FEBS Journal最新文献

Parkinson's disease patients suffer from both motor and nonmotor impairments. There is currently no cure for Parkinson's disease, and the most commonly used treatment, levodopa, only functions as a temporary relief of motor symptoms. Inhibition of the expression of the L-tryptophan-catabolizing enzyme tryptophan 2,3-dioxygenase (TDO) has been shown to inhibit aging-related α-synuclein toxicity in Caenorhabditis elegans. To evaluate TDO inhibition as a potential therapeutic strategy for Parkinson's disease, a brain-penetrable, small molecule TDO inhibitor was developed, referred to as NTRC 3531-0. This compound potently inhibits human and mouse TDO in biochemical and cell-based assays and is selective over IDO1, an evolutionary unrelated enzyme that catalyzes the same reaction. In mice, NTRC 3531-0 increased plasma and brain L-tryptophan levels after oral administration, demonstrating inhibition of TDO activity in vivo. The effect on Parkinson's disease symptoms was evaluated in a rotenone-induced Parkinson's disease mouse model. A structurally dissimilar TDO inhibitor, LM10, was evaluated in parallel. Both inhibitors had beneficial effects on rotenone-induced motor and cognitive dysfunction as well as rotenone-induced dopaminergic cell loss and neuroinflammation in the substantia nigra. Moreover, both inhibitors improved intestinal transit and enhanced colon length, which indicates a reduction of the rotenone-induced intestinal dysfunction. Consistent with this, mice treated with TDO inhibitor showed decreased expression of rotenone-induced glial fibrillary acidic protein, which is a marker of enteric glial cells, and decreased α-synuclein accumulation in the enteric plexus. Our data support TDO inhibition as a potential therapeutic strategy to decrease motor, cognitive, and gastrointestinal symptoms in Parkinson's disease.

Viral infection is a significant burden to health care worldwide. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, are widely used as cholesterol-lowering drugs. Recently, long-term statin therapy was shown to reduce the antiviral immune response; however, the underlying molecular mechanisms are unclear. Here, we found that simvastatin decreased polyinosinic-polycytidylic acid [poly(I:C)]-induced expression of antiviral interferon (IFN)-β and IFN-stimulated genes (ISGs) in the bronchoalveolar lavage fluid (BALF) and lungs of mice with high-fat diet-induced hyperlipidemia. Macrophages were the dominant cell type in the BALF of poly(I:C)-treated mice. We examined the effects of simvastatin in primary lung macrophages and found that simvastatin suppressed poly(I:C)-induced expression of IFN-β and ISGs. We examined the molecular mechanisms of statin-mediated inhibition of antiviral gene expression using murine macrophage-like cell line, J774.1/JA-4. Simvastatin and pitavastatin decreased poly(I:C)-induced expression of IFN-β and ISGs. Moreover, they repressed poly(I:C)-induced phosphorylation of IFN regulatory factor (IRF) 3 and signal transducers and activators of transcription (STAT) 1, which is involved in Janus kinase (JAK)/STAT signaling. Mevalonate and geranylgeranyl pyrophosphate (GGPP), but not cholesterol, counteracted the negative effect of statins on IFN-β and ISG expression and phosphorylation of IRF3 and STAT1. The geranylgeranyltransferase inhibitor suppressed poly(I:C)-induced expression of IFN-β and ISGs and phosphorylation of IRF3 and STAT1. These results suggest that statins suppressed the expression of IFN-β and ISGs in poly(I:C)-treated hyperlipidemic mice and murine macrophages and that these effects occurred through the inhibition of IRF3 and JAK/STAT signaling in macrophages. Furthermore, GGPP recovered the statin-suppressed IRF3 and JAK/STAT signaling in poly(I:C)-treated macrophages.

l-Asparaginase (a hydrolase converting l-asparagine to l-aspartic acid) was the first enzyme to be used in clinical practice as an anticancer agent after its approval in 1978 as a component of a treatment protocol for childhood acute lymphoblastic leukemia. Structural and biochemical properties of l-asparaginases have been extensively investigated during the last half-century, providing an accurate structural description of the enzyme isolated from a variety of sources, as well as clarifying the mechanism of its activity. This review provides a critical assessment of the current state of knowledge of primarily structural, but also selected biochemical properties of 'bacterial-type' l-asparaginases from different organisms. The most extensively studied members of this enzyme family are l-asparaginases highly homologous to one of the two enzymes from Escherichia coli (usually referred to as EcAI and EcAII). Members of this enzyme family, although often called bacterial-type l-asparaginases, have been also identified in such divergent organisms as archaea or eukarya. Over 100 structural models of l-asparaginases have been deposited in the Protein Data Bank during the last 30 years. One of the prime achievements of structure-centered approaches was the elucidation of the details of the mechanism of enzymatic action of this unique hydrolase that utilizes a side chain of threonine as the primary nucleophile. The molecular basis of other important properties of these enzymes, such as their substrate specificity, is still being evaluated. Results of structural and mechanistic studies of l-asparaginases are being utilized in efforts to improve the clinical properties of this important anticancer drug.

Breast cancer constitutes a heterogeneous disease. The expression profiles of estrogen receptors (ERs), as well as the expression patterns of extracellular matrix (ECM) macromolecules, determine its development and progression. Hyaluronan (HA) is an ECM molecule that regulates breast cancer cells' properties in a molecular size-dependent way. Previous studies have shown that 200-kDa HA fragments modulate the functional properties, morphology, and expression of several matrix mediators of the highly metastatic ERα^- /ERβ⁺ MDA-MB-231 cells. In order to evaluate the effects of HA fragments (< 10, 30 and 200-kDa) in ERβ-suppressed breast cancer cells, the shERβ MDA-MB-231 cells were used. These cells are less aggressive when compared with MDA-MB-231 cells. To this end, the functional properties, the morphology, and the expression of the molecules associated with breast cancer cells metastatic potential were studied. Notably, both cell proliferation and invasion were significantly reduced after treatment with 200-kDa HA. Moreover, as assessed by scanning electron microscopy, 200-kDa HA affected cellular morphology, and as assessed by qPCR, upregulated the epithelial marker Ε-cadherin. The expression profiles of ECM mediators, such as HAS2, CD44, and MMP7, were also altered. On the other hand, cellular migration and the expression levels of syndecan-4 (SDC-4) were not significantly affected in contrast to our observations regarding MDA-MB-231 cells. These novel data demonstrate that the molecular size of the HA determines its effects on ERβ-suppressed breast cancer cells and that 200-kDa HA exhibits antiproliferative effects on these cells. A deeper understanding of this mechanism may contribute to the development of therapeutic strategies against breast cancer.

Every quarter, The FEBS Journal presents some of its 'hidden gems' - original research and review-type articles that provide a significant advance or discuss recent developments in the molecular or cellular life sciences. These articles are of high value to the scientific community, and we like to take the opportunity to promote these contributions from previous issues of the journal, as we feel their scientific content merits a boost in exposure.

C-type lectin receptors (CLRs) belong to the family of pattern recognition receptors (PRRs). They have a critical role to play in the regulation of a range of physiological functions including development, respiration, angiogenesis, inflammation, and immunity. CLRs can recognize distinct and conserved exogenous pathogen-associated as well as endogenous damage-associated molecular patterns. These interactions set off downstream signaling cascades, leading to the production of inflammatory mediators, activation of effector immune cells as well as regulation of the developmental and physiological homeostasis. CLR signaling must be tightly controlled to circumvent the excessive inflammatory burden and to maintain the cellular homeostasis. Recently, MicroRNAs (miRNAs) have been shown to be important regulators of expression of CLRs and their downstream signaling. The delicate balance between miRNAs and CLRs seems crucial in almost all aspects of multicellular life. Any dysregulations in the miRNA-CLR axes may lead to tumorigenesis or inflammatory diseases. Here, we present an overview of the current understanding of the central role of miRNAs in the regulation of CLR expression, profoundly impacting upon homeostasis and immunity, and thus, development of therapeutics against immune disorders.

Olfactory receptors are primarily known to be expressed in the olfactory epithelium of the nasal cavity and therefore assist in odor perception. With the advent of high-throughput omics technologies such as tissue microarray or RNA sequencing, a large number of olfactory receptors have been reported to be expressed in the nonolfactory tissues. Although these technologies uncovered the expression of these olfactory receptors in the nonchemosensory tissues, unfortunately, they failed to reveal the information about their cell type of origin. Accurate characterization of the cell types should be the first step towards devising cell type-specific assays for their functional evaluation. Single-cell RNA-sequencing technology resolved some of these apparent limitations and opened new means to interrogate the expression of these extranasal olfactory receptors at the single-cell resolution. Moreover, the availability of large-scale, multi-organ/species single-cell expression atlases offer ample resources for the systematic reannotation of these receptors in a cell type-specific manner. In this Viewpoint article, we discuss some of the technical limitations that impede the in-depth understanding of these extranasal olfactory receptors, with a special focus on odorant receptors. Moreover, we also propose a list of single cell-based omics technologies that could further promulgate the opportunity to decipher the regulatory network that drives the odorant receptors expression at atypical locations.

Wikipedia is a widely used online reference work which cites hundreds of thousands of scientific articles across its entries. The quality of these citations has not been previously measured, and such measurements have a bearing on the reliability and quality of the scientific portions of this reference work. Using a novel technique, a massive database of qualitatively described citations, and machine learning algorithms, we analyzed 1 923 575 Wikipedia articles which cited a total of 824 298 scientific articles in our database and found that most scientific articles cited by Wikipedia articles are uncited or untested by subsequent studies, and the remainder show a wide variability in contradicting or supporting evidence. Additionally, we analyzed 51 804 643 scientific articles from journals indexed in the Web of Science and found that similarly most were uncited or untested by subsequent studies, while the remainder show a wide variability in contradicting or supporting evidence.

Lysosomes are degradative organelles in eukaryotic cells mediating the hydrolytic catabolism of various macromolecules to small basic building blocks. These low-molecular-weight metabolites are transported across the lysosomal membrane and reused in the cytoplasm and other organelles for biosynthetic pathways. Even though in the past 20 years our understanding of the lysosomal membrane regarding various transporters, other integral and peripheral membrane proteins, the lipid composition, but also its turnover has dramatically improved, there are still many unresolved questions concerning key aspects of the function of the lysosomal membrane. These include a possible function of lysosomes as a cellular storage compartment, yet unidentified transporters mediating the export such as various amino acids, mechanisms mediating the transport of lysosomal membrane proteins from the Golgi apparatus to lysosomes, and the turnover of lysosomal membrane proteins. Here, we review the current knowledge about the lysosomal membrane and identify some of the open questions that need to be solved in the future for a comprehensive and complete understanding of how lysosomes communicate with other organelles, cellular processes, and pathways.

This 75th birthday tribute to our Editorial Board member Alexander Wlodawer recounts his decades-long service to the community of structural biology researchers. His former and current colleagues tell the story of his upbringing and education, followed by an account of his dedication to quality and rigor in crystallography and structural science. The FEBS Journal Editor-in-Chief Seamus Martin further highlights Alex's outstanding contributions to the journal's success over many years.