Fucoxanthin induces human melanoma cytotoxicity by thwarting the JAK2/STAT3/BCL-xL signaling axis.

Melanoma is the most lethal skin malignancy. Fucoxanthin is a marine carotenoid with significant anticancer activities. Intriguingly, Fucoxanthin's impact on human melanoma remains elusive. Signal Transducer and Activator of Transcription 3 (STAT3) represents a promising target in cancer therapy due to its persistent activation in various cancers, including melanoma. Herein, we revealed that Fucoxanthin is cytotoxic to human melanoma cell lines A2758 and A375 while showing limited cytotoxicity to normal human melanocytes. Apoptosis is a primary reason for Fucoxanthin's melanoma cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk drastically abrogated Fucoxanthin-elicited clonogenicity blockage. Besides, Fucoxanthin downregulated tyrosine 705-phosphorylated STAT3 (p-STAT3 (Y705)), either inherently present in melanoma cells or inducible by interleukin 6 (IL-6) stimulation. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, abolished Fucoxanthin-elicited melanoma cell apoptosis and clonogenicity inhibition, supporting the pivotal role of STAT3 blockage in Fucoxanthin's melanoma cytotoxicity. Moreover, Fucoxanthin lowered BCL-xL levels by blocking STAT3 activation, while ectopic BCL-xL expression rescued melanoma cells from Fucoxanthin-induced killing. Lastly, Fucoxanthin was found to diminish the levels of JAK2 with dual phosphorylation at tyrosine residues 1007 and 1008 in melanoma cells, suggesting that Fucoxanthin impairs STAT3 signaling by blocking JAK2 activation. Collectively, we present the first evidence that Fucoxanthin is cytotoxic selectively against human melanoma cells while sparing normal melanocytes. Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management.

Methoxyhispolon Methyl Ether, a Hispolon Analog, Thwarts the SRC/STAT3/BCL-2 Axis to Provoke Human Triple-Negative Breast Cancer Cell Apoptosis In Vitro.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with few treatment options. A promising TNBC treatment approach is targeting the oncogenic signaling pathways pivotal to TNBC initiation and progression. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving TNBC malignant transformation, highlighting STAT3 as a promising TNBC therapeutic target. Methoxyhispolon Methyl Ether (MHME) is an analog of Hispolon, an anti-cancer polyphenol found in the medicinal mushroom Phellinus linteus. Still, MHME's anti-cancer effects and mechanisms remain unknown. Herein, we present the first report about MHME's anti-TNBC effect and its action mechanism. We first revealed that MHME is proapoptotic and cytotoxic against human TNBC cell lines HS578T, MDA-MB-231, and MDA-MB-463 and displayed a more potent cytotoxicity than Hispolon's. Mechanistically, MHME suppressed both constitutive and interleukin 6 (IL-6)-induced activation of STAT3 represented by the extent of tyrosine 705-phosphorylated STAT3 (p-STAT3). Notably, MHME-evoked apoptosis and clonogenicity impairment were abrogated in TNBC cells overexpressing a dominant-active mutant of STAT3 (STAT3-C); supporting the blockade of STAT3 activation is an integral mechanism of MHME's cytotoxic action on TNBC cells. Moreover, MHME downregulated BCL-2 in a STAT3-dependent manner, and TNBC cells overexpressing BCL-2 were refractory to MHME-induced apoptosis, indicating that BCL-2 downregulation is responsible for MHME's proapoptotic effect on TNBC cells. Finally, MHME suppressed SRC activation, while v-src overexpression rescued p-STAT3 levels and downregulated apoptosis in MHME-treated TNBC cells. Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent.

Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether.

Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME's cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/ß-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/ß-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.

Sertindole, an Antipsychotic Drug, Curbs the STAT3/BCL-xL Axis to Elicit Human Bladder Cancer Cell Apoptosis In Vitro.

Bladder cancer is the leading urinary tract malignancy. Epidemiological evidence has linked lower cancer incidence in schizophrenia patients to long-term medication, highlighting the anticancer potential of antipsychotics. Sertindole is an atypical antipsychotic agent with reported anticancer action on breast and gastric cancers. Yet, sertindole's effect on bladder cancer remains unaddressed. We herein present the first evidence of sertindole's antiproliferative effect and mechanisms of action on human bladder cancer cells. Sertindole was cytotoxic against bladder cancer cells while less cytotoxic to normal urothelial cells. Apoptosis was a primary cause of sertindole's cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk rescued cells from sertindole-induced killing. Mechanistically, sertindole inhibited the activation of signal transducer and activator of transcription 3 (STAT3), an oncogenic driver of bladder cancer, as sertindole lowered the levels of tyrosine 705-phosphorylated STAT3 along with that of STAT3's target gene BCL-xL. Notably, ectopic expression of the dominant-active STAT3 mutant impaired sertindole-induced apoptosis in addition to restoring BCL-xL expression. Moreover, bladder cancer cells overexpressing BCL-xL were refractory to sertindole's proapoptotic action, arguing that sertindole represses STAT3 to downregulate BCL-xL, culminating in the induction of apoptosis. Overall, the current study indicated sertindole exerts bladder cancer cytotoxicity by provoking apoptosis through targeted inhibition of the antiapoptotic STAT3/BCL-xL signaling axis. These findings implicate the potential to repurpose sertindole as a therapeutic strategy for bladder cancer.

Experimental Validation and Computational Predictions Join Forces to Map Catalytic C-H Activation in Ferrocene Metalated Porous Organic Polymers.

In recent times, a self-complementary balanced characteristic feature with the combination of both covalent bonds (structural stability) and open metal sites (single-site catalysis) introduced an advanced emerging functional nanoarchitecture termed metalated porous organic polymers (M-POPs). However, the development of M-POPs in view of the current interest in catalysis has been realized still in its infancy and remains a challenge for the years to come. In this work, we built benzothiazole-linked Fe-metalated porous organic polymer (Fc-Bz-POP) using ferrocene dicarboxaldehyde (FDC), 1,3,5-tris(4-aminophenyl) benzene (APB), and elemental sulfur (S8) via a template-free, multicomponent, cost-effective one-pot synthetic approach. This Fc-Bz-POP is endowed with unique features including an extended network unit, isolated active sites, and catalytic pocket with a possible local structure, in which convergent binding sites are positioned in such a way that substrate molecules can be held in close proximity. Prospective catalytic application of this Fc-Bz-POP has been explored in executing catalytic allylic "C-H" bond functionalization of cyclohexene (CHX) in water at room temperature. Catalytic screening results identified that a superior performance with a CHX conversion of 95% and a 2-cyclohexene-1-ol selectivity (COL) of 80.8% at 4 h and 25 °C temperature has been achieved over Fc-Bz-POP, thereby addressing previous shortcomings of the other conventional catalytic systems. Comprehensive characterization understanding with the aid of synchrotron-based extended X-ray absorption fine structure (EXAFS) analysis manifested that the Fe atom with an oxidation state of +2 in our Fc-Bz-POP catalytic system encompasses a sandwich structural environment with the two symmetrical eclipsed cyclopentadienyl (Cp) rings, featuring nearest-neighbor (NN) Fe-C (≈2.05 Å) intramolecular bonds, as validated by the Fe L3-edge EXAFS fitting result. Furthermore, in situ attenuated total reflection-infrared spectroscopy (ATR-IR) analysis data for liquid-phase oxidation of cyclohexene allow for the formulation of a molecular-level reaction mechanistic pathway with the involvement of specific reaction intermediates, which is initiated by the radical functionalization of the allyl hydrogen. A deep insight investigation from density functional theory (DFT) calculations unambiguously revealed that the dominant pathway from cyclohexene to 2-cyclohexene-1-ol is initiated by an allyl-H functionalization step accompanied by the formation of 2-cyclohexene-1-hydroperoxide species as the key reaction intermediate. Electronic properties obtained from DFT simulations via the charge density difference plot, Bader charge, and density of state (DOS) demonstrate the importance of the organic polymer frame structure in altering the electronic properties of the Fe site in Fc-Bz-POP, resulting in its high activity. Our contribution has great implications for the precise design of metalated porous organic polymer-based robust catalysts, which will open a new avenue to get a clear image of surface catalysis.

Near-Infrared Phototheranostic Iron Pyrite Nanocrystals Simultaneously Induce Dual Cell Death Pathways via Enhanced Fenton Reactions in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is considered more aggressive with a poorer prognosis than other breast cancer subtypes. Through systemic bioinformatic analyses, we established the ferroptosis potential index (FPI) based on the expression profile of ferroptosis regulatory genes and found that TNBC has a higher FPI than non-TNBC in human BC cell lines and tumor tissues. To exploit this finding for potential patient stratification, we developed biologically amenable phototheranostic iron pyrite FeS2 nanocrystals (NCs) that efficiently harness near-infrared (NIR) light, as in photovoltaics, for multispectral optoacoustic tomography (MSOT) and photothermal ablation with a high photothermal conversion efficiency (PCE) of 63.1%. Upon NIR irradiation that thermodynamically enhances Fenton reactions, dual death pathways of apoptosis and ferroptosis are simultaneously triggered in TNBC cells, comprehensively limiting primary and metastatic TNBC by regulating p53, FoxO, and HIF-1 signaling pathways and attenuating a series of metabolic processes, including glutathione and amino acids. As a unitary phototheranostic agent with a safe toxicological profile, the nanocrystal represents an effective way to circumvent the lack of therapeutic targets and the propensity of multisite metastatic progression in TNBC in a streamlined workflow of cancer management with an integrated image-guided intervention.

Studies of high-membered two-dimensional Ruddlesden-Popper Cs7Pb6I19 perovskite nanosheets via kinetically controlled reactions.

Two-dimensional (2D) all-inorganic Ruddlesden-Popper (RP) perovskite Cs7Pb6I19 nanosheets (NSs) were successfully developed for the first time by employing a structural recrystallization process with additional passivation of small organic sulfide molecules. The structure of Cs7Pb6I19 NSs is confirmed by powder X-ray diffraction measurements, atomically-resolved STEM measurements and atomic force microscopy (AFM) studies. Cs7Pb6I19 NSs with a specific n value of 6 exhibits unique absorption and emission spectra with intense excitons at 560 nm due to quantum confinement effects in 2D perovskite slabs. The formation mechanisms of 2D Cs7Pb6I19 NSs and 3D γ-CsPbI3 phases were investigated by in situ photoluminescence (PL) spectroscopy and the activation energies of their formation reactions were calculated to be 151 kJ mol-1 and 95.3 kJ mol-1, respectively. The phase stability of 2D Cs7Pb6I19 NSs can be maintained at temperatures below 14 °C for more than 4 weeks. The overall results indicate that 2D Cs7Pb6I19 NSs demonstrate unique optical properties and structural stability compared with other 3D perovskite materials. We have opened a new path to the future discovery of 2D perovskite structures with metastable phases by using this recrystallization method and the assistance of sulfur-derived organic molecules.

Hispolon Methyl Ether, a Hispolon Analog, Suppresses the SRC/STAT3/Survivin Signaling Axis to Induce Cytotoxicity in Human Urinary Bladder Transitional Carcinoma Cell Lines.

Bladder cancer is a leading human malignancy worldwide. Signal transducer and activator of transcription (STAT) 3 is an oncogenic transcription factor commonly hyperactivated in most human cancers, including bladder cancer. Notably, preclinical evidence has validated STAT3 blockade as a promising therapeutic strategy for bladder cancer. Hispolon Methyl Ether (HME) is a structural analog of hispolon, an anticancer component of the medicinal mushroom Phellinus linteus. Thus far, HME's anticancer activity and mechanisms remain largely unknown. We herein report HME was cytotoxic, more potent than cisplatin, and proapoptotic to various human bladder transitional carcinoma cell lines. Of note, HME blocked STAT3 activation, evidenced by HME-elicited reduction in tyrosine 705-phosphorylated STAT3 levels constitutively expressed or induced by interleukin-6. Significantly, HME-induced cytotoxicity was abrogated in cells expressing a dominant-active STAT3 mutant (STAT3-C), confirming STAT3 blockage as a pivotal mechanism of HME's cytotoxic action. We further revealed that survivin was downregulated by HME, while its levels were rescued in STAT3-C-expressing cells. Moreover, survivin overexpression abolished HME-induced cytotoxicity, illustrating survivin as a central downstream mediator of STAT3 targeted by HME. Lastly, HME was shown to lower tyrosine 416-phosphorylated SRC levels, suggesting that HME inhibits STAT3 by repressing the activation of SRC, a STAT3 upstream kinase. In conclusion, we present the first evidence of HME's anti-bladder cancer effect, likely proceeding by evoking apoptosis through suppression of the antiapoptotic SRC/STAT3/survivin signaling axis.

Bisphenol A induced apoptosis via oxidative stress generation involved Nrf2/HO-1 pathway and mitochondrial dependent pathways in human retinal pigment epithelium (ARPE-19) cells.

Bisphenol A (BPA) is an estrogen-like compound, and an environmental hormone, that is commonly used in daily life. Therefore, it may enter the human body through food or direct contact, causing BPA residues in blood and urine. Because most studies focused on the analysis of BPA in reproductive cells or tissues, regarding evidence the effect of BPA on human retinal pigment epithelium (ARPE-19) cells unavailable. Accordingly, the present study explored the cytotoxicity of BPA on ARPE-19 cells. After BPA treatment, the expression of Bcl-XL an antiapoptotic protein, in the mitochondria decreased, and the expression of Bax, a proapoptotic protein increased. Then the mitochondrial membrane potential was affected. BPA changed in mitochondrial membrane potential led to the release of cytochrome C, which activated caspase-9 to promote downstream caspase-3 leading to cytotoxicity. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) pathway play a major role in age-related macular degeneration. Our results showed that expression of HO-1 and Nrf2 suppressed by BPA. Superoxide dismutase and catalase, which Nrf2 downstream antioxidants, were degraded by BPA. AMP-activated kinase (AMPK), which can regulate the phosphorylation of Nrf2, and the phosphorylation of AMPK expression was reduced by BPA. Finally, BPA-induced ROS generation and cytotoxicity were reduced by N-acetyl-l-cysteine. Taken together, these results suggest that BPA induced ARPE-19 cells via oxidative stress, which was associated with down regulated Nrf2/HO-1 pathway, and the mitochondria dependent apoptotic signaling pathway.

Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells.

AIMS: The selective molecules for targeted therapy of triple-negative breast cancer (TNBC) are limited. Several kinases play pivotal roles in cancer development and malignancy. The study aims to determine if any kinases confer to malignancy of TNBC cells, which could serve as a theranostic target for TNBC. METHODS: Kinome siRNA library was used to screen selective genes required for the proliferation of TNBC cells. The involvement of DYRK1B in cancer malignancy was evaluated with migration, invasion assays, and spheroid culture. The expression of DYRK1B was confirmed with quantitative PCR and immunoblotting. The clinical correlation of DYRK1B in TNBC patients was examined with tissue microarray and The Cancer Genome Atlas (TCGA) database. RESULTS: Our results showed that silencing DYRK1B significantly suppressed cell viability in DYRK1B-high expressed TNBC cells, likely by arresting the cell cycle at the G1 phase. Nevertheless, silencing DYRK1B had marginal effects on DYRK1B-low expressed TNBC cells. Similarly, the knockdown of DYRK1B decreased tumorsphere formation and increased cell death of the tumorsphere. Moreover, inactivation of DYRK1B by either specific inhibitor or ectopic expressing catalytic mutant of DYRK1B inhibited cell viability and metastatic characteristics, including migration and invasion. In addition, DYRK1B protein expression was elevated in tumor tissues compared to that in adjacent normal tissues of TNBC patients. Further, DYRK1B gene expression was highly correlated with CCDC97 or ZNF581 genes in TNBC cells and patients. High co-expression of DYRK1B with CCDC97 or ZNF581 was significantly associated with unfavorable overall survival and disease-free survival of TNBC patients. CONCLUSIONS: our results suggest DYRK1B might be essential for promoting tumor progression and could be a theranostic target for TNBC. Silencing or inactivation of DYRK1B might be a potential targeted therapy for TNBC.

Air Pollutant Particles, PM2.5, Exposure and Glaucoma in Patients with Diabetes: A National Population-Based Nested Case-Control Study.

The global prevalence of diabetes mellitus (DM) has reached 20%. Air pollutants with a particle size of less than 2.5 µm (PM2.5) are a globally recognized risk factor for diabetes and glaucoma. We examined whether the risk of glaucoma would decrease or increase when patients with DM were exposed to different PM2.5 concentrations. Data were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan and the Air Quality Monitoring Network between 2008 and 2013. This nested case-control study involved 197 DM patients with glaucoma and 788 DM patients without glaucoma. Cases and controls were matched (1:4) by gender, age (±5 years), and index date (±6 months), and their data were entered in a logistic regression model adjusted for gender, age, urbanization level, income level, and comorbidities. The odds ratio (OR) of glaucoma at PM2.5 exposure concentration in the fourth quartile (Q4) compared with in the first quartile (Q1) was 1.7 (95% CI: 1.084-2.764). For glaucoma risk, the OR was 1.013 (95% CI: 1.006-1.020) at a PM2.5 exposure concentration in Q1, 1.004 (95% CI: 1.001-1.007) in the third quartile (Q3), and 1.003 (95% CI: 1.001-1.004) in Q4. In the subgroup analysis of patients living in non-emerging towns and non-agricultural towns, the OR for glaucoma in Q4 compared with in Q1 was 2.1 (95% CI: 1.229-3.406) and 1.8 (95% CI: 1.091-2.803), respectively (p trend = 0.001 and 0.011). For patients without migraine, the OR for glaucoma was 1.7 (95% CI: 1.074-2.782; p = 0.006). These results demonstrate that, for patients with DM, PM2.5 increased the risk of glaucoma and PM2.5 was an independent risk factor for glaucoma in patients with DM.

Electrocatalytic Reduction of NO3- to Ultrapure Ammonia on {200} Facet Dominant Cu Nanodendrites with High Conversion Faradaic Efficiency.

Nitrate (NO3-) reduction reaction (NtRR) is considered as a green alternative method for the conventional method of NH3 synthesis (Haber-Bosch process), which is known as a high energy consuming and large CO2 emitting process. Herein, the copper nanodendrites (Cu NDs) grown along with the {200} facet as an efficient NtRR catalyst have been successfully fabricated and investigated. It exhibited high Faradaic efficiency of 97% at low potential (-0.3 V vs RHE). Furthermore, the 15NO3- isotope labeling method was utilized to confirm the formation of NH3. Both experimental and theoretical studies showed that NtRR on the Cu metal nanostructure is a facet dependent process. Dissociation of NO bonding is supposed to be the rate-determining step as NtRR is a spontaneously reductive and protonation process for all the different facets of Cu. Density functional theory (DFT) calculations revealed that Cu{200} and Cu{220} offer lower activation energy for dissociation of NO compared to that of Cu{111}.

Effect of molecular mass and sulfate content of fucoidan from Sargassum siliquosum on antioxidant, anti-lipogenesis, and anti-inflammatory activity.

Macroalgae (seaweeds) are abundant in functional polysaccharides known for their unique biochemical activities. In this study, the antioxidant, anti-lipogenic, and anti-inflammatory activities of the fucoidan extracted from brown seaweed Sargassum siliquosum were investigated by 1,1-diphenyl-2-picrylhydrazyl (DPPH)-scavenging ability, lipid synthesis inhibition, and suppression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) production, respectively. To examine the effect of molecular mass on fucoidan's bioactivities above, the extracted fucoidan was subject to hydrogen peroxide-mediated partial hydrolysis to obtain lower molecular mass compounds within the range of 107.3-3.2 kDa. Results indicated that fucoidan's antioxidant activity increased with a corresponding decrease in molecular mass; the dosage for the half-maximal response (EC50) dropped from 2.58 to 1.82 mg/mL when the molecular mass decreased from 107.3 to 3.2 kDa. In addition, both the anti-lipogenesis and anti-inflammatory activities of fucoidan were significantly enhanced by 71.1% and 36.7%, respectively, when the molecular mass decreased to about 3 kDa. To further test the effect of sulfation on fucoidan's bioactivities, low molecular mass fucoidan was treated with SO3-DMF to increase the sulfate content. The results indicated that when sulfate content increased from 18.7% to 32.1%, EC50 of DPPH decreased from 1.82 mg/mL to 0.86 mg/mL and the anti-inflammatory activity also increased by 35.2%; however, the anti-lipogenesis activity decreased.

Algae-derived hydrocolloids in foods: applications and health-related issues.

Hydrocolloids are a class of food additives with broad applications in the food industry to develop structure in food ingredients. Hydrocolloids can be synthetic, plant-based, or animal-based. Increasing consumer awareness has led to the use of natural food ingredients derived from natural sources, making algae-derived hydrocolloids more appealing nowadays. Algae-derived hydrocolloids such as carrageenan, agar, and alginate are widely used in the food industry as thickening, gelling, and emulsifying agents. Carrageenans are sulfated polysaccharides with diverse structural specificities. The safety of carrageenan use in the food industry has been widely debated recently due to the reported pro-inflammatory activities of carrageenan and the probable digestion of carrageenan by the gut microbiota to generate pro-inflammatory oligosaccharides. In contrast, both agar and alginate are primarily nontoxic, and generally no dispute regarding the use of the same in food ingredients. This review provides an overview of the algae industry, the food additives, the algae-derived hydrocolloids, the applications of algae-derived hydrocolloids in food industries, health-related studies, and other sectors, along with future perspectives. Even though differences of opinion exist in the use of carrageenan, it is continued to be used by the food industry and will be used until suitable alternatives are available. In summary, algal hydrocolloids are 'label-friendly' and considered a safe option against synthetic additives.

Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia.

The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke to elucidate medicarpin's neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5 and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reduced brain infarction, and preserved the blood-brain barrier, supporting medicarpin's protective effect on stroke-induced injury. Immunohistochemistry analysis further revealed that medicarpin treatment decreased the expression/activation of p65NF-κB and caspase 3, especially near the infarct cortex, while promoting the expression of neurogenesis-associated proteins, including doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB). These changes of expression levels were accompanied by GSK-3 inactivation and ß-catenin upregulation. Notably, pretreatment with LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects of medicarpin, illustrating an essential role of PI3K/Akt activation in medicarpin's neuroprotective and reparative activities. In vitro studies revealed that medicarpin displayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulated microglial cells (BV2) with an IC50 around 5 ±1 (µM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygen-glucose deprivation with an IC50 around 13 ± 2 (µM). Collectively, this is the first report to demonstrate that medicarpin, isolated from Radix Hedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic (neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependent GSK-3 inactivation for upregulating ß-catenin, which in turn decreases the expression/activation of p65NF-κB and caspase 3 and promotes the expression of neurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain.

Structure and Biological Activity Analysis of Fucoidan Isolated from Sargassum siliquosum.

Fucoidans are heterologous polysaccharides commonly seen in brown macroalgae and are known for their biological activity including anticancer, antiangiogenic, immunomodulation, and antiviral properties. The brown macroalga Sargassum siliquosum was used for the extraction and analysis of fucoidan in this study. The S. siliquosum fucoidan was indicated as a galactofucoidan composed of sugars, uronate, and sulfate at a ratio of 12:1:4 and its purity was 85% based on the abovementioned three major components. Structural analysis by electrospray ionization collision-induced dissociation tandem mass spectroscopy revealed that the purified fucoidan consisted of a carbohydrate chain composed of (1→3)-linked or (1→4)-linked l-fucose residues, with sulfate groups at C-2 and C-4 positions. Galactose residues with (1→4)-linkages function as the branch points and they are located at the C-3 or C-4 position of fucose residues. Galactose residues are sulfated mainly at C-4 and C-6, while some sulfation can also be seen at C-2. The fucoidan purified from S. siliquosum demonstrated antioxidant, anti-inflammatory, and antilipogenic activities.

Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/ß-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis.

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/ß-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on ß-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/ß-catenin signaling in CRC cells. Notably, ectopic expression of a dominant-active ß-catenin mutant (∆N90-ß-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/ß-catenin signaling axis.

High UV-Vis-NIR Light-Induced Antibacterial Activity by Heterostructured TiO2-FeS2 Nanocomposites.

PURPOSE: Antibiotic resistance issues associated with microbial pathogenesis are considered to be one of the most serious current threats to health. Fortunately, TiO2, a photoactive semiconductor, was proven to have antibacterial activity and is being widely utilized. However, its use is limited to the short range of absorption wavelength. METHODS: In this work, heterostructured TiO2-FeS2 nanocomposites (NCs) were successfully prepared by a facile solution approach to enhance light-induced antibacterial activity over a broader absorption range. RESULTS: In TiO2-FeS2 NCs, FeS2 NPs, as light harvesters, can effectively increase light absorption from the visible (Vis) to near-infrared (NIR). Results of light-induced antibacterial activities indicated that TiO2-FeS2 NCs had better antibacterial activity than that of only TiO2 nanoparticles (NPs) or only FeS2 NPs. Reactive oxygen species (ROS) measurements also showed that TiO2-FeS2 NCs produced the highest relative ROS levels. Unlike TiO2 NPs, TiO2-FeS2 NCs, under light irradiation with a 515-nm filter, could absorb light wavelengths longer than 515 nm to generate ROS. In the mechanistic study, we found that TiO2 NPs in TiO2-FeS2 NCs could absorb ultraviolet (UV) light to generate photoinduced electrons and holes for ROS generation, including ⋅O2 - and ⋅OH; FeS2 NPs efficiently harvested Vis to NIR light to generate photoinduced electrons, which then were transferred to TiO2 NPs to facilitate ROS generation. CONCLUSION: TiO2-FeS2 NCs with superior light-induced antibacterial activity could be a promising antibacterial agent against bacterial infections.

Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/ß-catenin Signaling.

Colorectal cancer (CRC) is a highly prevailing cancer and the fourth leading cause of cancer mortality worldwide. Aberrant expression of antiapoptotic BCL-2 family proteins is closely linked to neoplastic progression and chemoresistance. Obatoclax is a clinically developed drug, which binds antiapoptotic BCL-2, BCL-xL, and MCL-1 for inhibition to elicit apoptosis. Survivin is an antiapoptotic protein, whose upregulation correlates with pathogenesis, therapeutic resistance, and poor prognosis in CRC. Herein, we provide the first evidence delineating the functional linkage between Obatoclax and survivin in the context of human CRC cells. In detail, Obatoclax was found to markedly downregulate survivin. This downregulation was mainly achieved via transcriptional repression, as Obatoclax lowered the levels of both survivin mRNA and promoter activity, while blocking proteasomal degradation failed to prevent survivin from downregulation by Obatoclax. Notably, ectopic survivin expression curtailed Obatoclax-induced apoptosis and cytotoxicity, confirming an essential role of survivin downregulation in Obatoclax-elicited anti-CRC effect. Moreover, Obatoclax was found to repress hyperactive WNT/ß-catenin signaling activity commonly present in human CRC cells, and, markedly, ectopic expression of dominant-active ß-catenin mutant rescued the levels of survivin along with elevated cell viability. We further revealed that, depending on the cell context, Obatoclax suppresses WNT/ß-catenin signaling in HCT 116 cells likely via inducing ß-catenin destabilization, or by downregulating LEF1 in DLD-1 cells. Collectively, we for the first time define survivin downregulation as a novel, pro-apoptotic mechanism of Obatoclax as a consequence of Obatocalx acting as an antagonist to WNT/ß-catenin signaling.

Photoactive Earth-Abundant Iron Pyrite Catalysts for Electrocatalytic Nitrogen Reduction Reaction.

The generation of ammonia, hydrogen production, and nitrogen purification are considered as energy intensive processes accompanied with large amounts of CO2 emission. An electrochemical method assisted by photoenergy is widely utilized for the chemical energy conversion. In this work, earth-abundant iron pyrite (FeS2 ) nanocrystals grown on carbon fiber paper (FeS2 /CFP) are found to be an electrochemical and photoactive catalyst for nitrogen reduction reaction under ambient temperature and pressure. The electrochemical results reveal that FeS2 /CFP achieves a high Faradaic efficiency (FE) of ≈14.14% and NH3 yield rate of ≈0.096 µg min-1 at -0.6 V versus RHE electrode in 0.25 m LiClO4 . During the electrochemical catalytic reaction, the crystal structure of FeS2 /CFP remains in the cubic pyrite phase, as analyzed by in situ X-ray diffraction measurements. With near-infrared laser irradiation (808 nm), the NH3 yield rate of the FeS2 /CFP catalyst can be slightly improved to 0.1 µg min-1 with high FE of 14.57%. Furthermore, density functional theory calculations demonstrate that the N2 molecule has strong chemical adsorption energy on the iron atom of FeS2 . Overall, iron pyrite-based materials have proven to be a potential electrocatalyst with photoactive behavior for ammonia production in practical applications.