Rhein kills Actinobacillus pleuropneumoniae, reduces biofilm formation, and effectively treats bacterial lung infections in mice.

Background. Actinobacillus pleuropneumoniae, a member of the Pasteurellaceae family, is known for its highly infectious nature and is the primary causative agent of infectious pleuropneumonia in pigs. This disease poses a considerable threat to the global pig industry and leads to substantial economic losses due to reduced productivity, increased mortality rates, and the need for extensive veterinary care and treatment. Due to the emergence of multi-drug-resistant strains, Chinese herbal medicine is considered one of the best alternatives to antibiotics due to its unique mechanism of action and other properties. As a type of Chinese herbal medicine, Rhein has the advantages of a wide antibacterial spectrum and is less likely to develop drug resistance, which can perfectly solve the limitations of current antibacterial treatments.Methods. The killing effect of Rhein on A. pleuropneumoniae was detected by fluorescence quantification of differential expression changes of key genes, and scanning electron microscopy was used to observe the changes in A. pleuropneumoniae status after Rhein treatment. Establishing a mouse model to observe the treatment of Rhein after A. pleuropneumoniae infection.Results. Here, in this study, we found that Rhein had a good killing effect on A. pleuropneumoniae and that the MIC was 25 µg ml-1. After 3 h of action, Rhein (4×MIC) completely kills A. pleuropneumoniae and Rhein has good stability. In addition, the treatment with Rhein (1×MIC) significantly reduced the formation of bacterial biofilms. Therapeutic evaluation in a murine model showed that Rhein protects mice from A. pleuropneumoniae and relieves lung inflammation. Quantitative RT-PCR (Quantitative reverse transcription polymerase chain reaction is a molecular biology technique that combines both reverse transcription and polymerase chain reaction methods to quantitatively detect the amount of a specific RNA molecule) results showed that Rhein treatment significantly downregulated the expression of the IL-18 (Interleukin refers to a class of cytokines produced by white blood cells), TNF-α, p65 and p38 genes. Along with the downregulation of genes such as IL-18, it means that Rhein has an inhibitory effect on the expression of these genes, thereby reducing the activation of inflammatory cells and the production of inflammatory mediators. This helps reduce inflammation and protects tissue from further damage.Conclusions. This study reports the activity of Rhein against A. pleuropneumoniae and its mechanism, and reveals the ability of Rhein to treat A. pleuropneumoniae infection in mice, laying the foundation for the development of new drugs for bacterial infections.

Drug repurposing-based nanoplatform via modulating autophagy to enhance chemo-phototherapy against colorectal cancer.

Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.

Study on the intervention effect of Epimedium before and after suet-oil-processed on kidney yang deficiency rats based on intestinal flora and fecal metabolomics.

Epimedium is a Chinese herbal medicine commonly used in clinical practice to reinforce yang. Previous studies have shown that Epimedium fried with suet oil based has the best effect on warming kidney and promoting yang. Evidence suggests a relationship between kidney yang deficiency syndrome (KYDS) and metabolic disorders of the intestinal microflora. However, the specific interaction between KYDS and the intestinal microbiome, as well as the internal regulatory mechanism of the KYDS intestinal microbiome regulated by Epimedium fried with suet oil, remain unclear. The purpose of this study was to investigate the regulatory effects of different processed products of Epimedium on intestinal microflora and metabolites in rats with kidney yang deficiency, and to reveal the processing mechanism of Epimedium fried with suet oil warming kidney and helping yang. 16 S rRNA and LC-MS/MS technology were used to detect fecal samples. Combined with multivariate statistical analysis, differential intestinal flora and metabolites were screened. Then the content of differential bacteria was then quantified using quantitative real-time fluorescence PCR. Furthermore, the correlation between differential bacterial flora and metabolites was analyzed using Spearman's method. The study found that the composition of intestinal flora in rats with kidney yang deficiency changed compared to healthy rats. Epimedium fried with suet oil could increase the levels of beneficial bacteria, while significantly reducing the levels of harmful bacteria. Real-time quantitative PCR results were consistent with 16 S rRNA gene sequencing analysis. Fecal metabolomics revealed that KYDS was associated with 30 different metabolites, involving metabolic pathways steroid hormone biosynthesis etc. Moreover, differential bacteria were closely correlated with potential biomarkers. Epimedium could improve metabolic disorders associated with KYDS by acting on the intestinal flora, with Epimedium fried with suet oil demonstrating the most effective regulatory effect. Its potential mechanism may involve the regulation of abnormal metabolism and the impact on the diversity and structure of the intestinal flora.

Integrated metabolome-microbiome analysis investigates the different regulations of Pudilan Xiaoyan oral liquid in young rats with acute pharyngitis compared to adult rats.

BACKGROUND: Pudilan Xiaoyan Oral Liquid (PDL) is a famous traditional Chinese prescription recorded in the Chinese Pharmacopeia, which is widely used to treat inflammatory diseases of the respiratory tract in children and adults. However, the endogenous changes in children and adults with PDL in the treatment of acute pharyngitis remain unclear. PURPOSE: The differential regulatory roles of PDL in endogenous metabolism and gut microbes in young and adult rats were investigated with a view to providing a preclinical data reference for PDL in medication for children. METHODS: An acute pharyngitis model was established, and serum levels of inflammatory factors and histopathology were measured. This study simulated the growth and development of children in young rats and explored the endogenous metabolic characteristics and intestinal microbial composition after the intervention of PDL by using serum metabolomic technique and 16S rRNA high-throughput sequencing technique. RESULTS: The results showed that PDL had therapeutic effects on young and adult rats with acute pharyngitis. Sixteen biomarkers were identified by metabolomics in the serum of young rats and 23 in adult rats. PDL can also affect intestinal microbial diversity and community richness in young and adult rats. Alloprevotella, Allobaculum, Alistipes, Bifidobacterium, and Enterorhabdus were prominent bacteria in young rats. Bacteria from the phylum Firmicutes of the adult rats changed more significantly under the treatment of PDL. In young rats, amino acid metabolism was the primary regulatory mode of PDL, whereas, in adult rats, glycerophospholipid metabolism was studied. CONCLUSION: The regulation of PDL on the serum metabolite group and intestinal microflora in young rats was different from that in adult rats, indicating the necessity of an independent study on children's medication. PDL may also exert therapeutic effects on young and adult rats by regulating gut microbial homeostasis. The results support the clinical application of PDL.

SLC35E1 promotes keratinocyte proliferation in psoriasis by regulating zinc homeostasis.

Keratinocyte hyperproliferation is a key pathogenic factor in psoriasis. However, the mechanisms that regulate keratinocyte hyperproliferation in this condition remain unclear. Here, we found that SLC35E1 was highly expressed in keratinocytes of patients with psoriasis and that Slc35e1-/- mice displayed a less severe imiquimod (IMQ)-induced psoriasis-like phenotype than their wild-type siblings. In addition, SLC35E1 deficiency inhibited keratinocyte proliferation in both mice and cultured cells. On a molecular level, SLC35E1 was found to regulate zinc ion concentrations and subcellular localization, while zinc ion chelation reversed the IMQ-induced psoriatic phenotype in Slc35e1-/- mice. Meanwhile, epidermal zinc ion levels were decreased in patients with psoriasis and zinc ion supplementation alleviated the psoriatic phenotype in an IMQ-induced mouse model of psoriasis. Our results indicated that SLC35E1 can promote keratinocyte proliferation by regulating zinc ion homeostasis and zinc ion supplementation has potential as a therapy for psoriasis.

Integrating strategies of metabolomics, network pharmacology, and experiment validation to investigate the processing mechanism of Epimedium fried with suet oil to warm kidney and enhance yang.

Introduction: Epimedium, a traditional Chinese medicine (TCM) commonly used in ancient and modern China, is one of the traditional Chinese medicines clinically used to treat kidney yang deficiency syndrome (KYDS). There are differences in the efficacy of Epimedium before and after processing, and the effect of warming the kidney and enhancing yang is significantly enhanced after heating with suet oil. However, the active compounds, corresponding targets, metabolic pathways, and synergistic mechanism of frying Epimedium in suet oil to promote yang, remain unclear. Methods: Herein, a strategy based on comprehensive GC-TOF/MS metabolomics and network pharmacology analysis was used to construct an "active compounds-targets-metabolic pathways" network to identify the active compounds, targets and metabolic pathways involved. Subsequently, the targets in kidney tissue were further validated by real-time quantitative polymerase chain reaction (RT-qPCR). Histopathological analysis with physical and biochemical parameters were performed. Results: Fifteen biomarkers from urine and plasma, involving five known metabolic pathways related to kidney yang deficiency were screened. The network pharmacology results showed 37 active compounds (13 from Epimedium and 24 from suet oil), 159 targets, and 267 pathways with significant correlation. Importantly, integrated metabolomics and network pharmacologic analysis revealed 13 active compounds (nine from Epimedium and four from suet oil), 7 corresponding targets (ALDH2, ARG2, GSTA3, GSTM1, GSTM2, HPGDS, and NOS2), two metabolic pathways (glutathione metabolism, arginine and proline metabolism), and two biomarkers (Ornithine and 5-Oxoproline) associated with improved kidney yang deficiency by Epimedium fried with suet oil. Discussion: These finds may elucidate the underlying mechanism of yang enhancement via kidney warming effects. Our study indicated that the mechanism of action mainly involved oxidative stress and amino acid metabolism. Here, we demonstrated the novel strategies of integrating metabolomics and network pharmacology in exploring of the mechanisms of traditional Chinese medicines.

Oxidant-Induced Bioconjugation for Protein Labeling in Live Cells.

Chemical proteomics is a powerful technology that can be used in the studies of the functions of uncharacterized proteins in the human proteome. It relies on a suitable bioconjugation strategy for protein labeling. This could be either a UV-responsive photo-crosslinker or an electrophilic warhead embedded in chemical probes that can form covalent bonds with target proteins. Here, we report a new protein-labeling strategy in which a nitrile oxide, a highly reactive intermediate that reacts with proteins, can be efficiently generated by the treatment of oximes with a water-soluble and a minimally toxic oxidant, phenyliodine bis (trifluoroacetate) (PIFA). The resulting intermediate can rapidly bioconjugate with amino acid residues of target proteins, thus enabling target identification of oxime-containing bioactive molecules. Excellent chemoselectivity of cysteine residues by the nitrile oxide was observed, and over 4000 reactive and/or accessible cysteines, including KRAS G12C, have been successfully characterized by quantitative chemical proteomics. Some of these residues could not be detected by conventional cysteine reagents, thus demonstrating the complementary utility of this method.

[Optimization and evaluation of Xiaoer Pudilan Xiaoyan Syrup based on characterization of material properties].

According to the taste analysis of Pudilan Xiaoyan Oral Liquid, the unpleasant taste of the oral liquid is mainly caused by the inherent taste of Chinese medicine and the taste introduced in the preparation process, which leads to its unpopularity among children. Therefore, aiming at the special children patient group, Xiaoer Pudilan Xiaoyan Syrup was developed via technology optimization and dosage form improvement to improve the unpleasant taste and enhance the medication compliance among children. Based on the material properties of Pudilan Xiaoyan Oral Liquid and Xiaoer Pudilan Xiaoyan Syrup extracts, the authors compared the properties(pH, density, turbidity, viscosity, chromaticity, particle size), taste, content of five quality markers and in vivo pharmacokinetic characteristics of these two preparations, to evaluate the suitability of Xiaoer Pudilan Xiaoyan Syrup. The results showed that compared with those of Pudilan Xiaoyan Oral Liquid, the pH, density, turbidity, viscosity and chromaticity of Xiaoer Pudilan Xiaoyan Syrup were significantly changed, and the unpleasant taste was reduced by 26%; the transfer rate of the main active ingredients chicoric acid was increased, while the transfer rate of baicalin had small difference from that of the oral liquid. In addition, pharmacokinetics revealed that the total absorption amount of baicalin in vivo was higher, and the time to peak T_(max) of baicalin and oroxindin in the syrup and the mean residence time MRT_(last )of corynoline in vivo were significantly prolonged. The absorption degree of Xiaoer Pudilan Xiaoyan Syrup and Pudilan Xiaoyan Oral Liquid in the body was the same: baicalin>oroxindin>corynoline. The new dosage form process was simpler than that of the original dosage form, safe, environmentally friendly, reasonable and feasible, meeting the mass production demand. This provided a basis for the reasonable and scientific optimization of Xiaoer Pudilan Xiaoyan Syrup, and also laid a foundation for its further safe and rational use, so as to expand the clinical application in children.

The Managing Cancer and Living Meaningfully (CALM) Intervention Alleviates Chemotherapy-Related Cognitive Impairment in Patients with Breast Cancer by Modulating Pan-Immune-Inflammation Values.

BACKGROUND: The number of patients with breast cancer is increasing worldwide, resulting in a growing number of patients with chemotherapy-related cognitive impairment (CRCI), which seriously affects their quality of life. CRCI is associated with inflammatory factors and systemic inflammatory markers such as pan-immune-inflammation value (PIV) and monocyte-to-lymphocyte ratio (MLR), which can reflect the level of inflammation in the body. While the Managing Cancer and Living Meaningfully (CALM) intervention has been demonstrated to alleviate CRCI in patients with breast cancer, the specific mechanism remains unclear. OBJECTIVE: This study evaluated the impact of the CALM intervention on systemic inflammation. METHODS: Ninety patients with breast cancer with CRCI were enrolled and randomized into care as usual (CAU) and CALM intervention groups. All patients were assessed using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Mini-Mental State Exam (MMSE), and Functional Assessment of Cancer Therapy-Breast (FACT-B) before and after the CAU/CALM intervention. The blood levels of inflammatory markers were also analyzed before and after the intervention. RESULTS: Compared to the CAU group, the CALM group showed significantly improved cognitive function and significantly decreased PIV (P < .05). PIV was significantly negatively correlated with FACT-Cog (P < .05). The levels of other inflammatory markers, including MLR, neutrophil-to-lymphocyte ratio (NLR), granulocyte-to-lymphocyte ratio (GLR), and systemic immune-inflammation index (SII), were also reduced in the CALM group. CONCLUSION: PIV is an important marker of inflammation. The CALM intervention may improve the cognitive function of patients by regulating the systemic inflammation marker PIV through the neuroimmune axis.

Screening immune adjuvants for an inactivated vaccine against Erysipelothrix rhusiopathiae.

In this study, we screened adjuvants for an inactivated vaccine against Erysipelothrix rhusiopathiae (E. rhusiopathiae). Inactivated cells of E. rhusiopathiae strain HG-1 were prepared as the antigen in five adjuvanted inactivated vaccines, including a mineral-oil-adjuvanted vaccine (Oli vaccine), aluminum-hydroxide-gel-adjuvanted vaccine (Alh vaccine), ISA201-biphasic-oil-emulsion-adjuvanted vaccine (ISA201 vaccine), GEL02-water-soluble-polymer-adjuvanted vaccine (GEL vaccine), and IMS1313-water-soluble-nanoparticle-adjuvanted vaccine (IMS1313 vaccine). The safety test results of subcutaneous inoculation in mice showed that Oli vaccine had the most severe side effects, with a combined score of 35, followed by the ISA201 vaccine (25 points), Alh vaccine (20 points), GEL vaccine (10 points), and IMS1313 vaccine (10 points). A dose of 1.5LD50 of strain HG-1 was used to challenge the mice intraperitoneally, 14 days after their second immunization. The protective efficacy of Oli vaccine and Alh vaccine was 100% (8/8), whereas that of the other three adjuvanted vaccines was 88% (7/8). Challenge with 2.5LD50 of strain HG-1 resulted in a 100% survival rate, demonstrating the 100% protective efficacy of the Oli vaccine, followed by the GEL vaccine (71%, 5/7), IMS1313 vaccine (57%, 4/7), ISA201 vaccine (43%, 3/7), and Alh vaccine (29%, 2/7). Challenge with 4LD50 of strain HG-1 showed 100% (7/7) protective efficacy of the Oli vaccine and 71% (5/7) protective efficacy of the GEL vaccine, whereas the protective efficacy of other three adjuvanted vaccine was 14% (1/7). The Alh and GEL vaccines were selected for comparative tests in piglets, and both caused minor side effects. A second immunization with these two adjuvanted vaccines conferred 60 and 100% protective efficacy, respectively, after the piglets were challenged via an ear vein with 8LD100 of strain HG-1. After challenge with 16LD100 of strain HG-1, the Alh and GEL vaccines showed 40% and 100% protective efficacy, respectively. Our results suggested that GEL is the optimal adjuvant for an inactivated vaccine against E. rhusiopathiae.

Effect of the COVID-19 Pandemic on Serum Vitamin D Levels in People Under Age 18 Years: A Systematic Review and Meta-Analysis.

BACKGROUND During the COVID-19 pandemic the implementation of a range of measures to suppress transmission, such as social distancing and home confinement resulted in limited sunlight exposure and physical inactivity in people under age 18 years, which can elevate the risk of vitamin D deficiency and insufficiency. The aim of this study was to systemically evaluate the effect of the COVID-19 pandemic on serum vitamin D levels in people under age 18 years. MATERIAL AND METHODS Following the PRISMA recommendations, we searched PubMed, Embase, and the Cochrane Database for trials from inception to November 3, 2021. All trials assessing the effects of the COVID-19 pandemic on serum vitamin D levels in people under age 18 years were included and analyzed. Mean differences (MDs) of serum 25-hydroxyvitamin D (25[OH] D) levels before and during the COVID-19 pandemic were calculated and pooled using a random-effects model. Risk differences were used to assess changes in the proportions of people under age 18 years with vitamin D deficiency. RESULTS Our analysis included 5 studies comprising 4141 people under age 18 years. The combined result MD of serum 25(OH)D levels before and during the COVID-19 pandemic as 3.28 ng/mL, 95% CI=0.95-5.62 ng/mL, P<0.01] indicated serum 25(OH)D levels were significantly lower during the COVID-19 pandemic. The decreased serum 25(OH)D level was not observed among infants (age under 1 year) (P=0.28). CONCLUSIONS During the COVID-19 pandemic, the serum vitamin D levels of people under age 18 years were significantly lower and vitamin D supplementation for people under age 18 years might reduce the risk of COVID-19. More research is needed to validate the present findings.

Polysaccharides from Platycodonis Radix ameliorated respiratory syncytial virus-induced epithelial cell apoptosis and inflammation through activation of miR-181a-mediated Hippo and SIRT1 pathways.

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in young children, but there are few safe and effective treatments for this disease. Platycodonis Radix is widely used as an antitussive and expectorant drug for preventing various diseases in lower respiratory tract, in which the polysaccharides are one of the main bioactivity constituents. In this study, the protective effects of the P. Radix polysaccharides (PRP) against RSV-induced bronchiolitis in juvenile mice and RSV-induced apoptosis of epithelial HEp-2 cells were investigated. The results showed that PRP obviously decreased the levels of IL-1ß, IL-4, IL-6, TNF-α, IFN-γ and TSLP in lung tissues, and reduced the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) of RSV-infected mice. Furthermore, it reduced the apoptosis of RSV-infected HEp-2 cells and remarkably inhibited the mRNA expressions of RSV L gene, which indicated that PRP affected transcription and replication of RSV in host cells. Compared with that in RSV-infected group, miR-181a-5p in the PRP-treated group presented the highest relative abundance and its expression was violently reduced by approximately 30%. Mechanistically, PRP had the similar effects as miR-181a-5p antagomir on RSV-induced apoptosis and inflammation in HEp-2 cells via upregulating BCL2, MLL3 and SIRT1, which could be reversed by miR-181a-5p mimic. Therefore, it demonstrated that PRP not only protected against RSV-induced lung inflammation in mice but also inhibited apoptosis of RSV-infected HEp-2 cells via suppressing miR-181a-5p and transcriptionally activating Hippo and SIRT1 pathways.

Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies.

Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of numerous tumor types and chronic pain. However, most of the reported TrkA inhibitors are ATP competitive pan-Trks inhibitors that lack subtype selectivity. A selective TrkA inhibitor may provide valuable therapeutic benefits. Here, we described the discovery of novel TrkA allosteric inhibitors by structure-based virtual screening. A promising hit (D5261, TrkA cell IC50 = 3.32 µM) was selected for further studies. The binding free energy between TrkA and D5261 was calculated. In addition, the preliminary structure-activity relationship (SAR) studies with D5261 were investigated. The results suggest that D5261 can be used as a starting point for development of TrkA allosteric inhibitors.

Tetrahydropalmatine Alleviates Hyperlipidemia by Regulating Lipid Peroxidation, Endoplasmic Reticulum Stress, and Inflammasome Activation by Inhibiting the TLR4-NF-κB Pathway.

Hyperlipidemia (HLP) is a lipid metabolism disorder that can induce a series of cardiovascular and cerebrovascular diseases, such as atherosclerosis, myocardial infarction, coronary heart disease, and stroke, which seriously threaten human health. Tetrahydropalmatine (THP) is a component of the plant Rhizoma corydalis and has been shown to exert hepatoprotective and anti-inflammatory effects in HLP. However, whether THP regulates lipid peroxidation in hyperlipidemia, endoplasmic reticulum (ER) stress and inflammasome activation and even the underlying protective mechanism against HLP remain unclear. An animal model of HLP was established by feeding a high-fat diet to golden hamsters. Our results showed that THP reduced the body weight and adipose index; decreased the serum content of ALT, AST, TC, TG, and LDL-C; decreased the free fatty acid hepatic lipid content (liver index, TC, TG, and free fatty acid); inhibited oxidative stress and lipid peroxidation; extenuated hepatic steatosis; and inhibited ER stress and inflammasome activation in high-fat diet-fed golden hamsters. In addition, for the first time, the potential mechanism by which THP protects against HLP through the TLR4-NF-κB signaling pathway was demonstrated. In conclusion, these data indicate that THP attenuates HLP through a variety of effects, including antioxidative stress, anti-ER stress, and anti-inflammatory effects. In addition, THP also inhibited the TLR4-NF-κB signaling pathway in golden hamsters.

Managing Cancer and Living Meaningfully (CALM) Intervention on Chemotherapy-Related Cognitive Impairment in Breast Cancer Survivors.

Objective: To evaluate the effectiveness and feasibility of Managing Cancer and Living Meaningfully (CALM), which is used to reduce chemotherapy-related cognitive impairment (CRCI), relieve psychological distress, and improve quality of life (QOL) in Chinese breast cancer survivors (BCs). Methods: Seventy-four BCs were enrolled in this study. All patients were randomly assigned to either the CALM group or the care as usual (CAU) group. All patients were evaluated by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Distress Thermometer (DT), and the Functional Assessment of Cancer Therapy-Breast (FACT-B) before and after CALM or CAU application to BCs with CRCI. We compared the differences in all these scores between the CALM group and the control group and analyzed the correlation between cognitive function and QOL. Results: Compared with the CAU group, the performance of the CALM group on the FACT-Cog, DT, and FACT-B showed significant differences before and after CALM (t = -18.909, -5.180, -32.421, P = .000, .000, .000, respectively). Finally, there was a positive correlation between cognitive function and QOL in breast cancer patients before (r = 0.579, P = .000) and after (r = 0.797, P = .000) treatment. Conclusions: The present results indicated that CALM has salutary effects on the improvement of cognitive impairment and QOL and relieves psychological distress in breast cancer patients, which may be due to a positive correlation between psychological distress and cognitive function or QOL.

Identification and characterization of N9-methyltransferase involved in converting caffeine into non-stimulatory theacrine in tea.

Caffeine is a major component of xanthine alkaloids and commonly consumed in many popular beverages. Due to its occasional side effects, reduction of caffeine in a natural way is of great importance and economic significance. Recent studies reveal that caffeine can be converted into non-stimulatory theacrine in the rare tea plant Camellia assamica var. kucha (Kucha), which involves oxidation at the C8 and methylation at the N9 positions of caffeine. However, the underlying molecular mechanism remains unclear. Here, we identify the theacrine synthase CkTcS from Kucha, which possesses novel N9-methyltransferase activity using 1,3,7-trimethyluric acid but not caffeine as a substrate, confirming that C8 oxidation takes place prior to N9-methylation. The crystal structure of the CkTcS complex reveals the key residues that are required for the N9-methylation, providing insights into how caffeine N-methyltransferases in tea plants have evolved to catalyze regioselective N-methylation through fine tuning of their active sites. These results may guide the future development of decaffeinated drinks.

Applications of Activity-Based Protein Profiling (ABPP) and Bioimaging in Drug Discovery.

Activity-based protein profiling (ABPP) and bioimaging have been developed in recent years as powerful technologies in drug discovery. Specifically, both approaches can be applied in critical steps of drug development, such as therapy target discovery, high-throughput drug screening and target identification of bioactive molecules. We have been focused on the development of various strategies that enable simultaneous activity-based protein profiling and bioimaging studies, thus facilitating an understanding of drug actions and potential toxicities. In this Minireview, we summarize these novel strategies and applications, with the aim of promoting these technologies in drug discovery.

Fast-track multidisciplinary treatment versus conventional treatment for colorectal cancer: a multicenter, open-label randomized controlled study.

BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.

Activation of the Nrf2-ARE signal pathway after blast induced traumatic brain injury in mice.

Background: Treatment of blast-induced traumatic brain injury (bTBI) has been hindered. Previous studies have demonstrated that oxidative stress may contribute to the pathophysiological process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway exhibits a protective effect after traumatic brain injury (TBI). This study explored whether the Nrf2-ARE pathway was activated in a modified bTBI mouse model. Method: Mice were randomly divided into six groups: the 6 h, 1 d, 3 d, 7 d and 14 d after bTBI groups and a sham group. The protein levels of nuclear Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) were detected using western blot, and HO-1 and NQO1 mRNA levels were determined by real-time quantitative polymerase chain reaction. Moreover, HO-1 and Nrf2 were localized using histological staining. Results: The protein level of the Nrf2-ARE pathway in the frontal lobe increased significantly in the 3 d after bTBI. The HO-1 and NQO1 mRNA levels also reached a peak in the frontal lobe 3 d after bTBI. The histological staining demonstrated higher expression of HO-1 in the frontal lobe and hippocampus 3 d after bTBI, when nuclear import of Nrf2 reached a peak in the frontal lobe. Conclusions: bTBI activated the Nrf2-ARE signaling pathway in the brain. The peak activation time in the frontal lobe may be 3 d after injury, and activating the Nrf2 pathway could be a new direction for treatment.