Effect of Laurus nobilis on bacteria and human transforming growth factor-ß1.

OBJECTIVE: In this study, we aimed to determine the phenolic compounds, the antibacterial activity of extract from Laurus nobilis leaves, and its possible effect on transforming growth factor-ß1 expression level in peripheral blood mononuclear cells. METHODS: The phenolic components of Laurus nobilis were identified by the high-performance liquid chromatography method. The antibacterial activity of this extract was determined by disk diffusion and broth microdilution methods. The transforming growth factor-ß1 expression was analyzed using the RT-qPCR method. RESULTS: Epicatechin was found in the highest amount and o-coumaric acid in the lowest amount. The half-maximal inhibitory concentration (IC50) was determined to be 55.17 µg/mL. The zones of inhibition and minimum inhibitory concentration for Staphylococcus aureus, Enterococcus faecalis, and Klebsiella pneumoniae were 15, 14, and 8 mm and 125, 250, and 1000 µg/mL, respectively. The change in transforming growth factor-ß1 expression levels was found to be statistically significant compared with the control groups (p<0.0001). CONCLUSION: Laurus nobilis extract was found to be effective against bacteria and altered the expression level of transforming growth factor-ß1 in peripheral blood mononuclear cells.

Essential oil supplementation in milk replacers: short- and long-term impacts on feed efficiency, the faecal microbiota and the plasma metabolome in dairy calves.

Early supplementation with oregano essential oil (EO) in milk replacer (MR) may improve growth, immune responses, the microbiota and the metabolome in dairy calves during pre-weaning and in adulthood. Sixteen female dairy calves (3 days of age) were divided in two groups (n = 8/group): the control group (no EO) and the EO group (0.23 ml of EO in MR during 45 days). After weaning, calves were kept in a feedlot and fed ad libitum. The animals were weighed, and blood and faecal samples were collected on days 3 (T0), 45 (T1) and 370 (T2) to measure the biochemical profile and characterise peripheral blood mononuclear cells (PBMCs; CD4+, CD8+, CD14+, CD21+ and WC1+), the metabolome and microbiota composition. The EO group only had greater average daily weight gain during the suckling (EO supplementation) period (P = 0.030). The EO group showed higher average CD14+ population (monocytes) values, a lower abundance of Ruminococcaceae UCG-014, Faecalibacterium, Blautia and Alloprevotella and increased abundances of Allistipes and Akkermansia. The modification of some metabolites in plasma, such as butyric acid, 3-indole-propionic acid and succinic acid, particularly at T1, are consistent with intestinal microbiota changes. The data suggest that early EO supplementation increases feed efficiency only during the suckling period with notable changes in the microbiota and plasma metabolome; however, not all of these changes can be considered desirable from a gut health point of view. Additional research studies is required to demonstrate that EOs are a viable natural alternative to antibiotics for improving calf growth performance and health.

Antiproliferative and immunomodulative potential of Citrullus colocynthis and its bioactive compounds in human lymphocytes and lung cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Citrullus colocynthis (L.) Schrad is a member of the Cucurbitaceae plant family which has been used in traditional medicine for the treatment of lung diseases such as asthma and bronchitis. AIM OF THE STUDY: The study was conducted to investigate antiproliferative and immunomodulating effects of C. colocynthis and isolated cucurbitacins on human T lymphocytes and lung epithelial cells in order to evaluate their potential in the treatment of airway diseases. MATERIALS AND METHODS: Different concentrations of an ethanolic extract of C. colocynthis fruits and cucurbitacins B (CuB), E (CuE) and E-glucopyranoside (CuE-Glu) were analysed for their cytotoxicity and immunomodulatory potential on Peripheral Blood Mononuclear Cells (PBMCs) of healthy donors and on the epithelial lung cancer cell line A549. Viability and proliferation were tested using WST1 and CFSE assays. Flow cytometric analysis of AnnexinV/PI staining was used to investigate cell death through apoptosis/necrosis. Effects on regulatory mechanisms of T lymphocytes, such as CD69 and CD25 marker activation, cytokine production of the cytokines interleukin 2 (IL2), tumor necrosis factor α (TNFα) and interferon γ (IFNy) were also analysed via flow cytometry. Influences on the activator protein 1 (AP1), nuclear factor of activated T-cells (NFAT) or nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB) pathways were analysed in the Jurkat reporter cell line. Cytokine secretion in A549 cells stimulated with virus-like particles was analysed using the bead-based Legendplex™ assay. RESULTS: Non-toxic concentrations of C. colocynthis and CuE-Glu showed dose-dependent effects on viability and proliferation in both T lymphocytes and A549 cells. The extracts inhibited lymphocyte activation and suppressed T cell effector functions, which was also shown by lower production of cytokines IL2, TNFα and IFNy. A dose dependent inhibition of the pathways NFκB, NFAT and AP1 in Jurkat cells could be observed. In A549 cells, especially CuE and CuE-Glu showed inhibitory effects on cytokine production following a simulated viral infection. Unglycosylated cucurbitacins were more effective in suppressing the immune function in lymphocytes than glycosylated cucurbitacins, however this activity is limited to cytotoxic concentrations. CONCLUSION: In our study we could confirm the immunmodulating effect of C. colocynthis and cucurbitacins B, E and E-glucopyranoside in vitro by suppression of different pathways of inflammation and T cell proliferation. Activity in a lung cell model using a virus-like stimulation shows promise for further research regarding cucurbitacins in airway diseases.

Brain Delivery of Biomimetic Phosphorus Dendrimer/Antibody Nanocomplexes for Enhanced Glioma Immunotherapy via Immune Modulation of T Cells and Natural Killer Cells.

Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having α4 and ß1 integrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Flavonoid extracted from Epimedium attenuate cGAS-STING-mediated diseases by targeting the formation of functional STING signalosome.

Hyperactivation of the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS-STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti-inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow-derived macrophages (BMDMs), THP-1 (Tohoku Hospital Pediatrics-1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS-STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN-ß, CXCL10 and ISG15) and pro-inflammatory cytokines (IL-6 and TNF-α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK-binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS-STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non-alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS-STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS-STING signalling pathway.

Heat treatment in health and disease: How water-filtered infrared-A (wIRA) irradiation affects key cellular mechanisms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy donors.

Heat treatment or hyperthermia is a promising therapy for many diseases, especially cancer, and can be traced back thousands of years. Despite its long history, little is known about the cellular and molecular effects of heat on human cells. Therefore, we investigated the impact of water-filtered infrared-A (wIRA) irradiation (39 °C, 60 min) on key cellular mechanisms, namely autophagy, mitochondrial function and mRNA expression, in human fibroblasts and peripheral blood mononuclear cells (PBMCs) from healthy donors and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Our results show an induction of autophagy in healthy fibroblasts and PBMCs from healthy donors and ME/CFS patients. ME/CFS patients have higher mitochondrial function compared to healthy donors. The wIRA treatment leads to a slight reduction in mitochondrial function in PBMCs from ME/CFS patients, thereby approaching the level of mitochondrial function of healthy donors. Furthermore, an activation of the mRNA expression of the autophagy-related genes MAP1LC3B and SIRT1 as well as for HSPA1, which codes for a heat shock protein, can be observed. These results confirm an impact of heat treatment in human cells on key cellular mechanisms, namely autophagy and mitochondrial function, in health and disease, and provide hope for a potential treatment option for ME/CFS patients.

Exploring peripheral biomarkers of response to simvastatin supplementation in schizophrenia.

Schizophrenia is one of the most debilitating mental disorders, and its diagnosis and treatment present significant challenges. Several clinical trials have previously evaluated the effectiveness of simvastatin, a lipid-lowering medication, as a novel add-on treatment for schizophrenia. However, treatment effects varied highly between patients and over time. In the present study, we aimed to identify biomarkers of response to simvastatin in recent-onset schizophrenia patients. To this end, we profiled relevant immune and metabolic markers in patient blood samples collected in a previous clinical trial (ClinicalTrials.gov: NCT01999309) before simvastatin add-on treatment was initiated. Analysed sample types included serum, plasma, resting-state peripheral blood mononuclear cells (PBMCs), as well as PBMC samples treated ex vivo with immune stimulants and simvastatin. Associations between the blood readouts and clinical endpoints were evaluated using multivariable linear regression. This revealed that changes in insulin receptor (IR) levels induced in B-cells by ex vivo simvastatin treatment inversely correlated with in vivo effects on cognition at the primary endpoint of 12 months, as measured using the Brief Assessment of Cognition in Schizophrenia scale total score (standardised ß ± SE = -0.75 ± 0.16, P = 2.2 × 10-4, Q = 0.029; n = 21 patients). This correlation was not observed in the placebo group (ß ± SE = 0.62 ± 0.39, P = 0.17, Q = 0.49; n = 14 patients). The candidate biomarker explained 53.4 % of the variation in cognitive outcomes after simvastatin supplementation. Despite the small sample size, these findings suggest a possible interaction between the insulin signalling pathway and cognitive effects during simvastatin therapy. They also point to opportunities for personalized schizophrenia treatment through patient stratification.

Immunomodulatory effect of Lacticaseibacillus casei CB054 supplementation in calves vaccinated against infectious bovine rhinotracheitis.

Probiotics are live microorganisms that, confer health benefits to the host when supplemented in adequate amounts. They can promote immunomodulation by inducing phagocyte activity, leukocyte proliferation, antibody production, and cytokine expression. Lactic acid bacteria (BAL) are important probiotic specimens with properties that can improves ruminant nutrition, productivity and immunity. The aim of the present study was to evaluate the immunomodulatory effect of the supplementation with Lacticaseibacillus casei CB054 in calve vaccinated against bovine infectious rhinotracheitis (IBR). Calve were vaccinated with a commercial IBR vaccine, on day 0 and received a booster dose on day 21. L. casei CB054 was orally administered (4 ×109 UFC) for 35 days, while a non-supplemented control group received Phosphate Buffer Saline (PBS). Stimulation of bovine splenocytes with L. casei CB054 markedly enhanced mRNA transcription levels of cytokines IL2, IL4, IL10 and IL17 genes. Calves supplemented with L. casei CB054 showed significantly higher (p < 0.05) specific anti-BoHV-1 IgG levels, higher serum neutralization, as well as higher mRNA transcription for IL2, IL4, IL10 and IL17 genes in Peripheral Blood Mononuclear Cells (PBMCs) comparing with control calves. Supplemented calve had an average weight gain of ∼14 kg more than non-supplemented during the experimental period. These results suggest that L. casei CB054 supplementation increase immunogenicity of a commercial IBR vaccine in cattle and improve weight gain.

Psychosocial predictors of the innate immune response to influenza vaccination.

Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research.

Functional properties of Ganoderma lucidum supplementation in canine nutrition.

Ganoderma lucidum (GL) is a mushroom that has been widely used in Asia for its immunostimulatory and anti-inflammatory capacity, which has been hypothesized to be attributed mainly to the recognition of its cell-surface patterns by cells of the immune system present in the gastrointestinal tract, resulting in a cascade of modulatory events. However, the nutraceutical properties of GL have not been tested in dogs. Forty adult beagles were used in a completely randomized design. The objective of the present study was to evaluate the effects of dietary inclusion of GL on peripheral blood mononuclear cells (PBMC; T cells, B cells, monocytes, and natural killers), vaccine response, nutrient digestibility, fecal fermentative end-products, and skin and coat quality of adult dogs. Dogs were fed a commercial dry extruded complete and balanced diet plus GL top-dressed daily upon feeding time. Four experimental treatments were used: 0% GL supplementation (control), 5 mg/kg BW of GL, 10 mg/kg BW of GL, or 15 mg/kg BW of GL. Following a 7 d adaptation to the control diet, dogs were fed their respective treatment diets for 28 d. They were challenged with vaccination of a modified live virus Canine Distemper, Adenovirus Type 1 (Hepatitis), Adenovirus Type 2, Parainfluenza, and Parvovirus and killed Rabies Virus on day 7 with blood collections on days 0, 14, and 28. The inclusion of GL in all dosages was well-accepted by all dogs, with no detrimental effect on macronutrient apparent total tract digestibility. There was a trend that the percentage of major histocompatibility II (MHC-II) from B cells was greater in dogs fed 15 mg/kg of GL (41.91%) compared to the control group (34.63%). The phagocytosis response tended to have treatment-by-time interaction among treatments; dogs fed 15 mg/kg of GL tended to have greater phagocytosis activity on day 28 than dogs from the control group and dogs fed 5 mg/kg of GL. The vaccine-specific serum immunoglobulin G (IgG) concentrations were higher in the group supplemented with 15 mg/kg of GL compared to treatment control 7 d after the vaccination for rabies. These data suggest that the inclusion of GL had no detrimental effects on any analyzed PBMC. Due to changes in immune parameters among treatments, GL may also exert beneficial immunostimulatory effects in healthy adult dogs when provided at a daily dose of 15 mg/ kg BW.

Ganoderma lucidum (GL) is a fungus from which products have become popular in the human food and health industry over the past decade. Due to this, a growing interest in using GL extracts in animal products has also developed. The current study investigated the nutritional properties of GL supplemented to adult beagles in three different inclusion levels in terms of body weight (BW; 5, 10, and 15 mg/kg BW). The results indicated no impact on the overall health, apparent total tract macronutrient digestibility (ATTD), fecal microbial DNA, and skin and coat health. The highlighted results included increased phagocytic activity and vaccine-specific response in the group of dogs supplemented with 15 mg/kg BW.

Diverse modulatory effects of bibenzyls from Dendrobium species on human immune cell responses under inflammatory conditions.

Dendrobium plants are widely used in traditional Chinese medicine. Their secondary metabolites such as bibenzyls and phenanthrenes show various pharmacological benefits such as immunomodulation and inhibitory effects on cancer cell growth. However, our previous study also showed that some of these promising compounds (i.e., gigantol and cypripedin) also induced the expression of inflammatory cytokines including TNF in human monocytes, and thus raising concerns about the use of these compounds in clinical application. Furthermore, the effects of these compounds on other immune cell populations, apart from monocytes, remain to be investigated. In this study, we evaluated immunomodulatory effects of seven known bibenzyl compounds purified from Dendrobium species in human peripheral blood mononuclear cells (PBMCs) that were stimulated with lipopolysaccharide (LPS). Firstly, using flow cytometry, moscatilin (3) and crepidatin (4) showed the most promising dose-dependent immunomodulatory effects among all seven bibenzyls, determined by significant reduction of TNF expression in LPS-stimulated CD14+ monocytes. Only crepidatin at the concentration of 20 µM showed a significant cytotoxicity, i.e., an increased cell death in late apoptotic state. In addition, deep immune profiling using high-dimensional single-cell mass cytometry (CyTOF) revealed broad effects of Dendrobium compounds on diverse immune cell types. Our findings suggest that to precisely evaluate therapeutic as well as adverse effects of active natural compounds, a multi-parameter immune profiling targeting diverse immune cell population is required.

Biomarker and transcriptomics profiles of serum selenium concentrations in patients with heart failure are associated with immunoregulatory processes.

BACKGROUND: Low selenium concentrations are associated with worse outcomes in heart failure (HF). However, the underlying pathophysiologic mechanisms remain incompletely understood. Therefore, we aimed to contrast serum selenium concentrations to blood biomarker and transcriptomic profiles in patients with HF. METHODS: Circulating biomarkers, whole blood transcriptomics and serum selenium measurements in a cohort of 2328 patients with HF were utilized. Penalized linear regression and gene expression analysis were used to assess biomarker and transcriptomics profiles, respectively. As a proof-of-principle, potential causal effects of selenium on excreted cytokines concentrations were investigated using human peripheral blood mononuclear cells (PBMCs). RESULTS: Mean selenium levels were 60.6 µg/L in Q1 and 122.0 µg/L in Q4. From 356 biomarkers and 20 clinical features, the penalized linear regression model yielded 44 variables with <5 % marginal false discovery rate as predictors of serum selenium. Biomarkers associated positively with selenium concentrations included: epidermal growth factor receptor (EGFR), IFN-gamma-R1, CD4, GDF15, and IL10. Biomarkers associated negatively with selenium concentrations included: PCSK9, TNFSF13, FGF21 and PAI. Additionally, 148 RNA transcripts were found differentially expressed between high and low selenium status (Padj.<0.05; log-fold-change<|0.25|). Enrichment analyses of the selected biomarkers and RNA transcripts identified similar enriched processes, including regulation processes of leukocyte differentiation and activation, as well as cytokines production. The mRNA expression of two selenoproteins (MSRB1 and GPX4) were strongly correlated with serum selenium, while GPX4, SELENOK, and SELENOS were associated with prognosis. In the in-vitro setting, PBMCs supplemented with selenium showed significantly lower abundance of several (pro-)inflammatory cytokines. CONCLUSION: These data suggest that immunoregulation is an important mechanism through which selenium might have beneficial roles in HF. The beneficial effects of higher serum selenium concentrations are likely because of global immunomodulatory effects on the abundance of cytokines. MSRB1 and GPX4 are potential modulators of and should be pursued in future research.

Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men.

Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD+), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD+ intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD+ levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD+ content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD+ levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD+ biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.

Peripheral blood mononuclear cell transcriptome profile in a clinical trial with subcutaneous, grass pollen allergoid immunotherapy.

INTRODUCTION: Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment in allergic airway diseases. Underlying immunological mechanisms and candidate biomarkers, which may be translated into predictive/surrogate measures of clinical efficacy, remain an active area of research. The aim of this study was to evaluate Pollinex Quattro (PQ) Grass AIT induced immunomodulatory mechanisms, based on transcriptome profiling of peripheral blood mononuclear cells. METHODS: 119 subjects with grass pollen induced seasonal allergic rhinitis (SAR) were randomized in a 2:2:1:1 ratio to receive a cumulative dose of PQ Grass as a conventional or extended pre-seasonal regimen, placebo, or placebo with MicroCrystalline Tyrosine. Gene expression analysis was an exploratory endpoint evaluated in a subgroup of 30 subjects randomly selected from the four treatment arms. Samples were collected at three time points: screening (baseline), before the start of the grass pollen season and at the end of the season. This study was funded by the manufacturer of PQ. RESULTS: Transcriptome analysis demonstrated that the most significant changes in gene expression, for both treatment regimens, were at the end of the grass pollen season, with the main Th1 candidate molecules (IL-12A, IFNγ) upregulated and Th2 signature cytokines downregulated (IL-4, IL-13, IL-9) (p < .05). Canonical pathways analysis demonstrated Th1, Th2, Th17 and IL-17 as the most significantly enriched pathways based on absolute value of activation z-score (IzI score ≥ 2, p < .05). Upstream regulator analysis showed pronounced inhibition of pro-inflammatory allergic molecules IgE, IL-17A, IL-17F, IL-25 (IL-17E) (IzI score ≥ 2, FDR < 0.05) and activation of pro-tolerogenic molecules IL-12A, IL-27, IL-35 (EBI3) at the end of the grass pollen season. CONCLUSION: Peripheral blood mononuclear cells transcriptome profile showed an inhibition of Th2, Th17 pro-inflammatory allergic responses and immune deviation towards Th1 responses. PQ Grass extended regimen exhibited a superior mechanistic efficacy profile in comparison with PQ conventional regimen.

Can curcumin supplementation break the vicious cycle of inflammation, oxidative stress, and uremia in patients undergoing peritoneal dialysis?

BACKGROUND & AIMS: Turmeric (a source of curcumin) is an excellent food to modulate oxidative stress, inflammation, and gut dysbiosis in patients with chronic kidney disease (CKD). However, no studies report the benefits of curcumin in patients undergoing peritoneal dialysis (PD). This study aims to evaluate the effects of curcuminoid supplementation on oxidative stress, inflammatory markers, and uremic toxins originating from gut microbiota in patients with CKD undergoing PD. METHODS: This longitudinal, randomized, single-blind, placebo-controlled trial evaluated 48 patients who were randomized into two groups: Curcumin (three capsules of 500 mg of Curcuma longa extract, with 98.42 % total curcuminoids) or placebo (three capsules of 500 mg of starch) for twelve weeks. In the peripheral blood mononuclear cells (PBMCs), the transcriptional expression levels of Nrf2, HOX-1 and NF-κB were evaluated by quantitative real-time PCR. Oxidative stress was evaluated by malondialdehyde (MDA) and total Thiol (T-SH). TNF-α and IL-6 plasma levels were measured by ELISA. P-cresyl sulphate plasma level, a uremic toxin, was evaluated by high-performance liquid chromatography (HPLC) with fluorescent detection. RESULTS: Twenty-four patients finished the study: 10 in the curcumin group (57.5 ± 11.6 years) and 14 in the placebo group (56.5 ± 10.0 years). The plasma levels of MDA were reduced after 12 weeks in the curcumin group (p = 0.01), while the placebo group remained unchanged. However, regarding the difference between the groups at the endpoint, no change was observed in MDA. Still, there was a trend to reduce the p-CS plasma levels in the curcumin group compared to the placebo group (p = 0.07). Likewise, the concentrations of protein thiols, mRNA expression of Nrf2, HOX-1, NF-κB, and cytokines plasma levels did not show significant changes. CONCLUSION: Curcuminoid supplementation for twelve weeks attenuates lipid peroxidation and might reduce uremic toxin in patients with CKD undergoing PD. This study was registered on Clinicaltrials.gov as NCT04413266.

Effects of Rumen-Protected L-Tryptophan Supplementation on Productivity, Physiological Indicators, Blood Profiles, and Heat Shock Protein Gene Expression in Lactating Holstein Cows under Heat Stress Conditions.

In this study, we examined the effects of rumen-protected L-tryptophan supplementation on the productivity and physiological metabolic indicators in lactating Holstein cows under heat stress conditions. The study involved eight early lactating Holstein cows (days in milk = 40 ± 9 days; milk yield 30 ± 1.5 kg/day; parity 1.09 ± 0.05, p < 0.05), four cows per experiment, with environmentally controlled chambers. In each experiment, two distinct heat stress conditions were created: a low-temperature and low-humidity (LTLH) condition at 25 °C with 35-50% humidity and a high-temperature and high-humidity (HTHH) condition at 31 °C with 80-95% humidity. During the adaptation phase, the cows were subjected to LTLH and HTHH conditions for 3 days. This was followed by a 4-day heat stress phase and then by a 7-day phase of heat stress, which were complemented by supplementation with rumen-protected L-tryptophan (ACT). The findings revealed that supplementation with ACT increased dry matter intake as well as milk yield and protein and decreased water intake, heart rate, and rectal temperature in the HTHH group (p < 0.05). For plateletcrit (PCT, p = 0.0600), the eosinophil percentage (EOS, p = 0.0880) showed a tendency to be lower, while the monocyte (MONO) and large unstained cells (LUC) amounts were increased in both groups (p < 0.05). Albumin and glucose levels were lower in the HTHH group (p < 0.05). The gene expressions of heat shock proteins 70 and 90 in the peripheral blood mononuclear cells were higher in the ACT group (HTHH, p < 0.05). These results suggest that ACT supplementation improved productivity, physiological indicators, blood characteristics, and gene expression in the peripheral blood mononuclear cells of early lactating Holstein cows under heat-stress conditions. In particular, ACT supplementation objectively relieved stress in these animals, suggesting that L-tryptophan has potential as a viable solution for combating heat-stress-induced effects on the cattle in dairy farming.

Wound healing mechanisms of Couroupita guianensis fruit pulp: An ethnomedicine used by traditional healers in India.

In connection to search for safe and alternative plant-based drugs, the wound healing mechanisms of an Indian ethnomedicine Couroupita guianensis fruit pulp was analyzed in this project work. Gas chromatography coupled with mass spectrometer (GC-MS) analysis revealed the existence of phytochemicals such as 2-furoic acid, 2,4-heptadienal, pyrazole and 8-hydroxyquinoline in the methanol extract. Methanol extract of C. guianensis exhibited remarkable radical scavenging activity against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) (89.88%), superoxide (91.51%), hydrogen peroxide (24.25%) and hydroxyl radicals (73.62%). Further, it showed remarkable anti-inflammatory (24.09-62.16%) and anti-bacterial activity (zone of inhibition, ZOI: 13.00 mm, minimum inhibitory concentration, MIC: 6.25 mg/mL and minimum bactericidal concentration, MBC: 12.51 mg/mL) and also controlled the growth rate of methicillin resistant Staphylococcus aureus (MRSA) within 30 min of treatment. The angiogenic potential of C. guianensis was proved in chick chorioallantoic membrane (CAM) model and it does not exhibit any toxicity in peripheral blood monocyte cells (PBMC) model.

A Cocktail of Natural Compounds Holds Promise for New Immunotherapeutic Potential in Head and Neck Cancer.

OBJECTIVE: To obtain detailed understanding on the gene regulation of natural compounds in altering prognosis of head and neck squamous cell carcinomas (HNSC). METHODS: Gene expression data of HNSC samples and peripheral blood mononuclear cells (PBMCs) of HNSC patients were collected from Gene Expression Omnibus (GEO). Differential gene expression analysis of GEO datasets were achieved by the GEO2R tool. Common differentially expressed gerres (DEGs) were screened by comparing DEGs of HNSC with those of PBMCs. The combination was further analyzed for regulating pathways and biological processes that were affected. RESULTS: Totally 110 DEGs were retrieved and identified to be involved in biological processes related to tumor regulation. Then 102 natural compounds were screened for a combination such that the expression of all 110 commonly DEGs was altered. A combination of salidroside, ginsenoside Rd, oridonin, britanin, and scutellarein was chosen. A multifaceted, multi-dimensional tumor regression was showed by altering autophagy, apoptosis, inhibiting cell proliferation, angiogenesis, metastasis and inflammatory cytokines production. CONCLUSIONS: This study has helped develop a unique combination of natural compounds that will markedly reduce the propensity of development of drug resistance in tumors and immune evasion by tumors. The result is crucial to developing a combinatorial natural therapeutic cocktail with accentuated immunotherapeutic potential.

Combined effects of green tea supplementation and eccentric exercise on nuclear factor erythroid 2-related factor 2 activity.

PURPOSE: This study investigated whether combining eccentric exercise and green tea supplementation synergistically increased nuclear factor erythroid 2-related factor 2 (NRF2) activity, a transcription factor responsible for coordinating endogenous antioxidant expression. METHODS: In a double-blinded, randomized, between-subjects design, 24 males (mean [SD]; 23 [3] years, 179.6 [6.1] cm, 78.8 [10.6] kg) performed 100 drop jumps following a 6 days supplementation period with either green tea (poly)phenols (n = 12; 500 mg·d-1) or a placebo (n = 12; inulin). NRF2/antioxidant response element (ARE) binding in peripheral blood mononuclear cells (PBMCs), catalase (CAT) and glutathione reductase (GR) activity, 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion, and differential leukocyte counts were measured pre-, post-, 1 h and 24 h post-exercise. RESULTS: Exercise did not increase NRF2/ARE binding (p = 0.12) (fold change vs rest: green tea = [post] 0.78 ± 0.45, [1 h] 1.17 ± 0.54, [24 h] 1.06 ± 0.56; placebo = [post] 1.40 ± 1.50, [1 h] 2.98 ± 3.70, [24 h] 1.04 ± 0.45). Furthermore, CAT activity (p = 0.12) and 8-OHdG excretion (p = 0.42) were unchanged in response to exercise and were not augmented by green tea supplementation (p > 0.05 for all). Exercise increased GR activity by 30% (p = 0.01), however no differences were found between supplement groups (p = 0.51). Leukocyte and neutrophil concentrations were only elevated post-exercise (p < 0.001 for all). CONCLUSION: Eccentric exercise, either performed alone or in conjunction with green tea supplementation, did not significantly increase NRF2 activity in PBMCs. TRIAL REGISTRATION NUMBER: osf.io/kz37g (registered: 15/09/21).