Berberine (BBR) has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR's plasma level ...is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MS(n)-IT-TOF) as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS) was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg). The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR's level in most of studied tissues was higher (or much higher) than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR's metabolites was also investigated paralleled with that of BBR. Thalifendine (M1), berberrubine (M2) and jatrorrhizine (M4), which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t) (area under the concentration-time curve) for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites) was higher than its concentration in the blood after oral administration. It might explain BBR's pharmacological effects on human diseases in clinic.
Total knee arthroplasty (TKA) is one of the most common surgeries performed to relieve joint pain in patients with end‐stage osteoarthritis or rheumatic arthritis of the knee. However, TKA is ...followed by moderate to severe postoperative pain that affects postoperative rehabilitation, patient satisfaction, and overall outcomes. Historically, opioids have been widely used for perioperative pain management of TKA. However, opioids are associated with undesirable adverse effects, such as nausea, respiratory depression, and retention of urine, which limit their application in daily clinical practice. The aim of this review was to discuss the current postoperative pain management regimens for TKA. Our review of the literature demonstrated that multimodal analgesia is considered the optimal regimen for perioperative pain management of TKA and improves clinical outcomes and patient satisfaction, through a combination of several types of medications and delivery routes, including preemptive analgesia, neuraxial anesthesia, peripheral nerve blockade, patient‐controlled analgesia and local infiltration analgesia, and oral opioid/nonopioid medications. Multimodal analgesia provides superior pain relief, promotes recovery of the knee, and reduces opioid consumption and related adverse effects in patients undergoing TKA.
Purpose
Microvascular invasion (MVI) is a valuable predictor of survival in hepatocellular carcinoma (HCC) patients. This study developed predictive models using eXtreme Gradient Boosting (XGBoost) ...and deep learning based on CT images to predict MVI preoperatively.
Methods
In total, 405 patients were included. A total of 7302 radiomic features and 17 radiological features were extracted by a radiomics feature extraction package and radiologists, respectively. We developed a XGBoost model based on radiomics features, radiological features and clinical variables and a three-dimensional convolutional neural network (3D-CNN) to predict MVI status. Next, we compared the efficacy of the two models.
Results
Of the 405 patients, 220 (54.3%) were MVI positive, and 185 (45.7%) were MVI negative. The areas under the receiver operating characteristic curves (AUROCs) of the Radiomics-Radiological-Clinical (RRC) Model and 3D-CNN Model in the training set were 0.952 (95% confidence interval (CI) 0.923–0.973) and 0.980 (95% CI 0.959–0.993), respectively (
p
= 0.14). The AUROCs of the RRC Model and 3D-CNN Model in the validation set were 0.887 (95% CI 0.797–0.947) and 0.906 (95% CI 0.821–0.960), respectively (
p
= 0.83). Based on the MVI status predicted by the RRC and 3D-CNN Models, the mean recurrence-free survival (RFS) was significantly better in the predicted MVI-negative group than that in the predicted MVI-positive group (RRC Model: 69.95 vs. 24.80 months,
p
< 0.001; 3D-CNN Model: 64.06 vs. 31.05 months,
p
= 0.027).
Conclusion
The RRC Model and 3D-CNN models showed considerable efficacy in identifying MVI preoperatively. These machine learning models may facilitate decision-making in HCC treatment but requires further validation.
Chestnut rose, R. roxburghii Tratt. (Rosaceae) (RR) is an important crop in China due to its nutritional and medicinal values. RR frequently produces trichomes on the surfaces of a diverse range of ...organs, however a genetic component exists to the control of trichome development, with some cultivars having significantly fewer trichomes to others. Certain varieties have fruits that are thickly covered with macroscopic trichomes, which is an undesirable trait for fruit processing and consumption. However, smooth‐fruit cultivars exist, such as R. roxburghii Tratt. f. esetosa Ku (RRE). Despite their economic importance, the anatomical features of trichomes have not been explored in detail for these two chestnut rose germplasms. Here, we investigate the ultrastructure of trichomes distributed on the stem, sepal, and fruit of RR and RRE using transmission electron microscopy (TEM). The internal structure of stem prickle trichomes in RR and RRE was oval in shape and did not contain nucleoli or other organelles. The cell walls of stem prickles in RR are thick and the intercellular spaces occupied with liquid, whereas the cells wall of stem prickles in RRE are thin and have air‐filled intercellular spaces. The cells of sepal acicular trichomes in RR and glandular trichomes (GTs) of sepals in RRE had similar vacuole sizes, cytoplasm content, intercellular spaces, and arrangement of plastids within cells. However, there were osmiophilic granules present in the GTs of RRE. The flagelliform trichomes in the sepals of the two germplasms are composed of oval or rod‐shaped cells. Although the flagelliform trichomes in the sepals of the two germplasms had a similar internal structure, and both contained starch grains and plastids with visible thylakoid membranes, the flagelliform trichomes in the sepals of RR had a thinner cell wall and a higher proportion of cytoplasm which was more evenly distributed across the cell. There were granules that stained heavily with osmium tetroxide which occurred infrequently in the flagelliform trichomes of sepals in RRE but were not observed in RR. On the acicular trichomes of fruit in RR, the flagelliform trichomes and the GTs of fruit in RRE shared similar cell morphology, arrangement and vacuole size as well as intercellular space. Both the fruit flagelliform trichomes and GTs in RRE contain granules which stain heavily with osmium tetroxide, and the GTs contain plastids and starch grains. These differences in trichome cell ultrastructure may be related to developmental processes or biological functions of the trichomes. These results also suggest that the two chestnut rose germplasms are good candidates for further study of trichome ontogeny in the genus and subsequent breeding of the smooth organ trait in this species.
TEM images of trichomes in sepal of R. roxburghii Tratt (RR) and R. roxburghii Tratt. f. esetosa Ku (RRE). (a) TEM of acicular trichomes in sepals of RR; (b–e): Local magnification map of a; (f) TEM of flagellate trichomes in sepals of RR; (g–j): Local magnification map of f; k: TEM map of flagellate trichomes in sepals of RRE; (l–o): Local magnification map of k; (p) TEM of GTs in sepals of RRE; (q–t) Local magnification map of p; cw: Cell wall; V: Vacuoles; PDT: Plastids with dilated thylakoids (triangle); starch grains (asterisk); plastids (white arrow); rod‐shaped cells (black arrow) Scale bars: 10 μm (a, f, k, p); 2 μm (b–e, g–j, l–o, q–t).
The cell walls of stem prickles in RR are thick and the intercellular spaces occupied with liquid, whereas the cells wall of stem prickles in R. roxburghii Tratt. f. esetosa Ku are thin and have air‐filled intercellular spaces.
Both the fruit flagelliform trichomes and GTs in R. roxburghii Tratt. f. esetosa Ku contain granules which stain heavily with osmium tetroxide, and the GTs contain plastids and starch grains.
There were granules that stained heavily with osmium tetroxide which occurred infrequently in the flagelliform trichomes of sepals in R. roxburghii Tratt. f. esetosa Ku, but were not observed in R. roxburghii Tratt.
Although the flagelliform trichomes in the sepals of the two germplasms contained starch grains and plastids with visible thylakoid membranes, the flagelliform trichomes of R. roxburghii Tratt had a thinner cell wall and a higher proportion of cytoplasm which was more evenly distributed across the cell.
Melatonin (N‐acetyl‐5‐methoxytryptamine) plays important roles in plant defences against a variety of biotic and abiotic stresses, including UV‐B stress. Molecular mechanisms underlying functions of ...melatonin in plant UV‐B responses are poorly understood. Here, we show that melatonin effect on molecular signalling pathways, physiological changes and UV‐B stress resistance in Arabidopsis. Both exogenous and endogenous melatonin affected expression of UV‐B signal transduction pathway genes. Experiments using UV‐B signalling component mutants cop1‐4 and hy5‐215 revealed that melatonin not only acts as an antioxidant to promote UV‐B stress resistance, but also regulates expression of several key components of UV‐B signalling pathway, including ubiquitin‐degrading enzyme (COP1), transcription factors (HY5, HYH) and RUP1/2. Our findings indicate that melatonin delays and subsequently enhances expression of COP1, HY5, HYH and RUP1/2, which act as central effectors in UV‐B signalling pathway, thus regulating their effects on antioxidant systems to protect the plant from UV‐B stress.
Several studies have demonstrated that melatonin plays a role in UV‐B responses, however, the molecular mechanism whereby melatonin affects the UV‐B pathway was not clear. This study examined the function of melatonin in molecular signaling pathways, physiological changes, and UV‐B stress resistance under UV‐B radiation in Arabidopsis. Exogenous melatonin treatment experiment indicated that melatonin could enhance the transcriptional level of genes on UV‐B signaling pathway and ameliorate ROS damage caused by UV‐B stress. This result was verified in SNAT overexpressing lines and knock‐down mutant.
Ischemic stroke is the major type of cerebrovascular disease usually resulting in death or disability among the aging population globally. Oxidative stress has been closely linked with ischemic ...stroke. Disequilibrium between excessive production of reactive oxygen species (ROS) and inherent antioxidant capacity leads to subsequent oxidative damage in the pathological progression of ischemic brain injury. Acupuncture has been applied widely in treating cerebrovascular diseases from time immemorial in China. This review mainly lays stress on the evidence to illuminate the possible mechanisms of acupuncture therapy in treating ischemic stroke through regulating oxidative stress. We found that by regulating a battery of molecular signaling pathways involved in redox modulation, acupuncture not only activates the inherent antioxidant enzyme system but also inhibits the excessive generation of ROS. Acupuncture therapy possesses the potential in alleviating oxidative stress caused by cerebral ischemia, which may be linked with the neuroprotective effect of acupuncture.
Microsatellite instability (MSI) has been approved as a pan-cancer biomarker for immune checkpoint blockade (ICB) therapy. However, current MSI identification methods are not available for all ...patients. We proposed an ensemble multiple instance deep learning model to predict microsatellite status based on histopathology images, and interpreted the pathomics-based model with multi-omics correlation. Methods: Two cohorts of patients were collected, including 429 from The Cancer Genome Atlas (TCGA-COAD) and 785 from an Asian colorectal cancer (CRC) cohort (Asian-CRC). We established the pathomics model, named Ensembled Patch Likelihood Aggregation (EPLA), based on two consecutive stages: patch-level prediction and WSI-level prediction. The initial model was developed and validated in TCGA-COAD, and then generalized in Asian-CRC through transfer learning. The pathological signatures extracted from the model were analyzed with genomic and transcriptomic profiles for model interpretation. Results: The EPLA model achieved an area-under-the-curve (AUC) of 0.8848 (95% CI: 0.8185-0.9512) in the TCGA-COAD test set and an AUC of 0.8504 (95% CI: 0.7591-0.9323) in the external validation set Asian-CRC after transfer learning. Notably, EPLA captured the relationship between pathological phenotype of poor differentiation and MSI (P < 0.001). Furthermore, the five pathological imaging signatures identified from the EPLA model were associated with mutation burden and DNA damage repair related genotype in the genomic profiles, and antitumor immunity activated pathway in the transcriptomic profiles. Conclusions: Our pathomics-based deep learning model can effectively predict MSI from histopathology images and is transferable to a new patient cohort. The interpretability of our model by association with pathological, genomic and transcriptomic phenotypes lays the foundation for prospective clinical trials of the application of this artificial intelligence (AI) platform in ICB therapy.
Melatonin (N-acetyl-5-methoxytryptamine) is involved in many developmental processes and responses to various abiotic stresses in plants. Most of the studies on melatonin focus on its functions and ...physiological responses in plants, while its regulation mechanism remains unknown. Caffeic acid 3-O-methyltransferase (COMT) functions at a key step of the biosynthesis process of melatonin. In this study, a COMT-like gene,
(Traes_1AL_D9035D5E0.1) was identified in common wheat (
L.). Transient transformation in wheat protoplasts determined that TaCOMT is localized in cytoplasm.
in wheat was induced by drought stress, gibberellin (GA)3 and 3-Indoleacetic acid (IAA), but not by ABA. In
transgenic
, melatonin contents were higher than that in wild type (WT) plants. Under D-Mannitol treatment, the fresh weight of the transgenic
was significantly higher than WT, and transgenic lines had a stronger root system compared to WT. Drought tolerance assays in pots showed that the survival rate of
-overexpression lines was significantly higher than that of WT lines. this phenotype was similar to that the WT lines treated with melatonin under drought condition. In addition, the
transgenic lines had higher proline content and lower malondialdehyde (MDA) content compared to WT lines after drought treatment. These results indicated that overexpression of the wheat
gene enhances drought tolerance and increases the content of melatonin in transgenic
. It could be one of the potential genes for agricultural applications.
Acupuncture is widely applied for treatment of various neurological disorders. This manuscript will review the preclinical evidence of acupuncture in mediating neural plasticity, the mechanisms ...involved.
We searched acupuncture, plasticity, and other potential related words at the following sites: PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and VIP information data base. The following keywords were used: acupuncture, electroacupuncture, plasticity, neural plasticity, neuroplasticity, neurogenesis, neuroblast, stem cell, progenitor cell, BrdU, synapse, synapse structure, synaptogenesis, axon, axon regeneration, synaptic plasticity, LTP, LTD, neurotrophin, neurotrophic factor, BDNF, GDNF, VEGF, bFGF, EGF, NT-3, NT-4, NT-5, p75NTR, neurotransmitter, acetylcholine, norepinephrine, noradrenaline, dopamine, monamine. We assessed the effects of acupuncture on plasticity under pathological conditions in this review.
Relevant references were reviewed and presented to reflect the effects of acupuncture on neural plasticity. The acquired literatures mainly focused on neurogenesis, alterations of synapses, neurotrophins (NTs), and neurotranimitters. Acupuncture methods mentioned in this article include manual acupuncture and electroacupuncture.
The cumulative evidences demonstrated that acupuncture could induce neural plasticity in rodents exposed to cerebral ischemia. Neural plasticity mediated by acupuncture in other neural disorders, such as Alzheimer's disease, Parkinson's disease, and depression, were also investigated and there is evidence of positive role of acupuncture induced plasticity in these disorders as well. Mediation of neural plasticity by acupuncture is likely associated with its modulation on NTs and neurotransmitters. The exact mechanisms underlying acupuncture's effects on neural plasticity remain to be elucidated. Neural plasticity may be the potential bridge between acupuncture and the treatment of various neurological diseases.
Dissolved oxygen (DO) in the water is a vital abiotic factor in aquatic animal farming. A hypoxic environment affects the growth, metabolism, and immune system of fish. Glycolipid metabolism is a ...vital energy pathway under acute hypoxic stress, and it plays a significant role in the adaptation of fish to stressful environments. In this study, we used multi-omics integrative analyses to explore the mechanisms of hypoxia adaptation in Genetically Improved Farmed Tilapia (GIFT, Oreochromis niloticus).
The 96 h median lethal hypoxia (96 h-LH50) for GIFT was determined by linear interpolation. We established control (DO: 5.00 mg/L) groups (CG) and hypoxic stress (96 h-LH50: 0.55 mg/L) groups (HG) and extracted liver tissues for high-throughput transcriptome and metabolome sequencing. A total of 581 differentially expressed (DE) genes and 93 DE metabolites were detected between the CG and the HG. Combined analyses of the transcriptome and metabolome revealed that glycolysis/gluconeogenesis and the insulin signaling pathway were down-regulated, the pentose phosphate pathway was activated, and the biosynthesis of unsaturated fatty acids and fatty acid metabolism were up-regulated in GIFT under hypoxia stress.
The results show that lipid metabolism became the primary pathway in GIFT under acute hypoxia stress. Our findings reveal the changes in metabolites and gene expression that occur under hypoxia stress, and shed light on the regulatory pathways that function under such conditions. Ultimately, this information will be useful to devise strategies to decrease the damage caused by hypoxia stress in farmed fish.
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