Bibenzyl-Phenylpropane Hybrids with Immunosuppressive Activities from Dendrobium Nobile Lindl.

Fifteen bibenyls and four fluorenones, including five new bibenzyl-phenylpropane hybrids, were isolated from the aerial part of Dendrobium nobile Lindl. Their structures were determined by spectroscopic methods. Bioassay on the LPS-induced proliferations of mouse splenic B lymphocytes, and Con A-induced T lymphocytes showed that compounds 1, 2, and 14 showed excellent immunosuppressive activities with IC50 values of 1.23, 1.01, and 3.87 µM, respectively, while compounds 3-4, 7, 10, 13, and 15 exhibited moderate immunosuppressive activities with IC50 values ranging from 6.89 to 14.2 µM.

Renal CIC-LEUTX rearranged sarcoma with multiple pulmonary metastases: a case report and literature review.

BACKGROUND: CIC-rearranged sarcomas (CRS) are a group of heterogeneous tumors which mostly occur in the soft tissues of limbs and trunk, and are highly invasive with poor prognosis. Here, we describe a rare case of CRS that occurred in the left kidney with a CIC-LEUTX rearrangement. CASE PRESENTATION: A 45-year-old male was admitted to hospital with a dry cough for more than two months without obvious cause. Physical examination and laboratory tests revealed no notable abnormality. The CT scan demonstrated a mass in the left kidney and multiple nodules in both lungs. The percutaneous core needle biopsy showed similar histomorphology and immunophenotype of small round cell malignant tumors. Genetic test revealed a CIC-LEUTX gene fusion. CONCLUSIONS: We present a rare primary renal CRS with multiple pulmonary metastases, and LEUTX is confirmed as the fusion partner of CIC gene for the first time in a renal case.

Cooperation of MLL1 and Jun in controlling H3K4me3 on enhancers in colorectal cancer.

BACKGROUND: Enhancer dysregulation is one of the important features for cancer cells. Enhancers enriched with H3K4me3 have been implicated to play important roles in cancer. However, their detailed features and regulatory mechanisms have not been well characterized. RESULTS: Here, we profile the landscape of H3K4me3-enriched enhancers (m3Es) in 43 pairs of colorectal cancer (CRC) samples. M3Es are widely distributed in CRC and averagely possess around 10% of total active enhancers. We identify 1322 gain variant m3Es and 367 lost variant m3Es in CRC. The target genes of the gain m3Es are enriched in immune response pathways. We experimentally prove that repression of CBX8 and RPS6KA5 m3Es inhibits target gene expression in CRC. Furthermore, we find histone methyltransferase MLL1 is responsible for depositing H3K4me3 on the identified Vm3Es. We demonstrate that the transcription factor AP1/JUN interacts with MLL1 and regulates m3E activity. Application of a small chemical inhibitor for MLL1 activity, OICR-9429, represses target gene expression of the identified Vm3Es, enhances anti-tumor immunity and inhibits CRC growth in an animal model. CONCLUSIONS: Taken together, our study illustrates the genome-wide landscape and the regulatory mechanisms of m3Es in CRC, and reveals potential novel strategies for cancer treatment.

Effect of physical activity on risk of Alzheimer's disease: A systematic review and meta-analysis of twenty-nine prospective cohort studies.

OBJECTIVE: Physical activity (PA) is beneficial in reductions of all-cause mortality and dementia. However, whether Alzheimer's disease (AD) risk is modified by PA remains disputable. This meta-analysis aims to disclose the underlying relationship between PA and incident AD. METHODS: Pubmed, Embase, Cochrane Library, and Web of Science were retrieved from inception to June 2023. Random-effects models were employed to derive the effect size, represented by hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Twenty-nine prospective cohort studies involving 2068,519 participants were included. The pooled estimate showed a favorable effect of PA on AD risk decline (HR 0.72, 95% CI 0.65-0.80). This association remained robust after adjusting for maximum confounders (HR 0.85, 95% CI 0.79-0.91). Subgroup analysis of PA intensity demonstrated an inverse dose-response relationship between PA and AD, effect sizes of which were significant in moderate (HR 0.85, 95% CI 0.80-0.93) and high PA (HR 0.56, 95% CI 0.45-0.68), but not in low PA (HR 0.94, 95% CI 0.77-1.15). Regardless of all participants or the mid-life cohort, the protection of PA against AD appeared to be valid in shorter follow-up (<15 years) rather than longer follow-up (≥15 years). In addition to follow-up, the robustness of the estimates persisted in supplementary meta-analyses, meta-regression analyses, and sensitivity analyses. CONCLUSION: PA intervention reduces the incidence of AD, but merely in moderate to vigorous PA with follow-up of less than 15 years, thus conditionally recommending the popularization of PA as a modifiable lifestyle factor to prevent AD.

Associations of 10 trace element levels in the whole blood with risk of three types of obesity in the elderly.

BACKGROUND: Currently, over 2 billion people worldwide suffer from obesity, which poses a serious health risk. More and more attention is being given to the effects of trace elements on obesity in recent years. Synergistic or antagonistic interactions among these elements can adversely or positively impact human health. However, epidemiological evidence on the relationship between trace element exposure levels and obesity has been inconclusive. METHODS: Baseline data of 994 participants from the Cohort of Elderly Health and Environment Controllable Factors were used in the present study. ICP-MS was used to measure the concentrations of 10 trace elements in the whole blood of the older population. Binary logistic regression, restricted cubic splines (RCS) models, and Bayesian kernel machine regression (BKMR) models were employed to assess single, nonlinear, and mixed relationships between 10 trace element levels and three types of obesity based on body mass index (BMI), waist circumference (WC), and body fat percentage (BFP) in the elderly. RESULTS: Based on BMI, WC and BFP, 51.8% of the included old population were defined as general overweight/obesity, 67.1% as abdominal obesity, and 36.2% as having slightly high/high BFP. After multivariable adjustment, compared with the lowest tertile, the highest tertile of blood selenium (Se) concentration was associated with an increased risk of all three types of obesity. Additionally, compared with the lowest tertile, higher tertiles of strontium (Sr) concentrations were associated with a lower risk of general overweight/obesity and having slightly high/high BFP, and the highest tertile of barium (Ba) was associated with a lower risk of having slightly high BFP, while higher tertiles of arsenic (As) concentrations were associated with an increased risk of having slightly high/high BFP, and the highest tertile of manganese (Mn) was associated with a higher risk of abdominal obesity. BKMR analyses showed a strong linear positive association between Se and three types of obesity. Higher blood levels of trace element mixture were associated with increased obesity risks in a dose-response pattern, with Se having the highest value of the posterior inclusion probability (PIP) within the mixture. CONCLUSIONS: In this study, we found higher Se levels were associated with an elevated risk of obesity and high levels of Ba, Pb and Cr were associated with a decreased risk of obesity. Studies with larger samples are needed to confirm these findings.

Clinicopathological and prognostic values of MET expression in pancreatic adenocarcinoma based on bioinformatics analysis.

Pancreatic adenocarcinoma (PAAD) is regarded as one of the most lethiferous cancers worldwide because treatment of pancreatic cancer remains challenging and mostly palliative. Little progress had been made to select certain reliable biomarkers as clinical prognosis. In this context, GSE28735 and GSE16515 were obtained from the Gene Expression Omnibus (GEO). GEO2R tool was used to recognize differentially expressed genes (DEGs). 351 DEGs were screened which included 230 up-regulated genes and 121 down-regulated genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze the DEGs and associated signal pathways in the DAVID database. A protein-protein interaction (PPI) network was then constructed to screen 10 hub genes by STRING database and Cityscape software. Analyses of 10 hub genes were performed on GEPIA database and GSCA database, which revealed that MET was high expressed and significantly associated with survival of PAAD patients. Immunohistochemical staining showed that MET was higher expressed in PAAD tissues than adjacent tissues in 20 samples. The clinicopathological analysis revealed that high expression of MET was associated with the degree of differentiation, lymph node metastasis, vascular cancer thrombus and nerve invasion in PAAD tissues (P < .05). Furthermore, the Tumor Immune Estimation Resource (TIMER) database analyzed the correlation between the MET expression level and immune infiltration levels, which elucidated that MET expression was appreciably positively correlated with the infiltration levels of myeloid-derived suppressor cells (MDSCs). Here, these results strongly indicate MET is an unique prognostic biomarker. Its expression level is correlated with certain clinicopathological features and immune cell infiltration.

NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis.

Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5+ (Cdh5+) cerebral vascular cells in naturally aging mice and confirmed it in human brain samples. Global or Cdh5+ cell-specific CX43 deletion in mice exacerbated BBB dysfunction during aging. The CX43-dependent effect was not due to its canonical gap junction function but was associated with reduced NAD+ levels and mitochondrial dysfunction through NAD+-dependent sirtuin 3 (SIRT3). CX43 interacts with and negatively regulates poly(ADP-ribose) polymerase 1 (PARP1). Pharmacologic inhibition of PARP1 by olaparib or nicotinamide mononucleotide (NMN) supplementation rescued NAD+ levels and alleviated aging-associated BBB leakage. These findings establish the endothelial CX43-PARP1-NAD+ pathway's role in vascular aging and identify a potential therapeutic strategy to combat aging-associated BBB leakage with neuroprotective implications.

Horsfielenigans A and B, Two Rearranged Lignans with Anti-Inflammatory Effects from Horsfieldia kingii.

Seven lignans were isolated from 70 % aqueous acetone extracts of the twigs and leaves of Horsfieldia kingii. Among these, new compounds 1-3 were identified by spectroscopic techniques, with horsfielenigans A and B (1 and 2) being particularly noteworthy for their rare ß-benzylnaphthalene skeleton, where compound 1 contains an oxabicyclo[3,2,1]octane moiety. In vitro evaluation of bioactivity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages revealed inhibitory effects by 1 (IC50 =7.3 µM) and 2 (IC50 =9.7 µM).

Immunosuppressive Bibenzyl-phenylpropane Hybrids from Dendrobium devonianum.

Two new bibenzyl-phenylpropane hybrids, dendrophenols A and B (1 and 2), along with nine known bibenzyls, were isolated from the aerial part of Dendrobium devonianum Paxt. Their structures were determined by extensive spectroscopic methods and methylation. Bioassays revealed that compounds 1-9 were specifically immunosuppressive to T lymphocytes with IC50 values ranging from 0.41 to 9.4 µM, of which compounds 1 (IC50 =1.62 µM) and 2 (IC50 =0.41 µM) were promising immunosuppressive agents for T lymphocytes with the selectivity indices of 19.9 and 79.5, respectively.

Chemical Synthesis Enables the Configurational Determination of Myristriol, a Highly Oxygenated Phenylpropanoid from Myristica fragrans Houtt.

A new phenylpropanoid, myristriol (1), along with 11 known ones were isolated from the seed kernel of Myristica fragrans Houtt. Their chemical structures were clearly elucidated by extensive spectroscopic analysis. In which, the relative configuration of 1 was finally determined as erythro-1 by comparison the NMR data of two synthetic erythro- and threo-diastereoisomers with that of natural 1.

Immunosuppressive diarylpropane dimer and spirocyclic-monomers from Horsfieldia kingii.

Horsfiequinone G (1), a dimeric diarylpropane featuring an unprecedentedly oxo-6/7/6 fused ring system, a new flavane, horsfielenide F (2), three naturally occurring spirocyclic monomers containing all-carbon quaternary centers, horspirotone A (3), horspirotone B (4), and methyl spirobroussonin B (5), along with horsfiequinone A (6) were isolated from Horsfieldia kingii. Their structures and absolute configurations were determined by the inspection of extensive spectroscopic data and electronic circular dichroism (ECD) calculations. Biological evaluations of these isolates revealed that compounds 1 - 3 and 5 - 6 exhibited specifically immunosuppressive activities against Con A-induced T lymphocytes with IC50 values ranging from 2.07 to 12.34 µM (selectivity indices = 2.3-25.2). Compound 1 also suppressed the secretion of inflammatory factors like IL-1ß and IL-6 in RAW264.7 cells which could present a new class of nonsteroidal anti-inflammatory agent. Finally, the primary structure-activity relationship (SAR) was also discussed.

Increased hypertension risk for the elderly with high blood levels of strontium and lead.

Hypertension has long been recognized as the global health burden. Heavy metal pollution may be one of the environmental risk factors of hypertension. However, the association remains unclear. We studied the levels of aluminum (Al), vanadium (V), manganese (Mn), arsenic (As), selenium (Se), strontium (Sr), barium (Ba), titanium (Ti), lead (Pb) and cobalt (Co) in whole blood, and the relationship between trace element exposure and hypertension in the elderly community-based Chinese population. A total of 1013 participants from the west of Anhui Province in China were consecutively enrolled in this study in 2016. The general sociodemographic characteristics, lifestyles, disease history and physical examination information were collected by face-to-face survey and physical examination. The levels of ten trace elements were determined by inductively coupled plasma mass spectrometry (ICP-MS). Multivariable logistic regression model was used to assess the association of trace element exposure with the risk of hypertension. Results showed that the odds ratio of hypertension in the highest quartile was 1.811 (95% CI 1.175-2.790, P trend = 0.005) and 1.772 (95% CI 1.121-2.800, P trend = 0.022), respectively, after adjusting for potential confounders, as compared with the lowest quartile of blood Pb and Sr levels.

Role of acyl-coenzyme A oxidase 1 (ACOX1) on palmitate-induced inflammation and ROS production of macrophages in large yellow croaker (Larimichthys crocea).

Acyl-coenzyme A oxidase 1 (ACOX1) is the rate-limiting enzyme in peroxisomal ß-oxidation, and it plays an essential role in mediating the inflammatory response and reactive oxygen species (ROS) metabolism in mammals. However, the role of ACOX1 in fish has not been completely elucidated. Herein, this study was conducted to investigate the role of large yellow croaker (Larimichthys crocea) ACOX1 (Lc-ACOX1) on palmitate (PA)-induced inflammation and ROS production. In this study, Lc-ACOX1 was cloned and characterized. The full-length CDS of Lc-acox1 was 1986 bp, encoding 661 amino acids. Tissue distribution results showed that the gene expression of Lc-acox1 was the highest in the intestine and the lowest in the spleen. Moreover, results showed that the mRNA expression of Lc-acox1 was upregulated by PA, with elevated pro-inflammatory gene expression, including il-1ß, il-6, il-8, tnf-α, cox2 and ifn-γ, as well as ROS content in macrophages of large yellow croaker. Furthermore, the role of Lc-ACOX1 in inflammation induced by PA was investigated by using the ACOX1 inhibitor TDYA. Treatment of macrophages with TDYA reduced the mRNA expression of pro-inflammatory genes induced by PA. Moreover, inhibition of ACOX1 reduced the elevated level of ROS caused by PA and increased the mRNA expression of antioxidant genes. In conclusion, this study first identified that fish ACOX1 was involved in the PA-induced inflammatory response and ROS production.

Isopentenylated Bibenzyls and Phenolic Compounds from Dendrobium chrysotoxum Lindl.

Two new isopentenyl bibenzyls, denchrysotonols A and B (1-2), along with 26 known phenolic compounds, were isolated from the stems of cultivated Dendrobium chrysotoxum Lindl. Their chemical structures were clearly elucidated by extensive spectroscopic analysis. Biological evaluation of isolated compounds revealed that phenanthrenes (14, 16-17, 20, and 22) and fluorenone 25 exhibited anti-inflammatory activities which inhibited nitric oxide (NO) production in LPS-activated RAW264.7 macrophages with the IC50 values ranging from 9.4 to 32.5 µM. Moreover, bibenzyls (1-2 and 7) showed good anti-proliferative activities against triple-negative breast cancer (TNBC) cells (HCC1806, MDA-MB-231, and MB-MB-468) with the IC50 values ranging from 8.1 to 18.6 µM, of which 1 and 2 seemed preferentially inhibit MDA-MB-231 cells.

Deep oxidation of norfloxacin by the electrochemical enhanced heterogeneous catalytic oxidation: The role of electric field and reaction optimization.

In this study, electrochemical (ECG-G: graphite anode and cathode, ECI-G: iron anode and graphite cathode) enhanced heterogeneous activation of peroxymonosulfate (PMS) by CoFe2O4 nanoparticles for the degradation of norfloxacin (NOR) in water was investigated. Although a higher NOR removal efficiency was achieved in ECI-G/CoFe2O4/PMS system, the generation of Fe3+ had resulted in the deposition of iron mud and affect the recovery of CoFe2O4. Under the optimum reaction conditions of CoFe2O4/PMS system, the final removal efficiency of NOR did not show significant difference in ECG-G/CoFe2O4/PMS system (96.0%) and CoFe2O4/PMS system (95.5%), but the value of apparent rate constant significantly increased in ECG-G/CoFe2O4/PMS system (0.21 min-1) compared with CoFe2O4/PMS system (0.11 min-1). Similar NOR degradation pathways were obtained in these two systems, and the TOC removal efficiency in ECG-G/CoFe2O4/PMS system (28.8%) is almost as low as CoFe2O4/PMS system (26.0%). Therefore, it can be proposed that the applied electric field through active electrodes can accelerate the reaction of heterogeneous catalytic oxidation, but does not participate much in NOR degradation. However, the TOC removal efficiency (30 min) could be reached 68.7% as the mass ratio of PMS to CoFe2O4 increased to 5:1 (250 mg L-1: 50 mg L-1). The ECG-G/CoFe2O4/PMS system is a promising low-cost technique for efficient mineralization of antibiotics in wastewater.

Effect of Lipoprotein(a) on Stroke Recurrence Attenuates at Low LDL-C (Low-Density Lipoprotein) and Inflammation Levels.

BACKGROUND: Lp(a) (lipoprotein(a)) contributes to cardiovascular disease mainly through proatherogenic and proinflammatory effects. Here, we aimed to evaluate whether a residual stroke risk of Lp(a) would remain when the LDL-C (low-density lipoprotein cholesterol) and inflammatory levels are maintained low. METHODS: This prospective cohort study included 9899 patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry who had measurements of plasma Lp(a) and were followed up for 1 year. Cutoffs were set at the 50 mg/dL for Lp(a). LDL-C was corrected for Lp(a)-derived cholesterol (LDL-Cc [LDL-C corrected]) and cutoffs were set at 55 and 70 mg/dL.The threshold values of IL-6 (interleukin 6) and hsCRP (high-sensitive C-reactive protein) were the median 2.65 ng/L and 2 mg/L. Multivariable-adjusted hazard ratio (HR) were calculated using Cox regression models for each category to investigate the associations of Lp(a) with stroke recurrence within 1 year. RESULTS: Among all patients, those with Lp(a) ≥50 mg/dL were at higher stroke recurrence risk than those with Lp(a) <50 mg/dL (11.5% versus 9.4%; adjusted HR, 1.20 [95% CI, 1.02-1.42]). However, the risk associated with elevated Lp(a) was attenuated in patients with LDL-Cc <55 mg/dL (high Lp(a) versus low Lp(a): 8.9% versus 9.0%; adjusted HR, 0.92 [95% CI, 0.65-1.30]) or IL-6 <2.65 ng/L (9.0% versus 7.8%; adjusted HR, 1.14 [95% CI, 0.87-1.49]). Notably, in the group with both low LDL-Cc and inflammation levels, the rate of patients with high Lp(a) did not significantly different from the rate of patients with low Lp(a; LDL-Cc <55 mg/dL and IL-6 <2.65 ng/L: 6.2% versus 7.1%; adjusted HR, 0.86 [95% CI, 0.46-1.62]; LDL-Cc <55 mg/dL and hsCRP <2 mg/L: 7.7% versus 7.6%; adjusted HR, 0.97 [95% CI, 0.57-1.66]). However, there was no interaction between the LDL-Cc, IL-6, hsCRP, and Lp(a) levels on stroke recurrence risk. CONCLUSIONS: Increased Lp(a) was significantly associated with stroke recurrence risk in patients with ischemic stroke/transient ischemic attack. However, at low LDL-Cc or IL-6 levels, the elevated Lp(a) -associated stroke recurrence risk was attenuated in a secondary prevention setting.

Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy.

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

Characterization of the diastaphenazine/izumiphenazine C biosynthetic gene cluster from plant endophyte Streptomyces diastaticus W2.

Two phenazine compounds, diastaphenazine and izumiphenazine C, with complex structures and promising antitumour activity have been isolated from the plant endophytic actinomycete Streptomyces diastaticus W2. Their putative biosynthetic gene cluster (dap) was identified by heterologous expression and gene knockout. There are twenty genes in the dap cluster. dap14-19 related to shikimic pathway were potentially involved in the precursor chorismic acid biosynthesis, and dapBCDEFG were confirmed to be responsible for the biosynthesis of the dibenzopyrazine ring, the nuclear structure of phenazines. Two transcriptional regulatory genes dapR and dap4 played the positive regulatory roles on the phenazine biosynthetic pathway. Most notably, the dimerization of the dibenzopyrazine ring in diastaphenazine and the loading of the complex side chain in izumiphenazine C could be catalysed by the cyclase homologous gene dap5, suggesting an unusual modification strategy tailoring complex phenazine biosynthesis. Moreover, metabolite analysis of the gene deletion mutant strain S. albus::23C5Δdap2 and substrate assay of the methyltransferase Dap2 clearly revealed the biosynthetic route of the complex side chain in izumiphenazine C.

Expression of CDK13 Was Associated with Prognosis and Expression of HIF-1α and beclin1 in Breast Cancer Patients.

OBJECTIVE: To investigate role and clinical significance of CDK13 in breast cancer patients. METHODS: A total of 189 cases of breast cancer were enrolled during March 2013 to March 2015. Immunohistochemistry (IHC) was used for measurement of CDK13, HIF-1α and beclin1. Clinical characteristics of age, BMI, TNM stage, pathological types, and tumor diameter, were recorded. Patients' 5-year overall survival and recurrence were followed up. All patients were followed up for 5 years or to the last follow-up. RESULTS: The expression levels of CDK13 and HIF-1αin breast cancer tissues were up-regulated and beclin1 was down-regulated than in the paracancerous non-tumor tissues. CDK13 was positively correlated with HIF-1α and negatively correlated with beclin1 in breast cancer tissues. The patients with higher expression of CDK13 showed significantly higher rates of TNM III-IV, higher rates of lymph node metastasis, distant metastasis and larger tumor size. The mortality and recurrence rates were higher in high expression CDK13 patients than in low CDK13 expression patients, however with no significant difference. K-M curve showed patients with higher CDK13 showed lower 5-year overall survival and lower disease-free survival time, however with no significant difference. CONCLUSION: CDK13 was overexpressed in breast cancer tissues, and patients with higher CDK13 had poorer clinical outcomes. Further studies are still needed to reveal the clinical significance of CDK13 in breast cancer.