Counteracting health risks by Modulating Homeostatic Signaling.

Homeostasis was initially conceptualized by Bernard and Cannon around a century ago as a steady state of physiological parameters that vary within a certain range, such as blood pH, body temperature, and heart rate [1,2]. The underlying mechanisms that maintain homeostasis are explained by negative feedbacks that are executed by the neuronal, endocrine, and immune systems. At the cellular level, homeostasis, such as that of redox and energy steady state, also exists and is regulated by various cell signaling pathways. The induction of homeostatic mechanism is critical for human to adapt to various disruptive insults (stressors); while on the other hand, adaptation occurs at the expense of other physiological processes and thus runs the risk of collateral damages, particularly under conditions of chronic stress. Conceivably, anti-stress protection can be achieved by stressor-mimicking medicinals that elicit adaptive responses prior to an insult and thereby serve as health risk countermeasures; and in situations where maladaptation may occur, downregulating medicinals could be used to suppress the responses and prevent subsequent pathogenesis. Both strategies are preemptive interventions particularly suited for individuals who carry certain lifestyle, environmental, or genetic risk factors. In this article, we will define and characterize a new modality of prophylactic intervention that forestalls diseases via modulating homeostatic signaling. Moreover, we will provide evidence from the literature that support this concept and distinguish it from other homeostasis-related interventions such as adaptogen, hormesis, and xenohormesis.

ß -Glucan Improves Protective Qi Status in Adults with Protective Qi Deficiency-A Randomized, Placebo-Controlled, and Double-Blinded Trial.

OBJECTIVE: To test the hypothesis that ß -glucan enhances protective qi (PQi), an important Chinese medicine (CM) concept which stipulates that a protective force circulates throughout the body surface and works as the first line of defense against "external pernicious influences". METHODS: A total of 138 participants with PQi deficiency (PQD) were randomized to receive ß -glucan (200 mg daily) or placebo for 12 weeks. Participants' PQi status was assessed every 2 weeks via conventional diagnosis and a standardized protocol from which a PQD severity and risk score was derived. Indices of participants' immune and general health status were also monitored, including upper respiratory tract infection (URTI), saliva secretory IgA (sIgA), and self-reported measures of physical and mental health (PROMIS). RESULTS: PQi status was not significantly different between the ß -glucan and placebo treatment groups at baseline but improved significantly in the ß -glucan (vs. placebo) group in a time-dependent manner. The intergroup differences [95% confidence interval (CI)] in severity score (scale: 1-5), risk score (scale: 0-1), and proportion of PQD participants (%) at finish line was 0.49 (0.35-0.62), 0.48 (0.35-0.61), and 0.36 (0.25-0.47), respectively. Additionally, ß -glucan improved URTI symptom (scale: 1-9) and PROMIS physical (scale: 16.2-67.7) and mental (scale: 21.2-67.6) scores by a magnitude (95% CI) of 1.0 (0.21-1.86), 5.7 (2.33-9.07), and 3.0 (20.37-6.37), respectively, over placebo. CONCLUSIONS: ß -glucan ameliorates PQi in PQD individuals. By using stringent evidence-based methodologies, our study demonstrated that Western medicine-derived remedies, such as ß -glucan, can be employed to advance CM therapeutics. (ClinicalTrial.Gov registry: NCT03782974).

Proof-of-Concept and Feasibility Study to Evaluate the Effect of ß-Glucan on Protective Qi Deficiency in Adults.

OBJECTIVE: To preliminarily explore the potential effect of ß-glucan on Chinese medicine (CM) concept protective qi deficiency (PQD), and the methodology for future definitive studies. METHODS: To have a standardized assessment of PQD, a list of 13 potentially PQD-relevant parameters were firstly created, each with defined quantitative or categorial scales. Using the data from 37 participants with (21 cases) or without (16 cases) PQD, multivariate logistic modeling was conducted to create a preliminary diagnostic PQD risk score. Subsequently, 21 participants diagnosed with PQD were treated with ß-glucan in a dose of 200 mg/day for 8 weeks. Data were collected for trial acceptability measures (rate of recruitment, withdrawal, and compliance), and the participants were assessed for PQD status at baseline and every 2 weeks thereafter. RESULTS: The preliminary logistic model consisted of 3 parameters (low voice and apathy, aversion to wind and cold, and Cun pulse). The resulting risk score demonstrated a degree of PQD-predicting accuracy that, as evaluated by statistical (discrimination and classification) methods, was higher than those obtained from any of the individual candidate parameters. The 21 PQD participants treated with ß-glucan demonstrated good receptibility and a time-dependent improvement in PQD status as evidenced by the decrease of PQD participant to 9.5% at the end of study. CONCLUSIONS: This study demonstrated the effect of proof-of-concept of ß-glucan on improving PQD and the proof-of-concept of a multivariate-model-derived diagnostic PQD risk score. It also indicated feasibility for future definitive studies. Studies like this embody an innovative approach that uses therapies derived from the mainstream biomedicine to enrich therapeutics guided by CM principle. (Trial registration No. NCT03829228).

Correction: Nicodemus-Johnson, J.; et al. Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways. Nutrients 2017, 9, 752.

We would like to submit the following correction to our recently published paper [1] due to the error in illustration of the abbreviation eFORGE. The details are as follows:[...].

Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways.

Epidemiological evidence strongly suggests that fruit consumption promotes many health benefits. Despite the general consensus that fruit and juice are nutritionally similar, epidemiological results for juice consumption are conflicting. Our objective was to use DNA methylation marks to characterize fruit and juice epigenetic signatures within PBMCs and identify shared and independent signatures associated with these groups. Genome-wide DNA methylation marks (Illumina Human Methylation 450k chip) for 2,148 individuals that participated in the Framingham Offspring exam 8 were analyzed for correlations between fruit or juice consumption using standard linear regression. CpG sites with low P-values (P < 0.01) were characterized using Gene Set Enrichment Analysis (GSEA), Ingenuity Pathway Analysis (IPA), and epigenetic Functional element Overlap analysis of the Results of Genome Wide Association Study Experiments (eFORGE). Fruit and juice-specific low P-value epigenetic signatures were largely independent. Genes near the fruit-specific epigenetic signature were enriched among pathways associated with antigen presentation and chromosome or telomere maintenance, while the juice-specific epigenetic signature was enriched for proinflammatory pathways. IPA and eFORGE analyses implicate fruit and juice-specific epigenetic signatures in the modulation of macrophage (fruit) and B or T cell (juice) activities. These data suggest a role for epigenetic regulation in fruit and juice-specific health benefits and demonstrate independent associations with distinct immune functions and cell types, suggesting that these groups may not confer the same health benefits. Identification of such differences between foods is the first step toward personalized nutrition and ultimately the improvement of human health and longevity.

Outcomes of Recurrent Rectal Cancer after Transanal Excision.

Successful surgical salvage after transanal excision (TAE) of rectal cancers has historically been considered feasible, but results vary. We examine our experience in surgical salvage of locally recurrent rectal cancers after TAE. A retrospective review of patients undergoing salvage surgery for locally recurrent early-stage rectal cancer after TAE from March 1990 to March 2008 at our institution is presented here. Seventy-eight patients underwent TAE for tumor invades submucosa (T1) rectal cancer. Average age of patients was 68.3 years. Recurrence occurred in 17 patients (21.8%). Median number of months between the first operation and the recurrence was 41 months. Sixteen out of 17 patients recurred locally whereas one had only distant recurrence. Fourteen were eligible for surgical salvage. Ten patients underwent abdominoperineal resection, whereas four underwent repeat local excision. Eleven deaths were noted and the median survival after the first operation was 70.3 months. Disease-free survival after salvage surgery was 53 per cent (9/17), with a median follow-up of 68 months from the original surgery. Disease-specific mortality was 47 per cent (8/17), with a median survival of 72 months from the original surgery. Five-year survival in the recurrence group was 11/16 (69%). In conclusion, TAE for T1 rectal cancer carries a higher risk of recurrence. Of the local recurrences, 87.5 per cent underwent microscopic negative margins (R0) resection at the time of salvage and had a five-year survival of 69 per cent. Long-term surveillance is encouraged, as recurrence can be seen even after 10 years from initial treatment. TAE can be considered for T1 rectal tumor with reasonable outcomes.

Barcoded pyrosequencing analysis of the microbial community in a simulator of the human gastrointestinal tract showed a colon region-specific microbiota modulation for two plant-derived polysaccharide blends.

The combination of a Simulator of the Human Intestinal Microbial Ecosystem with ad hoc molecular techniques (i.e. pyrosequencing, denaturing gradient gel electrophoresis and quantitative PCR) allowed an evaluation of the extent to which two plant polysaccharide supplements could modify a complex gut microbial community. The presence of Aloe vera gel powder and algae extract in product B as compared to the standard blend (product A) improved its fermentation along the entire simulated colon. The potential extended effect of product B in the simulated distal colon, as compared to product A, was confirmed by: (i) the separate clustering of the samples before and after the treatment in the phylogenetic-based dendrogram and OTU-based PCoA plot only for product B; (ii) a higher richness estimator (+33 vs. -36 % of product A); and (iii) a higher dynamic parameter (21 vs. 13 %). These data show that the combination of well designed in vitro simulators with barcoded pyrosequencing is a powerful tool for characterizing changes occurring in the gut microbiota following a treatment. However, for the quantification of low-abundance species-of interest because of their relationship to potential positive health effects (i.e. bifidobacteria or lactobacilli)-conventional molecular ecological approaches, such as PCR-DGGE and qPCR, still remain a very useful complementary tool.

Neurologic effects of exogenous saccharides: a review of controlled human, animal, and in vitro studies.

OBJECTIVES: Current research efforts are centered on delineating the novel health benefits of naturally derived saccharides, including growing interest in their abilities to influence neurologic health. We performed a comprehensive review of the literature to consolidate all controlled studies assessing various roles of exogenous saccharide compounds and polysaccharide-rich extracts from plants, fungi, and other natural sources on brain function, with a significant focus on benefits derived from oral intake. METHODS: Studies were identified by conducting electronic searches on PubMed and Google Scholar. Reference lists of articles were also reviewed for additional relevant studies. Only articles published in English were included in this review. RESULTS: Six randomized, double-blind, placebo-controlled clinical studies were identified in which consumption of a blend of plant-derived polysaccharides showed positive effects on cognitive function and mood in healthy adults. A separate controlled clinical study observed improvements in well-being with ingestion of a yeast beta-glucan. Numerous animal and in vitro studies have demonstrated the ability of individual saccharide compounds and polysaccharide-rich extracts to modify behavior, enhance synaptic plasticity, and provide neuroprotective effects. DISCUSSION: Although the mechanisms by which exogenous saccharides can influence brain function are not well understood at this time, the literature suggests that certain naturally occurring compounds and polysaccharide-rich extracts show promise, when taken orally, in supporting neurologic health and function. Additional well-controlled clinical studies on larger populations are necessary, however, before specific recommendations can be made.

The effect of dietary supplements on the quality of life of retired professional football players.

Professional football players may experience negative health consequences when they retire such as chronic pain, cognitive problems as well as other consequences of sports-related injuries. The purpose of this pilot study is to determine the effects of dietary supplementation with multiple nutrients on the quality of life of retired football players. Fifteen retired players received daily supplementation of fish oil with cholecalciferol, antioxidants, natural vitamins and minerals, polysaccharides and phytosterol-amino acid complex for 6 months. Using an open-labeled repeated measures design, volunteers completed self-report assessment measures at baseline, 1, 3 and 6 months. Outcome measures were CDC HRQOL-4, WHOQOL-BREF, POMS, MFQ and pain self-assessment. General health rating improvement on CDC HRQOL-4 from month 1 was sustained to month 6 (p<0.0001). Mental health days improved at 6 months (p<0.05). WHOQOL-BREF showed increased health satisfaction at all measurement points (p<0.05) and the Physical and Psychological Domain Scores at 6 months (p<0.05). MFQ General Rating of Memory improved at 3 and 6 months (p<0.05). Vigor scale in POMS was significant at 3 months (p<0.05). Decreased pain was noted only for the elbow at month 1 and the knee at month 3 (p<0.05). No adverse events were reported. Results of this study offer preliminary insight into using dietary supplements to support and optimize quality of life in retired football players. Further research using a placebo-controlled design is needed to characterize the potential benefit to physical and psychological well-being of multiple dietary supplementations for this cohort.

Immunomodulatory dietary polysaccharides: a systematic review of the literature.

BACKGROUND: A large body of literature suggests that certain polysaccharides affect immune system function. Much of this literature, however, consists of in vitro studies or studies in which polysaccharides were injected. Their immunologic effects following oral administration is less clear. The purpose of this systematic review was to consolidate and evaluate the available data regarding the specific immunologic effects of dietary polysaccharides. METHODS: Studies were identified by conducting PubMed and Google Scholar electronic searches and through reviews of polysaccharide article bibliographies. Only articles published in English were included in this review. Two researchers reviewed data on study design, control, sample size, results, and nature of outcome measures. Subsequent searches were conducted to gather information about polysaccharide safety, structure and composition, and disposition. RESULTS: We found 62 publications reporting statistically significant effects of orally ingested glucans, pectins, heteroglycans, glucomannans, fucoidans, galactomannans, arabinogalactans and mixed polysaccharide products in rodents. Fifteen controlled human studies reported that oral glucans, arabinogalactans, heteroglycans, and fucoidans exerted significant effects. Although some studies investigated anti-inflammatory effects, most studies investigated the ability of oral polysaccharides to stimulate the immune system. These studies, as well as safety and toxicity studies, suggest that these polysaccharide products appear to be largely well-tolerated. CONCLUSIONS: Taken as a whole, the oral polysaccharide literature is highly heterogenous and is not sufficient to support broad product structure/function generalizations. Numerous dietary polysaccharides, particularly glucans, appear to elicit diverse immunomodulatory effects in numerous animal tissues, including the blood, GI tract and spleen. Glucan extracts from the Trametes versicolor mushroom improved survival and immune function in human RCTs of cancer patients; glucans, arabinogalactans and fucoidans elicited immunomodulatory effects in controlled studies of healthy adults and patients with canker sores and seasonal allergies. This review provides a foundation that can serve to guide future research on immune modulation by well-characterized polysaccharide compounds.