The Aqueous Soluble Polyphenolic Fraction of Psidium guajava Leaves Exhibits Potent Anti-Angiogenesis and Anti-Migration Actions on DU145 Cells

The aqueous extract of Psidium guajava budding leaves (PE) bears an extremely high content of polyphenolic and isoflavonoids. Whether it could be used as an anti-tumor chemopreventive in view of anti-angiogenesis and anti-migration, we performed the assay methods including the MTT assay to examine the cell viability; the ELISA assay to test the expressions of VEGF, IL-6 and IL-8; the western blot analysis to detect TIMP-2; the gelatinolytic zymography to follow the expression of MMPs; the wound scratch assay to examine the migration capability; and the chicken chorioallantoic membrane assay to detect the suppressive angiogenesis. Results indicated that the IC50 of PE for DU145 cells was ∼0.57 mg ml−1. In addition, PE effectively inhibited the expressions of VEGF, IL-6 and IL-8 cytokines, and MMP-2 and MMP-9, and simultaneously activated TIMP-2 and suppressed the cell migration and the angiogenesis. Conclusively, PE potentially possesses a strong anti-DU145 effect. Thus, clinically it owns the potential to be used as an effective adjuvant anti-cancer chemopreventive

Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci

<p>Abstract</p> <p>Background</p> <p>Spinocerebellar ataxia type 8 (SCA8) involves the expression of an expanded CTG/CAG combined repeats (CR) from opposite strands producing CUG expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and a polyglutamine expansion protein (ataxin 8, ATXN8). The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad.</p> <p>Results</p> <p>Using stably induced cell models expressing 0, 23, 88 and 157 CR, we study the role of ATXN8OS transcripts in SCA8 pathogenesis. In the absence of doxycycline, the stable ATXN8OS CR cell lines exhibit low levels of ATXN8OS expression and a repeat length-related increase in staurosporine sensitivity and in the number of annexin positive cells. A repeat length-dependent repression of ATXN8OS expression was also notable. Addition of doxycycline leads to 25~50 times more ATXN8OS RNA expression with a repeat length-dependent increase in fold of ATXN8OS RNA induction. ChIP-PCR assay using anti-dimethyl-histone H3-K9 and anti-acetyl-histone H3-K14 antibodies revealed increased H3-K9 dimethylation and reduced H3-K14 acetylation around the ATXN8OS cDNA gene in 157 CR line. The repeat length-dependent increase in induction fold is probably due to the increased RNA stability as demonstrated by monitoring ATXN8OS RNA decay in cells treated with the transcriptional inhibitor, actinomycin D. In cells stably expressing ATXN8OS, RNA FISH experiments further revealed ribonuclear foci formation in cells carrying expanded 88 and 157 CR.</p> <p>Conclusion</p> <p>The present study demonstrates that the expanded CUG-repeat tracts are toxic to human cells and may affect ATXN8OS RNA expression and stability through epigenetic and post-transcriptional mechanisms.</p

Structural Characteristics and Antioxidative Capability of the Soluble Polysaccharides Present in Dictyophora indusiata

Dictyophora indusiata (Vent. ex Pers.) Fish Phallaceae (Chinese name Zhu-Sūn, the bamboo fungi) has been used as a medicinal mushroom to treat many inflammatory, gastric and neural diseases since 618 AD in China. We hypothesize that the soluble polysaccharides (SP) present in D. indusiata and their monosaccharide profiles can act as an important role affecting the antioxidative capability, which in turn would influence the biological activity involving anti-inflammatory, immune enhancing and anticancer. We obtained six SP fractions and designated them as D1, a galactoglucan; D2, a galactan; D3, the isoelectrically precipitated riboglucan from 2% NaOH; D4, a myoinositol; D5 and D6, the mannogalactans. The total SP accounted for 37.44% w/w, their molecular weight (MW) ranged within 801–4656 kDa. D3, having the smallest MW 801 kDa, exhibited the most potent scavenging effect against the α,α-diphenyl-β-picrylhydrazyl, •OH−, and •O2− radicals, yielding IC50 values 0.11, 1.02 and 0.64 mg mL−1, respectively. Thus we have confirmed our hypothesis that the bioactivity of D. indusiata is related in majority, if not entirely, to its soluble polysaccharide type regarding the MW and monosaccharide profiles

Major Functional Transcriptome of an Inferred Center Regulator of an ER(−) Breast Cancer Model System

We aimed to find clinically relevant gene activities ruled by the signal transducer and activator of transcription 3 (STAT3) proteins in an ER(−) breast cancer population via network approach. STAT3 is negatively associated with both lymph nodal category and stage. MYC is a component of STAT3 network. MYC and STAT3 may co-regulate gene expressions for Warburg effect, stem cell like phenotype, cell proliferation and angiogenesis. We identified a STAT3 network in silico showing its ability in predicting its target gene expressions primarily for specific tumor subtype, tumor progression, treatment options and prognostic features. The aberrant expressions of MYC and STAT3 are enriched in triple negatives (TN). They promote histological grade, vascularity, metastasis and tumor anti-apoptotic activities. VEGFA, STAT3, FOXM1 and METAP2 are druggable targets. High levels of METAP2, MMP7, IGF2 and IGF2R are unfavorable prognostic factors. STAT3 is an inferred center regulator at early cancer development predominantly in TN

Deactivation of TBP contributes to SCA17 pathogenesis

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by the expansion of polyglutamine (polyQ) within the TATA box-binding protein (TBP). Previous studies have shown that polyQexpanded TBP forms neurotoxic aggregates and alters downstream genes. However, how expanded polyQ tracts affect the function of TBP and the link between dysfunctional TBP and SCA17 is not clearly understood. In this study, we generated novel Drosophila models for SCA17 that recapitulate pathological features such as aggregate formation, mobility defects and premature death. In addition to forming neurotoxic aggregates, we determined that polyQ-expanded TBP reduces its own intrinsic DNA-binding and transcription abilities. Dysfunctional TBP also disrupts normal TBP function. Furthermore, heterozygous dTbp amorph mutant flies exhibited SCA17-like phenotypes and flies expressing polyQ-expanded TBP exhibited enhanced retinal degeneration, suggesting that loss of TBP function may contribute to SCA17 pathogenesis. We further determined that the downregulation of TBP activity enhances retinal degeneration in SCA3 and Huntington&apos;s disease fly models, indicating that the deactivation of TBP is likely to play a common role in polyQ-induced neurodegeneration

Impact of cognitive behavior therapy on osteoarthritis-associated pain, insomnia, depression, fatigue, and physical function in patients with knee/hip osteoarthritis: A systematic review and meta-analysis of randomized controlled trials

BackgroundThis meta-analysis aimed at evaluating the efficacy of cognitive behavior therapy (CBT) against osteoarthritis-associated symptoms in patients with knee/hip osteoarthritis.MethodsMedline, PubMed, Cochrane Library, and EMBASE databases were searched from inception to July 2022 to identify randomized controlled trials (RCTs) comparing the efficacy of CBT with other treatment approaches in adults with confirmed knee/hip osteoarthritis. The pain intensity (primary outcome) and the secondary outcomes including insomnia severity, sleep efficiency, physical function as well as the severity of depression and fatigue were assessed at two time points (i.e., immediately after treatment and during the follow-up period). The effect size is expressed as standardized mean difference (SMD) with SMDs of &lt; 0.2, 0.2–0.5, and 0.5–0.8, and &gt; 0.8 representing negligible, small, medium, and large effect sizes, respectively.ResultsFifteen RCTs were included for analysis. Immediately after CBT intervention, meta-analysis showed similar treatment effect in pain severity [SMD = –0.46, 95% confidence interval (CI): –0.95 to 0.04, 11 studies, 1557 participants] and other symptoms including depression (SMD = –0.26, 95% CI: –0.58 to 0.06, five studies, 735 participants), fatigue (SMD = –2.44, 95% CI:–6.53 to 1.65, two RCTs, 511 participants), and physical function (SMD = –0.11, 95% CI:–0.25 to 0.02, five RCTs, 720 participants) between CBT and control groups, while there was an improvement in insomnia severity (SMD = –0.65, 95% CI: –1.06 to –0.24, four RCTs, 639 participants, medium treatment effect) and sleep efficiency (SMD = 0.32, 95% CI: 0.04 to 0.59, three RCTs, 352 patients, small treatment effect). During follow-up, CBT improved pain severity (SMD = –0.52, 95% CI: –1.03 to –0.01, eight studies, 1447 participants, medium treatment effect), insomnia (SMD = –0.43, 95% CI: –0.85 to –0.01, three RCTs, 571 participants, small treatment effect), and depression (SMD = –0.39, 95% CI: –0.59 to –0.18, four RCTs, 791 participants, small treatment effect). Nevertheless, sleep efficiency, fatigue, and physical function were not improved in the follow-up period.ConclusionOur results may suggest the durability of CBT-associated treatment benefits, supporting its role as a potential promising alternative or complementary intervention for patients with knee/hip osteoarthritis, especially against pain and insomnia. Future large-scale investigations are warranted to verify our findings.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022331165]

Role of the CCAAT-Binding Protein NFY in SCA17 Pathogenesis

Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK-293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q61∼79, the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17