Interleukin-31: The “itchy” cytokine in inflammation and therapy

The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper-reactivity. In AD, IL-31 has been identified as one of the main “drivers” of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. T_H2 cells play a central role in AD and release high levels of T_H2-associated cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL-31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL-31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.     

Identification of potential inhibitors of Zika virus NS5 RNA-dependent RNA polymerase through virtual screening and molecular dynamic simulations

Zika virus (ZIKV) is one of the mosquito borne flavivirus with several outbreaks in past few years in tropical and subtropical regions. The non-structural proteins of flaviviruses are suitable active targets for inhibitory drugs due to their role in pathogenicity. In ZIKV, the non-structural protein 5 (NS5) RNA-Dependent RNA polymerase replicates its genome. Here we have performed virtual screening to identify suitable ligands that can potentially halt the ZIKV NS5 RNA dependent RNA polymerase (RdRp). During this process, we searched and screened a library of ligands against ZIKV NS5 RdRp. The selected ligands with significant binding energy and ligand-receptor interactions were further processed. Among the selected docked conformations, top five was further optimized at atomic level using molecular dynamic simulations followed by binding free energy calculations. The interactions of ligands with the target structure of ZIKV RdRp revealed that they form strong bonds within the active sites of the receptor molecule. The efficacy of these drugs against ZIKV can be further analyzed through in-vitro and in-vivo studies.     

Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe

Background

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe.

Hepatic and splanchnic perfusion and oxygenation after transjugular intrahepatic portosystemic shunt.

OBJECTIVE: in patients with cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) decreases the pressure in the portal vein by rerouting nearly all the portal blood flow to the systemic circulation. This may lead to hypoperfusion of the liver and worsening function. Our aim was to investigate whether TIPS actually reduced hepatic and splanchnic perfusion. METHODS: we studied 25 patients who required placement of a TIPS (20 for variceal bleeding and 5 for refractory ascites). We evaluated the clinical condition, laboratory results, blood velocity in the portal vein and hepatic artery by echo-Doppler ultrasonography, systemic hemodynamic-oxygenation status and hemodynamic-oxygenation status in the portal and suprahepatic veins before TIPS, 15 min after the procedure, and 30 days later. Hepatic and splanchnic perfusion were evaluated as the arteriovenous difference in O2 content and as the O2 extraction rates in the hepatic and splanchnic territories. RESULTS: TIPS induced an immediate decrease in portal pressure, a significant increase in systemic hyperdynamic state, and an increase in blood flow velocity in the portal vein and hepatic artery. Thirty days after the procedure these changes persisted, although they were somewhat attenuated. Although splanchnic and liver perfusion were not changed 15 min or 30 days after TIPS, there was a slight tendency toward a decrease in liver perfusion during follow-up. CONCLUSIONS: TIPS increased the hyperdynamic state in the systemic side. However, portal blood shunting did not change liver or splanchnic perfusion.     

Forty-one near full-length HIV-1 sequences from Kenya reveal an epidemic of subtype A and A-containing recombinants

OBJECTIVE: To further define the genetic diversity of HIV-1 in Kenya using approaches that clearly distinguish subtypes from inter-subtype recombinants. DESIGN: Near full genome sequencing and analysis were used, including sensitive new tools for detection and mapping of recombinants. METHODS: Purified peripheral blood mononuclear cell DNA from 41 HIV-1 positive blood donations collected from six hospitals across southern Kenya was used to amplify near full-length genomes by nested PCR. These were sequenced on an ABI 3100 automated sequencer and analyzed phylogenetically. RESULTS: Among 41 near full-length genomes, 25 were non-recombinant (61%) and 16 were recombinant (39%). Of the 25 pure subtypes, 23 were subtype A, one was subtype C and one was subtype D. Most recombinants consisted of subtype A and either subtype C or subtype D; a few contained A2, a recently identified sub-subtype. Two A2/D recombinants had identical breakpoints and may represent a circulating recombinant form. A third A2/D recombinant had the same structure as a previously described Korean isolate, and these may constitute a second A2-containing circulating recombinant form. CONCLUSIONS: In Kenya, 93% of HIV-1 genomes were subtype A or A-containing recombinant strains. Almost 40% of all strains were recombinant. Vaccine candidates tested in Kenya should be based on subtype A strains, but the methods used for evaluation of breakthrough infections during future vaccine trials should be capable of identifying non-A subtypes, the A2 sub-subtype, and recombinants.     

The effect of a six-month exercise program on very low-density lipoprotein apolipoprotein B secretion in type 2 diabetes

The dyslipidemia and insulin resistance of type 2 diabetes can be improved by aerobic exercise. The effect of 6 months supervised exercise on very low-density lipoprotein (VLDL) apolipoprotein B metabolism was investigated in patients with type 2 diabetes. Moderately obese patients (n = 18) were randomized into supervised (n = 9) and unsupervised (n = 9) exercise groups. All patients were given a training session and a personal exercise program and asked to exercise four times per week at 70% maximal oxygen uptake for 6 months. Patients in the supervised group had a weekly session with an exercise trainer. VLDL apolipoprotein (apo)B metabolism was measured with an infusion of 1-(13)C leucine before and after 6 months of the exercise program. Supervised exercise for 6 months resulted in a significant within-group decrease in percent hemoglobin A1c (P < 0.001), body fat (P < 0.004), nonesterified fatty acid (P < 0.04), and triglycerides (P < 0.05) and an increase in insulin sensitivity (P < 0.01). There was a decrease in VLDL apoB pool size (160.8 +/- 42.6 to 84.9 +/- 23.2 mg, P < 0.01) and VLDL apoB secretion rate (11.3 +/- 2.6 to 5.5 +/- 2.0 mg/kg.d, P < 0.05) with no change in fractional catabolic rate. In a between-group comparison, the decrease in VLDL apoB secretion rate in the supervised group did not achieve significance. This study demonstrates that in type 2 diabetes, a supervised exercise program reduces VLDL apoB pool size, which may be due to a decrease in VLDL apoB secretion rate.     

Annexin A1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair

Epithelial restitution is an essential process that is required to repair barrier function at mucosal surfaces following injury. Prolonged breaches in epithelial barrier function result in inflammation and further damage; therefore, a better understanding of the epithelial restitution process has potential for improving the development of therapeutics. In this work, we demonstrate that endogenous annexin A1 (ANXA1) is released as a component of extracellular vesicles (EVs) derived from intestinal epithelial cells, and these ANXA1-containing EVs activate wound repair circuits. Compared with healthy controls, patients with active inflammatory bowel disease had elevated levels of secreted ANXA1-containing EVs in sera, indicating that ANXA1-containing EVs are systemically distributed in response to the inflammatory process and could potentially serve as a biomarker of intestinal mucosal inflammation. Local intestinal delivery of an exogenous ANXA1 mimetic peptide (Ac2-26) encapsulated within targeted polymeric nanoparticles (Ac2-26 Col IV NPs) accelerated healing of murine colonic wounds after biopsy-induced injury. Moreover, one-time systemic administration of Ac2-26 Col IV NPs accelerated recovery following experimentally induced colitis. Together, our results suggest that local delivery of proresolving peptides encapsulated within nanoparticles may represent a potential therapeutic strategy for clinical situations characterized by chronic mucosal injury, such as is seen in patients with IBD.