BATF promotes group 2 innate lymphoid cell–mediated lung tissue protection during acute respiratory virus infection

BATF regulates ILC2-mediated tissue repair and inflammation resolution during acute respiratory virus infection.

Is it necessary to correct the intestinal microbiota disorders in chronic pancreatitis?

The frequency of intestinal microbiota disorders in patients with chronic pancreatitis (CP) is extremely high and can reach 97%. The bacterial overgrowth syndrome (SIBO) and the syndrome of increased epithelial permeability (SPEP), developing against the background of excretory insufficiency of the pancreas, affect the severity of the clinical picture of the disease, reduce the effectiveness of enzyme replacement therapy and generally contribute to the further progression of CP.The article presents a modern view on the mechanisms of the formation of SIBO and SPEP in CP. There is their aggravating effect on the course of the disease and the aggravation of disorders of the digestive and absorption processes that accompany them is shown and analyzed in the article.For decontamination of conditionally pathogenic and pathogenic flora, increasing the number and metabolic activity of indigenous microflora in patients with CP, the use of a non-absorbable broad-spectrum antibiotic rifaximin is effective. In order to restore the barrier function of the gastrointestinal mucosa, the drug of choice is rebamipid, a universal cytoprotector that affects all three levels of epithelial tissue protection (preepithelial, epithelial and subepithelial).Conclusion. CP is characterized by the complexity of its etiology and pathogenesis. Bacterial factors, in particular, SIBO and SPEP, play an essential role in the development of inflammatory changes in the pancreas. In the complex therapy of CP, it is advisable to take measures aimed at correcting disorders of the intestinal microbiota.

Differential Regulation of Myocardial E3 Ligases and Deubiquitinases in Ischemic Heart Failure

The pathological changes of ubiquitination and deubiquitination following myocardial infarction (MI) and chronic heart failure (CHF) have been sparsely examined. We investigated the expression of muscle-specific E3 ubiquitin ligases and deubiquitinases in MI and CHF. Therefore, mice were assigned to coronary artery ligation for 3 days or 10 weeks as well as for sham operation (each n = 10). Expression of E3 ligases (MAFBX, MURF1, CHIP, ITCH, MDM2) and deubiquitinases (A20, CYLD, UCH-L1, USP14, USP19) was determined. After MI and in CHF, the mRNA expression of MURF1, CHIP and MDM2 (all p < 0.05) was decreased. Protein expression analyses revealed that ITCH expression decreased in CHF (p = 0.01), whereas MDM2 expression increased in MI (p = 0.02) and decreased in CHF (p = 0.02). Except for USP19 mRNA expression that decreased at 3 days and 10 weeks (both p < 0.01), the expression of other deubiquitinases remained unaffected after MI and CHF. The expression of myocardial E3 ligases is differentially regulated following MI, raising the question of whether an upstream regulation exists that is activated by MI for tissue protection or whether the downregulation of E3 ligases enables myocardial hypertrophy following MI.

Disease Tolerance during Viral-Bacterial Co-Infections

Disease tolerance has emerged as an alternative way, in addition to host resistance, to survive viral-bacterial co-infections. Disease tolerance plays an important role not in reducing pathogen burden, but in maintaining tissue integrity and controlling organ damage. A common co-infection is the synergy observed between influenza virus and Streptococcus pneumoniae that results in superinfection and lethality. Several host cytokines and cells have shown promise in promoting tissue protection and damage control while others induce severe immunopathology leading to high levels of morbidity and mortality. The focus of this review is to describe the host cytokines and innate immune cells that mediate disease tolerance and lead to a return to host homeostasis and ultimately, survival during viral-bacterial co-infection.

The Non-Erythropoietic EPO Analogue (Cibinetide) Preserves Bone Mass in Mice

Background and aims: Erythropoietin (EPO) is a pleiotropic cytokine, which besides its classical role in driving erythropoiesis, displays tissue protective and immunomodulatory activities. EPO also induces bone loss. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. Cibinetide (CIB), a non-erythropoietic analogue of EPO, specifically binds to the heteromeric receptor and confers tissue protection. Our published findings that EPO stimulates osteoclast precursors and entrains a decrease in bone density, raise questions regarding the underlying molecular mechanisms. Here, we evaluated the role of the heteromeric complex in bone metabolism using CIB alone and in combination with EPO in vivo and in vitro. Results: CIB injections to 12-week-old female mice (120 µg/kg thrice weekly for 4 weeks) resulted in a significant increase in tissue mineral density in cortical bone by 5.8% (1416.4±39.27 vs 1338.74±16.56 mgHA/cm 3) and in trabecular bone by 5.2% (1056.52±30.94 vs 1004.13±16.91 mg HA/cm 3) (n=10 in each group, p&lt; 0.05 versus saline-injected controls), as measured by microCT (Figure 1A). To evaluate the capacity of CIB to attenuate EPO mediated bone loss, we administered CIB (300 µg/kg) for 5 consecutive days, to 13-week-old female mice that also received 2 injections of 120U EPO on days 1 and 4. Flow cytometry analysis revealed a 1.8-fold reduction in the number of osteoclast progenitors, defined as Lin -CD11b −CD115 +Ly6C hi, in the EPO + CIB injected mice, compared to the mice injected with EPO alone (n=7 in each group, p&lt; 0.05). Hemoglobin levels and TER119 + bone marrow (BM) erythroid progenitors were similar in both groups. In vitro, EPO administration to BM-derived macrophages (BMDM) enhanced osteoclastogenesis, whereas CIB had an opposite, dose-dependent effect. Combining CIB with EPO inhibited osteoclastogenesis in BMDM, suggesting that CIB overrides the pro-osteoclastogenic effect of EPO (Figure 1B). Conclusions: Our findings highlight the increasing complexity of EPOR signaling in bone and pave the way for clinical translation through potential combination therapy of EPO and CIB in anemic and in cancer patients. Adjunctive administration of CIB may prevent or attenuate bone loss while preserving the erythropoietic actions of EPO. This study was supported by a grant from the Dotan Hemato-oncology Fund, the Cancer Biology Research Center, Tel Aviv University to DN and YG. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Cross-platform transcriptomic profiling of the response to recombinant human erythropoietin

RNA-seq has matured and become an important tool for studying RNA biology. Here we compared two RNA-seq (MGI DNBSEQ and Illumina NextSeq 500) and two microarray platforms (GeneChip Human Transcriptome Array 2.0 and Illumina Expression BeadChip) in healthy individuals administered recombinant human erythropoietin for transcriptome-wide quantification of differential gene expression. The results show that total RNA DNB-seq generated a multitude of target genes compared to other platforms. Pathway enrichment analyses revealed genes correlate to not only erythropoiesis and oxygen transport but also a wide range of other functions, such as tissue protection and immune regulation. This study provides a knowledge base of genes relevant to EPO biology through cross-platform comparisons and validation.

Neuroimmune Circuits Activated by Vagus Nerve Stimulation

The interaction between the nervous system and the immune system has recently been well-recognized. Vagus nerve stimulation (VNS) presents potential as an anti-inflammatory therapy through activation of neuroimmune pathways. Detailed understanding of the neuroimmune pathways VNS evokes is critical in order to successfully use it in the clinic for the treatment of acute kidney injury, in which inflammation plays an important role. In this review, we describe recent findings regarding VNS-induced neuroimmune pathways responsible for anti-inflammation and tissue protection.

Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection

The majority of SARS-CoV-2 infections among healthy individuals result in asymptomatic to mild disease. However, the immunological mechanisms defining effective lung tissue protection from SARS-CoV-2 infection remain elusive. Unlike mice solely engrafted with human fetal lung xenograft (fLX), mice co-engrafted with fLX and a myeloid-enhanced human immune system (HNFL mice) are protected against SARS-CoV-2 infection, severe inflammation, and histopathology. Effective control of viral infection in HNFL mice associated with significant macrophage infiltration, and the induction of a potent macrophage-mediated interferon response. The pronounced upregulation of the USP18-ISG15 axis (a negative regulator of IFN responses), by macrophages was unique to HNFL mice and represented a prominent correlate of reduced inflammation and histopathology. Altogether, our work shed light on unique cellular and molecular correlates of lung tissue protection during SARS-CoV-2 infection, and underscores macrophage IFN responses as prime targets for developing immunotherapies against coronavirus respiratory diseases.

In-office tooth bleaching effectiveness with different soft-tissue barriers – randomized controlled trial

Objectives: To evaluate the tooth bleaching effectiveness of a 6% hydrogen peroxide paint-on varnish with two different types of soft-tissue protection materials. Methods: Twenty patients were screened according to inclusion and exclusion criteria, submitted to professional dental prophylaxis, and randomly allocated to one of the two groups. An in-office bleaching technique protocol was performed (VivaStyle Paint On PIus, lvoclar- Vivadent®, Liechtenstein) with two different soft-tissue protection materials: Group 1 – Vaseline; Group 2 – block-out resin. Bleaching effectiveness was evaluated with ΔE00 and ΔWID, calculated from the CIE L*a*b* values obtained by spectrophotometry analysis (SpectroShade). Appropriate statistical tests were performed to analyze intragroup differences in CIE L*a*b* and WID values and intergroup differences in ΔE00 and ΔWID with α=0.05. Results: Both groups presented statistically significant (P<0.01) differences in CIE L*a*b* and WID. Both ΔE00 and ΔWID surpassed the acceptability threshold (ΔE00 > 1.8; ΔWID > 2.60), and the ΔWID was mostly classified as hardly acceptable differences. Group 2 presented higher statistically significant (P<0.01) mean values with ΔE00 = 3.5 ± 1.5 and ΔWID = 8.6 ± 4.2. Conclusions: The 6% hydrogen peroxide paint-on varnish tooth bleaching technique showed clinical effectiveness. However, effectiveness varied with the soft-tissue protection material used, with better results when applying a block-out resin, thus suggesting its clinical recommendation.