms by which they contribute to ECD. Furthermore, we have reviewed the current therapeutics in atherosclerosis and explore their interaction with noncoding RNAs. Understanding the intricate regulatory network of noncoding RNAs in ECD may open up new opportunities for the development of novel therapeutic strategies to combat ECD.

A construct of adipose-derived mesenchymal stem cells-laden collagen scaffold for fertility restoration by inhibiting fibrosis in a rat model of endometrial injury.

Severe endometrium damage causes pathological conditions such as thin endometrium and intrauterine adhesion, resulting in uterine factor infertility. Mesenchymal stem cell (MSC) therapy is a promising strategy in endometrial repair; yet, exogenous MSCs still raise concerns for safety and ethical issues. Human adipose-derived mesenchymal stem cells (ADMSCs) residing in adipose tissue have high translational potentials due to their autologous origin. To harness the high translation potentials of ADMSC in clinical endometrium regeneration, here we constructed an ADMSCs composited porous scaffold (CS/ADMSC) and evaluated its effectiveness on endometrial regeneration in a rat endometrium-injury model. We found that CS/ADMSC intrauterine implantation (i) promoted endometrial thickness and gland number, (ii) enhanced tissue angiogenesis, (iii) reduced fibrosis and (iv) restored fertility. We ascertained the pro-proliferation, pro-angiogenesis, immunomodulating and anti-fibrotic effects of CS/ADMSC in vitro and revealed that the CS/ADMSC influenced extracellular matrix composition and organization by a transcriptomic analysis. Our results demonstrated the effectiveness of CS/ADMSC for endometrial regeneration and provided solid proof for our future clinical study.

Inhibition of EZH2 alleviates SAHA-induced senescence-associated secretion phenotype in small cell lung cancer cells.

Chemotherapy has been widely used in small cell lung cancer (SCLC) treatment in the past decades. However, SCLC is easy to recur after chemotherapy. The senescence of cancer cells during chemotherapy is one of the effective therapeutic strategies to inhibit the progression of cancer. Nevertheless, the senescence-associated secretion phenotype (SASP) promotes chronic inflammation of the cancer microenvironment and further accelerates the progression of tumors. Therefore, inducing the senescence of cancer cells and inhibiting the production of SASP factors during anticancer treatment have become effective therapeutic strategies to improve the anticancer effect of drugs. Here we reported that SCLC cells treated with an FDA-approved HDAC inhibitor SAHA underwent senescence and displayed remarkable SASP. In particular, SAHA promoted the formation of cytoplasmic chromatin fragments (CCFs) in SCLC cells. The increased CCFs in SAHA-treated SCLC cells were related to nuclear porin Tpr, which activated the cGAS-STING pathway, and promoted the secretion of SASP in cancer cells. Inhibition of EZH2 suppressed the increase of CCFs in SAHA-treated SCLC cells, weakened the production of SASP, and increased the antiproliferative effect of SAHA. Overall, our work affords new insight into the secretion of SASP in SCLC and establishes a foundation for constructing a new therapeutic strategy for SCLC patients.

Structurally Diverse Sesquiterpenoids from the Genus of Ainsliaea.

The genus of Ainsliaea embraces approximately 70 recognized species, many of which have been used to treat various diseases in folklore medicines. As the main metabolites of Ainsliaea plants, Ainsliaea sesquiterpenoids have drawn considerable attention in related scientific communities due to their intriguing structures and a variety of bioactivities. In this review, we intend to provide a full-aspect coverage of sesquiterpenoids reported from the genus of Ainsliaea, including 145 monomeric sesquiterpenoids and 30 oligomeric ones. Multiple aspects will be summarized, including their classification, distributions, structures, bioactivities, and biomimetic syntheses. In addition, their possible biosynthetic pathway will be discussed in detail.

A conductive multifunctional hydrogel dressing with the synergistic effect of ROS-scavenging and electroactivity for the treatment and sensing of chronic diabetic wounds.

Chronic diabetic wound with persistent inflammatory responses is still a serious threat to human health and life. Ideal wound dressings can be applied not only for covering the injury area, but also for regulating the inflammation to accelerate the wound healing and long-term monitoring of wound condition. However, there remains a challenge to design a multifunctional wound dressing for simultaneous treatment and monitoring of wound. Herein, an ionic conductive hydrogel with intrinsic reactive oxygen species (ROS)-scavenging properties and good electroactivity was developed for achieving the synergetic treatment and monitoring of diabetic wounds. In this study, we modified dextran methacrylate with phenylboronic acid (PBA) to prepare a ROS-scavenging material (DMP). Then the hydrogel was constructed by phenylboronic ester bonds induced dynamic crosslinking network, photo-crosslinked DMP and choline-based ionic liquid as the second network, and the crystallized polyvinyl alcohol as the third network, realizing good ROS-scavenging performance, high electroactivity, durable mechanical properties, and favorable biocompatibility. In vivo results showed that the hydrogel combined with electrical stimulation (ES) demonstrated good performance in promoting re-epithelization, angiogenesis and collagen deposition in chronic diabetic wound treatment by alleviating inflammation. Notably, with desirable mechanical properties and conductivity, the hydrogel could also precisely monitor movements of human body and possible tensile and compressive stresses of the wound site, providing timely alerts of excessive mechanical stress applied to the wound tissue. Thus, this "all-in-one" hydrogel exhibits great potential in constructing the next generation flexible bioelectronics for wound treatment and monitoring. STATEMENT OF SIGNIFICANCE: Chronic diabetic wounds characterized by overexpressed reactive oxygen species (ROS) are still a serious threat to human health and life. However, there remains a challenge to design a multifunctional wound dressing for simultaneous wound treatment and monitoring. Herein, a flexible conductive hydrogel dressing with intrinsic ROS-scavenging properties and electroactivity was developed for the combined treatment and monitoring of the wound. The antioxidant hydrogel combined with electrical stimulation synergistically accelerated chronic diabetic wound healing by regulating oxidative stress, alleviating inflammation, promoting re-epithelization, angiogenesis and collagen deposition. Notably, with desirable mechanical properties and conductivity, the hydrogel also presented great potential in monitoring possible stresses of the wound site. The "all-in-one" bioelectronics integrating the treatment and monitoring functions present great application potential for accelerating chronic wound healing.

The importance of temperature monitoring in predicting wound healing.

CONCLUSION: Upon wound formation, the wound temperature rises in the first 3-4 days until reaching its peak. It then falls at about one week after wound formation. In the second week after wound formation, the wound temperature decreases steadily to the baseline indicating a good wound condition and progression towards healing. While a continuous high temperature is often a sign of excessive inflammation or infection, which indicates urgent need of intervention and treatment.

Discovery of phenylcarbamoyl xanthone derivatives as potent neuroprotective agents for treating ischemic stroke.

Compounds of natural sources are widespread discovered in the treatment of ischemic stroke. Alpha-mangostin, a natural prenylated xanthone, has been found to display a therapeutic potential to treat ischemic stroke. However, the direct application of α-mangostin is limited due to its cytotoxicity and relatively low efficacy. Herein, structural modification of α-mangostin was necessary to improve its drug-ability. Currently, 34 α-mangostin phenylcarbamoyl derivatives were synthesized and evaluated for their neuroprotective activities by glutamate-induced excitotoxicity and H2O2-induced oxidative damage models in vitro. The results showed that compound 2 had the most therapeutic potential in both models. Whereafter, 2 has been proved to have powerful therapeutic effects by the MCAO ischemic stroke model in rats, which might be due to inhibition of inflammatory reaction and free radical accumulation. Besides, acute toxicity assay in rats showed that compound 2 had excellent safety. Overall, 2 could be a promising neuroprotective agent for the treatment of ischemic stroke deserving further investigations.

Mitochondrial-Targeted Delivery of Polyphenol-Mediated Antioxidases Complexes against Pyroptosis and Inflammatory Diseases.

Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery of drugs to mitochondria and efficient clearance of mtROS remain challenging. In current study, it is discovered that polyphenols such as tannic acid (TA) can mediate the targeting of polyphenol/antioxidases complexes to mitochondria. This affinity does not depend on mitochondrial membrane potential but stems from the strong binding of TA to mitochondrial outer membrane proteins. Taking advantage of the feasibility of self-assembly between TA and proteins, superoxide dismutase, catalase, and TA are assembled into complexes (referred to as TSC) for efficient enzymatic activity maintenance. In vitro fluorescence confocal imaging shows that TSC not only promoted the uptake of biological enzymes in hepatocytes but also highly overlapped with mitochondria after lysosomal escape. The results from an in vitro model of hepatocyte oxidative stress demonstrate that TSC efficiently scavenges excess mtROS and reverses mitochondrial depolarization, thereby inhibiting inflammasome-mediated pyroptosis. More interestingly, TSC maintain superior efficacy compared with the clinical gold standard drug N-acetylcysteine in both acetaminophen- and D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. In conclusion, this study opens a new paradigm for targeting mitochondrial oxidative stress to inhibit pyroptosis and treat inflammatory diseases.

Coordination of Polyketide Release and Multiple Detoxification Pathways for Tolerable Production of Fungal Mycotoxins.

Efficient biosynthesis of microbial bioactive natural products (NPs) is beneficial for the survival of producers, while self-protection is necessary to avoid self-harm resulting from over-accumulation of NPs. The underlying mechanisms for the effective but tolerable production of bioactive NPs are not well understood. Herein, in the biosynthesis of two fungal polyketide mycotoxins aurovertin E (1) and asteltoxin, we show that the cyclases in the gene clusters promote the release of the polyketide backbone, and reveal that a signal peptide is crucial for their subcellular localization and full activity. Meanwhile, the fungus adopts enzymatic acetylation as the major detoxification pathway of 1. If intermediates are over-produced, the non-enzymatic shunt pathways work as salvage pathways to avoid excessive accumulation of the toxic metabolites for self-protection. These findings provided new insight into the interplay of efficient backbone release and multiple detoxification strategies for the production of fungal bioactive NPs.

Validation of the vault prediction model based on the sulcus-to-sulcus diameter and lens thickness: a 925-eye prospective study.

BACKGROUND: To verify the accuracy and stability of the prediction formula based on the ciliary sulcus diameter and lens thickness and to analyse factors influencing the prediction results. METHODS: In total, 925 eyes from 506 subjects were enrolled in this prospective study between July 1, 2020, and June 30, 2021. Subjects were divided into four seasons, each spanning three months. The target vault was set to be between 300 µm and 700 µm according the prediction formula. The actual vault was measured one month postoperatively. The Bland-Altman test, 95% confidence intervals (95% CI) and 95% limits of agreement (95% LoA) were used to evaluate the agreement between the predicted vault and the actual vault. Eyes with absolute prediction errors greater than 300 µm were further analysed. RESULTS: The mean predicted vaults for the four seasons were 503 ± 99, 494 ± 96, 481 ± 92 and 502 ± 93 µm, while the mean actual vaults were 531 ± 189, 491 ± 179, 464 ± 179 and 529 ± 162 µm, respectively. The predicted and actual vaults of the overall subjects were 493 ± 95 and 500 ± 180 µm, respectively. Of the 925 eyes, 861 eyes (93.08%), 42 eyes (4.54%), and 22 eyes (2.38%) showed a normal vault, high vault, and low vault, respectively. Bland-Altman plots showed that the mean difference between the actual vault and predicted vault overall (± 95% LoA) was 6.43 ± 176.2 µm (-339 to 352 µm). Three UBM features may lead to large prediction errors (more than 300 µm): wide iris-ciliary angle (ICA), iris concavity and anteriorly positioned ciliary body. CONCLUSIONS: This study demonstrated the accuracy and stability of the prediction formula through the validation of a large sample size and a long time span. Wide ICA, iris concavity and anteriorly positioned ciliary body may have an effect on vault.

The Diagnosis of Early Gastric Cancer Based on Medical Imaging Technology and Mathematical Modeling.

The key to reducing the mortality of gastric cancer is early detection, early diagnosis, and early treatment of gastric cancer. Early diagnosis of gastric cancer is the key to early detection and diagnosis of gastric cancer. Early diagnosis and treatment of gastric cancer is of great significance for improving the curative effect and reducing mortality of gastric cancer. The purpose of this paper is to study the diagnosis of early gastric cancer based on medical imaging techniques and mathematical modeling. The effect of W-DeepLab network-assisted diagnosis of images under white light was analyzed, and the value of Narrow Band Imaging and Blue Laser Imaging in the diagnosis of early gastric cancer was compared. Because Blue Laser Imaging endoscopy can clearly observe the demarcation line and microvascular morphology; but when using Narrow Band Imaging observation, part of the demarcation line and microvascular morphology is not observed. The results show that Blue Laser Imaging is brighter than Narrow Band Imaging's endoscopic images, and it is easier to observe the microstructure of lesions under endoscopy, so as to accurately determine the nature of lesions.

An Acellular Scaffold Facilitates Endometrial Regeneration and Fertility Restoration via Recruiting Endogenous Mesenchymal Stem Cells.

Severe intrauterine adhesions (IUAs), characterized by inadequate endometrial repair and fibrosis, can lead to infertility. Stem cell-based therapies, which deliver mesenchymal stem cells (MSCs) to the wound site, hold a considerable promise for endometrium regeneration. However, some notable hurdles, such as stemness loss, immunogenicity, low retention and survival rate, limit their clinical application. Evidence shows a strategy of mobilizing endogenous MSCs recruitment can overcome the traditional limitations of exogenous stem cell-based therapies. Here, an acellular biomaterial named stromal derived factor-1 alpha (SDF-1α)/E7-modified collagen scaffold (CES) is explored. CES based on harnessing the innate regenerative potential of the body enables near-complete endometrium regeneration and fertility restoration both in a rat endometrium acute damage model and a rat IUA model. Mechanistically, the CES implantation promotes endogenous MSCs recruitment via a macrophage-coordinated strategy; then the homing MSCs exert the function of immunomodulation and altered local microenvironments toward regeneration. To conclude, CES, which can harness endogenous MSCs and overcome the traditional limitations of cell-based therapies, can serve as a clinically feasible and cell-free strategy with high therapeutic efficiency for IUA treatment.

New Jatrophane-Type Diterpenoids from Euphorbia kansui as Potential MDR Reversal Agents.

A serial jatrophane-type diterpenoids, comprised with three undescribed compounds kanesulones C-E (1-3) and four known ones (4-7), were obtained from the roots of Euphorbia kansui. The structures of compounds 1-3 were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS, the absolute configuration of 1 was revealed by single crystal X-ray diffraction. These isolates were assayed for their multidrug resistance reversing activities on human breast adenocarcinoma cell line MCF-7/ADR. Compound 1 possessed potential as low toxic MDR modulator that could promote the efficacy of anticancer drug adriamycin ca. 85-fold at 5 µM, as 12 times stronger than the positive drug verapamil.