Combining kinase inhibitors for optimally co-targeting cancer and drug escape by exploitation of drug target promiscuities.

Cancers resist targeted therapeutics by drug-escape signaling. Multitarget drugs co-targeting cancer and drug-escape mediators (DEMs) are clinically advantageous. DEM coverage may be expanded by drug combinations.

Nemonoxacin Has Immunoprotective Effects on Reducing Mortality in Lipopolysaccharide-Induced Mouse Sepsis Model.

Nemonoxacin is a novel non-fluorinated quinolone. The effect of nemonoxacin on modulation of host immune response is not known. We sought to determine whether nemonoxacin has immunoprotective effects on lipopolysaccharide (LPS)-induced mouse sepsis model.

The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells.

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) of trastuzumab and cytotoxic agent emtansine (DM1), has been approved for the therapy of metastatic HER2-positive breast cancer after prior treatment of trastuzumab and taxane. The impressive efficacy exhibited by T-DM1 has heightened the need for more further studies on the underlying mechanisms of T-DM1 cytotoxicity. Previous research suggested that autophagy was crucial for cancer therapy, but the role of autophagy in T-DM1 treatment has not been investigated.

Interleukin-22 ameliorated acetaminophen-induced kidney injury by inhibiting mitochondrial dysfunction and inflammatory responses.

Acetaminophen (APAP) overdose can lead to acute, severe kidney injury, which has recently attracted considerable attention among researchers and clinicians. Unfortunately, there are no well-established treatments for APAP-induced renal injury, and the molecular mechanism of APAP-induced kidney injury is still unclear. Herein, we explored the protective effects of interleukin (IL)-22 on APAP-induced renal injury and the underlying molecular basis.

Monitoring transmissibility and mortality of COVID-19 in Europe.

Objectives: As a global pandemic is inevitable, real-time monitoring of transmission is vital for containing the spread of COVID-19. The main objective of this study was to report the real-time effective reproduction numbers (R(t)) and case fatality rates (CFR) in Europe.

Methods: Data for this study were obtained mainly from the World Health Organization website, up to March 9, 2020.

Cyclophosphamide induces a significant increase in iron content in the liver and spleen of mice.

Objective: Oxidative stress is one of the major mechanisms of cyclophosphamide (CPX)-induced toxicities. However, it is unknown how CPX induces oxidative stress. Based on the available information, we speculated that CPX could increase iron content in the tissues and then induce oxidative stress.

Angiotensin II down-regulates transferrin receptor 1 and ferroportin 1 expression in Neuro-2a cells via activation of type-1 receptor.

Angiotensin II (ANGII) modulates expression of iron intake and export proteins in cultured neurons. However, the relevant mechanisms have not been fully elucidated. Here, we investigated the effects of ANGII and/or candesartan, a ANGII-Type-1 Receptor (AT1R) antagonist, and PD123319, a ANGII-Type-2 Receptor (AT2R) antagonist on expression of transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1)and ferritin as well as iron regulatory proteins (IRPs), hepcidin and nuclear factor E2-related factor 2 (Nrf2) in Neuro-2a cells.

Two new sterol derivatives isolated from the endophytic fungus YP-2.

Two new sterol derivatives, namely ergosterimide B () and demethylincisterol A (), along with eleven known metabolites (), were isolated from the rice fermentation culture of YP-2. The chemical structures were elucidated by detailed NMR and MS spectroscopic data and by comparison with reported data. Newly isolated compound and known compound were evaluated for their cytotoxicities against the A549 and HepG2 cell lines.

Local hepcidin increased intracellular iron overload via the degradation of ferroportin in the kidney.

Background: Hepcidin is a key regulator of iron homeostasis. Some studies showed that exogenous hepcidin decreased the expression of divalent metal transporter (DMT1) rather than ferroportin(FPN1) to regulate renal iron metabolism. This study explored the effects of hepcidin synthesized by the kidney and its mechanism of iron regulation.

Phosphorylated Rasal2 facilitates breast cancer progression.

Background: Rasal2 has diametric effects on progression of oestrogen receptor-positive (ER+) and -negative (ER-) breast cancers. The relevant causes are unknown. It is also unknown whether the effects of Rasal2 are mediated by an exosome-transport process.

Enhancement of FK520 production in Streptomyces hygroscopicus by combining traditional mutagenesis with metabolic engineering.

FK520 (ascomycin), a 23-membered macrolide with immunosuppressive activity, is produced by Streptomyces hygroscopicus. The problem of low yield and high impurities (mainly FK523) limits the industrialized production of FK520. In this study, the FK520 yield was significantly improved by strain mutagenesis and genetic engineering.

Dual-Blockade Immune Checkpoint for Breast Cancer Treatment Based on a Tumor-Penetrating Peptide Assembling Nanoparticle.

Cancer immunotherapy can enhance the antitumor effect of drugs through a combinatorial approach in a synergistic manner. However, the effective targeted delivery of various drugs remains a challenge. We generated a peptide assembling tumor-targeted nanodelivery system based on a breast cancer homing and penetrating peptide for the codelivery of a programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) (siPD-L1) and an indoleamine 2,3-dioxygenase inhibitor as a dual blockade of an immune checkpoint.

Cystathionine β-synthase (CBS) deficiency suppresses erythropoiesis by disrupting expression of heme biosynthetic enzymes and transporter.

The reduced iron usage induced by the suppression of erythropoiesis is a major cause of the systemic iron overload in CBS knockout (CBS) mice. However, the relevant mechanisms are unknown. Here, we examined changes in granulocyte/erythroid cell ratios, iron content, and expression of iron-metabolism proteins, including; two key enzymes involved in the heme biosynthetic pathway, ALAS2 (delta-aminolevulinate synthase 2) and FECH (ferrochelatase), a heme exporter from the cytosol and mitochondria, FLVCR (feline leukemia virus subgroup C cellular receptor) as well as EPO (erythropoietin), EPOR (erythropoietin receptor) and HIF-2α (hypoxia inducible factor-2 subunit α), in the blood, bone marrow or liver of CBS (homozygous), CBS (heterozygous) and CBS (Wild Type) mice.

A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer.

Purpose: We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non-small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance.

Experimental Design: Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine and efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelial-mesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape.

Results: MTI-31 potently inhibited cell proliferation (IC <1 μmol/L) and tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met, or KRAS (MED <10 mg/kg).

Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery.

Unlabelled: Epithelial-mesenchymal transition (EMT) is closely associated with the development of drug resistance. Lipid metabolism plays an important role in EMT. This work was to study the cholesterol-lowering drug simvastatin for reversing EMT-associated resistance to chemotherapy via lipid metabolism.

Endogenous HS production deficiencies lead to impaired renal erythropoietin production.

Introduction: Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (HS), an endogenously derived renal oxygen sensor.

Different Characteristics of Hepcidin Expression in IL-6+/+ and IL-6-/- Neurons and Astrocytes Treated with Lipopolysaccharides.

A region-specific regulation of inflammation on the expression hepcidin in the brain has been demonstrated, however, it remains unknown whether there is also a cell-specific regulation of inflammation on hepcidin in the brain. Here, we investigated the effects of lipopolysaccharides (LPS) on the expression of hepcidin mRNA and also the expression of IL-6 mRNA, the phosphorylation of STAT3 and the expression of ferroportin 1 (Fpn1) and ferritin light chain (Ft-L) proteins in neurons and astrocytes obtained from wild type (IL-6+/+) and IL-6 knockout (IL-6-/-) mice. We demonstrated that the responses of the expression of hepcidin and IL-6 mRNAs, the phosphorylation of STAT3, and the expression of Fpn1 protein to LPS in IL-6+/+ astrocytes and also the responses of the expression of hepcidin mRNA, the phosphorylation of STAT3 and the expression of Fpn1 protein to IL-6 in IL-6-/- astrocytes were much stronger than those in IL-6+/+ and IL-6-/- neurons.

Novel-smoothened inhibitors for therapeutic targeting of naïve and drug-resistant hedgehog pathway-driven cancers.

The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs.

Inhibition of DNMT suppresses the stemness of colorectal cancer cells through down-regulating Wnt signaling pathway.

Cancer stem cell (CSC) theory reveals a new insight into the understanding of tumorigenesis and metastasis. Recently, DNA methylation is suggested to be a potential epigenetic mechanism for maintenance of CSCs. What's more, studies have shown that DNA methyltransferase (DNMT) is essential for CSCs and deletion of DNMT can reduce tumorigenesis by limiting CSC pool.

Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites.

Chemoresistance remains a formidable hurdle against cancer therapy. Seeking for novel therapy strategies is an urgent need for those who no longer benefit from chemotherapy. Chemoresistance is usually associated with the dysfunction of intrinsic apoptosis.

Aspirin increases ferroportin 1 expression by inhibiting hepcidin via the JAK/STAT3 pathway in interleukin 6-treated PC-12 cells.

To understand the potential mechanisms involved in the beneficial effects of aspirin (ASA) in mood disorders, Alzheimer's (AD) and Parkinson's disease (PD), we investigated the effects of ASA on the expression of iron transport proteins transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1), and iron storage protein ferritin light chain (Ft-L) in interleukin-6 (IL-6)-treated PC-12 cells. We demonstrated that IL-6 alone could induce a severe decline in Fpn1 expression and cell viability, and an increase in Ft-L protein, while ASA could markedly diminish the effects of IL-6 on these parameters. We also found that IL-6 significantly increased hepcidin expression and janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation, while ASA also observably suppressed these IL-6-induced effects.