Morus alba L. (Sangzhi) alkaloids mitigate atherosclerosis by regulating M1/M2 macrophage polarization.

BACKGROUND: Atherosclerosis (AS) is an important cause of cardiovascular disease, posing a substantial health risk. Recognized as a chronic inflammatory disorder, AS hinges on the pivotal involvement of macrophages in arterial inflammation, participating in its formation and progression. Sangzhi alkaloid (SZ-A) is a novel natural alkaloid extracted from the mulberry branches, has extensive pharmacological effects and stable pharmacokinetic characteristics. However, the effects and mechanisms of SZ-A on AS remain unclear. PURPOSE: To explore the effect and underlying mechanisms of SZ-A on inflammation mediated by macrophages and its role in AS development. METHODS: Atherosclerosis was induced in vivo in apolipoprotein E-deficient mice through a high-fat and high-choline diet. We utilized macrophages and vascular endothelial cells to investigate the effects of SZ-A on macrophage polarization and its anti-inflammatory properties on endothelial cells in vitro. The transcriptomic analyses were used to investigate the major molecule that mediates cell-cell interactions and the antiatherogenic mechanisms of SZ-A based on AS, subsequently validated in vivo and in vitro. RESULTS: SZ-A demonstrated a significant inhibition in vascular inflammation and alleviation of AS severity by mitigating macrophage infiltration and modulating M1/M2 macrophage polarization in vitro and in vivo. Moreover, SZ-A effectively reduced the release of the proinflammatory mediator C-X-C motif chemokine ligand (CXCL)-10, predominantly secreted by M1 macrophages. This reduction in CXCL-10 contributed to improved endothelial cell function, reduced recruitment of additional macrophages, and inhibited the inflammatory amplification effect. This ultimately led to the suppression of atherogenesis. CONCLUSION: SZ-A exhibited potent anti-inflammatory effects by inhibiting macrophage-mediated inflammation, providing a new therapeutic avenue against AS. This is the first study demonstrating the efficacy of SZ-A in alleviating AS severity and offers novel insights into its anti-inflammatory mechanism.

Assessment of the response characteristics of pollution load in Huntai Basin under climate change.

This study establishes a calibrated SWAT (Soil and Water Assessment Tool) model for the Huntai Basin, driven by SSP126, SSP245, SSP585, and multi-model ensemble (MME) models in CMIP6 (Coupled Model Intercomparison Project-6), to investigate the effects of climate change on hydrological processes and pollution load in the Huntai Basin. The results show that the annual mean temperature and the annual precipitation will gradually increase. The nitrogen and phosphorus pollution loads in the basin exhibit a trend of decreasing-increasing-decreasing. The correlation between the nitrogen-phosphorus pollution load and the hydrological process strengthens with increasing radiative forcing. In the four scenarios, CO2 is a primary driving factor that contributes greatly to nitrogen and phosphorus pollution. The main differences are in the total driving factors, and SSP126 and SSP245 are less than those of other models. The total phosphorus and total nitrogen pollution in different climate models were higher than the average level during the benchmark period, except for ammonia nitrogen pollution, which was lower. The nitrogen and phosphorus pollution in SSP126 and SSP245 modes will reach the maximum in 2040s, and the pollution in other periods will be lower than that in SSP585 and MME scenarios. In the long run, the development state between SSP126 and SSP245 may be better appropriate for the Huntai Basin's future sustainable development. This paper analyzes the occurrence and influencing factors of nitrogen and phosphorus pollution under climate change to provide reference to the protection of water environment under changing environments.

Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors.

Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R-MC5R). The structural basis of subtype selectivity of the endogenous agonist γ-MSH and non-selectivity of agonist α-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R-Gs in complex with γ-MSH and MC5R-Gs in the presence of α-MSH or a potent synthetic agonist PG-901. The structures reveal that α-MSH and γ-MSH adopt a "U-shape" conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with MCRs via the HFRW motif. The C-terminus of γ-MSH occupies an MC3R-specific complementary binding groove likely conferring subtype selectivity, whereas that of α-MSH distances itself from the receptor with neglectable contacts. PG-901 achieves the same potency as α-MSH with a shorter length by rebalancing the recognition site and mimicking the intra-peptide salt bridge in α-MSH by cyclization. Solid density confirmed the calcium ion binding in MC3R and MC5R, and the distinct modulation effects of divalent ions were demonstrated. Our results provide insights into ligand recognition and subtype selectivity among MCRs, and expand the knowledge of signal transduction among MCR family members.

The Effects of Foot Reflexology on Vital Signs: A Meta-Analysis of Randomized Controlled Trials.

Introduction: We evaluated the effects of foot reflexology on bodily vital signs. Methods: Randomized controlled trials (RCTs) evaluating the effects of foot reflexology on vital signs were collected for a meta-analysis. Statistical analysis was conducted using RevMan5.4 software and pooled estimates of the effects were reported as mean differences (MDs) with 95% confidence intervals (CIs). Results: Thirteen studies, including 819 patients, met our inclusion criteria. Our results showed that systolic blood pressure (SBP) (MD = -4.62, 95% CI: -5.58 to -3.66; P < 0.00001), diastolic blood pressure (DBP) (MD = -3.32, 95% CI: -4.48 to -2.17; P < 0.00001), heart rate (HR) (MD = -4.76, 95% CI: -6.49 to -3.04; P < 0.00001), respiratory rate (RR) (MD = -0.77, 95% CI: -1.50 to -0.48; P < 0.00001), and pulse oxygen saturation (SpO2) (MD = 0.95, 95% CI: 0.39 to 1.52; P = 0.0009) showed statistical significance in the foot reflexology group. Conclusions: Short-term followup results showed that foot reflexology exerted positive effects on vital signs, reduced BP, HR, and RR and increased SpO2.

Control the greenhouse gas emission via mediating the dissimilatory iron reduction: Fulvic acid inhibit secondary mineralization of ferrihydrite.

Reducing methane emission is of great importance to control the global greenhouse effect. Dissimilatory iron reduction (DIR) coupling of organic matter decomposition may suppress methane production via reducing primary electron donors available for methanogenesis. However, during DIR, the amorphous iron oxides (e.g., ferrihydrite) are easy to transform into more stable crystalline iron minerals, which slowdowns the rate of DIR. Humic substance (HS) with redox activity has been extensively reported to facilitate DIR via "electron shuttles" mechanism, yet little known about the effect of HS on mediating the mineralization of iron oxides and the subsequent influences on DIR and methanogenesis. To clarify this, ferrihydrite and fulvic acid (FA) (as the model substance of HS) were supplied to anaerobic methanogenesis systems. Results showed that FA could significantly decrease the formation of crystalline iron oxides, enhance DIR rate by 13.72% and suppress methanogenesis by 25.13% compared to ferrihydrite supplemented only. By X-ray absorption spectra analysis, it was found that FA could complex with ferrihydrite via forming a Fe-C/O structure on the second shell of Fe atom. Quantum chemical calculation further confirmed that FA reduced the adsorption energy between Fe(II) and ferrihydrite. Our study suggested that rational use of HS to mediate mineralization pathway of iron oxides could efficiently improve the availability of iron oxides to drive DIR and control the conversion of organics into CH4 in natural or engineered systems.

TCPP-Isoliensinine Nanoparticles for Mild-Temperature Photothermal Therapy.

PURPOSE: Photothermal therapy (PTT) is promising for the treatment of tumors due to its advantages including minimally invasive, easy implementation and selective localized treatment. However, single PTT suffers from several limitations, such as constrained light penetration and low delivery efficiency, typically leading to heterogeneous heating and incomplete elimination of cancer cells. Therefore, combination of PTT with other therapies, eg, chemotherapy is desirable in order to achieve synergistic effects in cancer treatment. METHODS: Here, we designed a new type of TCPP-Iso combined nanoparticle for synergetic therapy for breast cancer. Specifically, photothermal agent tetra(4-carboxyphenyl) porphine (TCPP) and anti-cancer drug isoliensinine (Iso) were encapsulated in PEG-b-PLGA polymeric nanoparticles through a precipitation process. RESULTS: The obtained NPs displayed well-controlled size and high stability over time. Tuning TCPP-Iso/polymer ratio, or total concentration of drug and polymers led to increased hydrodynamic radius of NPs from 65 to 108 nm without disturbing the narrow size distribution. Besides, the formed NPs showed a consequently cumulative release of TCPP and of Iso. The temperature elevation ability of both TCPP NPs and TCPP-Iso NPs was TCPP-concentration dependent. Solutions of TCPP NPs that contained equivalent amount of TCPP with respect to TCPP-Iso NPs, presented the same trend and exhibited non-obvious difference in temperature elevation under certain laser power. The viability of MDA-MB-231 cells treated with TCPP-Iso NPs could be inhibited effectively at a relatively mild temperature (42-43°C) compared to the other groups, which may minimize heat damage to the surrounding healthy tissues. CONCLUSION: The results indicate that the TCPP-Iso combined NPs showed hardly any toxicity to normal tissue cell line, but displayed an efficient synergistic effect for killing cancer cells under laser irradiation. Our study demonstrates that the successful combination of TCPP and Iso realized a synergistic therapy effect at a relatively mild temperature, and the insights obtained here shall be helpful for designing new combined PTT agents for cancer treatment.

Enhancing anaerobic digestion of kitchen wastes via combining ethanol-type fermentation with magnetite: Potential for stimulating secretion of extracellular polymeric substances.

Magnetite, a common mineral that is abundant in the soils and sediments, has been widely documented to enhance the anaerobic digestion of organic wastes, whereas the mechanisms of magnetite promoting interspecies electron transfer are still unclear. In this study, under the conditions (ethanol-type fermentation) employed, magnetite stimulated the secretion of extracellular polymeric substances (EPS). Analysis of three-dimensional excitation emission matrix revealed that these EPS secreted in the presence of magnetite were primarily comprised of the redox-active organic functional groups. Electrochemical analysis showed that the EPS secreted with magnetite had the higher electron-accepting and electron-donating capacity than the EPS without magnetite. Syntrophomonas species capable of extracellularly transferring electron were enriched with supplementing magnetite. Together with the increased abundance of Methanospirillum and Methanobacterium species that could proceed direct interspecies electron transfer (DIET), the anaerobic digestion was likely improved due to the establishment of DIET with supplementing magnetite. As a result, anaerobic digestion of kitchen wastes was evidently enhanced. With decreasing the solid retention time to 30 d, the methane production rate only slightly declined to 18 ± 0.8 mL/g-VSS/d in the magnetite-supplemented digester, while almost no methane was detected in the digester without magnetite.

Magnetite-contained biochar derived from fenton sludge modulated electron transfer of microorganisms in anaerobic digestion.

Biochar, with redox moieties or conjugated π-bond, can act as electron shuttle or conductor to facilitate electron transfer of syntrophic metabolism to enhance anaerobic digestion. High pyrolysis temperature (>500 â„ƒ) is usually required to prepare conductive biochar, which however may cause biochar to loss redox moieties such as quinone/hydroquinone that are capable of serving as electron shuttle. Considering that magnetite is an excellent conductor which has been applied in improving syntrophic metabolism of anaerobic digestion, a novel magnetite-contained biochar was prepared using iron-rich Fenton sludge as raw material in this study. Amorphous iron oxides of Fenton sludge were transformed into magnetite at 400 â„ƒ of pyrolysis, while redox quinone/hydroquinone moieties of biochar were preserved well. Correspondingly, this magnetic biochar owned both high capacitance and excellent conductivity. When supplementing the biochar into an anaerobic digestion system, methane production was significantly enhanced. This study also offered a new approach to recycle Fenton sludge that is regarded as hazardous material.

Correction to "A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts".

[This corrects the article DOI: 10.1021/acscentsci.9b01125.].

A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts.

Subtype selectivity and functional bias are vital in current drug discovery for G protein-coupled receptors (GPCRs) as selective and biased ligands are expected to yield drug leads with optimal on-target benefits and minimal side-effects. However, structure-based design and medicinal chemistry exploration remain challenging in part because of highly conserved binding pockets within subfamilies. Herein, we present an affinity mass spectrometry approach for screening herbal extracts to identify active ligands of a GPCR, the 5-HT2C receptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT2C without activating the 5-HT2A or 5-HT2B receptors. Remarkably, this novel ligand exhibited exclusive bias toward G protein signaling for which key residues were identified, and it showed comparable in vivo efficacy for food intake suppression and weight loss as the antiobesity drug, lorcaserin. Our study establishes an efficient approach to discovering novel GPCR ligands by exploring the largely untapped chemical space of natural products.

Enhancing methanogenesis from anaerobic digestion of propionate with addition of Fe oxides supported on conductive carbon cloth.

In this study, a Fe2O3 supported on conductive carbon cloth (FC) was prepared and supplemented into anaerobic digestion reactors to improve propionate degradation. In the FC-supplemented reactors, the cumulative methane production and propionate degradation increased by 15.4% and 19.67% compared with those of the control, respectively. Less methane production with H2/CO2 as the sole substrate in the culture taken from the FC reactors suggested that interspecies hydrogen transfer in the FC reactors was weaker. These results suggested that direct interspecies electron transfer (DIET) was established in the FC reactors to improve the performance. Fe2O3 increased the secretion of electron shuttle components of extracellular polymeric substances to increase electron exchange capacity of biomass of the FC reactors, which further facilitated the DIET. Analysis on microbial communities confirmed that the abundance of microorganisms-related DIET in the FC reactors was higher than that in the control.

Beneficial effects of green tea on age related diseases.

Green tea (Camellia sinensis, Theaceace), has been extensively studied for its putative effects in prevention of age related diseases. Here, we discuss the increasing evidence that consumption of green tea has preventative effects in obesity, hypertension, insulin resistance, type II diabetes, atherosclerosis, coronary heart disease and Metabolic Syndrome (MetS). The catechins in green tea has been found to be beneficial in obesity induced by a high-fat diet. These effects are mainly attributable to the gallate esters of catechins, (-)-epicatechin gallate (ECG) and (-)-epigallocatechin-3- gallate (EGCG).

Monitoring the Early Response of Fulvestrant Plus Tanshinone IIA Combination Therapy to Estrogen Receptor-Positive Breast Cancer by Longitudinal 18F-FES PET/CT.

Endocrine monotherapy of breast cancers is generally hampered by the primary/acquired resistance and adverse sides in clinical settings. Herein, advantaging the multitargeting antitumor effects and normal organ-protecting roles of Chinese herbal medicine, the aim of this study was to investigate the enhanced synergistic efficacy of fulvestrant plus Tan IIA combination therapy in ER-positive breast cancers and to monitor the early response by longitudinal 18F-FES PET/CT imaging. The experimental results showed FUL + Tan IIA combination therapy significantly inhibited tumor growth of ER-positive ZR-75-1 tumor xenografts and exhibited distinct antitumor effects at an earlier time point after treatment than did the monotherapy of FUL or Tan IIA. Moreover, 18F-FES PET/CT imaging competently monitored the early response of FUL + Tan IIA combination therapy. The quantitative 18F-FES %ID/gmax in vivo was further confirmed by and correlated well with ERα expression ex vivo. In conclusion, the synergic effect of FUL + Tan IIA combination therapy to ER-positive breast cancers was verified in the preclinical tumor models and the early treatment response could be monitored by 18F-FES PET/CT.

Salvianolic Acid B Ameliorates Cognitive Deficits Through IGF-1/Akt Pathway in Rats with Vascular Dementia.

BackgroundAims: Salvianolic acid B (SalB) is a natural polyphenolic compound enriched in Salvia miltiorrhiza Bunge. Our study was designed to explore the role of Sal B on cognitive impairment in vascular dementia (VD) model rats, as well as its possible molecular mechanisms. METHODS: Rats were randomly divided into four groups (n = 15 for each group): Control group, Sal B group (normal Sprague Dawley rats treated with Sal B), VD group and VD + Sal B group. The VD group rats were established by permanent bilateral common carotid artery occlusion (BCCAO). Animals in the Control and Sal B group received the same operation without bilateral common carotid arteries occlusion. The animals in Sal B group and VD + Sal B group received Sal B (20 mg/kg) orally once a day for consecutive 6 weeks. We investigated the effects of SalB on BCCAO-induced cognitive deficits rats models via the Morris water maze experiment. To explore the mechanisms of Sal B on cognitive function, we detected the expression of IGF-1, Akt and p-Akt, and the rate of cell apoptosis in CA1 region. RESULTS: Our results observed that hippocampal IGF-1 was decreased in VD model rats, while SalB reversed the alteration of IGF-1 levels. The expression of hippocampal Akt showed no significant difference between control and VD group, however, p-Akt level was significantly decreased in VD group. After 6 weeks of SalB treatment, p-Akt level was significantly increased. A large number of apoptotic neurons were found in VD model rats, while SalB prevented apoptosis of hippocampal neurons in CA1 region in VD model rats. CONCLUSION: SalB significantly ameliorated cognitive deficits in BCCAO-induced VD model rats. The potential mechanism underlying the protective effects may be mediated through IGF-1/Akt pathway.

Amelioration of cognitive impairments in APPswe/PS1dE9 mice is associated with metabolites alteration induced by total salvianolic acid.

PURPOSE: Total salvianolic acid (TSA) is extracted from salvia miltiorrhiza; however, to date, there has been limited characterization of its effects on metabolites in Alzheimer's disease model-APPswe/PS1dE9 mice. The main objective of this study was to investigate the metabolic changes in 7-month-old APPswe/PS1dE9 mice treated with TSA, which protects against learning and memory impairment. METHODS: APPswe/PS1dE9 mice were treated with TSA (30 mg/kg·d and 60 mg/kg·d, i.p.) and saline (i.p.) daily from 3.5 months old for 14 weeks; saline-treated (i.p.) WT mice were included as the controls. The effects of TSA on learning and memory were assessed by a series of behavioral tests, including the NOR, MWM and step-through tasks. The FBG and plasma lipid levels were subsequently assessed using the GOPOD and enzymatic color methods, respectively. Finally, the concentrations of Aß42, Aß40 and metabolites in the hippocampus of the mice were detected via ELISA and GC-TOF-MS, respectively. RESULTS: At 7 months of age, the APPswe/PS1dE9 mice treated with TSA exhibited an improvement in the preference index (PI) one hour after the acquisition phase in the NOR and the preservation of spatial learning and memory in the MWM. Treatment with TSA substantially decreased the LDL-C level, and 60 mg/kg TSA decreased the CHOL level compared with the plasma level of the APPswe/PS1dE9 group. The Aß42 and Aß40 levels in the hippocampus were decreased in the TSA-treated group compared with the saline-treated APPswe/PS1dE9 group. The regulation of metabolic pathways relevant to TSA predominantly included carbohydrate metabolism, such as sorbitol, glucose-6-phosphate, sucrose-6-phosphate and galactose, vitamin metabolism involved in cholecalciferol and ascorbate in the hippocampus. CONCLUSIONS: TSA induced a remarkable amelioration of learning and memory impairments in APPswe/PS1dE9 mice through the regulation of Aß42, Aß40, carbohydrate and vitamin metabolites in the hippocampus and LDL-C and CHOL in the plasma.

Polydopamine-Functionalized Graphene Oxide Loaded with Gold Nanostars and Doxorubicin for Combined Photothermal and Chemotherapy of Metastatic Breast Cancer.

Breast cancer is the leading cancer type diagnosed in the female population, and cancer metastasis is the main reason for cancer-caused mortality. A novel nanoplatform is herein presented integrating polydopamine-functionalized nanosized reduced graphene oxide (NRGO), gold nanostars (GNS), and doxorubicin (DOX) (denoted as NRGO-GNS@DOX) for combinational treatment of metastatic breast cancer. Upon localized near infrared (NIR) laser irradiation, the NRGO-GNS@DOX nanocomposites induce significant cytotoxicity in 4T1 breast cancer cells due to a cumulative therapy effect of NRGO-GNS-elicited hyperthermia and DOX-induced cytotoxicity. Antitumor studies in orthotopic 4T1 breast tumor-bearing nude mice demonstrate that NRGO-GNS@DOX in combination with NIR laser irradiation inhibit the tumor growth and suppress the lung metastasis. Contribution of DOX-caused apoptosis of the cancer cells and hyperthermia-induced deconstruction of the tumor-associated blood vessels may account for the superior antitumor performance of the NRGO-GNS@DOX nanocomposites. These results imply a good potential of NRGO-GNS@DOX for combined photothermal and chemotherapy of the metastatic cancer.

High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis.

BACKGROUND: Schistosomiasis, a parasitic disease also known as bilharzia and snail fever, is caused by different species of flatworms, such as Schistosoma mansoni (S. mansoni). Thioredoxin glutathione reductase (TGR) from S. mansoni (SmTGR) is a well-characterized drug target for schistosomiasis, yet no anti-SmTGR compounds have reached clinical trials, suggesting that therapeutic development against schistosomiasis might benefit from additional scaffolds targeting this enzyme. METHODS: A high-throughput screening (HTS) assay in vitro against SmTGR was developed and applied to a diverse compound library. SmTGR activity was quantified with ThioGlo®, a reagent that fluoresces upon binding to the free sulfhydryl groups of the reaction product GSH (reduced glutathione). RESULTS: We implemented an HTS effort against 59,360 synthetic compounds. In the primary screening, initial hits (928 or 1.56 %) showing greater than 90 % inhibition on SmTGR activity at a final concentration of 10 µM for each compound were identified. Further tests were carried out to confirm the effects of these hits and to explore the concentration-dependent response characteristics. As a result, 74 of them (0.12 %) representing 17 chemical scaffolds were confirmed and showed a great concentration-dependent inhibitory trend against SmTGR, including structures previously shown to be lethal to schistosomal growth. Of these, two scaffolds displayed a limited structure-activity relationship. When tested in cultured larvae, 39 compounds had cidal activity in 48 h, and five of them killed larvae completely at 3.125 µM. Of these, three compounds also killed adult worms ex vivo at concentrations between 5 µM and 10 µM. CONCLUSION: These confirmed hits may serve as starting points for the development of novel therapeutics to combat schistosomiasis.

High-throughput screening of antagonists for the orphan G-protein coupled receptor GPR139.

AIM: To discover antagonists of the orphan G-protein coupled receptor GPR139 through high-throughput screening of a collection of diverse small molecules. METHODS: Calcium mobilization assays were used to identify initial hits and for subsequent confirmation studies. RESULTS: Five small molecule antagonists, representing 4 different scaffolds, were identified following high-throughput screening of 16 000 synthetic compounds. CONCLUSION: The findings provide important tools for further study of this orphan G-protein coupled receptor.

Tungsten oxide nanorods: an efficient nanoplatform for tumor CT imaging and photothermal therapy.

We report here a facile thermal decomposition approach to creating tungsten oxide nanorods (WO2.9 NRs) with a length of 13.1 ± 3.6 nm and a diameter of 4.4 ± 1.5 nm for tumor theranostic applications. The formed WO2.9 NRs were modified with methoxypoly(ethylene glycol) (PEG) carboxyl acid via ligand exchange to have good water dispersability and biocompatibility. With the high photothermal conversion efficiency irradiated by a 980 nm laser and the better X-ray attenuation property than clinically used computed tomography (CT) contrast agent Iohexol, the formed PEGylated WO2.9 NRs are able to inhibit the growth of the model cancer cells in vitro and the corresponding tumor model in vivo, and enable effective CT imaging of the tumor model in vivo. Our "killing two birds with one stone" strategy could be extended for fabricating other nanoplatforms for efficient tumor theranostic applications.