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Curcumin exhibits a broad spectrum of beneficial health properties that include anti-tumor and anti-cancer activities. The down-regulation of c-myc transcription via stabilizing the G-quadruplex structure formed at the promoter region of the human c-myc gene allows the repression in cancer growth. Small molecules can bind and stabilize this structure to provide an exciting and promising strategy for anti-cancer therapeutics. Herein, we investigated the interaction of Curcumin and its synthetic analogs with G-quadruplex DNA formed at the c-myc promoter by using various biophysical and biochemical assays. Further, its cytotoxic effect and mechanistic insights were explored in various cancer cell lines as well as in multicellular tumor spheroid (MCTS) model. The MCTS possesses almost similar microenvironment as avascular tumors, and micro-metastases can be used as a suitable model for the small molecule-based therapeutics development. Our study provides an expanded overview of the anti-cancer effect of a new Curcumin analog via targeting G-quadruplex structures formed at the promoter region of the human c-myc gene.

The Australian National COVID-19 Clinical Evidence Taskforce is a consortium of 31 Australian health professional organisations developing living, evidence-based guidelines for care of people with COVID-19, which are updated weekly. This article describes the methods used to develop and maintain the guidelines.

The guidelines use the GRADE methods and are designed to meet Australian NHMRC standards. Each week, new evidence is reviewed, current recommendations are revised, and new recommendations made. These are published in MAGIC and disseminated through traditional and social media. Relevant new questions to be addressed are continually sought from stakeholders and practitioners. For prioritized questions, the evidence is actively monitored and updated. Evidence surveillance combines horizon scans and targeted searches. An evidence team appraises and synthesizes evidence and prepares evidence-to-decision frameworks to inform development of recommendations. A guidelines leadership group oversees the development of recommendations by multidisciplinary guidelines panels and is advised by a consumer panel.

The Taskforce formed in March 2020, and the first recommendations were published 2weeks later. The guidelines have been revised and republished on a weekly basis for 24weeks, and as of October 2020, contain over 90 treatment recommendations, suggesting that living methods are feasible in this context.

The Australian guidelines for care of people with COVID-19 provide an example of the feasibility of living guidelines and an opportunity to test and improve living evidence methods.

The Australian guidelines for care of people with COVID-19 provide an example of the feasibility of living guidelines and an opportunity to test and improve living evidence methods.Rotenone, a mitochondrial complex I inhibitor, has been widely used to study the effects of mitochondrial dysfunction on dopaminergic neurons in the context of Parkinson's disease. Although the deleterious effects of rotenone are well documented, we found that young adult Caenorhabditis elegans showed resistance to 24 and 48 h rotenone exposures. To better understand the response to rotenone in C. elegans, we evaluated mitochondrial bioenergetic parameters after 24 and 48 h exposures to 1 μM or 5 μM rotenone. Results suggested upregulation of mitochondrial complexes II and V following rotenone exposure, without major changes in oxygen consumption or steady-state ATP levels after rotenone treatment at the tested concentrations. We found evidence that the glyoxylate pathway (an alternate pathway not present in higher metazoans) was induced by rotenone exposure; gene expression measurements showed increases in mRNA levels for two complex II subunits and for isocitrate lyase, the key glyoxylate pathway enzyme. Targeted metabolomics analyses showed alterations in the levels of organic acids, amino acids, and acylcarnitines, consistent with the metabolic restructuring of cellular bioenergetic pathways including activation of complex II, the glyoxylate pathway, glycolysis, and fatty acid oxidation. This expanded understanding of how C. elegans responds metabolically to complex I inhibition via multiple bioenergetic adaptations, including the glyoxylate pathway, will be useful in interrogating the effects of mitochondrial and bioenergetic stressors and toxicants.Cadmium (Cd) is recognized as a highly toxic heavy metal for humans in part because it is a multi-organ carcinogen. To clarify the mechanism of Cd carcinogenicity, we have established an experimental system using rat liver TRL1215 cells exposed to 2.5 μM Cd for 10 weeks and then cultured in Cd-free medium for an additional 4 weeks (total 14 weeks). Recently, we demonstrated, by using this experimental system, that 1) Cd stimulates cell invasion by suppression of apolipoprotein E (ApoE) expression, and 2) Cd induces DNA hypermethylation of the regulatory region of the ApoE gene. However, the underlying mechanism(s) as well as other potential genetic participants in the Cd-stimulated invasion are undefined. In the present work, we found that concurrent with enhanced invasion, Cd induced oxidative stress, coupled with the production of oxidative stress-sensitive metallothionein 2A (MT2A), which lead to down-modulation of ten-eleven translocation methylcytosine dioxygenase 1 (TET1 DNA demethylation) in addition tinduced malignant transformation.While flipping through my university's newspaper recently, I came across a startling headline "Ditch Your Therapist, Start a Finsta."1 A portmanteau of "fake" and "Instagram," Finstas are secondary Instagram accounts young people use to post less polished photos of themselves. Paradoxically meant to be more authentic than Rinsta (real + Instagram) accounts, Finstas are intended for small, curated audiences. The student journalist dispensed her advice boldly "Finsta is a good place for all the minutiae you don't want to share with your therapist, don't have time to share with your therapist, or don't want to be completely honest or authentic with your therapist about."1 Sure, I already knew my students and patients turned to social media for mental health advice. But the explicitness with which this author suggested carving up one's problems between social media and clinicians was striking.During my residency training in pediatrics and child/adolescent psychiatry (1973-1979), I wondered how pediatricians would identify children with psychosocial problems. Some behavioral problems were obvious because the school or parent had raised a concern. Most pediatricians would ask 1 or 2 psychosocial questions, and some, attuned to emotional issues, would identify children based on their clinical impressions. However, the few studies that had been done at the time indicated that the rates of psychosocial problems identified in pediatric primary care were far lower than predicted by epidemiological studies. Therefore, I began the work to create a screening questionnaire.

To compare postoperative objective knee stability and clinical outcomes between double-bundle (DB) anterior cruciate ligament reconstruction (ACLR) and single-bundle (SB) ACLR combined with lateral extra-articular tenodesis (LET).

ACL-injured patients with grade 3 pivot-shift who underwent either DB ACLR (DB ACLR group) or SB ACLR with LET (SB ACLR+LET group) were enrolled. All patients who met inclusion and exclusion criteria were retrospectively evaluated for knee laxity (the anterior translation and pivot-shift grade), clinical outcomes using the International Knee Documentation Committee (IKDC) examination form, Kellgren-Lawrence grade, graft maturation score on second-look arthroscopy, and revision rates at the last follow-up.

From an initial cohort of 171 consecutive patients over a 3-year period, 95 (56%) met inclusion and exclusion criteria. The SB ACLR+LET group (n= 47) showed significantly better results in pivot-shift grade at the last follow-up as compared with the DB ACLR group (n= 48) (P= .021). In the SB ACLR+LET group, 93.6% (44/47) were grade 0, whereas 72.9% (35/48) in the DB ACLR group were grade 0. learn more The SB ACLR+LET group (grade A 42, grade B 4 and grade C 1) showed significantly superior results in IKDC objective grade compared with the DB ACLR group (grade A 32; grade B 8; and grade C 8) (P= .017). However, no statistically significant difference could be shown in anterior translation, subjective functional IKDC score, or revision rate between the 2 groups. The mean follow-up duration was 49.7 ± 5.7 months.

SB ACLR+ LET demonstrated fewer pivot-shifts (P= .021) and superior IKDC objective grades (P= .017) than a DB ACLR at a mean follow-up of almost 50 months.

Level III, retrospective comparative study.

Level III, retrospective comparative study.Accumulation of amyloid beta (Aβ) soluble forms in the cerebral parenchyma is the mainstream concept underlying memory deficit in the early phase of Alzheimer's disease (AD). PKMζ plays a critical role in the maintenance of long-term memory. Yet, the role of this brain-specific enzyme has not been addressed in AD. We examined the impact of hippocampal PKMζ overexpression on AD-related memory impairment in rats. Oligomeric form of Aβ (oAβ) or vehicle was bilaterally microinjected into the dorsal hippocampus of male Wistar rats under stereotaxic surgery. One week later, 2 μl of lentiviral vector (108 T.U. / ml.) encoding PKMζ genome was microinjected into the dorsal hippocampus. Seven days later, behavioral performance was assessed using shuttle box and Morris water maze. The expression levels of GluA1, GluA2 and KCC2 were determined in the hippocampus using western blot technique. Our data showed that oAβ impairs both passive avoidance and spatial learning and memory. However, overexpression of PKMζ in the dorsal hippocampus restored the behavioral performance. This improving effect was blocked by microinjection of ZIP, a PKMζ inhibitor, into the hippocampus. oAβ or PKMζ did not significantly change GluA1 level in the hippocampus. Furthermore, PKMζ failed to restore elevated KCC2 level induced by oAβ. However, oAβ decreased GluA2 level, and overexpression of PKMζ restored its expression toward the control level. In conclusion, hippocampal overexpression of PKMζ restored memory dysfunction induced by amyloidopathy in part, through preserving hippocampal GluA2 containing AMPA receptors. PKMζ's signaling pathway could be considered as a therapeutic target to battle memory deficits in the early phase of AD.It is well established that exercise could protect against myocardial infarction (MI). Previously, we found that epoxyeicosatrienoic acids (EETs) could be induced by exercise and has been found to protect against MI via promoting angiogenic function of endothelial progenitor cells (EPCs). However, the underling mechanism of EETs in promoting EPC functions is unclear. C57BL/6 mice were fed with a novel soluble epoxide hydrolase inhibitor (sEHi), TPPU, to increase EET levels, for 1 week before undergoing MI surgery. Mice were then subjected to exercise training for 4 weeks. Bone marrow-derived EPCs were isolated and cultured in vitro. Exercise upregulated miR-126 expression but downregulated the protein levels of its target gene, Spred1, in EPCs from MI mice. TPPU further enhanced the effects of exercise on EPCs. Spred1 overexpression abolished the protective effects of TPPU on EPC functions. Downregulation of miR-126 by antagomiR-126 impaired the inhibitor effects of TPPU on Spred1 mRNA and protein expression.