Search

Aging is accompanied by muscle loss. In older adults with cancer sarcopenia (OACS), systemic inflammation, reduced food intake, and reduced physical activity led to a poor prognosis. This study was to investigate the prognostic ability of the inflammatory Geriatric Nutritional Risk Index (GNRI), which combines patient's inflammation, diet status, and physical activity status to predict overall survival of OACS.This prospective multi-center study enrolled 637 OACS, with an average age of 72.78 ± 5.98 years, of which 408 (64.1%) were males. We constructed the Inflammatory Functional Prognostic Index (IFPI) of OACS based on inflammatory GNRI scores, reduced food intake, and reduced physical activity. According to the IFPI, OACS was divided into high-, moderate-, and low-risk groups. Univariate and multivariate survival analyses analyzed the prognostic ability of the clinical parameters.Compared with OACS with a high GNRI score, the 1-, 3-, and 5-year hazard ratios (95% confidence interval) of OACS with a low GNRI score was 1.816 (1.076-3.063), 1.678 (1.118-2.518), and 1.627 (1.101-2.407), respectively. This result was consistent with that of the calibration curve. The subgroup analysis showed that the low GNRI score had a significant positive relation with patients with gastrointestinal cancer (PThe GNRI score was a short-term and long-term inflammatory prognostic indicator for OACS. The IFPI score could improve patient survival prediction.

Overweight or obese cancer patients are more likely to develop a proinflammatory status. The aim of this study was to investigate whether the nutrition-inflammation marker can provide additional prognostic information on top of well-established Eastern Cooperative Oncology Group performance status (ECOG-PS) in overweight or obese patients with cancer.A total of 1667 overweight or obese cancer patients were enrolled in this study. We assessed the prediction accuracy of 10 nutrition-inflammation markers by time-dependent receiver operating characteristic (ROC) and elucidated their association with overall survival by the Kaplan-Meier method and a Cox model.In this analysis, the majority of patients had a good performance status (ECOG-PS score ≤1; 88.3%). Both the area under ROC curves and the C-index of the lymphocyte-C-reactive protein ratio (LCR) demonstrated that LCR was the most significant nutrition-inflammation marker correlated with survival. In patients with good ECOG-PS, a low LCR was significantly associated with poorer prognosisand enhanced the predictive ability of one-year mortality. For specific tumor types, a low LCR was an independent prognostic factor for lung cancer, upper gastrointestinal cancer, and colorectal cancer, and it tended to be a significant predictor for breast cancer. In addition, those patients with a combined low LCR and poorer ECOG-PS (ECOG-PS score1) showed the worst prognosis.The LCR is more strongly associated with overall survival than other nutrition-inflammation markers, and it is able to further detect patients with worse prognosis on top of ECOG-PS in overweight or obese patients with cancer.

Innovations in synthetic chemistry have a profound impact on the drug discovery process, and will always be a necessary driver of drug development. As a result, it is of significance to develop novel simple and effective synthetic installation of medicinal modules to promote drug discovery. Herein, we have developed a NaClOmediated cross installation of indoles and azoles, both of which are frequently encountered in drugs and natural products. This effective toolbox provides a convenient synthetic route to access a library of Nlinked 2-(azol-1-yl) indole derivatives, and can be used for late-stage modification of drugs, natural products and peptides. Moreover, biological screening of the library has revealed that several adducts showed promising anticancer activities against A549 and NCI-H1975 cells, which give us a hit for anticancer drug discovery.

Background Systemic inflammation and cachexia are associated with adverse clinical outcomes in elderly patients with cancer. The Geriatric Nutritional Risk Index (GNRI) is a simple and useful tool to assess these conditions, but its predictive ability for elderly patients with cancer cachexia (EPCC) is unknown. Methods This multicentre cohort study included 746 EPCC with an average age of 72.00 ± 5.24 years, of whom 489 (65.5%) were male. The patients were divided into two groups (high GNRI group ≥91.959 vs. low GNRI group

Background Although systemic inflammation is an important feature of the cancer cachexia, studies on the association between systemic inflammation and prognostic of cancer cachexia are limited. The objective of this study is to evaluate whether the neutrophil‐to‐lymphocyte ratio (NLR) is associated with outcome and quality of life for patients with cancer cachexia and investigated any interaction between NLR and the clinical parameters. Methods This is a multicentre cohort study of 2612 cancer patients suffering from cachexia diagnosed between June 2012 and December 2019. The main parameters measured were overall survival (OS) time and all‐cause mortality. The association between NLR and all‐cause mortality was evaluated using hazard ratios (HRs) and the restricted cubic spline model with a two‐sided P‐value. Optimal stratification was used to solve threshold points. We also evaluated the cross‐classification of NLR for each variable of survival. Results Of the 2612 participants diagnosed with cancer cachexia, 1533 (58.7%) were male, and the mean (SD) age was 58.7 (11.7) years. Over a median follow‐up of 4.5 years, we observed 1189 deaths. The overall mortality rate for patients with cancer cachexia during the first 12 months was 30.2% (95%CI: 28.4%–32.0%), resulting in a rate of 226.07 events per 1000 patient‐years. An increase in NLR had an inverted L‐shaped dose–response association with all‐cause mortality. The optimal cut‐off point for NLR as a predictor of mortality in cancer patients with cachexia was 3.5. An NLR of 3.5 or greater could independently predict OS (HR, 1.51, 95%CI: 1.33–1.71). These associations were consistent across subtypes of cancer. Several potential effect modifiers were identified including gender, BMI, tumour type, KPS score and albumin in content. Increasing NLRs were independently associated with a worsening in the majority of EORTC QLQ‐C30 domains. Elevated baseline NLR was associated with low response and poor survival in patients treated with immunotherapy. Conclusions The baseline NLR status was found to be a significant negative prognostic biomarker for patients with cachexia; this effect was independent of other known prognostic factors.

Abscisic acid (ABA) induces chlorophyll degradation and leaf senescence; however, the molecular mechanism remains poorly understood, especially in woody plants. In this study, we found that MdABI5 plays an essential role in the regulation of ABA-triggered leaf senescence in Malus domestica (apple). Through yeast screening, three transcription factors, MdBBX22, MdWRKY40 and MdbZIP44, were found to interact directly with MdABI5 in vitro and in vivo. Physiological and biochemical assays showed that MdBBX22 delayed leaf senescence in two pathways. First, MdBBX22 interacted with MdABI5 to inhibit the transcriptional activity of MdABI5 on the chlorophyll catabolic genes MdNYE1 and MdNYC1, thus negatively regulating chlorophyll degradation and leaf senescence. Second, MdBBX22 interacted with MdHY5 to interfere with the transcriptional activation of MdHY5 on MdABI5, thereby inhibiting the expression of MdABI5, which also contributed to the delay of leaf senescence. MdWRKY40 and MdbZIP44 were identified as positive regulators of leaf senescence. They accelerated MdABI5-promoted leaf senescence through the same regulatory pathways, i.e., interacting with MdABI5 to enhance the transcriptional activity of MdABI5 on MdNYE1 and MdNYC1. Taken together, our results suggest that MdABI5 works with its positive or negative interaction partners to regulate ABA-mediated leaf senescence in apple, in which it acts as a core regulator. The antagonistic regulation pathways ensure that plants respond to external stresses flexibly and efficiently. Our results provide a concept for further study on the regulation mechanisms of leaf senescence.

Drought stress induces anthocyanin biosynthesis in many plant species, but the underlying molecular mechanism remains unclear. Ethylene response factors (ERFs) play key roles in plant growth and various stress responses, including affecting anthocyanin biosynthesis. Here, we characterized an ERF protein, MdERF38, which is involved in drought stress-induced anthocyanin biosynthesis. Biochemical and molecular analyses showed that MdERF38 interacted with MdMYB1, a positive modulator of anthocyanin biosynthesis, and facilitated the binding of MdMYB1 to its target genes. Therefore, MdERF38 promoted anthocyanin biosynthesis in response to drought stress. Furthermore, we found that MdBT2, a negative modulator of anthocyanin biosynthesis, decreased MdERF38-promoted anthocyanin biosynthesis by accelerating the degradation of the MdERF38 protein. In summary, our data provide a mechanism for drought stress-induced anthocyanin biosynthesis that involves dynamic modulation of MdERF38 at both transcriptional and post-translational levels.

Summary MYB transcription factors (TFs) have been demonstrated to play diverse roles in plant growth and development through interaction with basic helix‐loop‐helix (bHLH) TFs. MdbHLH33, an apple bHLH TF, has been identified as a positive regulator in cold tolerance and anthocyanin accumulation by activating the expressions of MdCBF2 and MdDFR. In the present study, a MYB TF MdMYB308L was found to also positively regulate cold tolerance and anthocyanin accumulation in apple. We found that MdMYB308L interacted with MdbHLH33 and enhanced its binding to the promoters of MdCBF2 and MdDFR. In addition, an apple RING E3 ubiquitin ligase MYB30‐INTERACTING E3 LIGASE 1 (MdMIEL1) was identified to be an MdMYB308L‐interacting protein and promoted the ubiquitination degradation of MdMYB308L, thus negatively regulated cold tolerance and anthocyanin accumulation in apple. These results suggest that MdMYB308L acts as a positive regulator in cold tolerance and anthocyanin accumulation in apple by interacting with MdbHLH33 and undergoes MdMIEL1‐mediated protein degradation. The dynamic change in MYB‐bHLH protein complex seems to play a key role in the regulation of plant growth and development.

Salviae miltiorrhizae radix et rhizoma is a traditional herbal medicine with anti-cancer activities. In this work, a trace peak enrichment approach combined with a cell proliferation assay was applied for screening cancer cell proliferation inhibitors from the extract of S. miltiorrhiza. A set of 123 peak fractions were prepared, and by comprehensive screening, 21 tanshinones were screened out as cancer cell proliferation inhibitors and their structures were tentatively identified by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis. The inhibitory activities of nine available screened tanshinones were validated, with their IC50 values ranging from 0.63 to 28.40 μM, indicating their activities strongly inhibit the proliferation of cancer cells. This study presents tanshinones that are potential cancer cell proliferation inhibitors and may explain the anti-cancer activity of S. miltiorrhiza.

Three new stilbenoids, including α-(3′-O-β-D-glucopyranosyl-5′-methoxyphenyl)-2-methoxy-3-methylbenzofuran (1), 4-methyl-(E)-resveratrol 3-(2″-p-hydroxybenzoyl)-O-β-D-glucopyranoside (2), and 5-O-methyl-(E)-resveratrol 3-(6″-acetyl)-O-β-D-glucopyranoside (3), together with six known stilbenoids and phenols, acetovanillone 1-(6′-vanilloyl)-O-β-D-glucopyranoside, eugenyl-O-β-D-glucopyranoside, α-(3′-hydroxy-5′-methoxy-2′-methylphenyl)-2-hydroxybenzofuran, α-(3′-hydroxy-5′-methoxyphenyl)-2-hydroxybenzofuran, pinosilvin 3-O-β-D-glucopyranoside, and (E)-resveratrol 3-(6″-galloyl)-O-β-D-glucopyranoside were isolated from the EtOH extract of the stem bark of Acanthopanax brachypus. Their structures were determined by spectral analysis including extensive 2D-NMR spectral analyses. Compounds 2 and 3 exhibited weak cytotoxicity against human tumor A549 cell line (IC50 values of 4.87 and 5.63 μM, resp.).

Androgens regulate body composition in youth and declining testosterone that occurs with aging is associated with muscle wasting, increased fat mass and osteopenia. Transgenic mice with targeted androgen receptor (AR) over-expression in mesenchymal stem cells (MSC) were generated to explore the role of androgen signaling in the regulation of body composition. Transgenic males, but not females, were shorter and have reduced body weight and visceral fat accumulation. Dual-energy X-ray absorptiometry (DXA) revealed significant reductions in fat mass with a reciprocal increase in lean mass, yet no difference in food consumption or locomotor activity was observed. Adipose tissue weight was normal in brown fat but reduced in both gonadal and perirenal depots, and reduced hyperplasia was observed with smaller adipocyte size in visceral and subcutaneous white adipose tissue. Although serum leptin, adiponectin, triglyceride, and insulin levels were no different between the genotypes, intraperitoneal glucose tolerance testing (IPGTT) showed improved glucose clearance in transgenic males. High levels of the AR transgene are detected in MSCs but not in mature fat tissue. Reduced fibroblast colony forming units indicate fewer progenitor cells resident in the marrow in vivo. Precocious expression of glucose transporter 4 (GLUT4), peroxisome proliferator-activated receptor γ (PPARγ), and CCAAT enhancer-binding protein α (C/EBPα) was observed in proliferating precursor cultures from transgenic mice compared to controls. In more mature cultures, there was little difference between the genotypes. We propose a mechanism where enhanced androgen sensitivity can alter lineage commitment in vivo to reduce progenitor number and fat development, while increasing the expression of key factors to promote smaller adipocytes with improved glucose clearance.

Two new natural products, i.e., 1-O,2-O-[(1S,2S)-1-(3-acetyl-2,4,6-trihydroxyphenyl)-3-hydroxypropane-1,3-diyl]-β-D-glucopyranose (=tomentoside I; 1) and (3β)-3-(acetyloxy)ferruginol 12-[6-O-(4-hydroxy-3,5-dimethoxybenzoyl)-β-D-glucopyranoside] (=tomentoside II; 2), were isolated from the EtOH extract of the root of Anemone tomentosa, together with five known compounds. Their structures were characterized by means of spectroscopic methods, especially by 1H-, 13C-, and 2D-NMR and HR-MS, as well as by chemical methods and comparison with literature data.

A straightforward synthesis of syn-1,3-aminoalcohols as well as their N-methyl derivatives is achieved by Ru-catalyzed rearrangement of isoxazolidines and subsequent aminolytic or reductive ring opening.

Bioassay-guided phytochemical investigation of the stalks of Microtropis triflora Merr. & F.L. Freeman led to the isolation of ten triterpenes 1 - 10, including one novel compound 3,24-epoxy-2α,24-dihydroxyfriedelan-29-oic acid (1). Their chemical structures were identified on the basis of spectroscopic analysis, including HR-ESI mass spectrometry, 1D- and 2D-NMR (1 H, 13 C, 1 H,1 H-COSY, HSQC, HMBC, and NOESY), and by comparison with the data reported. The cytotoxicities of compounds 1 - 10 against a panel of cultured human tumor cell lines (Bcap37, SMMC7721, HeLa, CNE) were evaluated. The new compound 1 showed moderate anti-tumor activities with IC50 values of 39.22, 29.24, 23.28, and 68.81 μm/ml, respectively. These results might be helpful for explaining the use of M. triflora in traditional medicine. Triterpenes are characteristic of Microtropis genus and could be useful as potential chemotaxonomic markers.

The purpose of this study was to examine the impact of CXC chemokines, i.e. macrophage inflammatory protein-2 (MIP-2) and KC, on leukocyte-endothelium interactions in detail and to evaluate the role of P-selectin by use of intravital microscopy in the mouse cremaster muscle. Administration of MIP-2 and KC provoked a dose (5 - 500 ng)- and time (0 - 4 h)-dependent increase in leukocyte rolling, adhesion and tissue recruitment. Neutrophils comprised more than 92% of the leukocyte response. Pretreatment with an antibody directed against P-selectin (RB40.34) significantly inhibited MIP-2- and KC-induced leukocyte rolling by more than 96%. This marked decrease in rolling abolished firm adhesion and extravascular accumulation of neutrophils (>89% reduction), suggesting that CXC chemokines induce P-selectin-dependent rolling, which in turn apparently is a precondition for the subsequent stationary adhesion and extravasation of neutrophils. Moreover, the extravascular recruitment of leukocytes was evaluated in whole-mounts of the cremaster muscle without preceding intravital microscopy. Using this approach, it was again observed that MIP-2- and KC-induced neutrophil accumulation was completely dependent onP-selectin function. In contrast to the CXC chemokines, administration of the classical chemoattractant formyl-methionyl leucyl phenylalanine (fMLP) did not provoke extravascular tissue accumulation of neutrophils. We could not detect gene expression of CXCR2 in murine endothelial cells, whereas neutrophils were positive, indicating that the stimulatory effect of CXC chemokines on leukocyte-endothelium interactions is not a direct effect on the endothelium but rather an indirect effect via activation of an intermediary tissue cell. However, challenge with MIP-2 and KC did not increase the number of degranulated mast cells. In conclusion, our data demonstrate that CXC chemokines induce all steps in the extravasation process of leukocytes, including rolling, adhesion and transmigration in vivo. Moreover, these results show that P-selectin plays a critical role in MIP-2 and KC provoked neutrophil recruitment as a critical mediator of initial leukocyte rolling. Additionally, our study suggest that a restricted action of MIP-2 and KC on neutrophils is far too simplistic to explain the complex mechanisms of action of CXC chemokines on neutrophil infiltration in vivo.