Assessing the safety of bioactive ingredients in infant formula that affect the immune system: recommendations from an expert panel.

Bioactive ingredients for infant formula have been sought to reduce disparities in health outcomes between breastfed and formula-fed infants. Traditional food safety methodologies have limited ability to assess some bioactive ingredients. It is difficult to assess the effects of nutrition on the infant immune system because of coincident developmental adaptations to birth, establishment of the microbiome and introduction to solid foods, and perinatal environmental factors. An expert panel was convened to review information on immune system development published since the 2004 Institute of Medicine report on evaluating the safety of new infant formula ingredients and to recommend measurements that demonstrate the safety of bioactive ingredients intended for that use. Panel members participated in a 2-d virtual symposium in November 2020 and in follow-up discussions throughout early 2021. Key topics included identification of immune system endpoints from nutritional intervention studies, effects of human milk feeding and human milk substances on infant health outcomes, ontologic development of the infant immune system, and microbial influences on tolerance. The panel explored how "nonnormal" conditions such as preterm birth, allergy, and genetic disorders could help define developmental immune markers for healthy term infants. With consideration of breastfed infants as a reference, ensuring proper control groups, and attention to numerous potential confounders, the panel recommended a set of standard clinical endpoints including growth, response to vaccination, infection and other adverse effects related to inflammation, and allergy and atopic diseases. It compiled a set of candidate markers to characterize stereotypical patterns of immune system development during infancy, but absence of reference ranges, variability in methods and populations, and unreliability of individual markers to predict disease prevented the panel from including many markers as safety endpoints. The panel's findings and recommendations are applicable for industry, regulatory, and academic settings, and will inform safety assessments for immunomodulatory ingredients in foods besides infant formula.

Impact of Food-Derived Bioactive Compounds on Intestinal Immunity.

The gastrointestinal system is responsible for the digestion and the absorption of nutrients. At the same time, it is essentially involved in the maintenance of immune homeostasis. The strongest antigen contact in an organism takes place in the digestive system showing the importance of a host to develop mechanisms allowing to discriminate between harmful and harmless antigens. An efficient intestinal barrier and the presence of a large and complex part of the immune system in the gut support the host to implement this task. The continuous ingestion of harmless antigens via the diet requires an efficient immune response to reliably identify them as safe. However, in some cases the immune system accidentally identifies harmless antigens as dangerous leading to various diseases such as celiac disease, inflammatory bowel diseases and allergies. It has been shown that the intestinal immune function can be affected by bioactive compounds derived from the diet. The present review provides an overview on the mucosal immune reactions in the gut and how bioactive food ingredients including secondary plant metabolites and probiotics mediate its health promoting effects with regard to the intestinal immune homeostasis.

Phytogenic Bioactive Compounds Shape Fish Mucosal Immunity.

Aquaculture growth will unavoidably involve the implementation of innovative and sustainable production strategies, being functional feeds among the most promising ones. A wide spectrum of phytogenics, particularly those containing terpenes and organosulfur compounds, are increasingly studied in aquafeeds, due to their growth promoting, antimicrobial, immunostimulant, antioxidant, anti-inflammatory and sedative properties. This trend relies on the importance of the mucosal barrier in the fish defense. Establishing the phytogenics' mode of action in mucosal tissues is of importance for further use and safe administration. Although the impact of phytogenics upon fish mucosal immunity has been extensively approached, most of the studies fail in addressing the mechanisms underlying their pharmacological effects. Unstandardized testing as an extended practice also questions the reproducibility and safety of such studies, limiting the use of phytogenics at commercial scale. The information presented herein provides insight on the fish mucosal immune responses to phytogenics, suggesting their mode of action, and ultimately encouraging the practice of reliable and reproducible research for novel feed additives for aquafeeds. For proper screening, characterization and optimization of their mode of action, we encourage the evaluation of purified compounds using in vitro systems before moving forward to in vivo trials. The formulation of additives with combinations of compounds previously characterized is recommended to avoid bacterial resistance. To improve the delivery of phytogenics and overcome limitations associated to compounds volatility and susceptibility to degradation, the use of encapsulation is advisable. Besides, newer approaches and dedicated methodologies are needed to elucidate the phytogenics pharmacokinetics and mode of action in depth.

Global survey of medicinal plants during lactation and postpartum recovery: Evolutionary perspectives and contemporary health implications.

ETHNOPHARMACOLOGICAL RELEVANCE: Cross-cultural comparison of plants used during lactation and the postpartum period offers insight into a largely overlooked area of ethnopharmacological research. Potential roles of phytochemicals in emerging models of interaction among immunity, inflammation, microbiome and nervous system effects on perinatal development have relevance for the life-long health of individuals and of populations in both traditional and contemporary contexts. AIM OF THE STUDY: Delineate and interpret patterns of traditional and contemporary global use of medicinal plants ingested by mothers during the postpartum period relative to phytochemical activity on immune development and gastrointestinal microbiome of breastfed infants, and on maternal health. MATERIALS AND METHODS: Published reviews and surveys on galactagogues and postpartum recovery practices plus ethnobotanical studies from around the world were used to identify and rank plants, and ascertain regional use patterns. Scientific literature for 20 most-cited plants based on frequency of publication was assessed for antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, antidepressant, analgesic, galactagogic and safety properties. RESULTS: From compilation of 4418 use reports related to 1948 species, 105 plant taxa were recorded ≥7 times, with the most frequently cited species, Foeniculum vulgare, Trigonella foenum-graecum, Pimpinella anisum, Euphorbia hirta and Asparagus racemosus, 81, 64, 42, 40 and 38 times, respectively. Species and use vary globally, illustrated by the pattern of aromatic plants of culinary importance versus latex-producing plants utilized in North Africa/Middle East and Sub-Saharan Africa with opposing predominance. For 18/20 of the plants a risk/benefit perspective supports assessment that positive immunomodulation and related potential exceed any safety concerns. Published evidence does not support a lactation-enhancing effect for nearly all the most-cited plants while antidepressant data for the majority of plants are predominately limited to animal studies. CONCLUSIONS: Within a biocultural context traditional postpartum plant use serves adaptive functions for the mother-infant dyad and contributes phytochemicals absent in most contemporary diets and patterns of ingestion, with potential impacts on allergic, inflammatory and other conditions. Polyphenolics and other phytochemicals are widely immunologically active, present in breast milk and predominately non-toxic. Systematic analysis of phytochemicals in human milk, infant lumen and plasma, and immunomodulatory studies that differentiate maternal ingestion during lactation from pregnancy, are needed. Potential herb-drug interaction and other adverse effects should remain central to obstetric advising, but unless a plant is specifically shown as harmful, considering potential contributions to health of individuals and populations, blanket advisories against postpartum herbal use during lactation appear empirically unwarranted.

Micronutrients and bioactive compounds in the immunological pathways related to SARS-CoV-2 (adults and elderly).

The new coronavirus pandemic is affecting the entire world with more than 25 million confirmed cases in August 2020 according to the World Health Organization. It is known that the virus can affect several tissues and can progress to a respiratory failure in severe cases. To prevent the progression to this stage of the disease and minimize all the damage caused by coronavirus (SARS-CoV-2) the immune system must be in its integrity. A healthy nutritional status are fundamental to efficient immunological protection and consequently a good response to SARS-CoV-2. Micronutrients and bioactive compounds perform functions in immune cells that are extremely essential to stop SARS-CoV-2. Their adequate consumption is part of a non-pharmacological intervention to keep the immune system functioning. This review has as main objective to inform how micronutrients and bioactive compounds could act in the essential immunological pathways could stop SARS-CoV-2, focusing on the functions that have already established in the literature and transposing to this scenario.

Plant-based vaccines and antibodies to combat COVID-19: current status and prospects.

Globally, researchers are undertaking significant efforts to design and develop effective vaccines, therapeutics, and antiviral drugs to curb the spread of coronavirus disease 2019 (COVID-19). Plants have been used for the production of vaccines, monoclonal antibodies, immunomodulatory proteins, drugs, and pharmaceuticals via molecular farming/transient expression system and are considered as bioreactors or factories for their bulk production. These biological products are stable, safe, effective, easily available, and affordable. Plant molecular farming could facilitate rapid production of biologics on an industrial scale, and has the potential to fulfill emergency demands, such as in the present situation of the COVID-19 pandemic. This article aims to describe the methodology and basics of plant biopharming, in addition to its prospective applications for developing effective vaccines and antibodies to counter COVID-19.

Characterization of phytochemical mixtures with inflammatory modulation potential from coffee leaves processed by green and black tea processing methods.

Our previous study reported that different tea processing methods along with the age of coffee leaves affected antioxidant and anti-inflammatory bioactivities; however, identification of phytochemical components or associated mixtures that contribute to the anti-/pro-inflammatory activities was not determined. Herein, we report results of additional experiments designed to characterize the phytochemical composition of fractionated coffee leaf extract, derived from Japanese-style-green-tea-process-young (JGTP-Y) and black-tea-process-mature (BTP-M) leaves and related these data to anti-/pro-inflammatory activities. The aqueous fraction of BTP-M coffee leaves induced nitric oxide (NO), iNOS, COX-2, IL-6 and IL-10 production in Raw 264.7 cells. A 40% methanol fraction possessed greatest anti-inflammatory activities in IFN-γ and LPS treated Raw 264.7 cells (P < 0.05). The anti-inflammatory activities of coffee leaf fractions could not only be attributed to chlorogenic acids, mangiferin, rutin, and caffeine content, but possibly subtle interactions of mixtures of bioactive molecules.

Regulation of the intestinal immune system by flavonoids and its utility in chronic inflammatory bowel disease.

Flavonoids are phytochemicals which can regulate the activity of the intestinal immune system. In patients with chronic inflammatory bowel disease (IBD) there is an overexpression and imbalance of the components of the inflammatory immune reactions which are chronically activated. Suppression of inflammation can be achieved by anti-inflammatory drugs which are used in clinical medicine but these can cause serious side effects. Flavonoids can have natural immunosuppressive properties and inhibit the activation of immune cells and its effectors (chemokines, TNF-, cytokines). Phytochemicals such as flavonoids bind to the nuclear Ah (aryl hydrocarbon) -receptor thereby stimulating protective enzyme activities. As shown by clinical evidence in patients and by experimental work some flavonoids (apigenin, epigallocatechin gallate) were effective in the inhibition of inflammation. Instead of or additionally to anti-inflammatory drugs flavonoids can be used in IBD patients to treat the over-reactive immunologic system. This is accomplished by upregulation of the Ah-receptor. Flavonoids interact with toll-like receptors expressing on the surface of immune cells, then they were internalized to the cytosol and transferred into the nucleus, where they were attached to the Ah-receptor. The Ah-receptor binds to the Ah-R nuclear translocator and via Ah response element beneficial protective enzymes and cytokines are induced, leading to upregulation of the anti-inflammatory system.

Phytochemicals as multi-target inhibitors of the inflammatory pathway- A modeling and experimental study.

The arachidonic acid pathway consists of several enzymes and targeting them is favored for developing anti-inflammatory drugs. However, till date the current drugs are generally active against a single target, leading to undesirable side-effects. Phytochemicals are known to inhibit multiple targets simultaneously and hence, an attempt is made here to investigate their suitability. A pharmacophore based study is performed with three sets of reported phytochemicals namely, dual 5-LOX/mPGES1, alkaloids and FLAP inhibitors. The analysis indicated that phenylpropanoids (including ferulic acid) and benzoic acids derivatives, and berberine mapped onto these pharmacophores with three hydrophobic centroids and an acceptor feature. 2,4,5-trimethoxy (7) and 3,4-dimethoxy cinnamic acids (8) mapped onto all the three pharmacophores. Experimental studies indicated that berberine inhibited 5-LOX (100 µM) and PGE2 (50 µM) production by 72.2 and 72.0% and ferulic acid by 74.3 and 54.4% respectively. This approach offers a promising theoretical combined with experimental strategy for designing novel molecules against inflammatory enzymes.

[SOME ASPECTS OF NON-SPECIFIC PROPHYLAXIS AND THERAPY OF ESPECIALLY DANGEROUS INFECTIONS].

Recently, due to spread of dangerous and especially dangerous infections much attention is given to development of complex approaches to their prophylaxis and therapy. Data on use of immune modulators, cytokines, probiotics, preparations of plant origin for non-specific prophylaxis of especially dangerous infections are analyzed in the review, and expediency of their combined use with specific and emergency prophlaxis of these diseases is evaluated.