Notopterygium Incisum Extract Promotes Apoptosis by Preventing the Degradation of BIM in Colorectal Cancer.

OBJECTIVE: Colorectal cancer (CRC), a prevalent malignancy worldwide, has prompted extensive research into anticancer drugs. Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities. This study investigated the effects of Notopterygium incisum, a traditional Chinese medicine named Qianghuo (QH), on CRC cells and the underlying mechanism. METHODS: The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2. Propidium iodide (PI) staining was utilized to detect cell cycle progression, and PE Annexin V staining to detect apoptosis. Western blotting was conducted to examine the levels of apoptotic proteins, including B-cell lymphoma 2-interacting mediator of cell death (BIM), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX) and cleaved caspase-3, as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide. The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis. The in vivo effects of QH extract on tumor growth were observed using a xenograft model. Lastly, APCMin+ mice were used to study the effects of QH extract on primary intestinal tumors. RESULTS: QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation, perturbation of cell cycle progression, and induction of apoptosis. Mechanistically, QH extract significantly increased the stability of BIM proteins, which undergo rapid degradation under unstressed conditions. Knockdown of BAX, the downstream effector of BIM, significantly rescued QH-induced apoptosis. Furthermore, the in vitro effect of QH extract was recapitulated in vivo. QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APCMin+ mice. CONCLUSION: QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.

Construction of a circRNA-Mediated ceRNA Network Reveals Novel Biomarkers for Aortic Dissection.

Background: Aortic dissection (AD) is a rare and lethal disorder with its genetic basis remains largely unknown. Many studies have confirmed that circRNAs play important roles in various physiological and pathological processes. However, the roles of circRNAs in AD are still unclear and need further investigation. The present study aimed to elucidate the underlying molecular mechanisms of circRNAs regulation in AD based on the circRNA-associated competing endogenous RNA (ceRNA) network. Methods: Expression profiles of circRNAs (GSE97745), miRNAs (GSE92427), and mRNAs (GSE52093) were downloaded from Gene Expression Omnibus (GEO) databases, and the differentially expressed RNAs (DERNAs) were subsequently identified by bioinformatics analysis. CircRNA-miRNA-mRNA ceRNA network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to predict the potential functions of circRNA-associated ceRNA network. RNA was isolated from human arterial blood samples after which qRT-PCR was performed to confirm the DERNAs. Results: We identified 14 (5 up-regulated and 9 down-regulated) differentially expressed circRNAs (DEcircRNAs), 17 (8 up-regulated and 9 down-regulated) differentially expressed miRNAs (DEmiRNAs) and 527 (297 up-regulated and 230 down-regulated) differentially expressed mRNAs (DEmRNAs) (adjusted P-value <0.05 and | log2FC | > 1.0). KEGG pathway analysis indicated that DEmRNAs were related to focal adhesion and extracellular matrix receptor interaction signaling pathways. Simultaneously, the present study constructed a ceRNA network based on 1 circRNAs (hsa_circRNA_082317), 1 miRNAs (hsa-miR-149-3p) and 10 mRNAs (MLEC, ENTPD7, SLC16A3, SLC7A8, TBC1D16, PAQR4, MAPK13, PIK3R2, ITGA5, SERPINA1). qRT-PCR demonstrated that hsa_circRNA_082317 and ITGA5 were significantly up-regulated, and hsa-miR-149-3p was dramatically down-regulated in AD (n = 3). Conclusion: This is the first study to demonstrate the circRNA-associated ceRNA network is altered in AD, implying that circRNAs may play important roles in regulating the onset and progression and thus may serve as potential biomarkers for the diagnosis and treatment of AD.

Autophagy inhibitors increase the susceptibility of KRAS-mutant human colorectal cancer cells to a combined treatment of 2-deoxy-D-glucose and lovastatin.

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (>3.75 µM) and 2-deoxy-D-glucose (>1.25 mM) synergistically reduced cell viability, arrested cells in the G2/M phase, and induced apoptosis. The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate, resulting in decreased production of ATP and lower steady-state ATP levels. Energy depletion markedly activated AMPK, inhibited mTOR and RAS signaling pathways, eventually inducing autophagy, the cellular pro-survival process under metabolic stress, whereas inhibition of autophagy by chloroquine (6.25 µM) enhanced the cytotoxic effect of the combination of lovastatin and 2-deoxy-D-glucose. These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells. Our findings suggest that concurrently targeting glycolysis, oxidative phosphorylation, and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.

Clinical characteristics, metabolic features, and phenotype of Chinese women with polycystic ovary syndrome: a large-scale case-control study.

AIM: The Rotterdam criteria extend the phenotypic spectrum of polycystic ovary syndrome (PCOS). The study was to investigate the clinical and biochemical features of a large-scale clinic based on the samples of Chinese women and to evaluate the value of Rotterdam criteria on Chinese PCOS women. METHODS: One thousand four hundred and four Chinese women were involved in our study, among whom, 719 cases were diagnosed as PCOS based on 2003 Rotterdam criteria, and 685 women without history of hyperandrogenism and with regular menstrual cycles were recruited as control. Clinical features, ultrasonographic (ovarian follicle number and volume), hormonal and metabolic parameters were commenced as outcome measures. RESULTS: Among 719 PCOS women, 6.1 % had hirsutism, 13.3 % had acne, 21.1 % had hyperandrogenism, 94.2 % had polycystic ovaries on ultrasonographic examination, and 88.6 % had menstrual abnormality. About one-third of the total PCOS patients were insulin resistant. The most frequent PCOS phenotype is the non-hyperandrogenic phenotype (O + P). Total testosterone, LH/FSH ratio, body mass index (BMI), and Ferriman and Gallwey scores (F-G) were all significantly higher in PCOS groups compared with non-PCOS group. Women with PCOS and obesity had higher serum testosterone, fasting insulin, longer menstrual cycle and larger ovarian follicle number, and LH/FSH ratio, estradiol or ovarian volume were similar between obese and normal BMI women. The LH level was statistically lower in the obese PCOS group. CONCLUSIONS: Rotterdam criteria are generally applicable to Chinese population. Chinese women with PCOS showed lower rates of hyperandrogenemia, hirsutism, obesity, and insulin resistance. Obesity aggravates menstrual irregularity and increases the follicle number and serum total testosterone level.

[Cognitive neuroscience of stress].

Stress has profound impacts on physiology, the brain, cognition and behaviour. In response to stress, the brain initiates several neuromodulatory and endocrine systems. This leads to the release of stress-sensitive mediators, including neuromodulators, hormones and neuropeptides, which in turn feed back on the brain and thus alters cognition and behaviour. As the progress of sophisticated cognitive neuroimaging techniques, cognitive neuroscientists have begun to elucidate the psychological and neural mechanisms underlying detrimental and beneficial effects of stress on emotion, cognition and behaviour in the human brain. Stress-related neuromodulations occur at various stages of information processing, from the initial vigilance, attention, executive functions, learning and memory, and emotion. We reviewed recent advances in cognitive neuroscience of stress and proposed a multidimensional model of stress for better understanding how stress-sensitive neuromodulatory and endocrine systems interplay to impact the brain, cognition and behaviour in humans.