Drug development is essential to the advancement of human health, however, the process is slow, costly, and at high risk of failure at all stages. A promising strategy for expediting and improving the probability of success in the drug development process is the use of naturally randomized human genetic variation for drug target identification and validation. These data can be harnessed using the Mendelian randomization (MR) analytic paradigm to proxy the lifelong consequences of genetic perturbations of drug targets. In this review, we discuss the myriad applications of the MR paradigm for human drug target identification and validation. We review the methodology and applications of MR, key limitations of MR, and potential future opportunities for research. Throughout the review, we refer to illustrative examples of MR analyses investigating the consequences of genetic inhibition of interleukin 6 signaling which, in some cases, have anticipated results from randomized controlled trials. As human genetic data become more widely available, we predict that MR will serve as a key pillar of support for drug development efforts.

Different factors, such as inflammation, oxidative stress, extracellular matrix degradation and apoptosis, affect the pathophysiology of chronic obstructive pulmonary disease (COPD), as a progressive disease characterised by permanent airflow limitation. Herbal supplements with anti-inflammatory and antioxidant properties can help treat certain chronic diseases. The current study aimed at investigating the preventive effects of crocin supplementation on the serum concentrations of IL-6, TNF-α, exercise capacity and pulmonary function tests (PFT) in patients with COPD. The present prospective randomised clinical trial equally divided fifty-seven patients with COPD into a placebo and an intervention group, who respectively received a placebo and crocin (15 mg twice day for 12 weeks) as a supplement. ELISA was used to measure serum levels of IL-6 and TNF-α, also PFT and exercise capacity based on 6-min walking distance test (6MWD), which was performed at the beginning and end of the study. Crocin improved the results of PFT (P < 0·05) and 6-MWD (P < 0·001) and exerted preventive effects by increasing the serum levels of IL-6 in patients with COPD compared with those in the placebo group (P < 0·05). Intervention with crocin significantly lowered serum levels of TNF-α at the end of the study (P < 0·01). The present findings suggest crocin supplementation improves exercise capacity and PFT in patients with COPD by reducing serum levels of inflammatory factors.

Current studies on inhibitory effects of n-3 PUFA on pro-inflammatory cytokines have inconsistent results. Thus, a meta-analysis of randomised controlled trials was conducted to identify the effects of n-3 PUFA administration on circulating IL-6 and TNF in patients with cancer. Studies that examined the effects of n-3 PUFA administration on circulating IL-6 and TNF in patients with cancer were identified by searching PubMed and EMBASE from January 1975 to February 2021. Differences in n-3 PUFA administration and control conditions were determined by calculating standardised mean differences (SMD) with 95 % CI. Twenty studies involving 971 patients met the inclusion criteria. The overall SMD were 0·485 (95 % CI 0·087, 0·883) for IL-6 and 0·712 (95 % CI 0·461, 0·962) for TNF between n-3 PUFA administration and control conditions. Sources of heterogeneity were not found through subgroup and meta-regression analyses. Publication bias was observed in TNF with a slight contribution to the effect size. n-3 PUFA can reduce circulating IL-6 and TNF levels in patients with cancer. Results supported the recommendation of n-3 PUFA as adjuvant therapy for patients with cancer, possibly excluding head and neck cancer, owing to their anti-inflammatory properties.

This study evaluated the association between ultra-processed foods (UPF) on serum IL-6 and to investigate the mediation role of adiposity. Participants were 524 adults from the EPITeen Cohort (Porto, Portugal) and 2888 participants from the 1982 Pelotas Birth Cohort (Pelotas, Brazil). Dietary intake was collected using FFQ when participants were 21 years of age in the EPITeen and 23 years in the Pelotas Cohort. Serum IL-6 and body fat mass were evaluated when participants were 27 and 30 years old in the EPITeen and Pelotas, respectively. Generalised linear models were fitted to test main associations. Mediation of body fat mass was estimated using G-computation. After adjustment for socio-economic and behaviour variables, among females from the EPITeen, the concentration of IL-6 (pg/ml) increased with increasing intake of UPF from 1·31 (95 % CI 0·95, 1·82) in the first UPF quartile to 2·20 (95 % CI 1·60, 3·01) and 2·64 (95 % CI 1·89, 3·69) for the third and fourth UPF quartiles, respectively. A similar result was found among males in the Pelotas Cohort, IL-6 increased from 1·40 (95 % CI 1·32, 1·49) in the first UPF quartile to 1·50 (95 % CI 1·41, 1·59) and 1·59 (95 % CI 1·49, 1·70) in the two highest UPF quartiles. The P-value for the linear trend was < 0·01 in both findings. The indirect effect through fat mass was NS. Our findings suggest that the consumption of UPF was associated with an increase in IL-6 concentration; however, this association was not explained by adiposity.

Long-chain n-3 fatty acids have been shown to regulate lipid metabolism and reduce fat accumulation in the liver. This trial investigated the effect of flaxseed oil, as a rich source of α-linolenic acid, on fatty liver and cardiometabolic risk factors in patients with non-alcoholic fatty liver disease (NAFLD). The randomised, double-blind, controlled trial was performed on sixty-eight NAFLD patients who were divided into flaxseed (n 34) and sunflower (n 34) oil groups. Patients were given a hypoenergetic diet (−2092 kJ/d) and 20 g/d of the corresponding oil for 12 weeks. Fatty liver grade, liver enzymes and cardiometabolic parameters were determined. The intention-to-treat approach was used for data analysis. Fatty liver grade significantly decreased in both groups (−0·68 in flaxseed v. −0·29 in sunflower, P = 0·002). Alanine aminotransferase and aspartate aminotransferase decreased in both groups (P < 0·01). Also, significant reduction was observed in blood glucose (P = 0·005) and fat mass (P = 0·01) in the flaxseed and muscle mass (P = 0·01) in the sunflower group. However, none of these alterations was significantly different between the groups. Weight, waist circumference and blood pressure were significantly decreased in both groups but only weight change was significantly different between the groups (P = 0·01). IL-6 did not significantly change in either group but showed a significant between-group difference (P = 0·03). Overall, the results showed that in the context of a low-energy diet and moderate physical activity, flaxseed oil may benefit NAFLD patients to improve fatty liver grade, weight and IL-6 compared with sunflower oil.

Infectious diseases impair Se metabolism, and low Se status is associated with mortality risk in adults with critical disease. The Se status of neonates is poorly characterised, and a potential impact of connatal infection is unknown. We hypothesised that an infection negatively affects the Se status of neonates. We conducted an observational case–control study at three intensive care units at the Charité-Universitätsmedizin Berlin, Germany. Plasma samples were collected from forty-four neonates. On the basis of clinical signs for bacterial infection and concentrations of IL-6 or C-reactive protein, neonates were classified into control (n 23) and infected (n 21) groups. Plasma Se and selenoprotein P (SePP) concentrations were determined by X-ray fluorescence and ELISA, respectively, at day of birth (day 1) and 48 h later (day 3). Se and SePP showed a positive correlation in both groups of neonates. Se concentrations indicative of Se deficit in adults (<20 µg/l) were observed in four infected neonates and one control subject, and three infected neonates had very low SePP concentrations (<0·5 mg/l). The univariate analysis revealed a significant difference in Se and SePP concentrations between the groups. Both parameters correlated inversely to IL-6 in neonates with severe inflammation (IL-6>500 ng/l). During antibiotic therapy, SePP increased significantly from day 1 (1·03 (sd 0·10) mg/l) to day 3 (1·34 (sd 0·10) mg/l), indicative of improved hepatic Se metabolism. We conclude that both Se and SePP are suitable biomarkers for assessing Se status in neonates and for identifying subjects at risk of deficiency.

Studies have emerged to demonstrate bidirectional changes in circulating cytokines of inflammation in active diabetic foot ulcers (DFU). To further expand the understanding of inflammatory status present in chronic active DFU, we comparatively assessed the associations of selected pro-inflammatory cytokines and 25-hydroxyvitamin D (25(OH)D) with the presence of DFU. In a cross-sectional setting, thirty patients with type 2 diabetes and active DFU matched with thirty control non-ulcerative patients with type 2 diabetes and twenty-eight healthy subjects underwent anthropometric and biochemical assessment of study parameters. Recruited patients with DFU were selected from the grade II active chronic DFU at the time of hospitalisation according to the University of Texas wound classification system. Patients with DFU and controls had comparable age, sexual distribution, diastolic blood pressure and TAG, LDL-cholesterol and glycated Hb. The trend changes from healthy controls towards DFU showed a significant increase for serum monocyte chemoattractant protein-1, IL-6, 25(OH)D and highly sensitive C-reactive protein and a decrease for IL-8. In the multivariate adjusted logistic regression model, 25(OH)D emerged as the only independent correlate of DFU (OR 2·194; 95 % CI 1·003, 4·415). Unprecedented increase of serum 25(OH)D in chronic active DFU is possibly related to a selective alteration in the inflammatory status. In particular, 25(OH)D and IL-8 seem to share a common pathway in the pathogenesis of diabetic foot.

Milk consumption decreases inflammatory stress in overweight and obese subjects. Casein is the major protein in milk and enhances the secretion of insulin that has anti-inflammatory activity. The aim of the present study was to compare the acute effect of meals rich in casein and carbohydrate and a combination of both nutrients on postprandial plasma concentrations of IL-6, a marker of inflammation, in obese women. A total of twenty-five obese women aged 38–68 years consumed isoenergetic meals rich in potato (POT) or casein (CA) or a combination of both these meals (POT + CA), in random order in a cross-over trial. After an overnight fast, blood samples were collected before and at 1 and 4 h after the meals and circulating concentrations of IL-6, glucose, insulin and NEFA were measured. Plasma IL-6 concentrations increased significantly (P < 0·001) during 4 h after the meals. The AUC of postprandial IL-6 concentrations was not significantly (P = 0·77) different among the meals. Postprandial serum insulin concentration AUC was significantly higher during the POT + CA meal compared with the POT meal (P = 0·001) and the CA meal (P < 0·05), which in turn was significantly higher than the POT meal (P < 0·05). These data show that while ingestion of CA alone or combined with POT acutely increases circulating insulin concentrations, it does not appreciably alter the postprandial increase in plasma IL-6 concentrations in obese women.

In this study we examined the genetic architecture of variation in the pro-inflammatory state, using an extended twin-family design. Within the Netherlands Twin Register Biobank, fasting Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), C-Reactive Protein (CRP), and fibrinogen levels were available for 3,534 twins, 1,568 of their non-twin siblings, and 2,227 parents from 3,095 families. Heritability analyses took into account the effects of current and recent illness, anti-inflammatory medication, female sex hormone status, age, sex, body mass index, smoking status, month of data collection, and batch processing. Moderate broad-sense heritability was found for all inflammatory parameters (39%, 21%, 45%, and 46% for TNF-α, IL-6, CRP and fibrinogen, respectively). For all parameters, the remaining variance was explained by unique environmental influences and not by environment shared by family members. There was no resemblance between spouses for any of the inflammatory parameters, except for fibrinogen. Also, there was no evidence for twin-specific effects. A considerable part of genetic variation was explained by non-additive genetic effects for TNF-α, CRP, and fibrinogen. For IL-6, all genetic variance was additive. This study may have implications for future genome-wide association studies by setting a clear numerical target for genome-wide screens that aim to find genetic variants regulating the levels of these pro-inflammatory markers.

Current treatments for different clinical forms of leishmaniasis are unsatisfactory, highly toxic and associated with increasing failure rates resulting from the emergence of resistant parasites. Leishmania (Viannia) braziliensis is the main aetiological agent of different clinical forms of American tegumentary leishmaniasis, including the mucosal form for which treatment has high failure rates. The aim of this work was to investigate the activity of the Morita-Baylis-Hillman adduct, methyl 2-{2-[hydroxy(2-nitrophenyl)methyl])acryloyloxy} benzoate in vitro against isolates of L. (V.) braziliensis obtained from patients with different clinical manifestations of tegumentary leishmaniasis: localized cutaneous leishmaniasis, mucosal leishmaniasis and disseminated cutaneous leishmaniasis. The adduct effectively inhibited the growth of promastigotes of the different isolates of L. (V.) braziliensis (IC50 ⩽ 7·77 μg/ml), as well as reduced the infection rate of macrophages infected with these parasites (EC50 ⩽ 1·37 μg/ml). It is remarkable to state that the adduct was more effective against intracellular amastigotes (P ⩽ 0·0045). The anti-amastigote activity correlated with an immunomodulatory effect, since the adduct was able to decrease the production of IL-6 and IL-10 by the infected macrophages. However, its effect was independent of nitric oxide production. This work demonstrates the anti-leishmanial activity of methyl 2-{2-[hydroxy(2-nitrophenyl)methyl])acryloyloxy} benzoate and suggests its potential in the treatment of human infections caused by L. (V.) braziliensis.

The reported effects of different families of fatty acids (FA; SFA, MUFA, n-3 and n-6 PUFA) on human health and the importance of macrophage respiratory burst and cytokine release to immune defence led us to examine the influence of palmitic acid (PA), oleic acid (OA), linoleic acid, arachidonic acid, EPA and DHA on macrophage function. We determined fungicidal activity, reactive oxygen species (ROS) and cytokine production after the treatment of J774 cells with non-toxic concentrations of the FA. PA had a late and discrete stimulating effect on ROS production, which may be associated with the reduced fungicidal activity of the cells after treatment with this FA. OA presented a sustained stimulatory effect on ROS production and increased fungicidal activity of the cells, suggesting that enrichment of diets with OA may be beneficial for pathogen elimination. The effects of PUFA on ROS production were time- and dose-dependently regulated, with no evident differences between n-3 and n-6 PUFA. It was worth noting that most changes induced after stimulation of the cells with lipopolysaccharide were suppressed by the FA. The present results suggest that supplementation of the diet with specific FA, not classes of FA, might enable an improvement in host defence mechanisms or a reduction in adverse immunological reactions.

Oligomers and polymers of flavan-3-ols (proanthocyanidins) are very abundant in the Mediterranean diet, but are poorly absorbed. However, when these polyphenols reach the colon, they are metabolised by the intestinal microbiota into various phenolic acids, including phenylpropionic, phenylacetic and benzoic acid derivatives. Since the biological properties of these metabolites are not completely known, in the present study, we investigated the effect of the following microbial phenolic metabolites: 3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 3-hydroxyphenylpropionic acid, 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid and 4-hydroxyhippuric acid (4-HHA), on modulation of the production of the main pro-inflammatory cytokines (TNF-α, IL-1β and IL-6). The production of these cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) pre-treated with the phenolic metabolites was studied in six healthy volunteers. With the exception of 4-HHA for TNF-α secretion, only the dihydroxylated compounds, 3,4-DHPPA and 3,4-DHPAA, significantly inhibited the secretion of these pro-inflammatory cytokines in LPS-stimulated PBMC. Mean inhibition of the secretion of TNF-α by 3,4-DHPPA and 3,4-DHPAA was 84·9 and 86·4 %, respectively. The concentrations of IL-6 in the culture supernatant were reduced by 88·8 and 92·3 % with 3,4-DHPPA and 3,4-DHPAA pre-treatment, respectively. Finally, inhibition was slightly higher for IL-1β, 93·1 % by 3,4-DHPPA and 97·9 % by 3,4-DHPAA. These results indicate that dihydroxylated phenolic acids derived from microbial metabolism present marked anti-inflammatory properties, providing additional information about the health benefits of dietary polyphenols and their potential value as therapeutic agents.