Autophagy is a conserved intracellular degradation process enclosing the bulk of cytosolic components for lysosomal degradation to maintain cellular homeostasis. Accumulating evidences showed that a ...specialized form of autophagy, known as xenophagy, could serve as an innate immune response to defend against pathogens invading inside the host cells. Correspondingly, infectious pathogens have developed a variety of strategies to disarm xenophagy, leading to a prolonged and persistent intracellular colonization. In this review, we first summarize the current knowledge about the general mechanisms of intracellular bacterial infections and xenophagy. We then focus on the ongoing battle between these two processes.
Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler ...et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.
The anatomically simple plants that first colonized land must have acquired molecular and biochemical adaptations to drought stress. Abscisic acid (ABA) coordinates responses leading to desiccation ...tolerance in all land plants. We identified ABA nonresponsive mutants in the model bryophyte Physcomitrella patens and genotyped a segregating population to map and identify the ABA NON-RESPONSIVE (ANR) gene encoding a modular protein kinase comprising an N-terminal PAS domain, a central EDR domain, and a C-terminal MAPKKK-like domain. anr mutants fail to accumulate dehydration tolerance-associated gene products in response to drought, ABA, or osmotic stress and do not acquire ABA-dependent desiccation tolerance. The crystal structure of the PAS domain, determined to 1.7-Å resolution, shows a conserved PAS-fold that dimerizes through a weak dimerization interface. Targeted mutagenesis of a conserved tryptophan residue within the PAS domain generates plants with ABA nonresponsive growth and strongly attenuated ABA-responsive gene expression, whereas deleting this domain retains a fully ABA-responsive phenotype. ANR orthologs are found in early-diverging land plant lineages and aquatic algae but are absent from more recently diverged vascular plants. We propose that ANR genes represent an ancestral adaptation that enabled drought stress survival of the first terrestrial colonizers but were lost during land plant evolution.
Relativistic millicharged particles (χq) have been proposed in various extensions to the standard model of particle physics. We consider the scenarios where they are produced at nuclear reactor core ...and via interactions of cosmic rays with the Earth’s atmosphere. Millicharged particles could also be candidates for dark matter and become relativistic through acceleration by supernova explosion shock waves. The atomic ionization cross section of χq with matter are derived with the equivalent photon approximation. Smoking-gun signatures with significant enhancement in the differential cross section are identified. New limits on the mass and charge of χq are derived, using data taken with a point-contact germanium detector with 500 g mass functioning at an energy threshold of 300 eV at the Kuo-Sheng Reactor Neutrino Laboratory.
Host immune peptides, including cathelicidins, have been reported to possess anticancer properties. We previously reported that LL-37, the only cathelicidin in humans, suppresses the development of ...colon cancer. In this study, the potential anticancer effect of FK-16, a fragment of LL-37 corresponding to residues 17 to 32, on cultured colon cancer cells was evaluated. FK-16 induced a unique pattern of cell death, marked by concurrent activation of caspase-independent apoptosis and autophagy. The former was mediated by the nuclear translocation of AIF and EndoG whereas the latter was characterized by enhanced expression of LC3-I/II, Atg5 and Atg7 and increased formation of LC3-positive autophagosomes. Knockdown of Atg5 or Atg7 attenuated the cytotoxicity of FK-16, indicating FK-16-induced autophagy was pro-death in nature. Mechanistically, FK-16 activated nuclear p53 to upregulate Bax and downregulate Bcl-2. Knockdown of p53, genetic ablation of Bax, or overexpression of Bcl-2 reversed FK-16-induced apoptosis and autophagy. Importantly, abolition of AIF/EndoG-dependent apoptosis enhanced FK-16-induced autophagy while abolition of autophagy augmented FK-16-induced AIF-/EndoG-dependent apoptosis. Collectively, FK-16 induces caspase-independent apoptosis and autophagy through the common p53-Bcl-2/Bax cascade in colon cancer cells. Our study also uncovered previously unknown reciprocal regulation between these two cell death pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but ...there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.
Abstract
The role of N
6
-methyladenosine (m
6
A) modification of host mRNA during bacterial infection is unclear. Here, we show that
Helicobacter pylori
infection upregulates host m
6
A methylases ...and increases m
6
A levels in gastric epithelial cells. Reducing m
6
A methylase activity via hemizygotic deletion of methylase-encoding gene
Mettl3
in mice, or via small interfering RNAs targeting m
6
A methylases, enhances
H. pylori
colonization. We identify LOX-1 mRNA as a key m
6
A-regulated target during
H. pylori
infection. m
6
A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for
H. pylori
catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of
Lox-1
, reduces
H. pylori
colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of
H. pylori
to human gastric sections. Our results indicate that m
6
A modification of host LOX-1 mRNA contributes to protection against
H. pylori
infection by downregulating LOX-1 and thus reducing
H. pylori
adhesion.
Summary
Background
Before stopping nucleos(t)ide analogue (NA) treatment in chronic hepatitis B (CHB), 6–12 months of consolidation therapy is recommended.
Aim
To investigate the effect of ...consolidation therapy on off‐treatment outcomes in CHB patients.
Methods
We included 94 patients who stopped NA after at least 1 year of therapy. Patients could be HBeAg‐positive or HBeAg‐negative at start‐of‐treatment, but were HBeAg‐negative and had undetectable HBV DNA at time of discontinuation. Consolidation therapy was defined as treatment after the first undetectable HBV DNA (and HBeAg loss for HBeAg‐positive patients) until NA cessation.
Results
At 3 years, 74% of the start‐of‐treatment HBeAg‐positive and 75% of the start‐of‐treatment HBeAg‐negative patients developed HBV DNA >2000 IU/mL at a single time point, whereas a persistent virological relapse (≥2 tests of HBV DNA >2000 IU/mL 6 months apart within 1 year) developed in 49% of the start‐of‐treatment HBeAg‐positive and 53% of the start‐of‐treatment HBeAg‐negative patients. For both HBeAg‐positive and HBeAg‐negative patients, consolidation therapy of ≥3 years was associated with lower persistent virological relapse rates compared to <1 year (1‐year relapse rate: 25% vs. 54%; P = 0.063 and 24% vs. 57%; P = 0.036, respectively). At 3 years, 9% of the HBeAg‐positive and 14% of the HBeAg‐negative patients became HBsAg‐negative. Prolonged consolidation therapy increased the likelihood of HBsAg loss. Two cirrhotic patients developed hepatic decompensation but both recovered.
Conclusions
After nucleos(t)ide analogue discontinuation, relapse was common in patients with chronic hepatitis B. Prolongation of consolidation therapy beyond 3 years decreased the risk of persistent virological relapse and increased the likelihood of HBsAg loss.
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with a dismal prognosis. However, driver genes and prognostic markers in HCC remain to be identified. It is hoped that in-depth ...analysis of HCC genomes in relation to available clinicopathological information will give rise to novel molecular prognostic markers.
We collected genomic data of 1,061 HCC patients from previous studies, and performed integrative analysis to identify significantly mutated genes and molecular prognosticators. We employed three MutSig algorithms (MutSigCV, MutSigCL and MutSigFN) to identify significantly mutated genes. The GISTIC2 algorithm was used to delineate focally amplified and deleted genomic regions. Nonnegative matrix factorization (NMF) was utilized to decipher mutational signatures. Kaplan-Meier survival and Cox regression analyses were used to associate gene mutation and copy number alteration with survival outcome. Logistic regression model was applied to test association between gene mutation and mutational signatures.
We discovered 11 novel driver genes, including
,
and
, with mutational prevalence ranging from 1% to 3%. Seven mutational signatures were also identified in HCC, some of which were associated with mutations of classical driver genes (e.g.,
,
) as well as alcohol consumption. Focal amplifications of
and other druggable targets, including
, were also revealed. Targeting AURKA by a small-molecule inhibitor potently induced apoptosis in HCC cells. We further demonstrated that HCC patients with
amplification displayed shortened overall survival independent of other clinicopathological parameters. In conclusion, our study identified novel cancer driver genes and prognostic markers in HCC, reiterating the translational importance of omics data in the precision medicine era.
SM03, an anti-CD22 recombinant IgG1 mAb, is currently in a phase III clinical trial for the treatment of rheumatoid arthritis (NCT04312815). SM03 showed good safety and efficacy in phase I systemic ...lupus erythematosus and phase II moderate to severe rheumatoid arthritis clinical trials. We propose the success of SM03 as a therapeutic to systemic autoimmune diseases is through the utilization of a novel mechanism of action unique to SM03. CD22, an inhibitory coreceptor of the BCR, is a potential immunotherapeutic target against autoimmune diseases. SM03 could disturb the CD22 homomultimeric configuration through disrupting
binding to α2,6-linked sialic acids, induce rapid internalization of CD22 from the cell surface of human B cells, and facilitate
binding between CD22 to human autologous cells. This in turn increased the activity of the downstream immunomodulatory molecule Src homology region 2 domain-containing phosphatase 1 (SHP-1) and decreased BCR-induced NF-κB activation in human B cells and B cell proliferation. This mechanism of action gives rationale to support the significant amelioration of disease and good safety profile in clinical trials, as by enabling the "self" recognition mechanism of CD22 via
binding to α2,6 sialic acid ligands on autologous cells, SM03 specifically restores immune tolerance of B cells to host tissues without affecting the normal B cell immune response to pathogens.
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