Identifying the natural products in the treatment of atherosclerosis by increasing HDL-C level based on bioinformatics analysis, molecular docking, and in vitro experiment.

BACKGROUND: Previous studies have demonstrated that high-density lipoprotein cholesterol (HDL-C) plays an anti-atherosclerosis role through reverse cholesterol transport. Several studies have validated the efficacy and safety of natural products in treating atherosclerosis (AS). However, the study of raising HDL-C levels through natural products to treat AS still needs to be explored. METHODS: The gene sets associated with AS were collected and identified by differential gene analysis and database query. By constructing a protein-protein interaction (PPI) network, the core submodules in the network are screened out. At the same time, by calculating node importance (Nim) in the PPI network of AS disease and combining it with Kyoto Encyclopedia of genes and genomes (KEGG) pathways enrichment analysis, the key target proteins of AS were obtained. Molecular docking is used to screen out small natural drug molecules with potential therapeutic effects. By constructing an in vitro foam cell model, the effects of small molecules on lipid metabolism and key target expression of foam cells were investigated. RESULTS: By differential gene analysis, 451 differential genes were obtained, and a total of 313 disease genes were obtained from 6 kind of databases, then 758 AS-related genes were obtained. The enrichment analysis of the KEGG pathway showed that the enhancement of HDL-C level against AS was related to Lipid and atherosclerosis, Cholesterol metabolism, Fluid shear stress and atherosclerosis, PPAR signaling pathway, and other pathways. Then we intersected 31 genes in the core module of the PPI network, the top 30 genes in Nims, and 32 genes in the cholesterol metabolism pathway, and finally found 3 genes. After the above analysis and literature collection, we focused on the following three related gene targets: APOA1, LIPC, and CETP. Molecular docking showed that Genistein has a good binding affinity for APOA1, CETP, and LIPC. In vitro, experiments showed that Genistein can up-regulated APOA1, LIPC, and CETP levels. CONCLUSIONS: Based on our research, Genistein may have the effects of regulating HDL-C and anti-atherosclerosis. Its mechanism of action may be related to the regulation of LIPC, CETP, and APOA1 to improve lipid metabolism.

Using Machine Learning to Leverage Biomarker Change and Predict Colorectal Cancer Recurrence.

PURPOSE: The risk of colorectal cancer (CRC) recurrence after primary treatment varies across individuals and over time. Using patients' most up-to-date information, including carcinoembryonic antigen (CEA) biomarker profiles, to predict risk could improve personalized decision making. METHODS: We used electronic health record data from an integrated health system on a cohort of patients diagnosed with American Joint Committee on Cancer stage I-III CRC between 2008 and 2013 (N = 3,970) and monitored until recurrence or end of follow-up. We addressed missingness in recurrence outcomes and longitudinal CEA measures, and engineered CEA features using current and past biomarker values for inclusion in a risk prediction model. We used a discrete time Superlearner model to evaluate various algorithms for predicting recurrence. We evaluated the time-varying discrimination and calibration of the algorithms and assessed the role of individual predictors. RESULTS: Recurrence was documented in 448 (11.3%) patients. XGBoost with depth = 1 (XGB-D1) predicted recurrence substantially better than all other algorithms at all time points, with AUC ranging from 0.87 (95% CI, 0.86 to 0.88) at 6 months to 0.94 (95% CI, 0.92 to 0.96) at 54 months. The only variable used by XGB-D1 was 6-month change in log CEA. Predicted 1-year risk of recurrence was nearly zero for patients whose log CEA did not increase in the last 6 months, between 12.2% and 34.1% for patients whose log CEA increased between 0.10 and 0.40, and 43.6% for those with a log CEA increase >0.40. Compared with XGB, penalized regression approaches (lasso, ridge, and elastic net) performed poorly, with AUCs ranging from 0.58 to 0.69. CONCLUSION: A flexible, machine learning approach that incorporated longitudinal CEA information yielded a simple and high-performing model for predicting recurrence on the basis of 6-month change in log CEA.

Iron and Steel Industry Emissions: A Global Analysis of Trends and Drivers.

The iron and steel industry (ISI) is important for socio-economic progress but emits greenhouse gases and air pollutants detrimental to climate and human health. Understanding its historical emission trends and drivers is crucial for future warming and pollution interventions. Here, we offer an exhaustive analysis of global ISI emissions over the past 60 years, forecasting up to 2050. We evaluate emissions of carbon dioxide and conventional and unconventional air pollutants, including heavy metals and polychlorinated dibenzodioxins and dibenzofurans. Based on this newly established inventory, we dissect the determinants of past emission trends and future trajectories. Results show varied trends for different pollutants. Specifically, PM2.5 emissions decreased consistently during the period 1970 to 2000, attributed to adoption of advanced production technologies. Conversely, NOx and SO2 began declining recently due to stringent controls in major contributors such as China, a trend expected to persist. Currently, end-of-pipe abatement technologies are key to PM2.5 reduction, whereas process modifications are central to CO2 mitigation. Projections suggest that by 2050, developing nations (excluding China) will contribute 52-54% of global ISI PM2.5 emissions, a rise from 29% in 2019. Long-term emission curtailment will necessitate the innovation and widespread adoption of new production and abatement technologies in emerging economies worldwide.

Hyperoside attenuates pyrrolizidine alkaloids-induced liver injury by ameliorating TFEB-mediated mitochondrial dysfunction.

Pyrrolizidine alkaloids (PAs) are potent hepatotoxins that can cause liver damage. Hyperoside (Hyp), a natural flavonoid, can be extracted from medicinal plants. Hyp displays hepatoprotective activity in various liver diseases. However, the potential effect and mechanism of action of Hyp in ameliorating PA-induced liver injury remain obscure. This study aimed to explore the protective effect of Hyp against PA-induced hepatotoxicity and its underlying mechanism. We established an in vitro model of PAs in mouse primary hepatocytes and developed a mouse model of acute PA toxicity to investigate the protective effect of Hyp. We found that Hyp notably attenuated PA-induced hepatotoxicity. RNA-sequencing showed that the beneficial effect of Hyp against PA-induced hepatotoxicity was associated with the transcription factor EB (TFEB)-peroxisome proliferator-activated receptor-γ coactivator-1-α (PGC1α) pathway. Our results confirmed that both the autophagy-lysosomal pathway and mitochondrial biogenesis were induced by Hyp through TFEB nuclear translocation in PA-induced liver injury. Furthermore, we demonstrated that activation of the mechanistic target of rapamycin complex 1 (mTORC1) by MHY 1485 decreased TFEB nuclear translocation and abrogated the protective effect of Hyp against PA-induced liver injury in mice. In contrast, inhibition of mTORC1 activity increased the level of TFEB and reduced hepatotoxicity induced by PAs in mouse livers. Likewise, Hyp-induced TFEB activation was validated in vitro. In conclusion, Hyp can activate the TFEB-mediated autophagy-lysosomal pathway and mitochondrial biogenesis through inhibition of mTORC1 activity, alleviating the liver injury induced by PAs, thus suggesting the potential value of Hyp in the treatment of PA-induced hepatotoxicity.

Underutilization or appropriate care? Assessing adjuvant chemotherapy use and survival in 3 heterogenous subpopulations with stage II/III colorectal cancer within a large integrated health system.

BACKGROUND: Clinical guidelines have recommended adjuvant chemotherapy (ACT) for patients with high-risk stage II colon cancer, although the survival benefit is unclear. ACT is also recommended for patients with stage III colon cancer to reduce the risk of recurrence and mortality. For stage II/III rectal cancer, however, the role of perioperative chemotherapy (PCT, adjuvant or neoadjuvant) remains controversial, resulting in substantial variation in its use in clinical practice. OBJECTIVES: To understand real-world use and predictors of ACT or PCT use and survival outcomes in 3 heterogeneous patient groups with colorectal cancer (CRC), and to inform the evidence gap between guideline-based care and clinical practice. METHODS: This retrospective cohort study included patients with an initial stage II/III CRC diagnosis between 2008 and 2013 identified from Kaiser Permanente Southern California electronic health record databases. Patients were eligible if they were aged 18-74 years at diagnosis and received primary curative surgery. We fitted mixed effects logistic regression models to evaluate predictors of ACT receipt and Cox proportional hazards models on propensity score-matched (PS-matched) samples to assess the association between ACT/PCT receipt and survival. RESULTS: We included 1,690 patients with colon cancer (stage II: 820 and stage III: 870) and 587 patients with rectal cancer (stage II: 241 and stage III: 346). We found that 65% of patients with high-risk stage II colon cancer, 15% of those with stage III colon, and 15% of those with stage II/III rectal cancer did not receive ACT/PCT. Patients with stage II colon cancer with T4 stage (odds ratio [OR] = 5.79, 95% CI = 3.33 - 10.06) and a lower comorbidity score were more likely to receive ACT (high vs low Charlson score: OR = 0.69, 95% CI = 0.55 - 0.87). Patients with stage III rectal cancer were more likely to receive PCT than those with stage II disease (OR = 7.85, 95% CI = 2.07 - 29.74). Patients with another cancer diagnosis prior to CRC diagnosis were less likely to receive PCT (OR = 0.37, 95% CI = 0.16 - 0.85). ACT/PCT use was associated with improved overall survival among patients with high-risk stage II colon cancer (PS-matched hazard ratio [HR] = 0.42, 95% CI = 0.25 - 0.70) and those with stage III CRC (stage III colon: PS-matched HR = 0.3, 95% CI = 0.25 - 0.36; stage III rectal: PS-matched HR = 0.2, 95% CI = 0.13 - 0.31). CONCLUSIONS: We found potential underuse of appropriate chemotherapy treatment in patients with high-risk stage II colon cancer and stage III CRC. Clinicians' and providers' decisions on ACT administration may not be fully guided by the risk of recurrence and 5-year survival benefits in stage II colon cancer. DISCLOSURES: This research was supported by the National Cancer Institute of the National Institutes of Health (NIH) (under R37-CA218413). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Effect of acupuncture in the acute phase of intracerebral hemorrhage on the prognosis and serum BDNF: a randomized controlled trial.

Background: Intracerebral hemorrhage (ICH) is a common cerebrovascular disease, with a high rate of disability. In the literature on Chinese traditional medicine, there is increasing evidence that acupuncture can help hematoma absorption and improve neurological deficits after cerebral hemorrhage. Brain-derived neurotrophic factor (BDNF), one of the most studied neurotrophic factors, is involved in a variety of neurological functions and plays an important role in brain injury recovery. We investigated the effect of acupuncture intervention in the acute phase of ICH on the prognosis and serum BDNF levels of several patient groups. Objective: To investigate the influence of acupuncture on the prognosis and brain-derived neurotrophic factor (BDNF) levels in patients in the acute phase of ICH. Methods: From November 2021 to May 2022, 109 subjects were consecutively enrolled, including patients with ICH, who were randomized into the acupuncture group (AG) and sham acupuncture group (SAG), and a control group (CG). The CG received the same acupuncture intervention as the AG, and the SAG received sham acupuncture, with 14 interventions in each group. The level of consciousness of patients with ICH was assessed and serum BDNF levels were measured in all three groups before the intervention and at 3 weeks after onset, and the level of consciousness and outcomes were assessed at 12 weeks after onset. Results: After the intervention, the level of consciousness of the AG improved significantly (P < 0.05); the BDNF level of only the AG increased significantly (P < 0.05); the changes in Glasgow Coma Scale (GCS) score and BDNF level were significantly greater in the AG than in the SAG (P < 0.05), especially for locomotion (P < 0.05). At 12 weeks post-onset, the AG showed better outcomes and recovery of consciousness than the SAG (P < 0.05).

Swelling of Multilayered Calcium Alginate Microspheres for Drug-Loaded Dressing Induced Rapid Lidocaine Release for Better Pain Control.

The development of effective drug-loaded dressings has been considered a hot research topic for biomedical therapeutics, including the use of botanical compounds. For wound healing, adequate dressings can provide a good microenvironment for drug release, such as lidocaine. Biological macromolecular materials such as alginate show excellent properties in wound management. This study involves the preparation and evaluation of biocompatible multilayered-structure microspheres composed of chitosan, porous gelatin, and calcium alginate microspheres. The multilayered structure microspheres were named chitosan@ porous gelatin@ calcium alginate microspheres (CPAMs) and the drugs were rapidly released by the volume expansion of the calcium alginate microspheres. The in vitro release curve revealed that the peak release of lidocaine from CPAMs was reached within 18[Formula: see text]min. After 21[Formula: see text]min, the remaining lidocaine was then slowly released, and the active drug release was converted to a passive drug release phase. The initial release effect of lidocaine was much better than that reported in the published studies. Additionally, blood coagulation experiments showed that CPAMs coagulated blood in 60[Formula: see text]s, and the blood liquidity of the CPAMs group was worse than that of the woundplast group. Therefore, the coagulation characteristics of CPAMs were superior to the commonly used woundplast containing lidocaine healing gel. These study outcomes indicated that the CPAMs acted as fast-release dressings for faster pain control and better coagulation properties.

Chinese Herbal Medicines Have Potentially Beneficial Effects on the Perinatal Outcomes of Pregnant Women.

Introduction: Tocolytic treatment is beneficial to pregnant women with a risk of premature labor or miscarriage. However, previous reports have shown that progestogen might not be effective and ritodrine may increase the risk of maternal vascular-related diseases. Chinese herbal products (CHP) are used as alternative therapies for pregnant women. The goal was to evaluate the efficacy of combined tocolytic therapy and CHP therapy in pregnancy outcomes for pregnant women in Taiwan. Materials and Methods: We conducted a retrospective cohort study based on the National Health Insurance Research Database. A total of 47,153 pregnant women treated with tocolytics aged 18-50 years from 2001 to 2015 were selected from two million random samples. According to the medical use of tocolytics and CHP, we divided the users into two groups: western medicine (WM) only (n = 40,961) and WM/CHP (n = 6,192) groups. A propensity score (PS)-matched cohort (6,192 pairs) was established based on baseline confounders. All participants were followed up to perinatal outcomes. Conditional logistic regression analysis was used to examine the effects of CHP use on the odds of miscarriage and preterm birth. Results: The adjusted odds ratio (OR) for premature birth in the WM/CHP group (n = 411, 6.64%) was significantly lower than in the WM group (n = 471, 7,61%) (0,86, 95% confidence interval [CI], 0.74-0.99). Further subgroup analysis based on the usage of formulae that activate blood and remove stasis or purgative formulae, the adjusted OR of preterm birth of those using these formulae was significantly lower in the WM/CHP group (n = 215, 6.32%) than that in the WM group (n = 265, 7.77%) (OR: 0.79, 95% CI: 0.65-0.96). Conclusion: We found that the combination of CHP and tocolytics can be beneficial to pregnant women in the prevention of premature birth. Further research is required to investigate causal relationships.

Modulation effect of acupuncture treatment on chronic neck and shoulder pain in female patients: Evidence from periaqueductal gray-based functional connectivity.

AIMS: Chronic neck and shoulder pain (CNSP) is a common neurological disorder, which females are more likely to suffer from. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. This study aimed to investigate altered PAG-based functional connectivity (FC) in female patients with CNSP related to healthy controls (HCs) and the effect of acupuncture for female patients with CNSP using PAG-based FC biomarkers. METHODS: PAG-based FC value was calculated based on resting-state functional images and then compared between patients with CNSP at pre-acupuncture, post-acupuncture, and HCs. Then, correlational analyses were performed to examine the relationships between increased PAG-based FC strength and improved clinical parameters in patients after acupuncture treatment. RESULTS: Before acupuncture treatment, compared to HCs, patients with CSNP showed altered PAG-based FC with widely distributed brain regions, including the left medial superior frontal gyrus, bilateral posterior insula (pIns), and cingulate gyrus. After treatment, patients with CNSP exhibited specially improved PAG-pIns FC compared to that before treatment, and no significant difference was observed in the increased PAG-pIns FC strength between HCs and patients with CNSP after treatment. Furthermore, pain catastrophizing reduction was significantly correlated with the increased PAG-pIns FC strength in patients after treatment. CONCLUSION: The effect of acupuncture treatment may relate to the increased PAG-pIns FC, which significantly correlated with pain catastrophizing reduction after treatment. These findings shed important mechanistic information on the role of therapeutic approaches in treating chronic neck and shoulder pain.

Characterization of natural herbal medicines by thin-layer chromatography combined with laser ablation-assisted direct analysis in real-time mass spectrometry.

The characterization and quality control of natural herbal medicines, such as traditional Chinese medicines (TCMs), is of great significance to ensure their potential efficacy and avoid severe side effects. Thin-layer chromatography (TLC) is a simple and classic approach for examining quality marker of natural products. Nevertheless, it is more difficult to further characterize the compounds adsorbed on the TLC plate. Herein, we reported a simple setup of laser ablation-assisted direct analysis in real-time mass spectrometry (LA-DART-MS), in which the coupling of mass spectrometry information to provide a predominant dimension in the identification of unknown chemical compositions separated on standard TLC plates, and it was applied for rapid characterization of various kinds of natural herbal medicines. The results showed that the introduction of low-cost small laser pointer had significantly improved the desorption process. The system was successfully applied in the analysis of alkaloids, flavonoids, anthraquinones, volatile oils, glycosides, organic acids, and eight different TCMs including Sophorae Flavescentis Radix, Angelicae Sinensis Radix, Acori Tatarinowii Rhizoma, Phellodendri Chinensis Cortex, Picrasmae Ramulus et Folium, Gynura Japonica, Rhei Radix et Rhizoma and Dendrobii Caulis. The obtained limits of detection (LODs) of this method for various types of reference substances were in the range of 4.6-162.2 ng/band on TLC plates. Furthermore, the quality control and identification of different species of Dendrobii Caulis herb was achieved. This study combines the advantages of TLC and ambient mass spectrometry to provide a good choice for the screening and identification of active ingredients and the quality evaluation of botanical samples.

Erythrocyte membrane bioengineered nanoprobes via indocyanine green-directed assembly for single NIR laser-induced efficient photodynamic/photothermal theranostics.

Traditional combinational photodynamic therapy (PDT) and photothermal therapy (PTT) were limited in clinical therapy of cancer due to exceptionally low drug payload and activation by light with separate wavelengths. We have accidentally discovered that zinc phthalocyanine (ZNPC, a typical hydrophobic photosensitizer) and indocyanine green (ICG, a clinically approved fluorescence probe) could be co-assembled into carrier-free nanodrugs (almost 100 wt%) for single NIR laser-induced efficient PDT/PTT. Interestingly, ICG could act as "transformers" for modulating the geometric shape of ZNPC/ICG co-assembling structures from needle-like/spindle-like structure via cubic structure finally to spherical structure. Unfortunately, the nanodrugs suffered from rapid immune clearance. The ZNPC-ICG nanoprobes were further embedded into the erythrocyte membrane (RBC)-camouflaged framework. The designed ZNPC-ICG@RBC could be efficiently accumulated within the tumor sites (continue for ~60 h) and rapidly internalized into cancer cells upon laser irradiation rather than macrophage RAW264.7 cells. Compared with the free ZnPC or ICG, the biomimetic ZNPC-ICG@RBC nanoprobes exhibited amplified therapeutic effects by simultaneously producing ROS and hyperthermia, thereby synergistically improving antitumor efficiency and eliminating the tumors without any regrowth under the guidance of fluorescence imaging. The co-delivery of ZnPC and ICG via a biomimetic carrier-free system might be a promising strategy for bimodal phototherapy of cancer.

Rapid identification and determination of pyrrolizidine alkaloids in herbal and food samples via direct analysis in real-time mass spectrometry.

Pyrrolizidine alkaloids (PAs) are naturally occurring plant toxins associated with severe liver damage if excessive ingestion. Herein, a novel analytical strategy on utilizing direct analysis in real-time mass spectrometry (DART-MS) was developed, and applied in analysis of six representative PAs. The calibration curves in the range of 10-1000 ng·mL-1 were established, and relative standard deviations (RSDs) were less than 10%. The limits of detection (LODs) and limits of quantitation (LOQs) were 0.55-0.85 ng·mL-1 and 1.83-2.82 ng·mL-1, respectively. The feasibility of method was indicated by analysing real samples including Gynura japonica, drug tablets, granules, and fresh cow's milk. Moreover, the results of DART-MS were in good agreement with those observed by high performance liquid chromatography mass spectrometry (HPLC-MS), but consumed less time without chromatographic separation. This research provides a facile fashion for safety assessment of herbal and food products containing PAs and presents promising applications in food, pharmaceutical and clinical analysis.

Assessment of left atrial remodeling in paroxysmal atrial fibrillation with speckle tracking echocardiography: a study with an electrophysiological mapping system.

This study aimed to evaluate left atrial (LA) remodeling and fibrosis in paroxysmal atrial fibrillation (AF) using speckle tracking echocardiography (STE) based on the findings with radiofrequency catheter ablation (RFCA) so as to predict atrial remodeling prior to ablation. A total of 40 patients with paroxysmal AF were enrolled and divided into two groups based on LA bipolar voltage detected during RFCA: those with low-voltage zone (LVZ) (LV group, n = 19) and those without LVZ (non-LV group, n = 21). The segmental and global LA reservoir, conduit and contractile strain (εs, εe, εa) were analyzed using two-dimensional STE before RFCA. The segmental and global εs, εe, εa (%) decreased in the LV group. Especially, the εs in anteroseptal upper (18.32 ± 7.94 vs. 31.61 ± 9.39) and lower segments (16.60 ± 7.23 vs. 29.23 ± 9.81), posteroseptal upper (22.24 ± 6.65 vs. 32.23 ± 10.57) and lower segments (18.24 ± 6.49 vs. 26.40 ± 7.12), and the global εs (23.85 ± 6.74 vs. 30.48 ± 8.67) significantly decreased in the LV group than in the non-LV group (all P < 0.05). The εs ≤ 24.07 in the anteroseptal upper segment was an effective parameter to differentiate the LV group (sensitivity, 84%; specificity, 81%, P < 0.001). Besides, global εs tended to be an independent determinant of the LVZ (odds ratio 1.347, P = 0.046). STE enables a noninvasive method to evaluate LA remodeling prior ablation.

Hyaluronic Acid-Methotrexate Conjugates Coated Magnetic Polydopamine Nanoparticles for Multimodal Imaging-Guided Multistage Targeted Chemo-Photothermal Therapy.

Combination cancer therapy with various kinds of therapeutic approaches could improve the effectiveness of treatment while reducing side effects. Herein, we elaborately developed a theranostics nanoplatform based on magnetic polydopamine (MPDA) coated with hyaluronic acid-methotrexate conjugates (MPDA@HA-MTX) for chemo-photothermal treatment (PTT). In this nanoplatform, Fe3O4 served as the core was applied as contrast agent for T2-weighted magnetic resonance imaging (MRI) and early phase magnet targeting. Meanwhile, PDA was used as a versatile shell for effective loading of chemotherapeutic doxorubicin (DOX) to achieve controlled release and PTT simultaneously. Moreover, HA-MTX conjugates could offer later-phase specific cellular dual-targeting ability during the therapy. Both in vitro and in vivo studies demonstrated that DOX-loaded MPDA@HA-MTX (MPDA/DOX@HA-MTX) exhibited the preferential tumor accumulation, enhanced specificity to target tumor cells, pH-/laser-responsive release, and high tumor cell-killing efficiency. By combined chemo-PTT under the guidance of fluorescence/MR imaging, the tumors in mice were completely eliminated after treatment, indicating that MPDA@HA-MTX nanoparticles have great potential as a novel drug-loading platform for imaging-guided multistage targeted chemo-photothermal combination therapy.

Zinc phthalocyanine-soybean phospholipid complex based drug carrier for switchable photoacoustic/fluorescence image, multiphase photothermal/photodynamic treatment and synergetic therapy.

For the purpose of precision theranostic of tumor, multifunctional drug delivery systems are always receiving great attentions. Here, we developed a zinc phthalocyanine-soybean phospholipid (ZnPc-SPC) complex based drug delivery system with doxorubicin (Dox) as loading cargo to achieve additional chemotherapy while the carrier itself could serve as multifunctional and switchable theranostic agent. In the early phase, the ZnPc-SPC complex assembled to nanostructure displaying photothermal therapy (PTT) and photoacoustic (PA) properties while in the late phase, the prepared NPs dis-assembled into ZnPc-SPC complex again performing photodynamic therapy (PDT) and low-background fluorescence (FL) image. With the decoration of folate receptors α (FRα) targeted MTX, Dox-loaded, MTX-decorated self-assembled ZnPc-SPC complex NPs (DZSM) was formed. In vitro and in vivo evaluations both indicated that DZSM presented high selectivity for FRα over-expressed tumor cells, excellent switchable PA/FL image, significant multiphase PTT/PDT effect, as well as great synergetic therapy potential, leading to notable inhibition of tumor growth.

Water-Soluble Dinitrosyl Iron Complex (DNIC): a Nitric Oxide Vehicle Triggering Cancer Cell Death via Apoptosis.

Nitric oxide (NO) is an important cellular signaling molecule that modulates various physiological activities. Angiogenesis-promoting activities of NO-donor drugs have been explored in both experimental and clinical studies. In this study, a structurally well characterized and water-soluble neutral {Fe(NO)2}(9) DNIC [(S(CH2)2OH)(S(CH2)2NH3)Fe(NO)2] (DNIC 2) was synthesized to serve as a NO-donor species. The antitumor activity of DNIC 2 was determined by MTT assay, confocal imaging, and Annexin-V/PI staining. The IC50 values of DNIC 2 were 18.8, 42.9, and 38.6 µM for PC-3, SKBR-3, and CRL5866 tumor cells, respectively. Moreover, DNIC 2 promoted apoptotic cell death via activation of apoptosis-associated proteins and inhibition of survival associated proteins. In particular, DNIC 2 treatment suppressed PC-3 tumor growth by 2.34- and 19.3-fold at 7 and 21 days, in comparison with the control group. These results indicate that water-soluble DNIC 2 may serve as a promising drug for cancer therapy.

Prescription patterns of Chinese herbal products for patients with sleep disorder and major depressive disorder in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal products (CHPs) are commonly prescribed for sleep disorder and major depressive disorder (MDD). The aim of this study was to investigate the prescription patterns of CHPs and Western medicine for patients with these disorders in Taiwan, and analyze the frequency of using single herbs (SHs) and herbal formulas (HFs). MATERIALS AND METHODS: In this retrospective population-based study secondary data analysis was performed using data from Taiwan's Longitudinal Health Insurance Database (LHID) between January 2007 and December 2011. In total, 1000,000 beneficiaries from the LHID were randomly selected from the 2010 registry for beneficiaries of the National Health Insurance Research Database. Patients with sleep disorder and MDD according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes 307.40 and 311, respectively. RESULTS: Among a total of 11,030 patients with sleep disorder, 9619 used Western medicine, 1334 used CHPs, and 77 used both, Among a total of 11,571 patients with MDD, 11,389 used Western medicine, 131 used CHPs, and 51 used both. Regardless of disorder type, women were predominant The majority of the patients were aged 22-44 years, had a monthly income of NT$17,281-NT$22,800, and lived in an area with Level 1 and Level 2 urbanization. Of the patients with sleep disorder, 1411 had used CHPs and visited a clinic 5298 times on average. Of the patients with MDD, 182 had used CHPs and visited a clinic 755 times on average. The three most commonly used SHs and HFs were Ziziphi Spinosae Semen, Polygoni Multiflori Caulis, and Polygalae Radix, and Jia-Wei-Xiao-Yao-San, Suan-Zao-Ren-Tang, and Chai-Hu-Chia-Lung-Ku-Mu-Li-Tang, respectively. CONCLUSION: Chinese herbal products including SHs and HFs are prescribed for patients with sleep disorder and MDD. However, the efficacy and safety of CHPs for sleep disorder and MDD need to be further evaluated.

In vitro culture and production of syringin and rutin in Saussurea involucrata (Kar. et Kir.) - an endangered medicinal plant.

BACKGROUND: Saussurea involucrata (Kar. et Kir.) commonly known as 'snow lotus' or 'Xue Lian' is an important plant in the traditional Chinese system of medicine. The plant contains flavonoids such as syringin and rutin. These compounds have been reported to be anti-rheumatic, anti-inflammatory and dilate blood vessels, lower blood pressure, prevent cardiovascular diseases, enhance immunity, and act as anti-aging, anti-cancer, and anti-fatigue agents. The species has become endangered due to the excessive collection of S. involucrata plants in the wild, slower plant growth and ecological destruction of natural habitats. There is a severe shortage of plant material, while the market demand is ever increasing. Hence, it is very important to apply tissue culture technique for plant propagation and production of the bioactive compounds of this species. RESULTS: Multiple shoot induction and proliferation in shoot base explants derived from in vitro raised seedlings of S. involucrata was achieved on 3/4 strength of Murashige and Skoog's (MS) basal medium (MSBM) supplemented with 1.0 mg/L-1 BA and 1.5 mg/L-1 NAA. Rooting was induced in 100 % shoots cultured on 1/2X MSBM supplemented with 1.0 mg/L-1 IBA for one week and then transfer to auxin free medium. The plantlets could be acclimatized successfully by sachet technique and established in the greenhouse. Maximum callus induction and proliferation in leaf segments was achieved on 1/2X MSBM supplemented with 0.5 mg/L-1 BA, 0.5 mg/L-1 NAA, 0.4 % gelrite and on incubation at 20 °C. Container closures had an influence on the quality and quantity of callus and production of the active compounds. The HPLC analysis showed much higher syringin content in in vitro shoots and callus as compared to commercially available market crude drug. CONCLUSION: The present study describes an in vitro culture protocol of Saussurea involucrata. The bioactive compounds, syringin and rutin could be produced through tissue culture technique without sacrificing the endangered Saussurea involucrata plants in the wild.

Rutin, a flavonoid and principal component of saussurea involucrata, attenuates physical fatigue in a forced swimming mouse model.

This study investigated the antifatigue effects of rutin, a flavonoid extracted from the ethyl acetate extract of S. involucrata. Mice were subjected to a weight-loaded forced swim test (WFST) on alternate days for 3 wk. Rutin was administered orally to the mice for 7 days in dosages of 15, 30, and 60 mg/kg body weight, and several biomarkers of physical fatigue were evaluated: swimming time, change in body weight, lipid peroxidation, lactic acid (LA), glycogen, and the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). On Day 7, the rutin-treated mice had a 3-fold longer exhaustive swimming time than the control mice, as well as significantly reduced blood LA concentrations. The 15, 30, and 60 mg/kg body weight rutin-supplemented groups displayed 11.2%, 22.5%, and 37.7% reduced malondialdehyde (MDA) concentrations, respectively, in brain and muscle tissues compared with the control exercised group. Our results indicated that the administration of rutin protected the mice against the depletion of SOD and GPx activities significantly. Following 7 days of rutin treatment, we sacrificed the mice and analyzed their soleus muscle and brain for peroxisome proliferator-activated receptor-α coactivator (PGC-1α) and sirtuin 1 (SIRT1) mRNA expression. We observed that rutin treatment increased PGC-1α and SIRT1 mRNA and protein expression. The changes in these markers of mitochondrial biogenesis were associated with increased maximal endurance capacity. The application of 2D gel electrophoresis to analyze the rutin-responsive protein profiles in the WFST mouse brain further revealed the upregulation of the CB1 cannabinoid receptor-interacting protein 1, myelin basic protein, Rho GDP dissociation inhibitor (GDI) alpha, and TPI, indicating that rutin might inhibit anxiety through the upregulation of the expression of anxiety-associated proteins. Western blot analysis of MAPK expression further confirmed the antianxiety effects of rutin. Our study results thus indicate that rutin treatment ameliorates the various impairments associated with physical fatigue.

3,4-Dihydroxytoluene, a metabolite of rutin, inhibits inflammatory responses in lipopolysaccharide-activated macrophages by reducing the activation of NF-κB signaling.

BACKGROUND: Saussurea involucrata (Kar. et Kir.) (S. involucrate), is a rare traditional Chinese medicinal herb. Rutin and hispidulin as well as their metabolites are flavonoids of the flavonol type that abound in S. involucrata, which has been reported to inhibit nonoxidative advanced glycation end products which was involved in physiological inflammation. This study aims to investigate the role of 3,4-dihydroxytoluene (DHT), a metabolite of rutin, in inflammatory inhibition and its involved mechanism. METHODS: This study utilized lipopolysaccharide (LPS) stimulated murine macrophage cell line RAW 264.7 as inflammatory model. The inhibitory effects of DHT were evaluated by the expression level of several inflammation markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 after LPS treatment. In addition, underlying mechanisms, the activation of mitogen-activated protein kinases (MAPKs) and NF-κB, were also investigated. RESULTS: Our results showed that DHT significantly suppressed the LPS-induced production of nitric oxide (NO), iNOS, and COX-2 in a dose-dependent manner without cytotoxicity. DHT also reduced the generation of proinflammatory cytokines majorly in tumor necrosis factor (TNF)-α and minor in interleukin (IL)-1ß and IL-6. In addition, LPS-stimulated I-κBα phosphorylation and degradation followed by translocation of the nuclear factor κB (NF-kB)-p65 from the cytoplasm to the nucleus were attenuated after DHT treatment. CONCLUSIONS: Combined, the results suggest that DHT might exert anti-inflammatory effects in vitro in LPS stimulated RAW 264.7 macrophages and is potential in adjuvant treatment in inflammation disease.