Cytokine Receptors—Regulators of Antimycobacterial Immune Response

Cytokine receptors are critical regulators of the antimycobacterial immune response, playing a key role in initiating and coordinating the recruitment and activation of immune cells during infection. They recognize and bind specific cytokines and are involved in inducing intracellular signal transduction pathways that regulate a diverse range of biological functions, including proliferation, differentiation, metabolism and cell growth. Due to mutations in cytokine receptor genes, defective signaling may contribute to increased susceptibility to mycobacteria, allowing the pathogens to avoid killing and immune surveillance. This paper provides an overview of cytokine receptors important for the innate and adaptive immune responses against mycobacteria and discusses the implications of receptor gene defects for the course of mycobacterial infection.     

Fetal Undernutrition Modifies Vascular RAS Balance Enhancing Oxidative Damage and Contributing to Remodeling

Fetal stress is known to increase susceptibility to cardiometabolic diseases and hypertension in adult age in a process known as fetal programming. This study investigated the relationship between vascular RAS, oxidative damage and remodeling in fetal programming. Six-month old Sprague-Dawley offspring from mothers that were fed ad libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. qPCR or immunohistochemistry were used to obtain the expression of receptors and enzymes. Plasma levels of carbonyls were measured by spectrophotometry. In mesenteric arteries from MUN rats we detected an upregulation of ACE, ACE2, AT₁ receptors and NADPH oxidase, and lower expression of AT₂, Mas and MrgD receptors compared to CONTROL. Systolic and diastolic blood pressure and plasma levels of carbonyls were higher in MUN than in CONTROL. Vascular morphology evidenced an increased media/lumen ratio and adventitia/lumen ratio, and more connective tissue in MUN compared to CONTROL. In conclusion, fetal undernutrition indices RAS alterations and oxidative damage which may contribute to the remodeling of mesenteric arteries, and increase the risk of adverse cardiovascular events and hypertension.     

Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression

The accumulation of mutations in cancer driver genes, such as tumor suppressors or proto-oncogenes, affects cellular homeostasis. Disturbances in the mechanism controlling proliferation cause significant augmentation of cell growth and division due to the loss of sensitivity to the regulatory signals. Nowadays, an increasing number of cases of liver cancer are observed worldwide. Data provided by the International Cancer Genome Consortium (ICGC) have indicated many alterations within gene sequences, whose roles in tumor development are not well understood. A comprehensive analysis of liver cancer (virus-associated hepatocellular carcinoma) samples has identified new and rare mutations in B-Raf proto-oncogene (BRAF) in Japanese HCC patients, as well as BRAF V600E mutations in French HCC patients. However, their function in liver cancer has never been investigated. Here, using functional analysis and next generation sequencing, we demonstrate the tumorigenic effect of BRAF V600E on hepatocytes (THLE-2 cell line). Moreover, we identified genes such as BMP6, CXCL11, IL1B, TBX21, RSAD2, MMP10, and SERPIND1, which are possibly regulated by the BRAF V600E-mediated, mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. Through several functional assays, we demonstrate that BRAF L537M, D594A, and E648G mutations alone are not pathogenic in liver cancer. The investigation of genome mutations and the determination of their impact on cellular processes and functions is crucial to unraveling the molecular mechanisms of liver cancer development.     

Effect of Acute Sprint Exercise on Myokines and Food Intake Hormones in Young Healthy Men

Physical exercise is known to influence hormonal mediators of appetite, but the effect of short-term maximal intensity exercise on plasma levels of appetite hormones and cytokines has been little studied. We investigated the effect of a 30 s Wingate Test, followed by a postprandial period, on appetite sensations, food intake, and appetite hormones. Twenty-six physically active young males rated their subjective feelings of hunger, prospective food consumption, and fatigue on visual analogue scales at baseline, after exercise was completed, and during the postprandial period. Blood samples were obtained for the measurement of nesfatin-1, ghrelin, leptin, insulin, pancreatic polypeptide (PP), human growth factor (hGH) and cytokine interleukin-6 (IL-6), irisin and plasma lactate concentrations, at 30 min before exercise, immediately (210 s) after exercise, and 30 min following a meal and at corresponding times in control sedentary males without ad libitum meal intake, respectively. Appetite perceptions and food intake were decreased in response to exercise. Plasma levels of irisin, IL-6, lactate, nesfatin-1 and ghrelin was increased after exercise and then it was returned to postprandial/control period in both groups. A significant rise in plasma insulin, hGH and PP levels after exercise was observed while meal intake potentiated this response. In conclusion, an acute short-term fatiguing exercise can transiently suppress hunger sensations and food intake in humans. We postulate that this physiological response involves exercise-induced alterations in plasma hormones and the release of myokines such as irisin and IL-6, and supports the notion of existence of the skeletal muscle–brain–gut axis. Nevertheless, the detailed relationship between acute exercise releasing myokines, appetite sensations and impairment of this axis leading to several diseases should be further examined.     

α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs

Boronic acids are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain that mimics the β-lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids in which the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two-step synthesis that relies on the solid and versatile copper-catalyzed azide–alkyne cycloaddition (CuAAC) followed by boronate deprotection. All of the compounds show very good inhibition of the Klebsiella pneumoniae carbapenemase KPC-2, with K_i values ranging from 1 nM to 1 μM, and most of them are able to restore cefepime activity against K. pneumoniae harboring bla_KPC-2. In particular, compound 1 e , bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (K_i=30 nM); it restored cefepime susceptibility in KPC-Kpn cells (MIC=0.5 μg/mL) with values similar to that of vaborbactam (K_i=20 nM, MIC in KPC-Kpn 0.5 μg/mL). Our findings suggest that α-triazolylboronates might represent an effective scaffold for the treatment of KPC-mediated infections.     

Characterization of Fenugreek (<Emphasis Type="Italic">Trigonella foenum-graecum</Emphasis>) Seed Lipids

The composition and content of lipids, fatty acids, triacylglycerols, tocopherols and sterols in nine fenugreek genotypes were analyzed. Lipid content in fenugreek seeds ranged from 5.8 to 15.2%. Major fatty acids were: linoleic acid (45.1–47.5%), α-linolenic (18.3–22.8%), oleic (12.4–17.0%), palmitic (9.8–11.2%) and stearic (3.8–4.2%) acids. The ratios of n-6 to n-3 fatty acids were between 2.1 and 2.7. Similar fatty acid distribution was observed in all analyzed samples with some deviations. α-Tocopherol was the predominant component found in the fenugreek lipid antioxidants, and it constituted over 84% of the total amounts of tocopherols. It amounts ranged from 620 to 910 mg/kg lipids. β-Sitosterol was the major sterol in all samples, varying from 14,203 to 18,833 mg/kg of lipids. Campesterol and cycloartenol were other major sterols, and these compounds including β-sitosterol constituted 56–72% of all sterols. Fenugreek seed lipids consisted predominantly triunsaturated (56.9–66.5%) and diunsaturated (32.2–41.6%) triacylglycerides. Among these components trilinolein (LLL; 12.9–20.5%) dominated followed by PLL (14.0–20.4%), LnLnO (7.8–17.7%), PLO (5.7–11.6%), OLL (6.9–10.6%), LLLn (3.2–9.6%), and LnLnL (3.5–7.6%). Results of the study show that fenugreek seed lipids may be a source of a nutraceutical ingredient for food applications.     

Synthesis of Novel Phosphonic‐Type Activity‐Based Probes for Neutrophil Serine Proteases and Their Application in Spleen Lysates of Different Organisms

Neutrophils are a type of granulocyte important in the “first line of defense” of the innate immune system. Upon activation, they facilitate the destruction of invading microorganisms by the production of superoxide radicals, as well as the release of the enzymatic contents of their lysozymes. These enzymes include specific serine proteases: cathepsin G, neutrophil elastase, proteinase 3, as well as the recently discovered neutrophil serine protease 4 (NSP4). Under normal conditions, the proteolytic activity of neutrophil proteases is tightly regulated by endogenous serpins; however, this mechanism can be subverted during tissue stress, thereby resulting in the uncontrolled activity of serine proteases, which induce chronic inflammation and subsequent pathology. Herein, we describe the development of low‐molecular‐weight activity‐based probes that specifically target the active sites of neutrophil proteases.     

Modeling the tryptic hydrolysis of pea proteins using an artificial neural network

Experimentally determined values for the degree of hydrolysis (DH) were used with an artificial neural network (ANN) model to predict the tryptic hydrolysis of a commercially available pea protein isolate at temperatures of 40, 45, and 50 °C. Analyses were conducted using the STATISTICA Neural Networks software on a personal computer. Input data were randomized to two sets: learning and testing. Differences between the experimental and calculated DH% were slight and ranged from 0.06% to 0.24%. The performance of the educated ANN was then tested by inputting temperatures ranging from 35 to 50 °C. Very strong correlations were found between calculated DH% values obtained from the ANN and those experimentally determined at all temperatures; the determination coefficients (R²) varied from 0.9958 to 0.9997. The results so obtained will be useful to reduce the time required in the design of enzymatic reactions involving food proteins.     

Long-term storage stability of selected potato starch – Non-starchy hydrocolloid binary gels

All 3, 4 and 5% potato starch gels containing either κ-carrageenan, guar gum or xanthan gum were prepared and their stability in terms of rheological and textural properties was checked on 30 day storage. It was shown that rheology of these binary potato starch – non-starchy hydrocolloid mixtures could be controlled by anionic character of the admixed hydrocolloid. Depending on the hydrocolloid added, gels made of the tuber starch can either retain their pattern typical for tuber starches or turn into that typical for gels of cereal starches. Hydrocolloids added plasticity to the binary gels but it was lost to a significant extent within the first day of storage. Resulting gels with dominating elastic character are rheologically and texturally fairly stable for subsequent 30 days of storage. Generally, hydrocolloids stabilized potato starch gel on long-time storage to the extent dependent on the gel concentration.     

I Saw You in the News: Mediated and Direct Intergroup Contact Improve Outgroup Attitudes

This study extends the boundary conditions of mediated contact theory by (a) differentiating between mediated contact quantity and quality, (b) examining whether mediated contact exerts effects above and beyond direct contact, and (c) offering causal and generalizable evidence on the effects of exposure to numerous individual outgroup members in news media. We match individual‐level data from a representative panel survey with data on the amount of coverage about members from two outgroups and with the results from validated sentiment analysis. Mediated contact, and especially its quantity, improved outgroup attitudes independently of direct contact. These findings emerged for both outgroups and across two outcome measures.