Robotic Actuation-Mediated Quantitative Mechanogenetics for Noninvasive and On-Demand Cancer Therapy.

Cell mechanotransduction signals are important targets for physical therapy. However, current physiotherapy heavily relies on ultrasound, which is generated by high-power equipment or amplified by auxiliary drugs, potentially causing undesired side effects. To address current limitations, a robotic actuation-mediated therapy is developed that utilizes gentle mechanical loads to activate mechanosensitive ion channels. The resulting calcium influx precisely regulated the expression of recombinant tumor suppressor protein and death-associated protein kinase, leading to programmed apoptosis of cancer cell line through caspase-dependent pathway. In stark contrast to traditional gene therapy, the complete elimination of early- and middle-stage tumors (volume ≤ 100 mm3) and significant growth inhibition of late-stage tumor (500 mm3) are realized in tumor-bearing mice by transfecting mechanogenetic circuits and treating daily with quantitative robotic actuation in a form of 5 min treatment over the course of 14 days. Thus, this massage-derived therapy represents a quantitative strategy for cancer treatment.

Gastrodin alleviates NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in trigeminal ganglion.

BACKGROUND: Increasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. PURPOSE: Our work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. METHODS/RESULTS: After being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. CONCLUSION: This work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.

Genome-wide identification, evolution, and role of SPL gene family in beet (Beta vulgaris L.) under cold stress.

BACKGROUND: SPL transcription factors play vital roles in regulating plant growth, development, and abiotic stress responses. Sugar beet (Beta vulgaris L.), one of the world's main sugar-producing crops, is a major source of edible and industrial sugars for humans. Although the SPL gene family has been extensively identified in other species, no reports on the SPL gene family in sugar beet are available. RESULTS: Eight BvSPL genes were identified at the whole-genome level and were renamed based on their positions on the chromosome. The gene structure, SBP domain sequences, and phylogenetic relationship with Arabidopsis were analyzed for the sugar beet SPL gene family. The eight BvSPL genes were divided into six groups (II, IV, V, VI, VII, and VIII). Of the BvSPL genes, no tandem duplication events were found, but one pair of segmental duplications was present. Multiple cis-regulatory elements related to growth and development were identified in the 2000-bp region upstream of the BvSPL gene start codon (ATG). Using quantitative real-time polymerase chain reaction (qRT-PCR), the expression profiles of the eight BvSPL genes were examined under eight types of abiotic stress and during the maturation stage. BvSPL transcription factors played a vital role in abiotic stress, with BvSPL3 and BvSPL6 being particularly noteworthy. CONCLUSION: Eight sugar beet SPL genes were identified at the whole-genome level. Phylogenetic trees, gene structures, gene duplication events, and expression profiles were investigated. The qRT-PCR analysis indicated that BvSPLs play a substantial role in the growth and development of sugar beet, potentially participating in the regulation of root expansion and sugar accumulation.

Comprehensive analysis of different types of ginsenosides in the different parts of American ginseng by targeted and nontargeted MS/MS scanning.

To comprehensively study the ginsenosides distribution in the various tissues of American ginseng, the qualitative and quantitative-targeted and nontargeted mass spectroscopic methods were established using the high-performance liquid chromatography coupled with Qtrap triple quadrupole mass spectrometry (HPLC-QtrapQQQ-MS). The total ginsenosides of the root, stem, and leaf of American ginseng were determined by a colorimetric method, and the contents showed the order from high to low root, stem, and leaf. Eighty-two kinds of ginsenosides were detected in the different parts of American ginseng by enhanced mass scan-information-dependent data acquisition (IDA)-enhanced product ion (EPI) scan mode, including 69 from the root, 62 from the stem, and 48 from the leaf. An HPLC-multiple reaction monitoring (MRM) method was established, and 28 representative ginsenosides were further quantified in the three parts. Nearly all ginsenosides had the highest contents in the root and the lowest content in the leaf. Three types of ginsenosides (protopanaxadiol [PPD]-, protopanaxatiol [PPT]-, and oleanolic acid [OA]-types) were analyzed by precursor ion-IDA-EPI and MRM-IDA-EPI scan modes. Root had the most abundant ginsenosides in PPD- and PPT-type ginsenosides. Meanwhile, the OA-type ginsenosides are significantly enriched in the stem and leaf of American ginseng. The results provided a supplement to the quality assessment of American ginseng. PRACTICAL APPLICATION: The distribution profile of ginsenosides in the parts of American ginseng is different. Except for the root, the stem, and leaf of American ginseng have the most abundant ginsenosides in oleanolic acid type. The results reported herein can help the manufacturers choose appropriate materials to extract the ginsenosides.

Identification of novel flavin-dependent monooxygenase from Strobilanthes Cusia reveals molecular basis of indoles' biosynthetic logic.

BACKGROUND: Strobilanthes cusia (Nees) Kuntze is a traditional medical plant distributed widely in south China. The indole compounds that originated from the plant are responsible for its pharmacological activities. However, the reason why indole ingredients are accumulated in this herb and how it is biosynthesized has remained largely unknown. RESULTS: In this study, metabolic and transcriptional profiling measurement experiments of different S. cusia organs were carried out to understand the underlying molecular basis of indoles' biosynthetic logic. A metabolic investigation demonstrated that the indoles are primarily accumulated mainly in aerial parts, particularly in leaves. RNA-seq was employed to reveal the organ specific accumulation of indoles in different S. cusia organs. Meanwhile, a flavin-dependent monooxygenase gene (ScFMO1) was found in S. cusia, and it has capacity to produce indoxyl from indole by the fermentation assay. Finally, we assessed the outcomes of transient expression experiment in tobacco and confirmed that ScFMO1 localizes in cytoplasm. CONCLUSIONS: Our results suggest that ScFMO1 plays a key role in biosynthesis of indoles (Indigo, indirubin, indican, etc.), it will be useful for illuminating the molecular basis of the medicinal indoles' biosynthesis and developing strategies for improving their yields.

Dihydrotanshinone I attenuates estrogen-deficiency bone loss through RANKL-stimulated NF-κB, ERK and NFATc1 signaling pathways.

Postmenopausal osteoporosis, a chronic condition that predominantly affects postmenopausal women, presents a significant impediment to their overall well-being. The condition arises from estrogen deficiency, leading to enhanced osteoclast activity. Salvia miltiorrhiza, a well-established Chinese herbal medicine with a history of clinical use for osteoporosis treatment, contains diverse active constituents that have shown inhibitory effects on osteoclast formation and bone loss. Dihydrotanshinone I (DTI), a phenanthrenonequinone compound derived from the root of Salvia miltiorrhiza, has been identified as a potential therapeutic agent, although its mechanism of action on osteoclasts remains elusive. In this study, we aimed to elucidate the inhibitory potential of DTI on RANKL-induced osteoclastogenesis. We observed the ability of DTI to effectively impede the expression of key osteoclast-specific genes and proteins, as assessed by Real-time PCR and Western Blotting analyses. Mechanistically, DTI exerted its inhibitory effects on osteoclast formation by modulating critical signaling pathways including NF-κB, ERK, and calcium ion signaling. Notably, DTI intervention disrupted the nuclear translocation and subsequent transcriptional activity of the NFATc1, thus providing mechanistic insights into its inhibitory role in osteoclastogenesis. To further assess the therapeutic potential of DTI, we employed an ovariectomized osteoporosis animal model to examine its impact on bone loss. Encouragingly, DTI demonstrated efficacy in mitigating bone loss induced by estrogen deficiency. In conclusion, our investigation elucidates the ability of DTI to regulate multiple signaling pathways activated by RANKL, leading to the inhibition of osteoclast formation and prevention of estrogen-deficiency osteoporosis. Consequently, DTI emerges as a promising candidate for the treatment of osteoporosis.

[Mechanism of Yanghe Decoction against subcutaneous tumor in pulmonary metastasis from breast cancer through HIF-1α signaling pathway regulating glycolysis:based on network pharmacology and animal experiment].

This study aims to explore the mechanism of Yanghe Decoction(YHD) against subcutaneous tumor in pulmonary metastasis from breast cancer, which is expected to lay a basis for the treatment of breast carcinoma with YHD. The chemical components of medicinals in YHD, and the targets of the components were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The disease-related targets were searched from GeneCards and Online Mendelian Inheritance in Man(OMIM). Excel was employed to screen the common targets and plot the Venn diagram. The protein-protein interaction network was constructed. R language was used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. A total of 53 female SPF Bablc/6 mice were randomized into normal group(same volume of normal saline, ig), model group(same volume of normal saline, ig), and low-dose and high-dose YHD groups(YHD, ig, 30 days), with 8 mice in normal group and 15 mice in each of the other groups. Body weight and tumor size was measured every day. Curves for body weight variation and growth of tumor in situ were plotted. In the end, the subcutaneous tumor sample was collected and observed based on hematoxylin and eosin(HE) staining. The mRNA and protein levels of hypoxia inducible factor-1α(HIF-1α), pyruvate kinase M2(PKM2), lactate dehydrogenase A(LDHA), and glucose transporter type 1(GLUT1) were detected by PCR and Western blot. A total of 213 active components of YHD and 185 targets against the disease were screened out. The hypothesis that YHD may regulate glycolysis through HIF-1α signaling pathway to intervene in breast cancer was proposed. Animal experiment confirmed that the mRNA and protein levels of HIF-1α, PKM2, LDHA, and GLUT1 in the high-and low-dose YHD groups were lower than those in the model group. YHD has certain inhibitory effect on subcutaneous tumor in pulmonary metastasis from breast cancer in the early stage, which may intervene pulmonary metastasis from breast cancer by regulating glycolysis through HIF-1α signaling pathway.

San Huang Xiao Yan recipe modulates the HMGB1-mediated abnormal inflammatory microenvironment and ameliorates diabetic foot by activating the AMPK/Nrf2 signalling pathway.

BACKGROUND: Diabetic foot (DF) is one of the serious complications of diabetes and lacks of therapeutic drugs. Abnormal and chronic inflammation promoting foot infection and wound healing delay are the main pathogenesis of DF. The traditional prescription San Huang Xiao Yan Recipe (SHXY) has been used in the clinical treatment of DF for several decades as approved hospital experience prescription and showed remarkable therapeutic effect, but the mechanisms by which SHXY treats DF are still unclear. PURPOSE: Objectives of this study were to investigate SHXY anti-inflammatory effect on DF and explore the molecular mechanism for SHXY. METHODS: We detected the effects of SHXY on DF in C57 mouse and SD rat DF models. Animal blood glucose, weight and wound area were detected every week. Serum inflammatory factors were detected by ELISA. H&E and Masson's trichrome were used to observe tissue pathology. Single-cell sequencing data reanalysis revealed the role of M1 macrophages in DF. Venn analysis showed the co-target genes between DF M1 macrophages and compound-disease network pharmacology. Western blotting was used to explored target protein expression. Meanwhile, RAW264.7 cells were treated with drug-containing serum of SHXY to further unravel the roles of target proteins during high glucose-induced inflammation in vitro. The Nrf2 inhibitor ML385 was used on RAW 264.7 cells to further explore the relationship between Nrf2, AMPK and HMGB1. The main components of SHXY were analysed by HPLC. Finally, the treatment effect of SHXY on DF were detected on rat DF model. RESULTS: In vivo, SHXY can ameliorate inflammatory, accelerate wound healing and upregulate expression of Nrf2, AMPK and downregulate of HMGB1. Bioinformatic analysis showed that M1 macrophages were the main inflammatory cell population in DF. Moreover, the Nrf2 downstream proteins HO-1 and HMGB1 were potential DF therapeutic targets for SHXY. In vitro, we also found that SHXY increased AMPK and Nrf2 protein levels and downregulated HMGB1 expression in RAW264.7 cells. Inhibiting the expression of Nrf2 impaired the inhibition effect of SHXY on HMGB1. SHXY promoted Nrf2 translocation into the nucleus and increased the phosphorylation of Nrf2. SHXY also inhibited HMGB1 extracelluar release under high glucose. In rat DF models, SHXY also exhibited significant anti-inflammatory effect. CONCLUSION: The SHXY activated AMPK/Nrf2 pathway to suppress abnormal inflammation on DF via inhibiting HMGB1 expression. These findings provide novel insight into the mechanisms by which SHXY treats DF.

Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance).

PURPOSE: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. EXPERIMENTAL DESIGN: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). RESULTS: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. CONCLUSIONS: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

Volcanic phosphorus supply boosted Mesozoic terrestrial biotas in northern China.

The Mesozoic terrestrial Jehol Biota of northern China exceeds the biomass and biodiversity of contemporaneous Lagerstätten. From 135 to 120 Ma, biotic radiation may have responded to the peak destruction of the North China Craton. However, the direct mechanistic link between geological and biological evolution is unclear. Phosphorus (P), a bio-essential nutrient, can be supplied by weathering of volcanics in terrestrial ecosystems. The middle-late Mesozoic volcanic-sedimentary sequences of northern China are amazingly rich in terrestrial organisms. Here we demonstrate episodic increases in P delivery, biological productivity, and species abundance in these strata to reveal the coevolution of volcanism and terrestrial biotas. A massive P supply from the weathering of voluminous volcanic products of craton destruction thus supported a terrestrial environment conducive to the high prosperity of the Jehol Biota. During the nascent stage of craton destruction, such volcanic-biotic coupling can also account for the preceding Yanliao Biota with relatively fewer fossils.

Sleep and cancer recurrence and survival in patients with resected Stage III colon cancer: findings from CALGB/SWOG 80702 (Alliance).

BACKGROUND: We sought to assess the influences of sleep duration, sleep adequacy, and daytime sleepiness on survival outcomes among Stage III colon cancer patients. METHODS: We conducted a prospective observational study of 1175 Stage III colon cancer patients enrolled in the CALGB/SWOG 80702 randomised adjuvant chemotherapy trial who completed a self-reported questionnaire on dietary and lifestyle habits 14-16 months post-randomisation. The primary endpoint was disease-free survival (DFS), and secondary was overall survival (OS). Multivariate analyses were adjusted for baseline sociodemographic, clinical, dietary and lifestyle factors. RESULTS: Patients sleeping ≥9 h-relative to 7 h-experienced a worse hazard ratio (HR) of 1.62 (95% confidence interval (CI), 1.01-2.58) for DFS. In addition, those sleeping the least (≤5 h) or the most (≥ 9 h) experienced worse HRs for OS of 2.14 (95% CI, 1.14-4.03) and 2.34 (95% CI, 1.26-4.33), respectively. Self-reported sleep adequacy and daytime sleepiness showed no significant correlations with outcomes. CONCLUSIONS: Among resected Stage III colon cancer patients who received uniform treatment and follow-up within a nationwide randomised clinical trial, very long and very short sleep durations were significantly associated with increased mortality. Interventions targeting optimising sleep health among indicated colon cancer patients may be an important method by which more comprehensive care can be delivered. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01150045.

Tea Polyphenols Reduce Inflammation of Orbital Fibroblasts in Graves' Ophthalmopathy via the NF-κB/NLRP3 Pathway.

OBJECTIVE: This study aimed to explore the effects of tea polyphenols (TP) on inflammation of orbital fibroblasts in Graves' ophthalmopathy (GO) and to provide new ideas for GO treatment. METHODS: Primary orbital fibroblasts were extracted from orbital adipose/connective tissues of patients with and without GO. Real-time quantitative PCR (RT-qPCR) was used to detect the expression of interleukin (IL)-6, IL-1ß, and monocyte chemotactic protein (MCP)-1 in non-GO and GO orbital fibroblasts. The CCK-8 assay was used to determine the appropriate concentration of TP for subsequent experiments. RT-qPCR and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the effects of TP on lipopolysaccharide (LPS)-induced production of inflammatory cytokines. Nuclear factor-κB (NF-κB) expression was measured using Western blotting analysis. NOD-like receptor 3 (NLRP3) expression was detected using both Western blotting analysis and immunofluorescence staining. RESULTS: The mRNA levels of IL-6, IL-1ß, and MCP-1 in GO orbital fibroblasts were significantly higher than those in non-GO cells. TP treatment significantly inhibited LPS-induced production of inflammatory factors, including IL-6, IL-1ß, and MCP-1. TP also inhibited the expression levels of NF-κB and NLRP3. Inflammation in the GO orbital fibroblasts was higher than that in non-GO cells. TP inhibited the production of inflammatory cytokines in GO orbital fibroblasts in vitro through the NF-κB/NLRP3 pathway. CONCLUSION: These findings suggest that TP may have a potential role in GO treatment.

Screening of Monoamine Oxidase Inhibitors from Seeds of Nigella glandulifera Freyn et Sint. by Ligand Fishing and Their Neuroprotective Activity.

Nigella glandulifera is a traditional medicinal plant used to treat seizures, insomnia, and mental disorders among the Tibetan and Xinjiang people of China. Recent pharmacological research indicates that the seeds of this plant have a neuroprotective effect; however, the chemical components responsible for this effect are unknown. Monoamine oxidase B (MAO-B) has been recognized as a target for developing anti-Parkinson's disease drugs. In this work, MAO-B functionalized magnetic nanoparticles were used to enrich the enzyme's ligands in extracts of N. glandulifera seeds for rapid screening of MAO-B inhibitors coupled with HPLC-MS. Tauroside E and thymoquinone were found to inhibit the enzyme with IC50 values of 35.85 µM and 25.54 µM, respectively. Both compounds exhibited neuroprotective effects on 6-OHDA-induced PC-12 cells by increasing the cell viability to 52% and 58%, respectively, compared to 50% of the injured cells. Finally, molecular docking indicated strong interactions of both inhibitors with the enzyme. This work shows that MAO-B functionalized magnetic nanoparticles are effective for rapid screening of anti-PD inhibitors from complex herbal mixtures and, at the same time, shows the promising potential of this plant's seeds in developing anti-PD drugs.

Protective effect of 13-methylberberine against mouse enteritis caused by MRSA.

ETHNOPHARMACOLOGICAL RELEVANCE: The emergence and spread of antibiotic resistance bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), urgently need to develop alternative strategies or novel antibacterial drugs. Coptis chinensis Franch., one ancient Chinese herb, has been widely used for the treatment of intestine disease, such as diarrhea. Alkaloids are the major active compounds of Coptis chinensis Franch., and has anti-inflammatory, antioxidant, and antimicrobial effects. AIM OF THE STUDY: The aim of the study was tried to investigate the potential antibacterial effects of the alkaloids from Coptis chinensis Franch. and explore the mechanism. MATERIALS AND METHODS: A checkerboard assay, time-killing analysis, membrane functions assay, transcriptome analysis, and inducible resistance test showed the antibacterial effects and mechanisms of alkaloids from Coptis chinensis Franch. Hemolytic assay and MRSA-infected RAW264.7 cells were used to evaluate anti-virulence and anti-inflammatory activities of 13-methylberberine (13-MB). MRSA-infected Vero cells and mouse enteritis models were used to evaluate the anti-infectious effect of 13-MB against MRSA both in vitro and in vivo. RESULTS: 13-methylberberine (13-MB) displayed high bactericidal efficiency against methicillin-resistant S. aureus (MRSA). Mechanistic studies showed that 13-MB rapidly killed MRSA by interfering with the proton motive force, ROS generation and membrane fluidity via direct interaction with membrane phospholipids. 13-MB suppressed the virulence of MRSA, modulated the host immune response, and effectively eliminated MRSA in Vero cells. Importantly, 13-MB suppressed weight loss, inflammatory response, bacterial colonization and intestinal lesion in mouse enteritis caused by 13-MB susceptible and resistant S. aureus. CONCLUSION: These results supported the 13-MB has promising potential to be developed as natural drug with antibacterial activity, anti-virulence activity, and host modulation activity for the treatment of enteritis caused by MRSA.

Screening of Monoamine Oxidase B Inhibitors from Fragaria nubicola by Ligand Fishing and Their Neuroprotective Effects.

Fragaria nubicola, known as Tibetan strawberry, is an edible plant possessing various health-promoting effects. However, its functional compositions were rarely studied. In this work, monoamine oxidase B (MAO-B) inhibitors in this plant were rapidly screened using the enzyme-functionalized magnetic nanoparticles coupled with UPLC-QTOF-MS. Two inhibitors, quercetin-3-O-ß-d-glucuronide-6″-methyl ester (1) and kaempferol-3-O-ß-d-glucuronide-6″-methyl ester (2), were identified from this plant with the IC50 values of 19.44 ± 1.17 and 22.63 ± 1.78 µM, respectively. Enzyme kinetic analysis and molecular docking were carried out to investigate the mechanism of inhibition. Contents of both compounds as well as those of total phenolics and flavonoids were quantified to be 24.76 ± 1.26, 35.59 ± 1.17, 837.67 ± 10.62, and 593.46 ± 10.37 µg/g, respectively. In addition, both compounds exhibited significant neuroprotective effects on 6-hydroxydopamine-induced PC12 cells. This is the first report on the neuroprotective components of F. nubicola, suggesting its potential for developing neuroprotective functional food.

Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

PURPOSE: To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer. METHODS: We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS. RESULTS: During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference [RD], 10.6%; 95% CI, 4.7 to 19.4; P < .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1; P < .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9; P < .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8; P < .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2; P = .003). CONCLUSION: Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.

Potential Mediators of Oxaliplatin-Induced Peripheral Neuropathy From Adjuvant Therapy in Stage III Colon Cancer: Findings From CALGB (Alliance)/SWOG 80702.

PURPOSE: We sought to evaluate the independent and interactive associations of planned treatment duration, celecoxib use, physical activity, body mass index (BMI), diabetes mellitus, and vitamin B6 with oxaliplatin-induced peripheral neuropathy (OIPN) among patients with stage III colon cancer enrolled in a clinical trial. METHODS: We conducted a prospective, observational study of 2,450 patients with stage III colon cancer enrolled in the CALGB/SWOG 80702 trial, randomly assigned to 6 versus 12 cycles of adjuvant fluorouracil, leucovorin, and oxaliplatin chemotherapy with or without 3 years of celecoxib. OIPN was reported using the Common Terminology Criteria for Adverse Events (CTCAE) during and following completion of chemotherapy and the FACT/GOG-NTX-13 15-17 months after random assignment. Multivariate analyses were adjusted for baseline sociodemographic and clinical factors. RESULTS: Patients assigned to 12 treatment cycles, relative to 6, were significantly more likely to experience higher-grade CTCAE- and FACT/GOG-NTX-13-reported neuropathy and longer times to resolution, while neither celecoxib nor vitamin B6 intake attenuated OIPN. Exercising ≥ 9 MET-hours per week after treatment relative to < 9 was associated with improvements in FACT/GOG-NTX-13-reported OIPN (adjusted difference in means, 1.47; 95% CI, 0.49 to 2.45; P = .003). Compared with patients with baseline BMIs < 25, those with BMIs ≥ 25 were at significantly greater risk of developing higher-grade CTCAE-reported OIPN during (adjusted odds ratio, 1.18; 95% CI, 1.00 to 1.40; P = .05) and following completion (adjusted odds ratio, 1.23; 95% CI, 1.01 to 1.50; P = .04) of oxaliplatin treatment. Patients with diabetes were significantly more likely to experience worse FACT/GOG-NTX-13-reported neuropathy relative to those without (adjusted difference in means, -2.0; 95% CI, -3.3 to -0.73; P = .002). There were no significant interactions between oxaliplatin treatment duration and any of these potentially modifiable exposures. CONCLUSION: Lower physical activity, higher BMI, diabetes, and longer planned treatment duration, but not celecoxib use or vitamin B6 intake, may be associated with significantly increased OIPN severity.

Anti-cervical cancer effects of Compound Yangshe granule through the PI3K/AKT pathway based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Yangshe granule is a characteristic Chinese preparation against cervical cancer used at Fudan University Shanghai Cancer Center, and it consists of Hedyotis Diffusae Herba, Solani Lyrati Herba, Rubiae Radix et Rhizoma, Echinopsis Radix, Angelicae Sinensis Radix, Codonopsis Radix and Atractylodis Macrocephalae Rhizoma. AIM OF THE STUDY: The objective of the current study was to investigate the preclinical efficacy of compound Yangshe granule against cervical cancer and elucidate the underlying mechanisms. MATERIALS AND METHODS: Antitumor effect of the preparation was investigated in U14 cells in vitro and subcutaneous xenograft mice in vivo. The underlying mechanisms were investigated by through network pharmacological analysis and identified by in vitro study. The components of compound Yangshe granule were collected from the Traditional Chinese Medicine Systems Pharmacology database, and the corresponding targets were predicted by the SwissTargetPrediction database. The targets involved in cervical cancer were collected from the GeneCards, Online Mendelian Inheritance in Man and DrugBank databases. A protein‒protein interaction network was constructed by using the String platform. The drug-disease-target network was plotted by Cytoscape software. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses were performed to investigate hub targets. RESULTS: After treatment with 0.5-10 mg/mL compound Yangshe granule, the survival rates of U14 cells gradually declined to 53.32% for 24 h, 23.62% for 48 h, and 12.81% for 72 h. The apoptosis rates of U14 cells gradually increased to 15.52% for 24 h, 23.87% for 48 h, and 65.01% for 72 h after treatment with 2-10 mg/mL compound Yangshe granule. After oral administration of compound Yangshe granule by xenograft mice, the tumor inhibition rates reached 52.27%, 74.62%, and 82.70% in the low, middle, and high dose groups, respectively. According to the network pharmacological analysis, quercetin, luteolin and naringenin were the most bioactive ingredients of the preparation. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that compound Yangshe granule may combat cervical cancer through the PI3K/AKT pathway. CONCLUSION: In summary, network pharmacology combined with biological experiments demonstrated that the main bioactive components including quercetin, luteolin and naringenin could inhibit the tumor growth by regulating the PI3K/AKT pathway and Bcl-2 family. Thus, compound Yangshe granule may be a promising adjuvant therapy for cervical cancer.

Higher adjuvant radioactive iodine therapy dosage helps intermediate-risk papillary thyroid carcinoma patients achieve better therapeutic effect.

Objective: This retrospective study aims to evaluate the therapeutic effect of varying dosages of adjuvant radioactive iodine (RAI) therapy on intermediate-risk papillary thyroid carcinoma (PTC) patients. Methods: This retrospective study involved a total of 427 intermediate-risk PTC patients, out of which 202 received a 3.7GBq dosage of RAI, and 225 received a 5.55GBq dosage. The evaluation involved assessing the therapeutic outcomes, number of treatment cycles, and successful remnant ablation rates in both dose groups, six months post-adjuvant RAI therapy. Univariate and multivariate logistic regression analyses were employed to identify factors linked with excellent response (ER). Following this, prognostic nomograms were constructed to provide a visual representation of the prediction models. Calibration curves, the concordance index (C-index), and the receiver operating characteristic (ROC) curve were employed to evaluate the predictive performance of these nomograms. The Hosmer-Lemeshow test was applied to assess the models' goodness-of-fit. Additionally, the clinical utility of the prognostic nomograms was appraised through decision curve analysis (DCA). Results: The high-dose (HD) group exhibited significantly higher proportions of ER, single treatment cycles, and successful remnant ablation rates (p<0.05). Being male, receiving a 3.7GBq dose, having an N1b stage, an sTg level ≥10ng/ml, or an sTg/TSH ratio ≥0.11 were independent risk factors for Non-ER. Two prognostic nomograms, "sTg Nomogram" and "sTg/TSH Nomogram", were established. The ranking of factors contributing to ER, in descending order, included the sTg or sTg/TSH ratio, N stage, therapy dosage, sex, and soft tissue invasion. The "sTg/TSH Nomogram" demonstrated a higher C-index compared to the "sTg Nomogram". The calibration curves indicated excellent calibration for both nomograms. DCA demonstrated that the net benefit of the "sTg/TSH Nomogram" was higher than that of the "sTg Nomogram". Conclusion: Higher initial RAI therapy doses can improve therapeutic efficacy for intermediate-risk PTC patients. The developed nomograms, particularly the "sTg/TSH Nomogram", could assist clinicians in optimal therapeutic decision-making.

CmHY5 functions in apigenin biosynthesis by regulating flavone synthase II expression in chrysanthemum flowers.

MAIN CONCLUSION: The predominant flavones in the ray florets of chrysanthemum flowers are apigenin and its derivatives. CmHY5 participates in apigenin biosynthesis by directly regulating the expression of FNSII-1 in chrysanthemum. Chrysanthemum (Chrysanthemum morifolium) flowers have been used for centuries as functional food and in herbal tea and traditional medicine. The chrysanthemum flower contains significant amounts of the biologically active compound flavones, which has medicinal properties. However, the mechanism regulating flavones biosynthesis in chrysanthemum flowers organs is still unclear. Here, we compared the transcriptomes and metabolomes of different floral organs between two cultivars with contrasting flavone levels in their flowers. We identified 186 flavonoids by metabolome analysis. The predominant flavones in the ray florets of chrysanthemum flowers are apigenin and its derivatives, of which the contents are highly correlated with the expression of flavones synthase II gene CmFNSII-1. We also determined that CmHY5 is a direct upstream regulator of CmFNSII-1 transcription. We showed that CmHY5 RNAi interference lines in chrysanthemum have lower contents of apigenin compared to wild-type chrysanthemum. Our results demonstrated that CmHY5 participates in flavone biosynthesis by directly regulating the expression of FNSII-1 in chrysanthemum.