Byrneholmgaard0456

uction mediates cefotaxime anticancer activity. Our findings provide an alternative treatment for nasopharyngeal carcinoma by showing that existing cephalosporin antibiotics are specific and selective anticancer drugs.Autoimmune diseases (ADs) are a class of chronic disease conditions with impaired tolerance to autoantigens. Currently, there is no effective treatment for ADs, and the existing medications have limitations due to non-specific targets and side effects. Accumulating evidence has shown that mesenchymal stem cells (MSCs) play a role in ADs treatment. These beneficial effects mainly rely on cell-to-cell communication through the secretion of extracellular vesicles (EVs) and soluble factors. MSC-derived EVs (MSC-EVs) could modulate adjacent and distinct cells by transferring various DNA, mRNA, non-coding RNAs, proteins, and lipids from parent cells to recipient cells. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate multiple target genes at the post-transcriptional level and are involved in chronic inflammatory and immune processes. Compared to fluid, MSC-EVs delivery can protect miRNAs from the degradation of ribonucleases, ensuring that miRNAs are able to perform their respective crucial roles in AD recipient cells. In this review, we discussed the therapeutic prospects and challenges of miRNAs secreted by MSC-EVs (MSC-EV-miRNAs) by reviewing the experimentally verified therapeutic outcomes of MSC-EV-miRNAs for several ADs, including rheumatoid arthritis (RA), autoimmune hepatitis (AIH), asthma, colitis, systemic sclerosis (SSc) and graft-versus-host disease (GVHD).

AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds.

A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data infrared;

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C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized.

Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling.

These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.

These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Prostaglandin E2 Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.

Type 2 diabetes mellitus (T2DM) is a chronic disease with hallmarks of hyperglycemia and hyperlipidemia. Long-term hyperglycemia damages the functions of multiple tissues and organs leading to a series of complications and disability or even death. Nuclear receptor farnesoid X receptor (FXR) antagonism has been recently discovered to exhibit beneficial effect on glucose metabolism in T2DM mice, although the underlying mechanisms remain unclear. Here, we performed the study on the discovery of new FXR antagonist and investigated the mechanism underlying the amelioration of FXR antagonism on glucose homeostasis in T2DM mice by using the determined FXR antagonist as a probe.

FXR antagonist Mebhydrolin was discovered by screening against the lab in-house FDA approved drug library through surface plasmon resonance (SPR), microscale thermophoresis (MST), AlphaScreen, mammalian one-hybrid and transactivation assays. Activity of Mebhydrolin in improving glucose homeostasis was evaluated in db/db and HFD/STZ-inducion of FXR against glucose metabolism in T2DM mice and highlighted the potential of Mebhydrolin in the treatment of T2DM.

Our work has revealed a novel mode for the regulation of FXR against glucose metabolism in T2DM mice and highlighted the potential of Mebhydrolin in the treatment of T2DM.Lack of efficient noninvasive biomarkers for differentiating prostate cancer (PCa) and benign prostate hyperplasia (BPH) is a serious concern for men's health worldwide. In this study, we aimed to improve the diagnostic capability of the existing noninvasive biomarkers for PCa. GC-MS-based untargeted metabolomics was employed to analyze plasma samples for 41 PCa patients and 38 BPH controls. Both univariate and multivariate statistical analyses were performed to screen for differential metabolites between PCa and BPH, followed by the selection of potential biomarkers through machine learning. The chosen candidate biomarkers were then verified by targeted analysis and transcriptome data. The results showed that twelve metabolites were significantly dysregulated between PCa and BPH, three metabolites including L-serine, myo-inositol, and decanoic acid could be potential biomarkers for discriminating PCa from BPH. Most importantly, ROC curve analysis demonstrated that the involvement of the three potential biomarkers has increased the area under the curve (AUC) value of cPSA and tPSA from 0.542 and 0.592 to 0.781, respectively. Therefore, it was concluded that the involvement of L-serine, myo-inositol, and decanoic acid can largely improve the diagnostic capability of the commonly used noninvasive biomarkers in the clinic for differentiating PCa from BPH.

We aimed to explore and to compare the association between the NT-proBNP and high-sensitivity troponin I (hs-cTnI) at early stages of acute bronchiolitis with echocardiographic alterations, clinical severity and outcomes.

A single centre, prospective observational study including previously healthy infants aged 1-12months with bronchiolitis admitted to a tertiary hospital from April 2019 to March 2020. All patients underwent clinical, laboratory and echocardiographic evaluation at the same time point within 12h of hospital admission. NT-proBNP>1121pg/ml and hs-cTnI>26ng/L were considered elevated. The primary outcome measure was the association of raised cardiac biomarkers with the need for PICU admission.

We enrolled 40 infants with median levels of NT-proBNP of 1176 (520-3030) pg/ml and hs-cTnI of 11.5 (5-21) ng/L at the time of hospital admission. Raised levels of NT-proBNP and hs-cTnI in 50% and 20% of cases, respectively. Of them, 15 (37%) required PICU admission during the hospitalization. Idmission during the hospitalization. Increased NT-proBNP was associated with PICU admission (adjusted OR 9.5 (CI95% 1.4-64); p = 0.020), prolonged hospitalization (β = 2.7; p = 0.012) and duration of oxygen administration (β = 2.7; p = 0.004) in the multivariate analysis. There were no differences in hs-cTnI levels regarding PICU admission (p = 0.866). Increased hs-cTnI levels were only associated with oxygen administration duration (Spearman rho = 0.38; p = 0.017), but this association disappeared in the multivariate analysis. Only NT-proBNP was associated with echocardiographic parameters of myocardial dysfunction (p less then 0.001), and pulmonary hypertension (p less then 0.001) CONCLUSION Early elevated NT-proBNP but not hs-cTnI could be used as a biomarker for myocardial strain and disease severity in bronchiolitis.Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders characterized by the deposition of hyperphosphorylated tau aggregates. Proteopathic tau seeds spread through the brain in a temporospatial pattern, indicative of transsynaptic propagation. It is hypothesized that reducing the uptake of tau seeds and subsequent induction of tau aggregation could be a potential approach for abrogating disease progression in AD. Here, we studied to what extent different endosomal routes play a role in the neuronal uptake of pre-formed tau seeds. Using pharmacological and genetic tools we identified dynamin-1, actin and Rac1 as key players. Furthermore, inhibition of PIKfyve, a protein downstream of Rac1, reduced both the trafficking of tau seeds into lysosomes as well as the induction of tau aggregation. Our work shows that tau aggregates are internalized by a specific endocytic mechanism and that their fate once internalized can be pharmacologically modulated to reduce tau seeding in neurons.Class switch recombination (CSR) is the process by which B cells switch production from IgM/IgD to other immunoglobulin isotypes, enabling them to mount an effective immune response against pathogens. Timely resolution of CSR prevents damage due to an uncontrolled and prolonged immune response. While many positive regulators of CSR have been described, negative regulators of CSR are relatively unknown. Using an shRNA library screen targeting more than 28,000 genes in a mouse B cell line, we have identified a novel, uncharacterized protein of 82kD (KIAA1841, NM_027860), which we have named SANBR (SANT and BTB domain regulator of CSR), as a negative regulator of CSR. The purified, recombinant BTB domain of SANBR exhibited characteristic properties such as homodimerization and interaction with co-repressor proteins, including HDAC and SMRT. Overexpression of SANBR inhibited CSR in primary mouse splenic B cells, and inhibition of CSR is dependent on the BTB domain while the SANT domain is largely dispensable. Thus, we have identified a new member of the BTB family that serves as a negative regulator of CSR. Future investigations to identify transcriptional targets of SANBR in B cells will reveal further insights into the specific mechanisms by which SANBR regulates CSR as well as fundamental gene regulatory activities of this protein.Proliferation of an in vitro population of cancer cells is described by a linear cell cycle model with n states, subject to provocation with m chemotherapeutic compounds. Minimization of a linear combination of constant drug exposures is considered, with stability of the system used as a constraint to ensure a stable or shrinking cell population. The main result concerns the identification of redundant compounds, and an explicit solution formula for the case where all exposures are nonzero. The orthogonal case, where each drug acts on a single and different stage of the cell cycle, leads to a version of the classic inequality between the arithmetic and geometric means. Moreover, it is shown how the general case can be solved by converting it to the orthogonal case using a linear invertible transformation. The results are illustrated with two examples corresponding to combination treatment with two and three compounds, respectively.The mineralocorticoid hormone aldosterone stimulates sodium reabsorption in the collecting ducts by increasing the activity of the epithelial sodium channel (ENaC). Being a rate-liming channel the loss of function mutations caused Pseudohypoaldosteronism 1 (PHA1). Despite elevated plasma aldosterone in PHA 1 patients the modulation of PHA 1 causing ENaC mutants with hormone has never been studied. After recording control ENaC current in PHA1 causing ENaC stop codon mutants we demonstrated the activation of aldosterone in the whole cell as well as single channel patch clamp assays. Single channel recoding experiments demonstrated that aldosterone can increase the open probability of all analyzed PHA 1 stop codon mutants and WT. Additionally, we demonstrated by western blot experiments that aldosterone can increase the expression of WT and PHA 1 stop codon mutants. Extensive whole cell patch clamp experiments demonstrated that C-terminal γ ENaC domain is necessary for aldosterone to activate whole cell current in HEK-293 cells.